Principles and Practice of

Surgical Oncology
Claire Berry
Principles and Practice of
Surgical Oncology
Principles and Practice of
Surgical Oncology

Claire Berry

White Press Academic

Minds, Motivated!
Principles and Practice of Surgical Oncology
by Claire Berry

www.whitepressacademics.com

© 2019 White Press Academic

All rights reserved. No portion of this book may be reproduced in any form without
permission from the publisher, except as permitted by U.S. copyright law. For
permissions contact:
[email protected]

Price: $295

Ebook ISBN: 978-1-68469-262-0

Published by:
600 S MAESTRI PL., #30460
NEW ORLEANS, LA, US, 70130
Website: www.whitepressacademics.com
Contents

Preface xi

1. Skin 1
Melanoma ......................................................................................................................................................................... 1
History ................................................................................................................................................................................ 2
Signs and Symptoms .................................................................................................................................................... 2
Cause .................................................................................................................................................................................. 3
Pathophysiology ............................................................................................................................................................. 4
Diagnosis ........................................................................................................................................................................... 5
Prevention ........................................................................................................................................................................ 9
Treatment ........................................................................................................................................................................ 10
Prognosis ......................................................................................................................................................................... 13
Epidemiology ................................................................................................................................................................ 13
Research .......................................................................................................................................................................... 14
Non-melanoma Skin Cancers ................................................................................................................................. 16
What is Non-melanoma Skin Cancer? ................................................................................................................. 16
What Causes Non-melanoma Skin Cancer and am I at Risk? ..................................................................... 16
What Screening Tests are Available? .................................................................................................................... 16
What are the Signs of Non-melanoma Skin Cancer? ..................................................................................... 17
How is Non-melanoma Cancer Diagnosed? ..................................................................................................... 17
Staging of Non-melanoma Skin Cancers ............................................................................................................ 18
How is Non-melanoma Skin Cancer Treated? ................................................................................................... 19
Follow-up Care and Survivorship ........................................................................................................................... 21

2. Breast 23
Signs and Symptoms .................................................................................................................................................. 23
Risk Factors ..................................................................................................................................................................... 24
Lifestyle ........................................................................................................................................................................... 24
Genetics ........................................................................................................................................................................... 25
Medical Conditions ..................................................................................................................................................... 25
Pathophysiology ........................................................................................................................................................... 25
Diagnosis ......................................................................................................................................................................... 26
Classification .................................................................................................................................................................. 27
Prevention ...................................................................................................................................................................... 29
Life-style .......................................................................................................................................................................... 29
Pre-emptive Surgery .................................................................................................................................................. 29
Medications .................................................................................................................................................................... 30
Screening ........................................................................................................................................................................ 30
Management ................................................................................................................................................................. 30
Surgery ............................................................................................................................................................................. 31
Medication ...................................................................................................................................................................... 31
Radiation ......................................................................................................................................................................... 32
Prognosis ......................................................................................................................................................................... 33
Prognostic Factors ........................................................................................................................................................ 34
Psychological Aspects ................................................................................................................................................ 35
Epidemiology ................................................................................................................................................................ 35
 vi
Hormones ....................................................................................................................................................................... 36
Birth Control ................................................................................................................................................................... 36
Menopausal Hormone Replacement ................................................................................................................... 36
Research .......................................................................................................................................................................... 36
Cryoablation ................................................................................................................................................................... 36
Breast Cancer Cell Lines ........................................................................................................................................... 36
Molecular Markers ....................................................................................................................................................... 37
Non-invasive or Invasive Breast Cancer .............................................................................................................. 37
Locally Advanced Breast Cancer (LABC) ............................................................................................................ 38
Classification .................................................................................................................................................................. 39
Clinical Features and Diagnosis ............................................................................................................................. 39
Staging ............................................................................................................................................................................. 40
Natural History .............................................................................................................................................................. 40
Multidisciplinary Therapy .......................................................................................................................................... 41
Primary Chemotherapy Results ............................................................................................................................. 41
Local/Regional Treatment and Local Control .................................................................................................... 44
Tolerance and Toxicity ................................................................................................................................................ 44
Dose Intensification .................................................................................................................................................... 45
Breast Conservation .................................................................................................................................................... 45
Inflammatory Breast Carcinoma ............................................................................................................................ 46
BRCA 1 and BRCA 2 in Breast Cancer and Ovarian Cancer ......................................................................... 47
Genes and Mutations .................................................................................................................................................. 47
Getting Tested ............................................................................................................................................................... 49
Breast and Ovarian Cancer Risk .............................................................................................................................. 50
Cancer Detection and Prevention Strategies ................................................................................................... 51
Other Cancers ............................................................................................................................................................... 55
Childbearing and Fertility Effects .......................................................................................................................... 56
Evolutionary Advantage ............................................................................................................................................ 57
Patent Enforcement and Litigation ....................................................................................................................... 57
Treatment ........................................................................................................................................................................ 58
Surgery and Radiation Therapy ............................................................................................................................... 58
Chemotherapy .............................................................................................................................................................. 58
Hormone Therapy and Targeted Therapy ............................................................................................................ 58

3. Gastrointestinal 59
Esophageal Cancer ...................................................................................................................................................... 59
Signs and Symptoms .................................................................................................................................................. 59
Causes .............................................................................................................................................................................. 60
Diagnosis ......................................................................................................................................................................... 63
Prevention ...................................................................................................................................................................... 64
Management ................................................................................................................................................................. 64
Prognosis ......................................................................................................................................................................... 65
Stomach Cancer/ Gastric Cancer ........................................................................................................................... 66
Signs and Symptoms .................................................................................................................................................. 66
Causes .............................................................................................................................................................................. 67
Diagnosis ......................................................................................................................................................................... 68
Prevention ...................................................................................................................................................................... 70
Management ................................................................................................................................................................. 70
Prognosis ......................................................................................................................................................................... 71
Small Intestine Cancer/ Small Bowel Cancer .................................................................................................... 71
Risk Factors ..................................................................................................................................................................... 71
Research .......................................................................................................................................................................... 72
Gallbladder Cancer ...................................................................................................................................................... 72
Signs and Symptoms .................................................................................................................................................. 72
Risk Factors ..................................................................................................................................................................... 73
Diagnosis ......................................................................................................................................................................... 73
Treatment ........................................................................................................................................................................ 73
Cholangiocarcinoma .................................................................................................................................................. 74
Signs and Symptom .................................................................................................................................................... 74
Risk Factors ..................................................................................................................................................................... 74
Pathophysiology ........................................................................................................................................................... 75
 vii
Diagnosis ......................................................................................................................................................................... 76
Staging ............................................................................................................................................................................. 77
Treatment ........................................................................................................................................................................ 77
Prognosis ......................................................................................................................................................................... 78
Pancreatic Cancer ........................................................................................................................................................ 79
Types ................................................................................................................................................................................. 79
Signs and Symptoms .................................................................................................................................................. 81
Risk Factors ..................................................................................................................................................................... 82
Pathophysiology ........................................................................................................................................................... 83
Diagnosis ......................................................................................................................................................................... 84
Staging ............................................................................................................................................................................. 85
Prevention and Screening ........................................................................................................................................ 87
Management ................................................................................................................................................................. 87
Outcomes ....................................................................................................................................................................... 90
Hepatocellular Carcinoma ........................................................................................................................................ 91
Signs and Symptoms .................................................................................................................................................. 91
Risk Factors ..................................................................................................................................................................... 91
'Pathogenesis ................................................................................................................................................................ 92
Diagnosis ......................................................................................................................................................................... 93
Prevention ...................................................................................................................................................................... 95
Treatment ........................................................................................................................................................................ 95
Prognosis ......................................................................................................................................................................... 98
Colorectal Cancer ........................................................................................................................................................ 98
Signs and Symptoms .................................................................................................................................................. 98
Cause ................................................................................................................................................................................ 99
Pathogenesis ................................................................................................................................................................. 99
Diagnosis ...................................................................................................................................................................... 101
Prevention ................................................................................................................................................................... 102
Treatment ..................................................................................................................................................................... 104
Prognosis ...................................................................................................................................................................... 106
Rectal Cancer ............................................................................................................................................................. 106
Symptoms .................................................................................................................................................................... 107
Causes ........................................................................................................................................................................... 107
Risk Factors .................................................................................................................................................................. 107
Prevention ................................................................................................................................................................... 108
Surgical Management of Liver Metastases from Colorectal Cancer ..................................................... 108
Treatment Options ................................................................................................................................................... 109
Surgical Treatment .................................................................................................................................................... 109
Hereditary Colorectal Cancer and Polyposis Syndromes .......................................................................... 114
Hereditary Colorectal Syndromes ...................................................................................................................... 114
Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy ....................................... 116
Interdisciplinary Concept ....................................................................................................................................... 116
Hyperthermic Intraperitoneal Chemotherapy .............................................................................................. 116
Neo-adjuvant Chemotherapy .............................................................................................................................. 117
Organ Preserving Cytoreductive Surgery ........................................................................................................ 117
Second Look Surgery ............................................................................................................................................... 117
Squamous Cell Carcinoma of the Anal Margin ............................................................................................. 118
Diagnosis and Staging ............................................................................................................................................. 118
Natural History and Spread Patterns .................................................................................................................. 119
Surgical Management ............................................................................................................................................. 119
Radiation Therapy ..................................................................................................................................................... 120
Adjuvant Chemotherapy ....................................................................................................................................... 120

4. Endocrine 121
Thyroid Cancer ........................................................................................................................................................... 121
Signs and Symptoms ............................................................................................................................................... 121
Causes ........................................................................................................................................................................... 121
Diagnosis ...................................................................................................................................................................... 122
Treatment ..................................................................................................................................................................... 126
Prognosis ...................................................................................................................................................................... 126
Pancreatic Neuroendocrine Tumors (PNETs) ................................................................................................. 128
 viii
Types .............................................................................................................................................................................. 128
Signs and Symptoms ............................................................................................................................................... 128
Diagnosis ...................................................................................................................................................................... 129
Staging .......................................................................................................................................................................... 129
Treatment ..................................................................................................................................................................... 132
Genetics ........................................................................................................................................................................ 133
Multiple Endocrine Neo-plasia (MEN) Syndromes ....................................................................................... 133
Terminology ................................................................................................................................................................ 133
Related Conditions ................................................................................................................................................... 133
History ........................................................................................................................................................................... 133
Comparison ................................................................................................................................................................. 134
Multiple Endocrine Neo-plasia Type 1 (MEN1) .............................................................................................. 135
Carcinoid Tumors ....................................................................................................................................................... 136
Signs and Symptoms ............................................................................................................................................... 136
Cause ............................................................................................................................................................................. 137
Treatment ..................................................................................................................................................................... 137
Goblet Cell Carcinoid .............................................................................................................................................. 138

5. Sarcoma 139
Introduction ................................................................................................................................................................ 139
Diagnosis ...................................................................................................................................................................... 139
Grade ............................................................................................................................................................................. 139
Awareness ................................................................................................................................................................... 139
Chondrosarcoma ....................................................................................................................................................... 140
Classification and grading ..................................................................................................................................... 140
Symptoms .................................................................................................................................................................... 140
Causes ........................................................................................................................................................................... 140
Diagnosis ...................................................................................................................................................................... 141
Treatment ..................................................................................................................................................................... 141
Prognosis ...................................................................................................................................................................... 141
Ewing's sarcoma ........................................................................................................................................................ 141
Presentation ................................................................................................................................................................ 142
Causes ........................................................................................................................................................................... 142
Diagnosis ...................................................................................................................................................................... 142
Treatment ..................................................................................................................................................................... 143
Prognosis ...................................................................................................................................................................... 144
Epidemiology ............................................................................................................................................................. 144
Research, information and support ................................................................................................................... 144
Hemangioendothelioma ....................................................................................................................................... 144
Classification ............................................................................................................................................................... 145
Signs and symptoms ................................................................................................................................................ 146
Treatment ..................................................................................................................................................................... 146
Osteosarcoma ............................................................................................................................................................ 146
Signs and symptoms ................................................................................................................................................ 146
Causes ........................................................................................................................................................................... 147
Mechanism .................................................................................................................................................................. 147
Diagnosis ...................................................................................................................................................................... 148
Treatment ..................................................................................................................................................................... 148
Epidemiology ............................................................................................................................................................. 149
Prognosis ...................................................................................................................................................................... 149
Sarcoma botryoides ................................................................................................................................................. 150
Clinical characteristics ............................................................................................................................................. 150
Histology ...................................................................................................................................................................... 150
Treatment and prognosis ....................................................................................................................................... 150
Epidemiology ............................................................................................................................................................. 150
Soft-tissue sarcoma .................................................................................................................................................. 150
Signs and symptoms ................................................................................................................................................ 150
Risk factors ................................................................................................................................................................... 150
Diagnosis ...................................................................................................................................................................... 151
Treatment ..................................................................................................................................................................... 151
Epidemiology ............................................................................................................................................................. 152
 ix
Tables ............................................................................................................................................................................. 152
Alveolar soft part sarcoma ..................................................................................................................................... 153
Angiosarcoma ............................................................................................................................................................ 154
Phyllodes tumor ........................................................................................................................................................ 154
Dermatofibrosarcoma protuberans ................................................................................................................... 155
Aggressive fibromatosis ......................................................................................................................................... 156
Desmoplastic small-round-cell tumor .............................................................................................................. 157
Epithelioid sarcoma .................................................................................................................................................. 159
Fibrosarcoma .............................................................................................................................................................. 166
Hemangiopericytoma ............................................................................................................................................. 167
Hemangiosarcoma ................................................................................................................................................... 167
Kaposi's sarcoma ....................................................................................................................................................... 169
Leiomyosarcoma ....................................................................................................................................................... 172
Liposarcoma ................................................................................................................................................................ 173
Lymphangiosarcoma ............................................................................................................................................... 174
Lymphoma .................................................................................................................................................................. 174
Undifferentiated pleomorphic sarcoma .......................................................................................................... 179
Malignant peripheral nerve sheath tumor ...................................................................................................... 180
Rhabdomyosarcoma ................................................................................................................................................ 181
Synovial sarcoma ....................................................................................................................................................... 186
Gastrointestinal stromal tumor ............................................................................................................................ 188
Classification ............................................................................................................................................................... 188
Signs and symptoms ................................................................................................................................................ 188
Pathophysiology ........................................................................................................................................................ 188
Diagnosis ...................................................................................................................................................................... 189
Management .............................................................................................................................................................. 191
Epidemiology ............................................................................................................................................................. 192

6. Gynecology 193
Ovarian cancer ........................................................................................................................................................... 193
Signs and symptoms ................................................................................................................................................ 193
Risk factors ................................................................................................................................................................... 194
Pathophysiology ........................................................................................................................................................ 197
Diagnosis ...................................................................................................................................................................... 198
Screening ..................................................................................................................................................................... 216
Prevention ................................................................................................................................................................... 217
Management .............................................................................................................................................................. 217
Prognosis ...................................................................................................................................................................... 222
Epidemiology ............................................................................................................................................................. 224
In pregnancy ............................................................................................................................................................... 225
Research ....................................................................................................................................................................... 225
Adnexal mass ............................................................................................................................................................. 227
Causes ........................................................................................................................................................................... 227
Treatment ..................................................................................................................................................................... 227
Ovarian tumor ............................................................................................................................................................ 228
Benign tumors ........................................................................................................................................................... 228
Cancer ........................................................................................................................................................................... 228
Clear-cell ovarian carcinoma ................................................................................................................................ 228
Description .................................................................................................................................................................. 228
Prognosis ...................................................................................................................................................................... 228
High-grade serous carcinoma .............................................................................................................................. 228
Risk factors ................................................................................................................................................................... 229
Pathophysiology ........................................................................................................................................................ 229
Diagnosis ...................................................................................................................................................................... 231
Prevention ................................................................................................................................................................... 232
Treatment ..................................................................................................................................................................... 232
Krukenberg tumor .................................................................................................................................................... 233
Signs and symptoms ................................................................................................................................................ 233
Cause and incidence ............................................................................................................................................... 233
Pathogenesis .............................................................................................................................................................. 233
Treatment and prognosis ....................................................................................................................................... 233
 x
Leydig cell tumour ................................................................................................................................................... 234
Presentation ................................................................................................................................................................ 234
Diagnosis ...................................................................................................................................................................... 234
Treatment ..................................................................................................................................................................... 234
Luteoma ....................................................................................................................................................................... 235
Presentation ................................................................................................................................................................ 235
Detection ..................................................................................................................................................................... 235
Treatment ..................................................................................................................................................................... 236
Causes ........................................................................................................................................................................... 236

Bibliography 237
Index 241
Preface

Cancer is a disease which is increasing day by day and so are the challenges to its treatment. Cancer which
was synonymous with death a few years ago is not so deadly now with better understanding of cancer biology
and availability of better technology for treatment of cancer patients. With use of multimodality treatment the
results have started improving. Surgery is commonly used for the prevention and treatment of cancer. Various
types of surgeries are performed based on the type of cancer, its intensity and its location. Surgery helps in
removing the tumor and surrounding tissue and has been considered as an effective way to treat various types of
cancer. Surgery is done after locating the cancerous tumour, finding its spread, and diagnosing cancer. It may
also be used to restore body's appearance and relieve the body of the side effects that may have been caused by
the disease or its treatment. The cancer surgery is also dependent on the growth and spread of the tumour.
Staging Surgery is used to find out the size of the tumour and its spread. This, along with the results of other
laboratory tests helps the doctor to decide on the kind of treatment the patient should receive. Surgical oncology
is the branch of surgery applied to oncology; it focuses on the surgical management of tumors, especially cancerous
tumors. As one of several modalities in the management of cancer, the specialty of surgical oncology, before
modern medicine the only cancer treatment with a chance of success, has evolved in steps similar to medical
oncology, which grew out of hematology, and radiation oncology, which grew out of radiology.
 Chapter 1

Skin

MEL ANOMA
MELANOMA
Melanoma, also known as malignant melanoma, is a type of cancer that develops from the pigment-containing
cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines,
or eye. In women, they most commonly occur on the legs, while in men they are most common on the back.
Sometimes they develop from a mole with concerning changes including an increase in size, irregular edges,
change in colour, itchiness, or skin breakdown. The primary cause of melanoma is ultraviolet light (UV) exposure
in those with low levels of skin pigment. The UV light may be from either the sun or from other sources, such
as tanning devices. About 25% develop from moles. Those with many moles, a history of affected family
members, and who have poor immune function are at greater risk. A number of rare genetic defects such as
xeroderma pigmentosum also increase risk. Diagnosis is by biopsy of any concerning skin lesion. Using sunscreen
and avoiding UV light may prevent melanoma. Treatment is typically removal by surgery. In those with slightly
larger cancers, nearby lymph nodes may be tested for spread.
2 Surgical Oncology: Theory and Multidisciplinary Practice

Most people are cured if spread has not occurred. For those in whom melanoma has spread, immunotherapy,
biologic therapy, radiation therapy, or chemotherapy may improve survival. With treatment the five-year survival
rates in the United States is 98% among those with localized disease and 17% among those in whom spread has
occurred. The likelihood that it will come back or spread depends how thick the melanoma is, how fast the cells
are dividing, and whether or not the overlying skin has broken down. Melanoma is the most dangerous type of
skin cancer. Globally, in 2012, it newly occurred in 232,000 people. In 2015 there were 3.1 million with active
disease which resulted in 59,800 deaths. Australia and New Zealand have the highest rates of melanoma in the
world. There are also high rates in Northern Europe and North America, while it is less common in Asia, Africa,
and Latin America. Melanoma is more common in men than women. Melanoma has become more common
since the 1960s in areas which are mostly populated with white people.

HISTORY
Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However,
one example lies in a 1960s examination of nine Peruvian mummies, radiocarbon dated to be approximately
2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases
to the bones. John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not
knowing precisely what it was, he described it as a “cancerous fungous excrescence”. The excised tumor was
preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that
microscopic examination of the specimen revealed it to be an example of metastatic melanoma. The French
physician Rene Laennec was the first to describe melanoma as a disease entity.
His report was initially presented during a lecture for the Faculte de Medecine de Paris in 1804 and then
published as a bulletin in 1806. The first English language report of melanoma was presented by an English
general practitioner from Stourbridge, William Norris in 1820. In his later work in 1857 he remarked that there
is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and
Therapeutical Remarks on That Disease). Norris was also a pioneer in suggesting a link between nevi and
melanoma and the possibility of a relationship between melanoma and environmental exposures, by observing
that most of his patients had pale complexions. He also described that melanomas could be amelanotic and later
showed the metastatic nature of melanoma by observing that they can disseminate to other visceral organs. The
first formal acknowledgment of advanced melanoma as untreatable came from Samuel Cooper in 1840. He
stated that the only chance for a cure depends upon the early removal of the disease (i.e., early excision of the
malignant mole)...’
More than one and a half centuries later this situation remains largely unchanged.
The word melanoma is from the Greek µελας melas meaning “dark”.

SIGNS AND SYMPTOMS

Early signs of melanoma are changes to the shape or colour of existing moles or, in the case of nodular
melanoma, the appearance of a new lump anywhere on the skin. At later stages, the mole may itch, ulcerate or
bleed.
Early signs of melanoma are summarized by the mnemonic “ABCDE”:
• Asymmetry
• Borders (irregular with edges and corners)
• Colour (variegated)
• Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser)
• Evolving over time.
Skin 3

These classifications do not, however, apply to the most dangerous form of melanoma, nodular melanoma,
which has its own classifications:
• Elevated above the skin surface
• Firm to the touch
• Growing.
Metastatic melanoma may cause non-specific paraneoplastic symptoms, including loss of appetite, nausea,
vomiting and fatigue. Metastasis of early melanoma is possible, but relatively rare: less than a fifth of melanomas
diagnosed early become metastatic. Brain metastases are particularly common in patients with metastatic
melanoma. It can also spread to the liver, bones, abdomen or distant lymph nodes.

CAUSE
Melanomas are usually caused by DNA damage resulting from exposure to ultraviolet light from the sun.
Genetics also plays a role. Having more than fifty moles indicates an increased risk melanoma might arise. A
weakened immune system makes it easier for cancer to arise due to the body’s weakened ability to fight cancer
cells.

UV Radiation
The ultraviolet radiation from tanning beds increases the risk of melanoma. The International Agency for
Research on Cancer finds that tanning beds are “carcinogenic to humans” and that people who begin using tanning
devices before the age of thirty years are 75% more likely to develop melanoma. Those who work in airplanes also
appear to have an increased risk, believed to be due to greater exposure to UV. Ultraviolet UVB light (wavelengths
between 315 – 280 nm) from the sun is absorbed by skin cell DNA and results in a type of direct DNA damage
called cyclobutane pyrimidine dimers (CPDs). Thymine-thymine, cytosine-cytosine or cytosine-thymine dimers
are formed by the joining of two adjacent pyrimidine bases within a DNA strand. Somewhat similarly to UVB,
UVA light (longer wavelengths between 400 – 315 nm) from the sun or from tanning beds can also be directly
absorbed by skin DNA (at about 100 to 1000 fold lower efficiency than UVB is absorbed). Studies suggest that
exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma.
Occasional extreme sun exposure (resulting in “sunburn”) is causally related to melanoma. Melanoma is most
common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be
strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common
in professional and administrative workers than unskilled workers. Other factors are mutations in or total loss of
tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development
of skin cancers, including melanoma. Possible significant elements in determining risk include the intensity and
duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Melanoma
rates tend to be highest in countries settled by migrants from northern Europe that have a large amount of direct,
intense sunlight that the skin of the settlers is not adapted to, most notably Australia. Exposure during childhood is
a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia. Having
multiple severe sunburns increases the likelihood that future sunburns develop into melanoma due to cumulative
damage. The sun and tanning beds are the main sources of UV radiation that increase the risk for melanoma and
living close to the equator increases exposure to UV radiation.

Genetics
A number of rare mutations, which often run in families, greatly increase melanoma susceptibility. Several
genes increase risks. Some rare genes have a relatively high risk of causing melanoma; some more common
4 Surgical Oncology: Theory and Multidisciplinary Practice

genes, such as a gene called MC1R that causes red hair, have a relatively lower elevated risk. Genetic testing
can be used to search for the mutations. One class of mutations affects the gene CDKN2A. An alternative
reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis
and in fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor
of CDK4, a cyclin-dependent kinase that promotes cell division. Mutations that cause the skin condition
xeroderma pigmentosum (XP) also increase melanoma susceptibility. Scattered throughout the genome, these
mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant (the
chances of a carrier to express the phenotype is high). Familial melanoma is genetically heterogeneous, and loci
for familial melanoma appear on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been
related to melanoma’s pathogenesis (disease development). The multiple tumor suppressor 1 (CDKN2A/MTS1)
gene encodes p16INK4a – a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs)
– which has been localised to the p21 region of human chromosome 9. Other mutations confer lower risk, but
are more common in the population. People with mutations in the MC1R gene, for example, are two to four
times more likely to develop melanoma than those with two wild-type (typical unaffected type) copies. MC1R
mutations are very common; in fact, all red-haired people have a mutated copy. Mutation of the MDM2 SNP309
gene is associated with increased risks for younger women. Fair- and red-haired people, persons with multiple
atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk. A
family history of melanoma greatly increases a person’s risk because mutations in several genes have been
found in melanoma-prone families. People with a history of one melanoma are at increased risk of developing
a second primary tumor. Fair skin is the result of having less melanin in the skin, which means there is less
protection from UV radiation. A family history could indicate a genetic predisposition to melanoma.

PATHOPHYSIOLOGY
The earliest stage of melanoma starts when melanocytes begin out-of-control growth. Melanocytes are found
between the outer layer of the skin (the epidermis) and the next layer (the dermis). This early stage of the
disease is called the radial growth phase, when the tumor is less than 1 mm thick. Because the cancer cells have
not yet reached the blood vessels deeper in the skin, it is very unlikely that this early-stage melanoma will
spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely
removed with surgery. When the tumor cells start to move in a different direction — vertically up into the
epidermis and into the papillary dermis — cell behaviour changes dramatically. The next step in the evolution
is the invasive radial growth phase, which is a confusing term; however, it explains the process of the radial
growth, in which individual cells start to acquire invasive potential. From this point on the melanoma is capable
of spreading. The Breslow’s depth of the lesion is usually less than 1 mm (0.04 in), while the Clark level is
usually 2.
The vertical growth phase (VGP) following is the invasive melanoma. The tumor becomes able to grow
into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor
thickness is usually more than 1 mm (0.04 in), and the tumor involves the deeper parts of the dermis. The host
elicits an immunological reaction against the tumor during the VGP, which is judged by the presence and
activity of the tumor infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary
tumor; this is called regression, which is the latest stage of development. In certain cases, the primary tumor is
completely destroyed and only the metastatic tumor is discovered. About 40% of human melanomas contain
activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the
Raf to MAP kinase pathway. In general, cancers are caused by damage to DNA. UVA light mainly causes
thymine-thymine dimers. UVA also produces reactive oxygen species and these inflict other DNA damage,
primarily single-strand breaks, oxidized pyrimidines and the oxidized purine 8-oxoguanine (a mutagenic DNA
Skin 5

change) at 1/10th, 1/10th and 1/3rd the frequencies of UVA-induced thymine-thymine dimers, respectively. If
unrepaired, CPD photoproducts can lead to mutations by inaccurate translesion synthesis during DNA replication
or repair. The most frequent mutations due to inaccurate synthesis past CPDs are cytosine to thymine (C>T) or
CC>TT transition mutations. These are commonly referred to as UV fingerprint mutations, as they are the most
specific mutation caused by UV, being frequently found in sun-exposed skin but rarely found in internal organs.
Errors in DNA repair of UV photoproducts, or inaccurate synthesis past these photoproducts, can also lead to
deletions, insertions and chromosomal translocations.
The entire genomes of 25 melanomas were sequenced. On average, about 80,000 mutated bases (mostly
C>T transitions) and about 100 structural rearragements were found per melanoma genome. This is much
higher than the approximately 70 mutations across generations (parent to child). Among the 25 melanomas,
about 6,000 protein-coding genes had missense, non-sense or splice site mutations. The transcriptomes of over
100 melanomas has also been sequenced and analyzed. Almost 70% of all human protein coding genes are
expressed in melanoma. Most of these genes are also expressed in other normal and cancer tissues, with some
200 genes showing a more specific expression pattern in melanoma compared to other forms of cancer. Examples
of melanoma specific genes are tyrosinase, MLANA and PMEL. UV radiation causes damage to the DNA of
cells, typically thymine dimerization, which when unrepaired can create mutations in the cell’s genes. When
the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in
protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become
uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of activating
transcription factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma
cells; studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer
progression. Cancer stem cells may also be involved.

DIAGNOSIS
Visual inspection is the most common diagnostic technique. Moles that are irregular in colour or shape are
typically treated as candidates. To detect melanomas (and increase survival rates), it is recommended to learn to
recognize them, to regularly examine moles for changes (shape, size, colour, itching or bleeding) and to consult
a qualified physician when a candidate appears.

ABCDE
A popular method for remembering the signs and symptoms of melanoma is the mnemonic “ABCDE”:
• Asymmetrical skin lesion.
• Border of the lesion is irregular.
• Colour: melanomas usually have multiple colors.
• Diameter: moles greater than 6 mm are more likely to be melanomas than smaller moles.
• Enlarging: Enlarging or evolving
However, many melanomas present as lesions smaller than 6 mm in diameter; and all melanomas are malignant
when they first appear as a small dot. Physicians typically examine all moles, including those less than 6 mm in
diameter. Seborrheic keratosis may meet some or all of the ABCD criteria, and can lead to false alarms. Doctors
can generally distinguish seborrheic keratosis from melanoma upon examination, or with dermatoscopy. Some
advocate replacing enlarging with evolution. Certainly moles that change and evolve will be a concern.
Alternatively, some practitioners prefer elevation. Elevation can help identify a melanoma, but lack of elevation
does not mean that the lesion is not a melanoma. Most melanomas in the US are detected before they become
elevated. By the time elevation is visible, they may have progressed to the more dangerous invasive stage.
6 Surgical Oncology: Theory and Multidisciplinary Practice

Nodular melanomas do not fulfill these criteria, having their own mnemonic, “EFG”:
• Elevated: the lesion is raised above the surrounding skin.
• Firm: the nodule is solid to the touch.
• Growing: the nodule is increasing in size.

Fig. ABCD rule illustration: On the left side from top to bottom: melanomas showing (A) Asymmetry,
(B) a border that is uneven, ragged, or notched, (C) coloring of different shades of brown, black, or tan and
(D) diameter that had changed in size. The normal moles on the right side do not have abnormal characteristics
(no asymmetry, even border, even colour, no change in diameter).
Skin 7

Ugly Duckling
A recent and novel method is the “ugly duckling sign”. It is simple, easy to teach, and highly effective.
Correlation of common lesion characteristics is made. Lesions that greatly deviate from the common
characteristics are labeled an “Ugly Duckling”, and a further professional exam is required. The “Little Red
Riding Hood” sign suggests that individuals with fair skin and light-colored hair might have difficult-to-diagnose
amelanotic melanomas. Extra care is required when examining such individuals, as they might have multiple
melanomas and severely dysplastic nevi.
A dermatoscope must be used to detect “ugly ducklings”, as many melanomas in these individuals resemble
non-melanomas or are considered to be “wolves in sheep’s clothing”. These fair-skinned individuals often have
lightly pigmented or amelanotic melanomas that do not present easy-to-observe colour changes and variations.
Their borders are often indistinct, complicating visual identification without a dermatoscope. Amelanotic
melanomas and melanomas arising in fair-skinned individuals are very difficult to detect, as they fail to show
many of the characteristics in the ABCD rule, break the “Ugly Duckling” sign and are hard to distinguish from
acne scarring, insect bites, dermatofibromas, or lentigines.

Biopsy
Following a visual examination and a dermatoscopic exam, or in vivo diagnostic tools such as a confocal
microscope, the doctor may biopsy the suspicious mole. A skin biopsy performed under local anesthesia is often
required to assist in making or confirming the diagnosis and in defining severity. Elliptical excisional biopsies
may remove the tumor, followed by histological analysis and Breslow scoring. Incisional biopsies such as
punch biopsies are usually contraindicated in suspected melanomas, because of the possibility of sampling
error or local implantation causing misestimation of tumour thickness. However, fears that such biopsies may
increase the risk of metastatic disease seem unfounded.
Total body photography, which involves photographic documentation of as much body surface as possible,
is often used during follow-up for high-risk patients. The technique has been reported to enable early detection
and provides a cost-effective approach (with any digital camera), but its efficacy has been questioned due to its
inability to detect macroscopic changes. The diagnosis method should be used in conjunction with (and not as
a replacement for) dermoscopic imaging, with a combination of both methods appearing to give extremely high
rates of detection.

Classification
Melanoma is divided into the following types:
• Lentigo maligna
• Lentigo maligna melanoma
• Superficial spreading melanoma
• Acral lentiginous melanoma
• Mucosal melanoma
• Nodular melanoma
• Polypoid melanoma
• Desmoplastic melanoma
• Melanoma with small nevus-like cells
• Melanoma with features of a Spitz nevus
• Uveal melanoma
• Vaginal melanoma.
8 Surgical Oncology: Theory and Multidisciplinary Practice

Laboratory
Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many patients with
metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates metastatic spread of
the disease to the liver. It is common for patients diagnosed with melanoma to have chest X-rays and an LDH
test, and in some cases CT, MRI, PET and/or PET/CT scans. Although controversial, sentinel lymph node
biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph
nodes. A diagnosis of melanoma is supported by the presence of the S-100 protein marker. HMB-45 is a
monoclonal antibody that reacts against an antigen present in melanocytic tumors such as melanomas. It is used
in anatomic pathology as a marker for such tumors. The antibody was generated to an extract of melanoma. It
reacts positively against melanocytic tumors but not other tumors, thus demonstrating specificity and sensitivity.
The antibody also reacts positively against junctional nevus cells but not intradermal nevi, and against fetal
melanocytes but not normal adult melanocytes. HMB-45 is non-reactive with almost all non-melanoma human
malignancies, with the exception of rare tumors showing evidence of melanogenesis (e.g., pigmented
schwannoma, clear cell sarcoma) or tumors associated with tuberous sclerosis complex (angiomyolipoma and
lymphangiomyoma).

Staging
Also of importance are the “Clark level” and “Breslow’s depth”, which refer to the microscopic depth of
tumor invasion. Melanoma stages: 5 year survival rates:

Fig. T stages of melanoma

Stage 0: Melanoma in situ (Clark Level I), 99.9% survival
Stage I/ II: Invasive melanoma, 89–95% survival
• T1a: Less than 1.0 mm primary tumor thickness, without ulceration, and mitosis < 1/mm2
• T1b: Less than 1.0 mm primary tumor thickness, with ulceration or mitoses ≥ 1/mm2
• T2a: 1.01–2.0 mm primary tumor thickness, without ulceration.
Stage II: High risk melanoma, 45–79% survival
• T2b: 1.01–2.0 mm primary tumor thickness, with ulceration
• T3a: 2.01–4.0 mm primary tumor thickness, without ulceration
• T3b: 2.01–4.0 mm primary tumor thickness, with ulceration
• T4a: Greater than 4.0 mm primary tumor thickness, without ulceration
• T4b: Greater than 4.0 mm primary tumor thickness, with ulceration.
Skin 9

Fig. F18-FDG PET/CT in a melanoma patient showing multiple lesions, most likely metastases
Stage III: Regional metastasis, 24–70% survival
• N1: Single positive lymph node
• N2: Two to three positive lymph nodes or regional skin/in-transit metastasis
• N3: Four positive lymph nodes or one lymph node and regional skin/in-transit metastases.
Stage IV: Distant metastasis, 7–19% survival
• M1a: Distant skin metastasis, normal LDH
• M1b: Lung metastasis, normal LDH
• M1c: Other distant metastasis or any distant metastasis with elevated LDH.
Based upon AJCC five-year survival from initial melanoma diagnosis with proper treatment.

PREVENTION

Avoiding Ultraviolet Radiation

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds), following sun protection measures
and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection.
Using artificial light for tanning was once believed to help prevent skin cancers, but it can actually lead to an
increased incidence of melanomas. The body uses UV light to generate vitamin D so there is a need to balance
getting enough sunlight to maintain healthy vitamin D levels and reducing the risk of melanoma; it takes around a
half hour of sunlight for the body to generate its vitamin D for the day and this is about the same amount of time
it takes for fair-skinned people to get a sunburn. Exposure to sunlight can be intermittent instead of all at one time.
10 Surgical Oncology: Theory and Multidisciplinary Practice

Sunscreen
Sunscreen appears to be effective in preventing melanoma. In the past, use of sunscreens with a sun protection
factor (SPF) rating of 50 or higher on exposed areas were recommended; as older sunscreens more effectively
blocked UVA with higher SPF. Currently, newer sunscreen ingredients (avobenzone, zinc oxide, and titanium
dioxide) effectively block both UVA and UVB even at lower SPFs. Sunscreen also protects against squamous
cell carcinoma, another skin cancer. Concerns have been raised that sunscreen might create a false sense of
security against sun damage.

TREATMENT
Confirmation of the clinical diagnosis is done with a skin biopsy. This is usually followed up with a wider
excision of the scar or tumor. Depending on the stage, a sentinel lymph node biopsy is done, as well, although
controversy exists around trial evidence for this procedure. Treatment of advanced malignant melanoma is
performed from a multidisciplinary approach.

Fig. Extensive malignant melanoma on a person’s chest

Surgery
Excisional biopsies may remove the tumor, but further surgery is often necessary to reduce the risk of
recurrence. Complete surgical excision with adequate surgical margins and assessment for the presence of
Skin 11

detectable metastatic disease along with short- and long-term followup is standard. Often this is done by a wide
local excision (WLE) with 1 to 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower
surgical margins, usually 0.2 to 0.5 cm. Many surgeons consider 0.5 cm the standard of care for standard
excision of melanoma-in-situ, but 0.2 cm margin might be acceptable for margin controlled surgery (Mohs
surgery, or the double-bladed technique with margin control). The wide excision aims to reduce the rate of
tumor recurrence at the site of the original lesion. This is a common pattern of treatment failure in melanoma.
Considerable research has aimed to elucidate appropriate margins for excision with a general trend towards less
aggressive treatment during the last decades. Mohs surgery has been reported with cure rate as low as 77% and
as high as 98.0% for melanoma-in-situ. CCPDMA and the “double scalpel” peripheral margin controlled surgery
is equivalent to Mohs surgery in effectiveness on this “intra-epithelial” type of melanoma. Melanomas that
spread usually do so to the lymph nodes in the area of the tumor before spreading elsewhere. Attempts to
improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many
complications, but no overall survival benefit. Recently, the technique of sentinel lymph node biopsy has been
developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of
nodes with tumor. Biopsy of sentinel lymph nodes is a widely used procedure when treating cutaneous melanoma.
Neither sentinel lymph node biopsy nor other diagnostic tests should be performed to evaluate early, thin
melanoma, including melanoma in situ, T1a melanoma or T1b melanoma ≤ 0.5mm. People with these conditions
are unlikely to have the cancer spread to their lymph nodes or anywhere else and already have a 97% 5-year
survival rate. Because of these things, sentinel lymph node biopsy is unnecessary health care for them.
Furthermore, baseline blood tests and radiographic studies should not be performed only based on identifying
this kind of melanoma, as there are more accurate tests for detecting cancer and these tests have high false-
positive rates. To potentially correct false positives, gene expression profiling may be used as auxiliary testing
for ambiguous and small lesions.
Sentinel lymph node biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular
melanoma and tumors of the limbs. A process called lymphoscintigraphy is performed in which a radioactive
tracer is injected at the tumor site to localize the sentinel node(s). Further precision is provided using a blue
tracer dye, and surgery is performed to biopsy the node(s). Routine hematoxylin and eosin (H&E) and
immunoperoxidase staining will be adequate to rule out node involvement. Polymerase chain reaction (PCR)
tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with
a negative sentinel lymph node actually had a small number of positive cells in their nodes. Alternatively, a
fine-needle aspiration biopsy may be performed and is often used to test masses. If a lymph node is positive,
depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. If the
disease is completely resected, the patient will be considered for adjuvant therapy. Excisional skin biopsy is the
management of choice. Here, the suspect lesion is totally removed with an adequate (but minimal, usually 1 or
2 mm) ellipse of surrounding skin and tissue. To avoid disruption of the local lymphatic drainage, the preferred
surgical margin for the initial biopsy should be narrow (1 mm). The biopsy should include the epidermal,
dermal, and subcutaneous layers of the skin. This enables the histopathologist to determine the thickness of the
melanoma by microscopic examination. This is described by Breslow’s thickness (measured in millimeters).
However, for large lesions, such as suspected lentigo maligna, or for lesions in surgically difficult areas (face,
toes, fingers, eyelids), a small punch biopsy in representative areas will give adequate information and will not
disrupt the final staging or depth determination. In no circumstances should the initial biopsy include the final
surgical margin (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from
the procedure. A large initial excision will disrupt the local lymphatic drainage and can affect further
lymphangiogram-directed lymphnode dissection. A small punch biopsy can be used at any time where for
logistical and personal reasons a patient refuses more invasive excisional biopsy. Small punch biopsies are
minimally invasive and heal quickly, usually without noticeable scarring.
12 Surgical Oncology: Theory and Multidisciplinary Practice

Add on Treatment
High-risk melanomas may require adjuvant treatment, although attitudes to this vary in different countries.
In the United States, most patients in otherwise good health will begin up to a year of high-dose interferon
treatment, which has severe side effects, but may improve the patient’s prognosis slightly. However, the British
Association of Dermatologists guidelines on melanoma state that interferon is not recommended as a standard
adjuvant treatment for melanoma. A 2011 meta-analysis showed that interferon could lengthen the time before
a melanoma comes back but increased survival by only 3% at 5 years. The unpleasant side effects also greatly
decrease quality of life. In Europe, interferon is usually not used outside the scope of clinical trials. Metastatic
melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and
photoacoustic detection.

Chemotherapy and Immunotherapy

Various chemotherapy agents, including temozolomide, dacarbazine (also termed DTIC), immunotherapy
(with interleukin-2 (IL-2) or interferon (IFN)), as well as local perfusion, are used by different centers. The
overall success in metastatic melanoma is quite limited. IL-2 (Proleukin) was the first new therapy approved
(1990 Europe, 1992 USA) for the treatment of metastatic melanoma in 20 years. Studies have demonstrated
that IL-2 offers the possibility of a complete and long-lasting remission in this disease, although only in a small
percentage of patients. Intralesional IL-2 for in-transit metastases has a high complete response rate ranging
from 40 to 100%. By 2005 a number of new agents and novel approaches were under evaluation and showed
promise. In 2009 Clinical trial participation was considered the standard of care for metastatic melanoma.
Therapies for metastatic melanoma include biologic immunotherapy agents ipilimumab, pembrolizumab, and
nivolumab; BRAF inhibitors, such as vemurafenib and dabrafenib; and a MEK inhibitor trametinib. Ongoing
research is looking at treatment by adoptive cell transfer. For this purpose, application of prestimulated or
modified T cells or dendritic cells is possible.

Lentigo Maligna
Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceedingly high
(up to 50%). This is due to the ill-defined visible surgical margin, and the facial location of the lesions (often
forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation
of the standard “bread-loafing” technique of fixed tissue histology — result in a high “false negative” error rate,
and frequent recurrences. Margin control (peripheral margins) is necessary to eliminate the false negative errors.
If bread loafing is used, distances from sections should approach 0.1 mm to assure that the method approaches
complete margin control. Mohs surgery has been done with cure rate reported to be as low as 77%, and as high as
95% by another author. The “double scalpel” peripheral margin controlled excision method approximates the
Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing
the vertical margin on the thin peripheral sections and staining methods. Some melanocytic nevi, and melanoma-
in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an
immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and
then treating the area with Aldara cream postoperatively for three months.

Radiation Therapy
Radiation therapy is often used after surgical resection for patients with locally or regionally advanced
melanoma or for patients with unresectable distant metastases. Kilovoltage x-ray beams are often used for these
Skin 13

treatments and have the property of the maximum radiation dose occurring close to the skin surface. It may
reduce the rate of local recurrence but does not prolong survival. Radioimmunotherapy of metastatic melanoma
is currently under investigation. Radiotherapy has a role in the palliation of metastatic melanoma.

PROGNOSIS
Features that affect prognosis are tumor thickness in millimeters (Breslow’s depth), depth related to skin
structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion,
presence of tumor-infiltrating lymphocytes (if present, prognosis is better), location of lesion, presence of
satellite lesions, and presence of regional or distant metastasis. Certain types of melanoma have worse prognoses
but this is explained by their thickness. Interestingly, less invasive melanomas even with lymph node metastases
carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences
tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged
excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion. When melanomas
have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy.
Extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic
have a more favourable prognosis than macrometastases. In some cases micrometastases may only be detected
by special staining, and if malignancy is only detectable by a rarely employed test known as the polymerase
chain reaction (PCR), the prognosis is better. Macrometastases in which malignancy is clinically apparent (in
some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is
extracapsular extension, the prognosis is worse still. In addition to these variables, expression levels and copy
number variations of a number of relevant genes may be used to support assessment of malignant melanoma
prognosis. When there is distant metastasis, the cancer is generally considered incurable. The five-year survival
rate is less than 10%. The median survival is 6–12 months. Treatment is palliative, focusing on life extension
and quality of life. In some cases, patients may live many months or even years with metastatic melanoma
(depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis.
Metastases to brain, bone and liver are associated with a worse prognosis. Survival is better with metastasis in
which the location of the primary tumor is unknown. There is not enough definitive evidence to adequately
stage, and thus give a prognosis for, ocular melanoma and melanoma of soft parts, or mucosal melanoma
(e.g. rectal melanoma), although these tend to metastasize more easily. Even though regression may increase
survival, when a melanoma has regressed, it is impossible to know its original size and thus the original
tumor is often worse than a pathology report might indicate. About 200 genes are prognostic in melanoma,
with both unfavourable genes where high expression is correlated to poor survival and favourable genes where
high expression is associated with longer survival times. Examples of unfavourable genes are MCM6 and
TIMELESS and an example of a favourable gene is WIPI1.

EPIDEMIOLOGY
Globally, in 2012, melanoma occurred in 232,000 people and resulted in 55,000 deaths. Australia and New
Zealand have the highest rates of melanoma in the world. It has become more common in the last 20 years in
areas that are mostly Caucasian. The rate of melanoma has increased in the recent years, but it is not clear to
what extent changes in behaviour, in the environment, or in early detection are involved.

Australia
Australia has a very high — and increasing — rate of melanoma. In 2012, deaths from melanoma occurred
in 7.3-9.8 per 100,000 population. In Australia, melanoma is the third most common cancer in either sex;
14 Surgical Oncology: Theory and Multidisciplinary Practice

indeed, its incidence is higher than for lung cancer, although the latter accounts for more deaths. It is estimated
that in 2012, more than 12,000 Australians were diagnosed with melanoma: given Australia’s modest population,
this is better expressed as 59.6 new cases per 100,000 population per year; >1 in 10 of all new cancer cases were
melanomas.
Melanoma incidence in Australia is matter of significance, for the following reasons:
• Australian melanoma incidence has increased by more than 30 per cent between 1991 and 2009.
• Australian melanoma age-standardised incidence rates were, as of 2008, at least 12 times higher than
the world average.
• Australian melanoma incidence is, by some margin, the highest in the world.
• Overall age-standardised cancer incidence in Australia is the highest in the world, and this is
attributable to melanoma alone. Age-standardised overall cancer incidence is similar to New Zealand,
but there is a statistically-significant difference between Australia and all other parts of the developed
world including North America, Western Europe, and the Mediterranean.

United States
In the United States about 9,000 people die from melanoma a year. In 2011 it affected 19.7 per 100,000, and
resulted in death in 2.7 per 100,000.
In 2013:
• 71,943 people in the United States were diagnosed with melanomas of the skin, including 42,430
men and 29,513 women.
• 9,394 people in the United States died from melanomas of the skin, including 6,239 men and 3,155 women.
The American Cancer Society’s estimates for melanoma incidence in the United States for 2017 are:
• About 87,110 new melanomas will be diagnosed (about 52,170 in men and 34,940 in women).
• About 9,730 people are expected to die of melanoma (about 6,380 men and 3,350 women).
Melanoma is more than 20 times more common in whites than in African Americans. Overall, the lifetime
risk of getting melanoma is about 2.5% (1 in 40) for whites, 0.1% (1 in 1,000) for African Americans, and 0.5%
(1 in 200) for Hispanics. The risk of melanoma increases as people age. The average age of people when the
disease is diagnosed is 63.

RESEARCH
Pharmacotherapy research for unresectable or metastatic malignant melanoma is ongoing.

Targeted Therapies
In clinical research setting other therapies, such as adoptive cell therapy or gene therapy, are being tested.
Two kinds of experimental treatments developed at the National Cancer Institute (NCI), have been used in
metastatic melanoma with tentative success. The first treatment involves adoptive cell therapy (ACT) using
TILs immune cells (tumor infiltrating lymphocytes) isolated from a person’s own melanoma tumor. These
cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily
reduces normal T cells in the patient’s body. TIL therapy following lymphodepletion can result in durable
complete response in a variety of setups. The second treatment, adoptive transfer of genetically altered autologous
lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient’s
lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface
of melanoma cells and kill them. A vaccine to train the immune system to fight cancer showed modest benefit
in late-stage testing in 2009 against melanoma.
Skin 15

BRAF Inhibitors
About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggested that B-Raf
inhibitors including Plexxicon’s vemurafenib could lead to substantial tumor regression in a majority of patients if
their tumor contain the B-Raf mutation. In June 2011, a large clinical trial confirmed the positive findings from
those earlier trials. In August 2011 Vemurafenib received FDA approval for the treatment of late-stage melanoma.
In May 2013 the US FDA approved dabrafenib as a single agent treatment for patients with BRAF V600E mutation-
positive advanced melanoma. Some researchers believe that combination therapies that simultaneously block
multiple pathways may improve efficacy by making it more difficult for the tumor cells to mutate before being
destroyed. In October 2012 a study reported that combining Dabrafenib with a MEK inhibitor trametinib led to
even better outcomes. Compared to Dabrafenib alone, progression-free survival was increased to 41% from 9%,
and the median progression-free survival increased to 9.4 months versus 5.8 months. Some side effects were,
however, increased in the combined study. In January 2014, the FDA approved the combination of dabrafenib and
trametinib for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma. Eventual resistance to
BRAF and MEK inhibitors may be due to a cell surface protein known as EphA2 which is now being investigated.

Ipilimumab
At the American Society of Clinical Oncology Conference in June 2010, the Bristol-Myers Squibb
pharmaceutical company reported the clinical findings of their drug ipilimumab. The study found an increase in
median survival from 6.4 to 10 months in patients with advanced melanomas treated with the monoclonal
ipilimumab, versus an experimental vaccine. It also found a one-year survival rate of 25% in the control group
using the vaccine, 44% in the vaccine and ipilimumab group, and 46% in the group treated with ipilimumab
alone. However, some have raised concerns about this study for its use of the unconventional control arm,
rather than comparing the drug against a placebo or standard treatment. The criticism was that although
Ipilimumab performed better than the vaccine, the vaccine has not been tested before and may be causing
toxicity, making the drug appear better by comparison. Ipilimumab was approved by the FDA in March 2011 to
treat patients with late-stage melanoma that has spread or cannot be removed by surgery. In June 2011, a
clinical trial of ipilimumab plus dacarbazine combined this immune system booster with the standard
chemotherapy drug that targets cell division. It showed an increase in median survival for these late stage
patients to 11 months instead of the 9 months normally seen. Researchers were also hopeful that perhaps 10–
20% of patients could live a long time. Some serious side-effects of revving up the immune system were seen in
some patients. A course of treatment costs $120,000. The drug’s brandname is Yervoy.

Surveillance Methods
Advances in high resolution ultrasound scanning have enabled surveillance of metastatic burden to the
sentinel lymph nodes. The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) is evaluating
ultrasound as an alternative to invasive surgical methods.

Oncolytic Virotherapy
In some countries oncolytic virotherapy methods are studied and used to treat melanoma. Oncolytic virotherapy
is a promising branch of virotherapy, where oncolytic viruses are used to treat diseases; viruses can increase
metabolism, reduce anti-tumor immunity and disorganize vasculature. Talimogene laherparepvec (T-VEC) (which
is a herpes simplex virus type 1–derived oncolytic immunotherapy), was shown to be useful against metastatic
melanoma in 2015 with an increased survival of 4.4 months.
16 Surgical Oncology: Theory and Multidisciplinary Practice

NON-MEL ANOMA SKIN CANCERS

NON-MELANOMA
Skin, which is a thin layer of tissue and the largest organ in the body, serves numerous functions. The most
obvious function of skin is serving as a barrier between the outside world and internal organs. It is made up of three
layers, the epidermis, the dermis and the hypodermis. The epidermis is the outermost layer. The dermis, which is
the layer underneath the epidermis, contains connective tissue, hair follicles and sweat glands. The hypodermis is
made up of fat and connective tissue. Over the course of years of exposure, skin is exposed to numerous potential
carcinogens, or cancer causing agents, most importantly the sun and its damaging ultraviolet rays.

WHAT IS NON-MELANOMA SKIN CANCER?

Non-melanoma skin cancer is any type of cancer affecting the skin that is not melanoma. Cancer cells are
abnormal cells that grow and can affect other organs in the body. There are numerous types of non-melanoma
skin cancers including: basal cell, squamous cell, angiosarcoma, cutaneous B and T cell lymphomas,
dermatofibrosarcoma protuberans, Merkel cell carcinoma, and sebaceous gland carcinoma. There are two
primary types of non-melanoma skin cancers - basal cell carcinoma (BCC) and squamous cell carcinoma
(SCC) and these are the two discussed in this article. These cancers derive their name from the cells in which
they originate. Both types of cells, basal and squamous, are located within the epidermis, or the outer layer of
our skin. Pre-malignant lesions generally precede the development of non-melanoma skin cancers.

WHAT CAUSES NON-MELANOMA SKIN CANCER AND AM I AT RISK?

Skin cancer is the most common type of cancer diagnosed each year. The incidence of skin cancers exceeds
that of all other cancers, and it is estimated that nearly half of cancers diagnosed every year will be skin cancers.
Over the past decade, the incidence of skin cancers has increased dramatically. About 5.4 million basal and
squamous cell skin cancers are diagnosed each year, with 8 out of 10 being basal cell and 2 out of 10 being
squamous cell. About 2,000 people in the US die each year from non-melanoma skin cancer but frequently
these are people with a compromised immune system. Although these cancers can be locally progressive, they
rarely metastasize or spread to other parts of the body. Because of early detection and the decreased metastatic
potential, non-melanoma skin cancer is often effectively treated and cured with only local treatment. Risk
factors for developing non-melanoma skin cancers are numerous, including fair complexion, occupational
exposures to radium and arsenic, personal history of atypical moles, history of skin cancers, family history of
skin cancers, smoking tobacco, immuno suppression from medications and HIV, chronic non-healing wounds
and previous burns, genetic syndromes such as basal cell nevus syndrome and xeroderma pigmentosum, and
HPV; however, the most common risk factor for development of skin cancer is exposure to ultraviolet radiation
from the sun. The vast majority (90%) of skin cancers will occur in individuals with no risk factors other than
excess sun exposure. Ultraviolet radiation from both sun exposure and tanning salons damage the epidermis
and the DNA in the cells found throughout the skin. This damage continues to occur with repeated exposure,
eventually leading to mutations that accumulate to cause cancerous cells. It has been shown that severe sunburns
are particularly damaging when they occur in children. Childhood sun exposure is the strongest correlate with
the development of basal cell carcinomas, while sun damage in the decade preceding diagnosis is closely
correlated with the development of squamous cell carcinomas.

WHAT SCREENING TESTS ARE AVAILABLE?

As we age, our years of sun exposure increase, and therefore the risk of skin cancer increases. Because of
this increasing risk of cancer with age, it is crucial to examine our own skin regularly and to notice changes
Skin 17

early. Be aware of the shapes and coloring of any freckles and moles you have. Skin cancer often develops from
an existing lesion, causing its appearance to change. Examine your skin routinely in a mirror, including your
back, face, lips, hands, forearms, and scalp. Furthermore, it is recommended that you follow up with your
physician regularly.
Early diagnosis is crucial in achieving the most appropriate treatment. Because skin cancers are related to
exposures, people who have previously developed skin cancers are at much higher risk for future skin cancers,
either in the primary (original) site or somewhere else on the body. Because of this, a complete skin exam
should be performed by a health care provider at regularly scheduled visits.

WHAT ARE THE SIGNS OF NON-MELANOMA SKIN CANCER?

BCC typically presents as a small pearly or crusty patch that fails to heal. Because they are painless and
typically develop slowly, they are often present for months to years before they are brought to the attention
of the health care provider. Often, BCC can be identified by blood vessels that are prominent within the
bump. As the lesions grow, crusting and bleeding ulcers that will not heal are frequently the reason individuals
present to their provider. The lesions are most often identified on the face, with more than 70% of BCC
diagnosed on the lips, cheeks, ears, nose, and scalp. Other regions of the body commonly diagnosed with
BCC include the back of the neck, the shoulders, the forearms and hands, the back, and lower legs. Although
the lesions are slow-growing and rarely develop the ability to spread to lymphatics or other parts of the body,
the lesions can progress locally, leading to destruction of nearby structures which can be disfiguring. Lesions
are frequently neglected because of their slow growth. As the BCC grows, it may invade adjacent areas,
including blood vessels, cartilage, and bone.
Risk factors for recurrence after treatment of basal cell carcinomas include depth of invasion, pathologic
sub-type, and perineural invasion. The appearance of squamous cell carcinoma is typically a small, painless,
elevated and crusty lump. As the lesions grow, they can become an ulceration and may bleed. SCCs tend to
develop more rapidly than BCCs, and unlike BCC, SCC can spread to the local lymphatic system. Risk factors
for lymph node involvement include tumors > 3 cm, poorly differentiated pathology, recurrent tumors, and
tumors with > 4 mm depth of invasion. They can also be rather aggressive locally, causing significant damage
and disfiguration to local structures.
Risk factors for recurrence after treatment of squamous cell carcinomas include perineural invasion, tumor
thickness, and poorly differentiated histology. The most common location of squamous cell carcinomas is
the face. Other areas at high risk include the back, shoulders, forearms and hands, and lower legs. Actinic
keratosis, which is a precancerous dry, scaly lesion, and carcinoma in situ (Bowen’s disease) are typically
located in areas of significant sun damage and often possess the potential to become malignant basal cell or
squamous cell carcinomas. These lesions initially develop into dysplasia, or atypical cells. Approximately 10%
of actinic keratoses will develop into invasive cancer.

HOW IS NON-MELANOMA CANCER DIAGNOSED?

When non-melanoma skin cancer is suspected, a biopsy is frequently performed to establish the diagnosis.
This biopsy removes either the entire lesion or part of it and the layers beneath it, allowing the depth of the
lesion to be accurately determined.
There are a number of different types of biopsies:
• Shave Biopsy: A blade is used to shave off the top layers of skin.
• Punch Biopsy: A tool that looks similar to a small, round cookie cutter is used to remove a deep
sample of skin.
18 Surgical Oncology: Theory and Multidisciplinary Practice

• Incisional Biopsy: A scalpel is used to remove part of the lesion.

• Excisional Biopsy: A scalpel is used to remove the entire lesion.
The sample of lesion is sent to a lab to be looked at by a pathologist who determines if the lesion is cancerous
and if cancerous what type of skin cancer it is. Along with the biopsy your provider will do a full physical exam
and health history. Your provider may order further testing to see if the cancer has spread. Imaging tests like
MRI, CT and chest x-rays may be used.

STAGING OF NON-MELANOMA SKIN CANCERS

Ark’s level, which describes depth of invasion by the tissue it invades (levels I-V). Clark’s level is an
indication of the depth of penetration only, not the stage of disease.
• Clark’s Level I involves the epidermis only (outermost level).
• Clark’s Level II involves the epidermis and the layer of skin immediately below, the papillary dermis.
• Clark’s Level III goes one layer deeper into the reticular dermis.
• Clark’s Level IV involves the deep dermis.
• Clark’s Level V invades beyond the skin layers into the subcutaneous fat.
Non-melanoma skin cancer is most commonly staged using the TNM staging system, which is determined
by the American Joint Committee on Cancer 7th edition (2010) The “T stage” represents the extent of the
primary tumor itself. The “N stage” represents the degree of involvement of the lymph nodes. The “M stage”
represents whether or not there is spread of the cancer to distant parts of the body. These are scored as follows:
>2 cm or has greater than 2 high-risk features.

Primary Tumor (T)

TX The primary tumor cannot be assessed.
T0 No evidence of primary tumor.
Tis Carcinoma in situ (tumor remained in epidermis).
T1 The tumor is 2cm across or smaller and has only 1 high risk feature.
T2 The tumor is larger than 2cm across, or is any size with 2 or more high-risk features.
T3 The tumor has grown into the facial bones.
T4 The tumor has grown into other bones in the body or into the base of the skull.
High risk features: These features help distinguish between some T1 and T2 tumors.
• The tumor is thicker than 2mm.
• The tumor has invaded down into the lower dermis or subcutis.
• The tumor has grown into tiny nerves in the skin.
• The tumor is on the ear or on part of the lip.
• The tumor cells look very abnormal under a microscope.

Regional Lymph Nodes (N)

NX Nearby lymph nodes cannot be assessed.
N0 The cancer has not spread to nearby lymph nodes.
N1 The cancer has spread to 1 nearby lymph node, which is on the same side of the body as the main tumor
and is 3cm or less across.
N2a The cancer has spread to 1 nearby lymph node, which is on the same side of the body as the main tumor
and is larger than 3cm but not larger than 6cm across.
N2b The cancer has spread to more than 1 nearby lymph node on the same side of the body as the main
tumor, none of which are larger than 6cm across.
N2c The cancer has spread to nearby lymph node(s) on the other side of the body from the main tumor, none
of which are larger than 6cm across.
N3 The cancer has spread to any nearby lymph node that is larger than 6cm across.
Skin 19

Metastasis (M)
M0 The cancer has not spread.
M1 The cancer had spread to other parts of the body.

Stages
0 Tis, N0, M0
I T1, N0, M0
II T2, N0, M0
III T3, N0, M0

T1 to T3, N1, M0
IV T1 to T3, N2, M0

Any T, N3, M0

T4, any N, M0

Any T, any N, M1
Although this system of cancer staging is quite complicated, it is designed to help physicians describe the
extent of the cancer, and therefore, helps to direct what type of treatment is given.

HOW IS NON-MELANOMA SKIN CANCER TREATED?

The treatment of SCC and BCC is dependent on location of the tumor, the age of the individual at diagnosis,
the extent of disease, and whether the area has been treated before. Non-melanoma skin cancers are generally
addressed with local treatments, including surgery, cryotherapy, and radiation. When lesions are discovered
and thought to be suspicious, they are frequently biopsied to ensure they are not a more aggressive type of skin
cancer. For lesions that are small and not locally progressive, the treatment options are numerous and include
Moh’s surgery, excisional surgery, cryotherapy, curettage and electrodessication, photodynamic therapy, topical
chemotherapy, and radiation therapy. In some instances, more than one treatment modality will be used to treat
the cancer.

Cryotherapy
This type of treatment involves freezing off the lesions with liquid nitrogen. Cryotherapy is best for very
small, well-defined superficial BCC and well-demarcated SCC. It is frequently used in patients that are not
ideal surgical candidates.

Excisional Surgery
This traditional simple surgical resection involves numbing the area with local anesthesia and removing the
entire area of concern with a border or margin of healthy tissue, generally 3-10 mm. The skin is then closed with
sutures (stitches) and the tissue is sent to a laboratory for a pathologist to ensure all the cancer has been removed.

Curettage and Electrodessication

The type of therapy is the most common method for treating BCC. The treatment involves local anesthesia
followed by removal of the tumor by curettage (scraping). The abnormality is scooped out with a curette until
20 Surgical Oncology: Theory and Multidisciplinary Practice

normal skin is appreciated. The entire area is then treated with an electrical current to stop any bleeding. The
difficulty with curettage is found in evaluating the margins (edges) and depth of the tumor. Similar to cryotherapy,
this technique is best for very small, well-defined superficial BCC and well-demarcated SCC.

Moh’s Surgery
Moh’s surgery is a procedure often performed by a dermatologist or a trained specialist in the office under
local anesthesia. With Moh’s surgery, very precise surgery is performed with attempts to remove the least
amount of tissue while the margins, or edges, of the resection are examined under a microscope immediately to
ensure all of the cancer is removed. While other types of resection can have recurrence rates as high as 50%,
Moh’s cure rates have been documented higher than 90%. This type of surgery is also very useful in traditionally
difficult areas, including the face. Indications for Moh’s surgery include large lesions where cosmesis can be
difficult and maximum skin preservation is crucial.

Radiation Therapy
Radiation therapy, which involves the use of non-invasive, painless, highly focused beams of ionizing energy,
is often used when lesions are in locations that are not easily addressed with surgery, such as eyelids, lips, the
nose, or ears. Radiation therapy involves daily treatments for several weeks. Radiation is used in the primary
treatment of non-melanoma skin cancers, achieving local control nearing 90%. Radiation is more frequently
used for skin cancers in the head and neck region as it offers improved cosmetic outcomes. The effectiveness of
radiation as a primary treatment is related to tumor size, with smaller tumors generally responding better. As
late skin effects from radiation are a concern, radiation is generally reserved for older patients. Radiation
therapy can also be used in conjunction with surgery when tumors are considered high risk or have positive
margins as well as with recurrent tumors.

Topical Medications and Chemotherapies

Topical medications are occasionally used to treat BCC. Fluorouracil (5-FU) is a type of chemotherapy
often used intravenously for other types of cancer; however, it is also approved for topical use for basal cell
carcinomas. The 5-FU cream is applied to the area twice daily for several weeks. Imiquimod is also an approved
topical medication for BCC. This cream, which is thought to work by stimulating the immune system, is applied
to the tumor five times a week for 6 weeks. This type of therapy is reserved for pre-malignant and very superficial
lesions.

Photodynamic Therapy
Photodynamic therapy is a treatment in which a topical photosensitizing agent is put on the lesion and then
the lesion is exposed to a to a wavelength of light. When the light is activated the photosensitizer reacts with the
oxygen causing destruction of the cancer cells.

Advanced Lesions
Locally advanced lesions that involve invasion into adjacent areas, the treatments are typically more aggressive.
Frequently, the surgery will involve reconstruction if a large amount of tissue will be removed. When
reconstruction must occur, a skin graft or muscle is often used to aid healing and reach an acceptable cosmetic
outcome. Radiation therapy will be used in addition to surgery to improve local control for lesions that are large
and/ or total resections are not possible. When tumors recur at the primary (original) site, treatment becomes
Skin 21

more complex and is often referred to specialists. The majority of recurrences occur within the first few years
following diagnosis. When possible, surgery to achieve negative margins is the best option. However, as lesions
often occur on the face near important structures such as the nose, lips, ears, and eyes, radiation is often used
when surgery would result in disfigurement.

Clinical Trials
Clinical trials are extremely important in furthering our knowledge of this disease. It is through clinical trials
that we know what we do today, and many exciting new therapies are currently being tested. Talk to your health
care provider about participating in clinical trials in your area. You can also explore currently open clinical
trials using the OncoLink Clinical Trials Matching Service.

FOLLOW-UP CARE AND SURVIVORSHIP

Patients with a history of non-melanoma skin cancer have been documented to be at greater risk of developing
a secondary skin cancer. Therefore, all patients require close follow-up. Patients with BCC should be evaluated
with a complete skin exam every 6 to 12 months for life. Patients with localized SCC should be evaluated with
a complete skin exam every 3 to 6 months for the first 2 years after diagnosis, then every 6 to 12 months for 3
years, and then annually. It is important for patients to continue to examine his or her own skin for any changes
or new lesions. As soon as you notice any changes you should contact your provider. It is also very important to
practice sun safety. Fear of recurrence, financial impact of cancer treatment, employment issues and coping
strategies are common emotional and practical issues experienced by non-melanoma skin cancer survivors.
Your health care team can identify resources for support and management of these practical and emotional
challenges faced during and after cancer. Cancer survivorship is a relatively new focus of oncology care. With
some 15 million cancer survivors in the US alone, there is a need to help patients transition from active treatment
to survivorship. What happens next, how do you get back to normal, what should you know and do to live
healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life
after cancer and helping you communicate knowledgeably with your health care providers. Create a survivorship
care plan today on OncoLink.
22 Surgical Oncology: Theory and Multidisciplinary Practice
Breast 23

Chapter 2

Breast
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the
breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, or a red scaly patch of skin.
In those with distant spread of the disease, there may be bone pain, swollen lymph nodes, shortness of breath,
or yellow skin. Risk factors for developing breast cancer include being female, obesity, lack of physical exercise,
drinking alcohol, hormone replacement therapy during menopause, ionizing radiation, early age at first
menstruation, having children late or not at all, older age, and family history. About 5–10% of cases are due to
genes inherited from a person’s parents, including BRCA1 and BRCA2 among others. Breast cancer most
commonly develops in cells from the lining of milk ducts and the lobules that supply the ducts with milk.
Cancers developing from the ducts are known as ductal carcinomas, while those developing from lobules are
known as lobular carcinomas. In addition, there are more than 18 other sub-types of breast cancer. Some cancers,
such as ductal carcinoma in situ, develop from pre-invasive lesions. The diagnosis of breast cancer is confirmed
by taking a biopsy of the concerning lump. Once the diagnosis is made, further tests are done to determine if the
cancer has spread beyond the breast and which treatments it may respond to. The balance of benefits versus
harms of breast cancer screening is controversial. A 2013 Cochrane review stated that it is unclear if
mammographic screening does more good or harm. A 2009 review for the US Preventive Services Task Force
found evidence of benefit in those 40 to 70 years of age, and the organization recommends screening every two
years in women 50 to 74 years old. The medications tamoxifen or raloxifene may be used in an effort to prevent
breast cancer in those who are at high risk of developing it. Surgical removal of both breasts is another preventative
measure in some high risk women. In those who have been diagnosed with cancer, a number of treatments may
be used, including surgery, radiation therapy, chemotherapy, hormonal therapy and targeted therapy. Types of
surgery vary from breast-conserving surgery to mastectomy. Breast reconstruction may take place at the time of
surgery or at a later date. In those in whom the cancer has spread to other parts of the body, treatments are
mostly aimed at improving quality of life and comfort. Outcomes for breast cancer vary depending on the
cancer type, extent of disease, and person’s age. Survival rates in the developed world are high, with between
80% and 90% of those in England and the United States alive for at least 5 years. In developing countries
survival rates are poorer. Worldwide, breast cancer is the leading type of cancer in women, accounting for 25%
of all cases. In 2012 it resulted in 1.68 million new cases and 522,000 deaths. It is more common in developed
countries and is more than 100 times more common in women than in men.

SIGNS AND SYMPTOMS

SYMPTOMS
The first noticeable symptom of breast cancer is typically a lump that feels different from the rest of the
breast tissue. More than 80% of breast cancer cases are discovered when the woman feels a lump. The earliest
breast cancers are detected by a mammogram. Lumps found in lymph nodes located in the armpits can also
indicate breast cancer. Indications of breast cancer other than a lump may include thickening different from the
24 Surgical Oncology: Theory and Multidisciplinary Practice

other breast tissue, one breast becoming larger or lower, a nipple changing position or shape or becoming
inverted, skin puckering or dimpling, a rash on or around a nipple, discharge from nipple/s, constant pain in part
of the breast or armpit, and swelling beneath the armpit or around the collarbone. Pain (“mastodynia”) is an
unreliable tool in determining the presence or absence of breast cancer, but may be indicative of other breast
health issues. Inflammatory breast cancer is a particular type of breast cancer which can pose a substantial
diagnostic challenge. Symptoms may resemble a breast inflammation and may include itching, pain, swelling,
nipple inversion, warmth and redness throughout the breast, as well as an orange-peel texture to the skin referred
to as peau d’orange. As inflammatory breast cancer does not present as a lump there can sometimes be a delay
in diagnosis. Another reported symptom complex of breast cancer is Paget’s disease of the breast. This syndrome
presents as skin changes resembling eczema, such as redness, discoloration, or mild flaking of the nipple skin.
As Paget’s disease of the breast advances, symptoms may include tingling, itching, increased sensitivity, burning,
and pain. There may also be discharge from the nipple. Approximately half of women diagnosed with Paget’s
disease of the breast also have a lump in the breast.
In rare cases, what initially appears as a fibroadenoma (hard, movable non-cancerous lump) could in fact be
a phyllodes tumor. Phyllodes tumors are formed within the stroma (connective tissue) of the breast and contain
glandular as well as stromal tissue. Phyllodes tumors are not staged in the usual sense; they are classified on the
basis of their appearance under the microscope as benign, borderline, or malignant. Occasionally, breast cancer
presents as metastatic disease—that is, cancer that has spread beyond the original organ. The symptoms caused
by metastatic breast cancer will depend on the location of metastasis. Common sites of metastasis include bone,
liver, lung and brain. Unexplained weight loss can occasionally signal breast cancer, as can symptoms of fevers
or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or
neurological symptoms. These symptoms are called non-specific, meaning they could be manifestations of
many other illnesses. Most symptoms of breast disorders, including most lumps, do not turn out to represent
underlying breast cancer. Fewer than 20% of lumps, for example, are cancerous, and benign breast diseases
such as mastitis and fibroadenoma of the breast are more common causes of breast disorder symptoms.
Nevertheless, the appearance of a new symptom should be taken seriously by both patients and their doctors,
because of the possibility of an underlying breast cancer at almost any age.

RISK FFA
ACTORS
CTORS
Risk factors can be divided into two categories:
• Modifiable risk factors (things that people can change themselves, such as consumption of alcoholic
beverages), and
• Fixed risk factors (things that cannot be changed, such as age and biological sex).
The primary risk factors for breast cancer are being female and older age. Other potential risk factors include
genetics, lack of childbearing or lack of breastfeeding, higher levels of certain hormones, certain dietary patterns,
and obesity. One study indicates that exposure to light pollution is a risk factor for the development of breast
cancer.

LIFESTYLE
Smoking tobacco appears to increase the risk of breast cancer, with the greater the amount smoked and the
earlier in life that smoking began, the higher the risk. In those who are long-term smokers, the risk is increased
35% to 50%. A lack of physical activity has been linked to about 10% of cases. Sitting regularly for prolonged
periods is associated with higher mortality from breast cancer. The risk is not negated by regular exercise,
though it is lowered. There is an association between use of hormonal birth control and the development of
premenopausal breast cancer, but whether oral contraceptives use may actually cause premenopausal breast
Breast 25

cancer is a matter of debate. If there is indeed a link, the absolute effect is small. Additionally, it is not clear if
the association exists with newer hormonal birth controls. In those with mutations in the breast cancer
susceptibility genes BRCA1 or BRCA2, or who have a family history of breast cancer, use of modern oral
contraceptives does not appear to affect the risk of breast cancer. The association between breast feeding and
breast cancer has not been clearly determined; some studies have found support for an association while others
have not. In the 1980s, the abortion–breast cancer hypothesis posited that induced abortion increased the risk of
developing breast cancer. This hypothesis was the subject of extensive scientific enquiry, which concluded that
neither miscarriages nor abortions are associated with a heightened risk for breast cancer. A number of dietary
factors have been linked to the risk for breast cancer. Dietary factors which may increase risk include a high fat
diet, high alcohol intake, and obesity-related high cholesterol levels. Dietary iodine deficiency may also play a
role. Evidence for fibre is unclear. A 2015 review found that studies trying to link fibre intake with breast cancer
produced mixed results. In 2016 a tentative association between low fibre intake during adolescence and breast
cancer was observed. Other risk factors include radiation and shift-work. A number of chemicals have also been
linked, including polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and organic solvents Although
the radiation from mammography is a low dose, it is estimated that yearly screening from 40 to 80 years of age
will cause approximately 225 cases of fatal breast cancer per million women screened.

GENETICS
Some genetic susceptibility may play a minor role in most cases. Overall, however, genetics is believed to be
the primary cause of 5–10% of all cases. Women whose mother was diagnosed before 50 have an increased risk
of 1.7 and those whose mother was diagnosed at age 50 or after has an increased risk of 1.4. In those with zero,
one or two affected relatives, the risk of breast cancer before the age of 80 is 7.8%, 13.3%, and 21.1% with a
subsequent mortality from the disease of 2.3%, 4.2%, and 7.6% respectively. In those with a first degree relative
with the disease the risk of breast cancer between the age of 40 and 50 is double that of the general population.
In less than 5% of cases, genetics plays a more significant role by causing a hereditary breast–ovarian cancer
syndrome. This includes those who carry the BRCA1 and BRCA2 gene mutation. These mutations account for
up to 90% of the total genetic influence with a risk of breast cancer of 60–80% in those affected. Other significant
mutations include p53 (Li–Fraumeni syndrome), PTEN (Cowden syndrome), and STK11 (Peutz–Jeghers
syndrome), CHEK2, ATM, BRIP1, and PALB2. In 2012, researchers said that there are four genetically distinct
types of the breast cancer and that in each type, hallmark genetic changes lead to many cancers.

MEDICAL CONDITIONS
Breast changes like atypical ductal hyperplasia and lobular carcinoma in situ, found in benign breast conditions
such as fibrocystic breast changes, are correlated with an increased breast cancer risk. Diabetes mellitus might
also increase the risk of breast cancer. Autoimmune diseases such as lupus erythematosus seem also to increase
the risk for the acquisition of breast cancer.

PATHOPHY
PATHOPHYSIOL
THOPHYSIOL OGY
SIOLOGY
Breast cancer, like other cancers, occurs because of an interaction between an environmental (external)
factor and a genetically susceptible host. Normal cells divide as many times as needed and stop. They attach to
other cells and stay in place in tissues. Cells become cancerous when they lose their ability to stop dividing, to
attach to other cells, to stay where they belong, and to die at the proper time. Normal cells will commit cell
suicide (programmed cell death) when they are no longer needed. Until then, they are protected from cell
suicide by several protein clusters and pathways. One of the protective pathways is the PI3K/AKT pathway;
26 Surgical Oncology: Theory and Multidisciplinary Practice

another is the RAS/MEK/ERK pathway. Sometimes the genes along these protective pathways are mutated in
a way that turns them permanently “on”, rendering the cell incapable of committing suicide when it is no longer
needed. This is one of the steps that causes cancer in combination with other mutations. Normally, the PTEN
protein turns off the PI3K/AKT pathway when the cell is ready for programmed cell death. In some breast
cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the “on” position, and
the cancer cell does not commit suicide. Mutations that can lead to breast cancer have been experimentally
linked to estrogen exposure. Abnormal growth factor signaling in the interaction between stromal cells and
epithelial cells can facilitate malignant cell growth. In breast adipose tissue, overexpression of leptin leads to
increased cell proliferation and cancer.
In the United States, 10 to 20 percent of people with breast cancer and people with ovarian cancer have a
first- or second-degree relative with one of these diseases. The familial tendency to develop these cancers is
called hereditary breast–ovarian cancer syndrome. The best known of these, the BRCA mutations, confer a
lifetime risk of breast cancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between
15 and 40 percent. Some mutations associated with cancer, such as p53, BRCA1 and BRCA2, occur in
mechanisms to correct errors in DNA. These mutations are either inherited or acquired after birth. Presumably,
they allow further mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant
organs. However, there is strong evidence of residual risk variation that goes well beyond hereditary BRCA
gene mutations between carrier families. This is caused by unobserved risk factors. This implicates
environmental and other causes as triggers for breast cancers. The inherited mutation in BRCA1 or BRCA2
genes can interfere with repair of DNA cross links and DNA double strand breaks (known functions of the
encoded protein). These carcinogens cause DNA damage such as DNA cross links and double strand breaks
that often require repairs by pathways containing BRCA1 and BRCA2. However, mutations in BRCA genes
account for only 2 to 3 percent of all breast cancers. Levin et al. say that cancer may not be inevitable for all
carriers of BRCA1 and BRCA2 mutations. About half of hereditary breast–ovarian cancer syndromes involve
unknown genes. GATA-3 directly controls the expression of estrogen receptor (ER) and other genes associated
with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due
to cancer cell invasion and metastasis.

DIAGNOSIS
DIAGNOSIS
Most types of breast cancer are easy to diagnose by microscopic analysis of a sample—or biopsy—of the
affected area of the breast. Also, there are types of breast cancer that require specialized lab exams. The two
most commonly used screening methods, physical examination of the breasts by a health care provider and
mammography, can offer an approximate likelihood that a lump is cancer, and may also detect some other
lesions, such as a simple cyst. When these examinations are inconclusive, a health care provider can remove a
sample of the fluid in the lump for microscopic analysis (a procedure known as fine needle aspiration, or fine
needle aspiration and cytology—FNAC) to help establish the diagnosis. The needle aspiration may be performed
in a health care provider’s office or clinic using local anaesthetic if required. A finding of clear fluid makes the
lump highly unlikely to be cancerous, but bloody fluid may be sent off for inspection under a microscope for
cancerous cells. Together, physical examination of the breasts, mammography, and FNAC can be used to diagnose
breast cancer with a good degree of accuracy. Other options for biopsy include a core biopsy or vacuum-
assisted breast biopsy, which are procedures in which a section of the breast lump is removed; or an excisional
biopsy, in which the entire lump is removed. Very often the results of physical examination by a health care
provider, mammography, and additional tests that may be performed in special circumstances (such as imaging
by ultrasound or MRI) are sufficient to warrant excisional biopsy as the definitive diagnostic and primary
treatment method.
Breast 27

CLASSIFICATION
Breast cancers are classified by several grading systems. Each of these influences the prognosis and can
affect treatment response. Description of a breast cancer optimally includes all of these factors.
• Histopathology. Breast cancer is usually classified primarily by its histological appearance. Most breast
cancers are derived from the epithelium lining the ducts or lobules, and these cancers are classified as
ductal or lobular carcinoma. Carcinoma in situ is growth of low-grade cancerous or precancerous cells
within a particular tissue compartment such as the mammary duct without invasion of the surrounding
tissue. In contrast, invasive carcinoma does not confine itself to the initial tissue compartment.
• Grade. Grading compares the appearance of the breast cancer cells to the appearance of normal
breast tissue. Normal cells in an organ like the breast become differentiated, meaning that they take
on specific shapes and forms that reflect their function as part of that organ. Cancerous cells lose
that differentiation. In cancer, the cells that would normally line up in an orderly way to make up
the milk ducts become disorganized. Cell division becomes uncontrolled. Cell nuclei become less
uniform. Pathologists describe cells as well differentiated (low grade), moderately differentiated
(intermediate grade), and poorly differentiated (high grade) as the cells progressively lose the features
seen in normal breast cells. Poorly differentiated cancers (the ones whose tissue is least like normal
breast tissue) have a worse prognosis.
• Stage. Breast cancer staging using the TNM system is based on the size of the tumor (T), whether or
not the tumor has spread to the lymph nodes (N) in the armpits, and whether the tumor has
metastasized (M) (i.e. spread to a more distant part of the body). Larger size, nodal spread, and
metastasis have a larger stage number and a worse prognosis.
The main stages are:
• Stage 0 is a pre-cancerous or marker condition, either ductal carcinoma in situ (DCIS) or lobular
carcinoma in situ (LCIS).
• Stages 1–3 are within the breast or regional lymph nodes.
• Stage 4 is ‘metastatic’ cancer that has a less favourable prognosis since it has spread beyond the
breast and regional lymph nodes.

Fig. Stage T1 breast cancer

28 Surgical Oncology: Theory and Multidisciplinary Practice

Fig. Stage T2 breast cancer

Fig. Stage T3 breast cancer

Breast 29

Where available, imaging studies may be employed as part of the staging process in select cases to look for
signs of metastatic cancer. However, in cases of breast cancer with low risk for metastasis, the risks associated
with PET scans, CT scans, or bone scans outweigh the possible benefits, as these procedures expose the patient
to a substantial amount of potentially dangerous ionizing radiation.
• Receptor status. Breast cancer cells have receptors on their surface and in their cytoplasm and nucleus.
Chemical messengers such as hormones bind to receptors, and this causes changes in the cell. Breast
cancer cells may or may not have three important receptors: estrogen receptor (ER), progesterone
receptor (PR), and HER2. ER+ cancer cells (that is, cancer cells that have estrogen receptors) depend
on estrogen for their growth, so they can be treated with drugs to block estrogen effects (e.g.
tamoxifen), and generally have a better prognosis. Untreated, HER2+ breast cancers are generally
more aggressive than HER2- breast cancers, but HER2+ cancer cells respond to drugs such as the
monoclonal antibody trastuzumab (in combination with conventional chemotherapy), and this has
improved the prognosis significantly. Cells that do not have any of these three receptor types (estrogen
receptors, progesterone receptors, or HER2) are called triple-negative, although they frequently do
express receptors for other hormones, such as androgen receptor and prolactin receptor.
• DNA assays. DNA testing of various types including DNA microarrays have compared normal
cells to breast cancer cells. The specific changes in a particular breast cancer can be used to
classify the cancer in several ways, and may assist in choosing the most effective treatment for
that DNA type.

PRE VENTION
PREVENTION

LIFE-STYLE
Women may reduce their risk of breast cancer by maintaining a healthy weight, drinking less alcohol,
being physically active and breastfeeding their children. These modifications might prevent 38% of breast
cancers in the US, 42% in the UK, 28% in Brazil and 20% in China. The benefits with moderate exercise
such as brisk walking are seen at all age groups including postmenopausal women. High levels of physical
activity reduce the risk of breast cancer by about 14%. Strategies that encourage regular physical activity and
reduce obesity could also have other benefits, such as reduced risks of cardiovascular disease and diabetes.
High intake of citrus fruit has been associated with a 10% reduction in the risk of breast cancer. Marine
omega-3 polyunsaturated fatty acids appear to reduce the risk. High consumption of soy-based foods may
reduce risk.

PRE-EMPTIVE SURGERY
Removal of both breasts before any cancer has been diagnosed or any suspicious lump or other lesion has
appeared (a procedure known as prophylactic bilateral mastectomy) may be considered in people with BRCA1
and BRCA2 mutations, which are associated with a substantially heightened risk for an eventual diagnosis of
breast cancer. Evidence is not strong enough to support this procedure in anyone but those at the highest risk.
BRCA testing is recommended in those with a high family risk after genetic counseling. It is not recommended
routinely. This is because there are many forms of changes in BRCA genes, ranging from harmless
polymorphisms to obviously dangerous frameshift mutations. The effect of most of the identifiable changes
in the genes is uncertain. Testing in an average-risk person is particularly likely to return one of these
indeterminate, useless results. It is unclear if removing the second breast in those who have breast cancer in
one is beneficial.
30 Surgical Oncology: Theory and Multidisciplinary Practice

MEDICATIONS
The selective estrogen receptor modulators (such as tamoxifen) reduce the risk of breast cancer but increase
the risk of thromboembolism and endometrial cancer. There is no overall change in the risk of death. They are
thus not recommended for the prevention of breast cancer in women at average risk but may be offered for those
at high risk. The benefit of breast cancer reduction continues for at least five years after stopping a course of
treatment with these medications.

SCREENING
Breast cancer screening refers to testing otherwise-healthy women for breast cancer in an attempt to achieve
an earlier diagnosis under the assumption that early detection will improve outcomes. A number of screening
tests have been employed including clinical and self breast exams, mammography, genetic screening, ultrasound,
and magnetic resonance imaging. A clinical or self breast exam involves feeling the breast for lumps or other
abnormalities. Clinical breast exams are performed by health care providers, while self-breast exams are
performed by the person themselves. Evidence does not support the effectiveness of either type of breast exam,
as by the time a lump is large enough to be found it is likely to have been growing for several years and thus
soon be large enough to be found without an exam. Mammographic screening for breast cancer uses X-rays to
examine the breast for any uncharacteristic masses or lumps. During a screening, the breast is compressed and
a technician takes photos from multiple angles. A general mammogram takes photos of the entire breast, while
a diagnostic mammogram focuses on a specific lump or area of concern. A number of national bodies recommend
breast cancer screening. For the average woman, the U.S. Preventive Services Task Force recommends
mammography every two years in women between the ages of 50 and 74, the Council of Europe recommends
mammography between 50 and 69 with most programmes using a 2-year frequency, and in Canada screening is
recommended between the ages of 50 and 74 at a frequency of 2 to 3 years. These task force reports point out
that in addition to unnecessary surgery and anxiety, the risks of more frequent mammograms include a small but
significant increase in breast cancer induced by radiation. The Cochrane collaboration (2013) states that the
best quality evidence neither demonstrates a reduction in cancer specific, nor a reduction in all cause mortality
from screening mammography. When less rigorous trials are added to the analysis there is a reduction in mortality
due to breast cancer of 0.05% (a decrease of 1 in 2000 deaths from breast cancer over 10 years or a relative
decrease of 15% from breast cancer). Screening over 10 years results in a 30% increase in rates of over-
diagnosis and over-treatment (3 to 14 per 1000) and more than half will have at least one falsely positive test.
This has resulted in the view that it is not clear whether mammography screening does more good or harm.
Cochrane states that, due to recent improvements in breast cancer treatment, and the risks of false positives
from breast cancer screening leading to unnecessary treatment, “it therefore no longer seems beneficial to
attend for breast cancer screening” at any age. Whether MRI as a screening method has greater harms or
benefits when compared to standard mammography is not known.

MANAGEMENT
MANAGEMENT
The management of breast cancer depends on various factors, including the stage of the cancer and the age
of the patient. Increasingly aggressive treatments are employed in accordance with the poorer the patient’s
prognosis and the higher the risk of recurrence of the cancer following treatment. Breast cancer is usually
treated with surgery, which may be followed by chemotherapy or radiation therapy, or both. A multidisciplinary
approach is preferable. Hormone receptor-positive cancers are often treated with hormone-blocking therapy
over courses of several years. Monoclonal antibodies, or other immune-modulating treatments, may be
administered in certain cases of metastatic and other advanced stages of breast cancer.
Breast 31

SURGERY
Surgery involves the physical removal of the tumor, typically along with some of the surrounding tissue.
One or more lymph nodes may be biopsied during the surgery; increasingly the lymph node sampling is performed
by a sentinel lymph node biopsy.
Standard surgeries include:
• Mastectomy: Removal of the whole breast.
• Quadrantectomy: Removal of one-quarter of the breast.
• Lumpectomy: Removal of a small part of the breast.
Once the tumor has been removed, if the patient desires, breast reconstruction surgery, a type of plastic
surgery, may then be performed to improve the aesthetic appearance of the treated site. Alternatively, women
use breast prostheses to simulate a breast under clothing, or choose a flat chest. Nipple prosthesis can be used
at any time following the mastectomy.

Fig. Chest after right breast mastectomy

MEDICATION
Drugs used after and in addition to surgery are called adjuvant therapy. Chemotherapy or other types of
therapy prior to surgery are called neo-adjuvant therapy. Aspirin may reduce mortality from breast cancer.
There are currently three main groups of medications used for adjuvant breast cancer treatment: hormone-
blocking agents, chemotherapy, and monoclonal antibodies.

Hormone Blocking Therapy

Some breast cancers require estrogen to continue growing. They can be identified by the presence of estrogen
receptors (ER+) and progesterone receptors (PR+) on their surface (sometimes referred to together as hormone
32 Surgical Oncology: Theory and Multidisciplinary Practice

receptors). These ER+ cancers can be treated with drugs that either block the receptors, e.g. tamoxifen, or
alternatively block the production of estrogen with an aromatase inhibitor, e.g. anastrozole or letrozole. The use
of tamoxifen is recommended for 10 years.
Letrozole is recommended for 5 years. Aromatase inhibitors are only suitable for women after menopause;
however, in this group, they appear better than tamoxifen. This is because the active aromatase in postmenopausal
women is different from the prevalent form in premenopausal women, and therefore these agents are ineffective
in inhibiting the predominant aromatase of premenopausal women. Aromatase inhibitors should not be given to
premenopausal women with intact ovarian function (unless they are also on treatment to stop their ovaries from
working).

Chemotherapy
Chemotherapy is predominantly used for cases of breast cancer in stages 2–4, and is particularly beneficial
in estrogen receptor-negative (ER-) disease. The chemotherapy medications are administered in combinations,
usually for periods of 3–6 months. One of the most common regimens, known as “AC”, combines
cyclophosphamide with doxorubicin. Sometimes a taxane drug, such as docetaxel, is added, and the regime is
then known as “CAT”.
Another common treatment is cyclophosphamide, methotrexate, and fluorouracil (or “CMF”). Most
chemotherapy medications work by destroying fast-growing and/or fast-replicating cancer cells, either by causing
DNA damage upon replication or by other mechanisms. However, the medications also damage fast-growing
normal cells, which may cause serious side effects. Damage to the heart muscle is the most dangerous complication
of doxorubicin, for example.

Monoclonal Antibodies
Trastuzumab, a monoclonal antibody to HER2 (a cell receptor that is especially active in some breast cancer
cells), has improved the 5-year disease free survival of stage 1–3 HER2-positive breast cancers to about 87%
(overall survival 95%). When stimulated by certain growth factors, HER2 causes cellular growth and division;
in the absence of stimulation by the growth factor, the cell will normally stop growing. Between 25% and 30%
of breast cancers overexpress the HER2 gene or its protein product, and overexpression of HER2 in breast
cancer is associated with increased disease recurrence and worse prognosis. When trastuzumab binds to the
HER2 in breast cancer cells that overexpress the receptor, trastuzumab prevents growth factors from being able
to bind to and stimulate the receptors, effectively blocking the growth of the cancer cells. Trastuzumab, however,
is very expensive, and its use may cause serious side effects (approximately 2% of patients who receive it suffer
significant heart damage). Further, trastuzumab is only effective in patients with HER2 amplification/
overexpression.

RADIATION
Radiotherapy is given after surgery to the region of the tumor bed and regional lymph nodes, to destroy
microscopic tumor cells that may have escaped surgery. It may also have a beneficial effect on tumor
microenvironment. Radiation therapy can be delivered as external beam radiotherapy or as brachytherapy (internal
radiotherapy).
Conventionally radiotherapy is given after the operation for breast cancer. Radiation can also be given at the
time of operation on the breast cancer. Radiation can reduce the risk of recurrence by 50–66% (1/2 – 2/3
reduction of risk) when delivered in the correct dose and is considered essential when breast cancer is treated
by removing only the lump (Lumpectomy or Wide local excision).
Breast 33

Fig. Internal radiotherapy for breast cancer

PR OGNOSIS
PROGNOSIS
Prognosis

Fig. Breasts after double mastectomy followed by nipple-sparing reconstruction with implants

Fig. An example of an advanced recurrent breast cancer with an ulcerating axillary mass
34 Surgical Oncology: Theory and Multidisciplinary Practice

Prognosis is usually given for the probability of progression-free survival (PFS) or disease-free survival
(DFS). These predictions are based on experience with breast cancer patients with similar classification. A
prognosis is an estimate, as patients with the same classification will survive a different amount of time, and
classifications are not always precise. Survival is usually calculated as an average number of months (or years)
that 50% of patients survive, or the percentage of patients that are alive after 1, 5, 15, and 20 years. Prognosis
is important for treatment decisions because patients with a good prognosis are usually offered less invasive
treatments, such as lumpectomy and radiation or hormone therapy, while patients with poor prognosis are
usually offered more aggressive treatment, such as more extensive mastectomy and one or more chemotherapy
drugs.

PROGNOSTIC FACTORS
Prognostic factors are reflected in the classification scheme for breast cancer including stage, (i.e., tumor
size, location, whether disease has spread to lymph nodes and other parts of the body), grade, recurrence of the
disease, and the age and health of the patient. The Nottingham Prognostic Index is a commonly used prognostic
tool. The stage of the breast cancer is the most important component of traditional classification methods of
breast cancer, because it has a greater effect on the prognosis than the other considerations. Staging takes into
consideration size, local involvement, lymph node status and whether metastatic disease is present. The higher
the stage at diagnosis, the poorer the prognosis. The stage is raised by the invasiveness of disease to lymph
nodes, chest wall, skin or beyond, and the aggressiveness of the cancer cells. The stage is lowered by the
presence of cancer-free zones and close-to-normal cell behaviour (grading). Size is not a factor in staging
unless the cancer is invasive. For example, Ductal Carcinoma In Situ (DCIS) involving the entire breast will
still be stage zero and consequently an excellent prognosis with a 10-year disease free survival of about 98%.
• Stage 1 cancers (and DCIS, LCIS) have an excellent prognosis and are generally treated with
lumpectomy and sometimes radiation. HER2+ cancers should be treated with the trastuzumab
(Herceptin) regime. Chemotherapy is uncommon for other types of stage 1 cancers.
• Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are generally
treated with surgery (lumpectomy or mastectomy with or without lymph node removal), chemotherapy
(plus trastuzumab for HER2+ cancers) and sometimes radiation (particularly following large cancers,
multiple positive nodes or lumpectomy).
• Stage 4, metastatic cancer, (i.e. spread to distant sites) has poor prognosis and is managed by various
combination of all treatments from surgery, radiation, chemotherapy and targeted therapies. Ten-
year survival rate is 5% without treatment and 10% with optimal treatment.
The breast cancer grade is assessed by comparison of the breast cancer cells to normal breast cells. The
closer to normal the cancer cells are, the slower their growth and the better the prognosis. If cells are not well
differentiated, they will appear immature, will divide more rapidly, and will tend to spread. Well differentiated
is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4
(depending upon the scale used). The most widely used grading system is the Nottingham scheme; details are
provided in the discussion of breast cancer grade. The presence of estrogen and progesterone receptors in the
cancer cell is important in guiding treatment. Those who do not test positive for these specific receptors will not
be able to respond to hormone therapy, and this can affect their chance of survival depending upon what treatment
options remain, the exact type of cancer, and how advanced the disease is. In addition to hormone receptors,
there are other cell surface proteins that may affect prognosis and treatment. HER2 status directs the course of
treatment. Patients whose cancer cells are positive for HER2 have a more aggressive disease and may be treated
with the ‘targeted therapy’, trastuzumab (Herceptin), a monoclonal antibody that targets this protein and improves
the prognosis significantly. Younger women with an age of less than 40 years or women over 80 years tend to
Breast 35

have a poorer prognosis than post-menopausal women due to several factors. Their breasts may change with
their menstrual cycles, they may be nursing infants, and they may be unaware of changes in their breasts.
Therefore, younger women are usually at a more advanced stage when diagnosed. There may also be biologic
factors contributing to a higher risk of disease recurrence for younger women with breast cancer. High
mammographic breast density, which is a marker of increased risk of developing breast cancer, may not mean
an increased risk of death among breast cancer patients, according to a 2012 report of a study involving 9232
women by the National Cancer Institute (NCI). On the other hand, more recent research has shown that women
with extremely low mammographic densities (<10%) hold a significantly worse prognosis compared to women
with other densities, irrespective of all possible confounding factors. Since breast cancer in males is usually
detected at later stages, outcomes are typically worse.

PSYCHOLOGICAL ASPECTS
The emotional impact of cancer diagnosis, symptoms, treatment, and related issues can be severe. Most
larger hospitals are associated with cancer support groups which provide a supportive environment to help
patients cope and gain perspective from cancer survivors. Not all breast cancer patients experience their illness
in the same manner. Factors such as age can have a significant impact on the way a patient copes with a breast
cancer diagnosis. Premenopausal women with estrogen-receptor positive breast cancer must confront the issues
of early menopause induced by many of the chemotherapy regimens used to treat their breast cancer, especially
those that use hormones to counteract ovarian function. On the other hand, a small 2007 study conducted by
researchers at the College of Public Health of the University of Georgia suggested a need for greater attention
to promoting functioning and psychological well-being among older cancer survivors, even when they may not
have obvious cancer-related medical complications. The study found that older breast cancer survivors showed
multiple indications of decrements in their health-related quality of life, and lower psychosocial well-being
than a comparison group. Survivors reported no more depressive symptoms or anxious mood than the comparison
group, however, they did score lower on measures of positive psychosocial well-being and reported more
depressed mood and days affected by fatigue. As the incidence of breast cancer in women over 50 rises and
survival rates increase, breast cancer is increasingly becoming a geriatric issue that warrants both further research
and the expansion of specialized cancer support services tailored for specific age groups.

EPIDEMIOLOGY
EPIDEMIOLOGY
Worldwide, breast cancer is the most common invasive cancer in women. It affects about 12% of women
worldwide. (The most common form of cancer is non-invasive non-melanoma skin cancer; non-invasive cancers
are generally easily cured, cause very few deaths, and are routinely excluded from cancer statistics.) Breast
cancer comprises 22.9% of invasive cancers in women and 16% of all female cancers. In 2012, it comprised
25.2% of cancers diagnosed in women, making it the most common female cancer. In 2008, breast cancer
caused 458,503 deaths worldwide (13.7% of cancer deaths in women and 6.0% of all cancer deaths for men and
women together). Lung cancer, the second most common cause of cancer-related death in women, caused
12.8% of cancer deaths in women (18.2% of all cancer deaths for men and women together). The incidence of
breast cancer varies greatly around the world: it is lowest in less-developed countries and greatest in the more-
developed countries. In the twelve world regions, the annual age-standardized incidence rates per 100,000
women are as follows: in Eastern Asia, 18; South Central Asia, 22; sub-Saharan Africa, 22; South-Eastern Asia,
26; North Africa and Western Asia, 28; South and Central America, 42; Eastern Europe, 49; Southern Europe,
56; Northern Europe, 73; Oceania, 74; Western Europe, 78; and in North America, 90. The number of cases
worldwide has significantly increased since the 1970s, a phenomenon partly attributed to the modern lifestyles.
Breast cancer is strongly related to age with only 5% of all breast cancers occurring in women under 40 years
36 Surgical Oncology: Theory and Multidisciplinary Practice

old. There were more than 41,000 newly diagnosed cases of breast cancer registered in England in 2011, around
80% of these cases were in women age 50 or older Based on U.S. statistics in 2015 there were 2.8 million
women affected by breast cancer. In the United States, the age-adjusted incidence of breast cancer per 100,000
women rose from around 102 cases per year in the 1970s to around 141 in the late 1990s, and has since fallen,
holding steady around 125 since 2003. However age-adjusted deaths from breast cancer per 100,000 women
only rose slightly from 31.4 in 1975 to 33.2 in 1989 and have since declined steadily to 20.5 in 2014.

HORMONES

BIRTH CONTROL
In breast cancer survivors, non-hormonal birth control methods should be used as first-line options.
Progestogen-based methods such as depot medroxyprogesterone acetate, IUD with progestogen or progestogen
only pills have a poorly investigated but possible increased risk of cancer recurrence, but may be used if
positive effects outweigh this possible risk.

MENOPAUSAL HORMONE REPLACEMENT

In breast cancer survivors, it is recommended to first consider non-hormonal options for menopausal effects,
such as bisphosphonates or selective estrogen receptor modulators (SERMs) for osteoporosis, and vaginal
estrogen for local symptoms. Observational studies of systemic hormone replacement therapy after breast cancer
are generally reassuring. If hormone replacement is necessary after breast cancer, estrogen-only therapy or
estrogen therapy with an intrauterine device with progestogen may be safer options than combined systemic
therapy.

RESEAR CH
RESEARCH
Treatments are being evaluated in trials. This includes individual drugs, combinations of drugs, and surgical
and radiation techniques Investigations include new types of targeted therapy, cancer vaccines, oncolytic virotherapy,
and immunotherapy. The latest research is reported annually at scientific meetings such as that of the American
Society of Clinical Oncology, San Antonio Breast Cancer Symposium, and the St. Gallen Oncology Conference in
St. Gallen, Switzerland. These studies are reviewed by professional societies and other organizations, and formulated
into guidelines for specific treatment groups and risk category. Fenretinide, a retinoid, is also being studied as a
way to reduce the risk of breast cancer (retinoids are drugs related to vitamin A).

CRYOABLATION
As of 2014 cryoablation is being studied to see if it could be a substitute for a lumpectomy in small cancers. There
is tentative evidence in those with tumors less than 2 centimeters. It may also be used in those in who surgery is not
possible. Another review states that cryoablation looks promising for early breast cancer of small size.

BREAST CANCER CELL LINES

A considerable part of the current knowledge on breast carcinomas is based on in vivo and in vitro studies
performed with cell lines derived from breast cancers. These provide an unlimited source of homogenous self-
replicating material, free of contaminating stromal cells, and often easily cultured in simple standard media.
The first breast cancer cell line described, BT-20, was established in 1958. Since then, and despite sustained
Breast 37

work in this area, the number of permanent lines obtained has been strikingly low (about 100). Indeed, attempts
to culture breast cancer cell lines from primary tumors have been largely unsuccessful. This poor efficiency
was often due to technical difficulties associated with the extraction of viable tumor cells from their surrounding
stroma. Most of the available breast cancer cell lines issued from metastatic tumors, mainly from pleural effusions.
Effusions provided generally large numbers of dissociated, viable tumor cells with little or no contamination by
fibroblasts and other tumor stroma cells. Many of the currently used BCC lines were established in the late
1970s. A very few of them, namely MCF-7, T-47D, and MDA-MB-231, account for more than two-thirds of all
abstracts reporting studies on mentioned breast cancer cell lines, as concluded from a Medline-based survey.

MOLECULAR MARKERS

Transcription Factors
NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at
the basis of metastasis formation. Indeed, NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in
breast carcinoma and NFAT3 (NFATc4) is an inhibitor of cell motility. NFAT1 regulates the expression of the
TWEAKR and its ligand TWEAK with the Lipocalin 2 to increase breast cancer cell invasion and NFAT3
inhibits Lipocalin 2 expression to blunt the cell invasion.

Metabolic Markers
Clinically, the most useful metabolic markers in breast cancer are the estrogen and progesterone receptors
that are used to predict response to hormone therapy. New or potentially new markers for breast cancer include
BRCA1 and BRCA2 to identify patients at high risk of developing breast cancer, HER-2 and SCD1 for predicting
response to therapeutic regimens, and urokinase plasminogen activator, PA1-1 and SCD1 for assessing prognosis.

NON-INVASIVE OR INV
NON-INVASIVE ASIVE BREAST CANCER
INVASIVE
Breast cancer usually begins either in the cells of the lobules, which are milk-producing glands, or the ducts,
the passages that drain milk from the lobules to the nipple. The pathology report will tell you whether or not the
cancer has spread outside the milk ducts or lobules of the breast where it started.

Fig. Non-Invasive Cells Larger Version

38 Surgical Oncology: Theory and Multidisciplinary Practice

Fig. Invasive Cells Larger Version

Non-invasive cancers stay within the milk ducts or lobules in the breast. They do not grow into or invade
normal tissues within or beyond the breast. Non-invasive cancers are sometimes called carcinoma in situ (“in
the same place”) or pre-cancers. Invasive cancers do grow into normal, healthy tissues. Most breast cancers are
invasive. Whether the cancer is non-invasive or invasive will determine your treatment choices and how you
might respond to the treatments you receive. In some cases, invasive and non-invasive breast cancer can both be
seen in the same specimen. This means that part of the cancer has grown into normal tissue and part of the
cancer has stayed inside the milk ducts or milk lobules. It would be treated as an invasive cancer. A breast
cancer also may be a “mixed tumor,” meaning that it contains a mixture of cancerous ductal cells and lobular
cells. This type of cancer is also called “invasive mammary breast cancer” or “infiltrating mammary carcinoma.”
It would be treated as a ductal carcinoma. If there is more than one tumor in the breast, the breast cancer is
described as either multifocal or multicentric. In multifocal breast cancer, all of the tumors arise from the
original tumor, and they are usually in the same section of the breast. If the cancer is multicentric, it means that
all of the tumors formed separately, and they are often in different areas of the breast.

LOC ALL
LOCALL Y AD
ALLY ADVVANCED BREAST CANCER (LABC)
(LABC)
Locally advanced breast cancer (LABC) is a very common clinical presentation of mammary carcinoma in
developing countries (30% to 60%). In spite of systematic screening, mammography programmes and extensive
public education campaigns for early detection of breast cancer in the USA, the incidence of LABC is still
approximately 10%-20%. LABC is a heterogeneous group of tumors of varying clinical presentations and
biological behaviour whose only common bonds are the presence of a large primary tumor, or extensive regional
lymph node involvement, and the absence of any evidence of distant metastases. Some patients have a rapid
neo-plastic evolution, whereas others present with a long history of tumor growth. Historically, patients with
LABC were treated with radical surgery and/or radiation therapy (RT). However the management of LABC
was dramatically transformed over the past two decades. Primary chemotherapy (CT) became an integral part
Breast 39

of the multidisciplinary management of LABC, probably prolonging the disease-free survival (DFS) and overall
survival (OS), and making breast conserving surgery a possibility for these patients. Because LABC is less
common in industrialized countries and the heterogeneity of this disease makes the performance of controlled
trials more complex, changes in the management of this area of breast cancer have received less public and
media attention than those occurring in early cases of breast cancer.

CLASSIFICATION
Patients with stage IIB, III and IV of the TNM classification are included in LABC. In this classification
system, patients are included if they have T3 or T4 tumors with any N stage, or any T category with N2 or N3 or
regional M1 involvement. A T3 tumor is greater than 5 cm in its greatest dimension. A T4 tumor may be of any
size but with direct extension to the chest wall or skin. Inflammatory breast carcinoma (IBC) is also included in
this category. For the classification of regional nodal involvement, N2 is defined as palpable, ipsilateral axillary
nodes fixed to one another or to other structures. N3 denotes the presence of ipsilateral internal mammary
nodes; and we define regional M1 as palpable, ipsilateral supraclavicular or infraclavicular nodes (previously
classified as N3). All T and N permutations included in stage IIB, III or IV comprised many distinct substage
possibilities. The presence of T4 or N3 or regional M1 lesions would result in inclusion in the stage IIIB/IV
unresectable subcategory. Most of the patients with either T3 or N2, but without T4, N3 or regional M1 lesions,
are included in the stage II/IIIA or operable subcategory. LABC also includes T2 tumors that are too large in
proportion to the size of the breast. IBC is a unique clinical-pathological entity that has recently been reviewed
by Jaiyesimi et al.. It is important to distinguish primary IBC from LABC with secondary, inflammatory changes.
In many patients with LABC characterized by slow, gradual growth, some inflammatory changes may appear
many months or years after the breast mass was first detected. Inflammatory changes in this context do not have
the ominous prognostic connotation of primary IBC.

CLINICAL FEATURES AND DIAGNOSIS

Because LABC is so heterogeneous and includes a wide range of subgroups and because of modifications in
staging classification, it is difficult to precisely estimate the frequency of LABC. While in developing countries
LABC represents up to 50% of the newly diagnosed breast cancers, in the USA it constitutes between 10% and
20% of all new breast cancers. The clinical diagnosis of LABC is usually not difficult. Patients uniformly
present with a large breast mass. Other symptoms often reported are edema, redness, nipple retraction, pain,
skin dimpling, an axillary mass and breast ulceration. Most physical findings are obvious upon inspection or
palpation. However, in younger women, some tumors infiltrate the breast diffusely and a discrete mass is
difficult to palpate. More than 75% of patients have clinically palpable axillary and/or supraclavicular adenopathy,
and 65%-90% of patients have pathologically confirmed lymph node metastasis; >50% have more than four
nodes involved.
Most of the LABCs are operable; only 25%-30% are diagnosed at an inoperable stage. Therefore, we can
extrapolate that only 5% of all newly diagnosed breast cancers in the USA are found in stage IIIB/IV (inoperable).
A physical examination, bilateral mammogram and ultrasound of the breast and its draining lymphatics
determine the extent of involvement within the breast and the nodal chains, the presence of additional tumor
foci within the same breast or the contralateral breast, and the extension of the tumor to deeper structures. A
core needle biopsy is quite effective in establishing the diagnosis and also allowing tumor samples to be obtained
for hormone receptors, DNA studies and other biomarkers. The sensitivity and specificity of fine-needle aspiration
are quite high in LABC. The only disadvantages of cytological diagnosis are the inability to differentiate between
in situ and invasive carcinoma, and scant material on which to perform additional studies. Excisional biopsies
are not indicated in patients with LABC.
40 Surgical Oncology: Theory and Multidisciplinary Practice

STAGING
Appropriate staging procedures should be performed in patients with LABC since the probability of distant
metastases is high. Approximately 20% of these patients, appropriately staged, have detectable distant metastases
at the time of diagnosis. We recommend that after a complete history, a physical examination be performed with
great attention to the evaluation of both breasts and all surrounding lymph node-bearing areas. All tumors
should be described by the longest perpendicular diameters in cm, and the presence of palpable axillary,
supraclavicular and subclavicular nodes, with exact measurements of their longest perpendicular diameters,
should be included.
A close-up photograph is useful in the staging of patients with T4 tumors. Ideally, the initial evaluation
should be done simultaneously by the medical oncologist, surgical oncologist and radiotherapist. After the
physical examination and bilateral mammogram, the following additional tests are recommended: a biochemical
profile, including tests of liver and renal function, and calcium level; chest x-ray; bone scans; radiographs of
areas that appear to be abnormal on the bone scan; computed tomography of the liver and an ultrasonography of
the breast and regional lymph nodes to precisely assess the tumor extent. The importance of an accurate initial
assessment of the extent of primary tumor burden cannot be overemphasized since the efficacy of subsequent
local treatment will depend mostly on this initial assessment.

NATURAL HISTORY
There is no recorded information about the natural history of untreated LABC. Many of the published series
of patients treated with radical surgery, RT or combinations of both were published 20 or 30 years ago. From the
surgical point of view, we can subdivide LABC into operable, stage IIB (T3, N0; previously classified as stage
IIIA) and IIIA, and inoperable, stage IIIB and regional IV (previously classified as stage IIIB) breast cancer.
Patient selection influenced outcome substantially more than treatment did. Some authors have tried to compare
the results of surgery alone to RT alone, or combinations of both. However, the groups were hardly comparable
because many of the tumors treated with RT alone were not suitable for surgical resection in the first place. For
instance, although most surgical series that included stage IIIB breast cancer included patients with pectoral
muscle fixation or skin involvement, most excluded cases with supraclavicular node involvement, arm edema
or chest wall fixation.
Since these patients are known to have the worst prognosis after local therapy alone, this exclusion probably
substantially improved the outcome of the surgical series. On the other hand, the older RT series had fewer
selective inclusion criteria, accepting all patients. Therefore, the outcomes in RT series were usually inferior to
those reported in surgical series. For all types of LABC, whether or not operable, distant metastases were the
most frequent type of treatment failure, and appeared in the majority of patients within 24 months after diagnosis.
In addition, a very high percentage of patients developed locoregional failure, whether the initial treatment
consisted of surgery alone or RT alone. The radical mastectomy was developed especially for LABC, but the
local failure rate after surgery alone may be as high as 60%.
The five- and 10-year survival rates for patients with LABC after radical mastectomy vary between 10%-
40% and 0%-30%, respectively. The outcomes in RT series were usually inferior to those reported in surgical
series. The five-year survival figures varied from 10% to 30%, and very few reports provided 10-year survival
figures, in part because few patients survived 10 years. Local recurrence rates ranged from 25% to 72%, suggesting
that even local control was often inadequate. Several investigators have shown a clear dose-response correlation
for RT. Therefore, the local control rate may vary, depending on the administered dose. Mastectomy combined
with preoperative or postoperative RT seemed to produce improved local and regional control rates but did not
modify survival rates since distant metastases were the ultimate determinants of outcome. When only local
therapies were used, the median DFS and OS durations for patients with LABC ranged from 8-12 months and
Breast 41

24 months, respectively. The 10-year survival in 3,575 patients with LABC after locoregional therapy was 22%
(Table ⇓). In conclusion, the outcome for patients with LABC treated with local therapies only was, in general,
consistently very poor.
Table. Survival of patients with LABC after local/regional therapy
Survival (10-year)
Treatment Patients # Alive (%)
Surgery 853 19
Radiotherapy 978 23
Combined surgery and radiotherapy 1,744 22
Total 3,575 22

MULTIDISCIPLINARY THERAPY
Theoretical and Clinical Considerations In the early 1970s, recognizing the high propensity of early breast
cancer to generate distant micrometastases, several groups pioneered the use of adjuvant systemic therapy as a
curative strategy against breast cancer. Based on these theoretical considerations and the poor prognosis of
patients with LABC, systemic combination CT was introduced as the primary treatment in these patients. In
this strategy, systemic therapy is known as neo-adjuvant or primary CT. This treatment was preferred because
the major problem in LABC is distant metastases, rather than the local disease. After CT is administered for
three to four cycles and its efficacy is assessed, regional therapy is administered in the form of surgery, RT, or
both, and is followed, in turn, by additional postoperative CT, followed by RT and hormonotherapy (>50 years,
estrogen receptor positive [ER]). The advantages and disadvantages of this strategy are detailed in Table ⇓. The
advantages include the earlier initiation of systemic therapy, before the vasculature of the tumor is altered by
surgery or RT, and before many resistant clones have the chance to arise. Furthermore, the medical oncologist
has the opportunity to assess the efficacy of systemic therapy in vivo. If systemic treatment is not effective, the
oncologist can discontinue the ineffective therapy, avoid unnecessary toxicity and institute an alternative form
of systemic therapy. Moreover, downstaging of a tumor may allow for breast-conserving surgery and render
inoperable tumors resectable. On the other hand, the disadvantages of this strategy include the lack of accurate
initial pathological staging and the potential for emerging drug resistance due to the large tumor burden. In
addition, if CT is ineffective, local treatment is delayed for several weeks.
Table. Primary chemotherapy
Advantages
∆ Early systemic treatment
∆ No postsurgical growth spurt
∆ Intact tumor vasculature
∆ In vivo assessment of response
∆ Decrease radical local therapy
∆ Downstaging
∆ Increase breast conservation
∆ Improving resectability
Disadvantages
∆ Delayed local treatment
∆ May induce drug resistance
∆ Large tumor burden
∆ Only clinical staging
∆ May increase risk of( surgical/RT complications

PRIMARY CHEMOTHERAPY RESULTS

Our group pioneered multidisciplinary therapy, including primary CT with anthracycline-containing regimens.
We enrolled 598 patients in three studies. In the first two studies, after three cycles of CT, local treatment in the
42 Surgical Oncology: Theory and Multidisciplinary Practice

form of a total mastectomy with level one and two axillary dissection, RT, or both were completed. After local
therapy, additional CT was administered. In the second study, the role of a non-cross-resistant postoperative CT
regimen (vinblastine, methotrexate, fluorouracil and folinic acid) was randomly investigated. In the third study,
all patients received four cycles of primary CT with an anthracycline-containing regimen. Doxorubicin was
given as a 72-h continuous infusion. In all, 367 patients with non-inflammatory LABC were evaluated in the
first two studies (174/193); 148 of them had stage IIB/IIIA, and 219 had stage IIIB/regional IV disease. After
primary CT, 63 (17%) and 250 (68%) patients achieved clinical complete remissions (CR) and partial remissions
(PR), respectively. All but nine patients were rendered disease-free after primary CT and initial local therapy. In
the first study, at a median follow up of 11 years, the median DFS for patients with stage IIB/IIIA disease had
not been reached; for the patients with stage IIIB/regional IV disease it was 30 months. The median OS for
stage IIB/IIIA disease had not been reached and for stage IIIB it was 48 months.
The five- and 10-year DFS rates for patients with stage IIB/IIIA disease were 71% and 40%, respectively.
The five- and 10-year DFS rates for patients with stage IIIB/regional IV disease were 33% and 30%, respectively.
The five-year OS rates for stage IIB/IIIA and stage IIIB/regional IV were 84% and 44%; the 10-year OS figures
were 56% and 26%, respectively. The five-year DFS and OS rates in the second study were similar to those of
the first study. Treatment with a noncross-resistant postoperative CT regimen did not significantly affect DFS
and OS. The high objective response rate was also confirmed in our third study. The objective response rate to
primary CT was 73% in 160 evaluable patients with LABC. Compared to our historical institutional experience,
the local control rate, and five- and 10-year DFS and OS rates for LABC were substantially improved by this
multidisciplinary programme. A number of other centers have developed similar strategies (Table ⇓). The common
theme is the use of primary or induction CT, followed by local treatment, which is “sandwiched” between
primary and adjuvant systemic treatments.
There are major variations in CT programmes, type and aggressiveness of local therapy, duration of treatment
and eligibility criteria. Several CT combinations have been used for the treatment of LABC, although in most
published trials an anthracycline-based regimen was preferred. The overall response and CR rates following
primary CT are depicted in Table 3!. As the table shows, 50%-95% of patients with LABC achieved an objective
response, including 5%-50% clinical CR rates. This latter range is somewhat deceiving since only two of the
many trials have shown CR rates in excess of 25%. The trial conducted by Lippman et al. reported a 52%
clinical CR rate, but it is likely that this CR rate was artificially high due to the methods used to evaluate and
define a CR. The trial conducted by Powles and associates, included mostly patients with stage I and stage II
breast cancer, and the higher CR rate reported might be due to patient selection rather than increased efficacy of
primary chemotherapy. As a consequence of this high frequency of objective responses, approximately 70% of
patients with LABC undergo downstaging (the primary tumor or regional lymph nodes decrease by at least one
stage category).
Table. LABC response to primary chemotherapy
Author Treatment Programme # Patients Treated # Patients with Complete Response (%)
>50 Response (%)
A = Adriamycin; V = Vincristine; F = 5-Fluorouracil; C = Cyclophosphamide; DES = Diethylstilbestrol; T = Tamoxifen;
P = Premarin; L = Leucovorin; M = Mitomycin; Pr = Prednisone; Vb = Vinblastine; Mi = Mitoxantrone; Me =
Methotrexate, Vi = Vindesin
Hortobagyi FAC × 3 174 152 (87) 17
Hortobagyi VACP × 3 193 161 (83) 18
Booser FAC × 4 160 116 (73) 8
DeLena AV × 4 74 64 (86) 4
DeLena AV × 3 132 70 (53) 15
Rubens AV × 4 12 6 (50) 17
Hobar FAC × 3 36 26 (72) 8
Conte DES-FAC × 3 39 28 (72) 15
Breast 43

Lippman CATPMFL × (3-11) 51 45 (88) 52

Cocconi CMF(T) × 4 49 23 (47) 8
Perloff CAFVPr × 3 113 78 (69) 18
Jacquillat VbTMAFPr × (2-4) 98 89 (91) 23
Powles MMiMe × 4 34 32 (94) 44
Rosso FAC × 3 113 73 (65) 10
Poddubnaya AMC/CMF 503 317 (63) 2
Calais MiViCF 80 41 (51) 18
Touboul FACV × 4 82 45 (55) 10
In most of these trials, a fixed number of primary CT cycles was employed. However, in a few trials
primary CT was continued until reaching maximal response. These trials have shown that there is immense
variability in the time required to achieve maximum response. Some patients reached maximal response after
one month, whereas others needed up to eight months to reach such a response. A clinical CR does not
necessarily represent a pathologically proven CR. In fact, the pathological CR rate varied from 3%-33% in
different trials and approximately only two-thirds of the patients with a clinical CR had a pathologically
proven CR (Table ⇓). Conversely, only two-thirds of the patients with a pathologically proven CR were
found to have a CR prior to surgical resection. Of course, patients treated with RT alone have no pathologically
demonstrable remission.
Table. Locally advanced breast cancer
Local Control
Author Treatment # Patients Median F/U Local Control Rate (%) IIB-IIIA/IIIB-IV
Hortobagyi CT ± S ± RT + CT 367 80 m 84 148/219
Touboul CT + RT ± S + CT 82 70 m 82 42/40
Cardenas CT + S/RT + CT 23 52 m 78 ?
Hobar CT + S ± RT + CT 36 34 m 81 13/21
Conte CT + S + CT ± RT 39 24 m 72 11/28
Jacquillat CT + RT + CT 98 40 m 87 30/68
Perloff CT + S/RT + CT 113 37 m 63 36/77
DeLena CT + RT + CT 67 36 m 69 5/62
DeLena CT + S + CT 65 36 m 70 7/58
Aisner CT + S + CT 27 24 m 59 “/27
Calais CT + S + RT + CT 80 38 m 94 ?
Boyages CT + RT + CT 35 24 m 71 8/27
DeLena CT + RT ± CT 110 18 m 54 5/105

Randomized Studies
Several randomized trials that included a substantial minority of patients with stage III breast cancer, or that
specifically targeted stage III breast cancer, demonstrated that adjuvant CT, or adjuvant CT and RT, increased
DFS and OS rates. What is not known at this time is whether the timing of systemic treatments (postoperative
versus preoperative) alters the probability of benefit. One randomized clinical trial suggested that adjuvant CT
after primary CT and RT resulted in longer time to progression and survival than the use of only primary CT and
RT Several small randomized trials failed to show an additional survival benefit of primary CT over postoperative
CT.
However, these trials included small numbers of patients, and sizable differences in outcome could have easily
been overlooked because of low statistical significance. More recently (Table ⇓)], several randomized trials were
instituted comparing primary (neo-adjuvant) and postoperative (adjuvant) CT. These trials included a mixture of
stage II and stage III patients. One of these trials was recently updated and suggested a survival benefit in favour
of primary CT. However, there was no benefit in DFS, making interpretation of these data more complex. Four
trials showed increased survival in patients who received primary CT; however, only one of these trials did reach
statistical significance. Longer follow-up in additional, larger studies will be needed to determine the relative
benefits of primary versus adjuvant therapies.
44 Surgical Oncology: Theory and Multidisciplinary Practice

Table. Randomized trials of primary versus postoperative chemotherapy for primary breast cancer
Author Treatment # Patients Response Rate Median Follow up Disease-Free (%) Alive (%)
32 patients did not receive CT
calculated from survival curve
Pierga Primary 200 64% 36 m 68 93
Post-op 190 NA 66 86
Ragaz Primary 69 — 48 m 57 69
Post-op 30 NA 47 60
Scholl Primary 196 82% 54 m 59 86
Post-op 194 NA 55 78
DeOliveira Primary 81 — 60 m 68 82
Post-op 90 NA 66 71
Rubens Primary 12 50% 40 m 50 50
Post-RT 12 — 42 50
Semiglazov Primary 137 69% 53 m 86 86
Post-RT 134 61% 72 79
Mauriac Primary 133 63% 34 m 80 95
Post-op 134 NA 79 88
Olsen Primary 119 77% 96 m NS 19
Post-RT 76% — 19

LOCAL/REGIONAL TREATMENT AND LOCAL CONTROL

After primary CT, some programmes have used surgical therapy alone, RT alone, or a combination of both
treatments. Two prospective randomized trials have been reported in which surgery was compared with RT
after primary CT. In both trials, surgery appeared to be equivalent to RT for local control and long-term survival.
However, the local control rate in the studies was relatively low, in the 60%-70% range. In contrast, those phase
II studies in which primary CT was followed by both surgery and RT have reported higher local control rates, in
some cases reaching 85% (Table ⇓). In our first two studies (367 patients), the locoregional failure rate for stage
IIB/IIIA and IIIB/regional IV were 7% and 26%, respectively.
Table. Locally advanced breast cancer—complete remissions after primary chemotherapy
Author Treatment Programme # Patients Clinical (%) Pathological (%)
Hortobagyi CT ± S + RT – CT 174 17 8
Booser CT + S + CT + RT 160 8 11
Hobar CT + S ± RT + CT 36 8 11
Conte CT + S + CT 39 15 8
Lippman CT ± S + RT + CT 51 52 33
Schwartz CT + S + CT ± RT 90 NA 3
Cocconi CT + S + CT + RT 49 8 14

TOLERANCE AND TOXICITY

The same side effects and toxicity usually associated with adjuvant CT have been routinely reported with
combined modality programmes that included primary CT. In our initial trial, the acute and chronic major side
effects included 19 febrile episodes, but no deaths related to infection. Nine patients developed clinical congestive
heart failure and two died as a result. Two patients developed acute non-lymphocytic leukemia. In general,
surgical complications and short- and long-term complications of radiotherapy also appear to be similar to what
had been previously reported in the literature. The use of primary CT does not appear to enhance surgical
complications compared to complications that occur after primary surgical procedures. It is not clear at this
time whether the sequential use of CT and RT results in additive or synergistic toxicity. In our own experience,
in the early days of combined modality therapy, RT with photons to the internal mammary chain in combination
with anthracycline-containing CT was associated with an increased risk of cardiac damage if the lesion originated
in the left breast. However, over the past decade, the use of electron beam therapy to cover the internal mammary
Breast 45

chain, and the administration of anthracyclines by a 72- to 96-h continuous infusion has eliminated this
overlapping toxicity. In patients whose tumors are not amenable to breast conservation, delayed chest wall
reconstruction is an alternative option.

Prognostic Factors
Initial tumor size, the presence of skin edema, tumor S-phase fraction, thymidine labeling index, number of
axillary nodes involved, ER, PR, histological and nuclear grade, extent of residual disease, and objective response
after primary CT are all important prognostic factors for this group of patients. In our first study, patients with
ER or unknown tumors had better DFS and OS rates than did those with ER. Response to primary CT correlated
closely with prognosis. Patients who achieved CR had DFS and OS rates considerably superior to those with a
PR or no change after the primary CT regimen. Compliance with the treatment regimen was also an important
prognostic factor for survival. It is of interest that pathologic lymph node involvement after primary CT retains
prognostic importance, and, in fact, in our evaluation by multivariate analysis, is the most important prognostic
indicator. Predictors of tumor response to primary CT have also been reported. Initial tumor size and nuclear
grade are independent predictors of response. Other predictors of tumor response to primary CT include S-
phase fraction, ER, and ploidy. A recent report suggested that patients with tumors with high S-phase fractions
responded more often than those with low S-phase fractions. The results of new prognostic factors such as p53
and c-erbB-2 oncogene expression were recently reviewed. Whether these prognostic indicators can select
individual patients who might benefit more than others from multidisciplinary strategies remains to be established.
Therefore, their clinical usefulness outside of a clinical trial remains in question.

DOSE INTENSIFICATION
One of the research directions to improve the survival of patients with LABC is dose intensification of
primary or postoperative CT. A recent study in patients with early breast cancer treated with anthracycline-
containing regimens demonstrated that doses lower than the standard dose produce an inferior DFS and OS. On
the other hand, a recent report from a randomized study with higher doses of cyclophosphamide plus granulocyte
colony-stimulating factor failed to show any additional benefit from higher doses. It is unclear if doses higher
than the standard dose would impact the outcome of these patients. Several reports of open phase II trials in
patients with LABC have suggested a higher response rate [55,56]. No definite survival benefits have been
reported; however, comparative trials are necessary to assess the relative value of dose intensification in this
group of patients. A randomized phase III study is under way at The University of Texas MD Anderson Cancer
Center. The preliminary results of this trial showed a higher objective response rate in the higher dose arm
(98% versus 76%), but the pathological CR rates were similar. The role of very high-dose CT with peripheral
hematopoietic stem cell rescue is being studied in patients with a higher risk of relapse after primary CT, such
as patients with four or more positive axillary nodes after primary CT. The role of this strategy is also being
investigated after primary CT as a consolidation CT.

BREAST CONSERVATION
Historically, patients with LABC were not considered candidates for breast-conserving surgery. The inclusion
of primary CT in the multidisciplinary treatment of patients with LABC resulted in 10%-40% of patients
achieving such a remarkable reduction in tumor size that treatment with a segmental mastectomy followed by
RT resulted in a realistic option for patients with LABC. The goal of this strategy is to obtain optimal local-
regional control with minimal disfigurement. Breast-conserving surgery for LABC was developed by several
institutions following the same criteria used for breast conservation in stage I or small stage II breast cancer.
46 Surgical Oncology: Theory and Multidisciplinary Practice

However, there is great variability in the methods and patients’ selection criteria utilized for breast conservation.
Whether the same criteria used for patients with early breast cancer are appropriate for breast conservation in
LABC is unknown. Other centers employed different multidisciplinary breast-sparing strategy, primary CT,
followed by RT, followed by postoperative CT. After primary CT, the primary tumor may disappear completely
or may partially decrease in size. The tumor may lose all its infiltrating components so that only residual non-
invasive carcinoma is left. It is unknown at this point which is the most frequent manner in which primary
tumors decrease in size after primary CT. However, documentation of downstaging is absolutely necessary in
order to define the optimal terms of surgical removal and to maximize local control. Only prospective collection
of data will determine what is the optimal limit of surgical excision, whether positive margins have the same
implications after primary CT as they do in untreated patients, and whether a persistent tumor with marked CT-
related changes compromises local control. Our current practice includes primary CT with a doxorubicin-
containing regimen for four cycles. Multidisciplinary evaluation is performed at baseline and after primary CT.
If patients fulfill the rigorous criteria (including absence of extensive intramammary lymphatic invasion, negative
resection margin, resolution of skin edema, small residual tumor size, no evidence of multicentric lesions or
diffuse calcifications, and appropriate tumor: breast size ratios) for breast conserving surgery, then this option
is offered to our patients with LABC, followed by postoperative CT. RT is given at the completion of all CT. In
summary, to augment the probability of breast conservation for LABC, several strategies can be pursued. Primary
CT could be followed by wide excision and RT for patients with excellent tumor reduction. Primary CT can be
followed by RT in patients with less marked tumor reduction to maximize downstaging and permit a limited
surgical resection. Chemotherapy can also be combined simultaneously with RT, expecting additive effects on
the primary tumor volume. Finally, primary CT can be followed by RT alone in those patients who had significant
tumor downstaging, after maximal response to CT. At this time it is unknown which of these strategies is
optimal in terms of tumor reduction, cosmetic outcome, and local control. Therefore, well-designed, multicentric
randomized clinical trials are needed to determine the optimal strategy.

INFLAMMATORY BREAST CARCINOMA

IBC is a very rare oncological entity. It constitutes only 1%-4% of breast cancer cases in the USA. IBC is a
clinical-pathological entity that has been defined in many different ways. We define IBC as a clinical entity
characterized by rapid onset and an evolution shorter than three months, with diffuse involvement of the breast,
usually without an underlying palpable mass. The physical exam is characterized by erythema, skin edema, and
the presence of ridging. Histopathological demonstration of dermal lymphatic invasion is considered confirmatory
evidence but is neither necessary nor pathognomic for the diagnosis. Like LABC, distant metastases were and
are the most frequent type of treatment failure, and a very high percentage of patients develop locoregional
failure. Few if any patients survive beyond two years. The results after treatment consisting of surgery alone
were totally inadequate. RT used as the only therapeutic strategy produced local control in a substantial fraction
of patients but was unable to modify the natural history of this entity. Anthracycline-containing primary CT
produces objective responses in 60%-80% of patients, and the majority of them are rendered disease-free with
the multidisciplinary therapy (primary CT and RT, or CT, surgery and RT). In contrast with historical experience,
five-year survival rates in the 30%-50% range have been reported consistently, and at 10 years, 30% of patients
remain alive, most of them free of metastatic breast cancer. In general, the DFS and OS data after multidisciplinary
therapy are similar to those achieved with stage IIIB/IV, non-inflammatory LABC. The results from our institute
were recently reviewed by Buzdar et al.; we treated 178 patients in four trials. Of these patients, 72% achieved
a major objective response, including 12% who achieved CR. Only one patient developed progressive disease
during primary CT. After primary CT and RT, 92% of patients were rendered disease-free. The median DFS and
OS for this group were 21 months and 40 months, respectively. The overall locoregional control rate was 82%.
Breast 47

At 10 years after diagnosis, 30% of patients remained disease-free and alive. Objective response (CR + PR) to
primary induction CT was the main prognostic factor. Fifty percent of patients with CR remained disease-free
after 10 years. In summary, the introduction of primary CT to the multidisciplinary management of IBC has
changed the uniformly lethal natural history of this unique entity. It is in this group of patients that the most
dramatic demonstration of the efficacy of multidisciplinary therapy that includes primary CT was observed.

BR
BRCCA 1 AND BRCA 2 IN BREAST CANCER AND OV
BRC ARIAN CANCER
OVARIAN
A BRCA mutation is a mutation in either of the BRCA1 and BRCA2 genes, which are tumour suppressor
genes. Hundreds of different types of mutations in these genes have been identified, some of which have
been determined to be harmful, while others have no proven impact. Harmful mutations in these genes may
produce a hereditary breast-ovarian cancer syndrome in affected persons. Only 5-10% of breast cancer cases
in women are attributed to BRCA1 and BRCA2 mutations (with BRCA1 mutations being slightly more common
than BRCA2 mutations), but the impact on women with the gene mutation is more profound. Women with
harmful mutations in either BRCA1 or BRCA2 have a risk of breast cancer that is about five times the normal
risk, and a risk of ovarian cancer that is about ten to thirty times normal. The risk of breast and ovarian cancer
is higher for women with a high-risk BRCA1 mutation than with a BRCA2 mutation. Having a high-risk
mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that
appears was actually caused by the mutation, rather than some other factor. High-risk mutations, which disable
an important error-free DNA repair process (homology directed repair), significantly increase the person’s risk
of developing breast cancer, ovarian cancer and certain other cancers. Why BRCA1 and BRCA2 mutations lead
preferentially to cancers of the breast and ovary is not known, but lack of BRCA1 function seems to lead to non-
functional X-chromosome inactivation. Not all mutations are high-risk; some appear to be harmless variations.
The cancer risk associated with any given mutation varies significantly and depends on the exact type and
location of the mutation and possibly other individual factors. Mutations can be inherited from either parent
and may be passed on to both sons and daughters. Each child of a genetic carrier, regardless of sex, has a 50%
chance of inheriting the mutated gene from the parent who carries the mutation. As a result, half of the people
with BRCA gene mutations are male, who would then pass the mutation on to 50% of their offspring, male or
female. The risk of BRCA-related breast cancers for men with the mutation is higher than for other men, but still
low. However, BRCA mutations can increase the risk of other cancers, such as colon cancer, pancreatic cancer,
and prostate cancer. Methods to diagnose the likelihood of a patient with mutations in BRCA1 and BRCA2
getting cancer were covered by patents owned or controlled by Myriad Genetics. Myriad’s business model of
exclusively offering the diagnostic test led to Myriad growing from being a startup in 1994 to being a publicly
traded company with 1200 employees and about $500M in annual revenue in 2012; it also led to controversy
over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the
landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.

GENES AND MUTATIONS

Both BRCA genes are tumor suppressor genes that produce proteins that are used by the cell in an
enzymatic pathway that makes very precise, perfectly matched repairs to DNA molecules that have double-
stranded breaks. The pathway requires proteins produced by several other genes, including CHK2, FANCD2
and ATM. Harmful mutations in any of these genes disable the gene or the protein that it produces. The
cancer risk caused by BRCA1 and BRCA2 mutations are inherited in a dominant fashion even though usually
only one mutated allele is directly inherited. This is because people with the mutation are likely to acquire a
second mutation, leading to dominant expression of the cancer. A mutated BRCA gene can be inherited from
either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutations
48 Surgical Oncology: Theory and Multidisciplinary Practice

rather than acquired or somatic mutations. Cancer caused by a mutated gene inherited from an individual’s
parents is a hereditary cancer rather than a sporadic cancer. Because humans have a diploid genome, each cell
has two copies of the gene (one from each biological parent). Typically only one copy contains a disabling,
inherited mutation, so the affected person is heterozygous for the mutation. If the functional copy is harmed,
however, then the cell is forced to use alternate DNA repair mechanisms, which are more error-prone. The loss
of the functional copy is called loss of heterozygosity (LOH). Any resulting errors in DNA repair may result in
cell death or a cancerous transformation of the cell. There are many variations in BRCA genes, and not all
changes confer the same risks. Some variants are harmless; others are known to be very harmful. Some single
nucleotide polymorphisms may confer only a small risk, or may only confer risk in the presence of other
mutations or under certain circumstances. In other cases, whether the variant is harmful is unknown.
Variants are classified as follows:
• Deleterious mutation: The change is proven to cause significant risks. Often, these are frameshift
mutations that prevent the cell from producing more than the first part of the necessary protein.
• Suspected deleterious: While nothing is proven, the variation is currently believed to be harmful.
• Variant of uncertain significance (VUS): Whether the change has any effect is uncertain. This is a
common test result, and most variations began in this category. As more evidence is acquired, these
are re-classified.
• Variant, favour polymorphism: While nothing is proven, the variation is currently believed to be harmless.
• Benign polymorphism: The change is classified as harmless. These may be reported as “no mutation”.
Deleterious mutations have high, but not complete, genetic penetrance, which means that people with the
mutation have a high risk of developing disease as a result, but that some people will not develop cancer despite
carrying a harmful mutation.

Fig. BRCA mutations are inherited in a genetically dominant fashion, from either parent.
Breast 49

GETTING TESTED

Indications
Genetic counseling is commonly recommended to people whose personal or family health history suggests
a greater than average likelihood of a mutation. Genetic counselors are allied health professionals who are
trained to explain genetics to people; some of them are also licensed as registered nurses or social workers. A
medical geneticist is a physician who specializes in genetics. The purpose of genetic counseling is to educate
the person about the likelihood of a positive result, the risks and benefits of being tested, the limitations of the
tests, the practical meaning of the results, and the risk-reducing actions that could be taken if the results are
positive. They are also trained to support people through any emotional reactions and to be a neutral person
who helps the client make his or her own decision in an informed consent model, without pushing the client to
do what the counselor might do. Because the knowledge of a mutation can produce substantial anxiety, some
people choose not to be tested or to postpone testing until a later date.
Relative indications for testing for a mutation in BRCA1 or BRCA2 for newly diagnosed or family members
include a family history among 1st (FDR), 2nd (SDR), or 3rd(TDR) degree relatives usually on the same side of
the family but not limited:
• A known mutation (BRCA1 or BRCA2) in a cancer susceptibility gene within the family
• Women affected with any Breast cancer diagnosed under the age of 30
• Women affected with triple negative breast cancer (TNBC) (estrogen receptor negative, progesterone
receptor negative, and HER2/neu negative) under the age of 50
• Two relatives (FDR/SDR) diagnosed under the age of 45
• Three relatives (FDR/SDR) diagnosed with average age of 50 or less
• Four relatives at any ages
• Ovarian cancer with either an additional diagnosed relative or a relative with male breast cancer
• A single family member with both breast and ovarian cancer
• Male breast cancer
• Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the
family
• Ashkenazi Jewish or Polish ancestry with one FDR family member affected by breast or ovarian
cancer at any age
Testing young children is considered medically unethical because the test results would not change the way
the child’s health is cared for.

Test Procedure
If the person chooses to be tested, then two types of tests are available. Both commonly use a blood sample,
although testing can be done on saliva. The quickest, simplest, and lowest cost test uses positive test results
from a blood relative and checks only for the single mutation that is known to be present in the family. If no
relative has previously disclosed positive test results, then a full test that checks the entire sequence of both
BRCA1 and BRCA2 can be performed. In some cases, because of the founder effect, Jewish ethnicity can be
used to narrow the testing to quickly check for the three most common mutations seen among Ashkenazi Jews.
Testing is commonly covered by health insurance and public health care programmes for people at high risk for
having a mutation, and not covered for people at low risk. The purpose of limiting the testing to high-risk
people is to increase the likelihood that the person will receive a meaningful, actionable result from the test,
rather than identifying a variant of unknown significance (VUS). In Canada, people who demonstrate their
50 Surgical Oncology: Theory and Multidisciplinary Practice

high-risk status by meeting specified guidelines are referred initially to a specialized programme for hereditary
cancers, and, if they choose to be tested, the cost of the test is fully covered. In the USA in 2010, single-site
testing had a retail cost of US$400 to $500, and full-length analysis cost about $3,000 per gene, and the costs
were commonly covered by private health insurance for people deemed to be at high risk. The test is ordered by
a physician, usually an oncologist, and the results are always returned to the physician, rather than directly to
the patient. How quickly results are returned depends on the test—single-site analysis requires less lab time—
and on the infrastructure in place. In the USA, test results are commonly returned within one to several weeks;
in Canada, patients commonly wait for eight to ten months for test results.

Test Interpretation
A positive test result for a known deleterious mutation is proof of a predisposition, although it does not
guarantee that the person will develop any type of cancer. A negative test result, if a specific mutation is known
to be present in the family, shows that the person does not have a BRCA-related predisposition for cancer,
although it does not guarantee that the person will not develop a non-hereditary case of cancer. By itself, a
negative test result does not mean that the patient has no hereditary predisposition for breast or ovarian cancer.
The family may have some other genetic predisposition for cancer, involving some other gene.

BREAST AND OVARIAN CANCER RISK

Women with deleterious mutations in either the BRCA1 or BRCA2 genes have a high risk of developing breast
and/or ovarian cancer. Because different studies look at different populations, and because different types of
mutations have somewhat different risks, the risk is best expressed as a range, rather than a single number.
Approximately 50% to 65% of women born with a deleterious mutation in BRCA1 will develop breast cancer by
age 70, and 35% to 46% will develop ovarian cancer by age 70. Approximately 40% to 57% of women with a
deleterious mutation in BRCA2 will develop breast cancer by age 70, and 13% to 23% will develop ovarian cancer
by age 70. Women with a breast cancer associated with a BRCA mutation have up to a 40% probability of developing
a new primary breast cancer within 10 years following initial diagnosis if they did not receive tamoxifen treatment
or have an oophorectomy. The woman’s ten-year risk for ovarian cancer is also increased by 6-12% under these
conditions. Statistics for BRCA-related ovarian cancer typically encompass not only cancer of the ovaries themselves,
but also peritoneal cancer and the very rare, but somewhat easier to detect, cancer of the Fallopian tubes. Women
with a BRCA mutation have more than 100 times the normal rate of Fallopian tube cancer. These three types of
these cancers can be difficult to distinguish in their advanced stages.

When Cancer Appears

BRCA-related breast cancer appears at an earlier age than sporadic breast cancer. It has been asserted that
BRCA-related breast cancer is more aggressive than normal breast cancer, however most studies in specific
populations suggest little or no difference in survival rates despite seemingly worse prognostic factors.
• BRCA1 is associated with triple-negative breast cancer, which does not respond to hormonal treatments
and cannot be usefully treated with some drugs, such as trastuzumab. Breast cancer often appears
about two decades earlier than normal.
• BRCA2 is associated primarily with post-menopausal breast cancer, although the risk of pre-
menopausal breast cancer is significant. It is typically highly responsive to hormonal treatments.
BRCA-related ovarian and Fallopian tube cancer is more treatable than average because it is unusually
susceptible to platinum-based chemotherapy like cisplatin. BRCA1-related ovarian cancer appears at younger
ages, but the risk for women with BRCA2 climbs markedly at or shortly after menopause.
Breast 51

Survival Impact
Likelihood of a 25-year-old woman surviving to age 70
(without screening or medical interventions to prevent cancer)
Group Percentage surviving to age 70
BRCA1 mutation 53
BRCA2 mutation 71
Typical woman 84
A 25-year-old woman with no mutation in her BRCA genes has an 84% probability to reach at least the age
of 70. Of those not surviving, 11% die from either breast or ovarian cancer, and 89% from other causes. Compared
to that, a woman with a high-risk BRCA1 mutation, if she had breast cancer screening but no prophylactic
medical or surgical intervention, would have only 59% chance to reach age 70, twenty-five percentage points
lower than normal. Of those women not surviving, 26% would die of breast cancer, 46% ovarian cancer, and
28% other causes. Women with high-risk BRCA2 mutations, with screening but with no prophylactic medical
or surgical intervention, would have only 71% chance to reach age 70, thirteen percentage points lower than
normal. Of those not surviving, 21% would die of breast cancer, 25% ovarian cancer and 54% other causes. The
likelihood of surviving to at least age 70 can be improved by several medical interventions, notably prophylactic
mastectomy and oophorectomy.

Male Breast Cancer

Men with a BRCA mutation have a dramatically elevated relative risk of developing breast cancer, but because
the overall incidence of breast cancer in men is so low, the absolute risk is equal to or lower than the risk for
women without a BRCA mutation. Approximately 1% to 2% of men with a BRCA1 mutation will develop breast
cancer by age 70. Approximately 6% of men with a BRCA2 mutation will develop breast cancer by age 70, which
is approximately equal to the risk for women without a BRCA mutation. Very few men, with or without a predisposing
mutation, develop breast cancer before age 50. Approximately half of men who develop breast cancer have a
mutation in a BRCA gene or in one of the other genes associated with hereditary breast–ovarian cancer syndromes.
Breast cancer in men can be treated as successfully as breast cancer in women, but men often ignore the signs and
symptoms of cancer, such as a painful area or an unusual swelling, which may be no bigger than a grain of rice,
until it has reached a late stage. Unlike other men, men with a BRCA mutation, especially a BRCA2 mutation, may
benefit from professional and self breast exams. Medical imaging is not usually recommended, but because male
BRCA2 carriers have a risk of breast cancer that is very similar to the general female population, the standard
annual mammogram programme can be adapted to these high-risk men.

CANCER DETECTION AND PREVENTION STRATEGIES

A variety of screening options and interventions are available to manage BRCA-related cancer risks. Screenings
are adjusted to individual and familial risk factors. As these screening methods do not prevent cancer, but
merely attempt to catch it early, numerous methods of prevention are sometimes practiced, with varying results.

Screening
An intensive cancer screening regimen is usually advised for women with deleterious or suspected deleterious
BRCA mutations in order to detect new cancers as early as possible. A typical recommendation includes frequent
breast cancer screening as well as tests to detect ovarian cancer. Breast imaging studies usually include a breast
MRI (magnetic resonance imaging) once a year, beginning between ages 20 and 30, depending on the age at
which any relatives were diagnosed with breast cancer. Mammograms are typically used only at advanced age
52 Surgical Oncology: Theory and Multidisciplinary Practice

as there is reason to believe that BRCA carriers are more susceptible to breast cancer induction by X-ray damage
than general population. Alternatives include breast ultrasonography, CT scans, PET scans, scintimammography,
elastography, thermography, ductal lavage, and experimental screening protocols, some of which hope to identify
biomarkers for breast cancer (molecules that appear in the blood when breast cancer begins). Ovarian cancer
screening usually involves ultrasonography of the pelvic region, typically twice a year. Women may also use a
blood test for CA-125 and clinical pelvic exams. The blood test has relatively poor sensitivity and specificity
for ovarian cancer. In both breast and ovarian screening, areas of tissue that look suspicious are investigated
with either more imaging, possibly using a different type of imaging or after a delay, or with biopsies of the
suspicious areas.

Prophylactic Medication
Oral contraceptives is associated with substantially lower risk of ovarian cancer in women with BRCA
mutations. A 2013 meta-analysis found that oral contraceptive use was associated with a 42% reduction of the
relative risk of ovarian cancer, the association was similar for BRCA1 and BRCA2 mutations. Use of oral
contraceptives was not significantly associated with breast cancer risk although a small increase of risk that did
not reach statistical significance was observed. A 2011 meta-analysis found that OC use was associated with a
43% relative reduction in risk of ovarian cancer in women with BRCA mutations, while data on the risk of
breast cancer in BRCA mutation carriers with oral contraceptive use were heterogeneous and results were
inconsistent. Selective estrogen receptor modulators, specifically tamoxifen, have been found to reduce breast
cancer risk in women with BRCA mutations who do not have their breast removed. It is effective as for primary
prevention (preventing the first case of breast cancer) in women with BRCA2 mutations, but not BRCA1 mutations,
and for secondary prevention (preventing a second, independent breast cancer) in both groups of women.
Taking tamoxifen for five years has been found to halve the breast cancer risk in women who have a high risk
of breast cancer for any reason, but potentially serious adverse effects like cataracts, blood clots, and endometrial
cancer, along with quality of life issues like hot flashes, result in some women discontinuing its use and some
physicians limiting its use to women with atypical growths in the breasts. Tamoxifen is contraindicated for
women who are most likely to be harmed by the common complications. Raloxifene (Evista), which has a
reduced risk of side effects, is used as an alternative, but it has not been studied in BRCA mutation carriers
specifically. Tamoxifen use can be combined with oophorectomy for even greater reduction of breast cancer
risk, particularly in women with BRCA2 mutations. Aromatase inhibitors are medications that prevent estrogen
production in the adrenal glands and adipose tissue. They have fewer side effects than selective estrogen receptor
modulators like tamoxifen, but do not work in premenopausal women, because they do not prevent the ovaries
from producing estrogen.

Prophylactic Surgery
Several type of preventive surgeries are known to substantially reduce cancer risk for women with high-risk
BRCA mutations. The surgeries may be used alone, in combination with each other, or in combination with non-
surgical interventions to reduce the risk of breast and ovarian cancer. Note that surgeries such as mastectomy
and oophorectomy do not completely eliminate the chance of breast cancer; cases have reportedly emerged
despite these procedures.
• Tubal ligation is the least invasive of these surgeries and appears to reduce ovarian cancer risk for
BRCA1 carriers by over 60%. Salpingectomy is another option which is more invasive than tubal
ligation and may result in additional risk reduction. Both of these can be performed anytime after
childbearing is complete. Unlike other prophylactic surgeries, these two surgeries do not reduce the
risk of breast cancer.
Breast 53

• Prophylactic (preventive) mastectomy is associated with small risks and a large drop in breast cancer
risk.
• Prophylactic salpingo-oophorectomy (removal of the ovaries and Fallopian tubes) results in a very
large reduction in ovarian cancer risk, and a large reduction in breast cancer risk if performed before
natural menopause. However, it also comes with the risk of substantial adverse effects if performed
at a young age.
• Hysterectomy has no direct effect on BRCA-related cancers, but it enables the women to use some
medications that reduce breast cancer risk (such as tamoxifen) with the risk of uterine cancer and to
use fewer hormones to manage the adverse effects of a prophylactic oophorectomy.
Whether and when to perform which preventive surgeries is a complex personal decision. Current medical
knowledge offers some guidance about the risks and benefits. Even carriers of the same mutation or from the
same family may have substantially different risks for the kind and severity of cancer they are likely to get, as
well as the age at which they may get them. Different people also have different values. They may choose to
focus on total cancer prevention, psychological benefits, current quality of life, or overall survival. The possible
impact of future medical developments in treatment or prognosis may also be of some importance for very
young women and family planning. The decision is individualized and is usually based on many factors, such as
earliest occurrence of BRCA-related cancer in close relatives. The protective effect of prophylactic surgery is
greater when done at young age; however, oophorectomy also has adverse effects that are greatest when done
long before natural menopause. For this reason, oophorectomy is mostly recommended after age 35 or 40,
assuming childbearing is complete. The risk of ovarian cancer is low before this age, and the negative effects of
oophorectomy are less serious as the woman nears natural menopause.
• For carriers of high-risk BRCA1 mutations, prophylactic oophorectomy around age 40 reduces the
risk of ovarian and breast cancer and provides a substantial long-term survival advantage. Having
this surgery at a very young age provides little or no additional survival advantage, but it does
increase the adverse effects from the surgery. Compared to no intervention, having this surgery
around age 40 increases the woman’s chance of reaching age 70 by fifteen percentage points, from
59% to 74%. Adding prophylactic mastectomy increases the expected survival by several more
percentage points.
• For carriers of high-risk BRCA2 mutations, oophorectomy around age 40 has a smaller effect. The
surgery increases the woman’s chance of reaching age 70 by only five percentage points, from 75%
to 80%. When only preventive mastectomy is done at age 40 instead, the improvement is similar,
with the expected chance rising from 75% to 79%. Doing both surgeries together around age 40 is
expected to improve the woman’s chance of reaching age 70 from 75% to 82%
For comparison, women in the general population have an 84% chance of living to age 70.

Prophylactic Mastectomy
In a woman who has not developed breast cancer, removing the breasts may reduce her risk of ever being
diagnosed with breast cancer by 90%, to a level that is approximately half the average woman’s risk. Bilateral
mastectomy is the removal of both breasts by a breast surgeon. The modified radical mastectomy is only used in
women diagnosed with invasive breast cancer.
Techniques for prophylactic mastectomies include:
• Simple mastectomy, which is recommended for women not having breast reconstruction, leaves
the least amount of breast tissue in the body and therefore achieves the greatest risk reduction. In
addition to prophylactic use, it is also used by women who have been diagnosed with earlier
stages of cancer.
54 Surgical Oncology: Theory and Multidisciplinary Practice

• Skin-sparing mastectomy removes the tissue of the breast, nipple, and areola, but leave the “excess”
skin in place for reconstruction. It has less visible scar tissue than a simple mastectomy.
• Nipple-sparing mastectomy removes the breast tissue, but leaves the nipple and the areola intact for
a more natural appearance.
• Subcutaneous mastectomy removes the breast tissue, but leaves the nipple and areola intact. The
scars are hidden in the inframammary fold under the breast.
• Areola-sparing mastectomy removes the breast tissue and the nipple, but not the areola.
• Nerve-sparing mastectomy is an effort to maintain the nerves that provide sensation to the skin over
the breasts. Breasts that have undergone any of these surgeries have much less tactile sensation than
natural breasts. Nerve-sparing techniques are an effort to retain some feeling in the breasts, with
limited and often only partial success.
Which technique is used is determined by the existence of any cancer and overall health, as well as by the
woman’s desire, if any, for breast reconstruction surgery for aesthetic purposes. Women who choose a flat-
chested appearance or use external breast prostheses typically choose simple mastectomy, with its greater risk
reduction. Breast reconstruction is usually done by a plastic surgeon, and may be started as part of the same
multi-hour surgery that removes the breasts. Multiple techniques for reconstruction have been used, with different
locations and amounts of scarring. Some techniques use tissue from another part of the body, such as fat tissue
from the lower abdomen or occasionally muscles from other parts of the torso. Others use breast implants,
possibly preceded by tissue expanders, to provide volume. Some reconstruction techniques require multiple
surgeries. Afterwards, some women have tattoos added to simulate breast areolas or have the skin reshaped to
form a nipple.

Prophylactic Salpingo-oophorectomy
Oophorectomy (surgical removal of the ovaries) and salpingectomy (surgical removal of the Fallopian tubes)
are strongly recommended to women with BRCA mutations. Salpingo-oophorectomy is the single most effective
method of preventing ovarian and Fallopian tube cancer in women with a BRCA mutation. However, a small
risk of primary peritoneal cancer remains, at least among women with BRCA1 mutations, since the peritoneal
lining is the same type of cells as parts of the ovary. This risk is estimated to produce about five cases of
peritoneal cancer per 100 women with harmful BRCA1 mutations in the 20 years after the surgery. BRCA2
related ovarian cancer tends to present in perimenopausal or menopausal women, so salpingo-oophorectomy is
recommended between ages 45 and 50. If it is done before menopause, then the women also benefit from a
reduced risk of breast cancer. The surgery is often done in conjunction with a hysterectomy (surgical removal of
the uterus) and sometimes a cervicectomy (surgical removal of the cervix), especially in women who want to
take tamoxifen, which is known to cause uterine cancer, or who have uterine fibroids. Multiple styles of surgery
are available, including laparoscopic (keyhole) surgery. Because about 5% of women with a BRCA mutation
have undetected ovarian cancer at the time of their planned surgery, the surgery should be treated as if it were
a removal of a known cancer. Salpingo-oophorectomy makes the woman sterile (unable to bear children).
Infertility services can be used to preserve her eggs, if wanted. However, as the benefits to the surgery are
greatest close to menopause, most women simply postpone the surgery until they have already borne as many
children as they choose to. The surgery also artificially induces menopause, which causes hot flashes, sleep
disturbances, mood swings, vaginal dryness, sexual difficulties, difficulty with word recall, and other medical
signs and symptoms. The side effects range from mild to severe; most can be treated at least partially. Many
women with a BRCA take hormone replacement therapy to reduce these effects: estrogen-progesterone
combinations for women who have a uterus, and unopposed estrogen for women whose uterus was removed.
Estrogen can cause breast cancer, but as the amount of estrogen taken is less than the amount produced by the
Breast 55

now-removed ovaries, the net risk is usually judged to be acceptable. Some sources assume that oophorectomy
before age 50 doubles the risk of cardiovascular disease and increases risk of hip fractures caused by osteoporosis
in the relevant population.

Non-medical Choices
Given the high risks and the low benefit of lifestyle choices in BRCA mutation carriers, no lifestyle choices
provide sufficient protection. Having her first child at a younger age, having more children than average, and
breastfeeding for more than one year decreases the risk of breast cancer for an average-risk woman. Studies
about this effect among BRCA mutation carriers have produced conflicting results, but generally speaking,
having children is believed to provide little or no protection against breast cancer for women with BRCA1
mutations, and to paradoxically increase the risk of breast cancer for women with BRCA2 mutations. Being
physically active and maintaining a healthy body weight prevents breast and other cancers in the general
population, as well as preventing heart disease and other medical conditions. Among women with a BRCA
mutation, being physically active and having had a healthy body weight as an adolescent has no effect on
ovarian cancer and delays, but does not entirely prevent, breast cancer after menopause. In some studies, only
significant, strenuous exercise produced any benefit. Obesity and weight gain as an adult are associated with
breast cancer diagnoses. Studies on specific foods, diets, or dietary supplements have generally produced
conflicting information or, in the case of dietary fat, soy consumption, and drinking green tea, have only been
conducted in average-risk women. The only dietary intervention that is generally accepted as preventing breast
cancer in BRCA mutation carriers is minimizing consumption of alcoholic beverages. Consuming more than
one alcoholic drink per day is strongly associated with a higher risk of developing breast cancer, and carriers
are usually encouraged to consume no more than one alcoholic drink per day, and no more than four total in a
week. In a study conducted with Ashkenazi Jewish women, it was observed that mutation carriers born before
1940 have a much lower risk of being diagnosed with breast cancer by age 50 than those born after 1940; this
was also observed in the non-carrier population. The reasons for the difference is unknown. Unlike the general
population, age at menarche and age at menopause has no effect on breast cancer risk for BRCA mutation
carriers.

OTHER CANCERS
Mutations have been associated with increased risk of developing any kind of invasive cancer, including
stomach cancer, pancreatic cancer, prostate cancer, and colon cancer. Carriers have the normal risks of developing
cancer (and other diseases) associated with increased age, smoking, alcohol consumption, poor diet, lack of
exercise, and other known risk factors, plus the additional risk from the genetic mutations and an increased
susceptibility to damage from ionizing radiation, including natural background radiation. Men with BRCA
mutations cannot get ovarian cancer, but they may be twice as likely as non-carriers to develop prostate cancer
at a younger age. The risk is smaller and disputed for BRCA1 carriers; up to one-third of BRCA2 mutation
carriers are expected to develop prostate cancer before age 65. Prostate cancer in BRCA mutation carriers tends
to appear a decade earlier than normal, and it tends to be more aggressive than normal. As a result, annual
prostate screening, including a digital rectal examination, is appropriate at age 40 among known carriers, rather
than age 50. Cancer of the pancreas tends to run in families, even among BRCA families. A BRCA1 mutation
approximately doubles or triples the lifetime risk of developing pancreatic cancer; a BRCA2 mutation triples to
quintuples it. Between 4% and 7% of people with pancreatic cancer have a BRCA mutation. However, since
pancreatic cancer is relatively rare, people with a BRCA2 mutation probably face an absolute risk of about 5%.
Like ovarian cancer, it tends not to produce symptoms in the early, treatable stages.
56 Surgical Oncology: Theory and Multidisciplinary Practice

Like prostate cancer, pancreatic cancer associated with a BRCA mutation tends to appear about a decade
earlier than non-hereditary cases. Asymptomatic screening is invasive and may be recommended only to BRCA2
carriers who also have a family history of pancreatic cancer. Melanoma is the most deadly skin cancer, although
it is easily cured in the early stages. The normal likelihood of developing melanoma depends on race, the
number of moles the person has, family history, age, sex, and how much the person has been exposed to UV
radiation. BRCA2 mutation carriers have approximately double or triple the risk that they would normally have,
including a higher than average risk of melanoma of the eye. Cancer of the colon is approximately as common
in both men and women in the developed world as breast cancer is among average-risk women, with about 6%
of people being diagnosed with it, usually over the age of 50. Like sporadic prostate cancer, it is a multifactorial
disease, and is affected by age, diet, and similar factors. BRCA mutation carriers have a higher than average risk
of this common cancer, but the risk is not as high as in some other hereditary cancers. The risk might be as high
as four times normal in some BRCA1 families, and double the normal risk among BRCA2 carriers. Like pancreatic
cancer, it may be that only some BRCA mutations or some BRCA families have the extra risk; unlike other
BRCA-caused cancers, it does not appear at an earlier age than usual. Normal colon cancer screening is usually
recommended to BRCA mutation carriers. Mutations in BRCA1 and BRCA2 are strongly implicated in some
hematological malignancies. BRCA1 mutations are associated acute myelogenous leukemia and chronic
myelogenous leukemia. Mutations of BRCA2 are also found in many T-cell lymphomas and chronic lymphocytic
leukemias.

CHILDBEARING AND FERTILITY EFFECTS

The dilemma of whether or not to have children is a significant source of stress for women who learn of their
BRCA mutations during their childbearing years. There is likely little or no effect of a BRCA gene mutation on
overall fertility, although women with a BRCA mutation may be more likely to have primary ovarian insufficiency.
BRCA mutation carriers may be more likely to give birth to girls than boys, however this observation has been
attributed to ascertainment bias. If both parents are carriers of a BRCA mutation, then pre-implantation genetic
diagnosis is sometimes used to prevent the birth of a child with BRCA mutations. Inheriting two BRCA1 mutations
(one from each parent) has never been reported and is believed to be a lethal birth defect. Inheriting one BRCA1
mutation and one BRCA2 mutation has been reported occasionally; the child’s risk for any given type of cancer
is the higher risk of the two genes (e.g., the ovarian cancer risk from BRCA1 and the pancreatic cancer risk from
BRCA2). Inheriting two BRCA2 mutations produces Fanconi anemia. Each pregnancy in genetically typical
women is associated with a significant reduction in the mother’s risk of developing breast cancer after age 40.
The younger the woman is at the time of her first birth, the more protection against breast cancer she receives.
Breastfeeding for more than one year protects against breast cancer. Pregnancy also protects against ovarian
cancer in genetically typical women. Although some studies have produced different results, women with BRCA
mutations are generally not expected to receive these significant protective benefits. Current research is too
limited and imprecise to permit calculation of specific risks.
However, the following general trends have been identified:
• For women with a BRCA1 mutation, the woman’s age when she first gives birth has no association
with her risk of breast cancer. Childbearing provides no protection against breast cancer, unless
the woman has five or more full-term pregnancies, at which point she receives only modest
protection. Similar to genetically typical women, pregnancy protects against ovarian cancer in
BRCA1 women. Breastfeeding for more than one year significantly protects against breast cancer.
This effect may be as high as 19% per year of breastfeeding, which is much higher than that seen
among genetically typical women. The effect, if any, of long-term breastfeeding on ovarian cancer
is unclear.
Breast 57

• For women with a BRCA2 mutation, each pregnancy is paradoxically associated with a statistically
significant increase in the risk for breast cancer. Unlike genetically typical women or women with
BRCA1 mutations, breastfeeding has no effect on either cancer in women with BRCA2 mutations.
Limited and conflicting data suggest that, also unlike other women, pregnancy does not reduce ovarian
cancer risk significantly in women with a BRCA2 mutation and might increase it.

EVOLUTIONARY ADVANTAGE
Several hypotheses propose that BRCA mutations might have evolutionary advantages, such as higher
intelligence. The Ashkenazi intelligence hypothesis was proposed by Gregory Cochran and asserts that a defect
in the BRCA1 gene might unleash neural growth. Studies have shown that BRCA1 mutations are not random,
but under adaptive selection, indicating that although BRCA1 mutations are linked to breast cancer, the mutations
likely have a beneficial effect as well.

PATENT ENFORCEMENT AND LITIGATION

A patent application for the isolated BRCA1 gene and cancer-cancer promoting mutations discussed above,
as well as methods to diagnose the likelihood of getting breast cancer, was filed by the University of Utah,
National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics in 1994; over the next year,
Myriad, in collaboration with investigators from Endo Recherche, Inc., HSC Research and Development Limited
Partnership, and University of Pennsylvania, isolated and sequenced the BRCA2 gene and identified key
mutations, and the first BRCA2 patent was filed in the U.S. by Myriad and other institutions in 1995. Myriad is
the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs. This
business model led to Myriad growing being a startup in 1994 to being a publicly traded company with 1200
employees and about $500M in annual revenue in 2012; it also led to controversy over high prices and the
inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for
Molecular Pathology v. Myriad Genetics lawsuit. The patents begin to expire in 2014. According to an article
published in the journal, Genetic Medicine, in 2010, “The patent story outside the United States is more
complicated.... For example, patents have been obtained but the patents are being ignored by provincial health
systems in Canada. In Australia and the UK, Myriad’s licensee permitted use by health systems, but announced
a change of plans in August 2008.... Only a single mutation has been patented in Myriad’s lone European-wide
patent, although some patents remain under review of an opposition proceeding. In effect, the United States is
the only jurisdiction where Myriad’s strong patent position has conferred sole-provider status.” Peter Meldrum,
CEO of Myriad Genetics, has acknowledged that Myriad has “other competitive advantages that may make
such [patent] enforcement unnecessary” in Europe. Legal decisions surrounding the BRCA1 and BRCA2 patents
will affect the field of genetic testing in general. In June 2013, in Association for Molecular Pathology v.
Myriad Genetics (No. 12-398), the US Supreme Court unanimously ruled that, “A naturally occurring DNA
segment is a product of nature and not patent eligible merely because it has been isolated,” invalidating Myriad’s
patents on the BRCA1 and BRCA2 genes. However, the Court also held that manipulation of a gene to create
something not found in nature could still be eligible for patent protection.

Breast Cancer During Pregnancy

Most breast cancers in pregnant women are found during a clinical breast exam. Pregnant women may get a
clinical breast exam as part of their prenatal care. Screening mammography isn’t used in pregnant women
because the radiation may harm the fetus. And, younger women (under age 40) usually don’t get screening
mammography. If a lump is found during the first trimester, tests such as breast ultrasound (rather than
58 Surgical Oncology: Theory and Multidisciplinary Practice

mammography) are used to check for breast cancer. After the first trimester, a pregnant woman may have a
diagnostic mammogram with a shield covering her abdomen to protect the fetus. Breast cancer can be hard to
detect in pregnant women. The increased size and change in the texture of the breasts during pregnancy can
make smaller cancers hard to feel. So, breast cancers in pregnant women may be diagnosed at a more advanced
stage than in non-pregnant women.

TREATMENT
• There are special treatment concerns for pregnant women who have breast cancer.
• Although cancer itself does not seem to affect the fetus, some breast cancer treatments can be harmful.
• Your treatment plan and the timing of your treatments are chosen to treat your cancer as well as
protect the fetus.

SURGERY AND RADIATION THERAPY

Breast cancer surgery is safe during pregnancy. Although the anesthesia used during surgery can cross the
placenta to the fetus, it doesn’t appear to cause birth defects or serious pregnancy problems. Breast reconstruction,
however, should be delayed until after the baby is born to avoid further anesthesia and the chance of blood loss.
Mastectomy (instead of lumpectomy) is usually recommended for pregnant women who are in their first trimester
and want to continue their pregnancy. Radiation therapy is needed after a lumpectomy and radiation can harm
the fetus. However, some women in their second or third trimester may consider lumpectomy. In these cases,
radiation therapy is delayed until after the baby is born. This delay does not affect prognosis. Some women in
their second or third trimester may have chemotherapy before surgery (neo-adjuvant chemotherapy).

CHEMOTHERAPY
Chemotherapy is not given during the first trimester, since this is the time when the chances for drug-related
birth defects and miscarriage are greatest. During the second and third trimesters, some chemotherapy drugs
can be used safely. However, chemotherapy should not be given after week 35 of pregnancy or within 3 weeks
of the due date (or planned delivery date). This gives a woman time to recover from chemotherapy before
delivery. Many women diagnosed in their third trimester often wait and have chemotherapy after giving birth.

HORMONE THERAPY AND TARGETED THERAPY

Hormone therapies (such as tamoxifen and aromatase inhibitors) and targeted therapies (such as trastuzumab
(Herceptin)) are not used at any point during pregnancy because of risks to the fetus.
Gastrointestinal 59

Chapter 3

Gastrointestinal

ESOPHAGEAL C
ESOPHAGEAL ANCER
CANCER
Esophageal cancer is cancer arising from the esophagus—the food pipe that runs between the throat and the
stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain
when swallowing, a hoarse voice, enlarged lymph nodes (“glands”) around the collarbone, a dry cough, and
possibly coughing up or vomiting blood. The two main sub-types of the disease are esophageal squamous-cell
carcinoma (often abbreviated to ESCC), which is more common in the developing world, and esophageal
adenocarcinoma (EAC), which is more common in the developed world. A number of less common types also
occur. Squamous-cell carcinoma arises from the epithelial cells that line the esophagus. Adenocarcinoma arises
from glandular cells present in the lower third of the esophagus, often where they have already transformed to
intestinal cell type (a condition known as Barrett’s esophagus). Causes of the squamous-cell type include tobacco,
alcohol, very hot drinks, poor diet, and chewing betel nut. The most common causes of the adenocarcinoma
type are smoking tobacco, obesity, and acid reflux. The disease is diagnosed by biopsy done by an endoscope (a
fibreoptic camera).
Prevention includes stopping smoking and eating a healthy diet. Treatment is based on the cancer’s stage
and location, together with the person’s general condition and individual preferences. Small localized squamous-
cell cancers may be treated with surgery alone with the hope of a cure. In most other cases, chemotherapy with
or without radiation therapy is used along with surgery. Larger tumors may have their growth slowed with
chemotherapy and radiation therapy. In the presence of extensive disease or if the affected person is not fit
enough to undergo surgery, palliative care is often recommended. As of 2012, esophageal cancer was the eighth-
most common cancer globally with 456,000 new cases during the year. It caused about 400,000 deaths that year,
up from 345,000 in 1990. Rates vary widely among countries, with about half of all cases occurring in China. It
is around three times more common in men than in women. Outcomes are related to the extent of the disease
and other medical conditions, but generally tend to be fairly poor, as diagnosis is often late. Five-year survival
rates are around 13% to 18%.

SIGNS AND SYMPTOMS

Prominent symptoms usually do not appear until the cancer has infiltrated over 60% of the circumference of
the esophageal tube, by which time the tumor is already in an advanced stage. Onset of symptoms is usually
caused by narrowing of the tube due to the physical presence of the tumor. The first and the most common
symptom is usually difficulty in swallowing, which is often experienced first with solid foods and later with
softer foods and liquids. Pain when swallowing is less usual at first. Weight loss is often an initial symptom in
cases of squamous-cell carcinoma, though not usually in cases of adenocarcinoma. Eventual weight loss due to
60 Surgical Oncology: Theory and Multidisciplinary Practice

reduced appetite and undernutrition is common. Pain behind the breastbone or in the region around the stomach
often feels like heartburn. The pain can frequently be severe, worsening when food of any sort is swallowed.
Another sign may be an unusually husky, raspy, or hoarse-sounding cough, a result of the tumor affecting the
recurrent laryngeal nerve. The presence of the tumor may disrupt the normal contractions of the esophagus
when swallowing. This can lead to nausea and vomiting, regurgitation of food and coughing.
There is also an increased risk of aspiration pneumonia due to food entering the airways through the abnormal
connections (fistulas) that may develop between the esophagus and the trachea (windpipe). Early signs of this
serious complication may be coughing on drinking or eating. The tumor surface may be fragile and bleed,
causing vomiting of blood. Compression of local structures occurs in advanced disease, leading to such problems
as upper airway obstruction and superior vena cava syndrome. Hypercalcemia (excess calcium in the blood)
may occur. If the cancer has spread elsewhere, symptoms related to metastatic disease may appear. Common
sites of spread include nearby lymph nodes, the liver, lungs and bone. Liver metastasis can cause jaundice and
abdominal swelling (ascites). Lung metastasis can cause, among other symptoms, impaired breathing due to
excess fluid around the lungs (pleural effusion), and dyspnea (the feelings often associated with impaired
breathing).

Fig. Endoscopic image of an esophageal adenocarcinoma

CAUSES
The two main types (i.e. squamous-cell carcinoma and adenocarcinoma) have distinct sets of risk factors.
Squamous-cell carcinoma is linked to lifestyle factors such as smoking and alcohol. Adenocarcinoma has been
linked to effects of long-term acid reflux. Tobacco is a risk factor for both types. Both types are more common
in people over 60 years of age.
Gastrointestinal 61

Squamous-cell Carcinoma
The two major risk factors for esophageal squamous-cell carcinoma are tobacco (smoking or chewing)
and alcohol. The combination of tobacco and alcohol has a strong synergistic effect. Some data suggest that
about half of all cases are due to tobacco and about one-third to alcohol, while over three-quarters of the
cases in men are due to the combination of smoking and heavy drinking. Risks associated with alcohol
appear to be linked to its aldehyde metabolite and to mutations in certain related enzymes. Such metabolic
variants are relatively common in Asia. Other relevant risk factors include regular consumption of very hot
drinks (over 65 °C or 149 °F) and ingestion of caustic substances. High levels of dietary exposure to
nitrosamines (chemical compounds found both in tobacco smoke and certain foodstuffs) also appear to be a
relevant risk factor. Unfavourable dietary patterns seem to involve exposure to nitrosamines through processed
and barbecued meats, pickled vegetables, etc., and a low intake of fresh foods. Other associated factors
include nutritional deficiencies, low socioeconomic status, and poor oral hygiene. Chewing betel nut (areca)
is an important risk factor in Asia. Physical trauma may increase the risk. This may include the drinking of
very hot drinks.

Adenocarcinoma
Male predominance is particularly strong in this type of esophageal cancer, which occurs about 7 to 10 times
more frequently in men. This imbalance may be related to the characteristics and interactions of other known
risk factors, including acid reflux and obesity. The long-term erosive effects of acid reflux (an extremely common
condition, also known as gastroesophageal reflux disease or GERD) have been strongly linked to this type of
cancer. Longstanding GERD can induce a change of cell type in the lower portion of the esophagus in response
to erosion of its squamous lining. This phenomenon, known as Barrett’s esophagus, seems to appear about 20
years later in women than in men, maybe due to hormonal factors. Having symptomatic GERD or bile reflux
makes Barrett’s esophagus more likely, which in turn raises the risk of further changes that can ultimately lead
to adenocarcinoma. The risk of developing adenocarcinoma in the presence of Barrett’s esophagus is unclear,
and may in the past have been overestimated. Being obese or overweight both appear to be associated with
increased risk. The association with obesity seems to be the strongest of any type of obesity-related cancer,
though the reasons for this remain unclear. Abdominal obesity seems to be of particular relevance, given the
closeness of its association with this type of cancer, as well as with both GERD and Barrett’s esophagus. This
type of obesity is characteristic of men. Physiologically, it stimulates GERD and also has other chronic
inflammatory effects.
Helicobacter pylori infection (a common occurrence thought to have affected over half of the world’s
population) is not a risk factor for esophageal adenocarcinoma and actually appears to be protective. Despite
being a cause of GERD and a risk factor for gastric cancer, the infection seems to be associated with a
reduced risk of esophageal adenocarcinoma of as much as 50%. The biological explanation for a protective
effect is somewhat unclear. One explanation is that some strains of H. pylori reduce stomach acid, thereby
reducing damage by GERD. Decreasing rates of H. pylori infection in Western populations over recent
decades, which have been linked to better hygiene and increased refrigeration of food, could be a factor in
the concurrent increase in esophageal adenocarcinoma. Female hormones may also have a protective effect,
as EAC is not only much less common in women but develops later in life, by an average of 20 years.
Although studies of many reproductive factors have not produced a clear picture, risk seems to decline for
the mother in line with prolonged periods of breastfeeding. Tobacco smoking increases risk, but the effect in
esophageal adenocarcinoma is slight compared to that in squamous cell carcinoma, and alcohol has not been
demonstrated to be a cause.
62 Surgical Oncology: Theory and Multidisciplinary Practice

Fig. Esophageal cancer (lower part) as a result of Barrettˆs esophagus

Related Conditions
• Head and neck cancer is associated with second primary tumors in the region, including esophageal
squamous-cell carcinomas, due to field cancerization (i.e. a regional reaction to long-term carcinogenic
exposure).
• History of radiation therapy for other conditions in the chest is a risk factor for esophageal
adenocarcinoma.
• Corrosive injury to the esophagus by accidentally or intentionally swallowing caustic substances is a
risk factor for squamous cell carcinoma.
• Tylosis with esophageal cancer is a rare familial disease with autosomal dominant inheritance that
has been linked to a mutation in the RHBDF2 gene, present on chromosome 17: it involves
thickening of the skin of the palms and soles and a high lifetime risk of squamous cell carcinoma.
• Achalasia (i.e. lack of the involuntary reflex in the esophagus after swallowing) appears to be a risk
factor for both main types of esophageal cancer, at least in men, due to stagnation of trapped food
and drink.
• Plummer–Vinson syndrome (a rare disease that involves esophageal webs) is also a risk factor.
• There is some evidence suggesting a possible causal association between human papillomavirus (HPV)
and esophageal squamous-cell carcinoma. The relationship is unclear. Possible relevance of HPV
could be greater in places that have a particularly high incidence of this form of the disease, as in
some Asian countries, including China.
Gastrointestinal 63

• There is an association between celiac disease and esophageal cancer. People with untreated celiac
disease have a higher risk, but this risk decreases with time after diagnosis, probably due to the
adoption of a gluten-free diet, which seems to have a protective role against development of
malignancy in people with celiac disease. However, the delay in diagnosis and initiation of a gluten-
free diet seems to increase the risk of malignancy. Moreover, in some cases the detection of celiac
disease is due to the development of cancer, whose early symptoms are similar to some that may
appear in celiac disease.

DIAGNOSIS

Clinical Evaluation
Although an occlusive tumor may be suspected on a barium swallow or barium meal, the diagnosis is best made
with an examination using an endoscope. This involves the passing of a flexible tube with a light and camera down
the esophagus and examining the wall, and is called an esophagogastroduodenoscopy. Biopsies taken of suspicious
lesions are then examined histologically for signs of malignancy. Additional testing is needed to assess how much
the cancer has spread. Computed tomography (CT) of the chest, abdomen and pelvis can evaluate whether the
cancer has spread to adjacent tissues or distant organs (especially liver and lymph nodes). The sensitivity of a CT
scan is limited by its ability to detect masses (e.g. enlarged lymph nodes or involved organs) generally larger than
1 cm.
Positron emission tomography is also used to estimate the extent of the disease and is regarded as more precise
than CT alone. Esophageal endoscopic ultrasound can provide staging information regarding the level of tumor
invasion, and possible spread to regional lymph nodes. The location of the tumor is generally measured by the
distance from the teeth. The esophagus (25 cm or 10 in long) is commonly divided into three parts for purposes of
determining the location. Adenocarcinomas tend to occur nearer the stomach and squamous cell carcinomas nearer
the throat, but either may arise anywhere in the esophagus.

Types
Esophageal cancers are typically carcinomas that arise from the epithelium, or surface lining, of the esophagus.
Most esophageal cancers fall into one of two classes: esophageal squamous-cell carcinomas (ESCC), which are
similar to head and neck cancer in their appearance and association with tobacco and alcohol consumption—
and esophageal adenocarcinomas (EAC), which are often associated with a history of GERD and Barrett’s
esophagus. A rule of thumb is that a cancer in the upper two-thirds is likely to be ESCC and one in the lower
one-third EAC. Rare histologic types of esophageal cancer include different variants of squamous-cell carcinoma,
and non-epithelial tumors, such as leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma,
among others.

Staging
Staging is based on the TNM staging system, which classifies the amount of tumor invasion (T), involvement
of lymph nodes (N), and distant metastasis (M). The currently preferred classification is the 2010 AJCC staging
system for cancer of the esophagus and the esophagogastric junction. To help guide clinical decision making,
this system also incorporates information on cell type (ESCC, EAC, etc.), grade (degree of differentiation – an
indication of the biological aggressiveness of the cancer cells), and tumor location (upper, middle, lower, or
junctional).
64 Surgical Oncology: Theory and Multidisciplinary Practice

PREVENTION
Prevention includes stopping smoking or chewing tobacco. Overcoming addiction to areca chewing in Asia
is another promising strategy for the prevention of esophageal squamous-cell carcinoma. The risk can also be
reduced by maintaining a normal body weight. According to the National Cancer Institute, “diets high in
cruciferous (cabbage, broccoli/broccolini, cauliflower, Brussels sprouts) and green and yellow vegetables and
fruits are associated with a decreased risk of esophageal cancer.” Dietary fibre is thought to be protective,
especially against esophageal adenocarcinoma. There is no evidence that vitamin supplements change the risk.

Screening
People with Barrett’s esophagus (a change in the cells lining the lower esophagus) are at much higher risk,
and may receive regular endoscopic screening for the early signs of cancer. Because the benefit of screening for
adenocarcinoma in people without symptoms is unclear, it is not recommended in the United States. Some areas
of the world with high rates of squamous-carcinoma have screening programmes.

MANAGEMENT
Treatment is best managed by a multidisciplinary team covering the various specialties involved. Adequate
nutrition must be assured, and appropriate dental care is essential. Factors that influence treatment decisions
include the stage and cellular type of cancer (EAC, ESCC, and other types), along with the person’s general
condition and any other diseases that are present. In general, treatment with a curative intention is restricted to
localized disease, without distant metastasis: in such cases a combined approach that includes surgery may be
considered. Disease that is widespread, metastatic or recurrent is managed palliatively: in this case, chemotherapy
may be used to lengthen survival, while treatments such as radiotherapy or stenting may be used to relieve
symptoms and make it easier to swallow.

Surgery
If the cancer has been diagnosed while still in an early stage, surgical treatment with a curative intention may
be possible. Some small tumors that only involve the mucosa or lining of the esophagus may be removed by
endoscopic mucosal resection (EMR). Otherwise, curative surgery of early-stage lesions may entail removal of
all or part of the esophagus (esophagectomy), although this is a difficult operation with a relatively high risk of
mortality or post-operative difficulties. The benefits of surgery are less clear in early-stage ESCC than EAC.
There are a number of surgical options, and the best choices for particular situations remain the subject of
research and discussion. As well as characteristics and location of the tumor, other factors include the patient’s
condition, and the type of operation the surgical team is most experienced with. The likely quality of life after
treatment is a relevant factor when considering surgery. Surgical outcomes are likely better in large centers
where the procedures are frequently performed. If the cancer has spread to other parts of the body, esophagectomy
is nowadays not normally performed. Esophagectomy is the removal of a segment of the esophagus; as this
shortens the length of the remaining esophagus, some other segment of the digestive tract is pulled up through
the chest cavity and interposed. This is usually the stomach or part of the large intestine (colon) or jejunum.
Reconnection of the stomach to a shortened esophagus is called an esophagogastric anastomosis. Esophagectomy
can be performed using several methods. The choice of the surgical approach depends on the characteristics
and location of the tumor, and the preference of the surgeon. Clear evidence from clinical trials for which
approaches give the best outcomes in different circumstances is lacking. A first decision, regarding the point of
entry, is between a transhiatial and a transthoracic procedure. The more recent transhiatial approach avoids the
Gastrointestinal 65

need to open the chest; instead the surgeon enters the body through an incision in the lower abdomen and
another in the neck. The lower part of the esophagus is freed from the surrounding tissues and cut away as
necessary. The stomach is then pushed through the esophageal hiatus (the hole where the esophagus passes
through the diaphragm) and is joined to the remaining upper part of the esophagus at the neck. The traditional
transthoracic approach enters the body through the chest, and has a number of variations. The thoracoabdominal
approach opens the abdominal and thoracic cavities together, the two-stage Ivor Lewis (also called Lewis–
Tanner) approach involves an initial laparotomy and construction of a gastric tube, followed by a right
thoracotomy to excise the tumor and create an esophagogastric anastomosis. The three-stage McKeown approach
adds a third incision in the neck to complete the cervical anastomosis. Recent approaches by some surgeons use
what is called extended esophagectomy, where more surrounding tissue, including lymph nodes, is removed en
bloc. If the person cannot swallow at all, an esophageal stent may be inserted to keep the esophagus open; stents
may also assist in occluding fistulas. A nasogastric tube may be necessary to continue feeding while treatment
for the tumor is given, and some patients require a gastrostomy (feeding hole in the skin that gives direct access
to the stomach). The latter two are especially important if the patient tends to aspirate food or saliva into the
airways, predisposing for aspiration pneumonia.

Chemotherapy and Radiotherapy

Chemotherapy depends on the tumor type, but tends to be cisplatin-based (or carboplatin or oxaliplatin)
every three weeks with fluorouracil (5-FU) either continuously or every three weeks. In more recent studies,
addition of epirubicin was better than other comparable regimens in advanced non-resectable cancer.
Chemotherapy may be given after surgery (adjuvant, i.e. to reduce risk of recurrence), before surgery (neo-
adjuvant) or if surgery is not possible; in this case, cisplatin and 5-FU are used. Ongoing trials compare various
combinations of chemotherapy; the phase II/III REAL-2 trial – for example – compares four regimens containing
epirubicin and either cisplatin or oxaliplatin, and either continuously infused fluorouracil or capecitabine.
Radiotherapy is given before, during, or after chemotherapy or surgery, and sometimes on its own to control
symptoms. In patients with localised disease but contraindications to surgery, “radical radiotherapy” may be
used with curative intent.

Other Approaches
Forms of endoscopic therapy have been used for stage 0 and I disease: endoscopic mucosal resection (EMR)
and mucosal ablation using radiofrequency ablation, photodynamic therapy, Nd-YAG laser, or argon plasma
coagulation. Laser therapy is the use of high-intensity light to destroy tumor cells while affecting only the treated
area. This is typically done if the cancer cannot be removed by surgery. The relief of a blockage can help with pain
and difficulty swallowing. Photodynamic therapy, a type of laser therapy, involves the use of drugs that are absorbed
by cancer cells; when exposed to a special light, the drugs become active and destroy the cancer cells.

Follow-up
Patients are followed closely after a treatment regimen has been completed. Frequently, other treatments are
used to improve symptoms and maximize nutrition.

PROGNOSIS
In general, the prognosis of esophageal cancer is quite poor, because most patients present with advanced
disease. By the time the first symptoms (such as difficulty swallowing) appear, the disease has already progressed.
66 Surgical Oncology: Theory and Multidisciplinary Practice

The overall five-year survival rate (5YSR) in the United States is around 15%, with most people dying within
the first year of diagnosis. The latest survival data for England and Wales (patients diagnosed during 2007)
show that only one in ten people survive esophageal cancer for at least ten years. Individualized prognosis
depends largely on stage. Those with cancer restricted entirely to the esophageal mucosa have about an 80%
5YSR, but submucosal involvement brings this down to less than 50%. Extension into the muscularis propria
(muscle layer of the esophagus) suggests a 20% 5YSR, and extension to the structures adjacent to the esophagus
predict a 7% 5YSR. Patients with distant metastases (who are not candidates for curative surgery) have a less
than 3% 5YSR.

STOMA
STOMACH C
OMACH ANCER/ GASTRIC CANCER
CANCER/
Stomach cancer, also known as gastric cancer, is cancer developing from the lining of the stomach. Early
symptoms may include heartburn, upper abdominal pain, nausea and loss of appetite. Later signs and symptoms
may include weight loss, yellowing of the skin and whites of the eyes, vomiting, difficulty swallowing and
blood in the stool among others. The cancer may spread from the stomach to other parts of the body, particularly
the liver, lungs, bones, lining of the abdomen and lymph nodes. The most common cause is infection by the
bacterium Helicobacter pylori, which accounts for more than 60% of cases. Certain types of H. pylori have
greater risks than others. Smoking, dietary factors such as pickled vegetables and obesity are other risk factors.
About 10% of cases run in families, and between 1% and 3% of cases are due to genetic syndromes inherited
from a person’s parents such as hereditary diffuse gastric cancer. Most cases of stomach cancers are gastric
carcinomas. This type can be divided into a number of subtypes. Lymphomas and mesenchymal tumors may
also develop in the stomach. Most of the time, stomach cancer develops in stages over years. Diagnosis is
usually by biopsy done during endoscopy. This is followed by medical imaging to determine if the disease has
spread to other parts of the body. Japan and South Korea, two countries that have high rates of the disease,
screen for stomach cancer. A Mediterranean diet lowers the risk of cancer as does the stopping of smoking.
There is tentative evidence that treating H. pylori decreases the future risk. If cancer is treated early, many cases
can be cured. Treatments may include some combination of surgery, chemotherapy, radiation therapy and targeted
therapy. If treated late, palliative care may be advised. Outcomes are often poor with a less than 10% five-year
survival rate globally. This is largely because most people with the condition present with advanced disease. In
the United States, five-year survival is 28%, while in South Korea it is over 65%, partly due to screening
efforts. Globally, stomach cancer is the fifth leading cause of cancer and the third leading cause of death from
cancer, making up 7% of cases and 9% of deaths. In 2012, it newly occurred in 950,000 people and caused
723,000 deaths. Before the 1930s, in much of the world, including most Western developed countries, it was the
most common cause of death from cancer. Rates of death have been decreasing in many areas of the world since
then. This is believed to be due to the eating of less salted and pickled foods as a result of the development of
refrigeration as a method of keeping food fresh. Stomach cancer occurs most commonly in East Asia and
Eastern Europe. It occurs twice as often in males as in females.

SIGNS AND SYMPTOMS

Stomach cancer is often either asymptomatic (producing no noticeable symptoms) or it may cause only non-
specific symptoms (symptoms that may also be present in other related or unrelated disorders) in its early
stages. By the time symptoms occur, the cancer has often reached an advanced stage and may have metastasized
(spread to other, perhaps distant, parts of the body), which is one of the main reasons for its relatively poor
prognosis. Stomach cancer can cause the following signs and symptoms: Early cancers may be associated with
indigestion or a burning sensation (heartburn). However, less than 1 in every 50 people referred for endoscopy
due to indigestion has cancer. Abdominal discomfort and loss of appetite, especially for meat, can occur. Gastric
Gastrointestinal 67

cancers that have enlarged and invaded normal tissue can cause weakness, fatigue, bloating of the stomach after
meals, abdominal pain in the upper abdomen, nausea and occasional vomiting, diarrhea or constipation. Further
enlargement may cause weight loss or bleeding with vomiting blood or having blood in the stool, the latter
apparent as black discolouration (melena) and sometimes leading to anemia. Dysphagia suggests a tumour in
the cardia or extension of the gastric tumour into the esophagus. These can be symptoms of other problems such
as a stomach virus, gastric ulcer, or tropical sprue.

CAUSES
Gastric cancer occurs as a result of many factors. It occurs twice as commonly in males as females. Estrogen
may protect women against the development of this form of cancer.

Infections
Helicobacter pylori infection is an essential risk factor in 65–80% of gastric cancers, but only 2% of people
with Helicobacter infections develop stomach cancer. The mechanism by which H. pylori induces stomach
cancer potentially involves chronic inflammation, or the action of H. pylori virulence factors such as CagA. It
was estimated that Epstein–Barr virus is responsible for 84,000 cases per year. AIDS is also associated with
elevated risk.

Smoking
Smoking increases the risk of developing gastric cancer significantly, from 40% increased risk for current
smokers to 82% increase for heavy smokers. Gastric cancers due to smoking mostly occur in the upper part of
the stomach near the esophagus. Some studies show increased risk with alcohol consumption as well.

Diet
Dietary factors are not proven causes and the association between stomach cancer and various foods and
beverages is weak. Some foods including smoked foods, salt and salt-rich foods, red meat, processed meat,
pickled vegetables, and bracken are associated with a higher risk of stomach cancer. Nitrates and nitrites in
cured meats can be converted by certain bacteria, including H. pylori, into compounds that have been found to
cause stomach cancer in animals. Fresh fruit and vegetable intake, citrus fruit intake, and antioxidant intake are
associated with a lower risk of stomach cancer. A Mediterranean diet is associated with lower rates of stomach
cancer, as is regular aspirin use. Obesity is a physical risk factor that has been found to increase the risk of
gastric adenocarcinoma by contributing to the development of gastroesophageal reflux disease (GERD). The
exact mechanism by which obesity causes GERD is not completely known. Studies hypothesize that increased
dietary fat leading to increased pressure on the stomach and the lower esophageal sphincter, due to excess
adipose tissue, could play a role, yet no statistically significant data has been collected. However, the risk of
gastric cardia adenocarcinoma, with GERD present, has been found to increase more than 2 times for an obese
person. There is a correlation between iodine deficiency and gastric cancer.

Genetics
About 10% of cases run in families and between 1% and 3% of cases are due to genetic syndromes inherited
from a person’s parents such as hereditary diffuse gastric cancer. A genetic risk factor for gastric cancer is a
genetic defect of the CDH1 gene known as hereditary diffuse gastric cancer (HDGC). The CDH1 gene, which
codes for E-cadherin, lies on the 16th chromosome. When the gene experiences a particular mutation, gastric
68 Surgical Oncology: Theory and Multidisciplinary Practice

cancer develops through a mechanism that is not fully understood. This mutation is considered autosomal
dominant meaning that half of a carrier’s children will likely experience the same mutation. Diagnosis of
hereditary diffuse gastric cancer usually takes place when at least two cases involving a family member, such as
a parent or grandparent, are diagnosed, with at least one diagnosed before the age of 50. The diagnosis can also
be made if there are at least three cases in the family, in which case age is not considered. The International
Cancer Genome Consortium is leading efforts to identify genomic changes involved in stomach cancer. A very
small percentage of diffuse-type gastric cancers arise from an inherited abnormal CDH1 gene. Genetic testing
and treatment options are available for families at risk.

Other
Other risks include diabetes, pernicious anemia, chronic atrophic gastritis, Menetrier’s disease (hyperplastic,
hypersecretory gastropathy), and intestinal metaplasia.

DIAGNOSIS
To find the cause of symptoms, the doctor asks about the patient’s medical history, does a physical exam, and
may order laboratory studies.
The patient may also have one or all of the following exams:
• Gastroscopic exam is the diagnostic method of choice. This involves insertion of a fibre optic camera
into the stomach to visualise it.
• Upper GI series (may be called barium roentgenogram).
• Computed tomography or CT scanning of the abdomen may reveal gastric cancer. It is more useful
to determine invasion into adjacent tissues or the presence of spread to local lymph nodes. Wall
thickening of more than 1 cm that is focal, eccentric and enhancing favours malignancy.
In 2013, Chinese and Israeli scientists reported a successful pilot study of a breathalyzer-style breath test
intended to diagnose stomach cancer by analyzing exhaled chemicals without the need for an intrusive endoscopy.
A larger-scale clinical trial of this technology was completed in 2014. Abnormal tissue seen in a gastroscope
examination will be biopsied by the surgeon or gastroenterologist. This tissue is then sent to a pathologist for
histological examination under a microscope to check for the presence of cancerous cells. A biopsy, with
subsequent histological analysis, is the only sure way to confirm the presence of cancer cells. Various gastroscopic
modalities have been developed to increase yield of detected mucosa with a dye that accentuates the cell
structure and can identify areas of dysplasia.
Endocytoscopy involves ultra-high magnification to visualise cellular structure to better determine areas
of dysplasia. Other gastroscopic modalities such as optical coherence tomography are being tested
investigationally for similar applications. A number of cutaneous conditions are associated with gastric cancer.
A condition of darkened hyperplasia of the skin, frequently of the axilla and groin, known as acanthosis
nigricans, is associated with intra-abdominal cancers such as gastric cancer. Other cutaneous manifestations
of gastric cancer include tripe palms (a similar darkening hyperplasia of the skin of the palms) and the Leser-
Trelat sign, which is the rapid development of skin lesions known as seborrheic keratoses. Various blood
tests may be done including a complete blood count (CBC) to check for anaemia, and a fecal occult blood
test to check for blood in the stool.

Histopathology
• Gastric adenocarcinoma is a malignant epithelial tumour, originating from glandular epithelium of
the gastric mucosa. Stomach cancers are overwhelmingly adenocarcinomas (90%). Histologically,
Gastrointestinal 69

there are two major types of gastric adenocarcinoma (Lauren classification): intestinal type or diffuse
type. Adenocarcinomas tend to aggressively invade the gastric wall, infiltrating the muscularis
mucosae, the submucosa and then the muscularis propria. Intestinal type adenocarcinoma tumour
cells describe irregular tubular structures, harbouring pluristratification, multiple lumens, reduced
stroma (“back to back” aspect). Often, it associates intestinal metaplasia in neighbouring mucosa.
Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may
present 3 degrees of differentiation: well, moderate and poorly differentiated. Diffuse type
adenocarcinoma (mucinous, colloid, linitis plastica or leather-bottle stomach) tumour cells are
discohesive and secrete mucus, which is delivered in the interstitium, producing large pools of mucus/
colloid (optically “empty” spaces). It is poorly differentiated. If the mucus remains inside the tumour
cell, it pushes the nucleus to the periphery: “signet-ring cell”.
• Around 5% of gastric malignancies are lymphomas (MALTomas, or MALT lymphoma).
• Carcinoid and stromal tumors may occur.

Staging
If cancer cells are found in the tissue sample, the next step is to stage, or find out the extent of the disease.
Various tests determine whether the cancer has spread and, if so, what parts of the body are affected. Because
stomach cancer can spread to the liver, the pancreas, and other organs near the stomach as well as to the lungs,
the doctor may order a CT scan, a PET scan, an endoscopic ultrasound exam, or other tests to check these areas.
Blood tests for tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) may
be ordered, as their levels correlate to extent of metastasis, especially to the liver, and the cure rate. Staging may
not be complete until after surgery. The surgeon removes nearby lymph nodes and possibly samples of tissue
from other areas in the abdomen for examination by a pathologist.
The clinical stages of stomach cancer are:
• Stage 0. Limited to the inner lining of the stomach. Treatable by endoscopic mucosal resection when
found very early (in routine screenings); otherwise by gastrectomy and lymphadenectomy without
need for chemotherapy or radiation.
• Stage I. Penetration to the second or third layers of the stomach (Stage 1A) or to the second layer
and nearby lymph nodes (Stage 1B). Stage 1A is treated by surgery, including removal of the omentum.
Stage 1B may be treated with chemotherapy (5-fluorouracil) and radiation therapy.
• Stage II. Penetration to the second layer and more distant lymph nodes, or the third layer and only
nearby lymph nodes, or all four layers but not the lymph nodes. Treated as for Stage I, sometimes
with additional neo-adjuvant chemotherapy.
• Stage III. Penetration to the third layer and more distant lymph nodes, or penetration to the fourth
layer and either nearby tissues or nearby or more distant lymph nodes. Treated as for Stage II; a cure
is still possible in some cases.
• Stage IV. Cancer has spread to nearby tissues and more distant lymph nodes, or has metastasized to
other organs. A cure is very rarely possible at this stage. Some other techniques to prolong life or
improve symptoms are used, including laser treatment, surgery, and/or stents to keep the digestive
tract open, and chemotherapy by drugs such as 5-fluorouracil, cisplatin, epirubicin, etoposide,
docetaxel, oxaliplatin, capecitabine or irinotecan.
The TNM staging system is also used. In a study of open-access endoscopy in Scotland, patients were
diagnosed 7% in Stage I 17% in Stage II, and 28% in Stage III. A Minnesota population was diagnosed 10% in
Stage I, 13% in Stage II, and 18% in Stage III. However, in a high-risk population in the Valdivia Province of
southern Chile, only 5% of patients were diagnosed in the first two stages and 10% in stage III.
70 Surgical Oncology: Theory and Multidisciplinary Practice

PREVENTION
Getting rid of H. pylori in those who are infected decreases the risk of stomach cancer, at least in those who
are Asian. A 2014 meta-analysis of observational studies found that a diet high in fruits, mushrooms, garlic,
soybeans, and green onions was associated with a lower risk of stomach cancer in the Korean population. Low
doses of vitamins, especially from a healthy diet, decrease the risk of stomach cancer. A previous review of
antioxidant supplementation did not find supporting evidence and possibly worse outcomes.

MANAGEMENT
Cancer of the stomach is difficult to cure unless it is found at an early stage (before it has begun to spread).
Unfortunately, because early stomach cancer causes few symptoms, the disease is usually advanced when the
diagnosis is made. Treatment for stomach cancer may include surgery, chemotherapy, and/or radiation therapy.
New treatment approaches such as immunotherapy or gene therapy and improved ways of using current methods
are being studied in clinical trials.

Surgery
Surgery remains the only curative therapy for stomach cancer. Of the different surgical techniques, endoscopic
mucosal resection (EMR) is a treatment for early gastric cancer (tumor only involves the mucosa) that was pioneered
in Japan and is available in the United States at some centers. In this procedure, the tumor, together with the inner
lining of stomach (mucosa), is removed from the wall of the stomach using an electrical wire loop through the
endoscope. The advantage is that it is a much smaller operation than removing the stomach. Endoscopic submucosal
dissection (ESD) is a similar technique pioneered in Japan, used to resect a large area of mucosa in one piece. If the
pathologic examination of the resected specimen shows incomplete resection or deep invasion by tumor, the
patient would need a formal stomach resection. A 2016 Cochrane review found low quality evidence of no difference
in short-term mortality between laparoscopic and open gastrectomy (removal of stomach), and that benefits or
harms of laparoscopic gastrectomy cannot be ruled out. Those with metastatic disease at the time of presentation
may receive palliative surgery and while it remains controversial, due to the possibility of complications from the
surgery itself and the fact that it may delay chemotherapy the data so far is mostly positive, with improved survival
rates being seen in those treated with this approach.

Chemotherapy
The use of chemotherapy to treat stomach cancer has no firmly established standard of care. Unfortunately,
stomach cancer has not been particularly sensitive to these drugs, and chemotherapy, if used, has usually served
to palliatively reduce the size of the tumor, relieve symptoms of the disease and increase survival time. Some
drugs used in stomach cancer treatment have included: 5-FU (fluorouracil) or its analog capecitabine, BCNU
(carmustine), methyl-CCNU (semustine) and doxorubicin (Adriamycin), as well as mitomycin C, and more
recently cisplatin and taxotere, often using drugs in various combinations. The relative benefits of these different
drugs, alone and in combination, are unclear. Clinical researchers are exploring the benefits of giving
chemotherapy before surgery to shrink the tumor, or as adjuvant therapy after surgery to destroy remaining
cancer cells.

Targeted Therapy
Recently, treatment with human epidermal growth factor receptor 2 (HER2) inhibitor, trastuzumab, has been
demonstrated to increase overall survival in inoperable locally advanced or metastatic gastric carcinoma over-
Gastrointestinal 71

expressing the HER2/neu gene. In particular, HER2 is overexpressed in 13–22% of patients with gastric cancer.
Of note, HER2 overexpression in gastric neo-plasia is heterogeneous and comprises a minority of tumor cells
(less than 10% of gastric cancers overexpress HER2 in more than 5% of tumor cells). Hence, this heterogeneous
expression should be taken into account for HER2 testing, particularly in small samples such as biopsies,
requiring the evaluation of more than one bioptic sample.

Radiation
Radiation therapy (also called radiotherapy) may be used to treat stomach cancer, often as an adjuvant to
chemotherapy and/or surgery.

PROGNOSIS
The prognosis of stomach cancer is generally poor, due to the fact the tumour has often metastasised by the
time of discovery and the fact that most people with the condition are elderly (median age is between 70 and 75
years) at presentation. The five-year survival rate for stomach cancer is reported to be less than 10 percent.
Almost 300 genes are related to outcomes in stomach cancer with both unfavourable genes where high expression
related to poor survival and favourable genes where high expression associated with longer survival times.
Examples of poor prognosis genes include ITGAV and DUSP1.

SMALL INTESTINE CANCER/ SMALL BO

CANCER/ WEL CANCER
BOWEL
In oncology, small intestine cancer, also small bowel cancer and cancer of the small bowel, is a cancer of the
small intestine. It is relatively rare compared to other gastrointestinal malignancies such as gastric cancer
(stomach cancer) and colorectal cancer. Small intestine cancer can be subdivided into duodenal cancer (the first
part of the small intestine) and cancer of the jejunum and ileum (the later two parts of the small intestine).
Duodenal cancer has more in common with stomach cancer, while cancer of the jejunum and ileum have more
in common with colorectal cancer.
Five year survival rates are 65%.
Several different subtypes of small intestine cancer exist.
These include:
• Adenocarcinoma
• Gastrointestinal stromal tumor
• Lymphoma
• Ileal carcinoid tumor.

RISK FACTORS
Risk factors for small intestine cancer include:
• Crohn’s disease
• Celiac disease
• Radiation exposure
• Hereditary gastrointestinal cancer syndromes: familial adenomatous polyposis, hereditary non-
polyposis colorectal cancer, Peutz-Jeghers syndrome
• Males are 25% more likely to develop the disease.
Benign tumours and conditions that may be mistaken for cancer of the small bowel:
• Hamartoma
• Tuberculosis.
72 Surgical Oncology: Theory and Multidisciplinary Practice

RESEARCH
Little research is conducted on these cancers due to their relative rarity when compared to the more common
colorectal cancers. APC-min mice which carry a gene deficiency corresponding to that of humans with FAP
also go on to develop small intestinal tumors, though humans do not.

GALLBL ADDER CANCER

GALLBLADDER
Gallbladder cancer is a relatively uncommon cancer. It has peculiar geographical distribution being common
in central and South America, central and eastern Europe, Japan and northern India; it is also common in certain
ethnic groups e.g. Native American Indians and Hispanics. If it is diagnosed early enough, it can be cured by
removing the gallbladder, part of the liver and associated lymph nodes. Most often it is found after symptoms
such as abdominal pain, jaundice and vomiting occur, and it has spread to other organs such as the liver. It is a
rare cancer that is thought to be related to gallstones building up, which also can lead to calcification of the
gallbladder, a condition known as porcelain gallbladder. Porcelain gallbladder is also rare. Some studies indicate
that people with porcelain gallbladder have a high risk of developing gallbladder cancer, but other studies
question this. The outlook is poor for recovery if the cancer is found after symptoms have started to occur, with
a 5-year survival rate close to 3%.

SIGNS AND SYMPTOMS

• Steady pain in the upper right abdomen
• Indigestion Dyspepsia (gas)
• Bile (dark green colour) in vomit.
• Weakness
• Loss of appetite
Gastrointestinal 73

• Weight loss
• Jaundice and vomiting due to obstruction.
Early symptoms mimic gallbladder inflammation due to gallstones. Later, the symptoms may be that of
biliary and stomach obstruction. Of note, Courvoisier’s law states that in the presence of a palpably enlarged
gallbladder which is non-tender and accompanied with mild painless jaundice, the cause is unlikely to be
gallstones. This implicates possible malignancy of the gallbladder or pancreas, and the swelling is unlikely due
to gallstones due to the chronic inflammation association with gallstones leading to a shunken, non-distensible
gallbladder. However, Ludwig Georg Courvoisier’s original observations, published in Germany in 1890, were
not originally cited as a ‘law’, and no mention of malignancy or pain (tenderness) was made. These points are
commonly missquoted or confused in the medical literature.

RISK FACTORS
• Gender—approx. twice more common in women than men, usually in seventh and eighth decades.
• Obesity increases the risk for gallbladder cancer.
• Chronic cholecystitis and cholelithiasis.
• Primary sclerosing cholangitis
• Chronic typhoid infection of gallbladder. Chronic Salmonella typhi carriers have 3 to 200 times
higher risk of gallbladder cancer than non-carriers and 1–6% lifetime risk of development of
cancer.
• Various single nucleotide polymorphisms (SNPs) have been shown to be associated with gallbladder
cancer. However, existing genetic studies in GBC susceptibility have so far been insufficient to
confirm any association.

DIAGNOSIS
Early diagnosis is not generally possible. People at high risk, such as women or Native Americans with
gallstones, are evaluated closely. Transabdominal ultrasound, CT scan, endoscopic ultrasound, MRI, and MR
cholangio-pancreatography (MRCP) can be used for diagnosis. A biopsy is the only certain way to tell whether
the tumorous growth is malignant or not.

Differential Diagnosis
Xanthogranulomatous cholecystitis (XGC) is a rare form of gallbladder disease which mimics gallbladder
cancer although it is not cancerous. It was first discovered and reported in the medical literature in 1976 by J.J.
McCoy, Jr., and colleagues.

TREATMENT
The most common and most effective treatment is surgical removal of the gallbladder (cholecystectomy)
with part of liver and lymph node dissection. However, with gallbladder cancer’s extremely poor prognosis,
most patients will die within a year of surgery. If surgery is not possible, endoscopic stenting of the biliary
tree can reduce jaundice and a stent in stomach may relieve vomiting.
Chemotherapy and radiation may also be used with surgery. If gall bladder cancer is diagnosed after
cholecystectomy for stone disease (incidental cancer), reoperation to remove part of liver and lymph nodes is
required in most cases. When it is done as early as possible, patients have the best chance of long-term
survival and even cure.
74 Surgical Oncology: Theory and Multidisciplinary Practice

CHOL ANGIOC
CHOLANGIOC AR
ANGIOCAR CINOMA
ARCINOMA
Cholangiocarcinoma, also known as bile duct cancer, is a form of cancer that is composed of mutated epithelial
cells (or cells showing characteristics of epithelial differentiation) that originate in the bile ducts which drain
bile from the liver into the small intestine. Other biliary tract cancers include gallbladder cancer and cancer of
the ampulla of Vater. Cholangiocarcinoma is a relatively rare neo-plasm that is classified as an adenocarcinoma
(a cancer that forms glands or secretes significant amounts of mucins). It has an annual incidence rate of 1–2
cases per 100,000 in the Western world, but rates of cholangiocarcinoma have been rising worldwide over the
past few decades.
Prominent signs and symptoms of cholangiocarcinoma include abnormal liver function tests, abdominal
pain, jaundice, and weight loss. Other symptoms such as generalized itching, fever, and changes in colour of
stool or urine may also occur. The disease is diagnosed through a combination of blood tests, imaging, endoscopy,
and sometimes surgical exploration, with confirmation obtained after a pathologist examines cells from the
tumor under a microscope. Known risk factors for cholangiocarcinoma include primary sclerosing cholangitis
(an inflammatory disease of the bile ducts), infection with the parasitic liver flukes Opisthorchis viverrini or
Clonorchis sinensis, some congenital liver malformations, and exposure to Thorotrast (thorium dioxide), a
chemical formerly used in medical imaging.
However, most people with cholangiocarcinoma have no identifiable risk factors. Cholangiocarcinoma is
considered to be an incurable and rapidly lethal cancer unless both the primary tumor and any metastases can be
fully removed by surgery. No potentially curative treatment exists except surgery, but most people have advanced
stage disease at presentation and are inoperable at the time of diagnosis. People with cholangiocarcinoma are
generally managed - though not cured - with chemotherapy, radiation therapy, and other palliative care measures.
These are also used as additional therapies after surgery in cases where resection has apparently been successful
(or nearly so).

SIGNS AND SYMPTOM

The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice
(yellowing of the eyes and skin occurring when bile ducts are blocked by tumor), abdominal pain (30%–50%),
generalized itching (66%), weight loss (30%–50%), fever (up to 20%), and changes in the colour of stool or
urine. To some extent, the symptoms depend upon the location of the tumor: patients with cholangiocarcinoma
in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the
bile ducts within the liver more often have pain without jaundice. Blood tests of liver function in patients with
cholangiocarcinoma often reveal a so-called “obstructive picture,” with elevated bilirubin, alkaline phosphatase,
and gamma glutamyl transferase levels, and relatively normal transaminase levels. Such laboratory findings
suggest obstruction of the bile ducts, rather than inflammation or infection of the liver parenchyma, as the
primary cause of the jaundice.

RISK FACTORS
Although most patients present without any known risk factors evident, a number of risk factors for the
development of cholangiocarcinoma have been described. In the Western world, the most common of these is
primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts which is closely associated
with ulcerative colitis (UC). Epidemiologic studies have suggested that the lifetime risk of developing
cholangiocarcinoma for a person with PSC is on the order of 10%–15%, although autopsy series have found
rates as high as 30% in this population. Certain parasitic liver diseases may be risk factors as well. Colonization
with the liver flukes Opisthorchis viverrini (found in Thailand, Laos PDR, and Vietnam) or Clonorchis sinensis
Gastrointestinal 75

(found in China, Taiwan, eastern Russia, Korea, and Vietnam) has been associated with the development of
cholangiocarcinoma. Control programmes aimed at discouraging the consumption of raw and undercooked
food have been successful at reducing the incidence of cholangiocarcinoma in some countries. Patients with
chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or hepatitis C), alcoholic liver
disease, or cirrhosis of the liver due to other causes, are at significantly increased risk of cholangiocarcinoma.
HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was
unclear whether HIV itself or other correlated and confounding factors (e.g. hepatitis C infection) were responsible
for the association.
Infection with the bacteria Helicobacter bilis and Helicobacter hepaticus species can cause biliary cancer.
Congenital liver abnormalities, such as Caroli’s syndrome (a specific type of five recognized choledochal cysts),
have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma. The rare
inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with
cholangiocarcinoma. The presence of gallstones (cholelithiasis) is not clearly associated with cholangiocarcinoma.
However, intrahepatic stones (called hepatolithiasis), which are rare in the West but common in parts of Asia,
have been strongly associated with cholangiocarcinoma. Exposure to Thorotrast, a form of thorium dioxide
which was used as a radiologic contrast medium, has been linked to the development of cholangiocarcinoma as
late as 30–40 years after exposure; Thorotrast was banned in the United States in the 1950s due to its
carcinogenicity.

PATHOPHYSIOLOGY
Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. Tumors occurring
in the bile ducts within the liver are referred to as intrahepatic, those occurring in the ducts outside the liver are
extrahepatic, and tumors occurring at the site where the bile ducts exit the liver may be referred to as perihilar.
A cholangiocarcinoma occurring at the junction where the left and right hepatic ducts meet to form the common
hepatic duct may be referred to eponymously as a Klatskin tumor. Although cholangiocarcinoma is known to
have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the
actual cell of origin is unknown.

Fig. Digestive system diagram showing bile duct location.

76 Surgical Oncology: Theory and Multidisciplinary Practice

Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise
from a pluripotent hepatic stem cell. Cholangiocarcinoma is thought to develop through a series of stages - from
early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma - in a process
similar to that seen in the development of colon cancer. Chronic inflammation and obstruction of the bile ducts,
and the resulting impaired bile flow, are thought to play a role in this progression. Histologically,
cholangiocarcinomas may vary from undifferentiated to well-differentiated.
They are often surrounded by a brisk fibrotic or desmoplastic tissue response; in the presence of extensive
fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive epithelium.
There is no entirely specific immunohistochemical stain that can distinguish malignant from benign biliary
ductal tissue, although staining for cytokeratins, carcinoembryonic antigen, and mucins may aid in diagnosis.
Most tumors (>90%) are adenocarcinomas.

DIAGNOSIS

Blood tests
There are no specific blood tests that can diagnose cholangiocarcinoma by themselves. Serum levels of
carcinoembryonic antigen (CEA) and CA19-9 are often elevated, but are not sensitive or specific enough to be
used as a general screening tool. However, they may be useful in conjunction with imaging methods in supporting
a suspected diagnosis of cholangiocarcinoma.

Abdominal Imaging
Ultrasound of the liver and biliary tree is often used as the initial imaging modality in patients with suspected
obstructive jaundice. Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be
sufficient to diagnose cholangiocarcinoma. Computed tomography (CT) scanning may also play an important
role in the diagnosis of cholangiocarcinoma.

Imaging of the Biliary Tree

While abdominal imaging can be useful in the diagnosis of cholangiocarcinoma, direct imaging of the bile
ducts is often necessary. Endoscopic retrograde cholangiopancreatography (ERCP), an endoscopic procedure
performed by a gastroenterologist or specially trained surgeon, has been widely used for this purpose. Although
ERCP is an invasive procedure with attendant risks, its advantages include the ability to obtain biopsies and to
place stents or perform other interventions to relieve biliary obstruction. Endoscopic ultrasound can also be
performed at the time of ERCP and may increase the accuracy of the biopsy and yield information on lymph
node invasion and operability.
As an alternative to ERCP, percutaneous transhepatic cholangiography (PTC) may be utilized. Magnetic
resonance cholangiopancreatography (MRCP) is a non-invasive alternative to ERCP. Some authors have
suggested that MRCP should supplant ERCP in the diagnosis of biliary cancers, as it may more accurately
define the tumor and avoids the risks of ERCP.

Surgery
Surgical exploration may be necessary to obtain a suitable biopsy and to accurately stage a patient with
cholangiocarcinoma. Laparoscopy can be used for staging purposes and may avoid the need for a more invasive
surgical procedure, such as laparotomy, in some patients.
Gastrointestinal 77

Fig. Photograph of cholangiocarcinoma in human liver.

Pathology
Histologically, cholangiocarcinomas are classically well to moderately differentiated adenocarcinomas.
Immunohistochemistry is useful in the diagnosis and may be used to help differentiate a cholangiocarcinoma
from hepatocellular carcinoma and metastasis of other gastrointestinal tumors. Cytological scrapings are often
non-diagnostic, as these tumors typically have a desmoplastic stroma and, therefore, do not release diagnostic
tumor cells with scrapings.

STAGING
Although there are at least three staging systems for cholangiocarcinoma (e.g. those of Bismuth, Blumgart,
and the American Joint Committee on Cancer), none have been shown to be useful in predicting survival. The
most important staging issue is whether the tumor can be surgically removed, or whether it is too advanced for
surgical treatment to be successful. Often, this determination can only be made at the time of surgery.
General guidelines for operability include:
• Absence of lymph node or liver metastases
• Absence of involvement of the portal vein
• Absence of direct invasion of adjacent organs
• Absence of widespread metastatic disease.

TREATMENT
Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be
fully resected (cut out surgically). Since the operability of the tumor can only be assessed during surgery in
78 Surgical Oncology: Theory and Multidisciplinary Practice

most cases, a majority of patients undergo exploratory surgery unless there is already a clear indication that the
tumor is inoperable. However, the Mayo Clinic has reported significant success treating early bile duct cancer
with liver transplantation using a protocolized approach and strict selection criteria. Adjuvant therapy followed
by liver transplantation may have a role in treatment of certain unresectable cases.

Adjuvant Chemotherapy and Radiation Therapy

If the tumor can be removed surgically, patients may receive adjuvant chemotherapy or radiation therapy
after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has
been totally excised), adjuvant therapy is of uncertain benefit. Both positive and negative results have
been reported with adjuvant radiation therapy in this setting, and no prospective randomized controlled
trials have been conducted as of March 2007. Adjuvant chemotherapy appears to be ineffective in patients
with completely resected tumors. The role of combined chemoradiotherapy in this setting is unclear.
However, if the tumor tissue margins are positive, indicating that the tumor was not completely removed
via surgery, then adjuvant therapy with radiation and possibly chemotherapy is generally recommended
based on the available data.

Treatment of Advanced Disease

The majority of cases of cholangiocarcinoma present as inoperable (unresectable) disease in which case
patients are generally treated with palliative chemotherapy, with or without radiotherapy. Chemotherapy has
been shown in a randomized controlled trial to improve quality of life and extend survival in patients with
inoperable cholangiocarcinoma. There is no single chemotherapy regimen which is universally used, and
enrollment in clinical trials is often recommended when possible. Chemotherapy agents used to treat
cholangiocarcinoma include 5-fluorouracil with leucovorin, gemcitabine as a single agent, or gemcitabine plus
cisplatin, irinotecan, or capecitabine. A small pilot study suggested possible benefit from the tyrosine kinase
inhibitor erlotinib in patients with advanced cholangiocarcinoma.

PROGNOSIS
Surgical resection offers the only potential chance of cure in cholangiocarcinoma. For non-resectable cases,
the 5-year survival rate is 0% where the disease is inoperable because distal lymph nodes show metastases, and
less than 5% in general. Overall mean duration of survival is less than 6 months in patients with metastatic
disease. For surgical cases, the odds of cure vary depending on the tumor location and whether the tumor can be
completely, or only partially, removed. Distal cholangiocarcinomas (those arising from the common bile duct)
are generally treated surgically with a Whipple procedure; long-term survival rates range from 15%–25%,
although one series reported a five-year survival of 54% for patients with no involvement of the lymph nodes.
Intrahepatic cholangiocarcinomas (those arising from the bile ducts within the liver) are usually treated with
partial hepatectomy.
Various series have reported survival estimates after surgery ranging from 22%–66%; the outcome may
depend on involvement of lymph nodes and completeness of the surgery. Perihilar cholangiocarcinomas (those
occurring near where the bile ducts exit the liver) are least likely to be operable. When surgery is possible, they
are generally treated with an aggressive approach often including removal of the gallbladder and potentially
part of the liver. In patients with operable perihilar tumors, reported 5-year survival rates range from 20%–50%.
The prognosis may be worse for patients with primary sclerosing cholangitis who develop cholangiocarcinoma,
likely because the cancer is not detected until it is advanced. Some evidence suggests that outcomes may be
improving with more aggressive surgical approaches and adjuvant therapy.
Gastrointestinal 79

PANCREATIC C
PANCREATIC ANCER
CANCER
Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply
out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. There
are a number of types of pancreatic cancer. The most common, pancreatic adenocarcinoma, accounts for about
85% of cases, and the term “pancreatic cancer” is sometimes used to refer only to that type. These
adenocarcinomas start within the part of the pancreas which makes digestive enzymes. Several other types of
cancer, which collectively represent the majority of the non-adenocarcinomas, can also arise from these cells.
One to two percent of cases of pancreatic cancer are neuroendocrine tumors, which arise from the hormone-
producing cells of the pancreas. These are generally less aggressive than pancreatic adenocarcinoma. Signs and
symptoms of the most common form of pancreatic cancer may include yellow skin, abdominal or back pain,
unexplained weight loss, light-colored stools, dark urine and loss of appetite. There are usually no symptoms in
the disease’s early stages, and symptoms that are specific enough to suggest pancreatic cancer typically do not
develop until the disease has reached an advanced stage. By the time of diagnosis, pancreatic cancer has often
spread to other parts of the body.
Pancreatic cancer rarely occurs before the age of 40, and more than half of cases of pancreatic
adenocarcinoma occur in those over 70. Risk factors for pancreatic cancer include tobacco smoking, obesity,
diabetes, and certain rare genetic conditions. About 25% of cases are linked to smoking, and 5–10% are
linked to inherited genes. Pancreatic cancer is usually diagnosed by a combination of medical imaging
techniques such as ultrasound or computed tomography, blood tests, and examination of tissue samples
(biopsy). The disease is divided into stages, from early (stage I) to late (stage IV). Screening the general
population has not been found to be effective. The risk of developing pancreatic cancer is lower among non-
smokers, and people who maintain a healthy weight and limit their consumption of red or processed meat. A
smoker’s chance of developing the disease decreases if they stop smoking, and almost returns to that of the
rest of the population after 20 years. Pancreatic cancer can be treated with surgery, radiotherapy, chemotherapy,
palliative care, or a combination of these.
Treatment options are partly based on the cancer stage. Surgery is the only treatment that can cure pancreatic
adenocarcinoma, and may also be done to improve quality of life without the potential for cure. Pain management
and medications to improve digestion are sometimes needed. Early palliative care is recommended even for
those receiving treatment that aims for a cure. In 2015, pancreatic cancers of all types resulted in 411,600
deaths globally. Pancreatic cancer is the fifth most common cause of death from cancer in the United Kingdom,
and the fourth most common in the United States. The disease occurs most often in the developed world, where
about 70% of the new cases in 2012 originated. Pancreatic adenocarcinoma typically has a very poor prognosis:
after diagnosis, 25% of people survive one year and 5% live for five years. For cancers diagnosed early, the
five-year survival rate rises to about 20%. Neuroendocrine cancers have better outcomes; at five years from
diagnosis, 65% of those diagnosed are living, though survival varies considerably depending on the type of
tumor.

TYPES
The many types of pancreatic cancer can be divided into two general groups. The vast majority of cases (about
99%) occur in the part of the pancreas which produces digestive enzymes, known as the exocrine component.
There are several sub-types of exocrine pancreatic cancers, but their diagnosis and treatment have much in common.
The small minority of cancers that arise in the hormone-producing (endocrine) tissue of the pancreas have different
clinical characteristics. Both groups occur mainly (but not exclusively) in people over 40, and are slightly more
common in men, but some rare sub-types mainly occur in women or children.
80 Surgical Oncology: Theory and Multidisciplinary Practice

Fig. The pancreas has multiple functions, served by the endocrine cells in the islets of Langerhans and
the exocrine acinar cells. Pancreatic cancer may arise from any of these and disrupt any of their functions.

Exocrine Cancers
The exocrine group is dominated by pancreatic adenocarcinoma (variations of this name may add “invasive”
and “ductal”), which is by far the most common type, representing about 85% of all pancreatic cancers. Nearly
all these start in the ducts of the pancreas, as pancreatic ductal adenocarcinoma (PDAC). This is despite the fact
that the tissue from which it arises – the pancreatic ductal epithelium – represents less than 10% of the pancreas
by cell volume, because it constitutes only the ducts (an extensive but capillary-like duct-system fanning out)
within the pancreas. This cancer originates in the ducts that carry secretions (such as enzymes and bicarbonate)
away from the pancreas. About 60–70% of adenocarcinomas occur in the head of the pancreas. The next most
common type, acinar cell carcinoma of the pancreas, arises in the clusters of cells that produce these enzymes,
and represents 5% of exocrine pancreas cancers. Like the ‘functioning’ endocrine cancers described below,
acinar cell carcinomas may cause over-production of certain molecules, in this case digestive enzymes, which
may cause symptoms such as skin rashes and joint pain. Cystadenocarcinomas account for 1% of pancreatic
cancers, and they have a better prognosis than the other exocrine types. Pancreatoblastoma is a rare form,
mostly occurring in childhood, and with a relatively good prognosis. Other exocrine cancers include
adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas,
Gastrointestinal 81

undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells. Solid
pseudopapillary tumor is a rare low-grade neo-plasm that mainly affects younger women, and generally has a
very good prognosis. Pancreatic mucinous cystic neo-plasms are a broad group of pancreas tumors that have
varying malignant potential. They are being detected at a greatly increased rate as CT scans become more
powerful and common, and discussion continues as how best to assess and treat them, given that many are
benign.

Neuroendocrine
The small minority of tumors that arise elsewhere in the pancreas are mainly pancreatic neuroendocrine
tumors (PanNETs). Neuroendocrine tumors (NETs) are a diverse group of benign or malignant tumors that
arise from the body’s neuroendocrine cells, which are responsible for integrating the nervous and endocrine
systems. NETs can start in most organs of the body, including the pancreas, where the various malignant types
are all considered to be rare. PanNETs are grouped into ‘functioning’ and ‘non-functioning’ types, depending
on the degree to which they produce hormones. The functioning types secrete hormones such as insulin, gastrin,
and glucagon into the bloodstream, often in large quantities, giving rise to serious symptoms such as low blood
sugar, but also favouring relatively early detection. The most common functioning PanNETs are insulinomas
and gastrinomas, named after the hormones they secrete. The non-functioning types do not secrete hormones in
a sufficient quantity to give rise to overt clinical symptoms. For this reason, non-functioning PanNETs are often
diagnosed only after the cancer has spread to other parts of the body. As with other neuroendocrine tumors, the
history of the terminology and classification of PanNETs is complex. PanNETs are sometimes called “islet cell
cancers”, even though it is now known that they do not actually arise from islet cells as previously thought.

SIGNS AND SYMPTOMS

Since pancreatic cancer usually does not cause recognizable symptoms in its early stages, the disease is
typically not diagnosed until it has spread beyond the pancreas itself. This is one of the main reasons for the
generally poor survival rates. Exceptions to this are the functioning PanNETs, where over-production of various
active hormones can give rise to symptoms (which depend on the type of hormone).
Bearing in mind that the disease is rarely diagnosed before the age of 40, common symptoms of pancreatic
adenocarcinoma occurring before diagnosis include:
• Pain in the upper abdomen or back, often spreading from around the stomach to the back. The
location of the pain can indicate the part of the pancreas where a tumor is located. The pain may be
worse at night and may increase over time to become severe and unremitting. It may be slightly
relieved by bending forward. In the UK, about half of new cases of pancreatic cancer are diagnosed
following a visit to a hospital emergency department for pain or jaundice. In up to two-thirds of
people abdominal pain is the main symptom, for 46% of the total accompanied by jaundice, with
13% having jaundice without pain.
• Jaundice, a yellow tint to the whites of the eyes or skin, with or without pain, and possibly in
combination with darkened urine. This results when a cancer in the head of the pancreas obstructs
the common bile duct as it runs through the pancreas.
• Unexplained weight loss, either from loss of appetite, or loss of exocrine function resulting in poor
digestion.
• The tumor may compress neighbouring organs, disrupting digestive processes and making it
difficult for the stomach to empty, which may cause nausea and a feeling of fullness. The
undigested fat leads to foul-smelling, fatty feces that are difficult to flush away. Constipation is
common.
82 Surgical Oncology: Theory and Multidisciplinary Practice

• At least 50% of people with pancreatic adenocarcinoma have diabetes at the time of diagnosis.
While long-standing diabetes is a known risk factor for pancreatic cancer, the cancer can itself
cause diabetes, in which case recent onset of diabetes could be considered an early sign of the
disease. People over 50 who develop diabetes have eight times the usual risk of developing
pancreatic adenocarcinoma within three years, after which the relative risk declines.

Other Findings
• Trousseau’s syndrome, in which blood clots form spontaneously in the portal blood vessels, the
deep veins of the extremities, or the superficial veins anywhere on the body, may be associated with
pancreatic cancer, and is found in about 10% of cases.
• Clinical depression has been reported in association with pancreatic cancer in some 10–20%
of cases, and can be a hindrance to optimal management. The depression sometimes appears
before the diagnosis of cancer, suggesting that it may be brought on by the biology of the
disease.
Other common manifestations of the disease include: weakness and tiring easily; dry mouth; sleep problems;
and a palpable abdominal mass.”

Symptoms of Spread
The spread of pancreatic cancer to other organs (metastasis) may also cause symptoms. Typically, pancreatic
adenocarcinoma first spreads to nearby lymph nodes, and later to the liver or to the peritoneal cavity, large
intestine or lungs. It is uncommon for it to spread to the bones or brain. Cancers in the pancreas may also be
secondary cancers that have spread from other parts of the body. This is uncommon, found in only about 2% of
cases of pancreatic cancer. Kidney cancer is by far the most common cancer to spread to the pancreas, followed
by colorectal cancer, and then cancers of the skin, breast, and lung. Surgery may be performed on the pancreas
in such cases, whether in hope of a cure or to alleviate symptoms.

RISK FACTORS
Risk factors for pancreatic adenocarcinoma include:
• Age, gender, and ethnicity; the risk of developing pancreatic cancer increases with age. Most cases
occur after age 65, while cases before age 40 are uncommon. The disease is slightly more common
in men than women, and in the United States is over 1.5 times more common in African Americans,
though incidence in Africa is low.
• Cigarette smoking is the best-established avoidable risk factor for pancreatic cancer, approximately
doubling risk among long-term smokers, the risk increasing with the number of cigarettes smoked
and the years of smoking. The risk declines slowly after smoking cessation, taking some 20 years to
return to almost that of non-smokers.
• Obesity; a BMI greater than 35 increases relative risk by about half.
• Family history; 5–10% of pancreatic cancer cases have an inherited component, where people have
a family history of pancreatic cancer. The risk escalates greatly if more than one first-degree relative
had the disease, and more modestly if they developed it before the age of 50. Most of the genes
involved have not been identified. Hereditary pancreatitis gives a greatly increased lifetime risk of
pancreatic cancer of 30–40% to the age of 70. Screening for early pancreatic cancer may be offered
to individuals with hereditary pancreatitis on a research basis. Some people may choose to have
their pancreas surgically removed to prevent cancer developing in the future.
Gastrointestinal 83

Pancreatic cancer has been associated with the following other rare hereditary syndromes: Peutz–Jeghers
syndrome due to mutations in the STK11 tumor suppressor gene (very rare, but a very strong risk factor);
dysplastic nevus syndrome (or familial atypical multiple mole and melanoma syndrome, FAMMM-PC) due to
mutations in the CDKN2A tumor suppressor gene; autosomal recessive ataxia-telangiectasia and autosomal
dominantly inherited mutations in the BRCA2 gene and PALB2 gene; hereditary non-polyposis colon cancer
(Lynch syndrome); and familial adenomatous polyposis. PanNETs have been associated with multiple endocrine
neo-plasia type 1 (MEN1) and von Hippel Lindau syndromes.
• Chronic pancreatitis appears to almost triple risk, and as with diabetes, new-onset pancreatitis may
be a symptom of a tumor. The risk of pancreatic cancer in individuals with familial pancreatitis is
particularly high.
• Diabetes mellitus is a risk factor for pancreatic cancer and (as noted in the Signs and symptoms section)
new-onset diabetes may also be an early sign of the disease. People who have been diagnosed with Type
2 diabetes for longer than ten years may have a 50% increased risk, as compared with non-diabetics.
• Specific types of food (as distinct from obesity) have not been clearly shown to increase the risk of
pancreatic cancer. Dietary factors for which there is some evidence of slightly increased risk include
processed meat, red meat, and meat cooked at very high temperatures (e.g. by frying, broiling or
barbecuing).

Alcohol
Drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic
cancer. However, considerable research has failed to firmly establish alcohol consumption as a direct risk
factor for pancreatic cancer. Overall, the association is consistently weak and the majority of studies have
found no association, with smoking a strong confounding factor. The evidence is stronger for a link with heavy
drinking, of at least six drinks per day.

PATHOPHYSIOLOGY

Precancer
Exocrine cancers are thought to arise from several types of precancerous lesions within the pancreas. But
these lesions do not always progress to cancer, and the increased numbers detected as a by-product of the
increasing use of CT scans for other reasons are not all treated. Apart from pancreatic serous cystadenomas
(SCNs), which are almost always benign, four types of precancerous lesion are recognized.
The first is pancreatic intraepithelial neo-plasia. These lesions are microscopic abnormalities in the pancreas
and are often found in autopsies of people with no diagnosed cancer. These lesions may progress from low to
high grade and then to a tumor. More than 90% of cases at all grades carry a faulty KRAS gene, while in grades
2 and 3 damage to three further genes – CDKN2A (p16), p53 and SMAD4 – are increasingly often found.
A second type are the intraductal papillary mucinous neo-plasms (IPMNs). These are macroscopic lesions,
which are found in about 2% of all adults. This rate rises to ~10% by age 70. These lesions have about a 25%
risk of developing into invasive cancer. They may have KRAS gene mutations (~40–65% of cases) and in the
GNAS Gs alpha subunit and RNF43, affecting the Wnt signaling pathway. Even if removed surgically, there
remains a considerably increased risk of pancreatic cancer developing subsequently.
The third type, pancreatic mucinous cystic neo-plasms (MCNs) mainly occur in women, and may remain
benign or progress to cancer. If these lesions become large, cause symptoms, or have suspicious features, they
can usually be successfully removed by surgery.
84 Surgical Oncology: Theory and Multidisciplinary Practice

A fourth type of cancer that arises in the pancreas is the intraductal tubulopapillary neo-plasm. This type was
recognised by the WHO in 2010 and constitutes about 1-3% of all pancreatic neo-plasms. Mean age at diagnosis
is 61 years (range 35–78 years). About 50% of these lesions become invasive. Diagnosis depends on histology
as these lesions are very difficult to differentiate from other lesions on either clinical or radiological grounds.

Invasive Cancer
The genetic events found in ductal adenocarcinoma have been well characterized, and complete exome
sequencing has been done for the common types of tumor. Four genes have each been found to be mutated in the
majority of adenocarcinomas: KRAS (in 95% of cases), CDKN2A (also in 95%), TP53 (75%), and SMAD4
(55%). The last of these are especially associated with a poor prognosis. SWI/SNF mutations/deletions occur in
about 10–15% of the adenocarcinomas. The genetic alterations in several other types of pancreatic cancer and
precancerous lesions have also been researched. Transcriptomics analyses and mRNA sequencing for the common
forms of pancreatic cancer have found that 75% of human genes are expressed in the tumors, with some 200
genes more specifically expressed in pancreatic cancer as compared to other tumor types.

PanNETs
The genes often found mutated in PanNETs are different from those in exocrine pancreatic cancer. For example,
KRAS mutation is normally absent. Instead, hereditary MEN1 gene mutations give rise to MEN1 syndrome, in
which primary tumors occur in two or more endocrine glands. About 40–70% of people born with a MEN1
mutation eventually develop a PanNet. Other genes that are frequently mutated include DAXX, mTOR and ATRX.

DIAGNOSIS
The symptoms of pancreatic adenocarcinoma do not usually appear in the disease’s early stages, and are
individually not distinctive to the disease. The symptoms at diagnosis vary according to the location of the cancer
in the pancreas, which anatomists divide (from left to right on most diagrams) into the thick head, the neck, and the
tapering body, ending in the tail. Regardless of a tumor’s location, the most common symptom is unexplained
weight loss, which may be considerable. A large minority (between 35% and 47%) of people diagnosed with the
disease will have had nausea, vomiting or a feeling of weakness. Tumors in the head of the pancreas typically also
cause jaundice, pain, loss of appetite, dark urine, and light-colored stools. Tumors in the body and tail typically
also cause pain. People sometimes have recent onset of atypical type 2 diabetes that is difficult to control, a history
of recent but unexplained blood vessel inflammation caused by blood clots (thrombophlebitis) known as Trousseau
sign, or a previous attack of pancreatitis. A doctor may suspect pancreatic cancer when the onset of diabetes in
someone over 50 years old is accompanied by typical symptoms such as unexplained weight loss, persistent
abdominal or back pain, indigestion, vomiting, or fatty feces. Jaundice accompanied by a painlessly swollen
gallbladder (known as Courvoisier’s sign) may also raise suspicion, and can help differentiate pancreatic
cancer from gallstones. Medical imaging techniques, such as computed tomography (CT scan) and endoscopic
ultrasound (EUS) are used both to confirm the diagnosis and to help decide whether the tumor can be surgically
removed (its “resectability”). On contrast CT scan, pancreatic cancer typically shows a gradually increasing
radiocontrast uptake, rather than a fast washout as seen in a normal pancreas or a delayed washout as seen in
chronic pancreatitis. Magnetic resonance imaging and positron emission tomography may also be used, and
magnetic resonance cholangiopancreatography may be useful in some cases. Abdominal ultrasound is less
sensitive and will miss small tumors, but can identify cancers that have spread to the liver and build-up of fluid
in the peritoneal cavity (ascites). It may be used for a quick and cheap first examination before other techniques.
A biopsy by fine needle aspiration, often guided by endoscopic ultrasound, may be used where there is uncertainty
Gastrointestinal 85

over the diagnosis, but a histologic diagnosis is not usually required for removal of the tumor by surgery to go
ahead. Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated
bilirubin, ã-glutamyl transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a
tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity, not
least because 5% of people lack the Lewis (a) antigen and cannot produce CA19-9. It has a sensitivity of 80% and
specificity of 73% in detecting pancreatic adenocarcinoma, and is used for following known cases rather than
diagnosis. The most common form of pancreatic cancer (adenocarcinoma) is typically characterized by moderately
to poorly differentiated glandular structures on microscopic examination. There is typically considerable desmoplasia
or formation of a dense fibrous stroma or structural tissue consisting of a range of cell types (including myofibroblasts,
macrophages, lymphocytes and mast cells) and deposited material (such as type I collagen and hyaluronic acid).
This creates a tumor microenvironment that is short of blood vessels (hypovascular) and so of oxygen (tumor
hypoxia). It is thought that this prevents many chemotherapy drugs from reaching the tumor, as one factor making
the cancer especially hard to treat.

STAGING

Exocrine Cancers
Pancreatic cancer is usually staged following a CT scan. The most widely used cancer staging system for
pancreatic cancer is the one formulated by the American Joint Committee on Cancer (AJCC) together with the
Union for International Cancer Control (UICC). The AJCC-UICC staging system designates four main overall
stages, ranging from early to advanced disease, based on TNM classification of Tumor size, spread to lymph
Nodes, and Metastasis. To help decide treatment, the tumors are also divided into three broader categories
based on whether surgical removal seems possible: in this way, tumors are judged to be “resectable”, “borderline
resectable”, or “unresectable”. When the disease is still in an early stage (AJCC-UICC stages I and II), without
spread to large blood vessels or distant organs such as the liver or lungs, surgical resection of the tumor can
normally be performed, if the patient is willing to undergo this major operation and is thought to be sufficiently
fit. The AJCC-UICC staging system allows distinction between stage III tumors that are judged to be “borderline
resectable” (where surgery is technically feasible because the celiac axis and superior mesenteric artery are still
free) and those that are “unresectable” (due to more locally advanced disease); in terms of the more detailed
TNM classification, these two groups correspond to T3 and T4 respectively.
• Pancreatic cancer staging (TNM classification).

Fig. Stage T1 pancreatic cancer

86 Surgical Oncology: Theory and Multidisciplinary Practice

Fig. Stage T2 pancreatic cancer

Fig. Stage T3 pancreatic cancer

Fig. Stage T4 pancreatic cancer

Gastrointestinal 87

Fig. Pancreatic cancer in nearby lymph nodes – Stage N1

Locally advanced adenocarcinomas have spread into neighbouring organs, which may be any of the following
(in roughly decreasing order of frequency): the duodenum, stomach, transverse colon, spleen, adrenal gland, or
kidney. Very often they also spread to the important blood or lymphatic vessels and nerves that run close to the
pancreas, making surgery far more difficult. Typical sites for metastatic spread (stage IV disease) are the liver,
peritoneal cavity and lungs, all of which occur in 50% or more of fully advanced cases.

PanNETs
The 2010 WHO classification of tumors of the digestive system grades all the pancreatic neuroendocrine
tumors (PanNETs) into three categories, based on their degree of cellular differentiation (from “NET G1”
through to the poorly differentiated “NET G3”). The U.S. National Comprehensive Cancer Network recommends
use of the same AJCC-UICC staging system as pancreatic adenocarcinoma. Using this scheme, the stage-by-
stage outcomes for PanNETs are dissimilar to those of the exocrine cancers. A different TNM system for
PanNETs has been proposed by the European Neuroendocrine Tumor Society.

PREVENTION AND SCREENING

Apart from not smoking, the American Cancer Society recommends keeping a healthy weight, and increasing
consumption of fruits, vegetables, and whole grains, while decreasing consumption of red and processed meat,
although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically. A 2014 review
of research concluded that there was evidence that consumption of citrus fruits and curcumin reduced risk of
pancreatic cancer, while there was possibly a beneficial effect from whole grains, folate, selenium, and non-fried
fish. In the general population, screening of large groups is not currently considered effective, although newer
techniques, and the screening of tightly targeted groups, are being evaluated. Nevertheless, regular screening with
endoscopic ultrasound and MRI/CT imaging is recommended for those at high risk from inherited genetics.

MANAGEMENT

Exocrine Cancer
A key assessment that is made after diagnosis is whether surgical removal of the tumor is possible, as this is
the only cure for this cancer. Whether or not surgical resection can be offered depends on how much the cancer
88 Surgical Oncology: Theory and Multidisciplinary Practice

has spread. The exact location of the tumor is also a significant factor, and CT can show how it relates to the
major blood vessels passing close to the pancreas. The general health of the person must also be assessed,
though age in itself is not an obstacle to surgery. Chemotherapy and, to a lesser extent, radiotherapy are likely
to be offered to most people, whether or not surgery is possible. Specialists advise that the management of
pancreatic cancer should be in the hands of a multidisciplinary team including specialists in several aspects of
oncology, and is, therefore, best conducted in larger centers.

Surgery
Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases. Although CT
scans help, in practice it can be difficult to determine whether the tumor can be fully removed (its “resectability”),
and it may only become apparent during surgery that it is not possible to successfully remove the tumor without
damaging other vital tissues. Whether or not surgical resection can be offered depends on various factors,
including the precise extent of local anatomical adjacency to, or involvement of, the venous or arterial blood
vessels, as well as surgical expertise and a careful consideration of projected post-operative recovery. The age
of the person is not in itself a reason not to operate, but their general performance status needs to be adequate
for a major operation. One particular feature that is evaluated is the encouraging presence, or discouraging
absence, of a clear layer or plane of fat creating a barrier between the tumor and the vessels. Traditionally, an
assessment is made of the tumor’s proximity to major venous or arterial vessels, in terms of “abutment” (defined
as the tumor touching no more than half a blood vessel’s circumference without any fat to separate it),
“encasement” (when the tumor encloses most of the vessel’s circumference), or full vessel involvement. A
resection that includes encased sections of blood vessels may be possible in some cases, particularly if preliminary
neo-adjuvant therapy is feasible, using chemotherapy and/or radiotherapy. Even when the operation appears to
have been successful, cancerous cells are often found around the edges (“margins”) of the removed tissue,
when a pathologist examines them microscopically (this will always be done), indicating the cancer has not
been entirely removed. Furthermore, cancer stem cells are usually not evident microscopically, and if they are
present they may continue to develop and spread. An exploratory laparoscopy (a small, camera-guided surgical
procedure) may therefore be performed to gain a clearer idea of the outcome of a full operation. For cancers
involving the head of the pancreas, the Whipple procedure is the most commonly attempted curative surgical
treatment. This is a major operation which involves removing the pancreatic head and the curve of the duodenum
together (“pancreato-duodenectomy”), making a bypass for food from the stomach to the jejunum (“gastro-
jejunostomy”) and attaching a loop of jejunum to the cystic duct to drain bile (“cholecysto-jejunostomy”). It
can be performed only if the person is likely to survive major surgery and if the cancer is localized without
invading local structures or metastasizing. It can, therefore, be performed only in a minority of cases. Cancers
of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy, which often also
entails removal of the spleen. Nowadays, this can often be done using minimally invasive surgery. Although
curative surgery no longer entails the very high death rates that occurred until the 1980s, a high proportion of
people (about 30–45%) still have to be treated for a post-operative sickness that is not caused by the cancer
itself. The most common complication of surgery is difficulty in emptying the stomach. Certain more limited
surgical procedures may also be used to ease symptoms: for instance, if the cancer is invading or compressing
the duodenum or colon. In such cases, bypass surgery might overcome the obstruction and improve quality of
life but is not intended as a cure.

Chemotherapy
After surgery, adjuvant chemotherapy with gemcitabine or 5-FU can be offered if the person is sufficiently
fit, after a recovery period of one to two months. In people not suitable for curative surgery, chemotherapy may
Gastrointestinal 89

be used to extend life or improve its quality. Before surgery, neo-adjuvant chemotherapy or chemoradiotherapy
may be used in cases that are considered to be “borderline resectable” in order to reduce the cancer to a level
where surgery could be beneficial. In other cases neo-adjuvant therapy remains controversial, because it delays
surgery. Gemcitabine was approved by the United States Food and Drug Administration (FDA) in 1997, after a
clinical trial reported improvements in quality of life and a 5-week improvement in median survival duration in
people with advanced pancreatic cancer. This was the first chemotherapy drug approved by the FDA primarily
for a non-survival clinical trial endpoint. Chemotherapy using gemcitabine alone was the standard for about a
decade, as a number of trials testing it in combination with other drugs failed to demonstrate significantly better
outcomes. However, the combination of gemcitabine with erlotinib was found to increase survival modestly,
and erlotinib was licensed by the FDA for use in pancreatic cancer in 2005. The FOLFIRINOX chemotherapy
regimen using four drugs was found more effective than gemcitabine, but with substantial side effects, and is
thus only suitable for people with good performance status. This is also true of protein-bound paclitaxel (nab-
paclitaxel), which was licensed by the FDA in 2013 for use with gemcitabine in pancreas cancer. By the end of
2013, both FOLFIRINOX and nab-paclitaxel with gemcitabine were regarded as good choices for those able to
tolerate the side-effects, and gemcitabine remained an effective option for those who were not. A head-to-head
trial between the two new options is awaited, and trials investigating other variations continue. However, the
changes of the last few years have only increased survival times by a few months. Clinical trials are often
conducted for novel adjuvant therapies.

Radiotherapy
The role of radiotherapy as an auxiliary (adjuvant) treatment after potentially curative surgery has been
controversial since the 1980s. The European Society for Medical Oncology recommends that adjuvant
radiotherapy should only be used for people enrolled in clinical trials. However, there is a continuing tendency
for clinicians in the US to be more ready to use adjuvant radiotherapy than those in Europe. Many clinical
trials have tested a variety of treatment combinations since the 1980s, but have failed to settle the matter
conclusively. Radiotherapy may form part of treatment to attempt to shrink a tumor to a resectable state, but
its use on unresectable tumors remains controversial as there are conflicting results from clinical trials. The
preliminary results of one trial, presented in 2013, “markedly reduced enthusiasm” for its use on locally
advanced tumors.

PanNETs
Treatment of PanNETs, including the less common malignant types, may include a number of approaches.
Some small tumors of less than 1 cm. that are identified incidentally, for example on a CT scan performed for
other purposes, may be followed by watchful waiting. This depends on the assessed risk of surgery which is
influenced by the site of the tumor and the presence of other medical problems. Tumors within the pancreas
only (localized tumors), or with limited metastases, for example to the liver, may be removed by surgery. The
type of surgery depends on the tumor location, and the degree of spread to lymph nodes. For localized
tumors, the surgical procedure may be much less extensive than the types of surgery used to treat pancreatic
adenocarcinoma described above, but otherwise surgical procedures are similar to those for exocrine tumors.
The range of possible outcomes varies greatly; some types have a very high survival rate after surgery while
others have a poor outlook. As all this group are rare, guidelines emphasize that treatment should be undertaken
in a specialized center. Use of liver transplantation may be considered in certain cases of liver metastasis.
For functioning tumors, the somatostatin analog class of medications, such as octreotide, can reduce the
excessive production of hormones. Lanreotide can slow tumor growth. If the tumor is not amenable to surgical
90 Surgical Oncology: Theory and Multidisciplinary Practice

removal and is causing symptoms, targeted therapy with everolimus or sunitinib can reduce symptoms and
slow progression of the disease. Standard cytotoxic chemotherapy is generally not very effective for PanNETs,
but may be used when other drug treatments fail to prevent the disease from progressing, or in poorly
differentiated PanNET cancers. Radiation therapy is occasionally used if there is pain due to anatomic
extension, such as metastasis to bone. Some PanNETs absorb specific peptides or hormones, and these
PanNETs may respond to nuclear medicine therapy with radiolabeled peptides or hormones such as iobenguane
(iodine-131-MIBG). Radiofrequency ablation (RFA), cryoablation, and hepatic artery embolization may also
be used.

Palliative Care
Palliative care is medical care which focuses on treatment of symptoms from serious illness, such as cancer,
and improving quality of life. Because pancreatic adenocarcinoma is usually diagnosed after it has progressed
to an advanced stage, palliative care as a treatment of symptoms is often the only treatment possible. Palliative
care focuses not on treating the underlying cancer, but on treating symptoms such as pain or nausea, and can
assist in decision-making, including when or if hospice care will be beneficial. Pain can be managed with
medications such as opioids or through procedural intervention, by a nerve block on the celiac plexus (CPB).
This alters or, depending on the technique used, destroys the nerves that transmit pain from the abdomen. CPB
is a safe and effective way to reduce the pain, which generally reduces the need to use opioid painkillers, which
have significant negative side effects. Other symptoms or complications that can be treated with palliative
surgery are obstruction by the tumor of the intestines or bile ducts. For the latter, which occurs in well over half
of cases, a small metal tube called a stent may be inserted by endoscope to keep the ducts draining. Palliative
care can also help treat depression that often comes with the diagnosis of pancreatic cancer. Both surgery and
advanced inoperable tumors often lead to digestive system disorders from a lack of the exocrine products of the
pancreas (exocrine insufficiency). These can be treated by taking pancreatin which contains manufactured
pancreatic enzymes, and is best taken with food. Difficulty in emptying the stomach (delayed gastric emptying)
is common and can be a serious problem, involving hospitalization. Treatment may involve a variety of
approaches, including draining the stomach by nasogastric aspiration and drugs called proton-pump inhibitors
or H2 antagonists, which both reduce production of gastric acid. Medications like metoclopramide can also be
used to clear stomach contents.

OUTCOMES
Pancreatic adenocarcinoma and the other less common exocrine cancers have a very poor prognosis, as they
are normally diagnosed at a late stage when the cancer is already locally advanced or has spread to other parts
of the body. Outcomes are much better for PanNETs: many are benign and completely without clinical symptoms,
and even those cases not treatable with surgery have an average five-year survival rate of 16%, although the
outlook varies considerably according to the type. For locally advanced and metastatic pancreatic
adenocarcinomas, which together represent over 80% of cases, numerous recent trials comparing chemotherapy
regimes have shown increased survival times, but not to more than one year. Overall five-year survival for
pancreatic cancer in the US has improved from 2% in cases diagnosed in 1975–77, and 4% in 1987–89 diagnoses,
to 6% in 2003–09. In the less than 20% of cases of pancreatic adenocarcinoma with a diagnosis of a localized
and small cancerous growth (less than 2 cm in Stage T1), about 20% of Americans survive to five years. About
1500 genes are linked to outcomes in pancreatic adenocarcinoma. These include both unfavourable genes,
where high expression is related to poor outcome, for example C-Met and MUC-1, and favourable genes where
high expression is associated with better survival, for example the transcription factor PELP1.
Gastrointestinal 91

HEPATOCELL
HEPA UL
OCELLUL AR CAR
ULAR CINOMA
CARCINOMA
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults, and is the most
common cause of death in people with cirrhosis. It occurs in the setting of chronic liver inflammation, and is
most closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol
or aflatoxin. Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency, markedly increase
the risk of developing HCC. Metabolic syndrome and NASH are also increasingly recognized as risk factors for
HCC. As with any cancer, the treatment and prognosis of HCC vary depending on the specifics of tumor
histology, size, how far the cancer has spread, and overall health. The vast majority of HCC occurs in Asia
and sub-Saharan Africa, in countries where hepatitis B infection is endemic and many are infected from
birth. The incidence of HCC in the United States and other developing countries is increasing due to an increase
in hepatitis C virus infections. It is more common in males than females for unknown reasons.

SIGNS AND SYMPTOMS

Most cases of HCC occur in people who already have signs and symptoms of chronic liver disease. They
may present either with worsening of symptoms or may be without symptoms at the time of cancer detection.
HCC may directly present with yellow skin, abdominal swelling due to fluid in the abdominal cavity, easy
bruising from blood clotting abnormalities, loss of appetite, unintentional weight loss, abdominal pain, nausea,
vomiting, or feeling tired.

RISK FACTORS
HCC mostly occurs in people with cirrhosis of the liver, and so risk factors generally include factors
which cause chronic liver disease that may lead to cirrhosis. Still, certain risk factors are much more highly
associated with HCC than others. For example, while heavy alcohol consumption is estimated to cause 60-
70% of cirrhosis, the vast majority of HCC occurs in cirrhosis attributed to viral hepatitis (although there
may be overlap).
Recognized risk factors include:
• Chronic viral hepatitis (estimated cause of 80% cases globally)
a. Chronic hepatitis B (approximately 50% cases)
b. Chronic hepatitis C (approximately 25% cases)
• Toxins:
a. Alcohol abuse: the most common cause of cirrhosis
b. Aflatoxin
c. Iron overload state (Hemochromatosis)
• Metabolic:
a. Non-alcoholic steatohepatitis: up to 20% progress to cirrhosis
b. Type 2 diabetes (probably aided by obesity)
• Congenital disorders:
a. Alpha 1-antitrypsin deficiency
b. Wilson’s disease (controversial; while some theorise the risk increases, case studies are rare and
suggest the opposite where Wilson’s disease actually may confer protection)
c. Hemophilia, although statistically associated with higher risk of HCC, this is due to coincident
chronic viral hepatitis infection related to repeated blood transfusions over lifetime.
The significance of these risk factors varies globally. In regions where hepatitis B infection is endemic, such
as southeast China, this is the predominant cause. In populations largely protected by hepatitis B vaccination,
92 Surgical Oncology: Theory and Multidisciplinary Practice

such as the United States, HCC is most often linked to causes of cirrhosis such as chronic hepatitis C, obesity,
and alcohol abuse. Certain benign liver tumors, such as hepatocellular adenoma, may sometimes be associated
with coexisting malignant HCC. There is limited evidence for the true incidence of malignancy associated with
benign adenomas; however, the size of hepatic adenoma is considered to correspond to risk of malignancy and
so larger tumors may be surgically removed. Certain subtypes of adenoma, particularly those with β-catenin
activation mutation, are particularly associated with increased risk of HCC. Children and adolescents are unlikely
to have chronic liver disease, however, if they suffer from congenital liver disorders, this fact increases the
chance of developing hepatocellular carcinoma. Specifically, children with biliary atresia, infantile cholestasis,
glycogen-storage diseases, and other cirrhotic diseases of the liver are predisposed to developing HCC in
childhood. Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may have none
of the typical risk factors, i.e. cirrhosis and hepatitis.

Diabetes Mellitus
The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5 to 7.1 times the non diabetic
risk) depending on the duration of diabetes and treatment protocol. A suspected contributor to this increased
risk is circulating insulin concentration such that diabetics with poor insulin control or on treatments that
elevate their insulin output (both states that contribute to a higher circulating insulin concentration) show far
greater risk of hepatocellular carcinoma than diabetics on treatments that reduce circulating insulin concentration.
On this note, some diabetics who engage in tight insulin control (by keeping it from being elevated) show risk
levels low enough to be indistinguishable from the general population. This phenomenon is thus not isolated to
diabetes mellitus type 2 since poor insulin regulation is also found in other conditions such as metabolic syndrome
(specifically, when evidence of non alcoholic fatty liver disease or NAFLD is present) and again there is evidence
of greater risk here too. While there are claims that anabolic steroid abusers are at greater risk (theorized to be
due to insulin and IGF exacerbation), the only evidence that has been confirmed is that anabolic steroid users
are more likely to have hepatocellular adenomas (a benign form of HCC) transform into the more dangerous
hepatocellular carcinoma.

‘PATHOGENESIS
Hepatocellular carcinoma, like any other cancer, develops when there are epigenetic alterations and mutations
affecting the cellular machinery that cause the cell to replicate at a higher rate and/or result in the cell avoiding
apoptosis. In particular, chronic infections of hepatitis B and/or C can aid the development of hepatocellular
carcinoma by repeatedly causing the body’s own immune system to attack the liver cells, some of which are
infected by the virus, others merely bystanders. Activated immune system inflammatory cells release free radicals,
such as reactive oxygen species and nitric oxide reactive species, which in turn can cause DNA damage and
lead to carcinogenic gene mutations. Reactive oxygen species also cause epigenetic alterations at the sites of
DNA repair. While this constant cycle of damage followed by repair can lead to mistakes during repair which in
turn lead to carcinogenesis, this hypothesis is more applicable, at present, to hepatitis C. Chronic hepatitis C
causes HCC through the stage of cirrhosis. In chronic hepatitis B, however, the integration of the viral genome
into infected cells can directly induce a non-cirrhotic liver to develop HCC. Alternatively, repeated consumption
of large amounts of ethanol can have a similar effect. The toxin aflatoxin from certain Aspergillus species of
fungus is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined
high prevalence of rates of aflatoxin and hepatitis B in settings like China and West Africa has led to relatively
high rates of hepatocellular carcinoma in these regions. Other viral hepatitides such as hepatitis A have no
potential to become a chronic infection and thus are not related to hepatocellular carcinoma.
Gastrointestinal 93

DIAGNOSIS
Methods of diagnosis in HCC have evolved with the improvement in medical imaging. The evaluation of
both asymptomatic patients and those with symptoms of liver disease involves blood testing and imaging
evaluation. Although historically a biopsy of the tumor was required to prove the diagnosis, imaging (especially
MRI) findings may be conclusive enough to obviate histopathologic confirmation.

Screening
HCC remains associated with a high mortality rate, in part related to initial diagnosis commonly at an
advanced stage of disease. As with other cancers, outcomes are significanty improved if treatment is initiated
earlier in the disease process. Because the vast majority of HCC occurs in people with certain chronic liver
diseases, especially those with cirrhosis, liver screening is commonly advocated in this population. Specific
screening guidelines continue to evolve over time as evidence of its clinical impact becomes available. In the
United States, the most commonly observed guidelines are those published by the American Association for the
Study of Liver Diseases (AASLD). The AASLD recommends screening people with cirrhosis with ultrasound
every 6 months, with or without measurement of blood levels of tumor marker AFP. Elevated levels of AFP are
associated with active HCC disease, although inconsistently reliable. At levels >20 sensitivity is 41-65% and
specificity is 80-94%. However, at levels >200 sensitivity is 31, specificity is 99%. On US, HCC often appears
as a small hypoechoic lesion with poorly defined margins and coarse irregular internal echoes. When the tumor
grows, it can sometimes appear heterogeneous with fibrosis, fatty change, and calcifications. This heterogeneity
can look similar to cirrhosis and the surrounding liver parenchyma. A systematic review found that the sensitivity
was 60 percent (95% CI 44-76%) and specificity was 97 percent (95% CI 95-98%) compared with pathologic
examination of an explanted or resected liver as the reference standard. The sensitivity increases to 79% with
AFP correlation. There remains controversy as to the most effective screening protocols. For example, while
there is data to support decreased mortality related to screening in people with hepatitis B infection, the AASLD
notes that “there are no randomized trials [for screening] in Western populations with cirrhosis secondary to
chronic hepatitis C or fatty liver disease, and thus there is some controversy surrounding whether surveillance
truly leads to a reduction in mortality in this population of patients with cirrhosis.”

Higher Risk People

In a person where there is higher suspicion of HCC, such as a person with symptoms or abnormal blood tests
(i.e. alpha-fetoprotein and des-gamma carboxyprothrombin levels), evaluation requires imaging of the liver by CT
or MRI scans. Optimally, these scans are performed with intravenous contrast in multiple phases of hepatic perfusion
in order to improve detection and accurate classification of any liver lesions by the interpreting radiologist. Due to
the characteristic blood flow pattern of HCC tumors, a specific perfusion pattern of any detected liver lesion may
conclusively detect an HCC tumor. Alternatively, the scan may detect an indeterminate lesion and further evaluation
may be performed by obtaining a physical sample of the lesion.

Imaging
Ultrasound, CT scan, and MRI may be used to evaluate the liver for HCC.
On CT and MRI, HCC can have three distinct patterns of growth:
• A single large tumor
• Multiple tumors
• Poorly defined tumor with an infiltrative growth pattern.
94 Surgical Oncology: Theory and Multidisciplinary Practice

A systematic review of CT diagnosis found that the sensitivity was 68 percent (95% CI 55-80%) and specificity
was 93 percent (95% CI 89-96%) compared with pathologic examination of an explanted or resected liver as
the reference standard. With triple-phase helical CT, the sensitivity 90% or higher, but this data has not been
confirmed with autopsy studies. However, MRI has the advantage of delivering high-resolution images of the
liver without ionizing radiation. HCC appears as a high-intensity pattern on T2 weighted images and a low-
intensity pattern on T1 weighted images. The advantage of MRI is that is has improved sensitivity and specificity
when compared to US and CT in cirrhotic patients with whom it can be difficult to differentiate HCC from
regenerative nodules. A systematic review found that the sensitivity was 81 percent (95% CI 70-91%) and
specificity was 85 percent (95% CI 77-93%) compared with pathologic examination of an explanted or resected
liver as the reference standard. The sensitivity is further increased if gadolinium contrast-enhanced and diffusion-
weighted imaging are combined. MRI is more sensitive and specific than CT. Liver Image Reporting and Data
System (LI-RADS) is a classification system for the reporting of liver lesions detected on CT and MRI.
Radiologists use this standardized system to report on suspicious lesions and to provide an estimated likelihood
of malignancy. Categories range from LI-RADS (LR) 1 to 5, in order of concern for cancer. A biopsy is not
needed to confirm the diagnosis of HCC if certain imaging criteria are met.

Pathology
Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary
(large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules are round to oval,
gray or green (if the tumor produces bile), well circumscribed but not encapsulated. The diffuse type is poorly
circumscribed and infiltrates the portal veins, or the hepatic veins (rarely). Microscopically, there are four
architectural and cytological types (patterns) of hepatocellular carcinoma: fibrolamellar, pseudoglandular
(adenoid), pleomorphic (giant cell) and clear cell. In well-differentiated forms, tumor cells resemble hepatocytes,
form trabeculae, cords, and nests, and may contain bile pigment in the cytoplasm. In poorly differentiated
forms, malignant epithelial cells are discohesive, pleomorphic, anaplastic, giant. The tumor has a scant stroma
and central necrosis because of the poor vascularization.

Staging
The prognosis of HCC is affected by the staging of the tumor as well as the liver’s function due to the effects of
liver cirrhosis. There are a number of staging classifications for HCC available; however, due to the unique nature
of the carcinoma in order to fully encompass all the features that affect the categorization of the HCC, a classification
system should incorporate; tumor size and number, presence of vascular invasion and extrahepatic spread, liver
function (levels of serum bilirubin and albumin, presence of ascites and portal hypertension) and general health
status of the patient (defined by the ECOG classification and the presence of symptoms). Out of all the staging
classification systems available the Barcelona Clinic Liver Cancer (BCLC) staging classification encompasses all
of the above characteristics. This staging classification can be used in order to select people for treatment.
Important features that guide treatment include the following:
• Size
• Spread (stage)
• Involvement of liver vessels
• Presence of a tumor capsule
• Presence of extrahepatic metastases
• Presence of daughter nodules
• Vascularity of the tumor.
Gastrointestinal 95

MRI is the best imaging method to detect the presence of a tumor capsule.
The most common sites of metastasis are the lung, abdominal lymph nodes, and bone.

PREVENTION
Since hepatitis B or C is one of the main causes of hepatocellular carcinoma, prevention of this infection is
key to then prevent hepatocellular carcinoma. Thus, childhood vaccination against hepatitis B may reduce the
risk of liver cancer in the future. In the case of patients with cirrhosis, alcohol consumption is to be avoided.
Also, screening for hemochromatosis may be beneficial for some patients. It is unclear if screening those with
chronic liver disease for hepatocellular carcinoma improves outcomes.

TREATMENT
Treatment of hepatocellular carcinoma varies by the stage of disease, a person’s likelihood to tolerate
surgery, and availability of liver transplant:
• Curative intention: for limited disease, when the cancer is limited to one or more areas of within the
liver, surgically removing the malignant cells may be curative. This may be accomplished by resection
the affected portion of the liver (partial hepatectomy) or in some cases by orthotopic liver
transplantation of the entire organ.
• “Bridging” intention: for limited disease which qualifies for potential liver transplantation, the person
may undergo targeted treatment of some or all of the known tumor while waiting for a donor organ
to become available.
• “Downstaging” intention: for moderately advanced disease which has not spread beyond the liver,
but is too advanced to qualify for curative treatment. The person may be treated by targeted therapies
in order to reduce the size or number of active tumors, with the goal of once again qualifying for
liver transplant after this treatment.
• Palliative intention: for more advanced disease, including spread of cancer beyond the liver or in
persons who may not tolerate surgery, treatment intended to decrease symptoms of disease and
maximize duration of survival.
Loco-regional therapy (also referred to as liver-directed therapy) refers to any one of several minimally-
invasive treatment techniques to focally target HCC within the liver. These procedures are alternatives to surgery,
and may be considered in combination with other strategies, such as a later liver transplantation. Generally,
these treatment procedures are performed by interventional radiologists or surgeons, in coordination with a
medical oncologist. Loco-regional therapy may refer to either percutaneous therapies (e.g. cryoablation), or
arterial catheter-based therapies (chemoembolization or radioembolization).

Surgical Resection
Surgical removal of the tumor is associated with better cancer prognosis, but only 10-15% of patients are
suitable for surgical resection due to the extent of disease or poor liver function. Surgery is only considered if
the entire tumor can be safely removed while preserving sufficient functional liver to maintain normal physiology.
Thus, pre-operative imaging assessment is critical in order to determine both the extent of HCC and to estimate
the amount of residual liver remaining after surgery. In order to maintain liver function, residual liver volume
should exceed 25% of total liver volume in a non-cirrhotic liver, greater than 40% in a cirrhotic liver. Surgery
on diseased or cirrhotic livers is generally associated with higher morbidity and mortality. The overall recurrence
rate after resection is 50-60%. The Singapore Liver Cancer Recurrence (SLICER) score can be used to estimate
risk of recurrence after surgery.
96 Surgical Oncology: Theory and Multidisciplinary Practice

Liver Transplantation
Liver transplantation, replacing the diseased liver with a cadaveric or a living donor liver, plays an increasing
role in treatment of HCC. Although outcomes following liver transplant were initially poor (20%-36% survival
rate), outcomes have significantly improved with improvement in surgical techniques and adoption of the Milan
criteria at US transplantation centers. Expanded Shanghai criteria in China have resulted in overall survival and
disease-free survival rates similar to those achieved using the Milan criteria. Studies from the late 2000s obtained
higher survival rates ranging from 67% to 91%. The risks of liver transplantation extend beyond risk of the
procedure itself. The immunosuppressive medication which are required after surgery to prevent rejection of the
donor liver also impair the body’s natural ability to combat dysfunctional cells. If tumor has spread undetected
outside the liver before the transplant, the medication effectively increases the rate of disease progression and
decreases survival. With this in mind, liver transplant “can be a curative approach for patients with advanced HCC
without extrahepatic metastasis”. Patient selection is considered a major key for success.

Ablation
• Radiofrequency ablation (RFA) uses high-frequency radio waves to destroy tumor by local heating.
The electrodes are inserted into the liver tumor under ultrasound image guidance using percutaneous,
laparoscopic or open surgical approach. It is suitable for small tumors (<5 cm). RFA has the best
outcomes in patients with a solitary tumor less than 4 cm. Since it is a local treatment and has
minimal effect on normal healthy tissue, it can be repeated multiple times. Survival is better for
those with smaller tumors. In one study, In one series of 302 patients, the three-year survival rates
for lesions >5 cm, 2.1 to 5 cm, and ≤2 cm were 59, 74, and 91 percent, respectively. A large
randomized trial comparing surgical resection and RFA for small HCC showed similar 4 year survival
and less morbidities for patients treated with RFA.
• Cryoablation: Cryoablation is a technique used to destroy tissue using cold temperature. The tumor is
not removed and the destroyed cancer is left to be reabsorbed by the body. Initial results in properly
selected patients with unresectable liver tumors are equivalent to those of resection. Cryosurgery involves
the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen is circulated
through the end of this device. The tumor and a half inch margin of normal liver are frozen to -190 °C
for 15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then re-frozen to -
190 °C for another 15 minutes. After the tumor has thawed, the probe is removed, bleeding is controlled,
and the procedure is complete. The patient will spend the first post-operative night in the intensive care
unit and typically is discharged in 3 – 5 days. Proper selection of patients and attention to detail in
performing the cryosurgical procedure are mandatory in order to achieve good results and outcomes.
Frequently, cryosurgery is used in conjunction with liver resection as some of the tumors are removed
while others are treated with cryosurgery.
• Percutaneous ethanol injection (PEI) well tolerated, high RR in small (<3 cm) solitary tumors; as of
2005, no randomized trial comparing resection to percutaneous treatments; recurrence rates similar
to those for postresection. However a comparative study found that local therapy can achieve a 5-
year survival rate of around 60% for patients with small HCC.

Arterial Catheter Based Treatment

• Transcatheter arterial chemoembolization (TACE) is performed for unresectable tumors or as a
temporary treatment while waiting for liver transplant (“bridge to transplant”). TACE is done by
injecting an antineoplastic drug (e.g. cisplatin) mixed with a radio-opaque contrast (e.g. Lipiodol)
Gastrointestinal 97

and an embolic agent (e.g. Gelfoam) into the right or left hepatic artery via the groin artery. The
goal of the procedure it to restrict the tumor’s vascular supply while supplying a targeted
chemotherapeutic agent. TACE has been shown to increase survival and to downstage HCC in patients
who exceed the Milan criteria for liver transplant. Patients who undergo the procedure may are
followed with CT scans and may need additional TACE procedures if the tumor persists. As of
2005, multiple trials show objective tumor responses and slowed tumor progression but questionable
survival benefit compared to supportive care; greatest benefit seen in people with preserved liver
function, absence of vascular invasion, and smallest tumors. TACE is not suitable for big tumors (>8
cm), the presence of portal vein thrombus, tumors with a portal-systemic shunt, and patients with
poor liver function.
• Selective internal radiation therapy (SIRT) can be used to destroy the tumor from within (thus
minimizing exposure to healthy tissue). Similar to TACE, this is a procedure in which an interventional
radiologist selectively injects the artery or arteries supplying the tumor with a chemotherapeutic
agent. The agent is typically Yttrium-90 (Y-90) incorporated into embolic microspheres that lodge in
the tumor vasculature causing ischemia and delivering their radiation dose directly to the lesion.
This technique allows for a higher, local dose of radiation to be delivered directly to the tumor while
sparing normal healthy tissue. While not curative, patients have increased survival. No studies have
been done to compare whether SIRT is superior to TACE in terms of survival outcomes, although
retrospective studies suggest similar efficacy. There are currently two products available, SIR-Spheres
and TheraSphere. The latter is an FDA approved treatment for primary liver cancer (HCC) which
has been shown in clinical trials to increase the survival rate of low-risk patients. SIR-Spheres are
FDA approved for the treatment of metastatic colorectal cancer but outside the US SIR-Spheres are
approved for the treatment of any non-resectable liver cancer including primary liver cancer.

Systemic
In disease which has spread beyond the liver, systemic therapy may be a consideration. In 2007, sorafenib,
an oral multikinase inhibitor, was the first systemic agent approved for first-line treatment of advanced HCC.
Trials have found modest improvement in overall survival: 10.7 months vs 7.9 months and 6.5 months vs 4.2
months. The most common side effects of sorafenib include a hand-foot skin reaction and diarrhea. Sorafenib is
thought to work by blocking growth of both tumor cells and new blood vessels. Numerous other molecular
targeted drugs are being tested as alternative first and second-line treatments for advanced HCC.

Other
• Portal Vein Embolization (PVE): This technique is sometimes used to increase the volume of healthy
liver, in order to improve chances of survival following surgical removal of diseased liver. For
example, embolization of the right main portal vein would result in compensatory hypertrophy of the
left lobe, which may qualify the patient for a partial hepatectomy. Embolization is performed by an
interventional radiologist using a percutaneous transhepatic approach. This procedure can also serve
as a bridge to transplant.
• High intensity focused ultrasound (HIFU) (as opposed to diagnostic ultrasound) is an experimental
technique which uses high-powered ultrasound waves to destroy tumor tissue.
• A systematic review assessed 12 articles involving a total of 318 patients with hepatocellular carcinoma
treated with Yttrium-90 radioembolization. Excluding a study of only one patient, post-treatment CT
evaluation of the tumor showed a response ranging from 29 to 100% of patients evaluated, with all
but two studies showing a response of 71% or greater.
98 Surgical Oncology: Theory and Multidisciplinary Practice

PROGNOSIS
The usual outcome is poor, because only 10–20% of hepatocellular carcinomas can be removed
completely using surgery. If the cancer cannot be completely removed, the disease is usually deadly within
3 to 6 months. This is partially due to late presentation with tumors, but also the lack of medical expertise
and facilities in the regions with high HCC prevalence. However, survival can vary, and occasionally
people will survive much longer than 6 months. The prognosis for metastatic or unresectable hepatocellular
carcinoma has recently improved due to the approval of sorafenib (Nexavar®) for advanced hepatocellular
carcinoma.

COLORECT
COLORECTAL C
ORECTAL ANCER
CANCER
Colorectal cancer (CRC), also known as bowel cancer and colon cancer, is the development of cancer from the
colon or rectum (parts of the large intestine). A cancer is the abnormal growth of cells that have the ability to
invade or spread to other parts of the body. Signs and symptoms may include blood in the stool, a change in bowel
movements, weight loss, and feeling tired all the time. Most colorectal cancers are due to old age and lifestyle
factors with only a small number of cases due to underlying genetic disorders. Some risk factors include diet,
obesity, smoking, and lack of physical activity. Dietary factors that increase the risk include red and processed
meat as well as alcohol. Another risk factor is inflammatory bowel disease, which includes Crohn’s disease and
ulcerative colitis.
Some of the inherited genetic disorders that can cause colorectal cancer include familial adenomatous polyposis
and hereditary non-polyposis colon cancer; however, these represent less than 5% of cases. It typically starts as a
benign tumor, often in the form of a polyp, which over time becomes cancerous. Bowel cancer may be diagnosed
by obtaining a sample of the colon during a sigmoidoscopy or colonoscopy. This is then followed by medical
imaging to determine if the disease has spread. Screening is effective for preventing and decreasing deaths from
colorectal cancer. Screening, by one of a number of methods, is recommended starting from the age of 50 to 75.
During colonoscopy, small polyps may be removed if found. If a large polyp or tumor is found, a biopsy may be
performed to check if it is cancerous.
Aspirin and other non-steroidal anti-inflammatory drugs decrease the risk. Their general use is not recommended
for this purpose, however, due to side effects. Treatments used for colorectal cancer may include some combination
of surgery, radiation therapy, chemotherapy and targeted therapy. Cancers that are confined within the wall of the
colon may be curable with surgery while cancer that has spread widely are usually not curable, with management
being directed towards improving quality of life and symptoms. The five-year survival rate in the United States is
around 65%. The individual likelihood of survival depends on how advanced the cancer is, whether or not all the
cancer can be removed with surgery, and the person’s overall health. Globally, colorectal cancer is the third most
common type of cancer, making up about 10% of all cases. In 2012, there were 1.4 million new cases and 694,000
deaths from the disease. It is more common in developed countries, where more than 65% of cases are found. It is
less common in women than men.

SIGNS AND SYMPTOMS

The signs and symptoms of colorectal cancer depend on the location of the tumor in the bowel, and whether
it has spread elsewhere in the body (metastasis). The classic warning signs include: worsening constipation,
blood in the stool, decrease in stool calibre (thickness), loss of appetite, loss of weight, and nausea or vomiting
in someone over 50 years old. While rectal bleeding or anemia are high-risk features in those over the age of 50,
other commonly described symptoms including weight loss and change in bowel habit are typically only
concerning if associated with bleeding.
Gastrointestinal 99

CAUSE
Greater than 75–95% of colorectal cancer occurs in people with little or no genetic risk. Risk factors include
older age, male gender, high intake of fat, alcohol, red meat, processed meats, obesity, smoking, and a lack of
physical exercise. Approximately 10% of cases are linked to insufficient activity. The risk from alcohol appears
to increase at greater than one drink per day. Drinking 5 glasses of water a day is linked to a decrease in the risk
of colorectal cancer and adenomatous polyps. Streptococcus gallolyticus is associated with colorectal cancer.
Some strains of Streptococcus bovis/Streptococcus equinus complex are consumed by millions of people daily
and thus may be safe. 25 to 80% of people with Streptococcus bovis/gallolyticus bacteremia have concomitant
colorectal tumors. Seroprevalence of Streptococcus bovis/gallolyticus is considered as a candidate practical
marker for the early prediction of an underlying bowel lesion at high risk population. It has been suggested that
the presence of antibodies to Streptococcus bovis/gallolyticus antigens or the antigens themselves in the
bloodstream may act as markers for the carcinogenesis in the colon.

Inflammatory Bowel Disease

People with inflammatory bowel disease (ulcerative colitis and Crohn’s disease) are at increased risk of
colon cancer. The risk increases the longer a person has the disease, and the worse the severity of inflammation.
In these high risk groups, both prevention with aspirin and regular colonoscopies are recommended. People
with inflammatory bowel disease account for less than 2% of colon cancer cases yearly. In those with Crohn’s
disease 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years. In those with
ulcerative colitis approximately 16% develop either a cancer precursor or cancer of the colon over 30 years.

Genetics
Those with a family history in two or more first-degree relatives (such as a parent or sibling) have a two to
threefold greater risk of disease and this group accounts for about 20% of all cases. A number of genetic
syndromes are also associated with higher rates of colorectal cancer. The most common of these is hereditary
non-polyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with
colorectal cancer. Other syndromes that are strongly associated with colorectal cancer include Gardner syndrome,
and familial adenomatous polyposis (FAP). For people with these syndromes, cancer almost always occurs and
makes up 1% of the cancer cases. A total proctocolectomy may be recommended for people with FAP as a
preventative measure due to the high risk of malignancy. Colectomy, removal of the colon, may not suffice as a
preventative measure because of the high risk of rectal cancer if the rectum remains. Most deaths due to colon
cancer are associated with metastatic disease. A gene that appears to contribute to the potential for metastatic
disease, metastasis associated in colon cancer 1 (MACC1), has been isolated. It is a transcriptional factor that
influences the expression of hepatocyte growth factor. This gene is associated with the proliferation, invasion
and scattering of colon cancer cells in cell culture, and tumor growth and metastasis in mice. MACC1 may be
a potential target for cancer intervention, but this possibility needs to be confirmed with clinical studies. Epigenetic
factors, such as abnormal DNA methylation of tumor suppressor promoters play a role in the development of
colorectal cancer.

PATHOGENESIS
Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the
gastrointestinal tract, most frequently as a result of mutations in the Wnt signaling pathway that increase signaling
activity. The mutations can be inherited or acquired, and most probably occur in the intestinal crypt stem cell.
100 Surgical Oncology: Theory and Multidisciplinary Practice

The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein.
The APC protein prevents the accumulation of β-catenin protein. Without APC, β-catenin accumulates to high
levels and translocates (moves) into the nucleus, binds to DNA, and activates the transcription of proto-oncogenes.
These genes are normally important for stem cell renewal and differentiation, but when inappropriately expressed
at high levels, they can cause cancer. While APC is mutated in most colon cancers, some cancers have increased
β-catenin because of mutations in β-catenin (CTNNB1) that block its own breakdown, or have mutations in
other genes with function similar to APC such as AXIN1, AXIN2, TCF7L2, or NKD1. Beyond the defects in
the Wnt signaling pathway, other mutations must occur for the cell to become cancerous. The p53 protein,
produced by the TP53 gene, normally monitors cell division and kills cells if they have Wnt pathway defects.
Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from a benign epithelial
tumor into an invasive epithelial cell cancer. Sometimes the gene encoding p53 is not mutated, but another
protective protein named BAX is mutated instead. Other proteins responsible for programmed cell death that
are commonly deactivated in colorectal cancers are TGF-β and DCC (Deleted in Colorectal Cancer). TGF-β
has a deactivating mutation in at least half of colorectal cancers. Sometimes TGF-β is not deactivated, but a
downstream protein named SMAD is deactivated. DCC commonly has a deleted segment of a chromosome in
colorectal cancer. Approximately 70% of all human genes are expressed in colorectal cancer, with just over 1%
of having increased expression in colorectal cancer compared to other forms of cancer. Some genes are oncogenes:
they are overexpressed in colorectal cancer. For example, genes encoding the proteins KRAS, RAF, and PI3K,
which normally stimulate the cell to divide in response to growth factors, can acquire mutations that result in
over-activation of cell proliferation. The chronological order of mutations is sometimes important. If a previous
APC mutation occurred, a primary KRAS mutation often progresses to cancer rather than a self-limiting
hyperplastic or borderline lesion. PTEN, a tumor suppressor, normally inhibits PI3K, but can sometimes become
mutated and deactivated. Comprehensive, genome-scale analysis has revealed that colorectal carcinomas can
be categorized into hypermutated and non-hypermutated tumor types. In addition to the oncogenic and inactivating
mutations described for the genes above, non-hypermutated samples also contain mutated CTNNB1, FAM123B,
SOX9, ATM, and ARID1A. Progressing through a distinct set of genetic events, hypermutated tumors display
mutated forms of ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF. The common theme
among these genes, across both tumor types, is their involvement in WNT and TGF-β signaling pathways,
which results in increased activity of MYC, a central player in colorectal cancer.

Field Defects
The term “field cancerization” was first used in 1953 to describe an area or “field” of epithelium that has
been preconditioned (by what were largely unknown processes at the time) to predispose it towards development
of cancer. Since then, the terms “field cancerization”, “field carcinogenesis”, “field defect”, and “field effect”
have been used to describe pre-malignant or pre-neoplastic tissue in which new cancers are likely to arise. Field
defects are important in progression to colon cancer. However, in most cancer research, as pointed out by Rubin
“The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete
neo-plastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator
phenotype human colorectal tumors occur before the onset of terminal clonal expansion.” Similarly, Vogelstein
et al. pointed out that more than half of somatic mutations identified in tumors occurred in a pre-neo-plastic
phase (in a field defect), during growth of apparently normal cells. Likewise, epigenetic alterations present in
tumors may have occurred in pre-neo-plastic field defects. An expanded view of field effect has been termed
“etiologic field effect”, which encompasses not only molecular and pathologic changes in pre-neo-plastic cells
but also influences of exogenous environmental factors and molecular changes in the local microenvironment
on neo-plastic evolution from tumor initiation to death.
Gastrointestinal 101

Epigenetics
Epigenetic alterations are much more frequent in colon cancer than genetic (mutational) alterations. As
described by Vogelstein et al., an average cancer of the colon has only 1 or 2 oncogene mutations and 1 to 5
tumor suppressor mutations (together designated “driver mutations”), with about 60 further “passenger”
mutations. The oncogenes and tumor suppressor genes are well studied and are described above under
Pathogenesis. However, by comparison, epigenetic alterations in colon cancers are frequent and affect hundreds
of genes. For instance, there are types of small RNAs called microRNAs that are about 22 nucleotides long.
These microRNAs (or miRNAs) do not code for proteins, but they can target protein coding genes and
reduce their expression. Expression of these miRNAs can be epigenetically altered. As one example, the
epigenetic alteration consisting of CpG island methylation of the DNA sequence encoding miR-137 reduces
its expression.
This is a frequent early epigenetic event in colorectal carcinogenesis, occurring in 81% of colon cancers and
in 14% of the normal appearing colonic mucosa adjacent to the cancers. The altered adjacent tissues associated
with these cancers are called field defects. Silencing of miR-137 can affect expression of about 500 genes, the
targets of this miRNA. Changes in the level of miR-137 expression result in changed mRNA expression of the
target genes by 2 to 20-fold and corresponding, though often smaller, changes in expression of the protein
products of the genes. Other microRNAs, with likely comparable numbers of target genes, are even more
frequently epigenetically altered in colonic field defects and in the colon cancers that arise from them. These
include miR-124a, miR-34b/c and miR-342 which are silenced by CpG island methylation of their encoding
DNA sequences in primary tumors at rates of 99%, 93% and 86%, respectively, and in the adjacent normal
appearing mucosa at rates of 59%, 26% and 56%, respectively.
In addition to epigenetic alteration of expression of miRNAs, other common types of epigenetic alterations
in cancers that change gene expression levels include direct hypermethylation or hypomethylation of CpG
islands of protein-encoding genes and alterations in histones and chromosomal architecture that influence gene
expression. As an example, 147 hypermethylations and 27 hypomethylations of protein coding genes were
frequently associated with colorectal cancers. Of the hypermethylated genes, 10 were hypermethylated in
100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers. In
addition, 11 hypermethylations and 96 hypomethylations of miRNAs were also associated with colorectal
cancers. Recent evidence indicates that early epigenetic reductions of DNA repair enzyme expression likely
lead to the genomic and epigenomic instability characteristic of cancer. As summarized in the articles
Carcinogenesis and Neo-plasm, for sporadic cancers in general, a deficiency in DNA repair is occasionally due
to a mutation in a DNA repair gene, but is much more frequently due to epigenetic alterations that reduce or
silence expression of DNA repair genes.

DIAGNOSIS
Colorectal cancer diagnosis is performed by sampling of areas of the colon suspicious for possible tumor
development, typically during colonoscopy or sigmoidoscopy, depending on the location of the lesion. It is
confirmed by microscopical examination of a tissue sample. Disease extent is usually determined by a CT scan
of the chest, abdomen and pelvis. Other potential imaging tests such as PET and MRI may be used in certain
cases. Colon cancer staging is done next and is based on radiology and pathology. As for all other forms of
cancer, tumor staging is based on the TNM system which considers how much the initial tumor has spread, if
and where there are lymph node metastasis and if there are metastases in more distant organs, usually liver. The
microscopic cellular characteristics of the tumor are reported from the analysis of tissue taken from a biopsy or
surgery. A pathology report contains a description of the microscopical characteristics of the tumor tissue,
102 Surgical Oncology: Theory and Multidisciplinary Practice

including both tumor cells and how the tumor invades into healthy tissues and finally if the tumor appears to be
completely removed. The most common form of colon cancer is adenocarcinoma (98% of cases). Other, rarer
types include lymphoma, adenosquamous and squamous cell carcinoma. Some subtypes have been found to be
more aggressive.

Macroscopy
Cancers on the right side of the large intestine (ascending colon and cecum) tend to be exophytic, that is, the
tumor grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and
presents with symptoms such as anemia. Left-sided tumors tend to be circumferential, and can obstruct the
bowel lumen, much like a napkin ring, and results in thinner calibre stools.

Microscopy
Adenocarcinoma is a malignant epithelial tumor, originating from superficial glandular epithelial cells lining
the colon and rectum. It invades the wall, infiltrating the muscularis mucosae layer, the submucosa, and then the
muscularis propria. Tumor cells describe irregular tubular structures, harbouring pluristratification, multiple
lumens, reduced stroma (“back to back” aspect). Sometimes, tumor cells are discohesive and secrete mucus,
which invades the interstitium producing large pools of mucus. This occurs in mucinous adenocarcinoma, in
which cells are poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the
periphery, this occurs in “signet-ring cell.” Depending on glandular architecture, cellular pleomorphism, and
mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well,
moderately, and poorly differentiated.

Immunochemistry
In cases where a metastasis from colorectal cancer is suspected, immunohistochemistry is used to ascertain
correct diagnosis. Proteins that are more specifically expressed in colorectal cancer and can be used as diagnostic
markers are cytokeratin 20, CDX2, SATB2 and CDH17. Most (50%) colorectal adenomas and (80–90%)
colorectal cancer tumors are thought to over express the cyclooxygenase-2 (COX-2) enzyme. This enzyme is
generally not found in healthy colon tissue, but is thought to fuel abnormal cell growth.

Tumor Budding
Tumor budding in colorectal cancer is loosely defined by the presence of individual cells and small clusters
of tumor cells at the invasive front of carcinomas. It has been postulated to represent an epithelial–mesenchymal
transition (EMT). Tumor budding is a well-established independent marker of a potentially poor outcome in
colorectal carcinoma that may allow for dividing people into risk categories more meaningful than those
defined by TNM staging, and also potentially guide treatment decisions, especially in T1 and T3 N0 (Stage
II, Dukes’ B) colorectal carcinoma. Unfortunately, its universal acceptance as a reportable factor has been
held back by a lack of definitional uniformity with respect to both qualitative and quantitative aspects of
tumor budding.

PREVENTION
It has been estimated that about half of colorectal cancer cases are due to lifestyle factors and about a quarter
of all cases are preventable. Increasing surveillance, engaging in physical activity, consuming a diet high in
fibre, and reducing smoking and alcohol consumption decrease the risk.
Gastrointestinal 103

Lifestyle
Current dietary recommendations to prevent colorectal cancer include increasing the consumption of whole
grains, fruits and vegetables, and reducing the intake of red meat and processed meats. Higher physical activity
is also recommended. Physical exercise is associated with a modest reduction in colon but not rectal cancer
risk. High levels of physical activity reduce the risk of colon cancer by about 21%. Sitting regularly for prolonged
periods is associated with higher mortality from colon cancer. The risk is not negated by regular exercise,
though it is lowered. The evidence for any protective effect conferred by fibre and fruits and vegetables is,
however, poor. The risk of colon cancer can be reduced by maintaining a normal body weight.

Medication
Aspirin and celecoxib appear to decrease the risk of colorectal cancer in those at high risk. Aspirin is
recommended in those who are 50 to 60 years old, do not have an increased risk of bleeding, and are at risk for
cardiovascular disease to prevent colorectal cancer. It is not recommended in those at average risk. There is
tentative evidence for calcium supplementation, but it is not sufficient to make a recommendation. Vitamin D
intake and blood levels are associated with a lower risk of colon cancer.

Screening
As more than 80% of colorectal cancers arise from adenomatous polyps, screening for this cancer is effective
not only for early detection but also for prevention. Diagnosis of cases of colorectal cancer through screening
tends to occur 2–3 years before diagnosis of cases with symptoms. Any polyps that are detected can be removed,
usually by colonoscopy or sigmoidoscopy, and thus prevent them from turning cancerous. Screening has the
potential to reduce colorectal cancer deaths by 60%. The three main screening tests are colonoscopy, fecal
occult blood testing, flexible sigmoidoscopy. Of the three, only sigmoidoscopy cannot screen the right side of
the colon where 42% of malignancies are found. Flexible sigmoidoscopy however has the best evidence for
decreasing the risk of death from any cause. Other options may include virtual colonoscopy and stool DNA
screening testing. Virtual colonoscopy via a CT scan appears as good as standard colonoscopy for detecting
cancers and large adenomas but is expensive, associated with radiation exposure, and cannot remove any detected
abnormal growths like standard colonoscopy can. Fecal occult blood testing (FOBT) of the stool is typically
recommended every two years and can be either guaiac-based or immunochemical. If abnormal FOBT results
are found, participants are typically referred for a follow-up colonoscopy examination. Yearly to every two year
FOBT screening reduces colorectal cancer deaths by 16% and among those participating in screening colorectal
cancer deaths can be reduced up to 23%, although it has not been proven to reduce all-cause mortality.
Immunochemical tests are accurate and do not require dietary or medication changes before testing. The stool
DNA screening test looks for biomarkers associated with colorectal cancer and precancerous lesions, including
altered DNA and blood hemoglobin. A positive result should be followed by colonoscopy. If used, screening is
recommended every 3 years, starting at age 50.

Recommendations
In the United States, screening is typically recommended between ages 50 to 75 years. For those between 76
and 85 years old, the decision to screen should be individualized. Several screening methods can be used,
including stool based tests every 3 years, sigmoidoscopy every 5 years and colonoscopy every 10 years. For
those at high risk, screenings usually begin at around 40. It is unclear which of these two methods is better.
Colonoscopy may find more cancers in the first part of the colon, but is associated with greater cost and more
104 Surgical Oncology: Theory and Multidisciplinary Practice

complications. For people with average risk who have had a high-quality colonoscopy with normal results, the
American Gastroenterological Association does not recommend any type of screening in the 10 years following
the colonoscopy. For people over 75 or those with a life expectancy of less than 10 years, screening is not
recommended. It takes about 10 years after screening for one out of a 1000 people to benefit. In Canada, among
those 50 to 75 years old at normal risk, fecal immunochemical testing or FOBT is recommended every two
years or sigmoidoscopy every 10 years. Colonoscopy is less preferred. Some countries have national colorectal
screening programmes which offer FOBT screening for all adults within a certain age group, typically starting
between ages 50 to 60. Examples of countries with organised screening include the United Kingdom, Australia,
and the Netherlands.

TREATMENT
The treatment of colorectal cancer can be aimed at cure or palliation. The decision on which aim to adopt
depends on various factors, including the person’s health and preferences, as well as the stage of the tumor.
When colorectal cancer is caught early, surgery can be curative. However, when it is detected at later stages (for
which metastases are present), this is less likely and treatment is often directed at palliation, to relieve symptoms
caused by the tumour and keep the person as comfortable as possible.

Surgery
If the cancer is found at a very early stage, it may be removed during a colonoscopy. For people with
localized cancer, the preferred treatment is complete surgical removal with adequate margins, with the attempt
of achieving a cure. This can either be done by an open laparotomy or sometimes laparoscopically. The colon
may then be reconnected or a person may have a colostomy. If there are only a few metastases in the liver or
lungs they may also be removed. Sometimes chemotherapy is used before surgery to shrink the cancer before
attempting to remove it. The two most common sites of recurrence of colorectal cancer are the liver and
lungs.

Chemotherapy
In both cancer of the colon and rectum, chemotherapy may be used in addition to surgery in certain cases.
The decision to add chemotherapy in management of colon and rectal cancer depends on the stage of the
disease. In Stage I colon cancer, no chemotherapy is offered, and surgery is the definitive treatment. The role of
chemotherapy in Stage II colon cancer is debatable, and is usually not offered unless risk factors such as T4
tumor or inadequate lymph node sampling is identified. It is also known that the people who carry abnormalities
of the mismatch repair genes do not benefit from chemotherapy. For stage III and Stage IV colon cancer,
chemotherapy is an integral part of treatment. If cancer has spread to the lymph nodes or distant organs, which
is the case with stage III and stage IV colon cancer respectively, adding chemotherapy agents fluorouracil,
capecitabine or oxaliplatin increases life expectancy. If the lymph nodes do not contain cancer, the benefits of
chemotherapy are controversial. If the cancer is widely metastatic or unresectable, treatment is then palliative.
Typically in this setting, a number of different chemotherapy medications may be used. Chemotherapy drugs
for this condition may include capecitabine, fluorouracil, irinotecan, oxaliplatin and UFT. The drugs capecitabine
and fluorouracil are interchangeable, with capecitabine being an oral medication while fluorouracil being an
intravenous medicine. Some specific regimens used for CRC are FOLFOX, FOLFOXIRI, and FOLFIRI.
Antiangiogenic drugs such as bevacizumab are often added in first line therapy. Another class of drugs used in
the second line setting are epidermal growth factor receptor inhibitors, of which the two FDA approved ones
are cetuximab and panitumumab. The primary difference in the approach to low stage rectal cancer is the
Gastrointestinal 105

incorporation of radiation therapy. Often, it is used in conjunction with chemotherapy in a neo-adjuvant fashion
to enable surgical resection, so that ultimately as colostomy is not required. However, it may not be possible in
low lying tumors, in which case, a permanent colostomy may be required. Stage IV rectal cancer is treated
similar to stage IV colon cancer.

Radiation Therapy
While a combination of radiation and chemotherapy may be useful for rectal cancer, its use in colon cancer
is not routine due to the sensitivity of the bowels to radiation. Just as for chemotherapy, radiotherapy can be
used in the neo-adjuvant and adjuvant setting for some stages of rectal cancer.

Immunotherapy
Immunotherapy with immune checkpoint inhibitors has been found to be useful for a type of colorectal
cancer with mismatch repair deficiency and microsatellite instability. Most people who do improve, however,
still worsen after months or years. Other types of colorectal cancer as of 2017 is still being studied.

Palliative Care
Palliative care is medical care which focuses on treatment of symptoms from serious illness, like cancer, and
improving quality of life. Palliative care is recommended for any person who has advanced colon cancer or has
significant symptoms. Involvement of palliative care may be beneficial to improve the quality of life for both
the person and his or her family, by improving symptoms, anxiety and preventing admissions to the hospital. In
people with incurable colorectal cancer, palliative care can consist of procedures that relieve symptoms or
complications from the cancer but do not attempt to cure the underlying cancer, thereby improving quality of
life. Surgical options may include non-curative surgical removal of some of the cancer tissue, bypassing part of
the intestines, or stent placement. These procedures can be considered to improve symptoms and reduce
complications such as bleeding from the tumor, abdominal pain and intestinal obstruction. Non-operative methods
of symptomatic treatment include radiation therapy to decrease tumor size as well as pain medications.

Follow-up
The aims of follow-up are to diagnose, in the earliest possible stage, any metastasis or tumors that develop
later, but did not originate from the original cancer (metachronous lesions). The U.S. National Comprehensive
Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon
cancer. A medical history and physical examination are recommended every 3 to 6 months for 2 years, then
every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but
are only advised for people with T2 or greater lesions who are candidates for intervention. A CT-scan of the
chest, abdomen and pelvis can be considered annually for the first 3 years for people who are at high risk of
recurrence (for example, those who had poorly differentiated tumors or venous or lymphatic invasion) and are
candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could
not be done during the initial staging because of an obstructing mass, in which case it should be performed after
3 to 6 months. If a villous polyp, a polyp >1 centimeter or high grade dysplasia is found, it can be repeated after
3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year. Routine PET
or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended. A
2016 systematic review concluded that more intense surveillance and close follow-up does not provide additional
survival benefits in non-metastatic colorectal cancers.
106 Surgical Oncology: Theory and Multidisciplinary Practice

Exercise
Exercise may be recommended in the future as secondary therapy to cancer survivors. In epidemiological
studies, exercise may decrease colorectal cancer-specific mortality and all-cause mortality. Results for the
specific amounts of exercise needed to observe a benefit were conflicting. These differences may reflect
differences in tumour biology and expression of biomarkers. Patients with tumors that lacked CTNNB1 expression
(β-catenin), involved in Wnt signalling pathway, required more than 18 Metabolic equivalent (MET) hours per
week, a measure of exercise, to observe a reduction in colorectal cancer mortality. The mechanism of how
exercise benefits survival may be involved in immune surveillance and inflammation pathways. In clinical
studies, a pro-inflammatory response was found in patients with stage II-III colorectal cancer who underwent 2
weeks of moderate exercise after completing their primary therapy. Oxidative balance may be another possible
mechanism for benefits observed. A significant decrease in 8-oxo-dG was found in the urine of patients who
underwent 2 weeks of moderate exercise after primary therapy. Other possible mechanisms may involve metabolic
hormone and sex-steroid hormones, although these pathways may be involved in other types of cancers. Another
potential biomarker may be p27. Survivors with tumors that expressed p27 and performed greater and equal to
18 MET hours per week were found to have reduced colorectal-cancer mortality survival compared to those
with less than 18 MET hours per week. Survivors without p27 expression who exercised were shown to have
worse outcomes. The constitutive activation of PI3K/AKT/mTOR pathway may explain the loss of p27 and
excess energy balance may up-regulate p27 to stop cancer cells from dividing.

PROGNOSIS
In Europe the five-year survival rate for colorectal cancer is less than 60%. In the developed world about a
third of people who get the disease die from it. Survival is directly related to detection and the type of cancer
involved, but overall is poor for symptomatic cancers, as they are typically quite advanced. Survival rates for
early stage detection are about five times that of late stage cancers. People with a tumor that has not breached
the muscularis mucosa (TNM stage Tis, N0, M0) have a five-year survival rate of 100%, while those with
invasive cancer of T1 (within the submucosal layer) or T2 (within the muscular layer) have an average five-year
survival rate of approximately 90%. Those with a more invasive tumor yet without node involvement (T3-4,
N0, M0) have an average five-year survival rate of approximately 70%. Patients with positive regional lymph
nodes (any T, N1-3, M0) have an average five-year survival rate of approximately 40%, while those with distant
metastases (any T, any N, M1) have an average five-year survival rate of approximately 5%. According to
American Cancer Society statistics in 2006, over 20% of people with colorectal cancer come to medical attention
when the disease is already advanced (stage IV), and up to 25% of this group will have isolated liver metastasis
that is potentially resectable. In this selective group, those who undergo curative resection experience a five-
year survival outcome in a third of the cases. Less than 600 genes are linked to outcomes in colorectal cancer.
These include both unfavourable genes, where high expression is related to poor outcome, for example the heat
shock 70 kDa protein 1 (HSPA1A), and favourable genes where high expression is associated with better
survival, for example the putative RNA-binding protein 3 (RBM3).

RECTAL C
RECTAL ANCER
CANCER
The rectum is the last several inches of the large intestine. It starts at the end of the final segment of your
colon and ends when it reaches the short, narrow passage leading to the anus. Cancer inside the rectum (rectal
cancer) and cancer inside the colon (colon cancer) are often referred to together as “colorectal cancer.” While
rectal and colon cancers are similar in many ways, their treatments are quite different. This is mainly because
the rectum sits in a tight space, barely separated from other organs and structures in the pelvic cavity. As a
Gastrointestinal 107

result, complete surgical removal of rectal cancer is challenging and highly complex. Additional treatment is
often needed before or after surgery — or both — to reduce the chance that the cancer will return. In the past,
long-term survival was uncommon for people with rectal cancer, even after extensive treatment. Thanks to
treatment advances over the past 30 years, rectal cancer can now, in many cases, be cured.

SYMPTOMS
Common symptoms include:
• A change in your bowel habits, such as diarrhea, constipation or more-frequent bowel movements
• Dark or red blood in stool
• Mucus in stool
• Narrow stool
• Abdominal pain
• Painful bowel movements
• Iron deficiency anemia
• A feeling that your bowel doesn’t empty completely
• Unexplained weight loss
• Weakness or fatigue.

CAUSES
Rectal cancer occurs when healthy cells in the rectum develop errors in their DNA. In most cases, the cause
of these errors is unknown. Healthy cells grow and divide in an orderly way to keep your body functioning
normally. But when a cell’s DNA is damaged and becomes cancerous, cells continue to divide — even when
new cells aren’t needed. As the cells accumulate, they form a tumor. With time, the cancer cells can grow to
invade and destroy normal tissue nearby. And cancerous cells can travel to other parts of the body. Inherited
gene mutations that increase the risk of colon and rectal cancer In some families, gene mutations passed from
parents to children increase the risk of colorectal cancer. These mutations are involved in only a small percentage
of rectal cancers. Some genes linked to rectal cancer increase an individual’s risk of developing the disease, but
they don’t make it inevitable.
Two well-defined genetic colorectal cancer syndromes are:
• Hereditary non-polyposis colorectal cancer (HNPCC). HNPCC, also called Lynch syndrome, increases the
risk of colon cancer and other cancers. People with HNPCC tend to develop colon cancer before age 50.
• Familial adenomatous polyposis (FAP). FAP is a rare disorder that causes you to develop thousands
of polyps in the lining of your colon and rectum. People with untreated FAP have a greatly increased
risk of developing colon or rectal cancer before age 40.
FAP, HNPCC and other, rarer inherited colorectal cancer syndromes can be detected through genetic testing.
If you’re concerned about your family’s history of colon cancer, talk to your doctor about whether your
family history suggests you have a risk of these conditions.

RISK FACTORS
The characteristics and lifestyle factors that increase your risk of rectal cancer are the same as those that
increase your risk of colon cancer.
They include:
• Older age. The great majority of people diagnosed with colon and rectal cancer are older than 50.
Colorectal cancer can occur in younger people, but it occurs much less frequently.
108 Surgical Oncology: Theory and Multidisciplinary Practice

• African-American descent. People of African ancestry born in the United States have a greater risk
of colorectal cancer than do people of European ancestry.
• A personal history of colorectal cancer or polyps. If you’ve already had rectal cancer, colon cancer
or adenomatous polyps, you have a greater risk of colorectal cancer in the future.
• Inflammatory bowel disease. Chronic inflammatory diseases of the colon and rectum, such as ulcerative
colitis and Crohn’s disease, increase your risk of colorectal cancer.
• Inherited syndromes that increase colorectal cancer risk. Genetic syndromes passed through
generations of your family can increase your risk of colorectal cancer. These syndromes include
FAP and HNPCC.
• Family history of colorectal cancer. You’re more likely to develop colorectal cancer if you have a
parent, sibling or child with the disease. If more than one family member has colon cancer or rectal
cancer, your risk is even greater.
• Dietary factors. Colorectal cancer may be associated with a diet low in vegetables and high in red
meat, particularly when the meat is charred or well-done.
• A sedentary lifestyle. If you’re inactive, you’re more likely to develop colorectal cancer. Getting
regular physical activity may reduce your risk of colon cancer.
• Diabetes. People with poorly controlled type 2 diabetes and insulin resistance may have an increased
risk of colorectal cancer.
• Obesity. People who are obese have an increased risk of colorectal cancer and an increased risk of
dying of colon or rectal cancer when compared with people considered normal weight.
• Smoking. People who smoke may have an increased risk of colon cancer.
• Alcohol. Regularly drinking more than three alcoholic beverages a week may increase your risk of
colorectal cancer.
• Radiation therapy for previous cancer. Radiation therapy directed at the abdomen to treat previous
cancers may increase the risk of colorectal cancer.

PREVENTION
Talk to your doctor about when you should start getting screened for colorectal cancer. Guidelines
generally recommend having your first colorectal cancer screening test at age 50. Your doctor may
recommend more-frequent or earlier screening if you have other risk factors, such as a family history of
colon or rectal cancer.
The most accurate screening test is a colonoscopy. In this test, a doctor examines the lining of your rectum
and large intestine using a long, flexible tube with a tiny video camera at its tip (colonoscope). The colonoscope
is inserted in the anus and advanced through the rectum and colon. As the scope’s camera moves through the
bowel, it sends a video of the rectal and colonic lining to a monitor the doctor sees. If a polyp or suspicious-
looking area of tissue is found, the doctor can also take samples of tissue from these areas with instruments
inserted in the colonoscope.

SUR GIC
SURGIC AL MANA
GICAL GEMENT OF LIVER MET
MANAGEMENT AST
METASTASES FR
ASTASES OM COL
FROM ORECT
COLORECTAL CANCER
ORECTAL
Colorectal cancer is the third most common cancer and the third leading cause of mortality among men and
women. In 2015, there will be an estimated 132,700 new cases and an estimated 49,700 deaths from colorectal
cancer. Approximately 30% to 50% of patients with this disease will develop liver metastases at the time of
presentation or later during the course of their disease. The focus of this article is to discuss the surgical
management of liver metastases in the context of other treatment options available to these patients. Surgical
resection can be curative in a subset of patients with limited disease and favourable biology.
Gastrointestinal 109

TREATMENT OPTIONS
The treatment of patients with metastatic colorectal cancer is multidisciplinary, involving surgeons (surgical
oncologist, hepatobiliary surgeons, and colorectal surgeons), medical oncologists, radiation oncologists, radiology,
interventional radiologists and oncologists, gastroenterologists, and ancillary staff. These patients should be
discussed in a tumor-board fashion and surgeons should be involved early in their care. Several treatment
options are available for patients with colorectal liver metastases, with chemotherapy and surgical resection
forming the backbone of treatment in these patients. There have been several advancements in the field of
chemotherapy, with three major classes of drugs being used: cytotoxic chemotherapy, including fluorouracil
with leucovorin, capecitabine, irinotecan, and oxaliplatin; angiogenesis inhibitors, including bevacizumab, ziv-
aflibercept, and regorafenib; and epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and
panitumumab.
These drugs have been studied extensively in phase III randomized clinical trials. In the United States,
unless otherwise contraindicated, patients receive multidrug regimens, including infusional fluorouracil,
leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without
angiogenesis inhibitors or EGFR inhibitors, on the basis of their expanded RAS (KRAS/NRAS/HRAS/BRAF)
mutational profile, as first-line therapy. Given its increased toxicity, fluorouracil, leucovorin, oxaliplatin, and
irinotecan (FOLFOXIRI) may be considered in highly select patients in whom a high response rate is desired
and an aggressive approach is warranted. Recent trials, including FIRE-3, PEAK, and Cancer and Leukemia
Group B (CALGB)/Southwest Oncology Group (SWOG) 80405, have attempted to compare anti-EGFR regimens
with anti–vascular endothelial growth factor (VEGF) regimens. Anti-EGFR regimens were associated with
higher response rates in the FIRE-3 and PEAK trials and a statistically significant increase in median overall
survival (OS) in the first-line setting (anti-EGFR v anti-VEGF OS: FIRE-3, 28.7 months v 25 months; PEAK,
34.2 months v 24.3 months).

SURGICAL TREATMENT

Hepatic Resection
Hepatic resection remains one of the major curative treatment options available to patients with liver
metastases. Decision making for these patients can be complex and several factors must be considered, including
medical tolerability and technical and oncologic feasibility. Evaluation for medical fitness remains paramount
before embarking on any treatment option in these patients.

Preoperative Imaging to Evaluate the Extent of Disease

A high-quality, preoperative, triple-phase computed tomography (CT) scan with thin cuts or a contrast-
enhanced dynamic magnetic resonance imaging (MRI), preferably with liver-specific contrast agents such as
gadoxetate disodium, is paramount to preoperative evaluation of liver metastases in these patients. In addition,
a complete staging work-up, including colonoscopy and chest CT in patients who had CT of the abdomen and
pelvis, or chest, abdomen, and pelvis CT in patients who were evaluated by liver MRI, is essential for evaluation
of extrahepatic disease.
The role of positron emission tomography/CT in colorectal liver metastases remains controversial, and
recent studies have questioned its routine use. The two goals of preoperative imaging are to identify the extent
of liver metastasis, and to determine the presence of any extrahepatic disease. Figure shows how proper imaging
can improve the detection of liver metastases.
110 Surgical Oncology: Theory and Multidisciplinary Practice

Fig. Role of appropriate imaging. An appropriately timed computed tomography (CT) scan with thin slices
can enhance the detection of liver metastases. (A) Regular CT scan with thick slices. (B) Thin-cut CT scan
with enhanced visualization of segment 7 lesion (arrow).

Limits of Resection
Historically, several criteria, which were based on size and number of metastases, expected margin of resection,
and presence of extrahepatic disease, excluded patients from undergoing liver resection. However, the availability
of portal vein embolization, ablation techniques, two-stage hepatectomies, preoperative chemotherapy, and
resections in the setting of extrahepatic metastases have led to a paradigm shift and an increase in number of
complex resections. In simplified terms, the focus of surgical resection has shifted from what is being removed
to what is being left behind. The limits of technical resection include leaving behind at least two contiguous
liver segments with adequate vascular inflow and outflow, adequate biliary drainage, and an adequate future
liver remnant. The terminology used for hepatic resection has been standardized. Most experts consider removal
of three or more segments as major hepatectomy. Decision making before surgery involves evaluation for the
following: number, size, and location of lesions and their relationship to inflow and outflow vessels; subtle
radiologic signs such as fatty liver disease and signs of portal hypertension such as splenomegaly (low platelet
count and impaired liver function tests can be an indicator of underlying liver damage); portal and retroperitoneal
lymphadenopathy; peritoneal carcinomatosis; other areas of metastases, including lung, mediastinum, bone,
etc; and size and function of the future liver remnant.

Evaluation of Future Liver Remnant Volume

Major or extended hepatectomy may lead to an inadequate future liver remnant that can be associated with
significant risk of hepatic insufficiency and subsequent mortality. Although the risk of hepatic insufficiency is
determined by several factors, the size of the future liver remnant continues to be one of the major determinants of
postoperative hepatic failure. Precise measurements of hepatic volume are needed before operating on any patient
who is likely to be left with an inadequate future liver remnant, because the size of the right and left hemilivers
varies considerably among the patients. The size of the future liver remnant can be calculated using three-dimensional
CT volumetry. The size of the future liver remnant has been used as a surrogate to predict postoperative outcomes.
In patients with normal liver function, a future liver remnant of at least 20% is recommended. For patients with
cirrhosis and for those treated with systemic chemotherapy because of the underlying liver dysfunction, a larger
future liver remnant size is recommended (40% for cirrhosis, 30% after systemic chemotherapy).

Portal Vein Embolization

A small future liver remnant may increase the risk of posthepatectomy liver failure; however, this can be
avoided by inducing ipsilateral atrophy of the tumor-bearing liver and compensatory hypertrophy of the future
Gastrointestinal 111

liver remnant by selectively occluding the blood flow to the tumor-bearing part of the liver. Portal vein
embolization is offered to patients with normal liver function and a future liver remnant of 25% to 30% and to
those with compromised liver function, such as postchemotherapy liver damage, cirrhosis/fibrosis, and cholestasis
and a future liver remnant of 35% to 40%. In the post–portal vein embolization period, the future liver remnant
undergoes rapid hypertrophy in the ensuing 3 to 4 weeks. In patients who have diabetes and cirrhosis, the
hypertrophy may be delayed, and an additional 3 to 4 weeks may be required to assess the complete response.
Figure shows the increase in the volume of the remnant liver after portal vein embolization.

Fig. Liver hypertrophy after portal vein embolization (PVE). (A, before; B, after) Shaded area
in green depicts increase in volume of the left lateral segment after PVE of the right side.
A recent meta-analysis by van Lienden et al has shown that the mean technical success rate of the procedure
is 99.3% and that 96.1% of patients undergo sufficient hypertrophy of the future liver remnant to allow resection.
The mean increase in future liver remnant size is 37.9% (range, 20.5% to 69.4%). Chemotherapy does not seem
to affect the hypertrophy, whereas patients with cirrhosis and fibrosis tend to undergo less hypertrophy than do
patients with normal livers. Less than 1% of patients may develop severe complications in the form of severe
cholangitis, liver abscesses, sepsis, or portal venous or mesentericoportal venous thrombosis precluding liver
resection. The originally planned liver resection may not be possible in approximately 20% of patients because
of intrahepatic tumor progression, extrahepatic tumor spread, insufficient hypertrophy, major complications, or
preoperative mortality or if the patient refuses. Portal vein embolization can be used as a stress test for the liver.
Patients who undergo sufficient hypertrophy may do well with resection, whereas those with insufficient
hypertrophy are more likely to experience complications and posthepatectomy liver failure. Similarly, any
disease progression seen during the period of portal vein embolization indicates aggressive tumors to begin
with, and resection may not change the course of the disease. Technical factors that can enhance hypertrophy
after portal vein embolization include embolization of segment 4 branches during right portal vein embolization
and the use of small spherical particles. All three of the following criteria should be taken into consideration to
prevent posthepatectomy liver failure: absolute increase of 5%; kinetic growth rate of ≥ 2% per week of the
future liver remnant; and overall size of future liver remnant (> 30% after chemotherapy, > 40% for early
cirrhosis or fibrosis).

Margins of Resection
R0 resection margins are the goal of surgical resection. A positive margin increases the risk of local recurrence
and compromises long-term survival. Older studies showed an advantage of a 1-cm resection margin over just
achieving a negative margin; however, studies performed in the era of modern chemotherapy argue that the
extent of the negative margin has minimal impact on the outcome. In addition, as more and more complex
resections are being undertaken, a 1-cm margin is not always feasible. The goal of surgery is to achieve an R0
resection margin.
112 Surgical Oncology: Theory and Multidisciplinary Practice

Chemotherapy: Resectable Versus Unresectable Disease

The role of adjuvant therapy in patients with resectable liver metastases is controversial. EORTC 40983
randomly assigned patients with resectable liver metastases to perioperative chemotherapy (FOLFOX4) versus
surgery alone. The use of perioperative chemotherapy resulted in an improvement in progression-free survival;
however, long-term data did not show any statistically significant benefit in OS. The advantages of chemotherapy
in patients with resectable disease remain controversial; however, most surgical oncologists recommend a short
course of chemotherapy 2 to 3 months before surgical resection to assess tumor response to systemic therapy.
Long periods of systemic therapy before resection can lead to two issues: chemotherapy-induced liver injury or
steatohepatitis, and disappearing colorectal liver metastases. In contrast to the treatment of resectable liver
metastases, chemotherapy remains the mainstay of therapy for patients with unresectable liver metastases.
With the advent of modern chemotherapy regimens, response rates to first-line chemotherapy using FOLFOX/
FOLFIRI and biologic agents, such as VEGF inhibitor or EGFR inhibitors, are up to 60% to 70%, and median
survival is up to 34 months in patients with metastases. However, progression-free survival still averages 10
months, and response rates in the second-line setting average only 30%. With modern chemotherapy, a subset
of patients (approximately 15% to 40%) with unresectable disease may convert to resectable disease, and these
patients have a long-term outcome comparable to those with an original diagnosis of resectable disease (ie, a 5-
year survival of 30% to 40%). Patients receiving chemotherapy who continue to have unresectable disease
either because of lack of adequate response or because of progression of disease have a poor prognosis. In
addition to the improved efficacy of systemic chemotherapy, factors that have contributed to the increase in
secondary resection rates include portal vein embolization, two-stage hepatectomies, ablation techniques,
expanding criteria for resection, and improved surgical and parenchymal transection techniques.

Two-stage Hepatectomy
In patients presenting with unresectable bilobar liver metastases who respond to systemic chemotherapy, a
two-stage hepatectomy approach has been proposed. Most of these patients have synchronous metastases at the
time of presentation.

Fig. Two-stage hepatectomy. Minor disease is resected first, followed by contralateral

portal vein embolization to maximize future liver remnant before major hepatectomy.
Gastrointestinal 113

In addition, one side of the liver is less affected than the other. In these patients, a limited resection could
clear the less affected side of the liver before the patient undergoes a future contralateral liver resection. In the
majority of these patients, systemic chemotherapy is administered initially, followed by a limited resection of
the left side. Right portal vein and segment 4 branch embolization is used next to increase the size of the left
lateral sector, and these patients then undergo an extended right hepatectomy. Figure depicts an example of a
patient who underwent this approach. Brouquet et al reported that 72% of the patients selected for this approach
were able to complete the second stage of the procedure. Progression of the disease was the main cause (61%)
for non-completion of the second stage.
After a median follow-up of 50 months, 5-year survival was 51% in the two-stage hepatectomy group compared
with 15% in those treated by chemotherapy alone. Lam et al performed a systematic review on the topic and
included 10 studies with a total of 459 patients in their quantitative analysis. Seventy-seven percent of the
patients were able to undergo the planned second stage, and the median survival of this cohort was 37 months.
In selected patients with unresectable bilobar colorectal liver metastases, a two-stage hepatectomy seems to be
safe. The duration of preoperative and interval chemotherapy between the two stages varies among institutions
and must be decided on a case-by-case basis.
There are several different possibilities for treatment sequencing:
• Chemotherapy, hepatectomy (first stage), hepatectomy (second stage), then chemotherapy;
• Chemotherapy, hepatectomy (first stage), portal vein embolization, hepatectomy (second stage), then
chemotherapy; and
• Chemotherapy, hepatectomy (first stage), portal vein embolization, chemotherapy (second stage),
hepatectomy, then chemotherapy.

Chemotherapy-associated Liver Injury or Steatohepatitis

The majority of patients receive chemotherapy before liver resection, with FOLFOX and FOLFIRI forming
the backbone of modern-day chemotherapy. Longer durations of chemotherapy are being used to increase cure
rates in resectable cases and for conversion therapy (ie, to convert unresectable to resectable disease); however,
the use of more than eight cycles of chemotherapy leads to chemotherapy-associated liver injury, without
increasing response rates. Therefore, longer durations of chemotherapy should be avoided, and liver surgeons
should be involved from the beginning in the multidisciplinary care of patients with colorectal liver metastases.
The goal of chemotherapy should be to facilitate resection rather than to maximize the response before resection.
Oxaliplatin is associated with sinusoidal damage, which can appear as blue liver intraoperatively. Therefore, a
longer duration of oxaliplatin therapy can give rise to portal hypertension, often noted on the preoperative CT
scan as splenomegaly and ascites. In addition, blue liver leads to increased perioperative blood loss without
increasing mortality. Irinotecan is associated with steatohepatitis, especially in patients with obesity and diabetes,
resulting in yellow liver. Irinotecan-associated steatohepatitis has been shown to increase the risk of
posthepatectomy liver failure; however, more recent data suggest that morbidity is not influenced by the type of
chemotherapy used.

Disappearing Liver Metastases

The response rates to modern chemotherapy have increased, resulting in complete radiographic response in
some patients; the lesions in these cases are termed disappearing liver metastases. The incidence of disappearing
liver metastases varies from 7% to 24%. Approximately 10% to 50% of these lesions can be detected in the
operating room. Disappearing liver metastases are more likely to occur in patients with smaller tumors or
multiple tumors and in those undergoing an increasing number of cycles of chemotherapy. The incidence of
114 Surgical Oncology: Theory and Multidisciplinary Practice

disappearing liver metastases varies with the imaging modality used. MRI with the appropriate contrast medium
has the highest sensitivity and specificity. Limiting the duration of chemotherapy to less than 3 months also
helps limit the number of disappearing liver metastases. Complete pathologic response is seen in approximately
two thirds of resected disappearing liver metastases. However, if left in situ, more than one half of these lesions
will recur. Factors associated with true pathologic response are seen in patients who undergo hepatic artery
infusion therapy, have normalization of carcinoembryonic antigen (CEA), underwent MRI as preoperative
imaging, have no steatosis, and have a body mass index less than 30. Rubbia-Brandt et al reported that pathologic
tumor regression corresponds to fibrosis overgrowth and a decrease in necrosis.
The degree of tumor regression predicts disease-free survival and OS, independent of the neo-adjuvant
chemotherapy used. Oxaliplatin-containing regimens are associated with higher tumor regression compared
with irinotecan-containing regimens. However, complete sterilization of the tumor after chemotherapy is rare
(< 5%), which further supports the notion of the resection of disappearing liver metastases. The management of
disappearing liver metastases remains controversial. Resection is the usual recommended treatment, if resection
of all original sites of disappearing liver metastases is feasible. If the original sites cannot be resected, it is
reasonable to resect macroscopic disease and leave disappearing liver metastases in situ because more than one
half of these tend to recur within a year. A recent study suggests that surveillance of disappearing liver metastases
after systemic chemotherapy was more beneficial and cost effective among patients older than 60 years and
with multiple factors predictive of true complete, pathologic response, such as normalization of CEA, hepatic
artery infusion therapy, body mass index ≤ 30 kg/m, and diagnosis of disappearing liver metastases made
through MRI.

Survival
Overall, 5-year survival after resection in patients with colorectal liver metastases varies from 40% to 60%
in large series, and 10-year survival is up to 30% in some series. Two large series of more than 2,000 patients
reported a 5-year survival of approximately 40%. Resection can be curative in a subset of patients with limited
disease and favourable biology; however, more than two thirds of these patients will have recurrences, and
most of these tend to occur within the first 2 years. Patient selection is the key. Several prognostic models have
been devised to act as adjunctive tools for patient selection, postoperative prognostication, and further
substratification for use of adjuvant therapy. The clinical risk score proposed by Fong et al in 1999 remains one
of the most commonly used prognostic scoring systems for resection of colorectal liver metastases. Some of the
scoring systems proposed by others have been discussed in detail elsewhere. Nodal status of the primary tumor,
disease-free interval, CEA levels, liver tumor burden, and the presence of extrahepatic disease remain some of
the common factors included in these scoring systems. Poor predictors include an increasing number and size
of the metastatic tumors, positive nodal status of the primary tumor, short disease-free interval, and high CEA.
Lack of tumor regression after chemotherapy also portends poor prognosis. Recently, molecular factors, such
as the presence of KRAS mutation and BRAF mutation, have been associated with poor prognosis.

HEREDITAR
HEREDITARYC
ARY OL
COLORECT
OLORECTAL C
ORECTAL ANCER AND POL
CANCER YPOSIS SYNDR
POLYPOSIS OMES
SYNDROMES

HEREDITARY COLORECTAL SYNDROMES

The following rare hereditary colorectal syndromes are precancerous conditions of the colon or rectum.
They cause many polyps to develop in the colon and rectum. These syndromes are caused by a mutated, or
changed, gene that can be passed from parents to children. They increase the risk of developing colorectal
cancer.
Gastrointestinal 115

• Lynch syndrome is also called hereditary non-polyposis colorectal cancer (HNPCC). It is the most
common type of hereditary colorectal syndrome. Most people with Lynch syndrome do not have an
unusual number of polyps, which are small growths on a mucous membrane. If they do have polyps,
they occur at an earlier age than in the general population and are more likely to become cancerous.
• Familial adenomatous polyposis (FAP) causes hundreds to thousands of polyps to develop on the
lining of the colon and rectum.
• Peutz-Jeghers syndrome causes many hamartomas, or hamartomatous polyps, to grow in the digestive
tract, including the colon and rectum.
• Juvenile polyposis syndrome causes hamartomas to grow in the digestive tract, including the colon
and rectum. These hamartomas usually form before age 20. Some people with this syndrome develop
only a few hamartomas in the digestive tract. Other people can have over 100 hamartomas.

Risk Factors
Your risk of having a hereditary colorectal syndrome depends on if family members have one of the mutated
genes linked to the syndrome.

Symptoms
The symptoms of a hereditary colorectal syndrome depend on the type of syndrome and the number of
polyps in the colon and rectum. You may not have any symptoms.
When there are many polyps, they can cause:
• Changes in bowel habits
• Bleeding from the rectum
• Pain or discomfort in the abdomen
• Anemia
• Blockage in the intestine (called bowel obstruction)
• Part of the intestine slides into another nearby part of the intestine.

Diagnosis
If you have symptoms or your doctor thinks you might have a hereditary colorectal syndrome, you will be
sent for tests.
Tests used to diagnose a hereditary colorectal syndrome may include:
• Gastroscopy (a type of endoscopy that looks at the inside of the esophagus and stomach)
• Colonoscopy
• Biopsy
• Genetic testing.

Treatment and Follow-up

Treatments offered for hereditary colorectal syndromes depend on the number of polyps and if you have symptoms.
Treatments may include:
• Removal of polyps (called polypectomy)
• Bowel resection with total colectomy or proctocolectomy.
You will have regular screening with colonoscopy or sigmoidoscopy, as well as other tests. These tests are
done to check the polyps and find cancer if it develops.
116 Surgical Oncology: Theory and Multidisciplinary Practice

CYTOREDUCTIVE SUR
CYT GER
SURGERY AND HYPER
GERY THERMIC INTR
HYPERTHERMIC APERIT
INTRAPERIT ONEAL
APERITONEAL
CHEMO THER
CHEMOTHER APY
THERAPY
In Peritoneal surface malignancies (PSM), tumor location is restricted to the abdominal cavity as opposed to
systemic metastatic disease. In the past, the majority of PSM patients underwent systemic chemotherapy which
was associated with poor quality of life and was ineffective with respect to prolonging survival. Thanks to the
pioneer work of Professor Paul Sugarbaker, a proactive surgical approach termed cytoreductive surgery (CRS),
aiming for maximal tumor resection, along with hyperthermic intraperitoneal chemotherapy (HIPEC) evolved
into a highly relevant treatment option for selected patients with limited peritoneal spread of various tumor
entities. The rationale for this particular approach is the restriction of tumor dissemination to the peritoneal
compartment justifying a radical surgical procedure followed by HIPEC. Although there is now evidence for
the superiority of CRS and HIPEC to systemic chemotherapy, this strategy has not made its way into clinical
routine since peritoneal spread is still considered as stage IV cancer when surgical resection is not an option any
more. However, there was a similar thinking for colorectal liver metastasis for a long time. Now, surgery
represents the main strategy even though its superiority has never been proven in a randomized phase III trial.
If cytoreductive surgery is scheduled, proactive surgery achieving total or almost total (remaining nodules < 2.5
mm) cytoreduction has to be the main aim In addition, hyperthermic intraperitoneal chemotherapy is administered
for eradication of microscopic residual disease. The most frequently cited paper on this topic was published by
Verwaal et al who first proved the benefit of this multimodal approach in a phase III trial comparing patients
with colorectal cancer undergoing CRS and HIPEC followed by systemic chemotherapy with systemic
chemotherapy. Up to now, there are several reports on long term survival if radical resection was performed.
Other entities for which this treatment is accepted are pseudomyxoma peritonei and mesothelioma. For selected
patients with ovarian and gastric cancer this option can be offered with good results. Since survival does not
significantly differ between completeness of cytoreduction CC0 or CC1, an oncologic resection with wide
resection margins seems not necessary in this content except for primary gastrointestinal cancer with peritoneal
carcinomatosis PC.

INTERDISCIPLINARY CONCEPT
The implementation of many new centers for PSM could mean that more and more patients are asking for
this therapeutic option. However, the perioperative setting has to be established first rather than the surgical
one. An experienced radiologist is mandatory to assess preoperative tumor load and to rule out contraindications
such as diffuse infiltration of the small bowel or extraperitoneal disease. The anaesthesiologists, nurses and
HIPEC technicians should visit centers and participate in workshops for HIPEC before initiating the programme.
Lastly, the medical oncologist becomes more and more important because there are numerous different
intraperitoneal as well as pre- and postoperative chemotherapy regimens. The founding of a peritoneal surface
malignancy group which meets regularly has had a great impact on scientific discussion between surgeons,
radiologists, anaesthesiologists. In addition, this facilitates the initiation of clinical multi-center and experimental
studies.

HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY

In most cases, intraperitoneal chemotherapy is administered after cytoreductive surgery and completion of
intestinal anastomoses, either immediately intraoperatively (HIPEC) or early postoperatively (EPIC). Technically,
this chemotherapy can be applied to an open or closed abdomen which varies between the different centers. The
rationale of HIPEC is the synergistic cytotoxic effect of heat, ideally 42-43 degree Celcius, and the
chemotherapeutic agent itself on tumor cells. There are various concepts varying in duration of exposition, in
Gastrointestinal 117

combination with for example intraoperative intravenous therapy and in type of the administered chemotherapy.
The effect of hyperthermic intraperitoneal chemotherapy itself has never been proven in a randomized controlled
trial and is still the focus of ongoing investigations. Nevertheless, there are numerous data of how HIPEC might
work and most surgeons, medical oncologists and last but not least patients believe in the effect of local
chemotherapy. The rationale for applying intraoperative chemotherapy under hyperthermic conditions is
improving both tissue as well as tumor oxygenation by vasodilation enhancing the cytotoxic effect of
chemotherapeutic agents. So far, however, nobody has demonstrated an effect on hyperthermia on tissue
oxygenation and there is no data whether this putative effect on pO2 (oxygen) might be sustained throughout
the entire HIPEC period. As learned from wound healing research, supplemental oxygen during HIPEC might
further enhance cytotoxicity since it has been shown to increase tissue oxygen tension. In addition of thinking
about the best timing for HIPEC, HIPEC in combination with supplemental oxygen could be a worthwhile
option in the future. Another future important issue could be testing chemotherapeutic sensitivity to improve
the cytotoxic effect of HIPEC. Such particular tests already exist for ovarian cancer with respect to platinum
resistance. This further strengthens the need for personalized intraoperative chemotherapy regimens.

NEO-ADJUVANT CHEMOTHERAPY
A quite high percentage of patients is not eligible for cytoreductive surgery at the time of surgical exploration.
Therefore, tumor downsizing by systemic chemotherapy and subsequent surgery might be an option. In liver
surgery, the concept of secondary resection after chemotherapy, both intravenous as well as regionally, is accepted
and response to preoperative chemotherapy can be considered as a prognostic factor. In PSM, neo-adjuvant
chemotherapy might also aid in categorizing patients in responders and non-responders with responders being
more likely to profit from CRS and HIPEC. One limitation is the difficulty to evaluate response to chemotherapy
since computed tomography (CT) or positron emission tomography (PET)/CT often do not sufficiently show
tumor spread. One ongoing phase II trial in Germany addressing perioperative chemotherapy is the COMBATAC
trial (multimodality treatment including neo-adjuvant and adjuvant chemotherapy with cetuximab and CRS
and HIPEC).

ORGAN PRESERVING CYTOREDUCTIVE SURGERY

Radical cytoreduction is many times associated with multivisceral resection because of diffuse organ
infiltration. When performing cytoreductive surgery, the surgeon should, however, aim for preserving as many
organs as possible. Moreover, the surgeon should leave as much as possible behind but without any oncological
compromise. This approach seems quite unfamiliar to surgeons who do not deal with peritoneal metastases. In
many cases, the small/large bowel can be preserved when addressed with patience for meticulous tumor resection
since tumor nodules are mainly located on the peritoneal surface and can be removed without opening the
bowel in most cases unless there is infiltrative growth. From an oncologic point of view, a radical oncologic
colon resection, except in primary colorectal cancer with peritoneal spread is not necessary in our opinion. The
surgical expertise should ideally include a broad surgical spectrum especially colorectal surgery. One technical
challenge is certainly the liver hilus with the sulcus rex, sulcus arancii and segment 1 region which is very
demanding to dissect with the risk of biliary or vascular damage when a certain experience in liver surgery is
helpful.

SECOND LOOK SURGERY

Peritoneal carcinomatosis index (PCI), representing intraabdominal tumor load is a prognostic factor for
survival. The lower the PCI, the better the prognosis maybe also due to the fact that a complete cytoreduction
118 Surgical Oncology: Theory and Multidisciplinary Practice

becomes more likely. Clinical signs of peritoneal metastases are often not specific and current imaging
methods often do not detect small tumor nodules. Given these findings, a second look protocol with a re-
laparotomy within one year of colorectal surgery in high risk patients was proposed. The high risk patient for
developing PSM suffers from either a perforated tumor or a local peritoneal spread at the time of primary
surgery. Current data revealed quite a high percentage of PSM in those patients. The second look protocol
was firstly described by Elias et al. Predicting the development of PSM in high risk patients is certainly a
mile stone in the treatment of peritoneal metastases. Although this approach is pro-active, it may further
prolong survival in those patients. The administration of HIPEC even in a patient without macroscopic
peritoneal disease needs further to be elucidated in randomized trials but seems to be promising so far. The
“ProphyloCHIP” trial (Trial Comparing Simple Follow-up to Exploratory Laparotomy Plus “in Principle”
HIPEC in Colorectal Patients) run by Prof Elias is addressing this particular point. In this randomised phase
III trial, colorectal cancer patients at risk to develop PC receive standard adjuvant chemotherapy after curative
resection. After having excluded recurrent disease within 6 mo of follow-up they are randomised to either
surveillance alone or explorative laparotomy and HIPEC. With this proactive approach, disease free and
overall survival may be increased.

SQUAMOUS CELL CAR

SQUAMOUS CINOMA OF THE ANAL MAR
CARCINOMA GIN
MARGIN
Squamous cell carcinoma of the anal margin or perianal skin is relatively uncommon, and most physicians,
even those practicing at large referral centers, encounter very few patients with this entity. The goal of
treatment is to cure the patient while preserving anal function, thus avoiding a permanent colostomy.
Traditionally, treatment has consisted of either local excision or, in advanced cases, abdominoperineal resection
(APR). In recent years, a few centers have reported promising results with radiotherapy alone or combined
with concomitant chemotherapy. The purpose of this paper is to review the epidemiology, diagnosis, staging,
natural history, and results of treatment for this disease. Squamous cell carcinoma of the anal margin is
defined as a lesion originating between the dentate line and the outer limit of the perianal skin, defined to be
5 cm from the anal verge in any direction. These lesions represent only one-fourth to one-third of all squamous
cell carcinomas of the anus and should be distinguished from squamous cell carcinoma of the anal canal,
which has a different natural history and a less favourable prognosis. Most patients with anal margin carcinoma
are 60 to 70 years old, but the age range of affected individuals is wide (approximately 25 to 90 years).
Although some authors have observed a slight female preponderance, others have reported that the disease is
more likely to occur in men.

DIAGNOSIS AND STAGING

Jensen et al observed the following symptoms in 76 patients with squamous cell carcinoma of the anal
margin treated in Denmark: palpable mass (100%), bleeding (78%), pain (70%), change in bowel habits (29%),
discharge (20%), and pruritus ani (20%). The median duration of symptoms was 6 months (range, 2 to 60
months). Associated condylomata and chronic fistulae are observed in approximately 15% of patients. Jensen
et al observed that an erroneous diagnosis was made at the first physician visit in 29% of patients with squamous
cell carcinoma of the anal margin, as compared with 55% of 125 patients with squamous cell carcinoma of the
anal canal. The majority of anal margin tumors tend to be well- or moderately differentiated keratinizing squamous
cell carcinomas; less than 10% of lesions are poorly differentiated or cloacogenic carcinomas. Squamous cell
carcinoma of the anal margin is staged according to either the American Joint Committee on Cancer (AJCC) or
Union Internationale Contre le Cancer (UICC) staging system. The AJCC staging system for anal margin
carcinoma is the same one used for other skin cancers (Table) and differs from the staging system used for the
anal canal. The AJCC and UICC systems for anal margin carcinoma are virtually identical.
Gastrointestinal 119

NATURAL HISTORY AND SPREAD PATTERNS

The primary tumor usually starts as a slow-growing nodule that remains localized to the perianal skin until
late in the course of the disease, when it may invade the anal canal. The lesion is usually ulcerated and may have
a significant palpable subcutaneous component. The sphincter muscle is rarely invaded. The distribution of
primary tumor size varies, depending on referral patterns. Pinna Pintor et al found the following UICC T-stage
distribution in 83 patients treated at St. Mark’s Hospital for Diseases of the Colon and Rectum in London: stage
T1, 14%; stage T2, 50%; stage T3, 32%; and stage T4, 4%. The medial inguinal nodes are the first-echelon
lymph node drainage for the anal margin, whereas the perirectal nodes are the first-echelon drainage for the
anal canal. The iliac nodes are also occasionally involved. The incidence of inguinal lymph node involvement
is approximately 15% to 25%, and is related to the size and histologic differentiation of the primary tumor.
Cummings et al reported on the relationship between primary tumor diameter and the risk of inguinal lymph
node invasion at diagnosis in a series of 29 patients treated at the Princess Margaret Hospital, Toronto. They
found inguinal node invasion in 0 of 13 (0%) of patients with tumors less than 5 cm in diameter, as compared
with 4 of 16 (25%) of those with tumors 5 cm or more. In 57 patients, Papillon and Chassard documented the
following rates of inguinal lymph node involvement, according to primary tumor size: less than 2 cm, 0 of 10
(0%); 2 to 5 cm, 9 of 38 (24%); and 5 cm or more, 6 of 9 (67%). Distant metastases are rare at presentation. The
pretreatment evaluation of the patient should take into account the spread patterns of the disease and should
include a chest roentgenogram and CT scan of the abdomen and pelvis. Computed tomography is obtained to
evaluate the presence and extent of lymph node metastases, exclude the unlikely possibility of liver metastases,
and complement the physical examination of the primary lesion.

SURGICAL MANAGEMENT
Early lesions of the anal margin may be successfully treated with local excision; a skin graft may be necessary
if the surgical defect cannot be closed primarily or healed by secondary intention. An APR is necessary for
resection of more advanced lesions. The inguinal lymph nodes are not dissected unless they are deemed to
harbour metastatic disease. Greenall et al reported on 31 patients treated with local excision alone at Memorial
Sloan-Kettering Cancer Center between 1950 and 1978. Local recurrence alone developed in nine patients
(29%), one patient had recurrences at both the primary site and the inguinal lymph nodes, and isolated inguinal
node metastases developed in three patients. Of the nine patients who experienced a local recurrence alone,
eight underwent a second local excision and one required an APR. The 5-year absolute and cause-specific
survival rates were 68% and 88%, respectively. Greenall et al described an additional 11 patients who underwent
a primary APR; one patient died postoperatively and two patients died secondary to recurrence. Seven patients
(64%) were alive and disease-free 5 years or more after surgery. At the Cleveland Clinic, 10 patients were
treated with local excision between 1951 and 1971, as reported by Al-Jurf et al. Local recurrence developed in
3 patients (30%), 2 of whom were salvaged by a second local excision. Seven patients were alive and disease-
free at 5 years or more, one patient died of intercurrent disease at 15 months, one patient was alive with disease
at 6 years, and one patient died of disease at 8 years. Schraut et al reported on 16 patients treated surgically at
the University of Chicago. The disease was controlled in 9 of 11 patients after a local excision and in 4 of 5 after
an APR. Beahrs and Wilson described 27 patients treated with local excision for in situ or superficial squamous
cell carcinoma of the anal margin at the Mayo Clinic between 1950 and 1970. The local control rate was not
stated; all patients apparently survived 5 years. In a series of 49 patients who underwent local excision alone or
combined with radiotherapy at St. Mark’s Hospital for Diseases of the Colon and Rectum, London, the 5-year
absolute and cause-specific survival rates were 65% and 68%, respectively. An additional 16 patients underwent
an APR alone or combined with radiotherapy; 5-year absolute and cause-specific survival rates were 38% and
40%, respectively. Local control rates after surgery were not presented.
120 Surgical Oncology: Theory and Multidisciplinary Practice

RADIATION THERAPY
Superficial, well-differentiated T1 and early T2 lesions may be irradiated through a perineal field alone
using either cobalt-60 or an electron beam. The inguinal nodes should be electively irradiated in patients with
more advanced and/or poorly differentiated lesions. In patients presenting with inguinal lymph node metastases
and/or advanced T3 and T4 primary lesions, the pelvic lymph nodes are also treated.

ADJUVANT CHEMOTHERAPY
Very limited data are available on the role of adjuvant chemotherapy in squamous cell carcinoma of the anal
margin. In addition to these data, one may extrapolate information on anal canal carcinoma, for which the value
of chemotherapy is better defined. In a study by Cummings et al, local control was obtained in 7 of 11 patients
(64%) treated with radiotherapy alone, as compared with 15 of 17 patients (88%) treated with radiotherapy and
concomitant fluorouracil and mitomycin. Adjuvant concomitant chemotherapy is probably indicated for patients
with tumors that are poorly differentiated, 5 cm or more, and/or associated with inguinal node metastases.
Currently, the optimal chemotherapy regimen consists of two cycles of fluorouracil and mitomycin, although it
may be possible to substitute cisplatin for mitomycin to decrease toxicity without sacrificing efficacy.
Endocrine 121

Chapter 4

Endocrine

THYR OID CANCER

THYROID
Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells
grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or
a lump in the neck. Cancer can also occur in the thyroid after spread from other locations, in which case it is not
classified as thyroid cancer. Risk factors include radiation exposure at a young age, having an enlarged thyroid,
and family history. There are four main types – papillary thyroid cancer, follicular thyroid cancer, medullary
thyroid cancer, and anaplastic thyroid cancer.
Diagnosis is often based on ultrasound and fine needle aspiration. Screening people without symptoms and
at normal risk for the disease is not recommended as of 2017. Treatment options may include surgery, radiation
therapy including radioactive iodine, chemotherapy, thyroid hormone, targeted therapy, and watchful waiting.
Surgery may involve removing part or all of the thyroid. Five year survival rates are 98% in the United States.
Globally as of 2015 3.2 million people have thyroid cancer. In 2012, 298,000 new cases occurred. It most
commonly occurs between the ages of 35 and 65. Women are affected more often than men. Those of Asian
descent are more commonly affected. Rates have increased in the last few decades which is believed to be due
to better detection. In 2015 it resulted in 31,900 deaths.

SIGNS AND SYMPTOMS

Most often the first symptom of thyroid cancer is a nodule in the thyroid region of the neck. However, many
adults have small nodules in their thyroids, but typically under 5% of these nodules are found to be cancerous.
Sometimes the first sign is an enlarged lymph node. Later symptoms that can be present are pain in the anterior
region of the neck and changes in voice due to an involvement of the recurrent laryngeal nerve. Thyroid cancer
is usually found in a euthyroid patient, but symptoms of hyperthyroidism or hypothyroidism may be associated
with a large or metastatic well-differentiated tumor. Thyroid nodules are of particular concern when they are
found in those under the age of 20. The presentation of benign nodules at this age is less likely, and thus the
potential for malignancy is far greater.

CAUSES
Thyroid cancers are thought to be related to a number of environmental and genetic predisposing factors,
but significant uncertainty remains regarding their causes. Environmental exposure to ionizing radiation
from both natural background sources and artificial sources is suspected to play a significant role, and there
are significant increased rates of thyroid cancer in those exposed to mantlefield radiation for lymphoma, and
those exposed to iodine-131 following the Chernobyl, Fukushima, Kyshtym, and Windscale nuclear disasters.
122 Surgical Oncology: Theory and Multidisciplinary Practice

Thyroiditis and other thyroid diseases also predispose to thyroid cancer. Genetic causes include multiple
endocrine neo-plasia type 2 which markedly increases rates, particularly of the rarer medullary form of the
disease.

DIAGNOSIS
After a thyroid nodule is found during a physical examination, a referral to an endocrinologist or a
thyroidologist may occur. Most commonly an ultrasound is performed to confirm the presence of a nodule and
assess the status of the whole gland. Measurement of thyroid stimulating hormone and anti-thyroid antibodies
will help decide if there is a functional thyroid disease such as Hashimoto’s thyroiditis present, a known cause
of a benign nodular goiter. Measurement of calcitonin is necessary to exclude the presence of medullary thyroid
cancer. Finally, to achieve a definitive diagnosis before deciding on treatment, a fine needle aspiration cytology
test is usually performed and reported according to the Bethesda system. In adults without symptoms screening
for thyroid cancer is not recommended.

Classification
Thyroid cancers can be classified according to their histopathological characteristics.
The following variants can be distinguished (distribution over various subtypes may show regional
variation):
• Papillary thyroid cancer (75% to 85% of cases) – often in young females – excellent prognosis.
May occur in women with familial adenomatous polyposis and in patients with Cowden syndrome.
• Newly reclassified variant: non-invasive follicular thyroid neo-plasm with papillary-like nuclear
features is considered an indolent tumor of limited biologic potential.
• Follicular thyroid cancer (10% to 20% of cases) – occasionally seen in people with Cowden syndrome.
Some include Hürthle cell carcinoma as a variant and others list it as a separate type.
• Medullary thyroid cancer (5% to 8% of cases) – cancer of the parafollicular cells, often part of
multiple endocrine neo-plasia type 2.
• Poorly differentiated thyroid cancer
• Anaplastic thyroid cancer (less than 5% of cases) is not responsive to treatment and can cause pressure
symptoms.
• Others
a. Thyroid lymphoma
b. Squamous cell thyroid carcinoma
c. Sarcoma of thyroid.
The follicular and papillary types together can be classified as “differentiated thyroid cancer”.
These types have a more favourable prognosis than the medullary and undifferentiated types.
• Papillary microcarcinoma is a subset of papillary thyroid cancer defined as measuring less than or
equal to 1 cm. The highest incidence of papillary thyroid microcarcinoma in autopsy series was
reported by Harach et al. in 1985, who found 36 of 101 consecutive autopsies were found to have
an incidental microcarcinoma. Michael Pakdaman et al. report the highest incidence in a
retrospective surgical series at 49.9% of 860 cases. Management strategies for incidental papillary
microcarcinoma on ultrasound (and confirmed on FNAB) range from total thyroidectomy with
radioactive iodine ablation to observation alone. Harach et al. suggest using the term “occult
papillary tumor” to avoid giving patients distress over having cancer. It was Woolner et al. who
first arbitrarily coined the term “occult papillary carcinoma” in 1960, to describe papillary
carcinomas ≤ 1.5 cm in diameter.
Endocrine 123

Staging
Cancer staging is the process of determining the extent of the development of a cancer. The TNM staging
system is usually used to classify stages of cancers but not of the brain.

Thyroid

Cancer has
spread to
the lungs
and bone

Fig. Stage M1 thyroid cancer

Tumour

Cancer cells Thyroid

in lymph
nodes close Windpipe
to the thyroid

Fig. Stage N1a thyroid cancer

124 Surgical Oncology: Theory and Multidisciplinary Practice

Fig. Stage N1b thyroid cancer

Fig. Stage T1a thyroid cancer

Thyroid
Tumour is
between Windpipe
1 and 2cm

Fig. Stage T1b thyroid cancer

Endocrine 125

Fig. Stage T2 thyroid cancer

Tumour is Thyroid
larger than Windpipe
4cm

Fig. Stage T3 thyroid cancer

Tumour has
grown into Thyroid
a nearby Windpipe
structure

Fig. Stage T4a thyroid cancer

126 Surgical Oncology: Theory and Multidisciplinary Practice

Tumour has
grown into a Thyroid
blood vessel or Windpipe
the bones of
the spine

Fig. Stage T4b thyroid cancer

Metastases
Detection of any metastases of thyroid cancer can be performed with a full body scintigraphy using iodine-
131.

TREATMENT
Thyroidectomy and dissection of central neck compartment is initial step in treatment of thyroid cancer in
majority of cases. Thyroid-preserving operation may be applied in cases, when thyroid cancer exhibits low
biological aggressiveness (e.g. well-differentiated cancer, no evidence of lymph node metastases, low MIB-1
index, no major genetic alterations like BRAF mutations, RET/PTC rearrangements, p53 mutations etc.) in
patients younger than 45 years. If the diagnosis of well-differentiated thyroid cancer (e.g. papillary thyroid
cancer) is established or suspected by FNA the surgery is indicated, whereas watchful waiting strategy is not
recommended in any evidence-based guidelines. Watchful waiting reduces overdiagnosis and overtreatment of
thyroid cancer among old patients. Radioactive Iodine-131 is used in patients with papillary or follicular thyroid
cancer for ablation of residual thyroid tissue after surgery and for the treatment of thyroid cancer. Patients with
medullary, anaplastic, and most Hurthle cell cancers do not benefit from this therapy. External irradiation may
be used when the cancer is unresectable, when it recurs after resection, or to relieve pain from bone metastasis.
Sorafenib and lenvatinib, are approved for advanced metastatic thyroid cancer. Numerous agents are in phase II
and III clinical trials.

PROGNOSIS
The prognosis of thyroid cancer is related to the type of cancer and the stage at the time of diagnosis. For the
most common form of thyroid cancer, papillary, the overall prognosis is excellent. Indeed, the increased incidence
of papillary thyroid carcinoma in recent years is likely related to increased and earlier diagnosis. One can look
at the trend to earlier diagnosis in two ways. The first is that many of these cancers are small and not likely to
develop into aggressive malignancies. A second perspective is that earlier diagnosis removes these cancers at a
time when they are not likely to have spread beyond the thyroid gland, thereby improving the long-term outcome
for the patient. There is no consensus at present on whether this trend towards earlier diagnosis is beneficial or
unnecessary.
Endocrine 127

The argument against early diagnosis and treatment is based on the logic that many small thyroid cancers
(mostly papillary) will not grow or metastasize. This viewpoint holds the overwhelming majority of thyroid
cancers are over diagnosed (that is, will never cause any symptoms, illness, or death for the patient, even if
nothing is ever done about the cancer). Including these over diagnosed cases skews the statistics by lumping
clinically significant cases in with apparently harmless cancers. Thyroid cancer is incredibly common, with
autopsy studies of people dying from other causes showing that more than one-third of older adults technically
have thyroid cancer, which is causing them no harm. It is easy to detect nodules that might be cancerous, simply
by feeling the throat, which contributes to the level of over diagnosis. Benign (non-cancerous) nodules frequently
co-exist with thyroid cancer; sometimes, it is a benign nodule that is discovered but surgery uncovers an incidental
small thyroid cancer. Increasingly, small thyroid nodules are discovered as incidental findings on imaging (CT
scan, MRI, ultrasound) performed for another purpose; very few of these people with accidentally discovered,
symptom-free thyroid cancers will ever have any symptoms, and treatment in such patients has the potential to
cause harm to them, not to help them. Thyroid cancer is three times more common in women than in men, but
according to European statistics, the overall relative 5-year survival rate for thyroid cancer is 85% for females
and 74% for males.
The table below highlights some of the challenges with decision making and prognostication in thyroid
cancer. While there is general agreement that stage I or II papillary, follicular or medullary cancer have a good
prognosis, it is not possible when evaluating a small thyroid cancer to determine which ones will grow and
metastasize and which will not. As a result, once a diagnosis of thyroid cancer has been established (most
commonly by a fine needle aspiration), it is likely that a total thyroidectomy will be performed. This drive to
earlier diagnosis has also manifested itself on the European continent by the use of serum calcitonin measurements
in patients with goiter to identify patients with early abnormalities of the parafollicular or calcitonin-producing
cells within the thyroid gland. As multiple studies have demonstrated, the finding of an elevated serum calcitonin
is associated with the finding of a medullary thyroid carcinoma in as high as 20% of cases. In Europe where the
threshold for thyroid surgery is lower than in the United States, an elaborate strategy that incorporates serum
calcitonin measurements and stimulatory tests for calcitonin has been incorporated into the decision to perform
a thyroidectomy; thyroid experts in the United States, looking at the same data sets have, for the most part, not
incorporated calcitonin testing as a routine part of their evaluation, thereby eliminating a large number of
thyroidectomies and the consequent morbidity.
The European thyroid community has focused on prevention of metastasis from small medullary thyroid
carcinomas; the North American thyroid community has focused more on prevention of complications associated
with thyroidectomy. It is not clear at this time who is correct. As demonstrated in the Table below, individuals
with stage III and IV disease have a significant risk of dying from thyroid cancer. While many present with
widely metastatic disease, an equal number evolve over years and decades from stage I or II disease. Physicians
who manage thyroid cancer of any stage recognize that a small percentage of patients with low-risk thyroid
cancer will progress to metastatic disease. Fortunately for those with metastatic thyroid cancer, the last 5 years
has brought about a renaissance in thyroid cancer treatment. The identification of some of the molecular or
DNA abnormalities for thyroid cancer has led to the development of therapies that target these molecular
defects. The first of these agents to negotiate the approval process is vandetanib, a tyrosine kinase inhibitor that
targets the RET proto-oncogene, 2 subtypes of the vascular endothelial growth factor receptor, and the epidermal
growth factor receptor. More of these compounds are under investigation and are likely to make it through the
approval process. For differentiated thyroid carcinoma, strategies are evolving to use selected types of targeted
therapy to increase radioactive iodine uptake in papillary thyroid carcinomas that have lost the ability to
concentrate iodide. This strategy would make it possible to use radioactive iodine therapy to treat “resistant”
thyroid cancers. Other targeted therapies are being evaluated, making it possible that life will be extended over
the next 5–10 years for those with stage III and IV thyroid cancer.
128 Surgical Oncology: Theory and Multidisciplinary Practice

Prognosis is better in younger people than older ones.

Prognosis depends mainly on the type of cancer and cancer stage.
5-year survival 10-year survival
Thyroid cancer type Stage I Stage II Stage III Stage IV Overall Overall
Papillary 100% 100% 93% 51% 96% or 97% 93%
Follicular 100% 100% 71% 50% 91% 85%
Medullary 100% 98% 81% 28% 80%, 83% or 86% 75%
Anaplastic (always stage IV) 7% 7% or 14% (no data)

PANCREATIC NEUR
PANCREATIC OENDOCRINE TUMORS (PNETS)
NEUROENDOCRINE
Pancreatic neuroendocrine tumors (PanNETs, PETs, or PNETs), often referred to as “islet cell tumors”, or
“pancreatic endocrine tumors” are neuroendocrine neo-plasms that arise from cells of the endocrine (hormonal)
and nervous system within the pancreas. PanNETs are a type of neuroendocrine tumor, representing about
one third of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Many PanNETs are benign, while
some are malignant. Aggressive PanNET tumors have traditionally been termed “islet cell carcinoma”.
PanNETs are quite distinct from the usual form of pancreatic cancer, the majority of which are
adenocarcinomas, which arises in the exocrine pancreas. Only 1 or 2% of clinically significant pancreas neo-
plasms are PanNETs.

TYPES
The majority of PanNETs are benign, while some are malignant. The World Health Organization (WHO)
classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor
grade rather than the anatomical origin. In practice, those tumors termed well or intermediately differentiated
PanNETs in the WHO scheme are sometimes called “islet cell tumors.” The high grade subtype, termed
neuroendocrine cancer (NEC) in the WHO scheme, is synonymous with “islet cell carcinoma”.
Types of PNET based on hormones produced
Type Location of tumor Biomarkers
Insulinoma Head, body, tail of pancreas insulin, proinsulin, C-peptide
Gastrinoma Gastrinoma triangle gastrin, PP
VIPoma Distal pancreas (body and tail) VIP
Glucagonoma Body and tail of pancreas glucagon, glycentin
Somatostatinoma Pancreatoduodenal groove, ampullary, periampullary somatostatin
PPoma Head or pancreas pancreatic polypeptide

SIGNS AND SYMPTOMS

Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan
performed for a different purpose. Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion,
or yellowing of the skin and whites of the eyes can arise from the effects of a larger PanNET tumor, either
locally or at a metastasis. About 40% of PanNETS have symptoms related to excessive secretion of hormones
or active polypeptides and are accordingly labeled as “functional”; the symptoms reflect the type of hormone
secreted, as discussed below. Up to 60% of PanNETs are non-secretory or non-functional, in which there is no
secretion, or the quantity or type of products, such as pancreatic polypeptide (PPoma), chromogranin A, and
neurotensin, do not cause a clinical syndrome although blood levels may be elevated. In total, 85% of PanNETs
have an elevated blood marker.
Functional tumors are often classified by the hormone most strongly secreted, for example:
• Gastrinoma: the excessive gastrin causes Zollinger–Ellison syndrome (ZES) with peptic ulcers and
diarrhea
Endocrine 129

• Insulinoma: hypoglycemia occurs with concurrent elevations of insulin, proinsulin and C peptide
• Glucagonoma: the symptoms are not all due to glucagon elevations, and include a rash, sore mouth,
altered bowel habits, venous thrombosis, and high blood glucose levels
• VIPoma, producing excessive vasoactive intestinal peptide, which may cause profound chronic watery
diarrhea and resultant dehydration, hypokalemia, and achlorhydria (WDHA or pancreatic cholera
syndrome)
• Somatostatinoma: these rare tumors are associated with elevated blood glucose levels, achlorhydria,
cholelithiasis, and diarrhea
• Less common types include ACTHoma, CRHoma, calcitoninoma, GHRHoma, GRFoma, and
parathyroid hormone–related peptide tumor.
In these various types of functional tumors, the frequency of malignancy and the survival prognosis have
been estimated dissimilarly, but a pertinent accessible summary is available.

DIAGNOSIS
Because symptoms are non-specific, diagnosis is often delayed. Measurement of hormones including
pancreatic polypeptide, gastrin, proinsulin, insulin, glucagon, and vasoactive intestinal peptide can
determine if a tumor is causing hypersecretion. CT and MRI may be used to determine location and size of
PNET.

STAGING
The 2010 WHO classification of tumors of the digestive system grades all the neuroendocrine tumors into
three categories, based on their degree of cellular differentiation (from well-differentiated “NET G1” through
to poorly-differentiated “NET G3”). The NCCN recommends use of the same AJCC-UICC staging system as
pancreatic adenocarcinoma. Using this scheme, the stage by stage outcomes for PanNETs are dissimilar to
pancreatic exocrine cancers. A different TNM system for PanNETs has been proposed by The European
Neuroendocrine Tumor Society.

The cancer is no more

than 2cm in size

Bowel Pancreas

Fig. Stage T1
130 Surgical Oncology: Theory and Multidisciplinary Practice

The cancer is more

than 2cm in size

Bowel Pancreas
Fig. Stage T2

The cancer has grown into the

tissues outside the pancreas

Bowel Pancreas

Fig. Stage T3
Endocrine 131

The cancer has grown outside

the pancreas and into one of the
blood vessels

Bowel Pancreas

Fig. Stage T4

There is cancer in
Cancer the lymph nodes

Bowel Pancreas
Fig. Involvement of nearby lymph nodes – Stage N1
132 Surgical Oncology: Theory and Multidisciplinary Practice

Cancer has spread

to the liver

Fig. Metastasis – stage M1

TREATMENT
In general, treatment for PanNET encompasses the same array of options as other neuroendocrine tumors, as
discussed in that main article. However, there are some specific differences, which are discussed here. In
functioning PanNETs, octreotide is usually recommended prior to biopsy or surgery but is generally avoided in
insulinomas to avoid profound hypoglycemia. PanNETs in Multiple endocrine neo-plasia type 1 are often
multiple, and thus require different treatment and surveillance strategies. Some PanNETs are more responsive
to chemotherapy than are gastroenteric carcinoid tumors. Several agents have shown activity. In well differentiated
PanNETs, chemotherapy is generally reserved for when there are no other treatment options. Combinations of
several medicines have been used, such as doxorubicin with streptozocin and fluorouracil (5-FU) and capecitabine
with temozolomide. Although marginally effective in well-differentiated PETs, cisplatin with etoposide has
some activity in poorly differentiated neuroendocrine cancers (PDNECs), particularly if the PDNEC has an
extremely high Ki-67 score of over 50%.
Several targeted therapy agents have been approved in PanNETs by the FDA based on improved progression-
free survival (PFS):
• Everolimus (Afinitor) is labeled for treatment of progressive neuroendocrine tumors of pancreatic
origin in patients with unresectable, locally advanced or metastatic disease. The safety and
effectiveness of everolimus in carcinoid tumors have not been established.
• Sunitinib (Sutent) is labeled for treatment of progressive, well-differentiated pancreatic
neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. Sutent
also has approval from the European Commission for the treatment of ‘unresectable or metastatic,
well-differentiated pancreatic neuroendocrine tumors with disease progression in adults’. A phase
III study of sunitinib treatment in well differentiated pNET that had worsened within the past 12
months (either advanced or metastatic disease) showed that sunitinib treatment improved
progression-free survival (11.4 months vs. 5.5 months), overall survival, and the objective response
rate (9.3% vs. 0.0%) when compared with placebo.
Endocrine 133

GENETICS
Pancreatic neuroendocrine tumors may arise in the context of multiple endocrine neo-plasia type 1or Von
Hippel–Lindau disease.
Analysis of somatic DNA mutations in well-differentiated pancreatic neuroendocrine tumors identified four
important findings:
• As expected, the genes mutated in NETs, MEN1, ATRX, DAXX, TSC2, PTEN and PIK3CA, are
different from the mutated genes previously found in pancreatic adenocarcinoma.
• One in six well-differentiated pancreatic NETs have mutations in mTOR pathway genes, such as
TSC2, PTEN and PIK3CA. The sequencing discovery might allow selection of which NETs would
benefit from mTOR inhibition such as with everolimus, but this awaits validation in a clinical trial.
• Mutations affecting a new cancer pathway involving ATRX and DAXX genes were found in about
40% of pancreatic NETs. The proteins encoded by ATRX and DAXX participate in chromatin
remodeling of telomeres; these mutations are associated with a telomerase-independent maintenance
mechanism termed ALT (alternative lengthening of telomeres) that results in abnormally long telomeric
ends of chromosomes.
• ATRX/DAXX and MEN1 mutations were associated with a better prognosis.

MULTIPLE ENDOCRINE NEO-PL

MULTIPLE ASIA (MEN) SYNDR
NEO-PLASIA OMES
SYNDROMES
The term multiple endocrine neo-plasia (MEN) encompasses several distinct syndromes featuring tumors of
endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others,
benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor
syndromes. MEN syndromes are inherited as autosomal dominant disorders.

TERMINOLOGY
The older names, “multiple endocrine adenomas” and “multiple endocrine adenomatosis” (MEA), have
been replaced by the current terminology. The term multiple endocrine neo-plasia is used when two or more
endocrine tumor types, known to occur as a part of one of the defined MEN syndromes, occurs in a single
patient and there is evidence for either a causative mutation or hereditary transmission. The presence of two or
more tumor types in a single patient does not automatically designate that individual as having MEN because
there is a small statistical chance that development of two “sporadic” tumors that occur in one of the MEN
syndromes could occur by chance. The term “multiple endocrine neo-plasia” was introduced in 1968, but
descriptions of the condition date back to 1903.

RELATED CONDITIONS
Although not officially categorized as multiple endocrine neo-plasia syndromes, Von Hippel-Lindau disease
and Carney complex are two other autosomal dominant endocrine tumor syndromes with features that overlap
the clinical features of the MEN syndromes. Although not transmitted in the germline, McCune-Albright
syndrome is a genetic disorder characterized by endocrine neo-plastic features involving endocrine glands that
overlap with those involved in MEN1 or MEN2.

HISTORY
• In 1903 Erdheim described the case of an acromegalic patient with a pituitary adenoma and three
enlarged parathyroid glands.
134 Surgical Oncology: Theory and Multidisciplinary Practice

• In 1953 Underdahl et al. reported a case series of 8 patients with a syndrome of pituitary, parathyroid,
and pancreatic islet adenomas.
• In 1954 Wermer noted that this syndrome was transmitted as a dominant trait.
• In 1959 Hazard et al. described medullary (solid) thyroid carcinoma.
• In 1961 Sipple described a combination of a pheochromocytoma, medullary thyroid carcinoma and
parathyroid adenoma.
• In 1966 Williams et al. described the combination of mucosal neuromas, pheochromocytoma and
medullary thyroid carcinoma.
• In 1968 Steiner et al. introduced the term “multiple endocrine neo-plasia” (MEN) to describe disorders
featuring combinations of endocrine tumors and proposed the terms ‘Wermer syndrome’ for MEN 1
and ‘Sipple syndrome’ for MEN 2.
• In 1974 Sizemore et al. showed that the MEN 2 category included two groups of patients with MTC and
pheochromocytoma: one with parathyroid disease and a normal appearance (MEN 2A) and the other
without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B).
• In 1988 the MEN1 locus was assigned to Chromosome 11 (11q13).
• In 1993 mutations in the RET oncogene were shown to be the cause of MEN 2A by Lois Mulligan,
working in the laboratory of Bruce Ponder in Cambridge.
• In 1998 the MEN1 gene was cloned.

COMPARISON
Percentages in table below refer to how large fraction of people with the MEN type develop the neo-plasia
type.
Feature MEN 1 MEN 2
MEN 2A MEN 2B FMTC
Eponym Wermer syndrome Sipple syndrome (multiple) (none)
OMIM 131100 171400 162300 155240
Pancreatic tumors gastrinoma (50%), - - -
insulinoma (20%),
VIPoma,
glucagonoma,
PPoma
Pituitary adenoma 66% - - -
Angiofibroma 64%* - - -
Lipoma 17%* - - -
Parathyroid hyperplasia 90% 50% - -
Medullary thyroid carcinoma - 100% 85% 100%
Pheochromocytoma - >33% 50% -
Marfanoid body habitus - - 80% -
Mucosal neuroma - - 100% -
Gene(s) MEN1 (131100) RET (164761) RET (164761) RET (164761),
NTRK1 (191315)
Approx. prevalence 1 in 35,000 1 in 40,000 1 in 1,000,000
(1 in 20,000 to (1 in 600,000 to
1 in 40,000) 1 in 4,000,000)
Initial description (year) 1954 1961 1965
*- of patients with MEN1 and gastrinoma
FMTC = familial medullary thyroid cancer
MEN 2B is sometimes known as MEN 3 and the designation varies by institution (c.f.
www.ClinicalReview.com). Although a variety of additional eponyms have been proposed for MEN2B (e.g.
Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann–Froboese syndrome), none ever gained
sufficient traction to merit continued use and, indeed, are all but abandoned in the medical literature. Another
Endocrine 135

early report was Schimke et al. in 1968. OMIM also includes a fourth form of multiple endocrine neo-plasia
(“MEN4”), associated with CDKN1B. The presentation is believed to overlap that of MEN1 and MEN2.

MULTIPLE ENDOCRINE NEO-PLASIA TYPE 1 (MEN1)

The MEN1 Gene

The MEN1 gene consists of ten exons, spanning about 10 kb, and encodes a 610 amino acid protein named
menin. The first exon and the last part of exon 10 are not translated. A main transcript of 2.8 kb has been
described in a large variety of human tissues (pancreas, thymus, adrenal glands, thyroid, testis, leukocytes,
heart, brain, lung, muscle, small intestine, liver, and kidney); an additional transcript of approximately 4 kb has
been detected in pancreas and thymus, suggesting a tissue-specific alternative splicing.

The Menin Protein

Menin is a 610 amino acid (67Kda) nuclear protein, highly conserved from mouse (98%), rat (97%) and,
more distantly, zebrafish (75%) and Drosophila (47%) (47-51). Human and mouse MEN1 amino acid sequences
share 95.8% identity and 98.4% similarity. Analysis of menin amino acid sequence did not reveal homologies
to any other known human or mammalian protein, sequence motif, or signal peptide. The absence of significant
homology to any other protein complicates efforts to elucidate the functions of menin.

Pathophysiology
MEN1 follows Knudson’s “two-hit” model for tumor suppressor gene carcinogenesis (30). The first hit is a
heterozygous MEN1 germline mutation, inherited from one parent (familial cases) or developed in an early
embryonic stage (sporadic cases) and present in all cells at birth. The second hit is a MEN1 somatic mutation,
usually a large deletion, that occurs in the predisposed endocrine cell as loss of the remaining wild-type allele
and gives cells the survival advantage needed for tumor development.

Mnemonic
A useful mnemonic to remember the associated neo-plasias is below:
MEN I (3 Ps) - Pituitary, Parathyroid, Pancreatic
MEN IIa (2Ps, 1M) - Pheochromocytoma, Parathyroid, Medullary Thyroid Ca
MEN IIb (1P, 2Ms) - Pheochromocytoma, Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma

MEN1 Mutations in Multiple Endocrine Neo-plasia Patients and Clinical

Genetics
MEN1 gene mutations can be identified in 70-95% of MEN1 patients and in about 20% of familial isolated
hyperparathyroidism cases. Almost all patients are heterozygous for mutations. One affected family has been
identified with individuals both homozygous and heterozygous for MEN1 mutations. In this family, there was
no difference in disease history between the homozygous and heterozygous mutation carriers. Fifty percent of
patients develop signs and symptoms by 20 years of age and more than 95% have symptoms by 40 years of age.
There is significant intra- and inter-familial variability in the age of onset, severity of disease, and tumor types.
Despite numerous studies, no genotype-phenotype correlations have been established, suggesting that unknown
genetic and environmental modifiers are involved in the expression of the MEN1 phenotype.
136 Surgical Oncology: Theory and Multidisciplinary Practice

Manifestations
Multiple Endocrine Neo-plasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterized
primarily by tumors of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic (GEP) tract
(30-80% of cases), and anterior pituitary (15-90% of cases). Other endocrine and non-endocrine neo-plasms
including adrenocortical and thyroid tumors, visceral and cutaneous lipomas, meningiomas, facial angiofibromas
and collagenomas, and thymic, gastric, and bronchial carcinoids also occur. The phenotype of MEN1 is broad,
and over 20 different combinations of endocrine and non-endocrine manifestations have been described. MEN1
should be suspected in patients with an endocrinopathy of two of the three characteristic affected organs, or
with an endocrinopathy of one of these organs plus a first-degree relative affected by MEN1 syndrome. MEN1
patients usually have a family history of MEN1.
Inheritance is autosomal dominant; any affected parent has a 50% chance to transmit the disease to his or her
progeny. MEN1 gene mutations can be identified in 70-95% of MEN1 patients. Many endocrine tumors in
MEN1 are benign and cause symptoms by overproduction of hormones or local mass effects, while other
MEN1 tumors are associated with an elevated risk for malignancy. About one third of patients affected with
MEN1 will die early from an MEN1-related cancer or associated malignancy. Entero-pancreatic gastrinomas
and thymic and bronchial carcinoids are the leading cause of morbidity and mortality. Consequently, the average
age of death in untreated individuals with MEN1 is significantly lower (55.4 years for men and 46.8 years for
women) than that of the general population.

Recommended Cancer Surveillance

A recommend surveillance programme for Multiple Endocrine Neo-plasia Type 1 has been suggested by the
International Guidelines for Diagnosis and Therapy of MEN syndromes group.

CARCINOID TUMORS
CARCINOID
Carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of
the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum,
ileum, appendix, and cecum) are associated with carcinoid syndrome. Carcinoid tumors are the most common
malignant tumor of the appendix, but they are most commonly associated with the small intestine, and they can
also be found in the rectum and stomach. They are known to grow in the liver, but this finding is usually a
manifestation of metastatic disease from a primary carcinoid occurring elsewhere in the body. They have a very
slow growth rate compared to most malignant tumors. The median age at diagnosis for all patients with
neuroendocrine tumors is 63 years.

SIGNS AND SYMPTOMS

While most carcinoids are asymptomatic through the natural lifetime and are discovered only upon surgery
for unrelated reasons (so-called coincidental carcinoids), all carcinoids are considered to have malignant
potential.
About 10% of carcinoids secrete excessive levels of a range of hormones, most notably serotonin (5-HT),
causing:
• Flushing (serotonin itself does not cause flushing). Potential causes of flushing in carcinoid syndrome
include bradykinins, prostaglandins, tachykinins, substance P, and/or histamine, diarrhea, and heart
problems. Because of serotonin’s growth-promoting effect on cardiac myocytes, a serotonin-secreting
carcinoid tumour may cause a tricuspid valve disease syndrome, due to the proliferation of myocytes
onto the valve.
Endocrine 137

• Diarrhea
• Wheezing
• Abdominal cramping
• Peripheral edema
The outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency. Niacin deficiency,
also known as pellagra, is associated with dermatitis, dementia, and diarrhea. This constellation of symptoms is
called carcinoid syndrome or (if acute) carcinoid crisis. Occasionally, haemorrhage or the effects of tumor bulk
are the presenting symptoms. The most common originating sites of carcinoid is the small bowel, particularly
the ileum; carcinoid tumors are the most common malignancy of the appendix. Carcinoid tumors may rarely
arise from the ovary or thymus. They are most commonly found in the midgut at the level of the ileum or in the
appendix. The next most common affected area is the respiratory tract, with 28% of all cases—per PAN-SEER
data (1973–1999). The rectum is also a common site.

Gastrointestinal
Carcinoid tumors are apudomas that arise from the enterochromaffin cells throughout the gut. Over two-
thirds of carcinoid tumors are found in the gastrointestinal tract.

Lung
Carcinoid tumors are also found in the lungs.

Other Sites/ Metastases

Metastasis of carcinoid can lead to carcinoid syndrome. This is due to the over-production of many substances,
including serotonin, which are released into the systemic circulation, and which can lead to symptoms of
cutaneous flushing, diarrhea, bronchoconstriction, and right-sided cardiac valve disease. It is estimated that
less than 6% of carcinoid patients will develop carcinoid syndrome, and of these, 50% will have cardiac
involvement.

CAUSE
Carcinoid syndrome involves multiple tumors in 1/5 of cases. The incidence of gastric carcinoids is increased
in achlorhydria, Hashimoto’s thyroiditis, and pernicious anemia.

TREATMENT
Surgery, if feasible, is the only curative therapy. If the tumor has metastasized (most commonly, to the liver)
and is considered incurable, there are some promising treatment modalities, such as radiolabeled octreotide
(e.g. Lutetium (Lu) DOTA-octreotate) or the radiopharmaceutical 131I-mIBG (meta iodo benzyl guanidine) for
arresting the growth of the tumors and prolonging survival in patients with liver metastases, though these are
currently experimental.
Chemotherapy is of little benefit and is generally not indicated. Octreotide or Lanreotide (somatostatin
analogues) may decrease the secretory activity of the carcinoid, and may also have an anti-proliferative effect.
Interferon treatment is also effective, and usually combined with somatostatin analogues. As the metastatic
potential of a coincidental carcinoid is probably low, the current recommendation is for follow up in 3 months
with CT or MRI, labs for tumor markers such as serotonin, and a history and physical, with annual physicals
thereafter.
138 Surgical Oncology: Theory and Multidisciplinary Practice

GOBLET CELL CARCINOID

This is considered to be a hybrid between an exocrine and endocrine tumor derived from crypt cells of the
appendix. Histologically, it forms clusters of goblet cells containing mucin with a minor admixture of Paneth
cells and endocrine cells. The growth pattern is distinctive: typically producing a concentric band of tumor
nests interspersed among the muscle and stroma of the appendiceal wall extending up the shaft of the appendix.
This makes the lesion difficult to suspect grossly and difficult to measure. Small tumor nests may be camouflaged
amongst the muscle or in periappendiceal fat; cytokeratin preparations best demonstrate the tumor cells; mucin
stains are also helpful in identifying them. They behave in a more aggressive manner than do classical appendiceal
carcinoids. Spread is usually to regional lymph nodes, peritoneum, and particularly the ovary. They do not
produce sufficient hormonal substances to cause the carcinoid or other endocrine syndromes. In fact, they more
closely resemble exocrine than endocrine tumors. The term ‘crypt cell carcinoma’ has been used for them, and
though perhaps more accurate than considering them carcinoids, has not been a successful competitor.
Sarcoma 139

Chapter 5

Sarcoma

INTR ODUCTION
INTRODUCTION
A sarcoma is a cancer that arises from transformed cells of mesenchymal origin. Thus, malignant tumors
made of cancellous bone, cartilage, fat, muscle, vascular, or hematopoietic tissues are, by definition, considered
sarcomas. This is in contrast to a malignant tumor originating from epithelial cells, which are termed carcinoma.
Human sarcomas are quite rare. Common malignancies, such as breast, colon, and lung cancer, are almost
always carcinoma. The term is from the Greek óÜñî sarx meaning “flesh”.

DIAGNOSIS

Classification

Tissue
Sarcomas are given a number of different names based on the type of tissue that they most closely resemble.
For example, osteosarcoma resembles bone, chondrosarcoma resembles cartilage, liposarcoma resembles fat,
and leiomyosarcoma resembles smooth muscle.

GRADE
In addition to being named based on the tissue of origin, sarcomas are also assigned a grade (low, intermediate,
or high) based on the presence and frequency of certain cellular and subcellular characteristics associated with
malignant biological behaviour. Low grade sarcomas are usually treated surgically, although sometimes radiation
therapy or chemotherapy are used. Intermediate and high grade sarcomas are more frequently treated with a
combination of surgery, chemotherapy and/or radiation therapy. Since higher grade tumors are more likely to
undergo metastasis (invasion and spread to locoregional and distant sites), they are treated more aggressively.
The recognition that many sarcomas are sensitive to chemotherapy has dramatically improved the survival of
patients. For example, in the era before chemotherapy, long-term survival for patients with localized osteosarcoma
was only approximately 20%, but now has risen to 60–70%.

AWARENESS
In the US, July is widely recognized as Sarcoma Awareness Month. The UK has a Sarcoma Awareness Week
July led by Sarcoma UK:the bone and soft tissue cancer charity. In December 2016, British medical company
140 Surgical Oncology: Theory and Multidisciplinary Practice

MidMeds launched Sarcoma Awareness Day in the UK, with the sole aim of raising awareness of the cancer.
The event gained both local and national press attention.

CHONDR OSAR
CHONDROSAR
OSARCCOMA
Chondrosarcoma is a cancer composed of cells derived from transformed cells that produce cartilage.
Chondrosarcoma is a member of a category of tumors of bone and soft tissue known as sarcomas. About 30% of
skeletal system cancers are chondrosarcomas. It is resistant to chemotherapy and radiotherapy. Unlike other
primary bone cancers that mainly affect children and adolescents, chondrosarcoma can present at any age. It
more often affects the axial skeleton than the appendicular skeleton.

CLASSIFICATION AND GRADING

Physicians grade chondrosarcoma using several criteria, but particularly on how abnormal the cancerous
cells appear under the microscope, and the growth rate of the tumors themselves, both of which are directly
linked to the propensity of the cancer to invade locally, and to spread widely to distant organs and sites in the
body (called metastasis). Grade 1 chondrosarcoma grows relatively slowly, has cells whose histological
appearance is quite similar to cells of normal cartilage, and have much less aggressive invasive and metastatic
properties. Grades 2 and 3 are increasingly faster-growing cancers, with more varied and abnormal-looking
cells, and are much more likely to infiltrate surrounding tissues, lymph nodes, and organs. Some, but not all,
authorities and medical facilities assign a “Grade 4” to the most anaplastic, undifferentiated cartilage-derived
tumors. The most common sites for chondrosarcoma to grow are the pelvis and shoulder, along with the superior
metaphyseal and diaphyseal regions of the arms and legs. However, chondrosarcoma may occur in any bone,
and are sometimes found in the skull, particularly at its base. ICD-O codes provide a more precise classification
of chondrosarcoma.
These “subtypes” are derived from, and reflect, both (a) the topographical location of the tumor, (b) the
histological characteristics of the cancerous cartilage cells, and (c) the makeup of the surrounding matrix material
associated with the tumor:
ICD-O Classification
9220 Chondrosarcoma NOS (“Not Otherwise Specified”)
9221 Juxtacortical chondrosarcoma
9231 Myxoid chondrosarcoma
9240 Mesenchymal chondrosarcoma
9242 Clear cell chondrosarcoma
9243 Dedifferentiated chondrosarcoma

SYMPTOMS
• Back or thigh pain
• Sciatica
• Bladder Symptoms
• Unilateral edema.

CAUSES
The cause is unknown. Patients may have a history of enchondroma or osteochondroma. A small minority
of secondary chondrosarcomas occur in patients with Maffucci syndrome and Ollier disease. It has been
associated with faulty isocitrate dehydrogenase 1 and 2 enzymes, which are also associated with gliomas and
leukemias.
Sarcoma 141

DIAGNOSIS
File:Metastatic chondrosarcoma at the lower lip.jpgFile:Metastatic chondrosarcoma at the lower lip.jpg
Imaging studies - including radiographs (“x-rays”), computerized tomography (CT), and magnetic resonance
imaging (MRI) - are often used to make a presumptive diagnosis of chondrosarcoma. However, a definitive
diagnosis depends on the identification of malignant cancer cells producing cartilage in a biopsy specimen that
has been examined by a pathologist. In a few cases, usually of highly anaplastic tumors, immunohistochemistry
(IHC)is required. There are no blood tests currently available to enable an oncologist to render a diagnosis of
chondrosarcoma. The most characteristic imaging findings are usually obtained with CT. Nearly all
chondrosarcoma patients appear to be in good health. Often, patients are not aware of the growing tumor until
there is a noticeable lump or pain. Earlier diagnosis is generally accidental, when a patient undergoes testing for
another problem and physicians discover the cancer. Occasionally the first symptom will be a broken bone at
the cancerous site. Any broken bone that occurs from mild trauma warrants further investigation, although there
are many conditions that can lead to weak bones, and this form of cancer is not a common cause of such breaks.

TREATMENT
Treatment depends on the location of the disease and the aggressiveness of the tumors. Because
chondrosarcomas are rare, they are treated at specialist hospitals with Sarcoma Centers. Surgery is the main
form of treatment for chondrosarcoma. Musculoskeletal tumor specialists or orthopedic oncologists are
usually chosen to treat chondrosarcoma, unless it is located in the skull, spine, or chest cavity, in which
case, a neurosurgeon or thoracic surgeon experienced with sarcomas is chosen. Often, a limb-sparing operation
can be performed, but in some cases amputation is unavoidable. Amputation of the arm, leg, jaw, or half of the
pelvis (called a hemipelvectomy) may be necessary in some cases.
There are two kinds of hemipelvectomy - internal and external.
• External hemipelvectomy - is removal of that half of the pelvis with the amputation of the leg. It is
also called the hindquarter amputation.
• Internal hemipelvectomy - is removal of that half of the pelvis, but the leg is left intact.
Amputation at the hip is called hip disarticulation and amputees who have had this amputation are also
called hip disartics. Chemotherapy or traditional radiotherapy are not very effective for most chondrosarcomas,
although proton therapy is showing promise with local tumor control at over 80%. Complete surgical ablation
is the most effective treatment, but sometimes this is difficult. Proton therapy radiation can be useful in awkward
locations to make surgery more effective. Recent studies have shown that induction of apoptosis in high-grade
chondrosarcoma, both directly and by enhancement of response to chemotherapy and radiation, is a valid
therapeutic strategy.

PROGNOSIS
Prognosis depends on how early the cancer is discovered and treated. For the least aggressive grade, about
90% of patients survive more than five years after diagnosis. People usually have a good survival rate at the low
grade volume of cancer. For the most aggressive grade, only 10% of patients will survive one year. Tumors may
recur in the future. Follow up scans are extremely important for chondrosarcoma to make sure there has been no
recurrence or metastasis, which usually occurs in the lungs.

EWING’S SAR
EWING’S COMA
SARC
Ewing’s sarcoma or Ewing sarcoma is a malignant small, round, blue cell tumor. It is a rare disease in which
cancer cells are found in the bone or in soft tissue. The most common areas in which it occurs are the pelvis, the
142 Surgical Oncology: Theory and Multidisciplinary Practice

femur, the humerus, the ribs and clavicle (collar bone). Since a common genetic locus is responsible for a large
percentage of Ewing sarcoma and primitive neuroectodermal tumors, these are sometimes grouped together in
a category known as the Ewing family of tumors. Ewing’s sarcoma occurs most frequently in teenagers and
young adults, with a male/female ratio of 1.6:1. Although usually classified as a bone tumor, Ewing’s sarcoma
can have characteristics of both mesodermal and ectodermal origin, making it difficult to classify. James Ewing
(1866–1943) first described the tumour, establishing that the disease was separate from lymphoma and other
types of cancer known at that time.

PRESENTATION
Ewing’s sarcoma is more common in males (1.6 male:1 female) and usually presents in childhood or early
adulthood, with a peak between 10 and 20 years of age. It can occur anywhere in the body, but most commonly
in the pelvis and proximal long tubular bones, especially around the growth plates. The diaphyses of the femur
are the most common sites, followed by the tibia and the humerus. Thirty percent are overtly metastatic at
presentation. Patients usually experience extreme bone pain. Rarely, it can develop in the vagina. Signs and
symptoms include: intermittent fevers, anemia, leukocytosis, increased sedimentation rate, and other symptoms
of inflammatory systemic illness. Also, depending on the type, progression, and location of the tumor, great
pain may occur. According to the Bone Cancer Research Trust (BCRT), the most common symptoms are:
localized pain, swelling, and sporadic bone pain with variable intensity. The swelling is most likely to be visible
if the sarcoma is located on a bone near the surface of the body, but when it occurs in other places deeper in the
body, like on the pelvis, it may not be visible.

CAUSES
Genetic exchange between chromosomes can cause cells to become cancerous. Most cases of Ewing’s sarcoma
(85%) are the result of a translocation between chromosomes 11 and 22, which fuses the EWS gene of
chromosome 22 to the FLI1 gene of chromosome 11. EWS/FLI functions as the master regulator. Other
translocations are at t(21;22) and t(7;22). Ewing’s sarcoma cells are positive for CD99 and MIC2, and negative
for CD45.

DIAGNOSIS
The definitive diagnosis is based on histomorphologic findings, immunohistochemistry and molecular
pathology. Ewing’s sarcoma is a small-blue-round-cell tumor that typically has a clear cytoplasm on H&E
staining, due to glycogen. The presence of the glycogen can be demonstrated with positive PAS staining and
negative PAS diastase staining. The characteristic immunostain is CD99, which diffusely marks the cell
membrane. Morphologic and immunohistochemical findings are corroborated with an associated chromosomal
translocation, of which several occur. The most common translocation, present in about 90% of Ewing sarcoma
cases, is t(11;22)(q24;q12), which generates an aberrant transcription factor through fusion of the EWSR1
gene with the FLI1 gene. The pathologic differential diagnosis is the grouping of small-blue-round-cell
tumors, which includes lymphoma, alveolar rhabdomyosarcoma, and desmoplastic small round cell tumor,
among others.

Differential Diagnosis
Other entities with similar clinical presentations include osteomyelitis, osteosarcoma (especially telangiectatic
osteosarcoma), and eosinophilic granuloma. Soft-tissue neo-plasms such as pleomorphic undifferentiated sarcoma
(malignant fibrous histiocytoma) that erode into adjacent bone may also have a similar appearance.
Sarcoma 143

Imaging Findings
On conventional radiographs, the most common osseous presentation is a permeative lytic lesion with
periosteal reaction. The classic description of lamellated or “onion-skin” type periosteal reaction is often
associated with this lesion. Plain films add valuable information in the initial evaluation or screening. The wide
zone of transition (e.g. permeative) is the most useful plain film characteristic in differentiation of benign
versus aggressive or malignant lytic lesions. Magnetic resonance imaging (MRI) should be routinely used in
the work-up of malignant tumors. It will show the full bony and soft tissue extent and relate the tumor to other
nearby anatomic structures (e.g. vessels). Gadolinium contrast is not necessary as it does not give additional
information over non-contrast studies, though some current researchers argue that dynamic, contrast-enhanced
MRI may help determine the amount of necrosis within the tumor, thus help in determining response to treatment
prior to surgery.
Computed axial tomography(CT) can also be used to define the extraosseous extent of the tumor, especially
in the skull, spine, ribs, and pelvis. Both CT and MRI can be used to follow response to radiation and/or
chemotherapy. Bone scintigraphy can also be used to follow tumor response to therapy. In the group of malignant
small round cell tumors which include Ewing’s sarcoma, bone lymphoma, and small cell osteosarcoma, the
cortex may appear almost normal radiographically, while permeative growth occurs throughout the Haversian
channels. These tumours may be accompanied by a large soft-tissue mass while almost no bone destruction is
visible. The radiographs frequently do not shown any signs of cortical destruction. Radiographically, Ewing’s
sarcoma presents as “moth-eaten” destructive radiolucencies of the medulla and erosion of the cortex with
expansion.

TREATMENT
Almost all patients require multidrug chemotherapy (often including ifosfamide and etoposide), as well as
local disease control with surgery and/or radiation. An aggressive approach is necessary because almost all patients
with apparently localized disease at the time of diagnosis actually have asymptomatic metastatic disease. Treatment
often consists of neo-adjuvant chemotherapy, which may include vincristine, doxorubicin, and cyclophosphamide
with ifosfamide and etoposide. After about three months of chemotherapy, the remaining tumor is surgically
resected, irradiated, or both. The surgical resection may involve limb salvage or amputation. Complete excision at
the time of biopsy may be performed if malignancy is confirmed at the time it is examined. Treatment lengths vary
depending on location and stage of the disease at diagnosis.
Radical chemotherapy may be as short as six treatments at 3-week cycles, but most patients undergo
chemotherapy for 6–12 months and radiation therapy for 5–8 weeks. Radiotherapy has been used for localized
disease. The tumor has a unique property of being highly sensitive to radiation, sometimes acknowledged by
the phrase “melting like snow”, but the main drawback is that it recurs dramatically after some time. Antisense
oligodeoxynucleotides have been proposed as possible treatment by down-regulating the expression of the
oncogenic fusion protein associated with the development of Ewing’s sarcoma resulting from the EWS-ETS
gene translocation. In addition, the synthetic retinoid derivative fenretinide (4-hydroxy(phenyl)retinamide) has
been reported to induce high levels of cell death in Ewing’s sarcoma cell lines in vitro and to delay growth of
xenografts in in vivo mouse models.

Fertility Preservation
In women, chemotherapy may damage the ovaries and cause infertility. To avail future pregnancies, the
woman may preserve oocytes or ovarian tissue by oocyte cryopreservation or ovarian tissue cryopreservation
prior to starting chemotherapy. However, the latter may reseed the cancer upon reinsertion of the ovarian tissue.
144 Surgical Oncology: Theory and Multidisciplinary Practice

If it is performed, the ovarian tissue should be examined for traces of malignancy at both the pathological and
molecular levels prior to the grafting of the cryopreserved tissue.

PROGNOSIS
Staging attempts to distinguish patients with localized from those with metastatic disease. Most commonly,
metastases occur in the chest, bone and/or bone marrow. Less common sites include the central nervous system
and lymph nodes. Five-year survival for localized disease is 70% to 80% when treated with chemotherapy. Prior
to the use of multi-drug chemotherapy, long-term survival was less than 10%. The development of multi-disciplinary
therapy with chemotherapy, irradiation, and surgery has increased current long-term survival rates in most clinical
centers to greater than 50%. However, some sources state it is 25–30%. Retrospective research in patients led by
Idriss M. Bennani-Baiti (Cancer Epigenetics Society) showed that two chemokine receptors, CXCR4 and CXCR7,
can be used as molecular prognosis factors. Patients who express low levels of both chemokine receptors have the
highest odds of long-term survival with >90% survival at 5 years post-diagnosis versus <30% survival at 5 years
for patients with very high expression levels of both receptors.

EPIDEMIOLOGY
Ewing’s sarcomas represent 16% of primary bone sarcomas. In the United States, they are most common in
the second decade of life, with a rate of 0.3 cases per million in children under 3 years of age, and as high as 4.6
cases per million in adolescents aged 15–19 years. Internationally, the annual incidence rate averages less than
2 cases per million children. In the United Kingdom, an average of six children per year are diagnosed, mainly
males in early stages of puberty. Due to the prevalence of diagnosis during teenage years, a link may exist
between the onset of puberty and the early stages of this disease, although no research confirms this hypothesis.
The oldest known patient diagnosed was at age 76, from the Mercer County, New Jersey, area. A grouping of
three unrelated teenagers in Wake Forest, NC, have been diagnosed with Ewing’s sarcoma. All three children
were diagnosed in 2011 and all attended the same temporary classroom together while the school underwent
renovation. A fourth teenager living nearby was diagnosed in 2009.
The odds of this grouping are considered significant. Ewing’s sarcoma shows striking differences in incidence
across human populations and is about 10- to 20-fold more common in populations from European descent as
compared to Africans. Consistently, a genome-wide association study (GWAS) conducted in several hundreds
European individuals with Ewing’s sarcoma and genetically-matched healthy controls identified three
susceptibility loci located on chromosomes 1, 10 and 15. A continuative study discovered that the Ewing’s
sarcoma susceptibility gene EGR2, which is located within the chromosome 10 susceptibility locus, is regulated
by the EWSR1-FLI1 fusion oncogene via a GGAA-microsatellite. Ewing’s sarcoma is the second most common
bone cancer in children and adolescents, with poor prognosis and outcome in ~70% of initial diagnoses and 10–
15% of relapses.

RESEARCH, INFORMATION AND SUPPORT

In the UK and Ireland, the Bone Cancer Research Trust funds research and provides information on Ewing’s
sarcoma and other bone cancers. This includes information for teenagers who have this condition. Melatonin, a
natural molecule without relevant side effects, has been previously shown to induce cytotoxicity in SK-N-MC
cells, a Ewing sarcoma cell line.

HEMANGIOENDOTHELIOMA
HEMANGIOENDOTHELIOMA
Hemangioendotheliomas are a family of vascular neo-plasms of intermediate malignancy.
Sarcoma 145

CLASSIFICATION
Hemangioendotheliomas may be classified as:
• Epithelioid hemangioendothelioma is an uncommon vascular tumor of intermediate malignancy that
was first described by Steven Billings, Andrew Folpe, and Sharon Weiss in 2003. These tumors are
so named because their histologic appearance resembles a proliferation of epithelioid cells, with
polygonal shape and eosinophilic cytoplasm.
• Composite hemangioendothelioma is a low-grade angiosarcoma typically occurring in adults, although
it has been described in infancy.
• Spindle-cell hemangioendothelioma) is a vascular tumor that was first described in 1986 by Sharon
Weiss, M.D., and commonly presents in a child or young adult who develops blue nodules of firm
consistency on a distal extremity. These tumors were reclassified by Dr. Weiss in 1996 as “spindle
cell hemangioma”, rather than hemangioendothelioma, due to the excellent prognosis observed in a
group of 78 patients.
• Retiform hemangioendothelioma (also known as a “Hobnail hemangioendothelioma”) is a low-grade
angiosarcoma, first described in 1994, presenting as a slow-growing exophytic mass, dermal plaque,
or subcutaneous nodule.
• Kaposiform hemangioendothelioma (also known as “Infantile kaposiform hemangioendothelioma”)
is an uncommon vascular tumor, first described by Niedt, Greco, et al. (Hemangioma with Kaposi’s
sarcoma-like features: report of two cases.(Niedt GW, Greco MA, Wieczorek R, Blanc WA, Knowles
DM 2nd. that affects infants and young children, with rare cases having also been reported in adults.
Pediatr Pathol. 1989;9(5):567-75.)
• Endovascular papillary angioendothelioma, also known as “Dabska tumor”, “papillary intralymphatic
angioendothelioma” (PILA), “Dabska-type hemangioendothelioma”, “hobnail hemangioendothelioma”,
and “malignant endovascular papillary angioendothelioma”, is a rare low-grade angiosarcoma of
lymphatic channels. Approximately 30 such tumors have been described in the medical literature.
Although included in the World Health Organization tumor classification, there is uncertainty as to
whether EPA is a distinct entity or a heterogenous group of tumours. The lesion usually presents as
a slow-growing tumor of the skin and subcutaneous tissues of the head, neck, or extremity, of infants
or young children. However, EPA has involved the testicle, deep muscle tissue as a neo-plastic
transformation of a larger existing benign cavernous hemangioma, bone and spleen, and has been
found in adults. Some reports indicate a good prognosis but metastasis is occasionally seen.
• Infantile hemangioendothelioma is a rare benign vascular tumour arising from mesenchymal tissue
and is usually located in the liver. It often presents in infancy with cardiac failure because of extensive
arteriovenous shunting within the lesion. It is the third most common liver tumor in children, the
most common benign vascular tumor of the liver in infancy, and the most common symptomatic
liver tumor during the first 6 months of life. These hemangioendotheliomas have 2 growth phases:
an initial rapid growth phase, which is followed by a period of spontaneous involution (usually
within the first 12 to 18 months of life). Detection of the hemangioendothelioma within the first 6
months of life is attributed to the initial rapid growth during this time; however, the tumor has been
detected with fetal ultrasonography.
Histopathologically, there are 2 types of hepatic hemangioendotheliomas:
• Type I: Hemagioendotheliomas of this type have multiple vascular channels that are formed by an
immature endothelial lining with stromal separation from bile ductules.
• Type II: These hemangioendotheliomas have an appearance that is more disorganized and
hypercellular, and there are no bile ductules.
146 Surgical Oncology: Theory and Multidisciplinary Practice

In children, distinguishing between a primary malignant liver tumor (hepatoblastoma) and a benign primary
hepatic lesion (hemangioendothelioma) is crucial. The absence of urinary catecholamines supports the diagnosis
of hemangioendothelioma. In patients with hemangioendotheliomas, elevations in α1-fetoprotein levels are
milder than those found in patients with hepatoblastomas. Infantile hepatic hemangioendothelioma is strongly
suggested by the presence of a vascular lesion on imaging studies. A complex, heterogeneous mass is often seen
on ultrasonograms; a complex tumor that lacks central enhancement can be see on CT scans; and the vascular
nature of the lesion along with dilation of the aorta proximal to the origin of the celiac artery and a decrease in
the diameter distally, indicating significant shunting, is seen on angiograms.
Because most hemangioendotheliomas in infants sponanteously involute and regress within the first 12
to 18 months of life, asymptomatic lesions are generally managed conservatively. Infants who have severe
anemia and/or thrombocytopenia can be given blood products; for those who have cardiac failure, diuretics
and digoxin are often given. To stop further growth and to speed regression of lesions in infants with more
significant clinical sequelae, treatment with corticosteroids or interferon-α-2a is administered. To slow
the growth of tumors that are rapidly enlarging, chemotherapy and radiation therapy have been used.
Surgical resection, partial hepatectomy, and embolization of afferent vessels should be considered for
severe cases.

SIGNS AND SYMPTOMS

They have been described as masses that fall between a hemangioma and angiosarcoma. They are vascular
tumors that commonly present with an enlarging mass and most commonly involve the lungs, liver, and
musculoskeletal system, although many other body sites have been reported, including the head and neck,
intestines, lymph nodes, pleura, retroperitoneum, heel, stomach.

TREATMENT
Treatment is varied and depends on the site and extent of tumor involvement, site(s) of metastasis,
and specific individual factors. Surgical resection, radiotherapy, and chemotherapy have all been used
to treat these masses, although studies on survival have yet to be conducted to delineate various treatment
regimens.

OSTEOSAR
OSTEOSARCCOMA
An osteosarcoma (OS) or osteogenic sarcoma (OGS) is a cancerous tumor in a bone. Specifically, it is an
aggressive malignant neo-plasm that arises from primitive transformed cells of mesenchymal origin (and
thus a sarcoma) and that exhibits osteoblastic differentiation and produces malignant osteoid. Osteosarcoma
is the most common histological form of primary bone cancer. It is most prevalent in teenagers and young
adults.

SIGNS AND SYMPTOMS

Many patients first complain of pain that may be worse at night, may be intermittent and of varying
intensity and may have been occurring for some time. Teenagers who are active in sports often complain
of pain in the lower femur, or immediately below the knee. If the tumor is large, it can present as overt
localised swelling. Sometimes a sudden fracture is the first symptom, because affected bone is not as
strong as normal bone and may fracture abnormally with minor trauma. In cases of more deep-seated
tumors that are not as close to the skin, such as those originating in the pelvis, localised swelling may not
be apparent.
Sarcoma 147

CAUSES
Several research groups are investigating cancer stem cells and their potential to cause tumors along with genes
and proteins causative in different phenotypes. Radiotherapy for unrelated conditions may be a rare cause.
• Familial cases where the deletion of chromosome 13q14 inactivates the retinoblastoma gene is
associated with a high risk of osteosarcoma development.
• Bone dysplasias, including Paget’s disease of bone, fibrous dysplasia, enchondromatosis, and hereditary
multiple exostoses, increase the risk of osteosarcoma.
• Li–Fraumeni syndrome (germline TP53 mutation) is a predisposing factor for osteosarcoma
development.
• Rothmund–Thomson syndrome (i.e. autosomal recessive association of congenital bone defects, hair
and skin dysplasias, hypogonadism, and cataracts) is associated with increased risk of this disease.
• Large doses of Sr-90 emission from nuclear reactor, nicknamed bone seeker increases the risk of
bone cancer and leukemia in animals, and is presumed to do so in people.
Despite persistent rumors suggesting otherwise, there is no clear association between water fluoridation and
cancer or deaths due to cancer, both for cancer in general and also specifically for bone cancer and osteosarcoma.
Series of research concluded that concentration of fluoride in water doesn’t associate with osteosarcoma. The
beliefs regarding association of fluoride exposure and osteosarcoma stem from a study of US National Toxicology
programme in 1990, which showed uncertain evidence of association of fluoride and osteosarcoma in male rats.
But there is still no solid evidence of cancer-causing tendency of fluoride in mice. Fluoridation of water has
been practiced around the world to improve citizens’ dental health. It is also deemed as major health success.
Fluoride concentration levels in water supplies are regulated, such as United States Environmental Protection
Agency regulates fluoride levels to not be greater than 4 milligrams per litre. Actually, water supplies already
have natural occurring fluoride, but many communities chose to add more fluoride to the point that it can
reduce tooth decay. Fluoride is also known for its ability to cause new bone formation. Yet, further research
shows no osteosarcoma risks from fluoridated water in humans. Most of the research involved counting number
of osteosarcoma patients cases in particular areas which has difference concentrations of fluoride in drinking
water. The statistic analysis of the data shows no significant difference in occurrences of osteosarcoma cases in
different fluoridated regions. Another important research involved collecting bone samples from osteosarcoma
patients to measure fluoride concentration and compare them to bone samples of newly diagnosed malignant
bone tumors. The result is that the median fluoride concentrations in bone samples of osteosarcoma patients
and tumor controls are not significantly different. Not only fluoride concentration in bones, Fluoride exposures
of osteosarcoma patients are also proven to be not significantly different from healthy people.

MECHANISM
Osteosarcomas tend to occur at the sites of bone growth, presumably because proliferation makes osteoblastic
cells in this region prone to acquire mutations that could lead to transformation of cells (the RB gene and p53
gene are commonly involved). Due to this tendency, high incidence of osteosarcoma is seen in some large dog
breeds (St. Bernards and Great Danes). The tumor may be localized at the end of the long bone (commonly in
the metaphysis). Most often it affects the proximal end of tibia or humerus, or distal end of femur. Osteosarcoma
tends to affect regions around the knee in 60% of cases, 15% around the hip, 10% at the shoulder, and 8% in the
jaw. The tumor is solid, hard, irregular (“fir-tree,” “moth-eaten”, or “sun-burst” appearance on X-ray examination)
due to the tumor spicules of calcified bone radiating in right angles. These right angles form what is known as
a Codman triangle, which is characteristic but not diagnostic of osteosarcoma. Surrounding tissues are infiltrated.
Microscopically: The characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the
tumor. Tumor cells are very pleomorphic (anaplastic), some are giant, numerous atypical mitoses. These cells
148 Surgical Oncology: Theory and Multidisciplinary Practice

produce osteoid describing irregular trabeculae (amorphous, eosinophilic/pink) with or without central
calcification (hematoxylinophilic/blue, granular)—tumor bone. Tumor cells are included in the osteoid matrix.
Depending on the features of the tumor cells present (whether they resemble bone cells, cartilage cells, or
fibroblast cells), the tumor can be subclassified. Osteosarcomas may exhibit multinucleated osteoclast-like
giant cells.

DIAGNOSIS
Family physicians and orthopedists rarely see a malignant bone tumor (most bone tumors are benign). The
route to osteosarcoma diagnosis usually begins with an X-ray, continues with a combination of scans (CT scan,
PET scan, bone scan, MRI) and ends with a surgical biopsy. A characteristic often seen in an X-ray is Codman’s
triangle, which is basically a subperiosteal lesion formed when the periosteum is raised due to the tumor. Films
are suggestive, but bone biopsy is the only definitive method to determine whether a tumor is malignant or
benign. Most times, the early signs of osteosarcoma are caught on X-rays taken during routine dental check-
ups. Osteosarcoma frequently develops in the mandible (lower jaw); accordingly, Dentist are trained to look for
signs that may suggest osteosarcoma. Even though radiographic findings for this cancer vary greatly, one usually
sees a symmetrical widening of the periodontal ligament space. If the dentist has reason to suspects osteosarcoma
or another underlying disorder, he or she would refer the patient to an Oral and Maxillofacial surgeon for
biopsy. A biopsy of suspected osteosarcoma outside of the facial region should be performed by a qualified
orthopedic oncologist. The American Cancer Society states: “Probably in no other cancer is it as important to
perform this procedure properly. An improperly performed biopsy may make it difficult to save the affected
limb from amputation.” It may also metastasise to the lungs, mainly appearing on the chest X-ray as solitary or
multiple round nodules most common at the lower regions.

Variants
• Conventional: osteoblastic, chondroblastic, fibroblastic OS
• Telangiectatic OS
• Small cell OS
• Low-grade central OS
• Periosteal OS
• Paraosteal OS
• Secondary OS
• High-grade surface OS
• Extraskeletal OS.

TREATMENT
A complete radical, surgical, en bloc resection of the cancer, is the treatment of choice in osteosarcoma. Although
about 90% of patients are able to have limb-salvage surgery, complications, particularly infection, prosthetic
loosening and non-union, or local tumor recurrence may cause the need for further surgery or amputation.
Mifamurtide is used after a patient has had surgery to remove the tumor and together with chemotherapy to kill
remaining cancer cells to reduce the risk of cancer recurrence. Also, the option to have rotationplasty after the
tumor is taken out exists. Patients with osteosarcoma are best managed by a medical oncologist and an orthopedic
oncologist experienced in managing sarcomas. Current standard treatment is to use neo-adjuvant chemotherapy
(chemotherapy given before surgery) followed by surgical resection. The percentage of tumor cell necrosis (cell
death) seen in the tumor after surgery gives an idea of the prognosis and also lets the oncologist know if the
Sarcoma 149

chemotherapy regimen should be altered after surgery. Standard therapy is a combination of limb-salvage orthopedic
surgery when possible (or amputation in some cases) and a combination of high-dose methotrexate with leucovorin
rescue, intra-arterial cisplatin, adriamycin, ifosfamide with mesna, BCD (bleomycin, cyclophosphamide,
dactinomycin), etoposide, and muramyl tripeptide. Rotationplasty may be used. Ifosfamide can be used as an
adjuvant treatment if the necrosis rate is low. Despite the success of chemotherapy for osteosarcoma, it has one of
the lowest survival rates for pediatric cancer. The best reported 10-year survival rate is 92%; the protocol used is
an aggressive intra-arterial regimen that individualizes therapy based on arteriographic response. Three-year event-
free survival ranges from 50% to 75%, and five-year survival ranges from 60% to 85+% in some studies. Overall,
65–70% patients treated five years ago will be alive today. These survival rates are overall averages and vary
greatly depending on the individual necrosis rate. Filgrastim or pegfilgrastim help with white blood cell counts
and neutrophil counts. Blood transfusions and epoetin alfa help with anemia. Computational analysis on a panel of
Osteosarcoma cell lines identified new shared and specific therapeutic targets (proteomic and genetic) in
Osteosarcoma, while phenotypes showed an increased role of tumor microenvironments.

EPIDEMIOLOGY
Osteosarcoma is the eighth-most common form of childhood cancer, comprising 2.4% of all malignancies in
pediatric patients, and about 20% of all primary bone cancers. Incidence rates for osteosarcoma in U.S. patients
under 20 years of age are estimated at 5.0 per million per year in the general population, with a slight variation
between individuals of black, Hispanic, and white ethnicities (6.8, 6.5, and 4.6 per million per year, respectively).
It is slightly more common in males (5.4 per million per year) than in females (4.0 per million per year). It
originates more frequently in the metaphyseal region of tubular long bones, with 42% occurring in the femur, 19%
in the tibia, and 10% in the humerus. About 8% of all cases occur in the skull and jaw, and another 8% in the pelvis.
Around 300 of the 900 people diagnosed in the United States will die each year. A second peak in incidence occurs
in the elderly, usually associated with an underlying bone pathology such as Paget’s disease of bone.

PROGNOSIS
Prognosis is separated into three groups.
• Stage I osteosarcoma is rare and includes parosteal osteosarcoma or low-grade central osteosarcoma.
It has an excellent prognosis (>90%) with wide resection.
• Stage II prognosis depends on the site of the tumor (proximal tibia, femur, pelvis, etc.), size of the
tumor mass, and the degree of necrosis from neo-adjuvant chemotherapy. Other pathological factors
such as the degree of p-glycoprotein, whether the tumor is cxcr4-positive, or Her2-positive are also
important, as these are associated with distant metastases to the lung. The prognosis for patients with
metastatic osteosarcoma improves with longer times to metastases, (more than 12 months to 4 months),
a smaller number of metastases, and their resectability. It is better to have fewer metastases than longer
time to metastases. Those with a longer length of time (more than 24 months) and few nodules (two or
fewer) have the best prognosis, with a two-year survival after the metastases of 50%, five-year of 40%,
and 10-year of 20%. If metastases are both local and regional, the prognosis is worse.
• Initial presentation of stage III osteosarcoma with lung metastases depends on the resectability of the
primary tumor and lung nodules, degree of necrosis of the primary tumor, and maybe the number of
metastases. Overall survival prognosis is about 30%.
Deaths due to malignant neo-plasms of the bones and joints account for an unknown number of childhood
cancer deaths. Mortality rates due to osteosarcoma have been declining at about 1.3% per year. Long-term
survival probabilities for osteosarcoma have improved dramatically during the late 20th century and approximated
68% in 2009.
150 Surgical Oncology: Theory and Multidisciplinary Practice

SARCOMA BO
SARC TR
BOTRY
YOIDES
TRY
Sarcoma botryoides or botryoid sarcoma or botryoid rhabdomyosarcoma is a subtype of embryonal
rhabdomyosarcoma, that can be observed in the walls of hollow, mucosa lined structures such as the nasopharynx,
common bile duct, urinary bladder of infants and young children or the vagina in females, typically younger
than age 8. The name comes from the gross appearance of “grape bunches” (botryoid in Greek).

CLINICAL CHARACTERISTICS
For botryoid rhabdomyosarcoma of the vagina, the most common clinical finding is vaginal bleeding but
vaginal bleeding is not specific for sarcoma botryoides: other vaginal cancers are possible. They may appear as
a polypoid mass, somewhat yellow in colour and are friable: thus, they (possibly) may break off, leading to
vaginal bleeding or infections.

HISTOLOGY
Under the microscope one can see rhabdomyoblasts that may contain cross-striations. Tumor cells are crowded in
a distinct layer beneath the vaginal epithelium ( cambium layer). Spindle-shaped tumor cells that are desmin positive.

TREATMENT AND PROGNOSIS

The disease used to be uniformly fatal, with a 5-year survival rate between 10 and 35%. As a result, treatment
was radical surgery. New multidrug chemotherapy regimens with or without radiation therapy are now used in
combination with less radical surgery with good results, although outcome data are not yet available.

EPIDEMIOLOGY
Sarcoma botryoides normally is found in children under 8 years of age. Onset of symptoms occurs at age 3
years (38.3 months) on average. Cases of older women with this condition have also been reported.

SOFT-TISSUE SARCOMA
SARC
A soft-tissue sarcoma is a form of sarcoma that develops in connective tissue, though the term is sometimes
applied to elements of the soft tissue that are not currently considered connective tissue.

SIGNS AND SYMPTOMS

In their early stages, soft-tissue sarcomas usually do not cause symptoms. Because soft tissue is relatively
elastic, tumors can grow rather large, pushing aside normal tissue, before they are felt or cause any problems.
The first noticeable symptom is usually a painless lump or swelling. As the tumor grows, it may cause other
symptoms, such as pain or soreness, as it presses against nearby nerves and muscles. If in the abdomen it can
cause abdominal pains commonly mistaken for menstrual cramps, indigestion, or cause constipation.

RISK FACTORS
Most soft-tissue sarcomas are not associated with any known risk factors or identifiable cause.
There are some exceptions:
• Studies suggest that workers who are exposed to chlorophenols in wood preservatives and phenoxy
herbicides may have an increased risk of developing soft-tissue sarcomas. An unusual percentage of
Sarcoma 151

patients with a rare blood vessel tumor, angiosarcoma of the liver, have been exposed to vinyl chloride
in their work. This substance is used in the manufacture of certain plastics, notably PVC.
• In the early 1900s, when scientists were just discovering the potential uses of radiation to treat disease,
little was known about safe dosage levels and precise methods of delivery. At that time, radiation was
used to treat a variety of non-cancerous medical problems, including enlargement of the tonsils, adenoids,
and thymus gland. Later, researchers found that high doses of radiation caused soft-tissue sarcomas in
some patients. Because of this risk, radiation treatment for cancer is now planned to ensure that the
maximum dosage of radiation is delivered to diseased tissue while surrounding healthy tissue is protected
as much as possible.
• Kaposi’s sarcoma, a rare cancer of the cells that line blood vessels in the skin and mucus membranes,
is caused by Human herpesvirus 8. Kaposi’s sarcoma often occurs in patients with AIDS (acquired
immune deficiency syndrome). Kaposi’s sarcoma, however, has different characteristics than typical
soft-tissue sarcomas and is treated differently.
• In a very small fraction of cases, sarcoma may be related to a rare inherited genetic alteration of the
p53 gene and is known as Li-Fraumeni syndrome. Certain other inherited diseases are associated with
an increased risk of developing soft-tissue sarcomas. For example, people with neurofibromatosis type
I (also called von Recklinghausen’s disease, associated with alterations in the NF1 gene) are at an
increased risk of developing soft-tissue sarcomas known as malignant peripheral nerve sheath tumors.
Patients with inherited retinoblastoma have alterations in the RB1 gene, a tumor suppressor gene, and
are likely to develop soft-tissue sarcomas as they mature into adulthood.

DIAGNOSIS
The only reliable way to determine whether a soft-tissue tumour is benign or malignant is through a biopsy.
There are two methods for acquisition of tumour tissue for cytopathological analysis;
• Needle Aspiration, via biopsy needle
• Surgically, via an incision made into the tumour.
A pathologist examines the tissue under a microscope. If cancer is present, the pathologist can usually
determine the type of cancer and its grade. Here, ‘grade’ refers to a scale used to represent concisely the
predicted growth rate of the tumour and its tendency to spread, and this is determined by the degree to which the
cancer cells appear abnormal when examined under a microscope. Low-grade sarcomas, although cancerous,
are defined as those that are less likely to metastasise. High-grade sarcomas are defined as those more likely to
spread to other parts of the body. For soft-tissue sarcoma there are two histological grading systems: the
National Cancer Institute (NCI) system and the French Federation of Cancer Centers Sarcoma Group (FNCLCC)
system. Soft tissue sarcomas commonly originate in the upper body, in the shoulder or upper chest. Some
symptoms are uneven posture, pain in the trapezius muscle and cervical inflexibility [difficulty in turning the
head]. The most common site to which soft tissue sarcoma spreads is the lungs.

TREATMENT
In general, treatment for soft-tissue sarcomas depends on the stage of the cancer. The stage of the sarcoma is
based on the size and grade of the tumor, and whether the cancer has spread to the lymph nodes or other parts of
the body (metastasized).
Treatment options for soft-tissue sarcomas include surgery, radiation therapy, and chemotherapy.
• Surgery is the most common treatment for soft-tissue sarcomas. If possible, the doctor will remove
the cancer and a safe margin of the healthy tissue around it. It is important to obtain a margin free of
tumor to decrease the likelihood of local recurrence and give the best chance for eradication of the
152 Surgical Oncology: Theory and Multidisciplinary Practice

tumor. Depending on the size and location of the sarcoma, it may, rarely, be necessary to remove all
or part of an arm or leg.
• Radiation therapy may be used either before surgery to shrink tumors or after surgery to kill any
cancer cells that may have been left behind. In some cases, it can be used to treat tumours that
cannot be surgically removed. In multiple studies, radiation therapy has been found to improve the
rate of local control, but has not had any influence on overall survival.
• Chemotherapy may be used with radiation therapy either before or after surgery to try to shrink the
tumor or kill any remaining cancer cells. The use of chemotherapy to prevent the spread of soft-
tissue sarcomas has not been proven to be effective. If the cancer has spread to other areas of the
body, chemotherapy may be used to shrink tumors and reduce the pain and discomfort they cause,
but is unlikely to eradicate the disease.
A combination of Taxotere and Gemzar could be an effective chemotherapy regimen in patients with advanced
soft-tissue sarcoma.

EPIDEMIOLOGY
Soft-tissue sarcomas are relatively uncommon cancers. They account for less than 1% of all new cancer
cases each year. This may be because cells in soft tissue, in contrast to tissues that more commonly give rise to
malignancies, are not continuously dividing cells. In 2006, about 9,500 new cases were diagnosed in the United
States. Soft-tissue sarcomas are more commonly found in older patients (>50 years old) although in children
and adolescents under age 20, certain histologies are common (rhabdomyosarcoma, synovial sarcoma). Around
3,300 people were diagnosed with soft tissue sarcoma in the UK 2011.

TABLES
Table. Major Types of Soft-Tissue Sarcomas in Adults
Tissue of Origin Type of Cancer Usual Location in the Body
Fibrous tissue Fibrosarcoma Arms, legs, trunk
Malignant fibroushystiocytoma Legs
Dermatofibrosarcoma Trunk
Fat Liposarcoma Arms, legs, trunk
Muscle
Striated muscle Rhabdomyosarcoma Arms, legs
Smooth muscle Leiomyosarcoma Uterus, digestive tract
Blood vessels Hemangiosarcoma Arms, legs, trunk
Kaposi’s sarcoma Legs, trunk
Lymph vessels Lymphangiosarcoma Arms
Synovial tissue(linings of joint Synovial sarcoma Legs
cavities, tendon sheaths)
Peripheral nerves Malignant peripheral nerve sheath Arms, legs, trunk
tumour/Neurofibrosarcoma
Cartilage and bone-forming tissue Extraskeletal chondrosarcoma Legs
Extraskeletal osteosarcoma Legs, trunk (not involving the bone)
Table. Major Types of Soft-Tissue Sarcomas in Children
Tissue of Origin Type of Cancer Usual Location in the Body Most common ages
Muscle
Striated muscle Rhabdomyosarcoma
Embryonal Head and neck, genitourinary tract Infant–4
Alveolar soft part sarcoma Arms, legs, head, and neck Infant–19
Smoothmuscle Leiomyosarcoma Trunk 15–19
Fibrous tissue Fibrosarcoma Arms and legs 15–19
Malignant fibroushistiocytoma Legs 15–19
Sarcoma 153

Dermatofibrosarcoma Trunk 15–19

Fat Liposarcoma Arms and Legs 15–19
Blood vessels Infantile hemangio-pericytoma Arms, legs, trunk, head, and neck Infant–4
Synovial tissue(linings Synovial sarcoma Legs, arms, and trunk 15–19
of joint cavities,
tendon sheaths)
Peripheral nerves Malignant peripheral nerve Arms, legs, and trunk 15–19
sheath tumors (also called
neurofibrosarcomas, malignant
schwannomas, and neurogenic
sarcomas)
Muscular nerves Alveolar soft part sarcoma Arms and legs Infant–19
Cartilage and bone- Extraskeletal myxoid Legs 10–14
forming tissue chondrosarcoma
Extraskeletal mesenchymal Legs 10–14
An earlier version of this article was taken from the US National Cancer Center’s Cancer Information
Service.

ALVEOLAR SOFT PART SARCOMA

Alveolar soft part sarcoma, abbreviated ASPS, is a very rare type of soft-tissue sarcoma, that grows slowly
and whose cell of origin is unknown. It arises mainly in children and young adults. ASPS can migrate (metastasize)
into other parts of the body, typically the lungs and the brain. ASPS is a sarcoma, and that indicates that this
cancer initially arises from tissue of embryonic mesenchymal origin. (The fertilized egg divides and redivides
forming a sphere. Early in embryogenesis, dimples appear in the poles of the sphere and burrow through the
sphere forming an inner passage that will ultimately form the gut. Malignancies arising from cells that were
originally part of the outer layer of the sphere and those that were part of the embryonic tunnel are termed
carcinomas; malignancies arising from the cells between the outer layer and the inner burrow are termed
sarcomas.) Typically, ASPS arises in muscles and deep soft tissue of the thigh or the leg (lower extremities), but
can also appear in the upper extremities (hands, neck, and head). While ASPS is a soft tissue sarcoma, it can
also spread and grow inside the bones. The term alveolar comes from the microscopic pattern, visible during
the analysis of slides of ASPS under the microscope in histopathology. The tumor cells seem to be arranged in
the same pattern as the cells of the small air sacks (alveoli) in the lungs. However, this is just a structural
similarity. ASPS was first described and characterized in 1952.

Causes
Chromosomal analysis of ASPS shows the breaking and joining of two chromosomes in the tumor cells. A
piece of chromosome X breaks and is joined to chromosome 17. This translocation creates a fusion between
two genes named ASPL and TFE3, which results in the formation of an aberrant protein (termed fusion protein)
that is not found in normal cells. Two sorts of fusions between chromosome X and chromosome 17 are found in
different ASPS tumors: Type one, and type two. Dr. Ladanyi at Memorial Sloan-Kettering Cancer Center, in
New York City, has pioneered this work. The first xenograft model of ASPS (for type one) was established in
mice by David Vistica at the National Cancer Institute in Frederick, MD in 2009.

Primary Diagnosis
ASPS may exist in the patient’s body for a long time before being diagnosed. It can grow large and push
aside surrounding tissues for a long time before causing any discomfort. Therefore, ASPS symptoms may either
be a painless swelling, or a soreness caused by compressed nerves or muscles, affecting the range of motion in
the area.
154 Surgical Oncology: Theory and Multidisciplinary Practice

Pathology
The definitive diagnosis of ASPS is based on its appearance under the microscope, i.e. its histomorphology,
and presence of the characteristic chromosomal translocation. ASPS’ histomorphologic features include an
alveolar-like pattern at low magnification and the presence of large cells with abundant eosinophilic cytoplasm
and eccentric nuclei. Calcifications are commonly present, as may be seen with slow growing neo-plasms.

Prognosis
Although ASPS displays a relatively indolent course, the ultimate prognosis is poor and is often characterized
by late metastases.

Epidemiology
ASPS is an extremely rare cancer. While sarcomas comprise about 1% of all newly diagnosed cancers, and
15% of all childhood cancers, ASPS comprises less than 1% of sarcomas. According to the American Cancer
Society, about 9530 new cases of soft tissue sarcoma will be diagnosed in the USA in 2006. This predicts under
100 new cases of ASPS. Such low numbers of occurrence seriously impede the search for a cure by making it
hard to gather any meaningful statistics about the disease. As a result, finding the best treatment option often
involves making a lot of educated guesses.

Research
• Sunitinib
• Cediranib new trial from England; adult doses have already been established, NCI is currently working
on doses for children.
Work out of Huntsman Cancer Institute (HCI) in Utah has demonstrated that ASPS might be driven in part
by lactate both being used as a fuel and driving angiogenesis.

ANGIOSARCOMA
Angiosarcoma is a cancer of the cells that line the walls of blood vessels or lymphatic vessels. The lining
of the vessel walls is called the endothelium. However, they should not be confused with cherry hemangiomas.
Most tumors of visceral blood and lymphatic vessel walls are cancerous (malignant). Because these cancers are
carried by the blood flow or lymphatic flow, they can more easily metastasize to distant sites, particularly the
liver and lungs. Angiosarcomas show signs of hemorrhage and necrosis. Pathologically, tumor cells show
increased nuclear to cytoplasm ratio, nuclear hyperchromasia, nuclear pleomorphism and high mitotic activity.
In dogs, hemangiosarcoma is relatively common, especially in larger breeds such as golden retrievers and
Labrador retrievers. In humans, hemangiosarcomas and lymphangiosarcomas of the skin are uncommon.
Angiosarcoma of the liver, a rare fatal tumor, has been seen in workers intensively exposed to the gas vinyl
chloride monomer (VCM) for prolonged periods while working in polyvinyl chloride (PVC) polymerization
plants. It has also been associated with individuals exposed to arsenic-containing insecticides and Thorotrast.

PHYLLODES TUMOR
Phyllodes tumors also cystosarcoma phyllodes, cystosarcoma phylloides and phylloides tumor, are typically
large, fast-growing masses that form from the periductal stromal cells of the breast. They account for less than
1% of all breast neo-plasms.
Sarcoma 155

Classification
Phyllodes tumors are a fibroepithelial tumor composed of an epithelial and a cellular stromal component.
They may be considered benign, borderline, or malignant depending on histologic features including stromal
cellularity, infiltration at the tumor’s edge, and mitotic activity. All forms of phyllodes tumors are regarded as
having malignant potential. A large series from the M.D. Anderson Cancer Centre reported the incidence of
each as benign (58%), borderline (12%), and malignant (30%). Malignant phyllodes tumours behave like sarcomas
and can develop blood-borne metastases. Approximately 10% of patients with phyllodes tumours develop
distant metastases and this can go up to 20% in patients with histologically malignant tumours. The commonest
sites for distant metastases are the lung, bone, and abdominal viscera. Rare sites of metastasis like to parotid
region have also been described. They are classified as a fibroepithelial tumor by ICD-O, but not by MeSH.
Younger women have a higher chance of having a benign phyllodes tumor.

Presentation
This is predominantly a tumor of adult women, with very few examples reported in adolescents. Patients
typically present with a firm, palpable mass. These tumors are very fast-growing, and can increase in size in just
a few weeks. Occurrence is most common between the ages of 40 and 50, prior to menopause. This is about 15
years older than the typical age of patients with fibroadenoma, a condition with which phyllodes tumors may be
confused. They have been documented to occur at any age above 12 years.

Treatment
The common treatment for phyllodes is wide local excision. Other than surgery, there is no cure for phyllodes, as
chemotherapy and radiation therapy are not effective. The risk of developing local recurrence or metastases is related
to the histologic grade, according to the above-named features. Despite wide excision, a very high percentage of
surgeries yielded incomplete excision margins that required revision surgery. Radiation treatment after breast-conserving
surgery with negative margins may significantly reduce the local recurrence rate for borderline and malignant tumors.
The authors of a 2012 study have derived a risk calculator for relapse risk of phyllodes tumors after surgery.

Spectrum
Phyllodes tumors are considered to be on a spectrum of disease that consists of fibroadenoma, fibroadenoma variant
and benign phyllodes. Some would extend the spectrum to include malignant phyllodes tumors and frank sarcoma.

DERMATOFIBROSARCOMA PROTUBERANS
Dermatofibrosarcoma protuberans (DFSP) is a rare tumor. It is a rare neo-plasm of the dermis layer of the
skin, and is classified as a sarcoma. There is only about one case per million per year. DFSP is a fibrosarcoma,
more precisely a cutaneous soft tissue sarcoma. In many respects, the disease behaves as a benign tumor, but in
2–5% of cases it can metastasize, so it should be considered to have malignant potential. It occurs most often in
adults in their thirties; it has been described congenitally, in children, and the elderly. It accounts for approximately
2–6% of soft tissue sarcoma cancers.

Presentation
Dermatofibrosarcoma protuberans can begin as a minor firm area of skin most commonly about to 1 to 5 cm
in diameter. It can resemble a bruise, birthmark, or pimple. It is a slow growing tumor and is usually found on
156 Surgical Oncology: Theory and Multidisciplinary Practice

the torso but can also be found on the arms, legs, head and neck. About 90% of DFSPs are low grade sarcomas.
About 10% are mixed; they contain a high-grade sarcomatous component (DFSP-FS); therefore, they are
considered to be intermediate-grade sarcomas. DFSPs rarely lead to a metastasis (fewer than 5% do metastasise),
but DFSPs can recur locally. DFSPs most often arise in patients who are in their thirties, but sometimes have
been described in children or the elderly.

Pathophysiology
More than 90% of DFSP tumors have the chromosomal translocation t(17;22). The translocation fuses the
collagen gene (COL1A1) with the platelet-derived growth factor (PDGF) gene. The fibroblast, the cell of origin
of this tumor, expresses the fusion gene in the belief that it codes for collagen. However the resulting fusion
protein is processed into mature platelet-derived growth factor which is a potent growth factor. Fibroblasts
contain the receptor for this growth factor. Thus the cell “thinks” it is producing a structural protein, but it
actually produces a self-stimulatory growth signal. The cell divides rapidly and a tumor forms. The tissue is
often positive for CD34.

Diagnosis
Dermatofibrosarcoma protuberans is diagnosed with a biopsy, when a portion of the tumor is removed for
examination. In order to ensure that enough tissue is removed to make an accurate diagnosis, the initial biopsy
of a suspected DFSP is usually done with a core needle or a surgical incision.

Treatment
Treatment is primarily surgical, with chemotherapy and radiation therapy sometimes used. The NCCN
guideline recommends CCPDMA or Mohs surgery for the best cure rate of DFSP. Mohs surgery can be extremely
effective. It will remove the tumor and all related pathological cells without a wide-area excision that may
overlook sarcoma cells that have penetrated muscle tissue. The standard of care for patients with DFSP is
surgery. Usually, complete surgical resection with margins of 2 to 4 cm (recommended) is performed. The
addition of adjuvant radiotherapy (irradiation) improves local control in patients with close or positive margins
during the surgery. A special surgical technique, the “Mohs micrographic surgery” (MMS), can be employed in
patients with DFSP.
MMS is technically possible if the DFSP is in an anatomically confined area. A high probability of cure of
DFSP can be attained with MMS as long as the final margins are negative. Patients who have a recurrent DFSP
can have further surgery, but the probability of adverse effects of surgery and/or metastasis is increased in these
patients. The Mohs surgery is highly successful. Imatinib is approved for treatment. As is true for all medicinal
drugs that have a name that ends in “ib,” imatinib is a small molecular pathway inhibitor; imatinib inhibits
tyrosine kinase. It may be able to induce tumor regression in patients with recurrent DFSP, unresectable DFSP
or metastatic DFSP. There is clinical evidence that imatinib, which inhibits PDGF-receptors, may be effective
for tumors positive for the t(17;22) translocation.

AGGRESSIVE FIBROMATOSIS
Aggressive fibromatosis is a rare condition marked by the presence of desmoid tumors. Desmoid tumors can
arise in virtually any part of the body, and are tumors that arise from cells called fibroblasts, which are found
throughout the body and provide structural support, protection to the vital organs, and play a critical role in
wound healing. These tumors tend to occur in women in their thirties, but can occur in anyone at any age. They
Sarcoma 157

can be either relatively slow-growing or malignant. However, aggressive fibromatosis is locally aggressive.
When they are aggressive they can cause life-threatening problems or even death when they compress vital
organs such as intestines, kidney, lungs, blood vessels, nerves etc. Most cases are sporadic, but some are associated
with familial adenomatous polyposis (FAP). Approximately 10% of individuals with Gardner’s syndrome, a
type of FAP with extracolonic features, have desmoid tumors. Histologically they resemble very low-grade
fibrosarcomas, but they are very locally aggressive and tend to recur even after complete resection. There is a
tendency for recurrence in the setting of prior surgery; in one study, two-thirds of patients with desmoid tumors
had a history of prior abdominal surgery. Risk factors for desmoid disease amongst FAP patients include female
sex, a 3' APC mutation, a positive family history and a history of previous abdominal surgery.

Classification
Desmoid tumors may be classified as extra-abdominal, abdominal wall, or intra-abdominal (the last is more
common in patients with FAP). It is thought that the lesions may develop in relation to estrogen levels or
trauma/operations. A 3' APC mutation is the most significant risk factor for intra-abdominal desmoid development
amongst FAP patients. FAP patients presenting with an abdominal wall desmoid pre-operatively are at an increased
risk of developing an intra-abdominal desmoid post-operatively. Desmoid tumours of the breast are rare. Although
benign, they can mimic breast cancer on physical examination, mammography and breast ultrasound and can
also be locally invasive. Even though they occur sporadically, they can also be seen as a part of Gardner’s
syndrome. A high index of suspicion and a thorough triple examination protocol is necessary to detect rare
lesions like a desmoid tumour which can masquerade as breast carcinoma. Desmoid tumour of the breast may
present a difficulty in the diagnosis especially where imaging studies are not conclusive and suggest a more
ominous diagnosis.

Treatment
Treatment may consist of watching and waiting, complete surgical removal, radiation therapy, antiestrogens
(ex. Tamoxifen), NSAIDs, chemotherapy or microwave ablation. Patients with desmoid tumors should be
evaluated by a multi-disciplinary team of surgeons, medical oncologists, radiation oncologists, geneticists and
nurses. There is no cure for desmoid tumors and when possible patients are encouraged to enlist in clinical
trials. A biopsy is always indicated as the definitive method to determine nature of the tumour. Management of
these lesions is complex, the main problem being the high rates of recurrence in FAP associated disease.
Conversely, for intra-abdominal fibromatosis without evidence of FAP, although extensive surgery may still be
required for local symptoms, the risk of recurrence appears to be lower. Wide surgical resection with clear
margins is the most widely practiced technique with radiation, chemotherapy, or hormonal therapy being used
to reduce the risk of recurrence. Current experimental studies are being done with Gleevec (Imatinib) and
Nexavar (sorafenib) for treatment of desmoid tumors, and show promising success rates.

DESMOPLASTIC SMALL-ROUND-CELL TUMOR

Desmoplastic small-round-cell tumor is an aggressive and rare cancer that primarily occurs as masses in the
abdomen. Other areas affected may include the lymph nodes, the lining of the abdomen, diaphragm, spleen,
liver, chest wall, skull, spinal cord, large intestine, small intestine, bladder, brain, lungs, testicles, ovaries, and
the pelvis. Reported sites of metastatic spread include the liver, lungs, lymph nodes, brain, skull, and bones.
The tumor is classified as a soft tissue sarcoma. It is considered a childhood cancer that predominantly strikes
boys and young adults. The disease rarely occurs in females, but when it does the tumors can be mistaken for
ovarian cancer. In dogs, mast cell tumors are the most frequent round cell tumor.
158 Surgical Oncology: Theory and Multidisciplinary Practice

Symptoms
There are few early warning signs that a patient has a DSRCT. Patients are often young and healthy as the
tumors grow and spread uninhibited within the abdominal cavity. These are rare tumors and symptoms are often
misdiagnosed by physicians. The abdominal masses can grow to enormous size before being noticed by the patient.
The tumors can be felt as hard, round masses by palpating the abdomen. First symptoms of the disease often
include abdominal distention, abdominal mass, abdominal or back pain, gastrointestinal obstruction, lack of appetite,
ascites, anemia, and/or cachexia. Other reported symptoms include unknown lumps, thyroid conditions, hormonal
conditions, blood clotting, kidney or urological problems, testicle, breast, uterine, vaginal, or ovarian masses.

Causes
There are no known risk factors that have been identified specific to the disease. The tumor appears to arise
from the primitive cells of childhood, and is considered a childhood cancer. Research has indicated that there is a
chimeric relationship between desmoplastic small-round-cell tumor (DSRCT) and Wilms’ tumor and Ewing’s
sarcoma. Together with neuroblastoma and non-Hodgkin’s lymphoma, they form the small cell tumors. DSRCT is
associated with a unique chromosomal translocation t(11;22)(p13:q12) resulting in an EWS/WT1 transcript that
is diagnostic of this tumor. This transcript codes for a protein that acts as a transcriptional activator that fails to
suppress tumor growth. The EWS/WT1 translocation product targets ENT4. ENT4 is also known as PMAT.

Pathology
The entity was first described by pathologists William L. Gerald and Juan Rosai in 1989. Pathology reveals
well circumscribed solid tumor nodules within a dense desmoplastic stroma. Often areas of central necrosis are
present. Tumor cells have hyperchromatic nuclei with increased nuclear/cytoplasmic ratio. On
immunohistochemistry, these cells have trilinear coexpression including the epithelial marker cytokeratin, the
mesenchymal markers desmin and vimentin, and the neuronal marker neuron-specific enolase. Thus, although
initially thought to be of mesothelial origin due to sites of presentation, it is now hypothesized to arise from a
progenitor cell with multiphenotypic differentiation.

Diagnosis

Differential Diagnosis
Because this is a rare tumor, not many family physicians or oncologists are familiar with this disease. DSRCT
in young patients can be mistaken for other abdominal tumors including rhabdomyosarcoma, neuroblastoma,
and mesenteric carcinoid. In older patients DSRCT can resemble lymphoma, peritoneal mesothelioma, and
peritoneal carcinomatosis. In males DSRCT may be mistaken for germ cell or testicular cancer while in females
DSRCT can be mistaken for Ovarian cancer. DSRCT shares characteristics with other small-round blue cell
cancers including Ewing’s sarcoma, acute leukemia, small cell mesothelioma, neuroblastoma, primitive
neuroectodermal tumor, rhabdomyosarcoma, and Wilms’ tumor.

Treatment
DSRCT is frequently misdiagnosed. Adult patients should always be referred to a sarcoma specialist. This is
an aggressive, rare, fast spreading tumor and both pediatric and adult patients should be treated at a sarcoma
center. There is no standard protocol for the disease; however, recent journals and studies have reported that
Sarcoma 159

some patients respond to high-dose (P6 Protocol) chemotherapy, maintenance chemotherapy, debulking operation,
cytoreductive surgery, and radiation therapy. Other treatment options include: hematopoietic stem cell
transplantation, intensity-modulated radiation Therapy, radiofrequency ablation, stereotactic body radiation
therapy, intraperitoneal hyperthermic chemoperfusion, and clinical trials.

Prognosis
The prognosis for DSRCT remains poor. Prognosis depends upon the stage of the cancer. Because the disease
can be misdiagnosed or remain undetected, tumors frequently grow large within the abdomen and metastasize
or seed to other parts of the body. There is no known organ or area of origin. DSRCT can metastasize through
lymph nodes or the blood stream. Sites of metastasis include the spleen, diaphragm, liver, large and small
intestine, lungs, central nervous system, bones, uterus, bladder, genitals, abdominal cavity, and the brain. A
multi-modality approach of high-dose chemotherapy, aggressive surgical resection, radiation, and stem cell
rescue improves survival for some patients. Reports have indicated that patients will initially respond to first
line chemotherapy and treatment but that relapse is common. Some patients in remission or with inoperable
tumor seem to benefit from long term low dose chemotherapy, turning DSRCT into a chronic disease.

Research
The Stehlin Foundation currently offers DSRCT patients the opportunity to send samples of their tumors
free of charge for testing. Research scientists are growing the samples on nude mice and testing various
chemical agents to find which are most effective against the individual’s tumor. Patients with advanced
DSRCT may qualify to participate in clinical trials that are researching new drugs to treat the disease.

Alternative Names
This disease is also known as: desmoplastic small round blue cell tumor; intraabdominal desmoplastic small
round blue cell tumor; desmoplastic small cell tumor; desmoplastic cancer; desmoplastic sarcoma; DSRCT.
There is no connection to peritoneal mesothelioma which is another disease sometimes described as desmoplastic.

EPITHELIOID SARCOMA
Epithelioid sarcoma is a rare soft tissue sarcoma arising from mesenchymal tissue and characterized by
epithelioid-like features. It accounts for less than 1% of all soft tissue sarcomas. It was first clearly characterized
by F.M. Enzinger in 1970. It commonly presents itself in the distal limbs (fingers, hands, forearms, or feet) of
young adults as a small, soft mass or a series of bumps. A proximal version has also been described, frequently
occurring in the upper extremities. Rare cases have been reported in the pelvis, vulva, penis, and spine.
Histologically, epithelioid sarcoma forms nodules with central necrosis surrounded by bland, polygonal cells
with eosinophilic cytoplasm and peripheral spindling. Epithelioid sarcomas typically express vimentin,
cytokeratins, epithelial membrane antigen, and CD34, whereas they are usually negative for S100, desmin, and
FLI-1. They typically stain positive for CA125. Epithelioid sarcoma most commonly strikes young adults, yet
no age group is immune. The disease has a tendency to develop local recurrences and metastasis thereafter to
regional lymph nodes, lung, bone, brain, and other locations, including the scalp. Generally speaking, epithelioid
sarcoma has a high rate of relapse after initial treatment and tends to recur locally (at or near the original tumor
site). Epithelioid sarcoma also demonstrates lymphatic spread (in 22-48% of cases), and metastasis (in 21-63%
of cases). These events, as well as advanced stage (progression) and grade (aggressiveness), are predictive of an
overall worse outcome. The overall five-year survival rate for epithelioid sarcoma is anywhere from 25 to 78%.
160 Surgical Oncology: Theory and Multidisciplinary Practice

Importantly, the 10-year and 15-year survival rate drops off significantly. Associated with a more positive
outcome are younger age, female vs. male sex, distal vs. proximal location, smaller tumor size, and negative
margins upon tumor resection.

Signs and Symptoms

In general, epithelioid sarcoma is a slow-growing and relatively painless tumor, often resulting in a lengthy
period of time between presentation and diagnosis. Due to its ambiguity, it is often misdiagnosed, mistaken as
a persistent wart or cyst. It most commonly presents itself in the distal limbs (fingers, hands, forearms, or feet)
as a small, soft mass or a series of bumps. It is most often described as a firm-to-hard palpable mass, either in
the deep soft tissue or in the dermis. Often, superficial lesions will ulcerate causing a mistaken diagnosis of a
poorly healing traumatic wound or wart. About 13% of patients will present with multifocal tumors, and about
13% of patients will present with metastatic disease.

Genetics
The most common genetic mutation (found in 80-90% of epithelioid sarcomas) is the inactivation of the
SMARCB1 gene, or the loss of INI-1 function, which is thought to be a major contributor to disease progression.
Epithelioid sarcoma typically contains chromosome 22q11.2 mutations or deletions and 8q gains, particularly
i(8) (>q10). Aberrations of 18q and 8q, as well as recurrent gains at 11q13, have also been observed. The
SMARCB1 gene (also termed BAF47, INI1, or hSNF5) is located on chromosome 22q11.2 and codes for a
member of the SWI/SNF chromatin remodeling complex. Loss of SMARCB1 function is the most common
genetic mutation observed in epithelioid sarcoma, and this dysfunction is likely a major driver of disease
progression. SMARCB1 is a core protein subunit of the 15 subunit SWI/SNF (or BAF) complex involved in
regulating the nucleosome architecture of our genome and has been shown to be a potent tumor suppressor
gene, meaning that its primary role is to control cell division and to even halt division under appropriate
circumstances (i.e. signals to over-replicate). As this tumor suppressor is commonly inactivated in epithelioid
sarcoma, cell division can fail to appropriately halt, resulting in unregulated cellular growth and the formation
of cancer tumors. Several research teams are currently developing techniques to reverse this loss of genetic
function characteristic of epithelioid sarcoma.

Molecular Biology

VEGF
VEGF (vascular endothelial growth factor) is often over-expressed in epithelioid sarcoma. This is a critical
pathway in angiogenesis, a process that cancer cells use to form new blood vessels, which provide necessary
elements to the tumor for tumor survival. Anti-VEGF agents such as pazopanib have shown promise across
several different carcinomas and in soft tissue sarcomas. In one case study, a patient with advanced metastatic
vulvar epithelioid sarcoma showed a partial resolution of both lung and pleural metastases when pazopanib was
administered, whereas all other therapies had failed

MET
MET (mesenchymal to epithelial transition) is another biological pathway that is likely involved in the
development and progression of epithelioid sarcoma. c-MET is a tyrosine kinase oncogene, and its signaling
pathway has been implicated in a variety of malignancies, including many cancers.
Sarcoma 161

Sonic Hedgehog and Notch

The Sonic hedgehog and Notch signaling pathways are also suspected to be up-regulated in epithelioid
sarcoma. These cell signaling pathways control cellular proliferation and differentiation. They are also involved
in cancer stem cell coordination and disease invasiveness and metastasis. Hhat inhibitors (such as RU-SKI 43)
block the Sonic hedgehog signaling pathway by inhibiting hedgehog palmitoyl acytl-transferase. Current trials
are investigating Notch inhibitors against epithelioid sarcoma.

mTOR
The frequent hyperactivation of mTOR (mammalian target of rapamycin) signaling has also been observed
in epithelioid sarcoma. The mTOR pathway has been described as a “master switch” for cellular catabolism and
anabolism, and it can enhance cell cycle progression, cell survival, and block normal cell death (apoptosis).
Interestingly, it has been demonstrated that simply blocking mTOR signaling can result in the reactivation of
the AKT pathway, negating much of the anti-mTOR’s efficacy. This reactivation of AKT has been shown to be
c-MET-dependent, resulting in the rationale that blocking both mTOR and c-MET concurrently would show
increased efficacy.

EGFR
The over-expression of epidermal growth factor receptor (EGFR) has been reported in a majority of
epithelioid sarcomas. EGFR is a member of the HER receptor family. Upon ligand binding, EGFR
phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions
such as proliferation, survival, and angiogenesis.
In-vitro and in-vivo laboratory experiments have demonstrated that the blockade of EGFR in epithelioid
sarcoma results in decreased cell proliferation, increased apoptosis, and abrogated invasion and migration
capacities. Of interest, while the simple blockade of EGFR with a single agent has shown limited results in
the clinical setting, when used as part of a combination regime (where an EGFR inhibitor is combined with
an mTOR inhibitor), a synergism has been observed, and superior tumor growth inhibition has been
demonstrated.

CD109
CD109 is often expressed in advanced epithelioid sarcoma and is thought to mark the cancer stem cell (or
cancer initiating cell) of the disease. Its level of expression has also been shown to be predictive of outcome.
Cancer stem cells are a small population of tumor cells characterized by general chemo-resistance, the ability to
self-renew, multi-differentiation potential, dormancy capabilities, and tumorigenesis. Therefore, cancer stem
cells are thought to play key roles in the progression and relapse of cancer.

Cyclin D1
Cyclin D1 is a protein requisite for cell cycle progression and has been shown to be up-regulated in epithelioid
sarcoma. Cyclin D-1 is a regulator of cyclin-dependent kinases (CDK4 and CDK6). It has been shown to
interact with the retinoblastoma protein (a tumor suppressor gene), CDK4 and CDK6, thyroid hormone receptor
beta, and nuclear receptor coactivator 1, among others.
Cyclin D and CDKs promote cell cycle progression by releasing transcription factors that are important for
the initiation of DNA replication. Abnormal levels of cyclin D-1 may promote rapid cell division in epithelioid
sarcoma.
162 Surgical Oncology: Theory and Multidisciplinary Practice

Diagnosis
Tissue biopsy is the diagnostic modality of choice. Due to a high incidence of lymph node involvement, a
sentinel lymph node biopsy is often performed. A common characteristic of epithelioid sarcoma (observed in
80% of all cases) is the loss of function of the SMARCB1 gene (also termed BAF47, INI1, or hSNF5).
Immunohistochemical staining of INI1 is available and can be used for the diagnosis of epithelioid sarcoma.
MRI is the diagnostic modality of choice for imaging prior to biopsy and pathologic diagnosis, with the primary
role being the determination of anatomic boundaries.

Staging
The staging for epithelioid sarcoma takes into account size and location of the primary tumor, lymph
node involvement, presence and location of metastasis, and histologic grade (a measure of disease
aggressiveness).

Treatment
Surgical resection of the tumor with wide margins remains the preferred method of treatment, and has shown
the most success against the disease. Recently, limb-sparing surgery has been explored with moderate success.
In cases of advanced, recurrent, or metastasized disease, or if the tumor is inoperable, chemotherapy and radiation
are the standard of care, although the overall success rates with these remains low.

Prognosis
The 5-year survival rate for epithelioid sarcoma patients is 50-70%, and the 10-year survival rate is 42-55%.
Children with epithelioid sarcoma tend to have slightly better outcomes than adults, with 5 year survival rates
around 65%. Pediatric patients also tend to display less lymphatic spread and metastasis. In addition to stage
and grade of the tumor, gender, site, age at diagnosis, tumor size and microscopic pathology have all been
shown to affect prognosis. Advanced stage and grade are associated with worse outcomes. Females tend to have
more favourable outcomes than males, proximal cases show worse outcomes than distal cases, and younger age
is associated with more positive outcomes. Tumors more than 2 cm in diameter and tumors with necrosis and
vascular invasion have been correlated with a worse outcome. The gold standard for chemotherapy is a
combination of doxorubicin and ifosfamide.
However, recent studies have suggested that the addition of ifosfamide to doxorubicin does not necessarily
lead to an increase in overall survival. Etoposide, vincristine, dactinomycin, and cyclophosphamide have also
traditionally been given. Newer chemotherapies, such as gemcitabine and pazopanib, are currently being tested
in clinical trials. Radiation therapy is also a treatment option when tumors are deemed inoperable or wide
surgical margins are not achievable. Radiation therapy in combination with chemotherapy has so far resulted in
only minimal improvements to response rates. Trials with brachytherapy (an internal radiation treatment that
delivers a high dose of radiation directly to the tumor and is thought to have fewer long-term side effects) have
produced some positive results.

New Therapeutic Strategies

Epithelioid sarcoma (especially advanced stage, recurrent, or metastasized disease) has been shown to be
resistant to traditional cancer therapies, necessitating further exploration of novel treatment methods and
techniques. Because of the relatively poor response of epithelioid sarcoma to traditional cancer treatments
(surgery, chemotherapy, and radiation), new treatment strategies are being looked to.
Sarcoma 163

New Chemotherapies
New chemotherapies are being explored in current clinical trials for epithelioid sarcoma, although, thus far,
none has shown significant improvement over the efficacy of doxorubicin/ifosfamide. These new agents include
gemcitabine, pazopanib, cixutumumab, temozolomide, dasatanib, bevacizumab, taxanes, and vinorelbine.
Aldoxorubicin is a new pro-drug of doxorubicin. Doxorubicin is the standard of care for advanced or metastic
epithelioid sarcoma, but has dose-limiting toxicities, namely acute and chronic cardiac toxicity. Doxorubicin
has achieved response rates in the 12-23% range for patients with soft tissue sarcomas. Aldoxorubicin is a new
version of doxorubicin that is designed to safely deliver a higher dose of the drug directly to the tumor, resulting
in increased efficacy and less toxicity. It works by entering the bloodstream, binding to the albumin in the
blood, traveling throughout the body, and releasing a doxorubicin payload when it encounters the acidic
microenvironment of a tumor. Several phase I and II studies are ongoing, and, thus far at least, little if any
cardiac toxicity has been observed. A maximum tolerated dose of aldoxorubicin has been established at 3.5
times the MTD of doxorubicin, and studies have indicated increased response rates for patients with soft tissue
sarcomas. What is unknown at this time are the potential long-term side-effects of this increased dose of
doxorubicin. Several studies have shown increased risk of the development of secondary cancers associated
with exposure to high-dose anthracyclines (such as doxorubicin). TH-302 is another novel prodrug in current
development. It targets tumor hypoxia, a common event in tumorigenesis where the tumor microenvironment is
depleted of oxygen and becomes hypoxic. Hypoxic niches in tumors tend to harbour slower-growing cancer
cells, making many chemotherapies ineffective in these areas. TH-302 directly targets these deep hypoxic
regions, and once within them, it releases a cytotoxic payload of bromo-isophosphoramide mustard directly to
the cancer cells. Given that epithelioid sarcoma is a slow-growing tumor, it is reasonable to hypothesize that ES
tumors would be highly hypoxic and show a favourable response to TH-302. Several studies have observed
increased efficacy of TH-302 when the hypoxic tumor microenvironment has been exasperated. Several phase
I, II, and III trials with TH-302 and TH-302 in combination with doxorubicin are ongoing, and promising results
have thus far been observed. Two phase 3 trials failed in 2015.

Immunotherapies
Immunotherapy is the strategy of using the body’s own immune system to fight cancer. It usually involves
“training” or “tweaking” the immune system so that it can better recognize and reject cancer cells. Different
immunotherapies can include manipulation of the body’s T-cells, NK cells, or Dendritic cells so they are more
effective against cancer cells. They can also include the administration of laboratory-produced antibodies specific
to tumor antigens to create or boost an immune response. Vaccine therapy is perhaps the immunotherapeutic
strategy with the most ongoing exploration in sarcomas at the current time, although, thus far at least, little
evidence has emerged indicating that active vaccination alone can lead to tumor regression. Multiple techniques
and treatment strategies are currently being studied in an effort to improve the objective response rate of vaccine
therapy. Vaccines can deliver various tumor-associated factors (tumor antigens) to the immune system, resulting
in a natural antibody and T-cell response to the tumor. Adoptive immunotherapy seeks to expand a population
of the body’s T-cells that will recognize a specific tumor antigen. T-cells can be harvested and then expanded
and genetically manipulated to recognize certain tumor markers. In an interesting case study, a patient with
advanced epithelioid sarcoma who had failed multiple therapies showed a strong response to expanded
lymphocytes and natural killer cells. Immune checkpoint inhibitors have recently shown promise against several
cancers and may hold promise against sarcomas as well. Tumors often evolve during disease progression, and
they can develop an expression of inhibitory proteins that deter recognition by the immune system and allow
the tumor to escape immune surveillance. By targeting these inhibitory proteins, a pathway is opened for the
164 Surgical Oncology: Theory and Multidisciplinary Practice

immune system to recognize the tumor. Two of these inhibitory proteins that have been studied recently are
CTLA-4 and PD1, and drugs targeting these proteins are in development and showing some promise.

Anti-angiogenic Therapies
Several anti-angiogenic agents are being explored in epithelioid sarcoma, a cancer that likely relies on
angiogenesis for survival and progression. These agents interfere with various pro-angiogenic factors, several
of which are known to be over-expressed in epithelioid sarcoma (VEGF and EGFR for example). Tumors
require a blood supply to provide them with oxygen and nutrients necessary for their survival. As tumors
expand and grow, they send out various signals (such as HIF1) that encourage new blood vessel development to
the tumor. Anti-angiogenic agents, such as bevacizumab, pazopanib, and sunitinib, attempt to slow or block the
growth of tumors by essentially cutting off their blood supply.

Targeted Therapies
Given the multiple genetic abnormalities and disrupted biological pathways observed in epithelioid sarcoma,
drugs targeting these unique tumor characteristics are being looked at for more effective treatments.

Tyrosine Kinase Inhibitors

Stromal tumors (GISTs). Tyrosine kinase (a subclass of protein kinases) is an enzyme that transfers a phosphate
group from an ATP molecule to a protein in a cell. It functions as an “on” or “off” switch for many cellular
functions, including signaling within the cell, and cell division. Tyrosine kinases can contain mutations that
cause them to become constitutively active, or stuck in the “on” position, resulting in unregulated cell division
(a hallmark of cancer). Tyrosine kinase Inhibitors block the action of these enzymes. Tyrosine kinase inhibitors
have been shown to inhibit the VEGF, EGFR, and MET, pathways that are frequently over-expressed in epithelioid
sarcoma. They also can be used against the c-KIT and JAK-STAT signaling pathways, which are involved in
many cancers and may be involved in epithelioid sarcoma. Temsirolimus is a tyrosine kinase inhibitor that
blocks the effects of the mTOR protein and inhibits the mTOR pathway. Interestingly, because of crosstalk
between cell signaling pathways, it has been shown that, while interfering with the mTOR pathway alone
produces only limited results in halting tumorigenesis, inhibiting both the mTOR and the EGFR pathways
concurrently shows an increased effect.

SINE
Selective inhibitors of nuclear export (SINE) compounds, such as selinexor and CBS9106, are being
investigated in several sarcomas and have recently shown promising results across a broad spectrum of both
hematological malignancies and solid tumors. These compounds work by blocking the export of tumor suppressor
genes from the cell’s nucleus to the cell’s cytoplasm, where they are rendered non-functional. Exportin 1 (a.k.a.
XPO1 or CRM1) is a nuclear export protein responsible for the export of over 200 proteins, including the vast
majority of tumor suppressor proteins. For tumor suppressor genes to carry out their normal function
(appropriately initiating apoptosis), they must be located in the nucleus of the cell. Many cancer cells have been
shown to express high levels of exportin1, resulting in the increased export of tumor suppressor proteins out of
the nucleus and therefore counteracting the natural apoptic processes that protect the body from cancer. SINE
compounds prevent the transport of these tumor suppressor proteins out of the nucleus, allowing them to function
normally and encourage apoptosis. Recently, researchers have observed a synergistic effect when using SINE
compounds in combination with traditional chemotherapies (such as doxorubicin). Of interest with respect to
epithelioid sarcoma and other diseases characterized by the loss of INI1 function, it has been demonstrated that
a loss of INI1 expression can result in the “unmasking” of a nuclear export signal, resulting in the transport of
Sarcoma 165

tumor suppressor proteins out of the nucleus of the cell, thus favouring tumorigenesis. It is therefore reasonable
to suspect that a SINE inhibitor would show efficacy against epithelioid sarcoma, as the disease is characterized
by a loss of INI1 function.

HDAC Inhibitors
Histone deacetylase (HDAC) inhibitors, such as vorinostat, have shown some promise in epithelioid sarcoma.
Researchers in Texas are investigating whether or not HDAC inhibitors can reverse the loss of INI1 function
that is characteristic of epithelioid sarcoma. HDAC inhibitors work by blocking events involved in DNA
replication and, therefore, in cell division. Blocking HDAC has been shown to encourage cancer cells to enter
apoptosis. Interestingly, several dietary phytochemicals have been shown to be effective HDAC inhibitors.
These include sulphorphane, indole-3-carbinol, and phenethyl isothiocyanates, found in broccoli, kale, and
watercress, and epigallocatecehin-3-gallate, found in green tea.

CDK Inhibitors
Because of the association with cyclin D1 CDK inhibitors are being studied. palbociclib is a CDK inhibitor
(approved for some breast cancer). Other experimental CDK inhibitors include abemaciclib and ribociclib.

Targeting the Cancer Stem Cell

Cancer stem cells (or cancer-initiating cells) are thought to be a small population of cells within the tumor
that are directly responsible for tumor formation. They are thought to be resistant to treatment and to have the
ability to form all the cells needed for tumor development. They are suspected to be a major contributing factor
in cancer progression and relapse after treatment. Certain “stem-like” cells have been found in epithelioid
sarcoma that are marked by CD109 (cluster of differentiation 109), providing a potentially drug-able target on
the cancer stem cell for the disease. Certain challenges to targeting CD109 do exist, however, as CD109 is
expressed in other areas of the body and not only in tumor cells.

Oncolytic Viral Therapy

Oncolytic viral therapy is an emerging cancer therapy that attempts to infect cancer cells with a genetically
engineered virus that can penetrate the DNA of the cell. The virus then
• Does direct damage to the cancer cell,
• Is spread throughout the cells of the tumor via cellular (DNA) multiplication (tumor cell division
and replication), and
• Provides a target for a direct immune response from the patient.
It has been noted that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the
cytopathic effect but strongly relies on the induction of an endogenous immune response against transformed
cells. Superior anticancer effects have been observed when oncolytic viruses are engineered to express (or be
co-administered with) immunostimulatory molecules such as GM-CSF. Telomelysin (OBP-301) is an adenovirus
that targets telomerase, an enzyme that is expressed in practically all cancer cells but not in normal cells. OBP-
301 has been studied in epithelioid sarcoma and shown to promote apoptosis and cell death.

CGTG-102
CGTG-102 (developed by Oncos Therapeutics) is an adenovirus currently in orphan drug status for soft
tissue sarcomas. It is modified to selectively replicate in p16/Rb-defective cells, which include most human
cancer cells. In addition, CGTG-102 codes for the granulocyte–macrophage colony-stimulating factor (GM-
CSF), a potent immunostimulatory molecule. While the CGTG-102 oncolytic adenovirus has shown efficacy as
166 Surgical Oncology: Theory and Multidisciplinary Practice

a single agent against several soft tissue sarcomas, it would also be appealing to use in combination with other
regimes, as oncolytic viruses have demonstrated very little overlap in side effects with traditional therapies
such as chemotherapy and radiation. CGTG-102 has recently been studied in combination with doxorubicin,
and a synergistic effect was observed. At least part of doxorubicin’s mechanism of action is as an inducer of
immunogenic cell death, and it has been suggested that immune response contributes to its overall anti-tumor
activity. Doxorubicin has been shown to increase adenoviral replication in soft tissue sarcoma cells as well,
potentially contributing to the observed synergistic effect in the virus/doxorubicin combination.

FIBROSARCOMA
Fibrosarcoma (fibroblastic sarcoma) is a malignant mesenchymal tumour derived from fibrous connective
tissue and characterized by the presence of immature proliferating fibroblasts or undifferentiated anaplastic
spindle cells in a storiform pattern. It is usually found in males aged 30 to 40. It originates in fibrous tissues of
the bone and invades long or flat bones such as femur, tibia, and mandible. It also involves periosteum and
overlying muscle.

Pathology
The tumor may present different degrees of differentiation: low grade (differentiated), intermediate malignancy
and high malignancy (anaplastic). Depending on this differentiation, tumour cells may resemble mature fibroblasts
(spindle-shaped), secreting collagen, with rare mitoses. These cells are arranged in short fascicles which split
and merge, giving the appearance of “fish bone” known as a herringbone pattern. Poorly differentiated tumors
consist in more atypical cells, pleomorphic, giant cells, multinucleated, numerous atypical mitoses and reduced
collagen production. Presence of immature blood vessels (sarcomatous vessels lacking endothelial cells) favours
the bloodstream metastasizing. There are many tumors in the differential diagnosis, including spindle cell
melanoma, spindle cell squamous cell carcinoma, synovial sarcoma, leiomyosarcoma, malignant peripheral
nerve sheath tumor and biphenotypic sinonasal sarcoma.

Clinical Presentation in Humans

Adult-type
Individuals presenting with fibrosarcoma are usually adults aged thirty to fifty five years, often presenting
with pain. In adults, males have a higher incidence for fibrosarcoma than females.

Infantile-type
In infants, fibrosarcoma (often termed congenital infantile fibrosarcoma) is usually congenital. Infants
presenting with this fibrosarcoma usually do so in the first two years of their life. Cytogenetically, congenital
infantile fibrosarcoma is characterized by the majority of cases having a translocation between chromosomes
12 and 15 (notated as t(12;15)(p13;q25)) that results in formation of the fusion gene, ETV6-NTRK3, plus individual
cases exhibiting trisomy for chromosomes 8, 11, 17, or 20. The histology, association with the ETV6-NRTK3
fusion gene as well as certain chromosome trisomies, and the distribution of markers for cell type (i.e. cyclin
D1 and Beta-catenin) within this tumor are similar to those found in the cellular form of mesoblastic nephroma.
Indeed, mesoblastic nephroma and congenital infantile sarcoma appear to be the same disease with the exception
that mesoblastic lymphoma originates in the kidney whereas congenital infantile sarcoma originates in non-
renal tissues.
Sarcoma 167

Ancillary Testing
Ancillary testing for fibrosarcoma includes IHC, where vimentin is positive, cytokeratin and S100 are negative,
and actin is variable.

HEMANGIOPERICYTOMA
A hemangiopericytoma (HPC) is a type of soft tissue sarcoma that originates in the pericytes in the walls of
capillaries. When inside the nervous system, although not strictly a meningioma tumor, it is a meningeal tumor
with a special aggressive behaviour. It was first characterized in 1942.

Description
Hemangiopericytoma located in the cerebral cavity is an aggressive tumor of the Mesenchyme with oval
nuclei with scant cytoplasm. “There is dense intercellular reticulin staining. Tumor cells can be fibroblastic,
myxoid, or pericytic. These tumors, in contrast to meningiomas, do not stain with epithelial membrane antigen.
They have a grade 2 or 3 biological behaviour, and need to be distinguished from benign meningiomas because
of their high rate of recurrence (68.2%) and metastases (Maier et al. 1992; Kleihues et al. 1993).”

Treatment
Depending on the grade of the sarcoma, it is treated with surgery, chemotherapy and/or radiotherapy.

HEMANGIOSARCOMA
Hemangiosarcoma is a rapidly growing, highly invasive variety of cancer that occurs almost exclusively in
dogs, and only rarely in cats, horses, mice, or humans. It is a sarcoma arising from the lining of blood vessels;
that is, blood-filled channels and spaces are commonly observed microscopically. A frequent cause of death is
the rupturing of this tumor, causing the patient to rapidly bleed to death. The term “angiosarcoma”, when used
without a modifier, usually refers to hemangiosarcoma. However, glomangiosarcoma (8710/3) and
lymphangiosarcoma (9170/3) are distinct conditions [in humans]. Hemangiosarcomas are commonly associated
with toxic exposure to thorium dioxide (Thorotrast), vinyl chloride, and arsenic.

Hemangiosarcoma in Dogs
Hemangiosarcoma is quite common in dogs, and more so in certain breeds including German Shepherd Dogs
and Golden Retrievers. It also occurs in cats, but much more rarely. Dogs with hemangiosarcoma rarely show
clinical signs until the tumor has become very large and has metastasized. Typically, clinical signs are due to
hypovolemia after the tumor ruptures, causing extensive bleeding. Owners of the affected dogs often discover that
the dog has hemangiosarcoma only after the dog collapses. The tumor most often appears on the spleen, right heart
base, or liver, although varieties also appear on or under the skin or in other locations. It is the most common tumor
of the heart, and occurs in the right atrium or right auricular appendage. Here it can cause right-sided heart failure,
arrhythmias, pericardial effusion, and cardiac tamponade. Hemangiosarcoma of the spleen or liver is the most
common tumor to cause hemorrhage in the abdomen. Hemorrhage secondary to splenic and hepatic tumors can
also cause ventricular arrythmias. Hemangiosarcoma of the skin usually appears as a small red or bluish-black
lump. It can also occur under the skin. It is suspected that in the skin, hemangiosarcoma is caused by sun exposure.
Occasionally, hemangiosarcoma of the skin can be a metastasis from visceral hemangiosarcoma. Other sites the
tumor may occur include bone, kidneys, the bladder, muscle, the mouth, and the central nervous system.
168 Surgical Oncology: Theory and Multidisciplinary Practice

Clinical Features
Presenting complaints and clinical signs are usually related to the site of origin of the primary tumor or to the
presence of metastases, spontaneous tumor rupture, coagulopathies, or cardiac arrhythmias. More than 50% of
patients are presented because of acute collapse after spontaneous rupture of the primary tumor or its metastases.
Some episodes of collapse are a result of ventricular arrhythmias, which are relatively common in dogs with
splenic or cardiac HSA. Most common clinical signs of visceral hemangiosarcoma include loss of appetite,
arrhythmias, weight loss, weakness, lethargy, collapse, pale mucous membranes, and/or sudden death. An enlarged
abdomen is often seen due to hemorrhage. Metastasis is most commonly to the liver, omentum, lungs, or brain.
A retrospective study published in 1999 by Ware, et al., found a 5 times greater risk of cardiac hemangiosarcoma
in spayed vs. intact female dogs and a 2.4 times greater risk of hemangiosarcoma in neutered dogs as compared
to intact males.

Clinicopathologic Findings
Hemangiosarcoma can cause a wide variety of hematologic and hemostatic abnormalities, including anemia,
thrombocytopenia (low platelet count), disseminated intravascular coagulation (DIC); presence of nRBC,
schistocytes, and acanthocytes in the blood smear; and leukocytosis with neutrophilia, left shift, and monocytosis.
A definitive diagnosis requires biopsy and histopathology. Cytologic aspirates are usually not recommended, as
the accuracy rate for a positive diagnosis of malignant splenic disease is approximately 50%. This is because of
frequent blood contamination and poor exfoliation. Surgical biopsy is the typical approach in veterinary medicine.

Treatments
Treatment includes chemotherapy and, where practical, removal of the tumor with the affected organ, such
as with a splenectomy. Splenectomy alone gives an average survival time of 1–3 months. The addition of
chemotherapy, primarily comprising the drug doxorubicin, alone or in combination with other drugs, can increase
the average survival time to 2-4 months, or more.
A more favourable outcome has been demonstrated in recent research conducted at University of Pennsylvania
Veterinary School, in dogs treated with a compound derived from the Coriolus versicolor (commonly known as
“Turkey Tail”) mushroom:
• “We were shocked,” Cimino Brown said. “Prior to this, the longest reported median survival time of dogs
with hemangiosarcoma of the spleen that underwent no further treatment was 86 days. We had dogs that
lived beyond a year with nothing other than this mushroom as treatment.”There were not statistically
significant differences in survival between the three dosage groups, though the longest survival time was
highest in the 100 mg group, at 199 days, eclipsing the previously reported survival time.
• The results were so surprising, in fact, that the researchers asked Penn Vet pathologists to recheck
the dogs’ tissue biopsies to make sure that the dogs really had the disease. “They reread the samples
and said, yes, it’s really hemangiosarcoma,” Cimino Brown said. Chemotherapy is available for
treating hemangiosarcoma, but many owners opt not to pursue that treatment once their dog is
diagnosed.
• “It doesn’t hugely increase survival, it’s expensive and it means a lot of back and forth to the vet for
the dog,” Cimino Brown said. “So you have to figure in quality of life.”
This treatment does not always work. So, one should always be prepared for their pet to have the same
survival time as a dog who is untreated. Visceral hemangiosarcoma is usually fatal even with treatment, and
usually within weeks or, at best, months. In the skin, it can be cured in most cases with complete surgical
removal as long as there is not visceral involvement.
Sarcoma 169

KAPOSI’S SARCOMA
Kaposi’s sarcoma (KS) is a type of cancer that can form in the skin, lymph nodes, or other organs. The skin
lesions are usually purple in colour. They can occur singularly, in a limited area, or be widespread. It may
worsen either gradually or quickly. Lesions may be flat or raised. Human herpesvirus 8 (HHV8) is found in the
lesions of all those who are affected. Risk factors include poor immune function, either as a result of disease or
specific medications, and chronic lymphedema. Five sub-types are described: classic, endemic,
immunosuppresion therapy-related, and epidemic. Classic KS tends to affect older men, be slow growing, and
affect the legs. Endemic KS occurs in young adult males in Africa and can be more aggressive. Immunosuppresion
therapy-related KS generally occurs in people following organ transplantation and mostly affects the skin.
Epidemic KS occurs in people with AIDS and many parts of the body can be affected. The diagnosis is by tissue
biopsy while the extent of disease may be determined by medical imaging. Treatment is based on the sub-type,
whether the condition is localized or widespread, and the person’s immune function. Localized skin lesions
may be treated by surgery, injections of chemotherapy into the lesion, or radiation therapy. Widespread disease
may be treated with chemotherapy or biologic therapy. In those with HIV/AIDS highly active antiretroviral
therapy (HAART) prevents and often treats KS. In certain cases the addition of chemotherapy may be required.
With widespread disease, death may occur. The condition is relatively common in people with HIV/AIDS and
following organ transplant as of 2017. Over 35% of people with AIDS may be affected. It was first described by
Moritz Kaposi in 1872. It became more widely known as one of the AIDS-defining illnesses in the 1980s. The
viral association for this cancer was discovered in 1994.

Signs and Symptoms

KS lesions are nodules or blotches that may be red, purple, brown, or black, and are usually papular. They
are typically found on the skin, but spread elsewhere is common, especially the mouth, gastrointestinal tract
and respiratory tract. Growth can range from very slow to explosively fast, and is associated with significant
mortality and morbidity.

Skin
Commonly affected areas include the lower limbs, back, face, mouth, and genitalia. The lesions are usually
as described above, but may occasionally be plaque-like (often on the soles of the feet) or even involved in skin
breakdown with resulting fungating lesions. Associated swelling may be from either local inflammation or
lymphoedema (obstruction of local lymphatic vessels by the lesion). Skin lesions may be quite disfiguring for
the sufferer, and a cause of much psychosocial pathology.

Mouth
The mouth is involved in about 30% of cases, and is the initial site in 15% of AIDS-related KS. In the mouth,
the hard palate is most frequently affected, followed by the gums. Lesions in the mouth may be easily damaged
by chewing and bleed or suffer secondary infection, and even interfere with eating or speaking.

Gastrointestinal Tract
Involvement can be common in those with transplant-related or AIDS-related KS, and it may occur in the
absence of skin involvement. The gastrointestinal lesions may be silent or cause weight loss, pain, nausea/
vomiting, diarrhea, bleeding (either vomiting blood or passing it with bowel motions), malabsorption, or intestinal
obstruction.
170 Surgical Oncology: Theory and Multidisciplinary Practice

Respiratory Tract
Involvement of the airway can present with shortness of breath, fever, cough, hemoptysis (coughing up
blood), or chest pain, or as an incidental finding on chest x-ray. The diagnosis is usually confirmed by
bronchoscopy when the lesions are directly seen, and often biopsied.

Cause
Kaposi’s sarcoma-associated herpesvirus (KSHV), also called HHV-8 is present in almost 100% of Kaposi
sarcoma lesions, whether HIV-related, classic, endemic, or iatrogenic.

Transmission
In Europe and North America, KSHV is transmitted through saliva. Thus, kissing is a theoretical risk factor
for transmission. Higher rates of transmission among gay and bisexual men have been attributed to “deep
kissing” sexual partners with KSHV. Another alternative theory suggests that use of saliva as a sexual lubricant
might be a major mode for transmission. Prudent advice is to use commercial lubricants when needed and avoid
deep kissing with partners with KSHV infection or whose status is unknown. KSHV is also transmissible via
organ transplantation and blood transfusion. Testing for the virus before these procedures is likely to effectively
limit iatrogenic transmission.

Classification
HHV-8, is responsible for all varieties of KS. Since Moritz Kaposi first described this cancer, the disease has
been reported in five separate clinical settings, with different presentations, epidemiology, and prognoses. All
of these forms are infected with KSHV and are different manifestations of the same disease but have differences
in clinical aggressiveness, prognosis and treatment.
• Classic Kaposi sarcoma most commonly appears early on the toes and soles as reddish,
violaceous, or bluish-black macules and patches that spread and coalesce to form nodules or
plaques. A small percentage of these patients may have visceral lesions. In most cases the
treatment involves surgical removal of the lesion. The condition tends to be indolent and chronic,
affecting elderly men from the Mediterranean region, Arabian countries or of Eastern European
descent. Countries bordering the Mediterranean basin have higher rates of KSHV/HHV-8 infection
than the remainder of Europe.
• Endemic KS, which has two types. Although this may be present worldwide, it has been originally
described later in young African people, mainly from sub-Saharan Africa. This variant is not related
to HIV infection and is a more aggressive disease that infiltrates the skin extensively.
a. African lymphadenopathic Kaposi sarcoma is aggressive, occurring in children under 10 years
of age, presenting with lymph node involvement, with or without skin lesions.
b. African cutaneous Kaposi sarcoma presents with nodular, infiltrative, vascular masses on the
extremities, mostly in men between the ages of 20 and 50, and is endemic in tropical Africa.
• Immunosuppression-associated Kaposi sarcoma had been described, but only rarely until the advent
of calcineurin inhibitors (such as ciclosporines, which are inhibitors of T-cell function) for transplant
patients in the 1980s, when its incidence grew rapidly. The tumor arises either when an HHV 8-
infected organ is transplanted into someone who has not been exposed to the virus or when the
transplant recipient already harbours pre-existing HHV 8 infection. Unlike classic Kaposi sarcoma,
the site of presentation is more variable.
Sarcoma 171

• AIDS-associated Kaposi sarcoma typically presents with cutaneous lesions that begin as one or
several red to purple-red macules, rapidly progressing to papules, nodules, and plaques, with a
predilection for the head, back, neck, trunk, and mucous membranes. In more advanced cases,
they can be found in the stomach and intestines, the lymph nodes, and the lungs. KS-AIDS
stimulated the greatest interest as one of the first illnesses associated with AIDS, and was first
described in 1981. It is over 300 times more common in AIDS patients than in renal transplant
recipients. In this case, HHV 8 is sexually transmitted among people also at risk for sexually
transmitted HIV infection.

Pathology
Despite its name, in general it is not considered a true sarcoma, which is a tumor arising from mesenchymal
tissue. The histogenesis of KS remains controversial. KS may arise as a cancer of lymphatic endothelium and
forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance.
KSHV proteins are uniformly detected in KS cancer cells. KS lesions contain tumor cells with a characteristic
abnormal elongated shape, called spindle cells. The most typical feature of Kaposi sarcoma is the presence of
spindle cells forming slits containing red blood cells. Mitotic activity is only moderate and pleomorphism is
usually absent. The tumor is highly vascular, containing abnormally dense and irregular blood vessels, which
leak red blood cells into the surrounding tissue and give the tumor its dark colour. Inflammation around the
tumor may produce swelling and pain. Variously sized PAS positive hyaline bodies are often seen in the cytoplasm
or sometimes extracellularly. The spindle cells of Kaposi sarcoma differentiate towards endothelial cells, probably
of lymph vessel rather than blood vessel nature. The consistent immunoreactivity for podoplanin supports the
lymphatic nature of the lesion.

Diagnosis
Although KS may be suspected from the appearance of lesions and the patient’s risk factors, definite diagnosis
can be made only by biopsy and microscopic examination. Detection of the KSHV protein LANA in tumor cells
confirms the diagnosis. In differential diagnosis, arteriovenous malformations, pyogenic granuloma and other
vascular proliferations can be microscopically confused with KS.

Prevention
Blood tests to detect antibodies against KSHV have been developed and can be used to determine whether a
person is at risk for transmitting infection to their sexual partner, or whether an organ is infected prior to
transplantation. However, these tests are not available except as research tools, and, thus, there is little screening
for persons at risk for becoming infected with KSHV, such as people following a transplant.

Treatment
Kaposi sarcoma is not curable, but it can often be treatable for many years. In KS associated with
immunodeficiency or immunosuppression, treating the cause of the immune system dysfunction can slow or
stop the progression of KS. In 40% or more of peoples with AIDS-associated Kaposi sarcoma, the Kaposi
lesions will shrink upon first starting highly active antiretroviral therapy (HAART). However, in a certain
percentage of such people, Kaposi sarcoma may again grow after a number of years on HAART, especially if
HIV is not completely suppressed. People with a few local lesions can often be treated with local measures such
as radiation therapy or cryosurgery.
172 Surgical Oncology: Theory and Multidisciplinary Practice

Weak evidence suggests that antiretroviral therapy in combination with chemotherapy is more effective than
either of those two therapies individually. Limited basic and clinical evidence suggest that topical beta-blockers,
such as timolol, may induce regression of localized lesions in classic as well as HIV-associated Kaposi sarcoma.
In general, surgery is not recommended, as Kaposi sarcoma can appear in wound edges. In general, more
widespread disease, or disease affecting internal organs, is treated with systemic therapy with interferon alpha,
liposomal anthracyclines (such as Doxil) or paclitaxel.

Awareness
It has been reported that only 6% of men who have sex with men are aware that KS is caused by a virus
different from HIV. Thus, there is little community effort to prevent KSHV infection. Likewise, no systematic
screening of organ donations is in place. In people with AIDS, Kaposi sarcoma is considered an opportunistic
infection, a disease that is able to gain a foothold in the body because the immune system has been weakened.
With the rise of HIV/AIDS in Africa, where KSHV is widespread, KS has become the most frequently reported
cancer in some countries. Because of their highly visible nature, external lesions are sometimes the presenting
symptom of AIDS. Kaposi sarcoma entered the awareness of the general public with the release of the film
Philadelphia, in which the main character was fired after his employers found out he was HIV-positive due to
visible lesions. By the time KS lesions appear, it is likely that the immune system has already been severely
weakened.

LEIOMYOSARCOMA
Leiomyosarcoma, also referred to as LMS, is a malignant (cancerous) smooth muscle tumor. A benign tumor
originating from the same tissue is termed leiomyoma. While it has been believed that leiomyosarcomas do not
arise from leiomyomas, there are leiomyoma variants for which classification is evolving. About 1 person in
100,000 gets diagnosed with LMS each year. Leiomyosarcoma is one of the more common types of soft-tissue
sarcoma, representing 10 percent to 20 percent of new cases. (Leiomyosarcoma of the bone is more rare.)
Sarcoma is rare, consisting of only 1 percent of cancer cases in adults. Leiomyosarcomas can be very
unpredictable. They can remain dormant for long periods of time and recur after years. It is a resistant cancer,
meaning generally not very responsive to chemotherapy or radiation. The best outcomes occur when it can be
removed surgically with wide margins early, while small and still in situ.

Mechanism
Smooth muscle cells make up the involuntary muscles, which are found in most parts of the body, including
the uterus, stomach and intestines, the walls of all blood vessels, and the skin. It is therefore possible for
leiomyosarcomas to appear at any site in the body. They are most commonly found in the uterus, stomach, small
intestine and retroperitoneum. Uterine leiomyosarcomas come from the smooth muscle in the muscle layer of
the uterus. Cutaneous leiomyosarcomas derive from the pilo-erector muscles in the skin. Gastrointestinal
leiomyosarcomas might come from smooth muscle in the GI tract or, alternatively, also from a blood vessel. At
most other primary sites—retroperitoneal extremity (in the abdomen, behind the intestines), truncal, abdominal
organs, etc.—leiomyosarcomas appear to grow from the muscle layer of a blood vessel (the tunica media). Thus
a leiomyosarcoma can have a primary site of origin anywhere in the body where there is a blood vessel. The
tumors are usually hemorrhagic and soft and microscopically marked by pleomorphism, abundant (15–30 per
10 high power fields) abnormal mitotic figures, and coagulative tumor cell necrosis. There is a wide differential
diagnosis, which includes spindle cell carcinoma, spindle cell melanoma, fibrosarcoma, malignant peripheral
nerve sheath tumor and even biphenotypic sinonasal sarcoma.
Sarcoma 173

Treatment
Surgery, with as wide a margin of removal as possible, has generally been the most effective and preferred
way to attack LMS. If surgical margins are narrow or not clear of tumor, however, or in some situations where
tumor cells were left behind, chemotherapy or radiation has been shown to give a clear survival benefit. While
LMS tends to be resistant to radiation and chemotherapy, each case is different and results can vary widely.
LMS of uterine origin do frequently, but not always respond to hormonal treatments.

LIPOSARCOMA
Liposarcoma is a cancer that arises in fat cells in deep soft tissue, such as that inside the thigh or in the
retroperitoneum. Liposarcoma is a rare type of cancer that bears a resemblance to fat cells when examined
under a microscope. They are typically large bulky tumors, and tend to have multiple smaller satellites that
extend beyond the main confines of the tumor. Liposarcomas, like all sarcomas, are rare.

Signs and Symptoms

Patients usually note a deep seated mass in their soft tissue. Only when the tumor is very large do symptoms
of pain or functional disturbances occur. Retroperitoneal tumors may present themselves with signs of weight
loss and emaciation and abdominal pain. These tumors may also compress the kidney or ureter leading to
kidney failure.

Diagnosis
The diagnosis is established by histologic examination of the tissue, i.e., biopsy or excision. Lipoblasts are
often present; these are cells with an abundant clear multi-vacuolated cytoplasm and an eccentric darkly staining
nucleus that is indented by the vacuoles.

Subtypes
Several subtypes of liposarcoma exist:
• Well-differentiated liposarcoma, synonymous with atypical lipomatous tumor—the former term is used
almost exclusively for lesions in the retroperitoneum, while the latter is used for lesions arising elsewhere
• Dedifferentiated liposarcoma—well-differentiated (high-grade) liposarcoma adjacent to a more poorly
differentiated tumor
• Myxoid/round cell liposarcoma.
• Pleomorphic liposarcoma.

Prognosis
The prognosis varies depending on the site of origin, the type of cancer cell, the tumor size, the depth, and
proximity to lymph nodes. Well-differentiated liposarcomas treated with surgery, intra-operative distilled water
lavage and radiation have a low recurrence rate (about 10%) and rarely metastasize. Five-year survival rates
vary from 100% to 56% based on histological subtype.

Epidemiology
Most frequent in middle-aged and older adults (age 40 and above), liposarcomas are the second most common of
all soft-tissue sarcomas following malignant fibrous histiocytomas. Annually 2.5 cases occur per million population.
174 Surgical Oncology: Theory and Multidisciplinary Practice

LYMPHANGIOSARCOMA
Lymphangiosarcoma is a rare malignant tumor which occurs in long-standing cases of primary or secondary
lymphedema. It involves either the upper or lower lymphedematous extremities but is most common in upper
extremities. Although its name implies lymphatic origin, it is believed to arise from endothelial cells and may
be more accurately referred to as angiosarcoma.

Signs and Symptoms

Lymphangiosarcoma may present as a purplish discoloration or a tender skin nodule in the extremity, typically
on the anterior surface. It progresses to an ulcer with crusting to an extensive necrotic focus involving the skin
and subcutaneous tissue. It metastasizes quickly.

Causes
It was previously a relatively common complication of the massive itot itot itot itot itot lymphedema of the
arm which followed removal of axillary (arm pit) lymph nodes and lymphatic channels as part of the classical
Halstedian radical mastectomy, as a treatment for breast cancer. The classical radical mastectomy was abandoned
in most areas of the world in the late 1960s to early 1970s, being replaced by the much more conservative
modified radical mastectomy and, more recently, by segmental breast tissue excision and radiation therapy.
Because of this change in clinical practice lymphedema is now a rarity following breast cancer treatment—and
post-mastectomy lymphangiosarcoma is now vanishingly rare. When it occurs following mastectomy it is known
as Stewart-Treves syndrome (which can be both lymphangiosarcoma and hemangiosarcoma following
mastectomy). The pathogenesis of lymphangiosarcoma has not been resolved, however several vague mechanisms
have been proposed. Stewart and Treves, proposed that a cancer causing agent is present in lymphedematous
limbs. Schreiber et al. proposed that local immunodeficiency as a result of lymphedema results in a
“immunologically privileged site” in which the sarcoma is able to develop.

Treatment
The most successful treatment for lymphangiosarcoma is amputation of the affected limb if possible.
Chemotherapy may be administered if there is evidence or suspicion of metastatic disease. Evidence supporting
the effectiveness of chemotherapy is, in many cases, unclear due to a wide variety of prognostic factors and
small sample size. However, there is some evidence to suggest that drugs such as paclitaxel, doxorubicin,
ifosfamide, and gemcitabine exhibit antitumor activity.

LYMPHOMA
Lymphoma is a group of blood cancers that develop from lymphocytes (a type of white blood cell). The
name often refers to just the cancerous versions rather than all such tumors. Signs and symptoms may include
enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired.
The enlarged lymph nodes are usually painless. The sweats are most common at night. There are dozens of
subtypes of lymphomas. The two main categories of lymphomas are Hodgkin’s lymphomas (HL) and the non-
Hodgkin lymphomas (NHL). The World Health Organization (WHO) includes two other categories as types of
lymphoma: multiple myeloma and immunoproliferative diseases. About 90% of lymphomas are non-Hodgkin
lymphomas. Lymphomas and leukemias are a part of the broader group of tumors of the hematopoietic and
lymphoid tissues. Risk factors for Hodgkin lymphoma include infection with Epstein–Barr virus and a history
of the disease in the family. Risk factors for common types of non-Hodgkin lymphomas include autoimmune
Sarcoma 175

diseases, HIV/AIDS, infection with human T-lymphotropic virus, immunosuppressant medications, and some
pesticides. Eating large amounts of red meat and tobacco smoking may also increase the risk. Diagnosis, if
enlarged lymph nodes are present, is usually by lymph node biopsy. Blood, urine, and bone marrow testing may
also be useful in the diagnosis. Medical imaging may then be done to determine if and where the cancer has
spread. Lymphoma most often spreads to the lungs, liver, and brain. Treatment may involve one or more of the
following: chemotherapy, radiation therapy, targeted therapy, and surgery. In some non-Hodgkin lymphomas,
an increased amount of protein produced by the lymphoma cells causes the blood to become so thick that
plasmapheresis is performed to remove the protein. Watchful waiting may be appropriate for certain types. The
outcome depends on the subtype with some being curable and treatment prolonging survival in most. The five-
year survival rate in the United States for all Hodgkin lymphoma subtypes is 85%, while that for non-Hodgkin
lymphomas is 69%. Worldwide, lymphomas developed in 566,000 people in 2012 and caused 305,000 deaths.
They make up 3–4% of all cancers, making them as a group the seventh-most common form. In children, they
are the third-most common cancer. They occur more often in the developed world than the developing world.

Signs and Symptoms

Lymphoma may present with certain non-specific symptoms; if the symptoms are persistent, an evaluation
to determine their cause, including possible lymphoma, should be undertaken.
• Lymphadenopathy or swelling of lymph nodes, is the primary presentation in lymphoma.
• B symptoms (systemic symptoms) – can be associated with both Hodgkin lymphoma and non-Hodgkin
lymphoma.
They consist of:
a. Fever
b. Night sweats
c. Weight loss
• Other symptoms:
a. Loss of appetite or anorexia
b. Fatigue
c. Respiratory distress or dyspnea
d. Itching.

Diagnosis
Lymphoma is definitively diagnosed by a lymph node biopsy, meaning a partial or total excision of a lymph
node examined under the microscope. This examination reveals histopathological features that may indicate
lymphoma. After lymphoma is diagnosed, a variety of tests may be carried out to look for specific features
characteristic of different types of lymphoma.
These include:
• Immunophenotyping
• Flow cytometry
• Fluorescence in situ hybridization testing.

Classification
Lymphomas in the strict sense are any neo-plasms of the lymphatic tissues (lympho- + -oma). The main
classes are malignant neo-plasms (that is, cancers) of the lymphocytes, a type of white blood cell that belongs
to both the lymph and the blood and pervades both. Thus, lymphomas and leukemias are both tumors of the
176 Surgical Oncology: Theory and Multidisciplinary Practice

hematopoietic and lymphoid tissues, and as lymphoproliferative disorders, lymphomas and lymphoid leukemias
are closely related, to the point that some of them are unitary disease entities that can be called by either name
(for example adult T-cell leukemia/lymphoma). Several classification systems have existed for lymphoma,
which use histological and other findings to divide lymphoma into different categories. The classification of a
lymphoma can affect treatment and prognosis.
Classification systems generally classify lymphoma according to:
• Whether or not it is a Hodgkin lymphoma
• Whether the cell that is replicating is a T cell or B cell
• The site from which the cell arises.
Lymphoma can also spread to the central nervous system, often around the brain in the meninges, known as
lymphomatous meningitis (LM).

Hodgkin Lymphoma
Hodgkin lymphoma accounts for about 15% of lymphomas. It differs from other forms of lymphoma in its
prognosis and several pathological characteristics. A division into Hodgkin and non-Hodgkin lymphomas is
used in several of the older classification systems. A Hodgkin lymphoma is marked by the presence of a type of
cell called the Reed–Sternberg cell.

Non-hodgkin Lymphomas
Non-Hodgkin lymphomas, which are defined as being all lymphomas except Hodgkin lymphoma, are more
common than Hodgkin lymphoma. A wide variety of lymphomas are in this class, and the causes, the types of
cells involved, and the prognosis vary by type. The incidence of non-Hodgkin lymphoma increases with age. It
is further divided into several subtypes.

WHO Classification
The WHO classification, published in 2001 and updated in 2008, is based upon the foundations laid within
the “revised European-American lymphoma classification” (REAL). This system groups lymphomas by cell
type (i.e. the normal cell type that most resembles the tumor) and defining phenotypic, molecular, or cytogenetic
characteristics. The five groups are shown in the table. Hodgkin lymphoma is considered separately within the
WHO and preceding classifications, although it is recognized as being a tumor of, albeit markedly abnormal,
lymphocytes of mature B cell lineage. Of the many forms of lymphoma, some are categorized as indolent (e.g.
small lymphocytic lymphoma), compatible with a long life even without treatment, whereas other forms are
aggressive (e.g. Burkitt’s lymphoma), causing rapid deterioration and death. However, most of the aggressive
lymphomas respond well to treatment and are curable. The prognosis, therefore, depends on the correct diagnosis
and classification of the disease, which is established after examination of a biopsy by a pathologist (usually a
hematopathologist).
Lymphoma subtypes (WHO 2008)
Mature B cell neo-plasms
Mature T cell and natural killer (NK) cell neo-plasms
Precursor lymphoid neo-plasms
Hodgkin lymphoma
Immunodeficiency-associated lymphoproliferative disorders

Previous Classifications
Several previous classifications have been used, including Rappaport 1956, Lennert/ Kiel 1974, BNLI,
Working formulation (1982), and REAL (1994). The Working formulation of 1982 was a classification of non-
Sarcoma 177

Hodgkin lymphoma. It excluded the Hodgkin lymphomas and divided the remaining lymphomas into four
grades (low, intermediate, high, and miscellaneous) related to prognosis, with some further subdivisions based
on the size and shape of affected cells. This purely histological classification included no information about cell
surface markers, or genetics, and it made no distinction between T-cell lymphomas and B-cell lymphomas. It
was widely accepted at the time of its publication, but is now obsolete. It is still used by some cancer agencies
for compilation of lymphoma statistics and historical rate comparisons. In 1994, the Revised European-American
Lymphoma (REAL) classification applied immunophenotypic and genetic features in identifying distinct
clinicopathologic entities among all the lymphomas except Hodgkin lymphoma. For coding purposes, the ICD-
O (codes 9590–9999) and ICD-10 (codes C81-C96) are available.

Staging
After a diagnosis and before treatment, a cancer is staged. This refers to determining if the cancer has
spread, and if so, whether locally or to distant sites. Staging is reported as a grade between I (confined) and
IV (spread). Staging is carried out because the stage of a cancer impacts its prognosis and treatment. The Ann
Arbor staging system is routinely used for staging of both HL and NHL. In this staging system, I represents
a localised disease contained within a lymph node group, II represents the presence of lymphoma in two or
more lymph nodes groups, III represents spread of the lymphoma to lymph nodes groups on both sides of the
diaphragm, and IV indicates spread to tissue outside the lymphatic system. Different suffixes imply involvement
of different organs, for example S for the spleen and H for the liver. Extra-lymphatic involvement is expressed
with the letter E. In addition, the presence of B symptoms or their absence is expressed with B and A,
respectively. B symptoms are defined as the presence of one of three symptoms: Unintentional weightloss of
10% body weight in the last 6 months, night sweats, and persistent fever of 38°C or more. CT scan or PET
scan imaging modalities are used to stage a cancer. PET scan is advised for FDG avid lymphomas, for
example Hodgkins Lymphoma as a staging tool that can even replace bone marrow biopsy. For other
lymphomas CT scan is recommended for staging. Age and poor performance status are established poor
prognostic factors, as well.

Treatment
Prognoses and treatments are different for HL and between all the different forms of NHL, and also depend
on the grade of tumour, referring to how quickly a cancer replicates. Paradoxically, high-grade lymphomas are
more readily treated and have better prognoses: Burkitt lymphoma, for example, is a high-grade tumour known
to double within days, and is highly responsive to treatment. Lymphomas may be curable if detected in early
stages with modern treatment.

Low-grade Lymphomas
Many low-grade lymphomas remain indolent for many years. Treatment of the non-symptomatic patient is
often avoided. In these forms of lymphoma, such as follicular lymphoma, watchful waiting is often the initial
course of action. This is carried out because the harms and risks of treatment outweigh the benefits. If a low-
grade lymphoma is becoming symptomatic, radiotherapy or chemotherapy are the treatments of choice; although
they do not cure the lymphoma, they can alleviate the symptoms, particularly painful lymphadenopathy. Patients
with these types of lymphoma can live near-normal lifespans, but the disease is incurable. Some centers advocate
the use of single agent rituximab in the treatment of follicular lymphoma rather than the wait and watch approach.
Watchful waiting is not a good strategy for all patients, as it leads to significant distress and anxiety in some
patients. It has been equated with watch and worry.
178 Surgical Oncology: Theory and Multidisciplinary Practice

High-grade Lymphomas
Treatment of some other, more aggressive, forms of lymphoma can result in a cure in the majority of cases,
but the prognosis for patients with a poor response to therapy is worse. Treatment for these types of lymphoma
typically consists of aggressive chemotherapy, including the CHOP or R-CHOP regimen. A number of people
are cured with first-line chemotherapy.
Most relapses occur within the first two years, and the relapse risk drops significantly thereafter. For
people who relapse, high-dose chemotherapy followed by autologous stem cell transplantation is a proven
approach.

Hodgkin Lymphoma
Hodgkin lymphoma typically is treated with radiotherapy alone, as long as it is localized. Advanced Hodgkin
disease requires systemic chemotherapy, sometimes combined with radiotherapy. Chemotherapy used includes
the ABVD regimen, which is commonly used in the United States. Other regimens used in the management of
Hodgkin lymphoma include BEACOPP and Stanford V. Considerable controversy exists regarding the use of
ABVD or BEACOPP. Briefly, both regimens are effective, but BEACOPP is associated with more toxicity.
Encouragingly, a significant number of people who relapse after ABVD can still be salvaged by stem cell
transplant.

Palliative Care
Palliative care, a specialized medical care focused on the symptoms, pain, and stress of a serious illness,
is recommended by multiple national cancer treatment guidelines as an accompaniment to curative treatments
for people suffering from lymphoma. It is used to address both the direct symptoms of lymphoma and many
unwanted side effects that arise from treatments. Palliative care can be especially helpful for children who
develop lymphoma, helping both children and their families deal with the physical and emotional symptoms
of the disease. For these reasons, palliative care is especially important for patients requiring bone marrow
transplants.

Prognosis
Five-year relative survival by stage at diagnosis
Stage at diagnosis Five-year relativesurvival (%) Percentageof cases (%)
Localized (confined to primary site) 82.3 26
Regional (spread to regional lymph nodes) 78.3 19
Distant (cancer has metastasized) 62.7 47
Unknown (unstaged) 68.6 8

Epidemiology
Lymphoma is the most common form of hematological malignancy, or “blood cancer”, in the developed
world. Taken together, lymphomas represent 5.3% of all cancers (excluding simple basal cell and squamous
cell skin cancers) in the United States and 55.6% of all blood cancers. According to the U.S. National Institutes
of Health, lymphomas account for about 5%, and Hodgkin lymphoma in particular accounts for less than 1% of
all cases of cancer in the United States. Because the whole system is part of the body’s immune system, patients
with a weakened immune system such as from HIV infection or from certain drugs or medication also have a
higher incidence of lymphoma.
Sarcoma 179

Research
The two types of lymphoma research are clinical or translational research and basic research. Clinical/
translational research focuses on studying the disease in a defined and generally immediately patient-applicable
way, such as testing a new drug in patients. Studies may focus on effective means of treatment, better ways
of treating the disease, improving the quality of life for patients, or appropriate care in remission or after
cures. Hundreds of clinical trials are being planned or conducted at any given time. Basic science research
studies the disease process at a distance, such as seeing whether a suspected carcinogen can cause healthy
cells to turn into lymphoma cells in the laboratory or how the DNA changes inside lymphoma cells as the
disease progresses. The results from basic research studies are generally less immediately useful to patients
with the disease, but can improve scientists’ understanding of lymphoma and form the foundation for future,
more effective treatments.

UNDIFFERENTIATED PLEOMORPHIC SARCOMA

Undifferentiated pleomorphic sarcoma (UPS), also undifferentiated pleomorphic sarcoma (PUS) and
previously malignant fibrous histiocytoma (abbreviated MFH), is a type of cancer and soft tissue sarcoma. It is
considered a diagnosis of exclusion for sarcomas that cannot be more precisely categorized. Other sarcomas are
cancers that form in bone and soft tissues, including muscle, fat, blood vessels, lymph vessels, and fibrous
tissue (such as tendons and ligaments).

Presentation
UPS occurs most commonly in the extremities and retroperitoneum, but has been reported in other sites.
Metastasis occurs most frequently in the lungs (90%), bones (8%), and liver (1%). In the extremities, it presents
itself as a painless enlarging soft tissue mass.

Diagnosis
It can be detected by magnetic resonance imaging (MRI), but a biopsy is required for the definitive diagnosis.
MRI findings typically show a well-circumscribed mass that is dark on T1-weighted images and bright on T2-
weighted images. Central necrosis is often present and identifiable by imaging, especially in larger masses.

Pathology
Undifferentiated pleomorphic sarcomas are, by definition, undifferentiated, meaning (as the name
implies) that they do not bear a resemblance to any normal tissue. The histomorphology, otherwise, is
characterized by high cellularity, marked nuclear pleomorphism, usually accompanied by abundant mitotic
activity (including atypical mitoses), and a spindle cell morphology. Necrosis is common and characteristic
of high grade lesions.

Treatment
Treatment consists of surgical excision (the extent of which ranges from tumor excision to limb amputation,
depending on the tumor) and in almost all cases radiation. Radiation eliminates the need for limb amputation
and there is level I evidence to show that it leads to equivalent rates of survival (Rosenberg et al. NCI Canada).
Radiation may be delivered either pre-op or post-op depending on surgeon and multidisciplinary tumor board’s
recommendations. Radiation can be omitted for low grade, Stage I excised tumors with >1 cm margin (NCCN).
180 Surgical Oncology: Theory and Multidisciplinary Practice

Chemotherapy remains controversial in MFH. The usual site of metastatic disease is the lungs, and metastases
should be resected if possible. Unresectable or inoperable lung metastasis may be treated with stereotactic body
radiation therapy (SBRT) with excellent local control. However, neither surgery nor SBRT will prevent emergence
of additional metastasis elsewhere in the lung. Therefore, role of chemotherapy needs to be further explored to
address systemic metastasis.

Prognosis
Prognosis depends on the primary tumor grade (appearance under the microscope as judged by a pathologist),
size, resectability (whether it can be completely removed surgically), and presence of metastases. The five-year
survival is 80%.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR

A malignant peripheral nerve sheath tumor (MPNST) (also known as “malignant schwannoma”,
“neurofibrosarcoma”, and “neurosarcoma”) is a form of cancer of the connective tissue surrounding nerves.
Given its origin and behaviour it is classified as a sarcoma. About half the cases are diagnosed in people with
neurofibromatosis; the lifetime risk for an MPNST in patients with neurofibromatosis type 1 is 8–13%. MPNST
with rhabdomyoblastomatous component are called malignant triton tumors. The first-line treatment is surgical
resection with wide margins. Chemotherapy (e.g. high-dose doxorubicin) and often radiotherapy are done as
adjuvant and/or neo-adjuvant treatment.

Classification
Malignant peripheral nerve sheath tumors are a rare type of cancer that arise from the soft tissue that surrounds
nerves. They are a type of sarcoma. Most malignant peripheral nerve sheath tumors arise from the nerve plexuses
that distribute nerves into the limbs—the brachial and lumbar plexuses—or from nerves as they arise from the
trunk.

Signs and Symptoms

Symptoms may include:
• Swelling in the extremities (arms or legs), also called peripheral edema; the swelling often is painless.
• Difficulty in moving the extremity that has the tumor, including a limp.
• Soreness localized to the area of the tumor or in the extremity.
• Neurological symptoms.
• Pain or discomfort: numbness, burning, or “pins and needles.”
• Dizzyness and/or loss of balance.

Causes
Soft tissue sarcomas have been linked within families, so it is hypothesized that neurofibrosarcoma may
be genetic, although researchers still do not know the exact cause of the disease. Evidence supporting this
hypothesis includes loss of heterozygosity on the 17p chromosome. The p53 (a tumor suppressor gene in the
normal population) genome on 17p in neurofibrosarcoma patients is mutated, increasing the probability of
cancer. The normal p53 gene will regulate cell growth and inhibit any uncontrollable cell growth in the
healthy population; since p53 is inactivated in neurofibrosarcoma patients, they are much more susceptible
to developing tumors.
Sarcoma 181

Genetics
A malignant peripheral nerve sheath tumor is rare, but is one of the most common frequent soft tissue
sarcoma in the pediatrics population. About half of these cases also happen to occur along with neurofibromatosis
type 1 (NF-1), which is a genetic mutation on the 17th chromosome which causes tumors along the nervous
system. The lifetime risk of patients with NF-1 developing MPNST has been estimated at 8–13%, while those
with only MPNST have a 0.001% in the general population. NF-1 and MPNST are categorized as autosomal
dominant disorders. This means when one receives an abnormal gene from one of their parents, they will
ultimately have that disorder. That person has a 50/50 chance of passing on that gene to their offspring. The
pedigree to the right describes this genetic pattern.

Diagnosis
The most conclusive test for a patient with a potential neurofibrosarcoma is a tumor biopsy (taking a sample
of cells directly from the tumor itself). MRIs, X-rays, CT scans, and bone scans can aid in locating a tumor and/
or possible metastasis.

Treatment
Treatment for neurofibrosarcoma is similar to that of other cancers. Surgery is an option; the removal of the
tumor along with surrounding tissue may be vital for the patient’s survival. For discrete, localized tumors,
surgery is often followed by radiation therapy of the excised area to reduce the chance of recurrence. For
patients suffering from neurofibrosarcomas in an extremity, if the tumor is vascularized (has its own blood
supply) and has many nerves going through it and/or around it, amputation of the extremity may be necessary.
Some surgeons argue that amputation should be the procedure of choice when possible, due to the increased
chance of a better quality of life. Otherwise, surgeons may opt for a limb-saving treatment, by removing less of
the surrounding tissue or part of the bone, which is replaced by a metal rod or grafts. Radiation will also be used
in conjunction with surgery, especially if the limb was not amputated. Radiation is rarely used as a sole treatment.
In some instances, the oncologist may choose chemotherapy drugs when treating a patient with neurofibrosarcoma,
usually in conjunction with surgery. Patients taking chemotherapy must be prepared for the side effects that
come with any other chemotherapy treatment, such as; hair loss, lethargy, weakness, etc.

Prognosis
Patient response to treatment will vary based on age, health, and the tolerance to medications and therapies.
Metastasis occurs in about 39% of patients, most commonly to the lung. Features associated with poor prognosis
include a large primary tumor (over 5 cm across), high grade disease, co-existent neurofibromatosis, and the
presence of metastases. It is a rare tumor type, with a relatively poor prognosis in children. In addition, MPNSTs
are extremely threatening in NF1. In a 10-year institutional review for the treatment of chemotherapy for
MPNST in NF1, which followed the cases of 1 per 2,500 in 3,300 live births, chemotherapy did not seem to
reduce mortality, and its effectiveness should be questioned. Although with recent approaches with the molecular
biology of MPNSTs, new therapies and prognostic factors are being examined.

RHABDOMYOSARCOMA
Rhabdomyosarcoma, or RMS, is an aggressive and highly malignant form of cancer that develops from
skeletal (striated) muscle cells that have failed to fully differentiate. It is generally considered to be a disease of
childhood, as the vast majority of cases occur in those below the age of 18. It is commonly described as one of
182 Surgical Oncology: Theory and Multidisciplinary Practice

the “small, round, blue cell tumours of childhood” due to its appearance on an H&E stain. Despite being a
relatively rare cancer, it accounts for approximately 40% of all recorded soft tissue sarcomas. RMS can occur
in any site on the body, but is primarily found in the head, neck, orbit, genitourinary tract, genitals, and extremities.
There are no clear risk factors for RMS, but the disease has been associated with some congenital abnormalities.
Signs and symptoms vary according to tumor site, and prognosis is closely tied to the location of the primary
tumor. Common site of metastasis include the lungs, bone marrow, and bones. There are many classification
systems for RMS and a variety of defined histological types.
Embryonal rhabdomyosarcoma is the most common type and comprises about 60% of cases. Patient outcomes
vary considerably, with 5 years survival rates between 35% and 95% depending on the type of RMS involved,
so clear diagnosis is critical for effective treatment and management. Unfortunately, accurate and quick diagnosis
is often difficult due to the heterogeneity of RMS tumors and a lack of strong genetic markers of the disease.
Treatment usually involves a combination of surgery, chemotherapy, and radiation. Sixty percent to 70% of
newly diagnosed patients with non-metastatic disease can be cured using this combined approach to therapy.
Despite aggressive multimodality treatment, less than 20% of patients with metastatic RMS are able to be cured
of their disease.

Epidemiology
Rhabdomyosarcoma is the most common soft-tissue sarcoma in children as well as the third most common
solid tumor in children. Recent estimates place the incidence of the disease at approximately 4.5 case per 1
million children/adolescents with approximately 250 new cases in the United States each year. With the vast
majority of cases of RMS occurring in children or adolescents, two-thirds of reported cases occur in youths
under the age of 10. RMS also occurs slightly more often in males than in females, with a ratio of approximately
1.3–1.5:1. In addition, slightly lower prevalence of the disease has been reported in black and Asian children
relative to white children. In most cases, there are no clear predisposing risk factors for the development of
RMS. It tends to occur sporadically with no obvious cause. However, RMS has been correlated with familial
cancer syndromes and congenital abnormalities including neurofibromatosis type 1, Beckwith-Wiedemann
syndrome, Li–Fraumeni syndrome, cardio-facio-cutaneous syndrome, and Costello syndrome. It has also been
associated with parental use of cocaine and marijuana.

Signs and Symptoms

RMS can occur in almost any soft-tissue site in the body; the most common primary sites are genitourinary
(24%), parameningeal (16%), extremity (19%), orbit (9%), other head and neck (10%), and miscellaneous
other sites (22%). RMS often presents as a mass, but signs and symptoms can vary widely depending on the site
of the primary tumor. Genitourinary tumors may present with hematuria, urinary tract obstruction, and/or a
scrotal or vaginal mass. Tumors that arise in the retroperitoneum and mediastinum can become quite large
before producing signs and symptoms.
Parameningeal tumors may present with cranial nerve dysfunction, symptoms of sinusitis, ear discharge,
headaches, and facial pain. Orbital tumors often present with orbital swelling and proptosis. Extremity tumors
generally present as a rapidly enlarging, firm mass in the relevant tissue. The cancer’s prevalence in the head,
face, and neck will often allow for earlier signs of the disease simply due to the obvious nature of tumors in
these locations. Despite the varying presentation and typically aggressive nature of the disease, RMS has the
potential to be diagnosed and treated early. The fourth IRSG study found that 23% of patients were diagnosed
in time for a complete resection of their cancer, and 15% had resection with only minimal remnants of the
diseased cells.
Sarcoma 183

Types
Given the difficulty in diagnosing rhabdomyosarcoma, definitive classification of subsets has proven difficult.
As a result, classification systems vary by institute and organization.
However, rhabdomyosarcoma can be generally divided into three histological subsets:
• Embryonal rhabdomyosarcoma (ERMS) is the most common histological variant, comprising
approximately 60–70% of childhood cases. It is most common in children 0–4 years old, with a
maximum reported incidence of 4 cases per 1 million children. ERMS is characterized by spindle-
shaped cells with a stromal-rich appearance, and the morphology is similar to the developing muscle
cells of a 6–8 week old embryo. Tumors often present in the head and neck as well as the genitourinary
tract. ERMS also has two defined subtypes, botryoid and spindle cell ERMS, and these subtypes are
associated with a favourable prognosis.
a. Subtypes of ERMS
(i) Botryoid ERMS is almost always found in mucosal lined organs including the vagina, bladder,
and nasopharynx (although presentation in the nasopharynx typically affects older children).
It often presents in patients <1 year old as a round, grape-like mass on the affected organ.
Histologically, cells of the botryoid variant are defined by a dense tumor layer under an
epithelium (cambium layer).
(ii) Spindle cell rhabdomyosarcoma comprises about 3% of all RMS cases. This subtype is very
similar to that of leiomyosarcoma (cancer of the smooth muscle tissue), and it has a fascicular,
spindled, and leiomyomatous growth pattern with notable rhabdomyoblastic differentiation.
It occurs most commonly in the paratesticular region, and the prognosis for this particular
form of RMS is excellent with a reported 5 year survival rate of 95%.
• Alveolar rhabdomyosarcoma (ARMS) is the second most common type. ARMS comprises
approximately 20–25% of RMS-related tumors, and it is equally distributed among all age groups
with an incidence of about 1 case per 1 million people ages 0 to 19. For this reason, it is the most
common form of RMS observed in young adults and teenagers, who are less prone to the embryonal
variant. This type of RMS is characterized by densely-packed, round cells that arrange around spaces
similar in shape to pulmonary alveoli, although variants have been discovered without these
characteristic alveolar spacings. ARMS tends to form more often in the extremities, trunk, and
peritoneum. It is also typically more aggressive than ERMS.
• Anaplastic (undifferentiated) rhabdomyosarcoma, also known as pleomorphic rhabdomyosarcoma,
is the final variant of RMS recognized in most classification systems. Anaplastic rhabdomyosarcoma
is defined by the presence of anaplastic cells with large, lobate hyperchromatic nuclei and multipolar
mitotic figures. These tumors display high heterogeneity and extremely poor differentiation. The
anaplastic cells may be diffuse or localized, with the diffuse variation correlating to a worse prognosis.
It occurs most often in adults, rarely in children, and is often discovered in the extremities. Due to
the lack of discernible separation among cancers of this type, clinicians will often label undiagnosed
sarcomas with little to no discernible features as anaplastic RMS. It is the most aggressive type of
RMS, and will often require intensive treatment.
There is also an extremely rare subtype of RMS that has been described as sclerosing rhabdomyosarcoma by
Folpe, et al, but it is not a currently recognized subtype by the NCI or WHO. This subtype has characteristic
histology involving hyaline sclerosis and pseudovascular development. Its origins are unclear, but some studies
have pointed to an association with embryonal RMS. Multiple classification systems have been proposed for
guiding management and treatment, and the most recent and widely used classification system is the “International
Classification of Rhabdomyosarcoma” or ICR. It was created by the IRSG in 1995 after their series of four
184 Surgical Oncology: Theory and Multidisciplinary Practice

multi-institutional trials aimed at studying the presentation, histology, epidemiology, and treatment of RMS
(IRSG I–IV). The ICR system is based on prognostic indicators identified in IRSG I–IV. Pleomorphic
rhabdomyosarcoma usually occurs in adults rather than children, and is therefor not included in this system.
Sclerosing rhabdomyosarcoma is also not included in this system due to its rare presentation and weak
classification schema.

Prognostic Factors
Prognosis in rhabdomyosarcoma patients has been shown to be dependent on age, tumor site, resectability of
tumor, tumor size, regional lymph node involvement, presence of metastasis, site and extent of metastasis, and
biological and histopathological characteristics of the tumor cells.

Diagnosis
Rhabdomyosarcoma is often difficult to diagnose due to its similarities to other cancers and varying levels of
differentiation. It is loosely classified as one of the “small, round, blue-cell cancer of childhood” due to its appearance
on an H&E stain. Other cancers that share this classification include neuroblastoma, Ewing sarcoma, and lymphoma,
and a diagnosis of RMS requires confident elimination of these morphologically similar diseases. The defining
diagnostic trait for RMS is confirmation of malignant skeletal muscle differentiation with myogenesis (presenting
as a plump, pink cytoplasm) under light microscopy. Cross striations may or may not be present. Accurate diagnosis
is usually accomplished through immunohistochemical staining for muscle-specific proteins such as myogenin,
muscle-specific actin, desmin, D-myosin, and myoD1. Myogenin, in particular, has been shown to be highly
specific to RMS, although the diagnostic significance of each protein marker may vary depending on the type and
location of the malignant cells. The alveolar type of RMS tends to have stronger muscle-specific protein staining.
Electron microscopy may also aid in diagnosis, with the presence of actin and myosin or Z bands pointing to a
positive diagnosis of RMS. Classification into types and subtypes is accomplished through further analysis of
cellular morphology (alveolar spacings, presence of cambium layer, aneuploidy, etc.) as well as genetic sequencing
of tumor cells. Some genetic markers, such as the PAX3-FKHR fusion gene expression in alveolar RMS, can aid in
diagnosis. Open biopsy is usually required to obtain sufficient tissue for accurate diagnosis. All findings must be
considered in context, as no one trait is a definitive indicator for RMS.

Staging
Following diagnosis and histopathological analysis, the patient will usually undergo magnetic resonance
imaging (MRI), ultrasonography, and a bone scan in order to determine the extent of local invasion and metastasis.
Further investigational techniques may be necessary depending on tumor sites. A parameningeal presentation
of RMS will often require a lumbar puncture to rule out metastasis to the meninges. A paratesticular presentation
will often require an abdominal CT to rule out local lymph node involvement, and so on. Patient outcomes are
most strongly tied to the extent of the disease, so it is important to map its presence in the body as soon as
possible in order to decide on a treatment plan. The current staging system for rhabdomyosarcoma is unusual
relative to most cancers. It utilizes a modified TNM (tumor-nodes-metastasis) system originally developed by
the IRSG. This system accounts for tumor size (> or <5 cm), lymph node involvement, tumor site, and presence
of metastasis. It grades on a scale of 1 to 4 based on these criteria. In addition, patients are sorted by clinical
group (from the clinical groups from the IRSG studies) based on the success of their first surgical resection. The
current Children’s Oncology Group protocols for the treatment of RMS categorize patients into one of four risk
categories based on tumor grade and clinical group, and these risk categories have been shown to be highly
predictive of outcome.
Sarcoma 185

Tumor Site Risk Classification

Head and neck (orbit), biliary tract, genitourinary (excluding bladder and prostate) Favourable
Cranial parameningial, bladder, extremities, prostate, other Unfavourable

Treatment and Outcomes

Treatment of rhabdomyosarcoma is a multidisciplinary practice involving the use of surgery, chemotherapy,
radiation, and possibly immunotherapy. Surgery is generally the first step in a combined therapeutic approach.
Resectability varies depending on tumor site, and RMS often presents in sites that don’t allow for full surgical
resection without significant morbidity and loss of function. Less than 20% of RMS tumors are fully resected
with negative margins. Fortunately, rhabdomyosarcomas are highly chemosensitive, with approximately 80%
of cases responding to chemotherapy. In fact, multi-agent chemotherapy is indicated for all patients with
rhabdomyosarcoma. Before the use of adjuvant and neo-adjuvant therapy involving chemotherapeutic agents,
treatment solely by surgical means had a survival rate of <20%. Modern survival rates with adjuvant therapy
are approximately 60–70%. There are two main methods of chemotherapy treatment for RMS. There is the
VAC regimen, consisting of vincristin, actinomyocin D, and cyclophosphamide, and the IVA regimen, consisting
of ifosfamide, vincristin, and actinomyocin D. These drugs are administered in 9–15 cycles depending on the
staging of the disease and other therapies used. Other drug and therapy combinations may also show additional
benefit. Addition of doxorubicin and cisplatin to the VAC regimen was shown to increase survival rates of
patients with alveolar-type, early-stage RMS in IRS study III, and this same addition improved survival rates
and doubled bladder salvage rates in patients with stage III RMS of the bladder.
Radiation therapy, which kill cancer cells with focused doses of radiation, is often indicated in the treatment
of rhabdomyosarcoma, and the exclusion of this treatment from disease management has been shown to increase
recurrence rates. Radiation therapy is used when resecting the entirety of the tumor would involve disfigurement
or loss of important organs (eye, bladder, etc.). Generally, in any case where a lack of complete resection is
suspected, radiation therapy is indicated. Administration is usually following 6–12 weeks of chemotherapy if
tumor cells are still present. The exception to this schedule is the presence of parameningeal tumors that have
invaded the brain, spinal cord, or skull. In these cases radiation treatment is started immediately. In some cases,
special radiation treatment may be required. Brachytherapy, or the placement of small, radioactive “seeds”
directly inside the tumor or cancer site, is often indicated in children with tumors of sensitive areas such as the
testicles, bladder, or vagina. This reduces scattering and the degree of late toxicity following dosing. Radiation
therapy is more often indicated in higher stage classifications. Immunotherapy is a more recent treatment modality
that is still in development. This method involves recruiting and training the patient’s immune system to target
the cancer cells. This can be accomplished through administering small molecules designed to pull immune
cells towards the tumors, taking immune cells pulled from the patient and training to attack tumors through
presentation with tumor antigen, or other experimental methods. A specific example here would be presenting
some of the patient’s dendritic cells, which direct the immune system to foreign cells, with the PAX3-FKHR
fusion protein in order to focus the patient’s immune system to the malignant RMS cells. All cancers, including
rhabdomyosarcoma, could potentially benefit from this new, immune-based approach.

Genetic Features
There are multiple genetic lesions associated with rhabdomyosarcoma, but there has been little consistent
data demonstrating an association between specific genetic abnormalities and outcome. However, alveolar and
embryonal types of RMS can be distinguished cytogenetically, and identification of specific genetic lesions can
allow for accurate classification of the ARMS subtype when the histopathological findings are equivocal or
unclear. This is valuable for clinical practice as the alveolar type presents a higher risk to the patient and will
186 Surgical Oncology: Theory and Multidisciplinary Practice

often require more aggressive treatment than the embryonal type. Up to 90% of alveolar RMS cases present
with a translocations of t(2;13)(q35,q14) or, less commonly, t(1;13)(p36,q15). Both involve the translocation of
a DNA binding domain of PAX, a member of the Paired Box family of transcription factors, to a transactivation
site on FKHR, a member of the forkhead/HNF-3 transcription factor family. The t(2;13) translocation results in
a fusion of the PAX3 gene with FKHR, while the t(1;13) translocation involves the fusion of PAX7 with FKHR.
PAX3 has a demonstrated role in muscle cell development, which supports its potential role in RMS. The
t(2;13) translocation can result in the PAX3-FKHR fusion product, which is indicative of classic cystic ARMS.
Cases of ARMS presenting with this fusion protein are said to be fusion-positive and are associated with a
poorer prognosis than fusion-negative ARMS.
Fortunately, the fusion protein presents a potential therapeutic target, but more research is needed to clarify
the role of PAX3-FKHR in ARMS. Embryonal RMS usually presents with a loss of heterozygosity (LOH) in the
short arm of chromosome 11 (p11,15.5). This region is associated with multiple oncogenes, and the potential
loss-of-function of this region is likely associated with the loss of a tumor suppressor. However, the specific
consequences of this LOH at (p11,15.5) have yet to be determined. The short arm of chromosome 11 is also the
site of the insulin-like growth factor 2 gene (IGF-2), which is often over-expressed in RMS. p53 loss-of-function
is associated with many cancers including rhabdomyosarcoma, and approximately 50% of RMS cases have
been shown to carry some form of mutation to the p53 gene. Other oncogenes often associated with
rhabdomyosarcoma, albeit with less frequency, include N-myc, N-ras, K-ras, p16, and c-Met. However, it is
unclear whether the mutation of the genes is directly related to the development of RMS. One study showed a
that 35% of embryonal RMS tumors contained activating mutations in either N- or K-ras, and it is worth noting
that ras activation has been shown to block myogenic differentiation, which could help explain its potential
role in rhabdomyosarcogenesis.

History
Rhabdomyosarcoma was first described by Weber, a German physician, in 1845, but it wasn’t until the paper
by Arthur Stout in 1946 that RMS was formally classified. The first thirty years of investigation were conducted
by the Intergroup Rhabdomyosarcoma Study Group (IRSG), an independent National Cancer Institute (NCI)-
funded cooperative that has become a part of the Children’s Oncology Group.

Research
Cancer stem cells of rhabdomyosarcoma have been identified and fibroblast growth factor receptor 3 has
been suggested as their marker. Preclinical animal studies that try to use conditionally replicating adenoviruses
against such cells are in progress.

SYNOVIAL SARCOMA
A synovial sarcoma (also known as: malignant synovioma) is a rare form of cancer which occurs primarily
in the extremities of the arms or legs, often in close proximity to joint capsules and tendon sheaths. It is a type
of soft tissue sarcoma. The name “synovial sarcoma” was coined early in the 20th century, as some researchers
thought that the microscopic similarity of some tumors to synovium, and its propensity to arise adjacent to
joints, indicated a synovial origin; however, the actual cells from which the tumor develops are unknown and
not necessarily synovial. Primary synovial sarcomas are most common in the soft tissue near the large joints of
the arm and leg but have been documented in most human tissues and organs, including the brain, prostate, and
heart. Synovial sarcoma occurs in about 2 per 100,000 people a year. They occur most commonly in the third
decade of life, with males being affected more often than females (ratio around 1.2:1).
Sarcoma 187

Signs and Symptoms

Synovial sarcoma usually presents with an otherwise asymptomatic swelling or mass, although general
symptoms related to malignancies can be reported such as fatigue.

Diagnosis
The diagnosis of synovial sarcoma is typically made based on histology and is confirmed by the presence of
t(X;18) chromosomal translocation.

Histopathology
Two cell types can be seen microscopically in synovial sarcoma. One fibrous type, known as a spindle or
sarcomatous cell, is relatively small and uniform, and found in sheets. The other is epithelial in appearance.
Classical synovial sarcoma has a biphasic appearance with both types present. Synovial sarcoma can also
appear to be poorly differentiated or to be monophasic fibrous, consisting only of sheets of spindle cells. Some
authorities state that, extremely rarely, there can be a monophasic epithelial form which causes difficulty in
differential diagnosis. Depending on the site, there is similarity to biphenotypic sinonasal sarcoma, although
the genetic findings are distinctive. Like other soft tissue sarcomas, there is no universal grading system for
reporting histopathology results. In Europe, the Trojani or French system is gaining in popularity while the NCI
grading system is more common in the United States. The Trojani system scores the sample, depending on
tumour differentiation, mitotic index, and tumour necrosis, between 0 and 6 and then converts this into a grade
of between 1 and 3, with 1 representing a less aggressive tumour. The NCI system is also a three-grade one, but
takes a number of other factors into account.

Molecular Biology
Most, and perhaps all, cases of synovial sarcoma are associated with a reciprocal translocation
t(x;18)(p11.2;q11.2). There is some debate about whether the molecular observation itself is definitive of synovial
sarcoma. The diagnosis of synovial sarcoma is typically made based on histology and is confirmed by the
presence of t(X;18). This translocation event between the SS18 gene on chromosome 18 and one of 3 SSX
genes (SSX1, SSX2 and SSX4) on chromosome X causes the presence of an SS18-SSX fusion gene. The
resulting fusion protein brings together the transcriptional activating domain of SS18 and the transcriptional
repressor domains of SSX. It also incorporates into the SWI/SNF chromatin remodeling complex, a well known
tumor suppressor. SS18-SSX is thought to underlie synovial sarcoma pathogenesis through dysregulation of
gene expression. There is some association between the SS18-SSX1 or SS18-SSX2 fusion type and both tumour
morphology and five-year survival.

Treatment
Treatment is usually multimodal, involving surgery, chemotherapy and radiotherapy:
• Surgery, to remove the tumor and a safety margin of healthy tissue. This is the mainstay of synovial
sarcoma treatment and is curative in approximately 20–70% of patients, depending on the particular
study being quoted.
• Conventional chemotherapy, (for example, doxorubicin hydrochloride and ifosfamide), to reduce the
number of remaining microscopic metastases. The benefit of chemotherapy in synovial sarcoma to
overall survival remains unclear, although a recent study has shown that survival of patients with
advanced, poorly differentiated disease marginally improves with doxorubicin/ifosfamide treatment.
188 Surgical Oncology: Theory and Multidisciplinary Practice

• Radiotherapy to reduce the chance of local recurrence. The benefit of radiotherapy in this disease is
less clear than for chemotherapy.

GASTR OINTESTINAL STR

GASTROINTESTINAL OMAL TUMOR
STROMAL
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neo-plasms of the
gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar
cells. They are defined as tumors whose behaviour is driven by mutations in the KIT gene (85%), PDGFRA
gene (10%), or BRAF kinase (rare). 95% of GISTs stain positively for KIT (CD117). Most (66%) occur in
the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in the GI
tract.

CLASSIFICATION
GIST was introduced as a diagnostic term in 1983. Until the late 1990s, many non-epithelial tumors of the
gastrointestinal tract were called “gastrointestinal stromal tumors”. Histopathologists were unable to specifically
distinguish between types we now know to be dissimilar molecularly. Subsequently, CD34, and later CD117
were identified as markers that could distinguish the various types. Additionally, in the absence of specific
therapy, the diagnostic categorization had only a limited influence on prognosis and therapy. The understanding
of GIST biology changed significantly with identification of the molecular basis of GIST, particularly c-KIT.
Historically, literature reviews prior to the molecular definition of GIST, and for a short time thereafter, asserted
that 70-80% of GISTs were benign.
The identification of a molecular basis for GIST led to the exclusion of many tumors that had been
considered as GIST previously, and also the incorporation of a much larger number of tumors that had been
labeled as other types of sarcomas and undifferentiated carcinomas. For example, some previous diagnoses
of stomach and small bowel leiomyosarcomas (malignant tumor of smooth muscle) would be reclassified as
GISTs on the basis of immunohistochemical staining. All GIST tumors are now considered to have malignant
potential, and no GIST tumor can be definitively classified as “benign”. Hence, all GISTs are eligible for
cancer staging in the AJCC (7th edition)/ UICC. Non-etheless, different GISTs have different risk assessments
of their tendency to recur or to metastasize, dependent on their site of origin, size, and number of mitotic
figures. Due to the change in definition, clinical pathways of care before the year 2000 are largely uninformative
in the current era.

SIGNS AND SYMPTOMS

GISTs may present with trouble swallowing, gastrointestinal bleeding, or metastases (mainly in the
liver). Intestinal obstruction is rare, due to the tumor’s outward pattern of growth. Often, there is a history
of vague abdominal pain or discomfort, and the tumor has become rather large by time the diagnosis is
made.

PATHOPHYSIOLOGY
GISTs are tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are non-
epithelial. About 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus.
Small tumors are generally benign, especially when cell division rate is slow, but large tumors disseminate to
the liver, omentum and peritoneal cavity. They rarely occur in other abdominal organs. GISTs are thought to
arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the
intestine. They serve a pacemaker function in controlling motility.
Sarcoma 189

Genetics
Most GISTs are sporadic. Less than 5% occur as part of hereditary familial or idiopathic multitumor syndromes.
These include, in descending order of frequency, neurofibromatosis Recklinghausen (NF-1), Carney’s triad
(gastric GIST, pulmonary chondroma and extra-adrenal paraganglioma), germline gain-of-function mutations
in c-Kit/PDGFRA, and the Carney-Stratakis syndrome. The Carney-Stratakis syndrome is a dyad of hereditary
GIST and paraganglioma, that is caused by germline mutations in the mitochondrial tumor suppressor gene
pathway involving the succinate dehydrogenase (SDH) subunits SDHD, SDHC and SDHB. Carney’s triad does
not feature SDH mutations.

c-KIT Mutations
Approximately 85% GISTs are associated with an abnormal c-KIT pathway. c-KIT is a gene that encodes
for a transmembrane receptor for a growth factor termed stem cell factor (scf). The abnormal c-KIT pathway
most commonly (85%) arises from mutation of the gene itself; a smaller subset of c-KIT-associated GISTs
are associated with constitutive activity of the KIT enzymatic pathway, found by immunoblotting. The c-KIT
product/CD117 is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast
cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be
a GIST, arising from ICC cells. The c-KIT molecule comprises a long extracellular domain, a transmembrane
segment, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part
(exon 11), which acts as a tyrosine kinase to activate other enzymes. Mutations make c-KIT function
independent of activation by scf, leading to a high cell division rate and possibly genomic instability. Additional
mutations are likely “required” for a cell with a c-KIT mutation to develop into a GIST, but the c-KIT mutation
is probably the first step of this process. Mutations in the exons 11, 9 and rarely 13 and 17 of the c-KIT gene
are known to occur in GIST. The tyrosine kinase function of c-KIT is important in the medical therapy for
GISTs, as described below.
• KIT-D816V point mutations in c-KIT exon 17 are responsible for resistance to targeted therapy
drugs like imatinib mesylate, a tyrosine kinase inhibitor.
• KIT-p.D419del (exon 8) - A subset of gastrointestinal stromal tumors previously regarded as wild-
type tumors carries somatic activating mutations in KIT exon 8 (p.D419del).

PDGFRA Mutations
Most GIST cells with wildtype (i.e. not mutated) c-kit instead have a mutation in another gene, PDGFR-α
(platelet derived growth factor receptor alpha), which is a related tyrosine kinase. Mutations in c-kit and PDGFrA
are mutually exclusive.

Wild-type Tumors
Lesser numbers of GISTs appear to be associated with neither c-kit nor PDGFR-α abnormalities. About 10-
15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-
derived growth factor receptor alpha (PDGFRA) (wt-GISTs). These tumors are currently defined by having no
mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene.

DIAGNOSIS
CT scanning is often undertaken. The definitive diagnosis is made with a biopsy, which can be obtained
endoscopically, percutaneously with CT or ultrasound guidance or at the time of surgery. A biopsy sample
190 Surgical Oncology: Theory and Multidisciplinary Practice

will be investigated under the microscope by a pathologist physician. The pathologist examines the
histopathology to identify the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-
30%). Smaller tumors can usually be confined to the muscularis propria layer of the intestinal wall. Large
ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and
necrose (die) on the inside, forming a cavity that may eventually come to communicate with the bowel
lumen. When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use
immunohistochemistry (specific antibodies that stain the molecule CD117 [also known as c-kit]). 95% of all
GISTs are CD117-positive (other possible markers include CD34, DOG-1, desmin, and vimentin). Other
cells that show CD117 positivity are mast cells. If the CD117 stain is negative and suspicion remains that the
tumor is a GIST, the newer antibody DOG-1 (Discovered On GIST-1) can be used. Also sequencing of Kit
and PDGFRA can be used to prove the diagnosis.

Imaging
The purpose of radiologic imaging is to locate the lesion, evaluate for signs of invasion and detect metastasis.
Features of GIST vary depending on tumor size and organ of origin. The diameter can range from a few millimeters
to more than 30 cm. Larger tumors usually cause symptoms in contrast to those found incidentally which tend
to be smaller and have better prognosis. Large tumors tend to exhibit malignant behaviour but small GISTs may
also demonstrate clinically aggressive behaviour. Plain radiographs are not very helpful in the evaluation of
GISTs. If an abnormality is seen, it will be an indirect sign due to the tumor mass effect on adjacent organs. On
abdominal x-ray, stomach GISTs may appear as a radiopaque mass altering the shape of the gastric air shadow.
Intestinal GISTs may displace loops of bowel and larger tumors may obstruct the bowel and films will show an
obstructive pattern. If cavitations are present, plain radiographs will show collections of air within the tumor
Calcification is an unusual feature of GIST but if present can be visible on plain films. Barium fluoroscopic
examinations and CT are commonly used to evaluate the patient with abdominal complaints. Barium swallow
images show abnormalities in 80% of GIST cases. However, some GISTs may be located entirely outside the
lumen of the bowel and will not be appreciated with a barium swallow. Even in cases when the barium swallow
is abnormal, an MRI or CT scan must follow since it is impossible to evaluate abdominal cavities and other
abdominal organs with a barium swallow alone. In a CT scan, abnormalities may be seen in 87% of patients and
it should be made with both oral and intravenous contrast. Among imaging studies, MRI has the best tissue
contrast, which aids in the identification of masses within the GI tract (intramural masses). Intravenous contrast
material is needed to evaluate lesion vascularity. Preferred imaging modalities in the evaluation of GISTs are
CT and MRI, and, in selected situations, endoscopic ultrasound. CT advantages include its ability to demonstrate
evidence of nearby organ invasion, ascites, and metastases. The ability of MRI to produce images in multiple
planes is helpful in determining the bowel as the organ of origin (which is difficult when the tumor is very
large), facilitating diagnosis.

Small GISTs
Since GISTs arise from the bowel layer called muscularis propria (which is deeper to the mucosa and
submucosa from a luminal perspective), small GIST imaging usually suggest a submucosal process or a mass
within the bowel wall. In barium swallow studies, these GISTs most commonly present with smooth borders
forming right or obtuse angles with the nearby bowel wall, as seen with any other intramural mass. The mucosal
surface is usually intact except for areas of ulceration, which are generally present in 50% of GISTs. Ulcerations
fill with barium causing a bull’s eye or target lesion appearance. In contrast-enhanced CT, small GISTs are seen
as smooth, sharply defined intramural masses with homogeneous attenuation.
Sarcoma 191

Large GISTs
As the tumor grows it may project outside the bowel (exophytic growth) and/or inside the bowel (intraluminal
growth), but they most commonly grow exophytically such that the bulk of the tumor projects into the abdominal
cavity. If the tumor outstrips its blood supply, it can necrose internally, creating a central fluid-filled cavity with
bleeding and cavitations that can eventually ulcerate and communicate into the lumen of the bowel. In that case,
barium swallow may show an air, air-fluid levels or oral contrast media accumulation within these areas. Mucosal
ulcerations may also be present. In contrast enhanced CT images, large GISTs appear as heterogeneous masses
due to areas of living tumor cells surrounding bleeding, necrosis or cysts, which is radiographically seen as a
peripheral enhancement pattern with a low attenuation center. In MRI studies, the degree of necrosis and bleeding
affects the signal intensity pattern. Areas of bleeding within the tumor will vary its signal intensity depending
on how long ago the bleeding occurred. The solid portions of the tumor are typically low signal intensity on T1-
weighted images, are high signal intensity on T2-weighted images and enhance after administration of gadolinium.
Signal-intensity voids are present if there is gas within areas of necrotic tumor.

Features of Malignancy
Malignancy is characterized by local invasion and metastases, usually to the liver, omentum and peritoneum.
However, cases of metastases to bone, pleura, lungs and retroperitoneum have been seen. In distinction to
gastric adenocarcinoma or gastric/small bowel lymphoma, malignant lymphadenopathy (swollen lymph nodes)
is uncommon (<10%) and thus imaging usually shows absence of lymph node enlargement. If metastases are
not present, other radiologic features suggesting malignancy include: size (>5 cm), heterogeneous enhancement
after contrast administration and ulcerations. Also, overtly malignant behaviour (in distinction to malignant
potential of lesser degree) is less commonly seen in gastric tumors, with a ratio of behaviourally benign to
overtly malignant of 3-5:1. Even if radiographic malignant features are present, these findings may also represent
other tumors and definitive diagnosis must be made immunochemically.

MANAGEMENT
In localized, resectable adult GISTs, if anatomically and physiologically feasible, surgery is the primary
treatment of choice. Surgery can be potentially curative, but watchful waiting may be considered in small
tumors in carefully selected situations. Post-surgical adjuvant treatment may be recommended. Lymph node
metastases are rare, and routine removal of lymph nodes is typically not necessary. Laparoscopic surgery, a
minimally invasive abdominal surgery using telescopes and specialized instruments, has been shown to be
effective for removal of these tumors without needing large incisions. The clinical issues of exact surgical
indications for tumor size are controversial. The decision of appropriate laparoscopic surgery is affected by
tumor size, location, and growth pattern. Radiotherapy has not historically been effective for GISTs and GISTs
do not respond to most chemotherapy medications, with responses in less than 5%. However, three medications
have been identified for clinical benefit in GIST: imatinib, sunitinib, and regorafenib. Imatinib (Glivec/Gleevec),
an orally administered drug initially marketed for chronic myelogenous leukemia based on bcr-abl inhibition,
also inhibits both c-kit tyrosine kinase mutations and PDGFRA mutations other than D842V, is useful in treating
GISTs in several situations. Imatinib has been used in selected neo-adjuvant settings. In the adjuvant treatment
setting, the majority of GIST tumors are cured by surgery, and do not need adjuvant therapy. An exception to
this is where the anatomical position of the tumour means that surgery is technically difficult or complex. For
example, rectal GIST often requires radical surgery to achieve complete resection, involving abdominoperineal
resection and permanent stoma. In these situations, the use of neo-adjuvant imatinib can significantly decrease
both tumour size and mitotic activity, and permit less radical sphincter-preserving surgery.
192 Surgical Oncology: Theory and Multidisciplinary Practice

A substantial proportion of GIST tumors have a high risk of recurrence as estimated by a number of validated
risk stratification schemes, and can be considered for adjuvant therapy. The selection criteria underpinning the
decision for possible use of imatinib in these settings include a risk assessment based on pathological factors
such as tumor size, mitotic rate, and location can be used to predict the risk of recurrence in GIST patients.
Tumors <2 cm with a mitotic rate of <5/50 HPF have been shown to have lower risk of recurrence than larger
or more aggressive tumors. Following surgical resection of GISTs, adjuvant treatment with imatinib reduces
the risk of disease recurrence in higher risk groups. In selected higher risk adjuvant situations, imatinib is
recommended for 3 years. Imatinib was approved for metastatic and unresectable GIST by the US FDA, February
1, 2002. The two-year survival of patients with advanced disease has risen to 75–80% following imatinib
treatment. If resistance to imatinib is encountered, the multiple tyrosine kinase inhibitor sunitinib (marketed as
Sutent) can be considered. The effectiveness of imatinib and sunitinib depend on the genotype. cKIT- and
PDGFRA-mutation negative GIST tumors are usually resistant to treatment with imatinib as is neurofibromatosis-
1-associated wild-type GIST. A specific subtype of PDGFRA-mutation, D842V, is also insensitive to imatinib.
Regorafenib (Stivarga) was FDA approved in 2013 for advanced GISTs that cannot be surgically removed and
that no longer respond to imatinib (Gleevec) and sunitinib (Sutent).

EPIDEMIOLOGY
GISTs occur in 10-20 per one million people. The true incidence might be higher, as novel laboratory methods
are much more sensitive in diagnosing GISTs. The estimated incidence of GIST in the United States is
approximately 5000 cases annually. This makes GIST the most common form of sarcoma, which constitutes
more than 70 types of cancer. The majority of GISTs present at ages 50–70 years. Across most of the age
spectrum, the incidence of GIST is similar in men and women. Adult GISTs are rare before age 40. Pediatric
GISTs are considered to be biologically distinct. Unlike GISTs at other ages, pediatric GISTs are more common
in girls and young women. They appear to lack oncogenic activating tyrosine kinase mutations in both KIT and
PDGFRA. Pediatric GISTs are treated differently than adult GIST. Although the generally accepted definition
of pediatric GIST is a tumor that is diagnosed at the age of 18 years or younger, “pediatric-type” GISTs can be
seen in adults, which affects risk assessment, the role of lymph node resection, and choice of therapy.
Gynecology 193

Chapter 6

Gynecology

OVARIAN C
OVARIAN ANCER
CANCER
Ovarian cancer is a cancer that forms in or on an ovary. It results in abnormal cells that have the ability to
invade or spread to other parts of the body. When this process begins, there may be no or only vague symptoms.
Symptoms become more noticeable as the cancer progresses. These symptoms may include bloating, pelvic
pain, abdominal swelling, and loss of appetite, among others. Common areas to which the cancer may spread
include the lining of the abdomen, lymph nodes, lungs, and liver. The risk of ovarian cancer increases in women
who have ovulated more over their lifetime. This includes those who have never had children, those who begin
ovulation at a younger age and those who reach menopause at an older age. Other risk factors include hormone
therapy after menopause, fertility medication, and obesity. Factors that decrease risk include hormonal birth
control, tubal ligation, and breast feeding. About 10% of cases are related to inherited genetic risk; women with
mutations in the genes BRCA1 or BRCA2 have about a 50% chance of developing the disease. The most common
type of ovarian cancer, comprising more than 95% of cases, is ovarian carcinoma. There are five main subtypes
of ovarian carcinoma, of which high-grade serous carcinoma is the most common. These tumors are believed
to start in the cells covering the ovaries, though some may form at the Fallopian tubes. Less common types of
ovarian cancer include germ cell tumors and sex cord stromal tumors. A diagnosis of ovarian cancer is
confirmed through a biopsy of tissue, usually removed during surgery. Screening is not recommended in
women who are at average risk, as evidence does not support a reduction in death and the high rate of false
positive tests may lead to unneeded surgery, which is accompanied by its own risks. Those at very high risk may
have their ovaries removed as a preventive measure. If caught and treated in an early stage, ovarian cancer is
often curable. Treatment usually includes some combination of surgery, radiation therapy, and chemotherapy.
Outcomes depend on the extent of the disease, the subtype of cancer present, and other medical conditions. The
overall five-year survival rate in the United States is 45%. Outcomes are worse in the developing world. In
2012, new cases occurred in 239,000 women. In 2015 it was present in 1.2 million women and resulted in
161,100 deaths worldwide. Among women it is the seventh-most common cancer and the eighth-most common
cause of death from cancer. The typical age of diagnosis is 63. Death from ovarian cancer is more common in
North America and Europe than in Africa and Asia.

SIGNS AND SYMPTOMS

Early Symptoms
Early signs and symptoms of ovarian cancer may be absent or subtle. In most cases, symptoms exist for
several months before being recognized and diagnosed. Symptoms can be misdiagnosed as irritable bowel
194 Surgical Oncology: Theory and Multidisciplinary Practice

syndrome. The early stages of ovarian cancer tend to be painless. Symptoms can vary based on the subtype.
Low malignant potential (LMP) tumors, also known as borderline tumors, do not cause an increase in
CA125 levels and are not identifiable with an ultrasound. The typical symptoms of an LMP tumor can
include abdominal distension or pelvic pain. Particularly large masses tend to be benign or borderline. The
most typical symptoms of ovarian cancer include bloating, abdominal or pelvic pain or discomfort, back pain,
irregular menstruation or postmenopausal vaginal bleeding, pain or bleeding after or during sexual intercourse,
loss of appetite, fatigue, diarrhea, indigestion, heartburn, constipation, nausea, feeling full, and possibly urinary
symptoms (including frequent urination and urgent urination).

Later Symptoms
The growing mass may cause pain if ovarian torsion develops. Symptoms can be caused by a mass pressing
on the other abdominopelvic organs or from metastases. If these symptoms start to occur more often or more
severely than usual, especially after no significant history of such symptoms, ovarian cancer is considered.
Metastases may cause a Sister Mary Joseph nodule. Rarely, teratomas can cause growing teratoma syndrome or
peritoneal gliomatosis. Some experience menometrorrhagia and abnormal vaginal bleeding after menopause in
most cases. Other common symptoms include hirsutism, abdominal pain, virilization, and an adnexal mass.

Children
In adolescents or children with ovarian tumors, symptoms can include severe abdominal pain, irritation of
the peritoneum, or bleeding. Symptoms of sex cord-stromal tumors produce hormones that can affect the
development of secondary sex characteristics. Sex cord-stromal tumors in prepubertal children may be manifested
by early puberty; abdominal pain and distension are also common. Adolescents with sex cord-stromal tumors
may experience amenorrhea. As the cancer becomes more advanced, it can cause an accumulation of fluid in
the abdomen. If the malignancy has not been diagnosed by the time it causes ascites, it is typically diagnosed
shortly thereafter. Advanced cancers can also cause abdominal masses, lymph node masses, or pleural effusion.

RISK FACTORS
Ovarian cancer is related to the amount of time spent ovulating. Thus not having children is a risk factor for
ovarian cancer, likely because ovulation is suppressed via pregnancy. During ovulation, cells are constantly
stimulated to divide while ovulatory cycles continue. Therefore, people who have not borne children are at
twice the risk of ovarian cancer than those who have. A longer period of ovulation caused by early first
menstruation and late menopause is also a risk factor. Both obesity and hormone replacement therapy also raise
the risk. The risk of developing ovarian cancer is less for women who have fewer menstrual cycles, no menstrual
cycles, breast feeding, take oral contraceptives, have multiple pregnancies, and have a pregnancy at an early
age. The risk of developing ovarian cancer is reduced in women who have had tubal ligation (colloquially
known as having one’s “tubes tied”), both ovaries removed, or hysterectomy (an operation in which the uterus,
and sometimes the cervix, is removed). Age is also a risk factor.

Hormones
Use of fertility medication may contribute to borderline ovarian tumor formation, but the link between the
two is disputed and difficult to study. Fertility drugs may be associated with a higher risk of borderline tumors.
Those who have been treated for infertility but remain nulliparous are at higher risk for epithelial ovarian
cancer; however, those who are successfully treated for infertility and subsequently give birth are at no higher
Gynecology 195

risk. This may be due to shedding of precancerous cells during pregnancy but the cause remains unclear. The
risk factor may instead be infertility itself, not the treatment. Hormonal conditions such as polycystic ovary
syndrome and endometriosis are associated with ovarian cancer, but the link is not completely confirmed.
Postmenopausal hormone replacement therapy (HRT) with estrogen likely increases the risk of ovarian cancer.
The association has not been confirmed in a large-scale study, but notable studies including the Million Women
Study have supported this link. Postmenopausal HRT with combined estrogen and progesterone may increase
contemporaneous risk if used for over 5 years, but this risk returns to normal after cessation of therapy. Estrogen
HRT with or without progestins increases the risk of endometrioid and serous tumors but lowers the risk of
mucinous tumors. Higher doses of estrogen increase this risk. Endometriosis is another risk factor for ovarian
cancer, as is pain with menstruation. Endometriosis is associated with clear-cell and endometrioid subtypes,
low-grade serous tumors, stage I and II tumors, grade 1 tumors, and lower mortality. Before menopause, obesity
can increase a person’s risk of ovarian cancer, but this risk is not present after menopause. This risk is also
relevant in those who are both obese and have never used HRT. A similar association with ovarian cancer
appears in taller people.

Genetics
A family history of ovarian cancer is a risk factor for ovarian cancer. People with hereditary non-polyposis
colon cancer (Lynch syndrome), and those with BRCA-1 and BRCA-2 genetic abnormalities are at increased risk.
The major genetic risk factor for ovarian cancer is a mutation in BRCA1 or BRCA2 DNA mismatch repair genes,
which is present in 10% of ovarian cancer cases. Only one allele need be mutated to place a person at high risk.
The gene can be inherited through either the maternal or paternal line, but has variable penetrance. Though mutations
in these genes are usually associated with increased risk of breast cancer, they also carry a substantial lifetime risk
of ovarian cancer, a risk that peaks in a person’s 40s and 50s. The lowest risk cited is 30% and the highest 60%.
Mutations in BRCA1 have a lifetime risk of developing ovarian cancer of 15–45%. Mutations in BRCA2 are less
risky than those with BRCA1, with a lifetime risk of 10% (lowest risk cited) to 40% (highest risk cited). On
average, BRCA-associated cancers develop 15 years before their sporadic counterparts, because people who inherit
the mutations on one copy of their gene only need one mutation to start the process of carcinogenesis, whereas
people with two normal genes would need to acquire two mutations.
In the United States, five of 100 women with a first-degree relative with ovarian cancer will eventually get
ovarian cancer themselves, placing those with affected family members at triple the risk of women with unaffected
family members. Seven of 100 women with two or more relatives with ovarian cancer will eventually get ovarian
cancer. In general, 5–10% of ovarian cancer cases have a genetic cause. BRCA mutations are associated with high-
grade serous non-mucinous epithelial ovarian cancer. A strong family history of endometrial cancer, colon cancer,
or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary non-polyposis
colorectal cancer (also known as Lynch syndrome), which confers a higher risk for developing a number of
cancers, including ovarian cancer. Lynch syndrome is caused by mutations in mismatch repair genes, including
MSH2, MLH1, MLH6, PMS1, and PMS2. The risk of ovarian cancer for an individual with Lynch syndrome is
between 10 and 12 percent. People of Icelandic descent, European Jewish descent/Ashkenazi Jewish descent, and
Hungarian descent are at higher risk for epithelial ovarian cancer. Estrogen receptor beta gene (ESR2) seems to be
a key to pathogenesis and response to therapy. Other genes that have been associated with ovarian cancer are
BRIP1, MSH6, RAD51C and RAD51D. CDH1, CHEK2, PALB2 and RAD50 have also been associated with ovarian
cancer. Several rare genetic disorders are associated with specific subtypes of ovarian cancer. Peutz–Jeghers
syndrome, a rare genetic disorder, also predisposes people to sex cord tumour with annular tubules. Ollier disease
and Maffucci syndrome are associated with granulosa cell tumors in children and may also be associated with
Sertoli-Leydig tumors. Benign fibromas are associated with nevoid basal cell carcinoma syndrome.
196 Surgical Oncology: Theory and Multidisciplinary Practice

Hereditary Breast–ovarian Cancer Syndrome

Hereditary breast–ovarian cancer syndromes (HBOC) are cancer syndromes that produce higher than normal
levels of breast cancer and ovarian cancer in genetically related families (either one individual had both, or
several individuals in the pedigree had one or the other disease).
The hereditary factors may be proven or suspected to cause the pattern of breast and ovarian cancer occurrences
in the family.

Hereditary Causes
A number of genes are associated with HBOC. The most common of the known causes of HBOC are:
• BRCA mutations: Harmful mutations in the BRCA1 and BRCA2 genes can produce very high rates
of breast and ovarian cancer, as well as increased rates of other cancers. Mutations in BRCA1 are
associated with a 39-46% risk of ovarian cancer and mutations in BRCA2 are associated with a 10-
27% risk of ovarian cancer.
Other identified genes include:
• TP53: Mutations cause Li-Fraumeni syndrome. It produces particularly high rates of breast cancer
among younger women with mutated genes, and despite being rare, 4% of women with breast cancer
under age 30 have a mutation in this gene.
• PTEN: Mutations cause Cowden syndrome, which produces hamartomas (benign polyps) in the colon,
skin growths, and other clinical signs, as well as an increased risk for many cancers.
• CDH1: Mutations are associated with lobular breast cancer and gastric cancer.
• STK11: Mutations produce Peutz–Jeghers syndrome. It is extremely rare, and creates a predisposition
to breast cancer, intestinal cancer, and pancreatic cancer.
• CHEK2: Approximately one out of 40 northern Europeans have a mutation in this gene, making it a
common mutation. Considered a moderate-risk mutation, it may double or triple the carrier’s lifetime
risk of breast cancer, and also increase the risk of colon cancer and prostate cancer.
• ATM: Mutations cause ataxia telangectasia; female carriers have approximately double the normal
risk of developing breast cancer.
• PALB2: Studies vary in their estimate of the risk from mutations in this gene. It may be moderate
risk, or as high as BRCA2.
Approximately 45% of HBOC cases involve unidentified genes, or multiple genes.

Prevention
People with BRCA1 and BRCA2 mutations are recommended to have a transvaginal ultrasound1-2 times per
year. Screening with CA-125 is also recommended. Prophylactic salpingo-oophorectomy (removal of the ovaries
and Fallopian tubes to prevent cancer) is recommended at age 35-40 for people with BRCA1 mutations and at
age 40-45 for people with BRCA2 mutations.

Environmental Factors
Industrialized nations, with the exception of Japan, have high rates of epithelial ovarian cancer, which may
be due to diet in those countries. Caucasian are at a 30–40% higher risk for ovarian cancer when compared to
Black and Hispanic people, likely due to socioeconomic factors; white women tend to have fewer children and
different rates of gynecologic surgeries that affect risk for ovarian cancer. Cohort studies have found a correlation
between dairy consumption and ovarian cancer, but case-control studies do not show this correlation. There is
mixed evidence regarding the effect of red meat and processed meat in ovarian cancer. Tentative evidence
suggests that talc, pesticides, and herbicides increase the risk of ovarian cancer. The American Cancer Society
Gynecology 197

notes that as of now, no study has been able to accurately link any single chemical in the environment, or in the
human diet, directly to mutations that cause ovarian cancer.

Other
Alcohol consumption does not appear to be related to ovarian cancer. Other factors that have been investigated,
such as smoking, low levels of vitamin D in the blood, presence of inclusion ovarian cysts, and infection with
human papilloma virus (the cause of some cases of cervical cancer), have been disproven as risk factors for
ovarian cancer. The carcinogenicity of perineal talc is controversial, because it can act as an irritant if it travels
through the reproductive tract to the ovaries. Case-control studies have shown that use of perineal talc does
increase the risk of ovarian cancer, but using talc more often does not create a greater risk. Use of talc elsewhere
on the body is unrelated to ovarian cancer. Sitting regularly for prolonged periods is associated with higher
mortality from epithelial ovarian cancer. The risk is not negated by regular exercise, though it is lowered.
Increased age (up to the 70s) is a risk factor for epithelial ovarian cancer because more mutations in cells can
accumulate and eventually cause cancer. Those over 80 are at slightly lower risk. Smoking tobacco is associated
with a higher risk of mucinous ovarian cancer; after smoking cessation, the risk eventually returns to normal. A
diet high in animal fats may be associated with ovarian cancer, but the connection is unclear. Diet seems to play
a very small role, if any, in ovarian cancer risk. Higher levels of C-reactive protein are associated with a higher
risk of developing ovarian cancer.

Protective Factors
Suppression of ovulation, which would otherwise cause damage to the ovarian epithelium and, consequently,
inflammation, is generally protective. This effect can be achieved by having children, taking combined oral
contraceptives, and breast feeding, all of which are protective factors. A longer period of breastfeeding correlates
with a larger decrease in the risk of ovarian cancer. Each birth decreases risk of ovarian cancer more, and this
effect is seen with up to five births. Combined oral contraceptives reduce the risk of ovarian cancer by up to
50%, and the protective effect of combined oral contraceptives can last 25–30 years after they are discontinued.
Regular use of aspirin or acetaminophen (paracetamol) may be associated with a lower risk of ovarian cancer;
other NSAIDs do not seem to have a similar protective effect. Tubal ligation is protective because carcinogens
are unable to reach the ovary and fimbriae via the vagina, uterus, and Fallopian tubes. Tubal ligation is also
protective in women with the BRCA1 mutation, but not the BRCA2 mutation. Hysterectomy reduces the risk,
and removal of both Fallopian tubes and ovaries (bilateral salpingo-oophorectomy) dramatically reduces the
risk of not only ovarian cancer, but breast cancer as well. This is still a topic of research, as the link between
hysterectomy and lower ovarian cancer risk is controversial. The reasons that hysterectomy may be protective
have not been elucidated as of 2015. A diet that includes large amounts of carotene, fibre, and vitamins with low
amounts of fat—specifically, a diet with non-starchy vegetables (e.g. broccoli and onions)—may be protective,
though research is still ongoing in this area. Higher caffeine intake and consumption of more than two cups of
tea a day have both been associated with lower ovarian cancer risk. Smoking tobacco is protective for sex cord-
stromal tumors.

PATHOPHYSIOLOGY
Ovarian cancer forms when errors in normal ovarian cell growth occur. Usually, when cells grow old or get
damaged, they die, and new cells take their place. Cancer starts when new cells form unneeded, and old or
damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called a growth
or tumor. These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.
198 Surgical Oncology: Theory and Multidisciplinary Practice

When an ovary releases an egg, the egg follicle bursts open and becomes the corpus luteum. This structure
needs to be repaired by dividing cells in the ovary. Continuous ovulation for a long time means more repair of
the ovary by dividing cells, which can acquire mutations in each division. Overall, the most common gene
mutations in ovarian cancer occur in NF1, BRCA1, BRCA2, and CDK12. Type I ovarian cancers, which tend to
be less aggressive, tend to have microsatellite instability in several genes, including both oncogenes (most
notably BRAF and KRAS) and tumor suppressors (most notably PTEN). The most common mutations in Type I
cancers are KRAS, BRAF, ERBB2, PTEN, PIK3CA, and ARID1A. Type II cancers, the more aggressive type,
have different genes mutated, including p53, BRCA1, and BRCA2. Low-grade cancers tend to have mutations in
KRAS, whereas cancers of any grade that develop from low malignant potential tumors tend to have mutations
in p53. Type I cancers tend to develop from precursor lesions, whereas Type II cancers can develop from a
serous tubal intraepithelial carcinoma. Serous cancers that have BRCA mutations also inevitably have p53
mutations, indicating that the removal of both functional genes is important for cancer to develop. In 50% of
high-grade serous cancers, homologous recombination DNA repair is dysfunctional, as are the notch and FOXM1
signaling pathways. They also almost always have p53 mutations. Other than this, mutations in high-grade
serous carcinoma are hard to characterize beyond their high degree of genomic instability. BRCA1 and BRCA2
are essential for homologous recombination DNA repair, and germline mutations in these genes are found in
about 15% of people with ovarian cancer. The most common mutations in BRCA1 and BRCA2 are the frameshift
mutations that originated in a small founding population of Ashkenazi Jews. Almost 100% of rare mucinous
carcinomas have mutations in KRAS and amplifications of ERBB2 (also known as Her2/neu). Overall, 20% of
ovarian cancers have mutations in Her2/neu. Serous carcinomas may develop from serous tubal intraepithelial
carcinoma, rather than developing spontaneously from ovarian tissue. Other carcinomas develop from cortical
inclusion cysts, which are groups of epithelial ovarian cells inside the stroma.

DIAGNOSIS

Examination
Diagnosis of ovarian cancer starts with a physical examination (including a pelvic examination), a blood test
(for CA-125 and sometimes other markers), and transvaginal ultrasound. Sometimes a rectovaginal examination
is used to help plan a surgery. The diagnosis must be confirmed with surgery to inspect the abdominal cavity,
take biopsies (tissue samples for microscopic analysis), and look for cancer cells in the abdominal fluid. This
helps to determine if an ovarian mass is benign or malignant. Ovarian cancer’s early stages (I/II) are difficult to
diagnose because most symptoms are non-specific and thus of little use in diagnosis; as a result, it is rarely
diagnosed until it spreads and advances to later stages (III/IV). Additionally, symptoms of ovarian cancer may
appear similar to irritable bowel syndrome. In patients in whom pregnancy is a possibility, BHCG level can be
measured during the diagnosis process. Serum alpha-fetoprotein, neuron-specific enolase, and lactate
dehydrogenase can be measured in young girls and adolescents with suspected ovarian tumors as younger
patients are more likely to have malignant germ cell tumors. A physical examination, including a pelvic
examination, and a pelvic ultrasound (transvaginal or otherwise) are both essential for diagnosis: physical
examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity), while
pelvic examination may reveal an ovarian or abdominal mass. An adnexal mass is a significant finding that
often indicates ovarian cancer, especially if it is fixed, nodular, irregular, solid, and/or bilateral. 13–21% of
adnexal masses are caused by malignancy; however, there are other benign causes of adnexal masses, including
ovarian follicular cyst, leiomyoma, endometriosis, ectopic pregnancy, hydrosalpinx, tuboovarian abscess, ovarian
torsion, dermoid cyst, cystadenoma (serous or mucinous), diverticular or appendiceal abscess, nerve sheath
tumor, pelvic kidney, ureteral or bladder diverticulum, benign cystic mesothelioma of the peritoneum, peritoneal
Gynecology 199

tuberculosis, or paraovarian cyst. Ovaries that can be felt are also a sign of ovarian cancer in postmenopausal
women. Other parts of a physical examination for suspected ovarian cancer can include a breast examination
and a digital rectal exam. Palpation of the supraclavicular, axillary, and inguinal lymph nodes may reveal
lymphadenopathy, which can be indicative of metastasis. Another indicator may be the presence of a pleural
effusion, which can be noted on auscultation.
When an ovarian malignancy is included in a list of diagnostic possibilities, a limited number of laboratory
tests are indicated. A complete blood count and serum electrolyte test is usually obtained; when an ovarian
cancer is present, these tests often show a high number of platelets (20–25% of people) and low blood sodium
levels due to chemical signals secreted by the tumor. A positive test for inhibin A and inhibin B can indicate a
granulosa cell tumor. A blood test for a marker molecule called CA-125 is useful in differential diagnosis and in
follow up of the disease, but it by itself has not been shown to be an effective method to screen for early-stage
ovarian cancer due to its unacceptable low sensitivity and specificity. CA-125 levels in premenopausal people
over 200 U/mL may indicate ovarian cancer, as may any elevation in CA-125 above 35 U/mL in post-menopausal
people. CA-125 levels are not accurate in early stage ovarian cancer, as fully half of stage I ovarian cancer
patients have a normal CA-125 level. CA-125 may also be elevated in benign (non-cancerous) conditions,
including endometriosis, pregnancy, uterine fibroids, menstruation, ovarian cysts, systemic lupus erythematosus,
liver disease, inflammatory bowel disease, pelvic inflammatory disease, and leiomyoma. HE4 is another candidate
for ovarian cancer testing, though it has not been extensively tested. Other tumor markers for ovarian cancer
include CA19-9, CA72-4, CA15-3, immunosuppressive acidic protein, haptoglobin-alpha, OVX1, mesothelin,
lysophosphatidic acid, osteopontin, and fibroblast growth factor 23. Use of blood test panels may help in
diagnosis. The OVA1 panel includes CA-125, beta-2 microglobulin, transferrin, apolipoprotein A1, and
transthyretin. OVA1 above 5.0 in premenopausal people and 4.4 in postmenopausal people indicates a high risk
for cancer. A different set of laboratory tests is used for detecting sex cord-stromal tumors. High levels of
testosterone or dehydroepiandrosterone sulfate, combined with other symptoms and high levels of inhibin A
and inhibin B can be indicative of an SCST of any type.
Current research is looking at ways to consider tumor marker proteomics in combination with other indicators
of disease (i.e. radiology and/or symptoms) to improve diagnostic accuracy. The challenge in such an approach
is that the disparate prevalence of ovarian cancer means that even testing with very high sensitivity and specificity
will still lead to a number of false positive results, which in turn may lead to issues such as performing surgical
procedures in which cancer is not found intraoperatively. Genomics approaches have not yet been developed
for ovarian cancer. CT scanning is preferred to assess the extent of the tumor in the abdominopelvic cavity,
though magnetic resonance imaging can also be used. CT scanning can also be useful for finding omental
caking or differentiating fluid from solid tumor in the abdomen, especially in low malignant potential tumors.
However, it may not detect smaller tumors. Sometimes, a chest x-ray is used to detect metastases in the chest or
pleural effusion. Another test for metastatic disease, though it is infrequently used, is a barium enema, which
can show if the rectosigmoid colon is involved in the disease. Positron emission tomography, bone scans, and
paracentesis are of limited use; in fact, paracentesis can cause metastases to form at the needle insertion site and
may not provide useful results. However, paracentesis can be used in cases where there is no pelvic mass and
ascites is still present. A physician suspecting ovarian cancer may also perform mammography or an endometrial
biopsy (in the case of abnormal bleeding) to assess the possibility of breast malignancies and endometrial
malignancy, respectively. Vaginal ultrasonography is often the first-line imaging study performed when an
adnexal mass is found. Several characteristics of an adnexal mass indicate ovarian malignancy; they usually are
solid, irregular, multilocular, and/or large; and they typically have papillary features, central vessels, and/or
irregular internal septations. However, SCST has no definitive characteristics on radiographic study. To
definitively diagnose ovarian cancer, a surgical procedure to inspect the abdomen is required. This can be an
open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During
200 Surgical Oncology: Theory and Multidisciplinary Practice

this procedure, suspicious tissue is removed and sent for microscopic analysis. Usually, this includes a unilateral
salpingo-oophorectomy, removal of a single affected ovary and Fallopian tube. Fluid from the abdominal cavity
can also be analyzed for cancerous cells. If cancer is found, this procedure can also be used to determine the
extent of its spread (which is a form of tumor staging).

Risk Scoring
A widely recognized method of estimating the risk of malignant ovarian cancer is the risk of malignancy
index (RMI), calculated based on an initial workup. An RMI score of over 200 or 250 is generally felt to
indicate high risk for ovarian cancer.
The RMI is calculated as:
RMI = ultrasound score x menopausal score x CA-125 level in U/ml.
Two methods can be used to determine the ultrasound score and menopausal score, with the resultant scores
being referred to as RMI 1 and RMI 2, respectively, depending on what method is used.
Feature RMI 1 RMI 2
Ultrasound abnormalities: • 0 = no abnormality • 0 = none
• multilocular cyst • 1 = one abnormality • 1 = one abnormality
• solid areas • 3 = two or more abnormalities • 4 = two or more abnormalities
• ascites
• intra-abdominal metastases
Menopausal score • 1 = premenopausal • 1 = premenopausal
• 3 = postmenopausal • 4 = postmenopausal
CA-125 Quantity in U/ml Quantity in U/ml
Another method for quantifying risk of ovarian cancer is the Risk of Ovarian Cancer Algorithm (ROCA),
observes levels over time and determines if they are increasing rapidly enough to warrant transvaginal ultrasound.
The Risk of Ovarian Malignancy algorithm uses CA-125 levels and HE4 levels to calculate the risk of ovarian
cancer; it may be more effective than RMI. The IOTA models can be used to estimate the probability that an
adnexal tumor is malignant. They include LR2 risk model, The Simple Rules risk (SRrisk) calculation and
Assessment of Different Neo-plasias in the Adnexa (ADNEX) model that can be used to assess risk of malignancy
in an adnexal mass, based on its characteristics and risk factors. The QCancer (Ovary) algorithm is used to
predict likelihood of ovarian cancer from risk factors.

Pathology
Ovarian cancers are classified according to the microscopic appearance of their structures (histology or
histopathology). Histology dictates many aspects of clinical treatment, management, and prognosis. The
gross pathology of ovarian cancers is very similar regardless of histologic type: tumors have solid and
cystic masses. According to SEER, the types of ovarian cancers in women age 20 and over are:
Percent of ovarian Percent of ovarian Histology Five-year RSR
cancersin women cancersin women
age 20+ age 20+ by
subdivision
89.7 Surface epithelial-stromal tumor (adenocarcinoma) 54.4
26.4 Papillary serous cystadenocarcinoma 21.0
15.9 “Borderline” adenocarcinoma(underestimated - short 98.2
data collection interval)
12.6 Adenocarcinoma, not otherwise specified 18.3
9.8 Endometrioid tumor 70.9
5.8 Serous cystadenocarcinoma 44.2
5.5 Papillary 21.0
4.2 Mucinous cystadenocarcinoma 77.7
Gynecology 201

4.0 Clear-cell ovarian tumor 61.5

3.4 Mucinous adenocarcinoma 49.1
1.3 Cystadenocarcinoma 50.7
5.5 Carcinoma
4.1 Carcinoma not otherwise specified 26.8
1.1 Sex cord-stromal tumour 87.8
0.3 Other carcinomas, specified 37.3
1.7 Mullerian tumor 29.8
1.5 Germ cell tumor 91.0
0.8 Teratoma 89.1
0.5 Dysgerminoma 96.8
0.3 Other, specified 85.1
0.6 Not otherwise specified 23.0
0.5 Epidermoid (squamous cell carcinoma) 51.3
0.2 Brenner tumor 67.9
0.2 Other, specified 71.7
Ovarian cancers are histologically and genetically divided into type I or type II. Type I cancers are of low
histological grade, and include endometrioid, mucinous, and clear-cell carcinomas. Type II cancers are of higher
histological grade and include serous carcinoma and carcinosarcoma.

Epithelial Carcinoma
Surface epithelial-stromal tumour, also known as ovarian epithelial carcinoma, is the most common type of
ovarian cancer, representing approximately 90% of ovarian cancers. It includes serous tumour, endometrioid
tumor, and mucinous cystadenocarcinoma. Less common tumors are malignant Brenner tumor and transitional
cell carcinoma of the ovary. Epithelial ovarian cancers develop from the epithelium, a layer of cells that covers
the ovary.

Serous Carcinoma
Most people with epithelial ovarian carcinoma, about two-thirds, have a serous carcinoma, though this
proportion is estimated as high as 80%. Low-grade serous carcinoma is less aggressive than high-grade serous
carcinomas, though it does not typically respond well to chemotherapy or hormonal treatments. Serous carcinomas
are thought to begin in the Fallopian tube. Histologically, serous adenocarcinomas have psammoma bodies.
Low-grade serous adenocarcinomas resemble Fallopian tube epithelium, whereas high-grade serous
adenocarcinomas show anaplasia and nuclear atypia. 50% of the time, serous carcinomas are bilateral, and in
85% of cases, they have spread beyond the ovary at the time of diagnosis. Most have a diameter over 15 cm.

Small-cell Carcinoma
Small-cell ovarian carcinoma is rare and aggressive, with two main subtypes: hypercalcemic and
pulmonary. It is typically fatal within 2 years of diagnosis. Hypercalcemic small cell ovarian carcinoma
overwhelmingly affects those in their 20s, causes high blood calcium levels, and affects one ovary.
Pulmonary small cell ovarian cancer usually affects both ovaries of older women and looks like oat-cell
carcinoma of the lung.

Primary Peritoneal Carcinoma

Primary peritoneal cancer or carcinoma is also known as serous surface papillary carcinoma, primary peritoneal
carcinoma, extra-ovarian serous carcinoma, primary serous papillary carcinoma, psammomacarcinoma. It was
historically classified under “carcinoma of unknown primary” (CUP). Primary peritoneal cancer (PPC, or PPCa)
is a cancer of the cells lining the peritoneum, or abdominal cavity. Some studies indicate that up to 15% of
serous ovarian cancers are thought to be actually primary peritoneal carcinomas in origin. Histomorphological
202 Surgical Oncology: Theory and Multidisciplinary Practice

and molecular biological characteristics suggest that serous carcinomas, which include ovarian serous carcinoma,
uterine serous carcinoma, Fallopian tube serous carcinoma, cervical serous carcinoma, and primary peritoneal
serous carcinoma really represent one entity.
• Theory: Ovarian and peritoneal epithelium share common embryonal origin, the coelomic epithelium
(mesodermal origin). Coelomic epithelium is thought to be of mesonephric origin. With the overall
point being that normal ovarian and peritoneal tissue is derived from the mesonephros. On the contrary,
fallopian tube epithelium, endometrium and endocervix are related to paramesonephros (Müllerian duct).
Surprisingly, epithelial ovarian cancer and primary peritoneal cancer are histologically similar to the
Mullerian epithelium; not their embryonal origin, the mesonephros. Either a metaplasia has occurred or
Mullerian remnants have been left behind in coelemic epithelium, which have turned oncogenic.
• Genetic causes: Although the precise causes are not known, a link with certain variants of BRCA1/2
has been described. Furthermore, women with BRCA1/2 mutation have a 5% risk of developing
primary peritoneal cancer even after prophylactic oophorectomy. Primary peritoneal carcinoma shows
similar rates of tumor suppressor gene dysfunction (p53, BRCA, WT1) as ovarian cancer and can
also show an increased expression of HER-2/neu. An association with vascular endothelial growth
factor has been observed.
• Prognosis and treatment: Prognosis and treatment is the same as for the most common type of
ovarian cancer, which is epithelial ovarian cancer. The median survival of primary peritoneal
carcinomas is usually shorter by 2–6 months time when compared with serous ovarian cancer. Studies
show median survival varies between 11.3–17.8 months. One study reported 19-40 month median
survival (95% CI) with a 5-year survival of 26.5%. Elevated albumin levels have been associated
with a more favourable prognosis.

Clear-cell Carcinoma
Clear-cell ovarian carcinomas do not typically respond well to chemotherapy and may be related to
endometriosis. They represent approximately 5% of all endometrial cancers. Japanese women develop clear-
cell ovarian cancer more frequently than other groups of women.

Clear-cell Adenocarcinoma
Clear-cell adenocarcinomas are histopathologically similar to other clear cell carcinomas, with clear cells
and hobnail cells. They represent approximately 5–10% of epithelial ovarian cancers and are associated with
endometriosis in the pelvic cavity. They are typically early-stage and therefore curable by surgery, but advanced
clear-cell adenocarcinomas (approximately 20%) have a poor prognosis and are often resistant to platinum
chemotherapy.

Endometrioid
Endometrioid adenocarcinomas make up approximately 15–20% of epithelial ovarian cancers. Because they
are typically low-grade, endometrioid adenocarcinomas have a good prognosis. These tumors frequently co-
occur with endometriosis or endometrial cancer.

Malignant Mixed Mullerian Tumor (Carcinosarcoma)

Mixed mullerian tumors make up less than 1% of ovarian cancer. They have epithelial and mesenchymal
cells visible and tend to have a poor prognosis.

Mucinous
Mucinous tumors include mucinous adenocarcinoma and mucinous cystadenocarcinoma.
Gynecology 203

Mucinous Adenocarcinoma
Mucinous adenocarcinomas make up 5–10% of epithelial ovarian cancers. Histologically, they are similar to
intestinal or cervical adenocarcinomas, and are often actually metastases of appendiceal or colon cancers.
Advanced mucinous adenocarcinomas have a poor prognosis, generally worse than serous tumors, and are
often resistant to platinum chemotherapy, though they are rare.

Pseudomyxoma Peritonei
Pseudomyxoma peritonei (PMP) is a clinical condition caused by cancerous cells (mucinous adenocarcinoma)
that produce abundant mucin or gelatinous ascites. The tumors cause fibrosis of tissues and impede digestion or
organ function, and if left untreated, the tumors and mucin they produce will fill the abdominal cavity. This will
result in compression of organs and will destroy the function of colon, small intestine, stomach, or other organs.
Prognosis with treatment in many cases is optimistic, but the disease is lethal if untreated, with death by cachexia,
bowel obstruction, or other types of complications. This disease is most commonly caused by an appendiceal
primary cancer (cancer of the appendix); mucinous tumors of the ovary have also been implicated, although in
most cases ovarian involvement is favoured to be a metastasis from an appendiceal or other gastrointestinal
source. Disease is typically classified as low- or high-grade (with signet ring cells). When disease presents with
low-grade histologic features the cancer rarely spreads through the lymphatic system or through the bloodstream.
Classification:
• There is substantial debate regarding histopathologic classification of pseudomyxoma peritonei. In
1995, Ronnett et al. proposed separating pseudomyxoma peritonei cases into two diagnostic categories:
adenoma (disseminated peritoneal adenomucinosis, DPAM) or carcinoma (peritoneal mucinous
carcinomatosis, PMCA) with a third category reserved for cases with intermediate features. In this
classification system, cases of DPAM were characterized by peritoneal lesions composed of abundant
extracellular mucin containing scant simple to focally proliferative mucinous epithelium with little
cytologic atypia or mitotic activity (in other words, most cells looked fairly normal and there was no
evidence of mitosis which would indicate that cells were rapidly dividing), with or without an
associated appendiceal mucinous adenoma. Cases of PMCA were characterized by peritoneal lesions
composed of more abundant mucinous epithelium with the architectural and cytologic features of
carcinoma (irregular cells, evidence that cells were rapidly dividing, and other criteria), with or
without an associated primary mucinous adenocarcinoma. Bradley et al. (2007) argued that continued
use of non-malignant terms, i.e., adenoma, for those frequent cases with low-grade features (such as
DPAM), is misleading because pseudomyxoma peritonei is a disease state that results from invasion
of the abdominal cavity by cells with uncontrolled growth. Bradley states that an adenoma, by
definition, is a tumor confined to the appendiceal mucosa with absolutely no evidence of invasion
beyond the muscularis mucosae.
• The term mucinous adenocarcinoma is used in different contexts depending on the reference material
used by the pathologist for disease classification. For example, neo-plasms characterized by high-
grade features, invasive glands and or signet ring cells, are termed adenocarcinoma in pathology
literature. However, some pathologists (e.g., Odze and Goldblum, Surgical Pathology of the GI Tract,
Liver, Biliary Tract and Pancreas, 2nd ed.) also use the term mucinous adenocarcinoma when referring
to low-grade, well-differentiated tumors lacking high-grade features. Low-grade mucinous
adenocarcinoma is used by the American Joint Committee on Cancer and World Health Organization
and is nearly or completely synonymous with the DPAM designation. For low-grade mucinous
adenocarcinoma, disease may be designated as “benign” because tumors do not invade deeply into
tissue and rarely metastasize to parenchyma of organs; this designation may be misleading and
204 Surgical Oncology: Theory and Multidisciplinary Practice

confusing to the layperson because pseudomyxoma peritonei is not a harmless condition, fatal if
untreated. High-grade or poorly differentiated mucinous adenocarcinoma has a generally poorer
prognosis, though surgical treatment with heated intra-peritoneal chemotherapy (HIPEC) is yielding
promising outcomes.
Signs and symptoms:
• Signs and symptoms of pseudomyxoma peritonei may include abdominal or pelvic pain and/or bloating,
distension, digestive disorders, weight changes, increased girth, and infertility.
Cause:
• The primary tumor appears to arise from the MUC2 expressing goblet cells and most commonly
from these cells in the appendix. The K-Ras and p53 genes may be involved in the oncogenesis. It
may be diagnosed with a range of conditions. While the majority of these cases are associated with
appendiceal carcinomas, other conditions may also be found, including disseminated peritoneal
adenomucinosis (DPAM), peritoneal carcinomas, several mucinous tumors (mucinous adenocarcinoma,
mucinous cystadenoma, and mucinous cystadenocarcinoma), as well as other disease states. Other
primary sites that have been reported include colon, rectum, stomach, gallbladder, bile ducts, small
intestine, urinary bladder, lung, breast, fallopian tubes, and the pancreas.
Diagnosis:
• This disease is often discovered during surgery for other conditions, e.g., hernia repair, following
which an experienced pathologist can confirm the diagnosis. Advanced stages may present as tumors
palpable on the abdomen or distention of the belly (“jelly belly” is sometimes used as a slang term
for the condition). Due to the rarity of this disease, it is important to obtain an accurate diagnosis so
that appropriate treatment may be obtained from a surgical oncologist who specializes in appendix
cancer. Diagnostic tests may include CT scans, examination of tissue samples obtained through
laparoscopy, and the evaluation of tumor markers. In most cases a colonoscopy is unsuitable as a
diagnostic tool because in most cases appendix cancer invades the abdominal cavity but not the
colon (however, spread inside the colon is occasionally reported). PET scans may be used to evaluate
high-grade mucinous adenocarcinoma, but this test is not reliable for detecting low-grade tumors
because those do not take up the dye which shows up on scans. New MRI procedures are being
developed for disease monitoring, but standard MRIs are not typically used as a diagnostic tool.
Diagnosis is confirmed through pathology.
Treatment:
• Treatment is variable, both due to its rarity and to its frequently slow-growing nature. Treatment
ranges from watchful waiting to debulking and hyperthermic intraperitoneal chemotherapy (HIPEC,
also called intraperitoneal hyperthermic chemotherapy, IPHC) with cytoreductive surgery.
• Surgical: The standard of care for mucinous adenocarcinoma with clinical condition PMP involves
cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), by surgical
oncologists who specialize in treating PMP. Some surgeons also apply early post-operative
intraperitonial chemotherapy (EPIC), adjunct to surgical cytoreduction and HIPEC. In situations where
surgery is not required immediately, patients can be monitored via CT scans, tumor marker laboratory
tests, and physical symptoms, to determine when, and if, surgery is warranted. Although some surgical
procedures may be rather extensive, patients can and do recover from surgery, and the majority of
these patients can and do live productive lives. In debulking, the surgeon attempts to remove as
much tumor as possible. CRS or cytoreductive surgery involves surgical removal of the peritoneum
and any adjacent organs which appear to have tumor seeding. Since the mucus tends to pool at the
bottom of the abdominal cavity, it is common to remove the ovaries, fallopian tubes, uterus, and
parts of the large intestine. Depending upon the spread of the tumor, other organs might be removed,
Gynecology 205

including but not limited to the gallbladder, spleen, and portions of the small intestine and/or stomach.
For organs that cannot be removed safely (like the liver), the surgeon strips off the tumor from the
surface.
• Chemotherapy: Chemotherapy (typically the agent Mitomycin C) may be infused directly into the
abdominal cavity after cytoreductive surgery to kill remaining microscopic cancerous tumors and
free floating cells. The heated chemotherapy (HIPEC) is perfused throughout the abdominal cavity
for an hour or two as the last step in the surgery, or ports are installed to allow circulation and/or
drainage of the chemicals for one to five days after surgery, known as early postoperative
intraperitoneal chemotherapy (EPIC). EPIC may be given in multiple cycles for several months after
surgery. Systemic chemotherapy may be administered as additional or adjuvant treatment. Due to
the increased availability of new chemotherapies developed for colon and colorectal cancer patients,
some patients have experienced stability in tumor growth with systemic chemotherapy. Systemic
chemotherapy is reserved for patients with advanced disease, recurrent disease, or disease that has
spread to the lymph nodes or distant sites. This disease may recur following surgery and chemotherapy.
Periodic post operative CT scans and tumor marker laboratory tests are used to monitor the disease
for any tumor regrowth.

Undifferentiated Epithelial
Undifferentiated cancers - those where the cell type cannot be determined - make up about 10% of epithelial
ovarian cancers and have a comparatively poor prognosis. When examined under the microscope, these tumors
have very abnormal cells that are arranged in clumps or sheets. Usually there are recognizable clumps of serous
cells inside the tumor.

Malignant Brenner Tumor

Brenner tumors are an uncommon subtype of the surface epithelial-stromal tumor group of ovarian neo-plasms.
The majority are benign, but some can be malignant. They are most frequently found incidentally on pelvic
examination or at laparotomy. Brenner tumours very rarely can occur in other locations, including the testes.
• Presentation: On gross pathological examination, they are solid, sharply circumscribed and pale
yellow-tan in colour. 90% are unilateral (arising in one ovary, the other is unaffected). The tumours
can vary in size from less than 1 centimetre (0.39 in) to 30 centimetres (12 in). Borderline and
malignant Brenner tumours are possible but each are rare.
• Diagnosis: Histologically, there are nests of transitional epithelial (urothelial) cells with longitudinal
nuclear grooves (coffee bean nuclei) lying in abundant fibrous stroma.
• Similar conditions: Transitional cell carcinoma is an even rarer entity, in which neo-plastic transitional
epithelial cells similar to transitional cell carcinoma of the bladder are seen in the ovary, without the
characteristic stromal/epithelial pattern of a Brenner tumour.
• Eponym: It is named for Fritz Brenner (1877–1969), a German surgeon who characterized it in
1907. The term “Brenner tumor” was first used by Robert Meyer, in 1932.

Transitional Cell Carcinoma

Transitional cell carcinoma (TCC) also urothelial carcinoma (UCC), is a type of cancer that typically occurs
in the urinary system. It is the most common type of bladder cancer and cancer of the ureter, urethra, and
urachus. It is the second most common type of kidney cancer, but accounts for only five to 10 percent of all
primary renal malignant tumors. TCC arises from the transitional epithelium, a tissue lining the inner surface of
these hollow organs. When the term “urothelial” is used, it specifically refers to a carcinoma of the urothelium,
meaning a TCC of the urinary system.
206 Surgical Oncology: Theory and Multidisciplinary Practice

Signs and symptoms:

• Signs and symptoms of TCC are entirely dependent on the location and extent of the cancer.
Causes:
• Urothelial carcinoma is a prototypical example of a malignancy arising from environmental
carcinogenic influences. By far the most important cause is cigarette smoking, which contributes to
approximately one-half of the disease burden. Chemical exposure, such as those sustained by workers
in the petroleum industry, the manufacture of paints and pigments (e.g., aniline dyes), and
agrochemicals are known to predispose one to urothelial cancer. Interestingly, risk is lowered by
increased liquid consumption, presumably as a consequence of increased urine production and thus
less dwell time on the urothelial surface. Conversely, risk is increased among long-haul truck drivers
and others in whom long urine dwell-times are encountered. As with most epithelial cancers, physical
irritation has been associated with increased risk of malignant transformation of the urothelium.
Thus, urothelial carcinomas are more common in the context of chronic urinary stone disease, chronic
catheterization (as in patients with paraplegia or multiple sclerosis), and chronic infections.
Some particular examples are listed below:
a. Certain drugs, such as cyclophosphamide, via the metabolites acrolein and phenacetin, are known
to predispose to TCC (the latter especially with respect to the upper urinary tract).
b. Radiation exposure
c. Somatic mutation, such as deletion of chromosome 9q, 9p, 11p, 17p, 13q, 14q and overexpression
of RAS (oncogene) and epidermal growth factor receptor (EGFR).
Pathology:
• TCCs are often multifocal, with 30–40% of patients having more than one tumor at diagnosis. The
pattern of growth of TCCs can be papillary, sessile, or carcinoma-in-situ (CIS). The most common
site of TCC metastasis outside the pelvis is bone(35%); of these bone metastases, 40 percent are in
the spine.
Diagnosis:
• Transitional refers to the histological subtype of the cancerous cells as seen under a microscope.
• Classification: The 1973 WHO grading system for TCCs (papilloma, G1, G2 or G3) is most commonly
used despite being superseded by the 2004 WHO grading (papillary neo-plasm of low malignant
potential [PNLMP], low grade, and high grade papillary carcinoma).
Treatment:
• Localized/early TCC of bladder:
a. Transitional cell carcinoma (TCC) can be very difficult to treat. Treatment for localized stage
TCC is surgical resection of the tumor, but recurrence is common. Some patients are given
mitomycin into the bladder either as a one-off dose in the immediate post-operative period (within
24 hrs) or a few weeks after the surgery as a six dose regimen.
b. Localized/early TCC can also be treated with infusions of BCG into the bladder. These are
given weekly for either 6 weeks (induction course) or 3 weeks (maintenance/booster dose). Side
effects include a small chance of developing systemic tuberculosis or the patient becoming
sensitized to the BCG causing severe intolerance and a possible reduction in bladder volume
due to scarring.
c. In patients with evidence of early muscular invasion, radical curative surgery in the form of a
cysto-prostatectomy usually with lymph node sampling can also be performed. In such patients,
a bowel loop is often used to create either a “neo-bladder” or an “ileal conduit” which act as a
place for the storage of urine before it is evacuated from the body either via the urethra or a
urostomy respectively.
Gynecology 207

• Advanced or metastatic TCC:

a. First-line chemotherapy regimens for advanced or metastatic TCC consists of gemcitabine and
cisplatin) (GC) or a combination of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC).
b. Taxanes or vinflunine have been used as second-line therapy (after progression on a platinum
containing chemotherapy).
c. Immunotherapy such as pembrolizumab is often used as second-line therapy for metastatic
urothelial carcinoma that has progressed despite treatment with GC or MVAC.
d. In May 2016 FDA granted accelerated approval to atezolizumab for locally advanced or metastatic
urothelial carcinoma treatment after failure of cisplatin-based chemotherapy. The confirmatory
trial (to convert the accelerated approval into a full approval) failed to achieve its primary endpoint
of overall survival.
Prostate:
• TCC can also be associated with the prostate.

Sex Cord-stromal Tumor

Sex cord–gonadal stromal tumour (or sex cord–stromal tumour) is a group of tumors derived from the stromal
component of the ovary and testis, which comprises the granulosa, thecal cells and fibrocytes. In contrast, the epithelial
cells originate from the outer epithelial lining surrounding the gonad while the germ cell tumors arise from the
precursor cells of the gametes, hence the name germ cell. In humans, this group accounts for 8% of ovarian cancers
and under 5% of testicular cancers. Their diagnosis is histological: only a biopsy of the tumour can make an exact
diagnosis. They are often suspected of being malignant prior to operation, being solid ovarian tumours that tend to
occur most commonly in post menopausal women. This group of tumours is significantly less common than testicular
germ cell tumours in men, and slightly less common than ovarian germ cell tumours in women.

Types
These tumours are of the following types, characterized by their abnormal production of otherwise apparently
normal cells or tissues.
Classification of sex cord–gonadal stromal tumours by their histology
Cell/tissue normal location
Ovary (female) Testicle (male) Mixed
Cell/tissue type Sex cord Granulosa cell tumour Sertoli cell tumour Gynandroblastoma
Gonadal stroma Thecoma, Fibroma Leydig cell tumour Gynandroblastoma
Mixed Sertoli-Leydig cell tumour Gynandroblastoma
Although each of the cell and tissue types normally occurs in just one sex (male or female), within a tumour
they can occur in the opposite sex. Consequently, depending on the specific histology produced, these tumours
can cause virilization in women and feminization in men.
Tumour types in order of prevalence:
• Women in the 50-55yo age group with post menopausal vaginal bleeding. Uncommonly, a similar
but possibly distinct tumour, juvenile granulosa cell tumour, presents in pre-pubertal girls with
precocious puberty. In both groups, the vaginal bleeding is due to oestrogen secreted by the tumour.
In older women, treatment is total abdominal hysterectomy and removal of both ovaries. In young
girls, fertility sparing treatment is the mainstay for non-metastatic disease.
• Sertoli cell tumour. This tumour produces Sertoli cells, which normally are found in the testicle.
This tumour occurs in both men and women.
• Thecoma. This tumour produces theca of follicle, a tissue normally found in the ovarian follicle.
The tumour is almost exclusively benign and unilateral. It typically secretes estrogen, and as a result
women with this tumour often present with postmenopausal bleeding.
208 Surgical Oncology: Theory and Multidisciplinary Practice

• Leydig cell tumour. This tumour produces Leydig cells, which normally are found in the testicle and
tend to secrete androgens.
• Sertoli-Leydig cell tumour. This tumour produces both Sertoli and Leydig cells. Although both cell
types normally occur in the testicle, this tumour can occur in the ovary.
• Gynandroblastoma. A very rare tumour producing both ovarian (granulosa and/or theca) and testicular
(Sertoli and/or Leydig) cells or tissues. Typically it consists of adult-type granulosa cells and Sertoli
cells, but it has been reported with juvenile-type granulosa cells. It has been reported to occur in the
ovary usually, rarely in the testis. Due to its rarity, the malignant potential of this tumour is unclear;
there is one case report of late metastasis.
• Sex cord tumour with annular tubules, abbreviated SCTAT. These are rare tumours that may be
sporadic or associated with Peutz-Jeghers syndrome.

Diagnosis
Definitive diagnosis of these tumours is based on the histology of tissue obtained in a biopsy or surgical
resection. In a retrospective study of 72 cases in children and adolescents, the histology was important to
prognosis. A number of molecules have been proposed as markers for this group of tumours. CD56 may be
useful for distinguishing sex cord–stromal tumours from some other types of tumours, although it does not
distinguish them from neuroendocrine tumours. Calretinin has also been suggested as a marker. For diagnosis
of granulosa cell tumour, inhibin is under investigation. On magnetic resonance imaging, a fibroma may
produce one of several imaging features that might be used in the future to identify this rare tumour prior to
surgery.

Prognosis
A retrospective study of 83 women with sex cord–stromal tumours (73 with granulosa cell tumour and 10
with Sertoli-Leydig cell tumour), all diagnosed between 1975 and 2003, reported that survival was higher
with age under 50, smaller tumour size, and absence of residual disease. The study found no effect of
chemotherapy. A retrospective study of 67 children and adolescents reported some benefit of cisplatin-based
chemotherapy.

Research
A prospective study of ovarian sex cord–stromal tumours in children and adolescents began enrolling
participants in 2005.

Germ Cell Tumor

A germ cell tumor (GCT) is a neo-plasm derived from germ cells. Germ cell tumors can be cancerous or
non-cancerous tumors. Germ cells normally occur inside the gonads (ovary and testis). Germ cell tumors
that originate outside the gonads may be birth defects resulting from errors during development of the
embryo.

Cause
Some investigators suggest that this distribution arises as a consequence of abnormal migration of germ cells
during embryogenesis. Others hypothesize a widespread distribution of germ cells to multiple sites during normal
embryogenesis, with these cells conveying genetic information or providing regulatory functions at somatic sites.
Extragonadal germ cell tumors were thought initially to be isolated metastases from an undetected primary tumor
in a gonad, but it is now known that many germ cell tumors are congenital and originate outside the gonads. The
Gynecology 209

most notable of these is sacrococcygeal teratoma, the single most common tumor diagnosed in babies at birth. Of
all anterior mediastinal tumors, 15–20% are germ cell tumors of which approximately 50% are benign teratomas.
Ovarian teratomas may be associated with anti-NMDA receptor encephalitis.

Classification
Germ cell tumors are classified by their histology, regardless of location in the body.
Germ cell tumors are broadly divided in two classes:
• The germinomatous or seminomatous germ cell tumors (GGCT, SGCT) include only germinoma
and its synonyms dysgerminoma and seminoma.
• The nongerminomatous or non-seminomatous germ cell tumors (NGGCT, NSGCT) include all other
germ cell tumors, pure and mixed.
The two classes reflect an important clinical difference. Compared to germinomatous tumors, non-
germinomatous tumors tend to grow faster, have an earlier mean age at time of diagnosis (~25 years versus ~35
years, in the case of testicular cancers), and have a lower 5 year survival rate. The survival rate for germinomatous
tumors is higher in part because these tumors are very sensitive to radiation, and they also respond well to
chemotherapy. The prognosis for non-germinomatous tumours has improved dramatically, however, due to the
use of platinum-based chemotherapy regimens.

Germinomatous
Tumor ICD-O Peak Age Benign or Histology Tumor marker
(yr) malignant
Germinoma (including 40–50 Malignant Sheets of uniform 10% have elevated
dysgerminoma and polygonal cells with hCG
seminoma) cleared cytoplasm;
ymphocytes in the
stroma
Dysgerminoma M9060/3
Seminoma M9061/3 Placental alkaline
phosphate (PLAP)

Non-germinomatous
Tumor ICD-O Peak Age (yr) Benign or malignant Histology Tumor marker
Embryonal carcinoma 9070/3 20–30 Malignant Poorly differentiated, secrete hCG,
pleomorphic cells in AFP
cords, sheets, or
papillary formation
Endodermal sinus 9071/3 3 Malignant Poorly differentiated 100% secrete
tumor, also known endothelium-like, AFP
as yolk sac tumor cuboidal, or columnar
(EST, YST) cells
Choriocarcinoma 9100/3 20–30 Malignant Cytotrophoblast and 100% secrete
syncytiotrophoblast hCG
without villus
formation
Teratoma including 9080/0- 0–3, 15–30 Mature teratoma, Very variable, but Pure tumors do
mature teratoma, 9080/3 dermoid cyst usually “normal” tissues are not secrete
dermoid cyst, benign (but follow-up common hCG, AFP
immature teratoma, required); others
teratoma with usually malignant
malignant
transformation
Polyembryoma 9072/3 15–25 ? ? ?
Gonadoblastoma 9073/1 ? ? ? ?
210 Surgical Oncology: Theory and Multidisciplinary Practice

Mixed
Tumor ICD-O Peak Age (yr) Benign or malignant Histology Tumor marker
Mixed 15–30 Malignant Depends on elements present Depends on
elements present
Mixed germ cell tumors occur in many forms. Among these, a common form is teratoma with endodermal
sinus tumor. Teratocarcinoma refers to a germ cell tumor that is a mixture of teratoma with embryonal carcinoma,
or with choriocarcinoma, or with both. This kind of mixed germ cell tumor may be known simply as a teratoma
with elements of embryonal carcinoma or choriocarcinoma, or simply by ignoring the teratoma component and
referring only to its malignant component: embryonal carcinoma and/or choriocarcinoma. They can present in
the anterior mediastinum.

Location
Despite their name, germ cell tumors occur both within and outside the ovary and testis.
• Head
a. Inside the cranium — pineal and suprasellar locations are most commonly reported
b. Inside the mouth — a fairly common location for teratoma
• Neck
• Mediastinum — account for 1% to 5% of all germ cell neo-plasms
Main article: mediastinal germ cell tumor
• Pelvis, particularly sacrococcygeal teratoma
• Ovary
Main article: Ovarian cancer
• Testis
Main article: Testicular cancer.
In females, germ cell tumors account for 30% of ovarian tumors, but only 1 to 3% of ovarian cancers in
North America. In younger women germ cell tumors are more common, thus in patients under the age of 21,
60% of ovarian tumors are of the germ cell type, and up to one-third are malignant. In males, germ cell tumors
of the testis occur typically after puberty and are malignant (testicular cancer). In neonates, infants, and children
younger than 4 years, the majority of germ cell tumors are sacrococcygeal teratomas. Males with Klinefelter
syndrome have a 50 times greater risk of germ cell tumors (GSTs). In these persons, GSTs usually contain non-
seminomatous elements, present at an earlier age, and seldom are gonadal in location.

Treatment
Women with benign germ cell tumors such as mature teratomas (dermoid cysts) are cured by ovarian
cystectomy or oophorectomy. In general, all patients with malignant germ cell tumors will have the same
staging surgery that is done for epithelial ovarian cancer. If the patient is in her reproductive years, an alternative
is unilateral salpingoophorectomy, while the uterus, the ovary, and the fallopian tube on the opposite side can
be left behind. This isn’t an option when the cancer is in both ovaries. If the patient has finished having children,
the surgery involves complete staging including salpingoophorectomy on both sides as well as hysterectomy.
Most patients with germ cell cancer will need to be treated with combination chemotherapy for at least 3 cycles.
The chemotherapy regimen most commonly used in germ cell tumors is called PEB (or BEP), and consists of
bleomycin, etoposide, a platinum-based antineoplastic (cisplatin).

Prognosis
The 1997 International Germ Cell Consensus Classification is a tool for estimating the risk of relapse after
treatment of malignant germ cell tumor. A small study of ovarian tumors in girls reports a correlation between
Gynecology 211

cystic and benign tumors and, conversely, solid and malignant tumors. Because the cystic extent of a tumor can
be estimated by ultrasound, MRI, or CT scan before surgery, this permits selection of the most appropriate
surgical plan to minimize risk of spillage of a malignant tumor. Access to appropriate treatment has a large
effect on outcome. A 1993 study of outcomes in Scotland found that for 454 men with non-seminomatous (non-
germinomatous) germ cell tumors diagnosed between 1975 and 1989, 5-year survival increased over time and
with earlier diagnosis. Adjusting for these and other factors, survival was 60% higher for men treated in a
cancer unit that treated the majority of these men, even though the unit treated more men with the worst
prognosis. Choriocarcinoma of the testicles has the worst prognosis of all germ cell cancers.

Dysgerminoma
A dysgerminoma is a type of germ cell tumor; it usually is malignant and usually occurs in the ovary. A
tumor of the identical histology but not occurring in the ovary may be described by an alternate name: seminoma
in the testis or germinoma in the central nervous system or other parts of the body. Dysgerminoma accounts for
less than 1% of ovarian tumors overall. Dysgerminoma usually occurs in adolescence and early adult life; about
5% occur in pre-pubertal children. Dysgerminoma is extremely rare after age 50. Dysgerminoma occurs in both
ovaries in 10% of patients and, in a further 10%, there is microscopic tumor in the other ovary. Abnormal
gonads (due to gonadal dysgenesis and androgen insensitivity syndrome) have a high risk of developing a
dysgerminoma. Most dysgerminomas are associated with elevated serum lactic dehydrogenase (LDH), which
is sometimes used as a tumor marker.
Presentation:
• They are exceptionally associated with hypercalcemia. On gross examination, dysgerminomas present
with a smooth, bosselated (knobby) external surface, and is soft, fleshy and either cream-coloured,
gray, pink or tan when cut. Microscopic examination typically reveals uniform cells that resemble
primordial germ cells. Typically, the stroma contains lymphocytes and about 20% of patients have
sarcoid-like granulomas.
• Metastases are most often present in the lymph nodes.
Treatment:
• Dysgerminomas, like other seminomatous germ cell tumors, are very sensitive to both chemotherapy
and radiotherapy. For this reason, with treatment patients’ chances of long-term survival, even cure,
is excellent.

Choriocarcinoma
Choriocarcinoma is a malignant, trophoblastic cancer, usually of the placenta. It is characterized by “early
hematogenous spread” to the lungs. It belongs to the malignant end of the spectrum in gestational trophoblastic
disease (GTD). It is also classified as a germ cell tumor and may arise in the testis or ovary.
Signs and symptoms:
• Increased quantitative chorionic gonadotropin (the “pregnancy hormone”) levels
• Vaginal bleeding
• Shortness of breath
• Hemoptysis (coughing up blood)
• Chest pain
• Chest X-ray shows multiple infiltrates of various shapes in both lungs
• Presents in males as a testicular cancer, sometimes with skin hyperpigmentation (from excess chorionic
gonadotropin cross reacting with the alpha MSH receptor), gynecomastia, and weight loss (from excess
chorionic gonadotropin cross reacting with the LH, FSH, and TSH receptor) in males
• Can present with decreased thyroid-stimulating hormone (TSH) due to hyperthyroidism.
212 Surgical Oncology: Theory and Multidisciplinary Practice

Cause:
• Hydatidiform mole (50% of cases)
• Spontaneous abortion (20% of cases)
• Ectopic pregnancy (2% of cases)
• Normal term pregnancy (20–30% of cases)
• Hyperemesis gravidarum
• Rarely, choriocarcinoma occurs in primary locations other than the placenta; very rarely, it occurs in
testicles. Although trophoblastic components are common components of mixed germ cell tumors,
pure choriocarcinoma of the adult testis is rare. Pure choriocarcinoma of the testis represents the
most aggressive pathologic variant of germ cell tumors in adults, characteristically with early
hematogenous and lymphatic metastatic spread. Because of early spread and inherent resistance to
anticancer drugs, patients have poor prognosis. Elements of choriocarcinoma in a mixed testicular
tumor have no prognostic importance.
• Choriocarcinomas can also occur in the ovaries.
Pathology:
• Characteristic feature is the identification of intimately related syncytiotrophoblasts and
cytotrophoblasts without formation of definite placental type villi. Since choriocarcinomas include
syncytiotrophoblasts (beta-HCG producing cells), they cause elevated blood levels of beta-human
chorionic gonadotropin.
• Syncytiotrophoblasts are large multi-nucleated cells with eosinophilic cytoplasm. They often surround
the cytotrophoblasts, reminiscent of their normal anatomical relationship in chorionic villi.
Cytotrophoblasts are polyhedral, mononuclear cells with hyperchromatic nuclei and a clear or pale
cytoplasm. Extensive hemorrhage is a common finding.
Treatment:
• Since gestational choriocarcinoma (which arises from a hydatidiform mole) contains paternal DNA
(and thus paternal antigens), it is exquisitely sensitive to chemotherapy. The cure rate, even for
metastatic gestational choriocarcinoma, is around 90–95%.
• At present, treatment with single-agent methotrexate is recommended for low-risk disease, while intense
combination regimens including EMACO (etoposide, methotrexate, actinomycin D, cyclosphosphamide
and vincristine (Oncovin) are recommended for intermediate or high-risk disease.
• Hysterectomy (surgical removal of the uterus) can also be offered to patients > 40 years of age or
those for whom sterilisation is not an obstacle. It may be required for those with severe infection
and uncontrolled bleeding.
• Choriocarcinoma arising in the testicle is rare, malignant and highly resistant to chemotherapy. The
same is true of choriocarcinoma arising in the ovary. Testicular choriocarcinoma has the worst
prognosis of all germ-cell cancers.

Immature (Solid) Teratoma

Immature, or solid, teratomas are the most common type of ovarian germ cell tumor, making up 40–50% of
cases. Teratomas are characterized by the presence of disorganized tissues arising from all three embryonic
germ layers: ectoderm, mesoderm, and endoderm; immature teratomas also have undifferentiated stem cells
that make them more malignant than mature teratomas (dermoid cysts). The different tissues are visible on
gross pathology and often include bone, cartilage, hair, mucus, or sebum, but these tissues are not visible from
the outside, which appears to be a solid mass with lobes and cysts. Histologically, they have large amounts of
neuroectoderm organized into sheets and tubules along with glia; the amount of neural tissue determines the
histologic grade.
Gynecology 213

Immature teratomas usually only affect one ovary (10% co-occur with dermoid cysts) and usually metastasize
throughout the peritoneum. They can also cause mature teratoma implants to grow throughout the abdomen in
a disease called growing teratoma syndrome; these are usually benign but will continue to grow during
chemotherapy, and often necessitate further surgery. Unlike mature teratomas, immature teratomas form many
adhesions, making them less likely to cause ovarian torsion. There is no specific marker for immature teratomas,
but carcinoembryonic antigen (CEA), CA-125, CA19-9, or AFP can sometimes indicate an immature teratoma.
Stage I teratomas make up the majority (75%) of cases and have the best prognosis, with 98% of patients
surviving 5 years; if a Stage I tumor is also grade 1, it can be treated with unilateral surgery only. Stage II though
IV tumors make up the remaining quarter of cases and have a worse prognosis, with 73–88% of patients surviving
5 years.

Mature Teratoma (Dermoid Cyst)

Mature teratomas, or dermoid cysts, are rare tumors consisting of mostly benign tissue that develop after
menopause. The tumors consist of disorganized tissue with nodules of malignant tissue, which can be of various
types. The most common malignancy is squamous cell carcinoma, but adenocarcinoma, basal-cell carcinoma,
carcinoid tumor, neuroectodermal tumor, malignant melanoma, sarcoma, sebaceous tumor, and struma ovarii
can also be part of the dermoid cyst. They are treated with surgery and adjuvant platinum chemotherapy or
radiation.

Yolk Sac Tumor/Endodermal Sinus Tumor

Yolk sac tumors, formerly called endodermal sinus tumors, make up approximately 10–20% of ovarian germ
cell malignancies, and have the worst prognosis of all ovarian germ cell tumors. They occur both before menarche
(in one-third of cases) and after menarche (the remaining two-thirds of cases). Half of people with yolk sac
tumors are diagnosed in stage I. Typically, they are unilateral until metastasis, which occurs within the peritoneal
cavity and via the bloodstream to the lungs. Yolk sac tumors grow quickly and recur easily, and are not easily
treatable once they have recurred. Stage I yolk sac tumors are highly treatable, with a 5-year disease free
survival rate of 93%, but stage II-IV tumors are less treatable, with survival rates of 64–91%. Their gross
appearance is solid, friable, and yellow, with necrotic and hemorrhagic areas. They also often contain cysts that
can degenerate or rupture. Histologically, yolk sac tumors are characterized by the presence of Schiller-Duval
bodies (which are pathognomonic for yolk sac tumors) and a reticular pattern. Yolk sac tumors commonly
secrete alpha-fetoprotein and can be immunohistochemically stained for its presence; the level of alpha-fetoprotein
in the blood is a useful marker of recurrence.

Embryonal Carcinoma
Embryonal carcinomas, a rare tumor type usually found in mixed tumors, develop directly from germ
cells but are not terminally differentiated; in rare cases they may develop in dysgenetic gonads. They
can develop further into a variety of other neo-plasms, including choriocarcinoma, yolk sac tumor, and
teratoma. They occur in younger people, with an average age at diagnosis of 14, and secrete both alpha-
fetoprotein (in 75% of cases) and hCG. Histologically, embryonal carcinoma appears similar to the
embryonic disc, made up of epithelial, anaplastic cells in disorganized sheets, with gland-like spaces
and papillary structures.

Polyembryoma
Polyembryomas, the most immature form of teratoma and very rare ovarian tumors, are histologically
characterized by having several embryo-like bodies with structures resembling a germ disk, yolk sac, and
amniotic sac. Syncytiotrophoblast giant cells also occur in polyembryomas.
214 Surgical Oncology: Theory and Multidisciplinary Practice

Squamous Cell Carcinoma

Primary ovarian squamous cell carcinomas are rare and have a poor prognosis when advanced. More typically,
ovarian squamous cell carcinomas are cervical metastases, areas of differentiation in an endometrioid tumor, or
derived from a mature teratoma.

Mixed Tumors
Mixed tumors contain elements of more than one of the above classes of tumor histology. To be classed as a
mixed tumor, the minor type must make up more than 10% of the tumor. Though mixed carcinomas can have
any combination of cell types, mixed ovarian cancers are typically serous/endometrioid or clear cell/endometrioid.
Mixed germ cell tumors make up approximately 25–30% of all germ cell ovarian cancers, with combinations of
dysgerminoma, yolk sac tumor, and/or immature teratoma. The prognosis and treatment vary based on the
component cell types.

Secondary Ovarian Cancer

Ovarian cancer can also be a secondary cancer, the result of metastasis from a primary cancer elsewhere
in the body. About 7% of ovarian cancers are due to metastases, while the rest are primary cancers.
Common primary cancers are breast cancer, colon cancer, appendiceal cancer, and stomach cancer
(primary gastric cancers that metastasize to the ovary are called Krukenberg tumors). Krukenberg tumors
have signet ring cells and mucinous cells. Endometrial cancer and lymphomas can also metastasize to
the ovary.

Low Malignant Potential Tumors

Low malignant potential ovarian tumors, also called borderline tumors, have some benign and some malignant
features. LMP tumors make up approximately 10%-15% of all ovarian tumors. They develop earlier than epithelial
ovarian cancer, around the age of 40–49. They typically do not have extensive invasion; 10% of LMP tumors
have areas of stromal microinvasion (<3mm, <5% of tumor). LMP tumors have other abnormal features, including
increased mitosis, changes in cell size or nucleus size, abnormal nuclei, cell stratification, and small projections
on cells (papillary projections). Serous and/or mucinous characteristics can be seen on histological
examination, and serous histology makes up the overwhelming majority of advanced LMP tumors. More
than 80% of LMP tumors are Stage I; 15% are stage II and III and less than 5% are stage IV. Implants of
LMP tumors are often non-invasive.

Staging
Ovarian cancer is staged using the FIGO staging system and uses information obtained after surgery, which
can include a total abdominal hysterectomy via midline laparotomy, removal of (usually) both ovaries and
Fallopian tubes, (usually) the omentum, pelvic (peritoneal) washings, assessment of retroperitoneal lymph
nodes (including the pelvic and para-aortic lymph nodes), appendectomy in suspected mucinous tumors, and
pelvic/peritoneal biopsies for cytopathology. Around 30% of ovarian cancers that appear confined to the ovary
have metastasized microscopically, which is why even stage-I cancers must be staged completely. 22% of
cancers presumed to be stage I are observed to have lymphatic metastases. The AJCC stage is the same as the
FIGO stage. The AJCC staging system describes the extent of the primary tumor (T), the absence or presence of
metastasis to nearby lymph nodes (N), and the absence or presence of distant metastasis (M). The most common
stage at diagnosis is stage IIIc, with over 70% of diagnoses.
Gynecology 215

FIGO
FIGO stages of ovarian cancer
Stage Description
I Cancer is completely limited to the ovary
IA involves one ovary, capsule intact, no tumor on ovarian surface, negative
washings
IB involves both ovaries; capsule intact; no tumor on ovarian surface; negative
washings
IC tumor involves one or both ovaries
IC1 surgical spill
IC2 capsule has ruptured or tumor on ovarian surface
IC3 positive ascites or washings
II pelvic extension of the tumor (must be confined to the pelvis) or primary
peritoneal tumor, involves one or both ovaries
IIA tumor found on uterus or fallopian tubes
IIB tumor elsewhere in the pelvis
III cancer found outside the pelvis or in the retroperitoneal lymph nodes,
involves one or both ovaries
IIIA metastasis in retroperitoneal lymph nodes or microscopic extrapelvic
metastasis
IIIA1 metastasis in retroperitoneal lymph nodes
IIIA1(i) the metastasis is less than 10 mm in diameter
IIIA1(ii) the metastasis is greater than 10 mm in diameter
IIIA2 microscopic metastasis in the peritoneum, regardless of retroperitoneal lymph
node status
IIIB metastasis in the peritoneum less than or equal to 2 cm in diameter,
regardless of retroperitoneal lymph node status; or metastasis to liver or
spleen capsule
IIIC metastasis in the peritoneum greater than 2 cm in diameter, regardless of
retroperitoneal lymph node status; or metastasis to liver or spleen capsule
IV distant metastasis (i.e. outside of the peritoneum)
IVA pleural effusion containing cancer cells
IVB metastasis to distant organs (including the parenchyma of the spleen or liver),
or metastasis to the inguinal and extra-abdominal lymph nodes

AJCC/TNM
The AJCC/TNM staging system indicates where the tumor has developed, spread to lymph nodes, and
metastasis.
AJCC/TNM stages of ovarian cancer
Stage Description
T Primary tumor
Tx Cannot be assessed
T0 No evidence
T1 Tumor limited to ovary/ovaries
T1a One ovary with intact capsule, no surface tumor, and negative ascites/peritoneal
washings
T1b Both ovaries with intact capsules, no surface tumor, and negative ascites/peritoneal
washings
T1c One or both ovaries with ruptured capsule or capsules, surface tumor, positive ascites
peritoneal washings
T2 Tumor is in ovaries and pelvis (extension or implantation)
T2a Expansion to uterus or Fallopian tubes, negative ascites/peritoneal washings
T2b Expansion in other pelvic tissues, negative ascites/peritoneal washings
T2c Expansion to any pelvic tissue, positive ascites/peritoneal washings
T3 Tumor is in ovaries and has metastasized outside the pelvis to the peritoneum (including
the liver capsule)
T3a Microscopic metastasis
216 Surgical Oncology: Theory and Multidisciplinary Practice

T3b Macroscopic metastasis less than 2 cm diameter

T3c Macroscopic metastasis greater than 2 cm diameter
N Regional lymph node metastasis
Nx Cannot be assessed
N0 No metastasis
N1 Metastasis present
M Distant metastasis
M0 No metastasis
M1 Metastasis present (excluding liver capsule, including liver parenchyma and cytologically
confirmed pleural effusion)
The AJCC/TNM stages can be correlated with the FIGO stages:
FIGO T N M
I T1 N0 M0
IA T1a N0 M0
IB T1b N0 M0
IC T1c N0 M0
II T2 N0 M0
IIA T2a N0 M0
IIB T2b N0 M0
IIC T2c N0 M0
III T3 N0 M0
IIIA T3a N0 M0
IIIB T3b N0 M0
IIIC T3c N0/N1 M0
IV Any Any M1

Grading
Grade 1 tumors have well differentiated cells (look very similar to the normal tissue) and are the ones with
the best prognosis. Grade 2 tumors are also called moderately well-differentiated and they are made up of cells
that resemble the normal tissue. Grade 3 tumors have the worst prognosis and their cells are abnormal, referred
to as poorly differentiated. Metastasis in ovarian cancer is very common in the abdomen, and occurs via
exfoliation, where cancer cells burst through the ovarian capsule and are able to move freely throughout the
peritoneal cavity. Ovarian cancer metastases usually grow on the surface of organs rather than the inside; they
are also common on the omentum and the peritoneal lining. Cancer cells can also travel through the lymphatic
system and metastasize to lymph nodes connected to the ovaries via blood vessels; i.e. the lymph nodes along
the infundibulopelvic ligament, the broad ligament, and the round ligament. The most commonly affected
groups include the paraaortic, hypogastric, external iliac, obturator, and inguinal lymph nodes. Usually, ovarian
cancer does not metastasize to the liver, lung, brain, or kidneys unless it is recurrent disease; this differentiates
ovarian cancer from many other forms of cancer.

SCREENING
There is no simple and reliable way to test for ovarian cancer in women who do not have any signs or
symptoms. Screening is not recommended in women who are at average risk, as evidence does not support a
reduction in death and the high rate of false positive tests may lead to unneeded surgery, which is accompanied
by its own risks. The Pap test does not screen for ovarian cancer. Ovarian cancer is usually only palpable in
advanced stages. Screening is not recommended using CA-125 measurements, HE4 levels, ultrasound, or adnexal
palpation in women who are at average risk. Risk of developing ovarian cancer in those with genetic factors can
be reduced. Those with a genetic predisposition may benefit from screening. This high risk group has benefited
with earlier detection. Ovarian cancer has low prevalence, even in the high-risk group of women from the ages
of 50 to 60 (about one in 2000), and screening of women with average risk is more likely to give ambiguous
Gynecology 217

results than detect a problem which requires treatment. Because ambiguous results are more likely than detection
of a treatable problem, and because the usual response to ambiguous results is invasive interventions, in women
of average risk, the potential harms of having screening without an indication outweigh the potential benefits.
The purpose of screening is to diagnose ovarian cancer at an early stage, when it is more likely to be treated
successfully. Screening with transvaginal ultrasound, pelvic examination, and CA-125 levels can be used instead
of preventive surgery in women who have BRCA1 or BRCA2 mutations. This strategy has shown some success.

PREVENTION
People with strong genetic risk for ovarian cancer may consider the surgical removal of their ovaries as a
preventive measure. This is often done after completion of childbearing years. This reduces the chances of
developing both breast cancer (by around 50%) and ovarian cancer (by about 96%) in people at high risk.
Women with BRCA gene mutations usually also have their Fallopian tubes removed at the same time (salpingo-
oophorectomy), since they also have an increased risk of Fallopian tube cancer. However, these statistics may
overestimate the risk reduction because of how they have been studied. People with a significant family history
for ovarian cancer are often referred to a genetic counselor to see if they if testing for BRCA mutations would
be beneficial. The use of oral contraceptives, the absence of ‘periods’ during the menstrual cycle, and tubal
ligation reduce the risk. There may an association of developing ovarian cancer and ovarian stimulation during
infertility treatments. Endometriosis has been linked to ovarian cancers. Human papillomavirus infection,
smoking, and talc have not been identified as increasing the risk for developing ovarian cancer.

MANAGEMENT
Once it is determined that ovarian, fallopian tube, or primary peritoneal cancer is present, treatment is
scheduled by a gynecologic oncologist (a physician trained to treat cancers of a woman’s reproductive system).
Gynecologic oncologists can perform surgery on and give chemotherapy to women with ovarian cancer. A
treatment plan is developed. Treatment usually involves surgery and chemotherapy, and sometimes radiotherapy,
regardless of the subtype of ovarian cancer. Surgical treatment may be sufficient for well-differentiated malignant
tumors and confined to the ovary. Addition of chemotherapy may be required for more aggressive tumors
confined to the ovary. For patients with advanced disease, a combination of surgical reduction with a combination
chemotherapy regimen is standard. Borderline tumors, even following spread outside of the ovary, are managed
well with surgery, and chemotherapy is not seen as useful. Second-look surgery and maintenance chemotherapy
have not been shown to provide benefit.

Surgery
Surgery has been the standard of care for decades and may be necessary in obtaining a specimen for diagnosis.
The surgery depends upon the extent of nearby invasion of other tissues by the cancer when it is diagnosed.
This extent of the cancer is described by assigning it a stage, the presumed type, and the grade of cancer. The
gynecological surgeon may remove one (unilateral oophorectomy) or both ovaries (bilateral oophorectomy).
The Fallopian tubes (salpingectomy), uterus (hysterectomy), and the omentum (omentectomy) may also be
removed. Typically, all of these organs are removed. For low-grade, unilateral stage-IA cancers, only the involved
ovary (which must be unruptured) and Fallopian tube will be removed. This can be done especially in young
people who wish to preserve their fertility. However, a risk of microscopic metastases exists and staging must
be completed. If any metastases are found, a second surgery to remove the remaining ovary and uterus is
needed. Tranexamic acid can be administered prior to surgery to reduce the need for blood transfusions due to
blood loss during the surgery. If a tumor in a premenopausal woman is determined to be a low malignant
218 Surgical Oncology: Theory and Multidisciplinary Practice

potential tumor during surgery, and it is clearly stage I cancer, only the affected ovary is removed. For
postmenopausal women with low malignant potential tumors, hysterectomy with bilateral salpingo-oophorectomy
is still the preferred option. During staging, the appendix can be examined or removed. This is particularly
important with mucinous tumors. In children or adolescents with ovarian cancer, surgeons typically attempt to
preserve one ovary to allow for the completion of puberty, but if the cancer has spread, this is not always
possible. Dysgerminomas in particular tend to affect both ovaries: 8–15% of dysgerminomas are present in
both ovaries.
People with low-grade (well-differentiated) tumors are typically treated only with surgery, which is often
curative. In general, germ cell tumors can be treated with unilateral surgery unless the cancer is widespread or
fertility is not a factor. In advanced cancers, where complete removal is not an option, as much tumor as
possible is removed in a procedure called debulking surgery. This surgery is not always successful, and is less
likely to be successful in women with extensive metastases in the peritoneum, stage- IV disease, cancer in the
transverse fissure of the liver, mesentery, or diaphragm, and large areas of ascites. Debulking surgery is usually
only done once. More complete debulking is associated with better outcomes: women with no macroscopic
evidence of disease after debulking have a median survival of 39 months, as opposed to 17 months with less
complete surgery. By removing metastases, many cells that are resistant to chemotherapy are removed, and any
clumps of cells that have died are also removed. This allows chemotherapy to better reach the remaining cancer
cells, which are more likely to be fast-growing and therefore chemosensitive.
Interval debulking surgery is another protocol used, where neo-adjuvant chemotherapy is given, debulking
surgery is performed, and chemotherapy is finished after debulking. Though no definitive studies have been
completed, it is shown to be approximately equivalent to primary debulking surgery in terms of survival, and
shows slightly lower morbidity. There are several different surgical procedures that can be employed to treat
ovarian cancer. For stage I and II cancer, laparascopic (keyhole) surgery can be used, but metastases may not
be found. For advanced cancer, laparoscopy is not used, since debulking metastases requires access to the
entire peritoneal cavity. Depending on the extent of the cancer, procedures may include a bilateral salpingo-
oophorectomy, biopsies throughout the peritoneum and abdominal lymphatic system, omentectomy,
splenectomy, bowel resection, diaphragm stripping or resection, appendectomy, or even a posterior pelvic
exenteration.
To fully stage ovarian cancer, lymphadenectomy can be included in the surgery, but a significant survival
benefit to this practice may not happen. This is particularly important in germ cell tumors because they frequently
metastasize to nearby lymph nodes. If ovarian cancer recurs, secondary surgery is sometimes a treatment option.
This depends on how easily the tumor can be removed, how much fluid has accumulated in the abdomen, and
overall health. It can be helpful in people who had their first surgery done by a generalist and in epithelial
ovarian cancer. Secondary surgery can be effective in dysgerminomas and immature teratomas. The major side
effect of an oophorectomy in younger women is early menopause, which can cause osteoporosis. After surgery,
hormone replacement therapy can be considered, especially in younger women. This therapy can consist of a
combination of estrogen and progesterone, or estrogen alone. Estrogen alone is safe after hysterectomy; when
the uterus is still present, unopposed estrogen dramatically raises the risk of endometrial cancer. Estrogen
therapy after surgery does not change survival rates. People having ovarian cancer surgery are typically
hospitalized afterwards for 3–4 days and spend around a month recovering at home. Surgery outcomes are
best at hospitals that do a large number of ovarian cancer surgeries. It is unclear if laparoscopy or laparotomy
is better or worse for FIGO stage I ovarian cancer. There is also no apparent difference between total abdominal
hysterectomy and supracervical hysterectomy for advanced cancers. Approximately 2.8% of people having a
first surgery for advanced ovarian cancer die within two weeks of the surgery (2.8% perioperative mortality
rate). More aggressive surgeries are associated with better outcomes in advanced (stage III or IV) ovarian
cancer.
Gynecology 219

Chemotherapy
Chemotherapy has been a general standard of care for ovarian cancer for decades, although with variable
protocols. Chemotherapy is used after surgery to treat any residual disease, if appropriate. In some cases, there
may be reason to perform chemotherapy first, followed by surgery. This is called “neo-adjuvant chemotherapy”,
and is common when a tumor cannot be completely removed or optimally debulked via surgery. Though it has
not been shown to increase survival, it can reduce the risk of complications after surgery. If a unilateral salpingo-
oophorectomy or other surgery is performed, additional chemotherapy, called “adjuvant chemotherapy”, can be
given. Adjuvant chemotherapy is used in stage 1 cancer typically if the tumor is of a high histologic grade
(grade 3) or the highest substage (stage 1c), provided the cancer has been optimally staged during surgery.
Bevacizumab may be used as an adjuvant chemotherapy if the tumor is not completely removed during surgery
or if the cancer is stage IV; it can extend progression-free survival but has not been shown to extend overall
survival. Chemotherapy is curative in approximately 20% of advanced ovarian cancers; it is more often curative
with malignant germ cell tumors than epithelial tumors. Chemotherapy in ovarian cancer typically consists of
platins, a group of platinum-based drugs, combined with non-platins. Common therapies can include paclitaxel,
cisplatin, topotecan, doxorubicin, epirubicin, and gemcitabine. Carboplatin is typically given in combination
with either paclitaxel or docetaxel; the typical combination is carboplatin with paclitaxel. Carboplatin is superior
to cisplatin in that it is less toxic and has fewer side effects, generally allowing for an improved quality of life
in comparison, though both are similarly effective. Three-drug regimens have not been found to be more effective,
and platins alone or non-platins alone are less effective than platins and non-platins in combination. Chemotherapy
can be given intravenously or in the peritoneal cavity. Though intraperitoneal chemotherapy is associated with
longer progression-free survival and overall survival, it also causes more adverse side effects than intravenous
chemotherapy. It is mainly used when the cancer has been optimally debulked. Intraperitoneal chemotherapy
can be highly effective because ovarian cancer mainly spreads inside the peritoneal cavity, and higher doses of
the drugs can reach the tumors this way. Chemotherapy can cause anemia; intravenous iron has been found to
be more effective than oral iron supplements in reducing the need for blood transfusions. Typical cycles of
treatment involve one treatment every 3 weeks, repeated for 6 weeks or more. Fewer than 6 weeks (cycles) of
treatment is less effective than 6 weeks or more. Germ-cell malignancies are treated differently than other
ovarian cancers — a regimen of bleomycin, etoposide, and cisplatin (BEP) is used with 5 days of chemotherapy
administered every 3 weeks for 3 to 4 cycles. Chemotherapy for germ cell tumors has not been shown to cause
amenorrhea, infertility, birth defects, or miscarriage. Maintenance chemotherapy has not been shown to be
effective. In people with BRCA mutations, platinum chemotherapy is more effective. Germ-cell tumors and
malignant sex-cord/stromal tumors are treated with chemotherapy, though dysgerminomas and sex-cord tumors
are not typically very responsive.

Platinum-sensitive or Platinum-resistant
If ovarian cancer recurs, it is considered partially platinum-sensitive or platinum-resistant, based on the time
since the last recurrence treated with platins: partially platinum-sensitive cancers recurred 6–12 months after
last treatment, and platinum-resistant cancers have an interval of less than 6 months. Second-line chemotherapy
can be given after the cancer becomes symptomatic, because no difference in survival is seen between treating
asymptomatic (elevated CA-125) and symptomatic recurrences. For platinum-sensitive tumors, platins are the
drugs of choice for second-line chemotherapy, in combination with other cytotoxic agents. Regimens include
carboplatin combined with pegylated liposomal doxorubicin, gemcitabine, or paclitaxel. Carboplatin-doublet
therapy can be combined with paclitaxel for increased efficacy in some cases. Another potential adjuvant
therapy for platinum-sensitive recurrences is olaparib, which may improve progression-free survival but has
220 Surgical Oncology: Theory and Multidisciplinary Practice

not been shown to improve overall survival. (Olaparib, a PARP inhibitor, was approved by the US FDA for use
in BRCA-associated ovarian cancer that had previously been treated with chemotherapy.) For recurrent germ
cell tumors, an additional 4 cycles of BEP chemotherapy is the first-line treatment for those tho have been
treated with surgery or platins. If the tumor is determined to be platinum-resistant, vincristine, dactinomycin,
and cyclophosphamide (VAC) or some combination of paclitaxel, gemcitabine, and oxaliplatin may be used as
a second-line therapy. For platinum-resistant tumors, there are no high-efficacy chemotherapy options. Single-
drug regimens (doxorubicin or topotecan) do not have high response rates, but single-drug regimens of topotecan,
pegylated liposomal doxorubicin, or gemcitabine are used in some cases. Topotecan cannot be used in people
with an intestinal blockage. Paclitaxel used alone is another possible regimen, or it may be combined with
liposomal doxorubicin, gemcitabine, cisplatin, topotecan, etoposide, or cyclophosphamide.

Radiation Therapy
Dysgerminomas are most effectively treated with radiation, though this can cause infertility and is being
phased out in favour of chemotherapy. Radiation therapy does not improve survival in people with well-
differentiated tumors. In stage 1c and 2 cancers, radiation therapy is used after surgery if there is the possibility
of residual disease in the pelvis but the abdomen is cancer-free. Radiotherapy can also be used in palliative care
of advanced cancers. A typical course of radiotherapy for ovarian cancer is 5 days a week for 3–4 weeks.
Common side effects of radiotherapy include diarrhea, constipation, and frequent urination.

Hormonal Therapy
Despite the fact that 60% of ovarian tumors have estrogen receptors, ovarian cancer is only rarely responsive
to hormonal treatments. Estrogen alone does not have an effect on the cancer, and tamoxifen and letrozole are
rarely effective. “Some women with borderline malignancy ovarian cancer and stromal ovarian cancer may
receive hormonal therapy.”

Immunotherapy
Immunotherapy is a topic of current research in ovarian cancer. In some cases, the antibody drug bevacizumab,
though still a topic of active research, is used to treat advanced cancer along with chemotherapy. It has been
approved for this use in the European Union.

Follow-up
Specific follow-up depends on, for example, the type and stage of ovarian cancer, the treatment, and the
presence of any symptoms. Usually, a check-up appointment is made about every 2 to 3 months initially, followed
by twice per year for up to 5 years. For epithelial ovarian cancers, the most common test upon follow-up is CA-
125 level. However, treatment based only on elevated CA-125 levels and not any symptoms can increase side
effects without any prolongation of life, so the implication of the outcome of a CA-125 test can be discussed
before taking it. The recommendation as of 2014 is recurrent cancer may be present if the CA-125 level is twice
normal. Treating a recurrence detected by CA-125 does not improve survival. For women with germ-cell tumors,
follow-up tests generally include alpha-fetoprotein (AFP) and/or human chorionic gonadotropin. For women
with stromal cancers, tests for hormones like estrogen, testosterone, and inhibin are sometimes helpful. Inhibin
can also be useful for monitoring the progress of sex-cord tumors, along with mullerian inhibiting substance.
AFP can also be used to monitor Sertoli- Leydig tumors. In dysgerminomas, lactate dehydrogenase and its two
isozymes (LDH-1 and LDH-2) are used to test for recurrence. Women with ovarian cancer may not need routine
Gynecology 221

surveillance imaging to monitor the cancer unless new symptoms appear or tumor markers begin rising. Imaging
without these indications is discouraged because it is unlikely to detect a recurrence, improve survival, and
because it has its own costs and side effects. However, CT imaging can be used if desired, though this is not
common. If a tumor is easily imaged, imaging may be used to monitor the progress of treatment.

Palliative Care
Palliative care focuses on relieving symptoms and increasing or maintaining quality of life. This type of
treatment’s purpose is not to cure the cancer but to make the woman more comfortable while living with cancer
that can not be cured. It has been recommended as part of the treatment plan for any person with advanced
ovarian cancer or patients with significant symptoms. In platinum-refractory and platinum-resistant cases, other
palliative chemotherapy is the main treatment. Palliative care can entail treatment of symptoms and complications
of the cancer, including pain, nausea, constipation, ascites, bowel obstruction, edema, pleural effusion, and
mucositis. Especially if the cancer advances and becomes incurable, treatment of symptoms becomes one of the
main goals of therapy. Palliative care can also entail helping with decision-making such as if or when hospice
care is appropriate, and the preferred place for the patient at end of life care. Bowel obstruction can be treated
with palliative surgery (colostomy, ileostomy, or internal bypass) or medicine, but surgery has been shown to
increase survival time. Palliative surgery may result in short bowel syndrome, enterocutaneous fistula, or re-
obstruction; or may not be possible due to the extent of obstruction. Other treatments of complications can
include total parenteral nutrition, a low-residue diet, palliative gastrostomy, and adequate pain control. Bowel
obstruction can also be treated with octreotide when palliative surgery is not an option. Cancer can also block
the ureters, which can be relieved by a nephrostomy or a ureteric stent. Ascites can be relieved by repeated
paracentesis or placement of a drain to increase comfort. Pleural effusions can be treated in a similar manner,
with repeated thoracentesis, pleurodesis, or placement of a drain. Radiation therapy can be used as part of the
palliative care of advanced ovarian cancer, since it can help to shrink tumors that are causing symptoms. Palliative
radiotherapy typically lasts for only a few treatments, a much shorter course of therapy than non-palliative
radiotherapy. It is also used for palliation of chemotherapy-resistant germ cell tumors.

Psychosocial Care
Ovarian cancer has a significant effect on quality of life, psychological health and well-being. Interventions
are available to help with the needs and social support. Many ovarian cancer survivors report a good quality of
life and optimism. Others reported a “spiritual change” that helped them find meaning during their experience.
Others have described their loss of faith after their diagnosis with ovarian cancer. Those who have gone
through treatment sometimes experience social isolation but benefit from having relationships with other
survivors. Frustration and guilt have been described by some who have expressed their inability to care for
their family. Self-esteem and body image changes can occur due to hair loss, removal of ovaries and other
reproductive structures, and scars. There is some improvement after hair grows in. Sexual issues can develop.
The removal of ovaries results in surgically-induced menopause that can result in painful intercourse, vaginal
dryness, loss of sexual desire and being tired. Though prognosis is better for younger survivors, the impact on
sexuality can still be substantial. Anxiety, depression and distress is present in those surviving ovarian cancer at
higher rates than in the general population. The same psychosocial problems can develop in family members.
Emotional effects can include a fear of death, sadness, memory problems and difficulty in concentrating. When
optimism was adopted by those at the beginning of their treatment, they were less likely to develop distress.
Those who have fear of the cancer recurring may have difficulty in expressing joy even when disease-free. The
more treatments that a woman undergoes, the more likely the loss of hope is expressed. Women often can cope
222 Surgical Oncology: Theory and Multidisciplinary Practice

and reduce negative psychosocial effects by a number of strategies. Activities such as traveling, spending
additional time with family and friends, ignoring statistics, journaling and increasing involvement in spiritually-
based events are adaptive.

PROGNOSIS
Ovarian cancer usually has a relatively poor prognosis. It is disproportionately deadly because it lacks any
clear early detection or screening test, meaning most cases are not diagnosed until they have reached advanced
stages. Ovarian cancer metastasizes early in its development, often before it has been diagnosed. High-grade
tumors metastasize more readily than low-grade tumors. Typically, tumor cells begin to metastasize by growing
in the peritoneal cavity. More than 60% of women presenting with ovarian cancer have stage-III or stage-IV
cancer, when it has already spread beyond the ovaries. Ovarian cancers shed cells into the naturally occurring
fluid within the abdominal cavity. These cells can then implant on other abdominal (peritoneal) structures,
including the uterus, urinary bladder, bowel, lining of the bowel wall, and omentum, forming new tumor growths
before cancer is even suspected. The five-year survival rate for all stages of ovarian cancer is 46%; the one-year
survival rate is 72% and the ten-year survival rate is 35%. For cases where a diagnosis is made early in the
disease, when the cancer is still confined to the primary site, the five-year survival rate is 92.7%. About 70% of
women with advanced disease respond to initial treatment, most of whom attain complete remission, but half of
these women experience a recurrence 1–4 years after treatment. Brain metastasis is more common in stage III/
IV cancer but can still occur in cancers staged at I/II. People with brain metastases survive a median of 8.2
months, though surgery, chemotherapy, and whole brain radiation therapy can improve survival. Ovarian cancer
survival varies significantly with subtype. Dysgerminomas have a very favourable prognosis. In early stages,
they have a five-year survival rate of 96.9%. Around two-thirds of dysgerminomas are diagnosed at stage I.
Stage-III dysgerminomas have a five-year survival of 61%; when treated with BEP chemotherapy after incomplete
surgical removal, dysgerminomas have a 95% two-year survival rate. Sex-cord-stromal malignancies also have
a favourable prognosis; because they are slow-growing, even those with metastatic disease can survive a decade
or more. Low malignant potential tumors usually only have a bad prognosis when there are invasive tumor
implants found in the peritoneal cavity. Complications of ovarian cancer can include spread of the cancer to
other organs, progressive function loss of various organs, ascites, and intestinal obstructions, which can be
fatal. Intestinal obstructions in multiple sites are the most common proximate cause of death. Intestinal obstruction
in ovarian cancer can either be a true obstruction, where tumor blocks the intestinal lumen, or a pseudo-obstruction,
when tumor prevents normal peristalsis. Continuous accumulation of ascites can be treated by placing a drain
that can be self-drained.

Prognostic Factors
There are a number of prognostic factors in ovarian cancer. Positive prognostic factors - those indicating
better chances of survival - include no residual disease after surgery (stage III/IV), complete macroscopic
resection (stage IV), BRCA2 mutations, young age (under 45 years), non-serous type, low histologic grade,
early stage, co-occurrence with endometrial cancer, and low CA-125 levels. There is conflicting evidence for
BRCA1 as a prognostic factor. Conversely, negative prognostic factors - those that indicate a worse chance
of survival - include rupture of the ovarian capsule during surgery, older age (over 45 years), mucinous type,
stage IV, high histologic grade, clear cell type, upper abdominal involvement, high CA-125 levels, the presence
of tumor cells in the blood, and elevated cyclooxygenase-2. Expression of various mRNAs can also be prognostic
for ovarian cancer. High levels of Drosha and Dicer are associated with improved survival, whereas high levels
of let-7b, HIF1A, EphA1, and poly(ADP-ribose) polymerase are associated with worse survival. Cancers that
are positive for WT1 carry a worse prognosis; estrogen-receptor positive cancers have a better prognosis.
Gynecology 223

Survival Rates
Overall five-year survival rates for all types of ovarian cancer are presented below by stage and histologic grade:
Stage Survival
I 90–95%
II 70–80%
III 20–50%
IV 1–5%
Histologic grade Survival
Low grade 88%
Intermediate grade 58%
High grade 27%
The survival rates given below are for the different types of ovarian cancer, according to American Cancer
Society. They come from the National Cancer Institute, SEER, and are based on patients diagnosed from 2004 to
2010.
Invasive epithelial ovarian cancer
Stage Relative five-year survival rate
I 90%
IA 94%
IB 92%
IC 85%
II 70%
IIA 78%
IIB 73%
III 39%
IIIA 59%
IIIB 52%
IIIC 39%
IV 17%
Ovarian stromal tumors
Stage Relative five-year
survival rate
I 95%
II 78%
III 65%
IV 35%
Germ cell tumors of the ovary
Stage Relative 5-yr
Survival Rate
I 98%
II 94%
III 87%
IV 69%
Fallopian tube carcinoma
Stage Relative five-year
survival rate
I 87%
II 86%
III 52%
IV 40%
Low malignant potential tumors
Stage Relative five-year
survival rate
I 99%
II 98%
III 96%
IV 77%
224 Surgical Oncology: Theory and Multidisciplinary Practice

Recurrence Rates
Ovarian cancer frequently recurs after treatment. Overall, in a 5-year period, 20% of stage I and II cancers
recur. Most recurrences are in the abdomen. If a recurrence occurs in advanced disease, it typically occurs
within 18 months of initial treatment (18 months progression-free survival). Recurrences can be treated, but the
disease-free interval tends to shorten and chemoresistance increases with each recurrence. When a dysgerminoma
recurs, it is most likely to recur within a year of diagnosis, and other malignant germ cell tumors recur within 2
years 90% of the time. Germ cell tumors other than dysgerminomas have a poor prognosis when they relapse,
with a 10% long-term survival rate.
Low malignant potential tumors rarely relapse, even when fertility-sparing surgery is the treatment of choice.
15% of LMP tumors relapse after unilateral surgery in the previously unaffected ovary, and they are typically
easily treated with surgery. More advanced tumors may take up to 20 years to relapse, if they relapse at all, and
are only treated with surgery unless the tumor has changed its histological characteristics or grown very quickly.
In these cases, and when there is significant ascites, chemotherapy may also be used. Relapse is usually indicated
by rising CA-125 levels and then progresses to symptomatic relapse within 2–6 months. Recurrent sex cord-
stromal tumors are typically unresponsive to treatment but not aggressive. It is the most deadly gynecologic
cancer.

EPIDEMIOLOGY
In 2014, the number of new cases that occurred in developed countries was about 9.4 per 100,000, compared
to 5.0 per 100,000 in developing countries. Globally, about 160,000 people died from ovarian cancer in 2010.
This was an increase from 113,000 in 1990. The number of new cases per year in Europe is approximately 5–15
per 100,000 women. In Europe, Lithuania, Latvia, Ireland, Slovakia, and the Czech Republic have the highest
incidences of ovarian cancer, whereas Portugal and Cyprus have the lowest incidences. In 2008, the five-year
survival rate was 44%. This has increased since 1977 when the survival rate was 36%.

United States
In 2010, in the United States, an estimated 21,880 new cases were diagnosed and 13,850 women died of
ovarian cancer. Around 1,800 of the new diagnoses were sex-cord or stromal tumors. In 2014, over 220,000
diagnoses of epithelial ovarian cancer were made yearly. The overall lifetime risk in the US is around 1.6% In
the US, ovarian cancer affects 1.3–1.4% and is the cause of death of about 1% of women. In the United States,
it is also the fifth-most common cancer in women but the fourth-most common cause of cancer death. This
decrease made it the ninth-most common cancer in women. The risks from developing specific types of ovarian
cancer varies. Germ cell tumors and sex cord-stromal tumors are less common than epithelial tumors. The
number of new cases a year in the US is 0.4 per 100,000 women and 0.2 per 100,000 women, respectively. In
young people, sex-cord stromal tumors and germ cell tumors total 1% of overall ovarian cancer. Ovarian cancer
represents approximately 4% of cancers diagnosed in women.

United Kingdom
It is the 5th most common cancer in UK women. In the UK, the incidence rate over the whole population is
21.6 per 100,000. In the United Kingdom as of 2014, approximately 7,000–7,100 yearly diagnoses with 4,200
deaths. The risk in the UK is similar, at 1.7%. Ashkenazi Jewish women carry mutated BRCA alleles five times
more often than the rest of the population, giving them a higher risk developing ovarian cancer. It is the fifth-
leading cause of cancer-related deaths in the US in 2008 and estimated to be 15,000. Ovarian cancer is the fifth-
Gynecology 225

most common cancer in women in the UK (around 7,100 women were diagnosed with the disease in 2011), and
it is the fifth-most common cause of cancer death in women (around 4,300 women died in 2012).

Ethnicity
Black women have twice the risk for sex cord-stromal tumors compared to non-Black women.

Older Women
In the US, the incidence rate in women over 50 is approximately 33 per 100,000. The rate of ovarian cancer
between 1993 and 2008 decreased in women of the 40–49 age cohort and in the 50–64 age cohort. Ovarian
cancer is most commonly diagnosed after menopause, between the ages of 60 and 64. Ninety percent of ovarian
cancer occurs in women over the age of 45 and 80% in women over 50. Older women are more likely to present
with advanced ovarian cancer.

IN PREGNANCY
Malignant germ cell tumors are the type of ovarian cancer most likely to occur during pregnancy. They are
typically diagnosed when an adnexal mass is found on examination (in 1–2% of all pregnancies), a tumor is seen
on ultrasound, or the parent’s level of alpha-fetoprotein is elevated. Dermoid cysts and dysgerminomas are the
most common germ cell tumors during pregnancy. Germ cell tumors diagnosed during pregnancy are unlikely to
have metastasized and can be treated by surgery and, in some cases, chemotherapy, which carries the risk of birth
defects. Yolk sac tumors and immature teratomas grow particularly quickly and are usually treated with chemotherapy
even during pregnancy; however, dysgerminomas that have been optimally debulked may be treated after childbirth.

RESEARCH

Screening
Screening by hysteroscopy to obtain cell samples obtained for histological examination is being developed.
This is similar to the current pap smear that is used to detect cervical cancer. The UK Collaborative Trial of
Ovarian Cancer Screening is testing a screening technique that combines CA-125 blood tests with transvaginal
ultrasound. Other studies suggest that this screening procedure may be effective. However, it’s not yet clear if
this approach could actually help to save lives—the full results of the trial will be published in 2015. One major
problem with screening is no clear progression of the disease from stage I (non-invasive) to stage III (invasive)
is seen, and it may not be possible to find cancers before they reach stage III. Another problem is that screening
methods tend to find too many suspicious lesions, most of which are not cancer, but malignancy can only be
assessed with surgery. The ROCA method combined with transvaginal ultrasonography is being researched in
high-risk women to determine if it is a viable screening method. It is also being investigated in normal-risk
women as it has shown promise in the wider population. Studies are also in progress to determine if screening
helps detect cancer earlier in people with BRCA mutations.

Prognosis Research
Research into various prognostic factors for ovarian cancer is also going on. Recent research shows that
thrombocytosis predicts lower survival and higher stage cancer. Ongoing research is also investigating the
benefits of surgery for recurrent ovarian cancer.
226 Surgical Oncology: Theory and Multidisciplinary Practice

Immunotherapy
While an active area of research, no immunotherapy has been shown to be effective as of 2013. However,
trials of the antibody and VEGF inhibitor bevacizumab, which can slow the growth of new blood vessels in the
cancer, have shown promising results, especially in combination with pazopanib, which also slows the process
of blood vessel growth. Bevacizumab has been particularly effective in preliminary studies on stage-III and -IV
cancer and has been cited as having at least a 15% response rate. It is being investigated particularly in mucinous
ovarian cancers.

Pharmacology
mTOR inhibitors were a highly investigated potential treatment in the 2000s and 2010s, but the side effects
of these drugs (particularly hyperglycemia and hyperlipidemia) were not well tolerated and the survival benefit
not confirmed. PI3 kinase inhibitors have been of interest, but they tend to be highly toxic and cause diarrhea.
Another investigated drug is selumetinib, a MAPK inhibitor. It improved survival, but did not correlate with
any mutations found in tumors. Bevacizumab can also be combined with platinum chemotherapy, a combination
that has had positive preliminary results in PFS, but equivocal results regarding overall survival. One disadvantage
to these treatments is the side effect profile, which includes high blood pressure and proteinuria. The drug can
also exacerbate bowel disease, leading to fistulae or bowel perforation. Vintafolide, which consists of an antifolate
conjugated with vinblastine, is also in clinical trials; it may prove beneficial because folate receptors are
overexpressed in many ovarian cancers. Another potential immunotherapy is trastuzumab, which is active against
tumors positive for Her2/neu mutations. Other angiogenesis inhibitors are also being investigated as potential
ovarian cancer treatments. Combretastatin and pazopanib are being researched in combination for recurrent
ovarian cancer. Trebananib and tasquinimod are other angiogenesis inhibitors being investigated. The monoclonal
antibody farletuzumab is being researched as an adjuvant to traditional chemotherapy. Another type of
immunotherapy involves vaccines, including TroVax. An alternative to BEP chemotherapy, a regimen of 3
cycles of carboplatin and etoposide, is a current topic of research for germ cell malignancies. Intraperitoneal
chemotherapy has also been under investigation during the 2000s and 2010s for its potential to deliver higher
doses of cytotoxic agent to tumors. Preliminary trials with cisplatin and paclitaxel have shown it is not well
tolerated, but does improve survival, and more tolerable regimens are being researched. Cisplatin and paclitaxel
are both being researched as intraperitoneal chemotherapy agents. A specific chemotherapy regimen for rare
clear-cell cancers is also under investigation: irinotecan combined with cisplatin. PARP inhibitors have also
shown promise in early trials, particularly in people with BRCA gene mutations, since the BRCA protein interacts
with the PARP pathway. It is also being studied in recurrent ovarian cancer in general, where preliminary
studies have shown longer PFS. Specifically, olaparib has shown greater survival compared to doxorubicin,
though this treatment is still being investigated. It is not clear yet which biomarkers are predictive of
responsiveness to PARP inhibitors. Rucaparib is another PARP inhibitor being researched in BRCA-positive
and BRCA-negative recurrent advanced ovarian cancer. Niraparib is a PARP inhibitor being tested in BRCA-
positive recurrent ovarian cancer. Tyrosine kinase inhibitors are another investigational drug class that may
have applications in ovarian cancer. Angiogenesis inhibitors in the receptor tyrosine kinase inhibitor group,
including pazopanib, cediranib, and nintedanib, have also been shown to increase progression free survival
(PFS), but their benefit for overall survival has not been investigated as of 2015. Preliminary research showed
that cediranib combined with platins in recurrent ovarian cancer increased the time to second recurrence by 3–
4 months and increased survival by 3 months. MK-1775 is a tyrosine kinase inhibitor that is being used in
combination with paclitaxel and carboplatin in platinum-sensitive cancers with p53 mutations. Nintedanib is
being researched as a potential therapy in combination with cyclophosphamide for people with recurrences.
Gynecology 227

Hormones and Radiation

Hormone therapies are a topic of current research in ovarian cancer, particularly, the value of certain
medications used to treat breast cancer. These include tamoxifen, letrozole, and anastrozole. Preliminary studies
have showed a benefit for tamoxifen in a small number of people with advanced ovarian cancer. Letrozole may
help to slow or stop growth of estrogen receptor positive ovarian cancer. Anastrozole is being investigated in
postmenopausal people with estrogen receptor-positive cancer. Research into mitigating side effects of ovarian
cancer treatment is also ongoing. Radiation fibrosis, the formation of scar tissue in an area treated with radiation,
may be relieved with hyperbaric oxygen therapy, but research has not been completed in this area. Treatment of
ovarian cancer may also cause people to experience psychiatric difficulties, including depression. Research is
ongoing to determine how counseling and psychotherapy can help people who have ovarian cancer during
treatment.

Inflammation
There are some indications that pelvic inflammatory disease may be associated with ovarian cancer,
especially in non-western countries. It may be due to the inflammatory process present with pelvic inflammatory
disease.

Clinical Trials
Clinical trials are monitored and funded by US governmental organizations to test treatment options to
see if they are safe and effective. These include NIH Clinical Research Trials and You (National Institutes of
Health), Learn About Clinical Trials (National Cancer Institute), Search for Clinical Trials (National Cancer
Institute), ClinicalTrials.gov (National Institutes of Health). Clinical trials are also conducted in Canada.

ADNEXAL MASS
An adnexal mass is a lump in tissue of the adnexa of uterus (structures closely related structurally and
functionally to the uterus such as the ovaries, fallopian tubes, or any of the surrounding connective tissue).
Adnexal masses can be benign or cancerous, and they can be categorized as simple or complex. One of the
most important factors used to determine the clinical suspicion of malignancy of an adnexal mass is the
sonographic appearance of the mass. Indications that the mass is at a higher risk of being malignant include:
presence of loculations, nodules, papillary structures, septations, size greater than 10 cm.

CAUSES
In premenopausal women, adnexal masses include ovarian cysts, ectopic (tubal) pregnancies, benign (non-
cancerous) or malignant (cancerous) tumors, endometriomas, polycystic ovaries, and tubo-ovarian abscess. In
females of reproductive age, adnexal masses can be physiologic or complex masses. Most common causes for
adnexal masses in premenopausal women are follicular cysts and corpus luteum cysts. Abscesses can form as a
complication of pelvic inflammatory disease. Other masses include endometriomas, polycystic ovaries, and
benign neo-plasms. In postmenopausal women, adnexal masses may be caused by cancer, fibroids, fibromas,
diverticular abscess.

TREATMENT
Removal is sometimes referred to as “adnexectomy”.
228 Surgical Oncology: Theory and Multidisciplinary Practice

OVARIAN TUMOR
OVARIAN
Ovarian tumors, or ovarian neo-plasms, are tumors arising from the ovary. They can be benign or malignant
(ovarian cancer).

BENIGN TUMORS
Benign tumors of the ovary include ovarian cysts, such as borderline tumor cysts.

CANCER
Ovarian cancer is classified according to the histology of the tumor, obtained in a pathology report. Histology
dictates many aspects of clinical treatment, management, and prognosis.
• Surface epithelial-stromal tumours, also known as ovarian epithelial tumors, are the most common
type of ovarian cancer. It includes serous tumour, endometrioid tumor, and mucinous tumour. They
can be benign (cystadenoma) or malignant (cystadenocarcinoma). Less common tumors are malignant
Brenner tumor and transitional cell carcinoma of the ovary.
• Sex cord-stromal tumor, including estrogen-producing granulosa cell tumor and virilizing Sertoli-
Leydig cell tumor or arrhenoblastoma, accounts for 8% of ovarian cancers.
• Germ cell tumor accounts for approximately 30% of ovarian tumors but only 5% of ovarian cancers,
because most germ cell tumors are teratomas and most teratomas are benign. Germ cell tumors tend
to occur in young women (20’s-30’s) and girls. Whilst overall the prognosis of germ cell tumors
tend to be favourable, it can vary substantially with specific histology: for instance, the prognosis of
the most common germ cell tumor (dysgerminomas) tends to be good, whilst the second most common
(endodermal sinus tumor) tends to have a poor prognosis. In addition, the cancer markers used vary
with tumor type: choriocarcinomas are monitored with beta-HCG; dysgerminomas with LDH; and
endodermal sinus tumors with alpha-fetoprotein.
• Mixed tumors, containing elements of more than one of the above classes of tumor histology.

CLEAR-CELL OVARIAN C
OVARIAN AR
CAR CINOMA
ARCINOMA
Clear cell ovarian tumors are part of the surface epithelial-stromal tumor group of ovarian cancers, accounting
for 6% of these cancers. Clear cell tumors are also associated with the pancreas and salivary glands.

DESCRIPTION
Typically, they are cystic neo-plasms with polypoid masses that protrude into the cyst. On microscopic
pathological examination, they are composed of cells with clear cytoplasm (that contains glycogen) and hob
nail cells (from which the glycogen has been secreted). The pattern may be glandular, papillary or solid.

PROGNOSIS
Benign and borderline variants of this neo-plasm are rare, and most cases are malignant. These tumors may
have a worse prognosis than serous tumors.

HIGH-GRADE SER
HIGH-GRADE OUS C
SEROUS AR
CAR CINOMA
ARCINOMA
High-grade serous carcinoma (HGSC) is a type of tumour that arises from the serous epithelial layer in the
abdominopelvic cavity and is mainly found in the ovary. HGSCs make up the majority of ovarian cancer cases
Gynecology 229

and have the lowest survival rates. HGSC is distinct from low-grade serous carcinoma (LGSC) which arises
from ovarian tissue, is less aggressive and is present in stage I ovarian cancer where tumours are localised to the
ovary. Although originally thought to arise from the squamous epithelial cell layer covering the ovary, HGSC is
now thought to originate in the Fallopian tube epithelium. HGSC is much more invasive than LGSC with a
higher fatality rate - although it is more sensitive to platinum-based chemotherapy, possibly due to its rapid
growth rate. In rare cases, HGSCs can develop from LGSCs, but generally the two types arise independently of
each other.

RISK FACTORS

Environmental Risk Factors

The ‘incessant ovulation’ theory is suggested by the strong correlation between the number of ovulatory
cycles of an individual and their risk of ovarian cancer. This trend is reflected in the protective effects of
pregnancy, parity and breastfeeding against ovarian cancer, and similar findings in epidemiological studies that
have indicated a reduction of risk associated with use of oral contraceptive pills. Ovulation is accepted as the
cause of ovarian cortical inclusion cysts, the precursor lesions of serous carcinomas, and lower numbers of
these cortical inclusion cysts are thought to be the mechanism by which reducing lifetime ovulations can lower
the risk of developing HGSC. Conversely, a temporal association with menopausal hormone therapy and incidence
of HGSC was found, and polycystic ovarian syndrome (PCOS) was shown to contribute to a doubling of the
risk of ovarian cancer. Endometriosis can increase risk for other ovarian cancer subtypes, but is not associated
with HGSC.

Genetic Risk Factors

More than 20% of ovarian cancer tumours have hereditary origin. The majority of these feature mutations in
the tumour suppressor BRCA genes, which tend to give rise to HGSC. A mutation in BRCA1 or BRCA2 can
confer a lifetime ovarian cancer risk of 40-50% and 10-20% respectively, with BRCA2 mutations strongly associated
with better clinical outcomes. A specific tumour protein 53 (TP53) expression pattern in the Fallopian tube epithelium
– the ‘p53 signature’ - is thought to be a precursor marker of HGSC. TP53-/- mice (in which the TP53 gene has
been deleted) do not develop ovarian carcinomas. However, TP53 mutations were found in 96% of HGSC cases.
A local abnormal TP53 expression may thus be indicative of HGSC. In women, pelvic HGSC show either a
complete absence of P53 expression, or overexpression, suggesting that any aberration of P53 leads to tumour
development. Additionally, overexpression of TP53 is associated with better clinical outcome whereas an absence
of the p53 protein is linked to an increased risk of HGSC tumour recurrence. A recent mouse model suggest that a
p53 mutation may induce HGSC arising from the ovary rather than the Fallopian tube.

PATHOPHYSIOLOGY

Cell Origin
HGSC are further distinguished from LGSC by ‘type I/II’ ovarian tumour nomenclature; type I referring to
tumour types (e.g. LGSCs) where precursor lesions within the ovary have been characterised, and type II
referring to tumour types (e.g. HGSCs) without association of such lesions, tumours understood to develop de
novo from the tubal and/or ovarian surface epithelium. This classification has more relevance to research rather
than to clinical practice. The serous membrane is a particular type of secretory epithelium which covers organs
230 Surgical Oncology: Theory and Multidisciplinary Practice

in body cavities and secretes serous fluid to reduce friction from muscle movement. Serous membrane lining
the abdominopelvic cavity is called the peritoneum; that lining heart and mediastinum is the pericardium, and
that lining the thoracic cavity and lungs is the pleura. Technically a ‘serous carcinoma’ can occur anywhere on
these membranes, but high-grade serous carcinoma is generally limited to the peritoneal area. While until
recently HGSC was thought to arise from simple differentiation of cortical inclusion cysts (CICs) of ovarian
surface epithelium (OSE), the cell origin of HGSC is now understood to be much more complex, with evidence
for other sites of origin, both intra- and extra-ovarian, having come to light.
Tissue Evidence for role as HGSC cell of origin
Ovary Supporting:
1. Metastatic HGSC arose in the ovaries of mouse triple knockouts of p53, PTEN and
Dicer in which the Fallopian tubes had been removed, as well as in double murine
knockouts of PTEN and p53 with intact Fallopian tubes.
2. The stem-cell-rich hilum region of the ovarian surface epithelium is a cancer-prone
area.
Opposing:
1. A convincing precursor of HGSC in the ovary has not yet been identified.
Coelomic epithelium Supporting:
'Coelomic hypothesis'
1. Due to the embryological relationship between the coelomic epithelium and the
Mullerian ducts, the coelomic epithelium is predisposed to differentiation via
Mullerian metaplasia into the different epithelial tumour tissue types (e.g. serous,
endometrioid, clear cell and mucinous). Cortical inclusion cysts of the OSE can
thus undergo differentiation into neoplasms.
2. This hypothesis can account for primary peritoneal carcinomas by implying that
extra-ovarian coelomic epithelium can similarly undergo Müllerian metaplasia.
Opposing:
1. There has so far been an absence of precursor lesions of ovarian carcinomas on
the OSE despite extensive histopathology.
Fallopian tube Supporting:
1. Precursor lesions (serous tubal intraepithelial carcinomas or 'STICs') found on the
fimbrial ends of the Fallopian tube of BRCA 1/2 women.
2. There is physical contact between the fimbriae and the ovary during ovulation
(supports 'incessant ovulation' hypothesis).
3. The fringes of the fimbriae come into contact with the pro-inflammatory follicular
fluid.
4. Identical TP53 mutations in STIC and concurrent HGSC were reported, suggesting
a clonal relationship.
5. In the triple p53-PTEN-Dicer knockout mice earlier mentioned, where the Fallopian
tubes were intact, HGSC arose from the tubes 100% of the time, eclipsing the
tumourgenicity of the ovary. Identical findings were found from PTEN-Dicer
knockouts.
6. A 2012 clinical trial of a screening technique found that 7 out of 9 identified HGSC
cases arose from the Fallopian tube fimbriae
7. Transfer of transformed serous Fallopian tube secretory epithelium into the
peritoneum of severe combined immunodeficiency (SCID) mice induced tumours
which resemble human HGSC.
8. Reliable HGSC precursors were found on the Fallopian tubes in the form of
abnormal TP53 expression patterns.
9. Serous fimbrial cells are less able to correct DNA damage and reverse mutations
than their ciliated counterparts, indicating how they might be particularly vulnerable
to the mutagenicity of the follicular fluid at ovulation.
Opposing:
1. A 2013 study shows that STICs only advance to form HGSC in the presence of a
BRCA mutation, remaining uninvasive in models without such mutations -
suggesting that HGSCs may arise from Fallopian tube tissue in individuals with
BRCA mutations, but not generally.
Extra-uterine Mullerian All epithelia of the female genital tract - Fallopian tubes, endometrium, endocervix,
epithelium (EUME) ectocervix, upper vagina - are derived from the embryonal Mullerian ducts. Extra-uterine
Mullerian epithelium includes the distal end of the Fallopian tubes (the fimbriae), and
Gynecology 231

instances of endosalpingiosis, endometriosis and endocervicosis.

Supporting:
1. High-grade serous extra-uterine carcinomas have been reported.
2. Intraovarian Müllerian cysts can be explained as examples of endosalpingiosis
within the ovary, rather than as results of Mullerian metaplasia in pre-existing
cortical inclusion cysts as per the coelomic hypothesis.
3. This hypothesis can also account for primary peritoneal carcinomas, as EUME can
be found far away enough from the ovary and fimbriae to give rise to tumors
without input from those organs.
4. The extensiveness of EUME can also explain the presence of paratubal and
paraovarian tumours.
5. Endosalpingiosis - a condition where Fallopian tube epithelium is found outside the
Fallopian tube - supports the likelihood of HGSC arising in the wider peritoneum.
6. Endosalpingiosis is associated with high incidence of borderline serous carcinoma
(38%) and HGSC (18%).
7. A central role of EUME in HGS carcinogenesis would account for cases of HGSC
that do not involve precursor STICs.
Opposing:
1. This is a relatively new hypothesis and requires further research using appropriate
models before conclusions can be drawn.
Border between ovary Supporting:
and Fallopian tube
(transition zone)
1. Transition zones in other epithelia are frequent sites of stem cells.
2. Such an epithelial transition zone may have more ambiguous stem cell fate
signalling, and thus may be vulnerable to carcinogenesis.
3. A number of epithelial transition zones, e.g. ectocervix junction, gastro-duodenal
junction, are implicated in the development of different epithelial cancers.
Opposing:
1. This is a relatively new hypothesis and requires further research using appropriate
models before conclusions can be drawn.
The common Mullerian origin of the Fallopian tubes, uterus, cervix, and upper vagina has resulted in the
proposal that peritoneal high-grade serous carcinoma is a spectrum of a single disease. Relevant animal models
of HGSC can only be developed when the cell origin is properly understood. However, as HGSC tends to
have the same clinical behaviour, regardless of its primary cell origin, determining cell origin is less important
for clinical treatment, but may be of relevance when looking for biomarkers. The specific process by which a
HGSC arises may be related to the BRCA mutation status of the individual, as well as the p53 mutation status.
A 2007 paper describes the process of determining cell of origin as “Tumour origin is typically assigned to the
organ presenting with the dominant tumour mass. The one exception is the peritoneum, which is classified as a
primary site only if a candidate origin is not found in the endometrium, tube or ovary”. It is recognised that
HGSC can have variable and complex primary origins, but understanding and determining this will give insight
into its pathogenesis.

Pathogenesis
Assuming a fimbrial origin, as observed in the majority of HGSC cases, the current understanding of HGSC
genesis suggests a process by which STIC fimbrial cells implant into the ovary as cortical inclusion cysts
through the ovulation rupture site. To account for instances where there is no STIC involvement, endosalpingiosis
or de novo metaplasia of ovarian surface epithelium inclusions are also possible. A much rarer occurrence is the
differentiation of HGSC from LGSC.

DIAGNOSIS
Symptoms include persistent bloating, postmenopausal bleeding, and/or appetite loss. Transvaginal
ultrasonography as well as cancer marker CA125 level analysis is often used to determine potential malignancy
232 Surgical Oncology: Theory and Multidisciplinary Practice

of suspect pelvic masses. Surgical staging is the procedure by which the abdominal cavity and lymph nodes are
examined for malignant tissue, usually via laparoscopy. Tissue biopsies may be taken for further analysis. It is
not until this histological analysis stage that actual diagnosis of HGSC can be made. If glands are seen to fuse
with intricate, extensive papillae featuring epithelial tufting with solid nests surrounded by a space alongside
irregular slit-like spaces, then serous carcinoma is suspected.
Distinguishing between LGSC and HGSC:
• Necrosis is common in HGSC and absent in LGSC, as are giant (multi- or mononucleated) tumour
cells.
• Psammoma bodies are more frequent in low-grade serous carcinoma.
• Tp53 expression is assessed for mutations, overexpression or absence – common features of high-
grade serous carcinomas.
• LGSCs are generally limited to micropapillary growth patterns, whereas HGSCs can exhibit admixed
patterns.
Distinction of HGSC from high-grade endometrioid carcinoma is not always possible. The progression of
HGSC may also be determined from examining the cadherin expression profile.

Screening
As ovarian cancer is rarely symptomatic until an advanced stage, regular pre-emptive screening is a particularly
important tool for avoiding the late stage at which most patients present. However, A 2011 US study found that
transvaginal ultrasound and cancer marker CA125 screening did not reduce ovarian cancer mortality. In contrast,
a more recent UK study found that up to 20% of ovarian cancer deaths could be prevented through annual
performance of these procedures.

PREVENTION
Prevention for an individual deemed at risk of HGSC has, up until recently, been (bilateral or unilateral)
removal of both the ovary and the Fallopian tube (salpingo-oophorectomy). With hormonal and even morbidity
issues resulting from ovary removal, and the increased evidence for the role of the Fallopian tubes HGSC
pathogenesis, optimisation of this procedure has been to remove just the Fallopian tube(s) (salpingectomy)
with the ovaries remaining until age of menopause - although critics of this argue that a reduced blood
supply to the ovaries may induce premature menopause regardless. Prophylactic salpingo-oophorectomy is
frequently performed in carriers of BRCA1 or BRCA2 mutations, although the benefits conferred by this
procedure may vary dependent on the specific mutation. Tubal ligation is a less impactful prophylactic treatment
shown to significantly reduce the risk of HGSC.

TREATMENT
Cytoreductive “debulking” surgery may be performed prior to chemotherapy treatment in order to decrease
the physical mass of the tumour and thus reduce the number of chemotherapy cycles needed. The typical
advanced presentation as well as extra-ovarian spread seen in HGSC can require aggressive debulking procedures.
In some cases total abdominal hysterectomy will be performed, in other cases where the patient intends to bear
children a salpingo-oophorectomy is performed instead. Typical chemotherapy is six cycles of intraperitoneally-
delivered platinum-base adjuvant chemotherapy with agents such as carboplatin. Measurements of blood CA125
levels are used to determine patient response to the treatment. Between 20% and 30% of patients relapse within
six months of treatment. Poly ADP ribose polymerase (PARP) inhibitors are another possible treatment, with
carriers of BRCA1/2 mutations being the most responsive
Gynecology 233

KRUKENBER
KRUKENBER G TUMOR
UKENBERG
A Krukenberg tumor refers to a malignancy in the ovary that metastasized from a primary site, classically the
gastrointestinal tract, although it can arise in other tissues such as the breast. Gastric adenocarcinoma, especially
at the pylorus, is the most common source. Krukenberg tumors are often (over 80%) found in both ovaries,
consistent with its metastatic nature.

SIGNS AND SYMPTOMS

Krukenberg tumors often come to the attention when they cause abdominal or pelvic pain, bloating, ascites,
or pain during sexual intercourse. Krukenberg tumors can occasionally provoke a reaction of the ovarian stroma
which leads to hormone production, that results in vaginal bleeding, a change in menstrual habits, or hirsutism,
or occasionally virilization as a main symptom. All these symptoms are non-specific and can also arise with a
range of problems other than cancer, and a diagnosis can only be made following confirmatory investigations
such as computed tomography (CT) scans, laparotomy and/or a biopsy of the ovary.

CAUSE AND INCIDENCE

Krukenberg tumors can be seen in all age groups, with an average age of 45 years. In most countries,
cancer that has metastasized to the ovary accounts for only about 1 to 2% of ovarian cancer; in the remainder,
the ovary itself is the primary cancer site. However, in Japan they represent a much higher percentage of
malignancies in the ovary (almost 20%) due to the increased prevalence of gastric cancer. Krukenberg tumors
account for about 15% of metastatic cancers that initially appear to have arisen in the ovary, and as such is
less common than metastasis arising from ovarian epithelial and germ-cell tumors. In people who have had
non-gynecologic malignancy, approximately 20% of adnexal masses are malignant, and 60% of these are
Krukenberg tumors.

PATHOGENESIS
Seeding across the abdominal cavity accounted for the spread of this tumor, but spread by way of the
lymphatic is considered more likely. The average age of diagnosis of Krukenberg tumors may partly relate
to the relatively increased vascularity of the ovaries. Microscopically, Krukenberg tumors are often
characterized by mucin-secreting signet-ring cells in the tissue of the ovary; when the primary tumor is
discovered, the same signet-ring cells are typically found. However, other microscopic features can
predominate. Krukenberg tumors are most commonly metastases from gastric cancer, particularly
adenocarcinoma, or breast cancer particularly invasive lobular breast carcinoma, but they can arise in the
appendix, colon, small intestine, rectum, gallbladder, and urinary bladder or gallbladder, biliary tract,
pancreas, ampulla of Vater or uterine cervix. Immunohistochemistry may help in diagnosing Krukenberg
tumors from primary ovarian neo-plasms but needs to be applied with discretion. For example, tumors that
are immunoreactive to CEA or cytokeratin 20 (CK20) and negative for cytokeratin 7 (CK7) may be more
likely to be of colorectal origin.

TREATMENT AND PROGNOSIS

Since Krukenberg tumors are secondary (metastatic), management might logically be driven by identifying
and treating the primary cancer. The optimal treatment of Krukenberg tumors is unclear. The role of surgical
resection has not been adequately addressed but if metastasis is limited to the ovaries, surgery may improve
survival. The role of chemotherapy and/or radiotherapy is uncertain but may sometimes be beneficial.
234 Surgical Oncology: Theory and Multidisciplinary Practice

LEYDIG CELL TUMOUR

LEYDIG
Leydig cell tumour, also Leydig cell tumor (US spelling), (testicular) interstitial cell tumour and (testicular)
interstitial cell tumor (US spelling), is a member of the sex cord-stromal tumour group of ovarian and testicular
cancers. It arises from Leydig cells. While the tumour can occur at any age, it occurs most often in young adults.
A Sertoli-Leydig cell tumour is a combination of a Leydig cell tumour and a Sertoli cell tumour from Sertoli
cells.

PRESENTATION
The majority of Leydig cell tumors are found in males, usually at 5–10 years of age or in middle adulthood
(30–60 years). Children typically present with precocious puberty. Due to excess testosterone secreted by
the tumour, one-third of female patients present with a recent history of progressive masculinization.
Masculinization is preceded by anovulation, oligomenorrhea, amenorrhea and defeminization. Additional
signs include acne and hirsutism, voice deepening, clitoromegaly, temporal hair recession, and an increase in
musculature. Serum testosterone level is high. In men testicular swelling is the most common presenting
feature. Other symptoms depend on their age and the type of tumour. If it is secreting androgens the tumour
is usually asymptomatic, but can cause precocious puberty in pre-pubertal boys. If the tumour secretes
oestrogens it can cause feminisation in young boys. In adults, this causes a number of problems including
gynaecomastia, erectile dysfunction, infertility, feminine hair distribution, gonadogenital atrophy, and a loss
of libido.

DIAGNOSIS
Presence of an ovarian tumour plus hormonal disturbances suggests a Leydig cell tumour, granulosa cell
tumour or thecoma. However, hormonal disturbances, in Leydig tumours, is present in only 2/3 of cases.
Testicular Leydig cell tumours can be detected sonographically, ultrasound examinations may be ordered in
the event of a palpable scrotal lump, however incidental identification of these lesions is also possible. A
conclusive diagnosis is made via histology, as part of a pathology report made during or after surgery. Reinke
crystals are classically found in these tumours and help confirm the diagnosis, although they are seen in less
than half of all Leydig cell tumours. Immunohistochemical markers of Leydig cell tumours include inhibin-
alpha, calretinin, and melan-A.

TREATMENT
The usual chemotherapy regimen has limited efficacy in tumours of this type, although Imatinib has shown
some promise. There is no current role for radiotherapy. The usual treatment is surgery. The surgery for females
usually is a fertility-sparing unilateral salpingo-oophorectomy. For malignant tumours, the surgery may be
radical and usually is followed by adjuvant chemotherapy, sometimes by radiation therapy. In all cases, initial
treatment is followed by surveillance. Because in many cases Leydig cell tumour does not produce elevated
tumour markers, the focus of surveillance is on repeated physical examination and imaging. In males, a radical
inguinal orchiectomy is typically performed. However, testes-sparing surgery can be used to maintain fertility
in children and young adults. This approach involves an inguinal or scrotal incision and ultrasound guidance if
the tumour is non-palpable. This can be done because the tumour is typically unifocal, not associated with
precancerous lesions, and is unlikely to recur. The prognosis is generally good as the tumour tends to grow
slowly and usually is benign: 10% are malignant. For malignant tumours with undifferentiated histology, prognosis
is poor.
Gynecology 235

LUTEOMA
A luteoma is a tumor that occurs in the ovaries during pregnancy. It is associated with an increase of sex
hormones, primarily progesterone and testosterone. The size of the tumor can range from 1 to 25 cm in diameter,
but is usually 6 to 10 cm in diameter and can grow throughout the duration of the pregnancy. However, luteomas
are benign and resolve themselves after delivery. This type of tumor is rare with only about 200 documented
cases; many of these cases were detected accidentally, so the actual rate of occurrence may be higher. The most
obvious symptom of a luteoma is masculinization of the mother and the possible masculinization of the fetus.
This occurs because of the release of testosterone by the luteoma. Testosterone is a sex hormone most abundant
in men although small amounts are naturally present in women. Testosterone is responsible for the male
characteristics such as deepening of the voice, growth of dark hair, and acne. While not life-threatening, the
development of male characteristics associated with luteomas can cause visible changes in the mother and can
have drastic effects on the formation of the fetus. Luteomas can cause the fetus to be born with an ambiguous
sex, which, depending on how the parents prefer to raise the infant, may result in the parents choosing a sex for
the fetus. Luteomas can be associated with female pseudohermaphroditism.

PRESENTATION
Women with a luteoma of pregnancy typically don’t show any symptoms. Only 36% of women actually
show signs of masculinization. These signs include acne, the growth of dark hair (especially on the face),
deepening of the voice, temporal balding, and clitoromegaly. An increase in testosterone levels in the mother
doesn’t necessarily mean masculinization will occur. During a normal pregnancy, the testosterone level will
increase slightly in the first and second trimester, but doubles in the third trimester. The testosterone level also
depends on the sex of the fetus; male fetuses cause a bigger increase in testosterone levels than female fetuses.
Male fetuses, when carried by a mother who develops male characteristics from a luteoma, are not highly
affected by the increase in testosterone in the mother due to this conditions. However, after birth, the male fetus
may have abnormally high levels of testosterone, but this resolves itself. There hasn’t been any ties between
luteomas and the male infant producing high amounts of testosterone by itself. Out of the 36% of women who
show male characteristics from the luteoma, 75% of female fetuses will also show signs of masculinization.
Female fetuses can have a variety of symptoms ranging from severe, requiring surgery, to mild, which resolves
itself after birth. The severity of the symptoms a female fetus undergoes depends on when the exposure occurs
and the duration of the exposure. If a female fetus is exposed to increased levels of testosterone in the first 7–
12 weeks of the pregnancy, labioscrotal fusion and clitoromegaly can occur. These conditions would need
correctional surgery if the infant was to be raised female. If testosterone exposure occurs after the first 12
weeks of pregnancy, no fusion will occur but the clitoris could still be enlarged. The enlarged clitoris usually
corrects itself after birth and the abnormally high testosterone levels will decrease as the body produces its own
hormones.

DETECTION
Luteomas are not often detected before delivery. Most luteomas are found during surgery if a caesarean
section is performed or when some other surgery is performed. Pre-delivery detection is not effective for many
reasons. Some tests, that can be performed pre-delivery, measure the amount of testosterone in the blood;
however, this is not a very useful detection method since normal pregnancies have increased amounts of
testosterone. Another method that would be useful to determine if a fetus is being exposed to testosterone is to
test the placenta and umbilical cord for testosterone. The placenta has a mechanism for converting hormones
from the mother into hormones that the fetus needs. If the amount of testosterone in the umbilical cord is higher
236 Surgical Oncology: Theory and Multidisciplinary Practice

than normal, the gene type of the fetus should be determined to see if the fetus is male or female. If the fetus is
female then the high levels of testosterone in the umbilical cord could be an indicator that a luteoma is present.
Unfortunately, this procedure can’t be safely performed until after the fetus has undergone differentiation (when
the sex of the fetus becomes apparent). But by this time the damage has already been done.

TREATMENT
No treatments for luteomas are currently available. The luteomas can be detected through ultrasound if
masculinization is apparent in the mother. The fetus can be tested for gene type and if the fetus is female and the
umbilical cord tests high for testosterone levels then the risks of masculinization of the fetus can be considered.
Interventions can’t be made to change the outcomes, but the potential risks can be analyzed in order to make
preparations. After the fetus is delivered the luteoma regresses on its own and only monitoring of the mother is
needed after delivery. Depending on the sex of the fetus, exposure time and duration, the parents may need to
decide if they will raise the child as male or female. Surgery may be necessary depending on what sex the child
is going to be raised.

CAUSES
There are a couple of conditions that predispose a woman to forming a luteoma during pregnancy. Polycystic
Ovary Syndrome is one such condition. This syndrome is associated with high hormone levels and the failure of
the ovaries to release an egg during the menstrual cycle, a symptom more often associated with menopause. The
high levels of hormones in polycystic ovary syndrome seem to predispose women to forming a luteoma during
pregnancy. A characteristic of luteomas is that they grow better in the presence of high levels of hormones that
function in normal growth, sexual development, and reproductive function. Polycystic Ovary Syndrome causes
an excess of hormones in the body including some of the hormones related to these functions. Women who have
already had a luteoma during a previous pregnancy have a higher high risk of having another luteoma. In this
situation, women can be counseled on the risks of another pregnancy and their alternatives. Other risk factors
associated with luteomas are multiple pregnancies, advanced maternal age, and Afro-Caribbean ethnicity.
Bibliogrpahy 237

Bibliography

Abrams HL, Spiro R, Goldstein N: Metastases in carcinoma. Analysis of 1000 autopsied cases. Cancer. (2000).
Adson MA, van Heerden JA, Adson MH, Wagner JS, IlstrupOM: Resection of hepatic metastases from colorectalcancer.
Arch Surg. 2004.
Altman E, Cadman E: An analysis of 1539 patients withcancer of unknown primary site. Cancer. 2006.
Barrie JR, Knapper WH, Strong EW: Cervical nodal metastasesof unknown origin. Am J Surg. 2000.
Berg AR, Linder J, Anderson RW, et al.: The undifferentiated malignant neoplasm. Identitification of lymphomaarising in
skeletal muscle by immunohistochemical analysis. JAMA. 2005.
Bloch KJ, Frankin E: Plasma cell dyscrasias and cryoglobulins. JAMA. 2002.
Bosman FT, Giard RWM, Kruseman ACN, Knijnenburg G,Spaander PJ: Human chorionic gonadotrophin andalpha-
fetoprotein in testicular germ cell tumours: a retrospective immunohistochemical study. Histopathology. 2000.
Byers RM: Modified neck dissection. A study of 967 cases from 1970 to 1980. Am J Surg. 2005.
Cady B: Lymph node metastasis.Indicators, but notgovernors of survival. Arch Surg. 2004.
Cancer Registry of Norway: Incidence of cancer in Norway1972-1976. Oslo. 2008.
Clary CF, Michel RP, Wang NS, Hanson RE: Metastaticcarcinoma. The lung as the site for the clinically undiagnosedprimary.
Cancer. 2003.
Coleman M: Chemotherapy for large-cell lymphoma:optimism and caution. Ann Intern Med. 2005.
Copeland EM, McBride CM: Axillary metastases froman unknown primary site. Ann Surg. 2003.
Dahl 0: Testicular carcinoma. A curable malignancy. ActaRadiol [Oncol]. 2005.
Devine KD: Cancer in the neck without obvious source. Mayo ClinProc. 2008.
Dickson R, Vargas DR: Occult primary of the head andneck. J Otolaryngol. 2009.
Didolkar MS, Fanous N, Elias EG, Moore RH: Metastaticcarcinomas from occult primary tumors. A study of 254 patients.
Ann Surg. 2007.
Fitzpatrick pJ, Kotalik JF: Cervical metastases from anunknown primary tumor. Radiology. 2004.
238 Surgical Oncology: Theory and Multidisciplinary Practice

Ford IF, Butcher DN, Masters JRW, Parkinson MC: Immunocytochemicallocalisation of prostate-specific antigen: specificity
and application to clinical practice. Br J Urol. 2005.
Frei E III: The National Cancer Chemotherapy Program. Science. 2002.
Gaber AO, Rice P, Eaton C, Pietrafitta n, Spatz E, Deckers PJ: Metastatic malignant disease of unknown origin. AmJ Surg.
2003.
Gatter KC, Alcock C, Heryet A, et al.: The differential diagnosis of routinely processed anaplastic tumors usingmonoclonal
antibodies. Am J ClinPathol. 2004.
Gatter KC, Mason DY, Heyderman E, Isaacson PG: Commentary: which antibodies for diagnostic pathology?
Histopathology. 2007.
Gown AM, Vogel AM: Monoclonal antibodies to humanintermediate filament proteins. III. Analysis of tumors. Am J
ClinPathol. 2005.
Hainsworth JD, Greco A: Testicular germ cell neoplasms. Am J Med. 2003.
Hainsworth JD, Einhorn LH, Williams SD, Stewart M, GrecoFA: Advanced extragonadal germ cell tumors: successful
treatment with combination chemotherapy. ProcAm SocClin Oncol. 2002.
Harrington KD: New trends in the management of lower extremity metastases. ClinOrthop. 2002.
Henderson IC, Canellos GP: Cancer of the breast. Thepast decade. N Engl J Med. 2000.
Hendrickson FR: Radiation therapy of metastatic tumors. SeminOncol. 2005.
Herrera GA, Turbat-Herrera EA, Lott RL: S-100 protein expression by primary and metastatic adenocarcinomas. AmJ
ClinPathol. 2008.
Holmes FF, Fouts TL: Metastatic cancer of unknown primary site. Cancer. 2000.
Jesse RH, Perez CA, Fletcher G: Cervical lymph nodemetastasis: unknown primary cancer. Cancer. 2003.
Karsell PR, Sheedy PF II, O’Connell MJ: Computed tomographyin search of cancer of unknown origin. JAMA. 2002.
Kirk D: Prostatic carcinoma. Br Med. 2005.
Kjaer M, Engelholm SA: The clinical course and prognosis of patients with renal adenocarcinoma with solitarymetastasis.
Int J RadiatOncolBioiPhys. 2002.
Klee GG, Go VLW: Laboratory report. Serum tumor markers. Mayo ClinProc. 2002.
King JW, DeSombre ER, Jensen EV, Greene GL: Comparisonof immunecytochemical and steroid-binding assaysfor estrogen
receptor in human breast tumors. Cancer. 2005.
King JW, Greene GL: Monoclonal antibodies localizeoestrogen receptor in the nuclei of target cells. Nature. 2004.
Kohler G, Milstein C: Continuous cultures of fused cellssecreting antibody of predefined specificity. Nature. 2005.
Koss LG: Thmors of the urinary bladder. AFIP, Washington (Atlas of tumor pathology, 2nd ser, fasc 11). 2005.
Koss LG: Diagnostic cytology and its histopathologicbases, 3rd edn. Lippincott, Philadelphia. 2009.
Koss LG: Mapping of the urinary bladder: its impact onthe concepts of bladder cancer. Hum Pathol. 2009.
Kurman RJ, Norris HJ: Endometrialneoplasia: hyperplasiaand carcinoma. In: Blaustein A (ed) Pathology of the female
genital tract, 3rd edn. Springer, Berlin Heidelberg New York. 2002.
Leary JJ, Brigati DJ, Ward DC: Rapid and sensitive colorimetricmethod for visualizing biotinlabeled DNA probeshybridized
to DNA or RNA immobilized on nitrocellulose: bioblots. ProcNatlAcadSci. 2003.
Le Beau MM, Westbrook CA, Diaz MO, Rowley JD, Oren M: Translocation of the p53 gene in t(15;17) in
acutepromyelocyticleukaemia. Nature. 2005.
Maniatis T, Kee SG, Efstratiadis A, Kafatos FC: Amplificationand characterization of a globin gene synthetized invitro.
Cell. 2006.
Bibliogrpahy 239

Mariani-Costantini R, Barbanti P, Colnaghi MI, Menard S,Clemente C, Rilke F: Reactivity of a monoclonal antibodywith
tissues and tumors from the human breast. Am JPathol. 2004.
Matthews MJ, Gazdar AF: Changing histology in malignanttumors: diagnostic and therapeutic significance. Eur JCancer
ClinOncol. 2005.
Miettinen M, Virtanen I, Talerman A: Intermediate filamentproteins in human testis and testicular germ-cell tumors. Am
J Pathol. 2005.
Miller GJ: An atlas of prostatic biopsies: dilemmas of morphologic variance. ProgSurgPathol. 2008.
Ming SC, Bajta A, Correa P, Elster K, Jarvi OH, Munoz N,Nagayo T, Stemmerman GN: Gastric dysplasia. Significance
and pathologic criteria. Cancer. 2004.
Moll R, Franke WW, Schiller DL: The catalog of humancytokeratins: patterns of expression in normal epithelia, tumorsand
cultured cells. Cell. 2002.
Mukai K, Schollmeyer JV, Rosai J: Immunohistochemicallocalization of actin: its application in surgical pathology. Am
J SurgPathol. 2001.
Muto T, HJR Bussey, Morson BC: The evolution of cancerof the colon and rectum. Cancer. 2005.
Nakazawa H, Rosen P, Lane N, Lattes R: Frozen sectionexperience in 3000 cases. Accuracy, limitations andvalue in
residency training. Am J ClinPathol. 2008.
Norton AJ, Ramsay AD, Smith SH, Beverley PCL, IsaacsonPG: Monoclonal antibody (UCHLl) that recognizes normal
and neoplastic T cells in routinely fixed tissues. JClinPathol. 2006.
O’Connor DT, Deftos LJ: Secretion of chromogranin Aby peptide-producing endocrine neoplasms. N Engl J Med. 2006.
Osborn M, Weber K: Thmor diagnosis by intermediate filament typing. A novel tool for surgical pathology. Lab Invest.
2003.
Sudhir Kumar Jain, David L Stoker and Raman Tanwar: Basic Surgical Skills and Techniques, Jaypee Brothers Medical
Publishers, 2018.
Handbook on Medical and Surgical Disposable Products, NIIR Project Consultancy Services, 2014.
UdaiVir Singh: Indo-Pak Relations : Beyond Surgical Strike, Pentagon Press, 2017.
Poonam Kapoor: Medical-Surgical Care Planning, Anmol, 2010.
Rashmi Ahuja: Medical-Surgical Nursing : Clinical Management for Positive Outcomes, Anmol, 2010.
R. Ranjan: Pakistan at Cross Roads Skirmishes and Surgical Strikes, Sumit Enterprises, 2017.
Nitin A Gokhale: Securing India the Modi Way: Pathankot, Surgical Strikes and More, Bloomsbury India, 2017.
D.G. Thatte: Surgical Anatomy in Ayurveda, Chaukhambha Orientalia, 2009.
Rajat Chauhan: The Pain Handbook: A Non-Surgical Way to Managing Back, Neck and Knee Pain, Penguin Random
House, 2016.
Swapan Kumar Maiti and Naveen Kumar: A Colour Book: Laparoscopic Techniques in Small Animal Surgery, New India
Publishing Agency, 2016.
Nasim H. Naqvi: A Study of Buddhist Medicine and Surgery in Gandhara : Vol. XI: x, MotilalBanarsidass, 2011.
Ellis: Cambridge Illustrated History of Surgery, Cambridge Univ Press.
Sonya R. Hardin and Roberta Kaplow: Cardiac Surgery Essentials for Critical Care Nursing, Jones and Bartlett Learning,
2011.
Ashok Garg, Luther L. Fry, GeofferyTabin, Francisco J. Gutierrez-Carmona and Suresh K. Pandey: Clinical Practice in
Small Incision Cataract Surgery (Phaco Manual) (with two CD), Jaypee Brothers, 2004.
R Dayananda Babu: Clinical Surgery Pearls, Jaypee Brothers Medical Publishers, 2018.
240 Surgical Oncology: Theory and Multidisciplinary Practice

Samiran Nundy and Dirk J. Gouma: Complications after Gastrointestinal Surgery, OUP India, 2017.
C.R. Ballal and C. Rajesh Ballal: Comprehensive Clinical Surgery, Ane Books, 2017.
HemantaPanigrahi and K.K. Sijoria: Concept of Plastic Surgery in Ayurveda, Chaukhambha Publishers, 2003.
Chandrakant P Taware: Evolving Trends in Oral and Maxillofacial Surgery, CBS Publishers, 2009.
A.K. Gangwar, Naveen Kumar and Kh. Sangeeta Devi: General Animal Surgery and Anesthesiology (With Theory and
Practicals), New India Publishing Agency, 2010.
A.M. Pawde; H.P. Aithal and M.M.S. Zama: Handbook on Field Veterinary Surgery, Daya Publishing House, 2015.
KanjivLochan: Illustrations on Ayurvedic Surgery and Pharmaceutics, Chaukhambha Pub, 2007.
Devaji Rao: Instant General Surgery 2013 , Ane Books Pvt. Ltd, 2012.
Greg McLatchie and David Leaper: Oxford Handbook of Clinical Surgery, Oxford University, 2002.
S Brian Jiang and Arisa E Ortiz: Reconstructive Dermatologic Surgery, Jaypee Brothers Medical Publishers, 2018.
MeenaTalim: Science of Medicine and Surgery in Buddhist India, Buddhist World Press, 2009.
P H Kulkarni: Surgery in Ayurveda: ShalyaShalakya, Sri Satguru Pub, 2008.
P.B. Patel and A.M.Patel: Veterinary Surgery: A Practical Guide, Daya Publishing House, 2016.
Arlene, D. H.: Patients with Cancer:Understanding the Psychological Pain. Philadelphia: Lippincott), 2000.
Barbara, B. B et al.: Breast Deriase for Clinicians. (New York: McGaw-Hill), 2001.
Black, J.M et al.: Medical Surgical Nursing. 4th ed. (Philadelphia: W.B.Saunders Co.,), 2003.
Connr H.Y et al.: Cancer Nursing: Principles and Practice. (Boston: Johns andBartlett), 2005.
Fischer, D.S.: Follow Up of Cancer: A Handbook for Physicians. 4th ed. (Philadelphia: Lippincott), 2006.
Harris, J. R et al.: Disease of the Breast. (Philadelphia: Lippincott), 2010.
Joiyce, M. Black et al.: Medical Surgical Nursing. Fourth Ed. (Philadelphia:W.B. Saunders Company, 2003).
Kornblith, A B: “Psychosocial Adaptation of Cancer Survivors in Holland”,in J.C. Rowland (ed.) Psycho Oncology.
(New York: Oxford UniversityPress), 2008.
Lewis, Jacqueline and Arnold, Hodder: Your Guide to Breast Cancer. (London: Royal Society of Medicine), 2005.
Ruth, McCorkle et al.: Cancer Nursing: A Comprehensive Text Book. (Philadelphia: W.B. Saunders Co.,), 2006.
Smeltzer, Susanne C et al.: Text Book of Medical Surgical Nursing. Vol. 2. (New Delhi: Lippincott Williams & Wilkins),
2009.
Vincent, T. D et al.: Cancer: Principles and Practice of Oncology. (Philadelphia: Lippincott Williams & Wilkins), 2008.
Winston, C. P.: Cancer Pain Management: Principles and Practice. (Boston:Butterworth Heinemann), 2007.
Index 241

Index

A
Ablation 65, 90, 96, 110, 112, 122, 126, 141, 157, 159
Aggressive 11, 17, 19, 20, 29, 30, 34, 50, 55, 78, 79, 102, 109, 111, 126, 128, 138, 140, 141, 143, 146,
149, 156, 157, 158, 159, 167, 169, 170, 176, 178, 181, 182, 183, 186, 187, 190,
192, 198, 201, 212, 217, 218, 224, 229, 232
Alcohol 23, 25, 29, 55, 59, 60, 61, 63, 67, 83, 91, 92, 95, 98, 99, 102, 108, 197
Antibodies 30, 31, 32, 99, 122, 163, 171, 190

B
Birth control 24, 36, 193
Blood 4, 11, 17, 49, 52, 58, 59, 60, 66, 67, 68, 69, 74, 76, 79, 81, 82, 84, 85, 87, 88, 91, 93, 97, 98, 103,
105, 107, 111, 113, 128, 129, 141, 146, 149, 151, 152, 153, 154, 155, 157, 158,
159, 160, 163, 164, 166, 167, 168, 169, 170, 171, 172, 174, 175, 178, 179, 181,
190, 191, 197, 198, 199, 201, 211, 212, 213, 216, 217, 219, 222, 225, 226, 232,
235
Breast cancer 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 157, 165, 174, 195, 196, 197, 214, 217,
227, 233
Budding 102

C
Cancer 1, 2, 3, 4, 5, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,
35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,
77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 94, 95, 96, 97, 98,
99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 114, 115, 116, 117, 118, 119,
121, 122, 123, 124, 125, 126, 127, 128, 133, 134, 136, 139, 140, 141, 142, 143,
144, 146, 147, 148, 149, 151, 152, 153, 154, 155, 157, 158, 159, 160, 161, 162,
242 Surgical Oncology: Theory and Multidisciplinary Practice

163, 164, 165, 167, 169, 170, 171, 172, 173, 174, 175, 177, 178, 179, 180, 181,
182, 183, 184, 185, 186, 188, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201,
202, 203, 204, 205, 206, 210, 211, 214, 215, 216, 217, 218, 219, 220, 221, 222,
223, 224, 225, 226, 227, 228, 229, 231, 232, 233
Care 7, 11, 12, 17, 21, 26, 30, 49, 57, 59, 64, 66, 70, 74, 79, 90, 96, 97, 105, 109, 113, 156, 162, 163, 178,
179, 188, 204, 217, 219, 220, 221
Cell origin 229, 230, 231
Chemotherapy 2, 12, 15, 19, 20, 23, 29, 30, 31, 32, 34, 35, 38, 41, 42, 44, 46, 50, 58, 59, 64, 65, 66,
69, 70, 71, 73, 74, 78, 79, 85, 88, 89, 90, 98, 104, 105, 109, 110, 111, 112, 113,
114, 116, 117, 118, 120, 121, 132, 139, 140, 141, 143, 144, 146, 148, 149, 150,
151, 152, 155, 156, 157, 159, 162, 166, 167, 168, 169, 172, 173, 174, 175, 177,
178, 180, 181, 182, 185, 187, 188, 191, 193, 201, 202, 203, 204, 205, 207, 208,
209, 210, 211, 212, 213, 217, 218, 219, 220, 221, 222, 224, 225, 226, 229, 232,
233, 234
Childbearing 24, 52, 53, 56, 217
Comparison 15, 34, 35, 53, 101, 134, 219
Conservation 41, 45, 46
Control 4, 11, 12, 15, 20, 24, 36, 40, 42, 43, 44, 45, 46, 65, 75, 79, 84, 85, 92, 119, 120, 141, 143, 152,
156, 160, 161, 180, 193, 196, 197, 221

D
Detection 7, 12, 13, 16, 30, 38, 51, 63, 81, 91, 93, 103, 106, 109, 110, 121, 126, 145, 171, 216, 217, 222,
235
Diabetes 25, 29, 68, 79, 82, 83, 84, 91, 92, 108, 111, 113
Diagnosis 1, 5, 7, 8, 9, 10, 16, 17, 19, 21, 23, 24, 26, 29, 30, 34, 35, 39, 40, 46, 47, 50, 56, 59, 63, 66, 68,
70, 73, 74, 76, 77, 79, 81, 82, 84, 85, 87, 90, 93, 94, 101, 102, 103, 112, 114, 115,
118, 119, 122, 126, 127, 129, 136, 139, 141, 142, 143, 144, 146, 148, 151, 153,
154, 156, 157, 158, 160, 162, 166, 168, 169, 170, 171, 172, 173, 175, 176, 177,
178, 179, 181, 182, 184, 187, 188, 189, 190, 191, 193, 198, 199, 201, 204, 205,
206, 207, 208, 209, 211, 213, 214, 217, 221, 222, 224, 231, 232, 233, 234
Diet 25, 55, 56, 59, 63, 66, 67, 70, 98, 102, 108, 196, 197, 221
Disease 2, 4, 7, 8, 11, 12, 14, 17, 18, 19, 21, 23, 24, 25, 29, 32, 34, 35, 39, 41, 42, 44, 45, 46, 47, 48, 55,
56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 73, 74, 75, 77, 78, 79, 81,
82, 83, 84, 85, 87, 90, 91, 92, 93, 95, 96, 97, 98, 99, 101, 103, 104, 106, 107,
108, 109, 110, 111, 112, 113, 114, 116, 118, 119, 121, 122, 127, 132, 133, 134, 135,
136, 137, 140, 141, 142, 143, 144, 147, 149, 150, 151, 152, 154, 155, 157, 158,
159, 160, 161, 162, 163, 165, 166, 168, 169, 170, 172, 174, 176, 177, 178, 179,
180, 181, 182, 184, 185, 187, 188, 192, 193, 195, 196, 199, 203, 204, 205, 206,
207, 208, 211, 212, 213, 216, 217, 218, 219, 220, 221, 222, 224, 225, 226, 227,
231

E
Early 2, 3, 4, 7, 11, 13, 15, 16, 17, 23, 30, 35, 36, 38, 39, 41, 44, 45, 46, 51, 55, 56, 60, 63, 64, 66, 69, 70,
72, 73, 76, 78, 79, 81, 82, 83, 84, 85, 99, 101, 103, 104, 106, 109, 111, 116, 119,
120, 127, 135, 136, 141, 142, 144, 148, 150, 151, 153, 158, 170, 172, 174, 177,
182, 185, 186, 193, 194, 198, 199, 202, 204, 205, 206, 211, 212, 217, 218, 222,
226
Enforcement 57
Environment 13, 35, 197
Evaluate 11, 42, 63, 93, 109, 117, 119, 190, 204
Index 243

Exercise 23, 24, 29, 55, 99, 103, 106, 197

F
Fertility 56, 143, 193, 194, 207, 217, 218, 224, 234

H
Hereditary 25, 26, 47, 48, 50, 51, 56, 66, 67, 68, 71, 82, 83, 84, 98, 99, 107, 114, 115, 133, 136, 147, 189,
195, 196, 229
Hormones 24, 29, 35, 36, 53, 61, 81, 89, 90, 106, 128, 129, 136, 194, 220, 227, 235, 236
Human 4, 5, 8, 62, 70, 77, 84, 100, 135, 139, 144, 151, 165, 169, 175, 186, 197, 212, 217, 220

I
Immunotherapy 2, 12, 15, 36, 70, 105, 163, 185, 207, 220, 226
Incidence 9, 14, 16, 35, 36, 38, 51, 62, 74, 75, 82, 91, 92, 113, 119, 122, 126, 137, 144, 147, 149, 155,
162, 166, 170, 176, 178, 182, 183, 192, 224, 225, 229, 233
Infection 44, 61, 66, 67, 73, 74, 75, 91, 92, 93, 95, 148, 169, 170, 171, 172, 174, 175, 178, 197, 212, 217
Inflammation 24, 67, 73, 74, 76, 84, 91, 99, 106, 169, 171, 197, 227
Information 11, 40, 55, 63, 76, 120, 143, 144, 153, 177, 208, 214
Injury 62, 112, 113

L
Laboratory 8, 14, 19, 68, 74, 134, 161, 163, 179, 192, 199, 204, 205
Lifestyle 24, 55, 60, 98, 102, 103, 107, 108
Litigation 57
Liver 3, 8, 13, 24, 40, 60, 63, 66, 69, 72, 73, 74, 75, 76, 77, 78, 82, 84, 85, 87, 89, 91, 92, 93, 94, 95, 96,
97, 101, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 116, 117, 119, 135, 136,
137, 145, 146, 151, 154, 157, 159, 167, 168, 175, 177, 179, 188, 191, 193, 199,
203, 205, 215, 216, 218
Liver transplantation 78, 89, 95, 96
Location 12, 13, 17, 19, 24, 34, 47, 59, 63, 64, 74, 75, 78, 81, 84, 88, 89, 98, 101, 102, 110, 116, 128, 129,
140, 141, 142, 143, 152, 160, 162, 182, 184, 191, 192, 206, 209, 210
Lung 9, 14, 24, 35, 60, 82, 95, 110, 135, 137, 139, 149, 155, 159, 160, 180, 181, 201, 204, 216

M
Management 11, 21, 30, 38, 39, 47, 64, 70, 79, 82, 87, 88, 98, 104, 108, 114, 119, 122, 157, 178, 182,
183, 185, 191, 200, 217, 228, 233
Mechanism 67, 68, 106, 133, 147, 166, 172, 229, 235
Medication 20, 31, 52, 96, 103, 104, 178, 193, 194
Microscopy 102, 184

N
Natural 40, 46, 47, 53, 54, 55, 96, 118, 119, 121, 136, 144, 147, 163, 164, 176

P
Pathology 8, 13, 17, 37, 47, 57, 77, 94, 101, 142, 149, 154, 158, 162, 166, 169, 171, 179, 200, 203, 204,
206, 212, 228, 234
Pharmacology 226
244 Surgical Oncology: Theory and Multidisciplinary Practice

Pregnancy 56, 57, 58, 194, 195, 198, 199, 211, 212, 225, 229, 235, 236
Prevention 9, 29, 30, 51, 52, 53, 64, 70, 87, 95, 99, 102, 103, 108, 127, 171, 196, 217, 232
Previous 16, 70, 84, 100, 108, 157, 176, 188, 236
Prognosis 12, 13, 26, 27, 29, 30, 32, 33, 34, 35, 37, 40, 41, 45, 53, 58, 65, 66, 71, 73, 78, 79, 80, 81, 84,
90, 91, 94, 95, 98, 106, 112, 114, 117, 118, 122, 126, 127, 128, 129, 133, 141, 144,
145, 148, 149, 150, 154, 159, 162, 170, 173, 176, 177, 178, 180, 181, 182, 183,
184, 186, 188, 190, 200, 202, 203, 204, 205, 208, 209, 210, 211, 212, 213, 214,
216, 221, 222, 224, 225, 228, 233, 234

R
Radiation therapy 2, 12, 19, 20, 23, 30, 32, 38, 58, 59, 62, 66, 69, 70, 71, 74, 78, 90, 97, 98, 105, 108,
121, 139, 143, 146, 150, 151, 152, 155, 156, 157, 159, 162, 169, 171, 174, 175,
180, 181, 185, 193, 220, 221, 222, 234
Recurrence 10, 11, 12, 13, 17, 20, 21, 30, 32, 34, 35, 36, 40, 65, 95, 96, 104, 105, 111, 119, 141, 148, 151,
155, 157, 167, 173, 181, 185, 188, 192, 206, 213, 219, 220, 221, 222, 224, 226,
229
Research 3, 11, 12, 14, 35, 36, 45, 56, 57, 64, 72, 82, 83, 87, 100, 117, 142, 144, 147, 154, 158, 159, 160,
168, 171, 179, 186, 197, 199, 208, 220, 225, 226, 227, 229

S
Screening 15, 16, 23, 25, 26, 30, 38, 51, 52, 55, 56, 57, 64, 66, 76, 79, 82, 87, 93, 95, 98, 103, 104, 108,
115, 121, 122, 143, 171, 172, 193, 196, 216, 217, 222, 225, 232
Skin 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 13, 14, 16, 17, 18, 19, 20, 21, 23, 24, 34, 35, 39, 40, 45, 46, 54, 56, 62,
65, 66, 68, 74, 79, 80, 81, 82, 91, 97, 118, 119, 128, 143, 145, 146, 147, 151, 154,
155, 167, 168, 169, 170, 172, 174, 178, 196, 211
Skin cancer 2, 5, 10, 16, 17, 18, 19, 21, 35, 56
Smoking 16, 24, 55, 59, 60, 61, 64, 66, 67, 79, 82, 83, 87, 98, 99, 102, 108, 175, 197, 206, 217
Solid 6, 59, 81, 134, 147, 158, 164, 182, 191, 198, 199, 200, 205, 207, 211, 212, 213, 228, 232
Spectrum 117, 155, 164, 192, 211, 231
Spread 1, 2, 3, 4, 8, 11, 13, 15, 16, 17, 18, 23, 24, 27, 34, 37, 60, 63, 64, 66, 68, 69, 70, 72, 79, 81, 82, 84,
85, 87, 88, 89, 90, 91, 94, 95, 96, 97, 98, 101, 104, 111, 116, 117, 118, 119, 121,
126, 138, 139, 140, 151, 152, 153, 157, 158, 159, 162, 165, 169, 170, 175, 176,
177, 178, 193, 200, 201, 204, 205, 211, 212, 215, 217, 218, 222, 232, 233
Stomach cancer 55, 66, 67, 68, 69, 70, 71, 214
Sunscreen 1, 10
Support 13, 21, 25, 29, 30, 35, 49, 93, 144, 156, 193, 216, 221
Surgery 1, 4, 10, 11, 12, 15, 19, 20, 21, 23, 29, 30, 31, 32, 34, 36, 38, 39, 40, 41, 44, 45, 46, 52, 53, 54,
58, 59, 64, 65, 66, 69, 70, 71, 73, 74, 76, 77, 78, 79, 82, 83, 85, 87, 88, 89, 90,
95, 96, 98, 101, 104, 105, 107, 110, 111, 112, 116, 117, 118, 119, 121, 126, 127, 132,
136, 137, 139, 141, 143, 144, 148, 149, 150, 151, 152, 155, 156, 157, 159, 162,
167, 169, 172, 173, 175, 180, 181, 182, 185, 187, 189, 191, 193, 198, 199, 202,
204, 205, 206, 208, 210, 211, 213, 214, 216, 217, 218, 219, 220, 221, 222, 224,
225, 232, 233, 234, 235, 236
Surveillance 15, 93, 102, 105, 106, 114, 118, 132, 136, 163, 221, 234
Symptoms 2, 3, 5, 23, 24, 25, 35, 36, 40, 52, 64, 68, 72, 73, 76, 77, 78, 79, 80, 81, 82, 84, 87, 88, 89,
92, 93, 94, 95, 96, 97, 100, 101, 102, 103, 105, 106, 107, 110, 111, 115, 116, 117,
118, 120, 135, 140, 142, 143, 144, 145, 146, 147, 148, 151, 152, 153, 155, 157,
161, 165, 167, 168, 170, 173, 174, 176, 186, 193, 194, 195, 197, 199, 200, 202,
206, 208, 210, 213, 214, 219, 220, 225, 226, 227, 232, 236
Index 245

T
Tolerance 44, 181
Transmission 133, 170
Treatment 1, 2, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 26, 27, 29, 30, 31, 32, 34, 35, 36, 38, 40, 41,
42, 43, 44, 45, 46, 50, 53, 58, 59, 64, 65, 68, 69, 70, 73, 74, 77, 78, 79, 85, 88,
89, 90, 91, 92, 93, 94, 95, 96, 97, 102, 104, 105, 107, 108, 109, 112, 113, 114,
115, 116, 117, 118, 121, 122, 126, 127, 132, 137, 141, 143, 146, 148, 149, 150, 151,
154, 155, 156, 157, 158, 159, 162, 163, 165, 167, 168, 169, 170, 171, 173, 174,
175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 191, 192, 193,
195, 200, 202, 203, 204, 205, 206, 207, 210, 211, 212, 214, 217, 218, 219, 220,
221, 222, 224, 226, 227, 228, 231, 232, 233, 234, 236
Tumor 2, 3, 4, 5, 7, 8, 10, 11, 13, 14, 15, 17, 18, 19, 20, 24, 27, 31, 32, 34, 37, 38, 39, 40, 41, 42, 45, 46,
47, 59, 60, 63, 64, 65, 69, 70, 71, 74, 75, 76, 77, 78, 79, 81, 83, 84, 85, 87, 88,
89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 106, 107, 109,
110, 111, 112, 114, 116, 117, 118, 119, 121, 122, 128, 129, 133, 135, 136, 137, 138,
139, 140, 141, 142, 143, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155,
156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 170, 171, 172,
173, 174, 176, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191,
192, 194, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209,
210, 211, 212, 213, 214, 215, 217, 218, 219, 220, 221, 222, 224, 225, 228, 233,
234, 235

U
UV radiation 3, 4, 5, 56

W
Women 1, 2, 3, 4, 14, 23, 24, 25, 29, 30, 31, 32, 34, 35, 36, 39, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,
59, 61, 67, 73, 79, 81, 82, 83, 98, 108, 121, 122, 127, 136, 143, 150, 155, 156,
192, 193, 194, 195, 196, 197, 199, 200, 201, 202, 207, 208, 210, 216, 217, 218,
220, 221, 222, 224, 225, 227, 228, 229, 235, 236