See Targeted Therapy available online at studentconsult.

com C H A P T E R

Female Genital System

and Breast 19
CHAPTER OUTLINE
Vulva 713 Endometriosis 721 Ectopic Pregnancy 732
Vulvitis 713 Abnormal Uterine Bleeding 722 Gestational Trophoblastic Disease 733
Nonneoplastic Epithelial Disorders 714 Proliferative Lesions of the Endometrium Hydatidiform Mole: Complete and Partial 733
Tumors 714 and Myometrium 723 Invasive Mole 733
Condylomas 714 Endometrial Hyperplasia 723 Gestational Choriocarcinoma 734
Carcinoma of the Vulva 715 Endometrial Carcinoma 724 Placental Site Trophoblastic Tumor 735
Extramammary Paget Disease 715 Endometrial Polyps 724 Preeclampsia/Eclampsia (Toxemia of
Vagina 716 Leiomyoma 725 Pregnancy) 735
Vaginitis 716 Leiomyosarcoma 726 Breast 736
Malignant Neoplasms 716 Fallopian Tubes 726 Clinical Presentations of Breast
Squamous Cell Carcinoma 716 Ovaries 727 Disease 736
Clear Cell Adenocarcinoma 716 Follicle and Luteal Cysts 727 Inflammatory Processes 737
Sarcoma Botryoides 717 Polycystic Ovarian Syndrome 727 Stromal Neoplasms 738
Cervix 717 Tumors of the Ovary 727 Benign Epithelial Lesions 738
Cervicitis 717 Surface Epithelial Tumors 727 Carcinoma 739
Neoplasia of the Cervix 717 Serous Tumors 728 Epidemiology and Risk Factors 741
Squamous Intraepithelial Lesion (SIL, Cervical Mucinous Tumors 729
Intraepithelial Lesion) 718 Endometrioid Tumors 729
Invasive Carcinoma of the Cervix 720 Brenner Tumor 729
Endocervical Polyp 720 Other Ovarian Tumors 730
Uterus 721 Diseases of Pregnancy 732
Endometritis 721 Placental Inflammations and
Adenomyosis 721 Infections 732

Vulva
The vulva is the external female genitalia and includes plaques and may be a reaction to urine, soaps, detergents,
the hair-bearing skin (labia majora) and mucosa (labia antiseptics, deodorants, or alcohol. Allergic dermatitis has
minora). Disorders of the vulva most frequently are inflam- a similar clinical appearance and may result from allergy to
matory, rendering them more uncomfortable than serious. perfumes; additives in creams, lotions, and soaps; chemical
Malignant tumors of the vulva, although life-threatening, treatments on clothing; and other antigens.
are rare. Vulvitis also may be caused by infections, which often
are sexually transmitted. The most important infectious
agents in North America are human papillomavirus (HPV),
VULVITIS the causative agent of condyloma acuminatum, vulvar
intraepithelial neoplasia (VIN), and one type of vulvar
One of the most common causes of vulvitis is reactive squamous carcinoma (discussed later); herpes simplex
inflammation in response to an exogenous stimulus, which virus (HSV-1 or HSV-2), the agent of genital herpes; N.
may be an irritant (contact irritant dermatitis) or an allergen gonorrhoeae, a cause of suppurative infection of the vul-
(contact allergic dermatitis). Scratching-induced trauma vovaginal glands; and Treponema pallidum, which causes
secondary to associated intense “itching” (pruritus) often primary chancre at vulvar sites of inoculation. Candida
exacerbates the primary condition. also is a cause of vulvitis, but is not sexually transmitted.
Contact irritant eczematous dermatitis manifests as well- An important complication of vulvitis is obstruction of
defined erythematous weeping and crusting papules and the excretory ducts of Bartholin glands. This blockage may
713
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714 C H A P T E R 19 Female Genital System and Breast

result in painful dilation of the glands (Bartholin cyst) and and both lesions may take the form of leukoplakia. Similar
abscess formation. white patches or plaques also are seen in a variety of other
benign dermatoses, such as psoriasis and lichen planus
Nonneoplastic Epithelial Disorders (Chapter 24), as well as in malignant lesions of the vulva,
such as squamous cell carcinoma in situ and invasive
Lichen Sclerosus squamous cell carcinoma. Thus, biopsy and microscopic
Lichen sclerosus is characterized by thinning of the epi- examination are often needed to differentiate these clini-
dermis, disappearance of rete pegs, a zone of acellular, cally similar-appearing lesions.
homogenized, dermal fibrosis, and a bandlike mononu-
clear inflammatory cell infiltrate (Fig. 19.1). It appears as
smooth, white plaques (termed leukoplakia) or papules that SUMMARY
in time may extend and coalesce. When the entire vulva is NONNEOPLASTIC EPITHELIAL DISORDERS
affected, the labia become atrophic and stiffened, and the
• Lichen sclerosus is characterized by atrophic epithelium, sub-
vaginal orifice is constricted. Lichen sclerosus occurs in all
epithelial dermal fibrosis, and bandlike chronic inflammation.
age groups but most commonly affects postmenopausal
• Lichen sclerosus carries a slightly increased risk for develop-
women and prepubertal girls. The pathogenesis is uncer-
ment of squamous cell carcinoma.
tain, but the presence of activated T cells in the subepithe-
• Lichen simplex chronicus is characterized by thickened epithe-
lial inflammatory infiltrate and the increased frequency
lium (hyperplasia), usually with a dermal inflammatory infiltrate.
of autoimmune disorders in affected women suggest an
• The lesions of lichen sclerosus and lichen simplex chronicus
autoimmune etiology. Lichen sclerosus is benign; however,
must be biopsied to distinguish them definitively from other
1% to 5% of women with symptomatic lichen sclerosus
causes of leukoplakia, such as squamous cell carcinoma of
develop HPV negative squamous cell carcinoma of the
the vulva.
vulva.

Lichen Simplex Chronicus

Lichen simplex chronicus is marked by epithelial thick-
ening (particularly of the stratum granulosum) and TUMORS
hyperkeratosis. Increased mitotic activity is seen in the
basal and suprabasal layers; however, there is no epithelial Condylomas
atypia (Fig. 19.1). Leukocytic infiltration of the dermis is
sometimes pronounced. These nonspecific changes are a Condyloma is the name given to any warty lesion of the
consequence of chronic irritation, often caused by pruritus vulva. Most such lesions can be assigned to one of two
related to an underlying inflammatory dermatosis. Lichen distinctive forms. Condylomata lata, not commonly seen
simplex chronicus appears as an area of leukoplakia. While today, are flat, minimally elevated lesions that occur in
no increased predisposition to cancer has been demon- secondary syphilis (Chapter 18). The more common condy-
strated when lesions are isolated, lichen simplex chronicus lomata acuminata may be papillary and distinctly elevated
often is present at the margins of established vulvar cancer, or somewhat flat and rugose. They may occur anywhere
suggesting some association with neoplastic disease. on the anogenital surface, sometimes as single but more
Lichen sclerosus and lichen simplex chronicus may often as multiple lesions. When located on the vulva,
coexist in different areas of the body in the same person, they range from a few millimeters to many centimeters in

A B
Fig. 19.1 Nonneoplastic vulvar epithelial disorders. (A) Lichen sclerosus. There is marked thinning of the epidermis, fibrosis of the superficial dermis, and
chronic inflammatory cells in the deeper dermis. (B) Lichen simplex chronicus displaying thickened epidermis and hyperkeratosis.

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 Tumors 715

course. The less common form is related to high-risk HPV

strains (especially HPV type 16) and occurs in middle-
aged women, particularly cigarette smokers. This form is
often preceded by precancerous changes in the epithelium
termed vulvar intraepithelial neoplasia (VIN). VIN pro-
gresses in many patients to greater degrees of atypia and
eventually to carcinoma in situ; however, progression to
invasive carcinoma is not inevitable and may occur only
after many years. Environmental factors such as cigarette
smoking and immunodeficiency appear to increase the risk
of such progression.
A second form of squamous carcinoma occurs in older
women, sometimes following a long history of reactive
epithelial changes, principally lichen sclerosus. It is pre-
ceded by a subtle lesion, differentiated vulvar intraepi-
A thelial neoplasia (dVIN), characterized by cytologic atypia
confined to the basal layer and abnormal keratinization.
If left untreated it may give rise to HPV negative, well-
differentiated, keratinizing squamous cell carcinoma.

MORPHOLOGY
VIN and early vulvar carcinomas commonly manifest as areas
of leukoplakia. In about one-fourth of the cases, the lesions
are pigmented owing to the presence of melanin. With time,
these areas are transformed into overt exophytic or ulcerative
endophytic tumors. HPV-positive tumors are often multifocal
and warty and tend to be poorly differentiated squamous cell
carcinomas, whereas HPV-negative tumors usually are unifocal
and typically are well-differentiated keratinizing squamous cell
B carcinomas.
Fig. 19.2 (A) Numerous condylomas of the vulva. (B) Histopathologic
features of condyloma acuminatum include acanthosis, hyperkeratosis, and
cytoplasmic vacuolization (koilocytosis, center). (A, Courtesy of Dr. Alex Ferenczy,
McGill University, Montreal, Quebec, Canada.)
Both forms of vulvar carcinoma tend to remain confined
to their site of origin for a few years but ultimately invade
and spread, usually first to regional lymph nodes. The risk
of metastasis correlates with the depth of invasion. As with
diameter and are red-pink to pink-brown (Fig. 19.2). On most carcinomas, outcome is dependent on tumor stage.
histologic examination, the characteristic cellular feature The overall 5-year survival is 70% to 93% for patients with
is koilocytosis (a cytopathic change characterized by peri- negative lymph nodes but decreases to 25% to 41% for
nuclear cytoplasmic vacuolization and a wrinkled nuclear patients with lymph node metastases.
contour), a hallmark of HPV infection (Fig. 19.2). Indeed,
more than 90% of condylomata acuminata are positive for Extramammary Paget Disease
HPV subtypes 6 and 11. HPV is sexually transmitted, and
identical lesions occur in men on the penis and around the Paget disease is an intraepidermal proliferation of epi-
anus in men and women. HPV 6 and 11 are low-risk viral thelial cells that can occur in the skin of the vulva or
types, and hence, vulvar condylomas do not commonly nipple of the breast (described later). However, unlike in
progress to cancer. However, women with condyloma acu- the breast, where Paget disease is virtually always associ-
minata are at risk of having other HPV-related lesions in ated with an underlying carcinoma, only a minority of
the vagina and cervix. cases of vulvar (extramammary) Paget disease have an
underlying tumor. Instead, vulvar Paget cells most com-
Carcinoma of the Vulva monly appear to arise from epidermal progenitor cells.
Paget disease manifests as a red, scaly, crusted plaque
Carcinoma of the vulva represents about 3% of all female that may mimic the appearance of an inflammatory derma-
genital tract cancers, occurring mostly in women older titis. On histologic examination, large cells with abundant
than age 60. Approximately 90% of carcinomas are squa- pale, finely granular cytoplasm and occasional cytoplas-
mous cell carcinomas; most of the other tumors are adeno- mic vacuoles infiltrate the epidermis, singly and in groups
carcinomas or basal cell carcinomas. (Fig. 19.3). The presence of mucin, as detected by periodic
There appear to be two distinct forms of vulvar squa- acid–Schiff (PAS) staining, is useful in distinguishing Paget
mous cell carcinomas that differ in pathogenesis and disease from vulvar melanoma, which lacks mucin.

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716 C H A P T E R 19 Female Genital System and Breast

Intraepidermal Paget disease may persist for years or

even decades without evidence of invasion. However,
when there is an associated tumor involving skin append-
ages, the Paget cells may invade locally and ultimately
metastasize. After metastasis occurs, the prognosis is poor.

SUMMARY
TUMORS OF THE VULVA
• HPV-related vulvar squamous cell carcinomas usually are
poorly differentiated lesions and sometimes are multifocal.
They often evolve from vulvar intraepithelial neoplasia.
• Non–HPV-related vulvar squamous cell carcinomas occur in
older women and usually are well differentiated and unifocal.
They are often preceded by “differentiated” vulvar intraepithe-
lial neoplasia associated with lichen sclerosus.
• Vulvar Paget disease is characterized by a red, scaly plaque
caused by proliferation of epithelial cells within the epidermis;
Fig. 19.3 Paget disease of the vulva. Large tumor cells with pale-pink cyto- usually, there is no underlying carcinoma, unlike Paget disease
plasm are seen infiltrating the epidermis. Chronic inflammatory cells are of the nipple.
present in the underlying dermis.

Vagina
In adult females, the vagina is seldom a site of primary active infection usually stems from sexual transmission of
disease. More often, it is involved secondarily by cancer a new strain.
or infections arising in adjacent organs (e.g., cervix, vulva,
bladder, rectum).
Congenital anomalies of the vagina fortunately are
uncommon and include entities such as total absence of MALIGNANT NEOPLASMS
the vagina, a septate or double vagina (usually associated
with a septate cervix and, sometimes, septate uterus), and Squamous Cell Carcinoma
congenital, lateral Gartner duct cysts arising from persis-
tent wolffian duct rests. Squamous cell carcinoma of the vagina is an extremely
uncommon cancer that usually occurs in women older than
60 years in the setting of risk factors similar to those associ-
VAGINITIS ated with carcinoma of the cervix (discussed later). Vaginal
intraepithelial neoplasia (VAIN) is a precursor lesion that
Vaginitis is a common condition that is usually transient is nearly always associated with HPV infection. Invasive
and of no clinical consequence. It is associated with the squamous cell carcinoma of the vagina is associated with
production of a vaginal discharge (leukorrhea). A large the presence of HPV DNA in more than half of the cases,
variety of organisms have been implicated, including bac- presumably derived from HPV-positive VAIN.
teria, fungi, and parasites. Many are normal commensals
that become pathogenic only in the setting of diabetes, Clear Cell Adenocarcinoma
systemic antibiotic therapy (which causes disruption of
normal microbial flora), immunodeficiency, pregnancy, or In 1970, clear cell adenocarcinoma, a very rare tumor, was
recent abortion. In adults, primary gonorrheal infection of identified in a cluster of young women whose mothers
the vagina is uncommon. The other organisms worthy of took diethylstilbestrol during pregnancy to prevent threat-
mention, because they are frequent offenders, are Candida ened abortion. Follow-up studies determined that the inci-
albicans and Trichomonas vaginalis. Candidal (monilial) dence of this tumor in persons exposed to diethylstilbestrol
vaginitis is characterized by a curdy white discharge. This in utero is low (<1 per 1000, albeit about 40 times greater
organism is part of the normal vaginal flora in about 5% than in the unexposed population). In about one-third of
of women, so the appearance of symptomatic infection exposed women, small glandular or microcystic inclu-
almost always involves one of the predisposing influences sions develop in the vaginal mucosa. These lesions appear
listed above or superinfection by a new, more aggressive as red, granular foci lined by mucus-secreting or ciliated
strain. T. vaginalis is sexually transmitted; it produces a columnar cells. This condition is called vaginal adenosis
watery, copious gray-green discharge in which parasites and is benign but is important to recognize because it is
can be identified by microscopy. Trichomonas also can from such precursor lesions that clear cell adenocarcinoma
be identified in about 10% of asymptomatic women; thus, arises.

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 Neoplasia of the Cervix 717

Sarcoma Botryoides and children younger than 5 years of age, but may occur
uncommonly in young women. It also may be found in
Sarcoma botryoides (embryonal rhabdomyosarcoma) is other sites, such as the urinary bladder and bile ducts.
a rare form of primary vaginal cancer that manifests as It is discussed further with other soft tissue tumors in
soft polypoid masses. It usually is encountered in infants Chapter 21.

Cervix
Most cervical lesions are relatively banal inflammations squamous intraepithelial lesions (SILs), which are precur-
(cervicitis), but the cervix also is the site of one of the most sors from which most invasive cervical carcinomas develop.
common cancers in women worldwide. HPV is detectable by molecular methods in nearly all
cases of cervical intraepithelial neoplasia (CIN) and cervi-
cal carcinoma. Important risk factors for the development
CERVICITIS of CIN and invasive carcinoma thus are directly related to
HPV exposure and include:
Inflammatory conditions of the cervix are extremely • Early age at first intercourse
common and may be associated with a purulent vaginal • Multiple sexual partners
discharge. Cervicitis can be subclassified as infectious or • Male partner with multiple previous sexual partners
noninfectious, although differentiation is difficult owing to • Persistent infection by high-risk strains of papillo-
the presence of normal vaginal flora including incidental mavirus
vaginal aerobes and anaerobes, streptococci, staphylococci,
enterococci, and Escherichia coli and Candida spp. Like most other DNA viruses, HPV uses host cell DNA
Much more important are Chlamydia trachomatis, Urea- polymerases to replicate its genome and produce virions.
plasma urealyticum, T. vaginalis, Neisseria gonorrhoeae, HSV-2 Virions must be shed from the surface of the squamous
(the agent of herpes genitalis), and certain types of HPV, all mucosa, yet under normal circumstances squamous cell
of which are often sexually transmitted. C. trachomatis is by maturation is accompanied by a cessation of DNA replica-
far the most common of these pathogens, accounting for as tion, which would prevent virus production. HPV “solves”
many as 40% of cases of cervicitis encountered in sexually this problem through the action of two viral oncoproteins,
transmitted infection clinics. Although less common, her- E6 and E7. The E6 and E7 proteins of “high risk” HPV
petic infections are noteworthy because maternal–infant variants inhibit p53 and RB, respectively (Chapter 6), two
transmission during childbirth may result in serious, some- potent tumor suppressors that act to suppress the division
times fatal systemic herpetic infection in the newborn. of squamous cells as they mature. E6 and E7 thus have a
Cervicitis commonly comes to attention on routine exam- central role in the life cycle of HPV and largely explain
ination or because of leukorrhea. It often is treated empiri- the carcinogenic activity of HPV in the cervix and other
cally with antibiotics that are active against chlamydia and sites that are prone to HPV infection (e.g., vulva, penis,
gonococcus. In some instances, nucleic acid amplification oropharynx).
tests are used on vaginal fluid to identify the presence of HPV variants are classified as high-risk or low-risk
these organisms as well as Trichomonas vaginalis. types based on their propensity to induce carcinogenesis.

NEOPLASIA OF THE CERVIX Mature squamous cells

Most tumors of the cervix are of epithelial origin and are

caused by oncogenic strains of HPV. During development,
the columnar mucus-secreting epithelium of the endocer-
vix is joined to the squamous epithelial covering of the Immature
exocervix at the cervical os. With the onset of puberty, squamous
the squamocolumnar junction undergoes eversion, causing cells
the columnar epithelium to become visible on the exo-
cervix. The exposed columnar cells, however, eventually Squamocolumnar
undergo squamous metaplasia, forming a region called junction
the transformation zone, where tumors most commonly
arise (Fig. 19.4).
Columnar
Pathogenesis glandular
cells
HPV, the causative agent of cervical neoplasia, has a
tropism for the immature squamous cells of the trans-
formation zone. Most HPV infections are transient and are Fig. 19.4 Cervical transformation zone showing the transition from mature
eliminated within months by the host immune response. glycogenated squamous epithelium, to immature metaplastic squamous cells,
A subset of infections persists, however, and some cause to columnar endocervical glandular epithelium.

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718 C H A P T E R 19 Female Genital System and Breast

Sexual Activity Squamous Intraepithelial Lesion (SIL, Cervical

Intraepithelial Lesion)
HPV
HPV-related carcinogenesis begins with the precancer-
ous epithelial change termed SIL, which usually pre-
HPV exposure (millions/yr) cedes the development of an overt cancer by many years,
sometimes decades. In support of this idea, SIL peaks in
Immune status incidence at about 30 years of age, whereas invasive carci-
Genetic vulnerability
Other factors
noma peaks at about 45 years of age.
The classification of cervical precursor lesions has
Low-risk HPV (6,11) High-risk HPV evolved with time. The current terminology is a two-tiered
episomal infection (16, 18, others) system that not only reflects the biology of the disease but
also patient management, replacing a three-tiered system.
• SIL is divided into low-grade squamous intraepithelial
Condyloma SIL (~1 million/yr) lesion (LSIL), still often referred to as cervical intraepi-
(hundreds of thousands/yr) thelial neoplasia I (CIN I), and high-grade squamous
Persistent intraepithelial lesion (HSIL), encompassing cervical
infection
intraepithelial neoplasia II and III (CIN II and III) of the
previous three-tiered system.
hSIL (50,000/yr) • LSIL is associated with productive HPV infection and
does not progress directly to invasive carcinoma. Actu-
Viral integration ally, most LSILs regress and only a small percentage
progress to HSIL.
Invasive cancer (13,000/yr) • HSIL demonstrates increased proliferation, arrested epi-
thelial maturation, and lower levels of viral replication.
LSIL is not treated as a premalignant lesion, whereas
Metastasis (5000/yr) HSIL is considered at high risk for progression to
carcinoma.
Fig. 19.5 Possible consequences of human papillomavirus (HPV) infection.
Progression is associated with integration of virus and acquisition of addi- Importantly, LSIL is 10 times more common than HSIL
tional mutations as discussed in the text. SIL, Squamous intraepithelial lesion; and while HSILs are precancerous, the majority of them
hSIL, High-grade cervical intraepithelial lesion. fail to progress to cancer and may even regress. Patient
management rests on the histopathologic diagnosis as dis-
cussed later. As shown in Table 19.1, the decision to treat
High-risk HPV infection is the most important risk factor HSIL and to observe LSIL is based on differences in the
for the development of SIL that can progress to carcinoma. natural histories of these two groups of lesions.
Two high-risk HPV viruses, types 16 and 18, account for Cervical precancerous lesions are associated with abnor-
approximately 70% of cases of SIL and cervical carcinoma. malities in cytologic preparations that can be detected
In general, infections with high-risk HPV types are more long before any abnormality is visible on gross inspection.
likely to persist, which is a risk factor for progression to Early detection of SIL is the rationale for the Papanicolaou
carcinoma. These HPV types also show a propensity to (Pap) test, in which cells are scraped from the transforma-
integrate into the host cell genome, an event that is linked tion zone and examined microscopically. The Pap smear
to progression. Low-risk HPV variants (e.g., types 6 and remains the most successful cancer-screening test ever
11) associated with the development of condylomas of the developed. In the United States, Pap screening has dramat-
lower genital tract (Fig. 19.5), by contrast, express E6 and ically lowered the incidence of invasive cervical tumors to
E7 variants with different or weaker activities and do not about 13,000 cases annually with a mortality of about 4000
integrate into the host genome, remaining instead as free per year; in fact, cervical cancer no longer ranks among the
episomal viral DNA. Despite the strong association of HPV top 10 causes of cancer deaths in U.S. women. Paradoxi-
infection with cancer of the cervix, HPV is not sufficient cally, the incidence of SIL has increased to its present level
to drive the neoplastic process. As mentioned later, HPV- of more than 50,000 cases annually. Increased detection
infected high-grade precursor lesions do not invariably has certainly contributed to this. The U.S. Food and Drug
progress to invasive cancer. Diverse other factors such as Administration has approved testing for HPV DNA in cer-
immune and hormonal status and coinfection with other vical scrapings. This test is highly sensitive but has lower
sexually transmitted agents are suspected to play a role.
Collectively these factors favor the acquisition of somati- Table 19.1 Natural History of Squamous Intraepithelial
cally acquired mutations that involve both oncogenes Lesions (SILs)
and tumor suppressor genes. Viral integration appear to Lesion Regress Persist Progress
contribute to transformation in two ways: 1) integration
LSIL (CIN I) 60% 30% 10% (to HSIL)
always disrupts an HPV gene that negatively regulates E6
and E7, which leads to their increased expression; and 2) HSIL (CIN II, III) 30% 60% 10% (to carcinoma)a
sometimes HPV integrates near a host cell oncogene such a
Progression within 10 years.
LSIL, Low-grade SIL; HSIL, high-grade SIL.
as MYC, leading to its overexpression as well.

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 Neoplasia of the Cervix 719

Normal LSIL HSIL HSIL

Fig. 19.6 Spectrum of squamous intraepithelial lesions (SIL) with normal squamous epithelium for comparison: LSIL with koilocytotic atypia; HSIL with
progressive atypia in all layers of the epithelium; and HSIL with diffuse atypia and loss of maturation (carcinoma in situ, far right image).

specificity than the Pap smear, and specific guidelines for

MORPHOLOGY
its use have not been well established. One consideration
is that while most women acquire HPV infections in their Fig. 19.6 illustrates the three stages of SIL. LSIL is characterized
early 20s, these are usually cleared by the immune system by dysplastic changes in the lower third of the squamous epithe-
and never progress to SIL, a process that occurs over many lium and koilocytotic change in the superficial layers of the
years. For this reason, HPV DNA screening is only recom- epithelium. In HSIL (CIN II), dysplasia extends to the middle third
mended for women aged 30 or older, as a positive test of the epithelium in the form of variation in cell and nuclear size,
at this age is more likely to identify an individual with heterogeneity of nuclear chromatin, and the presence of mitoses,
a persistent infection that may lead to cervical neoplasia. some atypical, above the basal layer extending into the middle
The quadrivalent HPV vaccine for types 6, 11, 16, and third of the epithelium. The superficial layer of cells in CIN II
18, and the more recently introduced 9-valent vaccine, still shows differentiation and occasional koilocytotic changes
are very effective in preventing HPV infections and are HSIL (CIN III) is marked by almost complete loss of differentia-
expected to greatly lower the frequency of genital warts tion, even greater variation in cell and nuclear size, chromatin
and cervical cancers associated with these HPV genotypes. heterogeneity, disorderly orientation of the cells, and abnormal
Despite its efficacy, vaccination does not supplant the need mitoses, changes that affect virtually all layers of the epithelium.
for routine cervical cancer screening—many at-risk women Koilocytotic change usually is absent. These histologic features
are already infected, and current vaccines protect against correlate with the cytologic appearances shown in Fig. 19.7.
only some of the many oncogenic HPV genotypes.

A B C D
Fig. 19.7 Cytologic features of squamous intraepithelial lesion (SIL) in a Papanicolaou smear. Superficial squamous cells may stain either red or blue.
(A) Normal exfoliated superficial squamous epithelial cells. (B) Low-grade squamous intraepithelial lesion (LSIL). (C and D) Both high-grade squamous
intraepithelial lesions (HSILs). Note the reduction in cytoplasm and the increase in the nucleus-to-cytoplasm ratio as the grade of the lesion increases. This
observation reflects the progressive loss of cellular differentiation on the surface of the cervical lesions from which these cells are exfoliated (see Fig. 19.6).
(Courtesy of Dr. Edmund S. Cibas, Brigham and Women’s Hospital, Boston, Massachusetts.)

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720 C H A P T E R 19 Female Genital System and Breast

SIL is asymptomatic and comes to clinical attention

through an abnormal Pap smear result. These cases are
followed up by colposcopy, in which acetic acid is used
to highlight the lesions so they can be biopsied. Women
with biopsy-documented LSIL are managed conserva-
tively with careful observation, whereas HSILs and persis-
tent LSIL are treated with surgical excision (cone biopsy).
Follow-up smears and clinical examination are required
in patients with HSIL, as these women remain at risk for
HPV-associated cervical, vulvar, and vaginal cancers.

Invasive Carcinoma of the Cervix

The most common cervical carcinomas are squamous
cell carcinomas (75%), followed by adenocarcinomas and
mixed adenosquamous carcinomas (20%) and small cell
Fig. 19.8 Cervical os with surrounding, invasive, exophytic cervical
neuroendocrine carcinomas (<5%). All of these types of carcinoma.
carcinomas are associated with HPV. Of interest, the rela-
tive proportion of adenocarcinomas has been increasing
in recent decades owing to the decreasing incidence of
invasive squamous carcinoma and suboptimal detection Clinical Features
of glandular lesions by Pap smear. Invasive cervical cancer most often is seen in women who
Squamous cell carcinoma has a peak incidence at the have never had a Pap smear or who have not been screened
age of about 45 years, some 10 to 15 years after detec- for many years. In such cases, cervical cancer often is
tion of precursor SIL. As already discussed, progression symptomatic, with patients coming to medical attention
of SIL to invasive carcinoma is variable and unpre- for unexpected vaginal bleeding, leukorrhea, painful coitus
dictable and requires HPV infection as well as muta- (dyspareunia), or dysuria. The primary treatment is hys-
tions in tumor suppressor genes and oncogenes. Risk terectomy and lymph node dissection; small microinvasive
factors for progression include cigarette smoking and carcinomas may be treated with cone biopsy. Radiation
human immunodeficiency virus (HIV) infection, the and chemotherapy are also of benefit in instances where
latter finding suggesting that immune surveillance plays surgery alone is not curative. Mortality is most strongly
a role in preventing progression. Although risk factors predicted by tumor stage and, in the case of neuroendo-
may help identify patients who are likely to progress crine carcinomas (which pursue an aggressive course) to
from SIL to carcinoma, the only reliable way to monitor cell type.
the disease course is with frequent physical examina-
tions coupled with Pap smears and biopsy of suspicious Endocervical Polyp
lesions.
Endocervical polyps are benign polypoid masses seen pro-
truding from the endocervical mucosa (sometimes through
the exocervix). They can be as large as a few centimeters
and have a smooth, glistening surface with underlying cys-
tically dilated spaces filled with mucinous secretions. The
MORPHOLOGY surface epithelium and lining of the underlying cysts are
composed of the same mucus-secreting columnar cells that
Invasive carcinomas of the cervix develop in the transforma-
line the endocervical canal. The stroma is edematous and
tion zone and range from microscopic foci of stromal invasion
may contain scattered mononuclear cells. Superimposed
to grossly conspicuous exophytic tumors (Fig. 19.8). Microscopi-
chronic inflammation may lead to squamous metaplasia
cally, the invasive tumors often consist of tongues and nests of
of the overlying epithelium and ulcerations. These lesions
squamous cells that produce a desmoplastic stromal response.
may bleed, thereby arousing concern, but they have no
Grading is based on the degree of squamous differentiation,
malignant potential.
which ranges from minimal to well-differentiated tumors that
elaborate keratin pearls. Rare tumors with neuroendocrine dif-
ferentiation resemble small cell carcinomas of the lung mor-
phologically. Tumors encircling the cervix and penetrating into SUMMARY
the underlying stroma produce a barrel cervix, which can be
CERVICAL NEOPLASIA
identified by direct palpation. Extension into the parametrial soft
tissues can affix the uterus to the surrounding pelvic structures. • Risk factors for cervical carcinoma are related to HPV expo-
The likelihood of spread to pelvic lymph nodes correlates with sure, such as early age at first intercourse, multiple sexual
the depth of tumor invasion and the presence of tumor cells in partners, and other factors including cigarette smoking and
vascular spaces. The risk of metastasis increases from less than immunodeficiency.
1% for tumors less than 3 mm in depth to more than 10% after • Nearly all cervical carcinomas are caused by HPV infec-
invasion exceeds 3 mm. tions, particularly high-risk HPV types 16, 18, 31, and 33;

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 Endometriosis 721

the HPV vaccine is effective in preventing infection result- • In cervical cancer, high-risk HPV is integrated in the host
ing from the HPV types most commonly associated with genome, an event that increases the expression of E6 and E7
carcinoma. and contributes to progression to cancer.
• HPV expresses E6 and E7 proteins that inactivate the p53 • The Pap smear is a highly effective screening tool for the
and RB tumor suppressors, respectively, resulting in increased detection of SIL and carcinoma and has significantly reduced
cell proliferation and suppression of DNA damage–induced the incidence of cervical carcinoma. HPV testing is currently
apoptosis. being used in conjunction with the Pap smear.

Uterus
The body (corpus) of the uterus is composed of the endo- in an enlarged, globular uterus, often with a thickened
metrium, consisting of glands and stroma, and the myo- uterine wall. Extensive adenomyosis may produce
metrium, made up of smooth muscle. The more frequent menorrhagia, dysmenorrhea, and pelvic pain, particu-
and significant disorders of the uterus are considered here. larly just prior to menstruation, and can coexist with
endometriosis.

ENDOMETRITIS
ENDOMETRIOSIS
Inflammation of the endometrium is classified as acute or
chronic depending on whether a neutrophilic or a lym- Endometriosis is defined by the presence of endometrial
phoplasmacytic infiltrate predominates, respectively. The glands and stroma in a location outside the uterus. It
diagnosis of chronic endometritis generally requires the occurs in as many as 10% of women in their reproductive
presence of plasma cells, as lymphocytes are present even years and in nearly half of women with infertility. It fre-
in the normal endometrium. quently is multifocal and often involves pelvic structures
Endometritis is a component of pelvic inflamma- (ovaries, pouch of Douglas, uterine ligaments, tubes, and
tory disease and is frequently a result of N. gonorrhoeae rectovaginal septum). Less frequently, distant areas of the
or C. trachomatis infection. Histologic examination shows peritoneal cavity or periumbilical tissues are involved.
a neutrophilic infiltrate in the superficial endometrium Uncommonly, distant sites such as lymph nodes, lungs,
coexisting with a stromal lymphoplasmacytic infiltrate. and even heart, skeletal muscle, or bone are affected.
Prominent lymphoid follicles may be seen, particularly Four hypotheses have been put forth to explain the
in chlamydial infection. Tuberculosis causes granulo- origin of dispersed endometriotic lesions, all of which are
matous endometritis, frequently with associated tuber- viable:
culous salpingitis and peritonitis. Although seen in the • The regurgitation theory, which is currently favored, pro-
United States mainly in immunocompromised persons, poses that menstrual backflow through the fallopian
tuberculous endometritis is common in countries in tubes leads to implantation.
which tuberculosis is endemic, and it should be included • The benign metastases theory holds that endometrial
in the differential diagnosis for pelvic inflammatory tissue from the uterus can “spread” to distant sites via
disease in women who have recently emigrated from blood vessels and lymphatics.
endemic areas. • The metaplastic theory, on the other hand, posits endo-
Endometritis also may be a result of retained products metrial differentiation of coelomic epithelium (mesothe-
of conception subsequent to miscarriage or delivery or the lium of pelvis and abdomen from which endometrium
presence of a foreign body such as an intrauterine device. originates) as the source.
Retained tissue or foreign bodies act as a nidus for ascend- • The extrauterine stem/progenitor cell theory, proposes that
ing infection by vaginal or intestinal tract flora. Removal circulating stem/progenitor cells from the bone marrow
of the offending tissue or foreign body typically results in differentiate into endometrial tissue.
resolution.
Clinically, all forms of endometritis manifest with fever, Studies suggest that endometriotic tissue is not just
abdominal pain, and menstrual abnormalities. In addition, misplaced but is also abnormal (Fig. 19.9). As compared
there is an increased risk of infertility and ectopic preg- to normal endometrium, endometriotic tissue exhibits
nancy due to damage and scarring of the fallopian tubes. increased levels of inflammatory mediators, particularly
prostaglandin E2. It is proposed that the inflammation
results from the recruitment and activation of macrophages
ADENOMYOSIS by factors made by endometrial stromal cells. Stromal cells
also make aromatase, leading to local production of estro-
Adenomyosis refers to the presence of endometrial tissue gen. These factors enhance the survival and persistence of
in the myometrium. Nests of endometrial stroma, glands, the endometriotic tissue within a foreign location (a key
or both are found deep in the myometrium interposed feature in the pathogenesis of endometriosis) and help to
between the muscle bundles. This endometrial tissue explain the beneficial effects of COX-2 inhibitors and aro-
induces reactive hypertrophy of the myometrium, resulting matase inhibitors in the treatment of endometriosis.

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722 C H A P T E R 19 Female Genital System and Breast

Fallopian Clinical Features

tube
Uterus The clinical manifestations of endometriosis depend on
the distribution of the lesions. Extensive scarring of the fal-
Endometriotic lopian tubes and ovaries often produces discomfort in the
cysts
lower abdomen and eventual sterility. Rectal wall involve-
ment may produce pain on defecation, whereas involve-
ment of the uterine or bladder serosa can cause dyspareunia
Ovary (painful intercourse) and dysuria, respectively. Almost all
cases feature severe dysmenorrhea and pelvic pain resulting
Retrograde PGE2 from intrapelvic bleeding and intraabdominal adhesions.
menstruation

Endometriotic implants ABNORMAL UTERINE BLEEDING

Stromal PGE2 and other Women commonly seek medical attention for abnormal
proinflammatory inflammatory uterine bleeding, such as menorrhagia (profuse or pro-
factors mediators
longed bleeding at the time of the period), metrorrhagia
(irregular bleeding between the periods), or postmeno-
COX2 COX2 Activated pausal bleeding. Common causes include dysfunctional
macrophages uterine bleeding, endometrial polyps, leiomyomas, endo-
metrial hyperplasia, and endometrial carcinoma.
Fig. 19.9 Proposed origins of endometriosis. The probable cause of uterine bleeding in any given case
varies depending on the age of the patient (Table 19.2).
Abnormal bleeding from the uterus in the absence of an
organic uterine lesion is called dysfunctional uterine bleeding.
The most common cause of dysfunctional uterine bleed-
MORPHOLOGY ing is anovulation (failure to ovulate). Anovulatory cycles
Endometriosis typically consists of functioning endome- result from hormonal imbalances and are most common
trium, which undergoes cyclic bleeding. Because blood collects at menarche and in the perimenopausal period because of
in these aberrant foci, they appear grossly as red-brown nodules fluctuations in the hypothalamus/pituitary/ovarian axis.
or implants. They range in size from microscopic to 1 to 2 cm Less common causes of anovulation are
in diameter and lie on or just under the affected serosal surface. • Endocrine disorders, such as thyroid disease, adrenal
Often, individual lesions coalesce to form larger masses. When disease, or pituitary tumors.
the ovaries are involved, the lesions may form large, blood-filled • Ovarian lesions, such as a functioning ovarian tumor
cysts that turn brown (chocolate cysts) as the blood ages (Fig. (granulosa cell tumors) or polycystic ovarian syndrome
19.10). With seepage and organization of the blood, widespread (see section on ovaries that follows).
fibrosis occurs, leading to adhesions among pelvic structures, • Generalized metabolic disturbances, such as obesity, mal-
sealing of the tubal fimbriated ends, and distortion of the fallopian nutrition, or other chronic systemic disorders.
tubes and ovaries. The diagnosis depends on finding both endo-
metrial glands and stroma at sites external to the endometrium. Dysfunctional uterine bleeding also may result from an
inadequate luteal phase, which is thought to stem from

Table 19.2 Causes of Abnormal Uterine Bleeding by Age

Group
Age Group Cause(s)
Prepuberty Precocious puberty (hypothalamic, pituitary, or
ovarian origin)
Adolescence Anovulatory cycle
Reproductive age Complications of pregnancy (abortion,
trophoblastic disease, ectopic pregnancy)
Proliferations (leiomyoma, adenomyosis, polyps,
endometrial hyperplasia, carcinoma)
Anovulatory cycle
Ovulatory dysfunctional bleeding (e.g.,
inadequate luteal phase)
Perimenopause Anovulatory cycle
Irregular shedding
Proliferations (carcinoma, hyperplasia, polyps)
Postmenopause Proliferations (carcinoma, hyperplasia, polyps)
Fig. 19.10 Ovarian endometriosis. Sectioning of ovary shows a large endo- Endometrial atrophy
metriotic cyst with degenerated blood (“chocolate cyst”).

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 Proliferative Lesions of the Endometrium and Myometrium 723

insufficient production of progesterone by the corpus

luteum.

SUMMARY
NONNEOPLASTIC DISORDERS OF
ENDOMETRIUM
• Adenomyosis refers to growth of endometrium into the myo-
metrium often with uterine enlargement.
• Endometriosis refers to endometrial glands and stroma
located outside the uterus and most often involves the pelvic
or abdominal peritoneum. Rarely, distant sites such as the
lymph nodes and the lungs also are involved.
• The ectopic endometrium in endometriosis undergoes cyclic
bleeding, and the condition is a common cause of dysmenor- A
rhea and pelvic pain.

PROLIFERATIVE LESIONS OF THE

ENDOMETRIUM AND MYOMETRIUM
The most common proliferative lesions of the uterine
corpus are endometrial hyperplasia, endometrial carcino-
mas, endometrial polyps, and smooth muscle tumors. All
tend to produce abnormal uterine bleeding as their earliest
manifestation.

Endometrial Hyperplasia
An excess of estrogen relative to progestin, if sufficiently
prolonged or marked, can induce exaggerated endome- B
trial proliferation (hyperplasia), which is an important
precursor of endometrial carcinoma. A common cause
of estrogen excess is obesity, as adipose tissue converts
steroid precursors into estrogens. Other potential causes
of estrogen excess include failure of ovulation (such as in
perimenopause), prolonged administration of estrogenic
steroids without counterbalancing progestin, and estrogen-
producing ovarian lesions (such as polycystic ovary syn-
drome and granulosa-theca cell tumors of the ovary).
Endometrial hyperplasia is placed in two categories
based on the presence of cytologic atypia: hyperplasia
without atypia and hyperplasia with atypia (Fig. 19.11).
The importance of this classification is that the presence of
cytologic atypia correlates with the development or concur-
rent finding of endometrial carcinoma. Hyperplasia without
cellular atypia carries a low risk (between 1% and 3%) for
progression to endometrial carcinoma, whereas hyperplasia C
with atypia, also called endometrial intraepithelial neoplasia
(EIN), is associated with a much higher risk (20%–50%). Fig. 19.11 Endometrial hyperplasia. (A) Anovulatory or “disordered” endo-
metrium containing dilated glands. (B) Hyperplasia without atypia, character-
When hyperplasia with atypia is discovered, it must be care- ized by nests of closely packed glands. (C) Hyperplasia with atypia, seen as
fully evaluated for the presence of cancer and usually war- glandular crowding and cellular atypia.
rants a hysterectomy in patients no longer desiring fertility.
In younger patients, treatment with high-dose progestins
may be used in an attempt to preserve the uterus. atypia (approximately 50%) and endometrioid carcinoma
Unopposed estrogen is also a risk factor for the most (>70%). Along with clinicopathologic and epidemiologic
common type of endometrial carcinoma (see later), and studies, these findings indicate that hyperplasia with
inactivation of the PTEN tumor suppressor gene has been atypia is a precursor lesion for endometrioid endometrial
identified at a substantial frequency in hyperplasia with carcinoma.

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724 C H A P T E R 19 Female Genital System and Breast

Endometrial Carcinoma Serous carcinomas typically grow in small tufts and papillae
with marked cytologic atypia. They can also form glands that at
In the United States and many other Western coun-
times create confusion with endometrioid carcinoma, however
tries, endometrial carcinoma is the most frequent cancer
serous carcinomas exhibit much greater cytologic atypia. Serous
occurring in the female genital tract. It generally appears
carcinomas behave aggressively and thus are by definition high
between the ages of 55 and 65 years and is uncommon
grade. Immunohistochemistry often shows diffuse, strong stain-
before age 40. Endometrial carcinoma can be broadly
ing for p53 in serous carcinoma (Fig. 19.12C–D), a finding that
divided into two histologically and pathogenically distinct
correlates with the presence of TP53 mutations (mutant p53
categories: endometrioid and serous carcinoma. There are
accumulates and hence is more easily detected by staining).
other less common types of endometrial carcinoma, such
as clear cell carcinoma and mixed Mullerian tumor (carci-
nosarcoma), but these will not be discussed further.
Clinical Features
Pathogenesis Endometrial carcinomas usually manifest with irregular
Endometrioid cancers arise in association with estrogen or postmenopausal bleeding. With progression, the uterus
excess in the setting of endometrial hyperplasia in peri- enlarges and may become affixed to surrounding struc-
menopausal women, whereas serous cancers arise in the tures as the cancer infiltrates surrounding tissues. Endo-
setting of endometrial atrophy in older postmenopausal metrioid carcinoma usually is slow to metastasize, but if
women. The endometrioid type accounts for 80% of cases left untreated, eventually disseminates to regional nodes
of endometrial carcinomas. These tumors are designated and more distant sites. With therapy, the 5-year survival
as endometrioid because of their histologic similarity to rate for early-stage endometrioid carcinoma is 90%, but
normal endometrial glands. Risk factors for this type of survival drops precipitously in higher-stage tumors. The
carcinoma include (1) obesity, (2) diabetes, (3) hyper- prognosis with serous carcinomas is strongly dependent
tension, (4) infertility, and (5) exposure to unopposed on operative staging but because of its aggressive behav-
estrogen. Many of these risk factors result in increased ior it often presents as high-stage disease with a poor
estrogenic stimulation of the endometrium and are associ- prognosis.
ated with endometrial hyperplasia. In fact, it is well rec-
ognized that prolonged estrogen replacement therapy and
estrogen-secreting ovarian tumors increase the risk of the SUMMARY
endometrioid type of endometrial carcinoma. Mutations
in mismatch repair genes and the tumor suppressor gene
ENDOMETRIAL HYPERPLASIA AND
PTEN are early events in the stepwise development of
ENDOMETRIAL CARCINOMA
endometrioid carcinoma. Women with germline muta- • Endometrial hyperplasia results from unopposed endogenous
tions in PTEN (Cowden Syndrome) and germline altera- or exogenous estrogen.
tions in DNA mismatch repair genes (Lynch Syndrome) • Risk factors for developing endometrial hyperplasia include
are at high risk for this cancer. TP53 mutations occur but anovulatory cycles, polycystic ovary syndrome, estrogen-
are relatively uncommon and are late events in the genesis producing ovarian tumor, obesity, and estrogen therapy
of this tumor type. without counterbalancing progestin.
The serous type of endometrial carcinoma is less common • Hyperplasia is classified based on cytologic atypia, which deter-
but also far more aggressive. It accounts, for roughly 15% mines the risk of developing endometrioid carcinoma.
of tumors and is not associated with unopposed estro- • On the basis of clinical and molecular data, two major types
gen or endometrial hyperplasia. Nearly all cases of serous of endometrial carcinoma are recognized:
carcinoma have mutations in the TP53 tumor suppressor • Endometrioid carcinoma is associated with estrogen excess
gene, whereas mutations in DNA mismatch repair genes and endometrial hyperplasia. Early molecular changes include
and in PTEN are rare. Serous tumors are preceded by a inactivation of DNA mismatch repair genes and the PTEN
lesion called serous endometrial intraepithelial carcinoma gene.
(SEIC) in which TP53 mutations are often detected, sug- • Serous carcinoma of the endometrium arises in older women
gesting an early role for such mutations in the develop- and usually is associated with endometrial atrophy and a
ment of this form of endometrial carcinoma. distinct precursor lesion, serous intraepithelial carcinoma.
Mutations in the TP53 gene are an early event, usually being
present in serous endometrial intraepithelial carcinoma as
well as invasive serous carcinoma.
MORPHOLOGY • Stage is the major determinant of survival in both types. Serous
tumors tend to manifest more frequently with extrauterine
Endometrioid carcinomas closely resemble normal endo-
extension and therefore have a worse prognosis than endo-
metrium and may be exophytic or infiltrative (Fig. 19.12A–B).
metrioid carcinomas.
They include a range of histologic types, including those showing
mucinous, tubal (ciliated), and squamous differentiation. Endo-
metrioid carcinomas often infiltrate the myometrium and can
enter vascular spaces (lymphovascular invasion). They may also Endometrial Polyps
metastasize to regional lymph nodes. Endometrioid carcinomas
are graded 1 to 3, based on the degree of differentiation.
These polyps are usually sessile and range from 0.5 to
3 cm in diameter. Larger polyps may project from the

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 Proliferative Lesions of the Endometrium and Myometrium 725

A B

C D
Fig. 19.12 Endometrial carcinoma. (A) Endometrioid type, grade 1, infiltrating myometrium and growing in a glandular pattern. (B) Endometrioid type, grade
3, has a predominantly solid growth pattern. (C) Serous carcinoma of the endometrium, with papilla formation and marked cytologic atypia. (D) Immunohis-
tochemical staining shows accumulation of p53, a finding associated with TP53 mutation.

endometrial mucosa into the uterine cavity. They are com- chromosomes 6 and 12 that also are found in a variety of
posed of endometrium resembling the basalis, frequently other benign neoplasms, such as endometrial polyps and
with small muscular arteries. Some glands are normal lipomas. Mutations in the MED12 gene, which encodes a
architecturally, but more often they are cystically dilated. component of the RNA polymerase transcription complex,
The stromal cells are monoclonal, often with a rearrange- have been identified in up to 70% of leiomyomas. The
ment of chromosomal region 6p21, and thus constitute the mechanism by which MED12 mutations contribute to the
neoplastic component of the polyp. development of leiomyomas is not presently understood.
Although endometrial polyps may occur at any age, Estrogens and possibly oral contraceptives stimulate the
they are most common around the time of menopause. growth of leiomyomas; conversely, these tumors shrink
Their main clinical significance is that they may produce postmenopausally.
abnormal uterine bleeding.

Leiomyoma
MORPHOLOGY
Benign tumors that arise from the smooth muscle cells
Leiomyomas are typically sharply circumscribed, firm gray-
in the myometrium are properly termed leiomyomas, but
white masses with a characteristic whorled cut surface. They
because of their firmness often are referred to clinically as
may occur singly, but more often occur as multiple tumors
fibroids. Leiomyomas are the most common benign tumor
that are scattered within the uterus, ranging from small nodules
in females, affecting 30% to 50% of women of reproductive
to large tumors (Fig. 19.13) that may dwarf the uterus. Some are
age, and are considerably more frequent in black women.
embedded within the myometrium (intramural), whereas others
These tumors are associated with several different recurrent
may lie immediately beneath the endometrium (submucosal)
chromosomal abnormalities, including rearrangements of

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726 C H A P T E R 19 Female Genital System and Breast

A B
Fig. 19.13 Uterine leiomyomas. (A) The uterus is opened to show multiple submucosal, myometrial, and subserosal gray-white tumors, each with a charac-
teristic whorled appearance on cut section. (B) Microscopic appearance of leiomyoma shows bundles of normal-looking smooth muscle cells.

leiomyomas, which frequently are multiple and usually

or the serosa (subserosal). In the latter location, tumors may
arise premenopausally.
extend out on attenuated stalks and even become attached to
Recurrence after surgery is common with these
surrounding organs, from which they may develop a blood supply
cancers, and many metastasize, typically to the lungs,
(parasitic leiomyomas). On histologic examination, the tumors
yielding a 5-year survival rate of about 40%. The outlook
are characterized by bundles of smooth muscle cells mim-
with anaplastic tumors is less favorable than with well-
icking the appearance of normal myometrium. Foci of fibrosis,
differentiated tumors.
calcification, and degenerative softening may be present.

MORPHOLOGY
Leiomyomas of the uterus often are asymptomatic,
Leiomyosarcomas typically take the form of soft, hemorrhagic,
being discovered incidentally on routine pelvic examina-
necrotic masses. The histologic appearance varies widely, from
tion. The most frequent presenting sign is menorrhagia,
tumors that closely resemble leiomyoma to wildly anaplastic
with or without metrorrhagia. Leiomyomas rarely, if ever,
neoplasms. Well-differentiated tumors may lie at the morpho-
transform into sarcomas, and the presence of multiple
logic interface between leiomyoma and leiomyosarcoma and
lesions does not increase the risk of malignancy.
are sometimes designated smooth muscle tumors of uncertain
malignant potential. The diagnostic features of leiomyosarcoma
Leiomyosarcoma include tumor necrosis, cytologic atypia, and mitotic
activity. Because increased mitotic activity is sometimes seen
Leiomyosarcomas of the uterus virtually always arise
in benign smooth muscle tumors, particularly in young women, an
de novo from the mesenchymal cells of the myome-
assessment of all three features is necessary to make a diagnosis
trium. They are almost always solitary and most often
of malignancy.
occur in postmenopausal women, in contradistinction to

Fallopian Tubes
The most common disorder of the fallopian tubes is the tubes, giving rise to blood-borne infections that seed
inflammation (salpingitis), almost invariably occurring to distant sites. Tuberculous salpingitis is far less common
as a component of pelvic inflammatory disease. Less and is almost always encountered in combination with
common abnormalities are ectopic (tubal) pregnancy and tuberculous endometritis. All forms of salpingitis may
endometriosis. produce fever, lower abdominal or pelvic pain, and pelvic
Inflammation of the fallopian tubes is almost always caused masses, which are the result of distention of the tubes with
by infection. In addition to gonorrhea, nongonococcal either exudate or inflammatory debris (Fig. 19.14). Adher-
organisms, such as Chlamydia, Mycoplasma hominis, coli- ence of the inflamed tube to the ovary and adjacent liga-
forms, and (in the postpartum setting) streptococci and mentous tissues may produce a tuboovarian abscess. This
staphylococci are the major offenders. The morphologic may in turn result in adhesions between the ovary and the
changes produced by gonococci are similar to those in the tubes when the inflammation subsides. Even more serious
male genital tract (Chapter 18). Infections with coliforms, are adhesions of the tubal plicae, which are associated with
streptococci, and staphylococci can penetrate the wall of increased risk of tubal ectopic pregnancy (discussed later).

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 Tumors of the Ovary 727

Damage to or obstruction of the tubal lumina may produce

permanent sterility.
Once thought to be uncommon, primary adenocarci-
nomas of the fallopian tube may be the site of origin for
many of the high-grade serous carcinomas long thought
to arise in the ovary. Studies have identified the pres-
ence of serous tubal intraepithelial carcinoma (STIC) in the
fimbriated ends of fallopian tubes. Like the precursor of
uterine serous carcinoma, STICs have mutations in TP53 in
more than 90% of cases. These lesions are found frequently
in fallopian tubes removed prophylactically from women
who carry mutations in BRCA1 and BRCA2 and less com-
monly in instances where tubes are removed from women
without known genetic risk factors. This has led to the
idea that sporadic “ovarian” serous carcinomas (discussed
Fig. 19.14 Pelvic inflammatory disease, bilateral and asymmetric. The tube later) also originate in the fallopian tube. Because the fim-
and ovary to the left of the uterus are totally obscured by a hemorrhagic briated end of the fallopian tube is intimately associated
inflammatory mass. The tube is adherent to the adjacent ovary on the other with the ovary and has access to the peritoneal cavity,
side. fallopian tube carcinomas frequently involve the ovary,
omentum, and peritoneal cavity at presentation.

Ovaries

FOLLICLE AND LUTEAL CYSTS TUMORS OF THE OVARY

Follicle and luteal cysts in the ovaries are so commonplace In the United States it is estimated that there will be over
that they may be considered variants of normal physiol- 20,000 ovarian cancer cases diagnosed in 2016 leading to
ogy. These innocuous lesions originate from unruptured over 14,000 deaths, making ovarian cancer the fifth leading
graafian follicles or from follicles that rupture and then contributor to cancer mortality in women. Tumors of the
immediately seal. Such cysts often are multiple and ovary are remarkably varied as they may arise from any
develop subjacent to the serosa of the ovary. They typi- of the three cell types in the normal ovary: the multipotent
cally are small (1–1.5 cm in diameter) and are filled with surface (coelomic) epithelium, the totipotent germ cells,
clear serous fluid. Occasionally, they become sufficiently and the sex cord–stromal cells. Neoplasms of epithelial
large (4–5 cm) to produce palpable masses and pelvic pain. origin account for the great majority of ovarian tumors and,
When small, they are lined by granulosa lining cells or in their malignant forms, account for almost 90% of ovarian
luteal cells, but as fluid accumulates, pressure may cause cancers (Table 19.3). Germ cell and sex cord–stromal cell
atrophy of these cells. Sometimes these cysts rupture, pro- tumors are much less frequent; although they consti-
ducing intraperitoneal bleeding and peritoneal symptoms tute 20% to 30% of ovarian tumors, they are collectively
(acute abdomen). responsible for less than 10% of malignant tumors of the
ovary.

POLYCYSTIC OVARIAN SYNDROME Surface Epithelial Tumors

Polycystic ovarian syndrome (formerly called Stein-Leventhal The majority of ovarian tumors arise from the fallopian
syndrome) is a complex endocrine disorder characterized tube or epithelial cysts in the cortex of the ovary (Fig.
by hyperandrogenism, menstrual abnormalities, polycys- 19.15). As mentioned, studies have shown that many of the
tic ovaries, chronic anovulation, and decreased fertility. It tumors thought to arise from the coelomic epithelium that
usually comes to attention after menarche in teenage girls covers the surface of the ovary are now thought to arise
or young adults who present with oligomenorrhea, hirsut- from the fimbriated end of the fallopian tube (Fig. 19.15).
ism, infertility, and sometimes with obesity. The epithelium lining the cortical cysts may be derived
The ovaries are usually twice the normal size, gray- from displaced ovarian surface epithelium or the lining of
white with a smooth outer cortex, and studded with fallopian tube. These can become metaplastic or undergo
subcortical cysts 0.5 to 1.5 cm in diameter. Histologic neoplastic transformation to give rise to a number of dif-
examination shows a thickened, fibrotic ovarian capsule ferent epithelial tumors. Benign lesions usually are cystic
overlying innumerable cystic follicles lined by granulosa (cystadenoma) and may have an accompanying stromal
cells with a hyperplastic luteinized theca interna. There is component (cystadenofibroma). Malignant tumors also
a conspicuous absence of corpora lutea in the ovary. may be cystic (cystadenocarcinoma) or solid (carcinoma).

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728 C H A P T E R 19 Female Genital System and Breast

Table 19.3 Frequency of Major Ovarian Tumors tumor suppressor genes. There is a higher incidence of
Percentage of carcinoma in unmarried women and married women with
Malignant Percentage That low parity. Of interest, prolonged use of oral contraceptives
Type Ovarian Tumors Are Bilateral reduces the risk. Around 5% to 10% of ovarian cancers are
Serous 47
familial, and most of these are associated with mutations
in the BRCA1 or BRCA2 tumor suppressor genes. As will
Benign (60%) 25
be discussed later, mutations in BRCA1 and BRCA2 also
Borderline (15%) 30 are associated with hereditary breast cancer. The average
Malignant (25%) 65 lifetime risk for ovarian cancer is approximately 30% in
Mucinous 3 BRCA1 carriers; the risk in BRCA2 carriers is somewhat
Benign (80%) 5 lower. In contrast with familial ovarian cancer, mutations
Borderline (10%) 10 in BRCA1 and BRCA2 are found in only 8% to 10% of
Malignant (10%) <5
sporadic ovarian cancers, which appear to arise through
alternative molecular mechanisms.
Endometrioid 20 30
carcinoma
Undifferentiated 10 — Serous Tumors
carcinoma
Serous tumors are the most common of the ovarian epithe-
Clear cell carcinoma 6 40
lial tumors overall, and also make up the greatest fraction
Granulosa cell tumor 5 5 of malignant ovarian tumors. About 60% are benign, 15%
Teratoma 1 are borderline, and 25% are malignant. Benign lesions are
Benign (96%) 15 usually encountered in patients between 30 and 40 years
Malignant (4%) Rare of age, and malignant serous tumors are more commonly
Metastatic 5 >50 seen between 45 and 65 years of age.
Others 3 —
There are two types of serous carcinomas, low-grade
and high-grade. The former arise from benign or border-
line lesions and progress slowly in a stepwise manner
to become invasive carcinoma. These low-grade tumors
Some ovarian epithelial tumors fall into an intermedi- are associated with mutations in genes encoding signal-
ate category currently referred to as borderline tumors. ing proteins, such as KRAS, a member of the RAS gene
Although the majority of borderline tumors behave in a family. The high-grade serous tumors develop rapidly.
benign manner they can recur and some can progress to As already mentioned, many of these high-grade lesions
carcinoma. arise in the fimbriated end of the fallopian tube via serous
Important risk factors for ovarian cancer include nul- tubal intraepithelial carcinoma, rather than ovarian coelo-
liparity, family history, and germline mutations in certain mic epithelium. TP53 mutations are virtually ubiquitous
in high-grade serous cancers, being present in over 95% of
Fallopian cases. Other frequently mutated genes include the tumor
Cystadenoma/ tube suppressors NF1 and RB, as well as BRCA1 and BRCA2 in
endometriosis familial ovarian cancers.
Inclusion
cyst Fimbriae
MORPHOLOGY
Most serous tumors are large, spherical to ovoid, cystic struc-
STIC tures up to 30 to 40 cm in diameter. About 25% of the benign
tumors are bilateral. In the benign tumors, the serosal cover-
ing is smooth and glistening. By contrast, the surface of adeno-
Borderline
tumor carcinomas often has nodular irregularities representing areas in
which the tumor has invaded the serosa. On cut section, small
cystic tumors may have a single cavity, but larger ones frequently
are divided by multiple septa into multiloculated masses. The
cystic spaces usually are filled with a clear serous fluid. Protruding
into the cystic cavities are papillary projections, which are more
prominent in malignant tumors (Fig. 19.16).
Type I Type II
Low-grade serous High-grade serous On histologic examination, benign tumors contain a single
Endometrioid layer of columnar epithelial cells that line the cyst or cysts.
Mucinous The cells often are ciliated. Psammoma bodies (concentrically
Fig. 19.15 Derivation, of various ovarian neoplasms. Type I tumors progress laminated calcified concretions) are common in the tips of papil-
from benign tumors through borderline tumors that may give rise to a low- lae. In high-grade carcinoma the cells are markedly atypical, the
grade carcinoma. Type II tumors arise from inclusions cysts/fallopian tube papillary formations are usually complex and multilayered, and by
epithelium via intraepithelial precursors that are often not identified. They definition nests or sheets of malignant cells invade the ovarian
demonstrate high-grade features and are most commonly of serous histology. stroma. Between clearly benign and obviously malignant forms
STIC, serous tubal intraepithelial carcinoma.

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 Tumors of the Ovary 729

MORPHOLOGY
On gross examination, mucinous tumors produce cystic masses
that may be indistinguishable from serous tumors except by the
mucinous nature of the cyst contents. However, they are more
likely to be larger and multicystic (Fig. 19.17A). Serosal
penetration and solid areas of growth are suggestive of
malignancy. Mucin-producing epithelial cells line the cysts (Fig.
19.17B). Malignant tumors are characterized by solid areas of
growth, piling up (stratification) of lining cells, cytologic atypia,
and stromal invasion.
A Compared with serous tumors, mucinous tumors are much
less likely to be bilateral. This feature is sometimes useful in
differentiating mucinous tumors of the ovary from metastatic
mucinous adenocarcinoma from a gastrointestinal tract primary
(the so-called “Krukenberg tumor”), which more often pro-
duces bilateral ovarian masses.
Ruptured ovarian mucinous tumors may seed the perito-
neum; however, these deposits typically regress spontaneously.
Stable implantation of mucinous tumor cells in the peritoneum
with production of copious amounts of mucin is called pseudo-
myxoma peritonei; in most cases, this disorder is caused by
metastatic spread of tumors in the gastrointestinal tract, primar-
ily the appendix (Chapter 15).
B
Fig. 19.16 Ovarian serous tumors. (A) Borderline serous cystadenoma
opened to display a cyst cavity lined by delicate papillary tumor growths. (B)
Cystadenocarcinoma. The cyst is opened to show a large, bulky tumor mass. The prognosis of mucinous cystadenocarcinoma is some-
(Courtesy of Dr. Christopher Crum, Brigham and Women’s Hospital, Boston, what better than that of its serous counterpart, although
Massachusetts.)
stage rather than histologic type (serous versus mucinous)
is the major determinant of outcome. Mutations in KRAS
are detected in approximately 50% of ovarian mucinous
lie borderline tumors, which exhibit less cytologic atypia and carcinomas, however this does not help distinguish them
typically no stromal invasion. Borderline tumors may seed the from metastatic GI tumors, which also have a high fre-
peritoneum, but fortunately the tumor implants usually are “non- quency of KRAS mutations.
invasive.” In general, malignant serous tumors spread throughout
the peritoneal cavity and to regional lymph nodes, including Endometrioid Tumors
periaortic lymph nodes; distant lymphatic and hematogenous
metastases are infrequent. These tumors may be solid or cystic; they sometimes
develop in association with endometriosis. On microscopic
examination, they are distinguished by the formation
The prognosis for patients with high-grade serous car- of tubular glands, similar to those of the endometrium,
cinoma is poor, even after surgery and chemotherapy, and within the lining of cystic spaces. Although benign and
depends heavily on the stage of the disease at diagnosis. borderline forms exist, endometrioid tumors usually
The 5-year survival for women with carcinoma confined are malignant. They are bilateral in about 30% of cases,
to one ovary is about 90%, but falls precipitously with and 15% to 30% of women with these ovarian tumors
higher stage tumors to less than 40% depending on the have a concomitant endometrial carcinoma. Similar to
exact stage. In contrast, borderline tumors are associated endometrioid-type carcinoma of the endometrium, endo-
with nearly 100% survival. Of note, women with tumors metrioid carcinomas of the ovary frequently have mutations
containing BRCA1/2 mutations tend to have a better in the PTEN tumor suppressor gene as well as mutations
prognosis than women whose tumors lack these genetic in other genes that also act by upregulating PI3K-AKT
abnormalities. signaling.

Mucinous Tumors Brenner Tumor

Mucinous tumors differ from serous tumors in two respects: The Brenner tumor is an uncommon, solid, usually unilat-
the neoplastic epithelium consists of mucin-secreting eral ovarian tumor consisting of abundant stroma contain-
cells; and mucinous tumors are considerably less likely ing nests of transitional-type epithelium resembling that of
to be malignant. Overall, only 10% of mucinous tumors the urinary tract. Occasionally, the nests are cystic and are
are malignant; another 10% are borderline, and 80% are lined by columnar mucus-secreting cells. Brenner tumors
benign. generally are smoothly encapsulated and gray-white on

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730 C H A P T E R 19 Female Genital System and Breast

Other Ovarian Tumors

Many other types of tumors of germ cell and sex cord–
stromal origin also arise in the ovary, but only the terato-
mas of germ cell origin are sufficiently common to merit
description. Table 19.4 presents some salient features of
other neoplasms of germ cell and sex cord origin.

Teratomas
Teratomas constitute 15% to 20% of ovarian tumors. A
distressing feature of these germ cell tumors is their predi-
lection to arise in the first 2 decades of life; to make matters
worse, the younger the person, the greater the likelihood of
malignancy. More than 90% of these germ cell neoplasms,
however, are benign mature cystic teratomas; the imma-
ture, malignant variant is rare.
Benign (Mature) Cystic Teratomas
Benign (mature) cystic teratomas are marked by the pres-
ence of mature tissues derived from all three germ cell
layers: ectoderm, endoderm, and mesoderm. Usually
these tumors contain cysts lined by epidermis replete
A with adnexal appendages—hence the common designa-
tion dermoid cysts. Most are discovered in young women
as ovarian masses or are found incidentally on abdominal
radiographs or scans because they contain foci of calcifica-
tion produced by toothlike structures contained within the
tumor. About 90% are unilateral, with the right side more
commonly affected. Rarely do these cystic masses exceed
10 cm in diameter. On cut section, they often are filled with
sebaceous secretion and matted hair that, when removed,
reveal a hair-bearing epidermal lining (Fig. 19.18). Some-
times there is a nodular projection from which teeth pro-
trude. Occasionally, foci of bone and cartilage, nests of
bronchial or gastrointestinal epithelium, or other tissues
are present.
For unknown reasons, these neoplasms sometimes
produce infertility and are prone to undergo torsion (in
10%–15% of cases), which constitutes an acute surgical
emergency. A rare, but fascinating, paraneoplastic compli-
cation is limbic encephalitis, which may develop in women
with teratomas containing mature neural tissue and often
remits with tumor resection. Malignant transformation,
usually to a squamous cell carcinoma, is seen in about 1%
of cases.
Immature Malignant Teratomas
Malignant (immature) teratomas are found early in life,
the mean age at clinical detection being 18 years. They
B typically are bulky and appear solid on cut section, and
they often contain areas of necrosis; uncommonly, cystic
Fig. 19.17 Ovarian mucinous cystadenoma. (A) Mucinous cystadenoma foci are present that contain sebaceous secretion, hair, and
with multicystic appearance and delicate septa. Note the presence of other features similar to those of mature teratomas. On
glistening mucin within the cysts. (B) Columnar cell lining of mucinous
microscopic examination, the distinguishing feature is the
cystadenoma.
presence of immature elements or minimally differenti-
ated cartilage, bone, muscle, nerve, or other tissues. As
with other tumors, the prognosis depends on grade and
cut section, ranging from a few centimeters to 20 cm in stage.
diameter. These tumors may arise from the surface epi-
thelium or from urogenital epithelium trapped within the Specialized Teratomas
germinal ridge. Although most are benign, both malignant A rare subtype of teratoma is composed entirely of special-
and borderline tumors have been described. ized tissue. The most common example is struma ovarii,

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 Tumors of the Ovary 731

Table 19.4 Salient Features of Ovarian Germ Cell and Sex Cord Neoplasms
Neoplasm Peak Incidence Usual Location Morphologic Features Behavior
Germ Cell Origin
Dysgerminoma Second to third Unilateral in Counterpart of testicular seminoma All malignant but only one-third
decade of life 80%–90% Sheets or cords of large clear cells metastasize; all radiosensitive;
Occur with Stroma may contain lymphocytes and 80% cure rate
gonadal occasional granulomas
dysgenesis
Choriocarcinoma First 3 decades of Unilateral Identical to placental tumor Metastasizes early and widely
life Two types of epithelial cells: cytotrophoblast Primary focus may degenerate,
and syncytiotrophoblast leaving only metastases
Resistant to chemotherapy
Sex Cord Tumors
Granulosa-theca Most Unilateral Composed of mixture of cuboidal granulosa May elaborate large amounts of
cell postmenopausal, cells and spindled or plump lipid-laden theca estrogen
but may occur cells Granulosa element may be
at any age Granulosa elements may recapitulate ovarian malignant (5%–25%)
follicle as Call-Exner bodies
Thecoma-fibroma Any age Unilateral Yellow (lipid-laden) plump thecal cells Most hormonally inactive
About 40% produce ascites and
hydrothorax (Meigs syndrome)
Rarely malignant
Sertoli-Leydig cell All ages Unilateral Recapitulates development of testis with Many masculinizing or
tubules or cords and plump pink Sertoli defeminizing
cells Rarely malignant
Metastases to Ovary
Older ages Mostly bilateral Anaplastic tumor cells, cords, glands, dispersed Primaries are gastrointestinal
through fibrous background tract (Krukenberg tumors),
Cells may be “signet ring” mucin-secreting breast, and lung

which is composed entirely of mature thyroid tissue that usually appear only when tumors are well advanced.
may actually produce hyperthyroidism. These tumors Ovarian tumors of surface epithelial origin usually are
appear as small, solid, unilateral brown ovarian masses. asymptomatic until they become large enough to cause
Other specialized teratomas include ovarian carcinoid, local pressure symptoms (e.g., pain, gastrointestinal
which in rare instances produces carcinoid syndrome. complaints, urinary frequency). Indeed, about 30% of all
ovarian neoplasms are discovered incidentally on routine
Clinical Features gynecologic examination. Larger masses, particularly
With all ovarian neoplasms, management poses a for- the common epithelial tumors, may cause an increase in
midable clinical challenge, because symptoms or signs abdominal girth. Smaller masses, particularly dermoid
cysts, sometimes twist on their pedicles (torsion), produc-
ing severe abdominal pain that mimics an acute abdomen.
Metastatic seeding of malignant serous tumors often
causes ascites, whereas functioning ovarian tumors often
come to attention because of the endocrinopathies they
produce.
Unfortunately, treatment of ovarian tumors remains
unsatisfactory; only a modest increase in survival has
been achieved since the mid-1970s. Screening methods that
detect early tumors are badly needed, but those evalu-
ated to date are of limited value. One such marker, the
protein CA-125, is elevated in the sera of 75% to 90% of
women with epithelial ovarian cancer. However, CA-125
is undetectable in up to 50% of women with cancer limited
to the ovary; conversely, it often is elevated in a variety
of benign conditions and nonovarian cancers. Hence,
its usefulness as a screening test in asymptomatic post-
Fig. 19.18 Mature cystic teratoma (dermoid cyst) of the ovary. A ball of menopausal women is limited. Currently, CA-125 mea-
hair (bottom) and a mixture of tissues are evident. (Courtesy of Dr. Christopher surements are of greatest value in monitoring response to
Crum, Brigham and Women’s Hospital, Boston, Massachusetts.) therapy.

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732 C H A P T E R 19 Female Genital System and Breast

S UMMARY • Sex cord–stromal tumors may display differentiation toward

granulosa, Sertoli, Leydig, or ovarian stromal cell type.
OVARIAN TUMORS
Depending on differentiation, they may produce estrogens or
• Tumors may arise from epithelium, sex cord–stromal cells, or androgens.
germ cells. • Germ cell tumors (mostly cystic teratomas) are the most
• Epithelial tumors are the most common malignant ovarian common ovarian tumor in young women; the vast majority
tumor and are more common in women older than 40 years are benign.
of age. • Germ cell tumors may differentiate toward oogonia (dysger-
• The major types of epithelial tumors are serous, mucinous, minoma), primitive embryonal tissue (embryonal), yolk sac
and endometrioid. Each has a benign, malignant, and borderline (endodermal sinus tumor), placental tissue (choriocarcinoma),
counterpart. or multiple tissue types (teratoma).
• Serous carcinoma is the most common and many arise in the
distal fallopian tube.

Diseases of Pregnancy
Diseases of pregnancy and pathologic conditions of the these cases, implantation occurs in the fallopian tube (tubal
placenta are important contributors to morbidity and mor- pregnancy); other sites include the ovaries and the abdomi-
tality for both mother and child. Discussed in this section nal cavity. Any factor that retards passage of the ovum
are a limited number of disorders in which knowledge of through the fallopian tube predisposes to ectopic preg-
the morphologic lesions contributes to an understanding nancy. In about half of the cases, slowed passage results
of clinical disease. from chronic inflammation and scarring in the oviduct;
intrauterine tumors and endometriosis may also hamper
passage of the ovum. In the other 50% of tubal pregnancies,
PLACENTAL INFLAMMATIONS AND no anatomic cause is evident. Ovarian pregnancies proba-
INFECTIONS bly result from rare instances in which the ovum is fertilized
just as the follicle ruptures. Gestation within the abdomi-
Infections may reach the placenta by either of two paths: nal cavity occurs when the fertilized egg drops out of the
(1) ascension through the birth canal or (2) hematogenous fimbriated end of the fallopian tube and implants on the
(transplacental) spread. peritoneum.
Ascending infections are by far the more common; in most
instances they are bacterial and are associated with pre-
MORPHOLOGY
mature rupture of the fetal membranes. On microscopic
examination, the chorioamnion shows neutrophilic infiltra- In all sites, early development of ectopic pregnancies proceeds
tion associated with edema and congestion (acute chorio- normally, with formation of placental tissue, the amniotic sac, and
amnionitis). With extension beyond the membranes, the decidual changes. With tubal pregnancies, the invading placenta
infection may involve the umbilical cord and placental eventually burrows through the wall of the fallopian tube, causing
villi, resulting in acute vasculitis of the cord (funisitis). intratubal hematoma (hematosalpinx), intraperitoneal
Ascending infections are caused by Mycoplasma, Candida, hemorrhage, or both. The tube is usually distended by freshly
and bacteria of the vaginal flora. clotted blood containing bits of gray placental tissue and fetal
Uncommonly, placental infections may arise by hema- parts. The histologic diagnosis depends on visualization of pla-
togenous spread of bacteria and other organisms; on histo- cental villi or, rarely, of the embryo.
logic examination, placental villi are the most frequently
affected structures (villitis). Syphilis, tuberculosis, liste-
riosis, toxoplasmosis, and various viruses (rubella, cyto- Until rupture occurs, an ectopic pregnancy may be indis-
megalovirus, herpes simplex virus) all can cause placental tinguishable from a normal pregnancy, with cessation of
villitis. Transplacental infections can affect the fetus and menstruation and elevation of serum and urinary placen-
give rise to the so-called “TORCH” complex (toxoplas- tal hormones. Under the influence of these hormones, the
mosis, other infections, rubella, cytomegalovirus infection, endometrium (in approximately 50% of cases) undergoes
herpes) (Chapter 7). the characteristic hypersecretory and decidual changes of
pregnancy. The absence of elevated gonadotropin levels
does not exclude the diagnosis because poor attachment
ECTOPIC PREGNANCY and necrosis of the ectopic placenta are common. Rupture
of an ectopic pregnancy may be catastrophic, with the
Ectopic pregnancy is defined as implantation of a fertil- sudden onset of intense abdominal pain and signs of an
ized ovum in any site other than the uterus, which may acute abdomen, often followed by shock. Prompt surgical
occur in as many as 1% of pregnancies. In more than 90% of intervention is necessary.

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 Gestational Trophoblastic Disease 733

Table 19.5 Features of Complete and Partial

SUMMARY Hydatidiform Mole
ECTOPIC PREGNANCY Feature Complete Mole Partial Mole
• Ectopic pregnancy is defined as implantation of the fertilized Karyotype 46,XX (46,XY) Triploid (69,XXY)
ovum outside of the uterine corpus. Approximately 1% of Villous edema All villi Some villi
pregnancies implant ectopically; the most common site is the Trophoblast Diffuse; Focal; slight
fallopian tube. proliferation circumferential
• Chronic salpingitis with scarring is a major risk factor for tubal Serum hCG Elevated Less elevated
ectopic pregnancy.
Tissue hCG ++++ +
• Rupture of an ectopic pregnancy is a medical emergency that,
if left untreated, may result in exsanguination and death. Risk of subsequent 2% Rare
choriocarcinoma
hCG, Human chorionic gonadotropin.

The incidence of complete hydatidiform mole is about 1

GESTATIONAL TROPHOBLASTIC to 1.5 per 2000 pregnancies in the United States and other
DISEASE Western countries. For unknown reasons, the incidence is
much higher in Asian countries. Moles are most common
Gestational trophoblastic disease refers to an abnor- before the age of 20 and after the age of 40 years, and a
mal proliferation of fetal trophoblast cells. The World history of the condition increases the risk for molar disease
Health Organization broadly divides these diseases into in subsequent pregnancies. Although molar disease for-
two categories: molar lesions and nonmolar lesions. The merly was discovered at 12 to 14 weeks of pregnancy
molar lesions are further divided into partial, complete, during investigation for a gestation that was “too large for
and invasive hydatidiform moles. The nonmolar category dates,” early monitoring of pregnancies by ultrasound has
consists of choriocarcinoma and other more uncommon lowered the gestational age at detection. In both complete
types of trophoblast-derived malignancies. All elaborate and partial moles, elevation of hCG in the maternal blood
human chorionic gonadotropins (hCG), which is detected and absence of fetal heart sounds are typical.
in the blood and urine at levels considerably higher than
those found during normal pregnancy. In addition to
aiding diagnosis, hCG levels in the blood or urine can be MORPHOLOGY
used to monitor treatment efficacy. Clinicians prefer the In advanced cases the uterine cavity is expanded by a deli-
umbrella term gestational trophoblastic disease because cate, friable mass of thin-walled, translucent cystic structures
the response to therapy, as judged by the hormone levels, (Fig. 19.19). Fetal parts are rarely seen in complete moles but
is significantly more important than pathologic subtyping are common in partial moles. On microscopic examination, the
of lesions. However, the genetics, pathology, and natural complete mole shows hydropic swelling of poorly vascularized
history of these disorders are sufficiently distinct to merit chorionic villi with a loose, myxomatous, edematous stroma.
discussion of each. The chorionic epithelium typically shows a proliferation of both
cytotrophoblasts and syncytiotrophoblasts (Fig. 19.20). Histo-
Hydatidiform Mole: Complete and Partial logic grading to predict the clinical outcome of moles has been
supplanted by monitoring of hCG levels. In partial moles,
The typical hydatidiform mole is a voluminous mass villous edema involves only a subset of the villi, and the tropho-
of swollen, sometimes cystically dilated, chorionic blastic proliferation is focal and slight. In most cases of partial
villi, appearing grossly as grapelike structures. Varying mole, some fetal cells are present, ranging from fetal red cells in
amounts of normal to highly atypical chorionic epithelium placental villi to, in rare cases, a fully formed fetus.
cover the swollen villi. There are two distinctive subtypes
of hydatidiform moles: complete and partial. Complete
hydatidiform moles are not compatible with embryogen- Overall, 80% to 90% of moles do not recur after thor-
esis and rarely contain fetal parts. All of the chorionic villi ough curettage, but 10% of complete moles are invasive
are abnormal, and the chorionic epithelial cells are diploid (described next). No more than 2% to 3% give rise to
(46,XX or, uncommonly, 46,XY). The partial hydatidiform choriocarcinoma.
mole is compatible with early embryo formation and there-
fore may contain fetal parts, has some normal chorionic Invasive Mole
villi, and is almost always triploid (e.g., 69,XXY) (Table
19.5). Both types result from abnormal fertilization with Invasive moles are complete moles that are locally invasive
an excess of paternal genetic material. In a complete mole but lack the metastatic potential of choriocarcinoma. An
the entire genetic content is supplied by two spermatozoa invasive mole retains hydropic villi, which penetrate the
(or a diploid sperm), yielding diploid cells containing only uterine wall deeply, possibly causing rupture and some-
paternal chromosomes, whereas in a partial mole a normal times life-threatening hemorrhage. On microscopic exami-
egg is fertilized by two spermatozoa (or a diploid sperm), nation, the epithelium of the villi shows atypical changes,
resulting in a triploid karyotype with a preponderance of with proliferation of both trophoblastic and syncytiotro-
paternal genes. phoblast components.

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734 C H A P T E R 19 Female Genital System and Breast

Asian and African countries, reaching a frequency of 1 in

2000 pregnancies. Approximately 50% of choriocarcinomas
arise from complete hydatidiform moles; about 25% arise
after an abortion, while the remainder manifest following
an apparently normal pregnancy. In most cases, choriocar-
cinoma presents as a bloody, brownish discharge accom-
panied by a rising titer of β-hCG in blood and urine, in the
absence of marked uterine enlargement, such as would be
seen with a mole. In general, the β-hCG titers are much
higher than those associated with a mole.

MORPHOLOGY
Choriocarcinomas usually appear as hemorrhagic, necrotic
Fig. 19.19 Complete hydatidiform mole, consisting of numerous swollen uterine masses. Sometimes the necrosis is so extensive that
(hydropic) villi. little viable tumor remains. Indeed, the primary lesion may “self-
destruct,” and only the metastases tell the story. Very early, the
tumor insinuates itself into the myometrium and into vessels. In
Although the marked invasiveness of this lesion makes contrast with hydatidiform moles and invasive moles,
removal technically difficult, metastases do not occur. chorionic villi are not formed; instead, the tumor is com-
Hydropic villi may embolize to distant organs, such as posed of anaplastic cuboidal cytotrophoblasts and syncy-
lungs or brain, but these emboli do not behave like true tiotrophoblasts (Fig. 19.21).
metastases and may regress spontaneously. Because of By the time a choriocarcinoma is discovered, widespread vas-
deeper invasion into the myometrium, an invasive mole cular spread usually has occurred to the lungs (50%), vagina (30%–
is difficult to remove completely by curettage, so if serum 40%), brain, liver, or kidneys. Lymphatic invasion is uncommon.
β-hCG remains elevated, further treatment is required. For-
tunately, in most cases cure is possible with chemotherapy.
Clinical Features
Gestational Choriocarcinoma
Despite the extremely aggressive nature of placental cho-
Choriocarcinoma, a very aggressive malignant tumor, riocarcinoma, these tumors are remarkably sensitive to
arises from gestational chorionic epithelium or, less fre- chemotherapy. Nearly 100% of affected patients are cured,
quently, from totipotential cells within the gonads (as a even those with metastases at distant sites such as the
germ cell tumor). These tumors are rare in the Western lungs. By contrast, response to chemotherapy with cho-
Hemisphere (they occur in about 1 per 30,000 pregnan- riocarcinomas that arise in the gonads (ovary or testis) is
cies in the United States), but are much more common in relatively poor. This striking difference in prognosis may
be related to the presence of paternal antigens on placental
choriocarcinomas that are lacking in gonadal lesions. Con-
ceivably, a maternal immune response against the foreign
(paternal) antigens helps clear the tumor by acting as an
adjunct to chemotherapy.

Fig. 19.20 Complete hydatidiform mole. In this microscopic image, dis-

tended hydropic villi (below) and proliferation of the chorionic epithelium Fig. 19.21 Choriocarcinoma. This field contains both neoplastic cytotro-
(above) are evident. (Courtesy of Dr. Kyle Molberg, Department of Pathology, phoblast and multinucleate syncytiotrophoblast. (Courtesy of Dr. David R.
University of Texas Southwestern Medical School, Dallas, Texas.) Genest, Brigham and Women’s Hospital, Boston, Massachusetts.)

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 Gestational Trophoblastic Disease 735

Placental Site Trophoblastic Tumor of the uteroplacental vascular bed. In normal pregnancy,
the musculoelastic walls of the spiral arteries are invaded
Placental site trophoblastic tumors are derived from the by trophoblasts, permitting them to dilate into wide vas-
placental site or intermediate trophoblast, a cell that has cular sinusoids. In preeclampsia and eclampsia, this vas-
morphologic and functional features that overlap with cular remodeling is impaired, the musculoelastic walls are
those of trophoblasts and syncytiotrophoblasts. These retained, and the channels remain narrow. Decreased utero-
uncommon diploid tumors, often XX in karyotype, typi- placental blood flow appears to result in placental hypoxia,
cally arise a few months after pregnancy. Because interme- placental dysfunction, and the altered release of circulating
diate trophoblasts do not produce hCG in large amounts, factors that regulate angiogenesis. Specifically, increases in
hCG concentrations are only slightly elevated. More typi- the anti-angiogenic factors soluble Flt1 (sFlt1) and soluble
cally, these tumors produce human placental lactogen. An endoglin (sEng) and reductions in proangiogenic factors,
indolent clinical course is typical, with a generally favorable such as VEGF, have been noted. These disturbances are
outcome if the tumor is confined to the endomyometrium. hypothesized to result in endothelial cell dysfunction, vas-
Of note, however, placental site trophoblastic tumors are cular hyperreactivity, and end-organ microangiopathy.
not as sensitive to chemotherapy as are other trophoblas- Although the exact basis of preeclampsia remains to be
tic tumors, and the prognosis is poor when spread occurs further defined, several serious consequences have been
beyond the uterus. associated with this condition:
• Placental infarction, stemming from chronic
hypoperfusion
• Hypertension, resulting from reduced endothelial produc-
SUMMARY tion of the vasodilators prostacyclin and prostaglandin
E2 and from increased production of the vasoconstrictor
GESTATIONAL TROPHOBLASTIC DISEASE thromboxane A2
• Molar disease is a result of an abnormal contribution of pater- • Hypercoagulability, due to endothelial dysfunction and
nal chromosomes to the conceptus. release of tissue factor from the placenta
• Partial moles are triploid and have two sets of paternal chro- • End-organ failure, most notably of the kidney and the
mosomes. They typically are accompanied by fetal tissue. There liver, which occurs in patients with full-blown eclamp-
is a low rate of persistent disease. sia. Approximately 10% of the patients with severe pre-
• Complete moles are diploid, and all chromosomes are paternal. eclampsia develop the so-called “HELLP syndrome”,
Rarely are embryonic or fetal tissues associated with a com- characterized by elevated liver enzymes, microangio-
plete mole. pathic hemolytic anemia, thrombocytopenia due to
• Among complete moles, 10% to 15% are associated with per- platelet consumption, and sometimes fullblown dis-
sistent disease that usually takes the form of an invasive mole. seminated intravascular coagulation (DIC).
Only 2% of complete moles progress to choriocarcinoma.
• Gestational choriocarcinoma is a highly invasive and frequently
metastatic tumor that, in contrast with ovarian choriocarci-
noma, is responsive to chemotherapy and curable in most cases.
MORPHOLOGY
• Placental site trophoblastic tumor is an indolent tumor of
intermediate trophoblast that produces human placental lac- The morphologic changes of preeclampsia and eclampsia are
togen. It can be cured surgically but once it spreads it does variable and correlate to some degree with the severity of the
not respond well to chemotherapy. disorder. Placental abnormalities include
• Infarcts, which can be a feature of normal pregnancy, but are
much more numerous with severe preeclampsia or eclampsia
• Retroplacental hemorrhages
Preeclampsia/Eclampsia (Toxemia of Pregnancy) • Premature maturation of placental villi associated with
villous edema, hypovascularity, and increased production of
The development of hypertension, accompanied by pro- syncytial epithelial knots
teinuria and edema in the third trimester of pregnancy, is • Fibrinoid necrosis and focal accumulation of lipid-containing
referred to as preeclampsia. This syndrome occurs in 5% macrophages (acute atherosis) of decidual vessels
to 10% of pregnancies, particularly with first pregnancies
in women older than 35 years. In those severely affected,
seizures may occur, and the symptom complex is then
termed eclampsia. By long-existing precedent, preeclamp-
sia and eclampsia sometimes are referred to as toxemia of Clinical Features
pregnancy. No blood-borne toxin has been identified, and Preeclampsia presents insidiously during weeks 24 to 25
this historically sanctified term is a misnomer. Recogni- of gestation with edema, proteinuria, and rising blood
tion and early treatment of preeclampsia have now made pressure. Should the condition evolve into eclampsia,
eclampsia, particularly fatal eclampsia, rare. renal function is impaired, blood pressure rises further,
While exact triggering events initiating these syn- and convulsions may occur. Prompt therapy early in the
dromes are unknown, a common feature underlying all course aborts the associated organ changes, with all abnor-
cases is insufficient maternal blood flow to the placenta malities resolving promptly after delivery or after cesarean
secondary to inadequate remodeling of the spiral arteries section.

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736 C H A P T E R 19 Female Genital System and Breast

Breast
Three important features distinguish the breast from other
organs. First, rather than being essential for survival,
CLINICAL PRESENTATIONS OF
the major function is the nutritional support of another BREAST DISEASE
individual, the infant. Second, the structure of the organ
undergoes marked changes throughout life: expansion The predominant symptoms and signs of diseases of the
of the lobular system after menarche, periodic remodel- breast are pain, inflammatory changes, nipple discharge,
ing during adulthood, especially during and after preg- “lumpiness,” or a palpable mass (Fig. 19.23A). However,
nancy, and ultimately involution and regression of lobules. few symptoms are so severe as to require treatment, and
Finally, breasts are visible and as a result have a social, the primary reason for investigating their cause is to evalu-
cultural, and personal significance not shared by other ate the possibility of malignancy. Most symptomatic breast
organs. All of these features play a role when consider- lesions (>90%) are benign. Of women with cancer, about
ing the origins, presentations, and treatment of breast 45% have symptoms, whereas the remainder come to atten-
disease. tion through screening tests (Fig. 19.23B).
The functional unit of the breast is the lobule, which • Pain (mastalgia or mastodynia) is a common symptom
is supported by a specialized intralobular stroma. The often related to menses, possibly due to cyclic edema
inner luminal epithelial cells produce milk during lacta- and swelling. Pain localized in a specific area is usually
tion. The basally located myoepithelial cells have contrac- caused by a ruptured cyst or trauma to adipose tissue
tile function to aid in milk ejection and also help support (fat necrosis). Almost all painful masses are benign, but
the basement membrane. The ducts are conduits for for unknown reasons a small fraction of cancers (about
milk to reach the nipple. The size of the breast is deter- 10%) cause pain.
mined primarily by interlobular stroma, which increases • Inflammation causes an edematous and erythematous
during puberty and involutes with age. Each normal con- breast. It is rare and is most often caused by infec-
stituent is a source of both benign and malignant lesions tions, which only occur with any frequency during
(Fig. 19.22). lactation and breastfeeding. An important mimic of

Luminal cells (blue) Nipple

Myoepithelial cells (black)
Intralobular stroma (green)
Interlobular stroma (red)
Papilloma

DCIS

Epithelial
hyperplasia

Normal lobule Phyllodes

Fibroadenoma
Invasive tumor
carcinoma

Hemangioma Angiosarcoma

NORMAL BENIGN MALIGNANT

Fig. 19.22 Origins of breast disorders. Benign epithelial lesions include intraductal papillomas that grow in sinuses below the nipple and epithelial hyperplasia
that arises in lobules. Malignant epithelial lesions are mainly breast carcinomas, which may remain in situ or invade into the breast and spread by metastasis.
Specialized intralobular stroma (green) cells may give rise to fibroadenomas and phyllodes tumors, whereas interlobular stroma (green) may give rise to a
variety of rare benign and malignant tumors.

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 Inflammatory Processes 737

Inflammation Nipple discharge

<1% are cancers Inflammatory changes
7% are cancers Pain
Nipple
discharge
Palpable
5% are cancers Palpable
5% are cancers mass
mass
Pain
Abnormal
mammogram
Lumpiness or
other symptoms 1% are cancers

A SYMPTOMS OF PATIENTS B PRESENTATIONS OF BREAST CANCERS

Fig. 19.23 Presenting symptoms of breast disease. (A) Common breast-related symptoms that bring patients to clinical attention. (B) Presentations of breast
cancer.

inflammation is “inflammatory” breast carcinoma (dis- lymph nodes at the time of diagnosis. In the United States,
cussed later). most cancers in women more than 50 years of age are now
• Nipple discharge may be normal when small in quan- detected by mammography (Fig. 19.23B). As with symp-
tity and bilateral. The most common benign lesion pro- tomatic breast lesions, the likelihood that an abnormal
ducing a nipple discharge is a papilloma arising in the mammographic finding is caused by malignancy increases
large ducts below the nipple (Fig. 19.22). Discharges that with age, from 10% at age 40 to more than 25% in women
are spontaneous, unilateral, and bloody are of greatest older than age 50.
concern for malignancy.
• Lumpiness, or a diffuse nodularity throughout the breast,
is usually a result of normal glandular tissue. When SUMMARY
pronounced, imaging studies may help to determine
whether a discrete mass is present. CLINICAL PRESENTATIONS OF BREAST DISEASE
• Palpable masses can arise from proliferations of stromal • Symptoms affecting the breasts are evaluated primarily to
cells or epithelial cells and are generally detected when determine if malignancy is present.
they are 2 to 3 cm in size (Fig. 19.22). Most (~95%) are • Regardless of the symptom, the underlying cause is benign in
benign; these tend to be round to oval and to have the majority of cases.
circumscribed borders. In contrast, malignant tumors • Breast cancer is most commonly detected by palpation of a
usually invade across tissue planes and have irregular mass in younger women and in unscreened populations and
borders. However, because some cancers grow decep- by mammographic screening in older women.
tively as circumscribed masses, all palpable masses
require evaluation.
• Gynecomastia is the only common breast symptom in
males. There is an increase in both stroma and epithelial INFLAMMATORY PROCESSES
cells resulting from an imbalance between estrogens,
which stimulate breast tissue, and androgens, which Inflammatory diseases of the breast are rare and may
counteract these effects. be caused by infections, autoimmune disease, or foreign
body–type reactions. Symptoms include erythema and
Regardless of presenting symptom, the likelihood of edema, often accompanied by pain and focal tenderness.
malignancy increases with age. For example, the risk of Because inflammatory diseases are rare, the possibility
nipple discharge being due to cancer increases from 7% that the symptoms are caused by inflammatory carcinoma
in women younger than 60 years of age to 30% in women should always be considered (discussed later).
older than 60. Similarly, only 10% of palpable masses in The only infectious agent to cause breast disease with
women younger than 40 years of age are carcinomas, as any frequency is Staphylococcus aureus, which typically
compared to 60% in women older than 50. gains entry via fissures in nipple skin during the first
Mammographic screening was introduced in the 1980s as weeks of breastfeeding. The invading organisms may lead
a means to detect early, nonpalpable asymptomatic breast to the formation of “lactational abscesses,” collections of
carcinomas before metastatic spread has occurred. Mam- neutrophils and associated bacteria in fibroadipose tissue.
mography has met this promise, as the average size of If untreated, tissue necrosis may lead to the appearance of
invasive carcinomas detected by mammography is about fistula tracks opening onto the skin. Most cases are treated
1 cm (significantly smaller than cancers identified by pal- adequately with antibiotics and continued expression of
pation), and only 15% will have metastasized to regional milk. Rarely, surgical incision and drainage is required.

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738 C H A P T E R 19 Female Genital System and Breast

STROMAL NEOPLASMS BENIGN EPITHELIAL LESIONS

The two types of stroma in the breast, intralobular and The majority of benign epithelial lesions are incidental
interlobular, give rise to different types of neoplasms (Fig. findings detected by mammography. Their major clini-
19.22). Historically, tumors derived from intralobular cal significance is their relationship to the subsequent risk
stroma have been cleanly divided into benign fibroadeno- of developing breast cancer. Benign changes are divided
mas and more cellular phyllodes tumors, which sometimes into three groups, nonproliferative disease, proliferative disease
recur following excision and rarely pursue a malignant without atypia, and proliferative disease with atypia, each
course. It is now appreciated that these tumors share driver associated with a different degree of breast cancer risk
mutations in the same genes and appear to be part of a (Table 19.6).
spectrum of related neoplasms. Nevertheless, the old clas- • Nonproliferative disease is not associated with an
sification is engrained in the medical lexicon and we will increased risk of breast cancer.
follow it here for simplicity’s sake. • Proliferative disease without atypia encompasses poly-
clonal hyperplasias that are associated with a slightly
MORPHOLOGY increased risk of breast cancer.
• Proliferative disease with atypia includes monoclonal
Tumors derived from intralobular stroma are comprised of both “precancers” that are associated with a modest increase
stromal cells and epithelial cells (i.e., they are “biphasic”), as the in the risk of breast cancer in both breasts; overall, 13%
neoplastic proliferation of specialized lobular fibroblasts also to 17% of women with these lesions develop breast
stimulates reactive proliferation of lobular epithelial cells. As the cancer.
intralobular fibroblasts proliferate, they push and distort the epi-
thelial cells so that they form elongated slitlike structures rather
than round acini. In benign fibroadenoma, the tumor mass has
circumscribed borders and low cellularity (Fig. 19.24A); mitoses MORPHOLOGY
are rare. By contrast, in phyllodes tumors the stromal cells
tend to outgrow the epithelial cells, resulting in bulbous nodules Nonproliferative disease consists of three major morphologic
of proliferating stromal cells that are covered by epithelium changes: cysts, fibrosis, and adenosis. It is termed “nonprolif-
(Fig. 19.24B), the characteristic “phyllodes” (Greek for “leaflike”) erative” because the lesions contain single layers of epithelial
growth pattern. In high-grade phyllodes tumors epithelium may cells. The most common nonproliferative breast lesions are
be scant or absent, producing a sarcomatous appearance. Overall, simple cysts lined by a layer of luminal cells that often undergo
about 2% of phyllodes tumors metastasize to distant sites. apocrine metaplasia (Fig. 19.25A). The apocrine secretions may
Lesions of interlobular stroma are monophasic (only com- calcify and be detected by mammography. When cysts rupture,
prised of mesenchymal cells) and include benign soft tissue chronic inflammation and fibrosis in response to the spilled
tumors found elsewhere in the body, such as hemangiomas debris may produce palpable nodularity of the breast (so-called
(Chapter 10) and lipomas (Chapter 21). The only malignancy “fibrocystic changes”). Proliferative disease without atypia
derived from interlobular stromal cells of note is angiosarcoma includes epithelial hyperplasia, sclerosing adenosis, complex scle-
(Chapter 21), which may arise in the breast after local radiother- rosing lesion, and papilloma. Each is associated with varying
apy. The morphologies of these lesions are described elsewhere. degrees of epithelial cell proliferation. For example, in epithelial

A B
Fig. 19.24 Intralobular stromal neoplasms. (A) Fibroadenoma. This benign tumor has an expansile growth pattern with pushing circumscribed borders.
(B) Phyllodes tumors. Proliferating stromal cells distort the glandular tissue, forming cleftlike spaces, and bulge into surrounding stroma.

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 Carcinoma 739

Table 19.6 Factors Associated With Development of Invasive Carcinoma

Factor Relative Riska Absolute Lifetime Riska
Women with no risk factors 1.0 3%
First-degree relative(s) with breast cancerb 1.2–9.0 4%–30%
Germline tumor suppressor gene mutation (e.g., BRCA1 mutation) 2.0–45.0 6% to >90%
Menstrual History
Age at menarche <12 years 1.3 4%
Age at menopause >55 years 1.5–2.0 5%–6%
Pregnancy
First live birth <20 years (protective) 0.5 1.6%
First live birth 20–35 years 1.5–2.0 5%–6%
First live birth >35 years 2.0–3.0 6%–10%
Never pregnant (nulliparous) 3.0 10%
Breast-feeding (slightly protective) 0.8 2.6%
Benign Breast Disease
Proliferative disease without atypia 1.5–2.0 5%–6%
Proliferative disease with atypia (ALH and ADH) 4.0–5.0 13%–17%
Carcinoma in situ (ductal or lobular) 8.0–10.0 25%–30%
Ionizing radiation 1.1–1.4 3.6%–4.6%
Mammographic density 3.0–7.0 10%–23%
Postmenopausal obesity and weight gain 1.1–3.0 3.6%–10%
Postmenopausal hormone replacement 1.1–3.0 3.6%–10%
Alcohol consumption 1.1–1.4 3.6%–4.6%
Alcohol consumption 1.1–1.4 3.6%–4.6%
a
Relative risk is the likelihood of developing cancer compared to a woman with no risk factors—whose relative risk is 1.0. Absolute lifetime risk is the fraction of women
expected to develop invasive carcinoma without a risk reducing intervention. For women with no risk factors, there is about a 3% chance of developing invasive breast cancer.
b
The most common family history is a mother who developed cancer after menopause. This history does not increase the risk of her daughters.

hyperplasia, increased numbers of both spindled myoepithelial CARCINOMA

cells and epithelioid luminal cells expand ductal and lobular spaces
(Fig. 19.25B). Breast carcinoma is the most common malignancy of
Proliferative disease with atypia includes atypical women globally (excluding nonmelanoma skin cancer)
lobular hyperplasia (ALH) and atypical ductal hyperplasia (ADH). and causes the majority of cancer deaths in women.
ALH closely resembles lobular carcinoma in situ (LCIS) and Although the incidence in the United States decreased
ADH closely resembles ductal carcinoma in situ (DCIS) (both slightly in 2002 and then stabilized (changes attributed
described later), but are more limited in extent. The cells in ADH to a decrease in the use of postmenopausal hormone
are uniform in appearance and form sharply marginated spaces therapy and a plateau in the number of women undergo-
or rigid bridges (Fig. 19.25C). ing mammographic screening), the worldwide incidence

A B C
Fig. 19.25 Benign epithelial breast disease. (A) Nonproliferative disease. An apocrine cyst is shown that is a common feature of nonproliferative breast
disease. (B) Proliferative breast disease is characterized by increased numbers of epithelial cells, as in this example of epithelial hyperplasia. (C) Proliferative
breast disease with atypia. The proliferating epithelial cells are monomorphic in appearance and pile up to form abnormal architectural structures.

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740 C H A P T E R 19 Female Genital System and Breast

and mortality is increasing at an alarming rate. The major 350

factors underlying this trend in developing countries are Estrogen receptor positive,

Breast cancer rate (per 100,000 women)

thought to be social changes that increase breast cancer HER2-negative
300
risk—specifically, delayed childbearing, fewer pregnan- HER2-positive
cies, and reduced breastfeeding—combined with a lack of 250 Estrogen receptor negative,
access to optimal health care. HER2-negative
The lifetime risk of breast cancer is 1 in 8 for women 200
living to age 90 in the United States. It is predicted that
about 250,000 breast cancers will be diagnosed in 2016 and 150
about 40,000 women will die of the disease—a toll among
cancers second only to lung cancer. Since the mid-1980s the 100
mortality rate has dropped from 30% to less than 20%. The
decrease is attributed to both improved screening, which 50
detects some cancers before they have metastasized, and
more effective systemic treatment. 0
Almost all breast malignancies are adenocarcinomas

5-9
-14
-19
-24
-29
-34
-39
-44
-49
-54
-59
-64
-69
-74
-79
-84
85
0-4

10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
(>95%). In the most clinically useful classification system,
Age at diagnosis
breast cancers are divided based on the expression of
hormone receptors—estrogen receptor (ER) and proges- Fig. 19.26 Age and the incidence of breast cancer subtypes.
terone receptor (PR)—and the expression of the human
epidermal growth factor receptor 2 (HER2, also known as
ERBB2), into three major groups: An alternative classification system with substantial
• ER positive (HER2 negative; 50%–65% of cancers) overlap relies on gene expression profiling. This system,
• HER2 positive (ER positive or negative; 10%–20% of which is currently used mainly in the context of clinical
cancers) research, divides breast cancers into four major types:
• Triple negative (ER, PR, and HER2 negative; 10%–20% • Luminal A. The majority are lower-grade ER-positive
of cancers) cancers that are HER2 negative
• Luminal B. The majority are higher-grade ER-positive
These three groups show striking differences in patient cancers that may be HER2 positive
characteristics, pathologic features, treatment response, • HER2-enriched. The majority overexpress HER2 and do
metastatic patterns, time to relapse, and outcome (Table not express ER
19.7 and Fig. 19.26). Within each group are additional his- • Basal-like. The majority by gene expression profiling
tologic subtypes (discussed later), some of which also have resemble basally located myoepithelial cells and are
clinical importance. ER-negative, HER2-negative

Table 19.7 Summary of the Major Biologic Types of Breast Cancer

HER2 Positive (ER Positive Triple Negative (ER, PR,
Feature ER Positive/HER2 Negative or Negative) and HER2 Negative)
Overall frequency 50%–65% 20% 15%
Typical patient groups Older women; men; cancers Young women; germline TP53 Young women; germline BRCA1
detected by screening; germline mutation carriers mutation carriers
BRCA2 mutation carriers
Ethnicity
European/American 70% 18% 12%
African/American 52% 22% 26%
Hispanic 60% 24% 16%
Asian/Pacific Islander 63% 26% 11%
Grade Mainly grade 1 and 2 Mainly grade 2 and 3 Mainly grade 3
Complete response to Low grade (<10%), higher grade ER positive (15%), ER negative 30%
chemotherapy (10%) (>30%)
Timing of relapse May be late (>10 years after Usually short (<10 years after Usually short (<8 years after
diagnosis) diagnosis) diagnosis)
Metastatic sites Bone (70%), viscera (25%), brain Bone (70%), viscera (45%), brain Bone (40%), viscera (35%), brain
(<10%) (30%) (25%)
Similar group defined by mRNA Luminal A (low grade), luminal B Luminal B (ER positive), HER2- Basal-like
profiling (high grade) enriched (ER negative)
Common special histologic types Lobular, tubular, mucinous, papillary Apocrine, micropapillary Carcinoma with medullary features
Common somatic mutations PIK3CA (40%), TP53 (26%) TP53 (75%), PIK3CA (40%) TP53 (85%)
PIK3CA encodes phosphoinositide 3-kinase (PI3K).

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 Carcinoma 741

Epidemiology and Risk Factors to exposure of the breast to estrogen produced by adipose
tissue. In keeping with this, obesity is only associated with
A large number of risk factors for breast cancer have been an increased risk of tumors that express ER.
identified (Table 19.6). Some of the more important risk
factors are summarized next. Pathogenesis
The three major subtypes of breast cancer defined by
Age and Gender. Breast cancer is rare in women younger differential expression of hormone receptors and HER2
than age 25, but increases in incidence rapidly after age 30 arise through more-or-less distinct pathways that involve
(Fig. 19.26); 75% of women with breast cancer are older the stepwise acquisition of driver mutations in the epi-
than 50 years of age, and only 5% are younger than 40. The thelial cells of the duct/lobular system (Fig. 19.27). Factors
incidence in men is only 1% of that in women. that contribute directly to the development of breast cancer
can be grouped into genetic, hormonal, and environmental
Family History of Breast Cancer. The greatest risk is categories.
for individuals with multiple affected first-degree rela-
tives with early-onset breast cancer. In most families, it Genetic. Driver mutations in cancer genes that contribute
is thought that various combinations of low penetrance, to breast carcinogenesis can be divided into those that are
“weak” cancer genes are responsible for increased risk. inherited and those that are acquired. The major germ-
However, approximately 5% to 10% of breast cancers line mutations conferring susceptibility to breast cancer
occur in persons who inherit highly penetrant germline affect genes that regulate genomic stability or that are
mutations in tumor suppressor genes (discussed later). For involved in progrowth signaling pathways. BRCA1 and
these individuals, the lifetime risk of breast cancer may be BRCA2 are classic tumor suppressor genes, in that cancer
greater than 90%. arises only when both alleles are inactivated or defective
(Chapter 6). BRCA1 and BRCA2 encode proteins that are
Geographic Factors. Significant differences in the inci- required for repair of certain kinds of DNA damage. They
dence and mortality rates of breast cancer have been are normally expressed in many different cells and tissues,
reported in various countries. The risk is significantly and why germline mutations in these genes lead mainly
higher in the Americas and Europe than in Asia and Africa. to an increased risk of breast and serous ovarian cancer
For example, the incidence and mortality rates are five (discussed earlier) remains mysterious. The degree of pen-
times higher in the United States than in Japan. Some risk etrance, age of onset, and susceptibility to other types of
factors must be modifiable because migrants from low- cancers differ among the many BRCA1 and BRCA2 germ-
incidence to high-incidence areas tend to acquire the rates line mutations, but most carriers develop breast cancer by
of their new home countries. Diet, reproductive patterns, the age of 70 years, as compared to about 12% of women
and breastfeeding practices are thought to be involved. with an average risk of breast cancer. For unclear reasons,
In line with this, breast cancer rates appear to be rising in BRCA2 mutations are primarily associated with ER-positive
parts of the world that are adopting Western habits. tumors, whereas BRCA1 mutations show a strong associa-
tion with triple-negative cancers (Fig. 19.27). Other mutated
Race/Ethnicity. The highest rate of breast cancer is in genes associated with familial breast cancer include TP53
women of European descent, largely because of a higher (the so-called “guardian of the genome”, Chapter 6) and
incidence of ER-positive cancers. Hispanic and African PTEN (an important negative regulator of the pro-growth
American women tend to develop cancer at a younger PI3K-AKT pathway), already mentioned earlier as a
age and are more likely to develop aggressive tumors. Such risk factor for endometrial carcinoma as part of Cowden
disparities are thought to result from a combination of dif- syndrome.
ferences in genetics, social factors, and access to health care As might be expected, the pathways in which famil-
and are an area of intense study. ial breast cancer genes function also are often disturbed
in sporadic breast cancers. Somatic mutations in BRCA1
Reproductive History. Early age of menarche, nulliparity, and BRCA2 are rare in sporadic cancers, but BRCA1 is
absence of breastfeeding, and older age at first pregnancy inactivated by methylation in up to 50% of triple-negative
are all associated with increased risk, probably because cancers. Somatic mutations in TP53 are common in breast
each increases the exposure of “at-risk” breast epithelial cancer, particularly triple-negative and HER2-positive
cells to estrogenic stimulation. tumors (Table 19.7), whereas mutations that activate PI3K-
AKT signaling are frequently found in sporadic ER-positive
Ionizing Radiation. Radiation to the chest increases the and HER2-positive breast cancers (Fig. 19.27).
risk of breast cancer if exposure occurs while the breast A common clinically important driver mutation in
is still developing. For example, breast cancer develops breast cancer is amplification of the HER2 gene. HER2
in 25% to 30% of women who underwent irradiation for is a receptor tyrosine kinase that promotes cell prolifera-
Hodgkin lymphoma in their teens and 20s, but the risk for tion and opposes apoptosis by stimulating the RAS- and
women treated later in life is not elevated. PI3K-AKT signaling pathways. Cancers that overexpress
HER2 are pathogenically distinct and highly proliferative.
Other Risk Factors. Postmenopausal obesity, postmeno- In the past they had a poor prognosis; however, the avail-
pausal hormone replacement, mammographic density, ability of therapeutic agents that specifically target HER2
and alcohol consumption also have been implicated as risk has markedly improved the prognosis for patients with
factors. The risk associated with obesity probably is due HER2-amplified tumors.

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742 C H A P T E R 19 Female Genital System and Breast

INVASIVE CANCER
Flat epithelial atypia Atypical ductal hyperplasia DCIS
ER positive
Germline BRCA2 HER2 negative
mutations (50-65% of
cancers)
1q 16q PIK3CA
gain loss mutations “Luminal”

ER POSITIVE PATHWAYS
HER2 Positive
(20% of cancers)
Normal
breast Germline HER2 “HER2
TP53 mutations amplification enriched”
Atypical apocrine adenosis DCIS
ER NEGATIVE PATHWAYS

ER negative
HER2 negative
(15% of cancers)
?
Germline BRCA1 TP53 BRCA1
mutations inactivation “Basal-like”
mutations
DCIS

Fig. 19.27 Major pathways of breast cancer development. The most common pathway (yellow arrow) leads to ER-positive cancers. Morphologically recognized
precursor lesions include flat epithelial atypia, ADH, and DCIS, all of which share certain genomic events with invasive ER-positive carcinomas, such gains of
chromosome 1, losses of chromosome 16, and mutations of PIK3CA (the gene encoding PI3K). By gene expression profiling, these cancers are classified as
“luminal.” This is the type of cancer that arises most commonly in individuals with germline BRCA2 mutations. Less common are cancers that overexpress
HER2 because of gene amplification (green arrow). These cancers may be positive or negative for ER and are usually associated with germline TP53 mutations.
A possible precursor lesion is atypical apocrine adenosis, which shares features with apocrine DCIS. The least common but molecularly most distinctive type
of breast cancer is negative for ER and HER2 (“triple negative”; blue arrow). These cancers have loss of BRCA1 and TP53 function and are genomically unstable.
The majority of triple-negative cancers are classified as “basal-like” by gene expression profiling.

Hormonal Influences. Estrogens stimulate the production

Breast cancers are classified morphologically according to
of growth factors, such as transforming growth factor-α,
whether they have penetrated the basement membrane. Those
platelet-derived growth factor, fibroblast growth factor,
that remain within this boundary are termed in situ carcinomas,
and others, which may promote tumor development
and those that have spread beyond it are designated invasive
through paracrine and autocrine mechanisms. In addi-
carcinomas. In this classification, the main forms of breast carci-
tion, ER regulates dozens of other genes in an estrogen-
noma are as follows:
dependent fashion, some of which are important for tumor
A. Noninvasive
development or growth. Hormonal influences likely drive
1. Ductal carcinoma in situ
proliferation during the development of cancers from
2. Lobular carcinoma in situ
precursor lesions (which typically strongly express ER)
B. Invasive
to fully malignant and even metastatic carcinomas. The
1. Invasive ductal carcinoma (includes all carcinomas that
clearest measure of the importance of estrogen is found
are not of a special type)—70% to 80%
in the therapeutic benefits of estrogen antagonists, which
2. Invasive lobular carcinoma— ~10% to 15%
reduce the development of ER-positive cancers in women
3. Carcinoma with medullary features— ~5%
at high risk and are mainstays in the treatment of estab-
4. Mucinous carcinoma (colloid carcinoma) — ~5%
lished ER-positive tumors.
5. Tubular carcinoma— ~5%
6. Other types
Environmental Factors. Environmental influences are
suggested by the variable incidence of breast cancer in Noninvasive (in Situ) Carcinoma
genetically homogeneous groups (e.g., Japanese women
There are two morphologic types of noninvasive breast carci-
living in Japan and the United States) and the geographic
noma: ductal carcinoma in situ (DCIS) and lobular carcinoma in
differences in breast cancer incidence, as discussed earlier.
situ (LCIS). The terms ductal and lobular are misleading, as both
types of CIS are thought to arise from cells in the terminal duct
MORPHOLOGY that give rise to lobules. LCIS usually expands involved lobules
(Fig. 19.28A), whereas DCIS distorts lobules into ductlike spaces
The most common location of tumors within the breast is in (Fig. 19.28B). By definition, both “respect” the basement mem-
the upper outer quadrant (50%), followed by the central portion brane and do not invade into stroma or lymphovascular channels.
(20%). About 4% of women with breast cancer have bilateral DCIS has a wide variety of histologic appearances, including
primary tumors or sequential lesions in the same breast. solid, comedo, cribriform, papillary, micropapillary, and “clinging”

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 Carcinoma 743

A B C
Fig. 19.28 Carcinoma in situ. (A) Lobular carcinoma in situ (LCIS). (B) Ductal carcinoma in situ (DCIS). DCIS partially involves the lobule in the lower half of
this photo and has completely effaced the upper lobules, producing a ductlike appearance. (C) Mammographic detection of calcifications associated with DCIS.

types. Nuclear appearances range from bland and monoto- Invasive (Infiltrating) Carcinoma
nous (low nuclear grade) to pleomorphic (high nuclear grade). The distinctive histologic patterns of the subtypes of invasive
The distinctive comedo subtype is characterized by exten- carcinoma are described first, followed by grading, which is used
sive central necrosis, which produces toothpastelike necrotic for all.
tissue that extrudes from transected ducts on application of Invasive ductal carcinoma is a term used for all carcino-
gentle pressure. Calcifications frequently are associated mas that cannot be subclassified into one of the specialized types
with DCIS (Fig. 19.28C), resulting from calcification of necrotic described below. A majority (70%–80%) of cancers falls into
debris or secretory material. DCIS constitutes only 5% of breast this group. This type of cancer usually is associated with DCIS.
cancers in unscreened populations but up to 30% in screened The microscopic appearance varies, ranging from tumors with
populations, largely because of the ability of mammography to well-developed tubules and low-grade nuclei (Fig. 19.29A) to
detect calcifications. Current treatment strategies for DCIS use tumors consisting of sheets of anaplastic cells. Most invasive
surgery and irradiation to eradicate the lesion. Treatment with ductal carcinomas produce a desmoplastic response, which
anti-estrogenic agents such as tamoxifen also is used to decrease replaces normal breast fat (resulting in a mammographic density;
the risk of recurrence of ER-positive DCIS. The prognosis is Fig. 19.29B) and eventually leads to the appearance of a hard,
excellent, with greater than 97% long-term survival. If untreated, palpable irregular mass. About 50% to 65% of ductal carcinomas
DCIS progresses to invasive cancer in roughly one-third of are ER positive, 20% are HER2 positive, and 15% are negative
cases, usually in the same breast and quadrant as the earlier for both ER and HER2 (Table 19.7).
DCIS. Invasive lobular carcinoma consists of infiltrating cells
Paget disease of the nipple is caused by the extension that are morphologically similar to the tumor cells seen
of DCIS up the lactiferous ducts and into the contiguous skin in LCIS; indeed, two-thirds of the cases are associated with
of the nipple, producing a unilateral crusting exudate over LCIS. These tumors comprise 10% to 15% of all breast car-
the nipple and areolar skin. Unlike Paget disease of the vulva cinomas. The cells invade stroma individually and often are
(described earlier), Paget disease of the nipple stems from in aligned in “single-file” (Fig. 19.29C). Although most manifest
situ extension of an underlying carcinoma. The prognosis of the as palpable masses or mammographic densities, a significant
carcinoma of origin is affected by the presence of Paget disease subgroup invade without producing a desmoplastic response;
and is determined by other factors (discussed under Clinical such tumors may be clinically occult and difficult to detect
Features). by imaging (Fig. 19.29D). The pattern of metastasis of lobular
LCIS has a uniform appearance. The cells are monomorphic, carcinoma is unique among breast cancers, as they frequently
have bland, round nuclei, and are found in loosely cohesive spread to cerebrospinal fluid, serosal surfaces, gastrointestinal
clusters within the lobules (Fig. 19.28A). LCIS is virtually always tract, ovary, uterus, and bone marrow. Almost all lobular carcino-
an incidental finding because, unlike DCIS, it is only rarely asso- mas express hormone receptors, whereas HER2 overexpression
ciated with calcifications. Therefore, the incidence of LCIS has is rare.
remained unchanged in mammographically screened populations. Carcinomas with medullary features are a special type
Approximately one-third of women with LCIS eventually develop of triple-negative cancer comprising about 5% of all breast
invasive carcinoma. Unlike DCIS, invasive carcinomas following cancers. These carcinomas typically grow as rounded masses
a diagnosis of LCIS may arise in either breast— 2 3 in the same that can be difficult to distinguish from benign tumors on imaging
breast and 13 in the contralateral breast. Thus, LCIS is both a (Fig. 19.29F). They consist of sheets of large anaplastic cells
marker of an increased risk of carcinoma in both breasts associated with pronounced lymphocytic infiltrates composed
and a direct precursor of some cancers. Current treatment predominantly of T cells (Fig. 19.29E). The presence of lympho-
options include close clinical and radiologic follow-up, chemopre- cytes is associated with a favorable prognosis, at least in part
vention with tamoxifen or, less commonly, bilateral prophylactic due to a better response to chemotherapy compared to poorly
mastectomy. differentiated carcinomas without lymphoid infiltrates. This type

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744 C H A P T E R 19 Female Genital System and Breast

A C E

B D F
Fig. 19.29 Growth patterns of invasive breast carcinomas. (A) Most grow as tubules (“ductal” carcinoma) and stimulate a reactive desmoplastic stromal
proliferation. In mammograms (B), these carcinomas appear as dense masses with spicular margins resulting from invasion of adjacent radiolucent breast
tissue. (C) Lobular carcinomas are composed of noncohesive tumor cells that invade as linear cords of cells and induce little stromal response. Accordingly,
in mammograms (D) lobular carcinomas often appear as relatively subtle, irregular masses (arrows). (E) Uncommonly, carcinomas consist of tightly adhesive
clusters of cells, as in this carcinoma with medullary features, or when there is abundant extracellular mucin production. (F) Such tumors may appear as
well-circumscribed masses in mammograms, mimicking the appearance of a benign lesion.

of carcinoma is seen frequently in women with germline BRCA1 All types of invasive breast carcinoma are assigned a grade
mutations, but most women with these carcinomas are not from 1 (low-grade) to 3 (high-grade) based on nuclear pleomor-
carriers. phism, tubule formation, and proliferation. Low-grade nuclei are
Mucinous (colloid) carcinoma is an ER-positive/HER2- similar in appearance to the nuclei of normal cells. High-grade
negative tumor that produces abundant amounts of extracellular nuclei are enlarged and have irregular nuclear contours result-
mucin. The tumors usually are soft and gelatinous because of the ing from abnormal DNA content and structure. Most low-grade
presence of mucin pools that create an expansile circumscribed carcinomas form well-defined tubules and may be difficult to
mass. distinguish from benign lesions, whereas high-grade carcinomas
Tubular carcinoma is another type of ER-positive/HER2- lose this capacity and invade as solid sheets or single cells.
negative cancer and is almost always detected on mammography Proliferation is evaluated by counting mitotic figures. The major-
as a small irregular mass. The tumor cells are arranged in well- ity of HER2-positive and triple-negative carcinomas are highly
formed tubules and have low-grade nuclei. Lymph node metas- proliferative, whereas ER-positive cancers show a wide range
tases are rare, and the prognosis is excellent. of proliferation.
Inflammatory carcinoma is defined by its clinical presen-
tation, rather than a specific morphology. Patients present with
a swollen erythematous breast without a palpable mass. The Clinical Features
underlying invasive carcinoma is generally poorly differentiated
As previously discussed, in unscreened populations
and diffusely infiltrates and obstructs dermal lymphatic spaces,
(including young women, for whom screening is not
causing the “inflamed” appearance; true inflammation is absent.
indicated) most breast cancers are detected as a palpable
Many of these tumors metastasize to distant sites; the overall
mass by the affected patient. Such carcinomas are almost
5-year survival is less than 50%, and understandably even lower
all invasive and are typically at least 2 to 3 cm in size.
in those with metastatic disease at diagnosis. About half express
At least half of these cancers will already have spread
ER and 40% to 60% overexpress HER2.
to regional lymph nodes. In older screened populations,

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 Carcinoma 745

approximately 60% of breast cancers are discovered before molecular inhibitors of HER2, outcomes were similar to
symptoms are present. About 20% are in situ carcinomas. patients with triple-negative carcinomas. However, com-
Invasive carcinomas detected by screening in older women plete response rates exceed 60% when targeted therapy is
are 1 to 2 cm in size and only 15% will have metastasized combined with chemotherapy, and the outlook for these
to lymph nodes. Palpable cancers in the older age group patients has been markedly improved.
are often “interval” cancers—cancers that appear suddenly • RNA expression profiling is a newer method of subclas-
between screening intervals. Understandably, interval sifying cancers. For breast cancers, many of the genes
cancers generally are highly proliferative and usually are that predict prognosis are involved in proliferation.
high grade. The greatest clinical value of these assays is their
The clinical outcome for a woman with breast cancer ability to identify patients with slow-growing, anti-
can be predicted based on the molecular and morphologic estrogen-responsive cancers who can be spared the
features of the cancer and its stage at the time of diagnosis. toxicity of chemotherapy.
Factors that influence outcome include the following: • Tumor stage. “Stage” is a measure of the extent of tumor
• Biologic type. The biologic type of cancer is evaluated by at the time of diagnosis and is important for all biologic
a combination of histologic appearance, grade (includ- types of carcinoma. It is based on features of the primary
ing proliferative rate), expression of hormone receptors, tumor (T), involvement of regional lymph nodes (N),
and expression of HER2. and the presence of distant metastases (M) (Fig. 19.30).
Proliferation is evaluated by mitotic count and is The AJCC/UICC staging system, used in the United
closely tied to responsiveness to cytotoxic chemother- States and Europe, classifies tumors as T1, T2, and T3
apy. This is because rapidly growing cancer cells are based on the tumor size, whereas T4 tumors have ulcer-
more sensitive to agents that damage DNA or otherwise ation of the skin, involvement of the deep muscles of
interfere with cell division. the chest wall, or are clinically diagnosed as inflamma-
Expression of estrogen or progesterone receptors pre- tory carcinoma. The majority of cancers first metastasize to
dicts response to anti-estrogen therapy. The growth of regional nodes, and nodal involvement is a very strong
hormone receptor–positive cancers can be inhibited for prognostic factor. Lymphatic drainage goes to one or
many years with therapy and it is possible for patients two sentinel lymph nodes in the axilla in most patients.
to survive for long periods with distant metastases. If these nodes are not involved, the remaining axillary
However, resistance often eventually develops—in nodes are usually free of carcinoma. Sentinel node biopsy
some cancers because of mutations in the gene for ER. has become the standard for assessing nodal involve-
In contrast, there is no targeted therapy available for ment, replacing more extensive lymph node dissections,
triple-negative cancers, which are treated with chemo- which are associated with significant morbidity. Distant
therapy. Cancers that do not respond to initial therapy metastases (M) are only detected in 5% of newly diag-
metastasize and usually cause the death of the patient. nosed women. Stage 0 is CIS, which is associated with
Overexpression of HER2 is seen in about 20% of breast survival rates greater than 95%. Stage I includes women
cancers. HER2 remains one of the best-characterized with smaller cancers and nodes either free of carcinoma
examples of an effective therapy that is directed against a or with only very small micrometastases. Survival is
tumor-specific molecular lesion. Before targeted therapy, ~86% at 10 years. Carcinomas are classified as Stage II
which may take the form of blocking antibodies or small either because of larger tumor size or because of up to

1.0
Stage 0
Stage 1
Breast cancer specific survival

0.8
Stage 2

0.6

Stage 3
0.4
Estrogen receptor positive cancers (solid lines)
Estrogen receptor negative cancers (dashed lines)
0.2

Stage 4
0.0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240
Follow-up time after diagnosis (months)
5 years 10 years 15 years 20 years
Fig. 19.30 Ten-year breast cancer specific survival according to AJCC stage for ER-positive and ER-negative cancers. Both stage and biologic type of cancer
are important determinants of survival. ER-positive invasive cancers have improved survival over ER-negative cancers at all stages, but this advantage diminishes
after 5 years because of late recurrences of ER-positive tumors. (Graph courtesy of Dr. Stephanie Wong; data from SEER-18, 1992–2012. http://seer.cancer.gov.)

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746 C H A P T E R 19 Female Genital System and Breast

three positive nodes. Survival declines to ~71% at Stage 7

Annual hazard rate for breast cancer death (%)

II. Stage III is the group of locally advanced cancers
defined by large size, involvement of skin or chest wall, 6
or by four or more positive nodes. Only ~54% of patients ER negative
survive 10 years. Stage IV is reserved for patients with 5
distant metastases, and survival is very poor (~11%).
The most likely site of a distant recurrence varies with
4
the biologic type of cancer. Triple-negative cancers and
HER2 cancers are more likely to metastasize to the brain
and viscera, in contrast to ER-positive cancers, which 3
most often metastasize to bones (Table 19.7).
2
Combining stage and biologic factors may provide a ER positive
more accurate assessment of outcome. For example, for 1
each cancer stage, the survival of patients with ER-positive
cancers is higher than patients with ER-negative cancers 5
years postdiagnosis, especially for Stages III and IV (Fig. 0 2 4 6 8 10 12
19.30). It must be noted, however, this advantage dimin- Time after initial breast cancer diagnosis (years)
ishes with time, with progressively smaller differences Fig. 19.31 Time to recurrence of breast cancers. The hazard ratio reflects
being seen at 10 years post-diagnosis and beyond (Fig. the risk of recurrence of each molecular type of breast cancer at various
19.30). This narrowing of survival differences is explained points in time after diagnosis. ER-negative cancers usually recur within the
by two factors. First, most deaths from ER-negative cancers first 8 years. Patients who survive beyond this interval are likely cured. In
happen within 5 years of diagnosis (Fig. 19.31). Women contrast, ER-positive cancers have a lower rate of recurrence, but remain at
who live beyond this point are those whose tumors have risk decades after the primary diagnosis.
had excellent responses to treatment, and many of these
women may be cured. Second, although the growth
of ER-positive cancers is held in check for years by anti-
estrogen therapy, this therapy is not curative and these 19.8), as already proven by marked improvement in sur-
cancers may eventually become resistant to treatment. vival of women with HER2-positive carcinomas follow-
Historically, virtually all women with untreated breast ing the introduction of therapies that target HER2. Newer
cancer died within 3 to 4 years. However, great strides have approaches to targeted therapy include inhibition of alter-
been made in treatment and now 80% of women with breast native DNA repair pathways in BRCA-mutated cancers
cancer who receive optimal therapy will survive. and blockage of the PI3K-AKT-signaling pathway. Immune
Endocrine therapy with tamoxifen and aromatase inhib- checkpoint blockade therapy (Chapter 6), is under evalu-
itors is very effective for ER-positive cancers, which may ation in patients with breast cancer. It is hoped that such
remain dormant for many years. new approaches will improve outcomes in subtypes that
Targeted therapy has the promise of being more effec- currently have a generally poor prognosis, such as triple
tive and less toxic than conventional chemotherapy (Table negative breast cancer.

Table 19.8 Targeted Treatment of Breast Cancer

Target Treatment Assay Comments
ER Estrogen deprivation (oophorectomy, IHC for nuclear ER Effective cytostatic (but not cytotoxic)
aromatase inhibitors) therapy for ER-positive cancer
Blockage of ER (tamoxifen)
HER2 Antibodies to HER2 IHC for membrane HER2 Effective for HER2-positive cancers
Cytotoxic therapy linked to HER2 antibody ISH for HER2 gene
Tyrosine kinase inhibitors amplification
Susceptibility to DNA Chemotherapy with agents causing DNA Sequencing of BRCA1 and May be effective for carcinomas arising
damage resulting damage that requires HRR (e.g., platinum BRCA2 in patients with germline BRCA1 or 2
from BRCA 1 and agents) mutations or cancers with somatic
BRCA2 mutations Inhibition of alternative DNA repair pathway loss of BRCA function
that cause defects (poly-ADP ribose polymerase or PARP
in HRR inhibitors)
PI3K/AKT pathway Inhibition of proteins in the pathway Activating mutations or >80% of breast cancers have alterations
pathway activation—not in this pathway
yet validated Effectiveness of treatment not yet
demonstrated
Immune checkpoint Blocking antibodies to PD-L1, PD-1, and IHC for immune checkpoint Under investigation in patients with
proteins other immune checkpoint proteins proteins—not yet validated triple-negative breast cancer
ER, Estrogen receptor; HRR, homologous recombination repair; IHC, immunohistochemistry; ISH, in situ hybridization.

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 Carcinoma 747

SUMMARY SUGGESTED READINGS

BREAST CARCINOMA Bulun SE: Mechanism of disease: endometriosis, N Engl J Med 360:268,
2009. [Excellent review of the molecular basis of endometriosis.]
• The lifetime risk of developing breast cancer for an American Cannistra S: Cancer of ovary, N Engl J Med 351:2519, 2004. [A compre-
woman is 1 in 8. hensive review.]
• A majority (75%) of breast cancers are diagnosed after the age DiCristofano A, Ellenson LH: Endometrial carcinoma, Annu Rev Pathol
of 50. 2:57, 2007. [A comprehensive discussion of pathogenesis.]
• The major risk factors for developing breast cancer are related Ehrmann DA: Polycystic ovary syndrome, N Engl J Med 352:1223,
to hormonal factors and inherited susceptibility. 2004. [A detailed review.]
• About 12% of all breast cancers are caused by identified germ- Fox H, Wells M: Recent advances in the pathology of the vulva, His-
line mutations; BRCA1 and BRCA2 genes account for one-half topathology 42:209, 2003. [A short update on vulvar pathology.]
Herrington CS: Recent advances in molecular gynaecological pathol-
of the cases associated with single-gene mutations.
ogy, Histopathology 55:243, 2009. [A review of molecular genetics of
• DCIS is a precursor to invasive ductal carcinoma and is most cervical, ovarian, and endometrial neoplasia.]
often found on mammographic screening as calcifications. Kathleen RC: Ovarian cancer, Annu Rev Pathol Mech Dis 4:287, 2009.
When carcinoma develops in a woman with a previous diag- [A good review on the subject with discussion of molecular genetics.]
nosis of untreated DCIS, it is usually is an invasive ductal Moody CA: Human papillomavirus oncoproteins: pathways to trans-
carcinoma in the same breast. formation, Nat Rev Cancer 10:550, 2010. [A review of current opinion
• LCIS is both a marker of increased risk and a precursor lesion. on cervical carcinogenesis.]
When carcinoma develops in a woman with a previous diag- Morice P, Leary A, Creutzberg C, et al: Endometrial cancer, Lancet
nosis of LCIS, two-thirds are in the same breast and one-third 387:1094, 2016. [A comprehensive review of the subject.]
is in the contralateral breast. Rich TA, Woodson AH, Litton J, et al: Hereditary breast cancer syn-
dromes and genetic testing, J Surg Oncol 111:6–80, 2015. [Soon many
• Invasive carcinomas are classified according to histologic type
individuals will know their entire DNA sequence. This review discusses
and biologic type: ER-positive/HER2-negative, HER2-positive, the complexities of detecting low- and moderate-penetrance susceptibility
and ER/PR/HER2-negative (triple-negative). The biologic types genes.]
of cancer have important differences in patient characteris- Seckl MJ, Sebire NJ, Berkowitz RS: Gestational trophoblastic disease,
tics, grade, mutation profile, metastatic pattern, response to Lancet 376:717, 2010. [A review of gestation trophoblastic including dis-
therapy, time to recurrence, and prognosis. cussion regarding management.]
• Prognosis is dependent on the biologic type of tumor, stage, Sonnenblick A, Fumagalli D, Sotiriou C, et al: Is the differentiation
and the availability of treatment modalities. into molecular subtypes of breast cancer important for staging, local
and systemic therapy, and follow up? Cancer Treat Rev 40:1089–
1095, 2014. [The translation of the biologic types of cancer into clinical
practice is discussed.]

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