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Hormonal Influences on the Breast

• ER is a nuclear hormone receptor that binds the estradiol
• ER often binds hundreds of kilobases upstream of promoters
to regulate transcription of large segments of DNA
– Estradiol –ER complex → transcription of genes (IGF and other
growth factors) → send a paracrine signal → act on GF receptors of
neighboring cells → proliferation
– ER regulates the expression of PR
• HER2 family consisting of Human Epidermal Growth Factor
Receptor act via an intricate regulation by the steroid hormones
estrogen and progesterone
– Receptor tyrosin-protein kinase; protooncogen

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Major Steroid Hormonal Influences on the Breast

Hormone Effect
Estrogen Required for ductal growth and branching during
adolescence
Required for lobulo-alveolar growth during pregnancy
Required for induction of progesterone receptor
Not necessary for maintenance of secretion or lactation
Progesterone Required or lobulo-alveolar differentiation and growth
Probable mitogen in normal estrogen-primed breast
Not necessary for ductal growth and branching

Carcinoma of the breast

• Account for 23% of all cancers in women globally and
27% in affluent countries, it is more than twice as common
as cancer at any other site
• Next killer to lung cancer
• the affluent populations 6% of women develop invasive
breast cancer before age 75 years.

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Risk factors
• The origin of breast cancer is multifactorial and
involves diet, reproductive factors, and hormones

• Geographical variations
• Family history of breast ca (first degree relatives)
• Increase in age
– Rare before 25yrs of age

Risk Factors…

• Reproductive lifestyle – highly associated with the

risk of breast cancer
– Breast Ca. is more frequently among women who have an early
menarche, remain nulliparous or, if parous, have few children with
a late age at first delivery (age >30)
• ANDI – Aberration of Normal Development and Involution
– Infertility, lack of breast feeding (short duration of feeding)
– Late age at menopause
– ? increased risk associated with induced abortion

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Risk Factors…
• Endogenous hormones
– incidence rates of breast Ca rise more steeply with age; before
menopause (approximately 8% per year) than after menopause
(approximately 2% per year)
• Exogenous estrogen
– Unopposed estrogen therapy, Oral contraceptives, Postmenopausal hormone-
replacement therapy (HRT)
– ARC has concluded that the combination of estrogen plus progestin is
carcinogenic to humans (class 1 carcinogen). In addition, unopposed
estrogen therapy increases the risk of breast cancer, with risk augmenting
with duration of use (higher risk for current or recent user). Furthermore,
this rise in risk is greatest among lean women, who have low levels of
circulating estrogen due to their low body mass.
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Reading assignment

The risk of breast cancer due to endogenous ovarian

hormone Vs endogenous non-ovarian sex hormones
(e.g. due to adiposity)

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Risk Factors…

• Obesity (postmenopausal BMI)

• Physical activity
• “Western lifestyle” (diet and exercise)
– folate may decrease risk
– red or fried/browned meat, is associated with a higher risk
• Alcohol
• History of breast Ca in contralateral breast
• Radiation exposure
• Carcinoma of the Endometrium
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Carcinoma of the breast

Etiology and pathogenesis
The major risk factors
- Genetic (family history)
- Hormonal

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Hereditary/familial
breast cancer
• Two high-penetrance genes have been
identified (BRCA1 and BRCA2)
• Additional polymorphisms and genes
have been recently identified. evidence
suggests a polygenic origin for this
disease
• About 25% of familial cancers (~3% of all
breast cancers) are due to BRCA1 and
BRCA2
• The general lifetime risk for female
carriers is 30-90%
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Carcinoma of the breast

• BRCA1 and BRCA2 carriers are also susceptible to
cancers such as ovary, colon, prostate, and pancreas
• The median age is about 20yrs earlier compared to those
without these mutations
• BRCA2 is associated more with male breast cancer;
bilateral breast cancer in patients <50 yr

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Carcinoma of the breast

Sporadic breast cancer
-the major risk factor is related to hormoneexposure
-estrogen has two major roles
1. Its metabolites can cause mutations or generate DNA
damaging free radicals
2.Its hormonal action drive the proliferation of premalignant
lesions and cancers

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Carcinoma of the
breast
Classification and distribution of breast cancers
- 95% are adenocarcinomas

- The rest are SCC, phyllodes tumor ,sarcomas and

lymphomas

- Carcinomas are divided into

Insitu and invasive carcinomas

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Carcinoma of the breast

In Situ carcinoma
Ductal carcinoma in situ
Lobular carcinoma in situ

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A. Non invasive (in Situ carcinoma)

- Neoplastic population of cells limited to ducts and
lobules by basement membrane

Intraductal carcinoma (DCIS)

• Tumor cells fill the ducts
• Can be noncomedo DCIS (solid, cribriform, papillary, and
micro papillary)
• Comedocarcinoma -solid sheets of high- grade malignant
cells and central necrosis “comedo like”

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• Carcinoma in situ usually can not be detected by either

palpation or visual inspection of the involved tissue

• Mastectomy for DCIS is curative in 95% of cases!

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Paget disease of the nipple

• rare manifestation of breast cancer (1-2% of cases)
• presents as a unilateral erythematous eruption with scale
dust ( looks like eczema)

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Paget disease of the

nipple
• Malignant cells (paget cells)
extend from DCIS within the
ductal system into nipple skin

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Lobular carcinoma in Situ (LCIS)

• Clusters of neoplastic cells fill intralobular ducts & acini

• It may lead to invasive ca after many years in the same or

contra lateral breast

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Invasive Carcinomas
Invasive ductal carcinoma , No special type
- These include the majority of carcinoma (70% to 80%)
that cannot be classified as any other type.

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Morphology

Gross-most are firm to hard with irregular borders

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An aggressive breast tumor_35/F

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Morphology

Microscopy -display wide spectrum of appearance from

well differentiated (mainly consisting of tubules) to poorly
differentiated solid tumors

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 Invasive lobular carcinoma

• Make up only 5% to 10% of breast carcinoma

• Tend to be bilateral, and multicentric within the same
breast
• Often diffusely infiltrating pattern that can make both
primary tumors and metastasis difficult to detect

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Gross-the tumor is rubbery & poorly circumscribed

Microscopy - usually single infiltrating tumor cells,

single cells in files

• E-cadherin is highly down regulated!

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Indian file

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Tubular carcinoma
- practically well- differentiated carcinoma with good
prognosis
Medullary carcinoma
Mucinous or colloid carcinoma
Invasive papillary carcinoma
Metaplastic carcinoma

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Clinical feature of breast carcinomas

• Usually as a solitary painless mass
• may be painful
• Unusual nipple discharge
• Retraction dimpling of the skin & nipple
• Fixation to the chest wall or overlying skin with
ulceration
• Obliteration of dermal lymphatics and thickening of
the skin….. peau d’ orange(orange peel)

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- Certain carcinomas tend to infiltrate widely through the

breast substance
- Involve dermal lymphatic
- Acute swelling and redness with tenderness of the breast
referred clinically as ‘’inflammatory carcinoma’’.

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• Spread of the tumor eventually occurs through the

lymphohematogeneous route.
• Mimics inflammation in a non-lactating women with
clinical appearance of mastitis!

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• Lymphatic dissemination -to the Axilla, supraclavicular

and cervical LNs, to the other breast, and the internal
mammary LNs.
• Hematogenous spread can lead to metastasis in any part.
• Most favored sites are lungs, bones, liver, adrenals,
brain and menings.

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Factors that influence course of breast ca

Major prognostic factors
1. Invasive carcinoma or In situ disease
2. Distant metastasis
3. Lymph node metastases
4. Tumor size
5. Locally advanced disease
6. Inflammatory carcinoma

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Minor prognostic factors

1.Histologic subtype
2.Tumor grade
3.Estrogen and progesterone receptors
4.Lymphovascular invasion
5.proliferative rate
6.HER2/neu(human epidermal growth factor receptor 2 or c-erb
B2 or neu)

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Molecular Subtypes of
Invasive Breast Cancer
• Molecular subtypes highlights potential new therapeutic
targets (anti-hormonal or anti HER-2 therapy)

Estrogen Receptor (ER)

ER –ve
ER +ve
ER induced expression PR-
of Progesterone no ER action; poor
receptor (PR+) outcome 64

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Molecular subtype …

HER-2
HER-2 –ve ER –ve TNBC
HER-2 +ve
HER-2 -ve - Poor natural HER-2 +ve ER +ve Luminal A
history;
- anti HER-2 Luminal B
therapy

• Triple Negative breast cancer (TNBC)

- Poor outcome; insensitive to anti-hormonal or anti HER-2 therapy

Molecular subtype …
Luminal A Luminal B

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Stromal Tumors
• Two types of breast stroma, Intralobular & interlobular , give
rise to distinct types of neoplasms

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Stromal Tumors
• Breast - specific biphasic tumors fibroadenoma & phyllodes
tumor arise in the intralobular stroma

• The interlobular stroma give rise to tumors found in

connective tissue in other sites of the body (eg lipoma)

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Fibroadenoma
• the most common benign tumor of the female breast
• more common before age 30,but can occur at any age of
reproductive life
• frequently multiple & bilateral
• The epithelium of the fibroadenoma is hormonally responsive
• The stroma only is neoplastic

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Morphology
Gross - Spherical nodules usually sharply circumscribed &
freely movable in the surrounding breast substance

Microscopy - usually delicate stroma, cellular & often myxoid

resembling intralobular stroma ,enclosing glandular &
cystic spaces lined by epithelium

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Fibro- Cysts Cancer

adenoma

Usual Age 15-25, usually puberty 30-50, regress after 30-90, most common over
and young adulthood, but menopause except with age 50
up to age 55 estrogen therapy
Number Usually single, may be Single or multiple Usually single, may coexist
multiple with other nodules
Shape Round, disclike, or lobular Round Irregular or stellate
Consistency May be soft, usually firm Soft to firm, usually elastic Firm or hard
Delimitation Well delineated Well delineated Not clearly delineated from
surrounding tissues
Mobility Very mobile Mobile May be fixed to skin or
underlying tissues
Tenderness Usually nontender Often tender Usually nontender
Retraction Signs Absent Absent May be present
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Phyllodes Tumor
• Although they can occur at any age, most present in the
sixth decade
• Most present as palpable mass
• They are low grade neoplasms which rarely metastasize

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Morphology
• vary in size from a few centimeters to massive lesions
involving the entire breast
• The larger lesions often have bulbous protrusions
(phyllodes is Greek for “leaflike”) due to presence of
nodules of proliferating stroma covered by epithelium

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Gynecomastia
• enlargement of the male breast may be unilateral or
bilateral
• Presents as button-like subareolar enlargement
• may occur as result of imbalance between estrogens ,
which stimulate breast tissue, & androgens which
counteract these effects
• At puberty or any time during adult life when there is
hyperestrinism

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The most important causes include

• Cirrhosis of the liver
• In older age relative increase in adrenal estrogens as the
androgenic function of the testis fails
• Drugs- alcohol, marijuana, heroin, antiretroviral therapy,
anabolic steroids used by body builders
• Klinefelter syndrome(XXY)
• Testicular neoplasms

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Microscopy -proliferation of a dense Collagenous

connective tissue with micropapillary hyperplasia of the
ductal linings

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Male Breast Carcinoma

• is a rare occurrence with a frequency ratio to breast cancer
in the female of less than 1:100

• Risk factors include first degree relatives with breast cancer,

Klinefelter syndrome, exposure to exogenous estrogen,
infertility, obesity, increasing age

• 4-14% of male breast cancer cases are attributed to BRCA2

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Male Breast Carcinoma

• Pathology of male breast cancer is similar to that of cancer
seen in women

• The carcinoma is found close to the overlying skin or

underlying thoracic wall so can easily invade these
structures

• Papillary carcinoma is the most common histologic type

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