Far Eastern University – Nicanor Reyes Medical Foundation Disorders of Development

Pathology B – Breasts Milk Line Remnants

Ronald Dy-Quiangco M.D.  Supernumerary nipples or breasts result from the persistence of
epidermal thickenings along the milk line, which extends from
the axilla to the perineum.
 The disorders that normally affect the normal breasts in their
normal positions, rarely affect these heterotropic, hormone-
responsive foci.

Accessory Axillary Breast Tissue

 Normal ductal system extends into the subcutaneous tissue of
the chest wall or the axillary fossa (axillary tail of Spence).
 Breast tissue may not be removed in these areas.
 Mastectomies reduce, but not eliminate, risk of breast cancer.

Congenital Nipple Inversion

 Failure to evert during development, common, may be unilateral
 Little significant, spontaneously correct during pregnancy.
 Acquired retraction is more of concern, since it may indicate
presence of an invasive caner or an inflammatory nipple disease.

Clinical Presentation of Breast Disease

 Three important features:

1. Major function is for nutritional support of the infant
2. Structure of the organ undergoes marked periodic changes
3. It is visible, hence socially, culturally, and personally significant
 Two major structures:
 Ducts
 Lobules
 Two types of epithelial cells:
 Luminal epithelial cells
 Myoepithelial cells  Pain (Mastalgia or Mastodynia), a common symptom that may
 Two types of stroma: be cyclic with menses or non-cyclic.
 Interlobular stroma  Diffuse cyclic pain may be due to premenstrual edema.
 Intralobular stroma  Non-cyclic pain is usually localized to one area of the breast
 6-10 major duct orifices open onto the skin surface at the nipples and may be caused by ruptured cysts, physical injury and
 Superficial portion is lined by keratinizing squamous cells that infections.
change to the double-layered epithelium of the remainder duct.  Palpable Masses must be distinguished from normal lumpiness.
 The terminal duct branches into a grape-like cluster of small acini  Most common palpable lesion are cysts, fibroadenomas, and
to form a lobule. invasive carcinomas.
 In pre-pubertal female and in males, the large duct ends at the  Benign palpable masses are most common in premenopausal
terminal ducts.  Malignancy increases with age.
 Only with the onset of pregnancy does the breast become  50% are located in the upper outer quadrant.
completely mature and functional.  10% in the remaining quadrants
 By the end of pregnancy, the breast is composed almost entirely  20% in the central or subareolar region.
of lobules separated by scant stroma.  Nipple Discharge is less common, most worrisome for carcinoma
 Immediately after birth, the lobules produce colostrum (high in when it is spontaneous and unilateral.
proteins), changing to milk (high in fat and calories) over the  Small discharge upon breast manipulation.
next 10 days as the progesterone levels drop.  Milky discharge (galactorrhea) is associated with ↑ prolactin
 Upon cessation of lactation, epithelial cells undergo apoptosis  Bloody or serous discharge are most commonly due to large
and the lobules regresses, but full regression does not occur and duct papillomas and cysts.
as a result pregnancy causes permanent increase in the size and  During pregnancy, bloody discharge can result from rapid
the number of lobules. growth and remodeling of the breasts.
rd
 After the 3 decade, long before menopause, the lobules and  Risk of malignancy increases with age, associated with
stroma start to involute, the interlobular stroma converts from carcinoma (7%) in women younger than 60, but in 30% of
radiodense stroma to radiolucent adipose tissue. older women.

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 Mammographic screening was introduced in 1980s as a means Duct Ectasia
to detect small, non-palpable, asymptomatic breast carcinoma.  Palpable perioareolar mass, associated with thick, white nipple
 Most common means to detect breast cancer. secretions and occasionally with skin retraction.
 Sensitivity and specificity increases with age due to  Pain and erythema are uncommon.
th th
replacement of fibrous, radiodense tissue with fatty  Tends to occur in 5 – 6 decade of life, in multiparous women.
radiolucent tissue in older women.  Not associated with smoking.
 Densities  Mimics the clinical and radiographic appearance of invasive CA.
 Lesions that replace adipose tissue, rounded densities are
benign such as fibroadenomas, cysts. Morphology
 Invasive carcinomas form irregular masses.  Ectatic dilated ducts filled with inspissated secretions and
 Calcifications numerous lipid-laden macrophages.
 Form on secretions, necrotic debris, or hyalinized stroma,  When ruptured, marked periductal and interstitial chronic
associated with benign lesions such as clusters of apocrine inflammatory reaction ensues.
cysts, hyalinized fibroadenomas, and sclerosing adenosis.  Granulomas may form around cholesterol deposits.
 Those associated with malignancy are small, irregular,
numerous, and clustered. Fat Necrosis
 Most common detected is ductal carcinoma in situ (DCIS).  Protean, closely mimic cancer, painless palpable mass, skin
 Ultrasonography – either cystic or solid. thickening/retraction, or mammographic densities/calcification.
 MRI – dense breast, extent, occult, implant rupture  Half have history of breast trauma or prior surgery.

Inflammations Morphology
 Rare, less than 1% of breast symptoms.  Acute lesions may be hemorrhagic and contain central areas of
liquefactive fat necrosis with neutrophils and macrophages.
Acute Mastitis  Proliferating fibroblasts and chronic inflammatory cells over the
st
 Typically occur during 1 month of breastfeeding caused by local next few days surround the injured area.
bacterial infection when the breast is most vulnerable to cracks  Replaced by scar tissue, or encircled by fibrous tissue.
and fissures of the nipples.
 S. aureus or less commonly streptococci invade breast tissue Lymphocytic Mastopathy (Sclerosing Lymphocytic Lobulitis)
 Breast is erythematous and painful with fever.  Presents with single or multiple hard palpable masses or
 At the outset, only 1 duct system is affected but may spread if mammographic densities.
not treated.  Difficult to obtain tissue with needle biopsy due to dense
 Staphylococci abscesses may be single or multiple, Streptococci collagenized stroma.
cause spreading infection in the form of cellulitis.  Atrophic ducts and lobules have thickened basement
membranes surrounded by a prominent lymphocytic infiltrate.
Squamous Metaplasia of Lactiferous Ducts  Most common in type 1 diabetes or autoimmune thyroid disease

Granulomatous Mastitis
 Manifestation of systemic granulomatous disease such as
Wegener’s granulomatosis, sarcoidosis, tuberculosis.
 Disorders localized to the breast.
 Granulomatous lobular mastitis is uncommon occurs only in
parous women, closely associated with lobules suggesting it may
be caused by hypersensitivity reactions during lactation.
 Cystic neutrophilic granulomatous mastitis caused by
Corynebacteria share common histologic pattern with
 Recurrent subareolar abscess, periductal mastitis, Zuska disease granulomatous lobular mastitis.
 Painful erythematous subareolar mass - bacterial abscess
 Fistula tract often tunnels under the smooth muscle of the Benign Epithelial Lesions
nipple and opens onto the skin at the edge of the areola.  Classified into 3 groups according to risk of developing cancer
 Many have inverted nipple, more than 90% are smokers. 1. Non-proliferative breast changes
2. Proliferative breast disease
Morphology 3. Atypical Hyperplasia
 Keratinizing squamous metaplasia of the nipple ducts.
 Keratin shed plugs the ductal system, causing dilation & rupture. Non-Proliferative Breast Changes (Fibrocystic Change)
 Intense chronic granulomatous inflammatory response.  Might mean “lumpy bumpy” breasts on palpation.
 With recurrence, secondary anaerobic bacterial infection may  Dense breast with cyst with benign histologic changes.
supervene and cause acute inflammation.

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Morphology 3.) Complex Sclerosing Lesion
 3 principal morphologic changes  Have components of sclerosing adenosis, papillomas, and
epithelial hyperplasia.
1.) Cystic change often with apocrine metaplasia  One member of this group, radical sclerosing lesions (radial
 Small cysts form by the dilation of the lobules, in turn may scar), has an irregular shape, closely mimicking invasive CA.
coalesce to form larger cysts.  Central nidus of entrapped glands in a hyalinized stroma is
 Contains turbid, semi-translucent fluid of a brown or blue color. surrounded by long radiating projections.
 Lined by flattened atrophic epithelium or metaplastic apocrine
cells which have abundant granular, eosinophilic cytoplasm and 4.) Papillomas
rounded nuclei and closely resemble the normal apocrine glands.  Grow within a dilated duct and composed of multiple branching
 Calcifications are common. fibrovascular cores.
 Cysts cause concern when they are solitary and firm on palpation  Epithelial hyperplasia and apocrine metaplasia are often present.
 Diagnosis is confirmed by disappearance of the mass on FNAB.  Large duct papillomas are situated in the lactiferous sinuses of
the nipple, and are usually solitary.
2) Fibrosis  Small duct papillomas are often multiple and located deeper
 Cysts frequently rupture releasing secretory materials. within the ductal system.
 The resulting chronic inflammation and fibrosis contribute to the  80% of large duct papillomas produce nipple discharge; some are
palpable nodularity of the breasts. bloody if the stalk undergoes torsion causing infarction.

3.) Adenosis Gynecomastia

 Increase in number of acini per lobule.  Enlargement of the male breast is the only benign lesion seen
 Normal feature of pregnancy. with any frequency in the male breast.
 Can occur in non-pregnant women as focal changes.  Button-like sub-areolar enlargement, may be unilateral/ bilateral
 Calcifications are occasionally present within lumens.  Increase in dense collagenous connective tissue associated with
 Acini are lined by columnar cells which may appear benign or epithelial hyperplasia of the duct lining with characteristic
show atypia (flat epithelial atypia). tapering micropapillae.
 Flat epithelial atypia is a clonal proliferation associated with  Lobule formation is never observed.
deletions in chromosome 16q.  Occurs as a result of an imbalance between estrogen that
 Earliest recognizable precursor of low-grade breast cancers, stimulates breast tissue, and androgens which counteracts it.
but does not convey an increased risk.  Appear at any time of life when there is cause for hyperestrinism
 Lactational adenomas – present as palpable masses in  Most important is cirrhosis of the liver, since it’s responsible
pregnancy or lactating women, consisting of normal-appearing for metabolizing estrogen.
breast tissue with lactational changes.  Drugs such as alcohol, marijuana, heroin, anti-retrovirals,
anabolic steroids.
Proliferative Breast Disease without Atypia  Occurs as part of Klinefelter Syndrome (XXY karyotype).
 Associated w/ small increase in risk of carcinoma of either breast  Associated with functioning testicular neoplasms such as
 Commonly detected as mammographic densities, calcifications, Leydig cell or Sertoli cell tumors.
or incidental findings in biopsies.
 Non-clonal lesions. Proliferative Breast Disease with Atypia
 Predictors of risk but unlikely to be true precursors of carcinoma.  Atypical hyperplasia is a clonal proliferation having some, but
not all, of the histologic features that are required for the
Morphology diagnosis of carcinoma in situ.
1.) Epithelial Hyperplasia  Moderate increased risk of carcinoma, includes 2 forms:
 Normal breast ducts and lobules are lined by double layer of  Atypical duct hyperplasia – 5-17% of specimens for calcifications
myoepithelial and luminal cells.  Atypical lobular hyperplasia – fewer than 5% of biopsies
 In epithelial hyperplasia, increased number of both cells fills and
distends the ducts and lobules. Morphology
 Irregular lumens can often be discerned at periphery of masses. 1.) Atypical Ductal Hyperplasia (ADH)
 Histologic resemblance to ductal carcinoma in situ (DCIS).
2.) Sclerosing Adenosis  Consists of monomorphic proliferation of regularly spaced cells.
 Increased number of acini that are compressed and distorted in  Sometimes with cribriform spaces, round – slit-like lumina
the central portion of the lesion.  Distinguished from DCIS in that in only partially fills the duct.
 Stromal fibrosis may completely compress the lumens to create
the appearance of sloid cords or double strands of cells with 2.) Atypical Lobular Hyperplasia (ALH)
dense stroma, mimicking invasive CA.  Consists of cells identical to lobular carcinoma in situ but the
 Palpable mass, radiologic density, calcifications. cells do not fill or distend more than 50% of the acini.
 Atypical cells may lie between the ductal basement membrane
and the overlying luminal cells.

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 ADH or ALH may have acquired chromosomal aberrations:
 Loss of 16q or gain of 17p changes also found in CIS
 ALH also show loss of E-cadherin expression, feature it shares
with lobular carcinoma in situ.

Clinical Significance of Benign Epithelial Change

 Non-proliferative changes DO NOT increase the risk of CA.
 Proliferative disease is associated w/ 1.5 to 2-fold increased risk
 Proliferative disease with atypia confers 4-5-fold increased risk.
 Both breasts are at increased risk, although the risk to the Risk Factors
ipsilateral breast may be slightly higher.  Germline mutations
 Risk reduction can be achieved by bilateral prophylactic  5-10% occurs in patients with mutations in the tumor
mastectomy or treatment with estrogen antagonists (Tamoxifen) suppressor genes, lifetime risk can be more than 90%.
 First-degree relatives with breast cancer
 15-20% can have affected first degree relative but do not
carry an identified gene mutation.
 Increased risk is probably due to interaction of low-risk
susceptibility genes and shared environmental factor.
 Race/Ethnicity
 Non-hispanic white women have the highest incidence in US.
 Germline BRCA1 and BRCA2 mutations are particularly
prevalent in Ashkenazi Jewish populations.
 Age
 Cancer risk increases throughout the woman’s lifetime
 Peaks at 70-80 years, declining slightly thereafter
 Age at menarche
 Menarche at ages younger than 11 increases risk by 20%
 Late menopause also increases the risk
 Age at first live birth
 Full-term pregnancy before age 20 halves the risk compared
to nulliparous women or in women who are older than age
35 at the time of their first birth.
 Benign breast disease
 Prior breast biopsy with atypical hyperplasia or proliferative
changes increases the risk of invasive carcinoma
 Estrogen exposure
Carcinoma of the Breasts  Menopausal hormone therapy increases the risk of breast
 Most common non-skin malignancy in women, second to lung CA, particularly when estrogen and progestin are given
cancer as cause of cancer deaths. together for a period of years.
 Almost all breast malignancies are adenocarcinomas.  Most excess are small ER (+) CA.
 Based on the expression of estrogen receptor (ER) and HER2, can  OCPs do not appear to increase risk of breast CA.
be divided into three major biologic subgroups:  Reducing endogenous estrogen by oophorectomy decreases
 ER-positive, HER2-negative – 50-65% of tumors risk of developing breast CA by 75%.
 HER2-positive, ER-positive or ER-negative – 10-20% of tumors  Tamoxifen or aromatase inhibitors decrease risk of ER (+) CA
 ER-negative, HER2-negative – 10-205 of tumors  Breast Density
 Women with very dense breasts have 4-6-fold higher risk of
Incidence and Epidemiology both ER (-) and ER (+) breast cancer compared to low density.
 Rare in women younger than age 25, but incidence increases  Persistently high breast density in older women may stem
rapidly after age 30. from failure of normal involution.
 ER (+) continue to increase with age.  Radiation exposure
 ER (-) and HER2 (+) remain relatively constant.  Any form of radiation to the chest results in higher rate.
 DCIS (Ductal carcinoma in situ) is rarely palpable and is almost  Risk is greatest with exposure at young ages and high dose.
always detected by mammography.
 Carcinoma of the contralateral breast of endometrium
 In the age of screening, the number of Stage I cancers (small
 1% with breast CA develops a second contralateral CA per yr.
node-negative CA) has increased in frequency while the number
 Most important risk factor is prolonged estrogen stimulation
of large nodule-positive or advanced stage CA (stage II-IV)
 Diet
decreased.
 Large studies have failed to find any correlation.
 Moderate to heavy alcohol consumption increases risk

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 Exercise Molecular mechanisms of Carcinogenesis and Tumor Progression
 Probable small protective effect for women.  Resident breast tissue stem cells have been hypothesized to be
 Breastfeeding the cell of origin for all breast cancers.
 The longer a women breastfeeds, the greater the reduction  Three major genetic pathways of carcinogenesis.
of the risk for breast CA.
 Lactation suppresses ovulation, and may trigger terminal 1.) ER (+), HER2 (-) arise via dominant pathway (50-60% of cases)
differentiation of luminal cells.  Most common subtype to those w/ germline mutation in BRCA2
 Environmental toxins  Associated with gains of chromosome 1q, losses of 16q, and
 Contaminants such as organochlorine pesticides have activating mutations in PIK3CA.
estrogenic effects of humans.  These same genetic lesions are found in flat epithelial atypia and
atypical ductal hyperplasia hypothesized to be precursor lesions
Etiology and Pathogenesis for this subtype of breast cancer.
 Breast cancers are clonal proliferation that arises from cells with  ER (+) cancers is termed luminal, as they resemble normal breast
multiple genetic aberrations, acquisition of which is influenced luminal cells in terms of mRNA expression, dominated by genes
by hormonal exposure and inherited susceptibility gene. regulated by estrogen.
 May be hereditary or sporadic.
2.) HER2 (+) arise via amplifications of HER2 gene on 17q (20%)
Familial Breast Cancer  May either be ER (+) or ER (-).
 12% of breast cancers occur due to inheritance of identifiable  Most common subtype of breast cancer in patients with
susceptibility gene or genes. germline mutations in TP53(Li-Fraumeni Syndrome)
 Probability of hereditary etiology increases when there are  Precursor lesion termed atypical apocrine adenosis.
multiple affected first-degree relatives, early onset cancers,  Distinct gene expression pattern dominated by genes related to
multiple cancers, or family members with other cancer. proliferation that are regulated by signaling pathways lying
 Single sporadic mutation in the remaining normal allele is all that downstream of HER2 receptor tyrosine kinase.
is required to completely lose tumor suppressor function.
 Major known susceptibility genes (all are tumor suppressors) 3.) ER (-), HER2 (-) arise via pathway independent of ER-mediated
(check Robbins 9th ed, p. 1054, table 23-3) changes and HER2 gene amplifications (15% of cases)
 BRCA1  BRCA2  Precursor lesions have yet to be identified.
 TP53  CHEK2  Most common in patients with germline BRCA1 mutations.
 Mutations in BRCA1 and BRCA2 are responsible for 80-90% of  Occur with increased frequency in African American.
single gene familial breast cancers, and about 3% of all breast CA  Sporadic tumors often have loss-of-function in TP53, mutations
 BRCA1 mutations markedly increase the risk of developing in BRCA1 are uncommon.
ovarian carcinoma, occurs in as many as 20-40% of carriers.  These have basal-like pattern of mRNA expression that includes
 BRCA2 mutations confer smaller risk of ovarian cancer (10- many genes that are expressed in normal myoepithelial cells.
20%) but are associated frequently with male breast cancer.
 BRCA1 and 2 are also at higher risk for other epithelial CA.
 BRCA1 (17q21) associated breast cancers are commonly poorly  Most common driver mutations involve
differentiated, have medullary features (a syncytial pattern with  Proto-oncogenes: PIK3CA, HER2, MYC, CCND1 – cyclin d1
pushing margins and lymphocytic response), very similar to ER (-)  Tumor suppressor genes: TP53, BRCA1, BRCA2
and HER2 (-) identified as basal-like by gene profiling.  Neoplastic epithelial cells do not develop in isolation but are
 BRCA2 (13q12.3) associated breast cancers also tend to be dependent on interactions with stromal cells in the local
relatively poorly differentiated but more often ER (+) microenvironment.
 Cancers occur in areas of greatest mammographic densities.
 Other hereditary breast cancers:  Increased amount of fibrous stroma is both a marker of risk and
 Remaining susceptibility genes (<10% of cases) biologically important for tumorigenesis.
 TP53 – Li-Fraumeni Syndrome  Stroma is complex mixture of fibroblasts, blood vessels,
 PTEN – Cowden Syndrome lymphatics, inflammatory cells, and ECM.
 STK11 – Peutz-Jeghers Syndrome
 ATM – Ataxia Telangiectasia  Final step of carcinogenesis, the transition of carcinoma in situ to
 CHEK2 invasive carcinoma.
 Majority of genetic changes observed in invasive carcinomas are
Sporadic Breast Cancer already present in the associated carcinoma in situ.
 Major risk factors are related to hormone exposure:  Remodeling of the breast during post-pregnancy involution,
 Gender which involves inflammatory and wound healing-like tissue
 Age at menarche and menopause reactions and is known to increase the risk of tumor invasion.
 Reproductive History  May facilitate the transition of carcinoma in situ to invasive CA.
 Breastfeeding
 Exogenous estrogens

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Types of Breast Carcinoma
 Almost all (>95%) are adenocarcinomas that first arise in the  Paget Disease of the nipple
duct/lobular system as carcinoma in situ.
 At the time of clinical detections (70%) will have breached the
basement membrane and invaded the stroma.
 Most evidence suggests all breast carcinomas actually arise from
cells in the terminal duct lobular unit.
 Classified as either: DCIS (Ductal) or LCIS (Lobular).

Carcinoma in Situ
Ductal Carcinoma in Situ (DCIS)
 A malignant clonal proliferation of epithelial cells limited to ducts
and lobules by the basement membrane.
 The term ductal was used to describe this lesion because when it  Rare manifestation of breast cancer (1-4%)
involves the lobules, the expanded acini take on an appearance  Unilateral erythematous eruption with a scale crust.
resembling small ducts.  Pruritus is common; lesions may be mistaken for eczema.
 Myoepithelial cells are preserved.  Malignant cells (Paget cells) extend from DCIS within the
 Can spread via the ductal system to involve the whole breast. ductal system via the lactiferous sinuses into the nipple skin
 Most are identified as result of calcifications associated with without crossing the basement membrane.
secretory material or necrosis, less commonly, periductal fibrosis  Tumor cells disrupt the normal epithelial barrier.
 Rarely produce nipple discharge.  Readily detected by nipple biopsy or exudate preparations.
 Almost all have underlying invasive carcinoma.
Morphology  In women with palpable mass, it is usually poorly
 Can be divided into: Comedo or Noncomedo differentiated, ER(-), overexpress HER2.
 Nuclear grade and necrosis are better predictors of local  In women without palpable mass have only DCIS.
recurrence and progression to invasion than architectural type.
 Comedo DCIS  Major risk factors for recurrence:
 May occasionally produce vague nodularity. 1. High nuclear grade and necrosis
 More often on mammography as clustered or linear and 2. Extent of the disease
branching areas of calcification. 3. Positive Surgical Margins
 Defined by 2 features:  Post-op radiation therapy and tamoxifen reduce recurrence risk
1. Tumor cells with pleomorphic, high-grade nuclei
2. Areas of central necrosis Lobular Carcinoma in Situ (LCIS)
 Noncomedo DCIS  Clonal proliferation of cells within ducts and lobules that grow in
 Lack the 2 features of comedo DCIS. a discohesive fashion usually due to an acquired loss of the
 Cribriform DCIS may have rounded (cookie cutter-like) spaces tumor suppressive adhesion protein E-cadherin (CDH1 gene).
within the ducts, or a solid DCIS pattern.  Cells expand but do not distort involved spaces, thus the
 Micropapillary DCIS produces bulbous protrusions without a underlying lobular architecture is preserved.
fibrovascular core, often in complex intraductal pattern.  Always an incidental biopsy finding.
 DCIS may produce true papilla with fibrovascular core that  LCIS is bilateral in 20-40% of cases (only 10-20% in DCIS).
lacks a myoepithelial cells, calcifications may also be seen.  Cells of atypical lobular hyperplasia, LCIS, and invasive CA are
morphologically identical.
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Morphology  The introduction of Trastuzumab (Herceptin), a humanized
 Consists of uniform population of cells with oval or round nuclei monoclonal antibody that binds and inhibits HER2, improve the
and small nucleoli involving the ducts and lobules. outlook of patients with HER2 overexpressiong cancers,
 Mucin-positive signet ring cells are present.  Multiple mechanisms of primary or acquired resistance:
 Lack of E-cadherin result in a rounded shape without attachment  Some tumors express truncated form of HER2 that lacks the
to adjacent cells. trastuzumab-binding site but retains kinase activity.
 Cells cannot form cribriform spaces or papilla (unlike in DCIS).  Some upregulate downstream pathways, such as PI-3 kinase.
 Pagetoid spread is commonly seen in the breast but LCIS does
NOT involve nipple skin. 3.) ER (-), HER2 (-), basal-like triple negative carcinoma, 15% of CA
 Necrosis and secretory activity are not seen  More common in young premenopausal women, as well as in
 Substrates for calcifications are NOT preset. African Americans (20-25% of carcinomas) and Hispanic (17%).
 Almost always express ER and PR, no overexpression of HER2.  Majority arising with BRCA1 mutations.
 Due to high proliferation and rapid growth, this presents
 LCIS is a risk factor for invasive CA, develops in 25-30% in women typically as palpable mass.
over 20-30 years’ time, or at a rate of 1% per year similar to that  Share a number of genetic similarities with serous ovarian CA.
of untreated DCIS.  Can metastasize when small, frequently to viscera and brain.
 The risk is almost as high in the contralateral breast as in the  30% completely respond to chemotherapy.
ipsilateral breast.  Local recurrence is common even after mastectomy.

Invasive Infiltrating Carcinoma Morphology

 One third can be classified morphologically into special histologic  Invasive CAs present on mammography as calcifications without
types, the remainder are called ductal or no special type (NST). an associated density are generally less than 1 cm in size.
 These breast cancers fall into 3 major molecular subtypes.  Usually present as mass of at least 2-3 cm in size.
 Mammographic and gross appearance varies widely depending
1.) ER (+), HER (-) also termed luminal (40-50%, most common on the stromal reaction to the tumor.
invasive breast cancer), can be divided into 2 sub-groups:  Mostly present as hard, irregular radiodense mass, associated
 ER (+), HER2 (-), low proliferation (40-55%) with a desmoplastic stromal reaction.
 Makes up the majority of cancers in older women and men  When cut, they produce a grating sound (similar to cutting a
 Most common type detected in mammography of women water chest nut) due to small, central pinpoint foci or streaks of
treated with menopausal hormone therapy. chalky-white desmoplastic stroma and foci of calcifications.
 Dominated by genes regulated by estrogen receptor.  Less commonly, may present as well-circumscribed masses
 Detected at an early stage. composed of sheets with scant stromal reaction.
 Lowest rate of local recurrence, cured by surgery.  May be imperceptible, composed of scattered neoplastic glands
 When they metastasize, it is after a long period (6 years) and or single tumor cells infiltrating normal fibrofatty tissue.
typically metastasizes to the bones.  Larger carcinomas may invade the pectoralis muscle and be
 Respond well to hormonal treatment. fixed on the chest wall or invade into the dermis and cause
 ER (+), HER2 (-), high proliferation (10%) dimpling of the skin.
 ER levels may be low and progesterone receptors may be low  If involving the central portion, nipple retraction may occur
or absent.  Rarely, presents as metastasis to an axillary node or distant
 Most common type associated with BRCA2 germline  Primary CA may be small or be obscured by dense tissue
mutation, mRNA expression is similar to other ER (+) CA.  May fail to produce desmoplastic response making it difficult
 Higher expression of genes related to proliferation. to detect by palpation
 Higher burden of chromosomal aberrations.  These occult tumors, detection may be via MRI or US.
 10% show complete response to chemotherapy.  All types of invasive carcinoma are graded using Nottingham
Histologic Score.
2.) HER2 (+), 20% of cancers, second most common invasive CA.  Scored for tubule formation, nuclear pleomorphism, and
 Half of these are ER (+), when present, ER expression is low. mitotic rate, points are added to divide them into:
 Progesterone receptors are often absent  Grade I – well differentiated
 These are relatively more common in young, non-white women.  Grade II – moderately differentiated
 More than half (53%) of familial breast CA with TP53 mutations  Grade III – poorly differentiated
(Li-Fraumeni) develop carcinomas (+) for both ER and HER2.  Grade I grown in tubular pattern with small round nuclei and
 mRNA profile show increased expression of HER2 and flanking have a low proliferation rate.
genes on the same amplicon, as well as those related to  Grade II may also show some tubule formation, but solid
proliferation. clusters of single infiltrating cells are also present, greater
 These have complex interchromosomal translocations, high degree of nuclear pleomorphism and mitotic figures
levels of HER2 amplification, and high mutational load.  Grade III invade as ragged nests or solid sheets of cells with
 Can metastasize when small, often to viscera and brain. enlarged irregular nuclei, high proliferative rates, areas of
 1/3 or more respond to antibodies that bind and block HER2. tumor necrosis are common.

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 ER (+), HER2 (-) carcinoma  Tubule formation is absent
 Many morphologic patterns are possible  Alveolar and solid variants - circumscribed cluster of tumor cells.
 Grades ranges from well to poorly differentiated.
 All well-differentiated are in this group. Mucinous (Colloid) carcinoma
 Mucinous, papillary, cribriform, and lobular patterns.  Soft or ruberry, similar to gray-blue gelatin.
 HER2 (+) carcinoma  Borders are pushing or circumscribed.
 Majority are poorly differentiated with only few moderate.  Tumor cells are arranged in clusters and small islands of cells
 No specific morphologic pattern. within large lakes of mucin.
 50% of apocrine CA and 40% micropapillary CA are HER2(+)
 Associated DCIS often more extensive. Tubular Carcinoma
 ER (-), HER2 (-) carcinoma  Well-formed tubules, mistaken for benign sclerosing lesion.
 Almost all are poorly differentiated.  Cribriform pattern may also be present.
 Many have circumscribed pushing borders with central  Apocrine snouts are typical, calcifications within the lumen.
fibrotic or necrotic center.  Frequently associated with flat epithelial atypia, atypical lobular
 Others have prominent lymphocytic infiltrate and fall into hyperplasia, LCIS, or low-grade DCIS.
the group of carcinomas with medullary features.
 Spindle cells, squamous, and matrix producing patterns. Papillary Carcinoma
 DCIS is very limited or not present  Produces true papillae, fronds of fibrovascular tissue lined by
tumor cells.
SPECIAL HISTOLOGIC SUBTYPES OF INVASIVE CARCINOMA
 Can be organized into groups based on ER, HER2 expression.  Two special histologic types frequently overexpress HER2
 Often harbor unique genetic aberrations.  Apocrine Carcinoma
 Resemble cells that line sweat glands.
Lobular Carcinoma  Enlarged round nuclei with prominent nucleoli and
 Clearest association of phenotype and genotype. abundant eosinophilic, occasionally granular cytoplasm.
 Show biallelic loss of CDH1, encoding for E-cadherin.  Micropapillary Carcinoma
 Discohesive, often fail to incite desmoplastic response.  A misnomer
 Pattern of metastatic spread, often involving the peritoneum  Forms hollow balls of cells that float within intercellular
and retroperitnum, leptomeninges, GIT, ovaries and uterus. fluid, creating structure that mimics true papilla
 Males and females with heterozygous CDH1 mutation have
increased risk of gastric signet ring cell carcinoma.  ER (-), HER2 (-) tumors often correspond to one of several
special histologic types.
Medullary Carcinoma  Medullary Carcinoma
 Characteristic of BRCA1-associated carcinomas.  Softer than other carcinomas due to minimal desmoplasia.
 Often present with circumscribed mass
 13% of BRCA1 carriers are of medullary type.
 Solid, syncytium-like sheets of large cells with pleomorphic
 Majority are not related to BRCA1, hypermethylation of BRCA1
nuclei and prominent nucleoli (75% of tumor mass).
promoter leading to downregulation of BRCA1 expression.
 Frequent mitotic figures.
 Presence of lymphocytic infiltrates within the tumors is
 Moderate to marked lymphoplasmacytic infiltrate
associated with higher survival rates and greater response to
surround and within the tumor.
chemotherapy.
 Pushing, non-infiltrative border.
 DCIS is minimal or absent.
Micropapillary Carcinoma
 Secretory Carcinoma
 Pattern of anchorage-independent growth.
 Mimics lactating breast by forming dilated spaces filled
 The cells are adherent to each other and express E-cadherin.
with eosinophilic materials.
 They lack adhesion to the stroma.
 Spindle cell carcinoma
 Low-grade adenosquamous carcinoma
Morphology of Special Type of Invasive Carcinomas
 Adenoid cystic carcinoma
 Almost always ER (+) and have gene expression profiles that
resemble luminal cancers.
 Inflammatory carcinoma
 Show extensive invasion and proliferation within lymphatic
Lobular Carcinoma
channels, causing swelling that mimics non-neoplastic lesions
 Most commonly forms hard irregular masses similar to other
 These are usually of high grade
breast cancers but may also have diffuse infiltrative pattern with
minimal desmoplasia.  Do not belong to any particular molecular subtype.
 Difficult to palpate or detect by imaging.
 Most common type presents as occult primary.
 Hallmark is the presence of discohesive infiltrating cells, often
including signet-ring cells with intracytoplasmic mucin droplets.

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Male Breast Cancer  Lymphovascular invasion
 Risk factors are similar to those in women.  Half of all invasive CA are present in the vascular spaces.
 3-8% is associated with Klinefelter syndrome and decreased  Strongly associated with lymph node metastasis.
testicular function.  Poor prognostic factor.
 4-14% is associated with BRCA2 mutations.  Risk factor for local recurrence.
 Also observed in BRCA1 mutations.  Extensive plugging of the dermis (Inflammatory carcinoma)
 The pathology of male breast cancer is similar to women.
 ER positivity is more common. Other Prognostic factors
 Because breast epithelium in men is limited to large ducts near  Molecular subtype – expression of ER and HER2
the nipple, carcinomas usually present as palpable subareolar  Special Histologic type
mass and/or as nipple discharge.  Some special types (tubular, mucinous, lobular, papillary,
 Carcinoma is close to overlying skin and underlying thoracic wall. adenoid cysts) have greater survival rate than with cancers of
 Same dissemination pattern in women. no special type.
 Metaplastic carcinoma or micropapillary CA – poor prognosis
Prognostic and Predictive Factors  Histologic Grade - Nottingham Histologic Score
 Depends on the biologic features of the carcinoma.  Proliferative Rate
 Depends on extent the cancer has spread at time of diagnosis  Can be measured by mitotic counts, by IHC detection of
 Tumors with distant metastasis or with inflammatory carcinoma proteins expressed by active dividing cells (Ki-67 and cyclins).
have poor prognosis.  Important for ER (+), HER2 (-) carcinomas, as majorities of
 Prognosis is determined by pathologic examination of the ER(-) and HER (+) have high proliferative rates.
primary carcinomas and the axillary lymph node.  Higher proliferation means poorer prognosis but may
respond better to chemotherapy.
Major prognostic factors  Estrogen and Progesterone Receptors
 Invasive carcinoma versus carcinoma in situ  80% are both ER and PR positive, responds to hormonal
 Excellent prognosis. manipulation.
 Only rarely do such patients die due to the subsequent  40% of those positive for only ER or PR respond.
development of invasive carcinoma or areas of invasion.  Cancers that fail to express either ER or PR have 10%
 Distant Metastasis likelihood of responding to hormonal therapy.
 Once distant metastasis is present, cure is unlikely.  HER2 – overexpression is associated with poorer survival
 Long-term remissions and palliation can be achieved,
especially in women with ER (+) tumors. (for AJCC staging and Scarf-Bloom-Richardson staging, refer to the last page)
 Lymph Node Metastasis
 Axillary lymph node status is the most important prognostic Therapeutic Approaches
factor for invasive carcinoma in the absence of distant mets.  Local and regional control using combinations of surgery and
 Biopsy is needed for accurate assessment. post-operative radiation.
 No nodal involvement, 10-year disease free survival rate is  Systemic control using hormonal or chemotherapy.
close to 70-80%.  Newer therapeutic strategies:
 Rate falls to 35-40% with one to three positive nodes.  Inhibition of membrane-bound growth factor receptors,
 Drops to 10-15% when more than 10 nodes are positive. stromal proteases, and angiogenesis
 Lymphatic vessels in most breasts CA drain first to one or two
Stromal Tumors
sentinel nodes can be identified with colored dyes.
 Two types of stroma in the breast
 Tumor Size
 Intralobular – fibroadenoma, phyllodes tumors
 Risk of axillary lymph node metastasis increases with size of
the primary tumor, but both are independent.  Interlobular
 Women with node-negative CA less than 1 cm have 10-year  May elaborate growth factors for epithelial cells resulting in
survival rate of more than 90%. proliferation of non-neoplastic epithelial component.
 Drops to 77% greater than 2 cm.  Interlobular stroma is the source of same types of tumors found
in connective tissues in other sites of the body.
 Size is less important for HER2 (+) and ER (-) carcinomas,
since they metastasize even when they are small.
Fibroadenoma
 Locally Advanced Disease
 Most common benign tumor of the female breast.
 Invasion to the skin or skeletal muscle are usually large.
 Most occur in women in their 20s and 30s.
 Hard to cure using surgery
 Frequently multiple and bilateral
 Inflammatory Carcinoma
 Palpable mass in younger women and mammographic density in
 Cancer presenting with breast erythema and skin thickening
older women.
have very poor prognosis, as most have distant metastasis.
 Epithelial component is hormonally responsive.
 Edematous skin is tethered to the breast by Cooper
 Typically an increase in size due to lactational changes.
ligaments and mimics the surface of an orange peel.
 This increase may be complicated by infarction and inflammation
 Appearance referred to as peau d’orange
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Morphology
 Vary in size, well circumscribed, ruberry, grayish white nodules
that bulge above the surrounding tissue, often contain slit-like Lesions arising in the Interlobular Stroma
spaces. Benign:
 Delicate and often myxoid stroma resembles normal stroma.  Myofibroblastoma – unusual, equally common in males
 Epithelium may be surrounded by stroma (pericaincular pattern)  Lipomas – often palpable
or compressed and distorted by it (intracanicular pattern). Malignant:
 In older women, it becomes hyalinized.  Angiosarcoma – occurs with any frequency, may be sporadic or
as complication of therapy, most sporadic occur in the
 Many are polyclonal hyperplasias of lobular stroma. parenchyma of young women.
 Women receiving cyclosporine A after renal transplant develop  Rhabdomyosarcoma
multiple bilateral fibroadenomas that regress after cessation of  Liposarcoma
treatment.  Leiomyosarcoma
 Chondrosarcoma
Phyllodes Tumor  Osteosarcoma
 Arise from intralobular stroma, much less common.
th
 Most present in the 6 decade. Other Tumors
 Majority are detected as palpable mass.  Malignancies arising from lymphocytes or skin or metastatic
 Cystosacoma phyllodes from other site comprise less than 5%.
 Associated with chromosomal changes with gains in  Non-hodgkin Lymphoma may arise primarily, most are B-cell
chromosome 1q being most frequent. type.
 Increased aberrations and overexpression of homeobox  T-cell lymphomas may arise in scar capsule associated with
transcription factor HOXB13 are associated with higher tumor breast implant possibly due to chronic inflammation.
grade and more aggressive behavior.

Morphology
 Vary in size.
 Larger lesions have bulbous protrusions (phyllodes = leaflike) due
to presence of nodules of proliferating stroma covered by
epithelium.
 These may extend to cystic spaces.
 Not an indication of malignancy if seen in large fibroadenomas
 Higher cellularity, mitotic rate, nuclear pleomorphism, stromal
overgrowth, and infiltrative borders compared to fibroadenomas
 High risk of recurrence.

Chaf chafki hola hoyale hafaha haqakea

(Autumn’s wind is blowing a quiet song for those who are tired)

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