Chapter 23: The Breast

Thursday, January 18, 2018

7:15 PM – Bobby steal yo gurl

• Reduction in breast cancer risk observed in women who give birth

to children at young ages
• permanent changes are produced by pregnancy --
permanent increase in the size and number of lobules

• Milk Line Remnants

• Persistence of epidermal thickenings along the milk line →
supernumerary nipples or breasts (polythelia and
polymastia)
• Hormone responsive foci, symptomatic during
pregnancy
• Normally inferior to normal breasts
• Come to attention due to premenstrual, painful
enlargements
• These areas are rarely affected by disorders that affect normally situated breasts

• Accessory Axillary Breast Tissue

• Normal ductal system may extend into the SQ tissue of the chest wall or axillary fossa (axillary tail of Spence)
• Areas not clinically identified as
breast tissue
• Prophylactic mastectomies reduce, but do
not eliminate the risk of breast cancer
because breast tissue in these areas may
not be removed == can be a site of
malignancy!
• Most breast tissue drains to axillary
lymph nodes

• Congenital Nipple Inversion

• Congenitally inverted nipples are usually of little significance
• correct spontaneously during pregnancy or with simple traction
• Acquired nipple retraction is of more concern
• may indicate invasive cancer or inflammatory nipple disease

• Breast Disorders
• Pain (mastalgia, mastodynia)
• Diffuse: Usually due to premenstrual edema
• Localized: Often due to ruptured cysts, physical injury, infection
• almost all painful masses are benign -- 10% of breast cancers present with pain

• Palpable Mass
• Distinguish from normal nodularity
• Most commonly masses are cysts, fibroadenomas, or
invasive carcinomas
• Usually benign in premenopausal women
• ↑ likelihood of malignancy with age
• 10% < 40 yrs.
• 60% > 50 yrs.
• This is how 1/3 of carcinomas are detected
• Screening has little effect on mortality because most
palpable cancers have metastasized

• Nipple Discharge
• Most worrisome for carcinoma if spontaneous, unilateral, and age >60
 • Milky (galactorrhea) is associated with ↑ prolactin, hypothyroidism, endocrine anovulatory syndromes, OCT, TCA,
methyldopa, phenothiazines
• Seen normally with manipulation or stimulation
• Blood or serous = papilloma or cyst
• Blood also seen in pregnancy due to rapid tissue remodeling
• Risk of malignancy in a woman with nipple discharge increases with age
• Think of cancer in patients >60 years old that present with spontaneous unilateral discharge

• Breast Carcinoma Location

• Upper outer: 50% (most common site in females because of
statistics; has the most breast tissue)
• 20% in central or subareolar region
• most common site in males because has the most
breast tissue in males
• 10% in all remaining quadrants

• What are the most common palpable masses in the breast?

• Cysts, fibroadenomas, invasive carcinomas
• Benign lesions more common à premenopausal women
• Malignant lesions are more common in post-menopausal women (corollary ^^)
• Only 1/3 of cancer are detected as a palpable mass

• Mammogram
• Definition
• Detects small, nonpalpable, asymptomatic breast carcinoma
• the principal signs of breast carcinoma are densities & calcifications
• Most common means to detect breast cancer
• ↑ sensitivity and specificity as patient ages: fibrous, radiodense tissue →
fatty, radiolucent tissue

• Densities
• Lesions that replace adipose tissues with radiodense tissue
• Rounded = usually benign fibroadenomas or cysts
• Irregular: Invasive carcinoma
• Identifies lesions 1cm in size vs 2-3cm by palpation

• Calcifications
• Form on secretions, necrotic debris or hyalinized stroma
• Usually benign lesions: Clusters of apocrine glands, hyalinized fibroadenomas, sclerosing adenosis
• If associated with malignancy: Small, irregular, numerous and clustered
• Ductal carcinoma in situ (DCIS) is seen in this manner
Inflammatory Disorders
• Inflammatory Disorders of the Breast
• Definition
• Rare outside of the locational period
• due to infections, autoimmune disease, or foreign body-type reactions to extravasated keratin or
secretions
• "Inflammatory breast cancer" mimics inflammation by obstructing dermal vasculature with tumor emboli. Always
consider in females with an erythematous, swollen breast.
• Types
• Acute mastitis
• Squamous metaplasia of lactiferous ducts
• Duct ectasia
• Fat necrosis
• Lymphocytic mastopathy (diabetic mastopathy)
• Granulomatous mastitis
• Acute Bacterial Mastitis
• Definition
• Cracks and fissures of the nipple cause the breast to be vulnerable to bacteria during the first month of breast
feeding
• Breast is erythematous, painful +/- fever

• Bugs involved
• Staphylococcus Aureus (or less commonly, streptococcus) invade the tissue involving a single duct system or sector
• If not treated can spread to the entire breast
• Staphylococcus = single or multiple abscesses
• Streptococcus = cellulitis

• Treatment: antibiotics, continue expression of breast milk; rarely requires surgical drainage

• Squamous Metaplasia of Lactiferous Ducts

• AKA: Subaerolar abscess, Periductal mastitis, Zuska disease

• Definition
• Painful, erythematous subareolar mass that appears to be a
bacterial abscess
• Recurrent: fistula tunnels under smooth muscle of the
nipple, opening to the skin at the edge of the areola
• Inverted nipple (not always carcinoma)

• Risk factors
• 90% of patients are smokers
• May be due to relative vitamin A deficiency or toxic substance
in tobacco smoke – vitamin A needed to maintain specialty
epithelial tissues – smoking causes VItA deficiency = squamous
metaplasia and block

• Morphology
• Keratinizing squamous metaplasia of the nipple ducts
• Ductal system is plugged by shed cells → dilation & eventually rupture of the duct
• Keratin spills into the surrounding periductal tissue → intense chronic granulomatous response
• Acute inflammation may occur 2º to anaerobic bacterial infection

• Treatment
• Commonly recur following drainage due to remaining keratinizing epithelium
• Curative if the duct & fistula tract are surgically removed

• Duct Ectasia – inflammation with dilation (ectasia) of subareolar ducts

• Definition
• Palpable peri-areolar mass
• Associated with thick, white nipple secretions +/- skin retraction
• Pain & erythema are rare
• irregular palpable mass mimics invasive carcinoma clinically and
on imaging

• Risk factors
• Susceptible females are multiparous & in their 5-6th decade
• No associated with smoking

• Morphology
• Ectatic dilated ducts with inspissated secretions and lipid laden
macrophages
 • Rupture → periductal and interstitial inflammatory reaction with lymphocytes and plasma cells also joining the
party
• Formation of granulomas around cholesterol deposits & secretions → irregular mass with skin and nipple
retraction

• Fat Necrosis in the breast

• Painless, palpable mass with skin thickening or retraction and/or mammographic densities or calcifications
• Acute: neutrophils + macrophages
• Chronic: fibroblasts and inflammatory cells lead to giant cells, calcifications and deposition of hemosiderin → scar
tissue (ill-defined, firm, grey-white nodules containing small chalky white foci)
• 50% of females have history of prior surgery or breast trauma

• Lymphocytic Mastopathy (sclerosing lymphocytic lobulitis) -- diabetic mastopathy

• Single or multiple hard, palpable masses or mammographic densities
• Dense collagenized stroma = difficult to needle biopsy
• Thick BM of atrophic ducts & lobules
• Surrounded by prominent lymphocytic infiltrate
• Most common in patients with T1DM or autoimmune thyroid disease -- thought to be autoimmune

• Granulomatous Mastitis
• May be due to systemic or localized granulomatous disease (TB,
sarcoidosis)
• Uncommon
• Occurs in parous females; associated with lobules
• possibly a hypersensitivity reaction to antigens
expressed by lactation
• TX: steroids

• Cystic neutrophilic granulomatous mastitis

• due to corynebacteria
• Localized infection of TB or fungi due to immunocompromise or adjacent to foreign objects (piercing or
prostheses)

• Benign Epithelial Lesions

• Detected by mammography or as incidental findings in surgical specimens
• 3 groups based on subsequent risk to develop breast carcinoma

Non-proliferative breast changes not associated with an increased risk of

• duct ectasia, cysts, apocrine breast cancer
change, mild hyperplasia,
adenosis, fibroadenoma

Proliferative breast disease (without small increase in the risk of subsequent

atypia) carcinoma in either breast; predictors of
• moderate/florid hyperplasia, risk but unlikely to be true precursors of
sclerosing adenosis, carcinoma
papilloma, complex
sclerosing lesion,
fibroadenoma with complex
features

Atypical hyperplasia has some but not all histological features

required for diagnosis of carcinoma in
situ; moderately increased risk of
carcinoma
• Non-proliferative Breast Changes (fibrocystic change)
• Definition
• Group of morphological fibrocystic changes
• No associated risk of breast cancer (non-proliferative)

• Morphologic changes
• Cystic change, often with apocrine metaplasia
• Fibrosis
• Adenosis

• Cysts
• due to lobule dilation
• May coalesce into larger cysts
• Unopened cysts contain turbid, semi-translucent brown-blue fluid (blue domed cyst)
• Lined with flattened, atrophic epithelium or metaplastic apocrine cells
• Calcifications are commonly seen on mammography (concerning if they are solitary or firm to palpation)
• Diagnosis: confirmed after disappearance of the cysts due to fine needle aspiration of contents

• Fibrosis
• Occurs due to release of secretory material into the stroma from (often) ruptured cysts
• Contributes to palpable nodularity of the breast

• Adenosis
• ↑ # of acini/lobule
• Normal in pregnancy or focal change in nonpregnant females
• Lined with columnar cells
• Chromosome 16q deletion = "flat epithelial atypia"
• earliest recognizable precursor lesion of low-grade breast cancer
• no increased risk of breast cancer (other steps in carcinogenesis are rate limiting)
• Mass and/or calcifications are seen in the lumens

• Lactational adenoma
• Palpable masses in pregnant or lactating
women
• Normal appearing breast tissue with
exaggerated lactational changes

• Proliferative Breast Disease without Atypia

• Definition
• Proliferations of epithelial cells without
atypia
• Small ↑ in risk of subsequent carcinoma of either breast
• predictors of risk but unlikely to be true precursors of carcinoma
• No clonal lesions or genetic changes

• Epithelial Hyperplasia
• ↑ # of luminal (ductal) and myoepithelial cells fill & distend ducts and lobules
• Normally: ducts & lobules are lined with a double layer of myoepithelial cells & luminal cells
• Irregular lumens in the periphery
• Usually an incidental finding
• Sclerosing Adenosis
• ↑ # of acini are compressed and distorted in the central portion of the
lesion
• Lumen compression due to stromal fibrosis (sclerosing part) → histologic
pattern that closely mimics invasive carcinoma

• Complex Sclerosing Lesion

• Sclerosing adenosis, papilloma, epithelial hyperplasia
• Radial scar: Irregularly shaped, mimics invasive carcinoma
• Central nidus of entrapped glands in hyalinized stroma surrounded
by long, radiating projections into stroma
• Not associated with prior trauma or surgery

• Papilloma
• Growth within a dilated duct
• Composed of intraductal lesions with fibrovascular cores lined by myoepithelial and luminal cells (both)
• 80% produce nipple discharge:
• Blood: infarct of stalk due to torsion
• Serous: intermittent blockage & release of secretions
• Usually solitary & seen in the lactiferous sinuses of the nipple
• Small duct = multiple & located deeper in the ductal system
• Often seen with epithelial hyperplasia & apocrine metaplasia
• apocrine metaplasia is not a pre-cursor to cancer (unlike
most other forms of metaplasia)

• Gynecomastia – imbalance between estrogens and androgens

• Definition
• Enlargement of the male breast; only benign lesion in the
male breast
• unilateral or bilateral buttonlike subareolar
enlargement
• Small ↑ risk of breast cancer

• Morphology
• ↑ in dense, collagenous connective tissue and epithelial
hyperplasia of the duct lining with tapering micro-papillae
• No lobule formation

• Causes
• Imbalance between estrogens and androgens due to:
• Puberty
• Aging
• Decreased testicular androgen production
• Hyperestrinism
• Liver cirrhosis (liver metabolizes estrogen)
 • Drugs (alcohol, marijuana, heroin, antiretroviral, steroids)
• Klinefelter or functional testicular neoplasms (XXY)

• Proliferative Breast Disease with Atypia

• Clonal proliferation with some, but not all, histological features of ductal carcinoma in situ (DCIS)
• moderate increase in the risk of carcinoma of the breast

• Atypical ductal hyperplasia

• Partially fills duct (ductal carcinoma in situ DCIS fills the duct)
• May have cribriform spaces
• Monomorphic epithelial proliferation

• Atypical lobular hyperplasia

• Cells identical to lobular carcinoma in situ (LCIS)
• Atypical lobular cells that do not fill/distend >50% lobule acini
• The atypical lobular cells may lie between the ductal basement membrane and the normal luminal cells
• Loss of E-cadherin (same as lobular carcinoma in situ)

• Genetics of both
• Moderate ↑ risk of carcinoma
• Chromosome 16q loss or 17p gain (also seen in CIS)
• Pagetoid spread

• Risk of carcinoma from benign epithelial lesions

• No ↑ risk of cancer if changes are non-proliferative
• 1.5-2x ↑ risk of cancer in proliferative disease
• 4-5x ↑ risk of cancer in proliferative disease with atypia
• < 20% develop breast cancer & may choose surveillance over
radical treatment options
• Risk is increased in both breasts, though ipsilateral may have higher risk
• Treatment may involve bilateral prophylactic mastectomy or estrogen antagonists (tamoxifen)
• Carcinoma of the Breast
• Definition
• Most common non-skin malignancy in females
• 2nd most common cause of cancer death in women after
lung cancer
• 1/8 chance of this disease in females who live to 90 years
old
• Almost all are adenocarcinomas and can be divided into 3
major biological groups:
• ER positive, HER2- negative == 50-65%
• ER positive / negative, HER2-positive == 10-20%
• ER negative, HER2- negative == 10-20%
• Epidemiology
• Rare in females < 25 years ßsee it in old chicks
• Rapid ↑ in incidence after 30

• Risk factors
• Increased risk due to western lifestyle: delayed pregnancy, fewer pregnancies, and decreased breastfeeding
• African American females have the highest mortality rate as they have less access to screening and they
have more aggressive cancers
• Germline mutations
• 1st degree relatives with breast cancer
• Race/ethnicity: non-Hispanic women have the greatest risk, Ashkenazi Jews are more likely to have BRCA1/2
mutations
• Age at menarche/menopause: increased risk with earlier menarche or later menopause
• Age of first birth: increased risk in patients with later pregnancy or no pregnancy
• Benign breast disease: atypical hyperplasia or proliferative disease
• Estrogen Exposure: Menopausal hormone therapy with estrogen and progestin over multiple years
• Most cancers are estrogen receptor positive carcinoma
• No associated risk with oral contraceptive therapy
• Oophorectomy (= ↓ estrogen) 75% ↓ chance of breast cancer
• Antiestrogenic drugs (tamoxifen or aromatase inhibitors) ↓ risk of estrogen receptor positive breast cancer
• Dense Breasts
• 4-6x ↑ risk of estrogen receptor positive or negative
• Clusters in families
• Related to other factors (late age at first birth, fewer children, hormone replacement therapy)
• May be due to failure of normal involution in older females

• Radiation
• Exposure at a young age to high doses
• Hodgkin patients in their teens & early 20 have a 20-30% ↑ risk over 10-30 years
• Older women do not incur this risk if exposed later in life

• Metabolism
• Moderate or heavy alcohol intake
• Obese postmenopausal females due to ↑ risk due to estrogen synthesis in fat depots
• Obese females < 40 ↓ risk due to anovulatory cycles & low progesterone levels
• Probable small protective effect for physically active females
• No associated risk with intake of any specific foods

• Breastfeeding
• the longer women breastfeed, the lower the risk
• lactation suppresses ovulation and may trigger terminal differentiation of luminal cells
• May explain lower rates in developing countries who do this for their infants longer
• Familial Breast Cancer pathogenesis
• 12% occur due to inheritance of an identifiable susceptibility gene(s)
• May be autosomal dominant
• BRCA1/2, TP53, CHEK2 (all tumor suppressors) ~8% of familial breast carcinomas
• germline mutation in TP53 == Li-Fraumeni syndrome; associated with HNPCC; most commonly --> HER2 (+)
• PTEN (Cowden syndrome), STK11 (Peutz-Jeghers syndrome), and ATM (ataxia telangiectasia) < 1%

• Greater probability if there are multiple first degree relatives affected, early onset cancers, multiple cancers or family
members with cancers

• BRCA1 & BRCA2 in breast carcinoma

• Responsible for 80-90% of 'single gene' occurrences
• 3% of all breast cancers
• 30-90% penetrance depending on the specific mutation
• Genetic testing is difficult due to variants, but carriers should be identified to reduce morbidity & mortality
• Also ↑ risk of other epithelial cancers (prostate or pancreatic)

• BRCA1
• Located on chromosome 17q21
• Marked ↑ in risk of ovarian carcinoma • BRCA2
• Often poorly differentiated • Located on chromosome 13.12.3
• Have medullary features (syncytial growth pattern • More frequently associated with male breast
with pushing margins & lymphocytic response) cancer
• Biologically similar to ER -ve, HER2 -ve breast • Relatively poorly differentiated; more likely ER +ve
cancers identified as "basal-like" by gene
expression
• profiling
• and also serous ovarian carcinomas

• Carcinoma of the Breast: Carcinogenesis

• ER(+), HER2(-)
• Arise via the dominant pathway of breast cancer development in 50-65% of cases
• most common subtype of breast cancer in individuals who inherit germline mutations of BRCA2
• most common form of invasive breast cancer
• Associated with chromosome 1q gains, chromosome 16q loss, and PIK3CA activating mutations
• Same mutations as seen in flat epithelial atypia & atypical ductal hyperplasia
• ^^ thought to be precursor lesions for this subtype of breast cancer
• ER (+) breast cancers are termed "luminal"
• most closely resemble normal breast luminal cells regarding mRNA expression
• Dominated by genes regulated by estrogen

• HER2(+)
• 20% of all breast cancers; can be ER (+) or (-)
• Associated with HER2 gene amplification on chromosome 17q
• HER2 == receptor tyrosine kinase – growth hormone receptor
• Can be overexpressed if there is ERBB2 mutations
• Dominated by genes related to proliferation regulated downstream of the RTK
• Most common type of cancer in patients with TP53 mutations (Li-Fraumeni syndrome)
• Precursor: atypical apocrine adenosis
• Can look for this by staining for HER2 or FISH amplification (best for follow up if results are inconclusive)

• ER(-), HER2(-)
• Arise through distinct pathway, independent of estrogen receptor mediated changes or HER2 amplifications
• 15% of all breast cancers
• Most common in patients with germline BRCA1
• sporadic forms often have loss of TP53 function instead of BRCA1
• BRCA1 can by methylated/silenced later via epigenetics
• ↑ frequency in African-American females
 • "basal-like" pattern of mRNA expression that includes many genes that are expressed in normal myoepithelial cells

• Driver mutations:
• PIK3CA, HER2, MYC, CCND1, TP53, BRCA1/2
• Subclonal heterogeneity contributes to tumor progression and resistance to treatment
• The neoplastic cells require the stroma for development (high density regions)
• Fibrous stroma is a marker for risk
• Associated with angiogenesis and inflammation
• May progress from CIS during post-pregnancy involution when there is lots of breast remodeling

• BRCA1 from the table • BRCA2 from the table

• 52% of all single gene hereditary cancers
• Risk of breast cancer by age 70: 40-90%
• Mutations are rare, inactivated in 50%
• Tumor suppressor, transcription regulation,
repair of dsDNA breaks
• Poorly differentiated
• Often triple negative (ER -ve, HER2-, ??? -ve)
• TP53 mutations are common
• Associated with other cancers: ovarian, male
breast, prostate, pancreas, fallopian tube
• 32% of all single gene hereditary cancers
• Risk of breast cancer by age 70: 30-90%
• Mutations and loss of expression are rare
• Tumor suppressor, transcription regulation,
repair of dsDNA breaks
• Biallelic germline mutations cause a rare form of
Fanconi anemia
• Associated with other cancers: ovarian,
male breast, prostate, pancreas, stomach,
melanoma, gallbladder, bile duct, phary

• TP53 from the table

• 3% of all single gene hereditary cancers
• Risk of breast cancer by age 70: > 90%
• Mutations in 20%
• LOH (loss of heterozygosity) = 30-42%
• Most frequent in triple (-) cancers
• Tumor suppressor
• Most commonly mutated gene in sporadic breast cancers
• 53% are ER(-), HER2(+)
• Associated with cancers: sarcoma, leukemia, brain, adenocortical carcinoma, etc.
Types of Breast Cancer -

• Adenocarcinomas
• 95% of all breast malignancies
• First arise in the duct/lobular system as CIS
• At presentation, 70% have breached the basement membrane and invaded the stroma (i.e. malignant)

• Carcinoma in Situ (CIS) – confined to BM, myoepithelial cells preserved – detected as micro ca
• Neoplastic proliferation of epithelial cells confined to ducts and lobules by the basement membrane (i.e. benign)
• May be classified as ductal or lobular (LCIS or DCIS)
• Actually arise from cells in the terminal duct lobular unit

• Ductal Carcinoma in Situ (DCIS) ß precursor lesion associated with breast cancer
• Definition
• Malignant clonal proliferation of epithelial cells limited to ducts and lobules by basement membrane
• Myoepithelial cells are preserved in involved ducts/lobules, though may be diminished
• Can spread through the ductal system → extensive lesions of an entire breast sector

• Diagnosis
• almost always detected by mammography
• identified as calcifications with secretory material, necrosis

• Less commonly identified as a density due to periductal fibrosis

• Rarely produces nipple discharge
• LCIS is bilateral in 20-40% of cases; DCIS is bilateral in 10-20% of cases

• Morphology
• Comedo or non-comedo
• Most have multiple growth patterns

• Risk factors for progression to invasive type

carcinoma
• Nuclear grade & necrosis predict local
recurrence and progression to invasion
better than architecture
• Extent of disease
• Positive surgical margins (multi-centric)

• Comedo DCIS Morphology

• Usually detected as clustered or linear and
branching areas of calcification on
mammography
• May occasionally produce nodularity
• Defined by two features
• tumors with pleomorphic, high grade
nuclei
• areas of central necrosis

• Non-comedo DCIS Morphology

• Lacks high grade nuclei or central necrosis
• Cribriform pattern: Rounded spaces within ducts (cookie cutter) or solid pattern
• Micropapillary pattern: Bulbous protrusions w/t fibrovascular core in complex intraductal patterns
• True papillae pattern: Fibrovascular core without myoepithelial cell layer

• Treatment
• Surgical excision and radiation/tamoxifen = Mostly curative
• Mastectomy = Cure in 95%
 • Breast conservation = ↑ risk of recurrence
• Untreated: 1% → invasive cancer in the same quadrant with similar grade and expression of ER/HER2
• Higher grade has a higher risk of progression
• Death rate = better than the general population as mammography may be a marker for socioeconomic status

• DCIS is treated locally, as subsequent invasive carcinomas usually occur at the same site
• LCIS confers bilateral risk

• Paget Disease of the Nipple

• Morphology
• Rare - presents as a unilateral erythematous eruption and scale crust (map-like)
• Pruritus is common, may be confused with eczema
• Malignant cells extend via the lactiferous sinuses into nipple skin, without crossing the
basement membrane → disruption of epithelial barrier = extracellular fluid leakage onto
nipple surface
• Paget cells are larger than surrounding keratinocytes and are seen singly or in small clusters
within the epidermis
• The cells have pale cytoplasm containing mucopolysaccharide that stains with periodic acid–
Schiff (PAS)

• Diagnosis
• Detected with nipple biopsy or cytology of exudate
• 50-60% have palpable mass that indicates there is also invasive carcinoma
• The carcinomas are poorly differentiated, ER(-) & HER2 (+)
• If there is no palpable mass, then there is typically only DICS

• Prognosis
• Prognosis depends on features of the underlying carcinoma and not by the skin manifestations

• Lobular CIS (LCIS)

• Definition
• Clonal proliferation of cells within ducts and lobules growing in a
discohesive fashion due to acquired loss-of-function mutation
of E-cadherin protein (CDH1 gene)
• Cells are identical to hyperplasia or invasive carcinoma
• Cells expand, but do not distort spaces, preserving the
underlying lobular architecture
• 2X chance of being bilateral than DCIS, must check the other
breast after being found

• Diagnosis
• Always an incidental biopsy finding, since it is not associated
with calcifications or stromal reactions that produce mammographic densities
• incidence did not decrease after introduction of mammographic screening
• E-cadherin (-)
• NO MASSES
• ER(+), PR(+), HER2(-)
• LCIS is bilateral in 20-40% of cases; DCIS is bilateral in 10-20% of cases

• Morphology
• Uniform population of cells with oval/round nuclei and small nucleoli
• Mucin (+) signet-ring cells
• Lack of E-cadherin = rounded cells not attached to adjacent cells (discohesive)
• Does not form cribriform spaces or papillae (like DCIS)
• Pagetoid spread: Cells seen between basement membrane & luminal cells
• No involvement with nipple skin
• No necrosis or secretions = no calcifications
 • LCIS is a risk factor for invasive carcinoma
• Develops in 25-35% of women over 20-30 years
• Risk is almost as high in the contralateral breast
• unlike DCIS
• 3x more likely to get an invasive lobular carcinoma from LCIS than DCIS
• most invasive carcinomas arising from LCIS are of other morphologies
• Treatment
• Typically, there is just close clinical follow up with mammographic screening since the risk of progression is similar
to DCIS

• Bilateral prophylactic mastectomy, tamoxifen can also be done

• Invasive (infiltrating) Carcinoma

• 1/3 classified on histological type and others are 'ductal' or no special type (NST)

• Invasive Carcinoma:
• ER(+), HER2(-), Low Proliferation
• Definition
• Most common subtype of cancer in older females and in males
• Most commonly detected via mammography
• Most common in females on hormone replacement therapy
• Often found at an early stage and cured by surgery, ↓ recurrence

• Treatment
• Gene expression is regulated by estrogen receptors
• Hormone therapy is standard, anti-estrogen (Tamoxifen)
• incomplete response to chemotherapy; chemotherapy adds little to hormone therapy
• Metastasis takes >6 years to occur → bone (most common)

• ER(+), HER2(-), High Proliferation

• Estrogen receptor levels may be low and progesterone receptor may be low or absent
• Most common carcinomas associated with BRCA2 germline mutations
• mRNA expression is similar to other ER(+) cancers
• ↑ expression of genes related to proliferation
• ↑ chromosomal aberrations
• 10% show a complete response to chemotherapy (vs. low proliferative)
• better prognosis than patients who do not respond

• HER2(+)
• Definition
• Second most common molecular subtype of invasive breast cancer
• 50% are ER(+), but there is low expression and absent progesterone receptor
• More common in young, non-white females
• Half of patients with TP53 mutations (Li-Fraumeni syndrome) are ER(+)/HER2(+)
• mRNA = ↑ HER2 expression & ↑ expression of proliferating genes
• Complex intra-chromosomal translocations
 • High mutation load

• Diagnosis
• Subtype is identified via protein over-expression or gene amplification assays
• Detect HER2 with antibody or FISH

• Pattern of spread
• Metastasize early, when small → viscera and brain

• Treatment
• 1/3 respond completely to targeted monoclonal antibody therapy (trastuzumab/Herceptin®) that bind &
block HER2 receptor activity = excellent prognosis
• Many patients have resistance to trastuzumab due to truncated HER2 without drug binding site but
retention of kinase activity or upregulation of downstream pathways (PI3K)

• ER(-), HER2(-) == "Basal-like" triple negative carcinoma

• Definition
• Most common in young, premenopausal females (especially African American or Hispanic)
• Presents as a palpable mass between mammographies due to high proliferation and rapid growth
• share a number of genetic similarities with serous ovarian carcinomas

• Genetics
• Majority of carcinomas arising in women with BRCA1 mutations are of this type
• Genetically similar to serous ovarian carcinoma
• Assay for protein or gene amplification MUST be done to determine if targeting ER or HER2 may be
indicated
• Features often overlap with other cancers (gene wise, 10% express ER, 15% express HER2)

• Pattern of spread
• Metastasize when small → viscera + brain

• Treatment
• 30% respond well to chemotherapy and cure is possible
• Recurrence within 5 years of treatment
• Local recurrence = common, even with mastectomy
• Prolonged survival after distant metastases is rare
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• Mammography
• Calcifications on mammography without densities are usually < 1cm
• without mammography screenings, present with 2-3cm mass
• Hard, irregular radiodense masses with a desmoplastic stromal reaction

• Morphology, general
• Grating sound when scraped (cutting water chestnut) due to small, central pinpoint foci or streaks of chalky white
desmoplastic stroma with occasional calcification
• Sometimes present with well-circumscribed masses with sheets of tumor cells with little stromal reaction

• Invasion of tissues
• Invasion of pectoralis muscles = fixed to chest wall
• Invasion of dermis = dimpling of skin
• Nipple retraction if tumor is central
• Detection in the axilla before the breast is rare
 • Nottingham Histologic Score Tubule Formation Nuclear Mitotic Rate
• Based on tubule formation, Pleomorphism
nuclear pleomorphism, and
mitotic rate Grade I tubular pattern small, round ↓ proliferation
• Points for each are added nuclei rate
together:
Grade may also show some tubule greater degree mitotic figures
• ER(+), HER2(-) Morphology II formation; solid clusters of of nuclear are present
• Variable differentiation (well- infiltrating cells pleomorphism
poor), with most of well Grade invade as ragged nests or enlarged, ↑ proliferation
differentiated tumors in this III solid sheets of cells irregular nuclei rate; areas of
group tumor necrosis
• "essentially all well
differentiated carcinomas are in this group" (ER +ve, HER2 -ve)
• May present with mucinous, papillary, cribriform or lobular patterns may predominate & be subclassified
• High proliferation type expresses Ki67

• HER2(+) Morphology
• Most are poorly differentiated; a few classified as moderately differentiated
• Not associated with any specific morphologic pattern
• 50% of apocrine and 40% of micropapillary carcinomas fit into this category
• Associated DCIS is more extensive than other types of carcinoma

• ER(-), HER2(-) Morphology

• Almost all are poorly differentiated
• Many have circumscribed pushing borders with central fibrotic or necrotic center
• Similar appearance, but with a prominent lymphocytic infiltrate (carcinoma with medullary features; medullary
carcinoma)
• medullary subtype fails under "triple negative"
• Spindle cell, squamous and matrix producing patterns may be seen
• DCIS is very limited or not present
• Express basal keratins

Special histological types of invasive carcinoma – multiple subtypes are recognized with distinctive morphologies & relatively unique
biological characteristics

• Special histological subtypes of ER (+), HER2 (-) low proliferation

• Well or moderately differentiated lobular, tubular, and mucinous

• Special histological subtypes of ER (+), HER2 (-) high proliferation

• Poorly differentiated lobular

• Special histological subtypes of HER2 (+), ER (+/-)

• Some apocrine

• Special histological subtypes of ER (-), HER2 (-)

• Medullary, adenoid cystic, secretory, metaplastic

• Special Histologic types of Invasive Carcinoma

• Lobular Carcinoma
• Biallelic loss of CDH1 which encode E-cadherin
• Tumors are discohesive and may not incite a desmoplastic response
• histologic hallmarks:
• discohesive infiltrating tumor cells
• signet-ring cells containing intracytoplasmic mucin droplets
• Females & males with heterozygous germline mutations have an ↑ risk of gastric signet ring cell carcinoma
 • Metastases to the peritoneum, retroperitoneum, leptomeninges (carcinomatous meningitis), GI tract, ovaries and uterus

• Medullary Carcinoma
• Many features of BRCA1 associated carcinomas
• 13% of cancers arising in BRCA1 carriers exhibit this subtype of carcinoma
• 60% of cancers arising in BRCA1 carriers have a subset of medullary features
• Most are not associated with BRCA1 mutations, 2/3 are downregulated (hypermethylation)
• presence of lymphocytic infiltrates within the tumors is associated with higher survival rates and a greater response to
chemotherapy
• improved outcomes related to host immune response to tumor antigens

• Micropapillary carcinoma
• Characteristic pattern of anchorage independent growth
• The cells still express E-cadherin and are adherent to each other, however they do not attach to the stroma

• Lobular Carcinoma Morphology

• Hard, irregular mass
• Diffuse infiltrative pattern with minimal
desmoplasia
• Difficult to palpate or detect with imaging
• Presence of discohesive, infiltrating tumor cells <<
E-cadherin negative
• Signet ring cells with intracytoplasmic mucin
droplets
• Indian filing: single cells lined up like a box cars
• No tubule formation
• Most common type of breast carcinoma to
present as an occult primary
• lobular subtypes of breast carcinoma are often
bilateral
• Mucinous (colloid) Carcinoma Morphology
• Soft or rubbery and has pale gray-blue gelatin
appearance
• Borders are pushing or circumscribed
• medullary carcinoma == pushing border
• Cells are clustered in small islands within large
mucin lakes
• Tubular Carcinoma Morphology
• Consists exclusively of well-formed tubules
• May be mistaken for a benign sclerosing lesion
• Cribriform pattern may be present
• Apocrine snouts are typical
• Calcifications may be seen in the lumens
• Associated with flat epithelial atypia, atypical
lobular hyperplasia, LCIS or low grade DCIS
• Apocrine Carcinoma Morphology
• HER2 (+)
• Cells resemble those that line sweat glands
• enlarged round nuclei with prominent
nucleoli and abundant eosinophilic or
granular cytoplasm
• Micropapillary Carcinoma Morphology
• Forms hollow balls of cells that float within
intercellular fluid creating structures that
mimic the appearance of true papillae
• Medullary Carcinoma Morphology
• most common subtype of ER(-), HER2(-)
• Soft due to minimal desmoplasia
• Presents as a well circumscribed mass
• Solid, syncytium sheets of large cells with large,
pleomorphic nuclei, prominent nucleoli (75% of
the tumor mass)
• Frequent mitotic figures
• Lymphoplasmacytic infiltrate surrounding & within
the tumor
• Pushing (non-infiltrative) border
• DCIS is minimal or absent
• WHO says to classify this as "carcinoma with
medullary features"
• Secretory Carcinoma
• ER(-), HER2(-)
• Mimics lactating breasts by forming dilated
spaces filled with eosinophilic material

• Papillary Carcinoma Morphology • Inflammatory Carcinoma

• Produces true papilla: Fronds of fibrovascular
tissue lined by tumor cells
• 2 special histologic types frequently overexpress
HER2
• Extensive invasion and proliferation within
lymphatic channels
• Causes swelling that mimics non-neoplastic
inflammatory lesions
• Typically high grade with very poor prognosis
• Poor prognosis – African American
• Do not belong to any specific molecular subtype
 Figure 1: inflammatory carcinoma - Peaud'orange

• Male Breast Cancer

• Definition
• Similar risk factors as females
• 3-8% of cases are associated with Klinefelter syndrome (XXY) and ↓ testicular function
• Diagnosed: 60-70 years old
• Genetics
• 4-14% are associated with BRCA2 mutations (also observed in BRCA1 carriers, though not as frequently)
• If a male is affected, there is a high chance of a germline BRCA2 mutation in the family
• Much more likely for tumors to be ER(+)

• Clinical
• Present as a 2-3cm palpable, subareolar mass +/- discharge
• Close to the skin & underlying thoracic wall
• Even if small, they can invade the structures → ulcerations
• Similar dissemination pattern as seen in women
• 50% have metastasized at presentation (lungs, brain, bone, liver)
• Typically present at higher stages than women but have similar prognosis
 • Without surgery patients die with extensive local disease causing ulceration of the skin – carcinoma en
cuirasse

• Treatment
• Mastectomy + axillary LN dissection

• Breast Cancer Prognosis

• Definition
• Based on biologic features (molecular and histological) and the extent of metastases at diagnosis
• distant metastases or inflammatory carcinoma == poor prognosis
• Remaining patients: based on pathology of tumor + lymph nodes

• Prognostic factors fall into two groups:

• those related to the extent of carcinoma (tumor burden or stage)
• Invasive vs carcinoma in situ: patients with carcinoma in situ are have much better prognosis.
• Distant metastases: cure is unlikely, but remission is possible (especially with ER +ve tumors)

• Those that related to extent of carcinoma - continued

• Lymph Node Metastases
• Axillary lymph node metastases
• Axillary metastases are the most important factor in absence of distant metastases
• 10 year survival = No nodal involvement = 70-80%
• 1-3 lymph nodes = 35-40%
• 10+ lymph nodes = 10-15%
• Sentinel LN Metastases
• sentinel lymph nodes are negative, it is unlikely that the cancer has spread any further & patients can be
spared complete axillary dissection
• 10-20% of females without axillary lymph nodes have recurrences with distant metastases

• Tumor Size
• Risk of axillary metastases ↑ with size of primary tumor (independent factors)
• Node (-), <1cm = 90% 10 year survival
• Node (-), > 2cm = 77% 10 year survival
• size is less important for HER2(+) and ER (-) carcinomas which may metastasize when small
• Proliferative rate is related and important in this subtype as well, however, may respond better to chemotherapy

• Locally Advanced Disease

• Inflammatory Carcinoma
• Present with breast erythema & skin thickening == very poor prognosis
• patients often have distant metastases
• Coopers ligaments tethered to edematous skin = peau d'orange
• Dermal lymphatics are filled with metastatic carcinoma that blocks lymphatic drainage
• Diffusely infiltrative, does not form discrete, palpable mass
• may be confused with a mastitis
• not of a uniform specific histology or molecular type, and thus are classified as "inflammatory" based on
clinical presentation
• 60% are ER(-) while 40-50% are HER2(+)
• Very poor prognosis (distant metastases is likely)
• 3-10% 3 year survival (worse in African American or younger females)

• lymphovascular invasion
• tumor cells are present within vascular spaces in about half of all invasive carcinomas
• strongly associated with the presence of lymph node metastases
• poor prognostic factor for local recurrence
 • extensive plugging of the lymphovascular spaces of the dermis with carcinoma cells (inflammatory carcinoma)
bodes a very poor prognosis

• those related to the underlying biology of the cancer (tumor grade?)

• Molecular subtype
• ER and HER2 positivity/negativity
• Most favorable: well differentiated, ER+, HER2, low proliferation
• Least favorable: poor differentiated, ER, and/or HER2+
•
• Special Histological Subtypes
• Tubular, mucinous, lobular, papillary, adenoid cystic > no defined subtype > micropapillary or metaplastic
carcinoma

• Histologic Grade
• Proliferative Rate
• measured by mitotic counts
• primarily important for ER (+) HER2 (-) carcinomas
• majority of ER (-) and/or HER2(+) carcinomas have high proliferative rates -- it’s a wash
• high proliferative rate == poor prognosis
• but potentially better response to chemotherapy

• Estrogen & Progesterone Receptors

• ER(+), PR(+): 80% respond to hormonal treatment
• (+) for ER or PR: 40-50% respond to hormonal treatment
• strongly ER (+): less likely to respond to chemotherapy
• ER(-), PR(-): < 10% respond to hormonal treatment, but more likely to respond to chemotherapy

• HER2 = HER2 overexpression is associated with poorer survival - main importance is as a predictor of response to agents
that target this receptor
• Carcinoma en Cuirasse ("carcinoma of the breastplate")
• Patients that don’t receive treatment and get extensive local
disease with ulceration of the skin
• Dreaded complication of breast cancer that should be avoided to
maintain quality of life
• Common in women of areas with limited resources

• Stromal Tumors of the Breast

• 2 types of stroma in the breast
• Intralobular: fibroadenoma, phyllodes tumors
• ^^ biphasic tumors
• Interlobular: tumors are similar to others found in CT
throughout the body (lipoma, angiosarcoma)

• Fibroadenoma (benign)
• Definition
• Polyclonal hyperplasia of the lobular stroma
• Most common benign tumor of the female breast
• not found in men since they don’t have interlobular
stroma
• Most commonly occurs in 20 to 30 year olds
• Present with palpable mass (older women have
mammographic densities, or clustered calcifications)

• Hormonal Response
• Epithelium is hormonally responsive
• ↑ in size due to lactational changes in pregnancy
• Complications: infarction, inflammation

• Morphology
• Can be very small to large
• Well-circumscribed, rubbery, greyish-white nodules that bulge above the surrounding tissue and contain slit-like
spaces
• Delicate and myxoid stroma resembles normal intra-lobular stroma
• The epithelium can either be surrounded by stroma (peri-canicular) or compressed and distorted by it (intra-
canicular)
• In older women, the stroma typically becomes densely hyalinized and the epithelium atrophic

• Causes
• Almost half of women receiving cyclosporine A after renal transplantation develop multiple and bilateral
fibroadenomas that regress after cessation of treatment
• May be associated with clonal cytogenic aberrations confined to the stromal component
• Considered a "proliferative change without atypia"
• mildly increased risk of subsequent cancer
• Phyllodes Tumor (cystosarcoma) == "leaf-like"
• Definition
• Tumors that arise from intralobular stroma, but are much less common than fibroadenomas
• Most common in the 6th decade
• Detected as a palpable mass or seen on mammography
• Most are not cystic and behave in a benign manner
• Genetics
• Chromosome 1q gains
• HOXB13 overexpression = higher tumor grade & more
aggressive clinical behavior

• Morphology
• Can be small to large, leaf-like
• Larger lesions have bulbous protrusions due to nodules
of proliferating stroma covered by epithelium
• In some, the protrusions extend to a cystic space
• Higher cellularity, mitotic rate, nuclear pleomorphism,
stromal overgrowth, infiltrative borders (vs.
fibroadenomas)
• High grade = difficult to distinguish from malignant sarcomas as they can have a foci of mesenchymal
differentiation

• Tumor spread
• Usually low grade that may recur but do not metastasize
• High grade often recurs unless treatment involves wide excision or mastectomy
• regardless of grade, lymphatic spread is rare, lymph node dissection is contraindicated

• Lesions of Interlobular Stroma == stromal cells without an epithelial component

• Tumors are uncommon, benign or malignant
• Myofibroblastoma: only breast tumor equally common in both genders
• Lipoma: fat containing lesions; benign; only importance is to distinguish them from malignancies
• Fibromatosis: clonal proliferation of fibroblasts and myofibroblasts that presents as an irregular infiltrating mass
that can involve both skin and muscle
• locally aggressive; does not metastasize
• Angiosarcoma (malignant)
• the only sarcoma that occurs with any frequency in the breast
• still less than 0.05% of breast malignancies
• Sporadic or complication of therapy (edema, or 5-10 years after radiation)
• Occur in the breast parenchyma of young females (35 year olds)
• High grade, poor prognosis