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• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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)
• 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)
• Genetics of both
• Moderate ↑ risk of carcinoma
• Chromosome 16q loss or 17p gain (also seen in CIS)
• Pagetoid spread
• 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
• 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
• 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
• 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
• Morphology
• Comedo or non-comedo
• Most have multiple growth patterns
• 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
• 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
• 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
• 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)
• 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)
• 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
Special histological types of invasive carcinoma – multiple subtypes are recognized with distinctive morphologies & relatively unique
biological characteristics
• 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
• 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
• 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
• 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
• 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
• 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
• 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