Breast Flashcards
Reduction in breast cancer risk observed in women who give birth at what age
Young
Why does having children at young ages decrease risk of breast cancer
Permanent changes are produced by pregnancy—increase in size and number of lobules.
What are persistent epidermal thickening along the milk line
Supernumerary nipples or breasts
Polythelia
Extra nipple
Polymastia
Extra breast
When do milk line remnants become evident..keep in mind they are hormone responsive foci inferior to normal breasts
Pregnancy, premenstrual painful enlargement
Do milk line remnants become diseased
Not really
Accessory axillary breast tissue
Normal ductal system may extend into the SQ tissue of the chest wall or axillary fossa (axillary tail of Spence)
Not clincial,y identified as breast tissue
Issue with accessory axillary breast tissue
Prophylactic mastectomies reduce but do not eliminate the risk of breast cancer bc breast tissue int hese areas may not be removed—can be a site of malignancy
Where does most breast tissue drain
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
acquired nipple retraction is of more concern
may indicate invasive cancer or inflammatory nipple disease
Breast pain
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
Breast 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, and invasive carcinomas
Benign lesions are more common in premenopausal women
Malignant lesions are more common in post-menopausal women (corollary ^^)
Only 1/3 of cancer are detected as a palpable mass
Mammogram
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
Calcification
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 of the breast
Rare outside of the lactational 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 of inflammatory disorders of the breast
Acute mastitis Squamous metaplasia of lactiferous ducts Duct ectasia Fat necrosis Lymphocytic mastopathy (diabetic mastopathy) Granulomatous mastitis
Acute bacterial mastitis
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 in acute bacterial mastitis
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
Treat acute bacterial mastitis
antibiotics, continue expression of breast milk; rarely requires surgical drainage
Squamous metaplasia of lactiferous ducts
AKA: Subaerolar abscess, Periductal mastitis, or 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 squamous metaplasia of lactiferous ducts
90% of patients are smokers
May be due to relative vitamin A deficiency or toxic substance in tobacco smoke
Morphology squamous metaplasia of lactiferous ducts
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 secondary to anaerobic bacterial infection
Treatment squamous metaplasia of lactiferous ducts
Commonly recur following drainage due to remaining keratinizing epithelium
Curative if the duct & fistula tract are surgically removed
Duct ecstasia
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 duct ecstasia
Susceptible females are multiparous & in their 5-6th decade
No associated with smoking
Morphology duct ecstasia
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
treatment: 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
three groups based on subsequent risk to develop breast carcinoma
Non-proliferative breast changes
Not associated with an increased risk of breast cancer
Proliferative breast disease (without atypia)
Small increase in the risk of subsequent carcinoma in either breast; predictors of risk but unlikely to be true precursors of carcinoma
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 (fibrocartilage change)
Group of morphological fibrocystic changes
No associated risk of breast cancer (non-proliferative
Morphological changes non proliferative breast changes (fibrocartilage change)
cystic change, often with apocrine metaplasia
Fibrosis
Adenosis
Cysts non proliferative breast changes (fibrocartilage change)
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 non proliferative breast changes
Occurs due to release of secretory material into the stroma from (often) ruptured cysts
Contributes to palpable nodularity of the breast
Adenosis non proliferative breast changes
↑ # 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
Lactational adenoma
Palpable masses in pregnant or lactating women
Normal appearing breast tissue with exaggerated lactational changes
Proliferative breast disease without atypia
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 proliferative breast disease without atypia
↑ # 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 proliferative breast disease without atypia
↑ # 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 proliferative breast disease without atypia
Sclerosing adenosis, papilloma, and 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 proliferative breast disease without atypia
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 proliferative breast disease without atypia
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 proliferative breast disease with atypia
Partially fills duct (ductal carcinoma in situ DCIS fills the duct)
May have cribriform spaces
Monomorphic epithelial proliferation
Atypical lobar hyperplasia proliferative breast disease with atypia
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 proliferative breast disease with atypia (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)
Breast carcinoma
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 three major biological groups:
estrogen receptor positive, HER2-negative == 50-65%
estrogen receptor positive/negative, HER2-positive == 10-20%
estrogen receptor negative, HER2-negative == 10-20%
Epidemiology breast carcinoma
Rare in females < 25
Rapid ↑ in incidence after 30
Risk factors breast carcinoma
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 breast carcinoma
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 breast carcinoma
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 and 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
Often poorly differentiated
Have medullary features (syncytial growth pattern with pushing margins & lymphocytic response)
Biologically similar to ER -ve, HER2 -ve breast cancers identified as “basal-like” by gene expression profiling
and also serous ovarian carcinomas
BRCA2
BRCA2
Located on chromosome 13.12.3
More frequently associated with male breast cancer
Relatively poorly differentiated; more likely to be ER +ve
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
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-HER-
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
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
BRCA2 from the table
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, pharynx
TP53 fromt he 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
Adenocarcinoma
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
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
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
Diagnose ductal carcinoma in site
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 ductal carcinoma in situ
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 DCIA 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 paget disease of nipple
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(-), and HER2 (+)
If there is no palpable mass, then there is typically only DICS
Prognosis paget disease
Prognosis depends on features of the underlying carcinoma and not by the skin manifestations
Lobar CIS
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
Diagnose lobar CIS
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 lobar CIS
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
IS 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
Treat lobar cis
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
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
Treat er+ HER2- low proliferation
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+ Her- 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
Diagnose HER2+
Subtype is identified via protein over-expression or gene amplification assays
Detect HER2 with antibody or FISH
Pattern of spread HER2+
Metastasize early, when small → viscera and brain
Treat HER2+
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
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 er- HER2-
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 er- HER2-
Metastasize when small → viscera + brain
Treatment er- HER2-
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
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
Based on tubule formation, nuclear pleomorphism, and mitotic rate
Points for each are added together
Grade1
Tubular pattern
Small, round nuclei
Decreased proliferation rate
Grade II
May also show some tubule formation; solid clusters of infiltrating cells
Greater degrees of nuclear pleomorphic
Mitosis figures are present
Grade III
Invade as ragged nests or solid sheets of cells
Enlarged, irregular nuclei
Increase proliferation rate; areas of tumor necrosis
Er+, HER2- morphology
Variable differentiation (well-poor), with most of well differentiated tumors in this group "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
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
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 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 metasplastic
Local carcinoma histological
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
Medulllary carcinoma histology
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 carinoma histology
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 «_space;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
Papillary carcinoma morphology
Produces true papilla: Fronds of fibrovascular tissue lined by tumor cells
two special histologic types frequently overexpress HER2
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
retory Carcinoma
ER(-), HER2(-)
Mimics lactating breasts by forming dilated spaces filled with eosinophilic material
Inflammatory carcinoma
Extensive invasion and proliferation within lymphatic channels
Causes swelling that mimics non-neoplastic inflammatory lesions
Typically high grade with very poor prognosis
Do not belong to any specific molecular subtype
Male breast cancer
Similar risk factors as females
3-8% of cases are associated with Klinefelter syndrome (XXY) and ↓ testicular function
Diagnosed: 60-70 years old
GEnetics of male breast cancer
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(+)
Clincial male breast cancer
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
Treat male breast cancer
Mastectomy and axillary LN dissection
Breast cancer prognosis
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, lymph node, tumor size, inflammation, lymphovascular invasion
those related to the underlying biology of the cancer (tumor grade
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
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
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
Proliferative grade
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 and 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
two 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
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 fibroadenoma (benign)
Epithelium is hormonally responsive
↑ in size due to lactational changes in pregnancy
Complications: infarction, inflammation
Morphology fibroadenoma (benign)
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 fibroadenoma (benign)
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 =leaf like
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 phyllodes tumor
Chromosome 1q gains
HOXB13 overexpression = higher tumor grade & more aggressive clinical behavior
Morphology phyllodes
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 phyllodes
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
