Lecture 9: The Breast Flashcards
How does the composition of breast change with aging and how is this related to imaging and ease of diagnosis?
- Young women = ↑ fibrous interlobular stroma which appears radiodense or white on imaging; makes diagnosing tougher.
- Older women have ↑ adipose tissue, which appears more radiolucent and helps with the interpretation of images
What 2 lesions of the breast arise in the intralobular stroma?
- Fibroadenoma
- Phyllodes tumor
What 4 lesions can arise in the interlobular stroma of the breast?
- Fat necrosis
- Lipoma
- Fibromatosis
- Sarcoma
What 4 lesions can arise in the large ducts of the breast?
- Duct ectasia
- Squamous metaplasia of lactiferous ducts
- Large duct papilloma
- Paget disease
What are milk line remnants and how do they most commonly come to attention clinically?
- Supernumerary nipples or breast, anywhere from axilla –> perineum
- Present as painful PRE-menstrual enlargements
What is the clinical significance of accessory axillary breast tissue; managed how clinically?
- Potential site for malignancy or other lesions
- Prophylactic mastectomies ↓ risk, but do NOT completely eliminate
Why is acquired nipple inversion of greater concern than congenital?
May indicate presence of an invasive cancer or an inflammatory nipple disease
Palpable masses of the breast are most commonly due to what 3 etiologies?
- Cysts
- Fibroadenomas
- Invasive carcinoma
In what setting is nipple discharge most worrisome?
When spontaneous and unilateral; especially >60 y/o
What is the most common cause of bloody or serous discharge from th nipple?
Large duct papilloma
What characteristics of a density detected on mammogram is associated with benign vs. malignant lesions?
- Benign = rounded densities
- Malignant = irregular masses
How is DCIS most commonly seen on mammograms?
Calcifications –> small, irregular, numerous and clustered
When does acute mastitis typically occur and what are the signs/sx’s?
- Typically during 1st month of breastfeeding
- Breast is erythematous and painful, and fever is common
Squamous metaplsia of lactiferous ducts (aka recurrent subareolar abscess, periductal mastitis, and Zuska) disease commonly presents with what signs and sx’s?
- Painful erythematous subareolar mass
- Inverted nipple
Risk factors for squamous metaplsia of lactiferous ducts (aka recurrent subareolar abscess, periductal mastitis, and Zuska) include?
- Smoking
- Vitamin A deficiency
What are the key morphological features of squamous metaplsia of lactiferous ducts (aka recurrent subareolar abscess, periductal mastitis, and Zuska)?
- Keratinizing squamous metaplasia of nipple ducts
- Intense chronic granulomatous inflammation
What are the distinguishing features, signs and sx’s of duct ectasia?
- Palpable periareolar mass w/ thick, white nipple secretions and occasionally skin retractionb
- NO pain or erythema!
Duct ectasia most commonly occurs in which age group and what is a risk factor?
- Women 40-60 y/o
- Usually multiparous (birthed more than one child)
In duct ectasia the ectatic ducts are filled with inspissated secretions and numerous what?
Lipid-laden macrophages
What is the common clinical presentation of fat necrosis of the breast and what is a risk factor?
- Painless, palpable mass + skin thickening or retraction
- May also have mammographic densities or calcifications
- 50% of women have hx of breast trauma or prior surgery
How does lymphocytic mastopathy (aka sclerosing lymphocytic lobulitis) most commonly present; associated with what underlying disorders?
- Single or multiple HARD palpable masses or mammographic densities
- Most common in women w/ T1DM or autoimmune thyroid disease
- Autoimmune basis
What are the 3 principal morphological changes associated with nonproliferative breast changes (fibrocystic change)?
- Cysts
- Fibrosis
- Adenosis
How can a FNA of a cyst associated with nonproliferative breast changes help confirm the diagnosis?
Dissapearance of the mass after FNA of its contents
The nonproliferative breast change, adenosis, is defined as what; and is a normal feature seen in which women?
- ↑ in the number of acini per lobule
- Normal feature of pregnancy
The acini of adenosis seen with nonproliferative breast change may show what histological change that is thought to be the earliest recognizable precursor of low-grade cancer?
Nuclear atypia (“flat epithelial atypia“)
Proliferative breast disease without atypia is characterized by what; what is the association with carcinoma?
- Benign lesions –> proliferation of epithelial cells w/o atypia and are
- Associated w/ small ↑ in risk for carcinoma
Which lesions of proliferative breast disease without atypia has an irregular shape and can closely mimic invasive carcinoma mammographically, grossly, and histologically?
Complex sclerosis lesion –> radial sclerosis lesion (aka radial scar)
What is the clinical significance of papilloma lesions as part of proliferative breast disease without atypia?
80% of large papillomas produce a nipple discharge can be bloody or serous
What are some of the underlying risk factors for gynecomastia?
- Cirrhosis of liver –> ↑ estrogen
- Drugs –> alcohol, marijuana, heroin, antiretroviral’s, and anabolic steroids
What is the seen microscopically in gynecomastia?
↑ in dense collagenous CT + epithelial hyperplasia of duct lining w/ tapering micropapillae (NO lobule formation)
Is gynecomastia associated with an increased risk for cancer?
Yes, small ↑ risk due to being proliferative breast disease without atypia
What is atypical breast disease with atypia and what are the 2 morphologic forms?
- Clonal proliferation having some, but not all, of the histo. features required for dx of CIS
- 2 forms = atypical ductal hyperplasia + atypical lobular hyperplasia
Which genetic feature of atypical lobular hyperplasia is shared with lobular carcinoma in situ?
Loss of E-cadherin
What is seen on biopsy of fat necrosis in the breast in both acute and chronic settings?
- Acute = liquefactive fat necrosis w/ neutrophils and macrophages
- Chronic = giant cells + calcifications and hemosiderin
Which in situ breast lesion is rarely palpable and almost always detected as calcifications on by mammography?
Ductal carcinoma in situ (DCIS)
Why is breast cancer in African American women associated with a higher overall mortality rate?
More likely to have biologically aggressive cancers –> ER-negative and a high nuclear grade
What is the average age of diagnosis for breast cancer in white women, hispanics and blacks?
- White women = 61 y/o
- Hispanics = 56 y/o
- Blacks = 46 y/o
BRCA1 and BRCA2 mutations are prevalent in which ethnicity?
Ashkenazi Jews
What is the most common risk factor shared between breast and endometrial carcinoma which ↑ risk for carcinoma of the contralateral breast?
Prolonged estrogenic stimulation
Based on the expression of estrogen receptors and HER2, what is the most common subtype of breast cancer?
Estrogen receptor (+) and HER2 (-)
Which genetic mutation associated with hereditary breast cancer is most frequenty assoc. w/ male breast cancer?
BRCA2
BRCA1 associated breast cancers commonly have what kind of differentiation and growth features?
- Poorly differentiated w/ “medullary features”
- Syncytial growth pattern w/ pushing margins and a lymphocytic response
BRCA1-associated cancers are biologically similar to breast cancers with which estrogen receptor and HER2 expression; are identified as what?
- ER (-) and HER2 (-)
- “Basal-like”
What is the differentiation of BRCA2-associated breast cancers like and they are more likely to have what ER expression?
Poorly differentiated, most often are ER (+)
Which genetic mutation is associated with breast (female and male), ovarian, prostate, pancreas, stomach, gallbladder, bile duct, and pharynx cancer + melanoma?
BRCA2
Li-Fraumeni syndrome is due to genetic mutation in what and is associated with what cancers?
- TP53
- Breast + sarcoma + leukemia + brain tumors + adrenocortical carcinoma
BRCA1 and BRCA2 are part of a large complex of proteins with what fuctions?
Repair dsDNA breaks through homologous recombination
Describe the pathway of breast cancer development starting with a germline BRCA2 mutations; which precursor lesions develop and what type of breast cancer?
- Germline BRCA2 –> Flat epithelial atypia
- Activating PIK3CA mutation —> Aytpical ductal hyperlasia
- DCIS —> ER (+) - HER2(-) “luminal” breast cancer
Flat epithelial atypia and atypical ductal hyperplasia often show which genetic mutations associated with developing ER(+) breast cancer?
Germline BRCA2 and activating PIK3CA
Describe the pathway to breast cancer including precursor lesions and mutations in pt’s with germline TP53 mutations?
- TP53 + HER2 amplification –> Atypical apocrine adenosis
- DCIS –> HER2 (+) breast cancer
What is the most common subtype of breast cancer in pt’s with Li-Fraumeni Syndrome?
HER2 positive
What is the precursor lesion of HER2 positive breast cancers?
Atypical apocrine adenosis —> DCIS
What is the most common subtype of breast cancer arising in patients with germline BRCA1 mutations?
ER (-) and HER2 (-) = “Basal-like”
Sporadic tumors that are ER(-) HER2(-) have which genetic mutations?
- Loss-of-function in TP53
- May have epigenetic silencing of BRCA1
What are the best predictors of local recurrence and progression to invasion for DCIS?
Nuclear grade and necrosis
What are the 2 features which define comedo DCIS?
1) Tumors cells with pleomorphic, high-grade nuclei
2) Areas of central necrosis
What are the morphological features of noncomedo DCIS, including cribiform and micropapillary DCIS?
- Cribiform may have rounded (cookie cutter-like) spaces within ducts
- Micropapillary has bulbous protrusions without a fibrovascular core, often arranged in complex intraductal patterns
*Pic on left = cribiform DCIS and on right = micropapillary DCIS
What is seen on mammography with comedo DCIS?
Clustered or linear and branching areas of calcification
Which ER and HER2 expression is most common of the carcinoma underlying Paget disease of the breast?
Poorly differentiated, ER (-) and HER2 (+)
If patient presents with Paget disease of breast but does not have a palpable mass then what do they have?
DCIS
What are the 3 major risk factors for recurrence and progression of DCIS?
1) High nuclear grade and necrosis
2) Extent of disease
3) Positive surgical margins
What is the proliferation of cells like in LCIS and how is it discovered clinically?
- Discohesive proliferation due loss of E-cadherin
- ALWAYS an incidental finding on biopsy, there are NO calcifications or mammographic findings
- As a result, its incidence did not ↑ after introduction of mammograms
Between DCIS and LCIS, which is found bilateral more often?
- LCIS is bilateral in 20-40% of cases****
- DCIS is bilateral in 10-20%
Which genetic mutation is associated with LCIS?
CDH1 leading to loss of E-cadherin
What is the typical morphology and characteristic cell types found with LCIS?
- Uniform population of cells w/ oval or round nucloli involving ducts and lobules
- Mucin (+) signet-ring cells are common
- Pagetoid spread is common, but LCIS does NOT involve nipple skin
LCIS is associated with what type of ER and HER2 expression?
- Almost always express ER (+) and PR (+)
- HER2 is NOT observed
LCIS is a risk factor for what?
Invasive lobular carcinoma in either breast!
ER-positive, HER2-negative, high proliferation breast cancer is the most common type of carcinoma associated with what germline mutation?
Germline BRCA2
ER-positive, HER2-negative, low proliferation breast cancer is most common type seen in which patients?
- Older women and men
- Most common type detected by mammographic screening
What is the recurrence and metastatic behavior of ER-positive, HER2-negative, low-proliferation breast cancers like?
- Lowest recurrence rate, late, >10 years
- Metastasis late —> bone and long survival w/ metastasis is possible
How does ER-positive, HER2-negative, low-proliferation respond to chemotherapy vs. high-proliferation types?
- Low-proliferation = poor response to chemo, but respond well to hormonal tx
- High-proliferation = has a higher % of complete response to chemo
ER-positive, HER2-negative, high-proliferation will have increased nuclear staining for what?
Ki67
What are the typical patient groups affected by HER2-positive breast cancers?
- Young women
- Non-white women
- TP53 mutation carriers = Li-Fraumeni
What is the metastasis and behavior of HER2-positive breast cancer like?
Can metastasize when small and early, often to viscera and brain, but also bone
Why have some HER2-positive cancers become associated with a better outcome?
- >1/3 respond completely to chemo agents designed to block HER2 (Herceptin)
- Cancers that respond have excellent prognosis
ER-negative, HER2-negative (“basal-like) breast cancers are most commonly seen in whom?
- Young premenopausal women
- African Americans
- Hispanics
ER-negative, HER2-negative (“basal-like) breast cancer shows a number of genetic similarities with what other carcinoma?
Serous ovarian carcinoma; associated w/ BRCA1
What are the recurrences and metastatic behavior of ER-negative, HER2-negative (“basal-like) like?
- Often metastastize when small and early –> viscera, brain and bone
- Recurrences is common and generally within 5 years
What is the response rate to chemo for ER-negative, HER2-negative (“basal-like) breast cancers?
30% completely respond to chemo
What is the hitological hallmark of lobular carcinoma?
Discohesive infiltrating tumors cells, often w/ signet-ring cells containing intracytoplasmic mucin
What is the characteristic pattern of metastatic spread with lobular carcinoma?
- Peritoneum and retroperitoneum
- Leptomeninges (carcinomatous meningitis)
- GI tract
- Ovaries (Kruckenberg) and Uterus
Which genetic mutations is observed in a majority of medullary carcinoma?
Hypermethylation of BRCA1 leading to ↓ regulation
What is the prognosis of medullary carcinoma and what histological finding is associated with higher survival rates?
- Good prognosis
- Presence of lymphocyte infiltrates in tumor assoc. with higher survival and greater response to chemo
Which special type of invasive breast cancer is associated with tumor cells arranged in clusters and small islands of cell within large lakes of mucin?
Mucinous (colloid) carcinoma
ER-negative, HER-negative tumors can have many histologic appearances, but which is most common?
Medullary carcinoma
Inflammatory carcinoma is more often seen in whom; what is prognosis; what is characteristic clinical finding?
- African Americans
- Very poor prognosis - 3 year survival of 3-10%
- Peau d’orange due to blockage of lymphatics by tumor
- Tumor extensively invades and proliferates WITHIN lymphatics
Tubular carcinoma is somtimes mistaken for what lesion; what immunohistochemical feature can help differentiate between the 2?
- Sometimes mistaken for benign sclerosing lesion, like a radial sclerosing lesion
- Immunostain for ER can help since almost all special subtypes of breast cancer are ER (+)
What is the most important prognostic factor for invasive breast carcinoma in the absence of distant metastases?
Axillary lymph node status
How is ER(+) and PR(+) related to therapeutic response?
- Majority respond to hormonal therapy
- Less likely to respond if only (+) for ER or PR
Breast cancers that are ER (-) or PR (-) respond best to what type of therapy?
Chemotherapy
Who is most often affected by Fibroadenomas and how do they present based on age?
- Most common BENIGN tumor of female breast; most occur 20-30 y/o
- Frequently multiple and bilateral palpable mass (younger women)
- Older women more likely to have radiographic density or clustered calcifications
Which benign tumor of the breast may fluctuate in size during pregnancy and menstrual periods; and is associated with women receiving cyclosporin A after renal transplants?
Fibroadenoma
Fibroadenomas are catergorized as what type of proliferative lesions of the breast and how is this related to risk of cancer?
- Proliferative changes WITHOUT atypia
- Confer a mild ↑ risk for cancer
How does the age of presentation for phyllodes tumor differ from that of fibroadenomas?
Most present in 50’s, which is 10 years later than fibroadenomas
Overexpression of which transcription factor is associated with higher tumor grade and more aggressive behavior when assoc. w/ phyllodes tumor?
HOXB13
How are phyllodes tumors distinguished from fibroadenomas based on histology?
- Bulbous protrusions look like a leaf
- Higher cellularity + mitotic rate
- Nuclear pleomorphism
- Stromal overgrowth + Infiltrative borders
How likely is lymphatic spread of a phyllodes tumor based on grade and what is a special clinical consideration?
- Regardless of grade, lymphatic spread = RARE
- Axillary LN dissection = contraindicated
Which benign tumor of the breast is unusual in that it is equally as common in both women and men?
Myofibroblastoma
Who do most sporadic angiosarcomas of the breast arise in, what is their grade and prognosis?
- Young women (mean age = 35 y/o)
- High grade and poor prognosis
What are risk factors acquired angiosarcomas of the breast and when do they arise?
- Secondary to radiation therapy
or
- Edema
- Most often arising 5-10 years after tx
