1. What are the RF of breast cancer?
    • Age, lower age at menarche, higher age at first live birth (delay terminal differentiation of milk-producing luminal cells), FH, Atypical hyperplasia, Ethnicity (non-hispanic white highest rate, others higher death rate, younger age, more poorly diff, more ER negative, more P53), combined progestrone estrogen HRT, higher breast density, radiation, breast or endometrial cancer, US and Europe, higher estrogen exposure, diet (heavy alcohol increases. caffeine decrease risk), Obesity (<40 y decrease risk due to anovulation and reduced progestrone, postmenopause increase)
    • Breastfeeding reduces risk as well as exercise and tamoxifen
    • smoking has no effect
  2. What are hereditary breast cancers?
    • BRCA1 (17q, mcc, rare in sporadic, triple negative , poorly differentiated, p53 mutation, basal type)
    • BRCA2 (13q, both BRCA are Tumor suppressor, transcriptional regulation, repair of double-stranded DNA breaks)
    • P53 (17p, highest association with sporadic cancers, mc in triple negative)
    • CHEK2 (22q, common after radiation exposure, Cell cycle checkpoint kinase, recognition and repair of DNA damage, activates BRCA1 and p53 by phosphorylation)
  3. What is the major RF for sporadic breast cancers?
  4. How does hormone help cancer?
    Hormonal exposure increases the number of potential target cells by stimulating breast growth during puberty, menstrual cycles, and pregnancy. Exposure also drives cycles of proliferation that place cells at risk for DNA damage. Once premalignant or malignant cells are present, hormones can stimulate their growth, as well as the growth of normal epithelial and stromal cells that may aid and abet tumor development.Estrogen may also play a more direct role in carcinogenesis. Metabolites of estrogen can cause mutations or generate DNA-damaging free radicals.
  5. What does the most early lesions (such as atypical ductal hyperplasia and atypical lobular hyperplasia) show ?
    Increased expression of hormone receptors and abnormal regulation of proliferation, LOH
  6. Where in breast cancer does profound DNA instability in the form of aneuploidy observed ?
    high-grade DCIS and some invasive cancers
  7. What is the most likely cell of origin for breast cancer?
    • ER-expressing luminal cell
    • (ER-negative carcinomas may arise from ER-negative myoepithelial cells)
    • (all breast carcinomas arise from cells in the terminal duct lobular unit)
  8. What is the mc invasive breast lesion detected by mamo?
    DCIS (calcification)
  9. What is the morphology of Invasive Lobular Carcinoma?
    • 3/4 mass, 1/4 diffuse infiltrate
    • Not more bilateral than ductal
    • The histologic hallmark is the presence of dyscohesive infiltrating tumor cells. Tubule formation is absent. The cytologic appearance is identical to the cells of atypical lobular hyperplasia and LCIS. Signet-ring cells containing an intracytoplasmic mucin droplet are common. 
  10. What is unique to lobular invasive cancer?
    Lobular carcinomas have a different pattern of metastasis than other breast cancers. Metastasis tends to occur to the peritoneum and retroperitoneum, the leptomeninges (carcinoma meningitis), the gastrointestinal tract, and the ovaries and uterus. 
  11. What is the difference between DCIS and LCIS?
    LCIS more bilateral, ER and PR+, HER2neu negative, in the young, more bilateral and more increase in risk other types of cancer as well as contralateral cancers. Also lost E-cadherin
  12. What is the morphology of medullary breast cancers?
    • These tumors produce little desmoplasia and are distinctly more yielding on palpation and cutting than typical breast carcinomas.
    • The tumor is soft, fleshy and well circumscribed.
    • Histologically, the carcinoma is characterized by (1) solid, syncytium-like sheets of large cells with vesicular, pleomorphic nuclei, and prominent nucleoli, which compose more than 75% of the tumor mass; (2) frequent mitotic figures; (3) a moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumor; and (4) a pushing (noninfiltrative) border. All medullary carcinomas are poorly differentiated. DCIS is minimal or absent.
  13. What are the molecular features of medullary cancers?
    • Medullary carcinomas have a slightly better prognosis than do NST carcinomas, despite the almost universal presence of poor prognostic factors.
    • HER2/neu negative
    • Lymph node metastases are rare
    • The syncytial growth pattern and pushing borders may stem from the overexpression of adhesion molecules, such as intercellular cell adhesion molecule and E-cadherin, which could potentially limit metastatic potential.
    • Medullary carcinomas have a basal-like gene expression profile.
    • Among cancers arising in BRCA1 carriers, many have a subset of medullary features. hypermethylation of the BRCA1 promoter is observed in 67% of medullary carcinomas.
  14. What are the features of mucinous (colloid) cancers?
    • Elderly women
    • Appearance of pale gray-blue gelatin.
    • Islands of cells within large lakes of mucin
  15. Describe the features of tubular carcinomas
    • 10% of <1 cm cancers
    • frequently bilateral
    • consist of tubules (w/o myoepithelial layer--> difference from sclerosing lesion) 
    • Tumor in direct contact with stroma
    • Apocrine snouts
    • Calcification
    • DCIS or LCIS
  16. What are the subtypes of DCIS?
    comedocarcinoma, solid, cribriform, papillary, and micropapillary
  17. What is the morphology of comedocarcinoma?
    Image Upload 1Pleomorphic cells with “high-grade” hyperchromatic nuclei and areas of central necrosis. The necrotic cell membranes commonly calcify and are detected on mammography as clusters or linear and branching microcalcifications. Periductal concentric fibrosis and chronic inflammation are common.
  18. What is the morphology of noncomedo DCIS?
    Noncomedo DCIS consists of a monomorphic population of cells with nuclear grades ranging from low to high.

    • In cribriform DCIS, intraepithelial spaces are evenly distributed and regular in shape (cookie cutter–like).
    • Solid DCIS completely fills the involved spaces.
    • Papillary DCIS grows into spaces along fibrovascular cores that typically lack the normal myoepithelial cell layer.
    • Micropapillary (if cancer poor px) DCIS is recognized by bulbous protrusions without a fibrovascular core, often arranged in complex intraductal patterns . Calcifications form on intraluminal secretions.
  19. What are the features of paget disease?
    • Unilateral erythematous eruption with a scale crust and pruritus
    • The tumor cells disrupt the normal epithelial barrier (but not BM), allowing extracellular fluid to seep out onto the nipple surface
    • if palpable mass is present, invasive cancer is highly likely (otherwise only DCIS)
  20. What is DCIS with microinvasion? 
    It is diagnosed when there is an area of invasion through the basement membrane into stroma measuring no more than 0.1 cm. Microinvasion is most commonly seen in association with comedocarcinoma. If only one or a few foci of microinvasion are present, the prognosis is very similar to DCIS.
  21. What is the feature of cancer that arise in DCIS?
    The majority of these cancers are in the same quadrant and have a similar grade and expression pattern of ER and HER2/neu as the DCIS.
  22. How can we decrease the risk of recurrence of DCIS after treatment?
    Radiation, wide excision> 1 cm, Tamoxifen
  23. What are the features of LCIS?
    • Incidental finding
    • Dyscohesive cells
    • Loss of Cadherin
    • Monomorphic population of small rounded cells
    • Mucin positive signet ring cells
    • Always PR ER+, HER2/neu negative
    • Tx with bilateral mastectomy or tamoxifen
    • Image Upload 2
  24. What are the six major prognostic indicators for breast cancer?
    • 1. Invasive versus in situ
    • 2. Distant metastasis
    • 3. LN (Macro >0.2 cm)
    • 4. Tumor size 
    • 5. Locally advanced disease (muscle, skin)
    • 6. Inflammatory cancer
  25. What are the minor prognostic indicator for breast cancer?
    • 1. Subtype (NST poorest)
    • 2. grade
    • 3. ER, PR (if positive higher response to hormone, lower to chemo therapy)
    • 4. HER2/neu (poorer, but better response to lapatinib and trastuzumab)
    • 5. Lymphovascular invasion
    • 6. mitosis rate (poorer, but better respond to chemo)
    • 7. DNA content (aneuploidy poorer)
    • 8.Response to neoadjuvant
    • 9. gene expression
  26. What is the mc CIS in breast?
  27. What is the mc cancer in breast?
    No Special Type (NST; Invasive Ductal Carcinoma)
  28. What is the morphology of NST cancer?
    • On gross examination, most tumors are firm to hard and have an irregular border. When cut or scraped, they typically produce a characteristic grating sound (similar to cutting a water chestnut) due to foci or streaks of chalky-white elastotic stroma and occasional small foci of calcification.
    • Well-differentiated carcinomas show prominent tubule formation, small round nuclei, and rare mitotic figures . Moderately differentiated carcinomas may have tubules, but solid clusters or single infiltrating cells are also present. These tumors have a greater degree of nuclear pleomorphism and contain mitotic figures. Poorly differentiated carcinomas often invade as ragged nests or solid sheets of cells with enlarged irregular nuclei. A high proliferation rate and areas of tumor necrosis are common.
    • Image Upload 3
  29. What are five subtypes of NST cancer based on Gene expression profiling?
    • luminal A (mc, ER positive and HER2/neu negative., posmenopausal, slow growing, moderate to well- diff, good response to hormone no response to chemotherapy)
    • luminal B (triple positive, among ER positive cancers more likely to respond to chemo and more likely to have LN)
    • Normal (well-differentiated ER-positive, HER2/neu-negative cancers characterized by the similarity of their gene expression pattern to normal tissue)
    • Basal-like (triple negative, markers of myoepithelial or stem cell such cytokeratin, keratin, p63, associated with medullary carcinomas, metaplastic carcinomas (e.g., spindle cell carcinomas or matrix-producing carcinomas), and carcinomas with a central fibrotic focus, BRCA1, poorer prognosis, and visceral and brain metastasis)
    • HER2 positive (amplification of the segment of DNA on 17q, ER negative, poor differentiated, high brain metastasis)
  30. What is the action of trastuzumab and lapatinib
    • Trastuzumab (Herceptin) is a humanized monoclonal antibody specific to HER2/neu. The combination of trastuzumab and chemotherapy is highly effective in treating carcinomas that overexpress HER2/neu. Trastuzumab does not cross the blood-brain barrier
    • LApatinib is a dual tyrosine kinase inhibitor lapatinib, that targets both EGFR and HER2/neu
  31. What is the morphology of male gynecomastia?
    An increase in dense collagenous connective tissue and marked micropapillary epithelial hyperplasia of the duct lining. Cells are regular. Lobule formation is rare. Periductal fibrosis is present
  32. What are the features of male breast cancer?
    • RF similar to female +Kleinfelter and BRCA2 (less commonly BRCA1)
    • Papillary more common, lobular less common, ER positive more common
    • Subareolar mass and discharge
    • Higher stage at diagnosis
    • Prognosis is similar to female
  33. Is gynecomastia a RF for breast cancer?
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