Pathology of the Breast II PDF

Pathology of the Breast II Breast Disorders Estimated New Cancer Cases in US 1.8 million new cases of general cancer 30% were breast cancer 15% of deaths were from breast cancer Breast Carcinoma Most common non-skin cancer in women 2nd most deadly cancer in women (lung) Usually arises from terminal...

Pathology of the Breast II Breast Disorders Estimated New Cancer Cases in US 1.8 million new cases of general cancer 30% were breast cancer 15% of deaths were from breast cancer Breast Carcinoma Most common non-skin cancer in women 2nd most deadly cancer in women (lung) Usually arises from terminal duct lobular unit Can occur in men (rare) Mostly effects older postmenopausal women o Rare before age 25 o Increases after age 30 Predisposing Factors Positive family history History of breast cancer in one breast Early menarche and late menopause (increased estrogen exposure) Diet high in animal fat Proliferative fibrocystic disease with atypical epithelial hyperplasia Obesity (fat cells convert testosterone to estrogen) First pregnancy after 30 years of age Breast Carcinoma Risk Factors High Risk (RR > 4.0) Intermediate Risk (RR = 2.1 - 4.0) Advanced age (>65 yrs) Atypical hyperplasia (biopsy proven) Certain inherited genetic mutations (BRCA1, BRCA2, TP53, PALB2) Ductal or lobular carcinoma in situ (DCIS/LCIS) Family hx of early ovarian cancer (age < 50 years) Multiple first-degree relatives with breast cancer Ionizing radiation exposure before age 30 Personal history of early breast cancer (age < 40) ***RR = Relative risk High endogenous estrogen or testosterone level (postmenopausal age) Late first pregnancy (age >35) Dense breasts ( > 50%, compared with 11-25% mammographically) One first-degree relative with breast cancer Ductal carcinoma in situ Certain inherited genetic mutations (eg. CHEK2, PTEN) High dose radiation to chest (Hodgkin lymphoma treatment) Low Risk (RR= 1.1 - 2) Reduced Risk (RR < 1.0) Prognosis Axillary lymph node metastases FIRST SITE of metastasis for breast cancer Most important prognostic factor for invasive cancer Detected by biopsy Sentinel node biopsy is often performed Metastasis Cancer spreads in body: Tissue Lymph system Blood Axillary lymph nodes and bones are first sites of breast cancer metastasis Alcohol consumption First full-term pregnancy (>30 years) Early menarche (age < 11 years) Ashkenazi Jewish heritage Weight gain Nulliparity Hx of breast or other cancers Long term hormone replacement therapy w estrogen, progesterone Treatment Surgery Radiation therapy Chemotherapy Hormone therapy (Aromatase inhibitor, tamoxifen) Targeted therapy (Monoclonal antibodies) Immunotherapy (Immune checkpoint inhibitors) Asian, Hispanic, or Pacific Islander race Breastfeeding = protective Age < 20 at first pregnancy = protective Tamoxifen (estrogen inhibitor) Prior risk-reduction breast surgery History of oophorectomy Exercise/active lifestyle Low bone mineral density Detection Palpable breast mass Mammography (89.3% accuracy) o Detects micro-calcifications o Occur in malignant lesions o Also seen in fat necrosis and sclerosing adenosis Risk of a false result Breast Carcinoma Major Types Ductal versus lobular o Ductal = resemble duct cells o Lobular = resemble lobules o Both types from TDLU In situ versus invasive: In situ is limited by basement membrane 95% are adenocarcinomas Arise from epithelial cells of ducts/lobules At diagnosis >70% have invaded the basement membrane Ductal carcinoma in situ (DCIS) progresses to invasive breast cancer Normal Breast Epithelial and stromal components Two layers of epithelial cells resting on basement membrane Ductal/Lobular cell layer Myoepithelial cell layer No atypical cytology or architecture No invasion No malignant potential Ductal Carcinoma in Situ (DCIS) Malignant growth of epithelial cells of TDLU Fills ductal lumen Cell proliferation in duct without basement membrane No mass Detected by mammography Forms microcalcifications (LCIS does not) Many subtypes based on histology Histology: Ductal epithelium layer with architectural proliferation and disorganization Comedo type: o High-grade cells o Central necrosis o Large tumor cells o Pleomorphic nuclei o Calcification Carcinoma in situ Proliferation of epithelium, WITHOUT stroma component Epithelial layer shows malignant architecture/cytology Myoepithelial layer and basement membrane maintained May progress to invasive carcinoma Clinically occult – may be detected by presence of microcalcifications and/or soft tissue densities on screening Types: o DCIS Ductal Carcinoma In Situ o Paget disease (DCIS + nipple skin) o LCIS Lobular carcinoma In Situ Paget Disease Extension of DCIS to nipple skin May cause bloody nipple discharge Paget cells are seen on biopsy Palpable mass in >50% cases ~50% have mass on mammogram Usually, invasive carcinoma found Lobular Carcinoma in Situ (LCIS) Proliferation of cells in ducts/lobules Limited by intact basement membrane Discohesive growth: loose intercellular connections o Loss of adhesion protein E-cadherin o Associated with gain of tumor cell motility and invasiveness Round cells clumped together Lobulocentric proliferation of small, monotonous, loosely cohesive cells that fill or distend lobular unit o DCIS → E-Cadherin + o LCIS → E-cadherin – No mass No calcification An incidental finding on biopsy Often bilateral May be multi-focal Risk factor for invasive carcinoma in both breasts Non-invasive lesion Management: surveillance +/- chemo prevention o Common drug: Tamoxifen (SERM) o Blocks endogenous estrogen effects SERM= Selective Estrogen Receptor Modifier Invasive Breast Carcinoma Late-stage breast cancer with ulceration and axillary lymph node metastasis Radiologic finding of a mass with infiltrating/spiculated border Invasive Ductal Carcinoma Most common invasive carcinoma (>80%) Biopsy: duct cells with stroma Common in patients > 65 years Rock-hard immobile mass Most commonly in outer quadrant of breast (more breast tissue) Variable Gross Pathologic Features: o Firm, solid mass (white) with infiltrating borders o Centrally necrotic mass with hemorrhage and expansile borders Histologic Subtypes: o Lobular carcinoma o Medullary carcinoma (common among BRCA1 gene carriers) o Inflammatory carcinoma o Mucinous carcinoma o Tubular carcinoma o Papillary carcinoma Invasive Lobular Carcinoma 10% of ALL breast carcinomas Incidence decreasing in US Often NOT well seen on mammograms Often bilateral with multiple lesions Cells grow in “single file” Lack E-cadherin adhesion protein expression (can’t stick together in clumps) Most harbor CDH1 mutation, resulting in loss of E-cadherin expression Inflammatory Carcinoma Carcinoma in dermal lymphatics Presents as inflamed, swollen breast due to blockage of lymphatics o Orange peel appearance o Mimics infection Aggressive, with 5-year disease-free survival Poor Prognosis since tumor is already in lymph Predictive Markers Important for prognosis and therapy: o Estrogen receptor positivity (ER+) o Progesterone receptor positivity (PR+) o Human epidermal growth factor receptor-2 (HER2) ER+ and PR+ tumors: respond to anti-estrogenic agents Tamoxifen (SERM) HER2+ tumors: respond to Trastuzumab (anti-HER2 receptor Ab) Triple negative tumors (ER-, PR-, HER2-) o Highly aggressive o Poor pharmacological prognosis o More common in women under 40 o African-American women: highest risk Familial Breast Cancer 10% of breast cancers BRCA1 and BRCA2 gene mutation: o Genes code for DNA repair proteins o Both gene mutations associated with breast cancer, bilateral o Cause of ~85% of single-gene familial cases o More common among Ashkenazi Jews o Germline gene mutation o Autosomal dominant o Incomplete penetrance: Not all individuals with disease mutation develop the disease o Also associated with other malignancies § BRCA1: Ovarian cancer § BRCA2: Male breast cancer and pancreatic cancer Molecular Risk factors Familial Breast Cancer (10%) Sporadic Breast Cancer (90%) Known Oncogenic mutations Hormonal mutations BRCA1 and BRCA2 (common) o Estrogen or Estrogen receptor TP53 o HER2 ATM Environmental exposures CHEK2 o Diethylstilbestrol (DES) PTEN o Radiation CDH1 Late menopause (>55 years) STK11 PALB2 Male Breast Cancer Incidence 1% compared to women Common type: Invasive ductal carcinoma Usually occurs 60 to 70 age: presents as subareolar mass +/- discharge Most breast tissue in males are near nipple Key Associations: o Klinefelter syndrome - extra X (3 to 8% cases) o BRCA2 gene mutations (4 to 14% cases)