Breast Carcinoma Dr. Ashraf A. Fatah Assistant professor Faculty of medicine Majma’ah University

Breast carcinoma- 0BJECTIVES The epidemiology & Impact. The etiology & morphology. Discuss the laboratory diagnosis. (Robbins Basic Pathology, 8th ed. P. 743- 750).

What is Breast Carcinoma? Breast ca. is groups of heterogeneous disease with a wide array of histological appearances, clinical characteristic , and prognosis. Breast ca. is most prevalent “non-skin” malignancy, primarily affects women but also can affect men(1%) (F>>M). Breast ca. is the second cause of cancer related death among women . WHO 2003- >1 million diagnosed worldwide yearly 1 out of 9 women who live to age 90- USA. Underlying Genetic& enviromental predisposing factors.

Anatomic origins of common breast lesions

Epidemiology- incidence Incidence of old female become to increase due to: Awareness ___________ II.Mammography Small DCIS lesion. ________________ III. Apply national Screening program for early detection

Epidemiology- Risks (BCRAT) Gender (M= 1% risk) Age (peak75-80,46y) Age menarche (early menarche & late menopause) Age at First Live Birth-1st pregnancy20 Late menopause.. Family hx:1st degree Genetic abn. BRCA1 and BRCA2 mutations Radiation therapy Atom bomb exposure Race/Ethnicity Atypical Hyperplasia& cancer in other breast. Breast density Obesity in young <40–decrease risk Estrogen exposure -replacement . Alcohol consumptio Tobacco,smoking& diet- still not clear

Epidemiology- Risks (BCRAT) Factors associate with decrease risk: Obesity:<40y female- anovulatory cycles. Coffee (caffeine)-consumption. Breast Lactation suppresses ovulation. Exercise- small protective effects. Reducing endogenous estrogens by drug or oophorectomy Major risk factors for the development of breast cancer are hormonal and genetic Conclusion: what is the major risk factors?

The impact of breast cancer Long-term side effects of treatment Emotional effects&Your relationships Changes to your body- esp. young ladies. Diet and physical activity Practical issues: work, money or insurance. Fund-burden for diagnosis, molecular workup and Researches

Breast carcinoma-0BJECTIVES Discuss the epidemiology & Impact of breast cancer. Define the etiology+morphology. Discuss the laboratory diagnosis. (Robbins Basic Pathology, 8th ed. P. 743- 750).

Breast carcinoma- Etiology Based on risks factors the etiology divided into two categories; 1. Hereditary breast cancer- 12% of cancer, Genetic mutation affect 1st degree relatives in BRCA1, BRCA2, P53, CHEK2 genes. 2. Sporadic breast cancer duet to Hormonal exposure- gender, age at menarche, menopause, reproductive hx, breastfeeding, exogenous estrogens(play a direct role in carcinogenesis)

BRCA1/BRCA2,P53 &CHEK2 tumor suppressor GENES BRCA1 (chr17): single gene hereditary cancer risk 52%= 2% of all breast ca.-poor differentiated with medullary feature, ER negative BRCA2(chr13) : single gene hereditary cancer risk 32%= 1% of all breast ca. poor differentiated, ER positive. P53 (chr17): single gene hereditary cancer risk 3%= <1% of all breast ca CHEK2(chr22)single gene hereditary ca= 5%

BRCA1/BRCA2, P53 tumor suppressor GENES These Genes mutations are associated : increased risk for Male breast ca(BRCA2) Pancreatic, prostate, ovarian ca. The majority of sporadic cancers occur in postmenopausal ,hormonal exposure and are ER positive. Metabolites of estrogen can cause mutations or generate DNA-damaging free radicals in cell.

BREAST CARCINOMA-MORPHOLOGY

The normal breast depend on a complex interplay between luminal cells, myoepithelial cells, stroma. A. Breast Duct syst. B. Lobules C. Nipple D. Fat + CT E. Vessels (Lymphatic blood) F. Attached to Chest Muscle & Ribs A. Cells lining duct B. Basement membrane C. Open central duct

Morphologic changes displayed from left to right according to the risk for subsequent invasive ca.

CLASSIFICATION OF BREAST CARCINOMA It is not one disease, but many, heterogeneous group. Greater>95% are adenocarcinoma from ducts and lobules- classified in to: In-situ carcinoma (15-30%)- increase with Mammography-(calcification+ periductal fibrosis ) (lobular & Ductal) Invasive carcinoma (infiltrating)(70-85%) (lobular & Ductal)

CLASSIFICATION OF BREAST CARCINOMA Distribution of Histologic Types of Breast Cancer Percentages Types 15- 30% Carcinoma In-situ 80% DCIS 20% LCIS 70- 85% Invasive carcinoma 79% IDC- NOS 10% Lobular carcinoma 6% Tubular/cribriform carcinoma 2 Mucinous (colloid) carcinoma Medullary carcinoma Papillary carcinoma < 1 Metaplastic carcinoma

Ductal carcinoma in-situ(DCIS) involve Ductal System. Vague palpable mass * +micro-calcification +\-Nipple discharge + periductal fibrosis limited to BM 5 VARIANTS (Comedo, solid, papillary, micropapillary, cribriform). A. Cells lining duct C. Intact basement membrane D. Open central duct

Cribriform - Solid DCIS Comedo DCIS

Paget’s disease DCIS-Epidermal erythematous&scales

Mammogram; calcification Papillary DCIS

Lobular carcinoma in situ(LCIS) Breast Lobular system 1 to 6% of all ca. Bilateral 20% No calcification A. Cells are identical and dyscohesive B. Cancer cells, but all contained within the lobules C. BM intact D.ER+PR positive, her2 is negative The cells lack the cell adhesion protein E-cadherin

Lobular carcinoma in-situ(LCIS)

Invasive ductal carcinoma IDC A. Duct System. B. irregular border, firm C. Peau d'orange app ( skin changes-tethering) D. +\- % LN metas. + desmoplastic stroma A. Cells lining duct B. Extra cancer like cells, but acontained within duct C. Intact basement membrane D. Open central duct

Invasive ductal carcinoma tumor with irregular border + calcifiacation, margins

Invasive ductal carcinoma

Invasive Lobular carcinoma ILC Involved lobular System. B. difficult to be detected. C. bilterality,multi-centeric, multifocality D. irregular border, firm. E. dyscohesive cells. Absent tubules. F. Cells arranged in single file, loose clusters or sheet, targetoid, occ. Signet-ring cell.G. minimal desmoplasia . H. ER positive, +\- LCIS& HER2/neu overexpression is very rare. Graded as: well, moderate, poor differentiation. Metastasis : occur to the peritoneum and retroperitoneum, the leptomeninges

Inavsive Lobular carcinoma

Vascular & lymphatic invasion(VLI) A. Veins in breast B. Lymph channels A. Cells lining duct B. Cancer cells, breaking through BM. C. Broken BM D. Cancer entering a lymph channel. E. Cancer entering vein.

Medullary carcinoma Circumscribed , rapid growing mass + pushing border solid, syncytium-like cohesive cell. The cells are highly pleomorphic with frequent mitoses Poorly differentiated lymphoplasmacytic infiltrate is prominent

Mucinous (colloid) carcinoma. Soft and Rubbery consistency+ border pushing. tumor cells are present as small clusters within large pools of mucin. The borders are typically well circumscribed, Often good prognosis

Tubular carcinoma completely composed of well-formed tubules lined by a single layer of well-differentiated cells Myoepithelial absent. Cribriform+ apocrine snout + calcification. ER+VE, Her2 -ve

Metastatic breast cancer-IDC

Breast carcinoma-0BJECTIVES Discuss the epidemiology & Impact of breast cancer. Define the etiology + morphology. Discuss the laboratory diagnosis. (Robbins Basic Pathology, 8th ed. P. 743- 750).

Signs and Symptoms lump or mass Often painless Discharge or bleeding Redness or pitting of skin over the breast, like the skin of an orange Change in size or contours of breast Change in color or of areola apperance

Symptoms In early breast ca Easily self palpated Nipple discharge May accompanied with axillary LN Late breast ca Local usually symptomatic Depends on metastatic sites

Diagnostic tools Breast sonography & guided BIOPSY Mammography Superior in dense breast, young age Mammography Superior in loose(fatty) breast, elder Cytology Fine-needle aspiration (FNA) Biopsy- histopathology Incision- Excision- MASTECTOMY\lump Immunohistochemical studies- receptor

CYTOLOGY&CORE ASSESSMENT

Macroscopic finding-Mastectomy specimen

Receptor status Hormone receptor Estrogen receptor (%)-diagnostic, therapeutic & prognostic Progesterone receptor (%) >10% predict response to hormone tx Lobular, tubular, mucinous usually positiv Her2/neu Associate with invasion, metastasis… Predict poor prognosis IHC stain, FISH

Breast carcinoma Her2\neu +ve ER postive

Ideal Histopathology diagnosis Size of tumor (TNM-STAGING) Grade Tubule Formation (Grading system) Nuclear Pleomorphism (Grading system) Mitotic Count (Grading system) Vascular lymphatic invasion(VLI) Perineural invasion(PNI) Nipple involvement- Paget’s disease Skin involvement Lymph node metastasis (TNM-STAGING) Homonal receptors status (ER, PR,Her2)

Bloom& Richardson grading system

The UICC\TNM classification

Molecular diagnosis of breast ca.

These tumors tend to be* Prevalence (approximate) Luminal A ER+ and/or PR+, HER2-, low Ki67 40% best prognosis. Luminal B ER+ and/or PR+, HER2+ (or HER2- with high Ki67) 20% Triple negative/basal-like ER-, PR-, HER2- 15-20% HER2 type ER-, PR-, HER2+ 10-15% *These are the most common profiles for each subtype. However, not all tumors within each subtype will have all these features. ER = estrogen receptor PR = progestrogne receptor  

PROGNOSTIC AND PREDICTIVE FACTORS Invasive carcinoma versus in situ disease. Distant metastases. Lymph node metastases. Tumor size. Locally advanced disease. Inflammatory carcinoma

Overview What is breast cancer? What are Causes and risks? How about some Epidemiology? What’s the deal with BRCA1 and BRCA2? What’s are the main type of breast carcinoma? How you described different morphological pattern? How we usually diagnosed breast mass\ tumor specially if it is suspicious? What’s the ideal histopathology report and how its is significant in our clinical life?