1. BREASTTUMORS Ch. 18 p (704 – 713)

2. LYMPHATIC DRAINAGE AXILLARY (MOSTLY) INTERNAL MAMMARY SUPRACLAVICULAR

4. Fibroadenoma

5. Cleft Fibroadenoma

6. Intraductal papilloma

7. Cystosarcoma phyllodes Phyllodes tumor arises from the interlobular stroma, In contrast to fibroadenomas, it is uncommon & is often larger in size and more cellular. Projections of stroma between the ducts create the leaflike pattern for which these tumors are named (from the Greek word phyllodes, meaning “leaflike”).

8. One in eight women will get breast cancer, and one third of women with breast cancer will die of the disease

10. Causes of Breast Cancer Hormonal Genetic Environmental

11. Risk Factors for Breast Cancer  Estrogen, (F / M = 100 / 1) Menstrual history & Reproductive history. - Long & Strong exposure; (Early menarch & late Menopause) - Pregnancy; (Nilliparous, Late 1 st pregnancy) - Lactation, decrease risk - Oophorectomy (decrease the risk to 1/3)  Age (Peak; 60 – 70y)  Family historty; (1 st degree, early age, bilat)/ 2 folds Benign breast disease (Hx of previous breast pathology) - Fibrocystic disease +/- epith hyperplasia +/- atypia. - CIS - 0X, 2X, 5X, 10X Geography  In 2002 Estrogen declared as carcinogen by National Toxicology Program

12. The two most common risk factors for breast cancer are: Being female Getting older Breast Cancer (C50): 2011-2013

13. Other Risk Factors for Breast Cancer Oral contraceptive Radiation Exposure Carcinoma of the contralateral breast or endometrium Obesity High fat diet Alcohol Smoking Environmental Toxins Breast augmentation. ABORTIONS?

14. Genetic changes  Proto-oncogen HER2/NEU - 30% - Poor prognosis RAS & MYC  Tumor suppressor gene Rb, p53, ER gene inactivation

15. Gene profiling of breast cancer  Gene profiling of breast cancer 1. ER +ve, HER2 –ne 2. ER +ve, HER2 +ve 3. ER -ne, HER2 +ve 4. ER -ne, HER2 –ne Different Outcome & Therapy.

16. Genetic Factors Inherited Mutations (10%) 10% breast cancers are familial - 90% are sporadic Positive Family History, especially in 1st degree relatives (mother, daughter, sister) confers increased risk for breast cancer Tumor suppressor genes (BRCA1, BRCA2) Risk is greatest with: First degree relative relatives with BILATERAL disease relatives affected at a YOUNG AGE

17.  BRCA1 Gene (17q21) “Breast-Ovarian” cancer gene “Early onset” breast cancer gene High grade breast Ca. Responsible for up to 50% of “inherited” breast cancers, (5% of all breast cancers)  BRCA2 Gene (13q); “Male Breast Cancer” gene

18. Breast Cancer Pathology  Ductal Ca. (85 – 93%)  Lobular Ca. (7 – 15%)  In Situ Carcinomas (CIS) (15 )  Invasive Carcinomas (85%)  Special Subtypes (> 5%)

19. Ductal Carcinoma in Situ Clinical: –DCIS usually does not present as a palpable mass. Mammogram: –The most common method of detection is by identifying mammographic calcifications MRI FNA Biopsy

20. Mammography showing a normal breast (left) and a cancerous breast (right). Mammography is the standard for detection of DCIS. MRI could help especially in high-grade DCIS -Calcification, -50 - 60% in ca. -20% in benign

21. Solid DCIS, Micropapillary Cribriforming DCIS Comedoca DCIS

22. Lobular carcinoma in situ Multicentric, Bilateral

23. Invasive Duct Ca 90% of infiltrating breast carcinomas

24. Infiltrating Ductal Carcinoma Gross: Firm & gritty, pale - white Micro: Grading; 1)tubule formation 2)nuclear grade 3)mitotic rate - Desmoplastic stromal response (fibrosis).

25. Infiltrating Lobular Carcinoma 2nd most common invasive breast ca. Multifocal & bilateral Same prognosis as infiltrating ductal ca, when matched for stage - Single cells & linear profiles of malignant cells with “Indian file pattern” - Dense fibrous tissue.

26. Invasive lobular carcinomaInvasive ductal carcinoma

27. Mucin Infiltrating ductal ca. Tubular type V. Good prognosis Infiltrating ductal ca. Medullary type (lots of lymphocytes) better prognosis Infiltrating ductal ca. Mucinous type Good prognosis Infiltrating ductal ca. Mucinous type Good prognosis

28. Peau d’orange of involved skin caused by lymphatic involvement and obstruction. Inflammatory Carcinoma invasive carcinoma involving superficial dermal lymphatic. Erythema & induration Inflammatory carcinoma: dermal lymphatic spaces containing tumor cells

29. Paget’s Disease Invasion of the SKIN of nipple or areola by malignant cells. Associated with in situ or invasive ca erythema, scaling, ulceration Intra-epidermal malignant cells

30. Extramammary Paget disease

31. Tumor grade  HISTOLOGY WHO grading Well differentiated Mod. differentiated Poor differentiated B-R grading Glands Nuclei Mitosis  CYTOLOGY –Nuclei Size Membrane Chromatin Nucleoli Nuclear grade 1-3 Good correlation with histologic grade

32. TNM stage grouping BREAST CANCER TNM stage grouping Stage 0 Stage 0TisN0M0 Stage I Stage IT1*N0M0 Stage IIA Stage IIAT0N1M0 T1* N1**M0 T2N0M0 Stage IIB Stage IIBT2N1M0 T3N0M0 Stage IIIA Stage IIIAT0, T1,* T2N2M0 T3N1, N2M0 Stage IIIB Stage IIIB T4Any NM0 Any TN3M0 Stage IV Stage IVAny TAny NM1 * Note: T1 includes T1 mic. ** Note: The prognosis of patients with N1a is similar to that of patients with pN0. AJCC ® Cancer Staging Manual, 5 th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.

33. TNM stage grouping BREAST CANCER TNM stage grouping TXPrimary tumor cannot be assessed T0No evidence of primary tumor TisCarcinoma in situ: Intraductal carcinoma, lobular carcinoma in situ, or Paget’s disease of the nipple with no tumor T1Tumor 2 cm or less in its greatest diameter T1mic Microinvasion more than 0.1 cm or less in its greatest diameter T1aTumor more than 0.1 cm but not more than 0.5 cm in its greatest diameter T1bTumor more than 0.5 cm but not more than 1 cm in its greatest diameter T1cTumor more than 1 cm but not more than 2 cm in its greatest diameter T2Tumor more than 2 cm but not more than 5 cm in its greatest diameter T3Tumor more than 5 cm in its greatest diameter T4Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below T4aExtension to chest wall T4bEdema (including peau d’orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast T4cBoth (T4a and T4b) T4dInflammatory carcinoma AJCC ® Cancer Staging Manual, 5 th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.

34. Commonly assessed prognostic factors BREAST CANCER Commonly assessed prognostic factors Slamon DJ. Chemotherapy Foundation. 1999;46. Winer E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1651-1717. Nuclear grade Estrogen/progesterone receptors HER2/neu overexpression Number of positive axillary nodes Tumor size Lymphatic and vascular invasion Histologic tumor type Histologic grade Molecular changes

35. 5-year survival as function of the number of positive axillary lymph nodes BREAST CANCER 5-year survival as function of the number of positive axillary lymph nodes 0% 20% 40% 60% 80% 5-Year Survival 0123456-1011-1516-20>20 Number of Positive Nodes Harris J, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1557-1616.

36. Histopathologic Grade If B-R score is 3, 4, 5 = low grade If B-R score is 6, 7 = Intermediate grade If B-R score is 8, 9 = High grade

37. Histologic grade 5-year survival as function of tumor grade BREAST CANCER 5-year survival as function of tumor grade

38. c-erbB-2 (HER-2/neu) Oncogene which shares extensive sequence homology with epidermal growth factor receptor (EGFR)

39. Total CancersPer Cent In Situ Carcinoma ** 15–30 Ductal carcinoma in situ, DCIS 80 Lobular carcinoma in situ, LCIS 20 Invasive Carcinoma 70–85 No special type carcinoma ("ductal") 79 Lobular carcinoma 10 Tubular/cribriform carcinoma (Better prognosis than average) 6 Mucinous (colloid) carcinoma (Better prognosis than average) 2 Medullary carcinoma (Better prognosis than average) 2 Papillary carcinoma 1 Metaplastic carcinoma, (Squamous)

40.  The “Triple Test”: – Clinical picture – Mammographic findings – Cytologic findings

41. MALE BREAST GYNECOMASTIA (related to hyperestrogenism)

42. Gynecomastia Reversible enlargement of male breast Unilateral or bilateral subareolar mass +/-pain Ductal and stromal proliferation, NO lobules Etiology - Systemic disease – hyperthyroidism, cirrhosis, CRF –Drugs; cimetidine, digitalis, tricyclic antidepressants, marijuana –Neoplasms -pulmonary, testicular germ cell tumors –Hypogonadism: testicular atrophy, exogenous estrogen, Klinefelter’s syndrome Periductal edema Epithelial hyperplasia

43. THE MALE BREAST  Carcinoma  Very rare occurrence; female cancer to male cancer ratio approx 100:1  Pathology and behavior is similar to cancers seen in women although with less breast tissue, skin involvement is more frequent  Associated with inherited BRCA2 mutation

44. Lecture Objectives Can you? 1. Discuss the etiology/pathologic features of different forms of benign non-neoplastic and neoplastic breast disease. 2. List the benign breast diseases that increase a patient’s risk of developing breast cancer and classify these conditions by the degree of risk.

45. Lecture Objectives Can you? 3. Outline other risk factors predisposing to breast cancer & incidence/prevalence of breast cancer. 4. Classify breast cancer into histologic subtypes and describe the pathologic features of each. 5. List the prognostic factors for breast cancer.