1. THE BREAST

2. Outline Histology Developmental Pathology of Breast (e.g. Milkline Remnants, Accesory breast tissue, etc.) Inflammatory Pathology of Breast (e.g. Mastitis, Fat Necrosis, etc.) Beningn epithlelial breast changes Neoplastic changes in Breast (Fibrocystic change, Non- Proliferative, Proliferative and Proliferative changes) Stromal tumor- Fibro adenoma and Phylloides tumor Paget's Disease of the breast. Breast Carcinoma Male Breast (Gynecomastia)

3. Developmental conditions Anatomic milkline from the axilla to the perineum Abnormally located epidermal thickening may give rise to supernumerary nipples. Few cases have persisting ductal system extending to the subcutaneus tissues as accessory breast tissue. Macromastia,subjective, may cause pain, Reduction mamoplasty.

4. Introduction  Modified sweat glands.  Lobes and lobules of gland  in fat tissue stroma.  Ducts emerge from acini of glands  Smaller ducts join to form lactiferous ducts  Lactiferous ducts merge just beneath the nipple to form a lactiferous sinus.  Then individually open on nipple

5. Figure 23-1 Anatomic origins of common breast lesions. © 2005 Elsevier

7. Normal Breast,Luminal (milk producing cells) and myoepithelial cells)

8. Breast Symptoms  Pain(Most common symptom) Most are benign.  Palpable Mass  Nipple discharge

9. Palpable masses  2nd most common breast symptom. A breast mass becomes palpable when >2cm  Distinguish a palpable mass from vague nodularities or lumpiness Lesions includes:Invasive carcinoma, fibroadenomas.  10% of palpable masses are malignant in under 40 yr olds compared to 60 % malignancy rate for palpable masses in over 54 yr.olds  50 % of carcinomas arise in upper outer quadrant.20% in central quadrant and 10% each in the other quadrants

10. Figure 19-23 Representation of the findings in a series of women seeking evaluation of apparent breast "lumps." Downloaded from: StudentConsult (on 23 November 2011 03:56 PM)

11. Nipple discharge  Note that galactorrhea is not associated with malignancies  Serous or bloody nipple discharge may be seen in a small percentage of breast cancers  The older the age, the higher the risk of a malignancy in a patient with bloody or serous discharge.

13. Mastitis Inflammation of the mammary gland Causes :  1. breast feeding (Acute mastitis)  2. Periductal mastitis  3. Mamary Duct Ectasia B 1. Breast feeding (Acute mastitis) A blocked milk duct Cracked or damaged skin or tissue around the nipple  Signs :red, hot, painful, or inflamed breasts with flu- like symptoms such as headache, nausea, high temperature Staph aureus Strept.

16. Mastitis Periductal mastitis (Zuska disease,recurent sub -areolar abscess)  Recurrent sub-areolar abscess  Painful mass that resembles infection  Not associated with lactation  90% of patients are smokers  Keratinizing squamous metaplasia of the nipple ducts.  ? Vitamin A deficiency, Toxic metabolites of tobacco.

17. Periductal mastitis

18. Mammary duct ectasia  Nonbacterial chronic inflammation of the breast associated with inspissation of breast secretions in the main excretory ducts.  Multiparous women  Ductal dilation with ductal rupture leads to reactive changes in the surrounding breast substance.  40- 50 year old women  Not Associated with smoking.

19. Fat Necrosis  Trauma, Prior surgical intervention  A zone of necrotic fat cells surrounded by lipid- filled macrophages and an intense neutrophilic infiltration, foreign body giant cells, calcium salts.  Eventually the focus is replaced by scar tissue or is encysted and walled off by collagenous tissue  Affects the interlobular stroma

20. Match the following  Periductal fibrosis  Acute mastitis  Fat Necrosis Smoking Breast feeding Trauma

21. Benign epithelial Lesions Non proliferative (Fibrocystic change Proliferative Breast diseases

22. Cysts(blue-domed cysts)

23. Fibrocystic Changes(non- proliferative) Symptoms and Signs  Breast pain (mastodynia) and/or tenderness is observed in the majority of patients.  Mastodynia may start a few days or 1 to 2 weeks before menstruation; it usually eases or subsides with the onset of or during menses  Nipple discharge is spontaneous or secretion can be expelled from the nipple  Diffuse lumpy feeling in the breast.  Examples: cysts,apocrine metaplasia, adenosis,  No cancer risk

24. Proliferative Breast Changes Without Atypia-mamographic densities,incidental findings. -Proliferation without cellular features suggestive of malignancy. E.g Epithelial,hyperplasia,Sclerosing adenosis,Papillomas.  Risk of cancer is mild.(2 times normal)

25. Sclerosing adenosis adenosiadenosis(increase acini and fibrosis in the lobule) Without Atypia -mamographic densities,incidental findings. -Proliferation without cellular features suggestive of malignancy. E.g Epithelialhyperplasia,Sclerosing adenosis,Papillomas.

26. Epithelial Hyperplasia Without Atypia -mamographic densities,incidental findings. -Proliferation without cellular features suggestive of malignancy. E.g Epithelialhyperplasia,Sclerosing adenosis,Papillomas..

27. Proliferative Breast Changes With Atypia  Atypical ductal hyperplasia(ADH),Atypical lobular hyper plasia(ALH) -Proliferation with cellular features suggestive of malignancy. Moderate risk of cancer(5 times increased risk)

28. Atypical ductal and atypical Lobular hyperplasia

29. Benign breast Neoplasms  Intralobular Stromal derived tumors.  Fibroadenoma - Phyllodes tumor

30. Fibroadenoma  Firm, noncancerous tumor of the breast.  It is round, painless, feels firm and rubbery, and can be easily moved around.  Peak age:20-30  Rapidly grow to a large size  Present with Palpable mass or mammographic density  Malignant transformation rare

31. Fibroadenoma  Fibroadenomas may enlarge during late menstrual period and tends to calcify or regress by menopause  Lobular stromal cells are the neoplastic component in fibro-adenomas

32. © 2005 Elsevier

34. Phyllodes tumor Cystosarcoma phyllodes  epithelial-stromal neoplasms with dominating stroma and leaf-like structure  Most are benign lesions.  15% are malignant.  0.3% of all breast tumors  30% recurrence; 10% metastasis  Age: older than with FA (average 45)  Well defined, uncalcified, lobulated, round or oval  Commonly with thin irregular cystic spaces

35. Quiz  A 30 year old woman complained that she has noticed a firm,painless, freely mobile mass located in the upper –outer quadrant of her left breast. The mass increases in size towards the end of her menstrual flow. Which of the following is the most likely diagnosis? A. Melanoma B. Fibroadenoma C. Fibrocystic change D. Breast cancer

37. Phyllodes tumor

38. INTRADUCTAL PAPILLOMA:  Benign solitary lesions within the ducts.  EPIDEMIOLOGY: Middle-aged and older women. SYMPTOMS:  Serous or Bloody Nipple discharge, nipple retraction.  Lump beneath nipple.  papillary clonal proliferations of duct epithelia cells composed of multiple branching papillae  Benign and are not the precursors of papillary carcinoma  TREATMENT: Surgical excision.

39. Breast Carcinoma  20% of all cancers in women  Commonest cause of death - 35-55y  1 in 8 women in US  Less incidence in Asia  Majority of cancers arise in the ducts.  Very rare before age 25  Commoner in Caucasian,developed countries more than developing.

40. Risk Factors:  Female..!, Age, Obesity, high fat,low fibre diet  Maternal relative with breast cancer.  Longer reproductive span.(early menarche,late menopause)  Nulliparity, Hormone replacement.  Later age at first pregnancy. (first pregnancy 30 yrs and above)  Atypical epithelial hyperplasia.  Previous breast cancer/Endometrial Ca.  Geographic factors –Western countries  BRCA1 and BRCA2 genes  Postmenopausal hormone replacement

41. Risk Factors: Radiation exposure Protective factors includes: Prolonged breast feeding, mastectomies, oophorectomy, use of SERM(Tamoxifen)

42. Etiology of Breast Carcinoma:

43. Genetics/Hereditary  BRCA-1(Also ovarian cancer, Pancreatic cancer)..tumor are poorly differentiated.  BRCA-2(Also pancreatic CA, male breast cancer)  BRCA-1 and 2 tumor suppresor genes with autosomal dominant pattern of inheritance.  Li Fraumeni syndrome(germline p53 mutation)  Cowden syndrome(multiple harmatoma syndrme due to PTEN mutation)  Peutz Jeghers syndrome (LKB1 muataion)  Her-2/neu

44. Sporadic Breast carcinoma  Majority of breast CA is sporadic  Hormonally and environmental factors  Most are ER positive and occur in Postmenopausal women.

45. Breast Carcinoma types  Epithelial  Non-invasive  Ductal carcinoma in situ (DCIS)  Lobular carcinoma in situ (LCIS)  Invasive  Ductal (85%)  Lobular (1%)  Mucinous (5%)  Papillary (<5%)  Medullary (<5%)  Mixed Connective tissue and Epithelial  Miscellaneous

46. CLASSIFICATION All Breast CA arise from epithelial cells in the TDLU >90% are adenocarcinomas and are divided into: 1.1. Carcinoma in situ(DCIS,LCIS)  Intact basement membrane  Carcinoma is limited to the lobule or ducts 22. Invasive carcinoma  Basement membrane is breached  Tissue invasion and metastasis is possible.

47. CLASSIFICATION  The classification into ductal or Lobular refers to the histological appearance and the biologic properties of the tumor rather than to the cell of origin.  Lobular carcinoma refers to a distinct subtype while the term Ductal refers to any histological type that is not otherwise specified.

48. © 2005 Elsevier

49. Direct precursor of invasive ductal carcinoma Visible on mamography because of calcification Most often picked up via mamography Clonal proliferation of cells in the ducts and lobules limited by basement membrane. Five subtypes: Comedone, Solid, cribriform, papillary and micro papillary Mastectomy is usually curative(95%) Incidence of DCIS increases with increase uptake of mamographic screening in any population. DUCTAL CARCINOMA IN-SITU

50. Paget disease of the nipple  Rare manifestation of breast cancer (1% to 4% of cases)  Unilateral erythematous eruption with scaly crust and Pruritus.  Malignant cells (Paget cells) extend from DCIS via the lactiferous sinuses, into nipple skin without crossing the basement membrane.  60% of women with the lesion would have an underlying mass and invasive cancer.

51. Pagets breast

52. Comedo type DCIS  Large central zones of necrosis with calcified debris. Also note the surrunding intense stromal fibrosis

53. Mammographic calcifications

54. LOBULAR CARCINOMA IN SITU  Incidental biopsy finding,  No calcifications or stromal reactions that produce mammographic densities.  Incidence is not affected by mamographic screening.  Bilateral in 20% to 40% of cases, compared with 10% to 20% of cases of DCIS.  LCIS is more common in young women, 80% to 90% of cases occurring before menopause.

55. LOBULAR CARCINOMA IN SITU  The cells of LCIS and invasive lobular carcinoma are identical.  Loss of expression of E-cadherin

56. LCIS

57. DCIS/LCIS(10 times cancer risk in both)  DCIS  LCIS  No loss of E-Cadherin  Palpable, calcification or densities on Mammography  10% bilateral  =>Invasive ductal CA  Cancer on on same side  Loss of E-Cadherin  Detection by mammography is low  20% bilateral  =>Invasive Lobular CA  Younger age  Bilateral risk of cancer

58. INVASIVE BREAST CARCINOMA

59.  Without mammographic screening, invasive carcinoma presents as a palpable mass.  Palpable tumors are associated with axillary lymph node metastases in over 50% of patients.  Larger carcinomas may be fixed to the chest wall or cause dimpling of the skin=> Nipple retraction  Lymphedema and thickening of the skin may occur as a result of lymphatic blockade Leading to peau d'orange.  Inflammatory carcinoma refers to tumors that present with a swollen, erythematous breast. They tend to have poor prognosis.(Commoner with African ancestry)

60. BREAST CANCER  Most common histologic type  70 - 80% of all breast cancer  Diagnosis of exclusion  Breast cancer NOS or NST. Invasive Ductal Carcinoma

61. BREAST CANCER  Grossly forms hard and stellate mass  Used to be call “scirrhous” ca  Typically metastasize to bone, liver and lung Invasive Ductal Carcinoma

62. Well differentated Invasive ductal cancer

63. Poorly differentiated Invasive Ductal Cancer

64. Invasive Lobular Carcinoma  Composed of small cells with linear arrangement 10% of all breast cancer  Commonly forms multifocal and multicentric lesions  Metastasize to meninges(carcinoma meningitis), serosal surfaces, ovaries and retroperitoneum. E-Cadherin mutations “Indian file” pattern

65. Invasive Lobular Carcinoma Indian file pattern

66. BREAST CANCER Tubular Carcinoma  Variant of ductal carcinoma  Usually small lesion detected by mammogram  5 - 10% of all breast cancers  Better prognosis  Small tubules composed of neoplastic cells with low grade nuclei.

67. BREAST CANCER Mucinous Carcinoma  5% of all breast cancers  Older age group  Abundant accumulation of extracellular mucin  Low grade tumor, grows slowly

68. BREAST CANCER Medullary Carcinoma  5 % of all breast carcinoma  Younger age group  Well circumscribed mass  Sheaths of tumor cells with high nuclear grade and intense lymphoplasmacytic infiltrate No Hormone receptors,no over expression of her-2 neu. (similar to basal type cancers) better prognosis than NST

69. Peu d ‘orange

70. Breast Carcinoma - Schirrous

71. Medullary Carcinoma: Large soft

72. Stage 1  Tumor < 2.0 cm in greatest dimension  No nodal involvement (N0)  No metastases (M0)

73. Stage II  Tumor > 2.0 < 5 cm or  Ipsilateral axillary lymph node (N1)  No Metastasis (M0)

74. Stage III  Tumor > 5 cm (T3) or ipsilateral axillary lymph nodes fixed to each other or other structures (N2)  involvement of ipsilateral internal mammary nodes (N3)  Inflammatory carcinoma (T4d)

75. Stage IV (Metastatic breast cancer)  Any T  Any N  Metastasis (M1)

76. PROGNOSTIC FACTORS Examination of the primary carcinoma and the axillary lymph nodes. correlated with survival : Invasive carcinoma versus in situ disease. Cure is possible when the carcinoma has not crossed the basement membrane.  Distant metastases. Cure is rare in the presence of distant metastasis.  Lymph node metastases. Axillary lymph node status (sentinel biopsy).Most Important prognostic factor for non metastatic disease.

77. SENTINEL LYMPH NODE

78. PROGNOSTIC FACTORS Tumor size.  Size of an invasive carcinoma is the second most important prognostic factor for non metastatic disease.  Risk of axillary lymph node metastases increases with the size of the primary tumor carcinomas 2 cm. Mammographically detected cancers are smaller and less likely to have metastasized.

79. PROGNOSTIC AND PREDICTIVE FACTORS Locally advanced disease. Large carcinomas with invasion into skin and muscle are usually beyond surgical salvage. Inflammatory carcinoma.  Presenting with swelling and skin thickening due to dermal lymphatic involvement have a poor prognosis.  3-year survival rate is only 3% to 10%.  Higher incidence with African descent and younger women

81. Other prognostic factors

82. Histology subtypes subtypes(Tubular,Mucinous,medullary,Lobular,Pap illary) have a better prognosis compared to the NST or invasive ductal carcinoma.  30 year survival rate of >60% COMPARED TO <30% OF DUCTAL TUMORS.

83. Hormone receptors and Her -2/neu  Progesterone, Estrogen and Over-expression of Human epidermal growth factor receptors( HER-2 /neu)  Well differentiated/low grade tumors usually express ER,PR and do not over express HER-2 /neu  Poorly differentiated /high grade tumors do not express ER/PR but usually over express HER-2/neu.  Demonstrated by Immunoperoxidase special stain.

84. Hormone receptors and Her -2/neu  Hormone receptor positive tumors have good response to anti-estrogen therapy such as Tamoxifen but have poor response to chemotherapy.  Tumors arising from the basal group of cells are usually negative for ER,PR and HER-2 /neu(Triple Negative).This tumors tend to have good prognosis.

85. Response to hormonal therapy or targeted Therapy  Estrogen and Progesterone receptor positive tumors have good response to hormonal manipulation.  Tumors that are HER 2/neu positive have shown good response to Trastuzumab (Herceptin)