Pathology of breast cancer

Pathology of breast cancer

1. Pathology of Breast Cancer Dr. Mohammed Fathy Bayomy Lecturer of Clinical Oncology Zagazig University

2. Tumors Affecting Breast

3. Tumors Affecting Breast (Cont.,)

4. Tumors Affecting Breast (Cont.,) 1- Epithelial tumours. WHO classification 2003 2- Myoepithelial lesions . 3- Mesenchymal tumours . 4- Fibroepithelial tumours . 5- Tumours of the nipple . 6- Malignant lymphoma . 7- Metastatic tumours . 8- Tumours of the male breast .

5. Tumors Affecting Breast (Cont.,)

6. Tumors Affecting Breast (Cont.,)

7. Gross Picture

8. Gross Picture (Cont.,)

9. Gross Picture (Cont.,)

10. Gross Picture (Cont.,)

11. Gross Picture (Cont.,)

12. Gross Picture (Cont.,)

13. Gross Picture (Cont.,)

14. Invasive Ductal Carcinoma Gross picture Irregular crab like, white fibrous appearance,& chalky streaks Retraction of the overlying skin

15. Invasive Ductal Carcinoma (Cont.,) Microscopic picture Diffuse sheets, nests, cords or as individual cells showing glandular/tubular differentiation.

16. Invasive Ductal Carcinoma (Cont.,) Microscopic picture: Extensive Intraduct Component (EIC) EIC positive 25% of the area within the invasive carcinoma is DCIS and DCIS is also present outside the area of invasive carcinoma. EIC positive Carcinomas in which DCIS is associated with a “small” (approximately 1 cm or less) invasive carcinoma or carcinomas. EIC negative Carcinomas do not fulfill the criteria for being positive for EIC. EIC negative Some carcinomas do not strictly fulfill the criteria for EIC but are associated with extensive DCIS in the surrounding tissue. In such cases it is helpful to provide some measure of the extent of DCIS in the specimen.

17. Invasive Ductal Carcinoma (Cont.,) Microscopic picture: histologic grading Grade 1 Carcinoma cells are disorganized, with enlarged cell nuclei (blue) some with nucleoli (dots in the nuclei); there are few mitoses. Grade 2 Carcinoma cells have larger cell nuclei in proportion to the amount of cytoplasm; the nuclei are vesicular or ‘bubbly’ and ‘folded’. Grade 3 Carcinoma cells are more irregularly shaped with varying enlarged nuclei; the nuclei are enlarged, vesicular and there are atypical nuclear mitoses.

18. Invasive Ductal Carcinoma (Cont.,) Microscopic picture: histologic grading

19. Invasive Ductal Carcinoma (Cont.,) Microscopic picture: histologic grading (Cont.,)

20. Invasive Ductal Carcinoma (Cont.,) Microscopic picture: histologic grading (Cont.,)

21. Invasive Lobular Carcinoma Microscopic picture Indian file pattern of invasion

22. Invasive Lobular Carcinoma Microscopic picture (Cont.,) Targetiod pattern of invasion

23. Invasive Lobular Carcinoma (Cont.,) Microscopic picture (Cont.,) Tumor cells small & uniform with round nuclei, Signet-ring cells are common.

24. Invasive Lobular Carcinoma (Cont.,) IHC Loss of E-cadherin expression is typical of lobular carcinoma cells. Note immunoreactivity of entrapped normal lobules.

25. Tubular Carcinoma Microscopic picture The neoplastic cells lining the tear-drop shaped tubules lack significant atypia. Haphazard distribution of rounded and angulated tubules with open lumens, lined by only a single layer of epithelial cells separated by abundant reactive, fibroblastic stroma

26. Tubulolobular Carcinoma Microscopic picture Combination of classic pattern of lobular invasion + group of cells form tubular structures

27. Mucinous Carcinoma Gross picture Grossly well circumscribed, crepitant to palpation Typical gelatinous gross appearance, sharply circumscribed quality

28. Mucinous Carcinoma (Cont.,) Gross picture (Cont.,)

29. Mucinous Carcinoma (Cont.,) Microscopic picture

30. Mucinous Carcinoma (Cont.,) Microscopic picture (Cont.,)

31. Mucinous Carcinoma (Cont.,) Microscopic picture (Cont.,)

32. Cribriform Carcinoma Microscopic picture Tumour has cribriform appearance similar to its in situ counterpart but with stromal invasion. Haphazard distribution of irregularly shaped and angulated invasive areas is in contrast with the rounded configuration of the ducts with cribriform DCIS on the left side of the field.

33. Invasive Papillary Carcinoma Microscopic picture

34. Invasive Micropapillary Carcinoma Microscopic picture

35. Adenoid cystic Carcinoma Microscopic picture

36. Metaplastic Carcinoma Microscopic picture

37. Metaplastic Carcinoma Microscopic picture (Cont.,)

38. Medullary Carcinoma Gross picture Well –circumscribed, soft, fleshy mass - little desmoplasia  more yielding on palpation and cutting. (medulla=marrow).

39. Medullary Carcinoma (Cont.,) Gross picture (Cont.,) Well –circumscribed, soft, fleshy mass - little desmoplasia  more yielding on palpation and cutting. (medulla=marrow).

40. Medullary Carcinoma (Cont.,) Microscopic picture Large tumor cells grow in a syncytial fashion, & are sharply separated from the surrounding stroma, which is heavily infiltrated by lymphocytes & plasma cells

41. Medullary Carcinoma (Cont.,) Microscopic picture (Cont.,)

42. Medullary Carcinoma (Cont.,) Microscopic picture (Cont.,)

43. Medullary Carcinoma (Cont.,) Microscopic picture (Cont.,)

44. Medullary Carcinoma (Cont.,) Microscopic picture (Cont.,)

45. Inflammatory Carcinoma Gross picture

46. Inflammatory Carcinoma (Cont.,) Microscopic picture Large tumour embolus in a dermal lymphatic

47. Pathogenesis Estrogen Receptor: Structure

48. Pathogenesis Estrogen Receptor: Pathway

49. Pathogenesis (Cont.,) Estrogen Receptor: Cross-talk

50. Pathogenesis (Cont.,) Estrogen Receptor: Cross-talk

51. Pathogenesis (Cont.,) ER & PR Testing

52. Pathogenesis (Cont.,) ER & PR Testing (Cont.,)

53. Pathogenesis (Cont.,) ER & PR Testing (Cont.,)

54. Pathogenesis (Cont.,) ER & PR Testing (Cont.,)

55. Pathogenesis (Cont.,) HER2 gene & Gene product

56. Pathogenesis (Cont.,) EGFR family

57. Pathogenesis (Cont.,) EGFR family (Cont.,)

58. HER2 HER1/EGFR HER4 HER3 Transmembrane domain Intracellular tyrosine kinase domains Extracellular ligand-binding domains Pathogenesis (Cont.,) EGFR family (Cont.,)

59. With the exception of HER2, HER proteins undergo a conformational change upon ligand binding that is essential for dimerization and signaling Ligand primes receptor for activity Closed conformation Open conformation Pathogenesis (Cont.,) HER2/ neu Receptor

60. HER2 does not require a ligand to be primed HER2 HER2 is always in an open conformation making it an ideal dimerization partner Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

61. Among all possible dimers, the HER2:HER3 pair has the strongest mitogenic signaling + + Signaling activity + + + + HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4 + + + + + + + + + Homodimers Heterodimers Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

62. Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

63. Phosphorylation of the tyrosine kinase domains of HER dimer pairs is regulated via allosteric interactions Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

64. Beyond HER2 overexpression: What is the role of other HER proteins as dimerization partners in HER2(+) breast cancer? Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

65. HER2 HER3 Phosphorylation of the tyrosine kinase domain initiates intracellular signaling Ligand-activated HER2:HER3 dimer HER2:HER3 trigger complementary oncogenic signals Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

66. HER2 signaling results in a multitude of cellular effects, including not only increased cellular proliferation, but also cell survival AKT PDK1 Cell cycle control Proliferation Apoptosis Survival RAS Sos Grb2 Shc MEK Angiogenesis Raf PI3K Cyclin D1 p27 BAD GSK3 ß NF κB mTOR MAPK HER2 HER3 P P P P P P P Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

67. Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

68. Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

69. Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

70. Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

71. Pathogenesis (Cont.,) HER2/ neu Receptor (Cont.,)

72. Pathogenesis (Cont.,) HER2 Testing

73. Pathogenesis (Cont.,) HER2 Testing (Cont.,)

74. Pathogenesis (Cont.,) HER2 Testing: IHC

75. Pathogenesis (Cont.,) HER2 Testing: Single probe-FISH Amplification of the HER2 gene Without amplification of the HER2 gene (arrows: two signals/nucleus)

76. Pathogenesis (Cont.,) HER2 Testing: Single probe-FISH (Cont.,)

77. Pathogenesis (Cont.,) HER2 Testing: Single probe-SISH

78. Pathogenesis (Cont.,) HER2 Testing: Dual probe (Color)-ISH

79. Pathogenesis (Cont.,) HER2 Testing: Dual probe-FISH

80. Pathogenesis (Cont.,) HER2 Testing: Dual probe-CISH HER2 gene amplified ( HER2 /CEN-17 ratio 2.0) Non-amplified specimen ( HER2 /CEN-17 ratio < 2.0)

81. Pathogenesis (Cont.,) HER2 Testing: Dual probe-SISH (DISH)

82. Pathogenesis (Cont.,) HER2 Testing: ASCO Recommendation

83. Pathogenesis (Cont.,) HER2 Testing: ASCO Recommendation (Cont.,)

84. Pathogenesis (Cont.,) HER2 Testing: ASCO Recommendation (Cont.,)

85. Pathogenesis (Cont.,) HER2 Testing: ASCO Recommendation (Cont.,)

86. Pathogenesis (Cont.,) HER2 Testing: UK Recommendation

87. Pathogenesis (Cont.,) Ki-67: low

88. Pathogenesis (Cont.,) Ki-67: high

89. Molecular Classification of IDC

90. Molecular Classification of IDC (Cont.,)

91. Molecular Classification of IDC (Cont.,)

92. Molecular Classification of IDC (Cont.,)

93. Molecular Classification of IDC (Cont.,)

94. Molecular Classification of IDC (Cont.,)

95. Molecular Classification of IDC (Cont.,)

96. Molecular Classification of IDC (Cont.,)

97. Molecular Classification of IDC (Cont.,)

98. Molecular Classification of IDC (Cont.,)

99. Molecular Classification of IDC (Cont.,)

100. Molecular Classification of IDC (Cont.,)

101. Molecular Classification of IDC (Cont.,)

102. Molecular Classification of IDC (Cont.,)

103. Molecular Classification of IDC (Cont.,)

104. Molecular Classification of IDC (Cont.,)

105. Molecular Classification of IDC (Cont.,)

106. Molecular Classification of IDC (Cont.,)

107. Molecular Classification of IDC (Cont.,)

108. Molecular Classification of IDC (Cont.,) Express ER Most common. Luminal A possess a higher expression of the ER and oestrogen-associated genes ESR1, GATA3 and FOXA1 Do not express HER2/ neu Ki-67 proliferation index- low Luminal A tumours are associated with a better prognosis Luminal A

109. Molecular Classification of IDC (Cont.,) Express ER Variable HER2/neu expression Increased frequency of TP53 mutations Ki-67 proliferation index- high Luminal B tumours are associated with worse prognosis compared to Luminal A Luminal B

110. Molecular Classification of IDC (Cont.,) Increased expression of genes located in the same region on chromosome 17q: human epidermal growth factor receptor 2 (ERBB2) and growth factor receptor bound protein 7 ( GRB7). Associated with a high histological grade, low expression of ER and PR. Poor clinical outcome. HER2/ neu over-expressing subtype

111. Molecular Classification of IDC (Cont.,) Hormone receptor (ER and PR) and HER2/ neu receptor negative. Expression of genes associated with myoepithelial cells: KRT5 (keratin 5), KRT17 (keratin 17), CNN1 ( calponin 1), CAV1 ( caveolin ) and LAMB1 (laminin). Aggressive with a poorer disease-free and overall survival than the other breast cancer subtypes. Triple Negative subtype

112. Molecular Classification of IDC (Cont.,)

113. Molecular Classification of IDC (Cont.,)

114. Molecular Classification of IDC (Cont.,)

115. Molecular Classification of IDC (Cont.,)

116. Molecular Classification of IDC (Cont.,)

117. Molecular Classification of IDC (Cont.,)

118. Molecular Classification of IDC (Cont.,)

119. Molecular Classification of IDC (Cont.,)

120. Molecular Classification of IDC (Cont.,)

121. Molecular Classification of IDC (Cont.,)