Pathology of breast cancer

1. Pathology of
Breast Cancer
Dr. MohammedFathyBayomy
Lecturer of ClinicalOncology
ZagazigUniversity

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
1. 25% of the area within
the invasive carcinoma
is DCIS and
2. 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. HER2HER1/EGFR HER4HER3
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
GSK3ß
NFκBmTOR
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.,)