Renal Tumors with Eosinophilic Cytoplasm: 2013 Classification. Jesse K. McKenney, MD Associate Head, Surgical Pathology

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1 Renal Tumors with Eosinophilic Cytoplasm: 2013 Classification Jesse K. McKenney, MD Associate Head, Surgical Pathology

2 Renal Epithelial Neoplasia History 1981: WHO Classification of Renal Neoplasms 1. Adenoma 2. Carcinoma (RCC or other)

3 Renal Cell Carcinoma: Classification 1997

4 Renal Cell Carcinoma: Classification 1997

5 AFIP, Third Series, Fascicle 11 (1994)

6 Renal Neoplasms with Eosinophilic Cytoplasm 1997 Renal cell carcinoma Clear cell, eosinophilic Chromophobe Papillary, eosinophilic Collecting duct Medullary Unclassified Misc Oncocytoma AML

7 Renal Neoplasms with Eosinophilic Cytoplasm 2012 Renal cell carcinoma subtypes Clear cell, eosinophilic Xp11/TFE3 Papillary, eosinophilic TFEB Chromophobe ACKD associated Collecting duct Birt-Hogg-Dubé Medullary Unclassified HLRCC Tubulocystic SDHB

8 Renal Neoplasms with Eosinophilic Cytoplasm 1. Chromophobe vs. Oncocytoma 2. Tumors Resembling Onco/Chromo 3. Eosinophilic, but not Onco/Chromo

9 1. Chromophobe RCC vs. Oncocytoma

10 Chromophobe RCC: Prototypical Features

11 Chromophobe RCC (Eosinophilic): Nuclear Features Tickoo et al. Am J Clin Pathol 1998;110(6):

12 Chromophobe RCC (Classic-Plant Cell Type)

13 Chromophobe RCC: (Classic-Plant Cell Type)

14 Chromophobe RCC: Morphologic Heterogeneity

15 Chromophobe RCC: Clear Broad Cell RCC alveolar architecture

16 Chromophobe RCC: Broad alveolar architecture

17 Chromophobe RCC: Small nested pattern

18 Chromophobe RCC: Mixed eosinophilic/classic

19 Chromophobe RCC: Oncocytoma-like Foci

20 Chromophobe RCC: Adenomatous

21 Chromophobe RCC: Adenomatous

22 Chromophobe RCC: Microcystic/Cribriform

23 Chromophobe RCC: Halos are Sufficient

24 Metastatic Chromophobe

25 Oncocytoma

26 Oncocytoma

27 Oncocytoma

28 Oncocytoma

29 Oncocytoma

30 Oncocytoma

31 Oncocytoma with Atypical Features Davis CJ et al. J Urogenital Pathol 1991; 1:41-52 Amin MB et al. Am J Surg Pathol 1997; 21:1-12 Perez-Ordonez et al. Am J Surg Pathol 1997; 21:871-83

32 Oncocytoma with Extrarenal Invasion

33 Oncocytoma with Extrarenal Invasion

34 Oncocytoma with Extrarenal Invasion

35 Oncocytoma with Intravascular Tumor

36 Oncocytoma

37 Oncocytoma with Degenerative Atypia

38 Prototypical Chromophobe RCC vs. Prototypical Oncocytoma

39 Oncocytic Gray Zone Tumors

40 Gray Zone Oncocytoma Chromophobe

41 RCC, Unclassified Chromophobe Oncocytoma

42 General classification strategies Managerial/Therapeutic Prognostic Follow-up Response to therapy Adjuvant therapy (in the future?) Biologic gold standard Cytogenetic abnormality Molecular abnormality Antigen expression

43

44 Adjunctive Studies in the Classification of Renal Neoplasia Immunohistochemistry Electron Microscopy Conventional cytogenetics FISH Gene expression array SNP array Sequencing mirna

45 Oncocytoma?

46 How Much Nuclear Variation is Allowable?

47 How Much Nuclear Variation is Allowable?

48 How Much Nuclear Variation is Allowable?

49 The Median Assumption Specific genetic Cytokeratin alteration 7 by? Oncocytoma Chromophobe Clinical Outcome Response to Therapy

50 Gray Zone Cases Kidney, left, radical nephrectomy: Oncocytic renal neoplasm of low malignant potential Low grade oncocytic renal neoplasm Renal cell carcinoma, low grade oncocytic type

51 Diagnosis?

52 Diagnosis?

53 Diagnosis?

54 Diagnosis?

55 CK7 Diagnosis?

56 Diagnosis Kidney, left, radical nephrectomy: Low grade oncocytic renal neoplasm (see comment)

57 Follow-up Liver Biopsy

58 Unclassified RCC

59 Unclassified RCC

60 Unclassified RCC

61 2. Other Renal Tumors That Resemble Oncocytoma and Chromophobe

62 Clear cell RCC

63 Clear Cell RCC

64 Clear RCC with cytoplasmic eosinophilia CAIX +, CD10+, CK7-

65 Clear Cell RCC: Rhabdoid

66 Birt-Hogg-Dubé Associated RCC

67 Birt-Hogg-Dubé Syndrome Autosomal dominant with incomplete penetrance (BHD gene 17p12-q11.2) Renal tumors Cutaneous lesions Fibrofolliculoma Trichodiscoma Spontaneous pneumothorax Colorectal neoplasia Medullary thyroid carcinoma Lipomas

68 RCC Associated with Birt-Hogg-Dubé

69 RCC Associated with Birt-Hogg-Dubé HOT

70 RCC Associated with Birt-Hogg-Dubé

71 Birt-Hogg-Dubé Associated Oncocytosis

72 Birt-Hogg-Dubé Associated Oncocytosis

73 Birt-Hogg-Dubé Associated Renal Neoplasm

74 Birt-Hogg-Dubé Associated Renal Neoplasm

75 Birt-Hogg-Dubé Syndrome: Recognition Multiple oncocytic renal tumors Hybrid forms Scattered clear cells or nodules within tumors Oncocytosis History of multiple chromophobe RCC Associated skin lesions Present earlier- 30 s

76 Tubulocystic RCC

77

78 Tubulocystic ********** Carcinoma

79 Tubulocystic ********** Carcinoma

80 Tubulocystic Carcinoma

81 Tubulocystic ********** Carcinoma

82 Epithelioid Angiomyolipoma

83 Angiomyolipoma

84 Angiomyolipoma: Classic

85 Epithelioid Angiomyolipoma Actin +, HMB-45 +, CK - PAX8 -, CD117 -

86 Atypical Epithelioid Angiomyolipoma

87 Atypical Epithelioid Angiomyolipoma

88 Atypical Epithelioid Angiomyolipoma

89 Atypical Epithelioid Angiomyolipoma

90 Atypical Epithelioid Angiomyolipoma

91 SDHB Mutant RCC

92 SDH Mutant RCC Families with hereditary paraganglioma syndrome occasionally have members with RCC Type 4: Germline SDHB mutations (PGL4)

93 Kreb Cycle

94

95 SDH Mutant RCC: Solid

96 SDH Mutant RCC: Cystic

97 SDH Mutant RCC: Inclusions

98 SDH Mutant RCC: Inclusions

99 SDH Mutant RCC: Inclusions Courtesy of: Dr. Anthony Gill, Royal North Shore, Sydney

100 Housley et al. Histopathol 2010;56:401 1) Inclusions are abnormal mitochondria 2) Contain degenerating cristae and ground substance, but retain the mitochondrial double membrane. 3) Mitochondria are as large as the adjacent nucleus.

101 SDH Mutant RCC Courtesy of: Dr. Anthony Gill, Royal North Shore, Sydney SDHB

102 Immunohistochemistry for SDH Courtesy of: Dr. Anthony Gill, Royal North Shore, Sydney SDHB lost SDHB normal

103 SDH Mutant RCC: Recognition Oncocytic renal neoplasm with eosinophilic cytoplasmic inclusions Verification of SDHB loss by IHC Associated neoplasms Family history of familial paraganglioma syndrome SDHB mutant GISTs

104 3. Eosinophilic, But Not Oncocytoma or Chromophobe

105 Translocation TFE3/Xp11.2

106 Xp11.2 Renal Translocation Carcinomas Characterized by translocation creating TFE3 gene fusion Heterogeneous morphology and immunophenotype Of RCC in children, common subtype Some associated with past chemotherapy Can be indolent, even with nodal mets Deaths reported Occurs in adults Aggressive compared to other types? More rapid course?

107 Xp11/TFE3 RCC

108 Xp11/TFE3 RCC

109 Xp11/TFE3 RCC

110 Lymph Node Core Biopsy: Xp11/TFE3 RCC

111 Xp11/TFE3 RCC: Well-formed papillae

112 Xp11/TFE3 RCC: Dimorphic

113 Xp11/TFE3 RCC: Dimorphic

114 Cytokeratin PAX8

115 Conventional Cytogenetics

116

117 FISH: TFE3 Break-apart

118 When should we test retrospectively? Unusual papillary carcinoma Abundant clear or granular cytoplasm Nested architecture Granular cytoplasm Psammoma bodies!!!!! Biphasic (dimorphic) pattern Central small cells with pyknotic nulclei surrounded by rim of larger cells

119 When should we test retrospectively? Immunohistochemical Screening Cytokeratin negative RCC CK mix CK 7 Capthesin-K positive (sufficient)? TFE3 positive (sufficient)? Technically challenging

120 Papillary RCC

121 Papillary RCC, Type I

122 Papillary RCC, Type I

123 Papillary RCC, Type I CK7

124 Papillary RCC, Type I

125 Papillary RCC solid type with eosinophilic cytoplasm

126 Papillary RCC solid type with eosinophilic cytoplasm

127 Papillary RCC solid type with eosinophilic cytoplasm

128 Papillary RCC, Type II

129 Papillary RCC, Type II

130 Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC)

131 HLRCC Autosomal dominant syndrome Leiomyomas of skin and uterus Renal cell carcinoma Germline activating mutation in fumarate hydratase

132 HLRCC Syndrome Spectrum of neoplasia Leiomyomas of skin and uterus Most patients develop cutaneous leiomyomas Early hysterectomy for myomas Renal carcinomas Often solitary and unilateral Low penetrance (20-35%)

133 Am J Surg Pathol 2007;31(10):

134 Renal Cell Carcinoma in HLRCC

135 Renal Cell Carcinoma in HLRCC

136 Renal Cell Carcinoma in HLRCC

137 Renal Cell Carcinoma in HLRCC: Perinucleolar Halo

138 Renal Cell Carcinoma in HLRCC: Type II Papillary

139 Renal Cell Carcinoma in HLRCC: Complex Secondary Papillae

140 Renal Cell Carcinoma in HLRCC: Solid

141 Renal Cell Carcinoma in HLRCC: Cribriform

142 Renal Cell Carcinoma in HLRCC: Spindled

143 HLRCC: Recognition Unusual RCC with features of type II Papillary RCC and perinucleolar halos Multiple cutaneous or uterine leiomyomas Uterine leiomyomas <30 years of age Differential Diagnosis (solitary, unilateral) Papillary RCC, Type II Collecting Duct Carcinoma Translocation RCC

144 Acquired Cystic Kidney Disease RCC

145 1) 35% of patients on dialysis get ACKD 2) 5.8% of these patients develop RCC 1) Increasing percent of patients get ACKD with increased number of years on dialysis 2) Reports that 3-7% develop RCC

146 ACKD-RCC most common subtype in ESRD Represented dominant mass in 23%

147

148 ACKD-RCC: Papillary Architecture

149 ACKD-RCC: Sieve-like Pattern

150 ACKD-RCC: Sieve-like Pattern

151 ACKD-RCC: Sieve-like Pattern

152 ACKD-RCC: Mixed Sieve and Papillary

153 Tickoo et al. SHS #1 SHS #2 SHS #3

154 Oxalate Crystals

155

156 Background Cysts: Variation

157 Background Cysts: Variation

158 Background Cysts: Eosinophilic Cells

159 Background Cysts: Oxalate Crystals

160 Background Cysts: Tumorlet

161 Immunophentype Antibody ACKD-RCC Papillary RCC CK7 - + Racemase + +

162 CK 7: Negative

163 Clinical Behavior Frequently present at lower stage because patients are on surveillance May explain relatively indolent course Metastases and tumor related deaths do occur

164 Summary 1. Chromophobe vs. Oncocytoma 2. Tumors Resembling Onco/Chromo 3. Eosinophilic, but not Onco/Chromo

165 Summary 1. Chromophobe vs. Oncocytoma -- Gray zone cases of LMP 2. Tumors Resembling Onco/Chromo 3. Eosinophilic, but not Onco/Chromo

166 Summary 1. Chromophobe vs. Oncocytoma 2. Tumors Resembling Onco/Chromo -- Clear cell RCC -- Birt Hogg Dubé RCC -- Low grade tubulocystic RCC -- Epithelioid Angiomyolipoma -- SDHB mutant RCC 3. Eosinophilic, but not Onco/Chromo

167 Summary 1. Chromophobe vs. Oncocytoma 2. Tumors Resembling Onco/Chromo 3. Eosinophilic, but not Onco/Chromo -- Translocation RCC -- Papillary RCC -- HLRCC -- ACKD RCC

168 Renal Tumors with Eosinophilic Cytoplasm Jesse K. McKenney, M.D. Cleveland Clinic

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