Renal Tumors with Eosinophilic Cytoplasm: 2013 Classification Jesse K. McKenney, MD Associate Head, Surgical Pathology
Renal Epithelial Neoplasia History 1981: WHO Classification of Renal Neoplasms 1. Adenoma 2. Carcinoma (RCC or other)
Renal Cell Carcinoma: Classification 1997
Renal Cell Carcinoma: Classification 1997
AFIP, Third Series, Fascicle 11 (1994)
Renal Neoplasms with Eosinophilic Cytoplasm 1997 Renal cell carcinoma Clear cell, eosinophilic Chromophobe Papillary, eosinophilic Collecting duct Medullary Unclassified Misc Oncocytoma AML
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
Renal Neoplasms with Eosinophilic Cytoplasm 1. Chromophobe vs. Oncocytoma 2. Tumors Resembling Onco/Chromo 3. Eosinophilic, but not Onco/Chromo
1. Chromophobe RCC vs. Oncocytoma
Chromophobe RCC: Prototypical Features
Chromophobe RCC (Eosinophilic): Nuclear Features Tickoo et al. Am J Clin Pathol 1998;110(6):782-87.
Chromophobe RCC (Classic-Plant Cell Type)
Chromophobe RCC: (Classic-Plant Cell Type)
Chromophobe RCC: Morphologic Heterogeneity
Chromophobe RCC: Clear Broad Cell RCC alveolar architecture
Chromophobe RCC: Broad alveolar architecture
Chromophobe RCC: Small nested pattern
Chromophobe RCC: Mixed eosinophilic/classic
Chromophobe RCC: Oncocytoma-like Foci
Chromophobe RCC: Adenomatous
Chromophobe RCC: Adenomatous
Chromophobe RCC: Microcystic/Cribriform
Chromophobe RCC: Halos are Sufficient
Metastatic Chromophobe
Oncocytoma
Oncocytoma
Oncocytoma
Oncocytoma
Oncocytoma
Oncocytoma
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
Oncocytoma with Extrarenal Invasion
Oncocytoma with Extrarenal Invasion
Oncocytoma with Extrarenal Invasion
Oncocytoma with Intravascular Tumor
Oncocytoma
Oncocytoma with Degenerative Atypia
Prototypical Chromophobe RCC vs. Prototypical Oncocytoma
Oncocytic Gray Zone Tumors
Gray Zone Oncocytoma Chromophobe
RCC, Unclassified Chromophobe Oncocytoma
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
Adjunctive Studies in the Classification of Renal Neoplasia Immunohistochemistry Electron Microscopy Conventional cytogenetics FISH Gene expression array SNP array Sequencing mirna
Oncocytoma?
How Much Nuclear Variation is Allowable?
How Much Nuclear Variation is Allowable?
How Much Nuclear Variation is Allowable?
The Median Assumption Specific genetic Cytokeratin alteration 7 by? Oncocytoma Chromophobe Clinical Outcome Response to Therapy
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
Diagnosis?
Diagnosis?
Diagnosis?
Diagnosis?
CK7 Diagnosis?
Diagnosis Kidney, left, radical nephrectomy: Low grade oncocytic renal neoplasm (see comment)
Follow-up Liver Biopsy
Unclassified RCC
Unclassified RCC
Unclassified RCC
2. Other Renal Tumors That Resemble Oncocytoma and Chromophobe
Clear cell RCC
Clear Cell RCC
Clear RCC with cytoplasmic eosinophilia CAIX +, CD10+, CK7-
Clear Cell RCC: Rhabdoid
Birt-Hogg-Dubé Associated RCC
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
RCC Associated with Birt-Hogg-Dubé
RCC Associated with Birt-Hogg-Dubé HOT
RCC Associated with Birt-Hogg-Dubé
Birt-Hogg-Dubé Associated Oncocytosis
Birt-Hogg-Dubé Associated Oncocytosis
Birt-Hogg-Dubé Associated Renal Neoplasm
Birt-Hogg-Dubé Associated Renal Neoplasm
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
Tubulocystic RCC
Tubulocystic ********** Carcinoma
Tubulocystic ********** Carcinoma
Tubulocystic Carcinoma
Tubulocystic ********** Carcinoma
Epithelioid Angiomyolipoma
Angiomyolipoma
Angiomyolipoma: Classic
Epithelioid Angiomyolipoma Actin +, HMB-45 +, CK - PAX8 -, CD117 -
Atypical Epithelioid Angiomyolipoma
Atypical Epithelioid Angiomyolipoma
Atypical Epithelioid Angiomyolipoma
Atypical Epithelioid Angiomyolipoma
Atypical Epithelioid Angiomyolipoma
SDHB Mutant RCC
SDH Mutant RCC Families with hereditary paraganglioma syndrome occasionally have members with RCC Type 4: Germline SDHB mutations (PGL4)
Kreb Cycle
SDH Mutant RCC: Solid
SDH Mutant RCC: Cystic
SDH Mutant RCC: Inclusions
SDH Mutant RCC: Inclusions
SDH Mutant RCC: Inclusions Courtesy of: Dr. Anthony Gill, Royal North Shore, Sydney
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.
SDH Mutant RCC Courtesy of: Dr. Anthony Gill, Royal North Shore, Sydney SDHB
Immunohistochemistry for SDH Courtesy of: Dr. Anthony Gill, Royal North Shore, Sydney SDHB lost SDHB normal
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
3. Eosinophilic, But Not Oncocytoma or Chromophobe
Translocation TFE3/Xp11.2
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?
Xp11/TFE3 RCC
Xp11/TFE3 RCC
Xp11/TFE3 RCC
Lymph Node Core Biopsy: Xp11/TFE3 RCC
Xp11/TFE3 RCC: Well-formed papillae
Xp11/TFE3 RCC: Dimorphic
Xp11/TFE3 RCC: Dimorphic
Cytokeratin PAX8
Conventional Cytogenetics
FISH: TFE3 Break-apart
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
When should we test retrospectively? Immunohistochemical Screening Cytokeratin negative RCC CK mix CK 7 Capthesin-K positive (sufficient)? TFE3 positive (sufficient)? Technically challenging
Papillary RCC
Papillary RCC, Type I
Papillary RCC, Type I
Papillary RCC, Type I CK7
Papillary RCC, Type I
Papillary RCC solid type with eosinophilic cytoplasm
Papillary RCC solid type with eosinophilic cytoplasm
Papillary RCC solid type with eosinophilic cytoplasm
Papillary RCC, Type II
Papillary RCC, Type II
Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC)
HLRCC Autosomal dominant syndrome Leiomyomas of skin and uterus Renal cell carcinoma Germline activating mutation in fumarate hydratase
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%)
Am J Surg Pathol 2007;31(10):1578-85
Renal Cell Carcinoma in HLRCC
Renal Cell Carcinoma in HLRCC
Renal Cell Carcinoma in HLRCC
Renal Cell Carcinoma in HLRCC: Perinucleolar Halo
Renal Cell Carcinoma in HLRCC: Type II Papillary
Renal Cell Carcinoma in HLRCC: Complex Secondary Papillae
Renal Cell Carcinoma in HLRCC: Solid
Renal Cell Carcinoma in HLRCC: Cribriform
Renal Cell Carcinoma in HLRCC: Spindled
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
Acquired Cystic Kidney Disease RCC
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
ACKD-RCC most common subtype in ESRD Represented dominant mass in 23%
ACKD-RCC: Papillary Architecture
ACKD-RCC: Sieve-like Pattern
ACKD-RCC: Sieve-like Pattern
ACKD-RCC: Sieve-like Pattern
ACKD-RCC: Mixed Sieve and Papillary
Tickoo et al. SHS #1 SHS #2 SHS #3
Oxalate Crystals
Background Cysts: Variation
Background Cysts: Variation
Background Cysts: Eosinophilic Cells
Background Cysts: Oxalate Crystals
Background Cysts: Tumorlet
Immunophentype Antibody ACKD-RCC Papillary RCC CK7 - + Racemase + +
CK 7: Negative
Clinical Behavior Frequently present at lower stage because patients are on surveillance May explain relatively indolent course Metastases and tumor related deaths do occur
Summary 1. Chromophobe vs. Oncocytoma 2. Tumors Resembling Onco/Chromo 3. Eosinophilic, but not Onco/Chromo
Summary 1. Chromophobe vs. Oncocytoma -- Gray zone cases of LMP 2. Tumors Resembling Onco/Chromo 3. Eosinophilic, but not Onco/Chromo
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
Summary 1. Chromophobe vs. Oncocytoma 2. Tumors Resembling Onco/Chromo 3. Eosinophilic, but not Onco/Chromo -- Translocation RCC -- Papillary RCC -- HLRCC -- ACKD RCC
Renal Tumors with Eosinophilic Cytoplasm Jesse K. McKenney, M.D. Cleveland Clinic