Renal Tumors with Eosinophilic Cytoplasm: 2013 Classification · Renal Tumors with Eosinophilic Cytoplasm: 2013 Classification. ... Mixed Sieve and Papillary. ... Renal Tumors with

Jesse K. McKenney, MDAssociate Head, Surgical Pathology

Renal Tumors with Eosinophilic Cytoplasm:

2013 Classification

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– Papillary, eosinophilic– Chromophobe– Collecting duct

• Medullary– Unclassified

– Xp11/TFE3– TFEB– ACKD associated– Birt-Hogg-Dubé– HLRCC– Tubulocystic– SDHB

Renal Neoplasms with Eosinophilic Cytoplasm

1. Chromophobe vs. Oncocytoma2. Tumors Resembling Onco/Chromo3. 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

Clear Cell RCCClear Cell RCCChromophobe RCC: Broad 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; 1:41-52Amin 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 Intravascular Tumor

Oncocytoma

Oncocytoma with Degenerative Atypia

Prototypical Chromophobe RCC

vs.

Prototypical Oncocytoma

Oncocytic

“Gray Zone”

Tumors

Gray Zone

Oncocytoma Chromophobe

RCC, Unclassified

OncocytomaChromophobe

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?



The Median Assumption

Oncocytoma Chromophobe

Clinical OutcomeResponse to Therapy

Specific genetic alteration by ?Cytokeratin 7

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?

Diagnosis?CK7

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 eosinophiliaCAIX +, 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


HOT


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


Epithelioid Angiomyolipoma

Angiomyolipoma

Angiomyolipoma: Classic

Epithelioid AngiomyolipomaActin +, HMB-45 +, CK -

PAX8 -, CD117 -

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 mitochondria2) Contain degenerating cristae and ground substance, but

retain the mitochondrial double membrane. 3) Mitochondria are as large as the adjacent nucleus.

•

SDH Mutant RCC

SDHBCourtesy of: Dr. Anthony Gill , Royal North Shore, Sydney

Immunohistochemistry for SDH

SDHB lost SDHB normalCourtesy of: Dr. Anthony Gill , Royal North Shore, Sydney

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 ICK7


Papillary RCCsolid 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: 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: Mixed Sieve and Papillary

SHS #1

SHS #2 SHS #3

Tickoo et al.

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


Summary

1. Chromophobe vs. Oncocytoma-- Gray zone cases of LMP

2. Tumors Resembling Onco/Chromo3. Eosinophilic, but not Onco/Chromo

Summary

1. Chromophobe vs. Oncocytoma2. 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


-- Translocation RCC-- Papillary RCC-- HLRCC -- ACKD RCC

Renal Tumors with Eosinophilic Cytoplasm

Jesse K. McKenney, M.D.Cleveland Clinic

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Renal Tumors with Eosinophilic Cytoplasm: 2013 Classification · Renal Tumors with Eosinophilic Cytoplasm: 2013 Classification. ... Mixed Sieve and Papillary. ... Renal Tumors with