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Kidney tumor - adult malignancies

Adult renal cell carcinoma

Chromophobe type, renal cell carcinoma


Reviewers: Sean Williamson, M.D. (see Reviewers page)
Revised: 7 August 2012, last major update June 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

See also Eosinophilic variant

General
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● Tumor cells with well-defined cell borders, cytoplasm is voluminous, pale and finely reticular, low grade nuclei
● First described in 1985 (Virchows Arch B Cell Pathol Incl Mol Pathol 1985;48:207)
Cell of origin: intercalated cell of cortical collecting duct

Epidemiology
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● 5% of adult renal epithelial tumors; ages 45+, no gender preference

Birt-Hogg-Dube’ syndrome
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● Multiple tumors (mean 5.3), mean age 51 years at first renal tumor diagnosis, usually bilateral chromophobe carcinomas, oncocytomas or hybrids, also may have oncocytosis (Am J Surg Pathol 2002;26:1542)
● Syndrome is autosomal dominant and features small dome-shaped papular fibrofolliculomas of face, neck and upper trunk, renal tumors, lung cysts and spontaneous pneumothorax
● Due to mutations in folliculin gene (FLCN) at 17p11.2 (Cancer Cell 2002;2:157)

Clinical description
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● Most are T1-T2 N0 M0 (i.e. confined within the renal capsule, Cancer 2004;100:1406) and have good prognosis (5 year survival is 78-92%, 3-6% die of disease)
● Same behavior as clear cell when stratified by grade/stage

Poor prognostic factors
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● Sarcomatoid change, microscopic necrosis, high stage, small vessel invasion (Am J Surg Pathol 2008;32:1822, Am J Surg Pathol 2011;35:962)

Case reports
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● 45 year old woman with tumor with sarcomatoid and squamous differentiation (Arch Pathol Lab Med 2008;132:1672)
● 72 year old man with tumor with sarcomatoid and collecting duct carcinoma components (Arch Pathol Lab Med 2003;127:e38)
● 74 year old man with tumor with osteosarcoma-like differentiation (Am J Surg Pathol 2002;26:1358)

Gross description
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● Well-circumscribed, tan brown (same color as cortex), geographic necrosis, mean 8 cm, small cysts, 8% multifocal, 3% bilateral
● Occasionally central scar

Gross images
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Well-circumscribed tumor


Central scar

Encapsulated nodular tumor of upper pole

Yellow-brown tumor with granular cut surface

Nodular tumor with focal hemorrhage and necrosis

Micro description
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● Compact architecture of nests or broad alveoli/trabeculae, composed of large polygonal cells with "hard" or distinct cell border ("vegetable cells", due to cytoplasmic retraction)
● Abundant cytoplasm with reticular pattern (light/pale, flocculent, not clear), also called type 3 cells, some have perinuclear halo or translucent zone (type 2 cells)
● Also type 1 cells that are small with solid, slightly granular, eosinophilic cytoplasm
● Usually lower grade nuclei, bunching of nuclear material at nuclear membrane; 50% have calcification
● Mitotic figures present but may be scant; usually no chicken wire vasculature (more fibrovascular than vascular)
● Fuhrman grading has no prognostic value (Am J Surg Pathol 2007;31:957)
● Recent study suggests that Paner grading system (Am J Surg Pathol 2010;4:1233) adds no prognostic value after considering TNM stage and sarcomatoid differentiation (Am J Surg Pathol;36:851)
● Type 1 cells: small cells with solid, slightly granular eosinophilic cytoplasm
● Type 2 cells: perinuclear halo or translucent zone
● Type 3 cells: large, polygonal cells with hard cell border, abundant cytoplasm with reticular pattern
● Note: formalin fixation may obscure cytoplasmic features (Arch Pathol Lab Med 2000;124:904)

Micro images
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Variably sized cells with abundant pale reticular or flocculent cytoplasm and distinct cell borders


Granular and transparent cells are intermixed in an irregular pattern

   
The transparent cells are oriented along the thin vascular septa


Multinucleated cells are occasionally seen

               
Various images


Nuclear grooves and inclusions


Obscured cytoplasmic features with formalin fixation


Birt-Hogg-Dubé associated tumors

           
Sarcomatoid features


Stain images:

Classic and eosinophilic variant and oncocytoma: H&E and Hale’s colloidal iron

Hale's colloidal iron #1; #2; #3; #4


CK7+


c-kit+ (Fig. E)


Parvalbumin+


E-cadherin+


MUC1+ (Fig. F)

Comparison with oncocytoma:
       
Left to right: S100A1-, EpCAM+, claudin7+

Cytology description
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● Single cells and small, discohesive, monolayered groups; cells vary in size from small to large
● Large cells show clear, flocculent cytoplasm with small, eccentric nuclei and frequent binucleation, occasional nuclear pseudoinclusions
● Small cells usually have dense, homogeneous cytoplasm, clear cytoplasmic spaces resembling perinuclear halos, binucleation and marginal nuclear location
● No necrosis, no basement membrane or other stromal material (Cytopathology 2009;20:44, Cancer 1997;81:122)

Cytology images
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Large round to oval cells (Diff-Quik)

Plant-like large cells with very sharp cell borders and small cells with dense cytoplasm and smaller nuclei

Cells have sharp cell borders, pale cytoplasm, round nuclei with slightly coarse chromatin and small nucleoli

Positive stains
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Most commonly used:
● Hale’s colloidal iron (stains acid mucopolysaccharides in microvesicles, diffuse and strong, reticular, J Pathol 1988;155:277, Am J Surg Pathol 1998;22:419)
● Low molecular weight keratin (CK 8/18), CK7 (diffuse and strong, Am J Clin Pathol 2007;127:225, compared to oncocytoma with scattered single cells)

Other positive stains:
● EMA/MUC1 (diffuse cytoplasmic, (Mod Pathol 2004;17:180)
● Parvalbumin (calcium binding protein, Mod Pathol 2001;14:760)
● CD117/c-kit (membranous, Mod Pathol 2004;17:611 Am J Surg Pathol 2004;28:676)
● E-cadherin, claudin7 (distal nephron marker, Arch Pathol Lab Med 2007;131:1541, Hum Pathol 2009;40:206)
● Kidney-specific cadherin (Am J Clin Pathol 2006;126:79, Mod Pathol 2005;18:933)

Variable expression:
● RCC-Ma, CD10 (Mod Pathol 2004;17:1455)

Negative stains
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● Vimentin (or weak), N-cadherin, low Ki-67 labeling index (Mod Pathol 1999;12:310, Mod Pathol 1998;11:1115)

Suggested panels
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● Chromophobe versus oncocytoma, papillary or clear cell: beta defensin1+, parvalbumin+, vimentin- in 100% (8/8) (Am J Surg Pathol 2003;27:199)
● Chromophobe versus oncocytoma or clear cell: vimentin-, GSTalpha-, EpCAM+ (strong) (Arch Pathol Lab Med 2007;131:1290)
● CK7+ diffusely positive in chromophobe vs scattered single cells in oncocytoma; second line markers include CD117+
● Chromophobe versus other renal carcinomas: CK7+, CK8+, CK18+ and vimentin- (Am J Surg Pathol 2005;29:747)

Electron microscopy description
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● 150-350 nm membrane bound microvesicles (possibly from mitochondrial outpouchings), abnormal but few mitochondria with tubulovesicular cristae, rare short and stubby microvilli (Am J Surg Pathol 2000;24:1247)
● Eosinophilic variant is similar but with more mitochondria

Electron microscopy images
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Cytoplasmic vesicles of 150 to 300 nm


Cytoplasmic vesicles are often paranuclear with mitochondria present in the more peripheral cytoplasm

Molecular / cytogenetics description
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● FISH may be more helpful than karyotyping (Am J Clin Pathol 2010;133:116)
● Multiple monosomies; usually hypodiploid (Hum Pathol 1998;29:1181)
● 80% show loss of 1, 2, 6, 10, 13, 17, 21 or Y
● Also mitochondrial (mt) DNA rearrangements
● Loss of 3p in 25% of cases; sarcomatoid tumors have different genetic abnormalities (Mod Pathol 2007;20:303)

Cytogenetics images
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Loss of chromosome 2 in chromophobe carcinoma versus no loss in oncocytoma

Differential diagnosis
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Oncocytoma: no hard cell membranes, no mitotic figures, no loss of chromosomes 2, 6, 10 or 17 (Mod Pathol 2005;18:161)
● Eosinophilic papillary or clear cell carcinomas: Hale’s colloidal iron negative


Eosinophilic variant of chromophobe renal cell carcinoma

General
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● 80% eosinophilic cells
● 40% of chromophobe carcinomas
● First described in 1988 (J Pathol 1988;155:277)
● No difference in prognosis from classic type (Eur J Surg Oncol 2008;34:687), but may mimic oncocytoma grossly/microscopically

Gross description
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● 11% bilateral, 22% multifocal, brown color resembles oncocytoma

Micro description
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● Large tumor cells with fine eosinophilic granularity, peripheral accentuation of cytoplasm, perinuclear halo, wrinkled nuclear membrane and coarse chromatin (resembles koilocytes), still some classic chromophobe cells
● Often focal areas resembling oncocytoma (Am J Surg Pathol 2008;32:1822)

Micro images
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Fig. C/D


Fig. 2A-2C


Hale's colloidal iron+ (Fig. C/D)


Parvalbumin+ (Fig. C/D)

Cytology description
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● Nuclear atypia present

Cytogenetics images
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Resembles oncocytoma due to monotonous population of cells with granular to focally fluffy cytoplasm, but also occasional cells with very large nucleus and focal, slight perinuclear clearing

Positive stains
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● Hale’s colloidal iron
● Also CK7, CK18

Negative stains
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● Vimentin

Cytogenetics description
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● Similar to classic chromophobe carcinoma (loss of #1, 2, 6, 10, and 17, Mod Pathol 2005;18:161)

Electron microscopy description
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● Abundant mitochondria with variable size and shape and predominantly tubulocystic cristae, also outpouchings of outer mitochondrial membranes resembling cytoplasmic microvesicles
● Abundant microvesicles, some containing homogenous, electron-dense, finely granular matrix similar to mitochondrial matrix

Differential diagnosis
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Eosinophilic variant of clear cell carcinoma: vimentin+, Hale’s colloidal iron negative, different cytogenetics
Oncocytoma: no classic areas of chromophobe carcinoma, no prominent cell membranes, no crinkled or raisinoid nuclei, no binucleation, Hale’s colloidal iron negative, CK7 positive in only individual scattered cells, no loss of chromosome 2, 6, 10 or 17, no abundant microvesicles

End of Kidney tumor - adult malignancies > Adult renal cell carcinoma > Chromophobe type, renal cell carcinoma


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