Posted November 15, 2011

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A 54-year-old woman underwent gallbladder ultrasound for abdominal pain and an incidental right upper pole kidney mass was discovered. A subsequent CT scan demonstrated a homogeneous non-cystic mass measuring 4.9 cm in greatest dimension. There was no involvement of the right adrenal gland and no lymph node enlargement. A right partial nephrectomy was performed. Grossly the tumor was tan with a lobulated cut surface. There was no apparent central scar. There was no capsular or renal sinus invasion. The renal vein was not involved.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 36, and is chromophobe renal cell carcinoma.

Criteria for Diagnosis and Comments:
The diagnosis is chromophobe renal cell carcinoma (ChRCC). Microscopically, the tumor cells show mild cytologic atypia with nucleoli visible only on intermediate power (200x) (Fuhrman grade 2) and ample granular amphophilic cytoplasm. There are large polygonal cells showing pale cytoplasm and thickened “plant-like” cell membranes as well as smaller cells with more granular eosinophilic cytoplasm and variable perinuclear clearing. An “alveolar” growth pattern is observed focally with areas showing ”picket fence” arrays of tall cuboidal to columnar tumor cells lining up along delicate longitudinally oriented vessels.

Five percent of renal epithelial neoplasms and 7% of renal cell carcinomas are ChRCC. In the current W.H.O. classification system, conventional (clear cell), papillary, chromophobe, translocation, and unclassified types of renal cell carcinoma are recognized. Older terminology included descriptions of “granular” and “eosinophilic” variants of renal cell carcinoma that may represent either conventional or ChRCC.

Stage I-II ChRCC are associated with significantly better survival compared to same stage conventional or papillary types. Fuhrman grade is usually low (1-2) in ChRCC given the typically small nucleoli. Still, ChRCC certainly has malignant potential and can be associated with sarcomatoid transformation and metastasis.

Renal oncocytoma is nearly always in the differential diagnosis for cases of ChRCC. Morphologically, oncocytomas are classically associated with central scarring and a “mahogany” (as opposed to “beige” for ChRCC) color grossly, prominent nesting, more rounded nuclear borders and prominent nucleoli. Multinucleation is thought to be more widespread and with more nuclei per cell than in ChRCC, but perinuclear clearing is less common and less pronounced in oncocytoma. Oncocytomas can show prominent cystic changes in which the cells are oriented in a linear fashion similar to ChRCC, but the alveolar architecture with underlying delicate vessels as well as the thickened cell walls are not seen.

One explanation for the morphologic similarity between ChRCC and oncocytoma is their common line of derivation. Both tumors show features of differentiation similar to the normal intercalated cell of the collecting duct. Very rare tumors have been reported with convincing features of both oncocytoma and ChRCC (“hybrid” tumors), an observation that is thought to support this theory of a common line of origin.

Electron microscopy is useful in differentiating oncocytoma from ChRCC, but is rarely needed if tumors are thoroughly sampled and carefully reviewed by light microscopy. The cytoplasm of tumor cells is replete with mitochondria in oncocytoma and membrane bound vesicles in ChRCC. Hale’s colloidal iron can also be useful in experienced hands, showing diffuse cytoplasmic staining in ChRCC and only focal luminal staining in oncocytoma. This stain is technically challenging to perform and often difficult to interpret.

Immunostaining for various cell adhesion proteins holds some promise for reliably differentiating ChRCC from oncocytoma and other renal cell carcinomas, but these data are not mature.

• Renal Oncocytoma
  Though often a challenge, these are classically differentiated from ChRCC by a darker color grossly and the presence of a central scar as well as a nested (as opposed to alveolar) growth pattern, a more uniform cell population (versus mixed large pale cells and small eosinophilic cells), round nuclear contours, absent perinuclear clearing, and more frequent multinucleation.
• Epithelioid Angiomyolipoma
  Polygonal cells with pale to granular eosinophilic cytoplasm can be seen in this tumor, though they typically have very prominent nucleoli (unlike ChRCC) and show at least focally spindled architecture or areas of triphasic angiomyolipoma. Expression of melanocytic markers (e.g. HMB45, Mart1, MiTF, and MelanA) also helps distinguish this from ChRCC.
• Metastatic Hepatocellular Carcinoma
  An uncommon, but recognized, occurrence; this can be usually be distinguished from primary ChRCC by greater cytologic atypia and prominent nucleoli, as well as greater lipid content in the tumor cells. Immunostaining for HepPar-1, cytoplasmic TTF-1 or detection of albumin mRNA by ISH is confirmatory.
• Conventional (Clear Cell) Renal Cell Carcinoma
  This is particularly a problem if the small eosinophilic cells of ChRCC are sparse. Conventional renal cell carcinomas can show slightly granular cytoplasm, though they often have a more diffuse growth pattern with a characteristic net-like arrangement of thin-walled vessels. Nucleoli are often more prominent (higher Fuhrman grade) in conventional renal cell carcinoma as well.