Case of the Month: Kidney

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2013, case 10, and is a chromophobe renal cell carcinoma.

Chromophobe renal cell carcinoma (chRCC) is a rare variant that represents approximately 5% of neoplasms of tubular renal epithelium. The mean age of occurrence is in the sixth decade. Clinically, the traditional triad of hematuria, pain and flank mass is present in only a small percentage of patients, and often indicates advanced disease. These tumors tend to be larger than clear cell and papillary RCC at presentation.

Macroscopically, chRCC is a well circumscribed, unencapsulated tumor with a typically pale beige and tan cut surface. Small areas of hemorrhage, necrosis, calcification, ossification or scarring may be present, but are not typical. Under light microscopy, chRCC is characterized by large polygonal cells with granular acidophilic cytoplasm arranged in nests, with interspersed thick-walled and eccentrically hyalinazed blood vessels. Chromophobe RCC as a rule has 2 types of cells but the proportion of each may vary. Tumors with cells containing abundant pale cytoplasm (typical variant) usually have a sheet-like or alveolar architecture and the cytoplasm can have a foamy appearance. The eosinophilic variant usually shows an alveolar, nested or sheet like architecture, with cells characterized by abundant eosinophilic cytoplasm, perinuclear clearing and peripheral accentuation of the cell membranes ("plant cell" appearance). Binucleation is typical and relatively common. Tumors with mixed histology (mixed variant) can also be seen, and are characterized by the eosinophilic cells being arranged in the center of the sheets or nests of tumor cells, with a rim of pale cells at the periphery. In general, the nested pattern appears to be more common in the eosinophilic variant, while tumors primarily composed of clear cells more often exhibit an alveolar or solid growth pattern. Tumor size, tumor necrosis and sarcomatoid features are associated with aggressive behavior. Metastases and local recurrence are associated mainly with sarcomatoid transformation.

A distinctive feature is diffuse, intense reticular staining of intracytoplasmic microvesicles by Hale colloidal iron, which highlights the content of mucopolysaccharides that is seen by electron microscopy. Immunohistochemical findings include positivity for pancytokeratin, CK7 (diffuse), EMA, parvalbumin, and CD117(KIT), and negative staining for vimentin, CD10 and AMACR. RCC marker may be variable (+/-). Lack of vimentin expression, in particular, is a helpful hint for diagnosis and has been reported for almost 100% of the chRCC cases in the literature.

Chromophobe RCC typically has a hypodiploid genome due to chromosomal losses of Y, 1, 2, 6, 10, 13q, 17 and 21. Birt-Hogg-Dube Syndrome (BHDS), an autosomal dominant condition characterized by benign cutaneous tumors and pulmonary cysts, also predisposes to the development of multifocal and bilateral chromophobe RCC and/or oncocytoma. BHDS is the consequence of inactivating mutations in the folliculin (FLCN) gene located on the short arm of chromosome 17 at position 11.2(17p11.2),which functions as a tumor suppressor gene. The most common renal cell tumor (50% of the cases) seen in BHDS is the oncocytic hybrid tumor, which is a hybrid between oncocytoma and chromophobe carcinoma. Chromophobe RCC and renal oncocytomas have been observed in 33% and 5% of BHDS patients, respectively.

The main morphologic differential diagnosis for chRCC involves renal neoplasms with eosinophilic cells, including: clear cell RCC with eosinophilic cells, renal oncocytomas, eosinophilic variant of papillary RCC (type 2) and epithelioid angiomyolipoma. Distinguishing chRCC from clear cell RCC with eosinophilic cytoplasm and oncocytomas can be diagnostically challenging. Chromophobe RCC demonstrates morphologic overlap with clear cell RCC, especially when showing eosinophilic cytoplasm. Light microscopic features of clear cell RCC include compact alveoli, tubules, prominent delicate vascular network and clear cytoplasm. Clear cell RCC are typically negative for Hale's colloidal iron, CK7 and CD117 and react with vimentin and CD10. Lack of expression for CD117 and parvalbumin is a typical feature of clear cell RCC. The classic cytogenetic finding in clear cell RCC is a deletion of chromosome 3p.

Distinguishing features of oncocytoma includes uniform cells with very round and regular nuclei, eosinophilic granular cytoplasm and edematous stroma. Oncocytoma may contain areas of nuclear pleomorphism and occasional foci with very large nuclei. Hale colloidal iron stain may be faintly positive, mainly near the luminal surface, and the tumor cells are focally positive for CK7. Immunostains for vimentin and RCC marker are usually negative. Losses in chromosome 1 are the classic cytogenetic finding.

Papillary renal cell carcinoma type 2 is included in the differential diagnosis of chRCC due to the eosinophilic appearance of the tumor cells. However, this type of RCC is characterized by a papillary or tubular architecture. The cells have high nuclear grade and prominent nucleoli. The accumulation of foamy histiocytes in the stroma is a characteristic feature. Immunohistochemical findings include positivity for the RCC marker, pancytokeratin, low molecular weight cytokeratins and CD10. Lack of immunoreactivity for CD117 and parvalbumin is also typical of papillary RCC. Papillary RCC is most commonly associated with trisomy of chromosome 7 and 17. The molecular pathway of Type 2 papillary RCC is probably associated with a mutation in the fumarate hydratase gene localized on chromosome 1, leading to upregulation of hypoxia-inducible factors.

Epithelioid angiomyolipoma is a malignant mesenchymal tumor characterized by the proliferation of epithelioid cells with granular eosinophilic cytoplasm. The cells often resemble ganglion cells with prominent nuclei and macronucleoli. Epithelioid angiomyolipoma expresses melanocytic markers (HMB-45, HMB-50, Mart 1/Melan-A and microphthalmia transcription factor), with variable expression of smooth muscle markers. CD117 expression has been reported in angiomyolipoma.

1. Which staining pattern is most consistent with chromophobe RCC?
   
   1. Vimentin-, Hale's colloidal iron+ (diffuse), CK7+ (diffuse), CD10-, CD117+
   2. Vimentin-, Hale's colloidal iron+ (focal), CK7+ (focal), CD10+, CD117+
   3. Vimentin-, Hale's colloidal iron-, CK7-, CD10-, CD117-
   4. Vimentin+, Hale's colloidal iron-, CK7-, CD10+, CD117-
2. Which histologic feature has been associated with metastases and local recurrence?
   
   1. Abundant microvesicles on ultrastructural examination
   2. Binucleation
   3. Fuhrman nuclear grade
   4. Sarcomatoid transformation
3. Which of the following statements regarding hereditary chromophobe RCC is not true?
   
   1. Aggressive behavior has been associated with the hereditary form of this tumor
   2. Birt-Hogg-Dube Syndrome is linked to FLCN gene mutation mapped to chromosome 17p11.2
   3. Birt-Hogg-Dube Syndrome is an autosomal dominant condition characterized by benign cutaneous tumors, pulmonary cysts and multifocal and bilateral renal cancer.
   4. The most common renal cell tumor seen in Birt-Hogg-Dube Syndrome is the oncocytic hybrid tumor.

1. Amin MB, et al. Chromophobe renal cell carcinoma: Histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 Cases. Am J of Surg Path. 2008; 32(12):1822-1834.
2. Deng FM, et al. Histologic variants of renal cell carcinoma: Does tumor type influence outcome? Urol Clin N Am. 2012; 39:119-132.
3. J.M. Hagenkord, et al. Clinical genomics of renal epithelial tumors. Cancer Genetics. 2011; Jun; 204: 285-297.
4. Liu L, et al. Immunohistochemical analysis of chromophobe renal cell carcinoma, renal oncocytoma, clear cell carcinoma: An optimal and practical panel for differential diagnosis. Arch Pathol Lab Med. 2007; 132: 1290-1297.
5. Makhlouf HR, el al. Expression of KIT (CD117) in angiomyolipoma. Am J Surg Pathol. 2002; 26(4):493-497.
6. Walter B, et al. Immunohistochemical marker panel differentiates between the three most common subtypes of renal cell carcinoma independent from histomorphologic criteria. Virchows Arch. 2012; 460:343–352.

2012
Evelyn Polanco, MD
PGY-1 Resident in Pathology
Medical College of Wisconsin

Saul Suster, MD
Surgical Pathology Committee
Medical College of Wisconsin
Milwaukee, WI

1. Vimentin-, Hale's colloidal iron+ (diffuse), CK7+ (diffuse), CD10-, CD117+ (a). 
2. Sarcomatoid transformation (d). 
3. Aggressive behavior has been associated with the hereditary form of this tumor (a).