How are atypical clear cell renal cell carcinoma (CCRCC) variants characterized on immunohistochemical stains?

Updated: Mar 11, 2019
  • Author: Ronald J Cohen, MB, BCh, PhD, FRCPA, FFPATH; Chief Editor: Liang Cheng, MD  more...
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Distinguishing between unusual variants of the common RCC histologic types and other types of tumors can be difficult. For example, CCRCCs composed predominantly of granular eosinophilic cells may show a morphological resemblance to the eosinophilic variant of chromophobe RCC (chRCC) or to oncocytoma. Immunohistochemical markers suggested for this distinction include E-cadherin, CD117/KIT, or parvalbumin, which are rarely expressed in CCRCC.

By contrast, E-cadherin is positive in 95-100% of chRCC and 47% of oncocytomas, [66, 75] CD117/KIT is positive in 55-88% of chRCCs and 59-100% of oncocytomas, [71, 72, 75] and parvalbumin expression is positive in 80-100% of both chRCCs and oncocytomas. [70, 74]

Other markers that may prove useful include the RCC marker and vimentin. These are commonly expressed in CCRCC, including the granular eosinophilic variant. [68, 69] By contrast, the RCC marker is expressed in only 0-4% of chRCC and 0-14% of oncocytomas, [67, 68, 75, 79] while immunostaining for vimentin is positive in only 1-25% of oncocytomas and is negative in chRCC. [63, 70, 75, 80]

Rare tumors composed mainly of clear cells but with a predominant papillary architecture tend to be classified as papillary RCC with extensive clear cell change. However, genetic analysis has, in some cases, found specific translocations characteristic of Xp11 translocation RCC, a tumor with clear and/or eosinophilic cells that can show both papillary architecture and a nested pattern with vascular stroma similar to compact-alveolar (nested) CCRCC.

Xp11 translocation RCCs usually occur in children but can occasionally arise in adults. They can be identified by nuclear immunostaining for the TFE3 protein. [11] In other such cases, genetic analysis has revealed alterations typical of CCRCC (loss of chromosomes 3p, 7, and 17) [81] or a combination of the alterations seen in CCRCC (loss of 3p and 14, gain of 5q) and papillary RCC (gain of chromosomes 7 and 12). [82]

Histologic typing of such tumors remains controversial because the immunostaining profiles for CCRCC and papillary RCC can be similar regarding vimentin, CD10, RCC marker, and EMA/MUC1. [75, 76] Because few CCRCCs express AMACR or CK7, these immunohistochemical markers may prove useful for distinguishing CCRCC from papillary RCC with extensive clear cell change and/or predominantly nonpapillary (solid) architecture. AMACR is expressed in 87-100% of papillary RCCs of both type I and type 2, [73, 75] while CK7 expression is present in 80-87% of papillary RCCs. [60, 61]

RCC with predominantly papillary architecture but extensive clear cell cytology can be characterized using both genetic analysis (chromosomes 3p, 7, 17, and Y) and immunostaining (AMACR, CK7, TFE3). In a study of 14 such cases, [83] the immunostaining and genetic profiles correlated well, and this approach allowed classification of 9 tumors as papillary RCC and 3 as CCRCCs, leaving only 2 cases as unclassified RCC.

CCRCC with extensive cystic degeneration must be distinguished from multilocular cystic renal cell carcinoma (MCRCC), which is recognized in the 2004 WHO classification as a separate type of low-grade tumor with a very good prognosis. [84] MCRCC may have clear cells lining the cysts and small nests of clear cells within the fibrous septa; however, this tumor can be distinguished from CCRCC with cystic change, or from CCRCC arising within the wall of a pre-existing cyst, by the absence of expansile solid nodules. [85]

Low-grade CCRCC with a predominant component of metaplastic smooth muscle stroma must be distinguished from mixed epithelial and stromal tumor of the kidney (MESTK), a benign tumor in which the epithelial components are predominantly cystic, clear cells are rare, the epithelial cells do not express S100 protein, and the spindled cells are immunopositive for ER in 64% and PR in 32% of cases. [86, 87]

By contrast, in all CCRCCs with smooth muscle stroma tested to date, cystic components were rare, the epithelial components were positive for S100, and the spindled cells were negative for ER and PR. [56, 57] The smooth muscle component of this CCRCC variant has a morphological resemblance to muscle-predominant renal angiomyolipoma or to leiomyoma but can be distinguished by immunostaining for HMB45, which is positive in the latter 2 tumor types. [88]


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