How are typical clear cell renal cell carcinomas (CCRCCs) 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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CCRCC tends to express the low molecular weight cytokeratins (CK) characteristic of simple epithelia (CK7, 8, 18, and 19), in particular, the CK expressed most strongly by epithelial cells of the proximal convoluted tubules (CK8 and 18). Between 94-100% of CCRCCs stain positively with antibodies against CK18, while 14-40% are positive for CK8.

Immunoreactivity for CK7 (14-20%) and CK19 (13-20%) is less common. [60, 61] Coexpression of these CK has been associated with genomic stability, low grade, and favorable prognosis in CCRCC. [62]

Expression of CK7 was observed in all of the recently reported CCRCC variants with smooth muscle stroma, consistent with their low nuclear grades; however, CK19 expression was not determined. [56, 57] Most (87-100%) CCRCCs strongly express the intermediate filament vimentin, [61, 63] whereas positive immunostaining for high-molecular-weight cytokeratins (CKs 1-6 and 9-16) is extremely rare. [60, 61]

Overexpression of the epithelial marker EMA/MUC1 (determined as cytoplasmic and/or total cell membrane staining) is seen in 77-100% of CCRCCs. The proportion of positive cells increases with tumor grade. [64, 65, 66, 67]

Positive staining for the proximal tubular brush border antigens CD10 and RCC marker is reported for 82-94% and 47-85% of CCRCCs, respectively. [67, 68, 69] Relatively few CCRCCs are positive for expression of E-cadherin (5-14%), CD117/KIT (0-15%), parvalbumin (8-22%), or AMACR (4-25%). [63, 66, 70, 71, 72, 73, 74, 75] Thus, a standard immunoprofile expected for CCRCC is vimentin+ /EMA+ /CD10+ /RCC marker+ /AMACR- /CK7- /CK19- /CD117- /E-cadherin- /parvalbumin-. [76]

In a 2012 study, epithelial adhesion molecule (EPCAM) was shown to impart independent prognostic value, particularly in low grade CCRCC. [77]

Immunostains for AMACR and CK7 are considered most useful for distinguishing CCRCC from papillary RCC, whereas vimentin, CK7, CD117, E-cadherin, and parvalbumin are considered most useful for distinguishing CCRCC from chromophobe RCC and oncocytoma. [75, 76] Recent evidence suggests that immunostaining for the calcium-binding protein secretagogin may also prove useful for distinguishing CCRCC from other RCC subtypes, with positive staining observed in 35/94 (37%) of CCRCCs but in none of 37 papillary RCC, 24 chromophobe RCC, or 30 oncocytomas. [78] This preliminary evidence also suggested an association between strong expression of secretagogin and a higher metastasis rate in CRCC; however, the numbers analyzed were small, and confirmation in a larger study is required.

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