Positive GPNMB Immunostaining Differentiates Renal Cell Carcinoma With Fibromyomatous Stroma Associated With TSC1/2/MTOR Alterations From Others

Abstract

Renal cell carcinoma with fibromyomatous stroma (RCCFMS) include ELOC/TCEB1 -mutated renal cell carcinoma (RCC) and those with TSC1/2 / MTOR alterations. Besides morphologic similarity, most of these tumors is known to be diffusely positive for carbonic anhydrase IX and cytokeratin 7 by immunohistochemistry. We previously showed strong and diffuse expression of GPNMB (glycoprotein nonmetastatic B) in translocation RCC and eosinophilic renal neoplasms with known TSC1/2/MTOR alterations. We retrospectively identified molecularly confirmed cases of TCEB1/ELOC -mutated RCC (7 tumors from 7 patients), and RCCFMS with alterations in TSC1/2/MTOR (6 tumors from 5 patients, 1 patient with tuberous sclerosis syndrome). In addition, we included 7 clear cell papillary renal cell tumors (CCPRCTs) and 8 clear cell RCC, as they can also present morphologic overlap with RCCFMS. Morphologically, RCCs with TSC1/2/MTOR alterations and those with TCEB1/ELOC mutations were indistinguishable and characterized by papillary, nested, or tubular architecture, with tumor cells with clear cytoplasm and low nuclear grade. By immunohistochemistry, cytokeratin 7 was positive in 5/7 (71%) of TCEB1/ELOC -mutated RCCs, 6/6 (100%) of RCCs with TSC1/2/mTOR alterations, and 7/7 (100%) of CCPRCTs ( P =not significant). Carbonic anhydrase IX was positive in 7/7 TCEB1/ELOC -mutated RCCs, 6/6 (100%) of RCCs with TSC1/2/MTOR alterations, and 7/7 (100%) of CCPRCTs ( P =NS). GPNMB was strongly and diffusely positive in all tumors with TSC1/2/MTOR alterations (6/6), while negative in all TCEB1/ELOC -mutated RCCs (0/6), or CCPRCTs (0/7) ( P =0.002). Two of 8 clear cell RCC showed focal weak staining, while 6/8 were negative. In conclusion, the results support the use of GPNMB to distinguish RCCFMS with TSC1/2/MTOR alterations from others with similar morphology.

Figure 1.. TCEB1/ELOC mutated renal cell carcinoma.

A. H&E-stained section shows a low power view of a tumor with papillary architecture and tumor cells with clear cytoplasm. B&C. Immunohistochemistry for CK7 (B) and CAIX (C) show strong and diffuse staining in tumor cells. D. Immunohistochemistry for GPNMB is negative.

Figure 2.. Two examples of renal cell carcinoma with fibromyomatous stroma and associated TSC1/2/mTOR alterations.

A&B. Both tumors show similar morphology characterized by papillary structures lined by tumor cells with clear cytoplasm and surrounded by fibromyomatous stroma. C. Immunohistochemistry of case in “A” shows positive staining for CK7 in tumor cells. D. Immunohistochemistry of case in “A” shows patchy staining for CAIX in tumor cells. E. Immunostaining for GPNMB on case in “A” shows strong and diffuse staining in tumor cells. F. Immunostaining for GPNMB on case in “B” shows strong and diffuse staining in tumor cells.

Figure 3.. Clear cell papillary renal cell tumor.

A. H&E-stained low power view of a clear cell papillary renal cell tumor showing a cystic and solid neoplasm with low grade tumor cells with clear cytoplasm. In contrast to the study cases, this tumor does not show prominent fibromyomatous stroma. B. Immunohistochemistry for CK7 shows diffuse staining of tumor cells. C. Immunohistochemistry for CAIX showing positive staining in tumor cells. D. Immunostaining for GPNMB is completely negative.