VHL mutations and dysregulation of pVHL- and PTEN-controlled pathways in multilocular cystic renal cell carcinoma

Abstract

Multilocular cystic renal cell carcinoma is a rare renal cell carcinoma with an excellent prognosis. To clarify the relationship with typical clear cell renal cell carcinoma, we evaluated 15 cases of multilocular cystic renal cell carcinomas diagnosed according to the 2004 WHO classification. Von Hippel Lindau (VHL) gene mutations were determined by whole genome amplification and direct sequencing. Carbonic anhydrase 9 (CAIX), a hypoxiainducible factor (HIF) target, paired box gene 2 (PAX2), cyclin-dependent kinase inhibitor p27 and glycogen synthase kinase 3-b (GSK3b) were immunohistochemically evaluated as members of the VHL protein (pVHL)-and phosphatase and tensin homolog (PTEN)-controlled pathways. VHL mutations were identified in 3 of 12 (25%) tumors. Inactivated GSK3b, decreased PTEN expression and PAX2 positivity were observed in the vast majority of the multilocular cystic renal cell carcinomas. Strong nuclear staining of p27 was seen in 14 of 15 cases. Compared with multilocular cystic renal cell carcinomas, expression frequencies of PAX2, p-GSK3b, PTEN and CAIX were similar in a set of low-grade, early-stage clear cell renal cell carcinomas, whereas only 30% had strong p27 positivity. These results are consistent with the hypothesis that multilocular cystic renal cell carcinomas are related at the molecular level with clear cell renal cell carcinomas. Maintenance of a strong subcellular p27 expression in all multilocular cystic renal cell carcinomas analyzed may in part explain the excellent prognosis of these tumor patients.

Spectrum of Preneoplastic and Neoplastic Cystic Lesions of the Kidney

“…In a recent study, VHL mutations were identified in 3 of 12 tumors (25%), and the tumor cells, in most cases, were strongly reactive to PAX2 and CAIX, similar to typical, low-grade clear cell RCC. 44 These findings are consistent with the concept of multilocular cystic RCC being a variant of clear cell RCCs. In line with the minimal tumor burden present in these tumors, prognosis is excellent; there was no recurrence or metastases on mean follow-up of more than 6.5 years in a more-recent study.…”

An overview of renal cell cancer: Pathology and genetics

“…The consequences of the mutations of the VHL gene are discussed in Sections 3 and 6. Recently, mutations of the VHL gene have been reported in multilocular cystic renal cell carcinoma and confirm the hypothesis that multilocular cystic renal cell carcinoma represent a subtype of clear cell renal cancer [54]. The relationship of leiomyomatous renal cell carcinoma and clear cell papillary renal cancer based on the presence or absence of VHL mutation and/or 3p losses is currently controversial.…”

Clear cell papillary renal cell carcinoma: differential diagnosis and extended immunohistochemical profile

“…10 Mutations of the VHL (von Hippel-Lindau) gene have also been detected in multilocular cystic renal cell carcinoma. 17 In contrast, clear cell papillary renal cell carcinoma has been found to lack both of these abnormalities, 2,5,7,8 lending further support to the distinction between the two lesions. Another differential diagnostic consideration for a tumor composed of compact and acinar arrangements of clear cells with a prominent cystic component is cystic clear cell renal cell carcinoma.…”