Renal cell carcinoma with unusual morphological features: the clinical utility of next-generation sequencing in distinguishing renal cell tumors.

Objectives: Clear cell and papillary renal cell carcinomas (RCC) are the two most common RCC subtypes, accounting for approximately 70% and 15% of kidney cancers, respectively. Clear cell RCC is commonly associated with VHL alterations, while papillary RCC typically exhibits chromosomal abnormalities such as +7, +17, and -Y. Furthermore, clear cell RCCs are less likely to exhibit PBRM1 and SETD2 alterations. This study aims to improve the accuracy of RCC diagnosis by investigating molecular alterations in RCC cases with clear cells, papillary structures, and other atypical histological features.

Methods: Nine RCC cases were retrospectively selected and analyzed using histologic slides and immunohistochemical staining for CAIX, RCC, CD10, CK7, P504S, Vimentin, and EMA. Next-generation sequencing was performed on all cases to identify genetic mutations, and cytogenetic analysis was conducted on one case.

Results: The cohort consisted of nine male patients aged 49 to 68 years (mean 61.4). Surgical specimens included six radical and three partial nephrectomies; seven tumors were located in the left kidney and two in the right. Tumor sizes ranged from 0.8 to 15.2 cm. Immunohistochemical analysis revealed positive staining for RCC (6/9), CAIX (3/4), CD10 (6/6), and CK7 (5/9). In six clear cell RCCs, next-generation sequencing identified VHL mutations in four tumors, PBRM1 alterations in three, and SETD2 mutations in one. Five tumors with papillary fronds, sarcomatous components, or unclassified features harboring VHL, PBRM1, and/or SETD2 mutations were reclassified as clear cell RCC. One clear cell RCC with leiomyomatous stroma showed mTOR mutations. A case of clear cell papillary renal cell neoplasm showed no reportable gene mutations. The role of a FANCA mutation in one papillary RCC remains uncertain. Cytogenetic analysis of one case (Case #5) revealed 50, X, -Y, +3, +7, +16, +17, +20, consistent with papillary RCC.

Conclusions: Next-generation sequencing is a useful method for categorizing RCCs with clear cells, papillary features, and unusual histology. Additionally, VHL mutations could be a promising target for personalized treatment in clear cell RCCs and their histologic variants.