Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: III: Molecular Pathology of Kidney Cancer

Abstract

Renal cell carcinoma (RCC) subtypes are increasingly being discerned via their molecular underpinnings. Frequently this can be correlated to histologic and immunohistochemical surrogates, such that only simple targeted molecular assays, or none at all, are needed for diagnostic confirmation. In clear cell RCC, VHL mutation and 3p loss are well known; however, other genes with emerging important roles include SETD2, BAP1, and PBRM1, among others. Papillary RCC type 2 is now known to include likely several different molecular entities, such as fumarate hydratase (FH) deficient RCC. In MIT family translocation RCC, an increasing number of gene fusions are now described. Some TFE3 fusion partners, such as NONO, GRIPAP1, RBMX, and RBM10 may show a deceptive fluorescence in situ hybridization result due to the proximity of the genes on the same chromosome. FH and succinate dehydrogenase deficient RCC have implications for patient counseling due to heritable syndromes and the aggressiveness of FH-deficient RCC. Immunohistochemistry is increasingly available and helpful for recognizing both. Emerging tumor types with strong evidence for distinct diagnostic entities include eosinophilic solid and cystic RCC and TFEB/VEGFA/6p21 amplified RCC. Other emerging entities that are less clearly understood include TCEB1 mutated RCC, RCC with ALK rearrangement, renal neoplasms with mutations of TSC2 or MTOR, and RCC with fibromuscular stroma. In metastatic RCC, the role of molecular studies is not entirely defined at present, although there may be an increasing role for genomic analysis related to specific therapy pathways, such as for tyrosine kinase or MTOR inhibitors.

1.

Although a diffuse membranous pattern of carbonic anhydrase IX staining usually would support a diagnosis of clear cell RCC, focal staining can be encountered in the setting of hypoxic or necrotic tissues. This papillary RCC has focal staining only at the edges of the papillary structures.

2.

Clear cell papillary RCC is composed most often of branched glandular structures with cells possessing clear cytoplasm. The nuclei are often aligned away from the basement membrane.

3.

This translocation-associated RCC has NONO-TFE3 fusion, which may exhibit nuclear alignment, similar to that of clear cell papillary RCC, although often with higher nuclear grade. FISH can show a subtle rearrangement pattern or it can be false-negative due to the close proximity of these genes on the X chromosome.

4.

Patients with von Hippel-Lindau disease have multiple clear cell RCC tumors and often renal cysts lined by cells with clear cytoplasm, which are thought to be precursors to neoplasms. This cyst is lined by cells with prominent clear cytoplasm and a slight heaping up of the lining cells.

5.

A) Care must be taken in interpreting SDHB immunohistochemistry. In this paraganglioma associated with SDHD mutation, the neoplastic cells show a weak diffuse cytoplasmic blush. This is considered SDHB immunohistochemistry ‘negative,’ as it contrasts strongly with the strong granular cytoplasmic (mitochondrial) staining in the internal positive controls provided by endothelial cells. B) SDH-deficient renal cell carcinoma showing typical features exhibits intracytoplasmic vacuoles/inclusions.

6.

Serial sections of an FH-deficient RCC stained with A) H&E, B) fumarate hydratase, and C) 2SC immunohistochemistry. A) In this case the neoplastic cells have prominent nucleoli but lack the typical papillary or tubulocystic-like architecture of more readily recognized FH-deficient RCC. B) FH immunohistochemistry shows negative staining in all neoplastic cells that contrasts with the positive granular cytoplasmic (mitochondrial) staining in the internal positive controls. C) 2SC immunohistochemistry is positive in a nuclear and cytoplasmic pattern in all the neoplastic cells.

7.

Eosinophilic solid and cystic RCC has been recently recognized to be composed of cells with voluminous eosinophilic cytoplasm, often containing granular basophilic stippling of the cytoplasm. Cysts are lined by cells with similar cytology.

8.

RCC with amplification of TFEB / 6p21 / VEGFA often has a papillary-like morphology, composed of clear or eosinophilic cells with prominent nucleoli, although it can exhibit multiple histologic patterns. These tumors appear to be highly aggressive.

9.

RCC with ALK gene rearrangement has been noted to contain mucin or myxoid material in a subset of cases. This tumor was found to have rearrangement between ALK and TPM3.