Renal Cell Tumors: Understanding Their Molecular Pathological Epidemiology and the 2016 WHO Classification: Beyond the Abstract

The WHO classification of renal cell tumors was last published in 2004; the latest WHO classification was published in 2016. During this interval of 12 years, there was a substantial increase in the knowledge of molecular pathological epidemiology of renal cell tumors. The revised WHO classification is based on the increased knowledge of their morphological, immunohistochemical, molecular, and epidemiological characteristics. Apart from the current major subtypes of renal cell carcinoma (RCC), i.e., clear cell RCC (65‒70% of all RCCs), papillary RCC (15‒20%), and chromophobe RCC (5‒7%), the new subtypes of renal cell tumors include multilocular cystic renal neoplasm of low malignant potential (excellent prognosis), clear cell papillary RCC (3‒4% of all RCCs; indolent), MiT family translocation RCC (1‒4%), tubulocystic RCC, (<1%; indolent), SDH-deficient RCC (0.05‒0.2%; indolent), acquired cystic disease (ACD)-associated RCC (indolent), and hereditary leiomyomatosis and RCC (HLRCC)-associated RCC (HLRCC syndrome; aggressive). These tumor subtypes are characterized by specific molecular, epidemiological, morphological, and immunohistochemical features.

Clear cell RCC is molecularly characterized by the sequence of VHL loss‒inappropriate stabilization of HIFs‒proangiogenic gene expression signature; mutations in genes involved with the PI3K/AKT pathway; and mutations in SETD2, BAP1, and MTOR. Aggressive clear cell RCC demonstrates a metabolic shift. Type 1 papillary RCC (scanty cytoplasm; better prognosis than that of type 2) is characterized by MET alteration. Type 2 papillary RCC (abundant eosinophilic cytoplasm) is characterized by CDKN2A (p16) silencing and SETD2 mutation. A subset of papillary RCC is characterized by aggressive behavior, CIMP-positive, and FH mutation. Chromophobe RCC is characterized by somatic mutation in mitochondrial DNA, mutations of TP53 and PTEN, and imbalanced chromosome duplication. MiT family translocation RCC is characterized by TFE3/TFEB rearrangement. SDH-deficient RCC is characterized by SDHB inactivation. HLRCC-associated RCC is characterized by germline mutation in FH. Emerging/provisional entities of RCCs in the 2016 WHO classification include ALK rearrangement-associated RCC, which is potentially responsive to ALK inhibitors.

Although we have obtained the knowledge of molecular pathological epidemiology of renal cell tumors and classified these tumors into a number of subtypes, the subclassification of renal cell tumors is currently less useful for clinicians to offer meaningful therapeutic suggestions to patients. In fact, we continue to use mostly traditional approaches for treating patients. Using the subclassification of renal cell tumors based on their molecular pathological epidemiology, we must thoroughly progress toward the use of clinical translation and precision medicine for treating patients.

Written by: Kentaro Inamura

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