Renal cell carcinoma (RCC) is a heterogenous disease composed of several different cancer types characterized by distinct histologies and genetic alterations, including mutation of the Krebs cycle enzyme genes for fumarate hydratase and succinate dehydrogenase (SDH). This report describes a patient with multifocal renal tumors that presented with a novel, biphasic histologic morphology with one component consisting of small cells growing in a diffuse pattern occasionally forming glandular and cystic structures, reminiscent of type 1 papillary RCC, and the other component having larger cells with abundant eosinophilic and clear cytoplasm and appearing in a solid pattern of growth. Genetic analysis of multiple tumors showed that all had a somatic mutation of the IDH2 gene that created the known pathogenic, gain-of-function p.R172M alteration that results in abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Analysis of multiple tumors demonstrated highly elevated levels of 2-HG and a CpG island methylator phenotype that is characteristic of 2-HG-related inhibition of the Ten-eleven translocation (TET) family of DNA demethylases. In combination with fumarate hydratase-deficient and succinate dehydrogenase-deficient RCCs that have increased levels of the fumarate and succinate oncometabolites, respectively, the mutation of isocitrate dehydrogenase 2 represents the third Krebs cycle enzyme alteration to be associated with oncometabolite-induced RCC tumorigenesis. This study associates the discovery of a new histologic presentation of RCC with the first report of an IDH2 gain-of-function mutation in RCC.
|Number of pages||6|
|Journal||American Journal of Surgical Pathology|
|State||Published - Jan 2021|
Bibliographical noteFunding Information:
Conflicts of Interest and Source of Funding: Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, including grants ZIA BC011028, ZIA BC011038, ZIA BC011089, and ZIC BC011044. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
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- Biphasic histology
- IDH2 renal cancer
- New kidney cancer
ASJC Scopus subject areas
- Pathology and Forensic Medicine