Multifocal renal cell carcinomas with somatic IDH2 mutation: Report of a previously undescribed neoplasm

Maria J. Merino, Christopher J. Ricketts, Vanessa Moreno, Ye Yang, Teresa W.M. Fan, Andrew N. Lane, Paul S. Meltzer, Cathy D. Vocke, Daniel R. Crooks, William M. Linehan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish
Pages (from-to)137-142
Number of pages6
JournalAmerican Journal of Surgical Pathology
Issue number1
StatePublished - Jan 2021

Bibliographical note

Publisher Copyright:
© 2020 Wolters Kluwer Health, Inc. All rights reserved.


  • Biphasic histology
  • IDH2
  • IDH2 renal cancer
  • New kidney cancer
  • RCC

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine


Dive into the research topics of 'Multifocal renal cell carcinomas with somatic IDH2 mutation: Report of a previously undescribed neoplasm'. Together they form a unique fingerprint.

Cite this