Mismatch Repair Deficient Glioma with Spatially Distinct IDH-mutant and IDH-Wildtype Components Arising in the Setting of Lynch Syndrome.

Mutations in MLH1, MSH2, PMS2, and MSH6 compromise DNA mismatch repair mechanisms and in the heterozygous state predispose patients to Lynch syndrome which is typified by reproductive and gastrointestinal solid tumors. Rarely, pathologic aberrations in these genes may underlie the development of primary central nervous system tumors. We present a report of an adult female with a multicentric, infiltrative supratentorial glioma involving the left anterior temporal horn and left precentral gyrus. Surgical treatment and neuropathological/molecular evaluation of these lesions revealed discordant IDH status and histologic grade at spatially distinct disease sites. A frameshift alteration within the MLH1 gene (p.R217fs*12, c.648delT) was identified in both lesions and subsequently identified in constitutional tissue, consistent with Lynch syndrome. Despite distinct histopathologic features and divergent IDH status of the patient's tumors, the molecular findings suggest that both sites of intracranial neoplasia may have developed as a consequence of underlying constitutional mismatch repair deficiency. This case illustrates the importance of characterizing the genetic profile of multicentric gliomas and highlights the oncogenic potential of germline mismatch repair gene mutations within the central nervous system.