A Novel Case of Glial Transdifferentiation in Renal Medullary Carcinoma Brain Metastasis

Authors

Maria A Gubbiotti
Ian E McCutcheon
Priya Rao
Giannicola Genovese
Linghua Wang
Artem Tarasov
Vladislav Putintsev
Amber Berlinski
Danil Stupichev
Kirill Kriukov
Suren Davitavyan
Basim Salem
Alexander Sarachakov
Dmitry Lebedev
Michael Hensley
Alexander Bagaev
Francesca Paradiso
Vladimir Kushnarev
Gleb Khegai
Nizar M Tannir
Pavlos Msaouel

Publication Date

1-20-2025

Journal

Acta Neuropathologica Communications

Abstract

Renal medullary carcinoma is a rare undifferentiated tumor of the kidney associated with sickle cell trait and characterized by INI1 (SMARCB1) loss. Although metastasis to lungs, lymph nodes, and bone is commonly reported, distant spread to the central nervous system almost never occurs. Here we present an unusual case of a patient with renal medullary carcinoma with metastasis to the brain following treatment which included tazemetostat, an EZH2 inhibitor. The metastatic brain lesion harbored morphologic, immunohistochemical, and methylation profile supportive of a primary CNS phenotype with loss of the trimethylated lysine 27 residue of histone 3 while maintaining INI1 loss and a specific gene fusion shared with the patient's tumor prior to initiation of tazemetostat therapy. Therefore, given the common genetic signatures in the brain metastasis and the patient's prior tumor, this case represents a rare event of glial transdifferentiation in a brain metastasis of renal medullary carcinoma following the use of an epigenetic modulator. As renal medullary carcinoma has been known to cleverly utilize adaptive mechanisms for survival, we propose that such cell plasticity seen in this case may have been provoked by the use of a drug that alters the epigenetic signature of the tumor cells. Thus, careful assessment of tumor biology following novel therapeutic treatment options must be performed in order to note such unexpected consequences of treatment.

Keywords

Humans, Kidney Neoplasms, Brain Neoplasms, Cell Transdifferentiation, Neuroglia, Male, Carcinoma, Medullary, Enhancer of Zeste Homolog 2 Protein, SMARCB1 Protein, Middle Aged, Benzamides, Biphenyl Compounds, Morpholines, Pyridones, Renal medullary carcinoma, INI1, SMARCB1, Glial transdifferentiation, Tazemetostat, EZH2, H3K27me3

DOI

10.1186/s40478-025-01929-w

PMID

39833894

PMCID

PMC11748356

PubMedCentral® Posted Date

1-20-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes