IDH2 Mutation Analysis in Undifferentiated and Poorly Differentiated Sinonasal Carcinomas for Diagnosis and Clinical Management

Abstract

A large number of tumor types arise from the mucosa of the sinonasal cavities. Although presenting clinically distinct behavior, due to poorly differentiated histologic features, they can be difficult to classify correctly. Our aim was to investigate whether IDH2 and IDH1 mutations may be specific to a subset of undifferentiated and poorly differentiated sinonasal carcinomas. A total of 125 tumor samples of 7 different histologic subtypes were analyzed for IDH mutations by sequencing and mutant-specific immunohistochemistry, and the results were correlated to clinical and follow-up data. The highest incidence of IDH2 mutations occurred in sinonasal undifferentiated carcinoma, with 11/36 (31%) cases affected. However, also, 1/9 neuroendocrine carcinomas, 2/4 high-grade non–intestinal-type adenocarcinomas, and 1/8 poorly differentiated squamous cell carcinomas carried the IDH2 mutation, whereas 1/48 intestinal-type adenocarcinomas harbored an IDH1 mutation. Immunohistochemical analysis of mutant IDH1/2 produced a number of false-negative results, but also 1 false-positive tumor was found. Disease-specific survival was more favorable in IDH2-mutant versus wild-type cases. Our data suggest that IDH-mutant sinonasal cancers, independent of their histologic subtype, may represent a distinct tumor entity with less aggressive clinical behavior. Clinically, patients with these mutations may benefit from specific IDH-guided therapies.

Sinonasal Squamous Cell Carcinoma, a Narrative Reappraisal of the Current Evidence

“…The differential diagnosis of poorly differentiated SNSCC is challenging and includes: SNUC (including those characterized by molecular identifiers, such as IDH2-mutant SNUC, SMARCA4-deficient carcinoma, and SMARCB1/INI1-deficient carcinoma), NECs, and adenoid cystic carcinoma [ 1 , 33 , 34 , 35 , 36 ].…”

Methylation Drivers and Prognostic Implications in Sinonasal Poorly Differentiated Carcinomas

“…Comparing NEC and SCC cases, we observed a higher number of mutations in NEC, especially in TP53 and IDH2 genes ( Figure S1 ). As all IDH2 gene mutations occurred in codon 172 (p.Arg172Gly p.Arg172Thr and p.Arg172Ser), and in the light of recent literature, we extended the analysis of this region to the whole series using hot-spot direct sequencing ( Figure 1 b), but no additional IDH2 -mutated cases were found ( Table S1 , Figure 2 ) [ 31 ].…”

A Genome-Wide Profiling of Glioma Patients with an IDH1 Mutation Using the Catalogue of Somatic Mutations in Cancer Database

“…IDH1 somatic mutations were found primarily in the central nervous system (68.7%) and to a lesser extent in hematopoietic and lymphoid systems (14.2%), which agrees with the types of cancers IDH1 mutations have been associated with [ 7 ]. Whereas IDH2 mutations were found primarily in hematopoietic and lymphoid systems (68.8%) and to a lesser extent in the central nervous system (9.2%) ( Figure 1 A,B) [ 6 , 55 ], all other tissues had less than 10% of IDH1 or IDH2 mutations. COSMIC presents data from both genome-wide screens and targeted screens with most data being collected from targeted screens ( Figure 1 B).…”

“…mutations have been associated with [7]. Whereas IDH2 mutations were found primarily in hematopoietic and lymphoid systems (68.8%) and to a lesser extent in the central nervous system (9.2%) (Figure 1A,B) [6,55], all other tissues had less than 10% of IDH1 or IDH2 mutations. COSMIC presents data from both genome-wide screens and targeted screens with most data being collected from targeted screens (Figure 1B).…”