Immunohistochemical Detection and Molecular Characterization of IDH-mutant Sinonasal Undifferentiated Carcinomas

Abstract

Recent studies have identified recurrent isocitrate dehydrogenase 2 (IDH2) mutations in a subset of sinonasal undifferentiated carcinomas (SNUCs); however, the true frequency of IDH mutations in SNUC is unknown. We evaluated the utility of mutation-specific IDH1/2 immunohistochemistry (IHC) in a large multi-institutional cohort of SNUC and morphologic mimics. IHC using a multispecific antibody for IDH1/2 (R132/R172) mutant protein was performed on 193 sinonasal tumors including: 53 SNUCs, 8 poorly differentiated carcinomas (PDCARs) and 132 histologic mimics. Mutant IDH1/2 IHC was positive in 26/53 SNUCs (49%; 20 strongly positive and 6 weak) and 3/8 PDCARs (37.5%; 2 strong; 1 weak) but was absent in all other tumor types (0/132). Targeted next-generation sequencing (NGS) on a subset of SNUC/PDCAR (6 strong and 3 weak positive for IDH1/2 IHC; 7 negative) showed frequent IDH2 R172X mutations (10/16) and a single IDH1 R132C mutation. All 6 cases with strong positive mutant IDH1/2 staining and NGS had IDH2 R172S/G mutations. The 3 IHC-weak cases all had IDH2 R172T mutations. Among the 7 tested cases that were negative for mutant IDH1/2 IHC, NGS detected 1 case each with IDH2 R172T and IDH1 R132C mutation. IDH-mutant carcinomas also had frequent mutations in TP53 (55%) and activating mutations in KIT (45%) or the PI3K pathway (36%). Mutation-specific IDH1/2 IHC identifies IDH mutations in SNUC, however, it lacks sensitivity for the full range of IDH mutations. These findings suggest that IDH-mutant sinonasal carcinoma may represent a distinct pathobiological entity with therapeutic implications that can be identified by a combined approach of multispecific IDH1/2 IHC and sequencing.

The role of a monoclonal antibody 11C8B1 as a diagnostic marker of IDH2-mutated sinonasal undifferentiated carcinoma

“…An implementation of immunohistochemical assays targeting specifically IDH2 mutant proteins may provide a rapid, inexpensive alternate and/or corroborating method for mutant protein detection and help select cases amenable for further IDH2 mutation confirmation. Except for a single study exploring the utility of a multi-specific antibody against IDH1/IDH2 mutant proteins in sinonasal tumors [11], monoclonal antibodies for specific detection of IDH2 R172S mutant protein have not been evaluated in formalin-fixed surgical specimens. In the present study, we examined the utility of a commercially available monoclonal antibody to IDH2 R172S in IDH2 R172-mutated tumors in order to establish an immunohistochemical protocol as a surrogate method for IDH2 R172S mutation detection.…”

HPV‐associated neuroendocrine carcinomas of the head and neck in FNA biopsies: Clinicopathologic features of a rare entity

“…25 TTF1 may be positive in HPV-NEC with small cell morphology, 2,14 and in our series, TTF1 was positive in 25% of tested cases. Additional immunohistochemistry studies that are helpful in excluding other entities include CK20, neurofilament protein, and polyomavirus for Merkel cell carcinoma; CK20 for salivary neuroendocrine carcinoma; MYB (or MYB FISH) for solid adenoid cystic carcinoma 26 ; S100, neuron-specific enolase, and calretinin for olfactory neuroblastoma; SMARCB1/ INI1 for basaloid examples of SMARCB1-deficient sinonasal carcinoma 27 ; mutant isocitrate dehydrogenase 1/2 for sinonasal undifferentiated carcinoma 28,29 ; desmin and myogenin for alveolar rhabdomyosarcoma; and CD99 and NKX2.2 for Ewing sarcoma. 30 All HPV-NEC cases in our series showed diffuse nuclear p16 expression, which is considered a highly sensitive surrogate marker for high-risk HPV because p16 accumulates secondary to the integration of the E7 oncoprotein, resulting in disruption of the Rb pathway.…”

Sinonasal Papillomas and Carcinomas: A Contemporary Update With Review of an Emerging Molecular Classification

“…Tumor cells typically express pancytokeratin and may show focal p63 expression but are negative for neuroendocrine markers. Recent targeted molecular profiling of SNUC revealed highly recurrent hotspot IDH2 codon R172 mutations in most tumors [28][29][30] ; importantly, no IDH2 mutations were detected in SMARCB1(INI-1)-deficient sinonasal carcinoma (see below for details), suggesting that IDH2 alteration may be a disease-defining oncogenic event for SNUC. Furthermore, although not yet widely available for clinical use, multispecific mutant IDH1/2 IHC may be diagnostically useful in the evaluation of poorly differentiated sinonasal carcinomas.…”

“…Furthermore, although not yet widely available for clinical use, multispecific mutant IDH1/2 IHC may be diagnostically useful in the evaluation of poorly differentiated sinonasal carcinomas. 28,30 SMARCB1(INI-1)-Deficient Sinonasal Carcinoma SMARCB1(INI-1)-deficient sinonasal carcinoma is a recently described diagnostic entity in head and neck pathology that may show overlapping clinicopathologic and morphologic features with other poorly differentiated or small round cell tumors of the sinonasal tract, including SNUC. [31][32][33][34] Although a significant subset of SMARCB1(INI-1)-deficient sinonasal carcinomas will show at least focal plasmacytoid/rhabdoid features (Figure 6, D), these tumors demonstrate tremendous morphologic diversity, and to date, no definitive morphologic differences have been described that can reliably distinguish SMARCB1(INI-1)deficient sinonasal carcinoma from SNUC.…”