Immunohistochemical detection and molecular characterization of IDH-mutant sinonasal undifferentiated carcinomas

Jeffrey K. Mito, Justin A. Bishop, Peter M. Sadow, Edward B. Stelow, William C. Faquin, Stacey E. Mills, Jeffrey F. Krane, Christopher A. French, Christopher D.M. Fletcher, Jason L. Hornick, Lynette M. Sholl, Vickie Y. Jo

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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.

Original languageEnglish (US)
Pages (from-to)1067-1075
Number of pages9
JournalAmerican Journal of Surgical Pathology
Volume42
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Mutation
Isocitrate Dehydrogenase
Immunohistochemistry
Carcinoma
Sinonasal undifferentiated carcinoma
Mutation Rate
Mutant Proteins
Phosphatidylinositol 3-Kinases
Neoplasms
Staining and Labeling
Antibodies

Keywords

  • IDH1
  • IDH2
  • sinonasal carcinoma
  • sinonasal undifferentiated carcinoma
  • SNUC

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Immunohistochemical detection and molecular characterization of IDH-mutant sinonasal undifferentiated carcinomas. / Mito, Jeffrey K.; Bishop, Justin A.; Sadow, Peter M.; Stelow, Edward B.; Faquin, William C.; Mills, Stacey E.; Krane, Jeffrey F.; French, Christopher A.; Fletcher, Christopher D.M.; Hornick, Jason L.; Sholl, Lynette M.; Jo, Vickie Y.

In: American Journal of Surgical Pathology, Vol. 42, No. 8, 01.08.2018, p. 1067-1075.

Research output: Contribution to journalArticle

Mito, JK, Bishop, JA, Sadow, PM, Stelow, EB, Faquin, WC, Mills, SE, Krane, JF, French, CA, Fletcher, CDM, Hornick, JL, Sholl, LM & Jo, VY 2018, 'Immunohistochemical detection and molecular characterization of IDH-mutant sinonasal undifferentiated carcinomas', American Journal of Surgical Pathology, vol. 42, no. 8, pp. 1067-1075. https://doi.org/10.1097/PAS.0000000000001064
Mito, Jeffrey K. ; Bishop, Justin A. ; Sadow, Peter M. ; Stelow, Edward B. ; Faquin, William C. ; Mills, Stacey E. ; Krane, Jeffrey F. ; French, Christopher A. ; Fletcher, Christopher D.M. ; Hornick, Jason L. ; Sholl, Lynette M. ; Jo, Vickie Y. / Immunohistochemical detection and molecular characterization of IDH-mutant sinonasal undifferentiated carcinomas. In: American Journal of Surgical Pathology. 2018 ; Vol. 42, No. 8. pp. 1067-1075.
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