Pan-TRK Immunohistochemistry Is Highly Correlated With NTRK3 Gene Rearrangements in Salivary Gland Tumors.

Abstract

AIMS:

Secretory carcinoma (SC) is characterized by ETV6 rearrangements, most often ETV6-NTRK3 fusion. Given its histologic overlap with other salivary gland tumors (SGTs), SCs can be difficult to diagnose without genetic confirmation. A recently developed pan-TRK (tropomyosin receptor kinase) antibody shows promise for identifying tumors with NTRK (neurotrophic tyrosine kinase receptor 3) fusions. The aim of this study was to evaluate the utility of pan-TRK immunohistochemistry in distinguishing SCs from mimics and selecting patients eligible for TRK inhibitor clinical trials. We examined whole-tissue sections from 111 SGTs with molecular characterization, including 26 SCs (23 with ETV6-NTRK3 fusion and 3 with ETV6-RET fusion detected by ligation-dependent reverse transcription-polymerase chain reaction, next-generation sequencing and 85 non-SC SGTs (no ETV6-NTRK3 fusion). Immunohistochemistry was performed with a pan-TRK rabbit monoclonal antibody. When any pan-TRK staining (nuclear or cytoplasmic with any staining intensity) was considered to indicate positivity, 22 of 23 SCs with ETV6-NTRK3 fusion (95.7%) and 33 of 85 non-SC (38.8%) salivary neoplasms were positive, mainly basal cell adenoma, pleomorphic adenomas, adenoid cystic carcinomas, and epithelial-myoepithelial carcinomas. All SCs with ETV6-RET fusion were entirely negative. When only nuclear pan-TRK staining with any staining intensity was considered positive, 18 of 23 SCs with ETV6-NTRK3 fusion (78.3%) were positive, 11 among them with diffuse staining (>30% of cells). All non-SCs and SCs with ETV6-RET fusion were entirely negative. In comparison to molecular analysis (ligation-dependent reverse transcription-polymerase chain reaction, next-generation sequencing), nuclear pan-TRK IHC has a sensitivity of 78.3% and a specificity of 100% for diagnosing SCs with ETV6-NTRK3 fusion, 69% and 100% for SCs (all fusions). Pan-TRK is a reasonable screening test for diagnosing SCs among SGTs when taking only nuclear staining into account. Although pan-TRK expression is not entirely sensitive for SCs, nuclear staining is highly specific for SCs with ETV6-NTRK3 fusion. The lack of pan-TRK immunoreactivity in a subset of SCs is suggestive of atypical exons 4 to 14 or exons 5 to 14 ETV6-NTRK3 fusion or non-NTRK alternative fusion partners such as ETV6-RET. Pan-TRK staining can serve as a strong diagnostic marker to distinguish SC from it mimics and to select patients eligible for TRK inhibitor clinical trials.

• Authors: Marie Csanyi-Bastien, Marie-Delphine Lanic, Ludivine Beaussire, Sandra Ferric, Arnaud François, Didier Meseure, Fabrice Jardin, Michel Wassef, Philippe Ruminy, Marick Laé
• Journal: The American journal of surgical pathology (Am J Surg Pathol) Vol. 45 Issue 11 Pg. 1487-1498 (11 01 2021) ISSN: 1532-0979 [Electronic] United States
• PMID: 33899788 (Publication Type: Comparative Study, Journal Article, Multicenter Study)
• Copyright: Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• ETV6-NTRK3 fusion protein, human
• NTRK3 protein, human
• Oncogene Proteins, Fusion
• Receptor, trkC

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics)
• Female
• France
• Gene Fusion
• Gene Rearrangement
• Genetic Predisposition to Disease
• High-Throughput Nucleotide Sequencing
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Male
• Middle Aged
• Multiplex Polymerase Chain Reaction
• Oncogene Proteins, Fusion (genetics)
• Phenotype
• Predictive Value of Tests
• Receptor, trkC (genetics)
• Reproducibility of Results
• Retrospective Studies
• Reverse Transcriptase Polymerase Chain Reaction
• Salivary Gland Neoplasms (genetics, pathology)
• Young Adult