Alena Skálová1,2, Martina Banečkova1,2, Lester D R Thompson3, Nikola Ptáková4, Todd M Stevens5, Luka Brcic6, Martin Hyrcza7, Michael Michal1,8,2, Roderick H W Simpson7, Thalita Santana9, Michal Michal1, Tomas Vaněček4, Ilmo Leivo10. 1. Department of Pathology. 2. Biopticka Laboratory Ltd. 3. Department of Pathology, Southern California Permanente Medical Group, Woodland Hills, CA. 4. Molecular Genetic Laboratory, Biopticka Laboratory Ltd, Plzen, Czech Republic. 5. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL. 6. Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria. 7. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary Laboratory Services, Foothills Medical Centre, Calgary, AB, Canada. 8. Biomedical Center, Faculty of Medicine in Plzen, Charles University. 9. Department of Oral Pathology, Faculty of Dentistry, University of São Paulo, São Paulo, Brazil. 10. Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.
Abstract
BACKGROUND: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements. DESIGN: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction. RESULTS: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts. CONCLUSIONS: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
BACKGROUND: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements. DESIGN: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction. RESULTS: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts. CONCLUSIONS: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
Authors: Zubair W Baloch; Sylvia L Asa; Justine A Barletta; Ronald A Ghossein; C Christofer Juhlin; Chan Kwon Jung; Virginia A LiVolsi; Mauro G Papotti; Manuel Sobrinho-Simões; Giovanni Tallini; Ozgur Mete Journal: Endocr Pathol Date: 2022-03-14 Impact factor: 3.943
Authors: Bin Xu; Kartik Viswanathan; Kavita Umrau; Thair A D Al-Ameri; Snjezana Dogan; Kelly Magliocca; Ronald A Ghossein; Nicole A Cipriani; Nora Katabi Journal: Histopathology Date: 2022-09-05 Impact factor: 7.778
Authors: Shankar Venkat; Sarah Fitzpatrick; Peter A Drew; Indraneel Bhattacharyya; Donald M Cohen; Mohammed N Islam Journal: Head Neck Pathol Date: 2021-03-03
Authors: Adam S Fisch; Israa Laklouk; Masato Nakaguro; Vânia Nosé; Lori J Wirth; Daniel G Deschler; William C Faquin; Dora Dias-Santagata; Peter M Sadow Journal: Hum Pathol Date: 2021-05-12 Impact factor: 3.526
Authors: Sandra N Freiberger; Muriel Brada; Christine Fritz; Sylvia Höller; Alexander Vogetseder; Milo Horcic; Michel Bihl; Michal Michal; Martin Lanzer; Martin Wartenberg; Urs Borner; Peter K Bode; Martina A Broglie; Tamara Rordorf; Grégoire B Morand; Niels J Rupp Journal: Neoplasia Date: 2021-04-18 Impact factor: 5.715