Salivary gland secretory carcinoma (SC), previously mammary analog SC, is a low-grade malignancy characterized by well-defined morphology and an immunohistochemical and genetic profile identical to SC of the breast. Translocation t(12;15)(p13;q25) resulting in the ETV6 :: NTRK3 gene fusion is a characteristic feature of SC along with S100 protein and mammaglobin immunopositivity. The spectrum of genetic alterations for SC continues to evolve. The aim of this retrospective study was to collect data of salivary gland SCs and to correlate their histologic, immunohistochemical, and molecular genetic data with clinical behavior and long-term follow-up. In this large retrospective study, we aimed to establish a histologic grading scheme and scoring system. A total of 215 cases of salivary gland SCs diagnosed between 1994 and 2021 were obtained from the tumor registries of the authors. Eighty cases were originally diagnosed as something other than SC, most frequently acinic cell carcinoma. Lymph node metastases were identified in 17.1% (20/117 cases with available data), with distant metastasis in 5.1% (6/117). Disease recurrence was seen in 15% (n=17/113 cases with available data). The molecular genetic profile showed ETV6 :: NTRK3 gene fusion in 95.4%, including 1 case with a dual fusion of ETV6 :: NTRK3 and MYB :: SMR3B . Less frequent fusion transcripts included ETV6 :: RET (n=12) and VIM :: RET (n=1). A 3-tiered grading scheme using 6 pathologic parameters (prevailing architecture, pleomorphism, tumor necrosis, perineural invasion (PNI), lymphovascular invasion (LVI), and mitotic count and/or Ki-67 labeling index) was applied. Grade 1 histology was observed in 44.7% (n=96), grade 2 in 41.9% (n=90), and grade 3 in 13.5% (n=29) of cases. Compared with low-grade and intermediate-grade SC, high-grade tumors were associated with a solid architecture, more prominent hyalinization, infiltrative tumor borders, nuclear pleomorphism, presence of PNI and/or LVI, and Ki-67 proliferative index >30%. High-grade transformation, a subset of grade 2 or 3 tumors, seen in 8.8% (n=19), was defined as an abrupt transformation of conventional SC into high-grade morphology, sheet-like growth, and a tumor lacking distinctive features of SC. Both overall survival and disease-free survival (5 and 10 y) were negatively affected by tumor grade, stage, and TNM status (each P <0.0001). SC is a low-grade malignancy with predominantly solid-microcystic growth patterns, driven by a gene fusion, most commonly ETV6 :: NTRK3 . There is a low risk for local recurrence and a good overall long-term survival, with a low risk for distant metastasis but a higher risk for locoregional lymph node metastasis. The presence of tumor necrosis, hyalinization, PNI and/or LVI, and positive resection margins correlate with higher tumor grade, less favorable prognosis, and increased mortality. The statistical results allowed us to design a 3-tiered grading system for salivary SC.

Bioptic Laboratory Ltd Plzen

Department of Cellular Pathology University of Liverpool Liverpool UK

Department of Histopathology St James's Hospital and Dublin Dental Hospital Trinity College Dublin Dublin Ireland

Department of Oral and Maxillofacial Pathology School of Dentistry Alborz University of Medical Sciences Karaj Iran

Department of Otorhinolaryngology University Hospital Olomouc and Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Department of Pathology and Laboratory Medicine University of Calgary Arnie Charbonneau Cancer Institute

Department of Pathology and Laboratory Medicine University of Calgary Calgary Laboratory Services Foothills Medical Centre Calgary AB Canada

Department of Pathology Charles University Faculty of Medicine in Plzen

Department of Pathology Kenyatta National Hospital Nairobi Kenya

Department of Pathology Medical University of Gdansk Gdansk Poland

Department of Pathology University of Alabama at Birmingham Birmingham AL

Department of Pathology Warmia and Mazury University Olsztyn

Diagnostic and Research Institute of Pathology Medical University of Graz Graz Austria

Division of Clinical Medicine Department of Histopathology University of Surrey Royal Surrey County Hospital Guildford Surrey

Division of Pathology Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia Modena Italy

Head and Neck Pathology Consultations Woodland Hills CA

Institute of Biomedicine Pathology University of Turku and Turku University Hospital Turku Finland

Institute of Pathology Faculty of Medicine University of Ljubljana Ljubljana Slovenia

Institute of Pathology University Hospital Erlangen Friedrich Alexander University Erlangen Nürnberg Erlangen EMN Erlangen Germany

Molecular Genetic Laboratory Bioptic Laboratory Ltd Plzen

The Fingerland Department of Pathology Charles University Faculty of Medicine and University Hospital Hradec Kralove Hradec Kralove

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