Clinicopathological investigation of secretory carcinoma cases including a successful treatment outcome using entrectinib for high-grade transformation: a case report

• Published in: BMC medical genomics Vol. 15; no. 1; p. 6
• Main Authors: Suzuki, Kensuke, Harada, Hiroshi, Takeda, Masayuki, Ohe, Chisato, Uemura, Yoshiko, Kawahara, Akihiko, Sawada, Shunsuke, Kanda, Akira, Sengupta, Bhaswati, Iwai, Hiroshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.01.2022; BioMed Central; BMC
• Subjects: Analysis; Benzamides; Biomarkers, Tumor - genetics; Biopsy; Cancer; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma - pathology; Care and treatment; Case Report; Clinical trials; Diagnosis; Entrectinib; ETV6-NTRK3; Exocrine glands; Fluorescence in situ hybridization; Gene fusion; Gene rearrangement; Genetic transformation; Head and neck; High-grade transformation; Histology; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Indazoles; Kinases; Metastases; Metastasis; Methods; Molecular genetics; Neck; Neoplasm Recurrence, Local; Next-generation sequencing; NTRK3 gene; Nucleoli; Oncogene Proteins, Fusion - genetics; p53 Protein; Patients; Prevention; Risk factors; S100 protein; Salivary gland; Salivary Gland Neoplasms - drug therapy; Salivary Gland Neoplasms - genetics; Salivary Gland Neoplasms - metabolism; Salivary gland tumors; Secretory carcinoma; Stat5 protein; Surgery; Therapeutic targets; Treatment Outcome; Tumor proteins; Tumors; United States; Entrectinib; Salivary gland; Next-generation sequencing; Secretory carcinoma; ETV6-NTRK3; High-grade transformation
• ISSN: 1755-8794; 1755-8794
• DOI: 10.1186/s12920-022-01155-6

Secretory carcinoma (SC) of the salivary gland is a recently described malignant tumor harboring characteristic ETV6-NTRK3 gene fusion. SC generally has a favorable clinical course, and is currently regarded as a low-grade carcinoma. However, a small subset of SCs demonstrates aggressive clinical features with histologically high-grade transformed morphology, the molecular pathogenesis of which has not yet been elucidated. In this study, we performed a clinicopathological and molecular genetic study of patients with SC of the head and neck displaying various clinical characteristics to investigate the differences of pathological and molecular genetics between low-grade and high-grade components of SC. Three cases with SC of the head and neck, including a conventional low-grade SC and two high-grade transformed SCs are described. High-grade transformed SCs with histological features such as nuclear polymorphism, distinctive nucleoli and increased mitotic activity developed locoregional recurrence and distant metastasis. Immunohistochemical analysis revealed that low- and high-grade components showed different expression patterns for S-100 protein and mammaglobin, whereas all examined components were positive for p-STAT5. p53-positive cell population was markedly higher in one case with high-grade transformed SC. The proliferative activity of high-grade components was markedly increased, with the Ki-67 labeling index ranging up to 30-32%. A fluorescence in situ hybridization study with an ETV6 (12p13) break apart probe revealed split signals in the nuclei in all 3 cases. A targeted next-generation sequencing-based fusion assay demonstrated that all 6 clinical samples from the 3 patients showed the presence of the ETV6-NTRK3 fusion transcripts. One patient with high-grade transformed SC showed a dramatic clinical response to the pan-TRK inhibitor, entrectinib, for the treatment of locoregional recurrence and pulmonary metastasis. High-grade transformed SC showed aggressive clinical and pathological features with increased Ki-67 labeling index. Molecular genetic study of gene rearrangement appears to be beneficial treatment as the presence of ETV6-NTRK3 translocation may represent a therapeutic target in SC, particularly the high-grade transformed type.