Case report: Secretory carcinoma of the breast with ETV6-NTRK3 fusion: clinicopathological features and molecular confirmation by FISH in two cases.

Background: Secretory carcinoma of the breast (SCB) is an extremely rare malignant neoplasm, accounting for less than 0.15% of all breast carcinomas. It is characterized by distinctive secretory activity, a frequently triple-negative immunophenotype, and recurrent ETV6-NTRK3 fusion (1-3). Case presentations: We report two Chinese women with SCB. Case 1 involved a 55-year-old woman with a 1.2-cm mass, and Case 2 involved a 43-year-old woman with a 3.8-cm mass. Both tumors showed characteristic morphology, including microcystic/tubulocystic, solid, tubular, and focally papillary growth patterns, abundant eosinophilic secretory material, granular eosinophilic or vacuolated cytoplasm, and minimal cytologic atypia. Immunohistochemistry revealed a triple-negative phenotype (ER-negative, PR-negative, and HER2-negative) with diffuse S-100 and CK5/6 positivity. Mammaglobin and MUC4 showed membranous positivity, whereas DOG1 was negative in tumor cells at ×100 magnification. These findings provided ancillary support for secretory differentiation and helped exclude acinic cell carcinoma. AB-PAS staining showed positive intracytoplasmic secretory material in tumor cells at ×200 magnification. ETV6-NTRK3 fusion was confirmed by FISH in both tumors (75% and 80% of tumor nuclei), supporting the diagnosis of SCB. Both patients underwent breast-conserving surgery. Case 1 had no nodal metastasis (0/2; T1cN0M0, AJCC 8th edition), whereas Case 2 had sentinel lymph node metastasis (1/3; T2N1aM0, AJCC 8th edition), followed by axillary lymph node dissection (0/23). Both patients received adjuvant chemotherapy and radiation therapy. No locoregional recurrence or distant metastasis was observed during short-to-intermediate follow-up of 18 months in Case 1 and 30 months in Case 2. However, these observations reflect only the current clinical status of the two patients and are insufficient to support conclusions regarding long-term prognosis. Conclusions: These cases highlight the diagnostic challenges of SCB and underscore the importance of integrating morphology, immunohistochemistry, and FISH-based molecular confirmation. ETV6-NTRK3 fusion may represent a potential therapeutic option only in selected patients with advanced, unresectable, recurrent, or metastatic NTRK fusion-positive disease. Neither patient in the present report had advanced disease, received TRK inhibitor therapy, or underwent functional validation of the fusion. Therefore, no conclusion regarding therapeutic efficacy can be drawn from these two localized cases. Long-term follow-up remains necessary because late recurrence and distant metastasis have been reported in the literature, and the short-to-intermediate follow-up in the present cases does not allow definitive prognostic conclusions.