In a new Journal of Medical Case Reports article, Dao Thi and colleagues describe a previously healthy 30-year-old Vietnamese woman who presented with isolated axillary lymphadenopathy. Histopathological examination demonstrated metastatic signet ring cell carcinoma with expression of CDX2, CK7, and CK20. HER2 immunohistochemistry was initially negative.
Despite extensive evaluation—including breast imaging, upper and lower gastrointestinal endoscopy, cross-sectional imaging, and PET/CT—no primary tumor was identified. Comprehensive genomic profiling showed low tumor mutational burden, microsatellite stability, and no clinically actionable alterations. The patient was diagnosed with signet ring cell carcinoma of unknown primary and received capecitabine plus oxaliplatin, achieving a partial response followed by maintenance capecitabine.
After three months of maintenance therapy, the disease progressed with pleural effusion, ascites, cervical lymphadenopathy, peritoneal involvement, and a right ovarian mass. Biopsy of the ovarian lesion again demonstrated metastatic signet ring cell carcinoma. However, HER2 expression was now strongly positive, with an immunohistochemical score of 3+. The ovarian specimen was assessed using the same antibody and platform as the original lymph-node specimen and was independently reviewed by two senior pathologists.
The patient subsequently received trastuzumab deruxtecan. After three cycles, imaging demonstrated stable disease, with reductions in pleural fluid, ascites, and peritoneal infiltration. Treatment was tolerated with only grade 1 fatigue and no identified interstitial lung disease. Disease progression occurred after approximately five months. Her progression-free survival from the initiation of trastuzumab deruxtecan was 5.2 months, and overall survival from diagnosis was 19.9 months.
The observed HER2 discordance may reflect spatial tumor heterogeneity, biological evolution during treatment, sampling differences, or technical variability. Comparative molecular analysis of the two metastatic sites was unavailable, and confirmatory in situ hybridization was not performed on the original HER2-negative specimen. The mechanism of the change therefore remains uncertain. Nevertheless, the case demonstrates how repeat biopsy during disease progression may reveal an actionable biomarker that was not present—or not detected—at the original diagnosis.
Clinical Take-Home Message
When cancer of unknown primary progresses or develops a new metastatic pattern, clinicians should consider repeat biopsy and biomarker reassessment when clinically appropriate. Tumor biology may differ between metastatic sites or change over time. Although a single case cannot establish treatment efficacy, identifying HER2 positivity in a later metastasis may provide a therapeutic opportunity when conventional options are limited.
Reference
Dao Thi TT, Hien TTT, Nguyen HL, et al. HER2-positive discordance in axillary metastasis of signet ring cell carcinoma of unknown primary: a case report. Journal of Medical Case Reports. 2026. https://doi.org/10.1186/s13256-026-06447-4.
Journal of Medical Case Reports is the world’s first international, PubMed-listed, medical journal devoted to publishing case reports from all medical disciplines and will consider any original case report that expands the field of general medical knowledge, and original research relating to case reports. The journal is open access, and strongly endorses the CARE guidelines for case reports, requiring authors to submit populated CARE checklists with submissions to improve transparency in reporting.