HER2-positive discordance in axillary metastasis of signet ring cell carcinoma of unknown primary: a case report

Signet ring cell carcinoma (SRCC) of unknown primary origin is a rare and challenging clinical entity. The diagnostic approach is complicated by the absence of a detectable primary tumor despite extensive investigation. The management of SRCC in cancer of unknown primary patients is further complicated by limited targeted therapeutics, especially when immunohistochemical status becomes discordant during disease progression. A 30-year-old Vietnamese female patient who initially presented with isolated axillary lymphadenopathy. Histopathological analysis revealed metastatic SRCC, with immunohistochemical findings suggesting a gastric origin. At the time of diagnosis, human epidermal growth factor receptor 2 (HER2) expression was negative. Extensive endoscopic and radiologic evaluations failed to identify a primary gastric lesion. The patient received first-line XELOX (capecitabine plus oxaliplatin) and achieved a partial response, but the disease rapidly progressed during maintenance therapy with new metastases involving the ovary, cervical lymph nodes, and peritoneum. A repeat ovarian biopsy demonstrated discordant HER2 expression, with HER2 status changing from negative to positive. Subsequent treatment with trastuzumab deruxtecan achieved disease stabilization. This case underscores the rarity and complexity of SRCC of unknown primary origin and highlights the clinical significance of discordant HER2 status during disease progression. Awareness of such molecular alterations may reveal new therapeutic opportunities and improve management strategies in this aggressive and elusive cancer subtype.