Abstract Background Breast cancer is the most frequently diagnosed malignancy among women, with invasive lobular carcinoma (ILC) comprising 15% of cases. ILC frequently harbors CDH1 mutations, resulting in the loss of E-cadherin as well as a dyscohesive growth pattern that hinders detection. Signet ring cell carcinoma of the breast, a rare but diagnostically significant variant with poor prognosis, can closely mimic primary gastric adenocarcinoma. Shared histomorphology, particularly in metastatic setting at diagnosis, predisposes to misclassification and consequent therapeutic misdirection. Case Presentation A 61-year-old woman presented to the emergency room with one-month of dysphagia, nausea, vomiting, and unintentional weight loss. Radiographic studies revealed abdominopelvic ascites, periportal lymphadenopathy, right adnexal enlargement, osseous lesions, and omental carcinomatosis. A biopsy of the gastric fundus was positive for invasive adenocarcinoma, diffuse type with signet ring features, supported by positive pan-cytokeratin AE1/AE3 staining. Further biopsy of an omental mass showed CK7 positivity and negativity for PAX8, CDX2, and CD20. Metastatic gastric adenocarcinoma was presumed, and capecitabine-oxaliplatin was commenced. Additional molecular profiling was completed, which revealed breast markers including ESR1, GATA 3, cytokeratin, and mammaglobin. A pathogenic loss of function variant in CDH1 was also detected. Further immunohistochemistry (IHC) on the omental specimen revealed ER 90%, PR 90%, and HER2 IHC 0. IHC of the omentum was also positive for GATA3, mammaglobin, and E-cadherin. These findings supported a diagnosis of metastatic lobular breast carcinoma with signet ring features. MRI breast did not identify a primary breast mass and there were no pathologic axillary lymph nodes. Following bilateral salpingo-oophorectomy, pathology for the right adnexal mass showed carcinoma of breast origin (ER 95%, PR 70% and HER2 IHC2+ and FISH negative). The treatment was switched to a first line aromatase inhibitor and CDK 4/6 inhibitor and the patient has since undergone multiple lines of therapy. Discussion Although breast cancer metastasizing to the stomach is rare—with an estimated incidence of just 0.04%—accurate diagnosis of primary origin of adenocarcinoma is vital due to the stark differences in management and outcomes. The clinical and morphological overlap between metastatic ILC with signet ring features and primary gastric carcinoma necessitates a high index of suspicion and thorough immunohistochemical analysis. ILC may metastasize in a diffuse pattern mimicking gastrointestinal malignancies and can present without an identifiable breast lesion. Literature has shown that ER, GCDFP-15, mammaglobin, and GATA3 are highly sensitive and specific for identifying breast origin, whereas CK20 and CDX2 are associated with gastrointestinal differentiation. Although not unique to breast tumors, CDH1 and PIK3CA alterations are detected in roughly 63-65% and 46% of invasive lobular carcinomas, respectively, versus only about 9.7% and 12% of gastric adenocarcinomas. Further studies are warranted to refine diagnostic algorithms that couple IHC with next-generation sequencing, clarifying when the addition of breast-specific markers is essential for definitive tumor origin assignment. Conclusion This case emphasizes the need for comprehensive diagnostic workup in atypical presentations and supports broader use of breast-specific IHC markers and molecular profiling in gastrointestinal biopsies with ambiguous or signet ring histology. Integrating markers such as ER, PR, GATA3, mammaglobin, and CDH1/PIK3CA profiling into a tiered diagnostic algorithm can prevent misclassification, facilitate timely therapy, and ultimately improve patient outcomes. Citation Format: J. Eckman, H. Jeon, S. Oh. When Signet Ring Cells Mislead: A Case of Metastatic Breast Cancer Presenting as Gastric Malignancy abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-06-21.
Eckman et al. (Tue,) studied this question.