Colorectal Carcinoma Metastatic to the Breast Mimicking Inflammatory Breast Cancer With Mismatch Repair Status Discordant From a Prior Endometrial Primary: A Case Report and a Review of the Literature.

Colorectal carcinoma (CRC) metastatic to the breast is exceedingly rare, with 46 cases compiled in a 2019 literature review and additional isolated reports since. The diagnostic challenge is substantially amplified in patients with a prior breast cancer history, in whom new breast lesions are reflexively attributed to recurrence rather than extramammary metastasis. A 71-year-old woman with a significant family history of malignancy presented with invasive lobular carcinoma of the left breast, treated with lumpectomy and hormonal therapy. Four months later, she was diagnosed with stage I endometrioid adenocarcinoma of the uterus; immunohistochemistry of the hysterectomy specimen revealed isolated PMS2 loss with preserved MLH1, MSH2, and MSH6 expression, and comprehensive germline testing of 35 hereditary cancer predisposition genes was negative, establishing a Lynch-like phenotype in that tumor. Approximately four years after her breast cancer diagnosis, she developed a maculopapular rash with skin thickening of the left breast, without a discrete mass; the clinical and mammographic presentation was concerning for inflammatory breast carcinoma. Punch biopsy demonstrated poorly differentiated adenocarcinoma with signet ring cell features, immunohistochemically positive for SATB2, CDX2, CK20, and CEA and negative for CK7, ER, PR, HER2, and GATA3, confirming colorectal origin and excluding breast cancer recurrence. Mismatch repair immunohistochemistry on the same specimen demonstrated retained expression of all four proteins, discordant with the endometrial primary and concordant with microsatellite instability-stable status and a tumor mutational burden of 3.7 mutations/Mb. Next-generation sequencing identified a TP53 splice region loss-of-function variant with RAS and BRAF wild-type status. Positron emission tomography revealed stage IV disease with hepatic metastasis, and colonoscopy identified synchronous cecal and recto-sigmoid masses. She was treated with four lines of systemic therapy and palliative radiation to the breast, and died approximately 20 months after the metastatic diagnosis. This case illustrates two points. First, any new breast lesion in a patient with prior malignancy requires histopathologic confirmation with comprehensive immunohistochemical analysis, as neither recurrence nor a primary breast process can be assumed. Second, mismatch repair status is a property of the individual tumor rather than of the patient; in patients with multiple primaries, each tumor requires independent testing, and molecular findings from one cannot be extrapolated to another.