IGF-2-mediated hypoglycemia in a patient with a phyllodes tumor of the breast: a rare presentation of non-islet cell tumor hypoglycemia

Summary: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome typically associated with mesenchymal or epithelial tumors that secrete insulin-like growth factor 2 (IGF-2). Breast tumors are an unusual cause of IGF-2-mediated hypoglycemia. We report the case of a 55-year-old woman with a large, fungating phyllodes tumor of the right breast who experienced recurrent fasting hypoglycemia. Biochemical evaluation during hypoglycemic episodes revealed suppressed insulin, C-peptide, β-hydroxybutyrate, and IGF-1, with normal IGF-2 levels but an elevated IGF-2:IGF-1 ratio. Imaging demonstrated a large necrotic breast mass, and subsequent histopathology confirmed a borderline phyllodes tumor with positive IGF-2 immunostaining. Following surgical resection, the patient's hypoglycemia resolved completely. This case highlights the importance of considering NICTH in patients with unexplained hypoglycemia and large tumors, even when IGF-2 levels are not elevated. Diagnosis may require immunohistochemistry or evaluation of the IGF-2:IGF-1 ratio. Surgical excision remains the definitive treatment. Learning points: Non-islet cell tumor hypoglycemia (NICTH) should be considered in patients with recurrent fasting hypoglycemia and a large tumor, even when IGF-2 levels are within the normal range. An elevated IGF-2:IGF-1 ratio can be a key diagnostic clue for IGF-2-mediated hypoglycemia and may be more reliable than absolute IGF-2 levels. Surgical resection of the tumor is typically curative in NICTH and should be prioritized when feasible, with resolution of hypoglycemia serving as both a diagnostic and a therapeutic confirmation.