MON-410 - Refractory Hypercalcemia and Paraneoplastic Diarrhea in Advanced Sporadic Retp.M918T-Mutated Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare RET-driven neuroendocrine malignancy that may present with diagnostically challenging paraneoplastic manifestations.

We report an 88-year-old woman admitted for aspiration pneumonia and gastroenteritis. During hospitalization, calcium levels rose persistently with inappropriately mild PTH elevation. Hypercalcemia was refractory to hydration and diuretics despite normal renal function. Denosumab and cinacalcet were initiated for suspected malignancy-related hypercalcemia with possible parathyroid involvement. Vitamin D deficiency was corrected.

Chest CT revealed multiple pulmonary nodules suggestive of metastases, while gastrointestinal and gynecologic evaluations were unrevealing. Thyroid ultrasonography then revealed a 2.3-cm TIRADS-5 left thyroid nodule with cervical lymphadenopathy. Fine-needle aspiration confirmed MTC with markedly elevated calcitonin. Tumor profiling identified a somatic RET p.M918T mutation, while germline RET testing was negative, ruling out MEN2 and confirming sporadic disease. Lenvatinib was selected due to limited access to preferred RET inhibitors.

Radiographs showed humeral fracture, while bone scintigraphy excluded metastases, indicating traumatic etiology. Hypercalcemia was therefore unlikely due to osteolytic disease and was interpreted as predominantly malignancy-related in the setting of high tumor burden, as demonstrated by PET imaging showing widely metastatic disease. Refractory high-volume diarrhea persisted despite empiric treatment; octreotide led to marked improvement, supporting a paraneoplastic mechanism. After months of lenvatinib and denosumab, calcium normalized and calcitonin decreased (1345.4 to 241.83 pg/mL), indicating biochemical response. Palliative care was eventually engaged, and the patient ultimately died from sepsis.

In this case, lack of classic biochemical features of autonomous parathyroid disease and calcium normalization after lenvatinib supported a malignancy-related, PTH-independent mechanism. This case illustrates the calcitonin paradox in MTC, wherein markedly elevated calcitonin fails to alter calcium homeostasis. Vitamin D was replaced to reduce PTH stimulation and prevent denosumab-induced hypocalcemia.

Distinguishing somatic from germline RET mutations is essential to differentiate sporadic MTC from MEN2, as somatic RET mutation alone is not equivalent to MEN2.

In advanced MTC, ectopic release of calcitonin and neuroendocrine peptides increases intestinal secretion, producing somatostatin-responsive paraneoplastic secretory diarrhea.

This case highlights diagnostic and therapeutic challenges of refractory hypercalcemia and paraneoplastic diarrhea in sporadic RET-mutated MTC and underscores the value of integrated biochemical, genetic, and imaging evaluation in complex endocrine oncology.

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