A Hidden Carcinoma with Mixed Squamous and Neuroendocrine Differentiation Revealed Through Paraneoplastic Hypercalcemia: A Case Report

Hypercalcemia of malignancy is most associated with squamous cell carcinomas, but can also be observed in many advanced cancers. It is usually mediated through parathyroid hormone-related protein and is known as humoral hypercalcemia of malignancy. We present a rare case of humoral hypercalcemia of malignancy associated with a poorly differentiated carcinoma exhibiting both neuroendocrine and epithelial differentiation. A 67-year-old man was found to have elevated serum calcium on presentation to the emergency department for shortness of breath and abdominal pain. Further investigation revealed low serum parathyroid hormone (indicating a non-parathyroid etiology of hypercalcemia) and elevated serum parathyroid hormone-related protein (supporting a diagnosis of humoral hypercalcemia of malignancy). Imaging revealed numerous disseminated subcutaneous nodules, peritoneal carcinomatosis with liver, cecal, lymph nodes, and bone metastases. Histopathology and immunohistochemistry revealed a poorly differentiated carcinoma exhibiting features of both squamous and neuroendocrine differentiation, along with a high level of cell proliferation. The patient was treated with intravenous fluids and intravenous bisphosphonates as per hypercalcemia management guidelines, with only minimal improvement in his serum calcium level. Our patient succumbed to the metabolic complications within a few days of presentation before the primary site could be identified or definitive treatment could be initiated. Hypercalcemia of malignancy is a common presentation of advanced cancer and is associated with poor prognosis. We describe a case of hypercalcemia of malignancy in a patient with a poorly differentiated carcinoma of unknown primary origin with neuroendocrine and squamous differentiation, which is a rare phenomenon.