Occult Hypercalcemia Unmasked: Insights From Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE) Syndrome Associated With a Gastrointestinal Lymphoma

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare inflammatory arthritis that may present as a paraneoplastic syndrome. We report a case of a 51-year-old woman who initially responded to high-dose steroids for RS3PE but later developed persistent hypercalcemia. Serum calcium ranged from 3.03 to 4.02 mmol/L, with suppressed parathyroid hormone (PTH), suggesting a non-parathyroid cause. Despite initial suspicion of infection-related hypercalcemia, calcium levels remained elevated after antimicrobial therapy. The 25-hydroxyvitamin D level was elevated, although serum 1,25-dihydroxyvitamin D was not directly measured. Immunohistochemistry revealed strong expression of parathyroid hormone-related protein (PTHrP) and 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1), indicating potential contributions from both humoral and vitamin D-mediated pathways. The patient received supportive treatment with diuretics, calcitonin, and denosumab, which successfully corrected hypercalcemia. Gastrointestinal endoscopy and biopsy ultimately confirmed diffuse large B-cell lymphoma (DLBCL). She then underwent anti-lymphoma chemotherapy, resulting in sustained remission and stable calcium levels. This case highlights the diagnostic challenges of RS3PE with hypercalcemia and the importance of considering underlying malignancy when standard therapy fails. It also demonstrates that PET-CT may fail to detect tumors in hollow organs and that gastrointestinal endoscopy should be considered in unresolved cases. Early recognition of tumor-associated hypercalcemia and a mechanism-based diagnostic approach are essential for effective treatment.