Potentially VEGF-A-associated paraneoplastic RS3PE syndrome in non-small cell lung cancer with likely benign pleuropericardial effusions mimicking malignancy

Summary Background Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is a rare inflammatory disease that manifests as a paraneoplastic manifestation of malignant tumors. Although its association with non-small cell lung cancer (NSCLC) is rare, vascular endothelial growth factor (VEGF)-A has been suggested to be involved in the pathogenesis. Cases with pleural and pericardial effusions are even rarer, and differentiation from metastasis of malignant tumors is important. Case presentation A 51-year-old Asian man presented with fever, bilateral edema, tenosynovitis, pleural effusion, and pericardial effusion. Cytology of both effusions was negative for malignant cells, but mediastinal lymph node biopsy revealed adenocarcinoma. He was diagnosed with RS3PE syndrome associated with NSCLC. Oral prednisolone and chemoradiotherapy improved the edema and effusions. Serum VEGF‑A measured after clinical improvement was lower than that observed at recurrence. After curative resection of synchronous double primary lung cancers (adenocarcinoma and squamous cell carcinoma) and adjuvant chemotherapy, central nervous system metastases developed 10 months later. This recurrence was accompanied by elevated serum and cerebrospinal fluid VEGF‑A levels and recurrence of RS3PE symptoms. Immunohistochemical analysis showed strong VEGF‑A expression in pretreatment tumor tissue, which decreased after treatment. Discussion and conclusion This case suggests that VEGF‑A may have contributed to paraneoplastic RS3PE syndrome in NSCLC. The association among the available VEGF‑A measurements, RS3PE activity, and cancer progression suggests that VEGF‑A may serve as a potential disease activity biomarker in selected patients. This case also highlights the importance of recognizing RS3PE syndrome as a paraneoplastic process and carefully evaluating pleuropericardial effusions and thrombotic complications in complex oncological patients.