Melanoma is the most deadly form of cutaneous malignancy, and accurate staging is critical for prognosis and management. Positron emission tomography/computed tomography (PET/CT) is commonly used in staging advanced disease, with increased (18)F-fluorodeoxyglucose (FDG) uptake indicating hypermetabolic activity. However, benign processes (e.g., sarcoidosis, foreign body reactions, immune-related granulomatous inflammation) may also be FDG-avid, creating potential for overstaging. We present two cases of metastatic melanoma with concurrent benign FDG-avid lymphadenopathy confirmed histologically, highlighting diagnostic and management implications. In case 1, a patient with scalp melanoma and biopsy-proven regional nodal metastasis developed progressive disease on immunotherapy. PET/CT demonstrated FDG-avid thoracic and abdominal lymphadenopathy concerning for stage IV disease. Fine needle aspiration of pulmonary nodes revealed non-necrotizing granulomas consistent with sarcoidosis, and subsequent neck dissection confirmed both metastatic melanoma and granulomatous inflammation. Recognition of benign distant FDG uptake prevented overstaging and enabled surgical management of true metastatic sites. In case 2, a patient with vulvar melanoma and a positive sentinel lymph node underwent immunotherapy, radiotherapy, and nodal excision. PET/CT later showed FDG-avid inguinal and axillary nodes. Excision demonstrated metastatic melanoma in the inguinal node, while the axillary node contained foreign material with giant cells. Histologic differentiation guided management, and the patient elected surveillance rather than additional systemic therapy, with no recurrence at 3 months. In both cases, FDG-avid nodes beyond the locoregional basin suggested distant metastasis, but histologic examination revealed both malignant and benign etiologies and clarified the anatomic distribution of each, allowing for appropriate staging. These findings underscore the importance of biopsy in atypical distributions and careful pathologic documentation of both metastatic and non-malignant processes to ensure accurate staging and appropriate treatment.
