Case Report: Exceptional response to perioperative pembrolizumab in UV-signature melanoma of unknown primary presenting as an isolated pulmonary metastasis.

Melanoma of unknown primary (MUP) rarely presents as an isolated pulmonary mass, and the role of neoadjuvant immunotherapy in this setting remains undefined. We report a 26-year-old peripartum woman with systemic lupus erythematosus (SLE) and Sjögren's syndrome who presented with a 12-cm centrally invasive pulmonary melanoma encasing the right pulmonary artery. Endobronchial biopsy confirmed melanoma, and genomic profiling demonstrated a very high tumor mutational burden (TMB; 39.2 mutations per megabase) and ultraviolet (UV) mutational signature, a profile most consistent with MUP. Given the extent of vascular involvement, the operative morbidity of upfront resection, and her autoimmune disease, single-agent neoadjuvant pembrolizumab (200 mg intravenously every 3 weeks) was initiated to facilitate resection while limiting the risk of immune-related toxicity. After three cycles, imaging demonstrated marked tumor regression, and the patient underwent right pneumonectomy with pulmonary artery reconstruction. Pathology demonstrated a complete pathologic response with no viable tumor and negative margins. She completed 15 adjuvant cycles, and surveillance imaging has shown no evidence of recurrence. To our knowledge, this is among the first reported cases of neoadjuvant PD-1 blockade enabling resection of MUP presenting as a solitary pulmonary mass. This case illustrates how immunogenomic features may inform therapeutic sequencing and how immunotherapy can support surgical decision-making in complex thoracic malignancies.