{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:10:43Z","timestamp":1788844243887,"version":"build-2803163510"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>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 Sj\u00f6gren\u2019s 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.<\/jats:p>","DOI":"10.3389\/fonc.2026.1860040","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T04:27:07Z","timestamp":1788841627000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Exceptional response to perioperative pembrolizumab in UV-signature melanoma of unknown primary presenting as an isolated pulmonary metastasis"],"prefix":"10.3389","volume":"16","author":[{"given":"Austin","family":"Drysch","sequence":"first","affiliation":[{"name":"Division of Thoracic Surgery, Northwestern University Feinberg School of Medicine","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genti","family":"Gjyzeli","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern University Feinberg School of Medicine","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Buttars","sequence":"additional","affiliation":[{"name":"Department of Pathology & Immunology, Washington University School of Medicine","place":["St. Louis, MO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunandana","family":"Chandra","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalvin","family":"Lung","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Northwestern University Feinberg School of Medicine","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1001\/jamadermatol.2022.0160","article-title":"Global burden of cutaneous melanoma in 2020 and projections to 2040","volume":"158","author":"Arnold","year":"2022","journal-title":"JAMA Dermatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2211437","article-title":"Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma","volume":"388","author":"Patel","year":"2023","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2402604","article-title":"Neoadjuvant nivolumab and ipilimumab in resectable stage iii melanoma","volume":"391","author":"Blank","year":"2024","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.1549","article-title":"Comparison of biomarker modalities for predicting response to pd-1\/pd-l1 checkpoint blockade: a systematic review and meta-analysis","volume":"5","author":"Lu","year":"2019","journal-title":"JAMA Oncol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1001\/jamadermatol.2024.4819","article-title":"Melanoma tumor mutational burden and indoor tanning exposure","volume":"161","author":"Hanrahan","year":"2025","journal-title":"JAMA Dermatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4065\/82.3.364","article-title":"Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis","volume":"82","author":"Markovic","year":"2007","journal-title":"Mayo Clin Proc"},{"key":"B7","article-title":"Primary mucosal melanomas: a comprehensive review","volume":"5","author":"Mihajlovic","year":"2012","journal-title":"Int J Clin Exp Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1159\/000334863","article-title":"Noncutaneous melanoma have distinct features from each other and cutaneous melanoma","volume":"81","author":"Tas","year":"2011","journal-title":"Oncology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyaf410","article-title":"Melanoma of unknown primary: a comprehensive review of immune-mediated pathogenesis and therapies","volume":"31","author":"Xu","year":"2025","journal-title":"Oncologist"},{"key":"B10","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.jaad.2014.09.029","article-title":"Metastatic melanomas of unknown primary show better prognosis than those of known primary: a systematic review and meta-analysis of observational studies","volume":"72","author":"Bae","year":"2015","journal-title":"J Am Acad Dermatol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-004310","article-title":"Improved prognosis and evidence of enhanced immunogenicity in tumor and circulation of high-risk melanoma patients with unknown primary","volume":"10","author":"Tarhini","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000537","article-title":"Brief communication: treatment outcomes for advanced melanoma of unknown primary compared with melanoma with known primary","volume":"47","author":"Persa","year":"2024","journal-title":"J Immunother"},{"key":"B13","doi-asserted-by":"publisher","first-page":"74","DOI":"10.3322\/canjclin.55.2.74","article-title":"Global cancer statistics, 2002","volume":"55","author":"Parkin","year":"2005","journal-title":"CA Cancer J Clin"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7819-1-26","article-title":"Primary Malignant melanoma of the lung: a case report","volume":"1","author":"Dountsis","year":"2003","journal-title":"World J Surg Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-0594-0","article-title":"Lung-only melanoma: uv mutational signature supports origin from occult cutaneous primaries and argues against the concept of primary pulmonary melanoma","volume":"33","author":"Yang","year":"2020","journal-title":"Mod Pathol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/1746-1596-7-123","article-title":"Primary pulmonary Malignant melanoma: a clinicopathologic study of two cases","volume":"7","author":"Gong","year":"2012","journal-title":"Diagn Pathol"},{"key":"B17","article-title":"Metastatic melanoma of unknown primary tumor","volume":"53","author":"Serna","year":"1994","journal-title":"Cutis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1097-0142(19981015)83:8<1664::aid-cncr23>3.0.co;2-g","article-title":"The national cancer data base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. the american college of surgeons commission on cancer and the american cancer society","volume":"83","author":"Chang","year":"1998","journal-title":"Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy226","article-title":"Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma","volume":"29","author":"Tetzlaff","year":"2018","journal-title":"Ann Oncol"},{"key":"B20","unstructured":"Nccn Clinical Practice Guidelines in Oncology: Melanoma: Cutaneous. Version 2.2026\n          \n          2026"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1200\/PO.23.00640","article-title":"Predictive impact of tumor mutational burden on real-world outcomes of first-line immune checkpoint inhibition in metastatic melanoma","volume":"8","author":"Andrews","year":"2024","journal-title":"JCO Precis Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-024-00932-9","article-title":"Tumour mutational burden: clinical utility, challenges and emerging improvements","volume":"21","author":"Budczies","year":"2024","journal-title":"Nat Rev Clin Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx026","article-title":"Circulating tumour DNA predicts response to anti-pd1 antibodies in metastatic melanoma","volume":"28","author":"Lee","year":"2017","journal-title":"Ann Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw443","article-title":"Anti-pd-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab","volume":"28","author":"Menzies","year":"2017","journal-title":"Ann Oncol"},{"key":"B25","article-title":"Drugs and lactation database (Lactmed)","year":""},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00525-8","article-title":"Immunotherapy for cancer treatment during pregnancy","volume":"22","author":"Borgers","year":"2021","journal-title":"Lancet Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1860040\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T04:27:08Z","timestamp":1788841628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1860040\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":26,"alternative-id":["10.3389\/fonc.2026.1860040"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1860040","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]},"article-number":"1860040"}}