{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:00:47Z","timestamp":1780459247489,"version":"3.54.1"},"reference-count":31,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background and Clinical Significance: Lymph node metastases from carcinoma of unknown primary origin (CUP) are a rare and diagnostically challenging entity, particularly when arising from thoracic malignancies with atypical clinical presentations. This study aims to illustrate the essential nature of multidisciplinary integration, with a particular emphasis on the role of the pathologist in identifying occult thoracic tumors. Case Presentation: We report three cases of patients presenting with cervical or systemic lymphadenopathy as the initial clinical manifestation. Comprehensive diagnostic workups included advanced imaging (CT, MRI, and PET), comprehensive histopathological analysis, and next-generation sequencing of circulating tumor DNA. Case one and case two were diagnosed as occult primary non-mucinous lung adenocarcinomas, based on the integration of morphological features and immunohistochemical co-expression of TTF-1 and Napsin A, despite the absence of identifiable lung lesions. One case harbored an ALK rearrangement, guiding effective targeted therapy with alectinib. Case three involved metastatic pleural epithelioid mesothelioma, which presented with systemic lymphadenopathy and was initially misclassified as metastatic adenocarcinoma. Diagnosis was confirmed by the loss of BAP1 expression by immunohistochemistry and the detection of a BAP1 S160fs*1 mutation, emphasizing the role of molecular pathology. Conclusions: Lymphadenopathy as the first manifestation of thoracic malignancy is a rare but clinically significant occurrence. In such atypical presentations, pathologists play a pivotal role in diagnosis, often leading the process when clinical or radiological clues are minimal or absent. Accurate histopathological assessment is essential to establish a correct diagnosis and guide appropriate therapy. A multidisciplinary approach remains the cornerstone of diagnostic precision in CUP cases.<\/jats:p>","DOI":"10.3390\/diagnostics16111618","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T14:10:22Z","timestamp":1779718222000},"page":"1618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["When Lymph Nodes Don\u2019t Lie: Report of Three Unusual Presentations of Thoracic Tumors"],"prefix":"10.3390","volume":"16","author":[{"given":"Stefano","family":"Luc\u00e0","sequence":"first","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, Via Luciano Armanni 5, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4642-6827","authenticated-orcid":false,"given":"Francesco","family":"Barbato","sequence":"additional","affiliation":[{"name":"Stroke Unit, Department of Emergency and Urgent Medicine, Santa Maria Delle Grazie Hospital, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amedeo","family":"Di Maio","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, Via Luciano Armanni 5, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6397-086X","authenticated-orcid":false,"given":"Liliana","family":"Montella","sequence":"additional","affiliation":[{"name":"Oncology Operative Unit, \u201cSanta Maria delle Grazie\u201d Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Farese","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Medical Oncology, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Di Guida","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Medical Oncology, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Leonardi","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, Piazza Miraglia, 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Giannatiempo","sequence":"additional","affiliation":[{"name":"Pathology Unit, Ospedale Evangelico Villa Betania, 80147 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Salvi","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, S.G. Moscati Hospital, 83100 Avellino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8588-7653","authenticated-orcid":false,"given":"Marco","family":"Montella","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, Via Luciano Armanni 5, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3396-8099","authenticated-orcid":false,"given":"Carminia Maria","family":"Della Corte","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Medical Oncology, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0782-8778","authenticated-orcid":false,"given":"Morena","family":"Fasano","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Medical Oncology, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Orditura","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Medical Oncology, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0628-613X","authenticated-orcid":false,"given":"Alfonso","family":"Fiorelli","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, Piazza Miraglia, 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floriana","family":"Morgillo","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Medical Oncology, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Franco","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, Via Luciano Armanni 5, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.4103\/njcp.njcp_149_18","article-title":"Metastatic squamous cell cancer with unknown primary origin in the mediastinal lymph node","volume":"21","author":"Agca","year":"2018","journal-title":"Niger. 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