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Volume 16
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Case Report

When Lymph Nodes Don’t Lie: Report of Three Unusual Presentations of Thoracic Tumors

by
Stefano Lucà
1,
Francesco Barbato
2,
Amedeo Di Maio
1,
Liliana Montella
3,
Stefano Farese
4,
Gaetano Di Guida
4,
Beatrice Leonardi
5,
Rosa Giannatiempo
6,
Rosario Salvi
7,
Marco Montella
1,
Carminia Maria Della Corte
4,
Morena Fasano
4,
Michele Orditura
4,
Alfonso Fiorelli
5,
Floriana Morgillo
4 and
Renato Franco
1,*
1
Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Via Luciano Armanni 5, 80138 Naples, Italy
2
Department of Emergency and Urgent Medicine, Stroke Unit, Santa Maria Delle Grazie Hospital, 80078 Pozzuoli, Italy
3
Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy
4
Department of Precision Medicine, Medical Oncology, Università degli Studi della Campania “Luigi Vanvitelli”, 80131 Naples, Italy
5
Division of Thoracic Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia, 2, 80138 Naples, Italy
6
Pathology Unit, Ospedale Evangelico Villa Betania, 80147 Naples, Italy
7
Division of Thoracic Surgery, S.G. Moscati Hospital, 83100 Avellino, Italy
*
Author to whom correspondence should be addressed.
Diagnostics 2026, 16(11), 1618; https://doi.org/10.3390/diagnostics16111618
Submission received: 26 February 2026 / Revised: 21 April 2026 / Accepted: 6 May 2026 / Published: 25 May 2026
(This article belongs to the Section Clinical Diagnosis and Prognosis)
Versions Notes

Abstract

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.
Keywords: carcinoma of unknown primary origin; systemic lymphadenopathy; occult primary non-mucinous lung adenocarcinoma; pleural epithelioid mesothelioma; multidisciplinary approach carcinoma of unknown primary origin; systemic lymphadenopathy; occult primary non-mucinous lung adenocarcinoma; pleural epithelioid mesothelioma; multidisciplinary approach

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MDPI and ACS Style

Lucà, S.; Barbato, F.; Di Maio, A.; Montella, L.; Farese, S.; Di Guida, G.; Leonardi, B.; Giannatiempo, R.; Salvi, R.; Montella, M.; et al. When Lymph Nodes Don’t Lie: Report of Three Unusual Presentations of Thoracic Tumors. Diagnostics 2026, 16, 1618. https://doi.org/10.3390/diagnostics16111618

AMA Style

Lucà S, Barbato F, Di Maio A, Montella L, Farese S, Di Guida G, Leonardi B, Giannatiempo R, Salvi R, Montella M, et al. When Lymph Nodes Don’t Lie: Report of Three Unusual Presentations of Thoracic Tumors. Diagnostics. 2026; 16(11):1618. https://doi.org/10.3390/diagnostics16111618

Chicago/Turabian Style

Lucà, Stefano, Francesco Barbato, Amedeo Di Maio, Liliana Montella, Stefano Farese, Gaetano Di Guida, Beatrice Leonardi, Rosa Giannatiempo, Rosario Salvi, Marco Montella, and et al. 2026. "When Lymph Nodes Don’t Lie: Report of Three Unusual Presentations of Thoracic Tumors" Diagnostics 16, no. 11: 1618. https://doi.org/10.3390/diagnostics16111618

APA Style

Lucà, S., Barbato, F., Di Maio, A., Montella, L., Farese, S., Di Guida, G., Leonardi, B., Giannatiempo, R., Salvi, R., Montella, M., Della Corte, C. M., Fasano, M., Orditura, M., Fiorelli, A., Morgillo, F., & Franco, R. (2026). When Lymph Nodes Don’t Lie: Report of Three Unusual Presentations of Thoracic Tumors. Diagnostics, 16(11), 1618. https://doi.org/10.3390/diagnostics16111618

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