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

Our plain-English summary of When Lymph Nodes Don't Lie: Report of Three Unusual Presentations of Thoracic Tumors, by S. Lucà, F. Barbato, A. Di Maio, et al (Diagnostics, 2026).

The study

• Authors: S. Lucà, F. Barbato, A. Di Maio, L. Montella, S. Farese, G. Di Guida, B. Leonardi, R. Giannatiempo, R. Salvi, M. Montella, C.M. Della Corte, M. Fasano, M. Orditura, A. Fiorelli, F. Morgillo, R. Franco
• Journal: Diagnostics
• Published: 2026;16(11)
• Type of article: Case report
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This case report described three men whose thoracic cancers first appeared as enlarged lymph nodes. In a 56-year-old man with autoimmune encephalitis and a 49-year-old never-smoker, cancer was found in lymph nodes but no lung tumor was seen on imaging. Tissue staining (CK7, TTF-1 and Napsin A) led to a diagnosis of spread from lung adenocarcinoma in both men. The second man's tumor had an ALK gene rearrangement. On the drug alectinib, his brain metastases shrank and eventually resolved. A 66-year-old man had an enlarged lymph node above the right collarbone, with fluid and thickening in the lining of the right lung. His tumor was at first thought likely to be lung adenocarcinoma. Loss of BAP1 protein and a BAP1 S160fs*1 mutation in DNA from his blood did not alone show the tumor was mesothelial, the authors noted; with his clinical, imaging and tissue findings, they were considered consistent with metastatic pleural epithelioid mesothelioma. He denied asbestos exposure. The authors concluded that precise diagnosis often relies on close collaboration between pathologists and clinicians.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report (case series of three patients), with a discussion comparing previously published cases
• Who was studied: three men: a 56-year-old with hypertension and HBV-related liver disease, a 49-year-old never-smoker, and a 66-year-old with no significant past medical history
• Exposure: No asbestos or other exposure was studied. The patient diagnosed with pleural epithelioid mesothelioma denied asbestos exposure and other occupational or environmental risk factors.
• Main results:
  • Case one (56-year-old man): imaging showed mediastinal and right supraclavicular lymph node enlargement without a clearly identifiable lung lesion. Biopsy led to a diagnosis of lymph node metastasis from primary non-mucinous lung adenocarcinoma.
  • Case two (49-year-old man): FISH testing showed an ALK gene rearrangement in the lymph node tumor, which was diagnosed as stage IV non-mucinous lung adenocarcinoma.
  • Case two: on alectinib, his brain metastases shrank and eventually resolved completely.
  • Case three (66-year-old man): the initial evaluation of the lymph node tumor favored occult primary non-mucinous lung adenocarcinoma.
  • Case three: testing of circulating cell-free DNA found a BAP1 S160fs*1 mutation (VAF 12.4%), and tissue staining showed loss of nuclear BAP1.
  • Case three: the diagnosis of metastatic pleural epithelioid mesothelioma was based on the clinical, imaging, tissue, staining and molecular findings taken together.
  • Case three: the patient started carboplatin plus pemetrexed and had completed three cycles at the time of reporting.
• The authors' conclusion: The authors concluded that peripheral lymph node enlargement may occasionally be the first and only sign of thoracic cancers. They stated that a precise diagnosis often relies on close collaboration within the multidisciplinary team, with clinicians giving pathologists complete clinical information.
• Limitations the authors state:
  • The authors noted that the BAP1 finding in case three is not, by itself, diagnostic of mesothelial lineage. They considered it consistent with mesothelioma only together with the other clinical, imaging and tissue findings.

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Lymphadenopathy, Next-Generation Sequencing (NGS), Lung Adenocarcinoma, Thyroid Transcription Factor-1 (TTF-1), Targeted Therapy, Epithelioid, Mesothelioma.

Related studies

• Cytokeratin 19 expression in primary thoracic tumors and lymph node metastases — K. Masai, K. Nakagawa, et al. (2014)
• An unusual presentation of malignant mesothelioma: the incidental finding of tumor in the hernia sac during herniorrhaphy — J. Brenner, P.P. Sordillo, et al. (1981)
• Well-Differentiated Papillary Mesothelial Tumor: An Unusual Radiologic Presentation: A Case Report — M. Abdelghafar, K. Anand, et al. (2023)
• Benign cystic mesothelioma: A case report on the presentation of an unusual tumor — Y. Salem, A. Farhan, et al. (2021)
• Asbestos content of lung tissue, lymph nodes, and pleural plaques from former shipyard workers — R.F. Dodson, M.G. Williams, et al. (1990)
• Intrapulmonary lymph nodes. Clinical, radiologic, and pathologic features — R.L. Kradin, P.W. Spirn, et al. (1985)

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