Penile Cancer Distant Metastasis or Primary Lung Cancer? - Using Focused Genomic Profiling of Tumor and Germline Mutations With Next-Generation Sequencing for Clinical Decision-Making

Sep 23, 2026

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Background: Distant metastasis in penile squamous cell carcinoma predicts very poor outcomes, making it critical to distinguish whether thoracic lesions in known PSCC represent penile spread or a new primary lung cancer. This case series evaluates how focused genomic profiling can resolve ambiguous lesion origin when routine methods fail. Cases: Three surgically treated PSCC patients with inguinal node-positive disease developed isolated hilar or concurrent lung lesions. Standard radiology, histopathology, and HPV/p16 biomarker analyses could not identify lineage. Targeted NGS detected TP53 mutations and an actionable ERBB2 mutation, helping separate metastatic PSCC from primary lung SCC. Conclusion: Focused NGS can provide molecular insights to support clinical decision-making, prognostication, and patient counseling.

LanguageEnglish

CategoryHealthcare

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Pages9

Reading Time23 min

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Introduction

Case Series

Molecular and Biomarker Analyses

Conclusion

Cancer Reports CASE SERIES OPEN ACCESS Penile Cancer Distant Metastasis or Primary Lung Cancer? Using Focused Genomic Profiling of Tumor and Germline Mutations With Next-Generation Sequencing for Clinical Decision-Making Christian A. Moen1,2 | Ida M. Nordanger1,2 | Ása Karlsdóttir3 | Alfred Honoré1,2 | Patrick Juliebø-Jones1,2 | Siri M. Blomberg4 | Torjan M. Haslerud4,5 | Christina Aamelfot6 | Pirjo-Riitta Salminen7 | Christian Beisland1,2 | Hildegunn H. Vetti8 | Daniela E. Costea2,9 | Ellen Berget9 1Department of Urology, Haukeland University Hospital, Bergen, Norway | 2Department of Clinical Medicine, University of Bergen, Bergen, Norway | 3Department of Oncology, Haukeland University Hospital, Bergen, Norway | 4Department of Radiology, Haukeland University Hospital, Bergen, Norway | 5Department of Radiology, Nuclear Medicine, Stavanger University Hospital, Stavanger, Norway | 6Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway | 7Section of Cardiothoracic Surgery, Department of Heart Disease, Haukeland University Hospital, Bergen, Norway | 8Western Norway Familial Cancer Center, Haukeland University Hospital, Bergen, Norway and VID Specialized University, Faculty of Health Studies, Bergen, Norway | 9Department of Pathology, Haukeland University Hospital, Bergen, Norway Correspondence: Christian A. Moen ([christian.arvei.moen@helse-bergen.no](christian.arvei.moen@helse-bergen.no)) Received: 12 November 2024 | Revised: 26 June 2025 | Accepted: 2 July 2025 Funding: The authors received no specific funding for this work. Keywords: ERBB2 mutation | genomic profiling | metastasis | next generation sequencing | penile squamous cell carcinoma | TP53 mutation ABSTRACT Background: The presence of a distant metastasis in penile squamous cell carcinoma (PSCC) is associated with a very poor prognosis. When isolated distant tumors are detected in patients with known PSCC, it is therefore important to accurately determine whether such lesions represent penile cancer metastasis or indeed a new primary cancer. This distinction can have a significant influence on both patient prognostication as well as recommended treatment regimens. Cases: In this case series, we present three patients surgically treated for inguinal node-positive PSCC. Two of the patients developed isolated lesions in the right hilar lymph nodes within 14 months after surgery, and one patient had a concurrent lesion in the right upper lobe at the time of diagnosis. None of the standard radiological or histopathological examinations could truly identify the origin of these lesions. Moreover, neither could biomarker analysis with p16INK4a and human papillomavirus (HPV) DNA status. However, focused genomic profiling of both penile and thoracic tumor tissue with next generation sequencing (NGS) technology identified specific mutations in the TP53 gene (2 cases) and a potentially actionable mutation in the ERBB2 gene (1 case) that additionally could aid in distinguishing possible primary lung SCC from metastatic PSCC. No germline mutations were detected. Conclusion: Focused NGS analysis of tumor tissue can provide molecular insights that may help clarify the possible origin of thoracic tumors in patients with PSCC. The results may support clinical decision-making and also be used for prognostication and patient counseling. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Author(s). Cancer Reports published by Wiley Periodicals LLC. Cancer Reports, 2025; 8:e70278 1 of 9 [https://doi.org/10.1002/cnr2.70278](https://doi.org/10.1002/cnr2.70278) 1 | Introduction The natural progression of penile squamous cell carcinoma (PSCC) has been described as an initial lymphatic spread to the inguinal and then to the pelvic lymph nodes [1]. Spread beyond this po

FAQs

Why is distinguishing distant metastasis from a primary lung cancer important in PSCC patients?

Because the origin of thoracic lesions strongly affects prognosis and determines appropriate treatment options.

What did standard radiological, histopathological, and HPV/p16 testing fail to determine?

They could not accurately identify whether the thoracic lesions originated from penile squamous cell carcinoma or represented a new primary malignancy.

Which genomic findings from focused NGS helped clarify the possible tumor origin?

TP53 mutations were identified in two cases, and a potentially actionable ERBB2 mutation was found in one case, supporting differentiation between metastatic PSCC and primary lung SCC.

Sep 23, 2026

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