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

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 p16 INK4a 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.