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Circulating and Soluble Biomarkers for Predicting Inguinal Lymph Node Metastasis in Penile Squamous Cell Carcinoma: A
Lucio Dell'atti1, Viktoria Slyusar2
1Department of Urology, University-Hospital of Marche, Ancona, Italy; dellatti@hotmail.com.
Background/Aim:
Regional lymph node status is the strongest prognostic determinant in penile squamous cell carcinoma (PSCC), yet current staging relies on invasive procedures with substantial morbidity. Numerous circulating and soluble biomarkers have been proposed to non-invasively predict lymph node metastasis (LNM), but this body of evidence has never been systematically mapped. This scoping review aimed to chart the extent, nature and maturity of the evidence on circulating and soluble biomarkers for LNM prediction in PSCC.
Materials And Methods:
A scoping review was conducted following the Joanna Briggs Institute methodology and reported according to the PRISMA Extension for Scoping Reviews (PRISMA-ScR). Bibliographic sources indexed in PubMed/MEDLINE, Embase, Scopus and Google Scholar were searched up to July 2026 using terms combining "penile neoplasms", "lymph node metastasis" and "biomarker/soluble/circulating/immune checkpoint". Studies reporting an association between a blood-derived biomarker and nodal status in PSCC were charted narratively by biomarker class. Tissue-based checkpoint biomarkers were additionally included when necessary to provide biological context for their circulating counterparts.
Results:
The evidence clusters into four principal classes of circulating/soluble biomarkers: (i) systemic inflammatory/nutritional markers (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, C-reactive protein), supported by dedicated meta-analyses and multiple retrospective cohorts; (ii) the tumor-associated antigen SCC-Ag, useful for monitoring but poorly sensitive for occult metastasis; (iii) immune-checkpoint-related proteins, mature at tissue level (PD-L1) but represented by a single dedicated study of soluble checkpoint proteins with weak external validation; and (iv) circulating nucleic acids (microRNA, cell-free/tumor DNA), essentially unexplored specifically for nodal prediction in PSCC despite validation in analogous squamous malignancies. HPV/p16 status, although prognostically informative, is tissue-based rather than circulating and was therefore charted separately as biological context rather than as a core circulating-biomarker class.
Conclusion:
Circulating biomarker research in PSCC remains fragmented and dominated by small, retrospective, single-center studies. Multi-marker panels, prospective multicenter validation leveraging rare-tumor consortia, and extension of liquid-biopsy approaches validated in other HPV-driven squamous cancers represent the most promising directions to reduce reliance on invasive nodal staging.