Prognostic predictors of lymph node metastasis in penile cancer: a systematic review

Purpose: Squamous cell carcinoma (SCC) of the penis is a rare disease in developed countries but is associated with significant morbidity and mortality. A crucial prognostic factor is the presence of inguinal lymph node metastases (ILNM) at the time of diagnosis. At least 25% of cases have micrometastases at the time of diagnosis. Therefore, we performed a literature review of studies evaluating factors, both clinical and pathological, predictive of lymph node metastases in penile SCC. Materials and methods: Studies were identified using PubMed and search terms included the following: penile cancer, penile tumor, penile neoplasm, penile squamous cell carcinoma, inguinal lymph node metastasis, lymph node metastases, nodal metastasis, inguinal node metastasis, inguinal lymph node involvement, predictors, and predictive factor. The number of patients and predictive factors were identified for each study based on OR, HR, or RR in multivariate analyses, as well as their respective significance values. These were compiled to generate a single body of evidence supportive of factors predictive of ILNM in penile SCC. Results: We identified 31 studies, both original articles and meta-analyses, which identified factors predictive of metastases in penile SCC. The following clinical factors were predictive of ILNM in penile SCC: lymphovascular invasion (LVI), increased grade, increased stage (both clinical and pathological), infiltrative and reticular invasion, increased depth of invasion, perineural invasion, and younger patient age at diagnosis. Biochemically, overexpression of p53, SOD2, Ki-67, and ID1 were associated with spread of SCC to inguinal lymph nodes. Diffuse PD-L1 expression, increased SCC-Ag expression, increased NLR, and CRP >20 were also associated with increased ILNM. Conclusions: A multitude of factors are associated with metastasis of SCC of the penis to inguinal lymph nodes, which is associated with poor clinical outcomes. The above factors, most strongly LVI, grade, and node positivity, may be considered when constructing a nomogram to risk-stratify patients and determine eligibility for prophylactic inguinal lymphadenectomy.