Inguinal lymph node dissection (ILND) is a core component in the management of penile squamous cell carcinoma (pSCC) with involvement, or a high risk of involvement, of the inguinal lymph nodes (LN). NCCN guidelines recommend bilateral ILND for patients with a clinically positive solitary non-bulky unilateral inguinal LN (cN1), and neoadjuvant chemotherapy for patients with clinically positive bilateral inguinal or any pelvic LNs. Available information is lacking regarding the risk of upstaging from cN1 to pN2/N3 at ILND. Patients upstaged to pN2/N3 are in a significantly higher-risk disease state and may have derived benefit from the pre-ILND identification of upstaging, potentially qualifying them for neoadjuvant chemotherapy or clinical trials. Our primary objective is to determine the risk factors and survival outcomes associated with upstaging from cN1 to pN2/N3 at ILND.

Patients with pT≥1cN1cM0 pSCC who underwent bilateral ILND, did not undergo PET/CT or DSLNB, and had complete data were identified in a large multi-institutional international cohort from 8 high volume referral centers in 7 countries who were diagnosed from 1980 – 2017. Baseline patient and tumor characteristics were described. Upstaging was defined as pN2-3 at ILND.  Multivariable logistic regression analysis was used to determine associations with upstaging (Covariates: Age, smoking status, HPV status, pT stage, and LVI). Multivariable Cox regression analysis was used to determine associations with overall survival (OS) (Covariates: Age, pT stage, LVI, Upstaging status). Kaplan-Meier estimates and log-rank testing were used to compare survival functions for upstaged and non-upstaged patients.

144 patients were included in the final study population. 80 patients (58%) were upstaged from cN1 to pN2-3. On multivariable analysis, upstaging was associated with pT3/4 (OR 4.1, 95CI 1.5-11.6, p<0.01) and pTX (OR 7.1, 95CI 1.6-51.1, p<0.01). Figure 1. Age, smoking status, HPV status, and LVI were not associated with upstaging. On multivariable Cox analysis, age (HR 1.03/yr, 95CI 1.01-1.06, p<0.01) and upstaging (HR 2.8, 95CI 1.3-5.9, p<0.01) were associated with worse OS. Patients who were upstaged had a 5-year OS of 49%, versus 86% for patients who were not upstaged. Figure 2.

The majority of cN1 pSCC patients were upstaged to pN2/N3, harboring a significantly higher-risk disease state than their clinical staging suggested, especially in those with higher pT stages. More intensive pre-operative imaging, such as the addition of PET/CT, may be warranted to identify upstaging prior to ILND and potentially qualify them for neoadjuvant chemotherapy or clinical trials.