AUA 2022: Survival in N3 Penile Cancer: Does Pelvic Lymphadenopathy Predict a Worse Prognosis than Inguinal Extra-Nodal Extension?

( In a podium presentation at the 2022 American Urologic Association Annual Meeting held in New Orleans and virtually, Dr. Churchill discussed the prognostic importance of pelvic lymph node involvement, compared to fixed (clinical) or extranodal extension (pathologic) inguinal lymphadenopathy in penile cancer. Overall, prognosis is poor for patients with advanced penile squamous cell cancer (PSCC) with lymph node (LN) disease. However, it is notable that, whether relying on clinical or pathologic characterization, N3 disease in the current TNM classification system may be defined based on the involvement of inguinal nodes or pelvic nodes. Clinical N3 (cN3) stage is defined based on the presence of fixed inguinal LN metastasis or pelvic lymphadenopathy (PLN). Similarly, pathologic N3 (pN3) stage is defined as metastasis in pelvic LN and/or extra-nodal extension (ENE) in any LN.

The authors sought to examine the hypothesis that patients with PLN on cross-sectional imaging would have worse prognosis than those with ENE present in inguinal LN (iENE) and without PLN.

To do so, they retrospectively analysed data for patients treated at a UK tertiary referral centre at The Christie NHS Foundation Trust between 2003 and 2021 with PSCC and suspicion of LN disease (cN+) at diagnosis. Patients were excluded if they had extra-pelvic LN or distant metastatic disease at diagnosis or if they did not have available cross-sectional imaging of the abdomen and pelvis within 6 months of definitive primary (penile) treatment. The primary outcome was OS (time from definitive primary surgery to death, censored for last follow-up). This was stratified by PLN present (PLN+) vs PLN absent and iENE present (PLN-iENE+). The PLN absent and iENE absent (PLN-iENE-) group was included as a referent.

The authors identified 199 patients who met inclusion criteria. Among these 199 patients, 110 were categorised as PLN-iENE-, 58 as PLN-iENE+ and 31 as PLN+. Baseline characteristics of age, primary tumour stage, and grade were similar across all groups.

Based on univariate Cox regression analysis, the authors identified an increased risk of death in the PLN-iENE+ group (HR=2.23, 95% CI 1.38-3.61, p=0.001) and the PLN+ group (HR=4.08, 95% CI 2.39-6.97, p<0.001) compared to the reference PLN-iENE- group. 

In a multivariable analysis, both extranodal extension and pelvic nodal involvement were associated with an increased risk of mortality compared to the control group. 

The authors further performed a pairwise analysis between those with inguinal ENE and those with pelvic nodal disease. While not statistically significant, for those with pelvic nodal disease, there was an increased risk of death (hazard ratio 1.62, 95% CI 0.96-2.75, p=0.072).

Thus, the authors concluded that, among patients with PSCC and clinical evidence of LN metastases, patients with evidence of inguinal extranodal extension or pelvic lymph node involvement have worse OS compared to those without either of these characteristics, as predicted by the current TNM classification system. However, they further demonstrate a prognostic subclassification of the N3 group with a worse prognosis seen for patients with pelvic nodal disease.

Presented by: James A. Churchill, MBBS, Specialty Doctor in Urology, The Christie NHS Foundation Trust