Histology-Specific Survival in Penile Squamous Cell Carcinoma: A SEER-Based Study Highlighting Human Papillomavirus Status and Prognostic Subtypes

<b>Background:</b> Penile squamous cell carcinoma (SCC) is now categorized based on human papillomavirus (HPV) status as HPV associated (SCCa) or HPV-independent. While most HPV-independent cases are of the usual type (Usual-SCCi), the prognostic significance of this subclassification-particularly between Usual-SCCi and other SCC HPV-independent variants (Variant-SCCi)-remains unclear. <b>Materials and Methods:</b> Using SEER data (2000-2021), patients with penile SCC were categorized into Usual-SCCi, Variant-SCCi (verrucous, papillary, and sarcomatoid), and SCCa groups. Cancer-specific survival (CSS) was evaluated using Kaplan-Meier estimates and Cox proportional hazard regression adjusted for demographic and clinical factors, with Firth's penalized likelihood correction applied when appropriate. Temporal trends and subtype-specific outcomes were also analyzed. <b>Results:</b> Among 6332 patients, 5706 (90.1%) were Usual-SCCi, 416 (6.6%) were Variant-SCCi, and 210 (3.3%) were SCCa. Overall, 5-year CSS (proportion of patients (%) [95% CI]) was the highest in Variant-SCCi (90.9% [87.8-94.0]), compared to Usual-SCCi (73.7% [72.4-75.0]) and SCCa (71.5% [63.3-80.8). Within Variant-SCCi, verrucous SCC had the most favorable outcome (94.1% [91.3-97.0]), followed by papillary (81.9% [68.2-98.4]) and sarcomatoid (63.4% [47.4-84.7]). Multivariable analysis confirmed verrucous SCC as being independently associated with significantly lower cancer-specific mortality (HR: 0.31 [95% CI, 0.20-0.45]; <i>p</i> < 0.001). Time-stratified analysis revealed that in the latter half of the study period, SCCa outcomes improved markedly, and no statistically significant differences in CSS were observed among the SCCa, papillary, and Usual-SCCi groups, leaving verrucous SCC as the only subtype with consistently superior survival (<i>p</i> < 0.001). <b>Conclusions:</b> The CSS of SCCa improved over time to become equivalent to those of the SCCi subtypes except for the verrucous SCCi variant, which had a significantly better CSS. Our study clearly demonstrates a temporal shift toward improved CSS in the SCCa subtype, which may be related to increased awareness following recognition as a separate entity in the WHO 2022 classification and other factors.