From biology to morphology and treatment: the current role of pathology in penile cancer - a narrative review.

Penile carcinoma is a rare but psychosexually devastating malignancy associated with the worst prognosis among male-specific genitourinary malignancies (prostate, testicular, and penile cancer). In addition to loss of the organ itself, patients frequently suffer from chronic lymphedema following inguinal lymph node dissection. Despite advances in oncology, the prognosis of penile cancer has not substantially improved over the past half century, and the disease has long remained underrepresented in basic research, clinical trials, and patient advocacy initiatives. During the 2020s, however, the situation has begun to change, with an increasing number of large studies and the emergence of the first meta-analyses focused on penile carcinoma. Current morphological and molecular studies aim to identify features of aggressive disease that may guide treatment escalation or de-escalation and thereby improve patients' quality of life. This review summarizes recent advances in the field, with particular emphasis on prognostic parameters accessible by routine histopathological examination. In many settings, simple pathological biomarkers may provide greater clinical utility than expensive molecular analyses. Special attention is devoted to the interplay between morphology, HPV status, immune microenvironment, and molecular alterations. The review discusses histological grading, morphological subtypes, HPV status and its correlation with morphology and mutational profiles, the prognostic significance of tumor-infiltrating lymphocytes and PD-L1 expression, and particularly tumor budding, which is strongly associated with aberrant p53 status and adverse prognosis. Future perspectives include refinement of penile carcinoma classification into: 1) HPV-associated, 2) HPV-independent, p53 wild-type, and 3) HPV independent, p53-altered tumors. Additional parameters with potential to improve prognostic stratification include tumor budding and the subjectively assessed peritumoral lymphocytic rim (brisk versus non-brisk), both of which appear suitable for routine reporting alongside conventional staging and grading. To sum up: Morphology really matters even in the molecular era.