Anal squamous cell carcinoma is predominantly driven by human papillomavirus infection across different geographic regions

Abstract Human papillomavirus (HPV) is considered the main etiological factor of anal squamous cell carcinoma (ASCC). However, it is not known whether there are geographical differences in terms of epidemiological features or prevalence of HPV infection. In addition, the existence and the contribution of other mechanisms to the carcinogenesis of this tumor is not clear. This study aimed at comparing the etiopathogenic and epidemiological characteristics of ASCC in Mozambique and Spain, two countries with markedly different epidemiological backgrounds regarding HPV and human immunodeficiency virus infection. All ASCCs diagnosed in two tertiary referral hospitals from Mozambique and Spain between 2019–2023 were included. HPV DNA detection and genotyping, as well as immunohistochemical staining for p16 and p53 were performed in all cases. 43 tumors were identified in Mozambique and 29 in Spain. No differences were identified in the percentage of HPV-associated tumors: 41/43 (95.3%) in Mozambique and 28/29 (96.6%) in Spain. HPV16 was the most frequently identified type in both countries, but other HPV types were more frequently found in the absence of HPV16 in Mozambique than in Spain (16/36, 44.4% vs. 2/28, 7.1%; p = 0.0016). In Mozambique, ASCC was less frequent in men (7/43; 16.3%, vs. 14/29; 48.3%; p = 0.007) and occurred in younger patients (44.1 ± 9.4 vs. 60.3 ± 12.6; p < 0.001). A small proportion of ASCC probably developed following HPV-independent mechanisms, with evidence suggesting two distinct pathways for these tumors, one with TP53 mutation and a second with wild type TP53 .