Laryngeal papilloma (LP) is driven primarily by infection with low-risk human papillomavirus (LR-HPV), most often types 6 and 11. However, the clinical relevance of the HPV genotype, viral load, and associated molecular markers in LP remains incompletely understood.

We retrospectively analyzed 30 patients with LP treated at the University of Ryukyu Hospital between 2010 and 2023. Their tumor samples were subjected to HPV genotyping, viral load quantification, and immunohistochemical profiling (p16, p21, p53, and Ki-67). Correlations of recurrence and remission data with virological and immunohistochemical findings were investigated.

HPV DNA was detected in 28 of the 30 patients (92.9%), with a predominance of HPV-6 (89.3%), and with HPV-11 accounting for 10.7%. HPV-6 subtyping identified 6a, 6b, and 6vc variants. Most lesions were multifocal and localized to the glottis. Surgical resection was performed in 26 patients, among whom the recurrence rate was 87.5%; complete remission was achieved in 34.6% of these patients, more often in younger patients with juvenile-onset and in those with lower Derkay scores. The viral load did not correlate with recurrence or remission. Immunohistochemistry revealed low p16 and p53 expression, while Ki-67 was consistently positive. Of note, p21 was strongly expressed throughout the epithelium in all LP cases with HPV infection, with a significantly greater frequency, than in papillomas at other head and neck sites without LR-HPV infection (p < 0.0001).

HPV genotype and viral burden do not predict recurrence or remission of LP. LPs have a unique molecular profile characterized by diffuse p21 expression and high proliferative activity. These findings underscore the need to consider LP as a distinct HPV-driven entity and highlight p21 as a potential biological marker of LR-HPV-associated disease.