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      HPV-related diseases in male patients: an underestimated conundrum

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          Abstract

          Purpose

          Human papillomavirus (HPV) infection is the most common sexually transmitted disease, in males and females worldwide. While the role of HPV in female diseases is well known and largely studied, males have negligibly been included in these programs, also because the proportion of women suffering and dying from HPV-related diseases is much larger than men. The aim of this review is to focus on HPV-related diseases in male patients.

          Methods

          We performed a literature analysis on the electronic database PubMed. We considered randomized trials, observational and retrospective studies, original articles having as topic the relationship between HPV male infection and the following items: oral, anal penile cancers, warts, condylomas, male infertility, altered sperm parameters, anti-sperm antibodies (ASA). We also included experimental in vitro studies focused on the effects of HPV infection on oocyte fertilization, blastocyst development, and trophoblastic cell invasiveness. In addition, studies describing the adjuvant administration of the HPV vaccination as a possible strategy to promote HPV clearance from semen in infected males were included.

          Results

          Regarding head and neck HPV-related diseases, the most important non-neoplastic disease is recurrent respiratory papillomatosis (RRP). Regarding neoplastic diseases, the proportion of head and neck cancers attributable to HPV has increased dramatically worldwide. In addition, nowadays, it is thought that half of head and neck squamous cell carcinomas (HNSCCs) cases in the United States are caused by infection with high-risk HPV. HPV is noteworthy in andrological practice too. It was described as having a high HPV prevalence, ranging between 50 and 70%, in male penile shaft, glans penis/coronal sulcus, semen as well as in scrotal, perianal, and anal regions. Moreover, in male patients, HPV infection has been associated, among other diseases, with penile cancers. HPV semen infection has been reported in about 10% in men from the general population and about 16% in men with unexplained infertility, although these data seem widely underestimated according to clinical experience. In particular, HPV semen infection seems to be most related to asthenozoospermia and to anti-sperm antibodies (ASAs).

          Conclusions

          HPV infection represents a health problem with a detrimental social and public impact. Despite this evidence, little has been done to date to widely promote vaccination among young males.

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          Most cited references151

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          Head and neck squamous cell carcinoma

          Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative or HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent premalignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporated additional information relevant to HPV-positive disease. The treatment approach is generally multimodal, consisting of surgery followed by chemotherapy plus radiation (chemoradiation or CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where co-morbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least toxic therapies.
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            Worldwide burden of cancer attributable to HPV by site, country and HPV type

            HPV is the cause of almost all cervical cancer and is responsible for a substantial fraction of other anogenital cancers and oropharyngeal cancers. Understanding the HPV‐attributable cancer burden can boost programs of HPV vaccination and HPV‐based cervical screening. Attributable fractions (AFs) and the relative contributions of different HPV types were derived from published studies reporting on the prevalence of transforming HPV infection in cancer tissue. Maps of age‐standardized incidence rates of HPV‐attributable cancers by country from GLOBOCAN 2012 data are shown separately for the cervix, other anogenital tract and head and neck cancers. The relative contribution of HPV16/18 and HPV6/11/16/18/31/33/45/52/58 was also estimated. 4.5% of all cancers worldwide (630,000 new cancer cases per year) are attributable to HPV: 8.6% in women and 0.8% in men. AF in women ranges from 20% in India and sub‐Saharan Africa. Cervix accounts for 83% of HPV‐attributable cancer, two‐thirds of which occur in less developed countries. Other HPV‐attributable anogenital cancer includes 8,500 vulva; 12,000 vagina; 35,000 anus (half occurring in men) and 13,000 penis. In the head and neck, HPV‐attributable cancers represent 38,000 cases of which 21,000 are oropharyngeal cancers occurring in more developed countries. The relative contributions of HPV16/18 and HPV6/11/16/18/31/33/45/52/58 are 73% and 90%, respectively. Universal access to vaccination is the key to avoiding most cases of HPV‐attributable cancer. The preponderant burden of HPV16/18 and the possibility of cross‐protection emphasize the importance of the introduction of more affordable vaccines in less developed countries.
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              Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review

              A. Kreimer (2005)
              Mucosal human papillomaviruses (HPV) are the cause of cervical cancer and likely a subset of head and neck squamous cell carcinomas (HNSCC), yet the global prevalence and type distribution of HPV in HNSCC remains unclear. We systematically reviewed published studies of HNSCC biopsies that employed PCR-based methods to detect and genotype HPV to describe the prevalence and type distribution of HPV by anatomic cancer site. Geographic location and study size were investigated as possible sources of variability. In the 5,046 HNSCC cancer specimens from 60 studies, the overall HPV prevalence was 25.9% [95% confidence interval (95% CI), 24.7-27.2]. HPV prevalence was significantly higher in oropharyngeal SCCs (35.6% of 969; 95% CI, 32.6-38.7) than oral SCCs (23.5% of 2,642; 95% CI, 21.9-25.1) or laryngeal SCCs (24.0% of 1,435; 95% CI, 21.8-26.3). HPV16 accounted for a larger majority of HPV-positive oropharyngeal SCCs (86.7%; 95% CI, 82.6-90.1) compared with HPV-positive oral SCCs (68.2%; 95% CI, 64.4-71.9) and laryngeal SCCs (69.2%; 95% CI, 64.0-74.0). Conversely, HPV18 was rare in HPV-positive oropharyngeal SCCs (2.8%; 95% CI, 1.3-5.3) compared with other head and neck sites [34.1% (95% CI, 30.4-38.0) of oral SCCs and 17.0% (95% CI, 13.0-21.6) of laryngeal SCCs]. Aside from HPV16 and HPV18, other oncogenic HPVs were rarely detected in HNSCC. Tumor site-specific HPV prevalence was higher among studies from North America compared with Europe and Asia. The high HPV16 prevalence and the lack of HPV18 in oropharyngeal compared with other HNSCCs may point to specific virus-tissue interactions. Small sample size and publication bias complicate the assessment of the prevalence of HPV in head and neck sites beyond the oropharynx.
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                Author and article information

                Contributors
                andrea.garolla@unipd.it
                Journal
                J Endocrinol Invest
                J Endocrinol Invest
                Journal of Endocrinological Investigation
                Springer International Publishing (Cham )
                0391-4097
                1720-8386
                28 September 2023
                28 September 2023
                2024
                : 47
                : 2
                : 261-274
                Affiliations
                [1 ]Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, ( https://ror.org/00240q980) Padua, Italy
                [2 ]Section of Otolaryngology, Department of Neurosciences, University of Padova, ( https://ror.org/00240q980) Padua, Italy
                Author information
                http://orcid.org/0000-0003-4736-9051
                Article
                2192
                10.1007/s40618-023-02192-3
                10859347
                37770654
                046de9be-5772-42ad-ba4d-0a7e01ad122c
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 June 2023
                : 28 August 2023
                Funding
                Funded by: Università degli Studi di Padova
                Categories
                Review
                Custom metadata
                © Italian Society of Endocrinology (SIE) 2024

                hpv,hpv-related diseases,head and neck cancer,male hpv,male infertility,sperm parameters

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