36.1 Introduction

Human papilloma viruses (HPV) are responsible for various diseases. At least 80% of all people become infected with HPV during their lifetime. The most common transmission route is sexual contact and intense skin contact; less than 1% of all infections occur during birth via vertical transmission.

Main risk factor for an infection is the number of sexual partners. Persistent HPV infections occur more frequently with tobacco smoking, a positive history of other sexually transmitted diseases, or with a compromised immune system, for example in case of HIV infections or organ transplantation.

HPV are divided into low-risk (lr) and high-risk (hr) types. This represents the probability of malignant transformation following persistent infections. Infections with lr types 6 and 11 often lead to genital warts, but can also cause penile cancer. A persistent infection with an hr type, especially 16, 18, 31, 33, 45, 52, and 58, can lead to cervical cancer, vaginal/neovaginal cancer, vulvar cancer, penile cancer, anal cancer, or head and neck cancer. HPV 16 is by far the most important oncogenic type, causing more than 50% of all HPV-related cancers [Reference Bosch, Broker and Forman1].

Since 2006, it is possible to prevent HPV infections and subsequently cancer with a vaccination. HPV screening is now the golden standard to reduce mortality of cervical cancer and possibly HPV-related diseases.

36.2 HPV

Almost everyone has contact with HPV at some point in their lifetime since the infections are related to skin and mucosal contact, and the prevalence reflects sexual activity. Before the onset of sexual activity, detection of HPV is not uncommon [Reference Doerfler, Bernhaus and Kottmel2]. However, after first sexual activity, a significant increase in the prevalence of HPV is observed. In women, the peak of prevalence of almost 30% is in the third decade, declining at the age of 30 years below 10%. This is the background of cervical cancer screening based on HPV testing after the age of 30. In contrast to females, men have a steep increase in the prevalence in their late teenage years up to 50%. It continues at this high level until they are in their seventies [Reference Giuliano, Lee and Fulp3].

In contrast to the well-documented prevalence in the majority of the population, HPV prevalence in trans people is not known, due to lack of data. So far, four studies have been published.

In the first study, an HPV screening of 35 trans people (14 trans men, 21 trans women) was performed. A prevalence of 40% was found; 93% had an hr HPV infection [Reference Loverro, Di Naro and Caringella4]. In another study of 150 trans men with a cervix, healthcare professional vs. self-testing HPV tests were compared: vaginal prevalence was 14% (healthcare professional) and 11.4% (self-testing) [Reference Reisner, Deutsch and Peitzmeier5]. In an international study, 13 trans women were included among others. In the subgroup analysis, the anal tests showed an HPV prevalence of 69% (9/13) [Reference Cranston, Carballo-Diéguez and Gundacker6]. A Dutch study showed an hr HPV prevalence of 20% in sexually active trans women, but no patient showed precancerous lesions [Reference van der Sluis, Buncamper and Bouman7].

36.3 HPV Vaccine

After demonstrating that a virus-like particle (VLP)-based HPV vaccine can prevent persistent infections and disease caused by HPV 16, the first generation of HPV vaccines was developed [Reference Koutsky, Ault and Wheeler8,Reference Pils and Joura9]. In 2006, the first licensed HPV vaccine was Gardasil® (Merck, US), protecting against infections and disease caused by the four HPV types HPV 6, 11, 16, and 18. In 2007, the bivalent HPV 16/18 vaccine Cervarix® (GSK, UK) became available. The first generation of these vaccines has demonstrated protection against HPV-related disease of the cervix, vulva, vagina, and anus. Both vaccines prevent oral infections with HPV 16, the type also responsible for oropharyngeal cancer. The quadrivalent vaccine also confers a high protection against genital warts [Reference Garland, Hernandez-Avila and Wheeler10–Reference Chaturvedi, Graubard and Broutian13].

The vaccines protect people regardless of their gender and sexual orientation. Since 2016, the nine-valent HPV 16/11/16/18/31/33/45/52/58 vaccine is the standard, providing a broad protection against seven oncogenic and two low-risk HPV types [Reference Joura, Giuliano and Iversen14,Reference Huh, Joura and Giuliano15].

The best time for vaccination is as early as possible. The vaccines are licensed from the age of nine and they should be applied soon after, preferably in a gender-neutral vaccination program. At this age, before the onset of puberty and the start of sexual activities, the prophylactic vaccines are most effective and elicit the highest antibody levels, which make two doses up to the age of 15 as effective as three doses later in life. In population-based studies, early vaccination was most effective [Reference Drolet, Bénard, Pérez and Brisson16]. However, these vaccines have demonstrated efficacy up to the age of 45 years in women [Reference Castellsagué, Muñoz and Pitisuttithum17] and up to the age of 26 years in men [Reference Van Damme, Meijer and Kieninger18]. In addition, a reduction of recurrence or subsequent disease after surgical treatment of HPV-related pre-cancer could be shown [Reference Joura, Garland and Paavonen19–Reference Ghelardi, Marrai and Bogani21].

Pediatric and school-based HPV vaccination programs are most likely to protect any individual, regardless of gender and sexual orientation, and provide protection against HPV infections and related disease at all sites affected by HPV and regardless of specific sexual activities.

Reisner et al. evaluated as secondary study objective the vaccination status of 150 American transgender men: 55.7% had received at least one HPV vaccination, 8.7% were unsure of their vaccination status. Among the vaccinated trans men, 85.7% completed the vaccination series and were on average 19.01 (SD 4.8) years old [Reference Reisner, Deutsch and Peitzmeier5].

36.4 Genital Warts

Genital warts (GWs) occur with an incidence of 142–191.1/100,000 per year in women and of 147.7–167.7/100,000 per year in men [Reference Hartwig, Baldauf and Dominiak-Felden22]. They are mainly caused by HPV type 6 and 11 [Reference Garland, Steben and Sings23]. Clinical manifestation can range from solitary warts to cauliflower-shaped lesions. The transmission occurs via intensive skin contact. The probability of transmission is highest in the presence of warts, as the viral load is highest here.

The interval between infection and clinical involvement is usually between 1 and 8 months. The probability of developing GWs after infection is 64% within 3 years. Symptoms are itching, burning, bleeding, or pain during intercourse. Thirty percent of all GWs heal spontaneously after about 4 months, but HPV infection is often persistent. Recurrence occurs in 20–30% within a few months. HPV clearance usually takes 2 years [Reference Lacey, Woodhall, Wikstrom and Ross24].

Therapeutically, depending on size and symptoms, surgical and destructive treatments and/or topical treatments with podophyllotoxin or imiquimod are available.

Two case reports on the successful treatment of GWs in transgender females have been published. In the first case report, a combination of destructive treatment followed by topical application with imiquimod was used [Reference Matsuki, Kusatake, Hein, Anraku and Morita25]. In the second case report, topical imiquimod therapy alone was prescribed [Reference Labanca and Mañero26].

It is important to note that hr HPV co-infections in the case of present GWs are described in 30–40%. Therefore, the increased incidence of HPV hr-induced cancers after GWs is 4.8 within 10 years (anal for men, RR 21.5; anal for women, RR 7.8, vulva RR 14.8, vagina RR 5.9, cervix RR 1.5, head and neck RR 2.8) [Reference Blomberg, Friis, Munk, Bautz and Kjaer27]. Thus, adequate screening for hr strains is particularly important when patients report a history of genital warts.

36.5 Cervical Cancer Screening

Five percent of all carcinomas are HPV associated. In detail, 99% of all cervical cancers, 88% of anal cancer, 70% of vaginal cancer, 25% of vulvar cancer, 30% of penile cancer, and 26% of head and neck cancers are due to persistent HPV infections. Of these, 80–90% are caused by infections with HPV 16, 18, 31, 33, 45, 52, or 58.

The main advantage of HPV-related cancers is that there are precancerous lesions which can be detected in a screening. They can then be treated before the cancer develops.

The introduction of the Papanicolaou (Pap) test led to a significant reduction of cervical cancer worldwide. Depending on age and national recommendations, Pap screening used to be recommended every 1 to 3 years. Since 2018, HPV screening alone is recommended every 5 years from the age of 30 on, if previous screening results were negative. The Pap smear only has relevance in presence of HPV infection [Reference Curry and Krist28].

It is important to note that cervical cancer screening is also recommended even if there is no penetrative sex. If the cervix is completely removed and the patient is HPV-negative with no history of abnormal Pap test, cervical cancer screening can be stopped, but other HPV-related cancers can still occur. Furthermore, it is worth paying attention to structures derived from parts of the glans penis as this region is known to be particularly at risk for acquiring HPV-related precancerous lesions. Creation of the neoclitoris and its vascular and neurogenic supply typically derives from the glans penis and – although rarely performed – a lump at the apex of the neovagina pretending to feel like a neocervix [29].

Independent of national health systems and screening strategies, acceptance of Pap-screening is lower for transgender men than for cisgender women. The probability of having had a Pap test during the last year varies between the studies. Based on CDC data, 27% of transgender men reported having had a Pap-test during the last year compared to 43% of cisgender women who participated in the screening [Reference Rollston30]. However, other studies showed more encouraging results: 36.9% [Reference Reisner, Deutsch and Peitzmeier5] and 61.3% [Reference McDowell, Pardee and Peitzmeier31] reported having had a Pap-smear in the last year. If an up-to-date Pap-test, defined as a negative Pap-smear during the last 3 years or other conditions under surveillance, is taken as a standard, 64.3% of transgender men compared to 73.5% of cisgender women attended screening [Reference Peitzmeier, Khullar, Reisner and Potter32].

Furthermore, it should be noted that the validity of Pap-smears in transgender men, especially in the case of long-term testosterone therapy which induces vaginal atrophy, is significantly lower than in cisgender women. This seems to be due both to the testosterone therapy and to the discomfort during the examination. Therefore patients should be informed that retesting may be necessary [Reference Peitzmeier, Reisner, Harigopal and Potter33].

In a study of 63 trans men, the acceptance of the screening was investigated. It was found that the self-collected HPV swab had a better acceptance than the healthcare-professional-collected swab. The Pap-test was rated worst as it was perceived as more invasive and provoked more gender dysphoria. In detail, the following hierarchy was published: self-swab > healthcare-professional-swab > Pap-test: 60.5% vs. healthcare-professional-swab > self-swab > Pap-test: 19.1% [Reference McDowell, Pardee and Peitzmeier31].

In terms of reliability, a study of 131 trans men with a cervix showed that while the healthcare-professional-collected smear was more accurate, the self-collected test had a higher acceptance rate. Fifteen of the 21 HPV positive cases (rate 71.4%) were detected by the self-collected test. Therefore, the authors assume that self-collected HPV swab could be a reasonable screening strategy, even though a gynecological examination is indispensable if the result is positive [Reference Reisner, Deutsch and Peitzmeier5].

Regarding the site of collection, a study by Loverro et al. showed that anal HPV typing provides more accurate results than a smear from the vagina or neovagina. Of the 35 (14 transgender men, 21 transgender female) subjects included, 14 were hr HPV positive. Out of them, 13/34 tested anal positive, while only 2/22 tested positive in the vaginal/neovaginal swap, and 1/12 in the penile sample [Reference Loverro, Di Naro and Caringella4]. A recommendation for a general anal test in trans persons cannot be given due to the small sample size, nor do guidelines exist for anal screening for other populations.

Small sample sizes are a general limitation of studies on transgender and gender nonconforming people. For instance, due to a lack of data about HPV-related cancers in transgender persons, no incidence is known. Only some case reports have been published:

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  – One HPV 16 positive vaginal carcinoma in a transgender man was published [Reference Schenck, Holzbach and Zantl34].

  
  
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  – Five HPV positive squamous cell carcinoma of the penile skin in a neovagina were reported [Reference Harder, Erni and Banic35–Reference Wang, Ferguson and Ionescu39].

  
  
• 
  

  – One case of cervical cancer was found during gender-affirmative surgery [Reference Urban, Teng and Kapp40].

Precancerous lesions have been reported twice in transgender persons: once on the cervix [Reference Driák and Samudovský41], once in two patients with hr HPV positive moderate-to-severe dysplasia on the neovagina and neovulva [Reference van der Sluis, Buncamper and Bouman42]. However, underreporting is likely.