Human papillomavirus (HPV) is responsible for cancers of the anogenital tract (cervix, anus, vulva, vagina, and penis) and cancers of the oropharynx. Sexual and/or gender minority (SGM) populations face barriers to health care and as a result experience disparate outcomes in cancer prevention. The goals of this document are to define SGM populations, to review the literature on HPV-related disease in SGM populations, and to provide recommendations for screening and prevention of HPV-related cancers in SGM populations. Our hope is that by providing this guidance, appropriate cancer screening for SGM patients will become more widely performed.

Box 1 provides an overview of the terminology and critical language used throughout this article. Using clinical organ/tissue-based terminology allows for separation of gender from anatomy and hormonal status and avoids excluding marginalized gender identities.1 We advocate the adoption of an organ-based screening approach, which is possible with knowledge of patient anatomy, sexual behaviors, and clinical history. This includes screening for cervical cancer per national recommendations, and screening for anal, vulvar, vaginal, and penile cancers based on risk factors and shared clinical decision making. A summary of recommendations for organ-based screening is provided in Table 1.

Box 1 SGM/LGBTQ+ Definitions.1–3

Lesbian, gay, bisexual, transgender, queer, intersex, asexual, and other (LGBT, LGBTQ+, LGBTQIA+): Often used as an umbrella term for people who are not cisgender or heterosexual. The “+” acknowledges that other groups are included within the LGBTQ umbrella (e.g., asexual, nonbinary, genderfluid etc.).

Sexual and/or gender minority (SGM): Used primarily in medicine and academia as an umbrella term to describe individuals who are neither heterosexual and/or cisgender. This is used by the National Institutes of Health, which recognizes SGM people as a health disparities population.

Sexual orientation (SO): A construct with the following 3 overlapping components: sexual identity, sexual attraction, and sexual behavior. Sexual identity, attraction, and behavior may or may not all “line up.” Someone might identify as a lesbian (identity), be attracted to cisgender women and nonbinary people (attraction), and have penis-in-vagina sex with cisgender men (behavior). Common sexual orientation terms that are sometimes used as identity terms are as follows: asexual, bisexual, heterosexual, lesbian, gay, pansexual, and queer. Common sexual behavior descriptors are women who have sex with women “WSW,” women who have sex with men “WSM,” women who have sex with women and men “WSWM,” men who have sex with men “MSM,” etc. These terms should be modified by cisgender/transgender terms and description of sexual activities (e.g., penis-in-vagina sex, penis-in-anus sex, oral-anal sex, oral-penile sex, vulva-to-vulva sex, etc.).

Sexual identity is how one thinks about themselves in relation to who they are attracted to, partner with sexually, romantically, emotionally, and who they have sex with. Sexual attraction is specific to who people are attracted to sexually but does not imply that someone is acting on those attractions. Sexual behavior describes who someone is having sex with and how. Although sometimes limited to describe the gender of sexual partners (e.g., WSW), using only the partner gender descriptor and not the descriptor of the sexual activity should be avoided, as it limits understanding of pregnancy risk/opportunity, sexually transmitted infection risk, and how to optimize sexual satisfaction. For example, two cisgender gay men (i.e., MSM may not engage in penis-in-anus sex and only engage in penis-in-mouth [oral] sex).

Gender: Societal and cultural attributes, norms, as well as expectations related to being a woman, man, or person of one or many other genders and differ by context, region, culture, and generation. Gender can be further broken down into gender identity and gender expression, which may not “line up” with each other or with society's expectations for an individual.

Gender identity (GI): One's internal held understanding of themselves as a girl/woman, boy/man, multiple genders, no genders, or outside of the gender binary. Gender identity cannot be known without asking someone directly. An individual's willingness to disclose a true answer may be related to their feeling of safety in a given encounter.

Gender expression: How someone expresses and performs their gender, which has to do with the clothes people wear, hair, make-up, accessories, vocal intonations, posture, etc. This is what is seen and experienced by others. This may or may not “line up” with their gender identity.

Sexual orientation and gender identity (SO/GI): As defined previously, this construction is often used together, increasingly in medicine and research, to describe these critical components of people's experiences.

Sex assigned at birth: This describes the phenotypic presentation of usually dimorphic sex characteristics of humans identified on examination of genitalia at birth and occasionally before birth. Common terms to describe sex assignment at birth are “female” and “male” and “intersex.”

Assigned female sex at birth (AFAB): Individuals born with a uterus, cervix, ovaries, and fallopian tubes and the capacity to develop milk-bearing breast tissue. Unless there are medical interventions, these individuals' natal puberty will usually be estrogen dominant, begin with breast bud development, and be associated with onset of menses, development of mature oocytes, and pregnancy capacity.

Assigned male at birth (AMAB): Individuals born with a penis, testes, and a prostate. Unless there are medical interventions, these individuals' natal puberty is usually testosterone/androgen driven and will be associated with penile and testicular enlargement and the development of viable sperm.

Intersex, having a difference of sex development “DSD,” or sometimes Assigned Intersex at Birth: These individuals may or may not have typically AFAB or AMAB genital phenotypes. There are a variety of conditions and intersex traits that may be classified as a DSD with different phenotypic expressions and medical implications.

Cisgender: A term, primarily used in academia, that describes individuals whose current gender identity is consistent with their sex assigned at birth. For example, a cisgender woman is someone who identifies as a woman and was assigned female sex at birth and was born with a uterus, cervix, ovaries, and fallopian tubes.

Transgender and gender diverse: Transgender and gender diverse people have a gender identity(ies) that differs from their sex assigned at birth.

Transgender man (TGM)/transmasculine individual: is someone who identifies as a man or on the masculine spectrum and was assigned female sex at birth.

Transgender woman (TGW)/transfeminine individual: is someone who identifies as a woman or on the feminine spectrum and was assigned male sex at birth.

Gender expansive/gender diverse: Are terms used to describe individuals whose identities and/or gender experiences are not a binary (i.e., man/woman) gender identity and may be of any sex at birth. In medical and investigational contexts, we would describe this person as a gender diverse person who was assigned female at birth or male at birth if necessary for their medical care or scientific question.

Gender-affirming processes and procedures: Are steps taken to align an individual's body and and/or secondary sex characteristics with their gender identity(ies). These processes can be broadly broken down into social, medical, and surgical activities.

Social gender-affirming processes: These include but are not limited to: name changes, pronoun changes, and changing of identifying documents such as drivers' licenses and insurance cards.

Medical gender-affirming processes: These include the exogenous administration of steroid hormones such as estrogens, progestins, and androgens and/or hormone blockers such as GnRH agonists, antagonists, and/or hormonally active agents like spironolactone and finasteride.

Surgical gender-affirming processes: This describes procedure including facial surgery, “top surgery” to enhance or reduce chest/breast tissue, or “bottom surgery” to change the appearance and/or function of the genitourinary and reproductive system. There are more than 2 dozen such procedures. These processes may impact lower genital tract disease as discussed elsewhere in this review.

TABLE 1 - Organ-Based Screening Recommendations for Screening for HPV-Related Cancers in SGM Populations Organ at risk Does the risk of HPV-related cancer in this organ warrant screening? What type of screening should be offered? Anus Yes—in individuals at higher risk 35 years and older, with screening initiated no later than age 45 a:
• People living with HIV
• Non-HIV immunosuppressed
• Men who have sex with men
• Transgender women
• History of vulvar HSIL or cancer
• Other groups with high incidence b
No—no risk factors present Anal cancer—DARE or anal cytology and/or hrHPV testing with DARE c Cervix Yes High-risk HPV testing, cervical cytology/hrHPV co-testing, or cervical cytology per national guidelines () d Oropharynx Yes Annual dental examination recommended (no available/validated screening tools in clinical practice) Penis/scrotum Yes—in individuals at higher risk:
• History of anogenital HSIL or cancer
No—no risk factors present Visual inspection of the penis/scrotum Vagina Yes—in individuals with history of cervical HSIL or cancer
No—no risk factors present Vaginal cytology and/or hrHPV testing e Vulva Yes—in individuals at higher risk:
• People living with HIV
• Non-HIV immunosuppressed
• History of anogenital HSIL or cancer
No—no risk factors present Visual inspection of the vulva

a Exact age to start screening is still to be determined, but generally 35–45 years old is the recommended timeframe to start; screening guidelines from the International Anal Neoplasia Society are forthcoming.

b Clifford et al. (2021).2

c Screening tool depends on availability of HRA services. Although hrHPV testing is not FDA approved in the anal canal, multiple studies demonstrate high sensitivity for anal HSIL detection.

d The United States Preventive Services Task Force 2018 and American Cancer Society 2020 recommendations.

e2019 ASCCP management guidelines recommend surveillance testing for at least 25 years after treatment of cervical high-grade squamous intraepithelial lesion; although hrHPV testing is not FDA approved in the vagina, the sensitivity of HPV testing compared with cytology alone for detection of vaginal lesions seems superior.

DARE indicates digital anal rectal examination; hrHPV, high-risk HPV; HSIL, high-grade squamous intraepithelial lesion.

Human papillomavirus causes approximately 5% of cancers worldwide. These include cancers of the anogenital tract (cervix, anus, vulva, vagina, and penis) and cancers of the oropharynx (see Figure 1). National guidelines exist in many countries for screening for cervical cancer, and the World Health Organization has screening and vaccination guidelines that, if optimally implemented worldwide, would ideally eliminate cervical cancer by 2030.3 In contrast to cervical cancer, the other HPV-related cancers do not have standardized screening recommendations, leading to gaps in knowledge and missed opportunities for screening for many patients.

FIGURE 1:

Annual incidence of HPV-associated cancers in the United States from the SEER Database, 2015–2019. Adapted from: Cancers associated with human papillomavirus, United States—2015–2019 USCS Data Brief, no. 31. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2022.

Sexual and/or gender minority or LGBTQIA+ (lesbian, gay, bisexual, transgender, queer, intersex, asexual, and other) populations often face additional barriers to appropriate health care. Front and foremost is bias and discrimination, which leads to lower utilization of health services.4

There is a long history of stigma and discrimination against sexual and/or gender minority people in society and in health care. In health care, this has resulted in negative experiences, disparate access to care, and inequitable health outcomes. These same barriers lead to a lack of visibility and focused inclusion of SGM people in health care research, leading the National Institutes of Health to declare SGM people as a health disparities population for research.5 Recognition that SGM people are underserved, understudied, and vulnerable to poor health is a notable step and highlights that we are lacking information to better serve this patient population. This includes a lack of information about general health care as it relates to SGM people (e.g., optimal smoking cessation strategies) and a lack of SGM-specific health and health care needs (e.g., family building for SGM people, screening for HPV-related diseases for people who have undergone gender-affirming processes and procedures). Barriers to care lead to poor health outcomes across multiple health domains, and this invisibility in health care research further limits our ability to adequately respond to their health needs. The lack of knowledge or confusion among both patients and providers about which groups should undergo screening tests for cervical or other HPV-related cancers can potentiate health care disparities; thus, it is imperative to provide clear direction and language to optimize screening for HPV-related cancers among SGM people.

The goal of this document is to define sexual and gender minority populations, to review the literature on HPV-related disease in these populations, and to provide recommendations for screening and prevention of HPV-related cancers in SGM populations. Our hope is that by providing this guidance, appropriate cancer screening for SGM patients will become more widely performed.

SGM/LGBTQ+ Definitions

In understanding the data and clinical guidelines for caring for SGM people, a few definitions of the principal terms and concepts are needed. Box 1 provides an overview of terminology and critical language used throughout this article.6–8

These terms will continue to evolve with our increased understanding of SGM needs and sensibilities. One individual may have a multiplicity of identities and experiences. For example, someone may identify as a gay and pansexual transgender man (TGM) who has sex with other TGM and cisgender men, or a transgender woman (TGW) may choose to retain male gender expression in clothing, body hair, etc., or a cisgender woman may identify as queer and lesbian and engage in different behaviors than someone who identifies as queer alone. The clinical considerations (e.g., sexually transmitted infections, pregnancy, risk for HPV-related cancers) are different in these scenarios. Clinicians and researchers should be attuned to this multiplicity and ask how people identify for sexual orientation and gender identity, as well as specifics of sexual behavior, so they can take care of whole person needs and calibrate clinical activities to individual patients.

In addition, clinicians and researchers should be aware that in different regions within the United States and around the world, different terminology is used. Furthermore, there are varying definitions for any term of experience and definitions shift over time. Terminology that is considered offensive and/or inaccurate in clinical and investigational settings (e.g., “transsexual” or “female-to-male”) may still be used by community members. We suggest using a patient's self-defined terminology and reflecting that to them in one-on-one clinical settings. Clinical documentation should ensure up-to-date and scientifically accurate terminology to aid in programmatic and investigational efforts while also being sensitive to a patient's self-identity, as patients frequently have access to their medical records online.9

Using clinical organ/tissue-based terminology allows for separation of gender from anatomy and hormonal status and avoids excluding marginalized gender identities.1 It is most accurate to discuss cervical cancer screening in reference to persons with a cervix (of any gender) and then specify whether that person has an estrogen or androgen dominant hormonal milieu. For example, a cisgender woman may have an androgen dominant environment due to exogenous testosterone use for libido or a transgender person may be using testosterone for gender affirmation. Other organizations concerned with sexual and reproductive health have adopted language practices that acknowledge this changing awareness and inclusion.10 In this review, we advocate for clinical organ/tissue-based discussions and risk stratification but acknowledge that past research has not consistently used this framework. Therefore, we will use the terms used by prior researchers as appropriate, that is, “women,” where the research may be lacking in definitions, inclusion, or clarity. It is our hope that going forward, clinicians and researchers will use the organ-based approach advocated in this review in conjunction with behavioral risk stratification to move toward simplified, risk-based guidelines for screening for HPV-related disease.

METHODS

A group of experts from the American Society for Colposcopy and Cervical Pathology (ASCCP), the society for anogenital and HPV-related diseases, was convened to address the lack of guidelines for screening for HPV-related cancers in the LGBTQIA population. The group was composed of clinical and research experts in HPV-associated diseases (D.J., L.F., N.J., D.T., C.C., L.D., M.K.), LGBTQ+ health (J.O., N.J., D.T., M.K.), and/or underserved populations (N.J., S.F., L.F., L.D.). Representatives from the International Anal Neoplasia Society (IANS; N.J., M.K., L.F., C.C.) and the American College of Obstetricians and Gynecologists Committee on Underserved Populations (S.F., L.D.) were identified through their respective society leadership and were also invited to participate. Through collaboration with these expert committee members, these recommendations have been endorsed by the IANS and ASCCP.

To carry out this narrative review, a comprehensive MEDLINE database search was performed for relevant studies, using search terms relevant to SGM populations. To narrow down the results to literature relevant to the topic of HPV-related disease in SGM populations, articles were excluded initially based on title, then by abstract, and then by full review. The literature review was divided into categories by organ/topic and by SGM population, including lesbian/women who have sex with women (WSW), gay/men who have sex with men (MSM), transgender male, transgender female, anus, cervix, vagina, vulva, penis/scrotum, and vaccination. Each co-author assigned to a category performed a thorough review of published literature and compiled a summary of relevant citations and recommendations, which were then reviewed centrally by 2 committee members, D.J. and M.K. The bibliographies of included articles were reviewed to identify other relevant works not identified by the primary search. National guidelines for screening for HPV-related cancers were reviewed. Studies presented at national and international meetings were also included as appropriate. The group met at the start of the project and upon completion of the literature review, to discuss findings and formulate recommendations for screening. All authors had the opportunity to vote for or against recommendations in Table 1 and the group unanimously voted to approve the final recommendations. Given the paucity of data for several of the categories, recommendations were made based on the best knowledge available/expert opinion.

RESULTS Cervix

The incidence of cervical cancer in the United States is 7.5 per 100,000 women per year; in countries without standardized screening, rates are as high as 85 per 100,000.11 Any individual with a cervix is at risk of HPV-related cervical neoplasia, regardless of gender identity or sexual orientation, and therefore should be offered both HPV vaccination and cervical cancer screening according to current guidelines12–14 (see Table 2). It may be necessary to inquire specifically about a patient's anatomy, and/or surgical history, including the presence or absence of a uterine cervix, as is done commonly with cisgender women who may have had a hysterectomy with removal of the cervix. The same question can be posed to transgender men to determine whether they need cervical cancer screening.

TABLE 2 - US Cervical Cancer Screening Guidelines Per the USPSTF, ASCCP, ACOG, and ACS Age USPSTF/ASCCP/ACOG recommendation Age ACS recommendation <21 No screening <25 No screening 21–29 Screen with cytology every 3 y 25–65 Screen with primary hrHPV testing every 5 y (preferred); screen with co-test every 5 y or cytology every 3 y (acceptable) 30–65 Screen with a co-test (cytology and hrHPV testing) every 5 y, hrHPV testing alone every 5 y, or cytology every 3 y >65 Discontinue screening if patient has had adequate negative prior screening results and no history of CIN 2+ >65 Discontinue screening if patient has had adequate negative prior screening results and no history of CIN 2+

ACS indicates American Cancer Society; CIN, cervical intraepithelial neoplasia; hrHPV, high-risk HPV.

Most cervical cancer screening literature in SGM populations centers on cisgender WSW. Between 8% and 20% of women report same-sexual behavior in at least one encounter in their lifetime.15 It is important to note the distinction between sexual identity and sexual behavior—WSW may not identify as lesbian or bisexual, and may continue to have male partners. Regardless, HPV has been isolated in the vaginal secretions of 13%–30% of WSW,16 similar to rates in heterosexual women.17,18 In addition, up to 12% of WSW have low-grade squamous intraepithelial lesion or greater on initial cytology screening.17 The similarities between WSW and women who have sex with men (WSM) may be in part because up to 79% of WSW report prior coitus with men,17,19 but even among WSW who report never having had a male sexual partner, antibodies to high-risk HPV (hrHPV) have been demonstrated in as many as 40% of women,20 compared with 45%–60% seroprevalence among women in the general population.21–23 Furthermore, risk factors for cervical neoplasia are prevalent among WSW, including high rates of smoking16,24,25 and high levels of sexual violence.26,27 These factors are compounded by lower rates of health care coverage and access to primary care providers.28,29 In fact, WSW may be up to 10-fold more likely to have never had cytology screening compared with WSM.28,30–34

Misinformation regarding risk of HPV-related cervical neoplasia among WSW is a concern among both patients and providers. Among WSW, up to one third may believe that HPV cannot be transmitted between 2 women.19,35,36 Concerningly, up to 10% of WSW report having been told by a health care provider that they do not need cervical cancer screening because they are not sexually active with men.17 Women having sex with women also report adverse experiences with health care providers such as the following: not offering cytology screening,37,38 providing biased care, displaying discomfort with LGBTQIA+ patients, using noninclusive language, having a noninclusive environment, negative interactions with providers,35,38–40 refusal of treatment, verbal abuse, and experiencing stigma, discrimination, and disrespect.4,39,41,42 Such adverse experiences with the health care environment may ultimately result in delayed screening and diagnosis of HPV-related neoplasias.37,43,44

Transgender men have similar risks for gynecologic cancers as cisgender females, although data are limited in terms of true prevalence estimates. There does not seem to be an increase in cancers related to testosterone gender-affirming hormone use.45,46 In the 2015 US Transgender Survey, 14% of TGM had had a hysterectomy.47 Transgender men who retain their cervix are at risk of HPV-related neoplasia regardless of hormone exposure or sexual partner anatomy. Transgender men historically have lower rates of cervical cancer screening participation and are 37% less likely to be up to date on cervical cancer screening compared with cisgender women.48–50 This has been linked to structural barriers, including lower rates of insurance coverage and high rates of unemployment, provider-level barriers, including adverse experiences with medical environments, and patient-level factors including discomfort with anatomy and screening procedures.48–50

Providers should be aware that testosterone therapy is a common gender-affirming treatment in TGM, and it often results in vaginal atrophy, which can further limit patient tolerance of the pelvic examinations and vaginal sex. Transgender men on testosterone therapy may be up to 10 times more likely to experience an unsatisfactory cytology report than cisgender patients,51 potentially leading to need for repeat tests. Transgender men may be less likely to return for repeat testing after unsatisfactory screening results, so providers can consider techniques to optimize adequate cervical sampling, including swabbing a wide circumference of the cervix and pretreatment with low-dose topical estrogen before examination.52 Alternatively, self-swab for HPV seems to be better tolerated by TGM patients and is preferred to provider screening in several studies.53–55 Though not yet approved by the US Food and Drug Administration, self-samples have overall high accuracy for detection of high-grade cervical intraepithelial neoplasia, with similar sensitivity to clinician-collected samples for polymerase chain reaction–based tests, slightly lower sensitivity than clinician-collected samples for signal-amplification tests, and slightly lower specificity for all tests.56 Discussing self-swab for HPV via a shared decision-making model may represent a reasonable and patient-centered strategy for cervical cancer screening in TGM.48,51,53,56,57

Recommendation

Screen all persons with cervices as per US Cervical Cancer Screening Guidelines: Per the US Preventive Services Task Force (USPSTF)/ASCCP/American College of Obstetricians and Gynecologists (ACOG) or the American Cancer Society (ACS) guidelines (Table 2). Self collected vaginal swabs should be recommended to patients as an option for sample collection once approved by the FDA.

Vagina

Vaginal cancer is an uncommon HPV-related malignancy.58 In the United States, the reported incidence rate of vaginal cancer is 0.4 per 100,000 individuals.59 The prevalence of HPV is comparable in the vagina and cervix, although noncarcinogenic genotypes may be detected more frequently in individuals without a cervix.60–62 However, the rarity of vaginal cancer in comparison with cervical cancer suggests that the cervical transformation zone may be uniquely susceptible to HPV-induced carcinogenesis. Because of the rarity of vaginal cancer, screening for vaginal cancer is not recommended in the general population.63

In contrast, individuals who have had cervical high-grade squamous intraepithelial lesion (HSIL) or cancer are at significantly increased risk of developing vaginal cancer.64 In individuals with cervical HSIL at the time of hysterectomy, the incidence rate of vaginal cancer in 25-year follow-up is 51.3 per 100,000, with an age-adjusted incidence rate ratio of 21 when compared with individuals with a benign cervical history. Similarly, individuals with a history of HSIL who underwent hysterectomy for benign indications have an incidence rate of 17.1 and an incidence rate ratio of 5.81.65 Current cervical cancer screening guidelines recommend that individuals who have had preinvasive lesions (HSIL/adenocarcinoma in situ) or invasive cervical cancer undergo continued surveillance testing for at least 25 years after treatment.63 Therefore, our recommendation concurs with current guidelines to continue surveillance in individuals with a history of cervical HSIL or cancer who subsequently undergo hysterectomy, with vaginal cytology and/or hrHPV testing, for at least 25 years after their treatment for cervical precancer.66,67 We further encourage clinicians performing gender-affirming hysterectomy to review the cervical cancer screening histories of patients to ensure adequate surveillance as well as avoid unnecessary screening in low-risk individuals.

Transgender women who undergo gender-affirming vaginoplasty may have some risk of HPV infection of the neovagina, but evidence is sparse regarding the clinical importance of these infections. High-risk HPV was detected in the neovagina in up to 20% of sexually active women who have undergone vaginoplasty, but no HPV infections were detected in the neovagina of sexually inactive women.68 However, cases of symptomatic HPV-related lesions of the neovagina are rare enough to warrant case reports in the literature.69,70 Women may present with pain or abnormal discharge of the neovagina, condyloma/leukoplakia, or coital bleeding or pain; histopathological results may range from condyloma to moderate to severe intraepithelial neoplasia in these cases.70 There are 4 reported cases of vaginal cancer in TGW with a neovagina.69 We recommend that women reporting symptoms of pain, abnormal discharge, or bleeding of the neovagina should have a thorough examination of the neovagina by providers, with consideration for vaginal cytology or hrHPV testing and biopsy of any abnormal appearing lesions.

Recommendation

No screening for vaginal cancer is indicated in individuals without a history of cervical HSIL or cancer who no longer retain a cervix. Continue vaginal surveillance testing in individuals with a history of cervical HSIL or cancer who subsequently undergo hysterectomy, with vaginal cytology and/or hrHPV testing, for at least 25 years after treatment.

Vulva

Vulvar cancer accounts for 6% of all cancers of the female reproductive tract and 0.7% of all cancers in women. The incidence rate is 2.4 cases per 100,000.71 There will be an estimated 6,470 cases of vulvar cancer and 1,670 deaths in 2022 in the United States.72 Vulvar cancer is generally divided into HPV-associated and HPV-independent cancers. The HPV-associated vulvar cancer, which accounts for approximately 20%–25% of vulvar squamous cell cancers, is preceded by vulvar HSIL.73 Studies show an increasing incidence of vulvar HSIL (vulvar intraepithelial neoplasia 2/3), the precursor to vulvar cancer, especially among women younger than 50 years. An analysis of vulvar intraepithelial neoplasia in the Surveillance Epidemiology and End Results database showed an increase of 411% from 1973 to 2000.74 Another study using the Surveillance Epidemiology and End Results has showed an average increase of 3.5% per year of cases of vulvar HSIL.75

Despite these increases in incidence, given the low overall incidence of vulvar cancer, no screening guidelines exist, although patients may be encouraged to practice vulvar self-examination to aid in the early detection of vulvar lesions.76 There are high-risk groups, which include people living with HIV (LWH), people with non-HIV immunosuppression, and individuals with a history of lower genital tract HSIL or HPV-related cancer of other sites.77–80 These risk factors apply regardless of sexual orientation or gender identity. In these high-risk groups, a visual inspection of the vulva at the time of gynecologic examination can serve as a simple way to detect vulvar HSIL or cancer.81

Recommendation

No screening recommended in the general population, regardless of sexual orientation or gender identity. Perform visual vulvar examination at the time of anogenital examination in people LWH, people with non-HIV immunosuppression, or those with a history of anogenital tract HSIL or cancer.

ANAL

Anal cancer is caused by HPV in 90% of cases.82,83 Like cervical cancer, the natural history of anal HPV lesions can progress from a self-limited HPV infection, to HSIL, to invasive anal cancer over the course of many years to decades. High-risk HPV is detectable in the anal canal via routine swab, and anal cytology has been recognized for the last 2 decades as a viable screening modality.84 Penile-anal intercourse provides a mechanism of HPV transmission, and detection rates of anal HPV among individuals who engage in penile-anal intercourse are high, up to 70% among MSM85–90 and reported as high as 98% among transgender women.91–93 That being said, penile-anal intercourse is not strictly necessary to get HPV into the anus. In individuals assigned female at birth, anal HPV rates are comparable with cervical HPV rates, and this does not depend on history of penile-anal intercourse.79 In MSM, it has been shown that condomless receptive anal intercourse and increased number of partners in the last 6 months has been associated with elevated risk of anal HPV infection.94

A recent systematic review and meta-analysis have demonstrated incidence rates for anal cancer based on risk group.2 Persons LWH are especially vulnerable to the dysplastic effects of HPV infection, and among MSM LWH, the highest risk group, the incidence of anal cancer was 85 per 100,000 persons, with even higher risks in older MSM LWH when stratified by age. By comparison, the incidence of anal cancer in the general population is 2 per 100,000 individuals.2 The incidence among MSM not LWH was 19 per 100,000; among men LWH who have sex with women (MSW) was 32 per 100,000, and among women LWH was 22 per 100,000. Furthermore, HIV co-infection may have a synergistic relationship with both HPV acquisition and persistence.95 Low CD4 count has been found to be positively associated with risk of high-grade anal intraepithelial neoplasia and anal cancer,84,96 and persistent anal cytologic abnormality is more likely with CD4 < 400.97 Conversely, protective factors for HPV infection include CD4 count greater than 500, adherence with highly active antiretroviral therapy, and undetectable viral load.98,99

The unique vulnerability of transgender women to both HIV infection and HPV-related disease warrants special attention. Because of commonalities in viral transmission mode, many of the risk factors for HIV acquisition in MSM and TGW extend to risk of HPV infection as well. Experiences of gender-based discrimination, violence, victimization, rejection, and social marginalization are pervasive among transgender women100–102 and are an identified risk factor for high-risk sexual behavior.102 Widespread discrimination against TGW limits social and economic position and forces many TGW to sex work as a means to survival,103 and rates of sexually transmitted infections are disproportionately high among TGW, increasing their vulnerability to HIV acquisition.104–106 In addition, receptivity during sex may be gender affirming for TGW, and because many TGW do not have access to genital surgery, penile-anal intercourse may provide TGW with an important means of gender affirmation.107,108

Individuals at high risk of anal cancer include MSM and TGW regardless of HIV status, as well as individuals with a history of anogenital HSIL or cancer, and immunocompromised individuals, particularly those with a history of solid organ transplant over 10 years ago. Screening for anal HSIL or cancer follows the same principles as for cervical cancer, using anal cytology and/or hrHPV testing as an initial screening methodology among high-risk groups. According to the 2016 high-resolution anoscopy (HRA) standards published by the IANS, anal cytology is useful to predict those at risk of HSIL, but has limited sensitivity and specificity, and thus should be used as a triage tool for referral to HRA for pathologic diagnosis.109,110 A recent systematic review of anal cancer screening strategies demonstrated a sensitivity of 81% and specificity of 62% of anal cytology in detecting HSIL or higher (HSIL+).111 Cytology also has a learning curve, with higher rates of unsatisfactory cytology compared with cervical cytology screening but usually with improvement over time as providers learn to sample the anal canal more thoroughly.112,113

In addition, hrHPV testing provides long-term risk stratification for precancerous anal lesions, but there are high positivity rates of hrHPV among MSM LWH, which limits its utility as a sole screening modality in this population.114 Among MSM LWH, hrHPV has a low positive predictive value and a high negative predictive value, with a relatively high sensitivity (96%) and low specificity (30%), but can improve diagnostic efficacy when performed in conjunction with anal cytology.115 Adding hrHPV testing to anal cytology (anal “co-testing”) in all populations improves the sensitivity for detection of HSIL+ to 93% but decreases the specificity to 33%.114 Also important to note, at this time, hrHPV testing does not have Food and Drug Administration (FDA) approval for the anus, which may limit its utility and is dependent on health care insurance policies.

The follow-up to abnormal anal cytology and/or hrHPV testing is HRA. High-resolution anoscopy with directed biopsy is the criterion standard for diagnosis of anal HSIL. Unfortunately, there is a shortage of trained HRA providers in many areas, leading to a bottleneck in diagnostic and treatment capabilities. Anal cytology should only be performed in areas where referral to a trained HRA provider is available. The IANS has published minimum standards for competency for HRA, but dedicated training efforts are needed to expand the number of HRA-trained providers available worldwide.110 Where referral to HRA-trained providers is not available, the IANS recommends performing digital anal rectal examination (DARE) to evaluate for palpable lesions in the anal canal. Digital anal rectal examination has the potential to identify cancerous lesions at an earlier stage and is simple, safe, and well tolerated.116

Until recently, formal recommendations for screening for anal cancer among high-risk individuals were lacking, because of a dearth of evidence that treating high-grade precancerous lesions (anal HSIL) would ultimately decrease the risk of progression to anal cancer. The Anal Cancer-HSIL Outcomes Research (ANCHOR) trial was a large-scale, multicenter randomized control trial to evaluate the safety and efficacy of treatment of anal HSIL among 4,446 individuals 35 years and older LWH. Most ANCHOR participants were members of SGM populations. The results showed a 57% reduction in the rate of progression to cancer in the treatment group versus the group undergoing active monitoring,117 and the trial was stopped early because of this treatment efficacy, bolstering the argument for screening and the need for clear screening recommendations. At this time, screening recommendations are being formulated for release by the IANS.

Anal HPV in TGW and MSM

Among TGW, anal HPV infection may be nearly ubiquitous, with detection rates for any anal HPV as high as 97%.92,93 HIV co-infection seems to accentuate these risks; in a study of 85 TGW and MSM, any anal HPV was detected in 100% of HIV-infected participants, and hrHPV was detected in 94% of participants.118 In the same study, 70% of participants tested positive for the oncogenic HPV subtype 16 and/or 18. It should, however, be acknowledged that this study, like many in the literature, aggregated TGW and MSM based on shared risk behavior (penile-anal sex) but was underpowered to determine risks unique to TGW. Importantly, while anal HPV is highly prevalent among TGW, Meites et al.86,119 demonstrated that only a minority (8%) of sexually active TGW will test positive for all HPV subtypes covered in the quadrivalent HPV vaccine, indicating that HPV vaccination would still provide protection.

Anal Squamous Intraepithelial Neoplasia in TGW and MSM

Because of limited sampling, many studies report anal squamous intraepithelial neoplasia (ASIL), which includes both anal low-grade squamous intraepithelial lesion and HSIL, but in studies with well-developed HRA programs, the rates of HSIL alone are approximately 5% in TGW.120 The largest studies of anal cytology in TGW suggest that at least 43% of TGW, including those not LWH, will have abnormal anal cytology,121,122 and the risks of cytologic anal ASIL are at least as high among TGW as they are among MSM. Among TGW LWH, anal ASIL may be nearly ubiquitous (95%), although most of these cytologic results (84%) may be low-grade abnormalities.123 Many TGW may have anogenital warts,92,93,124 likely contributing to the high rates of abnormal cytology and further underscoring the importance of screening in this population. In these studies of TGW, HPV-16 and HPV-18 were associated with greater degree of cytologic atypia.125 Notably, the same study observed that HIV infection was independently associated with higher viral loads of HPV-16 and HPV-18 in TGW, suggesting again that the HIV burden among TGW has widespread ramifications on risks of anal cancer.

Only 2 studies have provided histologic confirmation of anal ASIL in TGW but suggest that rates of histologic ASIL in MSM and TGW LWH may be nearly ubiquitous and are at least as high among TGW (91%) as they are among MSM (84%).123,126 Both studies also report similarly high rates of histologic anal HSIL (58%–59%). No studies to date have examined anal histology among TGW not LWH. In the ANCHOR Trial mentioned previously, one transgender individual developed anal cancer in the study (1/153 transgender participants or 0.65%), which was identical to the proportion of cisgender patients who developed anal cancer (30/4416 total participants or 0.65%).117

Anal Cancer in TGW and MSM

No studies to date have reported the risk of anal cancer among TGW. Risks of anal cancer in MSM not LWH are at least double and up to nine times the general population; in MSM LWH, the risk may be as high as 145 per 100,000, 9-fold the risk in those not LWH, and 60- to 150-fold the general population.2,127–129

There is a population of TGM who identify as MSM and engage in anal-receptive intercourse. Data on rates of anal HPV and risk of anal cancer in this population are lacking. Although TGM who identify as MSM are not currently defined as a high-risk population for the development of anal cancer, they should be screened for other identified risk factors, such as the history of previous anogenital HSIL or immunocompromised state. In the absence of data to inform standardized recommendations in TGM who identify as MSM without other risk factors for anal cancer, we recommend discussion between providers and patients and a shared decision-making model to determine whether to perform screening for anal cancer.

Recommendation

We recommend screening for anal cancer in individuals at high risk: MSM and TGW regardless of HIV status, all individuals LWH, solid organ transplant recipients, and individuals with a history of anogenital HSIL or cancer. Although the best age to initiate screening is still unclear, we recommend initiating screening by the age of 45 years, and no earlier than the age of 35 years. Where referral to HRA is available, individuals LWH should be screened via cytology ± hrHPV testing annually, and those not LWH every 1 to 2 years. Where HRA is not available, we recommend annual screening via DARE to evaluate for palpable lesions in the anal canal.

Penis/Scrotum

Rarely, HPV can cause cancer of the penis and scrotum, but the absolute incidence is low. Among MSM, there may be a higher burden of penile HPV infection,89 but the relation of this to HPV-related cancers of the penis is uncertain. Regarding prevention of penile/scrotal HPV infection among MSM, a recent large-scale systematic review of 62 observational studies demonstrated a clear role for circumcision in prevention of penile HPV infection and transmission,130 but no prospective trials have examined the role of vaccination in preventing HPV-related penile/scrotal disease. At present, routine screening specifically for penile/scrotal HPV is not recomm