Multizonal intraepithelial neoplasia of the lower genital tract and anus in women: terminology for defining the disease, an introduction by the British Society for Colposcopy and Cervical Pathology (BSCCP), International Anal Neoplasia Society (IANS), European Federation for Colposcopy (EFC) and British Society for the Study of Vulval Disease (BSSVD) scientific committees.

Introduction
People with persistent high-risk (oncogenic) human papillomavirus (HPV) infection are at increased risk of high-grade squamous intraepithelial lesions (HSIL) and squamous cell carcinoma (SCC) of the anogenital region. The lower anogenital squamous terminology (LAST) consensus recommends that squamous intraepithelial lesions are defined as low-grade (LSIL) and high-grade (HSIL) of all anogenital sites [1]. This terminology is widely implemented by American societies. In many European countries, intraepithelial neoplasia (-IN, with an accompanying grade) is the most commonly used term for describing pre-malignant lesions of the anogenital region. Multizonal describes disease in multiple (two or more) zones, where a zone represents a distinct anatomical anogenital site.
Treatment of cervical, vulval and vaginal high-grade intraepithelial neoplasia (equivalent to HSIL) to prevent cancer is well established in gynaecological practice. Recently, the treatment of anal HSIL has been shown to prevent anal SCC [2]. It is, however, poorly understood that women*1 with vulval, vaginal or cervical intraepithelial neoplasia (VIN, VaIN, CIN) can also have perianal and/or anal intraepithelial neoplasia (AIN) and that this should be both considered and actively looked for. Whilst organised cervical screening has been a success in reducing cervical cancer, other HPV-related anogenital cancers continue to increase in incidence [3]. Although management of high-risk cervical lesions is well-established as a cancer prevention strategy, management of HSIL occurring at adjacent anatomical sites is less standardised.
Vulval cancer is a rare disease, with a world age-standardised incidence rate of 0.9/100,000 [4]. The incidence is higher in high income countries. In the UK, it affects 3/100,000 women per year [5], and HPV-associated vulval cancer is increasing, especially in younger women [6, 7]. Vulval intraepithelial neoplasia is diagnosed in 3.8/100,000 women/year [8] and classified as either differentiated VIN (dVIN) or vulvar high-grade squamous intraepithelial lesions (vHSIL). While vHSIL is HPV-dependent and accounts for almost 90% of cases, dVIN usually develops on the background of chronic dermatoses such as lichen sclerosus [9]. Vaginal cancer is extremely rare; in the UK there are around 250 cases diagnosed annually [10]. Anal squamous cell cancer has a world age-standardised incidence rate of 0.6/100,000 for women [4]. Some of the highest rates of anal cancer have been reported in Europe, including the UK [11], particularly in women, with an estimated age-standardised incidence rate of 3.1/100,000 in women versus 1.8/100,000 in men [12]. For women over the age of 50 in the UK, the incidence rate is 4–9/100,000 [12]. In the USA, the incidence of anal SCC overtook that of cervical SCC for the first time in 2014 and 2015 in Caucasian women over 75 and 65 years old, respectively [13]. Similarly, in England, in 2019 the incidence rate of both vulval and anal SCC exceeded the incidence rates of cervical SCC in Caucasian women over 55 years of age [14].
And also immunosuppresion is an important risk factor for all HPV-related neoplasia. In women living with HIV, the incidence of anal cancer is 22/100,000 [15]. It is difficult to obtain precise estimates of AIN incidence, given that the majority of preinvasive lesions are not recorded in national registries, however, trends suggest that the incidence of AIN is increasing, and like VIN, this trend is particularly pronounced in women younger than 60 years [16]. Meanwhile, although cervical cancer rates have decreased amongst vaccinated cohorts, and herd immunity effects have been observed [17], the latency period between HPV infection and peak incidence of anal and vulval SCC means that the full impact of vaccination will not be fully realised for 20–30 years [18].
MZIN is objectively rare, however patients with this condition present a significant management challenge to gynaecological services and the presence of anal HPV-related disease is often underestimated. For this reason, this document has been prepared by the British Society for Colposcopy and Cervical Pathology (BSCCP), in collaboration with members of the International Anal Neoplasia Society (IANS), the European Federation for Colposcopy (EFC) and British Society for the Study of Vulval and Vaginal Disease (BSSVD), with the aim of summarising existing national screening practices for multizonal anogenital cancers in women, defining the terminology for use in referring to MZIN, as well as best practice for diagnosis and assessment.

Terminology: defining the umbrella term
The term multizonal to describe intraepithelial neoplasia affecting multiple anogenital sites is preferred to terms such as multifocal or multicentric disease or field effect, which in the past have been used interchangeably. Intraepithelial neoplasia may arise in the skin or mucosa on a background of non-HPV-related dermatoses (dVIN) or HPV-related disease. Slaughter et al. [19] first described the field effect of HPV, whereby daughter cells carried genetic alterations associated with HPV infection, however, the evidence for such monoclonal spreading is inconclusive. Now it is thought more likely that multiple different pathways contribute to the evolution of multizonal disease, including the persistence of high-risk HPV in multiple areas on the background of predisposing factors such as genetic risk and/or immunosuppression [20, 21]. Studies of HPV genetic variation have shown that it is possible that either a single infection, or alternatively several different HPV types cause can cause disease across multiple zones [19, 22].
The nomenclature provided in this article relates to MZIN, which is considered to involve more than one of the five zones in females: vulva, vagina, cervical, perianal and anal canal zones (Fig. 1). The perineum can be considered as part of the vulva however a separate definition of this anatomy allows for a more accurate description in the case of MZIN. We therefore define the perineum as the area beginning at the posterior fourchette and extending to the perianus. The same mechanisms may lead to an analogous scenario in men of penile, scrotal, perineal, perianal and anal canal. The natal cleft can be considered an extension of the perianal zone, but disease is often missed at this site. While MZIN may include either low-grade or high-grade IN, it is the early detection and treatment of high-grade IN of the anogenital zones which has the best evidence for prevention of cancer [23].
In terms of time frame, we define MZIN as either ‘synchronous’ or ‘metachronous’ disease. Synchronous refers to disease occurring in two different zones at the same time (with diagnoses made within 1 year). Disease diagnoses in differing anogenital zones, occurring outside of 12 months, is considered metachronous. The differential risk of cancer in synchronous versus metachronous disease requires further study. These women should still be considered at potentially greater risk of cancer and therefore referred for a specialist MZIN assessment.

Screening of the anogenital tract
Screening for HPV-related disease outside of the cervix, for example, of vulva, vagina, anal, perianal and penoscrotal areas, is not currently recommended in the general population, as the Wilson and Jungner principles of effective screening [24] are not met. The incidence of these cancers is lower, and the efficacy of early detection and treatment of preinvasive lesions for reducing both the incidence and mortality from these cancers is less established. Screening recommendations should balance the anticipated benefits for early disease detection and treatment against potential harm, and resource implications need to be considered.
In most countries, screening recommendations for pre-invasive anogenital disease outside of the cervix has been limited to persons already diagnosed with neoplasia of a single anogenital site, or where resources allow, in pre-defined high-risk groups. Under English guidance [25], newly diagnosed HIV-positive persons are eligible for an initial colposcopy (visualisation of the cervix using magnification and dilute acetic acid), plus international guidelines have suggested digital anorectal assessment (DARE) with an anal HPV test and anal cytology, followed by annual screening, where resources permit [26].
The increased risk of anal cancer in immunosuppressed persons, including HIV, has been well-documented. Clifford et al. [15] identified several high-risk groups for anal cancer in a meta-analysis, including: people living with HIV; men who have sex with men; solid organ transplant recipients (SOTRs); patients with autoimmune disease; and women diagnosed with cervical cancer and HPV-related vulvovaginal cancers and precancers, including high-grade VIN, VaIN or CIN [15]. In the 2022 landmark ANCHOR study [2], a phase-3 trial where 4459 participants living with HIV who were diagnosed with biopsy-proven anal HSIL were randomised to treatment or active monitoring with high-resolution anoscopy (HRA), treatment was confirmed to be effective for anal cancer prevention. Subsequently, international guidelines have been published to recommend screening for AIN and anal cancer in high-risk groups where incidence exceeds ten times that of the general population, i.e. 17/100,000, which notably includes women with previous or current VIN, vulval SCC and SOTR [27]. In persons with a history of cervical/vaginal HSIL or cancer, perianal warts, persistent cervical HPV16, the incidence of anal cancers is reported as less than 10/100,000 [28], consequently the IANS recommendation for anal screening is this group (risk category B) was that they could be included for screening based on shared decision making, provided there is adequate capacity ofr HRA (visualisation of the anal canal with magnification and dilute acetic acid) [27].
Despite limited research, there is increasing recognition by specialists managing anogenital cancers that women with MZIN are a high-risk group for cancer and may require tailored monitoring and assessment of all anogenital zones [29]. Although there are currently no formal screening programmes, there are a few units within the UK and elsewhere that are performing multizonal assessments of the anogenital tract in one setting. However, most women with MZIN are still seen by multiple separate specialists. Improved definition of MZIN, as well as symptom recognition in primary care may improve early detection and appropriate referral. In addition, educating women about increased risk is essential for improving early detection.
Although several consensus guidelines exist for the management of HPV-related disease in different anatomical areas, guidance on the specific assessment and management MZIN is lacking. A complete colposcopic examination for an abnormal cervical screening test should include at least an assessment of the vulva, perineum and vagina [30]. In people at high risk of MZIN (and cancer), such as those living with HIV, SOTR or people with a history of cervical, vulval or vaginal cancer (including hysterectomised patients), complete assessment needs to be expanded to all zones, including the anus and perianus [2, 31]. There is also a need to recognise the significantly increased risks of cancer [29] in people with MZIN, and for assessment by clinicians with the appropriate skills. Nonetheless, more frequent assessments must be balanced within the context of the resources available, and the additional psychological and physical effects of more regular assessment, and potential for overtreatment. Centralisation of care may improve management. Education of patients with MZIN and their primary care providers regarding symptoms and risk is also important so that red flag symptoms presenting to primary care are acted upon in a timely manner. Furthermore, there is a need to establish one terminology across specialties, as well as the overlapping disease pathology across anatomical zones, which simultaneously recognises the differences between zones. These improvements would also facilitate further research into this complex and challenging condition.

High-risk groups
The definition of high-risk groups helps to identify those who may benefit from regular review in clinic-based screening. Based on a small study comparing synchronous MZIN (n = 56) and non-MZIN (n = 197) groups [29], MZIN diagnosis appears to be more common in women who are current smokers, those taking immunosuppressants and those with previous HSIL at any site. There were non-statistically significant differences between the two groups associated with ever smoking, anal sexual intercourse, HIV positivity, and previous anogenital cancer at any site (Fig. 2). In this study, 98% of women with MZIN had a history of either HSIL or cancer in one of the anogenital zones. The higher frequency of HSIL likely led to the stronger statistical association observed for HSIL, over the association seen for cancer.

Assessment in the presence of symptoms of MZIN
While terminology for colposcopy is well-defined, terminology for MZIN remains unclear. The International Federation for Cervical Pathology and Colposcopy (IFCPC*2) terminology and colposcopy guidelines published in 2011 [32] have allowed enhanced reliability and reproducibility of clinical assessment findings during assessment of the cervix and vagina. Here, we expand the terminology specifically for MZIN. Most cases of intraepithelial neoplasia are asymptomatic which makes diagnosis challenging. Symptoms that patients can present with include:Persistent vulval or perianal itch and irritation.

Persistent pain or tenderness in affected zones.

Skin changes in the affected zones (discolouration, lump, erythema, excoriation, wet/weeping lesions, warts).

Per rectal bleeding and anal pain or mucus discharge (although in this context a diagnosis of colorectal/anal malignancy must first be excluded).

Anal fissures with atypical features (including atypical site i.e. not directly anterior or posterior); raised chronic fissures with palpable edges; new fissures in older patients (age 50+); any fissure not responding to six weeks of topical nitric oxide donor treatment (e.g. GTN 0.45%, Diltiazem 2%).

Sensation of rectal mass or fullness.

Postcoital or intermenstrual bleeding.

When women with symptoms of potential MZIN, (or from a high-risk group with any symptoms of anogenital IN) present in the primary care setting, or any secondary care setting without access to colposcopy and/or HRA, a thorough clinical assessment of all zones should be performed (Table 1).
The diagnosis of MZIN in primary or secondary care can be challenging. Therefore, symptoms of MZIN or identification of potential MZIN warrant a full examination in a specialist setting (Table 2).
The patterns of HSIL in the anus and perianus are similar to those in the lower genital tract. However, at present there are few gynaecologists trained to conduct HRA to the standards presented in the IANS 2016 guidelines [26, 33]. Existing practitioners with an interest should be supported to formally train in HRA to carry out a full multizonal assessment (MZA) (see Table 2), with support from MZIN specialists where required.
In patients with evidence of MZIN, where local skills are lacking in HRA, referral to colorectal surgery for assessment can be considered if there are (a) any symptoms of anal or perianal disease as outlined above, (b) any abnormality on the DARE or (c) the need for screening given the burden of disease elsewhere. The anal cancer screening guidance from IANS [27] suggests that annual DARE for high-risk groups is carried out by trained practitioners in regions where HRA is lacking [34]. Nonetheless, training in HRA is encouraged due to the recognition of the need for this service, particularly for women with MZIN.
Oropharyngeal HPV-related disease is rare and particularly so in women [35], with no currently available screening programme. Clinicians managing women with MZIN should remain aware of its common presentations. These include persistent throat soreness, a lump in the throat or neck and difficulty swallowing [36]. Referral to the relevant clinical specialty should be prompt.

Other considerations
To our knowledge, there are no studies exploring the psychological experience or needs of women with MZIN. There are negative psychological consequences associated with HPV-related disease, which may be heightened in MZIN, including stigma, fear of disease progression, reduced quality of life, sexual dysfunction and dissatisfaction with partner relationships [37–39]. MZIN patients may have extensive disease, and treatment can have particularly disfiguring results. It is important that the informational needs of women with MZIN are met and that patient concerns about MZIN and any associated treatment are acknowledged and supported [40].
Clinicians should consider the social determinants of health which have consequential effects on HPV-associated cancer incidence. Anal cancer has a higher incidence in lower socioeconomic groups [41]. Women from ethnic minority groups may have a lower awareness of their cancer risk, and lower uptake of screening or HPV vaccination [42]. HPV vaccination uptake can substantially reduce the incidence of CIN3 and cervical cancer across differing socioeconomic groups, including those demonstrating domains of deprivation [43]. Globally, there remains significant health inequalities for both cervical screening [44] and HPV vaccination coverage with disparity persisting for lower-income countries [42, 45]. Tackling misinformation is needed, particularly for parents who need to be informed about the protective effects of timely HPV vaccination for their adolescent children [46]. Black African or Black Caribbean women have been shown to be more likely to be diagnosed with anal SCC at a younger age and advanced stage [41]. Cultural barriers and the risk of stigma may result in hesitancy when discussing symptoms pertaining to the anogenital tract. There remains a gender bias that results in discrimination based on age, race, ethnicity, socio-economic status, sexual orientation, and gender identity that can heighten barriers in accessing healthcare services [47]. We encourage the use of inclusive language and access to translatable information for non-native English-speaking individuals.

Summary
This paper forms the first in a series of consensus papers referring to MZIN with the aim of providing consensus guidelines describing assessment and management. Through cross-specialty collaboration, we highlight the preference of the terminology of MZIN over other terms, and the definition of MZIN as either synchronous disease (occurring in more than two zones within 12 months) or metachronous (outside of 12 months).
While there are an increasing number of guidelines developed for anogenital neoplasia, MZIN remains poorly defined resulting in a wide variation in the assessment and management of such patients. As MZIN is rare, and its complexity requires multiple specialised skillsets, management by multidisciplinary teams is more appropriate and may optimise patient experience. Treatment should be individualised and tailored to the location and extent of disease, whilst adapting to the characteristics and risk factors of the woman, any special considerations, as well as previous history of HSIL or cancer.
This group intends to develop a set of consensus guidelines on the recommendations for the management of MZIN, including defining high-risk groups for clinic-based screening, defining the optimal tools for diagnosis and assessment of disease burden, issues related to training and quality control, identification of MZIN in primary care and psychosocial support.

Future aims

Development of consensus guidelines is needed, with multidisciplinary agreement on how best to deliver services for women at risk of or diagnosed with MZIN, especially in the context of previous anogenital HSIL.

Centralisation of care should be considered for patients with MZIN, this warrants further attention by relevant international societies

Enroling patients with MZIN into national research studies could allow for identification of specific clinical features or distinct biomarkers which predict MZIN versus single-site disease

It is recognised that MZIN carries a significant psychological burden, further investigation into psychological sequelae of the disease is needed to determine how these women can be best supported and treated.