Belgium

Updated anal cancer screening guidelines now provide a basis for expansion of screening to all at-risk populations

Feb 24, 2025

By Rebecca Millecamps, Fujirebio Europe

Anal squamous cell carcinoma (ASCC) is a cancer of the anal canal, with nearly all cases attributable to infection with human papillomavirus (HPV), particularly high-risk HPV type 16. Anal cancer remains relatively rare within the general population, but an increasing number of cases have been reported lately.1,10 The highest incidence rate of anal cancer is typically observed among men having sex with men (MSM) living with human immunodeficiency virus (HIV).2,5,10

Mortality rates for the disease are high, partially due to the fact that anal cancer is often only diagnosed at an advanced stage.1 Anal cancer does not always come with clear symptoms in its early stages, and most patients typically present with symptoms resembling benign disease such as fissures or hemorrhoids.3 .  Standardized screening of high-risk populations, through digital anorectal examination (DARE) and high-resolution anoscopy (HRA), can therefore be of great importance in supporting early diagnosis, treatment and follow-up.1,4

Screening guidelines for anal cancer prevention have traditionally focused on people with HIV, and focus on the detection of high-grade squamous intraepithelial lesions (HSIL). In the most recent clinical guidelines, however, the authors recommend expanding screening to other high-risk populations, such as MSM and transgender women without HIV, individuals with a history of other HPV-related diseases, or solid organ transplant recipients.4,5,6

We provide an overview of these recent anal cancer screening recommendations below from the International Anal Neoplasia Society (IANS).

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Screening guidelines5

Annual or biennial screening is recommended.

  1. High-risk populations: 

    • People with HIV: Especially MSM and transgender women aged 35 and older, all other people with HIV aged 45 and older.

    • MSM and transgender women without HIV aged 45 and older.

    • Individuals with a history of HPV-related diseases: This includes mainly those with a history of vulvar precancer or cancer. Screening initiation within 1 year after diagnosis of HPV-related disease.  For those with a history of cervical or vaginal precancer and cancer, screening with shared-decision making is recommended.

    • Solid organ transplant recipients: Screening is recommended ten years post-transplant.

    • Other immunosuppressed individuals: Those with conditions like rheumatoid arthritis, lupus, Crohn's disease, or ulcerative colitis.

  2. Screening methods:

    • Digital AnoRectal Examination (DARE): This is a primary screening tool used to detect abnormalities and should be performed routinely in high- risk populations.

  • Most patients will know about digital rectal exams, in which a healthcare practitioner inserts a gloved finger into the anus/rectum. These are primarily aimed at finding rectal cancers. With the most recent guidelines, the authors wish to make sure that healthcare providers also are focusing on the anus itself. Indeed, the objective of a DARE is to feel hard lumps, for instance, that might indicate the presence of cancer. But this form of examination does not allow for the detection of pre-cancers.7

  • During an HRA the anal canal is examined with a colposcope. The whole anus is visualized using the same sort of stain used for cervical examination, acetic acid, and biopsies are taken to see if it concerns anal precancer, also called high-grade squamous intraepithelial lesions, and to rule out cancer. 7

  • An HRA, compared to standard anoscopy, enables a more precise examination to detect precancer, guide treatment, and to prevent anal cancer. It does, however, require the use of specialized equipment and requires specific training for the healthcare professional. Also, HRA is not yet available everywhere.10

  • High-Resolution Anoscopy (HRA): Recommended for those with abnormal findings on initial screening.

  • Anal cytology test: Used to detect precancerous or cancer cells. 

    • Is acceptable for anal cancer screening, alone or with high-risk human papillomavirus (hrHPV) triage, or can also be used as triage of individuals testing hrHPV positive to reduce HRA referral.

  • hrHPV testing (with or without genotyping): Could be considered in settings without a cytology infrastructure or to reduce HRA for patients that test hrHPV positive.  

Use of hrHPV genotyping, specifically for HPV16, may help identify patients with a high risk of developing high-grade squamous intraepithelial lesion (HSIL) or cancer. 

Follow-up care after treatment8

  • Regular Monitoring: follow-up visits every 3 to 6 months for the first 3 years are recommended, then every 6 months or longer for the next several years.

  • Imaging Tests: Computed tomography (CT) scans or magnetic resonance imaging (MRI) may be done regularly to monitor for recurrence.

  • Survivorship Care Plan: Developing a plan with the healthcare provider to manage long-term effects and monitor for recurrence.

Comments

These newly published guidelines for anal cancer screening aim to standardize screening practices and to ensure that high-risk populations receive appropriate care. The guidelines represent a pivotal advancement, offering evidence-based recommendations that can enhance clinical practice.5,6,9 

Clinicians are encouraged to familiarize themselves with these updates to ensure they are providing the best possible care to their patients. By staying informed about these changes, healthcare providers can play a pivotal role in reducing the burden of anal cancer.

Most people living with HIV, even with HSIL, will not develop squamous cell carcinoma (SCC). The challenge is to determine who is at risk for HSIL, and, more specifically, whether the HSIL is at a higher risk-level for progression. This challenge is especially acute given the currently limited availability of clinicians trained in identifying and treating HSIL with HRA.5,6,12 

Despite the newly published guidelines, too many individuals, who get referred for HRA and for possible treatment, are actually at low risk for developing SCC. Identifying patients with HSIL, specifically those with more aggressive HSIL, could reserve HRA and a possible treatment only for patients who really are in need, and spare those with little risk of SCC.6,12

A major challenge for the correct implementation of the anal cancer screening guidelines is the generally limited availability of HRA infrastructure for referral of patients with abnormal screening results.5,6 An improved selection of HSIL patients that do require treatment therefore appears to be desirable. mRNA detection or p16/Ki-67 staining could be considered. Also, the determination of host cell methylation markers from anal swabs and/or histological material of anal dysplasia could be of importance to improve the selection of HSIL patients who require treatment.9-12

Recent studies have identified several cellular genes as potential markers for anal dysplasia.13-16 The ZNF582 gene yielded an area under the curve (AUC) of 0. 88 as marker for AIN3+ detection and is the most promising candidate so far, followed by ASCL1 (AUC 0.86) and SST (AUC 0.87). Increased methylation levels in these host cellular DNA markers have been associated with progression from normal tissue to anal precancerous lesions to ASCC.17 These methylation markers were determined in histological samples. Similar studies on anal swabs are ongoing.18,19. It is currently being investigated whether methylation markers can predict the spontaneous regression of higher-grade anal intraepithelial neoplasia (AIN) as a molecular biological marker.20

Closing remarks

Although anal cancer remains rare in the general population, there are high-risk populations that would benefit from anal cancer screening. It is therefore good news that the recent update of the INSA guidelines include not only MSM with HIV, but broaden the attention to other high-risk groups such as transgender women with HIV, individuals with a history of vulvar HSIL or cancer, and solid organ transplant recipients. 

Implementation of these guidelines requires addressing the limited availability of HRA providers.  An improved selection of HSIL patients that do require treatment will be important. Still work needs to be done to raise awareness, education of health care professionals regarding the interpretation, advantages and limitations of the use of biomarkers, and many more. However, promising tools are at our disposal and evidence is accumulating so there are good reasons to be optimistic about improved anal cancer care.

References

  1. Mignozzi S, et al. Global trends in anal cancer incidence and mortality. Eur J Cancer Prev. 2024 Mar 1;33(2):77-86.
  2. Clifford GM, Georges D, Shiels MS, et al. A meta-analysis of anal cancer incidence by risk group: Toward a unified anal cancer risk scale. Int. J. Cancer. 2021; 148: 38–47.
  3. English KJ. Anal carcinoma - exploring the epidemiology, risk factors, pathophysiology, diagnosis, and treatment. World J Exp Med. 2024 Sep 20;14(3):98525. 
  4. Roelandt P, De Looze D, De Schepper H, Ledouble V, Surmont M, Cuming T. Diagnosis and screening for anal intraepithelial neoplasia in Belgium: position statement. Acta Gastroenterol Belg. 2022 Oct-Dec;85(4):625-631.
  5. IANS consensus guidelines for anal cancer screening. Int. J. Cancer. 2024;154:1694-1702.
  6. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/whats-newASCCP Practice Advisory: Anal Cancer Screening
  7. Dr. Joel Palefsky Answers Our Questions About Anal Cancer https://www.ashasexualhealth.org/dr-joel-palefsky-answers-our-questions-about-anal-cancer.
  8. Living as an Anal Cancer Survivor - American Cancer Society
  9. Spindler L. et al. Société Nationale Française de Colo-Proctologie. Screening for precancerous anal lesions linked to human papillomaviruses: French recommendations for clinical practice. Tech Coloproctol. 2024 Jan 10;28(1):23. 
  10. Cohen CM, Clarke MA. Anal Cancer and Anal Cancer Screening. Clin Obstet Gynecol. 2023 Sep 1;66(3):516-533.
  11. German Austrian Guideline on Anal Dysplasia and Anal Cancer Screening in People living with HIV. Short Title: Anal Cancer Screening in People living with HIV. AWMF-Register-Nr.: 055/007 Version 2.0
  12. Stephen E. Goldstone: Methylation markers in anal swab specimens might identify those at greater risk for anal cancer over standard cytology screening. J Infect Dis. 2024 Dec 23:jiae628.  
  13. Phillips, S., Cassells, K., Garland, S.M. et al. Gene methylation of CADM1 and MAL identified as a biomarker of high grade anal intraepithelial neoplasia. Sci Rep 12, 3565 (2022).
  14. Lorincz AT. Et al. Methylation of HPV and a tumor suppressor gene reveals anal cancer and precursor lesions. Oncotarget. 2017; 8: 50510-20. 
  15. Chaiwongkot A. et al. Human papillomavirus 16 L1 gene methylation as a potential biomarker for predicting anal intraepithelial neoplasia in men who have sex with men (MSM). PLoS One. 2021; 16: e0256852. 
  16. van der Zee RP, et al. DNA methylation markers have universal prognostic value for anal cancer risk in HIV-negative and HIV-positive individuals. Molecular oncology. 2021; 15: 3024-36.
  17. van der Zee RP, et al. Cancer Risk Stratification of Anal Intraepithelial Neoplasia in Human Immunodeficiency Virus-Positive Men by Validated Methylation Markers Associated With Progression to Cancer. Clin Infect Dis, 2021; 72: 2154-63.
  18. Dias Gonçalves Lima F, et al. DNA methylation analysis on anal swabs for anal cancer screening in people living with HIV. J Infect Dis. 2024 Dec 24:jiae627.
  19. Valentine M. Ferré. Poster_CROI_Methylation_2023-133209635219741996
  20. Gonçalves Lima F, et al. DNA Methylation Analysis to predict Regression of high-grade anal Intraepithelial Neoplasia in HIV+ men (MARINE): a cohort study protocol. BMJ Open. 2022; 12: e060301.

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