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Anal Cancer

HIV-infected male patients who refer to conducting sexual risk practices that enable HPV transmission

HIV-infected male patients who neglect conducting sexual risk practices that enable HPV transmission

HIV-infected female patients disregarding sexual risk practices

digital-anorectal exam, liquid-based cytology, human papillomavirus testing, high-resolution anoscopy

Screening for anal squamous intraepithelial lesions

Pompeyo Viciana, MD, PhD

Karin Neukam, PharmD, PhD

César Sotomayor de la Piedra

There is increasing awareness of augmenting risk of anal cancer in people living with HIV, especially among men who have sex with men (MSM). High resolution anoscopy (HRA) represents the gold standard to detect pre-cancerous anal high-grade squamous intraepithelial lesions (HSIL), however, the procedure is time-consuming, costly and, most importantly, the learning curve is very flat. This yields a poor implementation of anal screening and, likely, to an excess of otherwise preventable anal cancer. Other screening methods include digital ano-rectal examination, anal-rectal cytology and human papillomavirus (HPV) genotyping, since infection with high-risk HPV genotypes has been identified as the main reason for the development of HSIL. To date, there is no consensus in screening strategies. Furthermore, it remains unclear whether, in whom and to which extend the currently available topic and invasive treatment options for HSIL should be applied, given that the natural history of the development of anal cancer remains poorly understood. The present cohort study aims to provide real-life data on the screening, management and follow-up of HIV-infected MSM is warranted for a better understanding of anal cancer in this setting.

The development of anal precancerous squamous intraepithelial lesions (SIL) and cancer of the anus is mainly caused by infection with high-risk human papillomavirus genotypes (HR-HPV). There is increasing awareness of marked (40 to 130-fold) risk of anal cancer in people living with HIV, especially among men who have sex with men (MSM). With the changing scenario of comorbidities in the HIV-infected population, given the success of modern antiretroviral therapy, anal cancer has emerged as a leading neoplasia across different cohorts in Western countries. In 2014, almost 30000 people were newly diagnosed with HIV in Europe, the majority of cases (77%) being men. This was largely driven by HIV transmission between MSM, which accounted for 42% of all HIV diagnoses. Hence, the incidence of anal cancer is likely to increase in the years to come.

The number of experts who support the necessity of implementing wide programs of anal cancer screening in at-risk populations is rapidly growing. Indeed, both the European Guidelines for treatment of HIV-infected adults and the Guidelines of the Spanish AIDS Society (GESIDA) currently recommend the screening of anal cancer in HIV-infected subjects at risk. It is likely that in years to come, a general recommendation to screen for anal cancer in patients with different conditions associated with immunosuppression is established, as experienced in other populations. In this context, since HIV-negative MSM and women with a history of anogenital dysplasia, as well as transplant patients, exhibit excess risk of anal cancer, these populations have been typically screened in center with ongoing anal cancer screening programs.

Digital ano-rectal examination (DARE) is mainly accepted as the first screening procedure for anal high-risk SIL (HSIL), followed by anal-rectal cytology. Both represent simple methods, however, cytology shows an alarmingly low negative predictive value and furthermore, in case of an abnormal cytology, the patient is referred to high resolution anoscopy (HRA) for biopsy of acetowhite lugol-negative lesions in the anal epithelium, suggestive of HSIL. HRA performance is similar to cervical colposcopy, but unfortunately, the training process is by far longer, hampering its implementation and availability to highly-specialized centers with large cohorts of people living with HIV under care.

Although histological HSIL was identified as precursor of anal cancer, it remains unclear if, which and in whom treatment is indicated, since not all patients progress, a considerable proportion even regresses spontaneously and recurrence rates are high. Treatments currently available include topical imiquimod or 5-fluorouracil, as well as surgical treatment. Due to the lack of data, no consensus of HSIL management has been reached.

Taken together what was mentioned above, real-life data on the screening, management and follow-up of HIV-infected MSM is warranted for a better understanding of anal cancer in this setting.

Seville Cohort of People Living With HIV at Risk for Anal Cancer

A Study to Screen for Anal Precancerous Squamous Intraepithelial Lesions and to Prevent Anal Cancer in a Real-life Setting of People Living With HIV at Different Risk: the Seville HIV Anal Cohort

The proportion of patients with cancer of the anal squamous intraepithelial cells stage 0, defined as anal high-risk squamous intraepithelial lesions (HSIL) according to the Lower Anogenital Squamous Terminology.

Incidence rates per person-years of cancer of the anal squamous intraepithelial cells stage 1-4 observed over time as defined by the National Cancer Institute of the National Institutes of Health, US Department of Health and Human Services (www.cancer.gov).

Instituto de Biomedicina de Sevilla

Hospitales Universitarios Virgen del Rocío

PharmD, PhD

Carcinoma in Situ

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Micol Lupi, BSc, MBBS, MRCS

Christos Kontovounisios, MD, PhD, FACS, FRCS

Micol Lupi

Christos Kontovounisios

Paris Tekkis

This is a study involving exome sequencing and immune profiling of matched tissue and blood samples from patients with both high-grade squamous intraepithelial lesions and anal squamous cell carcinoma. This is a collaborative project between Imperial College London and the Institute of Cancer Research (ICR), investigating the genetic predeterminants for the progression of anal HSIL to SCC as well as the immunogenetic profile of these conditions will be beneficial for risk stratification (with respect to identifying those individuals with anal HSIL most likely to progress to invasive disease), the identification of potential new drug targets and will add to our understanding of how the tumour microenvironment may influence treatment response and disease recurrence of both anal HSIL and SCC.

Patients, as identified by the colorectal MDT, are approached, and consented for tissue and blood collection on the day of their diagnostic procedure; the plasma and buffy coat are extracted from the EDTA tubes. A tissue biopsy is performed adjacent to the area sampled for diagnosis and flash frozen in liquid nitrogen. Once the diagnosis of anal cancer is confirmed, the FFPE diagnostic tissue, is requested from the Tissue Bank for the study.

The FFPE and the fresh frozen tissue samples are sliced and put on slides. Stained slides are reviewed by a consultant histopathologist, areas of anal HSIL and SCC are marked.

All samples are transferred to the ICR. Tumour DNA and RNA are extracted from the tissue samples and germline DNA from the buffy coat of the blood sample.

Exome sequencing followed by Bioinformatic analysis is carried out where somatic mutations are evaluated for impact on gene expression and compared between germline, anal HSIL and SCC samples. After a quality control process is complete, the entire dataset is compared with the germline DNA reads, thereby identifying somatic mutations. Candidate mutations are finally cross-referenced with the Cancer Genome Census and string analysis of relevant mutations is performed to assess for cancerogenic impact.

Bulk RNA and targeted RNA based T-Cell Receptor (TCR) sequencing will be carried out, with TCR sequencing also being performed on the blood. This will establish which immune cell types are present in the SCC vs HSIL (by transcriptomic deconvolution), and the repertoire of TCR in peripheral blood, HSIL and SCC. Multiplex immunofluorescence technology against distinct immune panels (established within the CTI), will further evaluate the SCC and HSIL immune microenvironments.

The immune-data will be linked to clinical outcome (both radiological and clinical), following radical chemoradiation.

Blood samples, FFPE and frozen biopsies of anal high-grade squamous intraepithelial lesions, FFPE and frozen biopsies of anal squamous cell carcinoma, normal control tissue.

Anal Intraepithelial Neoplasia and Anal Squamous Cell Carcinoma

The Role of Early Diagnosis and Treatment of Anal Intraepithelial Neoplasia in the Prevention of Anal Squamous Cell Carcinoma: Identifying Prognostic Biomarkers.

Imperial College London

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Seville Cohort of People Living With HIV at Risk for Anal Cancer	NCT03713229	Anal Squamous I...	Screening for a...	18 Years -	Hospitales Universitarios Virgen del Rocío
Anal Intraepithelial Neoplasia and Anal Squamous Cell Carcinoma	NCT05835960	Anal Cancer Anal Squamous I...		-	Imperial College London
Seville Cohort of People Living With HIV at Risk for Anal Cancer	NCT03713229	Anal Squamous I...	Screening for a...	18 Years -	Hospitales Universitarios Virgen del Rocío

Spots Global Cancer Trial Database for anal squamous intraepithelial neoplasia