Anal neoplasia

Risk factors for human papillomavirus disease

Multiple partners, smoking and anoreceptive intercourse all increase the likelihood of anal HPV carriage ^, but are not necessary for it. In women, anal HPV is most often caused by self-inoculation (wiping after opening bowels) with a sixfold higher anal HPV carriage after front-to-back compared to back-to-front wiping.

Anal pre-cancerous and malignant disease is higher in women with a previous history of genital HPV-related disease, particularly the vulva ( Fig. 8.1 ). Women with disease at multiple anogenital zones are termed to have multizonal intra-epithelial neoplasia, which poses a substantial risk of lower anogenital tract HPV-related SCC.

Given that HPV causes the vast majority of anogenital warts, pre-cancer and squamous cell cancer, it stands to reason that patients susceptible to infection are at greater risk in particular those with innate and acquired immune defects. For persons living with HIV (PLWH), years living with undetectable viral load (VL) versus detectable VL reduces the risk of ASCC by 44% and for every rise of 100 cells/μL CD4 nadir, the anal cancer risk drops by 40%. ^,

Other at-risk groups include solid organ transplant recipients especially more than 10 years after transplant, and patients on long-term pharmacological immune suppression for systemic lupus erythematosus, rheumatoid arthritis, Crohn’s and ulcerative colitis. Immune suppression seems to bring the disease forward with an accelerated path to SCC in patients’ 40s and 50s. Nonetheless, age in the absence of immune suppression is a sufficient risk factor: the incidence of anal SCC is higher in women than men in the general population with a median age of over 80 years ( Fig. 8.2 ).

Vaccination

There are increasing numbers vaccinated against HPV with substantial worldwide impact. The UK and other high-income countries began vaccinating girls against the oncogenic HPV types, 16 and 18, in 2008. Additional protection against genital warts, HPV 6, 11, followed with the quadrivalent vaccine. Protection is almost 100% against vaccine types in the HPV-naïve. Already this has led to a reduction in cervical disease and anogenital warts in not only women, but also men. Boys have been vaccinated since 2019 in the UK and 2011 in the United States, and a nonavalent vaccine is available covering types 6, 11, 16, 18, 31, 33, 45, 52, 58.

Vaccine-related reduction in ASCC will happen later than cervical cancer because of the lengthy lead time from infection to disease in the anus (20–40 years). HPV vaccination of the already-exposed person has been trialled in HIV negative MSM aged between 18 and 26 years in a placebo-controlled randomised controlled trial (RCT). Reduction of AIN by vaccine in the intention-to-treat arm was 50% and 77% in the per-protocol treatment group. However, no impact was seen when repeated in older MSM. A modest impact of the vaccine in HPV-DNA negative women up to the age of 45 years has been found. In the UK, HPV vaccination is available on the National Health Service for MSM up to the age of 45 years as this group has no herd protection from the vaccination of girls.

Management

Diagnosis is by physical examination, with histological confirmation not necessary unless there is concern of a risk of cancer caused by age, risk factors or unusually intense symptoms. Pain is unusual, although very dense warts can fissure between them, and clinical examination should not discover deep attachment to the submucosa/subcutaneous layers. Simple unenhanced proctoscopy is recommended, particularly for MSM, for anal canal warts ( Fig. 8.4 ). Vulvovaginal or penile examination may be indicated, and women should be sent for a cervical smear if not in the cervical screening programme.

A sexual health screen for other sexually transmitted infections (STIs) and counselling are suggested, with topical therapy and cryotherapy first-line treatments. For warts of the perianus, patient-applied creams are approved for external use and require 3–4 months of application: 5% imiquimod, a topical immune stimulant (toll-like receptor 7) is 35–75% effective, ^, and sinecatechins (green tea-derived immunomodulators, multiple pathways) have been shown to be 50–60% effective, albeit PLWH were excluded from trials. Provider-administrated therapy includes cryotherapy (success 44–87%), and topical ablation with trichloroacetic acid, success 60–90%. Recurrence rates are substantial for all treatments (25–60% at a year) and most cause local irritation and burning.

Low-volume anal canal warts do not necessarily require treatment, albeit the patient will be more infectious with active lesions. Options include the aforementioned non-surgical therapies used for the perianus, however, these are not licensed for intra-anal use and are less successful in the anal canal. Cryotherapy is not used inside the anal canal.

Surgeons tend to be referred cases of warts that are recalcitrant to treatment. Surgical excision, electrocautery/hyfrecation and laser have a success rate of 95–100% with recurrence rate of 20%. ^, This can be achieved under local anaesthetic (1% or 2% lidocaine with adrenaline, or a posterior pudendal nerve block with 40 mL of 0.25% levobupivacaine), although a general anaesthetic will be required for large volume disease. Electrocautery and laser are less likely to penetrate the deep dermis and cause scarring. FFP3 masks should be used due to the risk of aerosolised particles with laser and electrocautery. Site of excised lesions should be documented, and specimens sent for histology in the immune suppressed or patients over 40 years as warts can contain focal areas of high grade.

Surgical excision should be considered carefully: do not leave any less of the mucosa than you would at a haemorrhoidectomy as life-changing anal stenosis can result, particularly if the patient is also defunctioned. If the multiple lesions have a narrow base, then the base or pedicle can be transected, leaving normal skin/mucosa between wounds, allowing full excision. If the lesions are confluent, there is no harm in staging the procedure over two, three or even four visits to minimise the risk of stenosis.

Buschke–Lowenstein tumour: giant anal condyloma

Buschke and Lowenstein described giant condyloma acuminata (GCA) in 1925. It is a highly recurrent locally invasive tumour of low malignant potential associated with low-risk HPV types 6 and 11. GCA is large in diameter (6–12 cm) and also in depth (up to 4 cm), appearing as densely packed firm warts, broad-based with a finely irregular surface ( Fig. 8.5 ). Patients are predominantly male, often smokers. There is some overlap with verrucous SCC. Magnetic resonance imaging (MRI) shows the tumour superficially infiltrating usually with no invasion of underlying muscle and T2 hyperintensitivity.

There is no good evidence for treatment, but 5% imiquimod, photodynamic therapy, acitretin, cidofovir, chemotherapy combined with surgical excision, and chemoradiation (CRT) have all been tried. Patients often fail local ablation or excision, undergo skin grafts and end up with a defunctioning stoma, stenosis and eventual abdominoperineal excision.

Symptoms, signs, examination

Anal squamous intra-epithelial lesions (SIL) are usually asymptomatic while anal SCC is usually symptomatic. There are cases where extensive anal/perianal HSIL causes itching, soreness and pain, however, these should be carefully assessed and biopsied particularly at spots of ulceration or where the patient has pain to exclude focal SCC ( Fig. 8.6 ). Macroscopically, anal SIL can appear as warts, or flat pink or red lesions, or grey or darker pigmentation in brown or black skin. The pigmented areas tend to be irregular in outline. Closer inspection shows dots visible (abnormal vasculature) and some more advanced lesions are thickened. Vascular patterns of SIL are similar to those seen in the cervix at colposcopy. Some are impossible to detect with the naked eye.

For both perianal and anal canal SIL, the technique of high-resolution anoscopy (HRA) is considered the gold standard worldwide to visualise the SCJ and identify SIL for targeted biopsies. In a technique analogous to colposcopy, 5% aqueous acetic acid is used through an ordinary proctoscope with high-resolution real-time high-quality magnification by colposcope up to 30 times. Regions of active HPV mucosal infection turn cloudy white (acetowhite), and SILs are visible with abnormal vessel patterns showing as irregular lines (mosaic change), straight lines (striations) and dots (punctation) ( Fig. 8.7 ). Standards have been set for carrying out the procedure. Anal cytology can be carried out for detection of dysplasia from the anal canal before HRA (Floq swab in liquid-based cytology medium) as can swabs for high-risk HPV, but neither test yet has the sensitivity required for a screening programme for high-risk groups.

Anal canal SIL can be detected and biopsied at endoscopy with a retroflexed view and relaxation of the anorectal junction plus narrow band imaging, with the diagnosis a surprise to most endoscopists.

Prevalence

Anal HSIL is highly prevalent in high-risk groups. PLWH, especially MSM, have been the most studied with a prevalence of anal HSIL of 29–33%; ^, in women living with HIV prevalence is 27%, and 17% in those with no history of anal intercourse. The odds ratio for renal transplant recipients having anal HSIL, controlled for factors of age, lifetime sexual partners, anal intercourse and smoking was 11.2 for men and 8.3 for women, with an overall prevalence of 27/247 (11%). Of note, 4% of the female and 0.8% of the male non-transplanted controls had anal HSIL with no known risk factors.

Progression

Progression of anal HSIL to anal cancer is not inevitable and the diagnosis has to be put in context for patients. The risk of SCC varies from 1 in 456 per year for MSM living with HIV and 1:4000 per year for those without HIV to 9.5% at 5 years. There is also regression of anal HSIL, approximately 25% at 6 months. A study from the specialist unit in San Francisco demonstrates photo documentation of anal HSIL lesions left untreated, returning as invasive lesions at the same location in 27 patients.

DNA methylation of host and HPV genes in the anus – as for the cervix – seems to predict the progression of HSIL to cancer, and may enable the identification of at-risk lesions for treatment in the future, strengthening the case both for treatment and for screening. ^, In HIV-positive MSM, progression from LSIL or no SIL to HSIL was 55/1199 patients over 1–5 years. At present, the evidence is that AIN3 is more likely to progress than AIN2 p16+ve and less likely to regress and the relative risk of cancer for HSIL treated with ablation versus no treatment has been shown to be 0.3.