Diagnosis and management of anal intraepithelial neoplasia and anal cancerBMJ 2011; 343 doi: http://dx.doi.org/10.1136/bmj.d6818 (Published 04 November 2011) Cite this as: BMJ 2011;343:d6818
- J A D Simpson, academic surgical registrar,
- J H Scholefield, professor of surgery
- 1Division of Gastrointestinal Surgery, Queens Medical Centre Campus, Nottingham University Hospital, Nottingham NG7 2UH, UK
- Correspondence to: J A Simpson
- Accepted 5 September 2011
Human papillomavirus infection increases an individual’s risk of developing squamous cell carcinoma of the anus; cigarette smoking, high number of previous sexual partners, and previous pre-cancerous lesions of the cervix or vulva (in women) are also associated with increased risk
Although anal cancer is not an AIDS defining cancer, its incidence is increased in HIV positive individuals and in those who are immunosuppressed
Anal intraepithelial neoplasia usually precedes development of invasive squamous anal carcinoma and can present in various forms.
The management of anal cancer has changed in recent years; chemo-irradiation rather than surgery is the first choice treatment for most lesions.
Surgery may be the primary treatment modality for small perianal lesions which can be locally excised, but is now usually reserved for tumours that fail to respond to chemo-irradiation or for recurrent disease.
Anal cancer accounts for about 4% of large bowel malignancies, but data from the Surveillance Epidemiology and End Results programme show a considerable rise in incidence since 19751 from 0.8 to 1.7 per 100 000. The World Health Organization recently estimated that between 350 and 500 new cases of anal squamous cell carcinoma are detected each year in England and Wales.2
Observational studies have shown that individuals with genital human papillomavirus (HPV) infection and those who are immunosuppressed, including HIV positive patients, are at increased risk of developing anal cancer.3 4 A history of cervical or vulval HPV infection and premalignant changes also increases the risk of developing anal cancer, with a reported incidence rate ratio of between 3.97 and 31.09, dependent on age at diagnosis, compared with controls.5 General practitioners and practice nurses who screen women as part of national programmes for detecting cervical malignancy should be aware of the association between HPV infection and anal cancer.
The majority of anal cancers are of squamous cell origin and 80% are preceded by relatively innocuous skin changes. Early identification is important because anal cancer can often be prevented or treated with conservative management strategies, whereas late presentation often necessitates radical surgery associated with substantial morbidity. We discuss causes, diagnosis, and management of anal cancer, focusing particularly on recent changes in management strategies. We draw on the findings of systematic reviews and cite recognised guidelines where possible.
Sources and selection criteria
We searched PubMed for clinically relevant studies, and the Cochrane library, using the search terms anal cancer and anal intraepithelial neoplasia. We consulted the National Institute for Health and Clinical Excellence guidelines and the Association of Coloproctology position statements.
Who is most at risk?
Observational evidence from the UK has shown that in the past three decades, the greatest increase in incidence of anal cancer has occurred in women.6 7 Figure 1⇓ illustrates this trend as seen in south east England from the late 1800s through to 1964. The average age for diagnosis in both men and women is 57 years.
Population based case-control studies from Denmark and Swedenw1 showed that anal cancer is associated with HPV infection in 90% of patients,1 and a large case-control study found positive associations between incidence of anal cancer and various health and lifestyle factors.8 This study identified cigarette smoking as a substantial risk factor in both men and women (relative risks 9.4 and 7.7, respectively, compared with non-smoking controls);8 28% of patients with anal cancer gave a history of genital warts as a result of HPV infection, compared with only 1-2% of controls, and a history of receptive anal intercourse in men increased the relative risk of developing anal cancer by 33 times compared with controls with colon cancer. HIV infection in men who have sex with men was associated with approximately double the risk of developing anal cancer compared with men who have sex with men who were HIV negative.8 9
How do patients with anal cancer present?
Common presenting symptoms include anal pain, bleeding, discharge, pruritus, and ulceration (fig 2⇓). If the anal sphincters are infiltrated by tumour patients may report faecal incontinence and tenesmus. Locally advanced disease may present with perianal infection and fistula formation. It is important to identify palpable inguinal lymphadenopathy at presentation because worse outcomes, higher local failure, and decreased survival have been reported if nodal spread has occurred.10 Radiological assessment is required to detect distant metastases. Although metastases are not common, occurring in less than 10% of patients with anal cancer, the ACT 1 trial indicated that 40% of this patient subgroup died as a consequence of metastatic spread.11 Invasive anal cancer is occasionally an unexpected finding after excision of anal tags or haemorrhoids.
Red flag symptoms that should raise suspicion of anal cancer and for which a patient must be promptly referred for investigation are perianal bleeding, a palpable anal mass, and perianal ulceration.
Understanding anal anatomy
Definitions of anal anatomy are not consistent and surgeons, radiologists, and pathologists differ in how they classify structures. The following description is a pragmatic definition taken from the 2011 position statement for management of anal cancer from the Association of Coloproctology of Great Britain and Ireland12 and relates directly to figure 3⇓.
The anus can be divided into the anal canal and the anal margin; the former is 3.5-4 cm long in men and shorter in women. The anal canal begins where the rectum enters the puborectalis sling at the apex of the anal sphincter complex, and ends with the squamous mucosa blending with the perianal skin, which roughly coincides with the palpable intersphincteric groove. Immediately proximal to the dentate line, a narrow zone of transitional mucosa is variably present—the anal transition zone. Distal to this, the mucosa consists of squamous epithelium devoid of hairs and glands. The anal margin extends distal to the anal verge (the junction of the hair bearing skin) to a 5 cm circumferential area from it. Lymphatic drainage of the anal canal depends on location: below the dentate line drainage is to the inguinal group of nodes; above, lymph drains to the mesorectal, lateral pelvic and inferior mesenteric nodes.12
What is anal intraepithelial neoplasia and how do I recognise it?
Anal intraepithelial neoplasia usually precedes the development of invasive squamous anal carcinoma. It can involve both the perianal skin and anal canal. A population based, case-control study has shown that anal intraepithelial neoplasia is strongly associated with HPV infection.3 It can present as part of a multifocal disease process involving any or all sites of anogenital cancer.13 There are aetiological and clinical parallels between anal intraepithelial neoplasia, vulval intraepithelial neoplasia, and cervical intraepithelial neoplasia. A recent Association of Coloproctology Position statement suggests that the progression of anal intraepithelial neoplasia to invasive anal cancer more closely resembles the natural history of vulval intraepithelial neoplasia, with expected malignant transformation in about 10% of immunocompetent patients over five years.14
Patients may present with pruritus or anal discharge. Suspicious lesions may be raised, scaly, white plaques, erythematous, pigmented, fissured, or eczematous (fig 4⇓). 15 Anal intraepithelial neoplasia is present in 28-35% of excised anal condylomata.16 w2
How are suspicious lesions investigated?
Evaluation in primary care
Ask the patient about risk factors for anal cancer. Obtaining a careful medical history (including asking about chronic diseases) will help to evaluate a patient’s fitness for any future surgery and other treatment. Age over 75 years is associated with reduced tolerance to chemoradiotherapy and increased risk of local disease relapse.17 18 In view of the association with HPV it is also prudent for a thorough sexual history to be taken.
Although anal cancer is not an AIDS defining cancer (meaning that diagnosis of anal cancer does not indicate the conversion of HIV to AIDS), it is 30 times more common in HIV positive individuals. Therefore HIV status should be considered, and for known HIV positive patients it is sensible to obtain up to date results for viral load and CD4 count.12
Patients who describe perianal symptoms consistent with anal intraepithelial neoplasia or anal cancer require examination of the perineum, digital rectal examination, and examination of the inguinal area for palpable nodes. Consider vaginal examination in women because of the multifocal nature of the disease, specifically with a view to identifying lesions on the vulval skin or vaginal mucosa. Suspicious lesions may suggest the presence of vulval intraepithelial neoplasia and should trigger referral to a gynaecological specialist.
Note any changes in pigmentation of the perianal region, as well as ulceration and the presence of skin tags or condylomata. As part of the digital rectal examination it is important to document any palpable mass lesion, if possible indicating the distance from the anal verge at which the mass is felt and the proportion of the anal circumference that it occupies. Inspect the glove for blood from the anal canal.
Before referral to a specialist it is helpful to request a full blood count, serum urea and electrolytes, and, in HIV positive patients, an assessment of current CD4 status.
Diagnosing anal intraepithelial neoplasia
Diagnosis of anal intraepithelial neoplasia requires primary care practitioners to maintain a high index of suspicion particularly in patients with known risk factors who present with new symptoms. For a definitive diagnosis a biopsy of the suspicious area is needed. This will normally be performed by a specialist following referral.
Referral of patients with suspected anal cancer
Guidelines from the UK National Institute of Health and Clinical Excellence recommend that patients presenting with bleeding from the anus that has lasted longer than six weeks, a palpable mass on rectal examination, or anaemia without a known cause should be referred for urgent investigation for cancer. Pragmatically this means that they will be included in the two week wait rule and receive a diagnostic investigation within 14 days of referral, because urgent consultation with a specialist has been recognised as a priority.
Investigations undertaken in specialist care
After referral to a specialist, the patient is likely to undergo biopsy of the suspect lesion in order to establish a histological diagnosis. Biopsy often takes place as part of a formal examination under anaesthesia, which can also provide information about the size of the lesion and involvement of adjacent structures, and may be supplemented by sigmoidoscopy.
Imaging is used to inform tumour staging. Distant metastatic spread can be determined by computed tomography of the thorax, abdomen, and pelvis. Magnetic resonance imaging of the pelvis allows assessment of tumour size and local invasion and the involvement of local lymph nodes. Endoanal ultrasound provides a 360° image of the anal canal and is useful for assessing tumour depth, particularly if there is concern that the anal sphincters may be involved. It is useful for assessing local response to treatment but is limited by its restricted field of view and may miss lymph nodes in the mesorectum.
How is anal intraepithelial neoplasia treated?
The priorities of managing anal intraepithelial neoplasia are to minimise symptoms and prevent the development of anal cancer. A number of different strategies can be employed to achieve these end points.
Conservative management derives from a combination of single centre studies that have shown low rates of malignant transformation in immunocompetent patients with anal intraepithelial neoplasia19 w3 and high recurrence rates after aggressive surgery. Recurrences after surgery are thought to occur because of the inability to completely eradicate local HPV. Therefore patients with low grade anal dysplasia are followed up every six to 12 months.w4
No supporting evidence has been established for the use of chemoradiotherapy in anal intraepithelial neoplasia, but anecdotal reports have described success in vulval intraepithelial neoplasia. However the use of radiotherapy in particular may lead to the development of anal stenosis.
Local excision of small lesions preserves tissue histology, which can help to guide future management. Local excision is suitable for lesions that cover less than a third of the anal circumference. Before excision the surgeon will usually perform anal mapping to determine the extent of the disease. Mapping involves taking eight to 12 biopsies from around the anal margin and canal. It is useful to record the procedure on an operative mapping sheet or with digital photography.
Brown et al performed preoperative mapping and local excision on 34 patients with high grade anal intraepithelial neoplasia. On review 56% had margin involvement and 63% recurred within 12 months.w5 No patient developed carcinoma but five developed anal stenosis or faecal incontinence.
Wide local excision has also been considered for larger anal lesions, but these techniques present an even greater risk of postoperative complications and are probably overly aggressive for a disease process in which the natural history is still not fully understood. If the worst areas are excised then the remaining lesions can be managed expectantly.
Imiquimod is a nucleoside analogue of the imidazoquinoline family and has pro-inflammatory, anti-tumour, and anti-viral activity. It is prescribed as a 5% cream, and applied topically it can induce regression of anal intraepithelial neoplasia and eradication of HPV. A double blind randomised controlled trial showed sustained regression of high grade intraepithelial neoplasia in 61% of patients, with a median follow-up of 36 months.w6 In a separate review of cohort studies and case reports, imiquimod was associated with a complete regression in 48% of anal intraepithelial neoplasia lesions and a partial response in 34%. This was associated with a recurrence rate of 36% over 11-39 months of follow-up.w7 Most studies of imiquimod have assessed its use in HIV positive populations with short follow-up, and the drug has rarely been compared with other treatment strategies. Despite the relative success of this treatment, caution should be used when extrapolating this evidence to other populations of patients with anal intraepithelial neoplasia.
Vaccination against HPV was first approved in the United States in 2006. The evidence for its use in preventing cervical intraepithelial neoplasia and cervical malignancies as part of a population based immunisation programme is well established.w8 The quadrivalent vaccine has also shown efficacy against anogenital warts in phase II/III trials. However, clarification of some uncertainties—notably vaccine efficacy in men and HIV infected individuals, and the feasibility to offer vaccination programmes to both sexes—is required to establish the benefits of HPV vaccines for the prevention of malignant and premalignant anal lesions.
Case reports and small uncontrolled trials have supported the use of photodynamic therapy in anal intraepithelial neoplasia.w9 However this type of therapy is painful and often requires multiple treatments.w10 Larger series with long term follow up are required before it could be recommended as standard therapy.
Goldstone et alw11 retrospectively reviewed 75 cases of high grade anal intraepithelial neoplasia in which patients had received infrared coagulator ablative therapy. They quoted the probability of success as 81% after a single treatment, rising with repeated treatment and with no evidence of serious complications. However, the follow-up period was limited (one to two years) and the outcomes were not as good if the patient was HIV positive before treatment. Other reviews point to a high recurrence rate and substantial postoperative pain, also questioning the ability of ablation to clear HPV.14 Ablative therapies can include laser ablation, cryotherapy, and electrocautery, but none of these provide histology, which can be useful when planning a patient’s long term management.
Anal intraepithelial neoplasia is a complex disease process, the natural history of which remains unclear. Low grade dysplasia (anal intraepithelial neoplasia I and II) represents a much more indolent disease than high grade dysplasia (anal intraepithelial neoplasia III). Progression of disease and therefore associated treatment is more aggressive in HIV positive populations. With this in mind we have reproduced the treatment algorithm from the 2011 Association of Coloproctology guidelines (fig 5⇓).14
How is anal cancer classified and staged?
The current WHO classification of anal tumours (box) categorises by histological tissue types. Squamous cell carcinoma is the most common type of anal cancer, seen in 80-85% of patients.w12 Adenocarcinoma of the anus is less common, constituting 5-18% of cases.20 Other malignancies are very rare.
WHO histological classification of tumours of the anal canal
Intraepithelial neoplasia (dysplasia)
Squamous or transitional epithelium
Squamous cell carcinoma
Small cell carcinoma
Adapted from Salmo et al21
Squamous cell carcinoma of the anal canal can be graded histologically, but neither the histological type nor the degree of differentiation seem to influence prognosis strongly.22 Other authors have used anal cancer databases to perform multivariate analysis and establish factors that influence prognosis, which include the patient’s sex, tumour stage, node involvement, and response to radiotherapy or combined treatment.23 24 25After confirmation of the diagnosis of anal cancer, tumour staging is needed. Anal cancers are staged in accordance with the American Joint Committee on Cancer/tumour node metastasis (TNM) classification. Staging provides prognostic significance based on five year survival (table⇓).
How is anal cancer managed?
Anal cancer is a rare malignancy that requires care at specialist referral centres where diagnostic and treatment decisions can be referred to a single multidisciplinary team. This team ensures that treatment decisions are made involving experienced specialists from surgical, radiological, oncological, and gynaecological divisions. Given that 10% or less of patients with anal cancer have metastases at presentation, the mainstay of treatment is usually local control.
An important change in the recommended approach for treating anal cancer over the past two decades has been that chemoradiotherapy is now the first choice treatment for invasive anal cancer, with surgery reserved for salvage of local recurrence. The reasons for loss of enthusiasm for surgery as first line therapy included the high associated morbidity and frequent recurrence rates, presumably because although surgical resection removed the malignant tissue it could not eradicate the underlying HPV infection.
Six randomised trials of non-surgical treatment have been reviewed in the Association of Coloproctology position statement on anal cancer,27 which supports the use of combination chemoradiotherapy including 5-fluorouracil and mitomycin C, but also acknowledges that conclusions are based on a cohort of 1628 patients spread across trials with heterogeneous methodology.
Patients who receive chemoradiotherapy may lose fertility and may need a colostomy either before or after treatment. Pelvic radiotherapy can lead to faecal incontinence and the development of rectovaginal fistula. These complications may reduce a patient’s quality of life and patients should be counselled about them when treatment is discussed.
Well differentiated anal margin tumours less than 2 cm in diameter (T1 N0) or occupying less than half the anal circumference can initially be treated by local excision, which provides definitive treatment if all resection margins are clear.28 w13
Currently the main role for surgery in anal cancer is for “salvage treatment” after failure of chemoradiotherapy. A retrospective review showed that disease relapse is most likely within the first three years and rare after five years.29
Renehan and O’Dwyer recently reviewed the management of local disease relapse after treatment for anal cancer.30 Following examination of 13 studies that had reported oncological outcomes after salvage surgery for relapsed anal cancer they concluded that salvage surgery with abdominoperineal excision offers the only opportunity for cure in these patients. The excision margins for anal cancer surgery are wider than for rectal cancer and therefore perineal reconstruction and the assistance of urological, plastic, and gynaecological surgeons may be required. There are a number of reasons for the wider margins: firstly, to take account of local spread, the perineal skin resection is wider; secondly, the lateral oncological margin for salvage surgery is the level of the ischial tuberosity; thirdly, owing to the preoperative fibrosing effects of radiotherapy, a wide excision margin may be needed to ensure a well vascularised skin edge; and finally, involvement of adjacent pelvic organs is common.
The most frequent operation performed for anal cancer that has failed to respond to chemoradiotherapy is an abdominoperineal resection with perineal reconstruction. This operation involves the removal of the anal canal and rectum and the formation of a permanent stoma, usually sited on the left lower quadrant of the abdomen. Outcomes for this type of surgery have only been described in small, retrospective, single centre studies with heterogeneous methodology, but the results suggest a five year survival between 30% and 69%.29 w14-w18
Factors that have been associated with decreased survival include positive lymph nodes at presentation, increased tumour size, advanced age of the patient, comorbidities, and positive resection margins (that is, when pathology shows the tumour extending to the margin of resection, suggesting incomplete excision). Debate continues over whether the presence of persistent or recurrent disease as the reason for surgery has a true effect on survival. w14-w18
Perineal reconstruction refers to the use of local and distant tissue flaps or commercial material to fill the defect left after excision. This type of wound repair involves a risk of postoperative complications, with infection and breakdown reported in 35% to 72% of cases. w15 w16 w18
Rare anal tumours
Although true anal adenocarcinomas do occur, adenocarcinoma of the anal canal is more commonly a very low rectal cancer that has spread distally. True adenocarcinomas probably originate from the anal glands and then spread outwards to involve the anal sphincter. This is a very rare tumour that is sensitive to chemoradiotherapy.w19 w20
Malignant melanoma accounts for 1% of malignant anal canal tumours. In presentation, they may mimic a thrombosed haemorrhoid. Anal melanoma is an aggressive disease with early infiltration and distant spread resulting in poor overall prognosis. It is not sensitive to chemotherapy or radiotherapy. Review of 85 patients treated at a single centre showed a median survival of 19 months.w21 A recent systematic review compared abdominoperineal resection of the rectum with wide local excision and found no distinct survival advantage for either procedure.w22 As chances of cure are minimal, radical surgery should not be considered as a primary treatment, but local excision may provide useful palliation.
Tips for non-specialists
Maintain a high index of suspicion for anal intraepithelial neoplasia in patients presenting with anal pruritus or discharge and a suspicious scaly lesion or condylomata
Ask the patient about sexual history, previous diagnosis of HPV, cervical or vaginal intraepithelial pathology, HIV status, and previous excision of anal warts
Refer patients with bleeding from the anus that has lasted longer than six weeks, a palpable mass on rectal examination, or anaemia for urgent specialist consultation, using the two week cancer referral rule in the UK
Explain to patients that chemoradiotherapy is the first line treatment and may allow surgery to be avoided. However, a colostomy may still be needed before or after treatment and radiotherapy can lead to faecal incontinence and recto-vaginal fistula
Additional educational resources
For health professionals
Association of Coloproctology of Great Britain and Ireland guidelines (www.acpgbi.org.uk/resources/guidelines)—contains an up to date evidence based and detailed guideline on all aspects of care for patients with anal cancer
European Society for Medical Oncology (http://annonc.oxfordjournals.org/content/21/suppl_5/v87.full)—a more concise set of guidelines for the diagnosis, treatment, and follow-up of anal cancer
A Companion to Specialist Surgical Practice—Colorectal Surgery, 4th ed (ed Robin K S Phillips, Saunders for Elsevier, 2009)—the chapter on anal cancer contains everything a gastrointestinal surgeon would need to know about anal cancer in order to diagnose and arrange treatment for patients
Macmillan cancer support website (www.macmillan.org.uk/Cancerinformation/Cancertypes/Anal/Analcancer.aspx)—provides a clear explanation of what anal cancer is and what the treatment options are, along with a telephone number for patients to ask questions and receive support
Cancer Research UK (www.cancerhelp.org.uk/type/anal-cancer/about)—offers quick guidance about the symptoms, risks, and treatments of anal cancer and pragmatic advice about seeing a doctor.
Cite this as: BMJ 2011;343:d6818
Contributors: JADS was responsible article concept, design, drafting and revision. JHS was responsible for revising the article critically and final approval of the published version.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Not commissioned, externally peer reviewed.