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The role of viruses and sexual transmission in anal cancer

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VOL: 101, ISSUE: 09, PAGE NO: 38

Ruth Dunleavey, BSc, RGN, is clinical research nurse, St Vincent's Hospital, Sydney, Australia

Incidence of anal cancer

Incidence of anal cancer
Cancer of the anus is a rare condition, constituting 1.5 per cent of all gastrointestinal cancers in the US (Gervaz et al, 2003). Three hundred new cases are diagnosed in the UK each year (Martin and Bower, 2001).

Historically anal cancer has been more prevalent among women and older people (Maggard and Beanes, 2003), but its incidence is rising significantly among the young, male population - particularly men who have sex with men (MSM).

A significant number of men participate in receptive anal intercourse with other men but do not classify themselves as gay, homosexual or bisexual. There is therefore a concern that health messages will fail to reach this group if the wrong term is used.

The phrase 'men who have sex with men' aims to address this group in a non-confrontational way and is found increasingly in the literature.

Incidence of anal cancer in the general population is 1.3 per 100,000 women and 1.2 per 100,000 men (Workman, 2003). In men who have sex with men this number rises to 25-37 per 100,000. Infection with HIV significantly increases the risk of anal cancer, while homosexual males with Aids have a relative risk of developing the disease that is 84 times higher than that of the general population (Place et al, 2001).

Anal pathology
The anus is composed of the anal canal and the anal margin. The anal canal is 3.5cm long, extending from the upper to the lower part of the anal sphincter. The anal margin is the 5cm area of perianal skin as measured from the anal verge, which is the external section of the anus, where the hairless, non-pigmented epithelium of the anal canal meets the normal skin.

At the proximal end of the anal canal is the dentate line, a transitional zone where the glandular mucosa of the rectum meets the squamous mucosa of the anus. Eighty-five per cent of anal cancers arise in the anal canal with the remainder arising in the anal margin. Those in the canal are characterised by aggressive local growth and extension into underlying sphincters, while anal margin cancers have a more favourable prognosis and are more likely to behave like other skin cancers (Gervaz et al, 2003).

Several names are used to describe tumours arising from the squamous mucosa of the anus, such as basaloid, cloacogenic, epitheloid and mucoepitheloid. All are terms for squamous cell carcinomas (SCCs).

Approximately 5-17 per cent of anal cancers are adenocarcinomas. In some respects these have more in common with colon cancers (Beal et al, 2003) and their treatment is therefore slightly different. This article focuses only on the management of SCCs.

Presentation
Although half of patients presenting with anal cancer will have a superficial mass, only 30 per cent will have the sensation of a mass. For the remainder the tumour is detected on digital palpation (Klenke and Palefsky, 2003). Tumour size is an important prognostic variable - 80 per cent of mobile lesions of less than 2cm can be cured, compared with 50 per cent in those of 5cm or more.

Size also correlates with the likelihood of lymph node involvement - the larger the tumour the more likely it is to include nodal involvement (Ryan et al, 2000).

Twenty-five per cent of patients with anal cancer will have involvement of regional lymph nodes.

Other presenting symptoms include pain (30 per cent), bleeding (45 per cent) and a history of warts (50 per cent of gay men) (Ryan, 2000). Diagnosis is often delayed in MSMs because of previous anal pathology, as the symptoms of benign conditions such as anal fissures may mask the anal cancer.

The diagnostic process includes computerised tomography (CT) scans of the chest, abdomen, and pelvis to help define the internal extension of the infiltrating tumours and detect any enlargement of the pelvic nodes or distant metastases. Endorectal ultrasound is a useful tool for assessing the extent of tumour infiltration and also perianal lymph node involvement to a degree (Esiashvili et al, 2002).

The five-year survival rate for people with anal cancer is 53 per cent - the cancer-specific five year survival rate is 84 per cent. This survival rate has increased in successive decades since the 1970s (Maggard and Beanes, 2003).

Human papilloma virus
It was once believed that anal cancer was precipitated by local irritation or trauma such as haemorrhoids. However, understanding of the disease has increased significantly in the past 30 years and this is now known to be incorrect. Instead it seems to be closely associated with viral infection, and as with cervical cancer, the primary virus involved is the human papilloma virus (HPV).

In one of the seminal studies linking HPV with anal cancer (Frisch et al, 1997) telephone interviews were conducted with 324 female and 93 male patients with anal carcinoma in Sweden and Denmark. Two control groups were also interviewed, one composed of patients with colorectal cancer (n=534) and one of members of the general population (n=554). This generated a considerable amount of data on the risk factors associated with contracting the disease (Box 1).

In the second part of their study, Frisch et al (1997) obtained biopsy material from their anal cancer cohort and examined it for HPV infection - 88 per cent of the tumours were infected, 73 per cent with subtype HPV16. This subtype is not only known to be oncogenic, it is also prevalent in cervical cancer. Frisch et al (1997) concluded that anal cancer, like cervical cancer, is virally transmitted and is also a sexually transmitted disease.

As with cervical cancer, HPV infection alone is not sufficient to cause the disease - a large number of people are infected with the virus but never develop cancer. Other factors, which are not yet fully understood, appear to be necessary to trigger the conversion to malignancy.

Dysplasia
As with cervical cancer, a range of cellular abnormalities can be detected before anal cancer develops. These abnormalities can be graded, with the highest grade being associated with highest risk of transformation into a malignancy. In the cervix dysplasias are graded by the CIN system (cervical intraepithelial neoplasia) on a scale of I-IV. A similar system exists for anal cancer, with the anal intraepithelial neoplasia (AIN) graded between I and III. Different grades of AIN appear to be associated with different subtypes of HPV infection; HPV6 and 11 are commonly found with low-grade AIN, whereas 16 and 18 are associated with high-grade AIN (Workman, 2003).

The AIN stage is a histological diagnosis based on biopsy results. It is sometimes preceded by a cytological evaluation whereby a sample is taken from the anal area in a similar way to obtaining a cervical smear. High-grade and low-grade squamous intraepithelial lesions (HGSIL and LGSIL) can be detected in this way and may be precursors to anal cancer. Cytological evaluation can also reveal atypical squamous cells of undetermined significance (ASCUS), which may simply reflect inflammatory changes (Manavi and McMillan, 2004). The role of cytological analysis for screening purposes is discussed below.

In cases of cervical dysplasia it is known that 30 per cent of high-grade lesions will transform to invasive cancer if left untreated. However, in anal cancer the association between high-grade neoplasia and cancer is less well understood. It has been suggested that fewer than one per cent of cases of AIN will progress to anal cancer annually (Klencke and Palefsky, 2003).

As with cervical cancer, the mechanism whereby AIN transforms to anal cancer is not fully understood.

The presence of high-risk HPV alone is not enough - other factors must be in place such as loss of tumour suppressor gene function (Gervaz et al, 2003). The vast majority of AIN will not progress (as with CIN).

While the treatments for CIN are now reasonably well-established, there is currently no standard treatment for AIN. Surgery is an unappealing option because it is unlikely that the complete transformation zone could be removed without significant morbidity, such as anal stricture. Topical chemotherapy and laser therapy have been utilised to eradicate the disease but without great effect. Experimental vaccine therapies are also being studied but there are no conclusive results as yet.

Human immunodeficiency virus
The development of highly active antiretroviral treatment (HAART) has transformed HIV infection from a seemingly uncontrollable terminal illness to a chronic condition that can be managed.

The obvious benefit of this is that people with HIV now have a longer life expectancy, but this means many now survive for long enough to contract a different category of disease - notably malignancies. Since the progression of high-grade AIN to anal cancer may take several years, the improved survival rate for HIV patients that has been brought about by HAART may increase the incidence of anal cancer (Palefsky, 2000). Anal cancer is now a major problem among those with HIV/Aids, although it has not been designated an Aids-defining illness (Box 2).

The incidence of anal cancer is higher in people who are HIV-positive regardless of the mode of transmission of the virus - that is, not just in MSM. However, the combination of MSM and HIV infection renders patients at particularly high risk. AIN incidence is also higher in people with HIV infection - it is found in 65 per cent of men and 26 per cent women with the virus. Human papilloma virus infection is also more prevalent in those with HIV, who are two to six times more likely to have detectable anal HPV, regardless of gender (Klenke, 2002). As HIV progresses, the risk of anal cancer increases. In the two to five years prior to conversion to Aids the risk of developing anal cancer is 3.9 times greater than in healthy individuals, whereas on diagnosis of Aids it is 84.1 times greater (Workman, 2003).

It is unclear whether HIV has any direct effect on the development or progression of anal cancer although it seems likely that the general immunosuppression resulting from infection is likely to be a significant factor. Chronic immunosuppression has been shown to be a risk factor in other populations - for example people who have received renal allografts have 100 times greater risk of anogenital cancer than the general population (Ryan et al, 2000).

Treating and managing anal cancer
Until the 1970s surgery was the main intervention for anal cancer. All patients underwent an abdominoperineal resection (APR) - the removal of the anorectum and formation of a colostomy.

However, a seminal study by Nigro et al (1974) challenged this practice. Three patients were instead treated with combined radiotherapy and chemotherapy using 5FU and mitomycin C. Two of the patients then underwent AP resection and were found to be disease free. The third declined to undergo the operation but was disease free one year later. Anal cancer is now considered to be the only cancer of the gastrointestinal tract that can be cured without surgery (Ryan and Mayer, 2000).

However, surgery is not redundant. It is required for diagnosis, for salvage therapy and sometimes to create a temporary stoma in patients in whom significant toxicity is expected with chemoradiotherapy (Clark et al, 2004).

Survival rate statistics for anal cancer vary from 65 per cent to 100 per cent, although randomised controlled trials tend to match the lower end of this range - 65 per cent to 72 per cent (Maggard and Beanes, 2003).

The chemotherapy of choice for anal cancer is still 5FU - sometimes in combination with mitomycin C, although this has been challenged recently. The efficacy of chemotherapy relies on the concurrent administration of radiotherapy. The chemotherapy is thought to act as a radiosensitiser when given in conjunction with radiotherapy, potentiating the effect of the radiation.

In recent years there has been a trend to replace mytomycin C with cisplatin (Hung et al, 2003). Mytomycin is not known to be a radiosensitiser and is also quite toxic, whereas cisplatin appears to work synergistically with radiotherapy - and is used to treat cervical cancer. Radiotherapy is generally administered over five to six weeks and at relatively high doses (50-60Gy).

Chemoradiotherapy is associated with a range of relatively extreme toxicities, although few studies have specifically investigated these. In particular little attention has been paid to long-term toxicities and quality of life issues. Skin reaction is the most common acute side- effect of anal cancer treatment and includes erythema, pigmentation change and grade II and III desquamation. Although this sometimes leads to treatment interruption (Esiashvili, 2002), this is generally avoided because of the curative potential of chemoradiotherapy.

Impairment of anal function is another potential problem and depends largely on the extent of prior surgical intervention or subsequent biopsy. In some instances it may be permanent. Other potential problems include diarrhoea and fatigue. Despite the fact that a large proportion of patients will be MSM, there is almost no data on the effects of treatment on sexual function.

In total 30 per cent of patients will experience a major acute toxicity - this increases to 80 per cent in people with HIV infection (Kim et al, 2001). A number of studies have compared toxicity rates among people with and without HIV infection, prompted by observations that those with the virus fare less well. More recently studies seem to indicate that immunocompetence is an important factor, and those experiencing the most problems are likely to have CD34 counts of less than 200 (Workman, 2003). For this reason it has been suggested that the initiation of HAART at the same time as anti-cancer treatment may have a significant effect on outcome (Place et al, 2001). However, HAART appears to have no impact on AIN or HPV status.

Untreated anal cancer principally spreads by local extension into adjacent tissues and organs including the vagina and prostate gland (Gervaz et al, 2003). Most deaths are due to locoregional failure, with only 10-20 per cent resulting from distant spread (Place et al, 2001). The liver is the most common site for distant spread. Residual disease tends to be associated with large tumours. Recurrence is associated with small, aggressive tumours (Pocard et al, 1998), and in the case of failed chemoradiotherapy is often treated surgically with AP resection.

While patients undergoing therapy for anal cancer experience significant physical toxicity, the psychological aspects of the disease should not be underestimated. As mentioned previously, there is limited data on quality of life in these people, but the diagnosis of anal cancer is likely to cause embarrassment as well as physical discomfort. For homosexual males there are profound body image and sexuality issues, while for people with HIV infection there are added concerns about Aids. In addition many patients experience feelings of guilt, anger and confusion, which need to be expressed and managed.

Screening
Because the incidence of anal cancer is now so high among the MSM population - particularly among those with HIV infection - there has been considerable discussion as to whether regular screening should be instigated among these groups. A procedure similar to a cervical smear can be performed in which the anal area is swabbed and the cells sent for cytological analysis. Like the cervical smear, this is a simple outpatient investigation.

If cytological abnormality is detected a high-resolution anoscopy (HRA) can be conducted. This is similar to a colposcopy and allows imaging and biopsy of the anal area through the use of an endoscope. It can also be performed on an outpatient basis, although it can be painful if there are established anal lesions. Unfortunately there is a shortage of practitioners able to conduct HRA owing to the comparative rarity of anal cancer (Klenke and Palefsky, 2003).

The decision to add anal cancer to the list of diseases warranting screening should not be taken lightly. Testing can be expensive, while false positive results can lead to unnecessary procedures and patient anxiety, and false negatives to a delay in diagnosing serious disease.

Volberding (2000) gives a list of criteria by which to evaluate the suitability of a disease for a screening programme. He observes that the condition should be common and the cause of serious morbidity and mortality, treatable if detected in the early phase, predictable with a relatively long natural history and screening should be economically viable.

While anal cancer does not meet all these criteria it shares many characteristics with cervical cancer for which a number of successful screening programmes exist.

In order to assess the cost-effectiveness of anal screening programmes for high-risk groups Goldie et al (1999) built a model using data from previous studies to predict the rate of progression of anal cancer. They concluded that three-yearly screening among the MSM population could extend life expectancy by a similar amount and at a similar cost to screening for cervical cancer, which yields an average increase in life expectancy of 5.6 months. This is of course a hypothesis but it presents an argument for initiating screening among the gay male or MSM population.

Another area of interest in anal cancer is therapeutic vaccination, which would aim to improve cell-mediated immunity and thereby prevent the development of cancer. Similar approaches are being investigated in cervical cancer but vaccines are currently restricted to use in clinical trials.

Conclusion
There are a number of similarities between the disease process of anal and cervical cancer. Both have a latency period during which precancerous neoplasia can be detected from cytology samples. They also share an association with HPV and both are treated with chemoradiotherapy. Although successful screening programmes are under way for cervical cancer, the role of such measures among people at high risk of anal cancer and in particular those with HIV/Aids remains unproven. Research continues into improved therapy for anal cancer, with the role of HPV vaccines being examined in current trials.

Learning objectives
Each week Nursing Times publishes a guided learning article with reflection points to help you with your CPD. After reading the article you should be able to:

- Understand anal pathology and the presentation of anal cancer;

- Identify the role of human papilloma virus in precipitating anal cancer;

- Understand how HIV can increase risk of anal cancer;

- Explain the treatment and management strategies for anal cancer;

- Appreciate the potential role of screening in prevention of anal cancer.

Guided reflection
Use the following points to write a reflection for your PREP portfolio:

- Explain why you read this article and its relevance to your practice;

- Summarise the main points of the article;

- Identify a new piece of knowledge you learnt about anal cancer;

- Consider how you will use the article to develop your practice;

- Explain how you will follow up what you have learnt from this article.

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