Abstract

Squamous cell carcinoma of the anus (SCCA) is strongly associated with human papillomavirus (HPV) infection which represents the causative agent in 80%–85% of patients (usually from HPV16 or HPV18 subtypes in Europe) as is its precursor lesion anal intra-epithelial neoplasia (AIN) 3. Factors increasing the risk of HPV infection and/or modulating host response and the persistence of this infection appear to affect the epidemiology of this tumour. Anal intercourse and a high lifetime number of sexual partners increase the risk of persistent HPV infection in men and women, leading eventually to malignancy. Other important risk factors include human immunodeficiency virus (HIV), immune suppression in transplant recipients, use of immunosuppressants such as long-term corticosteroids, a history of other HPV-related cancers, autoimmune disorders, social deprivation and cigarette smoking. Cigarette smoking may also be important in the modulation/persistence of HPV infection and, hence, outcomes from treatment. Herpes simplex virus may play a secondary role in disease progression. Dietary habits, chronic inflammatory diseases and the presence of haemorrhoids do not appear to predispose to epidermoid anal cancer. Among men who have sex with men (MSM), the incidence of anal cancer is in the region of 35 per 100 000. In men who are HIV seropositive, the incidence increases to 75–135 per 100 000. The incidence is also higher among HIV seropositive women. Prolonged survival with highly active anti-retroviral treatment (HAART) is likely to lead to further increase in incidence among HIV-positive subjects. Epidermoid anal cancer is a rare disease accounting for 1%–2% of digestive tract tumours and 2%–4% of colon, rectal and anal tumours. The annual incidence is 1 in 100 000, is higher in women and is increasing [1.Jemal A. Simard E.P. Dorell C. et al.Annual Report to the Nation on the Status of Cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels.J Natl Cancer Inst. 2013; 105: 175-201Crossref PubMed Scopus (788) Google Scholar]. In Europe, ∼2000 males and ∼2300 females are diagnosed with anal cancer every year. Five-year survival has changed little in the last two decades. In the United States, the overall 5-year survival rates for 1994–2000 were 60% for men and 78% for women (SEER data). In Europe, 5-year survival varied between 66% (Central Europe) and 44% (Eastern Europe). SCCA commonly presents with bleeding; hence, diagnosis is often delayed because bleeding is attributed to haemorrhoids. SCCA may also present with any combination of a mass, non-healing ulcer, pain, bleeding, itching, discharge, faecal incontinence and fistulae. Not uncommonly lesions are palpated first by the patient. The diagnosis of anal cancer is made on biopsy-proven histology. Small, early cancers are sometimes diagnosed serendipitously following the removal of anal tags. More advanced lesions in the distal anal canal may extend on to the skin at the anal margin. Rarely patients present with inguinal lymphadenopathy. The existence of an identified viral aetiological agent and the ability to detect pre-neoplastic lesions may allow the development of screening and prevention programmes. Vaccination of girls against oncogenic HPV is now being recommended for the prevention of cervical cancer, and a recent report indicated that up to 80% of anal cancers could also be avoided with prophylactic quadrivalent HPV vaccine (against HPV types 6, 11, 16 and 18). But currently vaccination has no role when SCCA is actually present [2.Palefsky J.M. Giuliano A.R. Goldstone S. et al.HPV vaccine against anal HPV infection and anal intraepithelial neoplasia.N Engl J Med. 2011; 365: 1576-1585Crossref PubMed Scopus (664) Google Scholar]. Screening programmes using anal cytology and high-resolution anoscopy have been proposed for high-risk populations (MSM and HIV– women with a history of anal intercourse or other HPV-related anogenital malignancies) based on the achievements obtained in cervical cytology screening. However, no randomised control study has yet demonstrated the advantage of screening in these high-risk populations. Anal cancer may arise from a precursor dysplastic lesion—AIN—also known as anal squamous intra-epithelial lesions. The prevalence of AIN in the general population is low, but higher in 30%–40% of MSMs. Progression from AIN 1 and AIN 2 to AIN 3 is uncommon, as is progression from AIN 3 to invasive malignancy in immunocompetent patients, but appears more likely in immunosuppressed patients, and is influenced by HIV seropositivity, low CD4 count and serotype of HPV infection. HPV-associated tumours usually retain wild-type P53, and this explains why patients with HPV-associated tumours respond well to concurrent chemoradiotherapy. Data on the interaction with wild-type P53 in current or former cigarette smokers, as in head and neck cancer, are lacking. Both synchronous and metachronous HPV-related vaginal and cervical intra-epithelial and malignant squamous lesions are frequent and should be screened for in younger women. Histological confirmation is mandatory as other histologies are possible including adenocarcinoma, melanoma, gastrointestinal stromal tumours, poorly differentiated neuroendocrine tumours and lymphoma. Tumours of the anal margin are generally well differentiated and often occur in men, in contrast to canal tumours which are normally poorly differentiated and more common in women. Histological grading is subject to inter-observer variability, and considerable heterogeneity is seen in larger tumours. High-grade tumours have been thought to have a worse prognosis, but this has not been confirmed in multivariate analysis. Histological sub-classifications of basaloid, transitional, spheroidal and cloacogenic cell cancers have no additional confirmed bearing on management. Some authors report that a basaloid histological subtype has a higher risk of developing metastatic disease. The biology and prognosis of keratinising and non-keratinising tumours of the anal canal also appear to be similar. Verrucous carcinomas are a variant and are sometimes described as giant condylomas or Buschke–Lowenstein tumours, which may have a better prognosis than SCCA, for whom some consider surgery the best option. Lymph node involvement at diagnosis is observed in 30%–40% of cases while systemic spread is uncommon with distant extra-pelvic metastases recorded in 5%–8% at onset. The anal canal extends from the anorectal junction to the anal margin (see Figure 1). Useful palpable landmarks are the puborectal sling and the inter-sphincteric groove, respectively. The columnar, or cylindric, epithelium of the rectum extends to about 1 cm above the dentate line where the anal transitional zone begins. Below the dentate line, the epithelium is all squamous. The anal margin is the pigmented skin immediately surrounding the anal orifice, extending laterally to a radius of ∼5 cm. In practice, at diagnosis, the precise point of origin is often uncertain, and the distinction between anal canal and anal margin tumour is often difficult, if not impossible. Hence, some have classified into three distinct regions—i.e. intra-anal, perianal (visualised with gentle traction on the buttocks) and skin tumours (beyond a 5 cm radius from the anal opening). Proximally lymphatic drainage is to perirectal nodes along the inferior mesenteric artery. Immediately above the dentate line, drainage is to internal pudendal nodes, and to the internal iliac system. Infra-dentate and perianal skin drains to the inguinal, femoral and external iliac nodes. A relevant history is required to elicit symptoms, other relevant medical conditions, current medications and predisposing factors, which should be documented. Examination should include digital rectal examination (DRE) to examine the anal lesion and perirectal nodal involvement and, in women (particularly with low anteriorly placed tumours), a vaginal examination to determine the site and size of the primary tumour, vaginal/vaginal septal involvement, mucosal involvement and exophytic or ulcerative tumour or the presence of a fistula (Table 3). Vaginal involvement may require the prophylatic siting of a de-functioning stoma because of the risk of an anorectal-vaginal fistula. However, since only 50% of initial colostomies are reversed, this decision should be weighed carefully. Palpation of the inguinal nodes is important, particularly those superficial inguinal nodes, medial and close to the pubis. Proctoscopy by a specialist surgeon or radiation oncologist and, if painful, examination under anaesthesia (EUA) may be appropriate to facilitate biopsy (Table 3). It is also easier to determine anatomical relations to surrounding structures and to allow accurate clinical staging. It is advantageous if the treating radiation oncologist is present during this EUA to document precise measurements, as these are often critical for later target volume delineation in treatment planning. Colonoscopy is not required to assess pathology in the proximal bowel, because synchronous lesions are not reported for SCCA. With an indolent natural history and a low rate of distant metastases, anal cancer is usually amenable to locoregional treatment. Imaging should include magnetic resonance imaging (MRI) (Table 3) of the pelvis or, if not available, endo-anal ultrasound (EUS). Distant metastases can be assessed with computed tomography (CT) of the thorax and abdomen. MRI provides excellent contrast and spatial resolution, providing information on tumour size, local extent and spread, and invasion of adjacent organs and more accurate nodal involvement [3.Goh V. Gollub F.K. Liaw J. et al.Magnetic resonance imaging assessment of squamous cell carcinoma of the anal canal before and after chemoradiation: can MRI predict for eventual clinical outcome?.Int J Radiat Oncol Biol Phys. 2010; 78: 715-721Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Accurate assessment of tumour size and depth of mural invasion is possible with EUS, due to excellent spatial detail but is best reserved for small T1 lesions as the small field-of-view limits assessment of regional lymph nodes and infiltration of structures beyond the anal canal. Positron emission tomography (PET)/CT with [18F]fluorodeoxyglucose (FDG–PET/CT) has a high sensitivity in identifying involved lymph nodes, as the majority of anal carcinomas are FDG-avid. Several studies have shown that FDG–PET/CT can alter staging in ∼20% of cases, with a trend towards upstaging, and can alter treatment intent in ∼3%–5% of cases. The main impact of FDG–PET/CT on therapy stems from its high sensitivity in identifying involved lymph nodes and influencing radiation therapy planning by defining sites of metabolically active tumour. Therefore, FDG–PET has been recommended in the current USA National Comprehensive Cancer Network treatment recommendations. The tumour–node–metastasis (TNM) clinical staging system is based on accurate assessment of size (T stage), regional lymph node involvement (N) and metastatic spread (M). Nodal status is based on the distance from the primary site rather than the number of nodes involved, see Table 1. Nodal involvement of anal canal lesions differs from that of anal margin tumours.Table 1TNM staging. American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) seventh edition TNM clinical and pathological classification of anal cancerPrimary tumour (T) TXPrimary tumour cannot be assessed. T0No evidence of primary tumour. TisCarcinoma in situ (i.e. Bowen disease, high-grade squamous intra-epithelial lesion, and anal intra-epithelial neoplasia II–III.) T1Tumour ≤2 cm in greatest dimension. T2Tumour >2 cm but ≤5 cm in greatest dimension. T3Tumour >5 cm in greatest dimension. T4Tumour of any size invades adjacent organ(s), e.g. vagina, urethra, and bladder.Regional lymph nodes (N) NXRegional lymph nodes cannot be assessed. N0No regional lymph node metastasis. N1Metastases in perirectal lymph node(s). N2Metastases in unilateral internal iliac and/or inguinal lymph node(s). N3Metastases in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes.Distant metastasis (M) M0No distant metastasis. M1Distant metastasis.Anatomic stage/prognostic groups StageTNM 0TisN0M0 IT1N0M0 IIT2N0M0T3N0M0 IIIAT1N1M0T2N1M0T3N1M0T4N0M0 IIIBT4N1M0Any TN2M0Any TN3M0 IVAny TAny NM1In ref. [4.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook.7th edition. Springer, New York, NY2010Google Scholar], used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL, USA. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Open table in a new tab In ref. [4.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook.7th edition. Springer, New York, NY2010Google Scholar], used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL, USA. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Biopsy by needle aspiration biopsy is usually only carried out for clinically palpable inguinal nodes or those enlarged >10 mm on CT or MRI. Sentinel lymph node biopsy can reveal micrometastatic spread of disease, and may be more accurate than diagnostic imaging, but has not been properly evaluated. Squamous cell carcinoma antigen (SCCAg) is a serum tumour marker expressed by carcinomas of the anal canal, and may be related to tumour stage and/or nodal status, but its clinical utility in diagnosis and follow-up remains controversial. Anal cancers occur rarely, and factors influencing outcome and long-term survival have proved difficult to study with multivariate analysis. Several factors are relevant to initial decision-making (Table 2). The European Organisation for Research and Treatment of Cancer (EORTC)-22861 study demonstrated that skin ulceration, nodal involvement and male sex were independent variables associated with locoregional failure rate (LRF) and overall survival (OS) [5.Bartelink H. Roelofsen F. Eschwege F. et al.Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.J Clin Oncol. 1997; 15: 2040-2049Crossref PubMed Scopus (1006) Google Scholar]. The Radiation Therapy Oncology Group (RTOG) 9811 analysis supported the EORTC previously reported factors (clinically involved nodes and male sex), and also established tumour diameter >5 cm as an independent variable predicting disease-free survival (DFS) and OS. The ACT I analysis showed that palpable inguinal nodal status and gender are independently prognostic for OS, LRF and anal cancer death (ACD). In addition, after adjusting for sex and nodal status, presenting haemoglobin was a further prognostic factor for ACD. HIV testing is recommended in any patient with a lifestyle that puts them at risk of contracting HIV infections. Some argue that all patients with anal cancer should be screened for HIV [6.British HIV Association, British Association of Sexual Health and HIV, British Infection SocietyUK National Guidelines for HIV Testing 2008 www.bhiva.org/hivtesting2008.aspx (14 April 2014, date last accessed)Google Scholar].Table 2Factors to consider in treatment decision-making for anal cancerDisease-related factorsPatient-related factorsOtherClinical and radiological TNM stagePatient preferencesLocal expertise (brachytherapy etc.)Site of tumour (margin, canal, rectal)Biological age/renal function/Charlson geriatric assessmentGeriatricians with interest in oncologyExtent of tumour, i.e. involvement of vagina (risk of fistulation) in addition to sizeCo-morbidities/current medications and performance statusResponse to treatment (early and at 26 weeks)Socioeconomic and psychological factors/social supportNeed for symptom controlSeverity of initial symptomsSpecialist palliative careTNM, tumour–node–metastasis. Open table in a new tab TNM, tumour–node–metastasis. Before the widespread use of HAART, HIV-positive patients were considered to have enhanced toxicity from chemoradiation (CRT), particularly in patients with low CD4 counts 5 mm) can be obtained without compromising sphincter function [IV, C]. Local excision has not been shown to be efficacious for small tumours in the anal canal and is contra-indicated. Although more extensive and poorly differentiated lesions have a greater risk of being lymph node positive, it is important to do proper clinical and radiological staging also of smaller lesions in order to rule out the presence of positive nodes as this is a contra-indication to local excision. Piecemeal resections render assessment of resection margins in the specimen impossible and should not be carried out. In case of inadequate margins or R1 resection (occurs sometimes after a resection of 'anal tags' or 'haemorrhoids'), a further local excision may be considered after adequate staging, and clinical assessment provided R0 resection can be achieved. However, it is recommended that all patients having undergone a local resection, irrespective of resection margin, should be discussed by an appropriate multidisciplinary team (MDT) to facilitate decisions regarding re-excision or definitive CRT. Until the introduction of definitive CRT, abdomino-perineal excision (APE) was recommended for all other tumours (except those amenable to local excision). Primary APE was associated with local failure in up to half of cases, and 5-year survival rates in the region of 50%–70% were reported [IV, C]. Today, primary APE may be offered to patients previously irradiated in the pelvic region. Evidence supporting the effectiveness of CRT as a radical treatment has been provided by multiple phase II and case-series studies. Subsequent randomised trials have established the optimal regimen, although no individual randomised study has directly compared surgery versus CRT. Recommendations are based on the results of the phase II and six randomised phase III trials (EORTC 22861, UKCCCR ACT I, RTOG 87-04, RTOG 98-11, ACCORD-03, CRUK ACT II). 5-FU with MMC combined with radiotherapy are generally recommended, rather than 5-FU and cisplatin, MMC and cisplatin, any single drug or any combination of three drugs [I, A]. Stage I patients represent only 10%–15% in the majority of randomised CRT trials, hence application of overall data to T1 tumours is limited. However, for small tumours (T1), some investigators have used external beam radiotherapy alone, followed by a small volume boost either with photons, electrons or interstitial implantation. In contrast, early investigators [15.Nigro N.D. Vaitkevicius V.K. Considine Jr, B. Combined therapy for cancer of the anal canal: a preliminary report.Dis Colon Rectum. 1974; 17: 354-356Crossref PubMed Scopus (761) Google Scholar, 16.Cummings B.J. Keane T.J. O'Sullivan B. et al.Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C.Int J Radiat Oncol Biol Phys. 1991; 21: 1115-1125Abstract Full Text PDF PubMed Scopus (388) Google Scholar] reported that CRT, with the addition of MMC to 5-FU, demonstrated excellent local control in small tumours (50 Gy in patients with locally advanced anal cancer receiving combined modality therapy will improve the results—particularly in good responders. The second generation of randomised studies investigated the role of cisplatin as a replacement of MMC in combination with 5-FU and radiation. In these studies, cisplatin and FU were also used before or after CRT as neo-adjuvant or maintenance treatment, respectively. The results of these studies indicate that:(1)Cisplatin in combination with infused 5-FU and radiation does not improve either complete response rates or local control compared with MMC and does not reduce overall toxicity (but results in less myelotoxicity);(2)Neo-adjuvant chemotherapy before CRT has not improved either locoregional or distant control, and colostomy-free survival (CFS) is significantly worse [5.Bartelink H. Roelofsen F. Eschwege F. et al.Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.J Clin Oncol. 1997; 15: 2040-2049Crossref PubMed Scopus (1006) Google Scholar, 10.Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research.Lancet. 1996; 348: 1049-1054Abstract Full Text Full Text PDF PubMed Scopus (720) Google Scholar, 12.Ajani J.A. Winter K.A. Gunderson L.L. et al.Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.JAMA. 2008; 299: 1914-1921Crossref PubMed Scopus (625) Google Scholar]. More mature data suggest that local control and DFS are also worse [12.Ajani J.A. Winter K.A. Gunderson L.L. et al.Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.JAMA. 2008; 299: 1914-1921Crossref PubMed Scopus (625) Google Scholar]. Neo-adjuvant chemotherapy should not be given outside clinical trials [I].(3)Additional maintenance/consolidation chemotherapy following CRT has not impacted on local control, DFS or OS [11.Flam M. John M. Pajak T.F. et al.Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.J Clin Oncol. 1996; 14: 2527-2539Crossref PubMed Scopus (853) Google Scholar]. The 2-mont