Anal cancer is a malignant tumour arising from the anal canal or perianal region. Although relatively uncommon compared with colorectal cancers, its incidence has increased globally, particularly among populations with human papillomavirus (HPV) infection and immunosuppression. The majority of anal cancers are squamous cell carcinomas (SCC), accounting for approximately 80–90% of cases. Other less common histological types include adenocarcinoma, basal cell carcinoma, melanoma, and neuroendocrine tumours.

Anal cancer is distinct from rectal cancer in terms of its risk factors, biology, and treatment. Unlike rectal cancer, the primary treatment for most anal squamous cell carcinomas is combined chemoradiotherapy, which can achieve cure while preserving anal sphincter function. Surgery is generally reserved for persistent, recurrent, or selected resectable disease.

Epidemiology

Anal cancer is a relatively rare gastrointestinal malignancy.

Epidemiological characteristics include:

• Squamous cell carcinoma accounts for approximately 80–90% of cases.

• Incidence increases with age.

• More common among individuals with HPV infection.

• Increased prevalence in patients with HIV infection and immunosuppression.

• Higher incidence among individuals with a history of receptive anal intercourse.

• Rising incidence has been associated with increasing HPV prevalence.

In regions with high HIV prevalence, anal cancer represents an important emerging malignancy.

Risk factors

1. Human papillomavirus (HPV) infection

Persistent infection with high-risk HPV types, particularly HPV-16 and HPV-18, is the most important risk factor.

2. Human immunodeficiency virus (HIV) infection

HIV infection increases the risk of:

• Persistent HPV infection.

• Anal intraepithelial neoplasia.

• Anal squamous cell carcinoma.

3. Immunosuppression

Including:

• Organ transplant recipients.

• Long-term immunosuppressive therapy.

4. Smoking

Tobacco use contributes to HPV persistence and carcinogenesis.

5. Sexual behaviour

Risk is increased by:

• Multiple sexual partners.

• Receptive anal intercourse.

• History of sexually transmitted infections.

6. Previous HPV-related malignancies

Including:

• Cervical cancer.

• Vulvar cancer.

• Vaginal cancer.

• Penile cancer.

7. Chronic anal inflammation

Examples include:

• Chronic fistulae.

• Persistent anal ulcers.

• Chronic inflammatory conditions.

Pathophysiology

Most anal cancers develop from anal intraepithelial neoplasia (AIN) caused by persistent infection with oncogenic HPV.

The progression typically follows:

1. HPV infection.

2. Persistent viral infection.

3. Anal intraepithelial neoplasia.

4. High-grade dysplasia.

5. Invasive squamous cell carcinoma.

HPV oncogenes promote malignant transformation through:

• Inactivation of tumour suppressor proteins.

• Disruption of normal cell-cycle regulation.

• Increased cellular proliferation.

Tumour spread occurs through:

• Direct local invasion.

• Lymphatic spread.

• Hematogenous dissemination.

Regional lymphatic spread commonly involves:

• Perirectal nodes.

• Internal iliac nodes.

• Inguinal lymph nodes.

Clinical presentation

Patients may present with symptoms that resemble benign anorectal conditions, leading to delayed diagnosis.

Clinical manifestations depend on:

• Tumour size.

• Tumour location.

• Local invasion.

• Presence of metastases.

Symptoms

Local anorectal symptoms

• Rectal bleeding.

• Anal pain.

• Anal discomfort.

• Persistent anal itching (pruritus ani).

• Anal discharge.

Bowel-related symptoms

• Change in bowel habits.

• Constipation.

• Tenesmus.

• Sense of incomplete evacuation.

Mass-related symptoms

• Sensation of an anal lump.

• Difficulty with defecation.

• Obstructive symptoms.

Constitutional symptoms

• Weight loss.

• Fatigue.

• Reduced appetite.

Symptoms of advanced disease

• Pelvic pain.

• Groin swelling from lymph node involvement.

• Symptoms related to distant metastases.

Clinical signs

General findings

• Weight loss.

• Cachexia.

• Poor performance status.

Local anorectal findings

• Anal mass.

• Ulcerative lesion.

• Indurated lesion.

• Bleeding lesion.

Digital rectal examination findings

May reveal:

• Irregular anal canal mass.

• Ulceration.

• Circumferential lesion.

• Sphincter involvement.

• Fixation to surrounding tissues.

Lymph node findings

• Enlarged inguinal lymph nodes.

• Pelvic lymphadenopathy.

Signs of advanced disease

• Pelvic mass.

• Fistula formation.

• Features of metastatic disease.

Differential diagnosis

Differential diagnoses include:

• Hemorrhoids.

• Anal fissure.

• Perianal abscess.

• Anal fistula.

• Rectal cancer.

• Anal condyloma (anogenital warts).

• Crohn’s disease.

• Tuberculosis of the anorectal region.

• Anal melanoma.

Diagnostic criteria

Anal cancer should be suspected in patients presenting with:

• Persistent rectal bleeding.

• Anal pain.

• Anal mass.

• Persistent anal ulceration.

• Enlarged inguinal lymph nodes.

• Persistent anorectal symptoms not responding to standard treatment.

Definitive diagnosis requires:

• Clinical examination including digital rectal examination.

• Endoscopic assessment.

• Histological confirmation from biopsy.

Investigations

Laboratory investigations

Full blood count (FBC)

Used to assess:

• Anaemia.

• Baseline treatment status.

Renal function tests (RFTs)

Includes:

• Urea.

• Creatinine.

Liver function tests (LFTs)

Assess:

• Hepatic function.

• Potential metastatic involvement.

HIV testing and CD4 count

Important because:

• HIV infection is strongly associated with anal cancer.

• Results influence treatment planning and prognosis.

Imaging investigations

Chest X-ray (CXR)

Used to evaluate pulmonary metastases.

Abdominal and pelvic ultrasound

Useful for:

• Assessment of abdominal organs.

• Detection of metastatic disease.

CT scan of abdomen and pelvis

Used for:

• Local staging.

• Evaluation of lymph node involvement.

• Detection of distant metastases.

Endoscopic investigations

Sigmoidoscopy

Allows visualization of distal colorectal lesions.

Colonoscopy

Useful for:

• Excluding synchronous colorectal pathology.

• Obtaining tissue diagnosis when required.

Clinical examination

Digital rectal examination (DRE)

An essential component of assessment.

Evaluates:

• Tumour size.

• Tumour location.

• Mobility.

• Sphincter involvement.

Histopathology

Biopsy confirms:

• Histological subtype.

• Tumour differentiation.

• Presence of invasive malignancy.

Staging

Anal cancer is staged using the TNM staging system.

T – Primary tumour

Based on:

• Tumour size.

• Extent of local invasion.

N – Regional lymph nodes

Based on involvement of:

• Perirectal nodes.

• Internal iliac nodes.

• Inguinal nodes.

M – Distant metastases

Assessment for spread to:

• Liver.

• Lung.

• Bone.

• Other distant sites.

Management

Management should involve a multidisciplinary team including:

• Colorectal surgeons.

• Medical oncologists.

• Radiation oncologists.

• Pathologists.

• HIV specialists when appropriate.

Management pathway:

1. Confirm diagnosis by biopsy.

2. Stage disease.

3. Assess performance status.

4. Determine resectability.

5. Administer curative or palliative treatment.

6. Conduct long-term surveillance.

Non-pharmacological treatment

Surgical treatment

Abdominoperineal resection (APR)

Indicated for:

• Selected resectable disease.

• Residual disease after chemoradiotherapy.

• Persistent or recurrent tumours.

Procedure involves:

• Removal of anus.

• Removal of rectum.

• Permanent colostomy formation.

Radiotherapy

Radiotherapy is an essential component of treatment.

Adjuvant radiotherapy

For resectable disease:

• 45–50 Gy following surgery.

Neoadjuvant radiotherapy

For unresectable but operable disease:

• 45–50 Gy before surgery.

Palliative radiotherapy

Indicated for:

• Inoperable disease.

• Poor performance status.

• Symptom control.

Supportive care

Includes:

• Nutritional support.

• Pain management.

• Stoma care.

• Psychosocial support.

• HIV management where applicable.

Pharmacological treatment

Concurrent chemoradiotherapy

Regimen 1

Mitomycin C – 10 mg/m² – intravenous bolus – day 1 and day 29AND5-Fluorouracil (5-FU) – 1000 mg/m² – continuous intravenous infusion – day 1–4 and day 29–32 (using infusion pump)

Administered concurrently with radiotherapy.

Alternative regimen

Capecitabine – 825 mg/m² – oral – every 12 hours during radiotherapy (5 days per week)AND5-Fluorouracil (5-FU) – 1000 mg/m² – continuous intravenous infusion – day 1–4 and day 29–32 (using infusion pump)

Administered concurrently with radiotherapy.

Management of metastatic disease

Regimen 1 (FOLFOX-based)

Oxaliplatin – 85 mg/m² – intravenous infusion over 2 hours – day 1ANDLeucovorin – 400 mg/m² – intravenous infusion over 20 minutes – day 1AND5-Fluorouracil – 400 mg/m² – intravenous bolus – day 1

followed by:

5-Fluorouracil – 1200 mg/m²/day – continuous intravenous infusion – days 1–2

Frequency:

• Every 14 days.

Duration:

• 6–12 cycles.

May be administered with:

Bevacizumab – 5 mg/kg – intravenous infusion over 1 hour – day 1

OR

Cetuximab – 500 mg/m² – intravenous infusion over 2 hours – day 1

Regimen 2 (CAPEOX)

Oxaliplatin – 130 mg/m² – intravenous infusion over 2 hours – day 1ANDCapecitabine – 1000 mg/m² – oral – every 12 hours – day 1 to day 14

Frequency:

• Every 21 days.

Duration:

• 4–8 cycles.

May be combined with:

Bevacizumab – 5 mg/kg – intravenous infusion over 1 hour – day 1

Regimen 3

Capecitabine – 1000 mg/m² – oral – every 12 hours – day 1 to day 14

Frequency:

• Every 21 days.

Duration:

• 6 cycles.

Management according to underlying cause

Resectable disease with good performance status

Management:

1. Abdominoperineal resection (APR).

2. Adjuvant chemoradiotherapy (45–50 Gy).

3. Follow-up surveillance.

Unresectable disease with good performance status

Management:

1. Neoadjuvant chemoradiotherapy (45–50 Gy).

2. Reassessment of tumour response.

3. Surgical resection (APR) if resectable.

Inoperable disease or poor performance status

Management:

• Palliative radiotherapy.

• Symptom control.

• Palliative systemic therapy where appropriate.

• Supportive care.

Metastatic disease

Management:

• Systemic chemotherapy.

• Targeted therapy where indicated.

• Palliative radiotherapy.

• Best supportive care.

Referral

All patients with suspected or confirmed anal cancer should be referred to specialized oncology centres.

Urgent referral indications

• Rapidly enlarging anal mass.

• Significant rectal bleeding.

• Severe anal pain.

• Obstructive symptoms.

• Enlarged inguinal lymph nodes.

• Suspected metastatic disease.

• HIV-positive patients with suspicious anal lesions.

Complications

Disease-related complications

• Intestinal obstruction.

• Severe bleeding.

• Fistula formation.

• Local tissue destruction.

• Lymphatic obstruction.

• Metastatic disease.

Treatment-related complications

Surgery

• Wound infection.

• Colostomy complications.

• Perineal wound breakdown.

Chemotherapy

• Myelosuppression.

• Mucositis.

• Diarrhoea.

• Nausea and vomiting.

Radiotherapy

• Radiation dermatitis.

• Radiation proctitis.

• Radiation cystitis.

• Pelvic fibrosis.

Prognosis

Prognosis depends on:

• TNM stage.

• Tumour size.

• Nodal involvement.

• Presence of distant metastases.

• Response to chemoradiotherapy.

• HIV status and immune function.

Early-stage disease treated with definitive chemoradiotherapy has favourable outcomes. Advanced disease with nodal involvement or distant metastases is associated with reduced survival.

Prevention

Preventive measures include:HPV prevention

• HPV vaccination.

• Safe sexual practices.

• Early treatment of HPV-associated lesions.

HIV prevention and control

• HIV prevention programmes.

• Early HIV diagnosis.

• Antiretroviral therapy adherence.

Lifestyle modification

• Smoking cessation.

• Limiting alcohol consumption.

• Maintaining healthy body weight.

Screening of high-risk populations

Particularly among:

• HIV-positive individuals.

• Patients with prior HPV-related malignancies.

• Immunosuppressed patients.