Anal Cancer and Anal Intraepithelial Neoplasia (AIN)

Key Points ⚡

AIN is a premalignant dysplasia of anal and perineal epithelium driven by HPV infection; it can progress to anal cancer.
Anal cancer is rare (<1% of new UK cancers), but incidence is rising, especially in HIV-positive individuals and MSM.
HPV oncogenic strains (6, 11, 16, 18, 33) interfere with tumour suppressor proteins p53 and retinoblastoma via E5, E6, E7 proteins.
Risk factors: receptive anal intercourse, MSM, multiple partners, HIV, immunosuppression, smoking, prior cervical cancer.
Symptoms often absent; possible anal pain, bleeding, itching, mass, skin changes, incontinence, tenesmus.
Diagnosis requires examination under anaesthetic (EUA), biopsy, pelvic MRI, CT chest/abdomen/pelvis, PET scan, cervical screening (female), HIV testing.
Low-grade AIN may spontaneously resolve; high-grade requires topical, ablative, or surgical therapy; follow-up every 6 months for 5 years.
Anal cancer treated by MDT with chemoradiation (mitomycin + 5-FU), surgery if refractory; complications include incontinence, stenosis, marrow suppression, infertility.
Prognosis favourable with early detection: 1-year survival ~84%, 5-year ~57%; better in younger patients and females.

Introduction

AIN represents HPV-driven premalignant dysplasia of anal epithelium and may progress to anal cancer. Anal cancer is rare but preventable, requiring awareness of pathophysiology and treatment.

Epidemiology

<1% of UK cancers, incidence rising (1.4/100,000 in 1993 → 2.4/100,000 in 2017).
66% of cases in women, peak incidence 65-69 years.
High-risk: PLWH with receptive anal intercourse (HPV prevalence up to 87% men, 68% women).
HIV-infected patients have 20-40× higher risk and earlier onset.

Aetiology

Caused by HPV infection (non-enveloped dsDNA virus, Papillomaviridae family).
Oncogenic HPV strains (6, 11, 16, 18, 33) produce E5, E6, E7 proteins disrupting p53 and retinoblastoma tumour suppressors → dysplasia.
Anal dysplasia = AIN; progression parallels cervical intraepithelial neoplasia (CIN) leading to cancer.

Anatomy and Pathogenesis

Anal canal divided by pectinate (dentate) line into upper (transitional epithelium) and lower zones (squamous epithelium).
~90% anal cancers are squamous cell carcinomas at squamocolumnar junction.
Anal margin cancers spread to inguinal lymph nodes; proximal cancers spread to pelvic nodes.

Risk Factors

Sexual: receptive anal intercourse, MSM, multiple partners, high-risk sexual behaviors.
Immunosuppression: HIV infection, medical immunosuppression (e.g. transplant).
History: cervical cancer or cervical intraepithelial neoplasia, smoking.

Clinical Features

History

Often asymptomatic, ~20% anal cancers asymptomatic.
Symptoms: anal pain, bleeding, itching, palpable mass, skin changes, faecal incontinence, tenesmus.
Important history: HPV & vaccination, HIV status, sexual risk, immunosuppression, anal trauma, hemorrhoids, family colorectal cancer.

Examination

Visual inspection, inguinal lymph node palpation, digital rectal exam to assess mucosal abnormalities, sphincter tone, bowel function.
Females: vaginal and cervical exam to exclude spread or coexistent HPV disease.

Differential Diagnosis

Condition	Features
Haemorrhoids	Enlarged anal cushions, pain, bleeding
Rectal cancer	May not be palpable, requires colonoscopy
Anal fissure	Severe pain on defecation, bleeding
Anal fistula	Throbbing pain, pus/faecal discharge
Genital wart	HPV-related, usually painless
Pruritus ani	Dermatological itching

Investigations

EUA + biopsy with anoscopy for diagnosis and grading.
Imaging: pelvic MRI, CT chest/abdomen/pelvis, PET scan for staging.
Cervical screening in women, HIV testing in high-risk groups.
Lab: FBC, CRP, U&E, HIV serology.
Bedside: stool MC&S, rectal and cervical HPV swabs.
Ultrasound-guided lymph node biopsy if needed.

Diagnosis

AIN Staging

AIN1: dysplasia in lower 1/3 epithelium (low-grade).
AIN2: dysplasia in lower 2/3 epithelium (low-grade).
AIN3: full thickness dysplasia (high-grade).

Anal Cancer

TNM staging per AJCC and UICC guidelines.

Management

AIN

Low-grade: may observe as may regress.
High-grade: treat with topical agents (trichloroacetic acid, 5-FU), ablative therapies (infrared coagulation, electrocautery, laser), or surgery.
Follow-up: every 6 months with examination, anoscopy, biopsy for ≥5 years.

Anal Cancer

MDT approach involving colorectal surgeons, oncologists, radiologists, pathologists, nursing specialists.
Small anal margin tumours: wide local excision.
Standard: chemoradiation (mitomycin + 5-FU).
HIV-positive patients require tailored therapy based on immune status.
Advanced disease or CRT failure: abdominoperineal resection with permanent colostomy and possibly lymph node dissection.
Defunctioning stoma may be indicated for obstruction, pain, vaginal invasion.

Prevention

UK HPV vaccination for boys and girls (12-13 years) covers HPV 6, 11, 16, 18; soon to include 9-valent vaccine (additional types 33, 45, 52, 58).
Vaccination may reduce anal cancer incidence and recurrence of AIN.

Screening

Suggested in high-risk groups (HIV+, MSM, history of cervical cancer), though cost-effectiveness unclear and no formal guidelines exist.

Complications

From treatments: skin irritation, stenosis, sphincter dysfunction, leukopenia, thrombocytopenia, proctitis, cystitis, infertility, radiation-induced menopause.

Prognosis

Progression of AIN to cancer variable; high-grade AIN untreated may progress in 9-13% within 5 years.
Anal cancer: 1-year survival ~84%, 5-year survival ~57%. Better prognosis in younger and female patients.

References

Siddharthan RV et al. Anal intraepithelial neoplasia: diagnosis, screening, and treatment. Ann Gastroenterol, 2019.
Cancer Research UK. Anal cancer statistics.
Geh I et al. ACPGBI Guidelines for Anal Cancer, Colorectal Disease, 2017.
Krzowska-Firych J et al. HPV as an etiological factor in anal cancer. J Infect Public Health, 2019.
BMJ Best Practice. Anal Cancer – Aetiology.
Additional references as per source.