Anal cancer and anal intraepithelial neoplasia

• Anal cancer is a rare gastrointestinal cancer, dominated by squamous cell carcinoma of the anal canal, which is driven by human papillomavirus (HPV) in roughly four out of five cases.
• It is rising in incidence and is much more common in people living with HIV, in men who have sex with men, in immunosuppressed patients, and in people with other HPV-related disease.
• A precursor, anal high-grade squamous intraepithelial lesion (HSIL), can be detected by anal cytology and high-resolution anoscopy and, in the ANCHOR trial, treating it cut progression to invasive cancer by 57% in people living with HIV aged 35 and over.
• Locoregional disease is cured without removing the anus in most patients by chemoradiotherapy (5-fluorouracil plus mitomycin C with radiation), which is the historic Nigro protocol and still the standard.
• Advanced disease is treated with carboplatin plus paclitaxel; metastatic or refractory disease may respond to immune checkpoint inhibitors; persistent disease after chemoradiotherapy is treated with abdominoperineal resection as salvage.

By the end of this page you should be able to:

1. Explain the link between HPV, HIV and anal cancer, and name the groups at high risk.
2. Describe how anal squamous cell carcinoma spreads and how it presents.
3. Work through the differential diagnosis of anorectal bleeding, pain or a mass.
4. Stage anal cancer with the TNM system and choose the right imaging.
5. Apply the treatment algorithm: local excision, chemoradiotherapy, salvage surgery, and systemic therapy.
6. Outline a screening and follow-up programme for high-risk patients, including what the ANCHOR trial showed.

Anal canal versus anal margin. The anal canal runs from the anorectal ring to the anal verge. The anal margin (perianal skin) is the pigmented skin bordering the anal opening and extends laterally to a radius of about 5 cm. The two sites share diagnostic tests but are treated differently: tiny, truly superficial tumours on the margin may be suitable for local excision, whereas canal tumours are almost always treated with chemoradiotherapy. ^[3]

Anal intraepithelial neoplasia (AIN). The precursor lesion is graded under the Lower Anogenital Squamous Terminology (LAST) system as low-grade (LSIL) or high-grade (HSIL) squamous intraepithelial lesion. HSIL, which corresponds to AIN2 (when p16-positive) and AIN3, is the lesion that precedes invasive cancer. Reporting of "AIN 1/2/3" is still common and is equivalent to LSIL/HSIL.

Histological types. Squamous cell carcinoma and its variants (basaloid, cloacogenic) account for most cases. HPV-associated tumours often show strong, diffuse p16 staining and carry the HPV16 genotype. HPV-negative tumours are more often associated with TP53 mutations and are generally harder to treat.

Anal cancer is rare but rising. Worldwide, about 54,306 new cases of anal squamous cell carcinoma were estimated for 2022 ^[3]. It accounts for about 2% of all gastrointestinal neoplasms, with incidence rates of 0.7 to 1.7 per 100,000 per year in several Western countries ^[3]. In the United States it represents only 0.5% of new cancer diagnoses annually ^[2]. Its incidence rose by about 2.7% per year between 2001 and 2015 ^[1][3]. The cancer is more common in women and increases with age ^[3].

Stage at diagnosis, from one large case series: about 48% of tumours are still localised, 32% show regional nodal spread and 13% present with distant metastases ^[1].

HPV is the principal cause. HPV is found in 80 to 85% of anal squamous cell carcinomas, most often HPV16 ^[3], and up to 91% of cases have been attributed to HPV in some series, again with HPV16 dominant ^[2]. HPV-negative tumours are more often associated with TP53 and CDKN2A mutations and tend to be treatment-refractory ^[2].

HIV is the strongest population-level risk amplifier. People living with HIV have a markedly raised risk of anal cancer, which is why anal screening is directed at them ^[4]. The risk rises as CD4 counts fall, and immunosuppression from any cause (solid organ transplant, autoimmune disease) also matters ^[3].

Other risk factors ^[3]:

• Men who have sex with men, and women with HPV-related gynaecological neoplasia or precancerous lesions.
• Older age, female sex, smoking.
• Anal intercourse and multiple sexual partners.
• Previous pelvic radiotherapy.

HPV vaccination is the primary preventive measure ^[3]. It prevents the acquisition of the relevant HPV types and therefore the development of anal HSIL in young people, including young people living with HIV ^[4].

Most anal cancers follow a sequence familiar from the cervix: anal infection with a high-risk HPV genotype, persistent infection, squamous intraepithelial lesion, HSIL, and finally invasive carcinoma. High CD8-positive tumour-infiltrating lymphocytes and PD-L1 expression associate with better outcomes, while immune suppression allows lesions to progress ^[2].

Locally, the tumour invades through the sphincter complex into adjacent organs (vagina, urethra, bladder) and spreads to the mesorectal, inguinal, internal iliac and obturator nodes. Distant metastases most often involve the liver, lungs and non-regional lymph nodes ^[3]. A larger tumour and greater nodal involvement are linked to worse locoregional control and overall survival ^[3].

Gross and microscopic. The tumour is usually a firm, warty or ulcerated mass in the anal canal or on the margin. Microscopically it is a squamous cell carcinoma, sometimes with basaloid features. HSIL shows loss of maturation, nuclear atypia and a high proliferative rate in the lower two-thirds of the epithelium, with HPV effect.

Biomarkers. Diffuse p16 staining marks HPV-driven disease. HPV16-positive, p16-positive tumours carry the best prognosis and respond best to chemoradiotherapy ^[3].

Symptoms are non-specific and overlap with benign anorectal disease, which explains why diagnosis is often delayed. Common symptoms are anorectal bleeding (often bright red, after a bowel action), an anal lump, pain or discomfort, pruritus, discharge, and a change in bowel habit. A palpable inguinal node or pelvic pain suggests nodal spread ^[3].

Signs. Inspection may show a warty, ulcerated or fungating lesion at the verge or protruding from the canal. Palpation (carefully) assesses size, fixity to the sphincter and posterior vaginal wall, and inguinal nodes. A digital rectal examination (DRE) and, where available, high-resolution anoscopy are essential ^[3].

Red flags that demand biopsy rather than reassurance:

• Bleeding with a palpable or visible mass.
• A lesion that persists or enlarges despite reassurance or simple treatment.
• Hard, fixed inguinal nodes.
• Pain with defaecation in someone at high risk (HIV, MSM, previous HSIL).

Tissue diagnosis comes first. Any suspicious lesion is biopsied, ideally under direct vision; anoscopy or proctoscopy guides sampling of small lesions ^[3]. HIV testing should be offered where status is unknown ^[3].

Imaging for staging ^[3]:

• Pelvic MRI (with gadolinium, and diffusion-weighted imaging) is the preferred local modality: it shows tumour size, invasion of adjacent structures and pelvic nodal disease, all needed for T and N staging.
• Chest and abdominal CT (and pelvis) detect distant disease and locoregional nodes.
• PET-CT assists in staging and in radiotherapy planning, but should not replace conventional CT; it can guide assessment of metabolic response.
• Endoanal ultrasound is not recommended in the NCCN guidelines and is optional in the ESMO guidelines ^[2][5].

Staging is mandatory before treatment, and the case should be discussed by a multidisciplinary team ^[3].

T stage is measured by the greatest tumour diameter; nodal status separates N1a, N1b and N1c, a change from earlier editions ^[3].

There are no universally agreed methods or intervals for anal cancer screening, but high-risk groups are screened with cytology as the usual first test, followed by high-resolution anoscopy and biopsy ^[2]. The groups that warrant screening are people living with HIV (especially men who have sex with men), women with HPV-related gynaecological disease, transplant recipients and other immunosuppressed patients, and men who have sex with men regardless of HIV status ^[2][3].

The ANCHOR trial is the pivotal study ^[4]. It randomised 4,459 people living with HIV aged 35 and over with biopsy-proven anal HSIL (AIN3, or p16-positive AIN2) to immediate treatment of the lesion or active monitoring. Treatment (mostly office-based electrocautery, but also infrared coagulation, excision, topical imiquimod or 5-fluorouracil) was continued until HSIL resolved. Over a median of 25.8 months:

• Invasive anal cancer developed in 9 participants in the treatment group (173 per 100,000 person-years) versus 21 in the monitoring group (402 per 100,000 person-years). ^[4]
• Treatment reduced the rate of progression to cancer by 57% (95% confidence interval 6 to 80; p = 0.03). ^[4]
• Cumulative incidence of cancer at 48 months was 0.9% versus 1.8%. ^[4]

The trial supports screening and treatment of HSIL as standard care for people living with HIV aged 35 and over, with high-resolution anoscopy at least every 6 months, and may also be relevant to other high-risk groups, although results may not generalise to less experienced operators ^[4].

Practical screening flow.

HPV genotyping of a lesion is recommended ^[3].

Local excision of an early anal-canal tumour is generally not recommended, because clearance is usually incomplete and the combination of surgery plus chemoradiotherapy adds morbidity ^[3]. A superficially invasive squamous cell carcinoma or a small T1 tumour of the anal margin is the exception: excision with more than 1 mm histological clearance can be used, reserving chemoradiotherapy for high-risk pathology (positive margin, poor differentiation, advanced stage) ^[3].

Chemoradiotherapy is standard for stage I-III anal canal tumours and gives the best anal preservation. The backbone is the Nigro protocol, now half a century old and still standard: concurrent chemotherapy with 5-fluorouracil and mitomycin C delivered with radiotherapy ^[2].

Chemotherapy schedule (SEOM recommendation) ^[3]:

• 5-fluorouracil 1000 mg per m2 on days 1 to 4 and 29 to 32. ^[3]
• Mitomycin C either 12 mg per m2 on day 1, or 10 mg per m2 on days 1 and 29. ^[3]
• Radiotherapy to a total of 50.4 Gy, or 55 to 59 Gy in locally advanced disease. ^[3]

Alternatives:

• Capecitabine (825 mg per m2 twice daily on radiotherapy days) can replace infusional 5-fluorouracil with similar overall high-grade toxicity but less haematological toxicity ^[3].
• Mitomycin C plus 5-fluorouracil, or mitomycin C plus capecitabine, are both regarded as first-line chemoradiotherapy backbones ^[2].
• Cisplatin combined with 5-fluorouracil is not better than mitomycin-based chemoradiotherapy; the Intergroup and ACT II comparisons did not show superiority of cisplatin, and RTOG 98-11 favoured the mitomycin arm for disease-free survival ^[2][3].

Radiotherapy. Intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) is preferred over 3D-conformal radiotherapy because of less acute toxicity and fewer treatment interruptions ^[2][3]. Typical doses are 45 to 50 Gy for T1-T2 N0 disease, rising to 55-60 Gy for T3-T4 or node-positive disease ^[3]. Treatment gaps should be avoided because interruptions compromise locoregional control ^[3]. Plans cover the primary tumour, the anal canal, pelvic and inguinal nodes.

Response assessment. Tumour regression can continue for up to 6 months after treatment, so initial response is assessed from about 3 months, with careful digital rectal examination and imaging; up to 6 months may pass before calling persistent disease ^[2]. Suspicious persistent lesions are biopsied and restaged with CT (and MRI where needed) ^[2].

Persistent or recurrent disease after chemoradiotherapy is treated with abdominoperineal resection with permanent colostomy ^[2][3]. Salvage surgery carries a 5-year overall survival of 30 to 60% ^[3]. Isolated inguinal nodal recurrence may be treated with chemoradiotherapy, or with inguinal node dissection if the groin has already been irradiated ^[3].

Roughly 10 to 20% of patients develop extrapelvic recurrence, most often in the liver, lungs or lymph nodes, and about 10% have metastatic disease at diagnosis ^[2][3].

• First line: carboplatin (AUC 5 on day 1, every 28 days) plus paclitaxel (80 mg per m2 on days 1, 8 and 15), preferred over cisplatin and 5-fluorouracil on the basis of the InterAACT randomised phase II trial (median survival 20 versus 12.3 months, p = 0.014) ^[2][3].
• Alternatives: modified docetaxel, cisplatin and 5-fluorouracil (mDCF), 5-fluorouracil-based doublets, or FOLFCIS ^[2][3].
• Retifanlimab plus carboplatin-paclitaxel (POD1UM-303) improved progression-free survival (9.3 versus 7.4 months) and may become the new standard; results from ECOG-ACRIN 2176 (nivolumab with carboplatin and paclitaxel) are pending ^[3].
• Second line: immune checkpoint inhibitors — nivolumab or pembrolizumab — for refractory metastatic disease, with response rates around 11 to 24% and median survival of about 11 to 12 months ^[2][3].
• Oligometastatic liver disease may be considered for resection or ablation ^[3].

People living with HIV need particular care: antiretroviral therapy must be continued, with collaboration between oncology and infectious disease teams; CD4 counts are monitored, as low counts raise the risk of complications and reduce tolerance; and standard doses are usually given when HIV is well controlled ^[3]. Such patients have generally been included in trials when HIV was controlled ^[3].

More than half of cases occur in patients aged 65 or older (54%), and 5-year survival is lower than in younger patients (56% versus 68%) ^[3]. Fit older patients should receive radical chemoradiotherapy after a geriatric assessment; frail patients may be offered radiotherapy alone or reduced-intensity treatment, although dose reduction may compromise outcome ^[3].

Response is declared slowly. Clinical re-evaluation (digital rectal examination and palpation of inguinal nodes, with pelvic imaging) begins at about 3 months and continues for up to 6 months before calling persistent disease ^[2][3]. For patients who achieve a clinical complete response, examination is repeated every 3 to 6 months for 2 years, then every 6 to 12 months until 5 years have passed; annual chest, abdominal and pelvic CT is recommended for the first 3 years in patients who presented with stage II to III disease, while annual pelvic MRI in the first year is optional ^[3]. Fewer than 1% of relapses occur after 3 years ^[3]. PET-CT is not recommended during routine follow-up because radiotherapy-induced inflammation gives false positives ^[3].

• Treatment-related: acute grade 3-4 gastrointestinal, haematological, skin and genitourinary toxicity; long-term anorectal and sexual dysfunction; radiation fibrosis.
• Oncological: locoregional failure, distant metastases, stoma in 10 to 20% of patients before treatment ^[3].
• Salvage: high morbidity after abdominoperineal resection.

Prognosis is governed by stage: bulkier T3-T4 tumours with nodal involvement carry the worst locoregional control and survival ^[3]. HPV-driven (p16-positive) tumours respond best to chemoradiotherapy and carry a better prognosis than HPV-negative disease ^[2][3]. Relapses are uncommon after 3 years of follow-up, which is why prolonged surveillance beyond that is not routinely recommended ^[3].

• HPV vaccination for young people, including young people living with HIV, prevents the precursor lesions that lead to cancer ^[4].
• Cytology-based screening with high-resolution anoscopy is directed at high-risk groups and, in the ANCHOR trial, treating HSIL reduced progression to cancer by 57% in people living with HIV aged 35 and over ^[4].

• Pregnancy. Data are limited; decisions should be taken by a multidisciplinary team of obstetric, infectious disease and oncology specialists.
• Immunocompromised and transplant recipients. Higher risk, possibly faster progression; coordinate with their transplant or HIV team ^[3].

• Biopsy is the single essential step: any persistent or atypical lesion must be sampled; clinical diagnosis alone is unsafe.
• Where pelvic MRI is unavailable, physical examination with staging CT and careful digital rectal examination still allow sensible treatment decisions.
• Chemoradiotherapy needs a centre with radiotherapy capability; where this is absent, refer early, because outcomes with surgery performed alone are inferior.
• High-resolution anoscopy and trained operators may not be available; in that case, a careful annual examination of high-risk patients and prompt biopsy of abnormalities is the realistic fallback.

• Anal cancer is a rare but rising squamous cancer, driven by HPV in 80 to 85% of cases.
• HIV, MSM, transplant recipients, women with HPV-related gynaecological disease and smokers are at high risk.
• About 48% of tumours are localised at diagnosis, 32% regionally node-positive and 13% metastatic.
• Presentation is non-specific and mimics benign anorectal disease, so any persistent lesion needs a biopsy.
• Pelvic MRI and chest/abdominal CT are the staging investigations; PET-CT is optional; endoanal ultrasound is not routinely used.
• Pre-invasive HSIL is the target for screening; in the ANCHOR trial treating HSIL reduced progression to cancer by 57% in people living with HIV aged 35 and over.
• Chemoradiotherapy with 5-fluorouracil (or capecitabine) and mitomycin C is standard for locoregional disease, using 45-60 Gy of IMRT.
• Tumour response may take up to 6 months to declare; persistent disease is treated with salvage abdominoperineal resection. ^[2]
• Metastatic disease is treated first line with carboplatin plus paclitaxel; checkpoint inhibitors are second line. ^[2]
• HPV vaccination is primary prevention and should be offered to all eligible young people, including young people living with HIV.
• NCCN (version 3.2026) and ESMO (2021) and SEOM-GEMCAD-TTD (2025) guidelines differ in detail, for example in their recommendations on endoanal ultrasound and on the place of biopsy during follow-up; local protocol governs. ^[6]

Gastrointestinal cancers overview; colorectal cancer; HPV infection and vaccination; HIV infection; lower gastrointestinal bleeding; rectal cancer.