Anal cancer

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Anal cancer usually arises at the squamocolumnar transition through persistent high-risk HPV. Incidence is increased by HIV, transplant immune suppression, smoking and previous HPV-related lower-genital-tract disease. Symptoms overlap benign anorectal conditions: bleeding may be scant, and pain or a small ulcer can be repeatedly labelled fissure or haemorrhoid. Examination must include the perianal skin, canal, rectum and both groins.

Biopsy confirms histology and distinguishes canal squamous carcinoma from rectal-type adenocarcinoma, melanoma and skin tumours. Examination under anaesthesia permits safe mapping when pain or stenosis prevents clinic assessment. Pelvic MRI defines size, sphincters, adjacent organs and nodes. CT stages distant sites, while PET-CT can reveal involved inguinal or pelvic nodes for radiation planning. Suspicious groin nodes should be sampled because reactive HPV or skin inflammation can also enlarge them.

Definitive chemoradiotherapy is the organ-preserving standard for most localised anal SCC. Mitomycin and capecitabine or infusional fluorouracil sensitise tumour during pelvic and inguinal radiation. Surgery is reserved for selected small margin lesions and salvage of proven local failure. Response is deliberately assessed over time: radiation oedema and ulceration can persist, while viable tumour may continue to regress until about 26 weeks from treatment start.

Support makes curative treatment deliverable. Radiation dermatitis around perineum can become exquisitely painful; diarrhoea, cystitis, cytopenia and dehydration are common. Specialist skin care, analgesia, stool management, dietetics and treatment review are needed throughout. Later, patients need continence, pelvic-floor, vaginal dilator, sexual, menopause, fertility, bone and lymphoedema support. HIV care maintains virological control and checks chemotherapy and antiretroviral interactions.

Key points

Most anal canal cancers are HPV-associated squamous-cell carcinomas and are biologically and therapeutically distinct from low rectal adenocarcinoma.
Persistent bleeding, pain, ulcer, lump, discharge, pruritus or continence change requires inspection, digital rectal examination and inguinal-node palpation; haemorrhoids do not close the differential.
The diagnostic reference standard is adequate biopsy, often during examination under anaesthesia, while preserving sphincter anatomy and avoiding an uncontrolled excision that compromises later treatment.
Stage with high-resolution MRI pelvis and contrast CT chest and abdomen; PET-CT is useful for nodal clarification and radiotherapy planning but does not replace biopsy of a decisive atypical lesion.
Sample a suspicious inguinal node by ultrasound-guided FNA or core because confirmation changes stage and the radiation field.
Test HIV status with consent and assess other immunosuppression and anogenital HPV disease; effective antiretroviral therapy continues through cancer treatment with interaction review.
First-line curative treatment for most non-metastatic anal canal SCC is definitive chemoradiotherapy with mitomycin and fluoropyrimidine, preserving the anus and sphincters.
A small well-differentiated anal-margin cancer that can be excised with adequate margins without sphincter damage may undergo local excision; this exception should not be applied to typical canal disease.
Tumour regression can continue for approximately 6 months after chemoradiation. A shrinking residual lesion without progression is observed through the protocol response window rather than biopsied or operated on prematurely.
Persistent or recurrent local cancer is confirmed with biopsy and considered for salvage abdominoperineal excision in a specialist pelvic cancer centre.
Metastatic treatment commonly begins with carboplatin–paclitaxel in a fit patient, with later immune or other systemic options chosen from current approvals and prior treatment.
Proactive skin, bowel, urinary, analgesic, nutritional and sexual support helps patients complete uninterrupted radiotherapy and reduces avoidable late dysfunction.
HPV vaccination and cervical and other anogenital screening prevent related disease but do not replace assessment of a current anal symptom.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Persistent high-risk HPV

Oncogenic HPV, especially type 16, drives most anal squamous cancers through viral E6 and E7 disruption of p53 and retinoblastoma control.

Immunosuppression

HIV, solid-organ transplantation and long-term immune suppression reduce HPV clearance and increase anal intraepithelial neoplasia and cancer risk.

Tobacco and related HPV disease

Smoking and previous cervical, vulval, vaginal or penile high-grade lesions or cancer identify persistent field exposure and impaired local immunity.

Chronic perianal inflammation

Longstanding Crohn fistula, chronic wounds and prior radiation rarely create squamous or adenocarcinoma risk and can obscure recognition in scarred tissue.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
HPV transforms squamous epithelium
Persistent viral oncogene expression permits genomic instability and progression from high-grade squamous intraepithelial lesion to basement-membrane invasion.
2
Anatomical site changes drainage
Anal canal tumours drain to mesorectal, internal iliac and inguinal nodes, while margin lesions have predominantly superficial inguinal drainage.
3
Local growth threatens sphincter function
Tumour and treatment affect internal and external sphincters, perianal skin, vagina, prostate and pelvic floor, causing pain, incontinence and fistula.
4
Chemoradiation response continues slowly
Mitomycin–fluoropyrimidine radiosensitisation causes progressive tumour regression for months after treatment, so early residual thickening does not necessarily indicate viable cancer.
5
Persistent disease requires anatomical salvage
True local failure after definitive chemoradiation is managed by abdominoperineal excision when resectable because further local radiation is often limited.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Anal canal lesion

Bleeding, defaecatory pain, tenesmus, discharge, altered continence or a firm intraluminal mass suggests canal disease requiring biopsy.

Anal margin lesion

A visible ulcerated or keratinising perianal skin lesion may behave like cutaneous SCC but distance from the verge and sphincter involvement determine classification.

Inguinal nodal disease

A firm enlarging groin node may represent regional metastasis and should be imaged and sampled before defining the radiation field.

Locally advanced invasion

Fixation, severe pain, fistula, vaginal or prostate involvement, incontinence or hydronephrosis indicates extensive pelvic disease.

Perianal sepsisRed flag

Fever, fluctuance, spreading erythema or crepitus requires immediate antibiotics and colorectal source control before detailed elective staging.

Treatment toxicityRed flag

Moist desquamation, uncontrolled diarrhoea, fever, urinary pain, dehydration or cytopenic symptoms during chemoradiation requires same-day oncology assessment.

Red flags requiring action

Persistent anal bleeding, pain, ulcer, lump, discharge, pruritus or change in continence requires digital and visual examination even when haemorrhoids are known.
A hard irregular anal lesion, sphincter fixation, vaginal or prostatic involvement or a firm inguinal node suggests invasive or regional disease.
Fever, escalating perianal pain, spreading erythema, crepitus or immunosuppression raises abscess or necrotising infection requiring immediate surgery and antibiotics.
Severe diarrhoea, abdominal pain, dehydration, fever or cytopenia during chemoradiation requires assessment for treatment toxicity, infection and neutropenic enterocolitis.
New leg oedema, pelvic pain, urinary obstruction or neurological symptoms after treatment may indicate nodal or pelvic recurrence.
Persistent or enlarging tumour after an adequate post-chemoradiation observation period requires biopsy and salvage assessment, but early treatment inflammation alone is not failure.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line anorectal and inguinal examinationFirst stepFirst line
Why
Define site, size, fixation, sphincter relation, vaginal or prostate involvement and regional nodes before biopsy.
Interpretation and limitations
Record distance from anal verge and whether the lesion lies in canal or margin; perform examination under anaesthesia when pain or stenosis prevents adequate mapping.
02
Reference biopsy with histological typing
Why
Confirm invasive squamous carcinoma and distinguish adenocarcinoma, melanoma, lymphoma, Paget and benign inflammatory disease.
Interpretation and limitations
Obtain enough viable tissue for morphology and p16 or other lineage studies; do not perform a sphincter-damaging excision of a canal lesion merely to obtain diagnosis.
03
Reference high-resolution pelvic MRI
Why
Stage primary, sphincter complex, adjacent organs, mesorectal, internal iliac and inguinal nodes for radiation and surgical planning.
Interpretation and limitations
Correlate with examination and use the same protocol for response; post-treatment fibrosis and oedema can mimic residual disease early.
04
Contrast CT chest and abdomen
Why
Detect liver, lung, distant nodal and other metastatic disease and assess treatment fitness and alternative pathology.
Interpretation and limitations
Small pelvic details are better assessed on MRI; confirm a solitary high-consequence lesion when feasible before changing curative intent.
05
PET-CT and node sampling
Why
Clarify metabolically active pelvic or inguinal nodes and improve radiotherapy field definition.
Interpretation and limitations
HPV, skin and inflammatory disease can create false-positive groin uptake; sample an atypical or management-changing node by ultrasound-guided core or FNA.
06
HIV and immune assessment
Why
Identify modifiable immune suppression, drug interactions and infection risks that influence toxicity and follow-up.
Interpretation and limitations
Offer HIV testing with consent and obtain viral load, CD4 count and antiretroviral review when positive; HIV status alone should not deny curative chemoradiation.
07
Response examination with MRI
Why
Distinguish continuing regression from persistent or progressive local disease after chemoradiotherapy.
Interpretation and limitations
Assess clinically at protocol intervals and allow response through approximately 26 weeks when the lesion is shrinking and no progression occurs; biopsy suspected failure before salvage surgery.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Haemorrhoids and fissure

Common bleeding and pain syndromes can coexist with cancer; persistent lump, irregular ulcer, unexplained pain or altered continence still requires examination and biopsy.

Abscess or fistula

Fluctuance, fever and purulent drainage support infection, while chronic non-healing or indurated fistula tissue requires sampling after acute source control.

Inflammatory and infective ulcer

Crohn disease, syphilis, herpes and other infections can ulcerate the anus and require histology plus sexual-health and inflammatory assessment.

Rectal adenocarcinoma

A low rectal glandular primary can extend into anal canal but follows rectal MRI, surgical and systemic pathways rather than standard anal squamous chemoradiation.

Benign and malignant skin lesion

Condyloma, hidradenitis, melanoma, Paget disease and basal or other skin cancers occur at the margin and need lineage-specific pathology.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Persistent symptomExamine before attributing to benign diseaseFirst stepAnal bleeding, pain, lump, discharge, pruritus or continence change persists or recurs.

1Inspect perianal skin, perform digital rectal examination, proctoscopy and bilateral groin examination and assess sepsis, immune suppression and HPV-related history.
2Arrange urgent colorectal assessment and biopsy under local or general anaesthesia, using drainage and antibiotics first when uncontrolled abscess or necrotising infection is present.
3Once histology is known, obtain pelvic MRI, CT and selective PET-CT and node sampling and discuss in the anal-cancer MDT.

02Curative SCCPreserve sphincter with definitive chemoradiationDefinitiveStaging shows non-metastatic anal canal squamous carcinoma suitable for radical treatment.

1Complete radiation planning with groin and pelvic nodal definition, renal and marrow tests, DPD status, HIV and interaction review and fertility or sexual counselling.
2Deliver protocol mitomycin plus capecitabine or infusional fluorouracil with uninterrupted intensity-modulated radiotherapy, reviewing skin, bowel, urinary, pain and blood toxicity frequently.
3Assess regression clinically and by MRI over the defined post-treatment window and reserve biopsy and salvage surgery for persistent or progressive disease rather than early inflammatory thickening.

03Anal marginUse local excision only for a true small margin lesionA well-differentiated superficial tumour is confined to anal margin and adequate margins are feasible without sphincter compromise.

1Confirm anatomical classification, depth, nodes and histology in the specialist MDT rather than treating a canal extension as ordinary skin cancer.
2Perform wide local excision with adequate pathological margins and preserve sphincter and continence; avoid repeated excisions that create functional loss.
3Use chemoradiotherapy for involved margins not safely re-excisable, nodal disease, deeper or larger lesions or canal involvement and continue groin and local surveillance.

04Persistent or recurrentConfirm failure and refer for pelvic salvageTumour progresses during observation or remains convincingly viable after the expected regression period.

1Repeat examination, MRI and systemic staging and obtain biopsy of local disease or a suspicious node to distinguish viable cancer from radiation ulcer and fibrosis.
2Refer to a specialist exenterative or pelvic cancer MDT for abdominoperineal excision and flap reconstruction assessment, considering adjacent-organ and groin salvage.
3Integrate wound, pain, stoma, sexual, urinary, lymphatic and psychological rehabilitation and use palliative radiation or systemic therapy when complete salvage is not feasible.

05MetastaticTreat systemically and control local morbidityDistant metastatic disease is present at diagnosis or recurrence.

1Confirm histology and extent, assess performance, HIV and organ function and select carboplatin–paclitaxel or another current funded first systemic regimen.
2Use radiation, surgery or diversion for bleeding, pain, fistula and obstruction and reassess for limited metastatic treatment when anatomy and response support it.
3At progression, consider immune therapy, trials or later chemotherapy within current indications and integrate palliative and advance-care support before local symptoms become a crisis.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Radiosensitises anal squamous carcinoma and permits definitive organ-preserving treatment without routine primary abdominoperineal excision.

Mitomycin and capecitabine with radiotherapy

A common UK radical protocol gives mitomycin 12 mg/m² intravenously on radiotherapy day 1, maximum 20 mg, plus capecitabine 825 mg/m² orally twice daily on each radiotherapy treatment day; use the exact centre protocol.

Confirm DPD status and monitor marrow, renal function, infection, diarrhoea, mucositis, hand–foot syndrome and haemolytic–uraemic toxicity; review antiretroviral and anticoagulant interactions and stop capecitabine for significant early toxicity.

Provides preferred first-line systemic control for many fit patients with inoperable locally recurrent or metastatic anal squamous carcinoma.

Carboplatin and paclitaxel for advanced disease

A common 28-day regimen gives carboplatin AUC 5 intravenously on day 1 and paclitaxel 80 mg/m² intravenously on days 1, 8 and 15 for up to six cycles, modified for marrow, neuropathy and response.

Monitor hypersensitivity, neutropenia, infection, thrombocytopenia, neuropathy, alopecia and organ function and review interactions and prophylaxis in HIV or other immune suppression.

Reduces stool frequency and perianal skin exposure during chemoradiation after serious inflammatory, infective and obstructive causes are excluded.

Loperamide for uncomplicated treatment diarrhoea

For uncomplicated non-infective diarrhoea, give loperamide 4 mg orally initially then 2 mg after each loose stool to the locally specified daily maximum, with oral rehydration and same-day oncology contact when persistent.

Do not use as sole treatment with fever, neutropenia, severe pain, bloody stool, ileus or dehydration; these features require urgent investigations, intravenous support and protocol escalation.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Pain, bleeding and infection

Ulcerated tumour causes severe defaecatory pain, anaemia, discharge, abscess and fistula, impairing nutrition, sleep and treatment positioning.

Sphincter and pelvic dysfunction

Tumour or fibrosis causes urgency, incontinence, stenosis, sexual pain, vaginal narrowing and urinary or pelvic-floor dysfunction.

Nodal and distant spread

Inguinal and pelvic nodes can cause pain and leg oedema, while liver and lung metastases occur in advanced or recurrent disease.

Acute chemoradiation toxicity

Moist skin desquamation, mucositis, diarrhoea, cystitis, marrow suppression, infection, dehydration and pain can interrupt curative treatment.

Late radiation and salvage morbidity

Fibrosis, fracture, lymphoedema, sexual dysfunction, bowel change and permanent colostomy after salvage surgery affect long-term function and identity.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During chemoradiation, review blood count, renal function, weight, hydration, bowel and urinary symptoms, pain and perineal and groin skin at least weekly.
Maintain radiotherapy continuity where safely possible through proactive analgesia, skin dressings, antiemetics, diarrhoea treatment, dietetic support and rapid infection management.
Assess response clinically at defined early and later intervals with MRI, recognising ongoing regression up to approximately 26 weeks before declaring stable residual disease a failure.
After complete response, perform regular digital, proctoscopic and inguinal examinations with imaging according to stage and protocol and biopsy new progressive abnormalities.
Monitor late continence, stenosis, pelvic pain, sexual and vaginal function, menopause, fertility, pelvic fracture, lymphoedema and urinary symptoms and refer for rehabilitation.
For people with HIV, coordinate viral load, CD4, antiretroviral adherence, infection prevention and interactions throughout treatment and follow-up.
After salvage surgery, monitor perineal wound and flap, stoma, urinary and sexual function, hernia, lymphoedema and psychological adjustment.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Haemorrhoids do not end assessment

Common benign bleeding can coexist with a firm or ulcerated cancer, so persistent symptoms require direct visual and digital examination.

Groins belong to the examination

Inguinal nodes are regional for anal cancer and alter stage and radiation fields, unlike their role in a typical rectal primary.

Canal and margin are not interchangeable

A tiny cutaneous margin lesion may be excised, while similarly sized canal SCC usually receives chemoradiotherapy to preserve sphincter control.

Regression continues after radiation

Residual ulcer or thickening that is steadily shrinking can disappear over months, and premature biopsy or salvage surgery can cause avoidable harm.

HIV does not remove curative intent

With contemporary antiretroviral care, many patients tolerate standard definitive treatment; immune status and interactions guide support rather than automatic dose denial.

Skin care protects cancer treatment

Managing moist desquamation and pain is not cosmetic: it helps prevent infection, dehydration and interruption of a curative radiation course.

11Common pitfallsFrequent interpretation and management errors.

01
Treating recurrent bleeding as haemorrhoids without inspecting and palpating the anal canal.
02
Calling an anal canal SCC a low rectal adenocarcinoma and choosing the wrong treatment framework.
03
Excising a canal lesion through sphincter merely to obtain a diagnosis.
04
Omitting bilateral inguinal examination, imaging or biopsy of a suspicious node.
05
Using primary abdominoperineal excision for routine localised anal SCC instead of organ-preserving chemoradiation.
06
Declaring treatment failure from early inflammatory thickening while the lesion continues to regress.
07
Delaying antibiotics and drainage for perianal sepsis while completing elective staging.
08
Using loperamide alone for febrile, neutropenic or bloody diarrhoea.
09
Failing to discuss sexual, vaginal, fertility, continence and stoma outcomes before treatment.
10
Reducing curative therapy solely because a patient has well-controlled HIV without specialist review.