Anal cancer

Anal cancer is a rare malignancy localized to the anus and perianal region. The main risk factors for developing anal cancer are immunosuppression and human papillomavirus (HPV) infection. Squamous cell carcinoma (SCC) accounts for the majority of anal cancers; adenocarcinoma and other nonepidermoid cancers are less common. Clinical features include rectal pain, anal pruritus, and bleeding, but patients may be asymptomatic. Initial diagnostic steps include digital rectal examination (DRE) and inspection. Biopsy with histopathologic analysis confirms the diagnosis. Staging with imaging (e.g., CT scan with IV contrast) is necessary to evaluate the extent of disease and determine treatment. Chemoradiotherapy is often curative. Anal SCC has a favorable prognosis when treated in the early stages. Screening for anal cancer should be considered in individuals at high risk, especially those with HIV infection; universal screening is not recommended.

• Incidence: ∼ 8,000 cases diagnosed per year in the US ^[1]
• More common in individuals with HIV and men who have sex with men

Epidemiological data refers to the US, unless otherwise specified.

• Risk factors for anal cancer ^[2][3]
  • HPV infection (especially types 16 and 18), e.g., individuals with condylomata acuminata
  • Immunosuppression, e.g., HIV, recipient of solid organ transplant
  • Receptive anal intercourse
  • Tobacco use
  • History of any sexually transmitted infection
  • History of cervical, vaginal, or vulvar cancer
  • Female sex

Patients with condylomata acuminata (e.g., penile warts or a perianal verrucous mass) are at increased risk of anal cancer. ^[2]

• Rectal bleeding (most significant initial symptom)
• Anal pruritus
• A lump or tumor around the anus
• Tenderness and/or pain in the anal area
• Foreign body sensation and/or inguinal pain (in advanced disease) ^[2]

Up to 20% of patients with anal cancer do not have anogenital symptoms. ^[2]

General principles ^[2][4]

• Clinical evaluation includes DRE and inguinal lymph node examination.
• Diagnostic confirmation requires anoscopy and biopsy for histology and tumor grading. ^[2]
• Additional evaluations are required for:
  • Staging investigations to determine the TNM score
  • Identification of comorbidities (e.g., HPV, HIV)

Staging investigations ^[2]

Consider the following studies in consultation with a multidisciplinary team.

• Routine studies
  • CT chest and abdomen/pelvis with IV contrast
  • Endoanal ultrasound or MRI pelvis ^[2]
• Additional studies
  • CT head for patients with focal neurological deficits
  • FDG-PET/CT scan as an adjunct to CT scan
  • FNA or core biopsy of inguinal lymph nodes

Additional evaluation ^[2]

• Assessment for diseases associated with HPV infection, e.g.:
  • Papanicolaou smear
  • Penile examination for genital warts
• HIV testing (if HIV status is unknown)
• Colonoscopy to assess for synchronous tumors of the colon; see “Diagnostics for colorectal cancer.” ^[2]

• Histology: primarily squamous cell carcinoma; rarely adenocarcinoma or other nonepidermoid cancers
• Location
  • Above the anal verge: anal canal tumors
  • Below the anal verge: anal margin tumors

General principles ^[2][4]

• Therapy is guided by tumor grading, tumor staging, and patient performance status and preference.
• HPV vaccination is not recommended for patients with SCC or anal dysplasia. ^[2]
• For patients receiving chemoradiotherapy, offer pretreatment counseling.
  • Sperm or ova banking in patients of reproductive age
  • Prevention of vaginal stenosis after chemoradiation, e.g., with vaginal dilators

Locoregional disease ^[2][3]

• Chemoradiation therapy: : treatment of choice for all anal canal SCC and most anal margin SCC ^[2]
  • Preferred regimen: 5-fluorouracil (5-FU) PLUS mitomycin-C
  • May be curative while preserving anal sphincter function
• Surgical therapy
  • Wide local excision for anal margin SCC that is both:
    • Well-differentiated (tumor grade G1)
    • Stage 1 (TNM score T1N0M0 )
  • Abdominoperineal resection with colostomy ^[4]
    • Persistent or recurrent disease (salvage surgery)
    • Anal adenocarcinoma and other malignancies that do not respond to radiotherapy as well as SCC

Well-differentiated stage 1 anal margin SSCs may be effectively managed with wide local excision alone. Chemoradiation therapy is preferred for all other SCC locoregional lesions. ^[2]

Metastatic disease ^[2][3]

• Systemic chemotherapy: platinum-containing regimen (e.g., carboplatin PLUS paclitaxel) ^[3][4]
  • First-line therapy for distant metastatic disease in patients fit for therapy ^[4]
  • May be given with or without radiotherapy
• Immune checkpoint inhibitors (e.g., nivolumab or pembrolizumab): may be considered in patients with disease progression after systemic chemotherapy ^[2][3]
• Additional therapy: metastasectomy and/or radiofrequency ablation in certain cases ^[2]

• Metastasis
  • Local invasion of adjacent organs
  • Lymphatic spread (30% of patients): perirectal, paravertebral, inguinal, femoral
  • Hematogenous spread (< 10% of patients): liver, bone, lung ^[5]
• Local radiation injuries

We list the most important complications. The selection is not exhaustive.

• Anal cancer of the dentate line: The 5-year survival rate after radiochemotherapy is > 80%.
• Anal cancer of the anal verge: The prognosis is favorable if complete local excision is possible. The 5-year survival rate after rectal amputation is approx. 50%.

References:^[6]

Primary prevention of anal cancer ^[2][7]

Advise patients on modifiable risk factors for anal cancer.

• Educate patients on:
  • Prevention of HPV infection (e.g., HPV vaccination)
  • Prevention of HIV
• Offer support with smoking cessation.

Screening for anal cancer ^[2][7][8]

• Offer screening to individuals with risk factors for anal cancer. ^[2][7][8]
• Universal screening is not recommended. ^[2][8]

Anal SCC is preceded by high-grade squamous intraepithelial lesions (HSIL). Screening for anal cancer is aimed at detecting and treating HSIL in individuals with risk factors for anal cancer. ^[2][8][9]

Initiation of screening ^[7][8]

Screening algorithm ^[7][8][10]

• Access to high-resolution anoscopy (HRA): Perform anal cytology with or without HPV testing, followed by DRE. ^[7][8]
• No access to HRA: Perform DRE.

Lubricants used for DRE can affect cytology results. Always perform cytology testing before DRE. ^[7]

Anal cytology and HPV testing should only be performed if HRA is available to follow up abnormal results within 6 months. ^[8]

Management of abnormal results ^[8]

• Abnormal cytology or HPV test: Perform HRA with biopsy if needed.
• Abnormal DRE: Manage as suspected cancer (see “Diagnostics for anal cancer”).

Abnormal biopsy findings ^[2]

• Anal dysplasia ^[2]
  • Address modifiable risk factors for anal cancer.
  • Continue close surveillance for early progression to anal cancer.
• Anal cancer: See “Diagnostics of anal cancer” for further evaluation.

Management of patients with normal screening results

• Repeat screening based on risk factors.
  • Individuals with HIV: Continue screening annually. ^[7]
  • Individuals without HIV: Repeat screening every 1–2 years. ^[8]
• Educate patients on primary prevention of anal cancer.