Anal Cancer

Anal cancer accounts for 2.7% of all gastrointestinal tract cancers. Squamous cell carcinoma is the most common type of anal cancer. The patient can present with rectal bleeding (most common), change in bowel habits, perianal pruritic mass, or perianal painful ulceration. The diagnosis is established via biopsy. Staging is done through imaging studies. Depending on the stage, treatment options include chemoradiotherapy and/or surgery. If treated early, anal cancer has a favorable prognosis.

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Overview

Definition

Anal cancers are cancers arising in the anal canal or anal margin.

Anatomy:

  • Anal canal:
    • 2.5–3.5 cm long
    • From puborectalis sling (1–2 cm above dentate/pectinate line) to the mucocutaneous junction (where perianal skin begins)
  • Anal margin (verge):
    • Where anal canal connects to the skin
    • Skin in the anal verge: perianal skin

Histology:

  • Types of mucosa (from proximal to distal area):
    • Glandular
    • Transitional
    • Nonkeratinizing squamous (devoid of epidermal appendages; above the dentate line)
    • Keratinizing squamous: in the anal canal below the dentate line, and in the perianal skin
  • Pectinate/dentate line: area of transition from glandular to squamous mucosa
  • Clinical significance:
    • Tumors arising from the glandular area: adenocarcinoma
    • Tumors arising from the transitional and squamous mucosa: squamous cell carcinoma (SCC)
    • Tumors arising from the keratinizing squamous area and skin: perianal skin cancers, often SCC (same treatment approach as anal canal cancers)
Rectum and anal canal schematic

Anatomy of the anal canal

Image by Lecturio.

Epidemiology

  • 2.7% of all digestive tract cancers
  • Incidence: 8,500 cases per year in the United States
  • Rising incidence in young Black men and older (> 60) women
  • More common in women

Etiology

Risk factors for anal cancer:

  • Older age: > 50 years
  • Multiple sexual partners
  • Receptive anal intercourse
  • History of vulvar, vaginal, or cervical cancers in women
  • Human papillomavirus (HPV): subclinical infection or condylomas
  • Herpes simplex virus infection (HSV)
  • Chlamydia in women
  • Gonorrhea in men
  • Human immunodeficiency virus (HIV) infection
  • Immunosuppression (disease or medications)
  • Smoking

Pathophysiology and Clinical Presentation

Pathophysiology

  • Carcinogenesis of anal SCC:
    • Inflammatory response of the anal epithelium develops most commonly as a response to infection by HPV.
    • Inflammation progresses to the development of anal intraepithelia neoplasia (AIN): 
      • AIN 1: corresponds to low-grade squamous epithelial lesion (LSIL)
      • AIN 2 and 3: high-grade SIL (HSIL); pre-malignant
      • HSIL can progress to invasive SCC.
  • The progression to invasive cancer is promoted by HIV/immunosuppression and other risk factors (multiple HPV types, high-risk sexual behavior).

Histologic types

  • Anal canal: located above the anal verge
    • SCC: 
      • Most common tumor of the anal canal (75%)
      • Non-keratinizing SCC: above dentate line
      • Keratinizing SCC: below dentate line
    • Adenocarcinoma:
      • Rare
      • Arises from glandular elements in the anal canal
      • Natural history and treatment similar to rectal adenocarcinomas
    • Mucosal melanoma:
      • 3rd-most common site for primary malignant melanoma after skin and eyes 
      • Arises from melanocytes found in the transitional zone of the anal canal
      • Aggressive: distant metastases common at the time of diagnosis
  • Anal margin: below the anal verge (perianal skin cancers)
    • SCC
    • Bowen’s disease: SCC in situ (pre-malignant)
    • Paget’s disease of the anus (intraepithelial adenocarcinoma):
      • Primary: sweat gland morphology
      • Secondary: extension from adenocarcinoma of the rectum or perianal glands
    • Malignant melanoma of anal margin: similar to other cutaneous melanomas

Lymphatic drainage of anal cancers

  • Above dentate line: mesorectal and internal iliac nodes
  • Below dentate line: inguinal nodes

Clinical presentation

  • Asymptomatic (25%)
  • Bleeding per rectum (most common initial presentation)
  • A mass around the anus that may invade deeper tissues
  • Perianal ulceration and pruritus
  • Tenderness in the anal area
  • Fecal/flatus incontinence
  • Obstipation
  • Thrombosed hemorrhoid (a possible manifestation of anal melanoma)

Diagnosis and Staging

Clinical findings

  • History:
    • Typical clinical presentation
    • History of sexually transmitted diseases and other risk factors
  • Physical examination:
    • Large tumors or anal margin tumors may be directly visualized.
    • Digital rectal exam (DRE): may feel hard, immovable, non-tender lump 
    • Anoscopy: If a mass is seen, biopsy can be performed.
    • Inguinal lymphadenopathy
    • Gynecologic exam should be performed in women (looking for concomitant genital lesions/ condylomas).

Diagnostic tests

  • Biopsy: 
    • Definitive diagnosis
    • Anal mass can be excised if small enough or if a sample can be taken.
    • Fine needle aspiration (FNA) can also provide tissue diagnosis.
  • Laboratory studies:
    • Complete blood cell count (CBC) may show anemia.
    • HIV, HPV, and HSV testing should be considered depending on individual history.
  • Imaging for diagnosis and staging evaluation:
    • Factors evaluated:
      • Size of tumor
      • Local invasion
      • Lymph node involvement
      • Distant metastases
    • The following are utilized to determine the stage of disease:
      • Endoscopic ultrasound (EUS)
      • Computed tomography (CT) scan
      • Magnetic resonance imaging (MRI)
      • Positron-emission tomography (PET)

Staging

Table: Anal cancer TNM staging
Primary tumor (T)Regional lymph nodes (N)Distant metastasis (M)
Tx: primary tumor not assessedNx: regional lymph nodes cannot be assessedM0: no distant metastasis
T0: no evidence of primary tumorN0: no regional lymph node metastasisM1: distant metastasis
Tis: high-grade squamous intraepithelial lesionN1: metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes
  • N1a: metastasis in inguinal, mesorectal, or internal iliac lymph nodes
  • N1b: metastasis in external iliac lymph nodes
  • N1c: metastasis in external iliac with any N1a nodes
T1: tumor ≤ 2 cm
T2: tumor > 2 cm but ≤ 5 cm
T3: tumor > 5 cm
T4: tumor of any size invading adjacent organs, such as the vagina, urethra, or bladder
Source: American Joint Commitee on Cancer (AJCC), 8th edition
Table: Stages of anal cancer
StageTNM
0TisN0M0
IT1N0M0
IIAT2N0M0
IIBT3N0M0
IIIAT1–2N1M0
IIIBT4N0M0
IIICT3–4N1M0
IVAny TAny NM1

Management

Management of SCC

  • Localized (stage IIII):
    • Chemoradiotherapy: 
      • Preferred; provides cure and preserves anal sphincter
      • Fluorouracil + mitomycin + radiotherapy
    • Local excision: 
      • For small (< 1 cm) superficial tumors
      • < 3 mm basement membrane invasion
      • < 7 mm horizontal spread
    • Inguinal lymphadenectomy:
      • For persistent/recurrent inguinal lymph node disease after chemoradiation
      • Additional radiation to inguinal region also considered
  • Stage IV (metastatic diseases): 
    • Systemic chemotherapy
    • Immunotherapy (pembrolizumab, nivolumab)
    • Liver resection may play a role in patients with localized liver metastases.
  • Recurrent/persistent disease after chemoradiotherapy: 
    • Needs to be confirmed with biopsy
    • Surgery (abdominoperineal resection (APR)): Patients end up with a permanent colostomy.
    • Salvage chemoradiotherapy can be considered to avoid colostomy.
  • Surveillance:
    • DRE, anoscopy, and inguinal lymph node palpation:
      • Starts 8–12 weeks post-therapy
      • Every 3–6 months for 5 years
      • It may take up to 26 weeks post-treatment to show complete response.
    • CT scan or MRI of chest/abdomen/pelvis: Consider annually for 3 years.

Management of other cancer types

  • Adenocarcinoma:
    • Approach similar to rectal adenocarcinomas
    • APR or local excision for small/early tumors
    • Systemic chemotherapy for metastatic disease
  • Melanoma:
    • Local excision with adjuvant radiation
    • APR for more advanced disease
    • Systemic chemotherapy for metastatic disease

Prognosis and Complications

Prognosis

  • 5-year survival of SCC:
    • T1: 86%
    • T2: 86%
    • T3: 60%
    • T4: 45%
    • N0: 76%
    • Node-positive: 54%
    • For all stages with complete response to chemo/radiation (70%–80% of patients): 65%
  • 5-year survival of adenocarcinoma: 55% when treated surgically with no distant metastases
  • 5-year survival of melanoma:
    • Local disease: 43%
    • Spread to regional lymph nodes: 12.5%

Complications

  • Usually related to treatment
  • Chemotherapy:
    •  Bowel dysfunction
    •  Nausea/vomiting
  • Radiation:
    • Radiation proctitis (pain, rectal bleeding, diarrhea)
    • Sexual dysfunction (men and women)
  • Surgery: 
    • Strictures
    • Perianal fistulas
  • Wound infections

Differential Diagnosis

  • Chancroid: bacterial infection that causes open sores around the genitals. Caused by Haemophilus ducreyi. Chancroid is a sexually transmitted disease that can also spread through skin-to-skin contact with an infected person.
  • Anal fissure or fistula: a fissure is a small tear in the anal mucosa. The most common presenting symptom is anal pain. A fistula is an abnormal connection between anal/rectal mucosa and perianal skin. The condition is usually a consequence of recurrent/chronic infection, and one of the manifestations of Crohn’s disease.
  • Hemorrhoids: engorged/varicose veins of the anal canal and lower rectum. Can present as a bluish anal mass. Hemorrhoids can be painful (if they originate below the dentate line) or painless (above the dentate line).
  • Condylomata acuminatum: also referred to as anogenital warts; caused by HPV infection. Usually present as soft, skin-colored, fleshy lesions around the anus and genitals.
  • Psoriasis: usually presents as red or purple, typically non-scaly pruritic lesions. May be confused with yeast or parasitic infection. Can also cause rectal bleeding and pain with defecation.

References

  1. Babiker, H.M, Kashyap S, Mehta S.R. et al. (2020). Anal Cancer. https://www.ncbi.nlm.nih.gov/books/NBK441891/
  2. Parra R.S., Ribeiro de Almeida A.L, Badiale, G.B. et al. (2010). Melanoma of the anal canal. Retrieved November 18 2020, from DOI: 10.1590/s1807-59322010001000026
  3. Ryan D.P., Willett C.G. (2020). Classification and epidemiology of anal cancer. Retrieved 21 November 2020, from https://www.uptodate.com/contents/classification-and-epidemiology-of-anal-cancer?search=anal%20cancer&source=search_result&selectedTitle=3~124&usage_type=default&display_rank=3
  4. Ryan D.P., Willett C.G. (2020). Treatment of anal cancer. Retrieved 21 November 2020, from https://www.uptodate.com/contents/treatment-of-anal-cancer?search=anal%20cancer&source=search_result&selectedTitle=1~124&usage_type=default&display_rank=1
  5. Ryan D.P., Willett C.G. (2020). Clinical features and staging of anal cancer. Retrieved 21 November 2020, from https://www.uptodate.com/contents/clinical-features-and-staging-of-anal-cancer?search=anal%20cancer&source=search_result&selectedTitle=2~124&usage_type=default&display_rank=2
  6. Wegner R.E., White R.J, Hasan S. et al. (2019). Anal Adenocarcinoma: Treatment outcomes and trends in a rare disease entity. onlinelibrary.wiley.com/doi/full/10.1002/cam4.2076

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