By Arshad Ullah Khan, Karachi
Twenty years ago the standard definitive treatment for carcinoma of the anus was abdominal-perineal resection (APR). Organ preservation employing concomitant chemoradiation subsequently became the standard treatment for most anal cancer cases, with APR in reserve as a salvage procedure. It is noteworthy that there has never been a randomized comparison of APR with concomitant chemoradiation, nor is one likely to be done. We review the evolution of management and present treatment regimens of anal cancer.
Epidermoid (squamous cell) carcinoma is the most common histological variant and represents about 80% of anal cancer cases; somewhat less common is cloacogenic (basaloid transitional cell) carcinoma. Rare types are adenocarcinoma, originating from anal glands or fistula formation, and melanoma.
The anal canal extends from the rectum to the anal verge and measures 2.5 to 3 cm in length. The upper border of the anal sphincter determines its superior border. The dentate line is an anatomically important structure and is located in the superior aspect of the anus, reflecting the change from squamous epithelium to transitional epithelium. Transitional epithelium, at a higher level, is replaced by the columnar epithelium of the rectum. Transitional epithelium is similar to the lining of the urinary tract. The tumor originating from this area is called cloacogenic carcinoma. The anal margin is the junction of the hair-bearing skin and the mucous membrane of the anal canal. Tumors originating from the anal margin or more distally are staged as skin cancer; this is an important distinction as they rarely involve lymph nodes or lead to distant metastases. Studies that group anal margin cancers with anal canal cancers would be grouping two cancers with differences in expected outcomes.
EPIDEMIOLOGY AND ETIOLOGY
DISEASE INCIDENCE AND MORTALITY
Carcinoma of the anal canal was about one-tenth as common as rectal cancer in a 10-year registry study in Ontario, Canada, and this is in general agreement with U.S. data for 2001 published by The American Cancer Society. In the latter source, the annual incidence of anal cancer in the U.S. was given as 3,500 compared with 37,200 for rectal cancer. Five hundred deaths were projected, with a modest female predominance in incidence and deaths. Over 90% of patients presented with loco-regional disease and only 9% had distant metastasis. The disease also increased with age.
HIV INFECTION
There is an increased incidence of anal cancer among HIV-positive patients; it is twice as common in HIV-positive as it is in HIV-negative homosexual men, although it is not regarded as an AIDS-defining diagnosis. Anal cancers have been increasing in young male homosexuals, and anal receptive intercourse is a risk factor in young male homosexuals and, to a lesser degree, in females. The improved life expectancy in the HIV-positive population with the development of effective antiretroviral drugs may be contributing to the increased incidence of anal cancer in this population.
Human Papillomavirus (HPV) and Anal Cancer
Genital warts have been associated with anal cancer. Papillomaviruses may cause condylomata as precursor lesions. HPV type 16 is present in 30%-75% of cases of anal cancer; types 6, 11, and 18 in up to 10%. HPV appears to play a central role in disease pathogenesis, although herpes simplex virus (HSV) may play a secondary role in disease progression. High-grade intraepithelial lesions or intraepithelial neoplasia may progress to invasive cancer in a similar fashion to cervical cancer in women. It is known that these precancerous lesions do not regress with antiretroviral therapy.
OTHER CAUSES
Chronic inflammatory diseases do not predispose to anal cancer development, nor is there any clear-cut association found with a history of hemorrhoids. Cigarette smoking, however, was found to play lesions do not regress with antiretroviral therapy, A role in the etiology of anogenital cancers.
PROGNOSTIC FACTORS
TUMOR LOCATION AND SIZE
The most important prognostic factors have been defined by several studies: a tumor originating from the anal canal is more aggressive than one originating from peri-anal skin; the size of the tumor is also important, with higher T stage correlating with worse prognosis; differentiation and histologic type also play roles—epidermoid carcinoma has a better prognosis than adenocarcinoma; finally, prognosis is better in females than in males.
LYMPH NODE INVOLVEMENT
There is controversy concerning the adverse prognostic effect of lymph node involvement, specifically with inguinal lymphadenopathy. Moreover, in many series there is no differentiation between N1, N2, or N3 involvement. Historically, lymphadenopathy was found to carry a worse prognosis, with higher local failure rate and decreased survival, as reported in the multivariate analysis of a European Organization for Research and Treatment of Cancer (EORTC) trial. Another randomized trial associated the presence of lymphadenopathy with the necessity of a higher salvage APR rate. According to some investigators, younger aged patients have worse prognoses. Treatment delay may also have an adverse effect.
STAGING
— TNM definitions —
Primary tumor (T)
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: Tumor 2 cm or less in greatest dimension
T2: Tumor more than 2 cm but not more than 5 cm in greatest dimension
T3: Tumor more than 5 cm in greatest dimension
T4: Tumor of any size that invades adjacent organ(s), e.g., vagina,
urethra, bladder (involvement of the sphincter muscle(s) alone is not
classified as T4)
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in perirectal lymph node(s)
N2: Metastasis in unilateral internal iliac and/or inguinal lymph node(s)
N3: Metastasis in perirectal and inguinal lymph nodes and/or bilateral
internal iliac and/or inguinal lymph nodes
Distant metastasis (M)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
— Stage 0 —
Stage 0 anal cancer is carcinoma in situ. Rarely diagnosed, it is a very early
cancer that has not spread below the limiting membrane of the first layer of
anal tissue. Stage 0 anal cancer corresponds to the following TNM grouping:
Tis, N0, M0
— Stage I —
Stage I anal cancer is cancer that is 2 centimeters or less in greatest
dimension and that has not spread anywhere else. There is no sphincter
involvement. Stage I anal cancer corresponds to the following TNM grouping:
T1, N0, M0
— Stage II —
Stage II anal cancer is cancer that is more than 2 centimeters and that does
not involve adjacent organs or lymph nodes. Stage II anal cancer corresponds
to the following TNM groupings:
T2, N0, M0
T3, N0, M0
— Stage IIIA —
Stage IIIA anal cancer is cancer that has spread to perirectal lymph nodes or
to adjacent organs. Stage IIIA anal cancer corresponds to the following TNM
groupings:
T1, N1, M0
T2, N1, M0
T3, N1, M0
T4, N0, M0
— Stage IIIB —
Stage IIIB anal cancer is cancer that has spread to internal iliac and/or
inguinal nodes (unilateral or bilateral) or has spread to both adjacent organs
and perirectal lymph nodes. Stage IIIB anal cancer corresponds to the
following TNM groupings:
T4, N1, M0
Any T, N2, M0
Any T, N3, M0
— Stage IV —
Stage IV anal cancer is cancer that has spread to distant lymph nodes within
the abdomen or to other organs in the body. Stage IV anal cancer corresponds
to the following TNM groupings:
Any T, Any N, M1
DISEASE PRESENTATION
The most common presenting symptoms of anal cancer include pain, irritation, and bleeding in the anal area. The proper workup for anal cancer should begin with a careful physical examination including digital rectal examination and palpation of the inguinal nodal area. The nature of a suspicious lesion should be confirmed by biopsy. The disease is locally invasive and also spreads via lymphatic channels. Lymphadenopathy is clinically evident in about 20% of cases at presentation. Surgical exploration, however, discloses lymph node metastasis to be present in 30%-63% of cases in various series. Tumors originating above the dentate line metastasize via lymph nodes accompanying the lower hemorrhoidal veins up to the internal iliac nodes and then to the para-aortic chain. Tumors located at a lower level spread predominantly to the femoral and inguinal lymph nodes. Visceral metastasis is present in only about 10% of cases at presentation, with the most common sites of distant metastasis being lung and liver.
DIAGONOSIS
Computerized tomography scans of the chest, abdomen, and pelvis help define the internal extension of the infiltrating tumors, as well as enlargement of the pelvic nodes and distant metastasis. Endorectal ultrasound is a valuable tool for assessing the extent of tumor infiltration, also, to some degree, peri-anal lymph node involvement. The role of magnetic resonance imaging is undefined for anal cancer evaluation, although from available experience with rectal cancer, this diagnostic method may warrant further investigation.