Anal cancer is an uncommon malignancy with an annual incidence of approximately 6 per 1,000,000 and accounting for only a small percentage (4%) of all cancers of the lower gastrointestinal tract. However, the overall risk is rising.
Estimated new cases and deaths from anal cancer in the United States in 2009:
- New cases: 5,290.
- Deaths: 710.
Slightly higher in females than in males, male to female ratio: 1:2. However, cancer of the anal margin is more frequent in men. The incidence in men younger than 35 has increased and the sex ratio is reversed in this group which is also related to receptive anal intercourse.
Anal cancer most commonly develops in patients 50 to 60 years old (80%). The incidence in men younger than 35 has increased and the sex ratio is reversed in this group.
Race and ethnicity
Recently an increase in the incidence of anal cancer in Black men in the United States (relative to Whites and Hispanics) has been noticed.
Anal cancer more frequently afflicts urban than rural population.
Causes and risk factors
The presence of human papilloma virus infection (HPV), especially in male homosexuals are at a high risk.
Overall, the risk of anal cancer is rising, with data suggesting that persons engaging in certain sexual practices, such as receptive anal intercourse, or persons with a high lifetime number of sexual partners are at increased risk of anal cancer. These practices may have led to an increase in the number of individuals at risk for infection with human papillomavirus (HPV);
HPV: HPV infection is strongly associated with anal cancer development and may be a necessary step in its carcinogenesis. Researchers have found that 80 percent of the tumors were positive for HPV DNA. Of these, over 60 percent tested positive for a strain called HPV-16, and 7 percent contained a strain called HPV-18. Both strains of HPV are implicated in cervical-cancer development as well. An HPV produced protein E6, inactivates tumor suppressor gene p53. The presence of genital warts increases the risk by a factor of 30.
HIV: The association between HIV and anal cancer reflects the sexual practices (anal receptive intercourse) associated with these diseases rather than a causative relationship. Anal cancer is rare in intravenous drug abusers. The relative risk for homosexuals with AIDS is 80 and for heterosexuals with AIDS is 40.
Other infections: Chlamydial infection in women, herpes-simplex type 2 and gonorrhea in men have all been associated with an increased risk of developing anal cancer.
Anal-receptive intercourse in men but not women is associated with anal cancer (risk ratio 33). There is also an increased incidence in single men than married men (6-fold increase). Sexual activity particularly with multiple partners, is associated with an increased risk for anal cancer.
Kidney transplant patients are associated with a 100-fold increase in anogenital cancers.
Cigarette smokers have an 8-fold increase in anal cancer.
Diseases associated with anal cancer
- AIDS (relative risk 60).
- Anal diseases (fistulas, fissures, chronic local inflammation, hemorrhoids)
- Chron's disease
- Lymphogranuloma venereum
- Condylomata acuminata
- Carcinoma of the cervix
- Carcinoma of the vulva
Risk Factors with Strong Evidence:
- HPV (anogenital warts)
- History of receptive anal intercourse
- History of STDs
- >10 sexual partners
- History of cervical, vulvar, or vaginal cancer
- Immunosuppression after solid-organ transplantation.
Risk Factors with Moderately Strong Evidence:
- HIV infection
Long-term use of corticosteroids
It is important to define the various structures and histological landmarks in the anus due to their implications on staging, therapy and prognosis.
The dentate line (pectinate line) is a jagged line of mucosa that looks like teeth (hence, called dentate). Dentate line is also known as the anocutaneous line. Developmentally, this line represents the hindgut-proctodeum junction. It represents the junction between the columnar epithelium (as is most of the digestive tract - the line represents the end of the part of the body derived from the hindgut) and the stratified squamous epithelium (as is most of the skin).
A major problem complicating determination of anatomic site clinically or pathologically is the controversy over the anatomic definition of the anal canal itself. The surgical definition of the anal canal is the one most widely accepted for practical reasons and is the preferred definition of the American Joint Committee on Cancer (AJCC). However, it is based on clinically identifiable landmarks that are difficult or impossible for the pathologist to locate.
AJCC (surgical) division
Hence, surgically: the anal canal extends from the anorectal ring proximally to the anal verge distally.
Proximally: The anorectal ring is defined as the junction where the anal canal meets the rectum (the point where the rectum enters the puborectalis sling at the apex of the anal sphincter complex). This junction corresponds to the proximal level of the pelvic diaphragm, that is, the levator ani or the muscular floor of the pelvis. The anal canal changes from its cylindrical shape to the more capacious barrel shape of the rectum.
Distally: the anal verge is defined by the visible anus and its entry into the anal canal. It is also known as the squamous mucocutaneous junction (ie, the junction of the distal squamous mucosa of the anal canal with the perianal hair-bearing skin).
WHO (histological) division
According to the WHO definition the dentate line divides the anus into anal canal above it and the anal margin below it. Remember that the dentate line is also known as the anocutaneous line, therefore, it is expected to lie on the cutaneous margin.
The anal canal is defined by the WHO as the area from from the dentate line to the anorectal ring (above it). The histological lining of the anal canal is columnar epithelium and cancers arising from the anal canal are adenocarcinomas.
The anal margin consists of the anal area distal to the anal canal, including perianal skin. Histologically, the anal margin is covered by stratified squamous epithelium and cancers arising from the anal margin are squamous cell carcinomas.
Histology of the anal canal
This definition of the anal canal includes the anal transition zone (ATZ) and the dentate line, from which many of the most important and characteristic anal carcinomas develop.
The histology of the anal canal contains keratinizing squamous stratified epithelium which diminishes proximally, while the columnar epithelium of the intestinal mucosa gives rise to cuboidal epithelium within the anal canal, which fades gradually when the cutaneous epithelium of the perianal skin is encountered.
The anal transitional zone as described by Fenger incorporates all forms of epithelium, giving rise to a wide array of histologic types of anal epidermoid carcinomas. These can be divided into two categories, basaloid (cloacogenic) or squamous cell carcinoma.
The anal canal shows the following landmarks.
- The intersphincteric groove, often more palpable than visible, defines a plane that separates the internal from the external voluntary sphincters.
- The dentate line is defined by the columns of Morgagni.
Anal canal carcinomas are defined as tumors that are either wholly or partially situated across the dentate line. Tumors below the dentate line are considered anal margin carcinomas. Few anal margin tumors extend into the anal canal.
WHO Classification of Carcinoma of the Anal Canal
- Intraepithelial neoplasia
- Squamous or transitional epithelium
- Paget disease
- Squamous cell carcinoma
- Mucinous adenocarcinoma
- Small cell carcinoma
- Undifferentiated carcinoma
By convention, these histologic types are assigned grade 4. The term carcinoma, NOS (not otherwise specified) is not part of the WHO classification.
Histologic grades for anal canal squamous carcinoma are as follows.
- Grade X Grade cannot be assessed
- Grade 1 Well differentiated
- Grade 2 Moderately differentiated
- Grade 3 Poorly differentiated
If there are variations in the differentiation within the tumor, the highest (least favorable) grade is recorded as the overall grade.
Histologic grades for adenocarcinoma of the anal canal based on the proportion of gland formation by the tumor are suggested as follows.
- Grade X Grade cannot be assessed
- Grade 1 Well differentiated (greater than 95% of tumor composed of glands)
- Grade 2 Moderately differentiated (50% to 95% of tumor composed of glands)
- Grade 3 Poorly differentiated (49% or less of tumor composed of glands)
Small cell carcinomas and tumors with no differentiation or minimal differentiation that is discernible only in rare, tiny foci (undifferentiated carcinomas by WHO classification) are categorized as grade 4.
Squamous cell carcinoma and its variants
The previous edition of the WHO classification included 3 subtypes of squamous cell carcinoma (SCC): large cell keratinizing, large cell nonkeratinizing, and basaloid. However, because most SCCs of the anal canal show more than 1 subtype, the diagnostic reproducibility of these subtypes has been low. Furthermore, no significant prognostic differences between subtypes have been established.
Therefore, the WHO now recommends that the generic diagnostic term "squamous cell carcinoma" be used for all squamous tumors of the anal canal. However, additional descriptive comment regarding specific histologic features, such as predominant cell size, basaloid features, degree of keratinization, or adjacent intraepithelial neoplasia, is encouraged. Prominent basaloid features and small tumor cell size are related to infection with "high-risk" human papilloma virus. SCC with a predominantly basaloid differentiation pattern was formerly known as cloacogenic carcinoma, but this term is now considered obsolete.
Two variants of SCC of the anal canal deserve note because they differ in prognosis
from typical squamous tumors.
One is verrucous carcinoma (also known as giant condyloma or Buschke-Lowenstein tumor), which resembles a condyloma macroscopically but is larger and fails to respond to conservative therapy. These lesions are regarded as biologic intermediates between condylomas and SCCs, with a better prognosis than SCC. However, nearly half of these lesions undergo malignant transformation.
Another important variant is SCC with mucinous microcysts (well-formed cystic spaces containing Alcian blue- or PAS-stainable mucin). This entity has an unfavorable prognosis compared to SCC.
Finally, 2 rare types of anal canal carcinoma, anaplastic carcinoma and small cell carcinoma (high-grade neuroendocrine carcinoma), are tumors with aggressive biologic behavior and an unfavorable prognosis compared to typical SCC. Tumors of the more distal anal canal and especially anal margin (mucocutaneous junction) are generally purely squamous in type and show fewer basaloid or glandular features.
Symptoms and signs
About 25% of newly diagnosed patients with anal cancer do not have symptoms. Bleeding (more common in squamous cell carcinomas) or palpable mass occurs in 50% of patients. Pain or spasm is a symptom in 40% of cases. Sensation of a mass (not palpable) occurs in 25% and pruritus (more common in perianal cancers in 15%. Other complaints include constipation or diarrhea.
Coexistent conditions (ie, anal fistula, anal fissure, or hemorrhoids) are common. A high index of suspicion in the presence of a mass is warranted.
Physical examination should include digital anorectal examination, anoscopy, proctoscopy, and palpation of inguinal lymph nodes. Anorectal examination may have to be performed under sedation or general anesthesia in patients with severe pain and anal spasm.
The regional nodes for the anal canal are now considered to be the perirectal (anorectal, perirectal and lateral sacral), the internal iliac (hypogastric), and the inguinal (superficial and deep). All other nodal groups represent sites of distant metastasis. Tumors that arise in the anal canal usually spread initially to the anorectal and perirectal nodes, and those that arise at the anal margin spread to the superficial inguinal nodes.
Different patient series estimate regional lymph node metastasis as ranging from 20-40%.
Extrapelvic metastases at the time of first presentation are not common and are identified in fewer than 5%. Metastases occur as the sole site of failure in approximately 10% after successful treatment of the primary cancer and regional nodes. Metastases may occur via the portal or systemic venous systems or via lymphatics. They are found most frequently in the liver, lungs, and extrapelvic lymph nodes and occasionally in bone, skin, brain, and other sites.
Core needle biopsy or incisional biopsy (preferred) is the definitive method of establishing the initial diagnosis, the effectiveness of anal conservation treatment, and the diagnosis of recurrent disease. Anoscopy is used to visualize the region and a biopsy is done. Suggestive inguinal lymph nodes should be examined.
Should fear, pain, or any other condition interfere with adequate biopsy, examination and biopsy under anesthesia are warranted.
Anal cytology and anoscopy may prove to be useful screening methods for detecting, in high risk individuals, squamous intraepithelial lesions and other abnormalities related to HPV infection.
Staging and prognostic factors
Staging techniques -
Evaluation of local extent
CT scan or MRI
Imaging tests such as CT Scan, MRI are used to evaluate the local extent of the disease as well as the regional lymph node involvement.
Abnormal pelvic nodes identified on imaging are not usually subjected to fine-needle biopsy, and the diagnosis of metastasis in these nodes is based on radiologic criteria. The most common sites of metastases from cancers of the canal are the pelvic or paraaortic nodes.
1. Ultrasonography of the liver
Ultrasonography is inexpensive and readily available, but its value compared to single-slice helical CT (SSCT), MSCT, and MRI is limited as a consequence of reduced sensitivity and specificity. In general, the US appearance of liver metastases is nonspecific.
Sensitivity is operator dependent. It is valuable, inexpensive, quick, and portable, and it can depict lesions as small as 1 cm with a sensitivity approaching 80%.
The specificity of US in detecting liver metastases is poor, and its overall false-negative rate is 50%. However, the presence of multiple hepatic nodules of different sizes within the liver is nearly always due to metastases.
2. Abdominal CT
CT is the most sensitive technique for the detection of liver metastases.
- Contrast-enhanced scans offer a high degree of sensitivity, as high as 80-90%. The specificity is 99%.
1. Chest x-ray
A chest radiograph in two planes is indicated on a regular basis to screen for metastatic disease in the follow-up of patients with primary tumors that preferentially spread to the lungs.
- Sensitivity and specificity for chest radiography were 50 and 90%, respectively for nodules >5mm.
- It more accurately detects a 1-cm nodules 1cm or greater.
2. Chest CT
When metastatic nodules are identified, helical computed tomography (CT) of the chest should be performed to assess their number and characteristics.
- A high-resolution CT scan can identify nodules 3 mm in diameter.
CT has an overall sensitivity 62% in detecting pulmonary nodules (all sizes). However it underestimated the extent of the disease in 25%, and overestimated the extent of the disease in 14%.
Sensitivity is increased to 95% for intrapulmonary nodules ? 6 mm and 100% for intrapulmonary nodules > 10 mm.
The limitations of CT scan in this study were mainly associated with pleural-based nodules and intrapulmonary nodules < 6 mm.
Staging of anal cancer
- The TNM staging system for anal cancer
The 4 major prognostic factors are:
- Site (anal canal versus perianal skin),
- Size (primary tumors less than 2 centimeters in size have a better prognosis)
- Differentiation (well-differentiated tumors are more favorable than poorly differentiated tumors).
- Lymph Node Involvement: absence of nodal involvement or local extension.
When balanced with other factors, the prognosis for patients with squamous cell carcinoma of the anus and for those with cloacogenic carcinoma is similar.
Abdominoperineal resection leading to permanent colostomy was previously thought to be required for all but small anal cancers below the dentate line, but such surgery is no longer the treatment of choice. Chemotherapy concurrent with radiation therapy is now the treatment of choice.
Here again, it is important to define the anatomy of the anus. The anal margin is the defined as the area distal to the dentate line up to the junction between perineal skin and the hair-bearing skin of the buttocks. While the anal canal is defined as the area from the anorectal ring (above) to dentate line (below).
Patients with stage I or II are either treated with wide excision or chemoradiation (5-FU-Mitomycin are given every 4 weeks with radiotherapy).
Anal margin cancer
Cancers of the anal margin (distal to the dentate line until the junction between the perineal skin and the hair-bearing skin of the buttocks) are treated like skin cancer with either excision or local radiotherapy or chemoradiotherapy depending on the tumor size and differentiation.
T1 tumors of the anal margin that are well differentiated are treated primarily with local excision. If pathology report shows an inadequate margin then re-excision versus chemoradiation therapy is considered.
Larger tumor size (T2-4, N0) or Node positive (stage III) cancers of the anal margin are all treated with chemoradiation in the form of mitomycin/5FU and radiation at doses of 55-60Gy.
Anal canal cancer
Treatment of anal canal cancers (from anorectal ring, above, to dentate line, below) depends on the histology in addition to the tumor size.
Adenocarcinomas, which are not common behave like rectal cancers and have higher incidence of recurrence and metastasis. These are treated with the same protocols of rectal cancer.
Squamous cell cancers constitute 80% of anal cancers. Combination chemoradiotherapy is used for stages I-II and stage III. Patients with T1-2, N0 are treated with mitomycin (10mg/m2 D1)/5FU 750 mg/m2 continuous infusion D1-5 every 4wks with radiotherapy (5 days a week for 5 weeks + boost). Patients with larger tumor size (T3-4) or lymph node positive (stage III) are treated with mitomycin/5FU and radiotherapy at higher doses of 55-60Gy.
Metastatic disease (stage IV)
Chemotherapy in the form of cisplatin-5FU (also known as FUP) is used for systemic salvage.
Local recurrences and/or persistent disease after treatment with radiation therapy and chemotherapy or surgery as the primary treatment may be controlled by using the alternate treatment (surgery in the form of abdomino-perineal reseaction for local salvage after radiation and vice versa). Inguinal node recurrence are treated with inguinal node dissection
In some cases salvage 5FU-cisplatin plus a radiation boost can be used to treat residual after chemoradiation to avoid a permanent colostomy.