Practice Essentials
The term anal cancer usually refers to anal squamous cell carcinoma. [1] Previous histopathological terms for squamous cell carcinoma, including cloacogenic, large-cell keratinizing/nonkeratinizing, and basaloid carcinoma, have been removed from the most recent two World Health Organization (WHO) classification schemes. [2]
Anal squamous cell carcinoma is a distinct disease entity that, like cervical cancer, is primarily linked to human papillomavirus (HPV) infection. In both diseases, HPV-related inflammation leads to dysplasia and progression to cancer. [3] Interesting differences between those two disease processes, new indications for human papillomavirus (HPV) vaccines, and a marked increase in the diagnosis of anal cancer have brought more attention to this relatively uncommon disease entity.
Anal squamous cell carcinoma develops at the anal squamocolumnar junction and arises from a precancerous lesion called high-grade anal intraepithelial neoplasia (AIN-II, AIN-III). The presence of AIN in high-risk groups, especially HIV-positive patients, is an indication for ongoing surveillance by means of high-resolution anoscopy, close followup, topical medications, or other methods.
Patients with anal cancer often delay seeking medical care. In addition, anal cancer is often misdiagnosed, or the diagnosis is significantly delayed, during which time the patient receives treatment for other benign anorectal disease (eg, hemorrhoids). To avoid diagnostic delay, it is important to refer patients with persistent or unusual anal disease to a specialty surgeon.
Although the anus can be the site of numerous types of cancers—including adenocarcinoma, melanoma, and carcinoid, among others—this article focuses largely on squamous cell carcinoma. The treatment algorithms for those other disease entities tend to follow the algorithms specific to those cancer types, as opposed to the anal location.
Treatment of anal squamous cell carcinoma is with the combination of radiation and chemotherapy, including 5-fluorouracil and mitomycin at the beginning and at the end of a 4- to 6-week radiation regimen. Continued surveillance and re-evaluation is required.
Some T1, N0 anal margin cancers can be surgically excised without the need for further treatment. For more advanced disease, abdominoperineal resection (removal of the anus and placement of a permanent end-colostomy) was once the common treatment. Currently, this approach is limited almost exclusively to selected patients with chemoradiation-refractory or recurrent disease. (See Treatment.)
Pathophysiology
Anal squamous cell cancer is believed to be directly linked to the presence of a complex inflammatory process most commonly caused by HPV infection (particularly with serotypes 16 and 18) in the histologically unique area of the anal squamocolumnar epithelium. In one Scandinavian study, serotype 16 HPV DNA was detected in 73% of anal cancer specimens, and serotype 16, 18, or both was detected in 84% of specimens. In contrast, no rectal cancer specimens contained HPV DNA. [4]
Active HPV infection affects approximately 10% of women worldwide. The high-risk HPV serotypes 16 and 18, which are responsible for most high-grade intraepithelial lesions that may progress to cancer, along with the low-risk serotypes 6 and 11, have been targeted in a widely available quadrivalent HPV vaccine. Although a clear link between HPV vaccination and a decrease in cancer of the cervix may not yet be evident, the prevalence of those four serotypes is decreased by approximately 50% in vaccinated teenage girls and young women. [5] The relationship of HPV vaccination with anal cancer is less well studied.
Anal cancer research has adopted terminology that mirrors the grading of cervical dysplasia (ie, cervical intraepithelial neoplasia grades I, II, and III). Anal intraepithelial neoplasia (AIN) grade I is low-grade dysplasia (LGAIN), while AIN-II and AIN-III are high-grade dysplasia (HGAIN), which is then thought to progress to invasive cancer, as in the cervical model. The grading system takes into account histological attributes that include the following [6] :
-
Abnormalities in differentiation and maturation of the squamous layers
-
The depth of those abnormalities
-
Mitotic activity
-
Nuclear membrane changes
Terms such as Bowen disease and high-grade and low-grade squamous intraepithelial lesion (HSIL, LSIL) are generally less commonly used in the literature or in pathologic diagnoses in favor of AIN terminology.
The rate of progression from AIN to invasive squamous cell cancer and the risk factors for progression had been inadequately studied until fairly recently. Progression of AIN to invasive cancer of the anus has been shown to occur in 10-11% of cases. [7, 8] HIV-positive individuals have higher rates of conversion, even if their HIV disease is under control and despite lack of progression to AIDS. [9] Clearly, more clinical research is needed to permit a strong statement about rates and risk factors for progression.
Study of the natural history of AIN is complicated by the fact that it requires biopsy, which often results in excision of the tissue in question. A further complication is that pathophysiologically, cancer of the anal margin (perianal skin) may be more closely related to penile and vulvar cancers than to cervical cancer, and the former are much less well studied than the latter. [10]
In current algorithms, the perianal skin, anal transition zone, and anal canal are considered somewhat distinct; however, clinical data often use a single term, anal cancer, for diseaes in any of those areas. The American Joint Commission on Cancer (AJCC) makes a distinction in the anatomy, calling the region from the apex of the anorectal ring to the blending of the squamous mucosa/perianal skin the “anal canal.” A distinct anatomic area that may bear anal cancer is the “anal margin”, which radially extends from the end of the anal canal for 5-6 centimeters, depending on the individual’s body habitus and shape. [11]
Epidemiology
The incidence rate of anal cancer has been increasing in recent decades. In the era of greater compliance with screening protocols and greater compliance with cancer treatment in general, this apparent rise in incidence is worrisome and is attracting the attention of regulatory and professional bodies in the field. While the incidence of cervical cancer is falling by about 2% per year, the incidence of anal cancer has increased at a rate of approximately 2.1% per year over 2009–2018. [12]
According to Surveillance, Epidemiology and End Results (SEER) data, the annual incidence rate of new anal cancer cases from 2014-2018 was 2.0 per 100,000 men and women per year, while the number of deaths was 0.3 per 100,000 men and women. The lifetime risk of developing anal cancer, according to 2016-2018 SEER data, is 0.2%. [12]
A study of trends in squamous cell carcinoma of the anus (SCCA), using the US Cancer Statistics dataset, found that in 2001-2015 the incidence of SCCA rose 2.7% annually, with pronounced increases in persons age 50 years and older. The incidence of distant-stage SCCA tripled over that period, and that of regional-stage SCCA nearly doubled. From 2001-2016, anal cancer mortality rates increased 3.1% per year, with statistically significant increases in those age 50 years and older. [13]
The American Cancer Society estimates that about 9440 new cases of anal cancer (6290 in women and 3150 in men) will be diagnosed in 2022, and 1670 deaths will occur (930 in women and 740 in men). [14] Anal cancer accounts for only 2.8% of all digestive system malignancies. [15]
Risk factors for anal cancer include any of the following [16] :
-
Active HPV infection [4]
-
Smoking [7]
-
Men having sex with men (MSM) [17]
-
Anoreceptive sex
-
Immunosuppression, with a correlation with low T-cell counts [18]
-
HIV infection
-
Solid organ transplantation, especially in females ≥10 years after transplantation [19]
-
HPV‐related gynecological precancerous lesions or cancer (vulvar, cervical, or vaginal) [19]
Combinations of two or more factors pose particular risk. For example, a meta-analysis found that the highest incidence of anal cancer was in HIV-positive MSM age 60 years or older; in this group, the incidence rate was 107.5 per 100,000 person-years. [19]
Worldwide, HPV-related cancers account for approximately 4.8% of cancers and 14-15% in less-developed areas such as India and sub-Saharan Africa. HPV infection is a worldwide public health concern that is growing in importance. [20]
Cancer types other than squamous cell carcinoma are varied and account for only a minority of anal cancers—approximately 20%. [21] The epidemiology of non–squamous cell cancers of the anus (eg, melanoma, adenocarcinoma) tends to correlate more closely to those histological entities at other body sites.
Prognosis
The prognosis for patients with anal cancer, as for most cancers, is determined by the stage of disease at presentation. There appears to be a range in the indolence or aggressiveness of anal cancers, with faster or slower progression from the time of onset of symptoms. The details of these differences are not known at this time.
With anal cancer presentations at all stages, 5-year survival is 68.7%, according to SEER data from 2011 to 2017. Approximately 47% of patients have localized disease at presentation, and 5-year survival in this group is 81.9%, whereas in those who present with metastatic disease, 5-year survival is 34.5%. [12] The need for surgical treatment tends to correlate with poorer outcomes as it speaks to more locally and regionally advanced disease at presentation.
As advances in treatment for HIV infection have increased life expectancies in persons with HIV to the point where they are comparable to those of persons without HIV, the diagnosis of non-AIDS-defining cancers, including anal cancer, has also increased in persons with HIV. However, a systematic review and meta-analysis of mortality in anal cancer patients found that although cancer-specific mortality was slightly higher in persons with HIV than in those without HIV, the difference did not reach statistical significance (hazard ratio 1.15; 95% CI: 0.69-1.93). [22]
Several possible biomarkers have been studied as indicators of prognosis in anal cancer, including tumor-infiltrating lymphocytes status and plasma levels of squamous cell carcinoma antigen. However, these are yet to enter clinical practice. [23]
Patient Education
It is important for patients who are at increased risk for anal cancer to be aware of the anal area and to alert healthcare providers early to the presence of abnormalities there, such as the following:
-
Lumps
-
Masses
-
Bleeding
-
Nonhealing lesions
-
Irritation
-
Other poorly defined symptoms
Patients who may be at increased risk for anal cancer include the following:
-
Women who have had an abnormal Pap smear, cervical dysplasia, or cervical cancer
-
Patients who are immunocompromised from disease or medical therapy
-
HIV-positive patients
-
Men who have sex with men
For patient education information, see the Anal Cancer Directory. See also Anal Cancer Prevention from the National Cancer Institute.
-
Anal cancer with typical mass. Courtesy of Luay Ailabouni, MD, FACS, FASCRS.
-
Paget disease. Courtesy of Luay Ailabouni, MD, FACS, FASCRS.
-
Anal cancer. Courtesy of Luay Ailabouni, MD, FACS, FASCRS.
-
Anal cancer in the setting of condyloma (anal warts). Courtesy of Luay Ailabouni, MD, FACS, FASCRS.
Tables
Stage |
T |
N |
M |
0 |
Tis | N0 | M0 |
| I | T1 | N0 | M0 |
| IIA | T2 | N0 | M0 |
| IIB | T3 | N0 | M0 |
| IIIA | T1-2 | N1 | M0 |
| IIIB | T4 | N0 | M0 |
| IIIC | T3-4 | N1 | M0 |
| IV | Any T | Any N | M1 |
