Anal Cancer

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]

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.

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]

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.

Patients with anal cancer or its precursor lesion, anal intraepithelial neoplasia (AIN), may be asymptomatic or may present with a wide range of complaints, including the following[24] :

• Anal or pelvic pain and anal bleeding (approximately half of patients)
• Sensation of rectal mass (approximately 30%)
• Local wetness and irritation
• Prolapse of tissue
• Incontinence of flatus or liquid or solid stool
• Obstipation

Approximately 19% of patients wait 6 months or more to seek medical care after symptom onset. Once patients do present, delayed diagnosis or misdiagnosis is unfortunately frequent; in one review, 27% of anal cancers were diagnosed as hemorrhoids on the patient's first visit to a primary care provider.[25]

Denial or reluctance on the part of many patients to seek medical attention for such complaints, as well as the similarity of those signs and symptoms to the manifestations of benign anorectal disease, help explain why anal cancer has historically had a very long lag time (up to 2 years on average) between initial symptoms and diagnosis.[26] More recent data suggest that the average time to diagnosis from onset of symptoms is 7.4 months and 3.2 months after the first visit to a physician.[25]  A patient complaint such as "hemorrhoids", anal mass, or bleeding should always warrant a physical examination, with immediate referral to a colon and rectal surgeon for abnormal appearance, refractory disease, or presence of a mass.  

Although the link between human papillomavirus (HPV) and AIN/anal cancer is well established, a lack of history of anoreceptive sexual practice does not rule out the possibility of HPV infection in the anal area, as there may be a significant "drip-down effect." In addition, non–HPV-related anal squamous cell carcinoma may also occur; such cases are usually attributed to chronic inflammation.[27] However, a history of anoreceptive sexual practice does increase the likelihood of HPV infection and its persistence in the anal area,[28]  and also of AIN and anal cancer.

Physical examination findings in anal cancer are varied, as the process begins as a microscopic disease that then progresses. In contrast, colon cancer, which most often begins as an area of dysplasia in a polyp, usually is not a microscopic disease at onset.

Anal warts may or may not be present in a patient with anal cancer, as the HPV serotypes responsible for cancer often exist together with, but are distinct from, those that typically cause anogenital warts.[29] Perianal skin irritation from mucus, wetness, and fungal overgrowth may be evident. AIN-affected tissue may have visible mucosal texture changes, vascular pattern abnormalities, and color changes or may be visually indistinct from surrounding skin or mucosa.

A mass may be present in the anal canal, anal verge, or in the perianal skin (see the image below). It is important to make a distinction between these locations, as the specific anatomic location may help determine the treatment scheme of choice.

Anal cancer with typical mass. Courtesy of Luay Ailabouni, MD, FACS, FASCRS.

Usually, an anal cancer mass will have a weeping mucosal covering, with associated moisture changes in the surrounding tissue. The mass typically has a nodular texture and may be fixed to structures in the surrounding areas such as the sphincter complex, pelvic sidewall, vagina, or coccyx area.  

Digital rectal examination to determine the extent of disease as well as fixation to the sphincter or other surrounding structures is a critical examination maneuver. Examination of the inguinal and femoral lymph node basins for lymphadenopathy should be performed.

Anal cancer is typically found in one of the following three ways:

• As an incidental finding on biopsy for another reason
• During surveillance for anal intraepithelial neoplasia (AIN; precancerous lesion)
• Discovered de novo

Anoscopy and rigid proctoscopy to determine the size of the primary lesion and the extent of the spread of disease will guide preoperative staging. Incisional or punch biopsy of the lesion as well as core needle biopsy of suspected lymph node spread should also be performed. Pap smear testing of the anus and cervix can be performed to document the presence of high-risk serotypes of human papillomavirus (HPV).[30]

A biopsy result is the first step in the diagnostic algorithm. Rarely, the biopsy will reveal entities other than squamous cell carcinoma, such as the following:

• Adenocarcinoma
• Melanoma
• Gastrointestinal stromal tumor (GIST)
• Neuroendocrine tumor
• Basal cell carcinoma
• Paget disease
• Verrucous carcinoma
• Kaposi sarcoma
• Lymphoma

When biopsy identifies an entity other than squamous cell carcinoma, the subsequent workup will mirror more closely the workup of disease from that entity at other sites in the body.

In patients with anal squamous cell carcinoma, colonoscopy examination is also recommended, as there is a 15% incidence of colorectal neoplasm discovered at the time of diagnosis, though there is no known link between colorectal cancer and anal cancer[30] .

Imaging studies for all anal cancer patients should include a computed tomography (CT) scan of the chest, abdomen, and pelvis to evaluate for enlarged lymph nodes and metastatic spread. Female patients should be evaluated with a thorough gynecologic examination, including screening for cervical cancer. A positron emission tomography (PET)–CT scan can be considered in certain clinical scenarios. HIV testing may be appropriate and is advocated by many authorities, with a CD4 level when indicated.[30, 31]

Currently, no major regulatory or professional body recommends anal cancer screening for the general population, and controversy surrounds the questions of which patients are candidates for screening and what techniques should be used. Colorectal cancer screening in any form except colonoscopy has little to no likelihood of discovering anal cancer, though a digital rectal examination should be performed when a screening test is ordered or performed. Anal cancer may be discovered during colonoscopy or during the pre-procedure digital rectal examination, but the screening protocols designed for the discovery of colorectal cancer are not designed to discover anal cancer.

In general, screening is recommended in patients at high risk for anal cancer, such as the following:

• Some immunocompromised patients (eg, kidney or liver transplant recipients)
• Patients with anogenital warts
• HIV-positive men who have sex with men (MSM)
• Previous history of AIN  ^[32]

The HIV Medicine Association of the Infectious Diseases Society of America (IDSA) recommends screening by anal Papanicolaou (Pap) smear for the following HIV-positive patients[33, 34] :

• MSM
• Women with a history of receptive anal intercourse or abnormal cervical Pap smear
• HIV-positive people with anogenital warts. Nadir and cumulative CD4 may represent useful markers for identifying higher anal cancer risk.  ^{[35, 36, 37]}

Possible screening methods for anal cancer and AIN include the following:

• Anal Pap smear (sensitivity 85%, specificity 43%) ^[38]
• High-resolution anoscopy (HRA)
• Digital anorectal examination
• HPV testing

HRA serves as the gold standard of anal cancer screening. However, it is perhaps prohibitively expensive and poorly implementable.[39]

Staging is based on the widely used American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) system, to stratify patients into research, treatment, and survival groupings.[11] The primary tumor classification is based on size and depth of invasion, nodal status is based on location of the nodes, and metastatic disease is designated as present (M1) or absent (M0).

Primary tumor (T) designations are as follows:

• Tis - High-grade squamous intraepithelial lesion (previously termed carcinoma in situ, Bowen disease, anal intraepithelial neoplasia II–III, high-grade anal intraepithelial neoplasia)
• T1 - Tumor ≤ 2 cm
• T2 - Tumor  2–5 cm
• T3 - Tumor > 5 cm
• T4 - Any size tumor that invades adjacent organs (eg, vagina, bladder, urethra, but not anal sphincter complex)

Regional lymph node designations are as follows:

• N0 - No regional lymph node metastasis
• N1 - 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

Metastasis designations are as follows:

• M0 - No distant metastasis
• M1 - Distant metastasis

Anatomic stage/prognostic groups are listed in the Table below.

Table. Anatomic stage/prognostic group (Open Table in a new window)

See also Anal Cancer Staging.

For the majority of patients diagnosed with anal squamous cell carcinoma, treatment will consist of radiation therapy combined with radiosensitizing chemotherapeutic agents.[30, 31, 40] This treatment method has remained remarkably unchanged since its advent as the so-called Nigro Protocol in 1974.[41]  

Surgery plays a limited role in the treatment for anal cancer. National Comprehensive Cancer Network (NCCN) guidelines recommend that lesions in the anal margin, which starts at the anal verge and includes the perianal skin over a 5- to 6-cm radius from the squamous mucocutaneous junction, can be evaluated for local excision with adequate margins and subsequent observation, with no additional cancer-specific treatments.[31] However, this approach is reserved for patients with locally advanced disease, refractory disease, pretreatment incontinence, or other specific factors.

Symptom control

Symptom management is critical during the entire process of discovery, diagnosis, and treatment phases for the anal cancer patient. Anal and fecal incontinence can be alleviated or minimized by slowing of stool passage with bulking agents such as psyllium husk powder and, in the case of diarrhea, with antidiarrheal agents.

Hygiene issues and moisture-related skin breakdown are very common in anal cancer patients. Maintaining excellent post–bowel movement cleansing by means of sitz baths or showers can be of great benefit to patients. Dressings or clothing that wick moisture away from the skin can also provide great comfort. Barrier creams and off-loading strategies should be considered in the case of skin breakdown. Symptom control will require the design of a bowel and lifestyle regimen specific to the particular patient’s needs and goals.  

Cancer treatment

For localized disease, National Comprehensive Cancer Network (NCCN) guidelines recommend 5-fluorouracil (5-FU), mitomycin, and radiotherapy.[31] 5-FU is infused continuously during days 1-4 and days 29-32. Mitomycin is administered on days 1 and 29 as a bolus infusion. Alternatively, oral capecitabine (eg, 825 mg/m2 twice daily on days 1–5 weekly for 6 weeks) can be substituted for 5-FU.

In a randomized study, the RTOG 98-11 trial, that attempted to improve on the above regimen with substitution of cisplatin for mitomycin in non-metastatic disease, the mitomycin regimen proved superior. The primary endpoint of the study, 5-year disease-free survival, was 67.8% with 5-FU/mitomycin versus 57.8% with 5-FU/cisplatin (P= 0.006); 5-year overall survival also favored the mitomycin-containing regimen (78.3% vs 70.7%, respectively; P = 0.026).[42]  The NCCN considers 5-FU/cisplatin plus radiation therapy as a category 2B recommendation.[31]  Similarly, the ACCORD 03 trial, which evaluated the utility of induction chemotherapy prior to the chemoradiation regimen or additional radiation boost, showed no advantage to either alteration in protocol.[43]

Concurrent multifocal radiotherapy progresses 5 days per week for the full 32 days of treatment, with a total minimum dose of 45 Gy in 25 fractions of 1.8 Gy to the primary cancer, plus additional radiation to the inguinal nodal basins. Additional radiation is recommended for more advanced lesions or known nodal spread. An increased total radiation dose, even up to 65 Gy, and avoiding prolonged breaks are recommended based on limited but compelling data,[30]  although increased dose is associated with increased toxicity.  

Radiation therapy for anal cancer has historically involved two- or three-dimensional conformal (3DCRT techniques, but intensity-modulated radiation therapy.(IMRT) has become the most widely utilized radiation therapy technique for anal cancer, with 3DCRT used in a very small minority of patients.[44]  The NCCN currently recommends IMRT over 3DCRT for radiation therapy in anal cancer.[31]

Compared with non-IMRT radiation therapy, IMRT delivers significantly less radiation to normal tissue, leading to reduced rates of toxicity-related treatment interruption.[45]  Analysis of 8,108 patients diagnosed with non-metastatic anal cancer from 2004 to 2013 found that overall survival (OS) was longer with IMRT than with non-IMRT (hazard ratio [HR] 0.83, 95% CI: 0.74-0.94; P=0.002); 5-year OS rates were 74.6% vs 70.5%, respectively (P=0.0022).[46]   MRT does require specialized equipment and expertise and careful target design, however, and therefore may increase the cost of treatment.

At the conclusion of the chemoradiation regimen, a re-evaluation by the surgeon is conducted at 8-12 weeks. Subsequent management depends on whether the patient has remission of disease, persistent disease, or progression of disease.

Patients with complete remission of visible disease require surveillance with serial digital rectal examinations, inguinal examinations, and (if T3/4 or inguinal N+) annual computed tomography (CT) scans of the chest, abdomen, and pelvis (see Treatment/Long-Term Monitoring). Patients with local recurrence require surgical treatment with abdominoperineal resection (APR). If inguinal recurrence is found, inguinal dissection with possible chemotherapy is indicated. If distant metastasis is found after treatment, a cisplatin-based chemotherapeutic regimen is recommended.

If the patient has persistent disease, re-evaluation is indicated after 4 additional weeks, to allow completion of the effects of radiation therapy. If regression is then evident, serial examinations and CT scans are indicated. 

However, if biopsy after this observation period demonstrates progression of disease, then restaging should be completed. Local disease is managed surgically with APR, and followed up with subsequent examinations and CT scans. If evidence of metastatic disease is found after the above radiation/chemotherapy regimen, then the 5-FU/cisplatin chemotherapy regimen described below is indicated.

For metastatic disease at presentation, 5-FU is infused on a continuous basis for 5 days, along with cisplatin infusion on day 2. This regimen is repeated every 4 weeks.

In refractory metastatic anal cancer, immune checkpoint inhibitors (eg. pembrolizumab, nivolumab) have demonstrated promising efficacy. Research into the use of these agents for refractory cases is ongoing, and clinicians should consider enrolling patients with refractory metastatic anal cancer in one of these clinical trials.[47]

Pembrolizumab was also granted accelerated approval for unresectable or metastatic tumor mutational burden–high (TMB-H; ≥10 mutations/megabase) solid tumors in patients who have progressive disease despite treatment and who have no alternative treatment options. Approval was based on results of an analysis of 10 cohorts of previously treated patients with various unresectable or metastatic TMB-H solid tumors enrolled in the KEYNOTE-158 trial. Among the 13% of patients identified as TMB-H, the objective response rate was 29%, with a 4% complete response rate and 25% partial response rate. The median duration of response was not reached, with response durations of ≥12 months in 57% of patients and of ≥24 months in 50%.[48]

For more information, see Anal Cancer Treatment Protocols.

Surgery is indicated in anal cancer for T1, N0, well-differentiated lesions in the anal margin. If there is a reasonable expectation of adequate margins, then surgery can be attempted, as complete excision will eliminate the need for chemotherapy and radiation therapy. If the margins are inadequate, re-excision may be attempted or the above radiation/chemotherapy regimen should be initiated.

Historically, treatment of anal cancer was primarily surgical, with APR and permanent end-colostomy as the primary option. That treatment was associated with substantial morbidity and a relatively high recurrence rate.The 5-year survival was 40-70% after APR,[24] though those data represent studies dating back to the 1940s and may not serve as an accurate comparison to modern techniques. 

Nevertheless, with the impressive results from nonsurgical treatment (chemoradiation) and its elimination of the need for end-colostomy, APR has become only sparingly used in the treatment of anal cancer. APR for anal cancer consists of removal of the anorectum as well as any affected perianal skin and any satellite lesions. Creation of anatomic flaps to fill the void left by this radical excision is often necessary and plastic surgery consultants are usually required to provide such specialized and individualized perineal wound closure.[49]

At the time of APR, all patients require end-colostomy to provide distal elimination of the digestive tract. This colostomy is preferably created in the left lower quadrant, using a muscle-splitting technique to help prevent or forestall the appearance of paracolostomy hernia. The issue of paracolostomy hernia is more significant in those patients with end-colostomy, as there is no hope for reversal of the stoma and it will be present life-long.

Some surgeons advocate the placement of peristomal mesh at the time of creation and small studies have suggested that this may be a useful strategy.[50, 51] Consensus on this subject does not yet exist and at least two large randomized controlled studies to determine its benefit are currently in progress.[52, 53]

APR is indicated in cases of locoregional disease that initially responds completely to chemoradiation but recurs, and also in cases that persist or progress through chemoradiation, as well as in select patients who have fecal incontinence. Groin dissection is indicated when inguinal nodes are known to contain metastasis. Sentinel lymph node biopsy is under investigation and shows high detection rates.[54, 55] However, forgoing inguinal radiation therapy in patients with negative sentinel nodes is not recommended.[30, 54]

A wide variety of complications can affect the anal cancer patient, including the short-term adverse effects of active chemotherapy and long-term risks of radiation exposure. Because chemotherapy combined with radiation is the current standard of care for most anal cancer patients, complications of radiation are more common.Technique, volume, total dose, fraction size, and timeframe are all factors that may have effects on radiation complications.[56]

Radiation exposure causes microvascular changes that alter the efficiency of the wound healing process and platelet function in exposed tissues and also increases angiogenesis by means of expression changes in the tissues themselves.[57] In the era of narrowed, multifocal fields and intensity-modulated radiation therapy (IMRT), radiation complications have decreased and are likely to continue to do so,[58, 59] although they still may occur, even years after treatment, in 1%-20% of patients.[60]  

Inflammatory conditions, sexual dysfunction, and bowel dysfunction are the most common negative side effects of radiation therapy to the pelvis. Among the late inflammatory sequelae of radiation, the most common is proctitis of any kind, which most commonly manifests as rectal bleeding and other symptoms. Late rectal bleeding after pelvic radiation is fairly common, affecting 22% of 2D simulation and 7% of 3D simulation patients.[59]

Mild bleeding, urgency, frequency, and diarrhea are common manifestations of radiation proctitis in its milder forms. Most often, proctitis produces minimal complaints; however, bleeding from the rectum can be significant and difficult to control. The severity of early acute proctitis may possibly be a predictor of late chronic proctitis.[60]

Generally, short-course antibiotic therapy with a fluoroquinolone and metronidazole is an effective first choice for treatment. Other treatment modalities for bleeding in the rectum may include electrocautery and argon beam cautery of bleeding sites, topical applications of medications such as formalin in cases of more diffuse bleeding, hyperbaric oxygen, and even, rarely, surgical diversion or excision of the affected organ.   

Surgery for these high-risk individuals in the setting of proctitis comes with high morbidity and mortality and should be avoided if possible. If surgery is required, it should be performed at a tertiary care center.[61]

Stricture, fistula, and perforation are also complications of pelvic radiation related to poor healing and are unlikely to resolve without surgical intervention. Case reports of colorectal cancers in previous radiation fields have also been documented[62]  and are thought to be related to chronic inflammation in the field.

Prevention begins with recognition of the risk factors for anal cancer, which are as follows[16, 19] :

• Anal human papillomavirus (HPV) infection
• In women, a history of vulvar, cervical, or vaginal cancer or precancerous lesions
• HIV infection
• Immunosuppression (eg, in organ transplant recipients, individuals with autoimmune diseases)
• Certain sexual practices (receptive anal intercourse, having many sexual partners, sex between men)
• Cigarette smoking

Strategies for prevention of anal squamous cell carcinoma consist of vaccination against HPV and management of anal intraepithelial neoplasia (AIN). In the United States, 91% of anal cancers have been found to be positive for HPV, with HPV subtype 16 most commonly detected.[63] A systematic review and meta-analysis concluded that HPV16 is by far the most carcinogenic HPV type in the anus that may contribute to the progression of HSIL to anal cancer. HPV16 may prove to be a priority target for anal cancer screening and prevention.[64]

Initially approved in 2014, the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) is the only HPV vaccine available in the US. The 9vHPV vaccine covers HPV subtypes 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is indicated for males and females aged 9 through 45 years to prevent anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58. Additionally, it is indicated for prevention of precancerous AIN grades 1, 2, and 3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.[65]

In HIV-positive men who have sex with men (MSM), screening for anal cancer has been proposed as a cost-effective measure.[66] Possible screening methods could include anal Pap smears or anoscopy on an annual basis, or targeted anoscopy 5 years after the CD4 count drops below 200 cells/μL.[67]

Women, regardless of HIV status, with a history of high-grade lesion or cancer of the cervix, vulva, or vagina are another at-risk population that may benefit from screening. A 2019 systematic review and meta-analysis with paired anal and cervical samples demonstrated a strong association between anal HPV16 and high-grade lesions with cervical HPV16. Additional considerations include a history of anogenital warts and cigarette smoking, although these by themselves are not an indication for anal dysplasia screening.[68]

The use of topical creams in the setting of close long-term follow-up is considered appropriate for AIN lesions. Topical 5% imiquimod cream is considered appropriate for anal margin AIN lesions, as is 5% 5-fluorouracil (5-FU) cream. Good responses are reported; adverse effects are common but typically of low severity.[30]

Topical therapy may be especially useful in HIV-positive patients, who have a higher rate of conversion from AIN to cancer. The ANCHOR trial demonstrated a 57% reduced rate of progression to anal cancer in HIV-positive individuals with high-grade squamous intra-epithelial lesions (HSIL) receiving treatment versus active monitoring.[69] A large randomized phase III trial comparing ablative and topical treatment with observation for prevention of anal cancer in HIV-positive patients with high-grade AIN is in progress. Completion of the study is expected in 2027.[70]

A study in HIV-positive MSM by Richel et al reported a higher complete response rate in AIN treated with electrocautery than with imiquimod or topical 5-FU. Recurrence rates were high with all treatments.[71]

Targeted biopsy and destruction of the lesions, when visible, are considered the preferred methods of control for AIN. Anal mapping (ie, perianal mapping biopsies in advance of formal wide excision), while once routine, is generally not required, but is still used.[30]

Follow-up in patients with a history of anal cancer should include the following:

• Digital rectal examinations (DRE) and inguinal palpation every 3-6 months for 5 years
• Anoscopy every 6-12 months for 3 years
• Chest/abdomen/pelvis computed tomography (CT) scan annually for 3 years

In patients who have undergone abdominoperineal resection and colostomy placement, DRE and anoscopy are obviously eliminated from the regimen. CT scanning can also be avoided in cases of complete remission and when the original staging was not T3, T4, or inguinal lymph node positive.[31]

Use of the following additional imaging techniques has been recommended for detection of recurrent disease, although supporting data are currently limited:

• Three-dimensional endoanal ultrasound ^[72]
• Positron emission tomography (PET)/CT ^[73]  
• Magnetic resonance imaging (MRI) ^[74]

Guidelines for the management of anal cancer have been published by the following organizations:

• American Society of Colon and Rectal Surgeons (ASCRS) ^[30]
• National Comprehensive Cancer Network (NCCN) ^[31]
• European Society for Medical Oncology (ESMO) ^[75]
• Howard Brown Health ^[76]

Practice parameters, issued by the ASCRS in 2012 and revised in 2018, cover prevention, pretreatment evaluation, treatment, and post-treatment surveillance of anal squamous neoplasms. Recommendations for anal margin and anal intraepithelial neoplasia (AIN) are also provided.[30, 77]

Prevention

ASCRS recommendations for anal cancer prevention include the following:

• Use history, physical examination, and laboratory testing to identify patients at increased risk for anal squamous neoplasms (eg, HIV-positive individuals, men who have sex with men [MSM], women with a history of cervical dysplasia). (Strong recommendation based on moderate-quality evidence, 1B)
• Provide regular follow-up of patients with anal dysplasia, with history, physical examination, and discussion of screening options. (Weak recommendation based on moderate-quality evidence, 2B)
• Consider screening high-risk patients with anal cytology (or anal Papanicolaou tests [Pap smears]); HPV testing may be used as an adjunct. (Weak recommendations based on moderate-quality evidence, 2B)
• High-resolution anoscopy may be considered as a screening option for high-risk patients, when performed by appropriately trained clinicians. (Weak recommendation based on moderate-quality evidence, 2B)
• Topical imiquimod, fluorouracil, trichloroacetic acid, or cidofovir, with close long-term follow-up, are options for the treatment of low-grade or high-grade squamous intraepithelial lesions. (Weak recommendation based on moderate-quality evidence, 2B)
• Vaccination against human papillomavirus (HPV) in men and women under age 26 years for primary prevention is typically recommended; Vaccination of individuals with anal dysplasia for secondary prevention of dysplasia and cancer is not recommended. (Weak recommendation based on high-quality evidence, 2A)
• Patients who have been treated for anal dysplasia may be observed without regular cytology, HPV testing, or anoscopy; however, treatment of visible or palpable disease should be offered. (Weak recommendation based on low or very low-quality evidence, 2C)

Pretreatment evaluation

For the pretreatment evaluation, the ASCRS recommends performing the following:

• A disease-specific history and physical examination, emphasizing symptoms, risk factors, and signs of advanced disease (strong recommendation based on low-quality evidence, 1C)
• Endoscopic and radiologic evaluation, to help determine staging, and assess for metastatic disease (strong recommendation based on low-quality evidence, 1C)
• 2-(18F) fluoro-2-deoxy-D-glucose positron emission tomography (PET)/computed tomography (CT) may be considered as an adjunct radiologic study in the staging of anal SCCs, but does not replace CT scanning for clinical staging (strong recommendation based on low-quality evidence, 1C)

Treatment

ASCRS recommendations for treatment include the following:

• For all squamous cell carcinomas (SCCs) of the anal canal, and for most perianal SCCs, combined chemotherapy and radiation therapy is the primary treatment; chemoradiation therapy provides better locoregional control than radiotherapy alone (strong recommendation based on high-quality evidence, 1A).
• For the chemotherapy arm, mitomycin plus 5-fluorouracil (5-FU) is the first-line regimen for anal SCCs (strong recommendation based on high-quality evidence, 1A).
• Radiotherapy doses > 59 Gy provide no oncologic benefit (strong recommendation based on moderate-quality evidence, IB).
• Missed treatments should be avoided, because they are strongly associated with inferior disease control (Strong recommendation based on moderate-quality evidence, IB).
• Abdominoperineal resection is effective salvage therapy for persistent or recurrent disease (strong recommendation based on moderate-quality evidence, 1B).
• Consider systemic chemotherapy in pa­tients with distant metastasis. Metastasectomy, radiation, and radiofrequency ablation can be considered in selected cases (weak recommendation based on low- or very-low–quality evidence, 2C).

Additional treatment recommendations include the following:

• Perianal squamous cancers that are well-differentiated, node-negative, T1 lesions can be adequately treated with wide local excision with 1-cm margins of resection (strong recommendation based on low-quality evidence, IC)
• Patients with HIV or AIDS who present with anal cancer as the first manifestation of their immunosuppression, and who are not medically deconditioned, can be safely treated according to the same regimens as immunocompetent patients (strong rec-ommendation based on medium-quality evidence, IC).

Post-treatment surveillance

The ASCRS recommends that patients treated for anal cancer receive follow-up involving digital rectal examination, anoscopy, and imaging. Surveillance should typically start 8 to 12 weeks from the completion of chemoradiotherapy and should be continued for 5 years (strong recommendation based on moderate-quality evidence, 1B).

The NCCN guidelines cover the workup, treatment, and post-treatment surveillance of anal carcinoma.[31]

Workup

When biopsy confirms SCC of the anal canal or anal margin, the NCCN recommends the following workup:

• Digital rectal examination (DRE)
• Inguinal lymph node evaluation – Consider biopsy or fine needle aspiration (FNA) of suspicious nodes
• Chest/abdominal CT plus pelvic CT or MRI – Consider PET/CT scan
• Anoscopy
• Consider HIV testing + CD4 level if indicated
• Gynecologic exam for women, including screening for cervical cancer

Treatment

For primary treatment of locoregional SCC of the anal canal, recommended chemoradiation regimens include the following;

• Mitomycin/5-fluorouracil (5-FU) plus radiation therapy (RT)
• Mitomycin/capecitabine plus RT 
• 5-FU/cisplatin plus RT (category 2B)

For RT, the NCCN panel consensus was that intensity-modulated radiation therapy (IMRT) is preferred over 3-D conformal RT. Stereotactic body RT (SBRT) may be considered for patients with oligometastatic disease.

For metastatic SCC of the anal canal, the NCCN recommends primary treatment with 5-FU/cisplatin, with or without RT,  or enrolling the patient in a clinical trial.

For primary treatment of SCC of the anal margin, treatment recommendations vary by clinical stage, as follows:

• T1, N0, well differentiated – Local excision; if margins are adequate, observe; if margins are inadequate, treat with re-excision (preferred) or consider local RT with or without chemotherapy
• T1, N0, poorly differentiated; T2-T4, N0; or any T, N+  – Chemoradiation therapy
• Metastatic disease – 5-FU/cisplatin, with or without RT,  or clinical trial

Follow-up

The NCCN recommends evaluation in 8-12 weeks with physical examination plus DRE. For patients in complete remission, surveillance recommendations are as follows:

• DRE and inguinal node palpation every 3-6 mo for 5 y
• Anoscopy every 6-12 mo for 3 y
• For patients with T3-T4 disease or positive inguinal nodes – Chest/abdomen/pelvic CT with contrast annually for 3 y

If surveillance reveals recurrent disease, treatment recommendations are as follows:

• Local recurrence – Abdominopelvic resection (APR), plus groin resection if inguinal nodes are positive
• Inguinal node recurrence – Groin dissection; consider RT if patient had no prior groin RT, with or without 5-FU or mitomycin/capecitabine
• Distant metastasis – 5-FU/cisplatin or clinical trial

Surveillance after treatment for local recurrence includes the following:

• Inguinal node palpation every 3-6 mo for 5 y
• Chest/abdomen/pelvic CT with contrast annually for 3 y

Surveillance after treatment for inguinal node recurrence includes the following:

• DRE and inguinal node palpation every 3-6 mo for 5 y
• Anoscopy every 6-12 mo for 3 y
• Chest/abdomen/pelvic CT with contrast annually for 3 y

If initial post-treatment evaluation reveals persistent disease, the NCCN recommends re-evaluation in 4 wk; if serial exams show regression or stable disease, the NCCN recommends continued observation, re-evaluation in 3 mo, and biopsy at 6 mo. In cases of progressive disease, biopsy proven, recommendations are as follows:

• Locally recurrent – APR, plus groin resection if inguinal nodes are positive
• Metastatic disease – 5-FU/cisplatin or clinical trial

he ESMO guidelines cover diagnosis, treatment, and follow-up of anal cancer.[75]

Diagnosis

ESMO recommendations for diagnosis of anal cancer include the following:

• Digital anorectal examination (DRE) is essential for detection of lesions in the anal area.
• Biopsy is mandatory to confirm squamous cell carcinoma of the anus (SCCA)
• All suspicious anal lesions should be excised or biopsied. Targeted biopsy of anal lesions suspicious for anal intraepithelial neoplasia (AIN) is mandatory in high-risk groups to exclude invasive disease.
• Female patients with AIN should be screened for synchronous cervical, vulvar, and vaginal intraepithelial neoplasia.
• Consider HIV testing in patients with recurrent or multifocal AIN.
• High-resolution T2-weighted MRI is needed for optimal assessment of primary tumour and lymph nodes.
• Magnetic resonance imaging (MRI) may also be helpful to note the relationship of tumor/nodes to the sacral segment levels, which would also assist in RT planning.
• Lymph nodes can be difficult to interpret on MRI. Generally, they are more likely to be malignant if they exhibit mixed signal intensity and if breach of the lymph node capsule by tumor signal intensity is observed on high-resolution T2-weighted MRI.
• Contrast-enhanced computed tomography (CT) scanning of the thorax, abdomen, and pelvis is a requirement for all patients to assess potential metastatic disease sites at diagnosis and follow-up.
• Further characterization of enlarged inguinal nodes by ultrasound-guided fine needle aspiration may be helpful when confirmatory features of malignancy are not evident on either MRI or positron emission tomography/CT (PET-CT).
• PET-CT may be considered for staging and assist in RT planning.
• Assessment of human papillomavirus (HPV) or p16 status may be considered, as the results can help predict treatment response.

Treatment

Recommendations for primary treatment include the following:

• Radiation therapy (RT) with concomitant 5-fluorouracil (5-FU) and mitomycin C is recommended as standard of care for patients with localized SCCA. Capecitabine can be possibly used as an alternative to 5-FU.
• Chemoradiotherapy (CRT) for locally advanced anal cancer should be given with an RT dose of > 50 Gy; the optimal dose for different tumor stages is not known.
• Neoadjuvant or adjuvant chemotherapy is generally not recommended.
• Elderly patients who can tolerate treatment should be treated with curative CRT. Patients who cannot tolerate CRT may benefit from RT for local control.
• Intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), or 3D conformal RT are the recommended RT techniques, with RT dose constraints to normal tissue.
• The optimal RT dose for primary anal cancer is not known, but doses of at least  >45-50 Gy are recommended for T1-2N0 tumors, and doses of 50.4 Gy or higher for T3-4 or N1 tumors.

Recommendations for treatment of anal margin cancers include the following:

• Early anal margin cancers (cT1N0M0) can be treated definitively by local excision, with the goal of achieving histologic clearance of > 1 mm without damage to the anal sphincter muscle.
• CRT is recommended for anal margin cancers (T1N0M0) if the margin is ≤1 mm.

Recommendations for locally recurrent or residual disease include the following:

• Patients with locally residual or recurrent disease after CRT should be considered for salvage surgery.
• Residual or recurrent tumors may be considered for histologic confirmation.
• For patients with locally recurrent disease, MRI in conjunction with specialist multidisciplinary team assessment is important to optimize surgical cure].
• Involvement of the anal sphincter complex requires exenterative surgery, and imaging assessment should include a thorough assessment of the pelvic compartments to enable surgical planning (beyond total mesorectal excision).
• The mainstay of salvage surgery is abdomino-perineal excision, but more radical exenterative operations can be considered to achieve an R0 resection. APE for relapsed anal cancer is a different operation from that used for rectal cancer; perineal plastic reconstruction with musculo-cutaneous flaps should be considered in almost all cases.

Recommendations for advanced anal cancer in chemotherapy-naive patients include the following:

• Carboplatin plus paclitaxel should be considered a new standard of care.
• Cisplatin/5-FU/capecitabine, carboplatin, or docetaxel-based combinations are alternatives.
• Programmed cell death ligand 1 (PD-L1) inhibitors may be considered in patients whose disease has progressed on first-line therapy in clinical trials.

Follow-up

Patients in complete remission should be evaluated every 3-6 months for a period of 2 years, and every 6-12 months until 5 years, with clinical examination including DRE and palpation of the inguinal lymph nodes. Patients with locally advanced anal cancer may benefit from intensive MRI surveillance in the first 12 months.

The Howard Brown Health guidelines cover screening for anal cancer. Recommendations for screening include the following[76] :

• Persons living with HIV who are younger than 30 years of age should be screened annually with a DRE.
• Persons living with HIV at age 30 and above should be screened annually with anal cytology, DNA test for rectal high-risk HPV, and DRE.
• Persons of any age with a history of cancer of the cervix, vagina, and/or vulva should be screened immediately after diagnosis and then annually with anal cytology, DNA test for rectal high-risk HPV, and DRE.
• Persons age 30 and older with a history of high-grade squamous intra-epithelial lesions (HSIL) of the cervix, vagina, and/or vulva should be screened annually with anal cytology, DNA test for rectal high-risk HPV, and DRE.
• HIV-negative persons age 40 years and older who have regular anoreceptive penetrative sex or anoreceptive play with multiple partners should be screened annually. Screening should include anal cytology, DNA test for rectal high-risk HPV, and DRE.
• Recipients of solid organ transplants should be screened annually, starting 2 to 5 years post-transplant. Screening should include anal cytology, DNA test for rectal high-risk HPV, and DRE.

Additional considerations include the following:

• History of anogenital warts and cigarette smoking may help identifying risk but in and of itself is not an indication for anal dysplasia screening.
• Availability of a provider able to perform high-resolution anoscopy prior to cytology or DNA test for high-risk HPV is offered

Topical medications used off-label for the treatment of anal intraepithelial neoplasia (AIN) of the anal margin include imiquimod 5% cream (Aldara) and 5-fluorouracil (5-FU) 5% (Efudex). Imiquimod cream, which can be used only for anal margin lesions, is applied three times per week at bedtime for maximum of 16 weeks.[71, 78, 79] 5-FU cream is applied twice daily for 3-6 weeks.[71, 78, 79] Close surveillance of patients is required with both these treatments.

For systemic treatment of anal cancer, intravenous 5-FU (or its oral prodrug, capecitabine) and mitomycin are used as radiosensitizing agents. 5-FU and cisplatin are used for metastatic disease.

Class Summary

System agents are used adjunctively with radiation therapy or for metastatic disease.

Fluorouracil (Adrucil)

Intravenous 5-FU is used with mitomycin as a radiosensitizing agent for treatment of anal cancer. It is also used with cisplatin for metastatic disease. It is an antimetabolite that inhibits DNA synthesis during S phase by inhibition of thymidylate synthetase.

Mitomycin

Mitomycin is used IV with 5-FU as a radiosensitizing agent for treatment of anal cancer. It acts by crosslinking DNA, and thereby prevents replication and transcription.

Cisplatin

IV cisplatin is used with 5-FU for metastatic anal cancer. It is an alkylating agent and a platinum coordination compound that inhibits DNA synthesis; cross-links and denatures strands of DNA.

Capecitabine (Xeloda)

Fluoropyrimidine carbamate prodrug form of 5-fluorouracil (5-FU). Capecitabine itself is inactive. Undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA and to a lesser degree with RNA synthesis.

Class Summary

Agents in this class inhibit cell growth and proliferation.

Imiquimod (Aldara, Zyclara)

Imiquimod 5% cream is used off-label for anal margin lesions. It is applied 3 times per week at bedtime and then washed of in the morning. May apply for maximum of 16 weeks.

Fluorouracil topical (Efudex)

Topical (5-FU) 5% is used off-label for the treatment of AIN of the anal margin. It is applied twice daily for 3-6 weeks.

Class Summary

The 9-valent HPV vaccine is indicated for prevention of HPV-associated neoplasias and precancerous genital lesions. The 2-valent and 4-valent vaccines were discontinued from the US market in 2016.

Children and adolescents aged 15 years and younger need two, not three, doses of the HPV vaccine; this ACIP recommendation stems from the vaccine’s enhanced immunogenicity in preteens and adolescents aged 9-14 years. The schedule for older adolescents and young adults aged 15 through 45 years is three inoculations within 6 months.

Human papillomavirus vaccine, nonavalent (Gardasil 9)

Induces humoral immune response to 9 HPV subtypes: 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is indicated in males and females aged 9 through 45 years to prevent HPV-associated diseases.

Class Summary

Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells. PD-1 and PD-L1 inhibitors blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation.

Pembrolizumab (Keytruda)

It is indicated for unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mut/Mb] solid tumors in patients that have progressed following prior treatment and who have no alternative treatment options.