Anal Cancer – Causes, Symptoms, Diagnosis, Treatment

Anal Cancer/Cancers of the anal canal are rare, comprising approximately 10% of malignancies in the anorectal region, although its incidence has been increasing over the past several decades.[rx][rx] While the traditional approach to treatment was with abdominoperineal resection (APR), this has evolved in the modern era to concurrent chemoradiation as organ-preserving treatment.

Types of Anal Cancer

Several types of tumors may be found in the anus. While some of them are malignant (cancer), others are benign (not cancer) or precancerous (may develop into cancer). The main types of anal cancer are

• Benign tumors – Tumors that are benign are noncancerous tumors. In the anus, this can include polyps, skin tags, granular cell tumors, and genital warts (condylomas).
• Precancerous conditions – This refers to benign tumors that may become malignant over time, which is common in anal intraepithelial neoplasia (AIN) and anal squamous intraepithelial neoplasia (ASIL).
• Squamous cell carcinoma – Squamous cell cancer is the most common type of anal cancer in the United States. According to the American Cancer Society, it accounts for 9 out of 10 cases. These malignant tumors in the anus are caused by abnormal squamous cells (cells that line most of the anal canal).
• Bowen’s disease – This condition, also known as squamous cell carcinoma in situ, is characterized by abnormal cells on anal surface tissue that haven’t invaded deeper layers.
• Basal cell carcinoma – Basal cell carcinoma is a type of skin cancer that generally affects skin exposed to the sun. Because of this, it’s a very rare form of anal cancer.
• Adenocarcinoma – This is a rare form of cancer that arises from the glands surrounding the anus.
• Carcinoma in situ – is early cancer or precancerous cells. They are only on the surface cells of the anal canal. This also may be called Bowen’s disease.
• Squamous cell cancer – (carcinoma) forms in the cells that line the anus. This is the most common type of anal cancer.
• Adenocarcinomas – develop in the glands around the anus.
• Skin cancers, including basal cell and melanoma, often are found when they are in advanced stages.

Anatomy of Anal Cancer

The anal canal runs from the anal verge (the visible junction between the internal anal canal and hair-bearing keratinized external anal skin) to the anorectal ring (the location in which rectum enters puborectalis sling). The anal canal is approximately 3 to 5 cm in length. The dentate line is the anatomic boundary where mucosa changes from non-keratinized squamous epithelium to colorectal-type columnar mucosa proximally. It divides the upper and lower anal canal. The anal margin, also referred to as perianal skin, is a rim of tissue around the anus encompassed by a 5 cm radius, and it bears true squamous epithelium. Lymphatic drainage of anal cancers depends upon its location relative to the dentate line. Cancers above the dentate line drain to the presacral and internal iliac nodes. Cancers below the dentate line drain to superficial inguinal and femoral nodes.

Causes of Anal Cancer

High grade anal intraepithelial neoplasia (AIN) can be a precursor to anal cancer. AIN can result from an infection with human papillomavirus (HPV), predominantly serotypes 16 and 18. HPV spreads via skin-to-skin contact and sexual intercourse.[rx] Additional risk factors for anal cancer include HIV infection, promiscuous sexual behavior, smoking, chronic immunosuppression not due to HIV, and chronic inflammatory states such as Crohn disease.[rx][rx][rx][rx] HPV vaccines, when given before HPV exposure, reduce the rates of AIN and should be considered in populations at high risk for anal cancer.[rx]

Anal cancer develops when cells grow uncontrollably and form a tumor. Two types of cancer can form in the anus, depending on where the cancer starts.

• Squamous cell cancer – The anal canal connects the rectum to the outside of the body. Squamous cells line the canal. These flat cells look like fish scales under the microscope. Most anal cancers are squamous cell carcinomas because they develop from squamous cells.
• Adenocarcinoma: The point where the anal canal meets the rectum is called the transitional zone. It has squamous cells and glandular cells. Glandular cells produce mucus, which helps the stool pass through the anus smoothly. Adenocarcinoma can also develop from the glandular cells in the anus. Around 3–9% of anal cancers are of this type.

Risk factors

The risk factors for anal cancer include:

• HPV – There is growing evidence that some types of HPV increase the risk of various cancers. Researchers have linked the presence of HPV16 to various cancers, including cervical cancer and some head and neck cancers.
• Other cancers – People who have had another HPV-linked cancer seem to have a higher risk of anal cancer. For females, these include vaginal or cervical cancer, or a history of precancerous cells in the cervix. Males who have had penile cancer have a higher risk, also.
• HIV – People with HIV have a higher risk of developing anal cancer than people without the virus.
• Reduced immunity – People with a suppressed immune system have a higher risk. The immune system can be weaker in people with AIDS and those who take medications following a transplant.
• Sexual activity – Having multiple sex partners can increase the risk, as this increases the chance of exposure to HPV.
• Sex – Anal cancer is more common in females than in males. However, among African Americans, it is more common among males up to the age of 60 years, after which it is more likely to affect females.
• Age – As people get older, their chances of developing anal cancer increase.
• Smoking – Smokers have a significantly higher risk of several cancers, including anal cancer. Quitting may lower the risk.

Symptoms of Anal Cancer

• Bleeding from anus/rectum, especially during bowel movements.
• Having a lump or pain in the area.
• Itching (also known as pruritus).
• Seeing a change in bowel movements, such as frequency or consistency of the stools.
• Leaking stool.
• Feeling like you constantly need to have a bowel movement.
• bleeding from the bottom (rectal bleeding)
• itching and pain around the anus
• small lumps around the anus
• a discharge of mucus from the anus
• loss of bowel control (bowel incontinence)
• Bleeding from the anus
• Pain or pressure in your anal area
• Itching around your anus
• Fluid leaking from your anus
• Narrower stools or other changes in your bowel movements
• A lump or swelling near your anus
• Swollen lymph nodes in your anal or groin area

Diagnosis of Anal Cancer

Clinical presentation can include bleeding (45%), pain (30%), pruritus, perianal mass, fecal urgency, or change in the stool caliber.[rx] Locally advanced tumors may have the above symptoms as well as mucous discharge, lower extremity edema, or non-healing perianal wounds. Systemic metastasis of squamous cell anal cancer occurs in less than 10% of cases at presentation.[rx] The liver and lungs are the most common site of distant spread, and clinical presentation of metastatic disease is dependent upon location and tumor burden.

Tumors of the Anal Margin

Anal margin cancers are more commonly diagnosed at an earlier stage and therefore tend to have a better prognosis. Management of very early stage anal margin cancer is best by wide local excision or radiotherapy alone, similar to management of skin cancer.[rx] The recommended radiation dose in these cases is between 60 to 65 Gy in 6 to 7 weeks. More advanced disease of the anal margin is treated similarly to anal canal cancers.

Tumors of the Anal Canal

The traditional management of tumors of the anal canal was via an abdominoperineal resection (APR) resulting in a permanent colostomy. Since the 1980s, there has been a paradigm shift for nonsurgical organ-preserving treatment, and modern management consists of concurrent chemoradiation. While there are no randomized trials comparing APR with chemoradiation, superior colostomy-free survival rates with equivalent survival have established chemoradiation as the preferred modality of treatment.[rx] Current radiation techniques involve intensity-modulated radiation therapy (IMRT) to a minimum dose of 45 Gy via conventional fractionation. Concurrent chemotherapy includes a combination of mitomycin C (MMC), 5FU, capecitabine, or cisplatin. 

Suitability for Definitive Treatment

Performance status must be a consideration when determining a patient’s suitability for definitive treatment. Poor performance status may preclude adherence to conventional chemoradiation. Upfront APR may also be indicated if the patient has bowel incontinence or fistula present at baseline. Other relative reasons that may preclude definitive treatment include prior pelvic radiotherapy or surgery and any underlying medical, psychiatric, and/or social concerns.[rx]

HIV/AIDS Patients

People living with HIV have a 15 to 35-fold increase in anal cancer incidence.[rx] There is evidence that they have higher local relapse rates and higher rates of acute skin toxicity although there are no observable differences in complete response rates or 5-year OS.[rx] HIV-positive patients should continue on antiretroviral therapy throughout chemoradiation. Patients living with HIV should also be evaluated by their CD4 count, making appropriate chemotherapy adjustments to limit hematologic toxicity. Although concerns for increased hematological toxicity may exist in the HIV positive patient, standard MMC/ 5FU is the preferred chemotherapeutic regimen with superior outcomes when compared to cisplatin-based chemotherapy. In the setting of poorly controlled HIV with high viral load, >10000 copies, or very low CD4 count with significant concerns for hematologic toxicity, cisplatin-based chemotherapy is acceptable.

Surgical Oncology

Historically, APR was the standard of care for anal cancers, resulting in permanent colostomies. General principles for APR are similar to those of distal rectal cancer, which incorporate meticulous total mesorectal excision (TME) and removal of the distal colon, rectum, and anal sphincter complex using both anterior abdominal and perineal incisions. APR alone yields a poor 5-year overall survival rate of 50% and local recurrence rates of 30%.[rx] In an effort to reduce the rates of local recurrence, Nigro et al.[rx] pioneered a neoadjuvant regimen consisting of chemotherapy and radiation. In his report of 28 patients, 80% experienced a complete pathologic response. These promising results led to multiple randomized clinical trials of anal cancer to validate definitive chemoradiation as primary treatment of anal cancer. Therefore, the role of APR in the modern era is predominantly reserved for salvage treatment or patients with dysfunctional anal sphincter at diagnosis. Adenocarcinomas of the anal canal may also receive treatment with organ preservation.[rx]

Local excision with wide margins may be an alternative to chemoradiation in select patients with T1N0M0 anal canal cancers, as long as sphincter function can is preservable. However, the cure rates are markedly lower: 60% at 5 years, with local recurrence rates of 40%.[rx][rx] Therefore, local excision alone should be reserved for unique circumstances such as a patient with poor performance status and/or significant comorbidities.[rx]

Radiation Oncology

Radiation Alone

The efficacy of external beam radiation therapy (EBRT) alone in patients with anal cancer has undergone extensive study. In Taboul et al.,[rx] local control for primary tumors < 4 cm was 90% at 10 years, whereas it was 65% for primary tumors > 4 cm. Overall, 57% of patients maintained normal anal function. Newmen et al.[rx] reported similar results for radiation alone, in which they found that the probability of local control was related to the T stage. Overall, 74% of patients maintained a functional anus. Very few studies have reported on the efficacy of brachytherapy alone. James et al.[rx] used interstitial radiotherapy as primary treatment and found a 64% local control for tumors < 5 cm diameter at presentation.

Radiation Alone vs. Chemoradiation

After the Nigro protocol demonstrated a high rate of complete pathologic response to neoadjuvant chemoradiation, there was the development of multiple randomized clinical trials to validate definitive chemoradiation as primary treatment of anal cancer. Concurrent chemotherapy and radiation yield results superior to those of radiation alone or surgery alone. The two most prominent trials comparing radiation alone to chemoradiation include ACT I and EORTC 22861. The ACT I trial randomized patients to radiation alone vs. chemoradiation with 5FU/MMC. Results indicated improved 3-yr local control with chemoradiation vs radiation alone (64% vs 41%, p < 0.001).[rx] A recently published follow-up study on these patients demonstrates a persistent local control benefit after 13 years, with an absolute risk of locoregional recurrence reduced by 25%.[rx] Their results were similar to EORTC 22896, with the same randomization, which showed a 5-yr local control improvement from 50% to 68% (p = 0.02) with chemoradiation. Similarly, patients had an improved colostomy-free survival rate with chemoradiation.[rx]

Radiation Dose and Technique

The optimal dose and fractionation of radiation have yet to be fully elucidated. A minimum dose of at least 45 Gy is the current recommendation. One study showed that T1 lesions had effective treatment with a dose of 50 to 60 Gy.[rx] Several studies suggest that dose escalation results in higher local control rates.[rx][rx] However, the ACCORD 03 trial did not see a benefit in colostomy-free survival or complete response with higher boost doses of radiation up to 70 Gy.[rx] Therefore, conventional doses between 50.4 to 59.4 Gy are acceptable reserving doses at the higher end of the spectrum for bulkier disease.

Techniques associated with radiation therapy have evolved with the utilization of intensity-modulated radiation therapy (IMRT). This inverse planning method of external beam radiotherapy (EBRT) increases the therapeutic ratio by increasing conformal dose to the target structures while reducing dose to surrounding normal tissue.[rx] IMRT is clinically associated with decreased acute toxicity when compared to historical outcomes. RTOG 0529 is a phase II study evaluating patients with anal cancer treated with IMRT chemoradiation. T2N0 patients received treatment with a simultaneous integrated boost (SIB) plan prescribing 50.4 Gy to the primary tumor and 42 Gy to elective nodes in 28 fractions. T3-4N0 patients received treatment with a SIB plan delivering 54 Gy to the primary tumor and 45 Gy to elective nodes in 30 fractions. Positive nodes < 3 cm were treated to 50.4 Gy in 30 fractions, whereas nodes >=3cm were treated to 54 Gy in the same 30 fractions. Although the primary endpoint, reducing grade 2+ acute GI/GU toxicity by 15% compared to RTOG 9811, was not met, there was significant sparing of grade 2+ hematologic and grade 3+ dermatologic and GI toxicity.[rx] It is important to note that quality control and technical aspects of IMRT are challenging and conformal radiation therapy requires training in target volume contouring as demonstrated in RTOG 0529 by the number of plans failing central review. Various contouring atlases are available, including RTOG 0529, Myerson et al., and Ng et al.[rx][rx][rx]

Dose Constraints

The main purpose of dose constraints is to limit the acute and long-term toxicities associated with radiation to the pelvis when using IMRT. RTOG 0529 limited small and large bowel to V45 Gy < 20 cc, V35 Gy < 150 cc, and V30 Gy < 200 cc. This resulted in acute grade 2+ GI adverse events of 73% and acute grade 3+ GI adverse events of 21%. The same study limited bladder dose to V50 Gy <= 5%, V40 Gy <= 35%, and V35 Gy <= 50%. These constraints limited acute grade 2+ GU adverse events to 15% and acute grade 3+ GU adverse events to 2%.[rx] The overall rate of late GI grade 2+ adverse events was 10% and late GU grade 2+ adverse events was 4%.[rx]

Nodal Metastases

Lymph node positivity portends a poor prognosis and correlates with worse survival and colostomy rates.[rx] Radiation alone controls 70% of involved inguinal nodes, whereas chemoradiation controls 90% of involved inguinal nodes.[rx] Therefore, it is important to include mesenteric, iliac, and inguinal lymph nodes within the radiation fields.[rx][rx][rx]

Salvage Treatment

Despite the effectiveness of chemoradiation as definitive management, reports exist of locoregional failure rates of 10 to 30%.[rx][rx] Progressive or recurrent disease after definitive chemoradiation requires APR for salvage. Mullen et a.l[37] reported an actuarial 5-yr survival rate of 64% in 31 patients after radical salvage surgery. This study also showed that dose > 55 Gy as part of the initial chemoradiation regimen results in a better prognosis after radical salvage surgery.

Medical Oncology

MMC

RTOG 87-04 demonstrated a benefit to chemoradiation with MMC and 5FU vs. chemoradiation with 5FU alone.[rx] This study showed an improvement in 5-yr LC from 64% to 83% as well as a decreased colostomy rate from 22% to 9% (p = 0.002) with the addition of MMC.

Capecitabine

Capecitabine is an acceptable alternative to 5FU in the treatment of colon and rectal cancer with fewer hematologic toxicities, and it has therefore merited consideration as an alternative to 5FU in chemoradiation regimens for anal cancer. Although data for this regimen are limited, multiple retrospective studies have shown adequate LC, OS, and colostomy-free survival with this group of patients.[rx][rx]

Cisplatin

Cisplatin as a substitute for MMC has undergone evaluation in multiple phase II studies showing promising results for chemoradiation with 5FU and cisplatin.[rx][rx] Fewer hematologic and other toxicities are evident with cisplatin relative to MMC. The ACT II trial compared cisplatin with MMC and looked at the effect of additional maintenance chemotherapy following definitive chemoradiation. In this study, patients were randomly assigned to 5FU/MMC or 5FU/cisplatin with 50.4 Gy concurrent radiation. Each patient then underwent a second randomization receiving two cycles of maintenance therapy with 5FU and cisplatin vs. no maintenance therapy. There was no difference among any arm of the study, and because it was not a non-inferiority trial, they concluded that 5FU and MMC should remain the standard of care.[rx] Also, this trial confirmed that assessment for treatment response should not commence prior to 26 weeks unless there is a clear progression of the disease.[rx] RTOG 9811 was a two-arm trial evaluating the utilization of cisplatin as a replacement for MMC. Induction cisplatin plus concurrent chemoradiation with cisplatin/5FU was compared to the standard of concurrent chemoradiation with 5FU/MMC. Results were inferior in the cisplatin/5FU arm as compared to standard chemoradiation with 5FU/MMC.[rx] The use of induction cisplatin in this study may have confounded the results, because of the delay in the completion of therapy. The cisplatin arm resulted in worse 5-yr OS (70.7% vs 78.3%, p = 0.026), DFS (57.8% vs 67.8%, p = 0.006), and colostomy-free survival (65% vs 71.9%, p = 0.05) compared to the MMC arm.[rx] Chemoradiation with trimodal therapy including 5FU, MMC, and cisplatin was studied in a phase II trial, but found to be too toxic.[rx] Taken together, these studies support 5FU and MMC remaining the standard of care in concurrent chemoradiation with the possibility of using 5FU/cisplatin in the rare patient at high risk for excessive hematologic toxicity from MMC.

Induction

According to ACCORD 03, induction chemotherapy with 5FU and cisplatin offers no benefit in survival, complete response, or colostomy-free survival.[rx] This trial had two randomizations, one that looked at higher boost doses of radiation (as discussed previously), and the other evaluated two cycles of induction chemotherapy with 5FU/cisplatin vs. no induction chemotherapy. Additionally, RTOG 9811 as discussed above, demonstrated a detriment in OS, DFS, and colostomy-free survival with induction cisplatin.[rx]

Metastatic

First-line treatment of metastatic anal cancer includes a fluoropyrimidine-based regimen plus cisplatin. Additional regimens may include carboplatin plus paclitaxel or mFOLFOX. Second-line systemic therapies may include the anti-PD-1 antibody nivolumab, which has a 17% response rate in the KEYNOTE-028 study.[rx] Palliative radiation should be a consideration for symptomatic metastases, and chemoradiation may be an option for local control of bulky primary disease

Staging

Several clinical staging systems have been used in the past. The TNM (tumor, nodes, metastases) classification system developed by the American Joint Committee on Cancer (AJCC) is the most widely accepted classification system. TNM staging may use a combination of physical examination, positron emission tomography (PET), magnetic resonance imaging (MRI), and/or computed tomography (CT) to identify the primary tumor, involved nodes, and metastatic disease if present.[rx] If there is discordant or indeterminate imaging, pathologic staging with a sentinel lymph node biopsy may be an option.[rx] Unlike other GI malignancies, anal cancer T-stage is based primarily on tumor size rather than depth of invasion. A major change in the revision from AJCC 7th to 8th edition staging is with nodal staging. Previously lymph node staging was denoted as N1, N2, or N3 based on the location of regional nodes, which has undergone revision to a more straightforward N0-N1 designation based on the presence of lymph nodes. The N1 category now subdivides into N1a, N1b, and N1c based on the location of the nodes. This change is due to long-term outcomes of RTOG 98-11, demonstrating overall survival is impacted primarily by nodal positivity rather than the location of regional nodes.[rx]

AJCC 8th Edition:

Primary Tumor (T)

• TX: Primary tumor not assessed
• T0: No evidence of primary tumor
• Tis: High-grade squamous intraepithelial lesion
• T1: Tumor 2 cm or less
• T2: Tumor more than 2 cm but not more than 5 cm
• T3: Tumor more than 5 cm
• T4: Tumor of any size that invades adjacent organ(s) including vagina, urethra, or bladder

Regional Lymph Nodes (N)

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Regional lymph node metastasis present
• 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

Distant Metastasis (M)

• M0: No distant metastasis
• M1: Distant Metastasis

Anatomic Stage/Prognostic Groups:

• Stage 0:       Tis      N0        M0
• Stage I:        T1      N0        M0
• Stage IIA:     T2      N0        M0
• Stage IIB:     T3      N0        M0
• Stage IIIA:   T1-2    N1        M0
• Stage IIIB:   T4       N0        M0
• Stage IIIC:   T3-4    N1        M0
• Stage IV:     Any T  Any N   M1