Anal Cancer: The Basics

Christine Hill-Kayser, MD
Updated by Lara Bonner Millar, MD
Affiliation: The Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 23, 2012

What is the anus?

The anus is an organ that lies at the end of the digestive tract below the rectum. It consists of two sections: the anal canal and the anus (or anal verge). The anal canal is a 3-4 cm long structure that lies between the anal sphincter (one of the muscles controlling bowel movements) just below the rectum and the anal verge which represents the transition point between the digestive tract and the skin on the outside of the body. Muscles within the anal canal and anus control the passage of stool from the rectum to outside the body.

What is anal cancer?

Normally, cells in the body will grow and divide to replace old or damaged cells in the body. This growth is highly regulated, and once enough cells are produced to replace the old ones, normal cells stop dividing. Tumors occur when there is an error in this regulation and cells continue to grow in an uncontrolled way. Tumors can either be benign or malignant. Although benign tumors may grow in an uncontrolled fashion sometimes, they do not spread beyond the part of the body where they started (metastasize) and do not invade into surrounding tissues. Malignant tumors, however, will grow in such a way that they invade and damage other tissues around them. They also may spread to other parts of the body, usually through the blood stream or through the lymphatic system where the lymph nodes are located. Over time, the cells within a malignant tumor become more abnormal and appear less like normal cells. This change in the appearance of cancer cells is called the tumor grade, and cancer cells are described as being well-differentiated, moderately-differentiated, poorly-differentiated, or undifferentiated. Well-differentiated cells are quite normal appearing and resemble the normal cells from which they originated. Undifferentiated cells are cells that have become so abnormal that often we cannot tell what types of cells they started from.

Anal cancer is a malignant tumor of either the anal canal or anal verge. In the United States, 80% of anal cancers are squamous cell cancers, resembling the cells found in the anal canal, This is not true in other parts of the world, however. In Japan, 80% of anal cancers are adenocarcinomas, resembling the glandular cells seen in the rectum. Cancers of the anal verge may be referred to as "perianal skin cancers," because they usually behave more like skin cancers than like anal cancers. They may respond more poorly to treatment than other forms of anal cancers. Perianal skin cancers represent about 25% of all anal cancers. Occasionally, other types of cancer, such as melanoma, Kaposi's sarcoma, and lymphoma may develop in the anus. These other types of cancer will be discussed separately, and will not be addressed further in this review.

Anal cancers frequently begin as anal dysplasia. Anal dysplasia is made up of cells of the anus that have abnormal changes, but do not show evidence of invasion into the surrounding tissue. The most severe form of anal dysplasia is called carcinoma in situ. In the case of carcinoma in situ, cells have become cancerous, but have not begun to invade normal tissue yet. Over time, anal dysplasia changes to the point where cells become invasive and gain the ability to metastasize, or break way to other parts of the body. Anal dysplasia is sometimes referred to as anal intraepithelial neoplasia (AIN), or a "pre-cancer." When anal cancer does spread, it most commonly spreads through direct invasion into the surrounding tissue or through the lymphatic system. Spread of anal cancer through the blood is less common, although it can occur.

What causes anal cancer and am I at risk?

Each year, there are approximately 4,000 cases of anal cancer in the United States. In general, the incidence of anal cancers has been increasing over the past 30-40 years. The vast majority (85%) of cases are in Caucasians. The incidence of anal cancer increases with age: patients with anal cancer have an average (median) age of 62 years. Cancers of the anal canal are more common in women, while the incidence of cancers of the anal verge is roughly equal in both men and women.

Several factors have been associated with anal cancer. Most importantly, infection with the human papilloma virus (HPV) has been shown to be related to anal cancers and has been associated with several other cancers, including cervical cancer and cancers of the head and neck. HPV can be transmitted from person to person through sexual contact, so individuals with a history of multiple sexual partners, anal receptive intercourse, and genital warts are at an increased risk for infection. Probably due to the association between HPV and anal cancer, women with history of cervical cancer are at increased risk of developing anal cancer. Another sexually transmitted virus, the human immunodeficiency virus (HIV), has been linked to anal cancers, and individuals infected with HIV are at increased risk for infection with HPV. The relationship between HIV and anal cancer will be discussed in more detail in the next section (entitled "How are anal cancer and HIV/AIDS related?")

Several other factors have been linked to anal cancer. Anal cancer has been associated with smoking. Patients who smoke are three times more likely to develop anal cancer as those that don't smoke. The risk of anal cancer increases with the number of cigarettes smoked per day and the number of years that a person has been smoking.

There may be an association between anal cancer and suppression of the immune system. The rate of anal cancer is higher in patients who are immunosuppressed after organ transplants, although this relationship is not clear.

Although there appears to be an increased rate of anal cancer in patients who have benign anal conditions such as anal fistulae, anal fissures, perianal abscesses, or hemorrhoids, it does not appear that these benign conditions are a cause of anal cancer. Alternatively, an undiagnosed anal cancer may actually be causing these conditions, and then is subsequently diagnosed when the benign condition is being treated.

How are anal cancer and HIV/AIDS related?

HIV is the virus responsible for Acquired Immune Deficiency Syndrome (AIDS), a severe disease that results in loss of the ability of the body to fight off certain types of infections. The incidence of anal cancer is increased in patients with HIV. This is likely related to the fact that patients with HIV are at an increased risk for infection with HPV as well. This relationship between HIV and HPV is not related to the immune status or the sexual practices of the patient infected with HIV. The rate of infection of HPV is increased in patients with HIV even if they do not engage in anal receptive intercourse and do not have evidence of suppression of their immune system. A patient is considered to have progressed from being HIV positive to having AIDS if they develop certain infections or diseases that are uncommon except in AIDS patients. Currently, anal cancer is not considered an AIDS-defining illness. However, frequently, patients who have been newly diagnosed with anal cancer are tested for HIV if they have other risk factors for infection with HIV.

How can I prevent anal cancer?

Anal cancer is an uncommon cancer, and the risk of developing anal cancer is quite low. Avoidance of risk factors for anal cancer, however, will reduce the risk of development of anal cancer even further. By far, the most important factor in developing anal cancer is infection with HPV. Recently, Gardasil, a vaccine directed against HPV, has been developed. This vaccination is currently recommended only for girls and young women for prevention of cervical cancer. Vaccination against HPV would certainly be expected to reduce the incidence of anal cancer in both men and women, but, to date, no studies have been published confirming this. The vaccine has not been studied in boys and men, but data on this topic will likely be available in the future. A number of studies examining the role of HPV vaccines and anal cancer are currently under development.

Avoiding smoking and unsafe sexual practices can reduce the risk of anal cancer. This is because the immune system in people who smoke is less able to clear the HPV virus than those who do not smoke. In patients who are known to have anal dysplasia, careful surveillance can result in early detection of anal cancer, and a higher rate of cure with treatment.  Removal of areas of anal dysplasia is usually unsuccessful and the rate of recurrence of anal dysplasia after surgical or laser removal is very high. This is likely due to the fact that even if areas of dysplasia are removed, the patient remains infected with HPV, which can cause the development of additional areas of anal dysplasia.

What are the signs of anal cancer?

The most common initial symptom of anal cancer is rectal bleeding, which occurs in about half of patients with new anal cancers. Pain is somewhat less common, seen in about 30% of patients with new anal cancers; however, it can be quite severe. Occasionally, patients have the sensation of having a mass in the anus and may experience itching or anal discharge. In certain patients, these symptoms may be associated with the presence of warts in the anal region. Rarely, in advanced cases, anal cancers can disrupt the function of the anal muscles, resulting in loss of control of bowel movements. In general, these symptoms are vague and non-specific. As a result, in one-half to two-thirds of patients with anal cancer, a delay of up to 6 months occurs between the time when symptoms start and when a diagnosis is made.

How is anal cancer diagnosed?

When anal cancer is suspected, the physician should perform a thorough history and physical examination. The physical exam should consist of a digital rectal examination (DRE) as well as visualization of the anal canal using an anoscope or bronchoscope (a long, thin instrument that is inserted into the anus to allow the physician to see the inside of the anus and rectum). Ultimately, anal cancer can only be diagnosed with a biopsy. To perform a biopsy, the physician uses a needle or a small pair of scissors or clamps to remove a piece of the tumor. It is common for there to be some mild bleeding after a biopsy is taken, and this bleeding can last for a few days after the procedure. The tissue is then sent to a pathologist who looks at the tissue underneath a microscope to determine whether the tumor is cancerous or not. Because a number of benign tumors and lesions can resemble anal cancer on physical examination, a biopsy should always be performed before initiating treatment for anal cancer.

How is anal cancer staged?

Once a diagnosis of anal cancer is made, additional test should be ordered to determine the extent of the disease. A CT (CAT) scan or MRI of the abdomen and pelvis should be performed to look for abnormally enlarged lymph nodes, which can result from spread of the cancer, and to examine the liver for metastatic disease. A PET/CT is useful to assess the extent of disease including the lymph nodes, and to detect distant metastases.  In some cases, an ultrasound of the tumor using a probe that is inserted into the anus can be used to determine the amount of invasion of the tumor into the surrounding tissues.  Women with advanced tumors should also have a pelvic exam to assess if the tumor has invaded into the vagina.

Anal cancer is most commonly staged using the TNM staging system which is determined by the American Joint Committee on Cancer. The "T stage" represents the extent of the primary tumor itself. The "N stage" represents the degree of involvement of the lymph nodes. The "M stage" represents whether or not there is spread of the cancer to distant parts of the body. These are scored as follows:

T Stage

• TX: Primary Tumor cannot be assessed
• Tis: Carcinoma in situ
• T0: No evidence of primary tumor
• T1: Tumor < 2 cm in greatest dimension
• T2: Tumor is > 2 cm but < 5 cm in greatest dimension
• T3: Tumor is > 5 cm in greatest dimension
• T4: Tumor of any size that invades adjacent organs including the vagina, urethra, or bladder. Tumors that invade the rectal wall, perirectal skin or anal sphincter only do not qualify as T4 tumors

N Stage

• NX: Lymph nodes cannot be assessed

• N0: No evidence of spread to the lymph node
• N1: Spread of cancer to the lymph nodes directly adjacent to the rectum (perirectal lymph nodes)
• N2: Spread of the cancer to lymph nodes of the inguinal or internal iliac lymph node chains on one side only.
• N3: Spread of the cancer to lymph nodes of the inguinal or internal iliac lymph node chains on both sides OR cancer involvement of both the perirectal lymph nodes and the inguinal lymph nodes

M Stage

• M0: No evidence of distant spread of the cancer
• M1: Evidence of distant spread of the cancer to other organs, or to lymph node chains other than the ones lists under "N stage"

The stage of the cancer is reported by stating the stage of the T, the N, and the M. For example, a patient with a 4 cm tumor that had spread to perirectal lymph nodes, but did not invade into adjacent organs or spread to any other lymph nodes would be classified as T2N1M0.

The staging can be further condensed into a stage group, which takes the various combinations of TNM and places them into groups designated stage 0-IV (See below). While there is a system for stage grouping of anal cancers, these tumors are more commonly referred to by their direct TNM stage.

Stage	T	N	M
O	Tis	N0	M0
I	T1	N0	M0
II	T2	N0	M0
	T3	N0	M0
IIIA	T1	N1	M0
	T2	N1	M0
	T3	N1	M0
	T4	N0	M0
IIIB	T4	N1	M0
	Any T	N2	M0
	Any T	N3	M0
IV	Any T	Any N	M1

Although this system of cancer staging is quite complicated, it is designed to help physicians describe the extent of the cancer, and therefore, helps to direct what type of treatment is given.

How is anal cancer treated?

Radiation Therapy

Radiation therapy has become the mainstay of treatment of anal squamous cell cancer. The radiation comes in the form of high energy x-rays that are delivered to the patient only in the areas at highest risk for cancer. These x-rays are similar to those used for diagnostic x-rays, but they are of a much high energy. The high energy of x-rays in radiation therapy results in damage to the DNA of cells. Cancer cells divide faster than healthy cells, and so their DNA is more likely to be damaged than that of normal cells. Additionally, cancer cells are generally less able to repair damaged DNA than normal cells are, so cancer cells are killed more easily by radiation than normal cells are. Radiation therapy exploits this difference to treat cancers by killing cancer cells, while killing fewer cells in normal, healthy tissue.

Typically, radiation for anal cancer is given daily, Monday through Friday, for 5 to 6 weeks. The radiation treatments themselves are short, lasting only a few minutes. Like diagnostic x-rays, radiation treatments cannot be felt and do not hurt. Radiation is delivered like a beam of light, only affecting areas where it is aimed. In treatment of anal cancer, the radiation is usually aimed at the entire pelvis for the first 2-3 weeks so that any cells in the lymph nodes surrounding the anus are treated with radiation. After this, the radiation is aimed more specifically at the anus in the lower part of the pelvis.

Most commonly, radiation treatment for anal cancer can result in irritation to the skin. This reaction can be quite severe with redness, dryness, and breakdown of the skin. Often, patients will require a break during radiation treatment to allow the skin to heal prior to resuming treatment. Other side effects of radiation can include fatigue, diarrhea, and lowering of blood counts. Increasingly, a technique of radiation delivery called IMRT is being used in an attempt to decrease skin and gastrointestinal toxicities, as well as decrease treatment breaks.

Chemotherapy

Chemotherapy refers to medications that are usually given intravenously or in pill form. Chemotherapy travels throughout the bloodstream and throughout the body to kill cancer cells. This is one of the big advantages of chemotherapy. If cancer cells have broken off from the tumor and are somewhere else inside the body, chemotherapy has the chance killing them, while radiation does not. In the setting of anal cancer, chemotherapy is most commonly given at the same time as radiation. This will be discussed further below under the section entitled "Combined Modality (Chemoradiotherapy)."

A number of different chemotherapeutic agents exist, each with their own side effects. The preferred chemotherapies used in anal cancer are 5 flourouracil (5FU) and mitomycin C. Sometimes, mitomycin C may be replaced with cisplatin in order to reduce toxicities from chemotherapy. Exactly which chemotherapeutic agents are given for anal cancer varies according to the physician's preference. It is important to discuss the risk of each of these medications with your medical oncologist. Based on your own health status and the risks of side effects that you are willing to accept, the choice of chemotherapy can vary.

Chemotherapy is used in different situations to treat anal cancer. If the cancer is localized to the anus and pelvic lymph nodes, it may be used in combination with radiation therapy to achieve the best chance of killing all of the cancer cells (see "Combined Modality (Chemoradiotherapy)." If the cancer has spread to distant parts of the body, chemotherapy drugs such as cisplatin, carboplatin, and 5FU may be used without radiation to reduce the number of tumor cells and prevent or minimize symptoms all over the body. This is the case because chemotherapy is able to travel throughout the bloodstream, while radiation is not. In this setting, radiation may be used separately to relieve certain symptoms, such as pain, from cancer in other parts of the body. Unfortunately, if cancer is present in organs distant from the anus, chemotherapy is generally not very successful at controlling it.

Combined Modality (Chemoradiotherapy)

Chemotherapy has been shown to be radiosensitizing when given at the same time as radiation therapy. This means that the effect of the radiation is increased when given together with chemotherapy. Several large trials have shown that local control of the tumor is significantly improved when 5FU and mitomycin with chemotherapy are used, as compared to radiation alone. Using chemotherapy and radiation together has not been shown to change the rate of survival of patients when compared to radiation alone; however, using chemotherapy and radiation together has been shown to reduce the risk of cancer recurring (coming back) in the anus. For this reason, combined modality treatment is recommended for most patients with anal cancer, unless a certain patient is unable to tolerate chemotherapy and radiation together. If this is the case, the patient may have radiation with or without chemotherapy given at a separate time.

Surgery

Although surgery was the primary treatment for anal cancer 20 years ago, its role has greatly diminished since then. When performed, surgical resection usually is an abdominal perineal resection (APR), which consists of a wide excision of the anus, including the anal muscles, with placement of a permanent colostomy. A colostomy is performed by connecting the bowel to a hole in the abdominal wall (called a stoma). The stool that passes through the stoma is collected in a bag that is attached to the outside of the abdominal wall with adhesive. This bag can then be emptied by the patient as needed. Because the combination of chemotherapy and radiation for squamous cell carcinoma results in similar rates of local control and survival when compared to surgery, chemoradiation has been favored over surgery because it offers patients a good chance at preserving anal sphincter function, avoiding the need for permanent colostomy. In contrast, for adenocarcinomas of the anus, surgery is still recommended after chemoradiation.

There are several situations in which surgery should be considered up front for anal cancer. Patients with carcinoma in situor small, well-differentiated anal cancers that have not invaded into the anal sphincter can sometimes undergo a surgical excision without removing the anal muscles. In these early cases, the results of surgical excision can be quite good, and the patient can avoid the potential side effects of chemoradiotherapy. Alternatively, extensive anal cancers that have destroyed the anal sphincter, such that the patient cannot control bowel movements, are often treated with surgery (an APR). In these cases, patients have already lost their sphincter function, and require a colostomy to handle bowel movements. Because patients in this situation usually have very large tumors, they may require surgical removal of the tumor, which will usually be followed by radiation, with or without chemotherapy, after the operation. Surgery can also be performed in patients who cannot otherwise tolerate radiation therapy, or who do not want radiation therapy. Finally, surgery is often performed if cancer recurs in the anus following previous treatment with radiation therapy if additional chemotherapy and radiation cannot be given.

After I am treated for anal cancer, how will I be followed?

After treatment for anal cancer, patients are usually followed every 3-6 months for several years with or without CT scans. The most important aspect of follow-up after completion of treatment is a thorough physical examination including a digital rectal exam. Anal cancers can take some time to respond to treatment and often continue to shrink months after chemotherapy and radiation have ended. Therefore, it is not unusual to have a residual mass immediately after treatment. The presence of a residual mass does not mean that the treatment did not work. Overall, the chance of long-term cure of anal cancer depends on the extent of the disease at the time it was first diagnosed. Patients with smaller disease without lymph node involvement or distant metastases have a better chance at long-term tumor control than those with larger disease or with lymph node involvement or distant metastases. If anal cancers do recur, they usually do so within the first 2 years after treatment, although recurrences after 2 years can occur. In general, the further out from treatment a patient is without evidence of a recurrence, the better the chances that the cancer will never come back.

The treatment of anal cancer should be a cooperative effort among the patient, the radiation oncology, the medical oncologist, and the surgeon. It is important that all patients with anal cancer know about their disease so that they can make an informed decision about their treatment. This article was intended to help answer some of the common questions patients face when they have anal cancer. If you have any additional questions, please contact your doctor.

References

Cotter SE, Grigsby PW, Siegel BA, et al. FDG-PET in the evaluation of anal carcinoma Int J Rad Oncol Biol Phys 2006; 65: 720-725.

Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 165-73.

Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of U.S GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: comparison of concurrent chemoradiation with 5FU-mitomycin vs 5FU-cisplatin for disease-free and overall survival. Abstract # 367. ASCO 2011 Gastrointestinal Cancers Symposium. San Francisco, CA

Kachnic LA, Winter KA, Myerson J, et al. Two-year outcomes of RTOG 0529: A phase II evaluation of dose-painted IMRT in combination with 5-fluorouroacil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Abstract #368. ASCO 2011 Gastrointestinal Cancers Symposium. San Francisco, CA

Zeller JL, Lymn C, Glass RM. Anal Cancer. J Am Med Assoc. 2008:299(16). http://jama.ama-assn.org/content/299/16/1980.full.pdf