Anal Cancer: The Basics

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 will stop dividing. Tumors occur when there is an error in this regulation and cells continue to grow uncontrolled. Tumors can either be benign or malignant. Although benign tumors grow uncontrolled, then do not break off and spread beyond where they started and do not invade into surrounding tissues. Malignant tumors, however, will grow uncontrolled in such a way that they invade and damage other tissues around them. They also gain the ability to break off from where they started and 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 types of cells seen from the skin. However, this is not true in other parts of the world. In Japan , 80% of anal cancers are adenocarcinomas, resembling the glandular cells seen in the rectum. It appears that anal cancers frequently start 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 where the cells appear like cancer cells, but have not invaded beyond where the normal cells lie. Over time, anal dysplasia eventually changes to the point where they 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). 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. Cancers arising from the anal verge represent 25% of all anal cancers and are often treated like skin cancers; however, they often respond more poorly to treatment than do other skin cancers or cancers of the anal canal. Treatment of anal cancers will be discussed in more detail below (under "How is anal cancer treated?").
What causes anal cancer and am I at risk?
Each year, there are approximated 4000 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. 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. Because anal cancer appears to first start as anal dysplasia before progressing to anal cancer, patients with a history of AIN are at increased risk to develop anal cancer. 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. However, by avoiding the factors that are known to be related to anal cancer, the risk of developing anal cancer will become even lower. By far, the most important factor in developing anal cancer is infection with HPV. Recent studies have shown that giving vaccines against HPV prophylactically to patients at high risk for cervical cancer (which is also caused by HPV) reduces the risk that patients will develop cervical cancer. It is likely that HPV vaccines would result in a similar reduction in the risk of anal cancers; however, to date, no studies have been published confirming this. However, a number of studies examining the role of HPV vaccines and anal cancer are currently under development. In addition, it is possible that treatment of patients who are already infected with HPV with antiviral medications may also reduce the risk of anal cancers. Again, this method is still unproven and studies using antiviral treatment to prevent anal cancer are under development.
Avoiding smoking and unsafe sexual practices can reduce the risk of anal cancer. In patients who are known have anal dysplasia, careful surveillance can result in early detection of anal cancer, and a higher rate of cure with treatment. However, removal of areas of anal dysplasia is usually unsuccessful. 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?
In about 50% of cases, the initial symptom of anal cancer is bleeding. Pain is somewhat less common, seen in about 30% of patients presenting with anal cancer; however, it can be quite severe. Occasionally, patients have the sensation of having a mass in the anus and can experience itching or anal discharge. 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 protoscope (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 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 chest x-ray is often performed to look for spread of the cancer to the lungs. Occasionally, 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.
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
Tis Carcinoma in situ
T0 No evidence of primary tumor
T1 Tumor £ 2 cm in greatest dimension
T2 Tumor >2 cm but £ 5 cm in greatest dimension
T3 Tumor >5 cm in greatest dimension
T4 Tumor of any size that invades adjacent organs including the vagina, urethra, or bladder. Tumors that invade the anal sphincter only do not quality as T4 tumors
N Stage
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
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 including spread 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. While there is a system for stage grouping of anal cancers, these tumors are more commonly referred to by their direct TNM stage.
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 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, only of a much high energy. The high energy of x-rays in radiation therapy results in damage to the DNA of cells. Because cancer cells are not as good as normal, healthy cell at repairing DNA damage, radiation results in relatively more damage to the cancer cells than to normal cells. Radiation therapy exploits this difference to treat cancers while relatively sparing normal 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. It only goes where it is aimed. The side effects of treatment are limited to the areas being treated. 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.
Chemotherapy
Chemotherapy is a medication that is usually given intravenously or as a pill. It goes to 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 of finding those cells and killing them. With 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 most commonly used agents in anal cancer are 5-flourouracil (5-FU) with either mitomycin C or cisplatin. Exactly which chemotherapeutic agents are given for anal cancer varies according the physician given them. 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 can also be given if the cancer has spread to distant sites. In this setting, unless there are specific local symptoms from anal cancer, the mainstay of treatment becomes chemotherapy, because as discussed above, chemotherapy can travel throughout the entire body. Unfortunately, in this setting, chemotherapy has not been very successful at controlling the cancer.
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 chemoradiotherapy is used compared to radiation alone. However despite this improvement in local control of the tumor, no difference in overall survival has been seen with combined modality therapy compared to radiation alone. Regardless, combined modality therapy is now the standard treatment for most patients with anal cancer, unless the patient is unable to tolerate combined treatment.
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 therapy result 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 to place a permanent colostomy.
There are several situations in which surgery should be considered for anal cancer. Patients with carcinoma in situ or 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 be spared to 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 an APR. In these cases, patients have already lost their sphincter function, and require a colostomy to handle bowel movements. In these cases, surgical resection is often performed, and radiation with or without chemotherapy is given post-operatively. Surgery can also be performed in patients who cannot otherwise tolerate radiation therapy. Finally, surgery is often performed in the case of a local recurrence 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 who present 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.