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Adrenal Cancer: The Basics
S. Jack Wei, MD
Affiliation: The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 9, 2007
What are the adrenal glands?
The adrenal glands are small glands that are located just above each kidney (they are sometimes called the suprarenal glands for that reason). They are triangular in shape and consist of several distinct parts:
The central part of the gland is called the adrenal medulla and produces the chemicals epinephrine (also called adrenaline) and norepinephrine. Both of these chemicals are involved in regulation of the nervous system. Epinephrine controls the short-term stress response (aka fight-or-flight response). While norepinephrine also plays a role in short-term stress response, it functions in regulating mood and attention, as well.
The outside part of the gland surrounding the medulla is the adrenal cortex. This part of the adrenal gland is largely responsible for producing steroid hormones in the body. There are several types of steroid hormones that are produced by the adrenal glands. Mineralocorticoids (such as aldosterone) are steroid hormones that help regulate the salt levels in the body by controlling the absorption and excretion of salt and water in the kidneys. This in turn helps to regulate blood pressure. Glucocorticoids (such as cortisol) are steroid hormones that play a critical role in the regulation of sugar within the body. These hormones also help to regulate the fat stores within the body, act as a strong anti-inflammatory force, and play an important role in fetal development, particularly in lung maturation. The adrenal cortex also produces several sex steroid hormones, including androgens (critical for male sexual development) and precursors to estrogen (critical for female sexual development).
What are adrenal tumors, and what types of adrenal tumors are there?
Normally, cells in the body will grow and divide to replace old or damaged cells. 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 process, and cells continue to grow in an uncontrolled manner. Tumors can either be benign or malignant. Although benign tumors can grow in an uncontrolled way, they do not spread to other parts of the body (metastasize), nor do they invade surrounding tissues. Malignant tumors (also known as cancers) 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 start and spread to other parts of the body, usually through the blood stream or through the lymphatic system where the lymph nodes are located (a process known as metastasis).
The most common tumor of the adrenal gland is actually a benign tumor called an adrenal adenoma. In most patients, these benign tumors never cause a patient to have any symptoms and do not need to be treated. They are usually found when a patient has a CT (or CAT) scan of the body for an unrelated reason, and are thus sometimes called “incidentalomas”. The most common malignant tumors found in the adrenal gland are tumors that come from cancer cells that have metastasized (or spread) from other parts of the body to the adrenal gland through the blood stream. Several different types of cancer may spread to the adrenal glands, most commonly melanomas, lung cancers, and breast cancers. The adrenal glands are the fourth most common site in the body for cancer cells to metastasize to, after the lungs, liver, and bone.
Cancers can arise directly within the adrenal glands themselves; however, these are relatively rare. Cancers may arise directly from the adrenal cortex, and are called adrenal cortical cancers. These cancers can either be functioning (meaning they secrete excess steroid hormones) or non-functioning (meaning they do not secrete steroids). Functioning adrenal cortical cancers are more common than non-functioning cancers. Cancers can also arise within the adrenal medulla, the most common of which are pheochromocytomas. In children, neuroblastoma tumors can develop within the adrenal medulla. Pheochromocytomas and neuroblastomas are discussed elsewhere individually, will not be discussed further in this review.
Other types of adrenal cancers can occur, such as lymphoma; however, these cases are rare.
What are the signs of adrenal cortical tumors?
Both adrenal adenomas and adrenal cortical cancers can produce excess steroid hormones. Symptoms vary depending on the steroid that is produced. If too much aldosterone, which is a type of steroid hormone, is produced, Conn's syndrome (also known as primary hyperaldosteronism) can develop. Conn’s syndrome most commonly occurs with pituitary adenomas, but it can also occur in the setting of adrenal hyperplasia (an overgrowth of normal adrenal cortical tissue) and adrenal cortical cancers. Signs of Conn's syndrome include elevated blood pressure, decreased levels of potassium in the blood, and decreased levels of a chemical produced by the kidneys called renin in the blood. In most cases of Conn’s syndrome, elevations in blood pressure are mild to moderate. Other symptoms include weakness, muscle cramps, increased thirst, and increased frequency of urination.
Cortisol is a separate steroid hormone produced within the adrenal cortex. If a tumor produces excess cortisol, Cushing's syndrome (also known as hypercortisolism) can develop. This syndrome is seen not only with adrenal tumors, but can also be the result of excessive levels of adrenal cortical stimulating hormone (also known as ACTH, a hormone that is responsible for stimulating the adrenal glands to produce cortisol) produced by the pituitary gland or another tumor in the body. Cushing’s syndrome may also develop in patients who are taking steroids as medication for other disorders. The symptoms of Cushing's syndrome can vary greatly from patient to patient and involve a number of different parts of the body. Symptoms include weight gain and water retention resulting in a round face and collection of fat on the back of the shoulders and neck (so-called “buffalo hump”). Red streaks can appear on the skin known as striae. Excessive hair growth (called hirsutism) can also be seen. Excessive cortisol levels can interfere with the body's immune system predisposing a patient to unusual infections. Patients with Cushing's syndrome are at high risk for development of diabetes. Patients may also have mental changes, including mood swings, irritability, and in the worst case, psychotic episodes. In children, excessive cortisol can lead to premature sexual development and maturation (also called precocious puberty).
Adrenal tumors may also cause excess production of sexual hormones. If excess testosterone is produced, virilization can occur in either men or women. Virilization causes increased masculine characteristics, resulting in deepened voice, loss of hair, and increase in the size of the clitoris in women. Feminization may occur in men with excess estrogen production, and may cause sexual impotence and/ or breast growth (gynecomastia).
Adrenal tumors may also cause symptoms by occupying space in the abdomen. Patients with large adrenal tumors may experience feelings of abdominal fullness or localized pain. Patients may feel as though they are quickly full when eating and may experience weight loss. In some cases of large adrenal tumors, patients may actually feel a mass in their abdomen.
What causes adrenal cortical cancers and am I at risk?
Each year, there are approximately 500 cases of adrenal cortical cancers in the United States. These most commonly occur in patients between the ages of 30 and 50; however, children under the age of 5 develop adrenal cortical cancers at a higher rate than the rest of the population. Males are more likely to develop non-functioning adrenal carcinomas, while females are more likely to develop functioning adrenal carcinomas. In general, causes of adrenal cortical cancers are unknown. They are not associated with smoking, and do not run in families. Despite this, certain genetic mutations have been associated with adrenal cortical cancers, and research is ongoing in attempt to identify the causes of these cancers.
How can I prevent adrenal cortical cancers?
Given that the causes of adrenal cortical cancers are unclear, there are no known interventions that can reduce the risk of developing them.
How are adrenal cortical cancers diagnosed, and how do you tell them apart from adrenal adenomas?
Functioning adrenal cortical cancers and adenomas are frequently diagnosed because of the symptoms caused by steroid hormones. Patients with Cushing's syndrome need to be evaluated to see if the syndrome is caused by a problem in the adrenal glands, the pituitary gland, or another tumor somewhere else in the body. The first step is measuring the amount of cortisol in the urine (called a 24-hour urinary free cortisol test). This test is sometimes performed while giving the patient an extra dose of steroids to see how the body responds. After this is done, most patients undergo a dexamethasone suppression test where patients are given a high dose of the steroid dexamethasone. In normal patients and in patients with Cushing's syndrome due to a problem in the pituitary gland, a high dose of dexamethasone will cause the levels of cortisol in the blood and urine to decrease. In patients with adrenal tumors or another tumor in the body that produces ACTH, cortisol levels remain high even after a patient receives a high dose of dexamethasone.
In patients with excess levels of aldosterone, patients should be tested for blood levels of the chemical renin. In cases of hyperaldosteronism due to a tumor in the adrenal gland, renin levels will be low. In patients who have elevated aldosterone levels due to a problem with the blood vessels of the kidney (a condition called renal artery stenosis), renin levels in the blood are high.
In addition to tests for increased steroid production, radiographic imaging is an important part of the diagnosis of adrenal tumors. Computed Tomography (CT or CAT) scans are commonly used. CT scans use x-rays to form a three-dimensional picture of the inside of the body. If the adrenal tumor is larger than 6 centimeters (cm) on CT scan, it is much more likely to be an adrenal cancer than an adrenal adenoma. In most cases, CT scans can also differentiate between a normal adrenal gland and adrenal hyperplasia.
Ultrasound is sometimes used in the diagnosis of adrenal tumors. Ultrasounds use sound waves to form a picture of the inside of the body. At times, it can be difficult to tell if an adrenal tumor is an adenoma or a cancer. For tumors that are larger than 3 cm, ultrasound is a good method of telling the difference between the two.
Another type of imaging that is used when it is unclear if an adrenal tumor is an adenoma or cancer is Magnetic Resonance Imaging (MRI). MRI uses magnets to produce a very sharp picture of the inside of the body. Certain types of changes on MRI are more commonly seen in adrenal cancers than adenomas and can be used to tell the two apart.
Positron Emission Tomography (PET) scans use radioactively labeled sugar to find rapidly growing cells within the body. When cells are dividing quickly, they require a lot of energy, and the main source of energy in the body is sugar. Areas of actively dividing tissue will require more sugar than slowly dividing tissue. Because cancer cells are rapidly dividing and growing, they take up more the radioactively sugar than the surrounding tissue and this can be detected by the PET scanner. PET scans have been very useful in detect a number of different types of cancers. Its use in adrenal cancers is still being studied.
Ultimately, the only way to tell for sure if an adrenal tumor is an adrenal adenoma or cancer, part of the tumor must be examined underneath a microscope. In most cases of tumors or cancers, this is done by obtaining a biopsy of the tumor. A small piece of the tumor is taken, usually through a needle, and examined underneath a microscope. In the case of adrenal tumors, this procedure is usually performed while the patient is undergoing a CT scan, so that the radiologist can see where the needle is going in the body. In some cases, this can also be done using an ultrasound to guide the biopsy.
How are adrenal cortical cancers staged?
In addition to diagnosing adrenal cortical cancers, the radiographic imaging performed also helps to determine the stage of the patient. In general, patients with adrenal cortical cancer are divided into one of four stages.
Stage I: The cancer is smaller than 5 cm and has not spread outside of the adrenal gland.
Stage II: The cancer is larger than 5 cm and has not spread outside of the adrenal gland.
Stage III: The cancer has spread into the fat surrounding the adrenal gland or has spread to lymph nodes or other organs near the adrenal gland.
Stage IV: The cancer has spread to other parts of the body.
These stages may vary slightly based on the system that a patient’s physician chooses to use; the staging system described above is the most recent way of staging designed by the French Association of Endocrine Surgeons Study Group.
How are adrenal adenomas treated?
Most adrenal adenomas are detected on a CT scan or MRI scan that is performed for an unrelated reason. It is only necessary to treat them if they are causing symptoms. Otherwise, they can be followed with repeated scans periodically. In the event that an adenoma does need to be treated, surgical removal is the most frequent treatment used. In many cases, this can be performed using a laparoscopic procedure. A laparoscope is a small fiberoptic camera that can be inserted into the abdomen through small incisions. Other small instruments can also be inserted through these incisions. The adrenal adenoma can be resected while inside the body, without making a large incision in the abdomen, and removed through the small holes through which the camera and other instruments are inserted. Occasionally, because of the size or location of the adenoma, a laparoscopic procedure cannot be performed, and a large incision will need to be made in the abdomen in order to remove the tumor.
In the majority of cases of hyperaldosteronism, symptoms resolve with surgical removal of the adenoma; however, 30% of patients will have repeat episodes of high blood pressure even after the adenoma is removed. If the adrenal adenoma produces cortisol, the patient should take steroids by mouth before and for some time after the surgery until the body is able to produce these steroids on its own again.
How are adrenal cortical cancers treated?
Surgery
Currently, the only known way to cure adrenal cortical cancers is complete surgical removal of the tumor. Unfortunately, this is only possible for some patients with this disease. At least half of patients with adrenal cortical cancers have metastases or cancer invading into other organs, so that complete removal of the tumor is not possible. The best results with surgical resection have been with an en bloc resection, meaning that the entire tumor is removed in one piece. This also includes removing the entire kidney on the same side as the adrenal cancer. Because of this, it is unusual for adrenal cancers to be removed using a laparoscopic procedure, although as techniques of laparoscopic resection improve, more patients are being treated with this method. Occasionally, adrenal cancers will grow into the large blood vessel that carries blood back from the lower body to the heart (the vena cava). Even in these cases, complete removal of the cancer can sometimes be performed, but will require input from a general surgeon, an urologist, and a vascular surgeon.
Even in cases where the tumor cannot be removed in its entirety, surgical removal of as much tumor as possible can improve symptoms, particularly if they are due to excessive steroid secretion.
Chemotherapy
Chemotherapy refers to a group of medications that are given intravenously or orally as a pill. These drugs travel 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 killing them. A number of different chemotherapeutic agents exist, each with its own side effects. You should discuss the potential side effects of any chemotherapy you may receive with your medical oncologist.
The most common chemotherapy used in treatment of adrenal cortical cancers is mitotane. Mitotane acts to block the hormones produced by the cancer and can also kill adrenal cancer cells. Mitotane or other chemotherapy is almost always used when surgery is not possible, or if surgery is done, but some tumor remains in the body. In many cases, Mitotane is also used for patients after surgery even if every visible cancer cell has been removed. Streptozosin is a second chemotherapy drug that has been shown to work in combination with mitotane. Mitotane with or without streptozosin has been shown in clinical trial to reduce the risk of adrenal cortical cancers growing back after they are removed surgically. Even if cancers cannot be removed surgically because they have spread to other parts of the body, mitotane may cause tumors to shrink and reduce symptoms.
There are a number of other types of chemotherapy used for adrenal cancers. Exactly which chemotherapeutic agents are given varies according to the physician giving them. Based on your own health status and the risks of side effects that you are willing to accept, the choice of chemotherapy can vary.
Radiation Therapy
Radiation therapy is used in a number of cancers as both the main method of killing cancer cells or in combination with surgery (either before or after). 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 higher energy. The high-energy of x-rays in radiation therapy results in damage to the DNA of cells, causing tumor cells to die.
Radiation therapy is not part of the routine management of adrenal cancers, particularly in cases where the cancer is completely removed by surgery. Radiation has been tried in cases where surgical removal of the cancer is incomplete or in cases where the cancer comes back after surgery. In these cases, the radiation is usually delivered daily, Monday through Friday, 5 days a week, for a total of 5 to 7 weeks. In general, the side effects associated with this treatment include fatigue, skin redness and irritation, nausea, and diarrhea.
Other Drug Treatments
Patients who are treated for adrenal cortical cancers may have symptoms that are due to levels of hormones that are either too high or too low. Physicians may recommend other medications, such as ketoconazole or metyrapone, to treat these symptoms.
What are the results of treatment for adrenal cortical cancers?
In general, adrenal cortical cancers are curable only in cases where the entire tumor is removed at surgery. Unfortunately, these tend to be aggressive cancers. Even when complete surgical removal is performed, they have a tendency to come back. The likelihood of this happening after a complete surgical resection is dependent upon the stage of the tumor. The 5-year overall survival describes the percentage of patients who are alive at 5 years after cancer treatment. After total tumor removal for stage I and II adrenal cortical cancers, the 5-year overall survival rate is 40-60%. For stage III cancers, the 5-year overall survival is 20%. For stage IV patients, the 5-year overall survival is 10%. There is a small percentage of patients who have slow-growing adrenal cortical cancers that can take a number of years to progress. It is unclear why these adrenal cancers act differently than the majority of adrenal cancers; however, these cases explain why 10% of patients who have disease that has spread to other parts of the body at the time of diagnosis (stage IV) are still alive at 5 years after diagnosis, despite the generally aggressive nature of these cancers.
How are other cancers that have spread (metastasized) to the adrenal gland treated?
In most cases, when other cancers spread to the adrenal glands, they are treated with chemotherapy that is known to be effective against the original cancer type. In some cases, if the adrenal gland is the only site in the body where the cancer appears to have spread, surgical resection of metastatic cancer and the adrenal gland can be performed, followed by treatment to the primary site where the cancer started. This has been shown to be curative in a small number of patients, particularly in the case of lung cancer.
After I am treated for an adrenal cortical tumor, how will I be followed?
Shortly after treatment for functional (secreting) adrenal tumors, blood will be drawn to measure hormone levels in the body. If the hormone levels have returned to normal after therapy, regular follow-up will occur. You will be followed every 3-6 months for several years after treatment. In the case of non-functional (non-secreting) adenomas and adrenal cortical cancers, periodic follow-up MRI or CT of the abdomen will be obtained for the first few years.
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Anal Cancer: The Basics
S. Jack Wei, MD
Affiliation: The Abramson Cancer Center of the University of Pennsylvania
Last Modified: September 8, 2007 by Christine Hill-Kayser, MD
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. 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., Removal of areas of anal dysplasia is usually unsuccessful, however. 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 chest x-ray is often performed to look for spread of the cancer to the lungs. 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.
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 or less in greatest dimension
•  T2: Tumor is greater than2 cm but less than 5 cm in greatest dimension
•  T3: Tumor is greater than5 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 qualify 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 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. 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, 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.
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 most common 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 giving 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 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 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 for 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 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.