Thymoma
Thymoma
Definition
Thymomas are the most common tumor of the thymus.
Description
The thymus is located in the upper chest just below the neck. It is a small organ that produces certain white blood cells before birth and during childhood. These white blood cells are called lymphocytes and are an important part of the body's immune system. Once released from the thymus, lymphocytes travel to lymph nodes where they help to fight infections. The thymus gland becomes smaller in adulthood and is gradually taken over by fat tissue.
Although rare, thymomas are the most common type of thymic tumor. The term thymoma traditionally refers to a non-invasive, localized (only in the thymus) type of thymic tumor. Thymomas arise from thymic epithelial cells, which make up the covering of the thymus. Thymomas frequently contain lymphocytes, which are non-cancerous. Thymomas are classified as either noninvasive (previously called benign) or invasive (previously called malignant). Noninvasive thymomas are those in which the tumor is encapsulated and easy to remove. Invasive thymomas have spread to nearby structures (such as the lungs) and are difficult to remove. Approximately 30% to 40% of thymomas are of the invasive type.
Demographics
Thymoma affects men and women equally. It is usually diagnosed between the ages of 40 and 60 years. Thymomas are uncommon in children.
Causes and symptoms
The cause of thymoma is unknown. Cancer is caused when the normal mechanisms that control cell growth become disturbed, causing the cells to grow continually without stopping. This is caused by damage to the DNA in the cell.
Approximately 40% of the patients diagnosed with thymoma have no symptoms. The symptoms in the remaining 60% of patients are caused by pressure from the enlarged thymus on the windpipe (trachea) or blood vessels or by paraneoplastic syndromes . Paraneoplastic syndromes are collections of symptoms in cancer patients that cannot be explained by the tumor. Seventy-one percent of thymomas are associated with paraneo-plastic syndromes. The most common syndromes related to thymoma are pure red cell aplasia (having abnormally low levels of red blood cells), myasthenia gravis (a muscular disorder), and hypogammaglobulinemia (having abnormally low levels of antibodies). These conditions are autoimmune diseases, those in which the body mounts an attack against certain normal cells of the body. Regarding myasthenia gravis, 15% of patients with this syndrome have thymomas. Alternately, 50% of patients with thymomas have myasthenia gravis. The relationship between the two entities is not clearly understood, though it is believed that the thymus may give incorrect instructions about the production of acetypcholine receptor antibodies, thus setting the state for faulty neuromuscular transmission. The confirmed presence of either thymomas or myasthenia gravis should prompt investigation for the other condition.
Symptoms of thymoma may include:
- shortness of breath
- swelling of the face
- coughing
- chest pain
- muscle weakness (especially in the eyes, neck, and chest, causing problems with vision, swallowing, and breathing)
- weakness
- dizziness
- shortness of breath
- fatigue
Diagnosis
The physician will conduct a complete physical exam. He or she may be able to feel a fullness in the lower neck region. Routine blood tests may be performed. Imaging studies are necessary because the symptoms of thymoma can be caused by many other diseases. Thymomas can be identified by chest x ray , magnetic resonance imaging (MRI), and computed tomography (CT).
A biopsy may be performed, in which a small sample of the tumor is removed and examined under the microscope. However, because of the risk of "seeding" cancerous cells, biopsies are not routinely performed. There are a few different methods to biopsy a thymoma. For a mediastinoscopy , a wand-like lighted camera (endoscope) and special instruments are passed through a small cut in the lower neck. The surgeon can see the tumor on a monitor and can cut off small samples for microscopic analysis. Mediastinoscopy is performed under general anesthesia. Alternatively, a needle biopsy will be taken in which a long needle is passed through the skin and into the tumor. Fine needle biopsy uses a thin needle and larger-core needle biopsy uses a wider needle. Needle biopsies may be performed in conjunction with computed tomography imaging.
Patients who are having difficulty breathing may have a bronchoscopy performed to examine the wind pipe. An endoscope, in this case a bronchoscope, is inserted through the mouth and into the windpipe. The physician will look for tumors and may perform biopsies.
Treatment team
The treatment team for thymoma may include a hematologist, pulmonologist, immunologist, oncologist, thoracic surgeon, cardiologist, radiation oncologist, nurse oncologist, psychiatrist, psychological counselor, and social worker.
Clinical staging, treatments, and prognosis
Clinical staging
There is more than one type of staging system for thymoma but the Masaoka system, a surgical staging system developed in 1981, is used most often. Thymoma is categorized into four stages (I, II, III, and IV) which may be further subdivided (A and B) based on the spread of cancerous tissue. The Masaoka staging system is as follows:
- Stage I. The thymoma lies completely within the thymus.
- Stage II. The thymoma has spread out of the thymus and invaded the outer layer of the lung (pleura) or nearby fatty tissue.
- Stage III. The thymoma has spread to other neighboring tissues of the upper chest including the outer layer of the heart (pericardium), the lungs, or the heart's main blood vessels.
- Stage IVA. The thymoma has spread throughout the pericardium and/or the pleura.
- Stage IVB. The thymoma has spread to organs in other parts of the body.
In 1999, the World Health Organization (WHO) adopted a new classification system for thymic tumors. This system is a histologic classification, which means that it is based on the microscopic features of the cells that make up the tumor. The WHO classification system ranks thymomas into types A, AB, B1, B2, B3, and C, by increasing severity.
Treatments
The treatment for thymoma cancer depends on the stage of cancer and the patient's overall health. Because thymomas are so rare, there are no defined treatment plans. Treatment options include surgery, radiation therapy , and/or chemotherapy . Surgical removal of the tumor is the preferred treatment. Surgery is often the only treatment required for stage I tumors. Treatment of thymoma often relieves the symptoms caused by paraneoplastic syndromes.
A treatment that is intended to aid the primary treatment is called adjuvant therapy. For instance, chemotherapy may be used along with surgery to treat thymoma. Stages II, III, and IV thymomas are often treated with surgery and some form of adjuvant therapy.
SURGERY.
Thymoma may be treated by surgically removing (resecting) the tumor and some of the nearby healthy tissue. Removal of the entire thymus gland is called a thymectomy. Surgery on the thymus is usually performed through the chest wall by splitting open the breast bone (sternum), a procedure called a median sternotomy. When complete removal of the tumor is impossible, the surgeon will remove as much of the tumor as possible (debulking surgery, sub-total resection). In these cases, if the tumor has spread, surgery may include removal of other tissues such as the pleura, pericardium, blood vessels of the heart, lung, and nerves.
RADIATION THERAPY.
Radiation therapy uses high-energy radiation from x rays and gamma rays to kill the cancer cells. Radiation given from a machine that is outside the body is called external radiation therapy. Radiation therapy is often used as adjuvant therapy following surgery to reduce the chance of cancer recurrence. Radiation may be used to kill cancer cells in cases in which the tumor was only partially removed. It may be used before surgery to shrink a large tumor. Radiation therapy is not very effective when used alone, although it may be used alone when the patient is too sick to withstand surgery.
The skin in the treated area may become red and dry and may take as long as a year to return to normal. Radiation to the chest may damage the lung causing shortness of breath and other breathing problems. Also, the tube that goes between the mouth and stomach (esophagus) may be irritated by radiation causing swallowing difficulties. Fatigue, upset stomach, diarrhea , and nausea are also common complaints of patients having radiation therapy. Most side effects go away about two to three weeks after radiation therapy has ended.
CHEMOTHERAPY.
Chemotherapy uses anticancer drugs to kill the cancer cells. The drugs are given by mouth (orally) or intravenously. They enter the blood-stream and can travel to all parts of the body. Chemotherapy may be given before surgery to shrink a tumor, which is called neoadjuvant therapy. Thymoma cells are very sensitive to anticancer drugs, especially cisplatin , doxorubicin , and ifosfamide . Generally, a combination of drugs is given because it is more effective than a single drug in treating cancer. Corticosteroids are also used to treat thymoma.
The side effects of chemotherapy are significant and include stomach upset, nausea and vomiting , appetite loss (anorexia ), hair loss (alopecia ), mouth sores, and fatigue. Women may experience vaginal sores, menstrual cycle changes, and premature menopause. There is also an increased chance of infections.
Prognosis
The five-year survival rates for thymomas are 96% for stage I, 86% for stage II, 69% for stage III, and 50% for stage IV. Thorough (radical) surgery is associated with a longer survival rate. Almost 15% of thymoma patients develop a second cancer.
Thymomas rarely spread (metastasize) outside of the chest cavity. Metastasis is usually limited to the pleura. Invasive thymomas are prone to recurrence, even 10 to 15 years following surgery. The recurrence rates are drastically reduced and the five-year survival rates are drastically increased in patients who receive adjuvant radiation therapy.
Alternative and complementary therapies
Although alternative and complementary therapies are used by many cancer patients, very few controlled studies on the effectiveness of such therapies exist. Mind-body techniques such as prayer, biofeedback, visualization, meditation, and yoga have not shown any effect in reducing cancer but they can reduce stress and lessen some of the side effects of cancer treatments. Gerson, macrobiotic, orthomolecular, and Cancell therapies are ineffective treatments for cancer.
Clinical studies of hydrazine sulfate found that it had no effect on cancer and even worsened the health and well-being of the study subjects. One clinical study of the drug amygdalin (Laetrile) found that it had no effect on cancer. Laetrile can be toxic and has caused deaths. Shark cartilage, although highly touted as an effective cancer treatment, is an improbable therapy that has not been the subject of clinical study. Although the results are mixed, clinical studies suggest that melatonin may increase the survival time and quality of life for cancer patients.
Selenium, in safe doses, may delay the progression of cancer. Laboratory and animal studies suggest that curcumin, the active ingredient of turmeric, has anti-cancer activity. Maitake mushrooms may boost the immune system, according to laboratory and animal studies. The results of laboratory studies suggest that mistletoe has anticancer properties, however, clinical studies have not been conducted.
For more comprehensive information, the reader should consult the book on complementary and alternative medicine published by the American Cancer Society listed in the Resources section.
Coping with cancer treatment
The patient should consult his or her treatment team regarding any side effects or complications of treatment. Many of the side effects of chemotherapy can be relieved by medications. Patients should consult a psychotherapist and/or join a support group to deal with the emotional consequences of cancer and its treatment.
Clinical trials
As of early 2001, there were two active clinical trials studying thymoma. Both studies are sponsored by the National Cancer Institute. One trial (#E-1C99) was studying the effectiveness and toxicity of carboplatin and paclitaxel on thymoma. This study was open to patients with invasive, recurrent, or metastatic thymoma. The other study (#E-1C97) was studying the effectiveness and toxicity of octreotide both with and without prednisone for metastatic or recurrent thymoma. The National Cancer Institute web site has information on these and other studies. Patients should consult with their treatment team to determine if they are candidates for these or any other ongoing studies.
Prevention
Because there are no known risk factors for the development of thymoma there are no preventive measures. However, there may be an association between thymic cancer and exposure of the chest to radiation.
Special concerns
Damage to the lungs and/or esophagus caused by radiation therapy to the upper chest is a concern. Biopsy runs the risk of seeding tumor cells to other parts of the body.
Resources
BOOKS
Bruss, Katherine, Christina Salter, and Esmeralda Galan, eds. American Cancer Society's Guide to Complementary and Alternative Cancer Methods. Atlanta: American Cancer Society, 2000.
Cameron, Robert, Patrick Loehrer, and Charles Thomas. "Neo plasms of the Mediastinum." In Cancer: Principles and Practice of Oncology., DeVita, Vincent T., Samuel Hell man, and Steven Rosenberg, eds. Philadelphia: Lippincott Williams & Wilkins, 2001.
PERIODICALS
Giaccone, Giuseppe. "Treatment of Thymoma and Thymic Carcinoma." Annals of Oncology 11, Suppl. 3 (2000): 245-6.
Muller-Hermelink, H., and A. Marx. "Thymoma." Current Opinion in Oncology 12 (September 2000): 426-33.
Thomas, Charles, Cameron Wright, and Patrick Loehrer. "Thy moma: State of the Art." Journal of Clinical Oncology 17 (July 1999): 2280-9.
ORGANIZATIONS
American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA 30329. (800) ACS-2345. <http://www.cancer.org>.
Cancer Research Institute, National Headquarters. 681 Fifth Ave., New York, NY 10022. (800) 992-2623. <http://www.cancerresearch.org>.
National Institutes of Health. National Cancer Institute. 9000 Rockville Pike, Bethesda, MD 20982. Cancer Information Service: (800) 4-CANCER. <http://cancernet.nci.nih.gov>.
Belinda Rowland, Ph.D.
KEY TERMS
Adjuvant therapy
—A treatment that is intended to aid the primary treatment. Adjuvant treatments for thymic cancer are radiation therapy and chemotherapy.
Invasive
—A descriptive term for thymoma that has spread beyond the outer wall of the thymus.
Lymphocyte
—A type of white blood cell that is found in the thymus.
Neoadjuvant therapy
—Radiation therapy or chemotherapy used to shrink a tumor before surgical removal of the tumor.
Paraneoplastic syndrome
—A set of symptoms that is associated with cancer but is not directly caused by the cancer.
Pleura
—The outer covering of the lungs.
QUESTIONS TO ASK THE DOCTOR
- What histologic class of thymoma do I have?
- What stage of cancer do I have?
- Has the cancer spread?
- What is the five-year survival rate for patients with this stage of thymoma?
- Will you perform a biopsy?
- What type of biopsy will you perform?
- What is the risk of seeding during a biopsy?
- What are my treatment options?
- What are the risks and side effects of these treatments?
- What medications can I take to relieve treatment side effects?
- Are there any clinical studies underway that would be appropriate for me?
- What effective alternative or complementary treatments are available for thymoma?
- How debilitating is the treatment? Will I be able to continue working?
- What is the chance that the cancer will recur?
- What are the signs and symptoms of recurrence?
- What can be done to prevent recurrence?
- How often will I have follow-up examinations?
Thymoma
Thymoma
Definition
Thymomas are the most common tumor of the thymus.
Description
The thymus is located in the upper chest just below the neck. It is a small organ that produces certain types of white blood cells before birth and during childhood. These white blood cells are called lymphocytes and are an important part of the bodyôs immune system. Once released from the thymus, lymphocytes travel to lymph nodes where they help to fight infections. The thymus gland becomes smaller in adulthood and is gradually taken over by fat tissue.
Although rare, thymomas are the most common type of thymic cancer. They arise from thymic epithelial cells, which make up the covering of the thymus. Thymomas frequently contain lymphocytes, which are non-cancerous. Thymomas are classified as either non-invasive (previously called "benign") or invasive (previously called "malignant"). Noninvasive thymomas are those in which the tumor is encapsulated and easy to remove. Invasive thymomas have spread to nearby structures (such as the lungs) and are difficult to remove. Approximately 30% to 40% of thymomas are of the invasive type.
Thymoma affects men and women equally. It is usually diagnosed between the ages of 40 and 60 years. Thymomas are uncommon in children.
Causes and symptoms
The cause of thymoma is unknown. Cancer is caused when the normal mechanisms that control cell growth become disturbed, causing the cells to continually grow without stopping. This is caused by damage to the DNA in the cell.
Approximately 40% of the patients diagnosed with thymoma have no symptoms. The symptoms in the remaining 60% of patients are caused by pressure from the enlarged thymus on the windpipe (trachea) or blood vessels, or by paraneoplastic syndromes. Paraneoplastic syndromes are collections of symptoms in cancer patients that cannot be explained by the tumor. Seventy-one percent of thymomas are associated with paraneoplastic syndromes. The most common syndromes related to thymoma are pure red cell aplasia (having abnormally low levels of red blood cells), myasthenia gravis (a muscular disorder), and hypogammaglobulinemia (having abnormally low levels of antibodies). These conditions are autoimmune diseases—those in which the body mounts an attack against certain normal cells of the body.
Symptoms of thymoma may include:
- shortness of breath
- swelling of the face
- coughing
- chest pain
- muscle weakness (especially in the eyes, neck, and chest, causing problems with vision, swallowing, and breathing)
- weakness
- dizziness
- shortness of breath
- fatigue
Diagnosis
The physician will conduct a complete physical exam. He or she may be able to feel a fullness in the lower neck region. Routine blood tests may be performed. Imaging studies are necessary because the symptoms of thymoma can be caused by many other diseases. Thymomas can be identified by chest x ray, magnetic resonance imaging, and computed tomography.
A biopsy may be performed, in which a small sample of the tumor is removed and examined under the microscope. However, because of the risk of "seeding" cancerous cells, biopsies are not routinely performed. There are a few different methods to biopsy a thymoma. For a mediastinoscopy, a wand-like lighted camera (endoscope) and special instruments are passed through a small cut in the lower neck. The surgeon can see the tumor on a monitor and can cut off small samples for microscopic analysis. Mediastinoscopy is performed under general anesthesia. Alternatively, a needle biopsy will be taken in which a long needle is passed through the skin and into the tumor. Fine needle biopsy uses a thin needle and larger-core needle biopsy uses a wider needle. Needle biopsies may be performed in conjunction with CT imaging.
Patients who are having difficulty breathing may have a bronchoscopy performed to examine the wind pipe. An endoscope, in this case a bronchoscope, is inserted through the mouth and into the windpipe. The physician will look for tumors and may perform biopsies.
Treatment
Clinical staging
There is more than one type of staging system for thymoma; but the Masaoka system, a surgical staging system developed in 1981, is used most often. Thymoma is categorized into four stages (I, II, III, and IV), which may be further subdivided (A and B) based on the spread of cancerous tissue. The Masaoka staging system is as follows:
- Stage I. The thymoma lies completely within the thymus.
- Stage II. The thymoma has spread out of the thymus and invaded the outer layer of the lung (pleura) or nearby fatty tissue.
- Stage III. The thymoma has spread to other neighboring tissues of the upper chest, including the outer layer of the heart (pericardium), the lungs, or the heartôs main blood vessels.
- Stage IVA. The thymoma has spread throughout the pericardium and/or the pleura.
- Stage IVB. The thymoma has spread to organs in other parts of the body.
In 1999, the World Health Organization (WHO) adopted a new classification system for thymic tumors. This system is a histologic classification, which means that it is based on the microscopic features of the cells that make up the tumor. The WHO classification system ranks thymomas into types A, AB, B1, B2, B3, and C, by increasing severity.
The treatment for thymoma depends on the stage of cancer and the patients overall health. Because thymomas are so rare, there are no defined treatment plans. Treatment options include surgery, radiation therapy, and/or chemotherapy. Surgical removal of the tumor is the preferred treatment. Surgery is often the only treatment required for stage I tumors. Treatment of thymoma often relieves the symptoms caused by paraneoplastic syndromes.
A treatment that is intended to aid the primary treatment is called adjuvant therapy. For instance, chemotherapy may be used 1along with surgery to treat thymoma. Stages II, III, and IV thymomas are often treated with surgery and some form of adjuvant therapy.
Surgery
Thymoma may be treated by surgically removing (resecting) the tumor and some of the nearby healthy tissue. Removal of the entire thymus gland is called a thymectomy. Surgery on the thymus is usually performed through the chest wall by splitting open the breast bone (sternum), a procedure called a median sternotomy. When complete removal of the tumor is impossible, the surgeon will remove as much of the tumor as possible (debulking surgery, subtotal resection). In these cases, If the tumor has spread, surgery may include removal of such other tissues as the pleura, pericardium, blood vessels of the heart, lung, and nerves.
Radiation therapy
Radiation therapy uses high-energy radiation from x rays and gamma rays to kill the cancer cells. Radiation given from a machine that is outside the body is called external radiation therapy. Radiation therapy is often used as adjuvant therapy following surgery to reduce the chance of cancer recurrence. Radiation may be used to kill cancer cells in cases in which the tumor was only partially removed. It may be used before surgery to shrink a large tumor. Radiation therapy is not very effective when used alone, although it may be used alone when the patient is too sick to withstand surgery.
The skin in the treated area may become red and dry and may take as long as a year to return to normal. Radiation to the chest may damage the lung, causing shortness of breath and other breathing problems. Also, the tube that goes between the mouth and stomach (esophagus) may be irritated by radiation, causing swallowing difficulties. Fatigue, upset stomach, diarrhea, and nausea are also common complaints of patients having radiation therapy. Most side effects go away about two to three weeks after radiation therapy has ended.
Chemotherapy
Chemotherapy uses anticancer drugs to kill the cancer cells. The drugs are given by mouth (orally) or intravenously. They enter the bloodstream and can travel to all parts of the body. Chemotherapy may be given before surgery to shrink a tumor, which is called neoadjuvant therapy. Thymoma cells are very sensitive to anticancer drugs, especially cisplatin, doxorubicin, and ifosfamide. Generally, a combination of drugs is given because it is more effective than a single drug in treating cancer. Corticosteroids are also used to treat thymoma.
The side effects of chemotherapy are significant, and include stomach upset, vomiting, appetite loss, hair loss (alopecia, ) mouth sores, and fatigue. Women may experience vaginal sores, menstrual cycle changes, and premature menopause. There is also an increased chance of infections.
Alternative treatment
Although alternative and complementary therapies are used by many cancer patients, very few controlled studies on the effectiveness of such therapies exist. Mind-body techniques such as prayer, biofeedback, visualization, meditation, and yoga, have not shown any effect in reducing cancer; but they can reduce stress and lessen some of the side effects of cancer treatments. Gerson, macrobiotic, orthomolecular, and Cancell therapies are ineffective treatments for cancer.
Clinical studies of hydrazine sulfate found that it had no effect on cancer and even worsened the health and well-being of the study subjects. One clinical study of the drug amygdalin (Laetrile) found that it had no effect on cancer. Laetrile can be toxic and has caused deaths. Shark cartilage has been studied as a cancer treatment and is presently being studied by the FDA in clinical trials. Although the results are mixed, clinical studies suggest that melatonin may increase the survival time and quality of life for cancer patients.
Selenium, in safe doses, may delay the progression of cancer. Laboratory and animal studies suggest that curcumin, the active ingredient of turmeric, has anticancer activity. Maitake mushrooms may boost the immune system, according to laboratory and animal studies. The results of laboratory studies suggest that mistletoe has anticancer properties; however, clinical studies have not been conducted.
Prognosis
The five-year survival rates for thymomas are 96% for stage I, 86% for stage II, 69% for stage III, and 50% for stage IV. Thorough (radical) surgery is associated with a longer survival rate. Almost 15% of thymoma patients develop a second cancer.
Thymomas rarely spread (metastasize) outside of the chest cavity. Metastasis is usually limited to the pleura. Invasive thymomas are prone to recurrence, even 10 to 15 years following surgery. The recurrence rates are drastically reduced and the five-year survival rates are drastically increased in patients who receive adjuvant radiation therapy.
Prevention
Because there are no known risk factors for the development of thymoma, there are no preventive measures. However, there may be an association between thymic cancer and exposure of the chest to radiation.
Resources
BOOKS
Bruss, Katherine, Salter, Christing, and Esmeralda Galan, editors. American Cancer Society + s Guide to Complementary and Alternative Cancer Methods. Atlanta: American Cancer Society, 2000.
Cameron, Robert, Loehrer, Patrick, and Charles Thomas. "Neoplasms of the Mediastinum." In Cancer: Principles & Practice of Oncology, edited by Vincent DeVita, Hellman, Samuel, and Steven Rosenberg. Philadelphia: Lippincott Williams & Wilkins, 2001, pp. 1019-36.
PERIODICALS
Giaccone, Giuseppe. "Treatment of Thymoma and Thymic Carcinoma." Annals of Oncology 11, Supplement 3 (2000): 245-6.
Muller-Hermelink, H., and A. Marx. "Thymoma." Current Opinion in Oncology 12 (September 2000): 426-33.
Thomas, Charles, Wright, Cameron, and Patrick Loehrer. "Thymoma: State of the Art." Journal of Clinical Oncology 17 (July 1999): 2280-89.
ORGANIZATIONS
American Cancer Society. 1599 Clifton Road NE, Atlanta, GA 30329. (800) ACS-2345. 〈http://www.cancer.org〉.
Cancer Research Institute, National Headquarters. 681 Fifth Ave., New York, NY 10022. (800) 992-2623. 〈http://www.cancerresearch.org〉.
National Institutes of Health. National Cancer Institute. 9000 Rockville Pike, Bethesda, MD 20982. Cancer Information Service: (800) 4-CANCER. 〈http://cancernet.nci.nih.gov〉.
KEY TERMS
Adjuvant therapy— A treatment that is intended to aid the primary treatment. Adjuvant treatments for thymic cancer are radiation therapy and chemotherapy.
Invasive— A descriptive term for thymoma that has spread beyond the outer wall of the thymus.
Lymphocyte— A type of white blood cell that is found in the thymus.
Neoadjuvant therapy— Radiation therapy or chemotherapy used to shrink a tumor before surgical removal of the tumor.
Paraneoplastic syndrome— A set of symptoms that is associated with cancer but is not directly caused by the cancer.
Pleura— The outer covering of the lungs.