- Risk Factors
What is sarcoidosis?
The cause of sarcoidosis is unknown. The disease can appear suddenly and disappear. Or it can develop gradually and go on to produce symptoms that come and go, sometimes for a lifetime.
As sarcoidosis progresses, microscopic lumps of a specific form of inflammation, called granulomas, appear in the affected tissues. In the majority of cases, these granulomas clear up, either with or without treatment. In the few cases where the granulomas do not heal and disappear, the tissues tend to remain inflamed and become scarred (fibrotic).
Sarcoidosis was first identified over 100 years ago by two dermatologists working independently, Dr. Jonathan Hutchinson in England and Dr. Caesar Boeck in Norway. Sarcoidosis was originally called Hutchinson's disease or Boeck's disease. Dr. Boeck went on to fashion today's name for the disease from the Greek words "sark" and "oid," meaning flesh-like. The term describes the skin eruptions that are frequently caused by the illness.
What causes sarcoidosis?
Sarcoidosis is a spontaneous disease of unknown causes. There are no known predisposing risk factors for developing sarcoidosis.
The immune system is complex. Basically, B lymphocytes make antibodies to fight against infections, while T-lymphocytes patrol the tissues to fight off invaders in other ways.
The heightened cellular immune response in the diseased tissue is characterized by significant increases in activated T-lymphocytes with certain characteristic cell-surface antigens, as well as in activated alveolar macrophages. This pronounced, localized cellular response is also accompanied by the appearance in the lung of an array of lymphocyte-produced mediators generally called cytokines that are thought to contribute to the disease process. These include interleukin-1, interleukin-2, B-cell growth factor, B-cell differentiation factor, fibroblast growth factor, and fibronectin. Because several lung diseases follow respiratory tract infections, ascertaining whether a virus can be implicated in the events leading to sarcoidosis remains an important area of research.
Some recent observations seem to provide suggestive leads on this question. In these studies, the genes of cytomegalovirus (CMV), a common disease-causing virus, were introduced into lymphocytes, and the expression of the viral genes was studied. It was found that the viral genes were expressed both during acute infection of the cells and when the virus was not replicating in the cells. However, this expression seemed to take place only when the T-cells were activated by some injurious event.
In addition, the product of a CMV gene was found capable of activating the gene in alveolar macrophages responsible for the production of interleukin-1. Since interleukin-1 levels are found to increase in alveolar macrophages in patients with sarcoidosis, this suggests that certain viral genes can enhance the production of inflammatory components associated with sarcoidosis. Whether these findings implicate viral infections in the disease process in sarcoidosis is unclear.
Who is at risk of sarcoidosis?
Sarcoidosis was once considered a rare disease. We now know that it is a common chronic illness that appears all over the world. Indeed, it is the most common of the scarring lung disorders and occurs often enough in the United States for Congress to have declared a national Sarcoidosis Awareness Day in 1990.
Anyone can get sarcoidosis. It occurs in all races and both sexes. Nevertheless, the risk is greater if you are a young black adult, especially a black woman, or of Scandinavian, German, Irish, or Puerto Rican origin. No one knows why.
Because sarcoidosis can escape diagnosis or be mistaken for several other diseases, we can only guess how many people are affected. The best estimate today is that about 10 in 100,000 white people in the United States have sarcoidosis. Among black people, it occurs more frequently, in probably 35 out of 100,000 people. Some scientists, however, believe that these figures greatly underestimate the percentage of the U.S. population with sarcoidosis.
Sarcoidosis mainly affects people between 20-40 years of age. White women are just as likely as white men to get sarcoidosis, but the black female gets sarcoidosis two times as often as the black male. No one knows what causes sarcoidosis.
Sarcoidosis also appears to be more common and more severe in certain geographic areas. It has long been recognized as a common disease in Scandinavian countries. But it was not until the mid-'40s when a large number of cases were identified during a mass chest X-ray screening for the Armed Forces, that its high prevalence was recognized in North America.
What are the symptoms of sarcoidosis?
Sarcoidosis is a rare condition in which small patches of red and swollen tissues (granulomas) develop in organs in the body. It usually affects the lungs and skin. This condition may change the normal structure and possibly the function of an affected organ. Many people with sarcoidosis do not have any symptoms.
Others have only vague symptoms which include:
Organ-specific symptoms include:
- Lungs: Shortness of breath, wheezing, or a dry cough that may disappear over time
- Lymph nodes: Enlarged and sometimes tender lymph nodes, most often in the neck and chest, but sometimes under the chin, armpits, or groin
- Eyes: Burning, itching, tearing, redness, sensitivity to light, dryness, seeing black spots, blurred vision, reduced color vision, and, in rare cases, blindness
- Skin: Bumps, ulcers, or rarely flat areas of discolored skin that appear mostly near the nose or eyes or on the back, arms, legs, and scalp; painful and tender bumps can also appear on the ankles and shins.
- Bones and joints: Nodules (bone growths) causing pain in the hands and feet and sometimes pain and swelling in the ankles or other joints
- Spleen and liver: Fever, fatigue, or itching; there can be pain in the upper right part of the abdomen under the ribs.
- Heart: Shortness of breath, swelling in the legs, wheezing, coughing, and chest pain. One may have a feeling of an irregular or fast heartbeat at times or even pass out without warning.
- Salivary glands: Swelling (which may make the cheeks look puffy) and an overly dry mouth and throat
- Nervous system: Headaches, vision problems, weakness or numbness of an arm or a leg, drooping of one side of the face, loss of movement in the arms or legs, weakness, pain, or a “pins and needles” feeling
Symptoms can appear suddenly and then disappear. Sometimes, however, they can continue over a lifetime.
Diagnosis of sarcoidosis
Because sarcoidosis can involve inflammation in a variety of organs of the body, many types of doctors can be involved in the treatment of patients with sarcoidosis. Patients with sarcoidosis are best treated by a lung specialist or a doctor who has a special interest in sarcoidosis. Sarcoidosis specialists are usually located at major research centers.
Doctors who treat sarcoidosis include primary care providers as well as internists, pulmonologists, cardiologists, rheumatologists, dermatologists, and neurologists.
Preliminary diagnosis of sarcoidosis is based on the patient's medical history, routine tests, a physical examination, and a chest X-ray.
The doctor confirms the diagnosis of sarcoidosis by eliminating other diseases with similar features. These include such granulomatous diseases as:
What testing is used to diagnosis sarcoidosis?
While no single test can be relied on for a correct diagnosis of sarcoidosis, many types of tests are useful. X-rays and blood tests are usually the first procedures the doctor will order. Pulmonary function tests often provide clues to diagnosis. Other tests may also be used, some more often than others.
Many of the tests that the doctor calls on to help diagnose sarcoidosis can also help the doctor follow the progress of the disease and determine whether the sarcoidosis is getting better or worse.
The chest X-ray is often helpful to give the doctor a picture of the lungs, heart, as well as surrounding tissues containing lymph nodes (where infection-fighting white blood cells form) and give the first indication of sarcoidosis. For example, a swelling of the lymph glands between the two lungs can show up on an X-ray. When sarcoidosis becomes more advanced, an X-ray can also show scarring in affected areas of the lungs.
Pulmonary function test
By performing a variety of tests called pulmonary function tests (PFT), the doctor can find out how well the lungs are doing their job of expanding and exchanging oxygen and carbon dioxide with the blood. The lungs of sarcoidosis patients cannot handle these tasks as well as they should; this is because granulomas and fibrosis of lung tissue decrease lung capacity and disturb the normal flow of gases between the lungs and the blood. One PFT procedure calls for the patient to breathe into a machine, called a spirometer. It is a mechanical device that records changes in the lung size as air is inhaled and exhaled, as well as the time it takes the patient to do this.
Blood analyses can evaluate the number and types of blood cells in the body and how well the cells are functioning. They can also measure the levels of various blood proteins known to be involved in immunological activities, and they can show increases in serum calcium levels and abnormal liver function that often accompany sarcoidosis.
Blood tests can measure a blood substance called angiotensin-converting enzyme (ACE). Because the cells that makeup granulomas secrete large amounts of ACE, the enzyme levels are often high in patients with sarcoidosis. ACE levels, however, are not always high in sarcoidosis patients, and increased ACE levels can also occur in other illnesses.
This uses an instrument called a bronchoscope—a long, narrow tube with a light at the end—to wash out, or lavage, cells, and other materials from inside the lungs. This wash fluid is then examined for the number of various cells and other substances that reflect inflammation and immune activity in the lungs. A high number of white blood cells in this fluid usually indicate inflammation in the lungs.
Transbronchial biopsy allows microscopic examination of specimens of lung tissue obtained with a bronchoscope. A transbronchial biopsy demonstrating evidence of the type of granuloma found in sarcoidosis is considered the definitive test today.
In this procedure, the doctor injects the radioactive chemical element gallium-67 into the patient's vein. The gallium collects at places in the body affected by sarcoidosis and other inflammatory conditions. Two days after the injection, the body is scanned for radioactivity. Increases in gallium uptake at any site in the body indicate that inflammatory activity has developed at the site and give an idea of which tissue, and how much tissue, has been affected. However, since any type of inflammation causes gallium uptake, a positive gallium scan does not necessarily mean that the patient has sarcoidosis. This test is rarely used today.
The PET (positron emission tomography) scan injects a small amount of radioactive glucose and tracks where it accumulates. While granulomas do accumulate glucose preferentially, so do other forms of inflammation and other conditions.
This test involves injecting a standardized preparation of sarcoid tissue material into the skin. On the one hand, a unique lump formed at the point of injection is considered positive for sarcoidosis. On the other hand, the test result is not always positive even if the patient has sarcoidosis.
The Kveim test is not used often in the United States because no test material has been approved for sale by the U.S. Food and Drug Administration. However, a few hospitals and clinics may have some standardized test preparation prepared privately for their use.
An instrument called a slit lamp, which permits examination of the inside of the eye, can be used to detect silent damage from sarcoidosis.
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What are the 4 stages of sarcoidosis?
Sarcoidosis is a rare condition that causes small patches of red and swollen tissue (granulomas) in the organs of the body. It usually affects the lungs and skin. This condition may change the normal structure and possibly the function of an affected organ.
Siltzbach developed the staging of sarcoidosis based on radiographic findings:
- Stage 0: Normal appearance in chest radiography. In some cases, red and swollen tissue is noted in the lymph nodes. A normal chest X-ray does not exclude the diagnosis of sarcoidosis, particularly when cardiac or neurologic involvement is suspected. Computed tomography (CT) of the chest may be helpful.
- Stage I: Lymphadenopathy (enlarged lymph nodes)
- Stage II: Enlarged lymph nodes with shadows on chest X-ray due to lung infiltrates or granulomas
- Stage III: Chest X-ray shows lung infiltrates as shadows, which is a progressive condition.
- Stage IV (Endstage): Pulmonary fibrosis or scar-like tissue found on a chest X-ray. Chest X-ray usually demonstrates a honeycomb-like appearance in the lungs. Due to this scar-like tissue or honeycomb-like appearance, patients may have difficulty breathing. It is permanent damage.
What is the treatment for sarcoidosis?
Fortunately, many patients with sarcoidosis require no treatment. Symptoms, after all, are usually not disabling and do tend to disappear spontaneously.
When therapy is recommended, the main goal is to keep the lungs and other affected body organs working and to relieve symptoms. The disease is considered inactive once the symptoms fade. After many years of experience in treating the disease, corticosteroid drugs remain the primary treatment for inflammation and granuloma formation. Prednisone is probably the corticosteroid most often prescribed today.
Prednisone often improves the cough and pulmonary function tests in sarcoidosis. Unfortunately, if the lungs are severely affected by sarcoidosis, scarring develops in them. Prednisone will not clear the established scarring. In those unusual cases where sarcoidosis raises the calcium level in the blood, if lowering calcium and vitamin D intake is not sufficient to correct this, or the calcium elevation is symptomatic, then Prednisone can be rapidly effective at bringing the calcium level back to normal.
Because sarcoidosis can disappear even without therapy, doctors sometimes disagree on when to start the treatment, what dose to prescribe, and how long to continue the medicine. The doctor's decision depends on the organ system involved and how far the inflammation has progressed. If the disease appears to be severe, especially in the lungs, eyes, heart, nervous system, spleen, or kidneys, the doctor may prescribe a corticosteroid.
Corticosteroid treatment usually results in improvement. Symptoms often start up again, however, when it is stopped. Treatment, therefore, may be necessary for several years, sometimes for as long as the disease remains active or to prevent relapse.
Frequent checkups are important so that the doctor can monitor the illness and, if necessary, adjust the treatment.
Corticosteroids, for example, can have side effects: mood swings, swelling, and weight gain because the treatment tends to make the body hold on to water; high blood pressure; high blood sugar; and craving for food. Long-term use can affect the stomach, skin, and bones. This situation can bring on stomach pain, an ulcer, or acne or cause the loss of calcium from bones. However, if the corticosteroid is taken in carefully prescribed low doses, the benefits from the treatment are usually far greater than the problems.
Besides corticosteroids, various other drugs have been tried, but their effectiveness has not been established in controlled studies. These drugs include:
Several drugs that suppress alveolitis by killing the cells that produce granulomas have also been used:
- chlorambucil (Leukeran)
- azathioprine (Imuran)
- methotrexate (Rheumatrex, Trexall)
- cyclophosphamide (Cytoxan)
None have been evaluated in controlled clinical trials, and the risk of using these drugs must be compared closely with the benefits of preventing organ damage by the disease. They are not to be used by pregnant women.
Cyclosporine, a drug used widely in organ transplants to suppress immune reactions, has been evaluated in one controlled trial. It was found to be unsuccessful. More recently, thalidomide (Thalomid) has been used successfully in a limited number of patients and seems to improve lung function and heal skin lesions. Infliximab (Remicade) has been reported recently as effective in treating patients with sarcoidosis.
There are many unanswered questions about sarcoidosis. Identifying the agent that causes the illness, along with the inflammatory mechanisms that set the stage for the alveolitis, granuloma formation, and fibrosis that characterized the disease is the major aim of researchers of sarcoidosis. The development of reliable methods of diagnosis, treatment, and eventually, the prevention of sarcoidosis is the ultimate goal.
Originally, scientists thought that sarcoidosis was caused by an acquired state of immunological inertness (anergy). This notion was revised when the technique of bronchoalveolar lavage provided access to a vast array of cells and cell-derived mediators operating in the lungs of sarcoidosis patients. Sarcoidosis is now believed to be associated with a complex mix of immunological disturbances involving simultaneous activation, as well as depression, of certain immunological functions.
Immunological studies on sarcoidosis patients show that many of the immune functions associated with thymus-derived white blood cells, called T-lymphocytes or T-cells, are depressed. The depression of this cellular component of systemic immune response is expressed in the inability of the patients to evoke a delayed hypersensitivity skin reaction (a positive skin test), when tested by the appropriate foreign substances, or antigen, underneath the skin.
In addition, the blood of sarcoidosis patients contains a reduced number of T-cells. These T-cells do not seem capable of responding normally when treated with substances known to stimulate the growth of laboratory-cultured T-cells. Neither do they produce their normal complement of immunological mediators, cytokines, through which the cells modify the behavior of other cells.
In contrast to the depression of the cellular immune response, the B-cell activity—or humoral immune response of sarcoidosis patients is elevated. The humoral immune response is reflected by the production of circulating antibodies against a variety of exogenous antigens, including common viruses. This humoral component of systemic immune response is mediated by another class of lymphocytes known as B-lymphocytes, or
In another indication of heightened humoral response, sarcoidosis patients seem prone to develop autoantibodies (antibodies against endogenous antigens) similar to rheumatoid factors.
With access to the cells and cell products in the lung tissue compartments through the bronchoalveolar technique, it also has become possible for researchers to complement the above investigations at the blood level with analysis of local inflammatory and immune events in the lungs. In contrast to what is seen at the systemic level, the cellular immune response in the lungs seems to be heightened rather than depressed.
Currently, thalidomide is being studied as a treatment for sarcoidosis. Future research with viral models may provide clues to the molecular mechanisms that trigger alterations in white blood cell (lymphocyte and macrophage) regulation leading to sarcoidosis.
For difficult-to-treat (refractory) sarcoidosis and sarcoidosis involving the nervous system (neurosarcoidosis), recent research using biologic medications that inhibit tumor necrosis factor (TNF-blockers) has been beneficial. The TNF-blockers used were adalimumab (Humira) and infliximab (Remicade).
What is the prognosis for sarcoidosis?
The prognosis of sarcoidosis is generally very good. The prognosis ultimately depends on the location and severity of involvement with the sarcoid inflammation.
What is the mortality rate in sarcoidosis and how is it changing the pattern of cause of death?
Approximately 1% to 5% of patients with sarcoidosis die from its complications. Recent population studies have indicated that the mortality rate may be increasing over the past decade. The most prevalent lesion leading to death was advanced lung involvement (22/28 patients or 78%) with various late complications such as cardiorespiratory failure, gram-negative pneumonia, and fungal infections. Patients who died of central nervous system and cardiac sarcoidosis were younger and their clinical course was shorter. Sarcoidosis is associated with autoimmune diseases, pulmonary embolism, and cancer; however, the underlying mechanisms linking the diseases continue to be debated.
Is it possible to prevent sarcoidosis?
The cause of sarcoidosis remains unknown, so there is at present no known way to prevent or cure this disease. However, doctors have had a great deal of experience in the management of the illness. It should be noted that most people with sarcoidosis lead normal lives.
If you have sarcoidosis, you can help yourself by following sensible health measures. You should not smoke. You should also avoid exposure to other substances such as dust and chemicals that can harm your lungs.
If you have any symptoms of sarcoidosis, see your doctor regularly so that the illness can be watched and, if necessary, treated. Regular checkups with the doctor are important even if there are no symptoms present. Eye examinations by an eye specialist can detect early eye inflammation from sarcoidosis.
Although severe sarcoidosis can reduce the chances of becoming pregnant, particularly for older women, many young women with sarcoidosis have given birth to healthy babies while on treatment. Patients planning to have a baby should discuss the matter with their doctor. Medical checkups all through pregnancy and immediately thereafter are especially important for sarcoidosis patients. In some cases, bed rest is necessary during the last 3 months of pregnancy.
In addition to family and close friends, several local lung organizations, other nonprofit health organizations, and self-help groups are available to help patients cope with sarcoidosis. By keeping in touch with them, you can share personal feelings and experiences. Members also share specific information on the latest scientific advances, where to find a sarcoidosis specialist, and how to improve one's self-image.
What do we not know about sarcoidosis?
Sarcoidosis is currently thought to be associated with an abnormal immune response. It is not known whether the trigger that initiates the immune disturbance is a foreign substance, chemical, drug, virus, or some other substance.
In general, more than half of the time, sarcoidosis appears briefly and heals naturally, often without the patient knowing or doing anything about it. Some sarcoidosis patients are left with permanent lung damage. In 10%-15% of the patients, sarcoidosis can become chronic.
When either the granulomas or fibrosis seriously affect the function of a vital organ—the lungs, heart, nervous system, liver, or kidneys, for example -- sarcoidosis can be fatal. This occurs 1% to 5% of the time. Some people are more at risk than others. No one knows why.
No one can predict how sarcoidosis will progress in an individual patient. The patient's symptoms, race, and the doctor's findings can give some clues. For example, a sudden onset of general symptoms, such as weight loss or feeling generally ill, is usually taken to mean that the course of sarcoidosis will be relatively short and mild. Dyspnea and possibly skin sarcoidosis often indicate that the sarcoidosis will be more chronic and severe.
White patients are more likely to develop the milder form of the disease. Black people tend to develop more chronic and severe forms.
Sarcoidosis rarely develops before the age of 10 or after the age of 60. However, the illness—with or without symptoms—has been reported in younger as well as older people. When symptoms do appear in these age groups, the symptoms are those that are more general, for example, tiredness, sluggishness, coughing, and a general feeling of ill health.
What do we know about sarcoidosis?
Much about sarcoidosis remains unknown. Nevertheless, if you have the disease, you can be reassured about several things.
Sarcoidosis is usually not crippling. It often goes away by itself, with most cases healing in 24-36 months. Even when sarcoidosis lasts longer, most patients can go about their lives as usual. Sarcoidosis is not cancer. It is not contagious, and your friends and family will not catch it from you. Although it can occur in families, there is no evidence that sarcoidosis is passed from parents to children.
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American College of Rheumatology
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Current Opinion in Pulmonary Medicine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326053/>
The Stages of Pulmonary Sarcoidosis- What Do They Really Mean? https://www.stopsarcoidosis.org/stages-of-sarcoidosis/
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