Melatonin

Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae[1] to humans, at levels that vary in a diurnal cycle.

Many biological effects of melatonin are produced through activation of melatonin receptors,[2] while others are due to its role as a pervasive and extremely powerful antioxidant[3] with a particular role in the protection of nuclear and mitochondrial DNA.[4]

Melatonin was released into the general health supplement market in the United States in 1993, and met with good consumer acceptance and enthusiasm.[5]

In higher animals, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase.

Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus which receives information from the retina about the daily pattern of light and darkness.

Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.[6][7]

A study indicates that patients with nocturnal asthma may experience adverse effects from melatonin supplements. According to the study “Immunomodulatory Effects of Melatonin in Asthma”, even small amounts of supplemental melatonin worsen the symptoms of the inflammatory disease asthma by causing the body to release chemicals which provoke inflammation. The inflammatory chemicals include increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha [8].

Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.

Biological clock

See also: Phase response curve

In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, that is located in the center of the brain, on the dorsal surface of diencephalon. The melatonin signal forms part of the system that regulates the circadian cycle, but it is the Central nervous system that controls the daily cycle in most components of the paracrine and endocrine systems[9][10] rather than the melatonin signal (as was once postulated).

Normally, the production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness." The secretion of melatonin peaks in the middle of the night, and gradually falls during the second half of the night. Until recent history, humans in temperate climates were exposed to up to eighteen hours of darkness in the winter. In this modern world, artificial lighting typically reduces this to eight hours or less per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers,[11] and the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world.[12] As inadequate as blood concentrations may be in brightly-lit environments, some scientists now believe that people's overnight output of melatonin can be further jeopardized each time they interrupt their sleep and turn on a bright light (suggesting that the lower brightness level of a nightlight would be safer). Others suggest that such short exposures do no harm.[13]

Although the primary site of melatonin's action in humans is the melatonin receptors, it first evolved as an antioxidant. In many lower life forms, it serves only this purpose.[14]

Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.[3] Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.[15]

Recent research indicates that the beginning of the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine or AFMK rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neuralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.[14]

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[16]

The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.[17][18][19]

Immune system
While it is clear that melatonin interacts with the immune system,[20][21] the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete, clinical trials.

Melatonin is an immunoregulator that can enhance T cell production. When taken in conjunction with calcium, it is an immunostimulator and is used as an adjuvant in some clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders.

Many supplemental melatonin users have reported an increase in the vividness or frequency of dreams. High doses of melatonin (50mg) dramatically increased REM sleep time and dream activity in both narcoleptics and normal people.[22]

Many psychoactive drugs, such as LSD and cocaine, increase melatonin synthesis.[22] It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.[22]

In a 2005 editorial of the British Journal of Psychiatry, Ben Sessa suggested that psychotropic drugs be readmitted in the field of scientific enquiry and therapy.[23] Melatonin, being two endogenous hallucinogenic indoles like N,N-dimethyltryptamine (DMT), is likely to be research priorities in this reemerging field of psychiatry.[24]

Melatonin appears to have some use against circadian rhythm sleep disorders, such as jet lag and delayed sleep phase syndrome. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), and sexual dysfunction. A study by Alfred J. Lewy and other researchers at Oregon Health & Science University found that it may ameliorate SAD and circadian misalignment,[25] but as of 2006 it is known to affect the timing of endogenous melatonin production, raising the risk that it can exacerbate both clinical depression and SAD.[26] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[27]

Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain[28] and the heart;[29] however, this has not been tested in humans.

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[30] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer's disease. Thus, melatonin may be effective for treating Alzheimer's Disease.[31] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their body's production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called "sundowning," which has been shown in many studies to be effectively treated with melatonin supplements in the evening.[32]

ADHD is most commonly treated with methylphenidate which may cause insomnia in approximately 94% of its users. Research shows that after melatonin is administered to the patients, the time needed to fall asleep is significantly reduced. Before the melatonin was administered, the time needed to fall asleep ranged from 15 minutes to 240 minutes. After the melatonin was administred, the time needed to fall asleep ranged from 15 minutes to 64 minutes. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.[33]

Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[34]

Some resources warn women trying to conceive not to take a melatonin supplement.[35]

Melatonin has been shown to be effective in treating one form of depression, Seasonal Affective Disorder. [1]

Some studies have shown that melatonin has potential for use in the treatment of various forms of cancer, HIV, and other viral diseases; however, further testing is necessary to confirm this.[38]

Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms. (*Quoted from Ross Histology and Wheather's Functional Histology.)

The primary motivation for the use of melatonin as a supplement is as a natural aid to better sleep, with other incidental benefits to health and well-being due to its role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.

Victor Herbert, M.D., J.D., of the Mt. Sinai School of Medicine, cites studies from Massachusetts Institute of Technology that say melatonin pills sold as supplements contain three to 10 times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of nighttime rest. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses are just as effective at improving sleep quality.[39] High dose melatonin can even be counterproductive: Lewy & al[40] provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve." In their study, 0.5 mg of melatonin was effective while 20 mg wasn't. A practical implication of these results is that effective melatonin supplementation (for sleep problems) thus becomes very accessible: it costs a fraction of what most researchers thought it might cost. Melatonin supplementation for sleep problems is available without prescription in most cases in the United States. Melatonin supplements are available as oral supplements and transdermal melatonin or "melatonin sleep patch".

Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).[41]

Melatonin is practically nontoxic and exhibits almost no short-term side effects. However, melatonin derived from animal sources may be contaminated with viral material; synthetic melatonin may be taken to avoid this risk.[42] No studies have been conducted yet to determine whether there are any long-term side effects.

Even though it is seen as a relatively safe, benign drug, especially to herbal enthusiasts, it can cause some unwanted side effects, especially at high doses. The bodies of people under age 35 are usually able to produce an adequate supply of melatonin on their own.[citation needed] Ingesting melatonin supplements can cause hormone fluctuations,[2] irritability,[3] reduced blood flow (see below), and increased sleep disturbances, including vivid nightmares.[4]

Melatonin taken in combination with monoamine oxidase inhibitors (MAOIs) can lead to overdose because MAOIs inhibit the breakdown of melatonin by the body. Exogenous melatonin normally does not affect the endogenous melatonin profile in the short or medium-term, merely advancing the phase of endogenous melatonin production in time.

In individuals with auto-immune disorders, there is concern that melatonin supplementation may exacerbate symptoms due to stimulation of the immune system.[43]

Melatonin causes somnolence, and therefore should not be taken within five hours[citation needed] before driving, operating machinery, etc. As melatonin is almost always taken at the end of the waking day, this is generally not an issue.

Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate the symptoms by reducing nerve activity in those who experience the condition, the study found.[44]

Melatonin has been classified as a dietary supplement and made freely available in the USA.[45]

Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock.[46] In seasonal breeders which do not have long gestation periods, and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[47] and hamsters.[48] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.

Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.[49][50]

Leukemia

What is leukemia?

Leukemia is a type of cancer. Cancer is a group of many related diseases. All cancers begin in cells, which make up blood and other tissues. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place.

Sometimes this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. Leukemia is cancer that begins in blood cells.

Normal Blood Cells

Blood cells form in the bone marrow. Bone marrow is the soft material in the center of most bones.

Immature blood cells are called stem cells and blasts. Most blood cells mature in the bone marrow and then move into the blood vessels. Blood that flows through the blood vessels and heart is called the peripheral blood.

The bone marrow makes different types of blood cells. Each type has a special function:

White blood cells help fight infection.

Red blood cells carry oxygen to tissues throughout the body.

Platelets help form blood clots that control bleeding.

Leukemia Cells

In people with leukemia, the bone marrow produces abnormal white blood cells. The abnormal cells are leukemia cells. At first, leukemia cells function almost normally. In time, they may crowd out normal white blood cells, red blood cells, and platelets. This makes it hard for blood to do its work.

What are the types of leukemia?

The types of leukemia are grouped by how quickly the disease develops and gets worse. Leukemia is either chronic (gets worse slowly) or acute (gets worse quickly):

• Chronic leukemia — Early in the disease, the abnormal blood cells can still do their work, and people with chronic leukemia may not have any symptoms. Slowly, chronic leukemia gets worse. It causes symptoms as the number of leukemia cells in the blood rises.

• Acute leukemia — The blood cells are very abnormal. They cannot carry out their normal work. The number of abnormal cells increases rapidly. Acute leukemia worsens quickly.

The types of leukemia are also grouped by the type of white blood cell that is affected. Leukemia can arise in lymphoid cells or myeloid cells. Leukemia that affects lymphoid cells is called lymphocytic leukemia. Leukemia that affects myeloid cells is called myeloid leukemia or myelogenous leukemia.

There are four common types of leukemia:

• Chronic lymphocytic leukemia (chronic lymphoblastic leukemia, CLL) accounts for about 7,000 new cases of leukemia each year. Most often, people diagnosed with the disease are over age 55. It almost never affects children.

• Chronic myeloid leukemia (chronic myelogenous leukemia, CML) accounts for about 4,400 new cases of leukemia each year. It affects mainly adults.

• Acute lymphocytic leukemia (acute lymphoblastic leukemia, ALL) accounts for about 3,800 new cases of leukemia each year. It is the most common type of leukemia in young children. It also affects adults.

• Acute myeloid leukemia (acute myelogenous leukemia, AML) accounts for about 10,600 new cases of leukemia each year. It occurs in both adults and children.

Hairy cell leukemia is a rare type of chronic leukemia. This booklet does not deal with hairy cell leukemia or other rare types of leukemia. Together, these rare leukemias account for about 5,200 new cases of leukemia each year.

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Who is at risk for Leukemia?

No one knows the exact causes of leukemia. Doctors can seldom explain why one person gets this disease and another does not. However, research has shown that people with certain risk factors are more likely than others to develop leukemia. A risk factor is anything that increases a person’s chance of developing a disease.

Studies have found the following risk factors for leukemia:

• Very high levels of radiation — People exposed to very high levels of radiation are much more likely than others to develop leukemia. Very high levels of radiation have been caused by atomic bomb explosions (such as those in Japan during World War II) and nuclear power plant accidents (such as the Chernobyl [also called Chornobyl] accident in 1986).

Medical treatment that uses radiation can be another source of high-level exposure. Radiation used for diagnosis, however, exposes people to much lower levels of radiation and is not linked to leukemia.

• Working with certain chemicals — Exposure to high levels of benzene in the workplace can cause leukemia. Benzene is used widely in the chemical industry. Formaldehyde is also used by the chemical industry. Workers exposed to formaldehyde also may be at greater risk of leukemia.

• Chemotherapy — Cancer patients treated with certain cancer-fighting drugs sometimes later develop leukemia. For example, drugs known as alkylating agents are associated with the development of leukemia many years later.

• Down syndrome and certain other genetic diseases—Some diseases caused by abnormal chromosomes may increase the risk of leukemia.

• Human T-cell leukemia virus-I (HTLV-I)—This virus causes a rare type of chronic lymphocytic leukemia known as human T-cell leukemia. However, leukemia does not appear to be contagious.

• Myelodysplastic syndrome — People with this blood disease are at increased risk of developing acute myeloid leukemia.

In the past, some studies suggested exposure to electromagnetic fields as another possible risk factor for leukemia. Electromagnetic fields are a type of low-energy radiation that comes from power lines and electric appliances. However, results from recent studies show that the evidence is weak for electromagnetic fields as a risk factor.

Most people who have known risk factors do not get leukemia. On the other hand, many who do get the disease have none of these risk factors. People who think they may be at risk of leukemia should discuss this concern with their doctor. The doctor may suggest ways to reduce the risk and can plan an appropriate schedule for checkups.

What are symptoms of leukemia?

Like all blood cells, leukemia cells travel through the body. Depending on the number of abnormal cells and where these cells collect, patients with leukemia may have a number of symptoms.

Common symptoms of leukemia:

• Fevers or night sweats
• Frequent infections
• Feeling weak or tired
• Headache
• Bleeding and bruising easily (bleeding gums, purplish patches in the skin, or tiny red spots under the skin)
• Pain in the bones or joints
• Swelling or discomfort in the abdomen (from an enlarged spleen)
• Swollen lymph nodes, especially in the neck or armpit
• Weight loss

Such symptoms are not sure signs of leukemia. An infection or another problem also could cause these symptoms. Anyone with these symptoms should see a doctor as soon as possible. Only a doctor can diagnose and treat the problem.

In the early stages of chronic leukemia, the leukemia cells function almost normally. Symptoms may not appear for a long time. Doctors often find chronic leukemia during a routine checkup—before there are any symptoms. When symptoms do appear, they generally are mild at first and get worse gradually.

In acute leukemia, symptoms appear and get worse quickly. People with this disease go to their doctor because they feel sick. Other symptoms of acute leukemia are vomiting, confusion, loss of muscle control, and seizures. Leukemia cells also can collect in the testicles and cause swelling. Also, some patients develop sores in the eyes or on the skin. Leukemia also can affect the digestive tract, kidneys, lungs, or other parts of the body.

Amyloidosis

In medicine, amyloidosis refers to a variety of conditions in which amyloid proteins are abnormally deposited in organs and/or tissues, causing disease. A protein is amyloid if, due to an alteration in its secondary structure, it takes on a particular insoluble form, called the beta-pleated sheet.

Approximately 25 different proteins are known that can form amyloid in humans, most of them are constituents of the plasma.

Different amyloidoses can be systemic (affecting many different organ systems) or organ-specific. Some are inherited, due to mutations in the precursor protein. Other, secondary forms are due to different diseases causing overabundant or abnormal protein production-such as with over production of immunoglobulin light chains in multiple myeloma (termed AL amyloid), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to AA amyloid).

Amyloid can be diagnosed on histological examination of affected tissue. Amyloid deposits can be identified histologically by Congo red staining and viewing under polarized light where amyloid deposits produce a distinctive 'apple green birefringence'. Further, specific, tests are available to more precisely identify the amyloid protein. Biopsies are taken from affected organs (for example, the kidney), or often in the case of systemic amyloid, from the rectum or anterior abdominal adipose tissue. In addition, all amyloid deposits contain serum amyloid P component (SAP), a circulating protein of the pentraxin family. Radionuclide SAP scans have been developed which can anatomically localize amyloid deposits in patients.

Primary/Hereditary amyloidosis

These rare hereditary disorders are usually due to point mutations in precursor proteins, and are also usually autosomal dominantly transmitted.The precursor proteins are;

• transthyretin-the most commonly implicated protein.
• lysozyme
• apolipoprotein B
• fibrinogen
• apolipoprotein A1
• gelsolin

Secondary amyloidosis

These are far more common than the primary amyloidoses.

• AL amyloidosis (immunoglobulin light chains are the precursor protein, overproduced in multiple myeloma). This is sometimes, confusingly and erroneously, called 'primary amyloidosis'.
• AA amyloidosis (the precursor protein is serum amyloid A protein (SAA), an acute-phase protein due to chronic inflammation). In contrast to AL amyloid, this has previously been termed 'secondary amyloidosis'.These occur with a wide variety of diseases associated with chronic inflammation, such as Rheumatoid arthritis, Familial Mediterranean fever or chronic infection.
• Dialysis related amyloidosis (the precursor protein is beta-2-microglobulin which is not removed with dialysis, and thus accumulates in patients with end stage renal failure on dialysis).

Organ-specific amyloidosis

In almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or instead a downstream consequence of a common idiopathic agent. The associated proteins are indicated in parentheses.

Neurological amyloid

• Alzheimer's disease (Aβ 39-43)
• Parkinson's disease (alpha-synuclein)
• Huntington's disease (huntingtin)
• Transmissible spongiform encephalopathies caused by prion protein (PrP) were sometimes classed as amyloidoses, as one of the four pathological features in diseased tissue is the presence of amyloid plaques. These diseases include;
  • Creutzfeldt-Jakob disease (PrP in cerebrum)
  • Kuru (diffuse PrP deposits in brain)
  • Fatal Familial Insomnia (PrP in thalamus)
  • Bovine spongiform encephalopathy (PrP in cerebrum of cows)

Cardiovascular amyloid

• Cardiac amyloidosis
  • Senile cardiac amyloidosis-may cause heart failure
• Congophilic angiopathy

Other

• Amylin deposition can occur in the pancreas in some cases of type 2 diabetes mellitus

Non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) describes a group of cancers arising from lymphocytes, a type of white blood cell. It is distinct from Hodgkin lymphoma in its pathologic features, epidemiology, common sites of involvement, clinical behavior, and treatment. The non-Hodgkin lymphomas are a diverse group of diseases with varying courses, treatments, and prognoses.

Non-Hodgkin lymphoma may develop in any organ associated with the lymphatic system (e.g. spleen, lymph nodes, or tonsils). Most cases start with infiltration of lymph nodes, but some subtypes may be restricted to other lymphatic organs.

The diagnosis of non-Hodgkin lymphoma requires a biopsy of involved tissue. The numerous subtypes of non-Hodgkin lymphoma are typically grouped into three distinct categories based on their aggressiveness, or histologic grade. These categories are indolent (or low-grade), aggressive (or intermediate-grade), and highly aggressive (or high-grade). The treatment of indolent or low-grade lymphoma may initially involve a period of observation, while aggressive or highly aggressive non-Hodgkin lymphoma is typically treated with chemotherapy and/or radiation therapy.

The most common symptom of non-Hodgkin's lymphoma is a painless swelling of the lymph nodes in the neck, underarm (axilla), or groin.

Other symptoms may include the following:

• Unexplained fever
• Unexplained weight loss and anorexia (poor appetite)
• Constant fatigue
• Itchy skin
• Reddened patches on the skin

Such symptoms are non-specific and may be caused by other, less serious conditions.

If non-Hodgkin's lymphoma is suspected, the doctor asks about the person's medical history and performs a physical exam. The exam includes feeling to see if the lymph nodes in the neck, underarm, or groin are enlarged. In addition to checking general signs of health, the doctor may perform blood tests.

Excisional biopsy NHL specimen

The doctor may also order tests that produce pictures of the inside of the body. These may include:

• X-rays: Pictures of areas inside the body created by high-energy radiation.
• CT scan (computed tomography scan, also known as a "CAT scan"): A series of detailed pictures of areas inside the body. The pictures are created by a computer linked to an x-ray machine.
• PET scan (positron emission tomography scan): This is an imaging test that detects uptake of a radioactive tracer by the tumor. More often, the PET scan can be combined with the CT scan.
• MRI (magnetic resonance imaging): Detailed pictures of areas inside the body produced with a powerful magnet linked to a computer.

Less commonly used

• Lymphangiogram: Pictures of the lymphatic system taken with x-rays after a special dye is injected to outline the lymph nodes and vessels. This test is not used as often because of the adoption of CT scan and the PET scan technologies.
• Gallium scan: Gallium is a rare metal that behaves in the body in a fashion similar to iron, so that it concentrates in areas of inflammation or rapid cell-division, and hence is useful for imaging the entire lymphatic system for staging of lymphoma once the presence of the disease has been confirmed. PET scans have supplanted gallium scans for evaluation and follow up of NHL.

Biopsy

A biopsy is needed to make a diagnosis. A surgeon removes a sample of tissue, which a pathologist can examine under a microscope to check for cancer cells. A biopsy for non-Hodgkin's lymphoma is usually taken from lymph nodes that are enlarged, but other tissues may be sampled as well. Biopsies in internal lymph nodes can also taken as needle biopsies under the guidance of CT scans. Rarely, an operation called a laparotomy may be performed. During this operation, a surgeon cuts into the abdomen and removes samples of tissue to be checked under a microscope.

Types of non-Hodgkin's lymphoma

Over the years, doctors have used a variety of terms to classify the many different types of non-Hodgkin's lymphoma . Most often, they are grouped by how the cancer cells look under a microscope and how quickly they are likely to grow and spread. Current lymphoma classification is complex.

MeSH includes four different criteria for classifying NHL. (It is possible to be classified under more than one.)

• High-grade vs. intermediate vs. low-grade: Aggressive lymphomas, also known as intermediate and high-grade lymphomas, tend to grow and spread quickly and cause severe symptoms. Indolent lymphomas, also referred to as low-grade lymphomas, tend to grow quite slowly and cause fewer symptoms. One of the paradoxes of non-Hodgkin's lymphoma is that the indolent lymphomas generally cannot be cured by chemotherapy, while in a significant number of cases aggressive lymphomas can be.

• Diffuse vs. follicular: Follicular lymphoma tends to be indolent, and diffuse lymphoma tends to be aggressive.

• T-cell lymphoma vs. B-cell lymphoma
  • Gluten-sensitive enteropathy associated T-cell lymphoma or EATL

• Large cell lymphoma (such as anaplastic large cell lymphoma) vs. Small cell lymphoma vs. Mixed cell lymphoma

Details of the most popular classifications of lymphoma can be found in the lymphoma page.

Causes

The etiology, or cause, of most lymphomas is not known. Some types of lymphomas are associated with viruses. Burkitt's lymphoma, extranodal NK/T cell lymphoma, classical Hodgkin's disease and most AIDS-related lymphoma are associated with Epstein-Barr virus. Adult T-cell lymphoma/leukemia, endemic in parts of Japan and the Caribbean, is caused by the HTLV-1 virus. Lymphoma of the stomach (extranodal marginal zone B-cell lymphoma) is often caused by the Helicobacter bacteria.

The incidence of non-Hodgkin's lymphoma has increased dramatically over the last couple of decades. This disease has gone from being relatively rare to being the fifth most common cancer in the United States. At this time, little is known about the reasons for this increase or about exactly what causes non-Hodgkin's lymphoma.

Doctors can seldom explain why one person gets non-Hodgkin's lymphoma and another does not. It is clear, however, that cancer is not caused by an injury, and is not contagious; no one can "catch" non-Hodgkin's lymphoma from another person.

By studying patterns of cancer in the population, researchers have found certain risk factors that are more common in people who get non-Hodgkin's lymphoma than in those who do not. However, most people with these risk factors do not get non-Hodgkin's lymphoma, and many who do get this disease have none of the known risk factors.

The following are some of the risk factors associated with this disease:

• Age/sex. The likelihood of getting non-Hodgkin's lymphoma increases with age and is more common in men than in women.
• Weakened immune system (AIDS-related lymphoma). Non-Hodgkin's lymphoma is more common among people with inherited immune deficiencies, autoimmune diseases, or HIV/AIDS, and among people taking immunosuppressant drugs following organ transplants. (see Post-transplant lymphoproliferative disorder)
• Viruses. Human T-lymphotropic virus type I (HTLV-1) and Epstein-Barr virus are two infectious agents that increase the chance of developing non-Hodgkin's lymphoma.
• Environment. People who work extensively with or are otherwise exposed to certain chemicals, such as pesticides, solvents, or fertilizers, have a greater chance of developing non-Hodgkin's lymphoma.

People who are concerned about non-Hodgkin's lymphoma should talk with their doctor about the disease, the symptoms to watch for, and an appropriate schedule for checkups. The doctor's advice will be based on the person's age, medical history, and other factors.

Staging

If non-Hodgkin's lymphoma is diagnosed, the doctor needs to learn the stage, or extent, of the disease. Staging is a careful attempt to find out whether the cancer has spread and, if so, what parts of the body are affected. Treatment decisions depend on these findings.^[1]

The doctor considers the following to determine the stage of non-Hodgkin's lymphoma:

• The number and location of affected lymph nodes;
• Whether the affected lymph nodes are above, below, or on both sides of the diaphragm (the thin muscle under the lungs and heart that separates the chest from the abdomen);
• Whether the disease has spread to the bone marrow, spleen, or to organs outside the lymphatic system, such as the liver;

and the testes.

• Whether B symptoms (systemic symptoms) such as fever, chills, night sweats, or weight loss are present.

In staging, the doctor may use some of the same tests used for the diagnosis of non-Hodgkin's lymphoma. Other staging procedures may include additional biopsies of lymph nodes, the liver, bone marrow, or other tissue. A bone marrow biopsy involves removing a sample of bone marrow through a needle inserted into the hip or another large bone. A pathologist examines the sample under a microscope to check for cancer cells.

Stages of NHL

The various stages of NHL (the Ann Arbor staging classification, developed for Hodgkin's lymphoma) are based on how far the cancer has spread throughout and beyond the lymphatic system, and whether constitutional symptoms (fever, night sweats, or weight loss) are present.

Stage I

"Stage I" indicates that the cancer is located in a single region, usually one lymph node and the surrounding area. Stage I often will not have outward symptoms.

Stage II

"Stage II" indicates that the cancer is located in two separate regions, an affected lymph node or organ within the lymphatic system and a second affected area, and that both affected areas are confined to one side of the diaphragm - that is, both are above the diaphragm, or both are below the diaphragm.

Stage III

"Stage III" indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen.

Stage IV

"Stage IV" indicates that the cancer has spread beyond the lymphatic system and involves one or more major organs, possibly including the bone marrow or skin.

The absence of constitutional symptoms is denoted by adding an "A" to the stage; the presence is denoted by adding a "B" to the stage (hence the name B symptoms).

Staging in non-Hodgkin's lymphomas is far less significant in determining therapy than it is in Hodgkin's lymphoma

Prognosis

See also: International Prognostic Index

The most significant factor in overall prognosis is the grade, or aggressiveness, of the lymphoma. Indolent (low-grade) non-Hodgkin's lymphoma is generally not curable, but is typically slowly progressive and responds temporarily to therapy. Aggressive and highly aggressive (intermediate- and high-grade) NHL's are potentially curable with combination chemotherapy. Long-term survival or cure rates for these diseases vary with a number of prognostic factors.

International Prognostic Index

The International Prognostic Index, or IPI, is the most widely used prognostic system for non-Hodgkin's lymphoma. This system uses 5 factors:

• Age
• Lactate dehydrogenase level (a blood test)
• Performance status
• Clinical stage
• Sites of extranodal disease

However, it should be noted that the IPI was developed prior to the introduction of rituximab. As rituximab has become a standard part of therapy for B-cell NHL's, the impact on the prognostic value of the IPI is unclear.

FLIPI

For the subtype of NHL known as follicular lymphoma, a modified version of the IPI called the FLIPI (follicular lymphoma international prognostic index) has been developed. The factors which figure into the FLIPI are age, clinical stage, lactate dehydrogenase level, hemoglobinrituximab, so the same caveats apply as were mentioned with the IPI above. level, and number of nodal sites involved. As with the IPI, the FLIPI was developed and validated prior to the widespread use of

Treatment

The doctor develops a treatment plan to fit each patient's needs. Treatment for non-Hodgkin's lymphoma depends on the stage of the disease, the type of cells involved, whether they are indolent or aggressive, and the age and general health of the patient.

Non-Hodgkin's lymphoma is often treated by a team of specialists that may include a hematologist, medical oncologist, and/or radiation oncologist. Non-Hodgkin's lymphoma is usually treated with chemotherapy, radiation therapy, or a combination of these treatments. In some cases, bone marrow transplantation, biological therapies, or surgery may be options. For indolent lymphomas, the doctor may decide to wait until the disease causes symptoms before starting treatment. Often, this approach is called "watchful waiting."

Taking part in a clinical trial (research study) to evaluate promising new ways to treat non-Hodgkin's lymphoma is an important option for many people with this disease.

Chemotherapy and radiation therapy

Chemotherapy and radiation therapy are the most common treatments for non-Hodgkin's lymphoma, although bone marrow transplantation, biological therapies, or surgery are sometimes used. CHOP, with rituximab added in certain circumstances, is the most commonly used combination of chemotherapy.

Rituximab is an antibody-based therapy. Zevalin and Bexxar are government-approved options, requiring a Nuclear Medicine facility, but only two shots 1 week apart. There is mounting evidence that more patients have long-term remission if they use radioimmunotherapy first.

Radiation therapy (also called radiotherapy) is the use of high-energy rays to kill cancer cells. Treatment with radiation may be given alone or with chemotherapy. Radiation therapy is local treatment; it affects cancer cells only in the treated area. Radiation therapy for Non Hodgkin's lymphoma comes from a machine that aims the high-energy rays at a specific area of the body. There is no radioactivity in the body when the treatment is over.

Sometimes patients are given chemotherapy and/or radiation therapy to kill undetected cancer cells that may be present in the central nervous system (CNS). In this treatment, called central nervous system prophylaxis, the doctor injects anticancer drugs directly into the cerebrospinal fluid.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT), or Bone marrow transplantation (BMT) may also be a treatment option, especially for patients whose non-Hodgkin's lymphoma has recurred (come back). BMT provides the patient with healthy stem cells (very immature cells, found in the marrow, that produce blood cells), the function of which is to replace white blood cells that are damaged or destroyed by treatment with very high doses of chemotherapy and/or radiation therapy. The healthy bone marrow may come from a donor, or it may be "autologous" (marrow that was removed from the patient, stored, and then given back to the person following the high-dose treatment). Autologous transplants are preferred, as the recipient is less likely to reject the cells, the origins of which were the same entity. However, in order for an autologous transplant to be performed, certain physiological conditions must be optimal within the patient. If these conditions are not present, transplanted stem cells can come from other donors. Until the transplanted bone marrow begins to produce enough white blood cells, patients have to be carefully protected from infection due to the virtual elimination of the auto-immune system resulting from the high-intensity treatment. Without the introduction of the stem cells following the high dose treatment, the patient will not survive as the body will be unable to produce infection-fighting white blood cells. Patients usually stay in the hospital for several weeks and will be monitored for transplant rejection and overall health.

Immunotherapy

Biological therapy (also called immunotherapy) is a form of treatment that uses the body's immune system, either directly or indirectly, to fight cancer or to lessen the side effects that can be caused by some cancer treatments. It uses materials made by the body or made in a laboratory to boost, direct, or restore the body's natural defenses against disease. This approach is under close investigation. Biological therapy is sometimes also called biological response modifier therapy.

Measuring response to treatment

After treatment for non-Hodgkin's lymphoma, the response is classified as follows:

• Complete Response (CR). This indicates the disappearance of all detectable disease.
• Partial Response (PR). A reduction in the bulk of disease by at least 50%, but with some remaining disease.
• Stable Disease. Less than a partial remission, but no progression of disease and no new sites of disease.
• Progressive Disease. Growth in bulk of disease by >50%, or the appearance of new sites of disease.

If a complete remission is achieved, the patient is watched closely for any evidence of recurrent disease. Standard guidelines dictate that a patient be monitored for relapse every three months in the first year following a complete remission, every six months in the second year, and finally once annually in the third and later years. Diffuse large b-cell lymphoma is the most common type of lymphoma that is considered curable. Currently, if a patient maintains a complete remission for 3 years, the patient is considered cured. Generally most relapses of diffuse large b-cell lymphoma occur within the first year after a complete remission is obtained. Reoccurences after 3 years are rare but they do occur. The effect of Rituximab on relapse rates for diffuse large b-cell lymphoma is still largely unknown, though initial relapse rates since 2003 have been much lower than expected.

Patients with follicular lymphoma are generally not considered cured. Instead, they are categorized as in ongoing complete remission. Relapses occur steadily over time. Relapse rates are estimated to be 33%, 66%, and 100% for follicular lymphoma's Grades I, II, and III respectively.

Research has indicated that relapse rates can be lowered on patients with follicular lymphoma by giving supplemental radiation therapy, however, it is known that this additional therapy increases the chances of a second malignancy of unknown type later in life.

If the response to treatment falls short of a complete response, more treatment may be administered (using a different chemotherapy regimen), or watchful waiting may be utilized, depending on the goals of treatment.

Nutrition during treatment

Eating well during cancer treatment means getting enough food energy and protein to help prevent weight loss and regain strength. Good nutrition often helps people feel better and have more energy.

Some people with cancer find it hard to eat a balanced diet because they may lose their appetite. In addition, common side effects of treatment, such as nausea, vomiting, or mouth sores, can make eating difficult. Often, foods may taste or smell different. Also, people being treated for cancer may not feel like eating when they are uncomfortable or tired.

Doctors, nurses, and dietitians can offer advice on how to get enough food energy and protein during cancer treatment. Patients and their families also may want to read the National Cancer Institute (USA) booklet Eating Hints for Cancer Patients, which contains many useful suggestions.^[2]

Followup care

People who have had non-Hodgkin's lymphoma should have regular followup examinations after their treatment is over. Followup care is an important part of the overall treatment plan, and people should not hesitate to discuss it with their health care provider. Regular followup care ensures that patients are carefully monitored, any changes in health are discussed, and new or recurrent cancer can be detected and treated as soon as possible. Between followup appointments, people who have had Non Hodgkin's lymphoma should report any health problems as soon as they appear.

Hodgkin's lymphoma

Hodgkin's lymphoma, also known as Hodgkin's disease, is a type of lymphoma first described by Thomas Hodgkin in 1832. Hodgkin's lymphoma is characterized clinically by the orderly spread of disease from one lymph node group to another and by the development of systemic symptoms with advanced disease. Pathologically, the disease is characterized by the presence of Reed-Sternberg cells. Hodgkin's lymphoma was one of the first cancers to be cured by radiation. Later it was one of the first to be cured by combination chemotherapy. The cure rate is about 93%, making it one of the most curable forms of cancer.

Unlike some other lymphomas, whose incidence increases with age, Hodgkin's lymphoma has a bimodal incidence curve; that is, it occurs most frequently in two separate age groups, the first being young adulthood (age 15–35) and the second being in those over 55 years old although these peaks may vary slightly with nationality.^[1] Overall, it is more common in men, except for the nodular sclerosis variant (see below), which is more common in women.

The annual incidence of Hodgkin's lymphoma is about 1/25,000 people, and the disease accounts for slightly less than 1% of all cancers worldwide.

The incidence of Hodgkin's lymphoma is increased in patients with HIV infection.^[2] In contrast to many other lymphomas associated with HIV infection it occurs most commonly in patients with higher CD4 T cell counts.

Swollen but painless lymph nodes are the most common sign of Hodgkin's lymphoma, often occurring in the neck. The lymph nodes of the chest are often affected and these may be noticed on a chest x-ray.

Splenomegaly, or enlargement of the spleen, occurs in about 30% of people with Hodgkin's lymphoma. The enlargement, however, is seldom massive. The liver may also be enlarged due to liver involvement in the disease in about 5% of cases.

About one-third of people with Hodgkin's disease may also notice some systemic symptoms, such as low-grade fever, night sweats, weight loss, itchy skin (pruritus), or fatigue. Classically, involved nodes are painful after alcohol consumption, though this phenomenon is rare. Patients may also present with a cyclic high-grade fever known as Pel-Ebstein fever, although there is debate as to whether or not this truly exists. ^[3] Systemic symptoms such as fever and weight loss are known as B symptoms.

Hodgkin's lymphoma must be distinguished from non-cancerous causes of lymph node swelling (such as various infections) and from other types of cancer. Definitive diagnosis is by lymph node biopsy (removal of a piece of lymph node tissue for pathological examination). Blood testschemotherapy. Positron emission tomography (PET) is used to detect small deposits that do not show on CT scanning. In some cases a Gallium Scan may be used instead of a PET scan. are also performed to assess function of major organs and to assess safety for

Abdominal pain

Abdominal pain

From MayoClinic.com
Special to CNN.com

You've had abdominal pain for several hours, and there doesn't seem to be any relief in sight. Should you wait it out or seek help right away?

Abdominal pain is common. Episodes often stem from overeating or eating too much of a certain type of food. Sometimes a viral or bacterial infection is responsible. In other cases, the pain may be an early warning sign of something more serious.

Where does it hurt?

The number of organs in your abdomen and the complex signals they send can make it tough to pinpoint the cause of abdominal pain. Sometimes, the location of your pain can help narrow the list.

Navel area

Pain near your bellybutton can be related to a small intestine disorder or an inflammation of your appendix (appendicitis).

The appendix is a small, finger-shaped pouch that projects out from your colon on the lower right side of your abdomen. If it gets clogged or obstructed, it may become inflamed and filled with pus. Without treatment, an infected appendix can burst and cause a serious infection (peritonitis). In addition to abdominal pain, appendicitis may cause nausea, vomiting, loss of appetite, fever, and the urge to pass gas or have a bowel movement.

Upper middle abdomen

The epigastric area — directly above the navel in the upper middle section of the abdomen — is where you might feel pain associated with stomach disorders. Persistent pain in this area may also signal a problem with your upper small intestine (duodenum), pancreas or gallbladder.

Upper left abdomen

It's uncommon to experience pain here. When you do, it may suggest a colon, stomach, spleen or pancreas problem.

Upper right abdomen

Intense pain in the upper right abdomen is often related to inflammation of the gallbladder. The pain may extend to the center of your abdomen and penetrate to your back. Occasionally, an inflamed pancreas or duodenum can cause pain in this area as well.

Lower middle abdomen

Pain below the navel that spreads to either side may signify a colon disorder. For women, pain in this area may also indicate a urinary tract infection or pelvic inflammatory disease.

Lower left abdomen

Pain here most often suggests a problem in the lower colon, where food waste is expelled. Possible causes include inflammatory bowel disease or an infection in the colon known as diverticulitis.

Lower right abdomen

Inflammation of the colon may cause pain in your lower right abdomen. The pain of appendicitis may also spread to the lower right abdomen.

Migrating pain

Abdominal pain has the unusual ability to travel along deep nerve pathways and emerge at sites away from the source of the problem. Pain related to gallbladder inflammation, for example, can spread to your chest and your right shoulder. Pain from a pancreas disorder may radiate up between your shoulder blades. This is often called "referred pain."

Managing the pain

For mild abdominal pain caused by something you ate, it may help to sip water or suck on ice chips. When you feel better, try small amounts of bland foods, such as toast, applesauce or bananas. If stomach acid is an issue, an antacid may help.

When to see your doctor

Though most cases of abdominal pain aren't serious, sometimes medical treatment is essential. Consult your doctor if:

• The pain is severe, recurrent or persistent
• The pain gets worse
• The pain is accompanied by shortness of breath, dizziness, bleeding, vomiting or a high fever

Seek emergency help if:

• The abdominal pain is sudden and sharp
• The pain radiates to your chest, neck or shoulder
• You vomit blood
• You find blood in your stool or your stool turns black
• Your abdomen is swollen and tender

Be prepared to describe the pain, including where it hurts and what it feels like. Proper diagnosis and treatment can help you feel your best again.

Dyspepsia

What is dyspepsia?

Dyspepsia is a pain or an uncomfortable feeling in the upper middle part of your stomach. The pain might come and go, but it's usually there most of the time.

People of any age can get dyspepsia. Both men and women get it. About 1 of every 4 persons gets dyspepsia at some time.

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What are the signs of dyspepsia?

Here are some of the signs of dyspepsia:

• A gnawing or burning stomach pain
• Bloating
• Heartburn
• Nausea (upset stomach)
• Vomiting
• Burping

If you have these signs, or any kind of stomach pain or discomfort, talk to your family doctor.

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What causes dyspepsia?

Often, dyspepsia is caused by a stomach ulcer or acid reflux disease. If you have acid reflux disease, stomach acid backs up into your esophagus (the tube leading from your mouth to your stomach). This causes pain in your chest. Your doctor may do some tests to find out if you have an ulcer or acid reflux disease.

Some medicines, like anti-inflammatory medicines, can cause dyspepsia. Sometimes no cause of dyspepsia can be found.

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Is dyspepsia a serious condition?

Sometimes dyspepsia can be the sign of a serious problem--for example, a deep stomach ulcer. Rarely, dyspepsia is caused by stomach cancer, so you should take this problem seriously.

If you have dyspepsia, talk to your family doctor. This is especially important if any one of the following is true for you:

• You're over 50 years of age
• You recently lost weight without trying to
• You have trouble swallowing
• You have severe vomiting
• You have black, tarry bowel movements
• You can feel a mass in your stomach area

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How is dyspepsia treated?

Most often, medicine can take care of this condition.

If you have a stomach ulcer, it can be cured. You may need to take an acid-blocking medicine. If you have an infection in your stomach, you may also need to take an antibiotic.

If your doctor thinks that a medicine you're taking causes your dyspepsia, you might take another medicine.

A medicine that cuts down on the amount of acid in your stomach might help your pain. This medicine can also help if you have acid reflux disease.

Your doctor might want you to have an endoscopy if:

• You still have stomach pain after you take a dyspepsia medicine for 8 weeks.
• The pain goes away for a while but comes back again.

In an endoscopy, a small tube with a camera inside it is put into your mouth and down into your stomach. Then your doctor can look inside your stomach to try to find a cause for your pain.

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Do the medicines for dyspepsia have side effects?

The medicines for dyspepsia most often have only minor side effects that go away on their own. Some medicines can make your tongue or stools black. Some may cause headaches, nausea or diarrhea.

If you have side effects that make it hard for you to take medicine for dyspepsia, talk to your family doctor. Your doctor may have you take a different medicine or may suggest something you can do to make the side effects less bothersome.

Remember to take medicines just the way your doctor tells you. If you need to take an antibiotic, take all of the pills, even when you start feeling better.

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Can I do anything else to avoid dyspepsia?

You can do quite a bit to help yourself feel better:

• If you smoke, stop smoking.
• If some foods bother your stomach, try to avoid eating them.
• Try to reduce the stress in your life.
• If you have acid reflux, don't eat right before bedtime. Raising the head of your bed with blocks under two legs may also help.
• Unless your doctor tells you otherwise, don't take a lot of anti-inflammatory medicines like ibuprofen (one brand: Motrin), aspirin, naproxen (brand name: Aleve) and ketoprofen (brand name: Orudis). Acetaminophen (brand name: Tylenol) is a better choice for pain, because it doesn't hurt your stomach.

Dermoid Cyst

A dermoid cyst is a teratoma that contains developmentally mature skin, with hair follicles and sweat glands, sometimes luxuriant clumps of long hair, and often pockets of sebum, blood, fat, bone, nails, teeth, eyes, cartilage, and thyroid tissue. Because it contains mature tissue, a dermoid cyst almost always is benign. The rare malignant dermoid cyst usually develops squamous cell carcinoma.

Some authors use the term dermoid cyst as a frank synonym for teratoma, meaning any teratoma, regardless of its histology or location. Others use it to mean any mature, cystic teratoma. These uses appear to be most common in gynecology and dermatology.

The term dermoid is sometimes used to mean dermoid cyst but this is unfortunately vague.

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Dermoid cyst of the ovary : A bizarre tumor, usually benign, in the ovary that typically contains a diversity of tissues including hair, teeth, bone, thyroid, etc.

A dermoid cyst develops from a totipotential germ cell (a primary oocyte) that is retained within the egg sac (ovary). Being totipotential, that cell can give rise to all orders of cells necessary to form mature tissues and often recognizable structures such as hair, bone and sebaceous (oily) material, neural tissue and teeth.

Dermoid cysts may occur at any age but the prime age of detection is in the childbearing years. The average age is 30. Up to 15% of women with ovarian teratomas have them in both ovaries. Dermoid cysts can range in size from a centimeter (less than a half inch) up to 45 cm (about 17 inches) in diameter.

These cysts can cause the ovary to twist (torsion) and imperil its blood supply. The larger the dermoid cyst, the greater the risk of rupture with spillage of the greasy contents which can create problems with adhesions, pain etc. Although the large majority (about 98%) of these tumors are benign, the remaining fraction (about 2%) becomes cancerous (malignant).

Removal of the dermoid cyst is usually the treatment of choice. This can be done by laparotomy (open surgery) or laparoscopy (with a scope). Torsion (twisting) of the ovary by the cyst is an emergency and calls for urgent surgery.

Dermoid cysts of the ovary are also called simply dermoids or ovarian teratomas.