Histiocytic Disorders

Histiocytic  disorders are a group of diseases that occur when there is an  over-production of white blood cells known as histiocytes that can lead  to organ damage and tumor formation.  This group is made up of a wide  variety of conditions that can affect both children and adults.  In  order to reduce confusion, in 1987, the Histiocyte Society classified these disorders into three groups based on the types of histiocyte cells involved:

The  classification of these disorders has created a common name and  language for the different histiocytic disorders.  Guidelines for  diagnosis, treatment, and follow-up of the histiocytic disorders have  been created by the Histiocyte Society.  With the new system of  classification, cooperative international clinical studies have been  created for LCH and HLH.  In these studies, patients are registered by  their physicians to participate, and valuable information is gathered on  all of the patients who are registered.  The purpose is to evaluate  information in order to improve current treatment options and outcomes,  obtain information on new treatments, and  provide direction for what  research needs to be undertaken in the future.  Those patients who are  enrolled in clinical trials can benefit from the latest information  about the treatment and care of the histiocytic disorders, as well as  contribute to the international effort to improve outcome. Over the past  15-20 years, a vast amount of research, much of which has been funded  by the Histiocytosis Association, has improved the understanding of LCH  and HLH, as well as the more uncommon histiocytic disorders such as JXG,  ECD and RD.

Each of these diseases is very different, and the symptoms, rate of  occurrence, diagnostic testing, and treatments vary widely.  For more  information about a particular histiocytic disorder, please see the corresponding pages.

hemophagocytic syndromes

Hemophagocytic lymphohistiocytosis
(HLH) is a rare disorder of the immune system primarily affecting young infants and children, although it can develop for the first time at any age. According to a large, population-based study published in Sweden, it was estimated to occur in 1.2 cases per million children, which corresponds to 1 in 50,000 births. However, this number must be considered minimal, as there are probably many patients today who are not diagnosed. For the autosomal-recessive forms of HLH (FHL), there is believed to be an equal number of males and females diagnosed with this disease.  In addition, there are two known X-linked forms of FHL, affecting only males. HLH involves over-production and activation of normal infection-fighting cells called histiocytes and T cells. In contrast, often NK (natural killer) cell function is decreased. Decreased NK function is related to the consequence of genetic mutations which cause HLH.  HLH is often referred to as either the “primary” form which is hereditary, or the “secondary” form associated with infections, viruses, autoimmune diseases, and malignancies (or cancers). In the primary form, also known as familial hemophagocytic lymphohistiocytosis (FHL or FHLH), defective genes are inherited from either both parents (autosomal recessive) or from the mother alone. Since 1999, five genes have been identified which correspond with five subtypes of autosomal recessive HLH. The genes are PRF1(perforin), MUNC13-4, STX11(Syntaxin), STXBP2, and RAB27A. PRF1 encodes the protein (or toxin) normally involved in “killing” or eliminating abnormal immune cells. The proteins encoded by the other four genes facilitate the delivery of perforin to the cells which are to be killed.

While great progress has been made through research in recent years to define these genes, there remains a considerable proportion of FHL patients with as yet unknown underlying gene defects.  

Onset of disease occurs under the age of 1 year in an estimated 70% of cases. FHL is suspected if siblings are diagnosed with HLH or if symptomsvrecur when therapy has been stopped. Each full sibling of a child with FHL has a 25% chance of developing the disease, a 50% chance of carryingvthe defective gene (which is very rarely associated with any risk of disease), and a 25% chance of not being affected and not carrying the gene defect. So-called “secondary HLH” is often diagnosed in older patients, and there is no family history of this disease. It may be associated with vaccinations, viral infections such as Epstein-Barr, cytomegalovirus (CMV), or herpes virus, and other underlying diseases, principally autoimmune disorders and cancers, as mentioned previously. It is difficult to know whether a patient has primary or secondary HLH on the basis of symptoms, which may be very similar.  Therefore, genetic testing is usually recommended in order to make the proper diagnosis, regardless of age.  

​The first description of HLH was published in 1952, but it has only been in recent years that it has received more widespread attention. In 1985, physicians from around the world who were interested in studying the histiocytic disorders gathered in Philadelphia and formed the Histiocyte Society. Funds raised by the Histiocytosis Association, as well as national subgroups, have financed research that has led to significant breakthroughs in the diagnosis and treatment of HLH during the past 15 years. As awareness and understanding of this disease have increased worldwide, the diagnosis and survival rates have improved significantly. However, HLH remains a rapidly progressive disease requiring effective immunosuppressive and anti-inflammatory therapy.

Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis in Children

Histiocytosis is a rare blood disease that is caused by an excess of white blood cells called histiocytes. The histiocytes cluster together and can attack the skin, bones, lung, liver, spleen, gums, ears, eyes, and/or the central nervous system. The disease can range from limited involvement that spontaneously regresses to progressive multiorgan involvement that can be chronic and debilitating. In some cases, the disease can be life-threatening. In some ways, histiocytosis is similar to cancer and has historically been treated by oncologists with chemotherapy and radiation. Unlike cancer, histiocytosis sometimes goes into remission without treatment. The vast majority of people diagnosed with histiocytosis are children under the age of 10, but it is also found in adults of all ages. It is approximated that histiocytosis affects 1 in 200,000 children born each year in the United States. This illness is so rare, there is little research into its cause and treatment, and it is often referred to as an"orphan disease," meaning it strikes too few people to generate government- supported research.

Another histiocytic disorder is HLH (hemophagocytic lymphohistiocytosis), where there is an excess of both histiocytes and lymphocytes. This disease can be hereditary. Other histiocytic disorders include malignant histiocytosis and sinus histiocytosis.

Langerhans Cell Histiocytosis in Adults

What is Langerhans cell histiocytosis? Langerhans cell histiocytosis (LCH) is a rare disorder, which primarily affects children, but is also found in adults of all ages. Although some forms of this disease were originally described over a century ago, it has only been recently that LCH has begun to receive more attention, especially in adults. People affected with LCH produce too many dendritic histiocytes, a form of white blood cell found in normal, healthy people and intended to protect the body from foreign materials and infection. In people with LCH, however, these cells multiply excessively and accumulate in certain areas of the body, causing various problems. Since LCH has been studied over the years, it has acquired several different names as new information was derived about the disease and the syndromes that accompany it. Some of the more common terms previously used to refer to this disorder include Histiocytosis X, Eosinophilic Granuloma, Hand-Schuller-Christian Syndrome, Pulmonary Histiocytosis and Letterer-Siwe Disease. Other terms which have been used to describe the various syndromes considered to be LCH are Reticuloendotheliosis, Hashimoto-Pritzker Syndrome, Self-healing Histiocytosis, Pure Cutaneous Histiocytosis, Langerhans Cell Granulomatosis, Type I Histiocytosis, and Non-lipid Reticuloendotheliosis. Some of these terms may still be used by physicians today to specify the areas ofinvolvement and the course of the disease in individual patients. 

How many people are affected? Some of the best studies on the incidence of LCH have been done on children with the disease. It is estimated that one in 200,000 children are diagnosed each year. The rarity of LCH in adults makes its incidence difficult to assess, but if we can draw from research which has suggested that a little less than one third of LCH occurs in adults, then about 1 in 560,000 adults might be affected. What kinds of problems can be caused by Langerhans cell histiocytosis? Nearly any part of the body can be involved with LCH, though some sites are more common than others. A patient may have very limited involvement in only one body system or widespread involvement in several different sites and systems. Some of the body systems that may be affected by LCH in adults include the following: 

Skin (rashes or ulceration) Skin involvement is very common in adults with LCH and may include areas such as the scalp, face, anal area, vulva, and flexural areas of skin such as the groin, under the breasts, on the neck, under the arms, and behind the ears. Skin over involved lymph nodes or bones may also be affected and sometimes even the nails. Typical lesions of the skin may include small solid reddish elevations on the skin surface, knots under the skin, purplish-red spots, bleeding under the skin, rashes that are scaly and greasy, ulcerations, and small abscesses. Since many skin problems often are cause by dysfunction of other body systems, sometimes the type of skin lesions a patient has may signal that other areas in the patient are affected. 

Bone (single or multiple lesions) Bone lesions, another very common occurrence in adults with LCH, may cause pain, swelling, spontaneous fracture, or ulceration at the site, or they may cause no symptoms at all before detection. Although nearly any bone can be affected, skeletal involvement most commonly includes the skull, other flat bones such as the ribs, and long bones such as the arms and legs. 

Lung (dysfunction) The lungs are frequently affected in adults with LCH. As a matter of fact, some adults are diagnosed with primary eosinophilic granuloma (also called pulmonary Langerhans cell histiocytosis or Langerhans cell granulomatosis). Recent research suggests that there is a connection to smoking in this isolated form of LCH since some studies have shown that a significant percentage of patients with this form are smokers. This form may go into remission when the patient stops smoking. More often, however, lung involvement occurs with more widespread LCH and sometimes progresses to lung failure. The symptoms of lung involvement include shortness of breath, chest pain, dry cough, and in extreme cases, lung collapse. However, in many cases it may show no symptoms at all before being detected accidentally on a routine chest x-ray. 

Teeth/Gums (loose/lost teeth, swollen gums, ulcerations) The teeth and gums are often affected due to extensions of the disease from the jawbone to the structures and interior coverings of the mouth. Mouth ulcers may be mistaken for canker sores. 

Ears (chronic ear infections and/or discharge) Ear involvement, often a result of skull lesions expanding to the ear, may cause chronic draining, ulceration, and balance problems. 

Endocrine System (Pituitary gland and, rarely, the thyroid gland) Involvement of the pituitary gland can cause excessive thirst and urination, signs of a condition known as diabetes insipidus. A special test, called a water deprivation test, can be preformed to diagnose this condition. Although there is no cure for diabetes insipidus, it can be controlled with the use of a synthetic hormone. Other hormonal abnormalities cause by thyroid or pituitary involvement may result in menstrual problems for women and weight gain or loss.

Female Genital/Reproductive Tract (Vulva, vagina, and ovaries) Most commonly, LCH in this area causes inflammation, rash, and/or ulceration of the vulva, vagina, and/or cervix, but it may also affect the ovaries, causing dysfunction and possibly failure of these organs. 

Lymphoreticular System (dysfunction of liver, spleen, lymph nodes) These areas of the body are less commonly involved in adults with LCH, but when affect patients may experience enlarged lymph nodes, spleen and/or liver, which may result in fatigue and other illnesses or complications associated with dysfunction or failure of these organs.

Gastrointestinal System (Problems with stomach or intestines) Involvement in this body system is very rare in adults, but symptoms might include diarrhea, nausea, vomiting, and/or weight loss.

Central Nervous System (spinal cord and brain lesions) Another rarely affected body system is the central nervous system. Symptoms of CNS involvement may include staggering when walking, seizures, weakness of the arms, legs, or weakness of one side of the body. Since the pituitary gland could be affected, lesions of this system may also cause some of the same endocrine problems as mentioned above.

Other Symptoms Other general symptoms which may be difficult to connect specifically to one of the systems above include fever, weakness, fatigue, and sometimes weight loss. It is important to remember that patients may not all have all the areas of involvement mentioned above, nor would it be accurate to say that someone with only one system involved will not go on to develop problems in other systems. These are some of the many uncertainties surrounding this disease, and it is these uncertainties at diagnosis which can be extremely frustrating for both the patient and the physician. 

What tests are done to diagnose Langerhans Cell Histiocytosis? A diagnosis of LCH is usually made following a biopsy and microscope examination of the affected tissue. If the biopsy is positive for LCH, there are some other tests, which will be conducted to determine the extent of disease so that a treatment plan can be made. Since LCH can be present in many areas of the body, physicians will usually order blood tests, x-rays, urine tests, and CT scans, along with performing a complete physical examination, to check all of the commonly affected body systems. Sometimes other biopsies will be done if test results or abnormal findings during the physical exam cause the physician to suspect involvement of another area. 

What kind of doctor treats patients with Langerhans Cell Histiocytosis? Most often an oncologist/hematologist takes the main role in treating patients with LCH. However, since LCH can affect so many areas of the body, sometimes a team approach may be appropriate, and the oncologist may enlist the help of various types of specialists such as radiologists, surgeons, pulmonologists, dermatologists, dentists, and/or many others to give their input. 

How is Langerhans Cell Histiocytosis treated? Treatment of LCH depends upon the individual patient and the areas of involvement. As was mentioned before, some patients may have limited involvement, which does not progress or spread to other areas while others experience widespread involvement affecting vital organs. Consequently, the treatment varies with the extent of disease. Some patients may need no treatment while others benefit from limited surgery, small doses of radiation therapy, or chemotherapy. If it is determined that no treatment is necessary at the time of diagnosis, the physician will likely monitor the disease regularly to be sure that there is not further progression of the existing areas and that new areas of involvement can be detected and treated early. The ultimate goal of an overall treatment plan, of course, is to use as little treatment as possible to keep the disease under control to preserve quality of life and prevent it from damaging vital organs. 

Will patients recover from Langerhans cell histiocytosis? Most patients will survive the disease. Some may develop life-long problems while others remain symptom free. In some cases, however, the disease unfortunately may run a progressive course and be life threatening. The patient's chances for survival and maintaining good quality of life depend on the individual case, but research has suggested that the course is less favorable for elderly patients and/or those who have organ dysfunction. Also, the disease is often more serious if several sites are affected, especially if there is organ dysfunction. Limited involvement can also be serious, depending on the particular site(s) involved, the degree to which the disease continues to progress and involve other vital organs, and the patient's response to treatment. Overall, physicians will be able to discuss each patient's likelihood of responding and doing well, but patients must understand that it is often difficult for doctors to make definite predictions because LCH has clearly shown itself to be an unpredictable disease. 

What causes Langerhans cell histiocytosis? The cause of LCH is unknown, although there are some theories which have grown from the research conducted over the past few years. One theory, for example, is that LCH might be triggered by an unusual reaction of the immune system to something commonly found in the environment. Other research has suggested that the disease originates from an inflammatory process. However, even after years of research, the true cause of LCH is still a mystery. What is known is that LCH is not contagious-patients did not catch it from anyone and cannot infect anyone else with the disease. Furthermore, there is no information to suggest that the disease is hereditary. 

Is help available?  Langerhans cell histiocytosis much considered an "orphan disease," meaning it strikes too few people to generate government support for research. Working closely with the Histiocyte Society, an international group of physicians, the Histiocytosis Association consists of patients, family members, physicians, and friends working to find answers for the benefit of both children and adults with the disease. The Association's goals include public and professional support and stimulation and support of research which will, in turn, help to achieve the ultimate goal - finding the cause(s), effective treatment, and a cure for LCH.

rosai-dorfman disease

Sinus Histiocytosis with Massive Lymphadenopathy (SHML)

Rosai-Dorfman disease (RD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare histiocytic disorder which involves the over-production of a type of white blood cell called non Langerhans sinus histiocyte. These cells then accumulate, most often in the lymph nodes, but may occur in other areas of the body and can lead to organ damage. The reason that these cells over-produce is not known, although many possibilities have been considered, including viral, bacterial, infection, environmental, and genetic causes.

In 1969, two pathologists, Juan Rosai and Ronald Dorfman, reported a distinct histiocytic disorder in several patients with massive enlargement of the lymph nodes, as well as other symptoms. They named this condition sinus histiocytosis with massive lymphadenopathy, and the name has since come to be known as Rosai-Dorfman disease.

The true number of RD cases is not known, although it does occur worldwide and seems to affect equal numbers of males and females. It is most commonly seen in the first 10 years of life, but it also occurs in adult patients.

Because this disease is so rare, no large studies have been performed, and there is no established, widely-accepted treatment. However, RD is usually not life-threatening, and many patients do not require treatment.

The Histiocytosis Association continues to work closely with an international group of physicians, known as the Histiocyte Society, who are dedicated to studying the histiocytic disorders. Through their combined efforts, awareness about the disease has increased, more research has been undertaken, and progress has been made in the understanding of this disease.

*(As taken from the Histiocytosis Association website)