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 groups such as the Histiocytosis Association (U.S.), 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.


(source: histio.org)

hemophagocytic syndromes

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Hemophagocytic Lymphohistiocytosis

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 symptoms recur 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 carrying the 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. 


 (source: histio.org) 

Frequently Asked Questions about HLH

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What causes HLH?

 HLH can either be acquired (secondary HLH) or inherited (FHL). Both forms of the disease can be triggered by infections, although it is not known why this happens.


Secondary HLH may be triggered by vaccinations, viral infections such as Epstein-Barr, CMV (cytomegalovirus), herpes virus, or other underlying diseases such as cancer. 


In FHL, defective genes are inherited from one or both parents. Some other rare inherited immunodeficiencies may also be associated with HLH. The underlying immune defect and/or triggering events result in an abnormal immune response with activation of certain types of white blood cells (lymphocytes and macrophages) and the release of inflammatory proteins which then cause disease.


The true cause of HLH/FHL is not known. 

Is there a cure for HLH?

 HLH patients with an underlying genetic defect can only be cured when the defective immune system is replaced by a healthy one which is what happens with a hematopoietic stem cell transplant. Secondary HLH cases can usually be cured by treating the underlying disease and sometimes additional immunosuppressive/immunomodulating therapy. 

What are the different therapies/treatments commonly used to treat HLH?

Some cases of secondary HLH can resolve spontaneously or after treatment of the underlying disease. Other cases are treated with a combination of chemotherapy (VP-16, methotrexate), immunotherapy (ATG, cyclosporin), and steroids. Any triggering infection has to be treated with appropriate antimicrobial drugs. Patients with persistent or recurring HLH or those with FHL additionally require a hematopoietic stem-cell transplant for recovery.


Be sure to always seek your doctor's advice when seeking a treatment method. 

Can infants be tested at birth for HLH?

If an infant is suspected to have HLH because of an affected sibling, and if the affected sibling has a known genetic defect, then genetic screening can be performed at birth. 

How do I know if my child has primary HLH (inherited/FHL) or secondary HLH?

Each sibling of a child with FHL has a 25% chance of being affected. In related genetic disorders, including X-linked lymphoproliferative disease, each male child has a 50% chance of      being affected.


If a genetic defect is known in your family, genetic testing (before or after onset of symptoms) is available to identify siblings who may also be affected. There are several hospitals that provide information and perform genetic testing on a clinical basis,      including:

Cincinnati Children’s Hospital, Cincinnati, Ohio
http://www.cincinnatichildrens.org/hlh/

Karolinska University Hospital, Stockholm, Sweden 

Jan-Inge Henter, MD
jan-inge.henter@ki.se

University Medical Center, Hamburg, Germany, Gritta Janka, MD
janka@uke.uni-hamburg.de

Gene Tests Clinic Directory
http://www.ncbi.nlm.nih.gov/sites/GeneTests/clinic?db=GeneTests

What is MAS (macrophage activating syndrome)?

Macrophage activating syndrome is a severe, life-threatening illness caused by the excessive production of types of white blood cells called T cells and macrophages. MAS has strong similarities with familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic lymphohistiocytosis (HLH). The exact relationship between MAS and HLH is yet to be determined, although some researchers believe that MAS is a secondary HLH disorder. The term is typically used for the HLH-like syndrome that can occur in patients with systemic onset juvenile arthritis. 


(source: histio.org)

Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis in Children

Langerhans cell histiocytosis (LCH) is the most common of the  histiocytic disorders and occurs when the body accumulates too many  immature Langerhans cells, a subset of the larger family of cells known  as histiocytes.  


Langerhans cells are a type of white blood cell that  normally help the body fight infection.  In LCH, too many Langerhans  cells are produced and build up in certain parts of the body where they  can form tumors or damage organs.  The cause of this disease is unknown,  although many possibilities have been explored, including viruses,  exposure to toxins in the environment, family history and geography.  Most data support the concept that LCH is a diverse disease  characterized by a clonal growth of immature Langerhans cells that  appear to have mutations of BRAF  in about half the cases. LCH is not caused by a known infection.  It is  not contagious, nor is it believed to be inherited. Scientific  discussions on the definition of LCH continue to be debated in terms of  its classification as either an immune dysfunction or a rare cancer  (neoplastic and malignant or not malignant). There remain differing  opinions among experts as to whether it is definitively a cancer or not.


Histiocytosis was first described in the medical literature in the  mid to late 1800s.  Through the years, it has been known by various  names, such as histiocytosis X, eosinophilic granuloma, Letterer-Siwe  disease, Hashimoto-Pritzker disease, and Hand-Schüller-Christian  syndrome.  In 1973, the name Langerhans cell histiocytosis (LCH) was  introduced.  This name was agreed upon to recognize the central role of  the Langerhans cell. 


LCH is believed to occur in 1:200,000 children, but any age group can be affected, from infancy through adulthood.   In newborns and very young infants, it occurs in 1-2 per million.  It  is, however, believed to be under-diagnosed, since some patients may  have no symptoms, while others have symptoms that are mistaken for  injury or other conditions.  It occurs most often between the ages of  1-3 years and may appear as a single lesion or can affect many body  systems, such as skin, bone, lymph glands, liver, lung, spleen, brain,  pituitary gland and bone marrow.

Information has been collected in various studies which show that  bone involvement occurs in approximately 78% of patients with LCH and  often includes the skull (49%), hip/pelvic bone (23%), upper leg bone  (17%) and ribs (8%).  Skin LCH is seen in as many as 50% of patients.   Lung lesions are seen in 20% to 40% of patients, while 30% of patients  have lymph node involvement.

Symptoms depend on the location and severity of involvement.  It is usually diagnosed with a tissue biopsy,  in addition to other testing, such as x-rays and blood studies. A  biopsy of an involved site is necessary to make a definitive diagnosis.


While some limited cases of histiocytosis may not require treatment,  for patients with more extensive disease, chemotherapy may be  necessary.  Hematologists and oncologists, who treat cancer, also treat  children with Langerhans cell histiocytosis.


Most patients with LCH will survive this disease.  LCH in the skin,  bones, lymph nodes or pituitary gland usually gets better with treatment  and is called “low-risk.”  Some patients have involvement in the  spleen, liver and bone marrow.  This is called “high-risk disease” and  may be more difficult to treat.  Some patients may develop long-term  side effects such as diabetes insipidus,  stunted growth, loss of teeth, bone defects, hearing loss, or  neurologic problems; while other patients remain without side effects.   In a minority of cases, the disease can be life-threatening.


Certain factors affect the chance of recovery and options for  treatment.  These factors include the extent of the disease, whether  “risk organs” (liver, spleen, bone marrow) are involved, and how quickly  the disease responds to initial treatment.


Patients with LCH should usually have long term follow-up care to  detect late complications of the disease or treatment. These may include  problems of skeletal deformity or function, liver or lung problems,  endocrine abnormalities, dental issues or neurological and  neurocognitive dysfunction. 


 (source: histio.org) 

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. 


 (source: histio.org) 


Frequently Asked Questions about LCH

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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?

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.  

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.  


 (source: histio.org) 

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.


(source: histio.org)

FAQs about Rosai-dorfman

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What causes Rosai-Dorfman?

 Rosai-Dorfman involves over-production of a type of white blood cell called a non-Langerhans sinus histiocyte. The cause of this over-production is not yet known. 

Is there a cure for Rosai-Dorfman?

While many patients go into remission and live normal lives with or without treatment, we usually don’t use the term “cure.” There is no established period of inactive disease before RDD is considered cured. 

What are the different therapies/treatments commonly used to treat Rosai-Dorfman?

Many Rosai-Dorfman patients do not require treatment. Some patients with severe or persistent disease may need treatment with surgery, steroids, and/or chemotherapy. Rarely, radiation therapy is used. 

Can an infant be tested at birth for Rosai-Dorfman?

A biopsy of the affected tissue, rather than a blood test, is required for diagnosis and would therefore not be appropriate as a routine test unless this disease is suspected. 

What causes chronic pain in adults with Rosai-Dorfman?

Some pain and cramping can be a side effect of treatment, such as vinblastine and steroids. Pain may also be directly related to active disease. In cases of more chronic pain, some researchers suspect that cytokines, which are a type of messenger, stimulate white blood cells to release inflammatory molecules that produce pain 


(source: histio.org)