What is Histiocytosis?

Histiocytosis is a family name for a group of rare diseases (also referred to as histiocytic disorders) characterized by an abnormal increase and accumulation of certain immune cells known as histiocytes.  A histiocyte is a type of white blood cell which can be found in the skin, lungs, liver, spleen, lymph glands, bone marrow and blood stream.  These cells help protect the body against infection; however, in patients suffering from histiocytic disorders, histiocytes become activated, increase quickly in number and cluster together in the form of lesions or tumors that damage rather than protect the body.

The group of histiocytic disorders includes Langerhans Cell Histiocytosis (LCH), Hemophagocytic Lymphohistiocytosis (HLH), Rosai-Dorfman Disease (RDD), Erdheim Chester Disease (ECD) and Juvenile Xanthogranuloma (JXG).  Because these disorders are so rare, histiocytosis is often referred to as an "orphan disease" and does not receive much research funding from the federal government.  This means that funds raised from private donors, corporations, and foundations are vital to support research to better understand, more effectively treat, and someday cure histiocytic disorders.

Langerhans Cell Histiocytosis (LCH)

Langerhans Cell Histiocytosis (LCH) is a disease that occurs in both children (1 in 200,000) and adults (1 in 560,000).  Researchers are currently trying to determine whether LCH is a type of cancer or an immune disorder that results from changes in the immune system which causes histiocytes to become over-active and accumulate.

Childhood LCH patients may present with disease in one site or organ (single site or single system) or in multiple sites or organs (multisite or multisystem).  If organs are involved, the disease presentation also depends upon the organs and can be considered "low risk" (skin, bone, lymph nodes and pituitary gland) or "high-risk" (liver, spleen, lung, and bone marrow). Adult LCH patients may have symptoms and signs for many months or years before receiving a definitive diagnosis and treatment.  LCH in adults is often similar to that in children, except that one form of the disease, adult pulmonary LCH, has been found to have an association with smoking.

In single-site LCH, the disease presents with involvement of a single site or organ, including skin and oral mucosa, bone, lymph nodes and thymus, pituitary gland, and thyroid.  Single site LCH usually presents with a skin rash (often seen as cradle cap in infants or red papular rash in children/adults) or painful bone lesions in the skull, ribs, femurs, vertebra, or mandible.  Chronic ear discharge can also be a presenting symptom in some cases.

In multi-site or multi-system LCH, the disease presents in multiple organs or body systems including liver and spleen, lung, bone marrow, endocrine system, gastrointestinal system, and the central nervous system (CNS).  Patients with multi-site or multi-system disease may present with symptoms of fever, weight loss, diarrhea and edema, along with symptoms related to specific organ involvement including enlarged liver/spleen, rapid breathing or shortness of breath (lung involvement), excessive thirst and urination (endocrine/CNS involvement), or thrombocytopenia and anemia (bone marrow).

Treatment may include surgery, oral, topical, and intravenous medications and chemotherapy, or radiation therapy depending on the site and extent of disease.  Single skull lesions of the frontal, parietal, or occipital regions of the skull and single lesions of any other bone may be treated with curettage or a combination of curettage and steroid injections.  However, lesions in the mastoid, temporal, or orbital bones should be treated with chemotherapy due to an increased risk of developing Diabetes Insipidus (DI) or progressive neurologic symptoms.  The recommended duration of therapy for these patients and for other patients with "low risk" disease (bone, skin or lymph node involvement) is to undergo chemotherapy and receive steroids for 12 months.  Patients with high risk disease receive combination chemotherapy for a year but may be switched to a salvage protocol if a positive response is not seen within 6-12 weeks and, in rare cases, may require a bone marrow transplant.

Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and potentially fatal syndrome that results from inappropriate pro­longed activation of lymphocytes and macrophages.  The name describes the characteristic (but not diagnostic) pathological finding of hemophagocytiosis which involves macrophages engulfing and destroying all types of blood cells in the bone marrow, lymph nodes, spleen or liver.

"Primary" or "familial" HLH (also known as FHL) has been used to describe an autosomal recessive condition found in infants and young children diagnosed with HLH who also present with known gene mutations.  Older children, young adults, or children without identifiable mutations are sometimes described as having "secondary" or "acquired" HLH with the assumption that the condition is due to infection or other stimulus (such as Epstein Barr Virus) and not to genetic predisposition.

HLH can present with the following symptoms: fever, enlarged spleen or liver (hepatosplenomegaly), swollen or enlarged lymph nodes (lymphadenopathy), reduced blood cell and platelet counts (pancytopenia) and a skin rash or other cutaneous involvement.  Detecting cutaneous involvement can assist with the inital diagnosis as well as signalling possible reoccurrences or reactivation of HLH.  The spleen, lymph nodes, bone marrow, liver, skin, and membranes that surround the brain and spinal cord are other common sites of involvement.

FHL is uniformly fatal if not treated and requires the patient to undergone aggressive chemotherapy in preparation for a bone marrow transplant (BMT).  Without treatment, the median survival time reported in various studies is 2-6 months after diagnosis.  Patients who receive only chemotherapy may achieve temporary remission and have a 5 year survival rate of of less than 30%.  Even with a successful bone marrow transplant, FHL patients have been reported as having median three year survival rate of 55% due to post-BMT complications, such as fungal infections, acute respiratory distress, and graft versus host disease (GVHD).

Secondary HLH can be effectively treated with a combination of cyclosporin, steroids and chemotherapy with an additional chemotherapy agent (intrathecal methotrexate) being used in cases with central nervous system (CNS) involvement.  This therapy regimen is administered for 8 weeks but can be continued if disease reactivation occurs or, in more severe cases, a decision is made to proceed with bone marrow transplant.

Rosai-Dorfman Disease (RDD)

Rosai Dorfman Disease (RDD) is also known as sinus histiocytosis with massive lymphadenopathy (SHML) and is a benign disease which is characterized by overproduction and accumulation of histiocytes in the lymph nodes.  Patients with RDD present with massively enlarged lymph nodes, most frequently in the neck. However, in 25-40% of cases, RDD may occur in the skin, orbits, respiratory tract, bones, and central nervous system.

Although many cases do not require therapy, surgery may be useful for symptomatic treatment of large lymph nodes.  RDD patients with multi-organ involvement or dysfunction, and association with immune dysfunction require treatment.  A variety of therapies including steroids and chemotherapy have been used with success in some cases.  Recently, several case reports have described improvement or cure of RDD patients with a treatment prgram involving combination of steroids (dexamethasone) and chemotherapy agents (methotrexate/mercaptopurine, 2-chlorodeoxyadenosine and venorelbine/methotrexate).

Juvenile Xanthogranuloma (JXG)

Juvenile Xanthogranuloma (JXG) is a rare histiocytic disorder which is characterized by histiocytic lesions which can infiltrate the skin, soft tissue, and internal organs. These lesions, depending on their quantity and location, can affect the function of various organs, as well as the patient's immune system.  In some cases, the lesions can heal spontaneously but often require treatment with chemotherapy and corticosteroids.  In more serious cases, the lesions can cause permanent damage and can even be fatal when multiple organ systems are involved.

The majority (80-90%) of patients are children less than two years old who have solitary skin nodules on their head, neck, or trunk.  The lesion is usually the same color as surrounding skin but may be erythematous or yellowish.  Rarely, nodules may be in the subcutaneous fat, deep soft tissue, or in skeletal muscle. Extracutaneous involvement is usually restricted to the eye, specifically the iris.  Organ involvement is very rare and has been reported in the soft tissue, central nervous system, bone, lung, liver, spleen, pancreas, adrenal, intestines, kidneys, lymph nodes, marrow, and heart.

Patients presenting with only skin or soft tissue involvement all survive and the lesions spontaneously disappear over time in a majority of cases. S ome patients may receive steroid therapy in the form of oral medications or medications appled directly to the lesion.  Patients presenting with a single or only a few cutaneous lesions may choose to undergo an excisional biopsy to remove the lesion or lesions for cosmetic reasons.  Patients who present with systemic disease and risk organ involvement (CNS, liver, bone marrow) have a reduced likelihood of survival and must undergo treatment with steroids and chemotherapy.  Systemic JXG is associated with other diseases including neurofibromatosis type 1 and juvenile chronic myelogenous leukemia.

Erdheim-Chester Disease (ECD)

Erdheim Chester Disease (ECD) is a rare disease characterized by the abnormal multiplication and accumulation of histiocytes and macrophages in the long bones of the body.  Bone pain is the most frequent of all symptoms associated with ECD and mainly affects the lower limbs, knees, and ankles.  However, more than 50% of ECD patients also experience some sort of extraskeletal involvement which can include the skin, pituitary gland or organs (kidneys, brain lung or heart).

ECD generally affects older adults (mean age of 53 years) with many patients first presenting with fever, weakness, and weight loss in addition to bone pain in the lower extremities.  The second most common presenting symptom is diabetes insipidus. Some patients have cerebellar signs and focal neurologic deficits.

ECD patients are treated with steroids, radiation, 2-CdA (cladribine), lymphoma chemotherapy protocols, interferon, and anakinra.  Nearly 60% of ECD patients die of their disease and 36% of patients within 6 months of diagnosis.  The mean survival duration is less than 3 years.  Cardiac, pulmonary, or renal failure are the primary causes of death.