PEDS: Langerhans Cell Histiocytosis

Background

Langerhan's Histiocytosis (aka Histiocytosis X aka eosinophilic granuloma is an accumulation or proliferation of a clonal population of cells arrested at an early stage of activation and is functionally deficient. Langerhans cells are a family of related cells characterized by dentritic morphology and multiple thin membrane projections. Langerhans cells together with lymphocytes, eosinophils and normal histiocytes form infiltrates typical for Langerhans cell histiocytosis.

Langerhans' Cells are antigen presenting cells normally found in the skin, mucosa, spleen and lymphatics. Their normal function is to ingest bacteria and present antigens to B-cells for stimulating humoral immunity and to NK/T-cells.

Langerhans histiocytosis can affect skin, bone, lymph nodes, ear, gums, lungs, gastrointestinal tract, including the liver and the central nervous system. In Langerhan's Histiocytosis, these cells cause tissue damage by infiltration and excessive cytokin and prostaglandin production. The cells produce IL-1 and prostaglandin E2 which stimulate osteoclast activity. The tissue injury occurs from inflammatory response which impairs normal tissue structure and function.

Microscopically, an infiltrate of lymphocytes, eosinophils, PMNs and Langerhans cells are seen. Langerhans cells are associated with Birbeck Granules seen under electron microscopy. They also are associated with S100, CD1a as well as CD11 and CD14 IHC stains.

Epidemiology Demographics and Natural History

There are about 300 cases of LCH per year in the US. Males predominate the cases by 3:2.

LangerhansHistiocytosis X tends to involve the bones of children and the lungs of adults. It can involve any organ. It is divided into good and bad risk groups:

• Good Risk: unifocal lesion in the bone which is treated with focal therapy.
• Poor Risk: age < 2 years with organ dysfunction.

Langerhans Histiocytosis X is also associated with Hand-Schiller-Christian Disease. Hand-Schiller-Christian disease is a proliferation of lymphocytes that causes exopthalmos, skull lesions, diabetes insipidus and hemangiomas . This was first described by Hand in the early 20th/late 19th century who associated this triad with Langerhan's Histiocytosis. The triad is not that commonly seen in the disease. Hemangiomas are associated with poor prognosis disease.

Workup and Staging

In children < 2 years old, widespread seborrheic rash in the scalp or groin, lymphadenopathy and liver involvement are seen

. Diabetes insipidus is more often seen in children age > 2 years old. 20% - 50% of these children may demonstrate diabetes insipidus. Also seen in this age group are bone pain ± soft tissue mass, lung, oral mucosal and cerebral involvment.

Since Langerhan's Histiocytosis lesions are purely lytic in nature, bone scans are not useful in identifying the disease.

Workup

The general workup for Langerhan's Histiocytosis includes History and Physical, laboratory studies, skeletal survey (looking for lucency in the medullary cavity) and biopsy for tissue diagnosis. The bone lesions will appear lucent with "punched out" lesions on plain radiographs.

There is a staging system, the Greenberger Staging System used for LCH with I-V stages based on age and extent of disease.

Treatment and Prognosis

Radiation Therapy

The general indications for radiation therapy in Langerhan's Cell Histiocytosis (LCH) are:

The largest series for the use of radiation therapy in the relief of LCH related diabetes insipidus is a 45 case study from the Mayo data published in 1995. This study showed a 36% rate of diabetes insipidus improvement with radiation therapy. Kilpatric (1995 Cancer) reported that radiation therapy should be administered within 14 days of the onset of diabetes insipidus for best relief.

A German meta-analysis in 2006 (Strahlenther. Onk.) demonstrated local control rates of 96% and complete response rates of 93% for single system disease with radiation therapy.

Chemotherapy

Prednisone is first line therapy for LCH. If there is not a good response to prednisone then single agent chemotherapy including vinblastine or etoposide or vincristine can be used. Symptomatic skin lesions are treated with topical therapy consisting of nitrogen mustard or systemic steroid therapy.

Lesions of the eye, ear, spine or weight bearing bones are also managed with systemic steroids, or local radiation if no response to systemic therapy.

Symptomatic multifocal disease with organ dysfunction is also managed with high dose steroids. Second line therapy (if steroids don't work) includes single agent chemotherapy. If the patient is symptomatic due to organ failure, bone marrow transplant may be considered.

Surgery

Surgery is useful for curettage or excision of symptomatic bony disease along with local injection of steroids. Note that regression of LCH lesions have been reported even after a simple FNA with no further treatment. It has been postulated that even a small mechanical perterbation can initiate recovery without further treatment.

Observation

Asymptomatic Langerhans' Histiocytosis is observed, even if multifocal and even if there is organ dysfunction.

Prognosis and Outcomes

The overall survival for solitary LCH lesions is 100%

The OS for multi-system LCH without organ dysfunction is 82% - 96%

The OS for multi-system LCH with organ dysfunction is 33% - 54%.

Toxicity

The toxicity for pituitary irradiation TD 5/5 (hypopituitarism) is 40 - 45 Gy. GH levels are the first to decrease, followed by LH/FSH and then TSH/ACTH.

Radiation Oncology Synopsis