Table of Contents
- Definition of Langerhans Cell Histiocytosis
- Epidemiology of Langerhans Cell Histiocytosis
- Etiology of Langerhans Cell Histiocytosis
- Pathology of Langerhans Cell Histiocytosis
- Clinical Presentation of Langerhans Cell Histiocytosis
- Diagnosis of Langerhans Cell Histiocytosis
- Classification of Langerhans Cell Histiocytosis
- Treatment of Langerhans Cell Histiocytosis
- Review Questions
Definition of Langerhans Cell Histiocytosis
Langerhans cell histiocytosis (LCH) – also called Histiocytosis X – is a nonmalignant disease which is marked by proliferation of Langerhans cells. Langerhans cells are epidermal dendritic cells and present antigens to other defense cells. Other histiocytes circulate in the peripheral blood post maturation, their depositing in different organs and organ systems, e.g. Kupffer cells of the liver, explains the variety of clinical pictures.
These are abnormal cells that are produced in the bone marrow and have the capability of moving to the lymph nodes from the skin. The disease is also known as Hand–Schüller–Christian disease, Abt-Letterer-Siwe disease, or Hashimoto-Pritzker disease.
Epidemiology of Langerhans Cell Histiocytosis
Prevalence of histiocytosis X
The incidence is 0.4-1 in 100,000 with an age-based peak for a disseminated course of the disease in infants and toddlers. Localized disease has a peak incidence between ages 5 and 15. Boys are 1.3 times more susceptible than girls.
Etiology of Langerhans Cell Histiocytosis
Causes of Langerhans cell histiocytosis
A disturbed intercellular communication between effector cells, specifically T-cells and the antigen presenting Langerhans cells is assumed as pathophysiology. Proinflammatory mediators are released which contribute to a cytokine imbalance and therefore lead to a massive proliferation and accumulation of dendritic cells. Tissue damage and ultimately fibrosis is caused by the collection of histiocytes in the organs.
Although a clonal origin of the dendritic cells could be verified, certain indications of malignancy are missing.
A connection to nicotine abuse could be confirmed for isolated manifestation in the lungs.
Pathology of Langerhans Cell Histiocytosis
Histiocytosis X on a cellular level
Dendritic cells are marked by a tender eosinophilic cytoplasm and a nucleus akin to a coffee bean. Langerhans cells show typical Birbeck granules and typical antigen patterns. They are positive for S100, vimentin and CD1a. The Birbeck granules look like x-particles when examined by an electron microscope which explains the name. Furthermore, different inflammatory cells like eosinophilic and neutrophilic granulocytes, lymphocytes and plasma cells can be found in the granulomas.
Clinical Presentation of Langerhans Cell Histiocytosis
Eosinophilic granuloma as a form of Langerhans cell histiocytosis
Eosinophilic granuloma is a localized form of Histiocytosis X and largely affects bones. It accounts for 70 % of Histiocytosis X cases. Above all, it arises in the skull, spine, pelvis and long bones with the possibility of disease in more than one bone at the same time. A painful, pliable swelling can often be found covering the bone. In case of spinal involvement, compression fractures with development of so-called vertebra plana and neurologic deficiencies can occur.
Lesions in the jaw bones are noted by thooth loss or premature eruption of adult teeth.
Hand-Schüller-Christian-Disease as a form of Langerhans cell histiocytosis
Hand-Schüller-Christian-Disease is marked by multiple eosinophilic granulomas of the bone in addition to soft tissue involvement. It makes up 15-40 % of all Langerhans cell histiocytoses. In case of sella turcica involvement, children suffer from diabetes insipidus. Additional symptoms are growth abnormalities, fever, swollen lymph nodes, exophthalmos, dyspnoea and hepatosplenomegaly.
Abt-Letter-Siwe-Disease as a form of Langerhans cell histiocytosis
Occurences affecting the skin predominantly are defined as Abt-Letter-Siwe-Disease which makes up 10 % of Histiocystosis X cases. Skin presentation is reminiscent of seborrheic dermatitis on rump and scalp. Polymorphic maculopapular exanthema with hemorrhaging, ulceration and formation of crusts are observed. Additionally, hair may often be thinning and the children may suffer from fever. In many children, the oral mucosa is affected with whitish granulomatous plaques which exhibit a tendency for ulceration and bleeding. Generalized lymphomas and hepatosplenomegaly are observed. Also, thrombopenia with petechiae, anemia and granulocytopenia are possible symptoms occuring along with infiltration of the bone marrow.
Diagnosis of Langerhans Cell Histiocytosis
The diagnosis of Langerhans cell histiocytosis requires:
- Physical exam and history: this entails checking for general symptoms, which includes the signs of the disease; history of the patient should also be assed.
- Neurological exam: assessment and test to check the spinal cord and the nerve functions. Additionally, the exam aims at establishing the mental status, senses, and the function of the reflexes of the patient.
- Complete Blood Count with differential: checks the following
- Amount of hemoglobin in the red blood cells
- Portion of the blood samples making up the red blood cells
- Number of red blood cells as well as the platelets.
- Blood chemistry studies: procedure through which blood sample is examined to determine the substances released into the body by organs and tissues.
- Urinalysis: checks the color of the urine as well as its contents.
Radiologic diagnosis of Langerhans cell histiocytosis
The main diagnostic modality is by radiologic investigations.
Eosinophilic granuloma can be observed on a skull x-ray as osteolytic lesion with punched out appearance and clear margins surrounded by a sclerotic area or periosteal reaction. Observation of several lesions of the skull in Hans-Schüller-Christian-Disease is referred to as “geographic map skull”.
Computer tomography of the lung detects the so-called Cheerio sign. A thickening in the walls of the bronchial system is akin to the breakfast cereal in appearance.
In case of liver involvement, examination of the child leads to observation of edema and ascites formation while routine lab work will show coagulopathy, cholestasis and hyperbilirubinemia caused by a functional disturbance of the liver.
In case of involvement of the hypophyseal hypothalamic tract with diabetes insipudis as prevalent symptom, MRI will typically show a thickening of the infundibulum.
Further diagnosis of Langerhans cell histiocytosis
Completion of skeletal scintigraphy, bone marrow aspiration and lumbar puncture procedures as well as testing of endocrinological functioning of the hypophyseal anterior and posterior lobes serve to exclude disseminated disease.
Diagnosis is completed via biopsie which presents proof of Birbeck granules.
Classification of Langerhans Cell Histiocytosis
Division of Langerhans cell histiocytosis
According to the criteria of the Hystiocytosis Society, a differentiation is made between localized disease manifestation and disseminated disease. For purposes of therapy planning, patients are classified into categories of either high or low risk depending on the number of sytems with evidence of disease as well as the involvement of high risk organs such as liver, lung, spleen and the hematopoietic system.
|Single system disease||Multi system disease|
|Bones||2 or more organs or organ systems with or without organ function failure|
|Skin||High risk patients with risk organ participation|
|Lung||Low risk without risk organ participation|
|Central Nervous System|
Treatment of Langerhans Cell Histiocytosis
Surgical treatment of Langerhans cell histiocytosis
Treatment of eosinophilic granulomas consists of surgical curettage of the lesion. Radiation is justified in case of an inoperable or recidivating lesion.
Diagnostic therapy of Langerhans cell histiocytosis
Disseminates courses are treated with cytotastic therapy including Prednisone and Vinblastine which also minimizes delayed damage such as diabetes insipidus, stunted growth and deafness. Abt-Letterer-Siwe-Disease may necessitate a stem cell transplant.
Prognosis of Langerhans cell histiocytopsis
Generally, the prognosis is positive. Sponaneous arrest of disease is possible. Negative factors affecting prognosis are young age of the child, poor overall condition and organ infiltration. The involvement of high risk organs combined with poor therapy response within the first 6-12 weeks are independent prognosis criteria which, in about 75 % of cases, end fatally.
Malignant histiocytosis is marked by destructive infiltration of malignant histiocytes to lymph nodes, liver, spleen, bone marrow and skin. Boys are affected more often than girls, the rapidly progressing disease can occur at any age. Differentiation from benign histiocytosis is essential. Treatment is similar to b-cell lymphoma via chemotherapy.
Follow-up care of Langerhans cell histiocytosis
Follow-up care over the course of many years is important for all LCH patients. Follow-up care includes checking of known bone leasions via x-ray in regular time intervals until bone reconstruction can be observed. In case of systemic disease with involvement of other organs such as the lungs, regular functional tests are to be conducted. In case of reactivation, it is recommended to conduct the entire diagnostic program as in initial diagnosis.
Recurrence of the condition is common and may affect the ears, skins, bones, or the pituitary gland. The commonest time of recurrence is one year after cessation of medication intake.
The correct answers can be found below the references.
1. Which triad is characteristic for Hand-Schüller-Christian-Disease?
- Bone lesion, hyperprolactinemia, diabetes insipidus
- Skin invasion of Langerhans cells, exophthalmos, diabetes mellitus
- Skin invasion of Langerhans cells, hepatomegaly, enophthalmus
- Bone lesion, exophthalmos, diabetes insipidus
- Diabetes insipidus, hepatomegaly, lung restriction
2. Which organ or organ system does not belong to the list of risk organs in Langerhans cell histiocytosis?
- Central Nervous System
- Hematopoietic system
3. Initial treatment of an eosinophilic granuloma of the bone as part of Langerhans cell histiocytosis involves which procedure?
- Radiation with 6-10Gy total dose
- Chemotherapy with Prednisone and Vinblastine
- Aggressive chemotherapy and following stem cell transplant
- PUVA photochemotherapy
- Surgical curettage and orthopedic care