eMedicine Specialties > Dermatology > Malignant Neoplasms

Langerhans Cell Histiocytosis

Author: Christopher R Shea, MD, Professor and Chief, Section of Dermatology, Department of Medicine, University of Chicago
Coauthor(s): Markus D Boos, PhD, Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago
Contributor Information and Disclosures

Updated: Aug 26, 2009

Introduction

Background

Langerhans cell histiocytosis (LCH) is a group of idiopathic disorders characterized by the proliferation of specialized, bone marrow–derived Langerhans cells (LCs) and mature eosinophils.

In 1868, Paul Langerhans discovered the epidermal dendritic cells that now bear his name. The ultrastructural hallmark of the LC, the Birbeck granule, was described a century later. The term Langerhans cell histiocytosis is generally preferred to the older term, histiocytosis X. This newer name emphasizes the histogenesis of the condition by specifying the type of lesional cell and removes the connotation of the unknown (X) because its cellular basis has now been clarified.1

The working group of the Histiocyte Society has divided histocytic disorders into 3 different groups: (1) dendritic cell histiocytosis, (2) erythrophagocytic macrophage disorders, and (3) malignant histiocytosis. Langerhans cell histiocytosis belongs in group 1 and encompasses a number of diseases. The clinical spectrum includes on one end an acute, fulminant, disseminated disease called Letterer-Siwe disease; and, on the other end, solitary or few, indolent and chronic lesions of bone or other organs called eosinophilic granulomas. The intermediate clinical form called Hand-Schüller-Christian disease is characterized by multifocal, chronic involvement and classically presents as the triad of diabetes insipidus, proptosis, and lytic bone lesions. A congenital, self-healing form called Hashimoto-Pritzker disease has also been described.

Pathophysiology

The pathogenesis of Langerhans cell histiocytosis (LCH) is unknown. An ongoing debate exists over whether this is a reactive or neoplastic process. Arguments supporting the reactive nature of this disorder include the occurrence of spontaneous remissions, the extensive elaboration of multiple cytokines by dendritic cells (DCs) and T cells (ie, the so-called cytokine storm) in Langerhans cell histiocytosis lesions, and the good survival rate in patients without organ dysfunction.2 Furthermore, a rigorous investigation of potential chromosomal aberrations in Langerhans cell histiocytosis via analysis of ploidy, karyotype, single-nucleotide polymorphism arrays, and array-based comparative genomic hybridization did not reveal genetic abnormalities; these findings strongly support the idea of Langerhans cell histiocytosis as a reactive process.3
 
On the other hand, the infiltration of organs by a monoclonal population of aberrant cells, the possibility of lethal evolution, and the cancer-based modalities of successful treatment are all consistent with a neoplastic process.4,5 In addition, the demonstration of Langerhans cell histiocytosis as a monoclonal proliferation by X chromosome–linked DNA probes supports a neoplastic origin for this proliferation; however, the presence of this finding in distinct subtypes with different evolutions demands further investigations to elucidate its significance.

Evidence suggests a role for immune dysfunction in the pathogenesis of Langerhans cell histiocytosis, through the creation of a permissive immunosurveillance system. Abnormalities of suppressor cell number and function have been documented in several reports. Increased levels of messenger RNA for macrophage colony-stimulating factor and platelet-derived growth factor have been detected in cells from a pulmonary Langerhans cell histiocytosis lesion.

Detection of high serum levels of the proinflammatory cytokine interleukin 17A (IL-17A) in patients with Langerhans cell histiocytosis has given rise to speculation that IL-17A is involved in the pathogenesis of the disease. Further investigation into this phenomenon has led to the proposal that IL-17A induces DC/LC fusion into multinucleated giant cells that in turn recruit other inflammatory cells and cause local tissue destruction, creating the characteristic lesions of Langerhans cell histiocytosis.6 However, these findings have not been independently reproduced, and the role of IL-17A in the pathogenesis of Langerhans cell histiocytosis remains controversial.7

In addition, some studies indicate that expression of vascular endothelial growth factor (VEGF), Bcl-2 family proteins, and FADD, FLICE, and FLIP proteins in the Fas signaling pathway may be involved in the pathogenesis of Langerhans cell histiocytosis.8,9,10

Frequency

United States

Langerhans cell histiocytosis is a rare disease. The estimated annual incidence ranges from 0.5-5.4 cases per million persons per year. Approximately 1200 new cases per year are reported in the United States.

Mortality/Morbidity

More than half the patients younger than 2 years with disseminated Langerhans cell histiocytosis and organ dysfunction die of the disease, whereas unifocal Langerhans cell histiocytosis and most cases of congenital self-healing histiocytosis are self-limited. Multifocal chronic Langerhans cell histiocytosis is self-limited in most cases, but increased mortality has been observed among infants with pulmonary involvement.

Race

The prevalence of Langerhans cell histiocytosis seems to be higher among whites than in other races.

Sex

The incidence of Langerhans cell histiocytosis is greater in males than in females, with a male-to-female ratio of 2:1.

Age

Langerhans cell histiocytosis affects patients from neonates to adults, although it appears to be more common in children aged 0-15 years (reportedly approximately 4 cases per million population).11 The age at onset varies according to the variant of Langerhans cell histiocytosis.

  • Letterer-Siwe disease occurs predominantly in children younger than 2 years.
  • The chronic multifocal form, including Hand-Schüller-Christian syndrome, has a peak of onset in children aged 2-10 years.
  • Localized eosinophilic granuloma occurs mostly frequently in children aged 5-15 years.
  • Also see Histiocytosis.

Clinical

History

The clinical presentation of Langerhans cell histiocytosis (LCH) depends on the extent of dissemination.

  • Unifocal bony Langerhans cell histiocytosis is characterized by the development of solitary osseous lesions at any site. Unifocal bony Langerhans cell histiocytosis is least common in the hands and the feet. These lesions are often asymptomatic and are detected incidentally during investigation for unrelated disorders.
  • Patients with multisystem disease may have a protean history depending on the location of osteolytic lesions and the degree of organ dysfunction. Patients with Hand-Schüller-Christian syndrome (which occurs in 25% of patients with multifocal Langerhans cell histiocytosis) often present with recurrent episodes of otitis media and mastoiditis or with polyuria and polydipsia.
  • Letterer-Siwe disease presents with symptoms suggestive of a systemic infection or malignancy, including a generalized skin eruption, anemia, and hepatosplenomegaly.
  • The congenital form of Langerhans cell histiocytosis manifests as skin lesions at birth or during the early postnatal period. Cutaneous nodules and ulceration have onset early in life. Rarely, patients with purpuric lesions present with a blueberry-muffin appearance.12 Symptoms of organ involvement may also occur.

Physical

Signs of Langerhans cell histiocytosis (LCH) depend on the localization and the extent of the disease. The clinical spectrum of Langerhans cell histiocytosis is broad, and an individual case may differ markedly from the prototypes described.

  • Chronic unifocal Langerhans cell histiocytosis (eosinophilic granuloma of bone) classically presents as a solitary calvarial lesion in young adults; other frequent sites of involvement include a vertebra, rib, mandible, femur, ilium, and scapula.
    • Lesions are usually asymptomatic, but bone pain and a soft tissue mass may occur.
    • When calvarial lesions extend into the nervous system, a variety of neurologic manifestations may be seen.
    • Bony lesions may cause otitis media by destruction of the temporal and mastoid bones, proptosis secondary to orbital masses, loose teeth from infiltration of the mandibles, or pituitary dysfunction due to involvement of the sella turcica.
    • Spontaneous fractures can result from osteolytic lesions of the long bones; vertebral collapse with spinal cord compression has been described.
  • Solitary cutaneous disease presents with nodulo-ulcerative lesions in the oral, perineal, perivulvar, or retroauricular regions.
  • Solitary pulmonary lesions may be the presenting and only manifestation. In adults, the pulmonary system is the most frequently involved.
  • Rarely, solitary cerebral lesions may occur.
  • The classic multifocal form of Langerhans cell histiocytosis (Hand-Schüller-Christian disease) includes diabetes insipidus, exophthalmos, and bony defects, particularly of the cranium.
    • Lesions may affect a variety of systems, including liver (20%), spleen (30%), and lymph nodes (50%).
    • Pulmonary involvement may occur.
    • Osteolytic lesions of the long bones can lead to spontaneous fractures.
    • One third of patients have mucocutaneous lesions, most frequently infiltrated nodules and ulcerated plaques, especially in the mouth, axillae, and anogenital region. Other cutaneous manifestations include extensive coalescing, scaling, or crusted papules.
  • Patients with acute disseminated Langerhans cell histiocytosis (multiorgan involvement) present with fever, anemia, thrombocytopenia, pulmonary infiltrates, skin lesions, and enlargement of lymph nodes, spleen, and liver.
    • Cutaneous abnormalities are present in almost 80% of patients, frequently as the first sign.
    • The eruption may be extensive, involving the scalp, face, trunk, buttocks, and intertriginous areas. Lesions consist of closely set petechiae and yellow-brown papules topped with scale and crust. The papules may coalesce to form an erythematous, weeping or crusted eruption mimicking seborrheic dermatitis.
    • Intertriginous lesions are often exudative, and secondary infection and ulceration may occur.
    • Osteolytic lesions are not common in the disseminated form of Langerhans cell histiocytosis, but the mastoid can be affected, resulting in a clinical picture of otitis media, which may be the presenting complaint. Aural discharge, conductive hearing loss, and postauricular swelling have been described.13
    • Patients with pulmonary involvement present with chest pain, hemoptysis, dyspnea, failure to thrive, cystic changes, and pneumothorax; if lung disease is extensive, oxygen diffusion and lung capacity may be reduced.14,15
    • Neurologic involvement may produce seizures, vertigo, headache, ataxia, and cognitive defects.


Letterer-Siwe disease. Bilateral inguinal erosive...

Letterer-Siwe disease. Bilateral inguinal erosive plaques and erythematous papules on the abdomen. Courtesy of Dr Neil S. Prose.

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Letterer-Siwe disease. Bilateral inguinal erosive...

Letterer-Siwe disease. Bilateral inguinal erosive plaques and erythematous papules on the abdomen. Courtesy of Dr Neil S. Prose.



Abdominal area of an infant with multiple erythem...

Abdominal area of an infant with multiple erythematous papules covered by scale and/or crust.

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Abdominal area of an infant with multiple erythem...

Abdominal area of an infant with multiple erythematous papules covered by scale and/or crust.



Typical purpuric lesions in Langerhans cell histi...

Typical purpuric lesions in Langerhans cell histiocytosis (must be distinguished from seborrheic dermatitis).

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Typical purpuric lesions in Langerhans cell histi...

Typical purpuric lesions in Langerhans cell histiocytosis (must be distinguished from seborrheic dermatitis).

  • Congenital self-healing histiocytosis presents at birth or during the early neonatal period with firm, red-brown, painless papulonodules (1-10 mm in diameter) or vesicles and crusts scattered over the scalp, face, and, to a lesser extent, trunk and the extremities. Lesions may ulcerate. Solitary lesions may occur. Lesions may be followed by residual hypopigmented or hyperpigmented macules.

Causes

The etiology of Langerhans cell histiocytosis (LCH) remains unknown.

  • LC proliferation may be induced by a viral infection, a defect in intercellular communication (T cell–macrophage interaction), and/or a cytokine-driven process mediated by tumor necrosis factor, interleukin 11, and leukemia inhibitory factor.16 17,18
  • Cigarette smoking may play a role as a chronic irritant in the development of eosinophilic granuloma of the lung.

More on Langerhans Cell Histiocytosis

Overview: Langerhans Cell Histiocytosis
Differential Diagnoses & Workup: Langerhans Cell Histiocytosis
Treatment & Medication: Langerhans Cell Histiocytosis
Follow-up: Langerhans Cell Histiocytosis
Multimedia: Langerhans Cell Histiocytosis
References
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Further Reading

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Keywords

Langerhans cell histiocytosis, LCH, histiocytosis X, Langerhans cell granulomatosis, type II histiocytosis, nonlipid reticuloendotheliosis, Langerhans cells, LCs

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Contributor Information and Disclosures

Author

Christopher R Shea, MD, Professor and Chief, Section of Dermatology, Department of Medicine, University of Chicago
Christopher R Shea, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology, Arthur Purdy Stout Society, Association of Professors of Dermatology, Chicago Dermatological Society, Dermatology Foundation, Illinois Dermatological Society, International Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Markus D Boos, PhD, Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago
Disclosure: Nothing to disclose.

Medical Editor

Bernice R Krafchik, MBChB, FRCPC, Professor Emeritus, Department of Pediatrics, Section of Dermatology, University of Toronto
Bernice R Krafchik, MBChB, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Royal College of Physicians and Surgeons of Canada, and Society for Pediatric Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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