Langerhans Cell Histiocytosis

Background

Langerhans cell histiocytosis (LCH) is a group of idiopathic disorders characterized by the presence of cells with characteristics similar to bone marrow–derived Langerhans cells juxtaposed against a backdrop of hematopoietic cells, including T-cells, macrophages, and eosinophils.

In 1868, Paul Langerhans discovered the epidermal dendritic cells that now bear his name. The ultrastructural hallmark of the Langerhans cell, 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]

Although the epidermal Langerhans cell has been presumed to be the cell of origin in LCH, recent studies have called this belief into question. Specifically, a variety of other cellular populations have been identified that possess phenotypic characteristics similar to Langerhans cells, including expression of CD207 and Birbeck granules. Therefore, in addition to epidermal Langerhans cells, other potential cellular origins for LCH include dermal langerin⁺ dendritic cells, lymphoid tissue-resident langerin⁺ dendritic cells, and monocytes that can be induced by local environmental stimuli to acquire a Langerhans cell phenotype.^{[2, 3]}

Notably, LCH cells have been found to express markers of both resting epidermal Langerhans cells (CD1a, intracellular major histocompatibility complex II [MHCII], Birbeck granules) and activated Langerhans cells (including CD54 and CD58). As a result, the pathologic cells of LCH have been hypothesized to represent Langerhans cells in a state of arrested maturation.^[3] Taken together, these findings have led some to speculate that LCH is not a specific disease of epidermal Langerhans cells, but rather one of mononuclear phagocyte dysregulation.^[3]

The working group of the Histiocyte Society has divided histocytic disorders into 3 groups: (1) dendritic cell histiocytosis, (2) macrophage-related disorders, and (3) malignant histiocytosis.^[4] LCH belongs in group 1 and encompasses a number of diseases. On one end, the clinical spectrum includes 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.

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Pathophysiology

The pathogenesis of Langerhans cell histiocytosis (LCH) is unknown. It has been debated whether LCH is a reactive or neoplastic process. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive elaboration of multiple cytokines by dendritic cells and T-cells (the so-called cytokine storm) in LCH lesions, and the good survival rate in patients without organ dysfunction.^[5] Furthermore, a rigorous investigation of potential chromosomal aberrations in LCH via analysis of ploidy, karyotype, single-nucleotide polymorphism arrays, and array-based comparative genomic hybridization did not reveal consistent abnormalities; these findings were considered to support the idea of LCH as a reactive process.^[6]

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.^{[7, 8]} In addition, the demonstration, by use of X chromosome–linked DNA probes, of LCH as a monoclonal proliferation 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. Of note, recent genomic studies demonstrate activating, somatic BRAF mutations in the majority of human specimens. These observations support the concept of LCH as a myeloid neoplasm.^[9]

A 2010 study comparing gene expression of cells expressing CD207 (a marker of Langerhans cells) in LCH lesions with epidermal CD207⁺ control cells identified differential expression of more than 2000 genes between these 2 subsets. These differences were found in genes involved in cell cycle regulation, apoptosis, cell signaling, metastasis, and myeloid differentiation.^[10] Interestingly, this analysis found no differences in expression of proliferation markers between these subsets of CD207⁺ cells, consistent with the hypothesis that LCH may be a disease of abnormal cellular accumulation.

The extensive variability in gene expression between these 2 cellular populations has prompted speculation that LCH cells may develop from a population of cells distinct from epidermal Langerhans cells. Specifically, it is hypothesized that "misguided" blood-derived myeloid dendritic cells are recruited to specific anatomic sites and their subsequent stimulation of T-cell trafficking and local immunomodulation is responsible for the characteristic lesions of LCH.^[10] Notably, this hypothesis is consistent with either an oncogenic or reactive etiology for LCH, because what stimulates these misguided cells remains unclear.

Evidence suggests a role for immune dysfunction in the pathogenesis of LCH, through the creation of a permissive immunosurveillance system. Specifically, findings from immunohistochemical and immunofluorescence analyses of LCH biopsy specimens have led to the hypothesis that semimature LCH cells stimulate the expansion of a polyclonal population of regulatory T cells. These regulatory T cells may, in turn, inhibit the immune system (in part via the elaboration of interleukin (IL)–10 and prevent it from effectively resolving LCH lesions.^[11]

Detection of high serum levels of the proinflammatory cytokine IL-17A in patients with LCH has given rise to speculation that IL-17A is also involved in the pathogenesis of the disease. Further investigation into this phenomenon has led to the proposal that IL-17A induces dendritic cell/Langerhans cell fusion into multinucleated giant cells that in turn recruit other inflammatory cells and cause local tissue destruction, creating the characteristic lesions of LCH.^[12] However, these findings have not been independently reproduced, and the role of IL-17A in the pathogenesis of LCH remains controversial.^[13]

Some studies have also indicated 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 LCH.^{[14, 15, 16]} The E-cadherin-beta-catenin-Wnt signaling pathway has also been implicated in LCH, and down-regulation of E-cadherin may be associated with disease dissemination.^{[3, 17]}

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Etiology

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

Langerhans cell 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, IL-11, and leukemia inhibitory factor.^{[18, 19, 20]} Specifically, human herpesvirus 6 (HHV-6) has been proposed to contribute to the initiation and/or modulation of persistent LCH. However, other studies have not shown a correlation between HHV-6 and LCH, and their reported associations may represent coincidental findings.^{[21, 22]}

Cigarette smoking may play a role as a chronic irritant in the development of eosinophilic granuloma of the lung.

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Epidemiology

Frequency

Langerhans cell histiocytosis (LCH) 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.

Race

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

Sex

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

Age

Langerhans cell histiocytosis (LCH) affects patients from the neonatal period to adulthood, although it appears to be more common in children aged 0-15 years (reportedly approximately 4 cases per million population).^[23] The age at onset varies according to the variant of LCH, as follows^[3] :

• 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.
• Pulmonary LCH is more common during the third and fourth decades of life.^[3]

Also see Histiocytosis.

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Prognosis

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

The clinical course of Langerhans cell histiocytosis (LCH) is variable. Patients with unifocal disease generally have an excellent prognosis. After initial bone scanning and radiographic survey to assess the extent of the disease, follow-up studies after treatment should be performed at 6-month intervals for 3 years. If no additional lesions are present at 1 year, the development of subsequent lesions is unlikely. A full recovery is also expected in cases of solitary lymph node involvement or isolated skin disease.

Multifocal LCH has a variable prognosis, especially in patients at the extremes of age with pulmonary involvement. The prognosis is worse than in patients with unifocal disease but better than those with disseminated disease. Sixty percent of patients with multifocal disease have a chronic course, 30% of patients undergo complete remission, and 10% of patients with multifocal LCH die from the disease.^[24] Response to chemotherapy in the first 6 weeks (induction therapy) is among the most important prognostic indicators for multifocal LCH. A good response to chemotherapy during this period is associated with significantly improved survival.^{[4, 25]} Conversely, hematologic involvement or involvement of organs such as the lungs, spleen, and liver is associated with worse long-term outcomes.^[4]

Letterer-Siwe disease (disseminated) has a high mortality rate. The prognosis in these patients depends on the patient's age, the extent of disease, and the degree of organ dysfunction. The mortality rate is 50% or higher.

The congenital form of histiocytosis tends to resolve spontaneously within weeks to months.^[26] Although the absence of systemic disease at presentation and the tendency of resolution of the disease are favorable, long-term follow-up care to detect evidence of relapse or progression in these patients is suggested.^[26] Relapse in these patients has been reported up to 5 years after the initial disappearance of the disease. Cutaneous lesions usually disappear by 3 months, leaving residual hypopigmentation.

Infrequently, cases originally diagnosed as chronic focal LCH may progress to multifocal or even disseminated disease.

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History

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

Unifocal bony LCH is characterized by the development of solitary osseous lesions at any site. Unifocal bony LCH 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 LCH) 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 LCH 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.^[27] Symptoms of organ involvement may also occur.

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Physical Examination

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

Solitary cutaneous disease presents with noduloulcerative lesions in the oral, perineal, perivulvar, or retroauricular regions.^[28] Rarely, solitary cerebral lesions may occur. In adults with LCH, the pulmonary system is the most frequently involved organ system, and solitary pulmonary lesions may be the only manifestation. Chronic cough, dyspnea, chest pain, and recurrent pneumothoraces are typical signs and symptoms of pulmonary disease.^[29]

Because of its protean nature, LCH must be considered in more unusual presentations, including protein-losing enteropathy in infants and combined pulmonary-thyroid involvement in adults.^{[30, 31]}

Chronic unifocal LCH

Chronic unifocal LCH (eosinophilic granuloma of bone) classically presents as a solitary calvarial lesion in young adults; other frequent sites of involvement include 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. Mono-ostotic lesions of LCH may also appear in less common sites, such as the scapula.^[32]

Classic multifocal LCH (Hand-Schüller-Christian disease)

The classic multifocal form of LCH (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.

Acute disseminated LCH

Patients with acute disseminated LCH (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. Note the images below.

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

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

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

Osteolytic lesions are not common in the disseminated form of LCH, 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.^[33]

As described above, 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.^{[34, 35]}

Neurologic involvement may produce seizures, vertigo, headache, ataxia, and cognitive defects.

Congenital self-healing histiocytosis

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. Lesions may be solitary. Lesions may be followed by residual hypopigmented or hyperpigmented macules.

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Complications

Complications appear in 30-50% of patients with Langerhans cell histiocytosis (LCH). The most common complications are orthopedic disabilities, hearing impairment, diabetes insipidus, skin scarring, and neuropsychologic defects (eg, anxiety, depression, decreased intellect).^{[23, 36, 37]}

Patients with multisystem disease, craniofacial involvement, long-standing disease, or reactivation may be at increased risk of developing diabetes insipidus.^{[38, 39]} Regular neurological examinations and whole brain MRI are recommended to evaluate for CNS lesions of LCH and for evidence of neurodegeneration in patients with newly recognized diabetes insipidus.^[40]

Less common sequelae include chronic pulmonary dysfunction, liver cirrhosis, secondary malignancies such as acute lymphoblastic leukemia or solid tumors, and growth retardation.^[41]

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Laboratory Studies

Blood testing

Recommended baseline diagnostic evaluations for Langerhans cell histiocytosis (LCH) include CBC count with differential, reticulocyte count, erythrocyte sedimentation rate, direct and indirect Coombs test, and immunoglobulin levels.^[43] In case of anemia, leukopenia, or thrombocytopenia, a bone marrow aspirate is indicated. Coagulation studies may be indicated.

Liver function tests

These can include tests measuring total protein, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase values. If liver function test results are abnormal, a liver biopsy should be considered to differentiate LCH from cirrhosis.

Urinalysis

Urine specific gravity and osmolality are measured after overnight water deprivation to screen for diabetes insipidus.

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Imaging Studies

Chest radiography (posteroanterior and lateral)

Langerhans cell histiocytosis (LCH) can present as a micronodular and interstitial infiltrate in the mid zone and base of the lungs, with sparing of the costophrenic angles. Older lesions show a honeycomb appearance.

High-resolution CT scanning may be required if lung involvement is suspected based on radiography findings of pulmonary infiltrates or a cystic appearance.^[23]

Patients with radiographically demonstrated pulmonary involvement, in whom chemotherapy is being considered, require a biopsy of the lung preceded by bronchoalveolar lavage (BAL) to exclude opportunistic infections. If the BAL findings are diagnostic, the biopsy of the lung can be obviated.

Skeletal radiograph survey

Unifocal LCH presents as a single osteolytic lesion, usually affecting long or flat bones (in children, the calvaria and femurs; in adults, the ribs).

Multifocal LCH shows osteolytic lesions involving the calvaria, sella turcica, mandible, vertebrae, and/or long bones of the upper extremities.

Note the image below.

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On a plain skull radiograph, lesions are typically lytic, with sharp borders and a punched out appearance.

Although radionuclide bone scanning is suggested for establishing the extent of osseous involvement, the latter is not as sensitive as the skeletal radiograph survey in most patients.

MRI of the head and spine is also useful to identify craniofacial or vertebral bone lesions.

CT scanning or MRI

CT scanning or MRI of the hypothalamic-pituitary region may reveal abnormalities of these organs. In particular, magnetic resonance spectroscopy may be valuable in the early detection and evaluation of the neurodegenerative component.^[44]

Fluorodeoxyglucose positron-emission tomography scanning

Fluorodeoxyglucose (FDG) positron-emission tomography (PET) scanning may also be used when evaluating patients for LCH. In one study, FDG-PET scanning found 35% more sites of active disease than radiography, CT scanning, MRI, and bone scanning and was particularly effective at identifying bony lesions. FDG-PET scanning has therefore been suggested as a superior alternative to bone scanning in the early evaluation of patients with LCH.^[45] Notably, FDG-PET scanning has poor sensitivity for spinal lesions. FDG-PET scanning is able to identify LCH in tissues, including lymph nodes, spleen, and lung.

FDG-PET scanning may also be useful in measuring response to treatment, particularly in patients with only bony involvement who may not require periodic CT scanning or MRI evaluation.^{[45, 46]}

Also see Imaging in Eosinophilic Granuloma of the Skeleton.

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Other Tests

Other testing in Langerhans cell histiocytosis (LCH) patients may involve the following:

• Pulmonary function testing may help identify otherwise asymptomatic pulmonary involvement.^[23]
• A small bowel series and biopsy are indicated in cases of unexplained diarrhea, failure to thrive, and malabsorption.^[30]
• Hormonal studies of the hypothalamic-pituitary axis may reveal abnormalities.
• Visual and neurologic testing may be required.
• Consultation with an otolaryngologist for auditory testing may also be considered as needed.^{[4, 47]}
• The results of a small Swedish study evaluating LCH patients with known neurodegeneration on MRI suggest that serial monitoring of cerebrospinal fluid biomarkers (including neurofilament light chain [NF-L], Tau, and glial fibrillary acidic protein [GFAp]) may help evaluate disease onset, severity, and response to therapy in patients with neural involvement.^[48] However, more robust studies must be performed to evaluate this claim before such tests become common practice.

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Procedures

A biopsy of the skin is extremely helpful in establishing the diagnosis.

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Histologic Findings

The histologic picture unifies the varied presentations of Langerhans cell histiocytosis (LCH), which are influenced by the location and age of the lesions. Although lesions typically appear granulomatous, with a reactive background of macrophages, eosinophils, multinucleated giant cells, and T-cells, the key to diagnosis is to identify the pathologic Langerhans cells.^{[49, 41]} The latter cell resembles the normal Langerhans cell of the skin, except that it is not dendritic.

It consists of a large, ovoid, mononuclear cell that is 15-25 µm in diameter, with a folded nucleus, a discrete nucleolus, and a moderate amount of slightly eosinophilic homogeneous cytoplasm. When the indentation of the nucleus affects its center, it acquires a reniform pattern; however, if it is peripheral, the nucleus has a coffee-bean shape.

Special studies are useful for definitive identification of normal and pathologic Langerhans cells. The Birbeck granule is their distinctive ultrastructural hallmark. It consists of an intracytoplasmic membranous body that is 33 nm wide and 190-360 nm long, possessing a short, rodlike shape with a dotted line down the midline of the space between the membranes (resembling a zipper) and a terminal expansion in the form of a vesicle, giving a racquet appearance. Although these granules are resistant to destruction by formalin fixation and paraffin embedding, the sensitivity of detection in such specimens is slightly decreased. Birbeck granules are rarely detected in lesions of the liver, the gastrointestinal tract, and the spleen. Langerhans cells also contain laminated substructures of lysosomes, tuboreticular structures, and trilaminar membranous loops. Note the image below.

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Electron microscopy. Tennis racquet form of Birbeck granules with a small terminal expansion.

Ultrastructural methods and enzyme histochemical studies (alpha-D-mannosidase and adenosine triphosphatase [ATPase]) have largely been replaced by immunohistochemical techniques. S-100 protein is strongly expressed in a cytoplasmic pattern, while peanut agglutinin (PNA) has a characteristic cell surface and paranuclear dot expression. LCH cells are positive for major histocompatibility (MHC) class II and CD1a. Expression of langerin (CD207), a Langerhans cell–restricted protein that induces the formation of Birbeck granules and is constitutively associated with them, is a highly specific marker of Langerhans cells.^[50] The pathologic Langerhans cell expresses phenotypic markers of an activated normal Langerhans cell in its early stages. Fine-needle aspiration combined with immunohistochemistry of the cell preparation plays an important role in documenting organ involvement by LCH.

Note the images below.

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High-power views. Marked epidermotropism is noted (left). The lesional cells are large, with abundant pink cytoplasm and reniform nuclei. An admixture....

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High-power views. Diffuse immunoreactivity for S-100 protein (right). Langerhans cells and lymphocytes (left, hematoxylin and eosin).

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Widespread positivity for CD1a. Note the presence of epidermotropism (right). Langerhans cells and lymphocytes are present in the epidermis and the pa....

The Writing Group of the Histiocyte Society (1987) has proposed 3 levels of certainty in the diagnosis of LCH, based on clinical features, histopathology, and immunohistochemical techniques. A presumptive diagnosis is based on a typical clinical presentation and light microscopic findings. A designated diagnosis includes light microscopy in combination with positive S-100 and PNA staining studies. To make a definitive diagnosis, identification of Birbeck granules and CD1a antigens is required.

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Staging

The Histiocyte Society stratifies patients with Langerhans cell histiocytosis (LCH) into single-system LCH (SS-LCH) or multisystem LCH (MS-LCH).

SS-LCH includes involvement of one of the following systems (either unifocal or multifocal involvement):

• Bone
• Skin
• Lymph Node
• Lungs
• Central nervous system
• Other (eg, thyroid, thymus)

MS-LCH is defined as involvement of 2 or more organs or organ systems, irrespective of involvement of "risk organs." The following organ systems are classified as risk organs, and their involvement indicates a worse prognosis^[41] :

• Spleen
• Liver
• Hematopoietic system
• Lung

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Medical Care

No consensus exists for the optimal therapy for Langerhans cell histiocytosis (LCH), particularly in the case of multisystem organ disease. However, the Histiocyte Society has conducted a number of prospective, randomized control trials to study the effect of various chemotherapeutic regimens in the treatment of LCH, which have resulted in recommendations by the Histiocyte Society.

Generally, the choice of therapeutic regimen is based on disease severity. The International LCH Study of the Histiocyte Society proposes the stratification of LCH cases by the number of systems involved. They further categorize those cases with single-system involvement by the number of sites within that system (eg, monostotic vs polyostotic bone disease, solitary vs multiple lymph node involvement). In addition, the presence or the absence of risk-organ dysfunction is used to stratify patients with multisystemic disease; the presence of risk-organ dysfunction portends a poorer prognosis.

Notably, most trials for the treatment of LCH have been performed in pediatric populations, and their results have typically been extrapolated to adults. This has resulted in a call for more prospective, randomized trials looking specifically at the treatment of LCH in adults and whether changes in chemotherapeutic regimens and their duration may be appropriate.^[51]

Single-system disease

Solitary bone lesions are treated locally with curettage or excision. Painful bone lesions may require intralesional steroid injection (triamcinolone acetonide). Bisphosphonates such as zoledronic acid can also be used to reverse bone destruction and mitigate the pain of bony lesions.^[52] Early treatment with vinblastine and prednisolone has been suggested for bony lesions at vital anatomic locations requiring prompt resolution.^[23] Rarely, lesions that are unusually large and painful occur in inaccessible sites or involve vital structures require radiation therapy (3-6 Gy [300-600 rad]).

Polyostotic bone lesions are best treated with indomethacin or a short course of systemic steroids.^[53] A case report on pharmacologic management of single-system bony disease using naproxen indicates that multiple COX antagonists may be used in treating this form of LCH.^[54]

Localized skin disease is best treated with moderate-to-potent topical steroids (eg, mometasone furoate [Elocon] cream 0.1%, triamcinolone [Kenalog] cream 0.1%, fluocinolone [Synalar] ointment 0.025%) or superpotent topical steroids (eg, clobetasol propionate 0.05%). In cases of severe cutaneous involvement, topical nitrogen mustard (20% solution) may be used. Acitretin may also be an effective agent for patients with primarily cutaneous manifestations of LCH.^[55]

Psoralen plus ultraviolet A (PUVA) is another effective modality for cutaneous-only LCH or for cutaneous involvement in multisystemic disease. PUVA consists of photosensitizing psoralens (8-methoxypsoralen or 5-methoxypsoralen) either applied topically or ingested systemically 2 hours prior to treatment with long-wave ultraviolet A (320-400 nm). The purpose of this treatment is to induce remission of skin diseases by inducing a repeated and controlled phototoxic reaction. The photoconjugation of psoralens with DNA produces an antiproliferative reaction in the skin, generates programmed cell death (apoptosis), and induces down-regulation of the cutaneous immune system.^[56]

Ultraviolet B excimer laser has been found in at least one case report to offer effective adjuvant therapy in the management of cutaneous LCH, and it may be particularly useful for patients with comorbidities who cannot tolerate more aggressive treatment.^[57]

For single lymph node infiltration, excision is the treatment of choice. Regional lymph node enlargement can be treated with a short course of systemic steroids. Treatment-resistant nodes with sinus tracts to the skin may require systemic chemotherapy.

Smoking cessation is an important intervention in cases of pulmonary LCH.^[29]

Single-agent chemotherapy with cladribine (2-chlorodeoxyadenosine/2-CdA) may be a promising treatment for single-system pulmonary Langerhans cell histiocytosis.^[58]

Multisystem disease

Systemic chemotherapy is indicated for multisystem disease and cases of single-system disease not responsive to other treatment. The combination of cytotoxic drugs and systemic steroids is generally effective. Low-to-moderate doses of methotrexate, prednisone, and vinblastine are used.

Efficacy differences in chemotherapeutic agents

Multiple large clinical trials have examined differences in efficacy between chemotherapeutic agents.

One cooperative clinical trial in Europe used vinblastine, etoposide, and prednisolone for 6 weeks, followed by mercaptopurine, vinblastine, and prednisolone for 1 year. If soft tissue was involved, treatment was supplemented with etoposide, and, if the patient has organ dysfunction, methotrexate was added. Initial complete resolution occurred in 86% of patients, with a mortality rate of 9% and a disease-free survival rate of 77% at a median follow-up time of 6 years.^[59]

The LCH-I trial sponsored by the Histiocyte Society used etoposide or vinblastine for 24 weeks. These agents produced equivalent responses at week 6 and had similar effects on survival and disease recurrence. Lack of response at 6 weeks was associated with an increased likelihood of treatment failure and a worse prognosis. The survival rate was slightly better in the aforementioned European trial than in LCH-I, but the difference was not statistically significant. A greater probability of developing diabetes insipidus occurred in the LCH-I trial.^[25]

The LCH-II randomized clinical trial compared the effectiveness of 24 weeks of combined therapy with vinblastine, oral prednisone, and mercaptopurine, versus the same combination with the addition of etoposide. The overall survival in patients treated with etoposide was marginally improved compared with treatment without it; this effect was more pronounced in those patients with risk-organ involvement. However, although the addition of etoposide produced slightly more favorable therapeutic responses, it did not decrease the likelihood of disease recurrence.^[60] Ultimately, the Histiocyte Society concluded that early therapy intensification (when compared with the LCH-I trial) had a positive effect on survival.^[60] However, the addition of etoposide appeared to be of minimal therapeutic benefit and it use was not included in the recommendations of the Histiocyte Society released in April 2009.

The LCH-III study, a prospective, randomized clinical trial, evaluated the efficacy of adding methotrexate to vinblastine and prednisone in the treatment of LCH in multisystem-risk patients. It also included evaluation of the optimal duration of treatment (6 mo vs 12 mo) using prednisone and vinblastine for multisystem low-risk patients. Finally, it includes a pilot study for patients with single-system multifocal bone disease and localized special sites, including the CNS. Results of LCH-III resulted in the following recommendations from the Histiocyte Society:

• Risk patients should be treated with oral prednisone daily and intravenous vinblastine weekly for 6 weeks. Patients who continue to have active disease should repeat this regimen for another 6 weeks. Patients who have no active disease after 6-week induction therapy should begin continuation treatment with oral 6-mercaptopurine daily, supplemented with pulses of oral prednisone and intravenous vinblastine, for 12 months of total treatment. The addition of methotrexate to LCH treatment is not recommended in current practice.
• Low-risk patients should be treated with oral prednisone and intravenous vinblastine for 12 months total.
• Patients with multifocal bone disease or CNS risk should be treated with oral prednisone daily and intravenous vinblastine weekly for 6 weeks. Patients should then be supplemented with pulses of oral prednisone and intravenous vinblastine for 6 months of total treatment.

LCH-IV, an international treatment protocol sponsored by Dana-Farber Cancer Institute for children and adolescents with Langerhans cell histiocytosis (ClinicalTrials.gov identifier NCT02205762),  is currently recruiting participants. In this randomized, interventional study, patients who do not respond to standard first-line prednisone and vinblastine will be switched to the combination of cytosine arabinoside and 2-chlorodeoxyadenosine. Other stratifications of the study design include treatments with mercaptopurine and methotrexate, indomethacin, hematopoietic stem cell transplantation, and intravenous immunoglobulin.

Treatment of refractory disease

LCH-S-98, a prospective, phase II Histiocyte Society study evaluated 2-chlorodeoxyadenosine (2-CdA) as salvage monotherapy for patients with risk-organ involvement refractory to initial therapy with three agents (excluding 2-CdA) or patients with recurrent, low-risk LCH (ie, patients with non–risk-organ involvement, including multifocal bone disease).^[61] The study concluded that 2-CdA is active as salvage therapy for LCH, but that it is more effective in low-risk patients or patients with multifocal bone disease. Those patients with risk-organ involvement who responded to 2-CdA therapy had a good prognosis, while those who were refractory typically had grim outcomes. Notably, patients older than 2 years and those with a longer time between diagnosis and 2-CdA therapy had better responses, presumably because their disease was less aggressive.^[61]

Combination therapy with 2-chlorodeoxyadenosine and cytosine arabinoside (ARA-C) has been studied in patients with refractory, risk-organ‒positive LCH. The overall 5-year survival rate was 85%; thus, the combination of 2-chlorodeoxyadenosine and ARA-C appears to be an effective therapy for refractory multisystem LCH, albeit one associated with high toxicity.^[62]

A retrospective study evaluating the efficacy of 2-CdA (+/- arabinoside) in treating refractory LCH in 17 Japanese patients similarly concluded that 2-CdA is effective for the treatment of refractory disease.^[63] Notably, patients whose disease reactivated following the conclusion of their initial therapy had improved outcomes compared with those patients who had primary refractory disease or those who experienced reactivation during their initial chemotherapy. This same study also suggested that 2-CdA may be effective in the treatment of LCH with CNS involvement.^[63]

In LCH patients with a very poor prognosis (rapid disease progression, refractory to conventional treatment, or with disseminated risk-organ involvement), bone marrow transplantation (BMT) or reduced-intensity condition stem cell transplantation has shown promise as effective salvage therapy.^{[64, 65, 66]} A retrospective review of 87 instances of hematopoietic stem cell transplant (HSCT) for LCH provides cautious optimism about the benefits of this procedure.^[67] Specifically, the authors note that survival after HSCT has improved with time, and almost 75% of children now survive following transplantation, which the authors attribute in part to better supportive care following HSCT. Comparing myeloablative condition regimens with reduced intensity conditioning (RIC) regimens, there appeared to be no differences in transplantation-related mortality, although those undergoing RIC had higher relapse rates. These findings may reflect a selection bias where patients at higher risk were more cautiously treated with RIC regimens. Although a hopeful option for patients refractory to typical chemotherapy, the authors caution that the ideal conditioning regimen remains undefined; timing of such transplantations have also not been rigorously evaluated.^{[67, 68]}

Resistant LCH may also be treated with a combination of cyclosporin A, antithymocyte globulin, and prednisolone if patients do not have a matched donor for BMT.

Thalidomide has also been proposed as an agent for treating refractory/relapsing multisystem disease, but its efficacy appears to be limited to low-risk patients with only skin or bone involvement. Its use also is associated with significant toxicities, including pancytopenia and pulmonary failure.^[69]

Other treatment options

A paucity of clinical trials for the treatment of LCH in adults has lead to the report by Derenzini and colleagues of a monocentric, retrospective study on the use of intense MACOP-B therapy (a common therapeutic regimen in aggressive non-Hodgkin lymphoma) without continued maintenance therapy, in the treatment of adults with LCH.^[46]

In this study, 7 patients were treated with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) weekly for 12 weeks. A retrospective analysis of these patients showed a complete response (defined as no evidence of active disease, plus a regression of signs and symptoms at physical examination and on imaging) in all 7 patients, although 3 patients subsequently had reactivation of their disease. Taken together, the authors conclude that more intense initial therapy may induce a better disease response in adults than alternative regimens that induce partial response to induction chemotherapy followed by a maintenance regimen.^[46] However, these results require more formal evaluation.

Other potential treatments include monoclonal antibody targeting with indium–labeled anti-CD1a, cytokine inhibitors, alemtuzumab (anti-CD52), low-dose oral cyclophosphamide, and all-trans retinoic acid.^{[70, 71, 72]} Imatinib has been proposed as a potential therapy for LCH, owing to its ability to inhibit signaling through the platelet-derived growth factor (PDGF), macrophage-colony stimulating factor (MCSF), and c-kit receptors, which are present on the surface of histiocytes. However, clinical application of this therapy has shown mixed efficacy.^{[73, 74]} Finally, the discovery of oncogenic BRAF V600E mutation in more than half of LCH specimens^[75] suggests that B-RAF inhibitors such as vemurafenib could be applied to treatment of those cases shown to bear that mutation.

Vemurafenib was approved for Erdheim-Chester disease (ECD) with BRAF V600 mutation in November 2017. ECD is also known as polyostotic sclerosing histiocytosis. Early case reports describing use of vemurafenib to treat patients with multisystemic and refractory ECD carrying the BRAF V600E mutation showed positive results. Two of the patients also had skin or lymph node LCH involvement. In all three patients, vemurafenib treatment led to clinical and biologic improvement, which was maintained after 4 months of follow-up (although persistent disease activity was still observed).^[76] A phase 2 VE-Basket study (n=22) confirmed use of vemurafenib for patients who have ECD with the BRAF V600 mutation. Results from a basket study in 2015 showed a response rate of 43% in the cohort with ECD or Langerhans cell histiocytosis.^[77] Final results showed a best overall response rate of 54.5%.^[78]

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Consultations

Consultation with the following specialists may be warranted in patients with Langerhans cell histiocytosis (LCH):

• Referral to an orthopedic surgeon has important diagnostic and management implications when bone lesions are present.
• An otolaryngologist may aid in the treatment of otitis media caused by destruction of the temporal and mastoid bones.
• Consultation with an ophthalmologist is suggested for a vision check and an assessment of the need for decompression in patients with proptosis.
• Consultation with a dentist is indicated if loose teeth result from infiltration of the mandibles.
• Referral to an endocrinologist may help in the design of treatment of the endocrine abnormalities.
• Long-term hearing loss can cause significant morbidity, owing to ear involvement by LCH, as well as to the use of other medications (ie, aminoglycosides) as adjuncts to chemotherapy. It has been proposed that all LCH patients with ear involvement have regular audiometry and CT/MRI of the petrous temporal bones, as well as long-term follow up with an audiologist to monitor for hearing loss.^[47]

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Medication Summary

The goals of pharmacotherapy for Langerhans cell histiocytosis (LCH) are to reduce morbidity and to prevent complications.

• References

Prednisone (Deltasone, Liquid Pred, Meticorten, Orasone, Prednicen-M, Sterapred)

• Dosing, Interactions, etc.

Clinical Context:  Prednisone is also known as deltacortisone and deltadehydrocortisone. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Use the lowest effective dose in elderly patients. Pediatric dosing depends on the condition being treated and the response of the patient; the dose for infants and children should be based on severity and the response of the patient rather than on strict adherence to the dose indicated by age, weight, or body surface area.

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Prednisolone (AK-Pred, Articulose-50, Delta-Cortef, Econopred, Inflamase)

• Dosing, Interactions, etc.

Clinical Context:  Prednisolone is also known as delta hydrocortisone, metacortandralone, prednisolone acetate, and prednisolone sodium phosphate. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability.

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Methylprednisolone (Adlone, A-methaPred, depMedalone, Depoject, Depopred)

• Dosing, Interactions, etc.

Clinical Context:  Methylprednisolone is also known as 6-alpha-methylprednisolone, methylprednisolone acetate, and methylprednisolone sodium succinate. By reversing increased capillary permeability and suppressing PMN activity, it may decrease inflammation.

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Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

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Indomethacin (Indocin)

• Dosing, Interactions, etc.

Clinical Context:  Indomethacin is rapidly absorbed; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation; it inhibits prostaglandin synthesis.

• References

Class Summary

These agents are the most commonly used medications to control mild to moderate pain and to decrease inflammation.

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Mechlorethamine (Mustargen)

• Dosing, Interactions, etc.

Clinical Context:  Mechlorethamine forms interstrand and intrastrand cross-links in DNA, which, in turn, results in miscoding, breakage, and failure of replication, inhibiting cell growth. It is dispensed as either an aqueous solution or an ointment. The contents of a 10-mg vial are rehydrated with 50 mL of tap water. The patient should wear protective plastic gloves while applying the solution. Unused preparation may be stored in refrigerator.

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Vinblastine (Alkaban-AQ, Velban)

• Dosing, Interactions, etc.

Clinical Context:  Vinblastine inhibits microtubule formation, which, in turn, disrupts the formation of a mitotic spindle, causing cell proliferation to arrest at metaphase.

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Etoposide (Toposar, VePesid)

• Dosing, Interactions, etc.

Clinical Context:  Etoposide inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in the late S or early G2 portion of the cell cycle.

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Mercaptopurine (Purinethol)

• Dosing, Interactions, etc.

Clinical Context:  Mercaptopurine is a purine analog that inhibits DNA and RNA synthesis, causing cell proliferation to arrest.

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Methotrexate (Folex, Rheumatrex)

• Dosing, Interactions, etc.

Clinical Context:  Methotrexate is an antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. Adjust the dose gradually to attain a satisfactory response. Refer to individual protocols; it may be administered through various routes.

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2-CdA/Cladribine (Leustatin)

• Dosing, Interactions, etc.

Clinical Context:  2-CdA/Cladribine is a synthetic antineoplastic agent for continuous intravenous infusion. The enzyme deoxycytidine kinase phosphorylates this compound into active 5+-triphosphate derivative, which, in turn, breaks DNA strands and inhibits DNA synthesis. It disrupts cell metabolism, causing death to resting and dividing cells.

• References

Cytarabine (Cytosar-U, Tarabine PFS)

• Dosing, Interactions, etc.

Clinical Context:  Cytarabine is converted intracellularly to the active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. It is cell-cycle S-phase specific. Cytarabine blocks the progression from G1 to the S phase and, in turn, kills cells that undergo DNA synthesis in the S phase of the cell proliferation cycle.

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Vemurafenib (Zelboraf)

• Dosing, Interactions, etc.

Clinical Context:  Vemurafenib is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF-V600. It is indicated for Erdheim-Chester disease (ECD) with BRAF V600 mutation. This is the first FDA-approved treatment for ECD.

• References

Class Summary

These agents inhibit cell growth and proliferation.

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Methoxsalen (8-MOP, Oxsoralen, Oxsoralen Ultra)

• Dosing, Interactions, etc.

Clinical Context:  Methoxsalen inhibits mitosis by binding covalently to pyrimidine bases in DNA when photoactivated by UV-A. Doses are based on lean body weight.

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Class Summary

PUVA has been a successful therapy for some patients. The goal of treatment is to induce remission of skin diseases by repeated and controlled phototoxic reaction. Photoconjugation of psoralens with DNA produces an antiproliferative reaction in the skin, generates programmed cell death (apoptosis), and induces down-regulation of the cutaneous immune system.

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Zoledronate (Zometa)

• Dosing, Interactions, etc.

Clinical Context:  Zoledronate is used to treat multiple myeloma and solid tumor bone metastases. It is also used for hypercalcemia of malignancy. It inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors. The median duration of complete response (maintaining normalized calcium levels) and time to relapse is reported as 32 and 30 days, respectively. Administer daily calcium and vitamin D when used for multiple myeloma or metastatic bone disease.

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Class Summary

These agents inhibit bone resorption by osteoclasts and in turn mitigate associated bone pain.

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