Are You Confident of the Diagnosis?

Langerhans cell histiocytosis (LCH) is a rare multi-organ disease due to accumulation of Langerhans cells in various tissues. The lesional Langerhans cells have been shown to be clonal. However, the neoplastic nature of the disease is not fully proved. It is not a malignant condition by itself.

What to be alert for in the history

LCH is mostly found in children younger than 15 years old. According to the clinical presentation and the various internal organs involved, different names have been used in the past to describe this disease. All these conditions represent a spectrum of presentations of a single entity. There are some intermediate forms. Moreover, some children with self-regressing diseases in early infancy have shown later recurrence of LCH with a more chronic evolution.

The use of the descriptive term Langerhans cell histiocytosis should therefore be preferred to all previously cited names (recommendation of the Histiocyte Society). Patients may now be stratified according to the number of organs involved (single-system LCH or multisystem LCH).

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Multisystem LCH is defined as an involvement of 2 or more organs or organ systems, irrespective of involvement of risk organ.

One should be alert for a history of polyuria and polydipsia, suspect for pituitary involvement leading to diabetes insipidus through post-pituitary or sella turcica infiltration, and anti-diuretic hormone (ADH) insufficiency. One should also be alert for a history of recurrent episodes of otitis media and mastoiditis, suspect for bone involvement around the middle ear.

Characteristic findings on physical examination

The typical presentation consists in diffuse skin disease, predominantly involving the head and neck region, the trunk and the proximal limbs. Monolesional or paucilesional forms have been described and seem to portend a better prognosis (self-regression). There are several forms of LCH:

-Eosinophilic granuloma was used to describe a chronic unifocal LCH classically presenting as a solitary bone lesion in young adults, with no cutaneous involvement.

was characterized by multifocal, chronic involvement and classically presented as the triad of diabetes insipidus, proptosis, and lytic bone lesions. Cutaneous involvement was considered frequent in this form.-Hand-Schuller-Christian disease

-Letterer-Siwe disease was used to describe an acute, sometimes fulminant, disseminated disease, occurring predominantly in children younger than 2 years. Organs involved varied and included the skin, bone marrow, lymph nodes, spleen, liver, and lungs, with cutaneous abnormalities observed in as much as 80% of cases.

-Hashimoto-Pritzker disease, or congenital self-healing reticulohistiocytosis, was initially described in neonates, or during the first months of life, as a cutaneous LCH with self-regression (Figure 1).

Figure 1.

Purpuric papules with scale/crust on the face and the trunk. One of them is necrotic (This child had self-regressive Langerhans cell histiocytosis).’ title=’Figure 1. Purpuric papules with scale/crust on the face and the trunk. One of them is necrotic (This child had self-regressive Langerhans cell histiocytosis).

LCH also occurs in bone, skin, lymph node, lungs, central nervous system, other (eg, thyroid, thymus), spleen, liver, hematopoietic system, lungs.

-Persistent erythematous dermatitis in flexural areas, especially inguinal folds, diaper area, axillary folds, retroauricular region, with scale/crust, mild skin infiltration leading to small coalescing papules, and sometimes a purpuric aspect. The papules can have a yellow to erythematous color.

-The lesion may also involve the trunk, limbs, or any cutaneous surface.

– Characteristic scalp and face involvement (Figure 2: seborrheic dermatitis-like)

Figure 2.

Seborrhoeic-keratosis like presentation on the scalp of an infant.

-Tumoral nodules can be found, sometimes ulcerated or necrotic.

– In early phases of the disease, especially in neonates, a vesicular or pustular aspect can be found, adopting the same distribution (Figure 3).

Figure 3.

Multiple infiltrated erythematous papules with scale/crust on the back of an infant (Langerhans cell histiocytosis)

-Mucosal lesions have rarely been reported (oral, vulvar).

-Acral lesions are possible and may indicate a self-regressive form (Hashimoto-Pritzker disease).

Most of the organs can be involved. The most frequently involved ones are bone (80%), the skin (33%), the pituitary gland (25%). Other organs involved may be the lungs, liver, spleen, bone marrow (15%), lymph nodes (5% to10%), the middle ear, and the extra-pituitary central nervous system (2% to 4%).

Expected results of diagnostic studies

Diagnosis is presumptive in front of typical histopathologic findings on skin biopsy: skin dermal infiltrate of cells with folded or reniform nucleus and eosinophilic cytoplasm, suggestive of Langerhans cells (Figure 4,Figure 5). Additional features are represented by eosinophils, variable admixture of small lymphocytes and histiocytes, multinucleated cells, epidermal ulceration, epidermotropism of Langerhans cells, calcinosis (rare).

Figure 4.

At scanning magnification, one can appreciate a papillary dermis infiltrate of cells with edema (H&E, X100)

Figure 5.

At high power magnification, one can recognize Langerhans cells, with eosinophilic cytoplasm and reniform nucleus. There is exocytosis of Langerhans cells in the epidermis. (H&E, x400)

Diagnosis is designated when dealing with typical histopathologic findings and immunohistochemical expression of two of the following markers: adenosine triphosphatase, S100 protein, alpha-D-mannosidase, or peanut agglutinin. Except for S100 protein, these markers are rarely used nowadays.

Definitive diagnosis requires typical histopathologic findings and at least one of the following criteria: expression of CD1a (immunohistochemistry (Figure 6) or presence of Birbeck granules with electron microscopy. The Birbeck granule is a distinctive ultrastructural intracytoplasmic membranous body that is 33nm wide and 190 to 360nm long, possessing a short, rodlike shape with a dotted line down the midline of the space between the membrane (resembling a zipper) and a terminal expansion in the form of a vesicle, giving a racquet appearance. Nowadays, electron microscopy is hardly ever performed. CD1a expression by cells with a compatible cytology is easily demonstrated on formalin-fixed paraffin embedded tissue.

Figure 6.

Figure 6. The cells strongly express CD1a (immunohistochemical staining, X200).

Another specific marker of the Langerhans cells is CD207, or Langerin. Langerin is a Langerhans-cell restricted protein that induces the formation of Birbeck granules and is constitutively associated with them. Although the expression of CD207 does not yet appear in the diagnostic criteria of the Histiocyte Society. Identification of CD207 via immunohistochemistry may be formally used in the future to diagnose the disease.

Minimal blood/urine tests comprise complete blood cell count, liver function, renal function, inflammation markers (erythrocyte sedimentation rate), urine gravity and osmolality after overnight water deprivation. There is no specific serologic test. No genetic test is required.

Imaging studies should comprise complete skeletal radiograph survey and chest radiography, which are mandatory. Other imaging studies will depend on the clinical and biologic findings. Chest computed tomography (CT) will be performed in case of suspected lung involvement; brain and pituitary magnetic resonance imaging (MRI) in case of neurologic signs or signs of diabetes insipidus; ear CT scan in case of suspected ENT involvement; cholangio-MRI in case of suspected liver involvement.

Whole-body MRI or PET-TDM have not been validated in the workup examinations and, to date, they are not necessary for therapeutic decisions. However, these techniques seem promising, as they can detect involvement of many organs by the disease with a good sensitivity. Their use in the initial evaluation and in the follow-up of LCH patients will surely be further precised in the next few years.

Diagnosis confirmation

To make a precise diagnosis, correlation of clinical features, histopathology and immunohistochemichal studies is essential. Most of all, children must not be treated with chemotherapy without histopathologic confirmation of the diagnosis.

The clinical differential diagnosis of cutaneous LCH includes the following entities:

-Localized or diffuse seborrheic dermatitis (Leiner-Moussous disease): scaly erythematous rash on the seborrheic regions of the face and on the scalp

-Diaper dermatitis: erythematous scaly diaper area often with papulovesicular or bullous lesions, fissures, and erosions

-Atopic dermatitis: Lesions affect the creases, with erythema and exudation. They localize to the cheeks, the forehead and scalp, and the extensors of the lower legs, sparing the diaper area. Lesions are ill-defined, erythematous, scaly, and crusted (eczematous) patches and plaques

-Napkin psoriasis: sharply demarcated red shiny papules and plaques

-Candidiasis: erythema, maceration, fissures, peripheral pustules in the skin folds

-Scabies: characteristic distribution, burrows, erythematous papules and vesicles, nodules

-Acrodermatitis enteropathica: triad hair loss; diarrhea; erythematous, dry, and scaly patches distributed in aperiorificial and acral pattern

-Wiskott-Aldrich syndrome: recurrent bacterial sinopulmonary infections, eczema (atopic-like dermatitis), and a bleeding diathesis caused by thrombocytopenia and platelet dysfunction

-Perinatal herpes simplex infection, perinatal varicella, congenital candidiasis (vesiculo-pustular diffuse rash with fever in neonate)

-Acropustulosis of infancy: recurrent, self-limited, pruritic, vesicopustular eruption of the palms and the soles occurring in young children during the first 2 to 3 years of life

-Erythema toxicum neonatorum: rapidly resolving follicularly-based erythematous papulopustules present in the first days of life, with eosinophils on Tzanck preparation

-Mastocytoma: usually solitary nodule with a positive Darier sign

-Juvenile xanthogranuloma: solitary or multiple yellow-red papulo-nodules

According to the age of the lesion, the histopathologic aspect of cutaneous LCH may vary and the differential diagnosis includes the following entities: Langerhans cell hyperplasia (may be seen in scabies, insect bites, contact dermatitis); non-Langerhans cell histiocytoses (juvenile xanthogranuloma, Destombes-Rosai-Dorfman disease, Erdheim-Chester disease); leukemia cutis with monocytic differentiation (monocytic acute myeloid leukemia, chronic myelomonocytic leukemia).

Who is at Risk for Developing this Disease?

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

In France, estimated annual incidence is 4.6 cases per million persons per year in children younger than 15 years.

LCH can be found in any race. The prevalence of LCH seems to be higher among whites than in persons of other races, but no definitive comparative epidemiologic data are available.

LCH affects patients from the neonatal period to adulthood. It appears far more common in children younger than 15 years than in adults. Median age at diagnosis in children is 3.5 years. Incidence in infants reaches 15.3 cases per million per year and diminishes with age (2.0 cases per million persons per year in children older than 10 years).

The frequency of LCH is greater in males than in females, with a male-to-female ratio varying between 1.2 and 2.

No LCH risk factor is known for children. “Familial” cases of LCH in siblings have been reported, some of them affecting twins in the neonatal period. However, no clear explanation has been provided regarding these cases (although it raises the question of possible genetic factors or infectious triggers).

Pulmonary LCH is more common during the third and fourth decades of life. Smoking is a risk factor in these forms.

What is the Cause of the Disease?

The pathogenesis of LCH is still unknown. The epidermal Langerhans cell has been presumed to be the cell of origin of the disease. Specifically, lesional Langerhans cells in LCH have been shown to be in an intermediate state between resting and activated cells, expressing CD54, CD58 (activation markers), the receptor to GM-CSF, and CD1a and intracellular major histocompatibility complex II (resting markers). However, other cellular populations have been identified that possess phenotypic characteristics similar to intraepidermal Langerhans cells (ie, Langerin and Birbeck granules).

Other potential cellular origins for LCH now include dermal Langerin plus dendritic cells, lymphoid-tissue resident Langerin plus dendritic cells.

A debate still exists regarding the neoplastic or reactive nature of the disease. Arguments supporting the reactive process are the occurrence of spontaneous remissions, the extensive elaboration of multiple cytokines by the LCH cells and by the T cells in the LCH lesions, and the good survival rate in the patients without organ dysfunction. Furthermore, no genetic abnormalities have been found in LCH via analysis of ploidy, karyotype, single-nucleotide polymorphism arrays, and array-based comparative genomic hybridization.

LCH cells have been shown to be clonal by use of X chromosome-linked DNA probes on unifocal lesions in some cases. However, studies on multifocal diseases did not confirm this finding. Clonality is not sufficient to prove the neoplastic nature of the disease.

The disease seems to be due to accumulation rather than proliferation of the LCH cells. Indeed no difference in the gene expression of proliferation markers exists between epidermal CD207+ control cells and CD207+ cells in lesions of LCH. Local immunomodulation and creation of a permissive immunosurveillance system should be responsible for the local accumulation of LCH cells (semimature Langerhans cells). It has been shown that there is a local expansion of polyclonal regulatory T-cells in the lesions, which may in turn inhibit the immune system (in part via the elaboration of Interleukin-10) and prevent it from effectively clearing the LCH cells and from resolving the lesion.

Interleukin-17A has been involved in the formation of multinucleated giant cells in LCH, but this finding has not been demonstrated to be specific of LCH, nor to be causal of LCH.

E-cadherin expression by LCH cells in the skin may be associated with single-system cutaneous disease. Down-regulation of E-cadherin in LCH cells may be associated with dissemination.

To date, no molecular or immunohistochemical criteria is able to predict self-regression of the lesions in infants with cutaneous LCH.

Systemic Implications and Complications

Many organ systems may be involved by LCH cell infiltration, leading to various organ dysfunction. Baseline clinical and biological evaluations should orientate the specific imaging studies and other tests to consider, according to suspected organ involvement. Complications and sequelae appear in 30% to 50% of patients with LCH. The most common are orthopedic disabilities, hearing impairment, diabetes insipidus, skin scarring, and neuropsychological defects. Less common sequelae include chronic growth retardation, pulmonary dysfunction, liver cirrhosis, loose teeth, proptosis, and secondary malignancies (due to chemotherapeutic treatments).

Pituitary gland: Sella turcica infiltration and pituitary involvement are frequent. They may lead to diabetes insipidus through ADH deficiency. Other hormonal deficiencies may be found, especially growth hormone deficiency.

Work-up for diabetes insipidus with urine gravity and osmolality after overnight water deprivation is mandatory. Additional hormonal studies may be done in case of specific signs or presence of diabetes insipidus.

Hormone deficiencies represent definitive sequelae and require substitutive treatment.

Patients with multisystem disease, craniofacial involvement, long-standing disease, or reactivation may be at increased risk of developing diabetes insipidus.

Central nervous system (CNS): Neurologic involvement may consist in tumoral infiltration or in a neurodegenerative component. Neurologic involvement may produce seizures, vertigo, headache, ataxia, and cognitive defects. Neurologic involvement may be seen with computed tomography (CT) scan or (MRI) of the brain. Magnetic resonance spectroscopy may be valuable in the early detection of the neurodegenerative component.

Middle ear involvement leads to recurring otitis media and to secondary hearing loss. It should be managed by an otolaryngologist for auditory testing and a middle ear CT scan.

Lungs: Chest radiography is mandatory. Chest CT scan and pulmonary function testing may help identify otherwise asymptomatic pulmonary involvement. Lung involvement may induce chest pain, hemoptysis, dyspnea, failure to thrive, cystic changes and pneumothorax. It may rarely lead to respiratory distress and to death. Lung sequelae may combine pneumothorax and chronic pulmonary dysfunction due to fibrosis. In case of single-system lung disease, diagnosis may need to be proved by bronchoalveolar lavage or biopsy of the lung to demonstrate LCH cell infiltration.

Liver involvement may be assessed by biological evaluation of the liver functions and by cholangio-MRI. Long-term liver involvement can evolve to biliary tract involvement and to sclerosing cholangitis, leading to secondary biliary cirrhosis. However, liver cirrhosis is a very infrequent sequela. At the cirrhosis stage, liver sequelae are unresponsive to chemotherapy and may require liver transplantation.

Hematopoietic system: Hematologic involvement leads to anemia, thrombocytopenia and leukopenia. In case of CBC perturbation, a bone marrow aspirate is indicated. Hematologic involvement portends a poorer prognosis and is the main cause of disease-related death.

Bone: Osteolytic lesions usually affect long or flat bones when unifocal (calvaria and femur in children, the ribs in adults). Multifocal LCH can show diffuse osteolytic lesions. The lesions can induce bone pain and can lead to spontaneous fractures. Vertebral collapse with spinal cord compression has been described. Orbital masses can induce proptosis, and infiltration of the mandible induce loose teeth. Skeletal radiograph survey is mandatory. Orthopedic disabilities are among the most common complications of LCH.

Digestive tract: Its infiltration can lead to unexplained diarrhea, failure to thrive and malabsorption. Biopsies can elucidate the diagnosis.

Treatment Options

Treatment options are summarized in the Table I.

Table 1.
Medical Treatment Surgical procedures  Physical Modalities
Expectant observation/abstention of treatment Curettage or excision (bone) Orthopedic modalities (casting, bracing)
Topical corticosteroids Excision (lymph node) Phototherapy (PUVA)
Topical nitrogen mustard Intralesional steroid injection (bone) UVB Excimer laser
Oral steroids (prednisone) + vinblastine +- 6-mercaptopurine Radiation therapy 3-6Gy (inaccessible bone lesions)
Acitretin Smoking cessation
Cladribine (2-chlorodeoxyadenosine/2-Cda) +- cytosine arabinoside (Ara-C) 
Bone marrow transplantation
MACOP-B (adults)  

* Methotrexate, Adriamycin (doxorubicin), Cyclophosphamide, Oncovin (vincristine), Prednisone, Bleomycin

Optimal Therapeutic Approach for this Disease

No consensus exists for the optimal therapy of LCH. Generally, the choice of the therapeutic regimen and of the therapeutic strategy depends on the disease severity. Consultation with a hematologist is prudent at diagnosis.

Disease severity evaluation is based on the stratification between single-system disease and multisystem disease, and on the involvement of risk organs (spleen, liver, hematopoietic system, lungs).


Skin involvement without other organ involvement is relatively frequent. In neonates or infants with limited skin involvement (monolesional, paucilesional forms), therapeutic abstention can be proposed, with close follow-up of spontaneous regression (ie, expectant observation).

Otherwise, localized-to-moderate skin disease is best treated with moderate-to-potent topical steroids (eg, mometasone furoate cream 0.1%, triamcinolone cream 0.1%, fluocinolone ointment 0.025%, or superpotent topical steroids [eg, clobetasol propionate 0.05%]) daily.

In cases severe cutaneous involvement, topical nitrogen mustard (20% solution mechlorethamine) may be used daily. In case of irritation, or after 1 month of treatment, nitrogen mustard applications may be spaced, and limited to twice or thrice a week. True hypersensitivity reactions to nitrogen mustard are rare and may be type I (urticaria) or type IV (contact dermatitis).

Refractory skin-only disease in children may sometimes require the use of chemotherapy with oral prednisone and intravenous vinblastine for 12 months. Chemotherapy may be preferred to phototherapy (PUVA), which is of difficult to use in young children and may be more harmful in terms of sequelae.

In adults, skin-only disease may also be treated with acitretin or thalidomide, which have been reportedly effective in some cases. The reported dosing regimen for acitretin is 25mg once a day, and for thalidomide 50mg once a day.

UVB excimer laser has been used in rare cases to treat localized skin disease. It may be tried in selected cases, when people cannot tolerate more aggressive treatment. I would not recommend its use in the first line of treatment in children.

Solitary bone lesions are treated locally with curettage or excision, by an orthopedic surgeon. Painful bone lesions may require intralesional steroid injection (triamcinolone acetonide). Bisphosphonates can also be used to reverse bone destruction and alleviate the pain of bony lesions. Radiation therapy of bone lesions has been used in the past to treat single bone lesions. It should be avoided whenever possible.

Bony lesions at vital anatomic locations or in inaccessible sites should preferably be treated with vinblastine and prednisone. Multifocal bone lesions are best treated with indomethacin or a short course of systemic oral steroids. Referral to an orthopedic surgeon is mandatory in case of bone lesions. Orthopedic treatments (casting, bracing) may be necessary in active disease or due to sequelae.

Single lymph node infiltration is treated by lymph node resection. Regional or diffuse lymph node involvement requires systemic steroids or steroids + vinblastine.

Most of the time, single-system pulmonary LCH in children requires systemic steroids + vinblastine. Cladribine may also be a promising treatment in this situation. Smoking cessation is an important intervention in case of adult pulmonary LCH.


Systemic chemotherapy is indicated for multisystem disease and in cases of single-system disease not responsive to other treament. Referral to a pediatric oncologist/hematologist is of great help. Children may be included in large clinical trials that are still in process in order to define the best therapeutic regimens.

The Histiocyte Society provides the following recommendations:

High-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 therapy with oral 6-mercaptopurine daily, supplemented with pulses of oral prednisone and intravenous vinblastine, for 12 months of total treatment. The addition of methotrexate 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 for 6 weeks. Patients should then be supplemented with pulses of oral prednisone and intravenous vinblastine for 6 months of total treatment. Treatment of refractory disease is less well documented.

Cladribine (2-Cda) may be used as salvage monotherapy for patients with risk-organ involvement or patients with low-risk LCH refractory to initial therapy with steroids and vinblastine.

The combination of cladribine and Ara-C has shown promise as an effective combination for refractory multisystem LCH, especially for cases with hematopoietic involvement, which portend the poorest prognosis. However, it is associated with considerable bone-marrow toxicity. The French LCH study group recommends the combination of 2-Cda and Ara-C as a second line, and bone-marrow transplantation as a third line, in LCH with hematologic dysfunction.

Bone-marrow transplantation with reduced-intensity conditioning has shown promise as an effective salvage therapy. However, the optimal conditioning regimens and the timing of such transplantation have not been rigorously evaluated. Polychemotherapy with MACOP-B (Methotrexate, Adriamycin (doxorubicin), Cyclophosphamide, Oncovin (vincristine), Prednisone, and Bleomycin) without continued maintenance therapy has been used in small series of adults with LCH.

Patient Management

Explain the history of LCH to the patients and to the parents. They should know this is a chronic condition and that the patient will be followed up for some years. They should know that LCH is not a malignant condition, but rather an accumulation of cells that may involve different organs.

Explain that infiltration of the organs can lead to organ dysfunction that may be reversible or not. The goal of the treatment is therefore to prevent organ dysfunction and to clear the accumulation of cells. The therapy is proposed to reduce morbidity and to prevent complications and sequelae.

Patients and parents should know which organ involvement is at risk, and therefore which one requires intensification of the treatment. They should be especially aware of the poorer prognosis for refractory disease with hematologic dysfunction.

A majority of the patients have single-system disease (57%). Fourteen percent of cases at diagnosis show involvement of an organ at risk. About 60% of LCH patients receive systemic treatment with prednisone and intravenous vinblastine.

Survival is better in children older than 2 years. Mortality is more likely in children below 2 years with rapid evolution of the disease, except for self-regressing cutaneous forms in infancy.

Thorough initial evaluation and close follow-up is mandatory, even for children with self-regressive forms of the infancy type. Indeed, the clinical course of LCH is variable, and relapse in patients with self-regressive forms have been reported up to 5 years after the initial disappearance of the disease.

Cutaneous lesions in the self-regressing forms usually disappear by 3 months. Unifocal bone, lymph node or cutaneous disease has an excellent prognosis. Multifocal single-system disease has a variable prognosis. Multifocal skin disease has a very good prognosis. Pulmonary involvement especially portends a poorer prognosis than patients with unifocal disease, but better than patients with multisystem disease.

Sequelae will not regress, even after complete remission of LCH. The most common are orthopedic disabilities, diabetes insipidus, hearing impairment, skin scarring. Less frequent sequelae include chronic pulmonary dysfunction and liver cirrhosis. Multidisciplinary medical management is often required: consultation with, or referral to, an orthopedic surgeon, an otolaryngologist, ophthalmologist, endocrinologist, or hemato/oncologist may be warranted.

Unusual Clinical Scenarios to Consider in Patient Management

Unusual presentations of LCH are common because of its variable presentations. The diagnosis should be suspected in every child with chronic dermatitis, without obvious diagnosis. Perform skin biopsy if any doubt for LCH.

Think of LCH in children with polyuria and polydipsia. Have a close follow-up of polyuria-polydipsia and of growth retardation in children with a former history of LCH. Relapses frequently involve the sella turcica and the pituitary gland. Think of LCH in children with chronic diarrhea, failure to thrive, and malabsorption. Think of LCH in children with recurrent episodes of otitis media and mastoiditis.

What is the Evidence?

Egeler, RM, van Halteren, AG, Hogendoorn, PC, Laman, JD, Leenen, PJ. “Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell-macrophage lineage”. Immunol Rev. vol. 234. 2010. pp. 213-32. (A nice review of current biological knowledge of LCH cells and their relationship to dendritic cells, and their microenvironment.)

Favara, BE, Feller, AC, Pauli, M. “Contemporary classification of histiocytic disorders. The WHO Committee on Histiocytic/Reticulum cell proliferations. Reclassification Working Group of the Histiocyte Society”. Med Pediatr Oncol. vol. 29. 1997. pp. 157-66 . (The evidence for grouping in one entity [LCH] the diseases formerly separated in 4 groups [Letterer-Siwe, Hand-Schüller-Christian, Hashimoto-Pritzker diseases, and eosinophilic granuloma]. Relationship of LCH with other histiocytic disorders.)

Da Costa, CE, Szuhai, K, van Eijk, R. “No genomic aberrations in Langerhans cell histiocytosis as assessed by diverse molecular technologies”. Genes Chromosomes Cancer. vol. 48. 2009. pp. 239-49. (A well-documented study showing that there is no genomic aberration in LCH. This article strongly supports the reactive nature of the disease.)

Donadieu, J, Egeler, RM, Pritchard, J, Weitzman, S, Egeler, RM. “Langerhans cell histiocytosis: a clinical update”. Histiocytic disorders of children and adults. 2005. pp. 95-129. (An extensive review of the clinical presentations of the disease.)

Battistella, M, Fraitag, S, Hamel Teillac, D, Brousse, N, de Prost, Y, Bodemer, C. “Neonatal and early infantile cutaneous Langerhans cell histiocytosis: comparison of self-regressive and non-self-regressive forms”. Arch Dermatol. vol. 146. 2010. pp. 149-56. (This study of cutaneous LCH in the first months of life shows that there are no definitive criteria permitting to predict self-regression with certainty. All infants with LCH should be evaluated and monitored equally.)

Satter, EK, High, WA. “Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society”. Pediatr Dermatol. vol. 25. 2008. pp. 291-5. (An overview of the current recommendations for evaluation of the disease, prognosis, and monitoring of disease activity.)

Gadner, H, Grois, N, Potschger, U. “Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification”. Blood. vol. 111. 2008. pp. 2556-62. (The study validating the current first-line chemotherapy in multisystem disease: vinblastine and prednisone +/- 6-mercaptopurine.)

Bernard, F, Thomas, C, Bertrand, Y. “Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction”. Eur J Cancer. vol. 41. 2005. pp. 2682-9. (Pilot study of the combination therapy with 2-Cda and Ara-C for refractory LCH with worse prognosis.)

Steiner, M, Matthes-Martin, S, Attarbashi, A. “Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning”. Bone Marrow Transplant. vol. 36. 2005. pp. 215-25. (A study showing that RIC-stem cell transplantation is a feasible procedure, better tolerated than myeloablative stem cell transplantation, in the salvage approach for high-risk LCH.)

Haupt, R, Nanduri, V, Calevo, MG. “Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group”. Pediatr Blood Cancer. vol. 42. 2004. pp. 438-44. (A retrospective overview of the sequelae of LCH in surviving patients.)