Langerhan's Cell Histiocytosis

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Langerhan's Cell Histiocytosis (also known as Histiocytosis X) is a rare disease. It is not really a cancer, though it may behave like one in some respects. Histiocytes are normal cells found throughout the body, in this disease abnormally large numbers are found. LCH is more common in children but it is often seen in adults too. The disease will be classed as either single-system or multi-system depending on how many of the body's systems are effected.

In a study of 314 people treated for LCH at the Mayo Clinic (Howarth et al, Cancer 1999;85:2278-90) 69% had single-system disease and 31% had multi-system LCH. Approximately half of those treated at Mayo were under 25 years old at diagnosis. Of people with single-system disease the system involved was bone (52%), pulmonary (lung) (40%), skin/mucous membrane (7%) and other sites (1%). Bone involvement was more common in younger patients while pulmonary involvement was mostly seen in those over 15 years old at diagnosis.

Menu: Langerhan's Cell Histiocytosis

Information for Patients and Family

Information for Health Professionals / Researchers

Latest Research Publications

Information Patients and Family (7 links)

 Histiocytosis Association

A global nonprofit organization dedicated to addressing the unique needs of patients and families dealing with the effects of histiocytic disorders while leading the search for a cure. Founded in 1986, now has aproximately 7,000 members.

 Langerhans Cell Histiocytosis Treatment

National Cancer Institute
PDQ summaries are written and frequently updated by editorial boards of experts Further info.


 Langerhans' cell histiocytosis (LCH) in children

Macmillan Cancer Support
Content is developed by a team of information development nurses and content editors, and reviewed by health professionals. Further info.


 Cervical Cancer Screening

Centres for Disease Control and Prevention (CDC)
Information and links about cervical cancer screening.

 Histiocytosis Association of Canada

 Histiocytosis Research Trust

A charity registered in 1991 to promote and fund scientific research into uncovering not only the causes of the histiocytosis diseases, Langerhans' Cell Histiocytosis and Haemophagocytic Lymphohistiocytosis, but also ensuring early diagnosis, effective treatment and a cure.

 LCH in Children

Histiocytosis Association

Information for Health Professionals / Researchers (9 links)

• PubMed search for publications about Langerhans Cell Histiocytosis - Limit search to: [Reviews]

  PubMed Central search for free-access publications about Langerhans Cell Histiocytosis
  MeSH term: Histiocytosis, Langerhans-Cell
  US National Library of Medicine
  PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.

 Histiocyte Society

A nonprofit organization, of over 200 physicians and scientists from around the world committed to improving the lives of patients with histiocytic disorders by conducting clinical and laboratory research into the causes and treatment of this disease.

 Histiocytosis Association

A global nonprofit organization dedicated to addressing the unique needs of patients and families dealing with the effects of histiocytic disorders while leading the search for a cure. Founded in 1986, now has aproximately 7,000 members.

 Langerhans Cell Histiocytosis Treatment

National Cancer Institute
PDQ summaries are written and frequently updated by editorial boards of experts Further info.


 Langerhans' Cell Histiocytosis

Patient UK
PatientUK content is peer reviewed. Content is reviewed by a team led by a Clinical Editor to reflect new or updated guidance and publications. Further info.


 BRAF, a piece of the LCH puzzle

Blood
Commentary on a paper by Badalian-Very, which provides exciting insights into LCH by demonstrating that a subset of cases exhibit somatic mutations in the BRAF proto-oncogene. Free access for personal use only.

 Histiocytosis

Medscape
Referenced article by Cameron Tebb and Max Coppes covering background, presentation, diagnosis, workup, treatment and follow-up.

 Langerhans Cell Histiocytosis

Medscape
Detailed referenced article by Christopher Shea and William James covering background, presentation, diagnosis, workup, treatment, and follow-up.

 Pathologic Diagnosis of the Histiocytic Disorders of Childhood

Histiocyte Society
Referenced article by Ronald Jaffe, MB.BCh which covers Histiocyte Differentiation, Diagnostic Methods and complicating factors. (Doc)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

BACKGROUND: Isolated hypothalamic-pituitary Langerhans cell histiocytosis (HPLCH) is very rare. We investigated the clinicopathological characteristics, endocrine function changes, BRAF(V600E) mutations and treatments of isolated HPLCH.
METHODS: We identified seven patients with isolated HPLCH by reviewing the clinical and pathological files in our hospital from 2007 to 2015. The clinical characteristics of the seven patients were retrospectively reviewed, especially the endocrine function changes. Immunostaining and mutation profiling of BRAF(V600E) were performed.
RESULTS: The seven HPLCH patients included three men and four women, aged 9-47 years. All patients presented with symptoms of central diabetes insipidus (CDI), and four displayed anterior pituitary hypofunction as well. Magnetic resonance imaging showed hypothalamic-pituitary axis involvement in all patients. There was no evidence for the involvement of other organs in all seven patients. Langerhans cell histiocytosis was confirmed by neuroendoscopic procedures, and immunohistochemical staining showed that all cases (7/7) were positive for CD68, CD1a, Langerin, and S-100. The BRAF(V600E) mutation was detected in three of the six cases (3/6). Six patients had follow-up information; all received desmopressin acetate and high-dose corticosteroid therapy, and two patients received radiotherapy.
CONCLUSIONS: Our study indicated that all patients with isolated HPLCH had CDI as the earliest symptom, and more than half of the patients had anterior pituitary deficiencies. The BRAF(V600E) mutation is a common genetic change in HPLCH patients. Treatment of HPLCH patients is difficult, and the progressive loss of endocrine function is irreversible in most cases.

Related: BRAF

Several histiocytic disorders may affect the thoracic cavity. Pulmonary Langerhans cell histiocytosis (LCH) is the histiocytic disorder that most frequently manifests with thoracic involvement in adults and is associated with cigarette smoking. The histiocytic disorders follow variable clinical courses ranging from benign disease to life-threatening aggressive disorders. Although the pathogenesis is not fully understood, it is now apparent that some of these disorders are associated with activating mutations in cell proliferative/regulatory pathways. Management of these rare disorders must be individualized. Pharmacologic treatment may include the use of chemotherapeutic agents. Smoking cessation is imperative in the management of pulmonary LCH.

Related: BRAF Smoking and Smoking Cessation

BACKGROUND: BRAF (V-raf murine sarcoma viral oncogene homolog B1) is a serine-threonine protein kinase involved in cell survival, proliferation, and differentiation. The most common missense mutation of BRAF (mainly V600E) contributes to the incidence of various cancers, including Langerhans cell histiocytosis (LCH). BRAF inhibitors molecularly targeting the V600E mutation have been developed to counteract the effect of the mutation. To ensure the administration of effective pharmacotherapy, it is therefore imperative to develop an effective assay to screen LCH patients for the V600E mutation. However, tumor tissues of LCH typically contain many inflammatory cells which make a correct judgement of the mutation status difficult in the DNA sequence analysis.
RESULTS: In this study, we present a new, highly sensitive analyzing method combining PCR, restriction enzyme digestion, and a sequencing assay using DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue specimens. TspRI is a restriction enzyme that cleaves the sequence encompassing the wild-type BRAF codon 600 into two fragments, which cannot be used as a template for subsequent BRAF PCR amplification. We therefore evaluated the sensitivity of BRAF V600 mutation detection by amplifying the primary PCR product digested with TspRI and sequencing the secondary PCR products. The V600E mutation was detected in FFPE tissue samples from 32 LCH patients; our assay was able to identify mutations in four samples that gave inconclusive results, and ten that were negative, according to standard PCR and sequencing.
CONCLUSIONS: We presented a new and highly sensitive method to detect BRAF V600 mutations. This screening method is expected to play an important role to select the most effective therapies.

Related: BRAF

INTRODUCTION: Erdheim-Chester disease (ECD) is a rare, systemic form of non-Langerhans cell histiocytosis of the juvenile xanthogranuloma family with characteristic bilateral symmetrical long bone osteosclerosis, associated with xanthogranulomatous extra skeletal organ involvement. In ECD, central nervous system (CNS) and orbital lesions are frequent, and more than half of ECD pa tients carry the V600E mutation of the protooncogene BRAF. The synchronous or metachronous development of ECD and Langerhans cell histiocytosis (LCH) in the same patients is rare, and the possible connection between them is still obscure. Cladribine is a purine substrate analogue that is toxic to lymphocytes and monocytes with good hematoencephalic penetration.
CASE REPORT: We presented a 23-year-old man successfully treated with cladribine due to BRAF V600E-mutation-negative ECD with bilateral orbital and CNS involvement ECD developed metachronously, 6 years after chemotherapy for multisystem LCH with complete disease remission and remaining central diabetes insipidus. During ECD treatment, the patient received 5 single-agent chemotherapy courses of cladribine (5 mg/m2 for 5 consecutive days every 4 weeks), with a reduction in dose to 4 mg/m2 in a fifth course, delayed due to severe neutropenia and thoracic dermatomal herpes zoster infection following the fourth course. Radiologic signs of systemic and CNS disease started to resolve 3 months after the end of chemotherapy, and CNS lesions completely resolved within 2 years after the treatment After 12-year follow-up, there was no recurrence or appearance of new systemic or CNS xanthogranulomatous lesions or second malignancies.
CONCLUSION: In accordance with our findings and recommendations provided by other authors, cladribine can be considered an effective alternative treatment for ECD, especially with CNS involvement and BRAF V600E-mutation-negative status, when interferon-alpha as the first-line therapy fails.

Related: Cladribine BRAF

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, smoking-related, interstitial lung disease, and pulmonary hypertension (PH) is associated with mortality. We herein report a case of PLCH complicated by severe PH and respiratory impairment. After developing PH, the patient displayed a cystic pattern on chest high-resolution computed tomography (HRCT). This, in turn, corresponded with the scarring stage of PLCH. However, the patient's PH and respiratory impairment improve dramatically following smoking cessation. PLCH patients with a cystic pattern on chest HRCT may still be able to improve their PH and respiratory impairment when they are able to quit smoking.

Related: Smoking and Smoking Cessation

CONTEXT: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare histiocytic disorder that almost exclusively affects the lungs of smokers. PLCH is characterized by bronchiolocentric nodules and/or cysts in an upper and mid lung distribution with sparing of the costophrenic angles. The diagnosis can be challenging and often requires transbronchial biopsy or surgical lung biopsy. Pulmonary hypertension is a relatively common and sometimes severe complication of PLCH. The pathogenesis of PLCH is still debated. Recently, BRAF V600E mutation and BRAF expression have been identified in some patients with PLCH, suggesting that at least a subset of PLCH has a clonal proliferation. While smoking cessation is the first-line treatment of PLCH, some patients might require additional treatment and eventually transplant. Given that the lesional cells of PLCH express BRAF in some patients, MAPKinase pathway-targeted treatment might be useful for therapy-resistant patients.
OBJECTIVE: To present the more recently recognized clinical and pathologic aspects of PLCH, including pulmonary hypertension in PLCH, pathogenesis, and treatment, as well as the basic diagnostic approach to PLCH.
DATA SOURCES: Authors' own research, and search of literature database (PubMed) and UpToDate.
CONCLUSIONS: Despite the recent progress, more studies are needed to elucidate the biology of PLCH for identification of prognostic factors and appropriate treatment options, especially for therapy-refractory PLCH cases.

Related: BRAF Smoking and Smoking Cessation

Langerhans cell histiocytosis is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate. Langerhans cell histiocytosis has a highly variable clinical presentation, ranging from a single lesion to potentially fatal disseminated disease. The uncertainty as to whether Langerhans cell histiocytosis is a reactive or a neoplastic disease has resulted in a long-standing debate on this question, and the limited understanding of the pathogenesis of the disease has impeded clinical improvement for patients. The current standard of care for multisystem Langerhans cell histiocytosis, empirically derived chemotherapy with vinblastine and prednisone, cures fewer than 50% of patients, and optimal therapies for relapse and neurodegenerative disease remain uncertain. Recent research advances support a model in which Langerhans cell histiocytosis arises due to pathologic activation of the mitogen-activated protein kinase (MAPK) pathway in myeloid precursors. Redefinition of Langerhans cell histiocytosis as a myeloid neoplastic disorder driven by hyperactive ERK supports the potential of chemotherapy with efficacy against immature myeloid cells, as well as mutation-specific targeted therapy.

Related: Signal Transduction Vinblastine

OBJECTIVE: We compared the efficacy and clinical outcomes of vindesine and prednisone (VP) and cyclophosphamide, etoposide, vindesine, and prednisone (CEVP) regimens as first-line treatment for multisystem (MS) or multifocal single system (SS-m) adult Langerhans cell histiocytosis (LCH).
METHOD: Clinical features, treatment response, and survival of adults with Langerhans cell histiocytosis treated at our center from January 2001 to January 2015 were reviewed retrospectively.
RESULTS: Forty-five adult MS or SS-m LCH patients were treated (N=31, CEVP group; N=14, VP group). Both treatment groups had similar gender distributions, patient ages, and extent of disease. The non-active disease rate for both groups was 70.0% and 64.3% (P=0.775), respectively. Median follow-up was 74.9 (range: 2.8-183.6) months and recurrence rates were 71.0% and 78.6% (P=0.593), respectively. The need for second-line therapy was 64.5% and 71.4% (P=0.649), respectively, and mortality rates were 9.7% and 15.4% (P=0.586), respectively. Neutropenia occurred in 48.4% of CEVP-treated patients and 7.1% of VP-treated patients (P=0.008).
CONCLUSIONS: CEVP or VP regimens for the treatment of adult SS-m or MS LCH showed similar efficacies, and both regimens were associated with high disease recurrence and the need for second-line therapy.

Related: Cyclophosphamide Etoposide Vindesine

Isolated pulmonary involvement in pediatric Langerhans cell histiocytosis (LCH) is extremely rare. While the multisystem-LCH course varies from spontaneous remission to rapid deterioration with lethal outcome, single system involvement is generally associated with favorable prognosis. A child with isolated pulmonary LCH had an extremely rapid progression leading to respiratory failure, despite treatment with prednisone and vinblastine. Since lung hyperinflation and cystic degeneration contraindicated conventional mechanical ventilation, extracorporeal membrane oxygenation (ECMO) was chosen for 50 days as a bridge to lung transplantation. The mechanisms involved in disease progression and the usefulness of long-term ECMO are discussed.

Related: Vincristine

Although patients diagnosed as Langerhans cell histiocytosis (LCH) with bone lesion initially respond well to treatment, some may experience relapse or refractory disease. Pamidronate, a potent N-bisphosphonate, has been used in several primary bone diseases, benign bone tumors, and metastatic bone cancers. The mechanism includes an inhibitory effect on osteoclast activity by decreasing development and recruitment of osteoclast progenitors and promoting osteoclast apoptosis. Herein, we introduce a seven-month-old Thai girl who was diagnosed as multiple-relapse LCH with refractory bone lesions and was treated with standard and salvage steroid-based therapies. After receiving two courses of intravenous pamidronate, she had marked clinical and radiographical improvement without any adverse events. She has been in remission for two years after receiving six courses of therapy. This report supports the efficacy ofpamidronate in LCH-related bone lesions, but further studies in large cohort are warranted.

Related: Bisphosphonates Thailand Pamidronate (Aredia)

During a thoracic computed tomography (CT) scan, a 36-year-old male was diagnosed with a solitary oval pulmonary mixed ground-glass nodule in the right upper lobe of the lung. The edge of the nodule was well-defined, and its largest axial size was approximately 1.1 × 0.9 cm(2). This nodule was slightly lobulated, but not obviously speculated. Solid components, micro-cystic lucency shadow, small high-density rings and tiny vascular branches were all visible in the nodule. During hospitalization, a technetium 99 m methylene diphosphonate (Tc-99 m MDP) bone scan was performed, which showed a skeletal foci with abnormal uptake in the left iliac. A pulmonary lobectomy of the right upper lobe of the lung by video-assisted thoracoscopy was performed. In post-operative pathological photomicrographs, proliferative Langerhans' cells, eosinophils and lymphocytes were found. Immunohistochemistry showed that the expression of S-100 protein, CD1a, and CD68 antigen all stained positive. Since Langerhans' cell histiocytosis (LCH) that is also associated with isolated mixed ground-glass nodules is relatively rare, such a multi-systemic LCH case as identified herein, is reported.

Related: Lung Cancer

Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF-V600E in ~50%-60% of cases and MEK and ERK phosphorylation in 100% of examined cases, has changed the definition of LCH to a dendritic cell neoplasm with a strong inflammatory component. Current international LCH trials are focused on further improving the outcome of high-risk multisystem LCH patients, by decreasing the reactivation rate, optimizing early salvage regimens, and preventing late sequelae. Anecdotal responses to vemurafenib, a BRAF-V600E inhibitor, have been reported in a few cases of LCH and Erdheim-Chester disease. However, the development of resistance, as well as the potential risks of cutaneous and pancreatic cancers in patients with BRAF-V600E-mutated melanoma treated with single inhibitors, suggest the need for prospective trials with BRAF inhibitors, alone or in combination with other inhibitors of this pathway, for patients with refractory or multiply-relapsed LCH. The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies.

Related: MAP2K1 BRAF

Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Erdheim-Chester disease (ECD) represent histiocytic disorders with a wide range of clinical manifestations. Until recently, mechanisms of pathogenesis have been speculative and debate has focused on classification of these conditions as reactive versus neoplastic. Genomic studies have been challenged by scarce tissue specimens, as well as heterogeneous nature of the lesions with variable infiltration of pathologic histiocytes. Whole-exome sequencing recently revealed a very low frequency of somatic mutations in LCH, JXG, and ECD compared to other neoplastic disorders. However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD. In ECD, recurrent mutations in the PI3K pathway gene PIK3CA have also been described. The heterogeneous clinical manifestations of these disorders may therefore be the cumulative result of activation of MAPK mutations (along with modifying signals from other pathways) at distinct stages of myeloid differentiation. Implications of this model include redefinition of LCH, JXG, and ECD as a group of clinically diverse myeloid neoplastic disorders with a common mechanism of pathogenesis. This model supports refocusing therapeutic strategies for these diseases on a personalized approach based on specific mutations and the cell(s) of origin.

Related: MAP2K1 BRAF NRAS

Langerhans cell histiocytosis (LCH) can be associated with a variety of malignant neoplasms, the most common being malignant lymphoma, especially Hodgkin's lymphoma (HL). In this report, we describe the fine needle aspiration (FNA) cytologic features of a case with concurrent LCH and HL in a lymph node. A 20-year-old man presented with an enlarged left upper cervical lymph node. FNA smears from the swelling revealed numerous CD1a+ and S-100+ Langerhans-type cells (LCs) along with many eosinophils, neutrophils, and lymphocytes; there were also large atypical cells with enlarged nuclei having prominent nucleoli. The cytodiagnosis was LCH and the possibility of association with or trans-differentiation into a lymphoma was suggested. The histopathological diagnosis of the excised left cervical lymph node was classical HL-nodular sclerosis type (CHL-NS) with LCH. The lacunar type Reed-Sternberg (RS) cells were positive for CD30 and CD15, and the LCs were positive for CD1a and S-100 protein. PET/CT imaging demonstrated hypermetabolic lymph nodes in neck, abdomen, thorax and pelvis as well as pulmonary nodules and a splenic mass. The patient received 13 courses of chemotherapy and two years later, the enhanced CT revealed regressive course of the disease.

Related: Hodgkin's Lymphoma

This page last updated: 9th March 2017
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