Langerhans Cell Histiocytosis Cells Research Articles

Use of the JL1 Epitope, Which Encompasses the Nonglycosylation Site of CD43, as a Marker of Immature/Neoplastic Langerhans Cells

Langerhans cell histiocytosis (LCH) is the collective designation for a group of proliferative disorders of antigen-presenting cells in the epidermis. Over the past several decades, the etiology of LCH has been a controversial issue, particularly with respect to the pathologic process, that is, whether it is a neoplastic or inflammatory process. Recently, it was reported that the JL1 epitope, which encompasses the nonglycosylation site of CD43, is only exposed in the precursor stages of hematopoietic cells or in neoplastic conditions. We sought to investigate the possible utility of the JL1 monoclonal antibody as a diagnostic marker of LCH. In this study, we compared the staining characteristics of antibodies against the JL1 epitope with those of langerin and CD1a, which are widely used for the diagnosis of LCH. We found substantial differences in the staining patterns of these markers. The JL1 epitope could be bound by antibodies in cases of LCH and Langerhans cell (LC) sarcoma. In non-neoplastic lesions, JL1-positive LCs were found only in dermatitis, reflecting the immaturity of LCs in inflamed skin. However, anti-langerin antibodies were able to identify any form of LC, including those in normal skin, dermatitis, dermatopathic lymphadenopathy, and LCH. On the basis of these findings, we propose that the anti-JL1 antibody is a specific marker of immaturity, a feature that is shared in neoplastic LCs, and can be useful in the diagnosis of LCH.

B-RAF Mutant Alleles Associated with Langerhans Cell Histiocytosis, a Granulomatous Pediatric Disease

BackgroundLangerhans cell histiocytosis (LCH) features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or ‘LCH cells’. Badalian-Very et al. recently reported the presence of a canonical V600EB-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients.Methods and ResultsMutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using ‘next generation’ pyrosequencing. In 9 cases the mutation identified was V600EB-RAF. In 2 cases novel polymorphisms were identified. A somatic 600DLATB-RAF insertion mimicked the structural and functional consequences of the V600EB-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The 600DLATB-RAF and V600EB-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%–2% relative mutation abundance. A novel germ line T599AB-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, T599AB-RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation.ConclusionsOur data confirmed presence of the V600EB-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that V600EB-RAF and 600DLATB-RAF mutations are somatic mutants enriched in LCH CD1a+ cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line T599AB-RAF allele.

Recent advances in the understanding of Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a proliferative disease of cells that share phenotypic characteristics with the primary antigen presenting cells of the epidermis. Its clinical manifestations are highly variable, extending from very benign forms to a disseminated, aggressive disease that causes significant mortality. Although many of the fundamental pathogenetic features of LCH have been enigmatic, recent advances have led to a much clearer understanding of the disease. In particular, careful molecular analyses of mouse models and human LCH samples suggest that LCH's cell of origin may not be the epidermal LC itself but a myeloid-derived precursor. Advanced genomic technologies have revealed the presence of activating, somatic BRAF mutations in the majority of patient specimens. Together, these observations have produced a new picture of LCH as a myeloid neoplasm. These advances are likely to have profound implications for the use of targeted therapeutics in LCH.

Multiorgan Histiocytosis After B-Cell Acute Lymphoblastic Leukemia

The association of multiorgan histiocytosis after acute lymphoblastic leukemias is very rare as most cases are localized forms of Langerhans cell histiocytosis (LCH). We report on an 18-year-old man diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) with p16 deletion (9p21). He was treated with induction chemotherapy using the Spanish PETHEMA group protocol and achieved complete remission. Three months after the diagnosis of B-ALL, he developed a severe multiorgan histiocytosis that is clinically suggestive of LCH but lacked typical immunohistochemical features of LCH and indeterminate cell histiocytosis: CD1a was strongly positive, CD68 and S-100 protein were moderately positive, and langerin was negative. The drugs of the first-line treatment recommended for LCH had been part of the chemotherapy of B-ALL that the patient had received. Therefore, we prescribed the second-line treatment for LCH (cytarabine and 2'-chlorodeoxyadenosine), and he achieved partial remission. The patient died during the aplasia induced by the third cycle of chemotherapy from pneumonia. We could not demonstrate the transdifferentiation of tumoral lymphocytes into histiocytes, using p16 deletion (9p21) as a marker, because these cells did not share the mutation. Neither could we study immunoglobulin-H rearrangement as we had exhausted all the tissue samples. In the medical literature, there are a few reported cases of T-cell acute lymphoblastic leukemia followed by disseminated LCH and just 1 case of B-ALL followed by localized LCH affecting the bones. Therefore, our patient may be the first published case of B-ALL followed by histiocytosis, which had 2 singularities: it was multiorgan and the immunohistochemistry was not typical of LCH.

Tyrosine phosphatase SHP-1 is expressed higher in multisystem than in single-system Langerhans cell histiocytosis by immunohistochemistry

Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cell (LC)-like CD1a-positive cell (LCH cell) with unknown causes. LCH consists of two subtypes: single-system LCH (LCH-SS) with favorable prognosis and multisystem LCH (LCH-MS) with poor prognosis. LCH has been indicated as a neoplastic disorder from monoclonal characteristics of LCH cells. This study aimed to investigate an expression of tyrosine phosphatase SHP-1 in LCH, since its expression levels were variously reported in many tumors, overexpression in ovarian cancers (a candidate oncoprotein), and downregulation by methylation in gastric cancers, prostate cancers, malignant lymphomas, and leukemias (a putative tumor suppressor). By immunohistochemistry (IHC), the SHP-1 expression in LCs and LCH cells was compared in LCH (two subtypes: LCH-SS = 21, LCH-MS = 12), dermatopathic lymphadenopathy (DLA) (n = 9) and normal epidermal LCs (n = 3) near LCH lesion. IHC results were analyzed semiquantitatively using a Photoshop software. The mean intensity score (IS) of DLA, LCH-SS, LCH-MS, and LCs were 47, 100, 139, and 167 (in arbitrary unit), respectively. The IS had significant differences among LCH-SS, LCH-MS, and DLA (p < 0.01). SHP-1 is expressed significantly higher in LCH-MS than in LCH-SS. SHP-1 can be a progression marker of LCH. SHP-1 is also useful for differential diagnosis between LCH in lymph nodes and DLA.

Bone Marrow Findings at Diagnosis in Patients with Multisystem Langerhans Cell Histiocytosis

This study was designed to describe the bone marrow features of multisystem Langerhans cell histiocytosis (LCH) at diagnosis in patients with or without hematologic dysfunction. A retrospective review of bone marrow biopsies from patients with multisystem LCH was performed. Cases were diagnosed at the Garrahan Hospital between 1987 and 2004. Routine and immunohistochemistry techniques (hematoxylin-eosin, periodic acid-Schiff, Giemsa, Gomori reticulin, and CD1a, CD68, and CD61) were evaluated. Clinical outcome and laboratory data were obtained from the medical charts. Twenty-two bone marrow biopsies from patients with multisystem LCH were reviewed at onset of disease. Four patients had no hematologic dysfunction and the other 18 patients had monocytopenia (9), bicytopenia (7), or tricytopenia (2). Increased number and dysplasia of megakaryocytes were evident in 22/22 samples and emperipolesis was present in 21/22 (95%). Aggregates of histiocytes and hemophagocytosis were seen in 9/22 samples. Myelofibrosis was found in 16/17 (94%) evaluable samples at diagnosis. No association of myelofibrosis and cytopenias or clinical outcome was found. Positive CD1a confirmed the presence of LCH cells in 3/22 (14%) samples. Hemophagocytosis and poor outcome were significantly more common in patients with bilineage and trilineage cytopenias. Langerhans cell histiocytosis cells were rarely seen in the bone marrow of these patients (14%); increased histiocytes and hemophagocytosis were more commonly found (41%). Hemophagocytosis was associated with severe cytopenias. Bicytopenia and tricytopenia were associated with poor outcome (death). Myelofibrosis, megakaryocytic dysplasia, and emperipolesis were common findings.

Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell–macrophage lineage

In its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from self-resolving or well manageable to severe and even fatal. LCH lesions in skin, bone, and other sites contain high numbers of cells with phenotypic features resembling LCs admixed with macrophages, T cells, eosinophils, and multinucleated giant cells. Here we review current progress in the LCH field based on two central questions: (i) are LCH cells intrinsically aberrant, and (ii) how does the lesion drive pathogenesis? We argue that LCH cells may originate from different sources, including epidermal LCs, tissue Langerin(+) DCs, or mononuclear phagocyte precursors. Current and prospective in vitro and in vivo models are discussed. Finally, we discuss recent insights into plasticity of T-helper cell subsets in light of the lesion microenvironment. LCH continues to provide urgent clinical questions thereby inspiring innovative DC lineage research.

Langerhans cell histiocytosis: malignancy or inflammatory disorder doing a great job of imitating one?

Langerhans cell histiocytosis (LCH) is the unifying designation for a rare proliferative disorder that occurs predominantly in childhood and involves the main antigen-presenting cell of the epidermis. LCH can present in a multitude of ways, from a self-limited rash that resolves spontaneously to a systemic multi-organ disease with a 20% mortality rate. Because some forms behave in a relatively benign manner and are associated with an inflammatory cell infiltrate, it has been proposed that LCH might be a reactive disease. However, its neoplastic nature is suggested by the fact that the proliferating cells in LCH are clonal and overexpress p53. Nonetheless, no recurrent genomic, genetic or epigenetic abnormalities have been identified. Instead, a variety of molecular abnormalities that are consistent with disordered Langerhans cell maturation have been described. A faithful small animal model would aid our understanding of the pathophysiology of LCH but, to date, none exists. Challenges to the creation of a model include the lack of characteristically recurrent genetic abnormalities and the absence of a truly tissue-specific promoter to drive expression of genetic elements solely in Langerhans cells. Still, some of the phenotypic abnormalities in adhesion molecule or chemokine receptor expression might be modeled with sufficient precision to allow the testing of novel therapies.

A case of multisystem Langerhans cell histiocytosis with primary hypothyroidism followed by type 1 diabetes mellitus

We report a case of a 13-year-old female with Langerhans cell histiocytosis (LCH) and primary hypothyroidism followed by type 1 diabetes mellitus (DM), both of which are rare complications. In LCH diagnosis, imaging studies showed an enlargement of the thyroid gland, suggesting the involvement of LCH cells. While the pancreas appeared normal, insulin secretion markedly deteriorated 11 months after cessation of chemotherapy. Even without direct pancreatic involvement, there is a possibility that LCH could induce DM as a part of its long-term complications. In particular, thyroid involvement may be related to the onset of DM.

No genomic aberrations in Langerhans cell histiocytosis as assessed by diverse molecular technologies

The etiology of Langerhans cell histiocytosis (LCH), a disease characterized by uncontrolled proliferation of Langerhans cells, is unknown. Although some believe that LCH is reactive, others support a neoplastic origin. We tested the hypothesis that LCH is neoplastic by investigating potential consistent chromosomal aberrations in LCH cells. We used multiparameter DNA flow cytometry to analyze the DNA ploidy LCH cells in 20 cases, performed karyotype analysis in 31 cases, array-based comparative genomic hybridization (arrayCGH) and single nucleotide polymorphism (SNP) arrays with DNA from flow-sorted CD1a-positive and CD1a-negative cells in 19 cases. Ploidy analysis revealed diploid DNA content in all cases. The karyotype of all patients analyzed was normal, excluding the presence of balanced translocations. ArrayCGH and SNP arrays did not show genome abnormalities. Despite positive TP53 protein immunohistochemical staining, sequencing of exon 5 to 8 of p53 gene showed no alterations in 7 cases. This study strongly suggests that gross chromosomal abnormalities do not cause LCH. Although we cannot exclude cryptic point mutations in as yet unidentified genes, this study of 72 LCH cases shows that LCH may be the result of restricted oligoclonal stimulation rather than unlimited neoplastic proliferation. (c) 2008 Wiley-Liss, Inc.

Clinical and immunohistochemical evaluation of the vulvar Langerhans cell histiocytosis

We present the case of a woman with diabetes insipidus with subsequent genital and multiorgan Langerhans cell histiocytosis (LCH). A monolateral and slightly infiltrated erythematous plaque of the vulva was observed. Hematoxylin and eosin and immunophenotypic studies were performed. The primary antibodies used were monoclonal antibody to S100, CD1a, CD34, HLA-DR, PCNA, CD45Ro, CD40, and langerin. The histology of the infiltrates revealed a granulomatous reaction pattern, with extensive aggregates of histiocyte proliferation. The histiocytes, morphologically characterized by a pale staining of cytoplasm surrounding a grooved reniform nucleus, sometimes contained small distinct nucleoli. Lymphocytes, eosinophils, macrophages, and both plasma cells and giant cells typically infiltrated the lesions. Cells CD1a+ and S100+ infiltrated the epidermic and were dispersed over the infiltrates as well as in clusters, and around the vessels. A considerable number of CD40-expressing cells were restricted to CD1a+ LCH cells. The specimen contained a high percentage of langerin+ cells in both the dermis and the epidermis. The clinical manifestations of LCH affecting the genital area can be diverse, and in most patients take the form of ulcers or erythematous plaques. Histopathologic examination of the lesion evidences a mixture of Langerhans cell histiocytes (CD1a+, S100+, HLADr+, CD207+, CD 40+), lymphocytes (predominantly helper [CD4] CD 45 Ro+), eosinophils, and macrophages. Each of the cell types produces a "cytokine storm." Many of the cytokines favor recruitment of Langerhans cell progenitors and rescue the Langerhans cell histiocytes from apoptosis.

Langerhans cell histiocytosis of mediastinal node

The predominant clinical and radiological features of Langerhans Cell Histiocytosis (LCH) in children are due to osseous involvement. Extra-osseous disease is far less common, occurring in association with bone disease or in isolation. In the present study, LCH was presumptively diagnosed on Ultrasound guided Fine needle aspiration cytology (FNAC) of the mediastinal lymph node in a 18 month-old child. The diagnosis was confirmed by histological examination of the biopsy material.S-100 protein localization in the LCH cells is often positive on immunohistochemistry.

Prominent Langerhans’ cell migration in the arthropod bite reactions simulating Langerhans’ cell histiocytosis

Epidermal Langerhans' cells (LCs) play pivotal roles in cutaneous immune responses. An encounter with antigens or other stimuli causes the mobilization and migration of LCs. Therefore, some dermatoses, which originated from antigenic stimuli or trauma, can show LC migration. Recently, we experienced several cases of anthropod bites that showed marked inflammatory infiltrates with eosinophils and CD1a-positive LCs. It was difficult to differentiate these cases from Langerhans' cell histiocytosis (LCH). The degree and pattern of LC infiltration in the skin of arthropod bite reaction was evaluated. The characteristics of CD1a immunohistochemical expression in the arthropod bite reactions were compared with those of LCH. A few arthropod bite cases (approximately 36%) showed extensive CD1a-positive LCs in the dermis, especially in the perivascular area. In addition, the CD1a expression patterns of LCs in the arthropod bite reactions were dendritic, whereas that of tumor cells in LCH were distinctly membranous and cytoplasmic. Some arthropod bite reactions can show marked CD1a-positive LCs in the dermis, especially in the perivascular area. The dendritic CD1a immunohistochemical staining pattern in arthropod bite reactions is useful in helping to differentiate from LCH.

Expansion of Regulatory T Cells in Patients with Langerhans Cell Histiocytosis

BackgroundLangerhans cell histiocytosis (LCH) is a rare clonal granulomatous disease that affects mainly children. LCH can involve various tissues such as bone, skin, lung, bone marrow, lymph nodes, and the central nervous system, and is frequently responsible for functional sequelae. The pathophysiology of LCH is unclear, but the uncontrolled proliferation of Langerhans cells (LCs) is believed to be the primary event in the formation of granulomas. The present study was designed to further investigate the nature of proliferating cells and the immune mechanisms involved in the LCH granulomas.Methods and FindingsBiopsies (n = 24) and/or blood samples (n = 25) from 40 patients aged 0.25 to 13 y (mean 7.8 y), were studied to identify cells that proliferate in blood and granulomas. We found that the proliferating index of LCs was low (∼1.9%), and we did not observe expansion of a monocyte or dendritic cell compartment in patients. We found that LCH lesions were a site of active inflammation, tissue remodeling, and neo-angiogenesis, and the majority of proliferating cells were endothelial cells, fibroblasts, and polyclonal T lymphocytes. Within granulomas, interleukin 10 was abundant, LCs expressed the TNF receptor family member RANK, and CD4+ CD25high FoxP3high regulatory T cells (T-regs) represented 20% of T cells, and were found in close contact with LCs. FoxP3+ T-regs were also expanded compared to controls, in the blood of LCH patients with active disease, among whom seven out of seven tested exhibited an impaired skin delayed-type hypersensitivity response. In contrast, the number of blood T-regs were normal after remission of LCH.ConclusionsThese findings indicate that LC accumulation in LCH results from survival rather than uncontrolled proliferation, and is associated with the expansion of T-regs. These data suggest that LCs may be involved in the expansion of T-regs in vivo, resulting in the failure of the host immune system to eliminate LCH cells. Thus T-regs could be a therapeutic target in LCH.

Differences in telomerase expression by the CD1a+ cells in Langerhans cell histiocytosis reflect the diverse clinical presentation of the disease

Langerhans cell histiocytosis (LCH) is a disease characterized by an uncontrolled clonal proliferation of Langerhans cells, whose aetiology is still unclear. The clonal nature of LCH could support the hypothesis that it is a neoplastic disease with unlimited growth potential. One requirement for unlimited proliferation is the maintenance of telomere length. In a group of 70 patients, we set out to investigate whether a telomere maintenance mechanism is indeed active in LCH cells. This work showed that LCH cells from all restricted skin LCH lesions (6/6) expressed telomerase as assessed by human telomere reverse transcriptase (hTERT) immunohistochemistry, whereas LCH cells from the majority of the bone lesions analysed did not express hTERT (26/34). Interestingly, in contrast to the solitary bone lesions, LCH cells from lesions of multi-system patients always expressed telomerase (11/11), regardless of the lesional site. In situ telomeric repeat amplification protocol (TRAP) assays performed on different lesional sites showed that this telomerase was active. In addition, the telomere length of LCH cells from a hTERT-positive skin multi-system lesion was long and homogeneous when compared to that in the LCH cells from hTERT-negative bone single-system LCH lesions, which was heterogeneous in length. No evidence for an alternative lengthening of telomeres mechanism was found in hTERT-negative lesions. The difference in telomerase expression and telomere length at the different lesional sites and in biopsies from patients with solitary versus multi-system disease appears to reflect the diverse clinical presentation and course of this disease. The results from this study have important implications for understanding the nature of this disease.

Expression of CD56 antigen in Langerhans cell histiocytosis associated with T-lymphoblastic lymphoma in a same lymph node

Association of T-lymphoblastic lymphoma (LBL) and Langerhans cell histiocytosis (LCH) in the same lymph node is very rare. Herein, we report such two cases with expression of CD56 in Langerhans cells. Immunohistochemically, lymphoblasts were positive for anti-polyclonal CD3 antibody, CD34, CD7, CD99, and terminal deoxynucleotidyl transferase. LCH cells were positive for anti-S100 protein, CD1a, CD4, CD56, and CD68. Although those two populations were separated topographically, many histiocytes intermingled with lymphoblasts in the paracortex and a few lymphoblasts were scattered within the intrasinusoidal sheets of histiocytes. Neither admixed eosinophils nor multinucleated giant cells were observed. The pathogenetic mechanism of CD56 expression in LCH associated with LBL is discussed.

Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis

Langerhans-cell tumours are controversial with regard to the state of differentiation, cause, and whether they represent true neoplastic disease. Langerhans-cell histiocytosis has been associated with malignant disease (especially acute leukaemias),1 but the biological basis for this link is unknown. We report two cases of Langerhans-cell histiocytosis arising in the context of precursor T-lymphoblastic leukaemia/lymphoma. The Langerhans-cell histiocytosis cells and the precursor T lymphoblastic leukaemia/lymphoma cells had identical rearrangements of the gene for T-cell receptor γ, confirming a clonal relation between the two neoplastic diseases.

Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a disease that can involve one or multiple organ systems characterized by an accumulation of CD1a+ Langerhans-like cells as well as several other myeloid cell types. The precise origin and role of one of these populations, the multinucleated giant cell (MGC), in this disease remains unknown. This work shows that in three different lesional tissues, bone, skin, and lymph node, the MGCs expressed the characteristic osteoclast markers, tartrate-resistant acid phosphatase and vitronectin receptor, as well as the enzymes cathepsin K and matrix metalloproteinase-9. Although, in bone lesions, the osteoclast-like MGCs were only CD68+, in the nonostotic sites, they coexpressed CD1a. The presence of osteoclast-like MGCs may be explained by the production of osteoclast-inducing cytokines such as receptor activator of nuclear factor κB ligand and macrophage colony-stimulating factor by both the CD1a+ LCH cells and T cells in these lesions. As osteoclast-derived enzymes play a major role in tissue destruction, the osteoclast-like nature of MGCs in all LCH lesions makes them a potential target for the treatment of this disease.

The Role of Vascular Endothelial Growth Factor in Langerhans Cell Histiocytosis

In angiogenesis, new blood vessels are generated from pre-existing ones. It plays a major role in tumor growth and metastasis. The main pro-angiogenic factor is the vascular endothelial growth factor (VEGF). VEGF displays high specificity for vascular endothelial cells and also elicits a pronounced angiogenic response in a variety of in vivo models. VEGF withdrawal has been shown to result in regression of vasculature in tumors. The pathogenic and the angiogenic processes of Langerhans cell histiocytosis (LCH) are not yet clear. The purpose of this study was to investigate the extent of the angiogenic response in LCH tumors. The authors examined tissue sections from LCH patients with single lesion (5 patients) or multisystem disease (5 patients). The preparations were examined by using monoclonal anti-VEGF antibody, CD34, and factor VIII-like antigen. VEGF was expressed in 70% of the cases examined. All the multisystem lesions were positive, as were two of the five single-lesion tumors. LCH cells expressed VEGF. The blood vessel density was significantly higher within the lesion than in normal margins. The findings that VEGF was expressed in LCH cells and that all multisystem lesions were VEGF producers raise the possibility of using anti-angiogenic drugs to treat these patients. Further studies to explore the role of angiogenesis in LCH are warranted.

Langerhans cell histiocytosis in adults: more questions than answers?

Langerhans cell histiocytosis (LCH) may affect patients of any age but in adults the features of this disease are still poorly defined. Most reports are based on single-specialty experience and there are only a few describing relatively large series of patients. Although child and adult patients share several features of the disease, and may either have localised or disseminated disease, the proportion of cases with lung involvement is much higher in adults and is partly explained by cigarette smoking. Persisting uncertainty about the pathogenesis of LCH has certainly limited current treatment alternatives. In particular, no clinical trial has been conducted in adults so far and most information derives from description of one or a few cases, often reported retrospectively. On the basis of the background provided by the data collected in its International Registry, the Histiocyte Society is about to start the first prospective, cooperative adult LCH study, aimed at: (a) establishing a common platform for clinical evaluation; (b) testing in adult patients the efficacy of the best standard chemotherapy regimen for children—a combination of prednisone and vinblastine—developed by the Society's trials; (c) describing the natural history of the disease, the impact of cigarette smoking withdrawal and the efficacy of steroid monotherapy in pulmonary LCH. Research studies, ancillary to this trial, offer unique opportunities of addressing some of the open questions in LCH including: the genetic component of the disease as supported by evidence of familial clustering and chromosomal instability, the issue of ‘LCH cells’ clonality, the relation between pulmonary disease, cigarette smoking, and immune system polymorphisms that might increase individual susceptibility to LCH. A concerted joint effort between paediatricians and adult specialists could be the key to the development of insights into LCH in all age groups affected by this distressing and often debilitating condition.