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.

JournalsIn 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.

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Information for Health Professionals / Researchers (9 links)

Latest Research Publications

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

Schönfeld N, Dirks K, Costabel U, et al.
A prospective clinical multicentre study on adult pulmonary Langerhans' cell histiocytosis.
Sarcoidosis Vasc Diffuse Lung Dis. 2012; 29(2):132-8 [PubMed]
BACKGROUND: To date the clinical picture of pulmonary Langerhans' cell histiocytosis has been described only in retrospective reports. For a better understanding, the German Scientific Study Group on the Treatment of Lung Disease (WATL) conducted an open, prospective, clinical observation study.
METHODS: During the period between 1994 and 2002 77 patients (40 men and 37 women) were recruited. The median observation period was 38.2 (3.2-86.7) months.
RESULTS: At the initial examination 50 patients were active smokers, 26 ex-smokers and 1 had never smoked. 36% of the patients showed reduced vital capacity, 28% signs of airways obstruction. On chest radiography, 74% of the patients who stopped smoking (24/50) showed regression, while 13% remained unchanged and 13% revealed progression. In the group that continued to smoke (25/50) chest radiography showed regression in 58% of cases, no change in 25% and progression in 17%. The difference was not significant, which was also true for lung function values. 3 patients died within the observation period.
CONCLUSION: The data underline the key role of smoking as the sole known risk factor. A significant effect of smoking cessation on the course could not be confirmed. The overall prognosis was good in this series as compared to previous reports.


Heaney ML
Saving orphans: BRAF targeting of histiocytosis.
Blood. 2013; 121(9):1487-8 [PubMed]
In this issue of Blood, Haroche and colleagues report significant therapeutic activity of the BRAF inhibitor, vemurafenib, in 3 patients with rare histiocytic conditions, Erdheim-Chester disease and Langerhans cell histiocytosis.


Ryan PL, Piper KM, Hughes FJ
Langerhans cell histiocytosis: a diagnostic dilemma.
Dent Update. 2012; 39(10):716-8, 720 [PubMed]
Langerhans cell histiocytosis (LCH) is a rare clonal neoplastic disorder of unknown aetiology which can present with a diverse range of clinical presentations. It encompasses a diverse number of idiopathic conditions which can involve multiple body systems and is characterized by bone marrow-derived Langerhans cell proliferation. The disease can affect multiple body systems and lesions can be solitary or widespread. We present a case of a multifocal eosinophilic granuloma (LCH) in a young adult female with clinical signs and symptoms similar to aggressive periodontitis. Clinical Relevance: Langerhans cell histiocytosis is a rare disease which can have a similar clinical presentation to aggressive periodontitis.


Murakami I, Morimoto A, Oka T, et al.
IL-17A receptor expression differs between subclasses of Langerhans cell histiocytosis, which might settle the IL-17A controversy.
Virchows Arch. 2013; 462(2):219-28 [PubMed]
Langerhans cell histiocytosis (LCH) is a lymphoproliferative disorder consisting of abnormal Langerhans cell-like cells and other lymphoid cells. LCH presents as either a multisystem LCH (LCH-MS) or a single-system LCH (LCH-SS). Currently, neither the pathogeneses nor the factors that define these disease subclasses have been elucidated. The interleukin (IL)-17A autocrine LCH model and IL-17A-targeted therapies have been proposed and have engendered much controversy. Those authors showed high serum IL-17A levels in LCH and argued that serum IL-17A-dependent fusion activities in vitro, rather than serum IL-17A levels, correlated with LCH severity (i.e. the IL-17A paradox). In contrast, others could not confirm the IL-17A autocrine model. So began the controversy on IL-17A, which still continues. We approached the IL-17A controversy and the IL-17A paradox from a new perspective in considering the expression levels of IL-17A receptor (IL-17RA). We detected higher levels of IL-17RA protein expression in LCH-MS (n = 10) as compared to LCH-SS (n = 9) (P = 0.041) by immunofluorescence. We reconfirmed these data by re-analyzing GSE16395 mRNA data. We found that serum levels of IL-17A were higher in LCH (n = 38) as compared to controls (n = 20) (P = 0.005) with no significant difference between LCH subclasses. We propose an IL-17A endocrine model and stress that changes in IL-17RA expression levels are important for defining LCH subclasses. We hypothesize that these IL-17RA data could clarify the IL-17A controversy and the IL-17A paradox. As a potential treatment of LCH-MS, we indicate the possibility of an IL-17RA-targeted therapy.


Haroche J, Cohen-Aubart F, Emile JF, et al.
Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.
Blood. 2013; 121(9):1495-500 [PubMed]
Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography [PET], computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.


Haupt R, Minkov M, Astigarraga I, et al.
Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years.
Pediatr Blood Cancer. 2013; 60(2):175-84 [PubMed]
These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work-up, and treatment and long-term follow-up of LCH patients are presented.


Topal AA, Malkani RH, Bhat G, Vishnani RT
Recalcitrant pruritus as primary manifestation of synchronous Hodgkins lymphoma and Langerhans cell histiocytosis.
Acta Medica (Hradec Kralove). 2012; 55(2):104-6 [PubMed]
We present a 73 year old female with intractable pruritus and nonspecific cutaneous rash for a period of 9 months. She had recieved symptomatic therapy with no improvement. A complete examination revealed axillary and abdominal lymphadenopathy. A biopsy confirmed the diagnosis of Hodgkins lymphoma with Langerhans cell histiocytosis. She received 5 cycles of chemotherapy with resolution of pruritus and reduction in axillary and abdominal lymphadenopathy. The patient presented 6 months later with relapse and succumbed to the illness. Simultaneous occurrence of Langerhans cell histiocytosis and Hodgkins lymphoma may lead to misdiagnosis. The awareness of such an association is important to make an accurate diagnosis and guide appropriate therapy.


Hutter C, Kauer M, Simonitsch-Klupp I, et al.
Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells.
Blood. 2012; 120(26):5199-208 [PubMed]
Langerhans cell histiocytosis (LCH) is an enigmatic disease defined by the accumulation of Langerhans cell-like dendritic cells (DCs). In the present study, we demonstrate that LCH cells exhibit a unique transcription profile that separates them not only from plasmacytoid and myeloid DCs, but also from epidermal Langerhans cells, indicating a distinct DC entity. Molecular analysis revealed that isolated and tissue-bound LCH cells selectively express the Notch ligand Jagged 2 (JAG2) and are the only DCs that express both Notch ligand and its receptor. We further show that JAG2 signaling induces key LCH-cell markers in monocyte-derived DCs, suggesting a functional role of Notch signaling in LCH ontogenesis. JAG2 also induced matrix-metalloproteinases 1 and 12, which are highly expressed in LCH and may account for tissue destruction in LCH lesions. This induction was selective for DCs and was not recapitulated in monocytes. The results of the present study suggest that JAG2-mediated Notch activation confers phenotypic and functional aspects of LCH to DCs; therefore, interference with Notch signaling may be an attractive strategy to combat this disease.


Llamas-Velasco M, Cannata J, Dominguez I, et al.
Coexistence of Langerhans cell histiocytosis, Rosai-Dorfman disease and splenic lymphoma with fatal outcome after rapid development of histiocytic sarcoma of the liver.
J Cutan Pathol. 2012; 39(12):1125-30 [PubMed]
The coexistence of skin-limited Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD) is an exceptional finding. The association of lymphomas and histiocytosis is also infrequent. We report the case of a 68-year-old man which presented an exceptional association of cutaneous LCH and RDD and splenic marginal zone lymphoma. He was stable for few years. Suddenly, the patient was admitted into Hematology Department with a remarkable enlargement of spleen and liver without enlargement of lymphadenopathies or skin lesions flare. He died 24 h later despite treatment with systemic chemotherapy combined with prednisone. Pre-mortem biopsy showed infiltration with histiocytic sarcoma. We think that a transdifferentiation phenomenon could explain our case, although we could not show a clonal relationship between the cutaneous and the liver diseases. We also want to pay attention to the fact that a fast transformation to a more aggressive disease can occur long time after the presentation of the first lesion, a problem that stresses the importance of performing a close and permanent follow-up of these patients.


Yuasa M, Fujiwara S, Oh I, et al.
Rapidly progressing fatal adult multi-organ Langerhans cell histiocytosis complicated with fatty liver disease.
J Clin Exp Hematop. 2012; 52(2):121-6 [PubMed]
Langerhans cell histiocytosis (LCH) is a clonal neoplasm that shows diverse clinical manifestations and courses of disease progression. The etiology and pathophysiology of LCH remain uncertain. We describe the clinical course of a 23-year-old Japanese woman with multi-system LCH, who showed rapid progression after steroid reduction and developed multi-organ failure. Liver biopsy showed LCH infiltration with fatty degeneration. She was treated with cytarabine, vincristine, and prednisolone according to the Japan LCH study group 02 protocol, without any clinical improvement. Low expression of Ki67 and bcl-2 failed to explain the rapid clinical course. Panhypopituitarism and hypothalamic dysfunction may have caused nonalcoholic fatty liver disease and liver failure. This case indicates that some multi-system LCH patients with hypopituitarism and hypothalamic dysfunction show very rapid progression and are difficult to treat.


Soares EC, Quidute AR, Costa FW, et al.
Monostotic Langerhans' cell histiocytosis in a child with central diabetes insipidus.
J Clin Pediatr Dent. 2012; 36(4):377-81 [PubMed]
Langerhans'cell histiocytosis (LCH) comprises a rare group of reticuloendothelial system disorders that can produce focal or systemic manifestations. Diabetes insipidus is considered to be an important indicator of serious underlying diseases in children, including LCH. We report the case of a young patient with monostotic LCH confined to the mandibular ramus, who was diagnosed with the disease after presenting symptoms of central diabetes insipidus and was satisfactorily treated with multi-agent chemotherapy. Additionally, we discuss the clinical, radiographic, histological and immunohistochemical findings, as well as the multidisciplinary approach of this important disease, which should receive attention by dental practitioners, especially when it occurs in children.


Tajik P, Nazari S, Javaherizadeh H
Langerhans cell histiocytosis with thyroid involvement in a 3 year-old child - a case report.
Pol Przegl Chir. 2012; 84(8):411-4 [PubMed]
Langerhans cell histiocytosis (LCH), a monoclonal disease of histiocytes, may involve several organ systems but rarely primarily involves the thyroid gland. This report presents an extremely rare case of LCH of the thyroid in a 3-year-old boy who presented with a neck mass for several weeks. LCH of the thyroid should be considered in the differential diagnosis of a child with a thyroid mass. Pulmonary examination should be done in these patients.


Strehl JD, Stachel KD, Hartmann A, Agaimy A
Juvenile xanthogranuloma developing after treatment of Langerhans cell histiocytosis: case report and literature review.
Int J Clin Exp Pathol. 2012; 5(7):720-5 [PubMed] Free Access to Full Article
The synchronous or metachronous development of Langerhans cell histiocytosis and non-Langerhans cell histiocytosis in the same patient is rare. To date, only seven cases of xanthogranulomas developing in young patients with a history of Langerhans cell histiocytosis and systemic therapy have been reported in the literature. As of yet, the pathogenesis and the clinical significance of this phenomenon are unclear. We report the case of a 3 year old boy who developed juvenile Xanthogranulomas on the forehead and right upper eye lid 1.5 years after systemic therapy for monosystemic Langerhans cell histiocytosis of the bone and complete disease remission.


Alexandrescu S, Tatevian N, Czerniak BA, et al.
Morphoproteomics provides support for TGF-β pathway signaling in the osteoclastogenesis and immune dysregulation of osteolytic Langerhans cell histiocytosis.
Int J Clin Exp Pathol. 2012; 5(6):503-11 [PubMed] Free Access to Full Article
Langerhans cell histiocytosis (LCH) has a challenging and still unclear pathogenesis. A body of literature points to impaired maturation of the lesional dendritic cells, and to immune dysregulation in the form of increased FoxP3 cells. Various cytokine abnormalities such as expression of transforming growth factor (TGF)-β have been reported, as well as abnormalities in lipid content in LCH cells. Morphoproteomic techniques were applied to identify the signal transduction pathways that could influence histogenesis and immune regulation in osteolytic LCH. Five pediatric cases of osteolytic LCH were examined, using antibodies against CD1a, S100, CD68, CD8, FoxP3, phosphorylated (p)-STAT3 (Tyr705), protein kinase C (PKC)-α, phospholipase (PL)D1, fatty acid synthase (FASN), and zinc finger protein, Gli2. Positive and negative controls were performed. A FoxP3(+)/CD8(+) cell ratio was calculated by counting the FoxP3+ and CD8+ cells in 10 high power fields for each case. There is induction of sonic hedgehog (SHH) mediators consistent with TGF-β signaling pathway through Smad3-dependent activation of Gli2, findings supported by the plasmalemmal and cytoplasmic expression of PKC-α and PLD1, and nuclear expression of Gli2, in lesional cells. The FoxP3+/CD8+ cell ratio is increased, ranging from 1.7-7.94. There is moderate cytoplasmic expression of FASN in most of the Langerhans cells, a finding that supports previously published phospholipid abnormalities in LCH and is consistent with PKC-α/PLD1/TGF-β signaling. With our study, we strongly suggest that the TGF-β cell signaling pathway is a major player in the pathogenesis of LCH, leading to non-canonical induction of nuclear Gli2 expression, thereby contributing to osteoclastogenesis in LCH histiocytes. It could also cause a state of immune frustration in LCH, by inducing the transformation of CD4(+)CD25(-) cells into CD4(+)/FoxP3(+) cells. This coincides with the clinical evidence of a response to thalidomide in patients with osteolytic LCH, given its reported ability to reduce TGF-beta 1 and FoxP3 cells. Such TGF-β signaling in osteoclastogenesis and immune dysregulation, and the presence of FASN in the majority of cells, have additional therapeutic implications for osteolytic LCH.


Idriss MH, Temam F, Woldeyes M
Adult Langerhans cell histiocytosis in a middle aged Ethiopian woman.
Ethiop Med J. 2012; 50(2):193-200 [PubMed]
Langerhans' cell histiocytosis represents a diverse group of rare disorders characterized by proliferation and infiltration of various organs by bone marrow-derived abnormal Langerhans' cells. These diorders exhibit varied patterns of organ involvement, age distribution, prognosis and clinical manifestation. Here in we discuss an adult presentation of the disease in a 43 years old lady and summarize the latest recommendations regarding the classification, pathogenesis, work up and treatment of adult patients with these disorders.


Jeh SK, Jee WH, Hong SJ, et al.
Extracranial skeletal Langerhans cell histiocytosis: MR imaging features according to the radiologic evolutional phases.
Clin Imaging. 2012 Sep-Oct; 36(5):466-71 [PubMed]
PURPOSE: The purpose was to describe the magnetic resonance (MR) findings of extracranial skeletal Langerhans cell histiocytosis according to the radiologic evolutional phases.
MATERIALS AND METHODS: Twenty-two patients with pathologically confirmed extracranial skeletal Langerhans cell histiocytosis were included. The lesions were classified as early, mid, and late phases according to the radiologic evolutional phases. MR images were retrospectively analyzed regarding signal intensity, internal hypointense band, fluid levels, periosteal reaction, adjacent bone marrow and soft tissue abnormal signal, and patterns of contrast enhancement in each phase.
RESULTS: According to the radiologic evolutional phases, there were 4 patients with early phase, 16 with mid phase, and 2 with late phase. All cases showed hypointense to intermediate signal intensity on T1-weighted images. On T2-weighted images, 12 (55%) of the 22 lesions were hyperintense, and 10 (45%) showed intermediate signal. All lesions showed diffusely heterogeneous signal on T2-weighted images. Internal low-signal bands of the lesions were observed in 13 cases (59%). There were two cases with fluid levels in mid phase. Periosteal reaction was observed in 13 (59%) cases. Adjacent bone marrow or soft tissue abnormal signal was observed in 20 cases (91%), respectively. According to early, mid, and late phases, bone marrow and soft tissue abnormal signals were observed in 100%, 100%, and 0% cases, respectively. Soft tissue mass was seen in eight cases (36%). Ten (46%) lesions showed cortical destruction, including one patient with a pathologic fracture. Among 21 patients with contrast infusion, diffuse enhancement was observed in 19 patients (90%), and marginal and septal enhancement was seen in 2 patients (10%).
CONCLUSION: MR imaging was helpful in the diagnosis of extracranial skeletal Langerhans cell histiocytosis, particularly in early and mid phases.


Cantu MA, Lupo PJ, Bilgi M, et al.
Optimal therapy for adults with Langerhans cell histiocytosis bone lesions.
PLoS One. 2012; 7(8):e43257 [PubMed] Free Access to Full Article
BACKGROUND: There is little data on treatment of Langerhans cell histiocytosis (LCH) in adults. Available data is on small numbers of patients with short follow-up times and no comparison of results from different treatment regimens. We analyzed the responses of adult LCH patients with bone lesions to three primary chemotherapy treatments to define the optimal one.
METHODS AND FINDINGS: Fifty-eight adult patients with bone lesions, either as a solitary site or as a component of multisystem disease, were analyzed for disease location and response to surgery, curettage, steroids, radiation, vinblastine/prednisone, 2-Chlorodeoxyadenosine (2-CdA), or cytosine arabinoside (ARA-C). The mean age of patients was 32 years, with equal gender distribution. Twenty-nine patients had 1 lesion; 16, 2 lesions; 5, 3 lesions; and 8 had 4 or more. Most bone lesions were in the skull, spine, or jaw. Chemotherapy, surgery, curettage, or radiation, but not steroids alone, achieved improvement or resolution of lesions in a majority of patients. Comparison of the three chemotherapy regimens revealed 84% of patients treated with vinblastine/prednisone either did not respond or relapsed within a year, whereas 59% of patients treated with 2-CdA and 21% treated with ARA-C failed. Toxicity was worse with the vinblastine/prednisone group as 75% had grade 3-4 neuropathy. Grade 3-4 cytopenias occurred in 37% of the 2-CdA -treated patients and 20% of the ARA-C-treated patients. The major limitation of this study is it is retrospective and not a clinical trial.
CONCLUSIONS: ARA-C is an effective and minimally toxic treatment for LCH bone lesions in adults. In contrast, vinblastine/prednisone results in poor overall responses and excessive toxicity.


Badalian-Very G, Vergilio JA, Fleming M, Rollins BJ
Pathogenesis of Langerhans cell histiocytosis.
Annu Rev Pathol. 2013; 8:1-20 [PubMed]
Langerhans cell histiocytosis (LCH) combines in one nosological category a group of diseases that have widely disparate clinical manifestations but are all characterized by accumulation of proliferating cells with surface markers and ultrastructural features similar to cutaneous Langerhans cells (LCs). Despite this unified nosology, important questions about LCH remain unanswered. First, despite having phenotypic features of LCs, LCH cell gene-expression patterns differ from those in LCs. Although this observation suggests that LCH may arise from an earlier precursor, it is not necessarily inconsistent with the hypothesis that LCs are the cell of origin for LCH. Second, LCH's prominent inflammatory component and occasional benign clinical course suggest that LCH may not be a neoplasm. However, the demonstration that LCH cells are clonal, along with the recent discovery of activating BRAF mutations in LCH cells, strongly suggests that LCH is a neoplastic disease. These new observations point the way to rationally targeted therapies.


Mueller RJ, Siegel A, Seltzer M, McKnight TA
Langerhans cell histiocytosis of the auditory canal detected by 18F-FDG PET/CT.
Clin Nucl Med. 2012; 37(9):908-9 [PubMed]
A 24-year-old woman presented with recurrent bilateral ear infections since childhood and a more recent history of partial hearing loss, discharge, and ear pain. Biopsy of the left external auditory canal revealed Langerhans cell histiocytosis. An F-FDG PET/CT was done to look for additional sites of disease. Increased metabolic activity was seen within both external ear canals.


Sahm F, Capper D, Preusser M, et al.
BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis.
Blood. 2012; 120(12):e28-34 [PubMed]
Langerhans cell histiocytosis (LCH) is a clinically and histologically heterogeneous disorder. Its classification as either reactive inflammatory or neoplastic has been a matter of debate. However, the recent finding of frequent BRAFV600E mutations in LCH argues for the latter. The exact cell type that harbors the mutation and is responsible for proliferation remains to be identified. We here apply a BRAFV600E mutation-specific antibody to detect the BRAF mutant cells in lesions from 89 patients with LCH. We found BRAFV600E mutations in 34 of 89 (38%) lesions. In lesions with the BRAFV600E mutation, the majority of cells coexpressing S-100 and CD1a harbored mutant BRAFV600E protein. These cells also expressed CD14 and CD36, whereas various fractions exhibited CD207. On the other hand, CD80 and CD86 expression was also present on BRAFV600E-positive cells. Thus, cells of variable maturation, exhibiting an immunohistochemical profile compatible either with myeloid cell or with dedifferentiated Langerhans cell antigens, carry the BRAFV600E mutation. In conclusion, we identify and characterize the neoplastic cells in LCH with BRAFV600E mutations by applying a mutation-specific marker and demonstrate feasibility for routine screening.


Hashmi MA, Haque N, Chatterjee A, Guha S
Langerhans cell histiocytosis of long bones: MR imaging and complete follow up study.
J Cancer Res Ther. 2012 Apr-Jun; 8(2):286-8 [PubMed]
Langerhans cell histiocytosis (LCH) is a relatively rare disease affecting the reticuloendothelial system in the pediatric age group. It can affect bones, lung, liver, spleen, lymph nodes and skin. MR imaging is particularly informative in diagnosis and management of bone LCH. In this report, we present the initial and 23 months post-treatment MR images of a femoral LCH lesion in a 12-year-old child to describe the role of MRI in bone LCH.


Akefeldt SO, Finnström O, Gavhed D, Henter JI
Langerhans cell histiocytosis in children born 1982-2005 after in vitro fertilization.
Acta Paediatr. 2012; 101(11):1151-5 [PubMed]
AIM: In a recent Swedish study, comparing data from the Swedish Cancer Register with the Medical Birth Register including data on IVF, an increased risk of Langerhans cell histiocytosis (LCH) was found in children born 1982-2005 after IVF. Here, we aimed to verify the LCH diagnoses and examine whether any special forms of the disease were overrepresented in this population.
METHODS: Medical records for all children with LCH conceived by IVF were acquired and the diagnosis confirmed or discarded. Disease characteristics were compared with data from children diagnosed with LCH 1992-2001 in the Stockholm County.
RESULTS: We verified LCH in seven children born after IVF, all born prior to 2002. These children did not have milder disease forms. The odds ratio (OR) to develop LCH for the whole group born after IVF was 3.2 [95% confidence interval (CI), 1.4-7.3] and for children born before 2002, 5.2 [95% CI, 2.3-11.9], compared with children in Stockholm County 1992-2001.
CONCLUSION: LCH was overrepresented in children born after IVF prior to 2002. Affected children did not have milder disease forms. These findings may be valuable to understand LCH aetiology. Additional studies on a putative correlation between IVF and LCH in the offspring are encouraged.


Ma XL, Shen KL, Wang B
A child with pulmonary and liver Langerhans'-cell histiocytosis.
Chin Med J (Engl). 2012; 125(9):1675-6 [PubMed]
Clinical categories of Langerhans cell histiocytosis (LCH) include single and multi-system disease. Pulmonary LCH is rare, which is an unusual interstitial lung disease with the characteristics of monoclonal proliferation and infiltration of Langerhans' cells to organs. We report our experience of a rare LCH case of multiple organs such as pulmonary and liver as the main clinical manifestation. The patient was treated with chemotherapy which included prednisone, vinblastine, methotrexate and 6-mercaptopurine for 52 weeks and follow up all along. The patient has a favorable clinical outcome.


Harari S, Torre O, Cassandro R, et al.
Bronchoscopic diagnosis of Langerhans cell histiocytosis and lymphangioleiomyomatosis.
Respir Med. 2012; 106(9):1286-92 [PubMed] Article available free on PMC after 01/09/2013
Limited data are available regarding the role of bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBB) as diagnostic tools in pulmonary Langerhans' Cell Histiocytosis (LCH) and lymphangioleiomyomatosis (LAM). The aim of this study was to review our experience regarding the value of these two techniques in the diagnosis of these cystic lung diseases. Records of 452 patients with the presumptive diagnosis of interstitial lung disease were reviewed; 67 had a clinical-radiological diagnosis of either LCH (n = 27) or LAM (n = 40). Of 16 patients with LCH who underwent BAL, four specimens (25%) contained cells which had positive immunoreactivity for CD1a. Of three patients with negative BAL fluid who had TBB, only one had a positive tissue diagnosis. Ten LCH patients were diagnosed by surgical lung biopsy of which five had negative BAL fluid. The remaining 12 patients were diagnosed by clinical and radiologic features. Standard examination of BAL fluid was of no diagnostic value in LAM. TBB was performed in seven patients and was diagnostic in six, not resulting in complications. All 13 patients who underwent surgical lung biopsies had a positive histopathologic diagnosis The remaining 21 patients were diagnosed by clinical and radiologic features. We suggest that BAL may assist in the diagnosis of LCH whereas TBB may be useful in the diagnosis of LAM, thus avoiding the need for surgical biopsy.


Rumy A, Massez A, Fricx C, et al.
Atypical presentation of a Langerhan's cell histiocytosis of the forearm in a child.
JBR-BTR. 2012 Mar-Apr; 95(2):77-9 [PubMed]
We report a case of a 2-year-old child presenting with right forearm pain. Based on imaging analysis, the initial diagnosis was osteomyelitis but the final diagnosis demonstrated by histology was Eosinophilic Granuloma (EG) of the forearm. We detail the rare radiological presentation of such a lesion, the various clinical presentations and the work-up advised in this context.


Caponetti GC, Miranda RN, Althof PA, et al.
Immunohistochemical and molecular cytogenetic evaluation of potential targets for tyrosine kinase inhibitors in Langerhans cell histiocytosis.
Hum Pathol. 2012; 43(12):2223-8 [PubMed]
Langerhans cell histiocytosis is a rare disorder of Langerhans cells, a component of the dendritic cell system, with an unknown pathogenesis. Conventional therapy for patients with Langerhans cell histiocytosis is usually effective, but some patients are refractory to treatment or develop toxicity. Thus, there is a need for innovative therapies. Recently, some cases of Langerhans cell histiocytosis were reported to express platelet-derived growth factor receptors α and β or c-KIT by immunohistochemistry, and some of these patients had a clinical response to imatinib mesylate. Other hematologic disorders with PDGFRα or PDGFRβ gene rearrangements also have responded to imatinib mesylate. The aim of this study was to evaluate immunohistochemical and molecular markers in Langerhans cell histiocytosis that would identify cases for possible treatment with tyrosine kinase inhibitors. We investigated formalin-fixed, paraffin-embedded tissue sections from 14 cases of Langerhans cell histiocytosis. As controls, we included cases of inflammatory dermatitis (n = 5) and dermatopathic lymphadenitis (n = 7). We performed immunohistochemistry for S100, CD1a, c-KIT, and platelet-derived growth factor receptors α and β. Fluorescence in situ hybridization analysis to detect rearrangements of the PDGFRα or PDGFRβ genes was also performed. Four (28.5%) of 14 cases of Langerhans cell histiocytosis were positive for platelet-derived growth factor receptor α, whereas absent/weak expression was seen in 10 cases and all controls. All cases were negative for platelet-derived growth factor receptor β and c-KIT. The fluorescence in situ hybridization studies were also negative in all 8 cases with adequate quality DNA. Our findings suggest that a subset of cases of Langerhans cell histiocytosis may be treated with tyrosine kinase inhibitors due to the expression of platelet-derived growth factor receptor α. Clinical trials that evaluate the use of tyrosine kinase inhibitors in Langerhans cell histiocytosis seem warranted and should evaluate these markers.


Minkov M
Langerhans cell histiocytosis: pragmatic empirism on the road to rational cure.
Expert Opin Pharmacother. 2012; 13(12):1671-3 [PubMed]
Langerhans cell histiocytosis (LCH) is a rare disease characterized by the accumulation of clonal dendritic cells in different organs. Most recent findings (e.g., activating BRAF mutations) favor the hypothesis that LCH may represent a neoplasm with varying behavior, but the ultimate pathogenesis remains to be uncovered. In view of the gaps in the basic understanding of the disease, its clinical management foots on empirical knowledge and is pragmatically oriented. Some of the current guidelines for clinical and radiological evaluation are based on outdated knowledge and therefore appropriately designed prospective studies are urgently needed. Furthermore, there is a need for biological markers, for disease activity and treatment-response assessment. The upcoming prospective clinical trial of the Histiocyte Society, LCH-IV, is expected to address the most burning issues concerning optimal patient management.


Maria Postini A, del Prever AB, Pagano M, et al.
Langerhans cell histiocytosis: 40 years' experience.
J Pediatr Hematol Oncol. 2012; 34(5):353-8 [PubMed]
OBJECTIVES: Our study analyzes 40 years' experience with pediatric Langerhans cell histiocytosis patients.
MATERIALS AND METHODS: Between June 1968 and December 2009, 121 patients (79 males, 42 females; median age 4.13 y) were diagnosed at our center (74% monosystemic disease; 26% multisystemic), treated according to current protocols. We evaluated the response, the survival, and the neuroendocrinological sequelae.
RESULTS: Overall survival (OS) for all patients was 93% at 10 years from diagnosis, event-free survival (EFS) 77%. OS for patients younger than 2 years and older than or equal to 2 years was 82% and 97% (P = 0.003); EFS 48% and 87% (P = 0.001). OS for patients diagnosed before and after April 1, 1991 was 84% and 98% (P = 0.007), EFS 66% and 85% (P = 0.03). OS for monosystemic and multisystemic disease was 100% and 71% (P < 0.001); EFS 88% and 45% (P < 0.001). OS for "risk" patients (involvement of bone marrow, spleen, liver, lungs) and "low-risk" patients was 50% and 94% (P = 0.007), EFS 37% and 54% (P = 0.06). Fourteen patients developed diabetes insipidus, 7 patients growth hormone deficiency, 2 hypothyroidism, and 1 neurodegeneration.
CONCLUSIONS: Our study confirms improvement of pathogenetic knowledge and treatment over the last 20 years. Age at diagnosis older than or equal to 2 years and standardized treatment are associated with improved prognoses. Multisystemic involvement, especially with "risk" organs seem to be correlated to a worse outcome.


Lajolo C, Campisi G, Deli G, et al.
Langerhans's cell histiocytosis in old subjects: two rare case reports and review of the literature.
Gerodontology. 2012; 29(2):e1207-14 [PubMed]
BACKGROUND: Langerhans cell histiocytosis (LCH) is a proliferative disease of histiocyte-like cells that generally affects children; LCH onset is rare in adults; immunohistochemistry is essential to obtain the correct diagnosis, and treatment protocols are controversial.
OBJECTIVE: To describe two new cases of adult onset oral LCH.
CASE REPORTS: Case 1: a 71-year-old woman, complaining of diffuse oral pain, presented with erythematous mucosal lesions; the panoramic radiograph and CT scan showed multiple mandible radiolucent areas. Immunohistochemical assay for S-100, CD1a and langerin test was essential in reaching the correct diagnosis. Case 2: a 77-year-old female patient presented with a non-painful, non-bleeding, slightly elevated erythematous palatal lesion of 6 months duration, together with a genital vulvar lesion of uncertain nature. The pathology confirmed the diagnosis of LCH. Many therapies (etoposid, radiotherapy) could induce only a clinical partial remission; Cladribine induced a complete recovery.
CONCLUSION: The first case was difficult to diagnose: the clinical presentation and course of the disease (LCH) in the elderly are multiple and unpredictable. An immunohistochemistry study is often essential to obtain the correct diagnosis. The second case required several therapeutic interventions: even though some cases regress spontaneously, others require systemic chemotherapy.


Donadieu J, Chalard F, Jeziorski E
Medical management of langerhans cell histiocytosis from diagnosis to treatment.
Expert Opin Pharmacother. 2012; 13(9):1309-22 [PubMed]
INTRODUCTION: Langerhans cell histiocytosis (LCH) is a heterogeneous disease, involving the accumulation of langerhans cells in various organs. The physician's perception of the disease varies considerably depending on their experience, the presentation of the disease or the short-term treatment outcome. As this disease is very rare, only a limited number of large surveys exist in the literature and many aspects of the management of patients remain obscure or controversial. AREAS COVERED: An expert opinion on the diagnosis and medical management of LCH is presented in this paper. The diagnostic procedures, including differential diagnosis, initial clinical workup and criteria for initiating therapy are reviewed, as well as disease evaluation criteria and therapeutic approaches. Controversial issues in the medical management of LCH patients (aged less than 18 years) are also briefly discussed. EXPERT OPINION: Further fundamental and clinical research is still needed in this field. Progress may be expected from collaborations organized at national and international levels, among collaborative groups and expert networks. Collections of tissue and blood samples in biobanks must also be organized. New international protocols will be opened to patient accrual and represent an opportunity to further develop global research.


This page last updated: 22nd May 2013
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