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Langerhans cell histiocytosis: update for the pediatricianSheila Wand R. Maarten aDivision of Pediatric Hematology/Oncology, The Hospital for Sick Children, Toronto and University Langerhans cell histiocytosis is the commonest of the histiocytic disorders. Owing to of Toronto, Toronto, Canada and bImmunology,Hematology/Oncology and Bone Marrow Transplant, the relative rarity of the condition, it remains a disease in which the diagnosis is often Leiden University Medical Center, Leiden, delayed or missed and in which many questions remain unanswered, ranging from etiology and pathogenesis to therapy. The management is often frustrating for care- Correspondence to Sheila Weitzman, MB, Division of givers and parents/patients. The purpose of the review is therefore to raise awareness of Hematology/Oncology, The Hospital for Sick Children,555 University Avenue, Toronto, Ontario M5G 1X8, the disease and to highlight the clinical findings that should make the pediatrician or primary care-giver suspect the diagnosis, as well as current thinking regarding Tel: +1 416 813 6910; fax: +1 416 813 5327;e-mail: management of the various and diverse manifestations of this disease.
Recent findings Current Opinion in Pediatrics 2008, 20:23–29 We discuss new and interesting insights into the biology of Langerhans cellhistiocytosis that raise the possibility of future targeted therapy. Important points in thediagnosis, investigation and management of the various forms of the disease are alsodiscussed.
SummaryWe present a review of childhood Langerhans cell histiocytosis, highlighting newinsights into pathogenesis and management of the various forms of this complexdisease.
Keywordsdendritic cell, Langerhans cell histiocytosis, pediatric, review Curr Opin Pediatr 20:23–29ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins hans cells found within nodes in response to a variety of diseases including neoplasms Previously absolute Langerhans cell histiocytosis (LCH), a disorder of anti- criteria for diagnosis depended on finding CD1a by gen-presenting cells, is the commonest disorder of the immunohistochemistry or Birbeck granules by electron mononuclear phagocytic system. Owing to the relative microscopy. Currently, the presence of Birbeck granules rarity of the condition, it remains a disease in which the is assumed by immunohistochemical demonstration of diagnosis is often delayed or missed and in which many langerin (CD207), a mannose-specific lectin whose intra- questions remain unanswered, ranging from etiology and cellular component is found in association with Birbeck granules with 100% concordance Positivity of one orboth of these markers now defines the Langerhans cell The article is not intended as a comprehensive review of LCH, but is intended instead to discuss some recentadvances in the biology of the disease as well as advancesin therapy and to highlight important points for the pediatricians who care for these patients  The histopathology of LCH is that of a granulomatouslesion containing pathologic Langerhans cells as well as LCH is characterized by clonal proliferation and excess normal inflammatory cells such as T cells, eosinophils and accumulation of pathologic Langerhans cells. The dis- macrophages, together with multinucleated giant cells.
ease varies widely in clinical presentation from localized The latter were recently shown to be osteoclast-like and involvement of a single bone to a widely disseminated able to produce cytokines that can cause osteolysis .
Diagnosis of Langerhans cell histiocytosis In LCH, the pathologic LCH cells appear to be in an The diagnosis is clinicopathologic, based on classical arrested state of activation and/or differentiation .
clinical findings and histologic/immunohistochemical LCH cells are prevented from leaving their periphe- criteria, to avoid misdiagnosis of reactive normal Langer- ral tissue sites, where they accumulate and express 1040-8703 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
inflammatory chemokines, resulting in their own recruit- In adults, cigarette smoking is a clear risk factor for ment and retention, as well as that of other inflammatory pulmonary LCH. The exact relationship of this some- cells including T lymphocytes It has long been times polyclonal lung disease to the monoclonal forms of known that erratic and uncontrolled production of the disease remains to be elucidated, particularly in view various cytokines creates a ‘cytokine storm’ The of a Swedish study which raised the possibility of an pattern of cytokine expression favors recruitment of increased risk for the development of lung LCH in adult Langerhans cell progenitors, as well as their maturation survivors of pediatric LCH who smoke .
and rescue from apoptosis, thereby explaining thepathologic accumulation of LCH cells Thecytokines produced directly contribute to the patho- logic sequelae, including fibrosis, bone resorption and LCH can present at any age from the neonate until oldage. It has become increasingly clear that patients present Of recent interest is the role of the multinucleated giant mainly with three different forms of disease. At one end cell (MNGC). These cells are osteoclast-like and able to of the spectrum are patients with single-system disease cause osteonecrosis Furthermore, it has been with a 100% survival with minimal or no therapy. At the demonstrated that normal dendritic cells can fuse to other end are patients, usually very young children, with form MNGCs in the presence of macrophage colony- disseminated life-threatening LCH that can involve any stimulating factor and receptor activator of NF-kB ligand organ, although kidney and gonad are usually spared.
(RANKL) both of which are highly expressed by Between the two extremes are patients whose disease LCH cells Paradoxically, however, the transdiffer- runs a chronic fluctuating course that eventually ‘burns entiation of dendritic cells into MNGCs is inhibited by out’, but often leaves serious residual disabilities See interferon-g, a cytokine found in abundance in LCH for a brief summary of clinical features of lesions produced by LCH cells, T cells and macrophages Investigators, therefore, are seekinga different mechanism for development of the MNGCsthat appear to play an important role in LCH lesions.
Recognition of such a mechanism will allow the devel- opment of more specific targeted therapies for all forms Bone is the commonest single organ in childhood LCH and the majority present with a single bone lesion with anexcellent outcome. The commonest presentation ofLCH in childhood is with a single mass lesion on the Etiology of Langerhans cell histiocytosis skull. All bones may be involved, however, except for the The discovery that all forms of LCH except adult pul- hands and feet. The usual presentation is with swelling monary LCH are monoclonal suggests that this and/or pain that initially may be present only at night may be a neoplastic process with varying biologic beha- LCH is the commonest cause of vertebra plana in vior. Monoclonality is not proof of malignancy, however, children and an associated soft tissue mass may result and a case can be made both for and against this being in significant neurologic impairment In most primarily a malignant disease Recent findings of loss single bone lesions, curettage of the center of the lesion of heterozygosity on chromosomes 1, 4, 6, 7, 9,16, 17 and gives diagnostic tissue and usually starts the healing 22, as well as chromosomal instability and elevated process. Surgical resection is unnecessary and may lead expression of cell-cycle-related proteins or oncogene to long-term deformity. Observation is limited to lesions products, such as p53, H-ras and c-myc, suggesting in ‘nonrisk’ bones, in patients with a pathologic diagnosis disrupted cell-cycle regulation, are more persuasive evi- Controversy exists regarding ‘special site’ bones in the Recent studies of telomerase expression by CD1a cells in anterior part of the skull, face and base of skull. Most LCH lesions as well as the telomere length short- will heal with curettage alone, but those that have a ening in Langerhans cells in all stages of disease , significant soft tissue component extending internally, lend support to this being a neoplastic disorder, although particularly if it involves the dura, should be considered the possibility of an initiating infectious, malignant as risk bones for progression to diabetes insipidus or immune event is still possible An alternative and neurologic disease, and should be candidates for hypothesis is that this is a reactive disease, resulting low-risk chemotherapy (Grois, personal communi- from environmental or other triggers, which lead to cation). Low-dose radiation therapy remains an effec- the aberrant reaction between Langerhans cells and tive modality, but it is usually restricted to involvement of critical organs such as the spinal cord or optic nerve.
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Langerhans cell histiocytosis Weitzman and Egeler Table 1 Summary of clinical features of LCH in children nonsteroidal anti-inflammatory drugsbisphosphonates observationtopical steroidtopical tacrolimusexcision (no mutilating surgery)chemotherapyother prednisone/6-mercaptopurine Æmethotrexate) Â 12 Low risk (two or more organs; no risk organs) a Limited to involvement of critical organs, i.e. spinal cord, optic nerve.
b Vertebra plana without a soft tissue mass can be carefully observed without a biopsy.
c Neonates and young infants with skin-only LCH may progress to ‘risk’ multisystem disease with a much lower survival.
e Although still included in current protocols, lung as the only risk organ will not ¼ ‘risk’ LCH in future trials.
f Duration of therapy is based on the current open randomized trial (LCH-III) and may change depending on the outcome. Other study group protocolsinclude other drugs, including vincristine, cytosine arabinoside and doxorubicin.
For single or multiple lesions, indomethacin, a potent comprising 300 patients from Argentina showed that prostaglandin E2 inhibitor, and other nonsteroidal anti- permanent consequences occurred in 71% of patients inflammatory drugs (NSAIDs), have proven efficacious The use of bisphosphonates is sup-ported by the report of da Costa et al., who demonstrated Important points for the pediatrician regarding bone that the bony destruction is likely mediated by osteo- clast-like giant cells that produce matrix-degradingenzymes, resulting in destructive lesions and bone pain  LCH should be considered in all young patients who The role of NSAIDs and bisphosphonates in pre- present with a skull mass, jaw pain, swelling and/or venting reactivations and late complications is unclear, loose teeth, chronic ear drainage, with dermatitis of as is the long-term effect of bisphosphonates in young the auricular canal, mastoiditis and cholesteatoma or proptosis, swelling and redness of the eyelid.
 The classical radiologic finding is a punched-out lytic Evaluation of response in bone is difficult. [18F]Fluor- lesion in bone, but some LCH lesions can resemble an odeoxyglucose (FDG)-PET, a sensitive technique for aggressive bone sarcoma with destruction of bone and identifying metabolically active LCH, has been shown periosteal elevation This is seen particularly in to detect more lesions than conventional methods at facial or base of skull lesions, but may be seen in diagnosis and reactivation, and FDG avidity correlates with response Availability, expense, irradiation dose  Biopsy to confirm the diagnosis is necessary for all and need for sedation in young children may limit its lesions except those presenting with vertebra plana utility. Reactivations occur at a rate of 3–12% for unifocal without a soft tissue mass, when the risk of biopsy bone, 11–25% for multifocal bone and 50–70% for outweighs the potential benefit. These patients need bone as part of multisystem LCH The greater the careful follow-up to exclude malignancy.
reactivation rate, the higher the incidence of diabetes  Multifocal bone and bone associated with multisystem insipidus and other late complications A recent study LCH are treated for two reasons, to treat pain, but Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
more importantly to try to prevent permanent con- involvementHypothalamic –pituitary axis (HPA) disease is consideredto be a major risk factor for central nervous system (CNS) LCH. Diabetes insipidus occurs in about 24% of patients Skin involvement occurs in 50% of patients with isolated overall and is commonest in patients with multi- ‘skin-only’ disease in about 10% The commonest system LCH Diabetes insipidus may present at presentation is with a ‘seborrhea-like’ eruption, which may diagnosis (6% of 1741 patients in a recent review or it or may not be purpuric, often initially misdiagnosed as may occur later, usually in patients with the chronically ‘cradle-cap’. Other skin manifestations include papules, reactivating form of the disease Anterior pituitary vesicles, crusted plaques, nodules and purpuric nodules deficits may follow diabetes insipidus and include Patients with skin-only LCH may have spontaneous growth hormone deficiency, precocious or delayed regression, regression and reactivation in skin or pro- puberty, thyroid deficiency, amenorrhea, hyperprolacti- gression, particularly in the infant, to disseminated, nemia, morbid obesity sleeping disorders and sometimes fatal disease. Hashimoto–Pritzker disease disorders of thermoregulation . The risk of other (congenital self-healing reticulohistiocytosis) is a skin-only endocrinopathies in diabetes insipidus patients may be LCH associated with spontaneous involution. There are as high as 57% at 10 years after diabetes insipidus onset no reliable pathologic criteria that distinguish congenital Treatment of growth hormone deficiency with self-healing reticulohistiocytosis from skin LCH, and a growth hormone has proven to be safe and effective, recent study failed to show a significant difference in and did not induce reactivations or second malignancies histology or expression of markers such a E-cadherin, Most cases of diabetes insipidus are irreversible at presentation. Nonetheless, the current recommendationis to treat recent-onset diabetes insipidus to try to prevent Important points for the pediatrician are: the other late effects. Optimal therapy, however, isunclear. Owing to the potential for late effects, radiation (1) LCH should be considered whenever seborrheic therapy should be restricted to nonresponsive growing dermatitis or diaper dermatitis fails to respond to masses The pituitary is outside the blood–brain barrier (BBB) and standard LCH chemotherapy as well (2) All young babies with skin-only LCH should be care- as drugs, such as 2-chlorodeoxyadenosine (2-CdA), fully followed as approximately 50% will which cross the BBB will likely treat active HPA- progress to multisystem disease, which may be fatal LCH. Dhall et al. found that eight of 12 patients treated with 2-CdA for CNS mass lesions had a complete (3) In general skin-only LCH has a good prognosis and response, while four had a sustained partial response.
should not be overtreated. Surgical excision should Eleven of 12 remained progression-free. There was, be undertaken for small isolated lesions only and no however, no reversal of neurocognitive dysfunction mutilating surgery is ever necessary.
and/or diabetes insipidus that was already present atthe time of therapy.
Multisystem Langerhans cell histiocytosisFor therapeutic purposes multisystem LCH is divided into two categories based on the risk of mortality from disease. Risk LCH includes all patients with disease in Active CNS LCH, first seen as extra-parenchymal lesions two or more organs including a risk organ, defined until in areas where the BBB is deficient (leptomeninges, recently as involvement of liver, spleen, lung and hema- choroid plexus, pineal gland) may progress to chronic topoietic system. The latter is defined by the presence of neurodegeneration due to demyelination and gliosis from anemia, neutropenia and/or thrombocytopenia, and is not cytokine/chemokine-mediated neural damage or an excluded by the absence of morphologic infiltration of autoimmune reaction to the preceding LCH This devastating end-stage disease is observed in 3–5% of associated with secondary hemophagocytosis – a com- patients with LCH, but may occur in 10% or more of mon finding in young patients who died from disease in a patients with diabetes insipidus. Clinical findings include French study (Donadieu, personal communication).
cerebellar dysfunction, psychomotor retardation and Recently several studies have concluded that, in pediatric neuropsychologic problems with severe disability and patients, lung involvement as the only ‘risk’ organ does even death It is unclear how many asymptomatic not give an increased risk of death and lung will be patients with neurodegeneration seen on MRI scans will removed as a ‘risk’ organ in future Histiocyte Society progress to debilitating symptomatic neurodegeneration.
Brain-stem evoked potentials have proved useful in Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Langerhans cell histiocytosis Weitzman and Egeler detecting subtle abnormalities Brain FDG-PET patients alive in continuous complete remission (median scans may be helpful in defining active as well as burnt- 25 months) following allogeneic SCT The major out lesions There is no known effective therapy for cause of failure was transplant-related mortality .
patients with late progressive CNS disease. Prevention of LCH may be an ideal disease for reduced intensity reactivations and of diabetes insipidus is likely to be very conditioning, as suggested by the survival of nine of important in prevention of late effects.
11 patients in a recent study This concept is thesubject of an open Histiocyte Society study, designed forpatients who fail the 2-CdA/ara-C salvage study.
Permanent consequencesResults of the late effects study of the Histiocyte Society For patients who respond to initial therapy, survival is suggest that, with a minimum of 3 years of follow-up, at very good. Reactivation, if it occurs, usually occurs in least 71% of multisystem and 24% of single-system nonrisk organs such as skin or bone and is rarely fatal; patients have at least one permanent consequence, the however, permanent consequences occur in as many as most commonly reported being diabetes insipidus Other than the CNS permanent consequence discussedabove, orthopedic problems, facial asymmetry, residual One of the major challenges facing investigators is to proptosis, loss of teeth and hearing loss are seen.
design therapy that prevents reactivations and hopefully Second malignancies, particularly acute T lymphoblastic the significant permanent consequences. Review of leukemia, occur in LCH patients with a much 391 multisystem patients registered on LCH-II showed higher than expected frequency Others include that for multifocal bone patients local therapy resulted in solid tumors, lymphoma and myeloid and lymphoid a 52% reactivation rate, compared with 45% with single- drug and 20% with two-drug therapy In addition,retrospective evidence of a significantly decreased inci- Most of the serious permanent consequences occur in dence of diabetes insipidus in the German DAL studies, patients with multisystem disease with lesions involving which gave therapy for 12 months rather than the the facial bones and base of skull, particularly those 6 months utilized in most other studies, suggests that whose disease has a chronically relapsing and remitting prolonged low-toxicity therapy may be optimal for course and particular attention needs to be paid to chronically reactivating disease. The open LCH-III the therapy of these patients. Extensive surgical resec- protocol is, in part, designed to determine whether tions should be avoided, and the use of carcinogenic prolongation of therapy can reduce reactivations in low drugs and radiation therapy should be limited to life- and high-risk multisystem LCH patients.
Late chronic Langerhans cell histiocytosis Late fibrosis, possibly due to the effect of excess inflam- matory cytokines such as transforming growth factor-b Treatment of multisystem LCH is given to improve , may occur in liver or lung. Late chronic liver disease survival and to prevent late sequelae. Patients with presents as sclerosing cholangitis and biliary cirrhosis extensive disease, but without involvement of ‘risk’ progressing to liver failure while in the lungs organs, have an excellent survival with minimal therapy.
progression to pulmonary fibrosis may lead to respiratory For patients with ‘risk’ multisystem LCH, results of the failure Clinically and radiographically, it is difficult large randomized cooperative group trials suggest that to differentiate active LCH from end-stage fibrosis early therapy with relatively nontoxic chemotherapy Organ transplantation is the only proven effective improves survival and may reduce the incidence of late therapy for end-stage lung and liver disease, and the complications All these studies show that a results appear to be durable for most patients, although lack of response to chemotherapy at 6 weeks is the single recurrence of LCH in the transplanted organ has been most important predictor of poor survival Poor responders have a very poor outcome, but recent datafrom the Japanese LCH study group as well as aFrench pilot study using 2-CdA and high-dose cytosine arabinoside (ara-C) suggest that early switch of LCH remains a dilemma for treating physicians. Despite poor responders to intensive salvage regimens improves the relative rarity of the disease, pediatricians need to survival. The majority of patients who fail these intensive maintain awareness of the condition in order to reduce salvage regimens die and hematopoietic stem cell the delay in diagnosis and therapy, and to minimize the transplantation (SCT) should be considered early for this frustration felt by parents/patients. In this review, we group. A review of the literature found 15/27 (56%) have attempted to highlight a few of the major advances Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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