Macrophage Activation and Hemophagocytic Syndrome in Langerhans Cell Histiocytosis: Report of 30 Cases

Macrophage activation and secondary hemophagocytic syndrome are rarely reported in association with Langerhans cell histiocytosis (LCH). The authors reviewed their pathology files for cases of LCH in which evidence of macrophage activation coexisted and report 30 such cases indicating that the association is not that rare and may even be underdiagnosed unless specifically sought. Available clinical data were collected and correlated with pathological findings. Of the 30 cases of LCH with varying degrees of macrophage activation, 29 had multisystem disease. The cases were graded from I to V on the basis of evidence for, and severity of, macrophage activation; cases in category I had evidence of fully developed hemophagocytic syndrome whereas those in category V had limited evidence of macrophage activation. There were seven cases with fully developed hemophagocytic syndrome (category I) and an additional five with hemophagocytosis and some but not all of the features of hemophagocytic syndrome (category II). Most of these 12 cases were young children with high-risk LCH and poor prognosis; 4 are known to have died. Coexisting hemophagocytic syndrome in these cases of LCH may have contributed to their poor prognosis. The association of LCH with macrophage activation, though more than coincidental, is of unknown pathogenesis, but the role of T lymphocytes and cytokines is prominent in both disorders and is presumed to link the two. Received September 25, 2001; accepted October 2, 2001.     

Development of Langerhans cell histiocytosis associated with chronic active Epstein-Barr virus infection

Chronic active Epstein-Barr virus (CAEBV) infection is characterized by a status of lymphoproliferative disease of EBV-infected cells, resulting in chronic or recurrent infectious mononucleosis-like symptoms. CAEBV is always accompanied by life-threatening complications. We report the case of a 2-year-old female patient with CAEBV who subsequently developed Langerhans cell histiocytosis (LCH) presenting with bilateral exophthalmos, bone, and skin involvement. In situ hybridization for EBER revealed EBV-infected B-cells present in lesional tissue implying that interactions between EBV-infected B-cells and lesional Langerhans cells may be associated with the development of LCH.     

Langerhans cell histiocytosis mimicking molluscum contagiosum: A case series

Langerhans cell histiocytosis (LCH) is a disorder characterized by accumulation of Langerhans‐like cells in one or various organs. A correct staging work‐up is essential since there are multiorgan presentations with a poor prognosis. We report three patients with LCH skin lesions mimicking molluscum contagiosum in association with both high and low risk organ involvement. This peculiar cutaneous presentation can be a clue for the diagnosis of LCH, a disease with potentially severe systemic involvement.     

Normal monocyte-derived dendritic cell function in patients with Langerhans-cell-histiocytosis

BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disease, characterized by the lesional accumulation of dendritic Langerhans cells together with T cells and eosinophils. The cause of this disease is unknown. Langerhans cells are bone marrow-derived dendritic cells (DCs), which can develop from CD34(+) hematopoietic progenitor cells as well as from monocytes. PROCEDURE: To test whether LCH patients have a general functional defect present in cells of their DC lineage, we generated immature DCs by culturing monocytes from nine patients with single- or multisystem LCH with GM-CSF and IL-4, and analyzed their phenotype and function before and after an in vitro maturation stimulus. Immature DCs were analyzed for their phenotype and cytokine production, DCs matured in response to TNF-alpha plus PGE(2) were analyzed for their phenotype, their stimulatory capacity in MLR, cell aggregation, and activation-induced apoptosis. RESULTS: In summary, no difference was found between both immature as well as mature DCs generated from patients and controls regarding the expression of CD1a, CD80, CD86, MHC class I, and MCH class II antigens. Similarly, no difference was found regarding IL-10, -12, and TNF-alpha production, as well as regarding cell aggregation and apoptosis in response to external stimuli. CONCLUSIONS: The absence of gross functional abnormalities in DCs generated from monocytes from patients with LCH makes the existence of a severe functional defect affecting all cells of the DC lineage in these patients unlikely.     

Recurrent viral associated hemophagocytic syndrome in a child with Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) with subsequent viral-associated hemophagocytic syndrome (VAHS) or secondary hemophagocytic lymphohistiocytosis (HLH) is extremely rare. A 15-month-old girl with disseminated LCH experienced three episodes of VAHS during maintenance therapy. Viral infection, with influenza A, herpes simplex, and adenovirus, respectively, was documented at each episode. She recovered each time after interruption of maintenance therapy. The occurrence of fever and pancytopenia in patients with chemotherapy-treated LCH can be associated with VAHS and not with relapsing LCH.     

Langerhans cell histiocytosis in a premature baby presenting with skin-isolated disease: case report and literature review

Langerhans cell histiocytosis (LCH) in premature babies is extremely rare as is a vesicular skin rash, while gastrointestinal involvement is associated with a poor outcome. We report a case of LCH in a premature baby presented with isolated vesiculo-papulo-macular skin lesions and insidiously developed gastrointestinal symptoms, haematological and severe pulmonary involvement. We also reviewed a few cases of LCH in premature babies in the English language medical literature. LCH in preterm babies appears to be a severe systemic disease, usually lethal in-utero or post delivery. CONCLUSION: Careful observation should be applied to newborns with skin-only Langerhans cell histiocytosis in order to identify in time progression to potentially fatal systemic disease.     

Defective alloantigen-presenting capacity of 'Langerhans cell histiocytosis cells'.

The functional activity of skin cells derived from an infant who died of multisystem Langerhans cell histiocytosis (LCH) was examined. Involved and non-involved skin was obtained at postmortem examination within three hours of death; normal epidermal Langerhans cells and 'LCH cells' were separated by means of dispase digestion. The functional activity of different populations of CD1a positive cells was assessed using the conventional six day allogeneic mixed cell reaction. Compared with Langerhans cells from a healthy control, LCH cells showed minimal functional activity. However, Langerhans cells from non-involved skin showed normal and Langerhans cells overlying involved skin showed augmented functional activity. These findings suggest that LCH is a disease in which abnormal Langerhans cells accumulate and/or proliferate in various tissues but it does not affect the entire Langerhans cell population.     

Thymic Langerhans cell histiocytosis mimicking lymphoma

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal expansion of antigen presenting Langerhans cells. Different clinical features can be seen according to the involved organs and systems. Multisystem disease with organ dysfunction is more common in infants, whereas single system disease is usually observed in older children. The disease can affect any system or organ throughout the body. Thymus is a rarely involvement site reported in LCH and usually is accompanied by skin, bone or lung disease. Here we report a 12-year-old male with thymic involvement by LCH clinically mimicking lymphoma.     

Fetal and neonatal histiocytoses

PURPOSE: The histiocytoses are a group of disorders of the monophagocytic system having a variety of clinical and pathological findings. They occur less often during the perinatal period than later in life. Their biologic behavior, response to therapy, and histologic types are not the same. METHODS: The study consisted of 221 fetuses and neonates collected from the literature and from personal files. RESULTS: Langerhans' cell histiocytosis (LCH), the hemophagocytic lymphohistiocytoses (HLH), and juvenile xanthogranuloma (JXG), in order of rank, were the main histiocytoses occurring in the perinatal period. HLH accounted for the highest mortality (74%) followed by disseminated LCH (52%) and JXG (11%). All neonates with LCH and JXG limited to the skin and/or subcutaneous tissue survived with or without treatment. CONCLUSIONS: This study suggests that there is an increased incidence of spontaneous regression of certain histiocytic lesions in neonates as compared to older individuals. Cutaneous forms JXG and LCH had the highest incidence of regression followed by infection associated HLH.     

Langerhans cell histiocytosis of the sphenoid sinus: a case report

Langerhans cell histiocytosis (LCH), previously known as histiocytosis X, is a rare disorder characterized by clonal proliferation and excess accumulation of pathologic Langerhans cells causing local or systemic effects. Bone is the most common organ involved and a single skull lesion is the most frequent presentation of childhood LCH. However, sphenoid sinus is an uncommon condition of involvement in LCH. Here we report a case of LCH in the sphenoid sinus, which occurred in a seven-year-old girl who presented initially with headache. The girl had suffered from headache for one month before she went to an otorhinolaryngologist one week before. Magnetic resonance imaging (MRI) showed a lesion of inflammatory granuloma. Surgery was performed and the disease was diagnosed pathologically as single-site LCH via hematoxylin-eosin (H&E) and immunohistochemical staining.     

Nail involvement in langerhans cell histiocytosis

Nail involvement, which is distinctly uncommon in Langerhans cell histiocytosis (LCH), is characterized by various features like longitudinal grooving, purpuric striae, hyperkeratosis, subungual pustules, deformity, loss of nail plate, paronychia, onycholysis, and pitting. Here the authors report the case of a child who presented with isolated nail unit changes due to Langerhans cell histiocytosis before the evolution of systemic features. The authors suggest that LCH should be considered in differential diagnoses of nail changes that are resistant to therapy.     

Congenital solid neck mass: a unique presentation of Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) presenting in the neonatal period is very rare. In most cases, a self-limited cutaneous disease is the exclusive manifestation. We report an unusual case of neonatal LCH presenting with a large congenital solid neck mass without skin lesions. LCH should be considered in the differential diagnosis of solid masses in neonates and prompt physicians to search for visceral organ involvement.     

Expression of cell cycle-related gene products in Langerhans cell histiocytosis

BACKGROUND The pathogenesis of Langerhans cell histiocytosis (LCH), a disease characterized by an abnormal accumulation of the dendritic Langerhans cells, is still unknown. Based on the monoclonality of the CD1a+ cell and reports of familial clustering, it is hypothesized that a genetic alteration at a cellular level may be causative. This genetic change may have an effect on the cellular mechanisms controlling proliferation and apoptosis.MATERIALS AND METHODS LCH-lesions were studied for the expression of Ki-67, present in the nucleus of proliferating cells. Furthermore, the expression of cell cycle-related gene products TGF-beta receptor I and II, MDM2, p53, p21, p16, Rb, and Bcl2 were studied. The TGF-betaR genes play a role in tumor suppression, whereas Bcl2 inhibits apoptosis. The remaining genes are part of either the p53-p21 and/or p16-Rb pathways, which induce cell cycle arrest or apoptosis in response to DNA damage.RESULTS In 30 biopsies the diagnosis of LCH could be confirmed on the basis of CD1a positivity (27 bone and 3 skin). All cases showed scattered nuclear-positive staining for the proliferation marker Ki-67. In more than 90% (n >/=27) of these cases, expression of TGFbeta receptor I and II, MDM2, p53, p21, p16, Rb, and Bcl2 was detected in lesional LCH cells. The overexpression was in general heterogeneous, ranging from limited focal staining of scattered cells within the lesion to strong diffuse staining.CONCLUSIONS These findings suggest that the cellular mechanisms that sense and respond to DNA-damage, namely the p53-p21 pathway and the p16-Rb pathway, are activated. The expression of Ki-67 indicates that the cells in LCH are proliferating. The observed overexpression of Bcl2 may play a role in the activation of p53 and p16 and/or the arrest of apoptosis.     

KL-6: marker for pulmonary involvement in Langerhans cell histiocytosis in infants

The purpose of this study was to investigate serum KL-6 levels in an infant with Langerhans cell histiocytosis (LCH) and pulmonary involvement. The histologic diagnosis of LCH was established by skin biopsy. Imaging of the chest confirmed marked interstitial shadowing throughout both lung fields. Acutely, serum KL-6 was elevated to 9,400 U/mL. Following induction chemotherapy, clinical manifestations of LCH improved and the levels of serum KL-6 returned to within normal limits. During the maintenance therapy phase, there was a resurgence of the LCH, but without involvement of the lungs, and the levels of KL-6 remained normal. The authors conclude that KL-6 may be a useful marker for pulmonary involvement in infants with LCH.     

Congenital Langerhans cell histiocytosis mimicking a "blueberry muffin baby"

Congenital Langerhans cell histiocytosis (LCH) is a rare condition with great diversity. A case of congenital skin-only LCH presenting as a "blueberry muffin baby" with a spontaneous regression by the age of 8 months is reported here. New insights into clinical manifestations and prognosis, which is not uniformly positive, are discussed. A thorough examination and a careful follow-up should be provided to these patients. Systemic therapy is warranted in multi-system disease; no consensus on treatment exists in case of LCH isolated to skin. The diagnosis of congenital self-healing LCH should be made only retrospectively.     

Skelettbefall bei Langerhanszellhistiozytose

Langerhans cell histiocytosis is a reactive disorder of the dendritic cell system and is characterized by proliferation of cells bearing the phenotype of the normal Langerhans cells. Bone lesions are the most common manifestation of LCH and account for about 1% of all childhood bone tumors. They occur in about 80% of paediatric cases of LCH, either in the form of isolated bony disease (single system LCH) or within the context of a multisystem disease (multisystem LCH). Images of LCH bone lesions are not pathognomonic, and histopathological confirmation of the diagnosis is therefore mandatory. LCH confined to the skeleton has an excellent prognosis, and only local treatment (curettage, intralesional steroids) is given in most cases. In cases of extended lesions in weight-bearing bones or of multiple bone lesions systemic therapy may be indicated.     

Elevated serum levels of the decoy receptor osteoprotegerin in children with Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in the bone, skin, and other sites in the body. The pathogenesis of the disease remains unknown. We measured serum levels of the decoy receptor osteoprotegerin (OPG), an important regulator of bone metabolism as well as immune responses, in 18 children with single system (SS) or multi-system (MS) forms of LCH and 20 pediatric controls. OPG levels were significantly increased in LCH patients at diagnosis when compared with controls, and pretreatment levels of OPG were elevated in MS compared with SS patients. Moreover, OPG levels in LCH patients were elevated in patients with involvement of risk organs (liver, lungs, hematopoietic system, or spleen) when compared with patients without risk organ involvement, indicative of an association between OPG values and disease severity. We also observed a positive correlation between serum levels of OPG and tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, at the time of onset of disease. These findings show, for the first time, that serum OPG levels are elevated in LCH patients, and suggest that OPG may play a role in the pathogenesis of this enigmatic disease.     

Concurrent Langerhans cell histiocytosis and myelodysplasia in children

BACKGROUND: Langerhans cell histiocytosis (LCH) is characterized by the proliferation of abnormal histiocytes (Langerhans cells), whose origin as a reactive process or a neoplastic disorder is still poorly understood. Although LCH has been recorded as being associated with malignant neoplasms, concurrence of LCH and myelodysplastic syndrome has not been reported so far. PROCEDURE: We report on four children aged 23, 25, 26, and 53 months with multisystem LCH with organ dysfunction (bone marrow and liver) whose bone marrow pictures, taken at diagnosis, revealed the presence of myelodysplastic abnormalities (RA, RAEB, RAEB-t). RESULTS: We suggest that the commonly used expression of "organ dysfunction," which refers to clinical and functional alterations, could be explained by a myelodysplastic-like disorder. CONCLUSIONS: The contemporary presence of both events may provide a better understanding of the pathogenesis of LCH, especially in young children with multisystem disease and organ dysfunction, who are known to have a very poor outcome.