Pediatric Langerhans Cell Histiocytosis Research Articles

Tumor Necrosis Factor, Interleukin 11, and Leukemia Inhibitory Factor Produced by Langerhans Cells in Langerhans Cell Histiocytosis

: The etiology and pathophysiology of Langerhans cell histiocytosis (LCH) remain elusive. The 3-year survival in pediatric multisystem LCH is still around 80%, and children with risk organ involvement (i.e., liver, spleen, hematopoietic system, or lungs) have a less favorable outcome. To further elucidate the pathogenesis of LCH in the search for a rationale cure, the authors investigated intracellular synthesis of tumor necrosis factor (TNF), interleukin (IL)-11, and leukemia inhibitory factor (LIF) from biopsied lesions. : Lesional cells were obtained by fine-needle aspiration biopsy from nine children with LCH. The study was accomplished by the use of an immunofluorescence staining method that allowed cytokine-producing cells to be differentiated from cytokine-binding cells. : All patients had histiocytes expressing TNF. Seven patients had histiocytes expressing IL-11 and six patients had histiocytes expressing LIF. The two children with the highest proportion of histiocytes displaying TNF and the three with the highest proportion of histiocytes expressing IL-11 and LIF all had risk organ involvement. Two-color staining revealed that histiocytes expressing TNF, IL-11, and LIF co-expressed CD1a molecules. : These observations suggest that LCH represents a cytokine-driven condition partially mediated by TNF, IL-11, and LIF. These three cytokines are all osteoclastogenic, suggesting a pathogenetic pathway for the osteolytic lesions in LCH. Furthermore, thrombocytosis in LCH may be explained by IL-11 and LIF activity.

Cerebellar Ataxia in Pediatric Patients With Langerhans Cell Histiocytosis

The pathogenetic mechanisms of the central nervous system (CNS) problems associated with Langerhans cell histiocytosis (LCH) are not well established. Effective treatment strategies for these CNS complications are not yet available, while diabetes insipidus, also associated with LCH, can be managed effectively. Three Japanese boys with LCH who developed cerebellar ataxia were evaluated. Similar pediatric cases from the literature are also discussed. All three patients initially developed multifocal LCH lesions during early childhood (age <3 years) that responded well to chemotherapy; however, two of the three patients later developed diabetes insipidus. Ataxia, associated with mild developmental delay, was noted in the patients between the ages of 4 to 8 years. Analysis of these three cases, along with previously reported cases, indicates that the median age of onset of LCH was 2.5 (range 0.1-6.5) years and the median age of onset of cerebellar lesions/ataxia was 7 (range 3.5-16.5) years. Although the incidence of cerebellar LCH involvement is low, delayed onset of CNS disease must be monitored during follow-up care of pediatric LCH patients. Brain magnetic resonance imaging is strongly recommended for early detection of cerebellar lesions, but it remains to be determined whether there are any therapeutic measures to prevent exacerbation of CNS disease.

Cladribine Activity in Adult Langerhans-Cell Histiocytosis

Langerhans-cell histiocytosis (LCH) results from the accumulation of tissue histiocytes derived from the same progenitor cells as monocytes. Because cladribine is potently toxic to monocytes, we conducted a phase II trial of cladribine. Cladribine was administered to 13 LCH patients at 0.14 mg/kg per day by 2-hour intravenous infusion for 5 consecutive days, every 4 weeks for a maximum of six courses. Median age was 42 years (range, 19 to 72) and median pretreatment disease duration was 99 months (range, 6 to 252). One patient was untreated, one had received prior prednisone only, one prior radiation only, six prior radiation and chemotherapy, and four prior surgery, radiation, and chemotherapy. Seven patients had cutaneous involvement, six multifocal osseous, six pulmonary, two each with soft tissue and nodal involvement, and four had diabetes insipidus. Of 13 patients, 12 were evaluable for response and all for toxicity. After a median of three courses (range, 1 to 6), seven (58%) patients achieved complete responses (two pathologic and five clinical) and two (17%) patients achieved partial responses; overall response rate, 75%. Median response follow-up duration was 33 months (range, 1 to 65). Seven patients experienced grade 3 to 4 neutropenia. Only one patient had a documented infection, dermatomal herpes zoster. At a median follow-up of 42 months (range, 5 to 76), 12 patients remain alive and one patient has died. Thus, cladribine has major activity in adult LCH and warrants further investigation in both pediatric and adult LCH as a single agent and in combination with other drugs.