Diego Rosso

LANGERHANS CELL HISTIOCYTOSIS: Retrospective Evaluation of 123 Patients at a Single Institution

The aim of this study was to retrospectively evaluate clinical characteristics at diagnosis and outcome of patients with Langerhans cell histiocytosis (LCH). From October 1987 to March 1996, 133 patients with confirmed LCH were admitted to Hospital JP Garrahan in Buenos Aires (123 evaluable). Median age was 5 years (range 15 days to 18 years). Initial organ involvement included bone 114 patients, ear 34, skin 30, liver 18, lung 14, lymph nodes 14, spleen 12, diabetes insipidus 9, and bone marrow 2. Nineteen patients had organ dysfunction, pulmonary 14, hematological 14, and hepatic 12. Two groups were defined: Group A included patients with single system disease (uni- or multifocal) and group B multisystem (with or without organ dysfunction). In group A (n = 82), 24 patients were treated with chemotherapy (prednisone and vinblastine), 21 with surgery, 15 received radiotherapy, and 22 were only observed. Patients of group B (n = 41) were treated with chemotherapy consisting of prednisone and vinblastine, DALHX 83, or LCH1-based chemotherapy. At a median follow-up of 3 years (range 1 month-8 5/12 years) 93% of patients of group A and 39% of group B survive free of reactivation. In group B, 22% had a reactivation and 39% died of progressive disease. Sequelae were detected in 35 patients (28%), which included diabetes insipidus in 17, hearing loss in 13, bony sequelae in 11, sclerosing cholangitis in 6, and lung fibrosis with bullae in 6. Two patients had a subsequent malignant disease. A total of 17 (14%) patients died and 16 of them belonged to the group B: 13 died of progressive disease, 2 due to sclerosing cholangitis (with sepsis in one case and encephalitis in the other one), 1 with progressive disease and associated myelofibrosis, and 1 patient of group A with active disease and brain stem tumor. Patients who had organ dysfunction had a reactivation free survival of 32%. All these patients survived with sequelae. Logistic regression analysis showed that organ dysfunction and hematological involvement had significant predictive values in relation to death. Patients of group A had an excellent survival rate, whereas in those of group B a high mortality was found, especially in the subgroup of patients with organ dysfunction. Laheys criteria should be revised. Sequelae were also more common in this group.

Outcome in children with pulmonary Langerhans cell histiocytosis

The aim of this study was to evaluate features and outcome of children with Langerhans cell Histiocytosis (LCH) and pulmonary involvement.

Reactivation and risk of sequelae in Langerhans cell histiocytosis

To evaluate disease reactivation in patients with Langerhans cell histiocytosis (LCH) and its impact on adverse sequelae.

Prognostic value of soluble interleukin 2 receptor levels in Langerhans cell histiocytosis

Summary. We investigated the prognostic significance of soluble interleukin 2 receptor (sIL‐2r) levels in the pre‐ and post‐treatment serum of paediatric patients with Langerhans cell histiocytosis (LCH). Serum levels of sIL‐2r from 32 LCH patients and 14 healthy controls were determined using enzyme‐linked immunosorbent assay. The LCH patients were classified, evaluated and treated according to the Histiocyte Societys protocols. The following clinical stages were considered: single‐system disease (A) divided into single‐site (A1; n=4), multiple‐site (A2; n=9), and multisystem disease (B) without organ dysfunction (B1; n=5) and with organ dysfunction (B2; n=14). Pretreatment concentrations of sIL‐2r were markedly increased at diagnosis in LCH patients compared with controls [in pg/ml, median (range) 9200 (1124–40000) versus 610 (343–800)], P < 0·0001. Levels differed significantly between stages A [3250 (1124–11000)] and B [22750 (3400–40000)], P < 0·05, and between substages A2 and B2, P < 0·05. There was a significant correlation between clinical stages and sIL‐2r serum levels, r=0·7996 (P < 0·0001). Patients with ≥ 17500 pg/ml of sIL‐2r had a 30‐month survival of 0·417 (SEM: 0·142) compared with those with levels < 17500 pg/ml, who presented a 30‐month survival of 0·848 (SEM: 0·100) (log‐rank, P < 0·0001). In multivariate analysis, sIL‐2r levels ≥ 17500 pg/ml were found to have greater predictive strength than other well‐known prognostic factors.

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 ofdisease. 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.

Serum levels of interleukin-1 receptor antagonist and tumor necrosis factor-alpha are elevated in children with Langerhans cell histiocytosis.

Purpose Langerhans cell histiocytosis (LCH) is a rare disease with variable prognosis in which lesions and clinical features suggest that pro- and anti-inflammatory cytokines may be involved in its pathogenesis. The authors wished to evaluate whether serum levels of interleukin-1 receptor agonist (IL-1Ra) and tumor necrosis factor-alpha (TNF-&agr;) are elevated in children with LCH and decrease after chemotherapy. Patients and Methods Circulating levels of IL-1Ra and TNF-&agr; were measured in 23 and 8 children with LCH, respectively, and 7 pediatric controls using commercially available ELISA kits. All patients fulfilled the Histiocyte Society LCH Protocols criteria for diagnosis, stratification, and treatment. Results Pretreatment concentrations of IL-1Ra and TNF-&agr; were found to be significantly elevated in patients with LCH compared with controls. Among LCH substages, a significant difference in IL-1Ra values was observed between individuals with single-system single-site disease vs. multisystem disease with risk-organ dysfunction. In all eight patients evaluated, IL-1Ra levels decreased after 6 weeks of chemotherapy. Lower values of TNF were observed in three patients after treatment. A positive and significant correlation between IL-1Ra and TNF serum concentrations was found. Conclusions Patients with LCH have elevated levels of IL-1Ra and TNF, which decrease after chemotherapy.

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: Long term results of the cooperative HLH-2004 study

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P =020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.

Importance of multi-lineage hematologic involvement and hypoalbuminemia at diagnosis in patients with "risk-organ" multi-system Langerhans cell histiocytosis.

Aim To perform a risk factor analysis in patients with “risk organ” multi-system Langerhans cell histiocytosis at diagnosis. Methods From 1987 to 2007, 77 patients were analyzed. A univariate analysis of the variables, age <2 years, lungs, spleen and hepatic involvement, presence of ≥2 risk involved organs, hypoalbuminemia and the presence of isolated anemia, anemia with thrombocytopenia with or without leukopenia at diagnosis was performed. Statistically significant variables were combined and entered into a multivariate analysis. Results Fifty-six and 66 evaluable patients had hematologic and hepatic involvement at diagnosis, respectively. Among the hematologic patients, the subgroup of anemia with thrombocytopenia with or without leukopenia showed a significantly lower 5-year survival than the subgroup of isolated anemia (0.19 vs. 0.87, respectively; P=0.0001). Of all the patients, those with hypoalbuminemia had a 5-year survival of 0.16 compared with those with normal albumin levels, who had a 5-year survival of 0.65 (P<0.0001). In multivariate analysis, only anemia with thrombocytopenia with or without leukopenia and hypoalbuminemia were the independent risk factors (relative risk 3.77; confidence interval, 1.7-8.4; P<0.0011 and relative risk 2.59; confidence interval, 1.24-5.4; P<0.0112). Conclusions Anemia with thrombocytopenia with or without leukopenia and hypoalbuminemia, were associated with worse prognosis in multi-system Langerhans cell histiocytosis. Other therapeutic strategies should be considered at diagnosis or early during the initial treatment for this high risk subgroup of patients.

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)-α, 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.

Impact of reactivation on the sequelae of multi-system Langerhans cell histiocytosis patients—response

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