Jorge Braier

Risk factors for diabetes insipidus in langerhans cell histiocytosis

Diabetes insipidus (DI) is the most frequent central nervous system (CNS)‐related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life‐long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied.

Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH)-III tested risk-adjusted, intensified, longer treatment of multisystem LCH (MS-LCH), for which optimal therapy has been elusive. Stratified by risk organ involvement (high [RO+] or low [RO-] risk groups), > 400 patients were randomized. RO+ patients received 1 to 2 six-week courses of vinblastine+prednisone (Arm A) or vinblastine + prednisone + methotrexate (Arm B). Response triggered milder continuation therapy with the same combinations, plus 6-mercaptopurine, for 12 months total treatment. 6/12-week response rates (mean, 71%) and 5-year survival (84%) and reactivation rates (27%) were similar in both arms. Notably, historical comparisons revealed survival superior to that of identically stratified RO+ patients treated for 6 months in predecessor trials LCH-I (62%) or LCH-II (69%, P < .001), and lower 5-year reactivation rates than in LCH-I (55%) or LCH-II (44%, P < .001). RO- patients received vinblastine+prednisone throughout. Response by 6 weeks triggered randomization to 6 or 12 months total treatment. Significantly lower 5-year reactivation rates characterized the 12-month Arm D (37%) compared with 6-month Arm C (54%, P = .03) or to 6-month schedules in LCH-I (52%) and LCH-II (48%, P < .001). Thus, prolonging treatment decreased RO- patient reactivations in LCH-III, and although methotrexate added no benefit, RO+ patient survival and reactivation rates have substantially improved in the 3 sequential trials. (Trial No. NCT00276757 www.ClinicalTrials.gov).

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.

Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry.

OBJECTIVE To assess multisystem Langerhans cell histiocytosis reactivation and its impact on morbidity and mortality. STUDY DESIGN Retrospective analysis of 335 patients with MS-LCH and documented complete disease resolution (NAD1). RESULTS The probability of a reactivation within 5 years of NAD1 was 46%. The first reactivation occurred within 2 years after NAD1 in most of the patients. Of 134 events, 35% were confined to skeleton, 24% were single-system nonbony lesions, 24% were multisystem reactivations without risk-organ involvement, and 10% with risk-organ involvement. In 7%, the location was unspecified. Only 3 deaths (2.2%) were documented within the context of a first reactivation. Second disease resolution (NAD2) was achieved in 85% of the cases. The probability of a second reactivation within 5 years of NAD2 was 44%. The risk for permanent consequences in patients with reactivations was higher, compared with patients without reactivation (RHR 2.2, P = .046). CONCLUSIONS Reactivation is a frequent and early event in MS-LCH, but involvement of risk organs at reactivation is rare and mortality is minimal. However, reactivations increase the risk for permanent consequences by about 2-fold. Prospective trials targeting reduction of acute morbidity and permanent disabilities through nontoxic treatment of the reactivations are warranted.

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.

Isolated pulmonary Langerhans cell histiocytosis presenting with recurrent pneumothorax

We describe the outcome of a 20‐month‐old female and a 6‐year‐old male, both of whom had acutely developed severe respiratory distress with tachypnea, cyanosis and, in Patient 2, thoracic pain. Chest X‐ray and CT scan showed interstitial pulmonary involvement and a bullous process with bilateral pneumothoraces for both children. Pulmonary biopsy confirmed the diagnosis of Langerhans cell histiocytosis (LCH). Laboratory testing and skeletal radiography did not reveal any other involvement of LCH. The patients received chemotherapy (prednisone, vinblastine, 6‐mercaptopurine). They had recurrent episodes of pneumothorax during follow‐up and placement of chest tubes was the treatment chosen. They were asymptomatic, with regression of bullae and disappearance of pneumothorax at 58 and 63 months of follow‐up, respectively. Pulmonary function tests done during follow‐up were normal in both patients. Despite severe pulmonary involvement, conservative surgical treatment and moderate chemotherapy produced good results in these two rare cases. Pediatr Blood Cancer 2007;48:241–244.