Oussama Abla

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Langerhans cell histiocytosis: Current concepts and treatments

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of cells with the phenotype of activated Langerhans cells. The diagnosis of LCH is often delayed or missed. Many questions about LCH remain to be answered, including whether it is caused by a malignancy or by immune dysregulation. Data from the early 1990s showed that LCH consisted of an accumulation of monoclonal LCH cells, suggesting a neoplastic disorder. However, further investigations with current sophisticated techniques have not shown consistent genomic aberrations. Recent data which suggests a role for an IL-17A dependant pathway of dendritic cell fusion in LCH remains to be proven. The most recent data taken together swing the pendulum towards an immunologic aberration. The clinical course of LCH is highly variable, ranging from a self-healing solitary bone lesion to widely disseminated life-threatening disease. Patients with multisystem (MS) disease with organ dysfunction, particularly those refractory to front line therapy, and those with multiple reactivations of disease associated with significant permanent sequelae represent the greatest challenge. Early switch of refractory patients to salvage therapies has contributed to the improvement in survival of MS-LCH patients. Due to the rarity of LCH in children and adults, patients must be enrolled on multi-national clinical trials, whenever possible, to advance our knowledge of the optimal therapeutic strategies and long-term outcomes.

Langerhans cell histiocytosis and Erdheim-Chester disease.

Purpose of reviewTo provide an updated overview of the pathogenesis and treatment of Langerhans cell histiocytosis (LCH) and Erdheim–Chester disease (ECD). Recent findingsThere is ongoing debate as to the exact pathogenesis of these disorders and their classification as reactive versus neoplastic. Proinflammatory cytokines are known to play a role in both LCH and ECD and strengthen the hypothesis that, at least in part, they are disorders of immune dysregulation. The recent discovery of activating mutations in the proto-oncogene BRAF in a subset of LCH patients suggests that LCH is in fact a neoplastic disorder. Understanding of the mechanisms that promote proliferation and migration of histiocytes has led researchers to explore targeted immune-modulatory therapies for ECD. Similarly for LCH, alternative chemotherapeutic agents and reduced-intensity hematopoietic stem cell transplant are being evaluated for refractory disease. SummaryMore research is needed to better understand the cause of these disorders and may help in identifying new targeted therapies, particularly for patients with refractory or relapsed disease. Multinational trials are ongoing for LCH and are urgently needed for ECD.

Predictors of Viridans Streptococcal Shock Syndrome in Bacteremic Children With Cancer and Stem-Cell Transplant Recipients

PURPOSE To describe episodes of viridans streptococcal bacteremia (VSB) in a cohort of children with cancer and stem-cell transplant (SCT) recipients and to determine predictors of viridans streptococcal shock syndrome (VSSS) in this group of children. PATIENTS AND METHODS For this retrospective review, we included episodes of VSB isolated between March 1997 and September 2002, in children (<or= 18 years) with a diagnosis of cancer or SCT patients. The primary outcome was VSSS, defined as hypotension requiring intravascular volume expansion or inotropic support and/or respiratory insufficiency necessitating assisted ventilation. RESULTS Eighty-eight episodes of VSB occurred in 79 children. The mean age of the children was 6.7 years (range, 0.6 to 18.0 years). The most common underlying diagnosis was acute myelogenous leukemia (AML) in 31 (35%) of 88 episodes, and 38 (43%) of 88 had undergone SCT. VSSS occurred in 16 (18%) of 88 episodes, and two children died from VSSS. Two variables were predictive of VSSS, namely peak temperature at presentation (odds ratio [OR], 6.3; 95% CI, 2.1 to 19.0; P =.001) and inpatient status (OR, 5.9; 95% CI, 1.3 to 28.0; P =.02). Diagnosis of AML (OR, 1.1; 95% CI, 0.4 to 3.5; P =.8), receipt of SCT (OR, 1.9; 95% CI, 0.6 to 5.7; P =.2), high-dose cytarabine (OR, 0.6; 95% CI, 0.1 to 3.2; P =.6), and mucositis (OR, 0.8; 95% CI, 0.3 to 2.6; P =.7) were not predictive of VSSS. CONCLUSION VSSS occurred in 18% of episodes of VSB in children with cancer or SCT recipients. Peak temperature before antibiotic therapy and inpatient status were predictive of VSSS.

Primary CNS Lymphoma in Children and Adolescents: A Descriptive Analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG)

Purpose: To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL). Experimental Design: A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries. Results: Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively. Conclusion: This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival. Clin Cancer Res; 17(2); 346–52. ©2011 AACR.

Updates on histiocytic disorders

Histiocytic disorders are rare entities that are becoming more recognized as our understanding of the molecular pathogenesis lead to novel diagnostic tests and targeted drug development. A symposium held at the American Society of Pediatric Hematology/Oncology (ASPHO) 2013 Annual Meeting discussed new insights into histiocytic disorders. This review highlights the symposium presentations, divided into three sections encompassing Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH) and Rosai Dorfman disease (RDD) including subsections on pathogenesis, clinical diagnostic criteria and novel insights into treatment. Details of other histiocytic disorders as well as the standard treatment guidelines have been published elsewhere and are beyond the scope of this discussion [Haupt et al. (2013). Pediatr Blood Cancer 60:175–184; Henter et al. (2007). Pediatr Blood Cancer 48:124–131]. Pediatr Blood Cancer 2014;61:1329–1335.

Features at presentation predict children with acute lymphoblastic leukemia at low risk for tumor lysis syndrome

Tumor lysis syndrome (TLS) is a well‐recognized complication of acute lymphoblastic leukemia (ALL). The ability to predict children at differing risk of TLS would be an early step toward risk‐based approaches. The objectives of the current study were 1) to describe the prevalence and predictors of TLS in childhood ALL and 2) to develop a sensitive prediction rule to identify patients at lower risk of TLS.

A case series of pediatric primary central nervous system lymphoma: Favorable outcome without cranial irradiation

To describe the outcome of childhood primary central nervous system lymphoma (PCNSL) treated with chemotherapy alone or with chemotherapy plus cranial radiotherapy (CRT).

Uncommon histiocytic disorders: Rosai-Dorfman, juvenile xanthogranuloma, and Erdheim-Chester disease.

Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim-Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E(+) ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.

Evaluating the ability to detect change of health‐related quality of life in children with Hodgkin disease

We evaluated 4 different health‐related quality of life (HRQL) measures prospectively to determine their ability to detect change over time: the Health Utilities Index Mark 2 and Mark 3, the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core and Cancer Module, the EuroQol EQ‐5D visual analogue scale (EuroQol), and the Lansky Play‐Performance Scale.