Abla, Oussama

Abstract Malignant histiocytic neoplasms (MHNs) are rare tumors derived from the mononuclear phagocyte system (MPS), encompassing histiocytic sarcoma, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, and other high-grade MPS lineage tumors. Despite advances in understanding histiocytic neoplasms, MHNs remain diagnostically challenging and lack standardized treatment algorithms. Current classification systems differ in lineage framing and fail to address mixed or ambiguous phenotypes, contributing to diagnostic uncertainty and inconsistent care. To address these gaps, the Histiocyte Society convened an international working group of pathologists and oncologists, including World Health Organization and International Consensus Classification contributors, to harmonize nomenclature, define minimum diagnostic criteria, and develop pragmatic treatment recommendations. Using a modified Delphi process and case-based review, the group formulated >40 consensus statements spanning classification, pathology, molecular testing, clinical evaluation, and therapeutic strategies. Key recommendations include the adoption of a unified MHN designation, use of a minimum immunophenotypic panel, integration of broad molecular profiling, and the documentation of previous hematopoietic malignancy. Treatment algorithms emphasize surgical resection for unifocal disease and targeted therapy or immune checkpoint inhibition for multifocal disease when actionable mutations or programmed death ligand 1 expression are present. These consensus recommendations aim to reduce diagnostic ambiguity, standardize reporting, and improve outcomes for both pediatric and adult patients. Future priorities include international registries to refine risk stratification and biomarker-driven trials exploring targeted therapy, immunotherapy, and combination approaches.

Abstract ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Abstract 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.

Abstract 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.