ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition
Authors: Kemps Paul G. , Picarsic Jennifer , Durham Benjamin H. , Hélias-Rodzewicz Zofia , Hiemcke-Jiwa Laura , van den Bos Cor , van de Wetering Marianne D. , van Noesel Carel J. M. , van Laar Jan A. M. , Verdijk Robert M. , Flucke Uta E. , Hogendoorn Pancras C. W. , Woei-A-Jin F. J. Sherida H. , Sciot Raf , Beilken Andreas , Feuerhake Friedrich , Ebinger Martin , Möhle Robert , Fend Falko , Bornemann Antje , Wiegering Verena , Ernestus Karen , Méry Tina , Gryniewicz-Kwiatkowska Olga , Dembowska-Baginska Bozenna , Evseev Dmitry A. , Potapenko Vsevolod , Baykov Vadim V. , Gaspari Stefania , Rossi Sabrina , Gessi Marco , Tamburrini Gianpiero , Héritier Sébastien , Donadieu Jean , Bonneau-Lagacherie Jacinthe , Lamaison Claire , Farnault Laure , Fraitag Sylvie , Jullié Marie-Laure , Haroche Julien , Collin Matthew , Allotey Jackie , Madni Majid , Turner Kerry , Picton Susan , Barbaro Pasquale M. , Poulin Alysa , Tam Ingrid S. , El Demellawy Dina , Empringham Brianna , Whitlock James A. , Raghunathan Aditya , Swanson Amy A. , Suchi Mariko , Brandt Jon M. , Yaseen Nabeel R. , Weinstein Joanna L. , Eldem Irem , Sisk Bryan A. , Sridhar Vaishnavi , Atkinson Mandy , Massoth Lucas R. , Hornick Jason L. , Alexandrescu Sanda , Yeo Kee Kiat , Petrova-Drus Kseniya , Peeke Stephen Z. , Muñoz-Arcos Laura S. , Leino Daniel G. , Grier David D. , Lorsbach Robert , Roy Somak , Kumar Ashish R. , Garg Shipra , Tiwari Nishant , Schafernak Kristian T. , Henry Michael M. , van Halteren Astrid G. S. , Abla Oussama , Diamond Eli L. , Emile Jean-François 
Published: November 2021

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.