ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.
Original languageEnglish
Article numberPMID: 34727172
Pages (from-to)256-280
Number of pages25
JournalBlood
Volume139
Issue number2
DOIs
Publication statusPublished - 13 Jan 2022

Bibliographical note

Funding Information:
P.G.K. received a grant from Leiden University Medical Center. A.G.S.v.H. is supported by Stichting 1000 kaarsjes voor Juultje. E.L.D. is supported by the National Institutes of Health/National Cancer Institute Core Grant (P30 CA008748), National Cancer Institute (R37 CA259260-01), the Frame Fund, Applebaum Foundation, and Joy Family West Foundation. J.-F.E. is supported by the Programme de Recherche Translationnelle sur le Cancer from the French National Cancer Institute (PRT-K19-143).

Publisher Copyright:
© 2022 American Society of Hematology

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