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

Paul G. Kemps, Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Jennifer Picarsic, Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Benjamin H. Durham, Human Oncology and Pathogenesis Program, Department of Medicine, and.
Zofia Hélias-Rodzewicz, Department of Pathology, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne, France.
Laura Hiemcke-Jiwa, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Cor van den Bos, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Marianne D. van de Wetering, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Carel J. van Noesel, Department of Pathology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Jan A. van Laar, Department of Internal Medicine and Immunology, and.
Robert M. Verdijk, Department of Pathology, Erasmus Medical Center University Medical Center Rotterdam, Rotterdam, The Netherlands.
Uta E. Flucke, Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
Pancras C. Hogendoorn, Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
F J. Woei-A-Jin, Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
Raf Sciot, Department of Pathology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
Andreas Beilken, Department of Pediatric Hematology and Oncology, and.
Friedrich Feuerhake, Department of Pathology, Hannover Medical School, Hannover, Germany.
Martin Ebinger, Department I - General Pediatrics, Children's Hospital, Hematology and Oncology.
Robert Möhle, Department of Hematology and Oncology, and.
Falko Fend, Department of Pathology and Neuropathology and Comprehensive Cancer Center, University Hospital Tuebingen, Tuebingen, Germany.
Antje Bornemann, Department of Pathology and Neuropathology and Comprehensive Cancer Center, University Hospital Tuebingen, Tuebingen, Germany.
Verena Wiegering, Department of Oncology, Hematology and Stem Cell Transplantation, University Children's Hospital Würzburg, Würzburg, Germany.
Karen Ernestus, Department of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
Tina Méry, Division of Pediatric Hematology and Oncology, Department of Pediatrics, Klinikum Chemnitz, Chemnitz, Germany.
Olga Gryniewicz-Kwiatkowska, Department of Oncology, Children's Memorial Health Institute, Warsaw, Poland.
Bozenna Dembowska-Baginska, Department of Oncology, Children's Memorial Health Institute, Warsaw, Poland.
Dmitry A. Evseev, Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
Vsevolod Potapenko, Department of Hematology and Oncology, Municipal Educational Hospital N°31, Saint Petersburg, Russia.
Vadim V. Baykov, Department of Pathology, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia.
Stefania Gaspari, Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
Sabrina Rossi, Pathology Unit, Laboratories Department, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
Marco Gessi, Department of Pathology and.

Document Type

Article

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.

Medical Subject Headings

Adolescent; Adult; Anaplastic Lymphoma Kinase (analysis, antagonists & inhibitors, genetics); Child; Child, Preschool; Female; Histiocytic Disorders, Malignant (complications, drug therapy, genetics, pathology); Humans; Infant; Male; Nervous System Diseases (etiology, genetics, pathology); Oncogene Proteins, Fusion (analysis, antagonists & inhibitors, genetics); Protein Kinase Inhibitors (therapeutic use); Retrospective Studies; Young Adult

Publication Date

1-13-2022

Publication Title

Blood

E-ISSN

1528-0020

Volume

139

Issue

2

First Page

256

Last Page

280

PubMed ID

34727172

Digital Object Identifier (DOI)

10.1182/blood.2021013338

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