ALK+ histiocytosis: A new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

Abstract

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in three 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 35 cases, including 33 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: 6/35), other patients with multisystemic disease (Group 1B: 10/35), and patients with single-system disease (Group 2: 19/35). Seventeen patients of the entire cohort (49%) had neurologic involvement (seven and ten from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in one quarter 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 phosphorylatedERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 23 patients, while CLTC-ALK, TFG-ALK, EML4-ALK and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in ten patients treated with ALK inhibition, nine 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.L6368007722022-01-11 <br />