ALK-positive 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 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 (seven and twelve 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-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while 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, ten 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.

Failure of crizotinib based systemic treatment in ALK positive histiocytosis involving the central nervous system: a case report and literature review

“…In this study, we first reported the case of a one-year-and-four-month-old boy with ALK-positive histiocytosis in the suprasellar region. After combining the high-quality results of large international collaboration on ALK-positive histiocytosis with our case [ 14 ], we believe that this case may provide a reference for patients involving CNS.…”

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

“…These neoplasms, in particular Langerhans cell histiocytosis/sarcoma, Erdheim-Chester disease, juvenile xanthogranuloma, RDD and histiocytic sarcoma, commonly show mutations in genes of the MAPK pathway, such as BRAF, ARAF, MAP2K1, NRAS and KRAS, albeit with highly variable frequencies, indicating a unifying genetic landscape for diverse histiocytoses and histiocytic neoplasms. ALK-positive histiocytosis furthermore converges on the MAPK pathway, which is one of the signaling pathways mediating ALK activation [87,88]. Insights on genetic alterations have significant treatment implications, because of availability of highly effective therapy targeting components of the activated signaling pathway, such as BRAF and MEK inhibitors [88][89][90][91][92].…”

“…ALK-positive histiocytosis furthermore converges on the MAPK pathway, which is one of the signaling pathways mediating ALK activation [87,88]. Insights on genetic alterations have significant treatment implications, because of availability of highly effective therapy targeting components of the activated signaling pathway, such as BRAF and MEK inhibitors [88][89][90][91][92].…”

“…ALK-positive histiocytosis, which shows a broad clinicopathologic spectrum unified by the presence of ALK gene translocation (most commonly KIF5B :: ALK ) and remarkable response to ALK-inhibitor therapy, has been better characterized in recent studies [ 88 , 96 ]. The multisystem systemic form that typically occurs in infants, with involvement of liver, spleen and/or bone marrow, runs a protracted course but often resolves slowly, either spontaneously or with chemotherapy.…”

“…The multisystem systemic form that typically occurs in infants, with involvement of liver, spleen and/or bone marrow, runs a protracted course but often resolves slowly, either spontaneously or with chemotherapy. Other multisystem and single-system cases occur in any age group, with involvement of two or more organs or one organ alone, respectively, most commonly central/peripheral nervous system and skin; the disease has a favourable outcome with systemic and/or surgical therapy [ 88 , 97 ]. The histiocytes in ALK-positive histiocytosis can assume variable appearances including large oval cells, foamy cells and spindle cells, some with multinucleation (including Touton giant cells) or emperipolesis.…”