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

ALK-related histiocytosis (formerly 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-related histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-related 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 ALK, 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-related histiocytosis, and provides guidance for the clinical management of this emerging histiocytic entity.


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histiocytes to be disparate from lesional ALK + cells without immunoreactivity for 312 macrophage/histiocyte markers were termed "atypical ALK-rearranged histiocyte-rich 313 tumors" and not included in the primary study cohort. Also, histiocytosis cases with ALK 314 immunoreactivity but without ALK rearrangements by comprehensive molecular analysis (i.e.

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RNA sequencing) were not included in the primary study cohort. Cases excluded for these 316 two reasons are characterized separately. Written informed consent for this study was

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Thirty-nine patients meeting criteria for ALK-related histiocytosis were identified and 399 included in the study (Tables 1-3; Supplementary Tables 1-3). In addition, three patients with 400 atypical ALK-rearranged histiocyte-rich tumors were recognized (Table 3), and ten patients 401 were identified with histiocytoses demonstrating ALK immunoreactivity but no ALK 402 rearrangement by RNA sequencing (Supplementary Table 4). These thirteen patients without 403 complete criteria for ALK-related histiocytosis diagnosis were excluded from the primary 404 study cohort and are described separately.  Infants with systemic disease with liver and hematopoietic involvement (Group 1A) 420 Patients in Group 1A ranged from zero days to five months of age, and presented with 421 hepatomegaly, anemia and thrombocytopenia. In addition, 5/6 had splenomegaly, 5/6 422 Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2021013338/1832402/blood.2021013338.pdf by guest on 11 November 2021 displayed leukocytosis and some had measurable liver dysfunction, such as elevated liver 423 enzymes, high bilirubin and/or decreased serum protein and albumin levels. In three cases, 424 focal lesions were seen in the liver ( Figure 2). Coagulation profiles were available for 4/6 425 patients (Supplementary Table 2 (Table 3).

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When tested for OCT-2 expression 58 , 14/23 (61%) were positive. When tested for p-ERK    573 We present here a collaborative international study of ALK-related histiocytosis with detailed 574 clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements.

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This study defines a new clinicopathologic spectrum, and highlights frequent neurologic  Our Group 1A patients were similar to the cases originally described by Chan et al. 29 . In 592 addition to liver, spleen and hematopoietic involvement, our patients had lesions in the lungs, 593 kidneys and/or skin. Unlike in LCH 66 , in which liver, spleen and/or hematopoietic 594 involvement constitutes "risk organ" involvement associated with increased mortality, this  Altogether, while there is overlap in histomorphology and immunophenotype, we believe that 618 sufficient evidence is available for the designation of ALK-related histiocytosis as a separate 619 histiocytic entity from both ECD and "extracutaneous/systemic JXG", as previously proposed 620 by others 45 .

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The findings in our patients with single-system disease (Group 2) were similar to that which 623 has been observed previously (Supplementary Table 5), with the nervous system and 624 skin/soft tissue as common sites of disease and surgical resection often being definitive. We 625 expand the clinical spectrum by describing patients with localized bone involvement. When 626 compared to previously reported cases with single-system disease, our cohort includes more 627 cases with isolated neurologic involvement (52% vs. 19%), and more children (87% vs.   (Table 2). 643 However, given that this is a retrospective study, it remains undefined whether ALK 644 inhibition should be implemented as first-line treatment or when disease is refractory to 645 conventional therapies. Also, our study does not address the optimal treatment regimen or 646 duration for ALK inhibition, which is an enduring question for targeted therapy of