ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion

In 2008, we presented three cases of ALK-positive histiocytosisas a novel systemic histiocyticproliferation of early infancy with hepatosplenomegalyand dramatic hematological disturbances. This series of 10 cases (including the original three cases) describes an expanded clinicopathological spectrum and the molecular findings of this histiocyticproliferation. Six patients had disseminated disease: five presented in early infancy with eventual disease resolution, and the sixth presented at 2 years of age and died of intestinal, bone marrow, and brain involvement. The other four patients had localized diseaseinvolving nasal skin, foot, breast, and intracranial cavernous sinus– the first three had no recurrence after surgical resection, while the cavernous sinuslesion showed complete resolution with crizotinibtherapy. The lesional histiocyteswere very large, with irregularly folded nuclei, fine chromatin, and abundant eosinophilic cytoplasm, sometimes with emperipolesis. There could be an increase in foamy histiocytesand Touton giant cellswith time, resembling juvenile xanthogranuloma. Immunostaining showed that the histiocyteswere positive for ALK, histiocyticmarkers ( CD68, CD163) and variably S100, while being negative for CD1a, CD207, and BRAF- V600E. Next-generation sequencing-based anchored multiplex PCR (Archer® FusionPlex®) performed in six cases identified KIF5B-ALK gene fusion in five and COL1A2-ALK fusion in one. There was no correlation of gene fusion type with disease localization or dissemination. The clinicopathological spectrum of ALK-positive histiocytosisis broader than originally described, and this entity is characterized by frequent presence of KIF5B-ALK gene fusion. We recommend that every unusual histiocyticproliferative disorder, especially disseminated lesions, be tested for ALK expression because of the potential efficacy of ALK inhibitortherapy in unresectable or disseminated disease.