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.

中文翻译：

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ALK 阳性组织细胞增多症：一种新的临床病理学谱，强调神经系统受累和对 ALK 抑制的反应。

ALK 阳性组织细胞增多症是一种罕见的组织细胞肿瘤亚型，于 2008 年首次在 3 名患有涉及肝脏和造血系统的多系统疾病的婴儿中被描述。该实体随后被记录在病例报告和系列中，以占据更广泛的复发性 KIF5B-ALK 融合的临床病理学范围。然而，ALK 阳性组织细胞增多症的完整临床病理学和分子谱仍知之甚少。在这里，我们描述了迄今为止最大规模的 ALK 阳性组织细胞增多症研究，其中包括 39 例病例的详细临床病理数据，其中 37 例已确诊为 ALK 重排。临床谱包括不同的临床表型组：患有肝脏和造血系统受累的多系统疾病的婴儿，如最初所述（组 1A：6/39），其他多系统疾病患者（第 1B 组：10/39）和单系统疾病患者（第 2 组：23/39）。整个队列中有 19 名患者 (49%) 患有神经系统受累（分别来自 1B 组和 2 组 7 名和 12 名患者）。几乎三分之一的病例的组织学包括典型的黄色肉芽肿特征，而大多数病例表现出更密集的细胞、单一形态的外观，没有脂质化的组织细胞，但有时更呈纺锤形或上皮样形态。肿瘤组织细胞巨噬细胞标记物呈阳性，并且通常具有磷酸化细胞外信号调节激酶的强表达，证实了 MAPK 通路的激活。在 27 名患者中检测到 KIF5B-ALK 融合，而在单个病例中检测到 CLTC-ALK、TPM3-ALK、TFG-ALK、EML4-ALK 和 DCTN1-ALK 融合。在接受 ALK 抑制治疗的 11/11 名患者中观察到了强劲且持久的反应，其中 10 名患者出现神经系统受累。本研究介绍了 ALK 阳性组织细胞增多症的现有临床病理学和分子状况，并为这种新兴组织细胞实体的临床管理提供指导。