Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Blood. 2022 Jan 13;139(2):256-280. doi: 10.1182/blood.2021013338.
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.
ALK 阳性组织细胞增生症是一种罕见的组织细胞肿瘤亚型，于 2008 年首次在 3 例多系统疾病累及肝脏和造血系统的婴儿中描述。此后，在病例报告和系列中已证实存在该疾病，其临床表现谱更广泛，且存在反复的 KIF5B-ALK 融合。然而，ALK 阳性组织细胞增生症的完整临床病理和分子谱仍未得到充分描述。在此，我们描述了迄今为止最大的 ALK 阳性组织细胞增生症研究，该研究包括 39 例病例的详细临床病理数据，其中 37 例经证实存在 ALK 重排。临床谱包括明显的临床表型组：最初描述的多系统疾病伴有肝脏和造血系统受累的婴儿（组 1A：6/39），其他多系统疾病患者（组 1B：10/39），以及单系统疾病患者（组 2：23/39）。整个队列中有 19 名患者（49%）存在神经系统受累（分别来自组 1B 和 2 的 7 名和 12 名患者）。组织学包括近三分之一病例的经典黄色瘤特征，而大多数病例表现为更密集的细胞、单形性外观，无脂肪化组织细胞，但有时呈梭形或上皮样形态。肿瘤性组织细胞对巨噬细胞标志物呈阳性反应，并且经常强烈表达磷酸化细胞外信号调节激酶，证实 MAPK 通路的激活。在 27 例患者中检测到 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 例患者中观察到强烈和持久的反应，其中 10 例伴有神经系统受累。本研究介绍了 ALK 阳性组织细胞增生症的现有临床病理和分子特征，并为这种新兴组织细胞实体的临床管理提供了指导。
