Abstract：
Inflammatory myofibroblastic tumors arising in infants are rare, poorly investigated and mostly reported as isolated cases or as a part of larger series thus, their clinicopathological and molecular features are essentially unknown. Archival files from two large pediatric institutions and a tumor registry were queried for pediatric inflammatory myofibroblastic tumors. Available material from patients ≤12 months of age was reviewed. Additional immunostains (ALK-1, D240, WT1) and ALK-FISH studies were performed as needed. Targeted anchored multiplex PCR with next-generation sequencing was done in all cases. A total of 12 of 131 infantile cases (mean 5.5 months) were identified (M:F of 2:1). Anatomic locations included intestinal/mesenteric (n = 6), head/neck (n = 3), and viscera (n = 3). Half of tumors showed a hypocellular myxoid pattern, perivascular condensation, and prominent vasculature with vague glomeruloid structures present in four of them. The remaining cases exhibited a more cellular pattern with minimal myxoid component. ALK-1 immunohistochemistry was positive in most cases (11/12) with cytoplasmic-diffuse (n = 6), cytoplasmic-granular (n = 2), and dot-like (n = 3) staining patterns. ALK fusion partners identified in five cases included EML4, TPM4, RANBP2, and a novel KLC1. Three inflammatory myofibroblastic tumors showed fusions with other kinases including TFG-ROS1 and novel FN1-ROS1 and RBPMS-NTRK3 rearrangements. Favorable outcome was documented in most cases (10/11) with available follow-up (median 17 months) while three patients were successfully treated with crizotinib. In summary, infantile inflammatory myofibroblastic tumors are rare and can exhibit paucicellular, extensively myxoid/vascular morphology with peculiar immunophenotype mimicking other mesenchymal or vascular lesions. All tumors harbored kinase fusions involving ALK, ROS1, and NTRK3 including three novel fusion partners (KLC1, FN1, and RBPMS, respectively). A favorable response to crizotinib seen in three cases supports its potential use in infants as seen in older patients. Awareness of these unusual morphologic, immunophenotypic, and molecular features is critical for appropriate diagnosis and optimized targeted therapy.
摘要：
在婴儿中出现的炎性肌纤维母细胞瘤很少见，调查不力，大多报告为孤立病例或作为较大系列的一部分，他们的临床病理和分子特征基本上是未知的。查询了来自两个大型儿科机构和肿瘤登记处的档案文件，以查找小儿炎性肌纤维母细胞瘤。审查了年龄≤12个月的患者的可用材料。根据需要进行其他免疫染色（ALK-1，D240，WT1）和ALK-FISH研究。在所有情况下都进行了具有下一代测序的靶向锚定多重PCR。在131例婴儿病例中，总共确定了12例（平均5.5个月）（M：F为2：1）。解剖位置包括肠/肠系膜（n=6），头/颈（n=3），和内脏(n=3)。一半的肿瘤表现为低细胞粘液样模式，血管周围冷凝,和突出的脉管系统，其中四个存在模糊的肾小球结构。其余病例表现出更多的细胞模式，粘液样成分最少。ALK-1免疫组织化学在大多数病例（11/12）中呈阳性，具有细胞质弥漫性（n=6），细胞质颗粒（n=2），和点状(n=3)染色模式。在5例病例中鉴定的ALK融合伴侣包括EML4、TPM4、RANBP2和新型KLC1。三种炎性肌纤维母细胞瘤显示与其他激酶融合，包括TFG-ROS1和新型FN1-ROS1和RBPMS-NTRK3重排。在大多数病例（10/11）中记录了良好的结果，并进行了随访（中位数17个月），而三名患者成功接受了克唑替尼治疗。总之,婴儿炎性肌纤维母细胞瘤很少见，可以表现为少细胞，广泛的粘液样/血管形态，具有模仿其他间充质或血管病变的特殊免疫表型。所有肿瘤都含有涉及ALK的激酶融合，ROS1和NTRK3，包括三个新的融合伴侣（KLC1，FN1和RBPMS，分别)。在三例病例中观察到的对克唑替尼的良好反应支持了其在婴儿中的潜在用途，如在年龄较大的患者中所见。意识到这些不寻常的形态学，免疫表型,和分子特征对于适当的诊断和优化的靶向治疗至关重要。
