Molecular Characterization of Inflammatory Myofibroblastic Tumors With Frequent ALK and ROS1 Gene Fusions and Rare Novel RET Rearrangement. Am J Surg Pathol. 2015,[Epub ahead of print]

Abstract  Approximately 50% of conventional inflammatory myofibroblastic tumors (IMTs) harbor ALK gene rearrangement and overexpress ALK. Recently, gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in 1 patient PDGFRB. However, it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study, we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1, and RET by fluorescence in situ hybridization. In addition, next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1-rearranged IMTs, all except 1 presenting in children, mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 immunohistochemistry. Two of the cases showed TFG-ROS1 fusions. Interestingly, 1 adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly, 90% of fusion-negative IMTs were seen in adults, whereas >90% of pediatric IMT showed gene rearrangements. EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in lung cancer.

大约50%的炎性肌纤维母细胞肿瘤（IMTs）伴有ALK基因重排和过表达。最近已证明涉及其它激酶的基因融合，如ROS1和PDGFRB，与IMT的发病机制有关，然而新出现的基因分型是否与IMT的临床病理特征相关仍然未知。本研究作者对一大组临床表现不同的IMT进行了分子遗传学研究，并分析了潜在存在的基因型-表型之间的相关性。纳入本研究标准的病例包括典型的形态学和可用于分子研究的组织学标本，缺乏ALK免疫表达不是一个主要的排除因素。由于涉及到某些激酶的基因融合可同时出现在IMT和肺癌中，作者通过荧光原位杂交技术评估了ALK、ROS1、PDGFRB、NTRK1及 RET的异常情况。另外，4例进行了新一代配对RNA测序和融合序列测定，发现2例中存在EML4-ALK融合。62例IMTs（儿童25例，成人37例），35例（56%）显示了ALK基因重排；7例（20%）存在EML4-ALK倒置，主要发生于儿童肺和软组织，其中2例发生在新生儿；6例（10%）有ROS1重排，主要发生在成人肺和腹腔内，仅1例发生在儿童，形态学长梭形细胞束状增生，ROS1免疫组化常阳性；2例显示了TFG-ROS1融合。有趣的是1例成人IMT中显示了以前未报到过的RET基因重排。本研究结果表明68%（42/62）的IMTs以激酶融合为特征，为制定合理的靶向治疗策略提供了一个理论依据。融合阴性的IMTs 90%发生在成人，而>90%的儿童IMT显示了基因重排。EML4-ALK倒置和ROS1融合是IMT中融合异常最常出现的，而肺癌中同样可出现这种情况。