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Uterine Inflammatory Myofibroblastic Tumors Frequently Harbor ALK Fusions With IGFBP5 and THBS1.

子宫炎性肌纤维母细胞肿瘤通常存在ALK与IGFBP5和THBS1基因的融合

Haimes JD,Stewart CJR,Kudlow BA,Culver BP,Meng B,Koay E,Whitehouse A,Cope N,Lee JC,Ng T,McCluggage WG,Lee CH

Abstract

Inflammatory myofibroblastic tumor (IMT) can occur in a number of anatomic sites, including the uterus. Like its soft tissue counterpart, uterine IMT frequently expresses ALK and harbors ALK genetic rearrangements. The aim of this study is to fully characterize the genetic fusions that occur in uterine IMT. We studied 11 uterine IMTs with typical histology and 8 uterine myxoid smooth muscle tumors (5 leiomyomas, 1 smooth muscle tumor of uncertain malignant potential, and 2 leiomyosarcomas) in which the differential of IMT was considered, using a RNA-sequencing-based fusion assay to detect genetic fusions involving ALK, ROS1, RET, NTRK1/3, and other genes. ALK was expressed in 10 of 11 IMTs and 1 tumor initially categorized as a myxoid leiomyoma (granular cytoplasmic staining with paranuclear accentuation). Fusion transcripts involving ALK were identified in 9 of 10 ALK immunopositive IMTs, with 3 harboring IGFBP5-ALK, 3 harboring THBS1-ALK, 2 harboring FN1-ALK, and 1 harboring TIMP3-ALK. Among the smooth muscle tumors, IGFBP5-ALK fusion transcript was identified in only 1 ALK immunopositive case. Further review revealed that although a diagnosis of IMT was considered for the ALK immunopositive myxoid leiomyoma, this diagnosis was not initially rendered only because fluorescence in situ hybridization analysis was interpreted as negative for ALK genetic rearrangement; this case is best reclassified as an IMT. Notably, all the ALK fusions identified in our study included the transmembrane domain-encoding exon 19 of ALK. Our findings confirm the high frequency of ALK fusions in uterine IMT, with an enrichment of novel 5' ALK fusion partners (IGFBP5, THBS1, and TIMP3) and exon 19-containing ALK fusion. Given that IGFBP5 and FN1 are both situated on the same chromosome as ALK, fluorescence in situ hybridization analysis for ALK rearrangement may not be reliable and a negative result should not exclude a diagnosis of uterine IMT if the histologic features and ALK immunostaining findings are supportive.

摘要

炎性肌纤维母细胞肿瘤(IMT)可发生于包括子宫在内的多个解剖部位。和发生在软组织的IMT一样,子宫IMT通常也表达ALK,并存在ALK基因重排 。本研究的目的是充分描述子宫IMT的基因融合特征。作者研究了11例具有经典形态的子宫IMT和需与IMT鉴别的8例子宫黏液性平滑肌肿瘤(包括5例平滑肌瘤、1例恶性潜能未定的平滑肌肿瘤和2例平滑肌肉瘤)。通过RNA-测序法检测ALK ROS1RETNTRK1/3与其它基因的融合情况。10/11IMTs 1例先前被归类为粘液性平滑肌瘤的病例ALK阳性表达(颗粒状胞浆着色或核旁聚集)。10ALK免疫组化阳性的IMTs中,9例存在ALK基因融合,其中3例存在IGFBP5-ALK融合、3例存在THBS1-ALK融合、2例存在FN1-ALK融合、1例存在TIMP3-ALK融合。在子宫平滑肌肿瘤中,仅1例免疫组化ALK阳性的病例检测到了IGFBP5-ALK融合。进一步回顾性分析显示,对于免疫组化ALK阳性的黏液性平滑肌瘤,起初仅仅因为荧光原位杂交分析ALK基因重排阴性而未诊断为IMT,这样的病例最好被重新归类为IMT。作者的研究发现所有的ALK融合涉及到编码19号外显子的跨膜结构域。本文研究进一步证实了子宫IMT中存在高频率ALK基因融合,丰富了5'ALK的融合伴侣(IGFBP5THBS1TIMP3)和19号外显子与ALK融合。 如果组织形态学特征和免疫表型ALK阳性均支持IMT的话,考虑到IGFBP5 FN1基因均位于与ALK基因相同的染色体上,荧光原位杂交分析ALK重排可能不可靠,阴性结果并不能排除子宫IMT的诊断。

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