Histopathologic and Molecular Characterization of Uterine Leiomyoma–like Inflammatory Myofibroblastic Tumor

Abstract

Uterine leiomyoma (UL) is a common benign neoplasm which can sometimes be difficult to differentiate from the uterine inflammatory myofibroblastic tumor (IMT) based on morphology alone. IMT is a myofibroblastic/fibroblastic neoplasm which has typically been considered to be rare in the uterus. Its clinical behavior is usually indolent although aggressive variants exist. The majority of IMTs harbor genomic rearrangement of anaplastic lymphoma kinase (ALK), while ALK fusion has not been thus far detected in ULs. We analyzed 2263 ULs of which 9 (0.4%) had tyrosine-kinase activation. Seven of the samples were ALK immunopositive: 6 had an ALK fusion gene and 1 overexpressed an ALK transcript skipping exons 2 to 3, Moreover, 1 sample had a RET, and 1 a PDGFRB fusion gene. While no recurrent somatic mutations were found, 1 patient had an ALK germline mutation. Seven tumors showed leiomyoma-like morphology, 1 tumor had slightly loose, and 1 fibrous growth pattern. Six tumors had mild to moderate lymphocyte infiltration, while no immune cell infiltration was detected in 3 cases. None of the tumors showed aggressive behavior. Except for strong ALK positivity (7/9 tumors) the protein expression profile of the tumors was identical to ULs and distinct from other mesenchymal uterine tumors. In gene expression level, these tumors and the known UL subclasses did not separate perfectly. However, vitamin C metabolism and epithelial-mesenchymal transition pathways were uniquely enriched in these lesions. The overall similarity of the analyzed tumors to UL raises the question whether an UL diagnosis would be more proper for a subset of uterine IMTs.

A Novel CASC15-ALK and TFG-ROS1 Fusion Observed in Uterine Inflammatory Myofibroblastic Tumor

“…In contrast, the majority of uterine IMTs are characterized by ALK rearrangements, with an isolated case of an ETV6-NTRK3 , TIMP3-RET , TIMP3-ROS1 , FN1-ROS1 , SORBS1-RET , or IGFBP5-PDGFRB fusion. (Table 1) 6,10–13 . The ALK fusion partners identified in IMT of the female genital tract include IGFBP5 , THBS1 , FN1 , DES , TIMP3 , SYN3 , SEC31A , TNS1 , and TPM3 3,5,7–10 .…”

“…The majority of IMTs in the gynecologic tract are characterized by genetic fusion involving anaplastic lymphoma kinase (ALK) because of chromosome rearrangement (1,(4)(5)(6). The ALK fusion partners identified in IMT of the gynecologic tract include IGFBP5, THBS1, FN1, DES, TIMP3, SEC31A, TPM3, TNC, and TNS1 (3,5,(7)(8)(9)(10)(11). In sporadic cases, genomic fusions involving additional receptor tyrosine kinases, such as ETV6-NTRK3, TIMP3-RET, TIM-P3-ROS1, FN1-ROS1, and SORBS1-RET, and a case with IGFBP5-PDGFRB fusion have been identified in IMT cases lacking ALK genetic rearrangements/fusions (Table 1) (6,(10)(11)(12)14).…”

“…The ALK fusion partners identified in IMT of the gynecologic tract include IGFBP5, THBS1, FN1, DES, TIMP3, SEC31A, TPM3, TNC, and TNS1 (3,5,(7)(8)(9)(10)(11). In sporadic cases, genomic fusions involving additional receptor tyrosine kinases, such as ETV6-NTRK3, TIMP3-RET, TIM-P3-ROS1, FN1-ROS1, and SORBS1-RET, and a case with IGFBP5-PDGFRB fusion have been identified in IMT cases lacking ALK genetic rearrangements/fusions (Table 1) (6,(10)(11)(12)14). Herein, we report 1 case of uterine IMT harboring a TFG-ROS1 fusion and 1 case harboring a novel fusion involving ALK, specifically the cancer susceptibility candidate 15-anaplastic lymphoma kinase (CASC15)-ALK.…”

Case Report: Clinical response to anaplastic lymphoma kinase inhibitor-based targeted therapy in uterine inflammatory myofibroblastic tumor harboring ALK-IGFBP5 fusion

“…Symptoms and signs vary depending on the site of the tumor, while patients with uterine IMT commonly present with pain, tenderness, and abnormal vaginal bleeding ( 2 ). The recurrence rate of uterine IMT is approximately 25%, even though surgery has long been recognized as the preferred treatment ( 3 ), which lays a solid foundation for the development of chemotherapy and target therapy to optimize treatment strategies.…”

“…Structural rearrangements commonly lead to the expression and activation of ALK, which then create considerable opportunities for chimeric fusion. ALK has now been accepted as a specific diagnostic marker and driver gene for IMT of the uterus ( 6 ), and several ALK fusion partners have been identified retrospectively, for instance, FN1 , DES , DCTN1 , TNS1 , IGFBP5 , TIMP3 , TNC , TPM3 , THBS1 , and SEC31 ( 3 , 7 – 10 ). ALK fusion has been confirmed as a therapeutic target for patients with ALK-positive tumors, such as non-small cell lung cancer (NSCLC) ( 11 ).…”