Uterine Inflammatory Myofibroblastic Tumors

Abstract

Inflammatory myofibroblastic tumor (IMT) of the uterus is a rare mesenchymal tumor with largely benign behavior; however, a small subset demonstrate aggressive behavior. While clinicopathologic features have been previously associated with aggressive behavior, these reports are based on small series, and these features are imperfect predictors of clinical behavior. IMTs are most commonly driven by ALK fusions, with additional pathogenic molecular alterations being reported only in rare examples of extrauterine IMTs. In this study, a series of 11 uterine IMTs, 5 of which demonstrated aggressive behavior, were evaluated for clinicopathologic variables and additionally subjected to capture-based next-generation sequencing with or without whole-transcriptome RNA sequencing. In the 6 IMTs without aggressive behavior, ALK fusions were the sole pathogenic alteration. In contrast, all 5 aggressive IMTs harbored pathogenic molecular alterations and numerous copy number changes in addition to ALK fusions, with the majority of the additional alterations present in the primary tumors. We combined our series with cases previously reported in the literature and performed statistical analyses to propose a novel clinicopathologic risk stratification score assigning 1 point each for: age above 45 years, size≥5 cm,≥4 mitotic figures per 10 high-power field, and infiltrative borders. No tumors with 0 points had an aggressive outcome, while 21% of tumors with 1 to 2 points and all tumors with ≥3 points had aggressive outcomes. We propose a 2-step classification model that first uses the clinicopathologic risk stratification score to identify low-risk and high-risk tumors, and recommend molecular testing to further classify intermediate-risk tumors.

Uterine Leiomyoma-Like Inflammatory Myofibroblastic Tumor Without Myxoid Matrix or Inflammatory Cell Infiltration: A Case Report of a Potential Diagnostic Pitfall

“…1,11 Nevertheless, additional genetic alterations, such as TP53 mutation or bi-allelic CDKN2A deletion, have been associated with aggressive behavior. [13][14][15] In conclusion, uterine IMTs are relatively uncommon, particularly in the absence of typical symptoms. As such, IMTs are frequently misdiagnosed or go unnoticed.…”

“…1,11 Nevertheless, additional genetic alterations, such as TP53 mutation or bi-allelic CDKN2A deletion, have been associated with aggressive behavior. 13-15…”

Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets

“…46 In the study by Ladwig et al, uterine IMTs with an indolent behaviour showed isolated ALK fusions, while aggressive uterine IMTs additionally harboured numerous mutations and deletions. 47 As the scope of this study was to detect the main molecular drivers of IMT, we did not perform DNA analysis on the ALK/ROS1 fusion-positive IMTs and therefore could not evaluate potential additional genetic alterations in the IMTs which might influence biological behaviour. However, as the vast majority of ALK fusion-positive IMTs (excluding EIMS) follow an indolent course, more research on kinase fusion-negative IMTs seems more urgently needed.…”

“…described two cases of recurrent IMT with a PIK3CA and KIT mutation, respectively, present in the recurrence, but not in the primary IMT 46 . In the study by Ladwig et al ., uterine IMTs with an indolent behaviour showed isolated ALK fusions, while aggressive uterine IMTs additionally harboured numerous mutations and deletions 47 . As the scope of this study was to detect the main molecular drivers of IMT, we did not perform DNA analysis on the ALK/ROS1 fusion‐positive IMTs and therefore could not evaluate potential additional genetic alterations in the IMTs which might influence biological behaviour.…”

Uterine Sarcoma With EML4::NTRK3 Fusion: A Spectrum of Mesenchymal Neoplasms Harboring Actionable Gene Fusions

“…Molecular overlap may also be noted. Most IMTs are associated with ALK rearrangements, but other tyrosine kinase genes, such as ROS1 and RET, rearrangements can be the driver event (3,26). Interestingly, one of the ALK gene fusion partners described in IMT is EML4, and EML4::ALK rearrangements are frequent in non-small cell lung adenocarcinoma (27,28).…”