The inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm with an uncertain biological behavior. Initially described by Brunn in 1939 as an "interesting benign" lung tumor, IMTs have since been reported in various organs [1]. Regarding the female genital tract, most cases have been documented in the uterus [2]. Histologically, IMTs exhibit three basic growth patterns: myxoid (fasciitis-like appearance), fascicular/compact cellular (resembling smooth muscle), and hyalinized/fibrous (dense collagen with inconspicuous tumor cells) [3]. A lymphoplasmacytic inflammatory infiltrate is present in a majority of cases. Tumors with predominant fascicular growth, minimal atypia, and sparse inflammatory infiltrate closely mimic benign leiomyomas, posing a diagnostic challenge [4]. The integration of immunohistochemical testing alongside the broader availability of molecular methods has significantly enhanced the accurate diagnosis of IMTs.

Anaplastic lymphoma kinase (ALK) gene rearrangement is a key oncogenic driver in the pathogenesis of IMTs and occurs in approximately 90 % of uterine IMTs [5]. Additionally, ALK immunostaining positivity is observed in the same proportion of cases [3]. Common ALK fusion partners include IGFPB5, TIMP3, FN1, DES, TNS1, and THBS1. The TIMP3::ALK and THBS1::ALK fusions are particularly frequent in pregnancy-associated IMTs [5], [6], [7]. ALK-fusions involving RANBP2 and RRBP1 have been detected in a highly aggressive variant known as epithelioid inflammatory myofibroblastic sarcoma [8], [9]. In ALK-negative uterine IMTs, candidate fusion genes include ROS1, RET, PDGFRB, NTRK3, and INSR [4], [7], [10], [11], [12].

While most IMTs are indolent, approximately 25 % of cases have the potential to behave aggressively [3]. However, predicting the biological behavior of IMTs continues to be challenging. Factors such as tumor size, mitotic activity, necrosis, infiltrative borders, and lymphovascular invasion have been linked with aggressive outcomes [13], [14]. The 5th edition of the WHO classification of female genital tract tumors lists the suspicious features as size (>7 cm), moderate to severe atypia, high mitotic index, necrosis, and lymphovascular space invasion [15]. Recently a clinicopathological risk stratification score (CRSS) combined with NGS analysis has been suggested for intermediate-risk patients, allowing for the prediction of biological behavior [16]. The utility has been validated on additional 30 IMTs (13 malignant and 3 benign), recommending a combination of CRSS with p16 immunohistochemistry as a promising and cost-effective tool for predicting the aggressive outcome in those patients where NGS is not available [17].

We performed morphological, immunohistochemical, and DNA/RNA NGS analysis of 9 primary IMT cases (6 indolent and 3 aggressive) in order to use these data to evaluate the recently suggested algorithms for the prediction of clinical behavior, as finding proper algorithm to reveal IMT behaving in an aggressive manner is essential for patient outcome. The other aim was to describe the spectrum of alterations, and to search for a specific identifier of aggressive behavior.