Abstract

Background. Inflammatory myofibroblastic tumors (IMTs) are rare neoplasms in children. Traditionally, surgical resection has been the primary treatment modality with limited efficacy reported for conventional chemotherapy and radiation therapy. Recently, targeted therapies have emerged as potential options for selected cases. This study aimed to evaluate the demographic, clinical, laboratory, and radiological characteristics, as well as treatment outcomes, in children diagnosed with IMTs.

Methods. This study involved a retrospective review of medical records for eight children diagnosed with IMTs between 1990 and 2022. We collected demographic, clinical, laboratory, and radiological data, as well as treatment outcomes. Data on tumor characteristics, surgical procedures, and chemotherapy or targeted therapy treatments were extracted.

Results. The mean age at diagnosis was 9 years. None presented with metastatic disease at the time of diagnosis. Anaplastic lymphoma kinase (ALK) positivity was identified in tumor tissue from five patients. Among the six patients who underwent surgical resection, three achieved negative surgical margins. Of the three patients with positive surgical margins, one underwent re-resection, local and metastatic recurrences were noted in another, and one was started on crizotinib. A patient with an inoperable tumor at diagnosis was initiated on crizotinib and achieved complete remission. Ceritinib was administered to a patient with YWHAE-ROS fusion, resulting in more than 90% reduction in tumor volume. The median follow-up time was 67.5 months. The five-year overall survival and event-free survival rates for the cohort were 85.7% and 72.9%, respectively.

Conclusions. While surgical resection remains the cornerstone of treatment for IMTs, favorable outcomes can be achieved with chemotherapy and targeted therapies in selected cases. Increasing the utilization of targeted therapies may be beneficial, particularly through molecular studies aimed at minimizing the side effects associated with conventional chemotherapy.

Keywords: inflammatory myofibroblastic tumor, ALK inhibitor, crizotinib, ceritinib, childhood

Introduction

Inflammatory myofibroblastic tumors (IMTs) are rare tumors that typically occur in soft tissues, particularly in children and young adults, although they can arise at any age. They were previously known as inflammatory pseudotumors and are characterized by a proliferation of mesenchymal spindle cells along with a prominent inflammatory cell component. IMTs may lead to various clinical courses due to tumor size, localization and capacity to invade neighboring tissues. Epithelioid inflammatory myofibroblastic sarcoma (EIMS), which is a variant of IMT, is characterized by the proliferation of epithelioid and spindle-shaped myofibroblasts within a background of inflammatory cells. While IMTs are generally benign or low-grade tumors, EIMS presents with more aggressive features and a higher potential for recurrence and metastasis.1,2-4

Historically, surgical resection has been the primary treatment of IMTs, with little documented efficacy of traditional chemotherapy or radiation therapy.1-3,5

Comprehensive genomic analyses have identified various gene rearrangements, most notably involving the anaplastic lymphoma kinase (ALK) gene, which occurs in over 40% of IMT cases.6,7 Different patterns of ALK staining can be observed in both IMTs and EIMS, but the RANBP2-ALK fusion is specific to EIMS. Cases that do not exhibit ALK fusion are considerably less common and may involve translocations associated with ROS1, PDGFRB, NTRK3, RET, and IGF1R.8

In recent years, targeted therapies have been utilized for inoperable cases with identifiable targetable fusions. Therefore, the identification of specific molecular markers not only helps in diagnosing IMTs and differentiating them from other tumors with similar histological features but also is crucial for yielding new therapeutic targets and further refining existing treatment strategies. In this study, we share the treatment strategies applied to our patients diagnosed with IMT.

Materials and Methods

Medical records of children with IMT diagnosed and treated between 1990-2022 at the pediatric oncology clinic of a referral hospital were retrospectively reviewed. Demographic, clinical and radiological characteristics, treatment and outcome of the patients were evaluated. Follow-up time was recorded as the period from diagnosis to February 2023 or until the last visit. All patients were diagnosed histopathologically. In recent years, ALK has been investigated by immunocytochemistry (IHC) and ALK and other fusions were investigated by flourescence in situ hybridization (FISH) and real time polymerase chain reaction (RT-PCR).9

Non-mutilating surgical complete resection was performed whenever possible. In unresectable cases or in cases where surgery would lead to unacceptable morbidity, diagnosis was established by a tru-cut biopsy and neoadjuvant chemotherapy was initiated. In cases with incomplete resection, chemotherapy was used postoperatively. Chemotherapy consisted of adriamycin and ifosfamide.

The patients were evaluated by physical examination, complete blood count and biochemical tests before and during treatment and as necessary. None of the patients received radiation therapy.

This study was reviewed and approved by the Institutional Ethics Committee of İstanbul University, Oncology Institute (2023/1627454).

Statistical analyses

Statistics were calculated using IBM SPSS® 26 (Armonk, New York, U.S.). Kaplan-Meier method was used for survival analysis. Overall survival was calculated from the date of diagnosis to the date of last information on follow-up or death. Event-free survival was calculated from the date of diagnosis to the date of the first event, such as progression, relapse, or death from any cause.

Results

Patient characteristics are summarized in Table I. There were eight patients (5 male, 3 female), with a mean age at diagnosis of 9 years (range: 8 months to 17 years). Six patients had IMT and two had EIMS. None of the patients presented with metastatic disease at the time of diagnosis.

*The patient with a YWHAE-ROS fusion.

ALK: anaplastic lymphoma kinase AWD: alive with disease, EMS: Epithelioid inflammatory myofibroblastic sarcoma, F: female, IA: ifosfamide, adriamycine, ICE: ifosfamide, carboplatinum, etoposide, IMT: Inflammatory myofibroblastic tumor, M: male, NED: no evidence of disease, VAC: vincristine, adriamycine, cyclophosphamide.
Table I. Patients’ characteristics
Age/Sex Histopathology Localization ALK status Metastasis at diagnosis Treatment Surgical margin Recurrence / Progression Further treatment Latest status Follow-up period (months) Event-free survival (months)
12 y/M IMT Intestine Positive No Resection Negative No NED 163 163
10 y/M IMT Retroperitoneum Positive No Resection Positive Local and metastatic
(lung, omentum, liver, bone)		 4 courses with VAC, and 12 courses with ICE after progression with VAC EX 14 -
8 y/M EMS Back Unknown No Resection First positive. Negative after re-resection No NED 124 124
7 y/M IMT Retroperitoneum Positive No Crizotinib after resection for 12 mo. Positive No NED 99 98
12 y/F IMT Right lower extremity Positive No

Crizotinib

for 7 mo.

 Only biopsy Local
(2 mo after stopping crizotinib)		 Crizotinib NED 23 4
7 y/M IMT Liver Unknown No Resection Negative No NED 174 174
8 mo/F EMS Intestine Positive No Resection Negative No NED 36 35
17 y/F* IMT Right lower extremity Negative* No Resection Negative Local
(At 16 mo)		 One course with IA and ceritinib after toxicity with chemotherapy AWD 9 4

Three of the six patients (including one with EIMS) who underwent surgical resection alone achieved negative surgical margins and are currently under follow-up with no evidence of disease (NED). Among the other two patients who underwent surgical resection alone, both had positive surgical margins. One of these patients underwent re-resection for EIMS and is currently under follow-up without any events. A patient who underwent surgical resection at diagnosis and had positive surgical margins received crizotinib treatment for one year and is currently under follow-up in complete remission. Crizotinib treatment was initiated for a patient diagnosed with an inoperable tumor. After seven months of treatment, the patient achieved complete remission as confirmed by magnetic resonance imaging (MRI) (Fig. 1). Following evaluation by the multidisciplinary tumor board, it was decided to discontinue the treatment. However, local recurrence was detected on MRI two months after the cessation of crizotinib (Fig. 2). Although the patient reported no complaints and exhibited no significant findings on physical examination, crizotinib was restarted due to the infiltrative nature of the tumor and the potential morbidities associated with surgical intervention. Two months after resuming crizotinib, MRI showed a complete response (Fig. 3). The patient has been continuing treatment for four months.

Fig. 1. MRI findings before treatment and complete regression of mass after treatment. a) Coronal T2 weighted image showed large lobulated soft tissue mass infiltrating the muscles in the anterior part of right lower extremity, extending into the groin. b) Sagittal T1-weighted image with fat suppression after intravenous administration of gadolinium showed homogenous enhancement of the mass and bone involvement (arrow). Contrast TSE image demonstrated a hypointense intermuscular mass. c,d) Axial fat supressed T1 weighted images before (c) and after (d) intravenous administration of gadolinium showed homogenous enhancement of the mass surrounding the femoral neurovascular bundle. e) Coronal and f) axial T1-weighted image with fat suppression after intravenous administration of gadolinium showed complete regression of mass after treatment.
Fig. 2. MRI images at local recurrence. a) Coronal and b) axial T1-weighted image with fat suppression after intravenous administration of gadolinium showed homogenous enhancement of the mass (arrows) without bone involvement infiltrating the muscle plane in the proximal right lower extremity.
Fig. 3. Complete regression of the mass two months after re-treatment. a) Coronal and b) axial T1-weighted image with fat suppression after intravenous administration of gadolinium showed complete regression of the mass two months after re-treatment.

Another patient diagnosed with ALK-negative IMT, who had undergone surgical resection with negative margins, was subsequently treated with conventional chemotherapy consisting of ifosfamide and doxorubicin following disease recurrence. The patient presented with symptoms including cachexia, fever, and hypercalcemia after the recurrence of the disease. The etiological factors for the fever and hypercalcemia were investigated, and it was ultimately determined that these symptoms might be related to malignancy. Despite treatment with intravenous fluids and furosemide, the hypercalcemia remained refractory. After the first cycle of chemotherapy, the patient developed febrile neutropenia, which progressed to life-threatening acute respiratory distress syndrome (ARDS), necessitating 10 days of intensive care and the hypercalcemia was refractory to chemotherapy. Molecular analysis of the tumor tissue via next-generation sequencing (NGS) revealed the presence of a YWHAE-ROS fusion. Consequently, the patient was initiated on ceritinib treatment, which has demonstrated comparable activity to crizotinib against ROS1. As a result, treatment with ceritinib was initiated, which has shown comparable efficacy to crizotinib against ROS1. Within the first week of treatment, hypercalcemia improved, and the patient’s appetite significantly increased by the second week. Remarkably, the previously bedridden patient was able to mobilize. A follow-up MRI conducted three months post-initiation of treatment demonstrated a reduction of over 90% in tumor size. The patient has continued on ceritinib for six months. The patient has been using ceritinib for 6 months.

The median follow-up time for the entire cohort was 67.5 months (range: 9–174 months). The five-year overall survival and event-free survival rates for the group were 85.7% and 72.9%, respectively.

Discussion

Inflammatory myofibroblastic tumors, first described by Brunn et al. in 1939, are rare neoplasms that primarily occur in the lungs, abdomen, and orbit.10,11 They most commonly present within the first two decades of life, although they can arise at any age and can vary widely in size and location.1-4 Histologically benign, IMTs may exhibit locally aggressive behavior and, in rare cases, can metastasize.3,5

The primary treatment for IMTs has historically been complete surgical resection, although this can often be challenging and associated with significant morbidity. Incomplete resection has been linked to a high recurrence rate. Other treatment options, such as nonsteroidal anti-inflammatory drugs (NSAIDs), high-dose corticosteroids, chemotherapy, and radiotherapy, may carry serious side effects and their efficacy remains unclear.2,3

Approximately half of the observed IMTs involve a clonal translocation that activates the ALK receptor tyrosine kinase gene located at chromosome band 2p23, in conjunction with various partner genes. The frequency of ALK rearrangements is notably high among pediatric and young adult patients with IMT.6,12

In cases of IMTs that are negative for ALK fusion genes, other fusion genes such as c-ros oncogene 1 (ROS1), neurotrophin tropomyosin receptor kinase (NTRK), platelet-derived growth factor receptor (PDGFR), and RET have been identified.9 Additionally, certain partner genes associated with ALK or other fusion genes may correlate with clinical features. For example, EIMS is a subtype of IMT that exhibits aggressive behavior and is often associated with specific fusion genes like RANBP2-ALK and RRBP1-ALK. While numerous potential fusion genes have been identified in IMT, conducting gene panel testing at the initial stages can be cost-prohibitive. If the IHC method can help narrow down the candidates for fusion genes, it could be advantageous in reducing both the cost and time required for diagnosis.13-16

Following the study by Mosse et al.17 indicating the effectiveness and safety of crizotinib in pediatric patients with ALK-positive tumors, we began to consider its use in patients with inoperable tumors where ALK status was known at the time of diagnosis, as well as in cases with positive surgical margins. In one of the patients in this study, complete remission was achieved after seven months of crizotinib used as neoadjuvant therapy, leading to the discontinuation of treatment. However, a local recurrence was noted two months later, and a complete response was achieved two months after resuming crizotinib.

According to the existing literature, responses to crizotinib can vary among tumors, and there is no definitive guidance on the optimal duration of treatment for patients who respond positively.18-27 Tumor regression is often observed early in the treatment course.4,18 In a study involving eight cases of ALK-positive IMTs, crizotinib was discontinued in five patients after a median treatment duration of one year (range: 0.2 to 3.0 years). These patients were subsequently followed for a median of 1.7 years (range: 0.3 to 3.7 years), during which four achieved complete remission (CR) and one had stable disease (SD). This suggests that treatment may be safely discontinued without a rapid recurrence, in contrast to observations in anaplastic large cell lymphoma.17,28

Disease progression or recurrence has also been reported both during and after the cessation of crizotinib treatment. Cases of progression or recurrence occurring during or after crizotinib treatment are summarized in Supplementary Table 1.25-34

Following the previous reports by Lovly et al.12 and Comandini et al.35, here we represent the third case in the literature carrying YWHAE1-ROS1 fusion detected by NGS. Ceritinib, a selective oral tyrosine kinase inhibitor (TKI) of ALK, operates similarly to crizotinib but lacks MET-inhibiting capabilities and received FDA approval for treating ALK-positive non-small cell lung cancer (NSCLC) resistant to crizotinib. In enzymatic assays, ceritinib demonstrated 20 times greater potency against ALK compared to crizotinib and exhibited comparable efficacy against ROS. Additionally, ceritinib exhibited comparable efficacy to crizotinib against ROS1. In an open-label multicenter phase II study, ceritinib demonstrated robust clinical activity in NSCLC patients with ROS1 rearrangement, achieving a 62% objective response rate. The median progression-free survival was 9.3 months for all patients and 19.3 months for those who were crizotinib-naïve.36-38 Ceritinib has also exhibited clinical effectiveness in patients with IMT. Li et al.39 reported the first instance of using ceritinib to treat a ROS1-rearranged IMT, resulting in a partial response. By opting for ceritinib in our case, we were able to avoid the severe side effects associated with chemotherapy while achieving a high success rate in a remarkably short period.

This study has a few limitations. The small sample size (eight patients) limits generalizability, and the retrospective design introduces potential biases in treatment protocols and follow-up care. Not all patients underwent comprehensive molecular profiling, which could have missed other therapeutic targets. Additionally, the lack of long-term data on the side effects of targeted therapies like crizotinib and ceritinib is a significant gap. Lastly, a direct comparison between traditional chemotherapy and targeted therapies was not included.

Future studies should aim to include larger, multi-center cohorts to validate these findings. Expanding molecular profiling using next-generation sequencing could uncover additional therapeutic targets. Long-term studies are needed to assess the durability and safety of targeted therapies, and research should focus on identifying optimal treatment durations. Prospective trials comparing targeted therapies with conventional chemotherapy regimens would provide valuable insights into the best treatment approaches for IMTs.

In conclusion, the identification of molecular alterations in rare malignancies, such as IMTs, is essential for guiding personalized treatment strategies with targeted therapies. Tailoring treatment based on specific molecular profiles allows for the use of TKIs, which have demonstrated significant efficacy while often reducing the adverse effects associated with conventional chemotherapy. This personalized approach not only enhances treatment outcomes but also improves the overall quality of life for patients. By prioritizing a comprehensive diagnostic workup and focusing on individualized treatment plans, we can ensure that each patient receives the most appropriate and effective care, ultimately advancing the management of rare oncological conditions.

The authors declare that there is no conflict of interest to disclose.

Acknowledgements

We thank Assoc. Prof. Dr. Ahmet Salduz, İstanbul University, İstanbul Faculty of Medicine, Department of Orthopedics and Traumatology; Prof. Dr. Gökçen Ünverengil, İstanbul University, İstanbul Faculty of Medicine, Department of Pathology; Prof. Dr. Sebuh Kuruoglu, İstanbul University-Cerrahpaşa, Department of Radiology for orthopedics, pathology and radiology consultations.

Ethical approval

This study was approved by İstanbul University, Oncology Institute Ethics Committee (13.02.2023-1627454). Informed consent was obtained from the parents.

Author contribution

The authors confirm contribution to the paper as follows: Study conception and design: RK; data collection: ÜMY, BB, BZ; analysis and interpretation of results: ÜMY; draft manuscript preparation: ÜMY. All authors reviewed the results and approved the final version of the manuscript.

Source of funding

The authors declare the study received no funding.

Conflict of interest

The authors declare that there is no conflict of interest.

Supplementary materials
Supplementary Table 1

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Copyright © 2025 The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.

How to cite

1.
Yıldırım ÜM, Kebudi R, Zülfikar B, Bilgiç B. Inflammatory myofibroblastic tumors in children: clinical characteristics and treatment outcomes with a focus on targeted therapies. Turk J Pediatr 2025; 67: 51-60. https://doi.org/10.24953/turkjpediatr.2025.5463