Anaplastic Lymphoma Kinase Positive Aggressive Adult Lung Primary Inflammatory Myofibroblastoma Tumor: A Case and Literature Review

Abstract

Inflammatory myofibroblastoma tumor (IMT) is a rare mesenchymal neoplasm that develops in the lungs, retroperitoneum, or abdominopelvic region, and is most common in children and adolescents; although IMT usually has a good prognosis, some cases still show local invasion, recurrence, and even distant metastasis. Effective standard treatment for locally advanced or metastatic IMT is limited, but therapy with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) improves the prognosis in some patients with ALK protein expression or ALK gene fusions. This case reports a 39-year-old woman with recurrent fever, cough, sputum, chest tightness, and shortness of breath for more than 2 weeks. Contrast-enhanced computed tomography (CT) revealed a mass in the upper lobe of the right lung with ill-defined borders involving the mediastinum, pleura, and right hilum. Multiple pleural nodules and right-sided pleural effusion were also observed. IMT was diagnosed by lung biopsy, and ALK positive was confirmed by immunohistochemistry. The patient’s lung CT was reviewed after 3 weeks of treatment with brigatinib, and the right lung lesion and multiple metastases in the right pleura, hilar region, and mediastinum were significantly smaller than before. Additionally, the right pleural effusion was reduced, and the clinical symptoms were significantly improved compared to prior evaluations. Unlike most IMT cases, this patient’s tumor showed highly malignant biology, with pleural metastasis at the initial diagnosis, as well as rapid progression and a favorable response to ALK TKI. Brigatinib represents a potential therapeutic option for the treatment of IMT.

Introduction

Inflammatory myofibroblastoma tumor (IMT) is a rare mesenchymal neoplasm that constitutes 1% of all lung tumors. Patients are generally children and young adults. While IMT can occur in various locations, including the abdomen, pelvis, and extremities, the lung remains the most common site. Currently, IMT is classified as an intermediate neoplasm and has a propensity for local recurrence, although metastasis is rarely observed, except for the relatively recently described overtly malignant forms.^1,2

We reported a case of an aggressive adult patient with pulmonary IMT (PIMT).

Case Report

This case reported a 39-year-old female who presented to the hospital with recurrent fever with cough and sputum, chest tightness and shortness of breath for more than 2 weeks. She had no history of smoking and denied any occupational exposure, including asbestos, silica, mining, welding, or radon exposure. She has no family history of lung disease or lung cancer. There was no history of pulmonary computed tomography (CT) examination.

On February 26th, 2024, enhanced CT of the lungs showed a mass in the upper lobe of the right lung, which was poorly demarcated from the mediastinum, pleura, and the right hilum, multiple nodules in the right pleura, and pleural effusion in the right pleural cavity. The longest diameter of the mass was 9.04 cm (Figure 1). Then, ultrasonographic bronchoscopy was performed, suggesting an extrinsic compressive stenosis of the right main bronchus, and ultrasound detected an extraluminal mass in the right main bronchus.

Figure 1.

Chest CT images. This timeline showed the changes of the longest diameter of right lung lesion, which progressed rapidly and regressed after ALK TKI therapy.

Abbreviations: CT, computed tomography; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor.

On March 4,2024, an ultrasonic bronchoscopic aspiration biopsy of the right lung lesion and an ultrasound-guided percutaneous lung aspiration biopsy were performed. Histopathological examination revealed spindle-shaped tumor cells embedded in a fibrotic stroma, with mild nuclear atypia and rare mitotic figures. An inflammatory background was also observed, with long oval or vesicular nucleoli, small nucleoli, inconspicuous cell atypia, and rare nuclear division. Tumor cells were arranged in a disorderly manner and were unevenly dense. Interstitial mucus degeneration was obvious. Pleural effusion exfoliated cells are suggestive of pleural metastasis (Figure 2).

Figure 2.

Histological findings. Pathology based on ultrasound-guided percutaneous lung aspiration biopsy of the right lung lesion showed that nuclear heterogeneous cells were seen in the fibrotic tissue, myofibroblastic tumor was possible.

The differential diagnosis includes inflammatory leiomyosarcoma, ALK‑positive epithelioid fibrous histiocytoma, and certain ALK‑rearranged soft‑tissue sarcomas, which may share overlapping spindle cell morphology and ALK expression. In contrast to IMT, these entities often lack the characteristic polymorphous inflammatory infiltrate, show more pronounced cytologic atypia, or demonstrate distinct immunophenotypic signatures (eg, stronger desmin and h‑caldesmon staining in leiomyosarcoma; keratin expression and epithelioid morphology in ALK‑positive epithelioid fibrous histiocytoma). Incorporating SMA, desmin, cytokeratin, EMA, CD34, S100, and h‑caldesmon into the diagnostic panel helps further delineate these entities. The observed histologic features in our case, together with ALK immunopositivity and the inflammatory background, favor a diagnosis of IMT and argue against alternative ALK‑positive spindle cell tumors.

Due to limited biopsy material, it was difficult to define the specific type of tumor, so lung imaging and CT-guided percutaneous lung biopsy were performed again.

On March 20,2024, a repeat lung enhancement CT revealed a rapidly progressing right lung mass, right pleural metastases, and right pleural effusion with hilar and mediastinal metastases, showing 14.20 cm in the longest diameter of the mass (Figure 1). At the same time, the patient’s cough and chest tightness, and shortness of breath increased significantly.

On March 27,2024, the final pathologic diagnosis was spindle cell soft tissue tumor, first considered inflammatory myofibroblastoma, ALK immunohistochemistry (+) (Ventana ALK-D5F3-CDx assay). Immunohistochemistry demonstrated ALK positivity with a low proliferative index (Ki‑67 ~5%). The tumor cells were positive for CD34, SMA (partial), β‑catenin, and desmin (focal), and negative for STAT6 and CD117, supporting a diagnosis of inflammatory myofibroblastic tumor. Next-generation sequencing was not done for financial constraints. No extrapulmonary lesions were found.

After completing the second biopsy, the patient was given targeted therapy with brigatinib.

The patient’s lung CT was reviewed after 3 weeks of treatment with brigatinib. The right lung lesion and multiple metastases in the right pleura, hilar, and mediastinum were significantly reduced compared with the previous. The right pleural effusion was reduced, and clinical symptoms were significantly improved compared to previously (Figure 1). Overall response was partial remission.

The longest diameter of the tumor on the follow-up lung CT, on April 11, 2025, was 2.96 cm (Figure 1).

This patient has been on brigatinib and no resection for 14 months with no disease progression or significant adverse events. Tumor markers were not elevated, like carcinoembryonic antigen, throughout the treatment. Underlying disease prior to treatment was anemia grade 1. No adverse reactions related to therapeutic agents were found.

Discussion

Our patient was finally diagnosed with pulmonary inflammatory myofibroblastic tumor combined with ALK protein expression after two lung puncture biopsies. Unlike most IMT cases, this patient’s tumor exhibited highly malignant biology with pleural metastases at initial diagnosis, as well as rapid progression. Despite the extensive tumor load, this patient’s disease showed a rapid and significant remission to brigatinib that lasted for at least 14 months. This response suggests that aberrantly expressed, persistently activated ALK plays a major role in the growth and maintenance of the patient’s tumor, supporting the dependence of the IMT subset on ALK-mediated signaling. Brigatinib showed a new option for the treatment of IMT.

IMT is a rare tumor composed of myofibroblasts and fibroblastic spindle cells with an inflammatory infiltrate. Lung IMT accounts for 20% of primary lung tumors in children and less than 1% of primary lung tumors in adults.^1,3,4

Symptoms strongly depend on the location of the tumor. Pulmonary IMT usually presents fever and cough, often accompanied by dyspnea, arthralgia, clubbed fingers, night sweats, vomiting, and hemoptysis. Central IMT is often recognized earlier. Usually, IMT is an incidental finding, as many patients remain asymptomatic.⁵

The incidence of ALK rearrangements in IMT is relatively high, with approximately 50–60% of IMT cases carrying ALK fusions. In addition, other fusion genes have been detected, such as ROS1, neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF1R), and RET fusion genes.⁶ ALK has many fusion partners such as TPM3, TPM4, CLTC, CARS, RANBP2, ATIC, NUMA1, SQSTM1, etc. ALK expression is higher in younger patients and in extrapulmonary IMT.⁷ A study by Camela et al found that only 16% of the pulmonary IMTs reviewed were ALK-positive.⁵

It has been reported that patients with ALK gene rearrangements in IMT usually have a favorable prognosis, and ALK-negative lesions are more likely to develop distant metastases. However, ALK positivity has also been reported to be associated with local recurrence of IMT, and the detection of ALK fusion genes is important for predicting the prognosis of patients with IMT regarding tumor recurrence and metastasis.

A key limitation of this case is the absence of comprehensive molecular profiling. Next-generation sequencing (NGS) was not performed, which prevented identification of the specific ALK fusion partner as well as assessment for co-occurring genomic alterations. Fusion partner identification has emerging prognostic relevance in IMT, as different ALK fusion types may be associated with variable biological behavior, patterns of metastasis, and differential sensitivity or resistance to ALK tyrosine kinase inhibitors. Furthermore, without NGS, the generalizability of this case is limited because we cannot determine whether additional driver alterations or resistance mechanisms might have contributed to the aggressive clinical course or influenced the depth and durability of response to brigatinib. Incorporating comprehensive molecular profiling in future cases will help refine prognostication, guide optimal TKI selection and sequencing, and enhance understanding of the biological diversity within ALK-positive IMT.

The preferred treatment for IMT is complete surgical resection. There is no established standard of care for unresectable and advanced IMT. In this case, an ALK inhibitor may provide a durable response in unresectable or metastatic ALK-positive IMT.

A study of crizotinib for IMT in 2010 showed a clinical response in patients with ALK rearrangements.⁸ A prospective clinical trial of crizotinib for IMT showed partial responses in 3 of 7 IMT patients.⁹ An expanded cohort of this trial enrolled 14 patients with IMT and had an 86% response rate to crizotinib.¹⁰ Long-term follow-up showed a median progression-free survival (PFS) of 18 months in ALK-rearranged patients treated with crizotinib.¹¹ Several case reports have been published on the therapy of ALK TKIs for patients with IMT, including crizotinib, ceritinib, alectinib, loratinib, and brigatinib.^12–14 Relapses due to secondary ALK mutations have been reported.^7,15,16

Besides first-generation crizotinib approved the indication for IMT, other ALK TKIs have limited data. The detailed characteristics and treatment outcomes of first-line second/third-generation ALK TKI investigations are summarized in Table 1.^17–21

Table 1.

Summary of the Reported Cases of PIMT Receiving second/Third-Generation ALK TKI

Authors	Age/Sex	Primary Site	Metastatic site	ALK Fusion Partner	ALK TKI	Line	Best Response	PFS (months)	Treatment
Saiki et al17	26/M	Lung		EML4-ALK	Alectinib	First	PR	4.4+	Alectinib
Han et al18	56/F	Lung	Subcutaneous tissue and bone	EML4-ALK	Alectinib	First	PR	16+	Excision→Alectinib
Chanthong et al19	7/F	Lung	Brain	NR	Alectinib	First	CR	23	Excision→Vincristine, actinomycin D, and cyclophosphamide*5 cycles→Prednisolone, ibuprofen and celecoxib→Alectinib
Zheng et al20	34/F	Mediastinum		EML4-ALK	Loratinib	First	CR	15+	Loratinib→Excision→Loratinib
Sakoda et al21	73/F	Lung	Brain	EML5-ALK	Alectinib	First	PR	6+	Alectinib

Abbreviations: PIMT, pulmonary inflammatory myofibroblastic tumor; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor; M, male; F, female; EML, echinoderm microtubule-associated protein-like; NR, not reported; PR, partial response; CR, complete response; PFS, progression-free survival.

Brigatinib was selected as first‑line therapy in this patient for both biological and practical reasons. Although crizotinib is the only ALK inhibitor formally approved for IMT, next‑generation ALK inhibitors have demonstrated greater potency across a broader spectrum of ALK fusion variants and have reported clinical activity in aggressive or rapidly progressive disease. Brigatinib in particular offers enhanced kinase inhibition, activity against several secondary ALK resistance mutations, and strong efficacy in thoracic and mediastinal disease. Given the patient’s unusually aggressive baseline presentation—with rapid tumor enlargement and extensive pleural, hilar, and mediastinal involvement—initiating a more potent second‑generation TKI was considered essential to achieve rapid disease control. In addition, brigatinib was readily available in our center and presented a favorable tolerability profile for sustained treatment. These factors collectively informed the decision to use brigatinib as first‑line therapy rather than crizotinib or alectinib.

Real‑world evidence further contextualizes the durable response achieved with brigatinib in this case. Observational cohort studies in ALK‑positive NSCLC have consistently shown that next‑generation ALK TKIs demonstrate prolonged treatment durability and extended time‑to‑treatment‑discontinuation (TTD) outside of clinical trial settings. Large real‑world databases report that brigatinib exhibits sustained treatment persistence comparable to alectinib and superior to crizotinib, supporting its use in scenarios where long‑term disease control is a primary goal. Although these studies were conducted in NSCLC rather than IMT, the pharmacologic similarities and shared ALK‑driven biology provide useful context for interpreting the 14‑month durable response observed in our patient.^22,23

In the event of future disease progression, subsequent management would depend on the pattern of progression and underlying resistance mechanisms. Given that next-generation sequencing was not performed in this case, comprehensive molecular profiling would be essential to identify potential secondary ALK resistance mutations and guide TKI selection. For ALK-positive IMT, switching to another next-generation ALK inhibitor—such as lorlatinib, alectinib, or ceritinib—has shown activity in case reports and small series, particularly after progression on first- or second-generation ALK TKIs. Localized progression could be managed with focal radiotherapy or surgery when feasible, while systemic progression may require alternative TKIs, corticosteroid-based or cytotoxic regimens, or enrollment in clinical trials evaluating novel targeted approaches. These considerations highlight the importance of individualized therapeutic strategies and long-term follow-up in aggressive ALK-positive IMT.

The clinical implications of this case are that pulmonary inflammatory myofibroblastic tumor (PIMT), although rare and typically of low malignant potential, should be considered in the differential diagnosis of large primary lung masses in young and middle‑aged adults with nonspecific respiratory symptoms, and that rapid radiologic progression warrants repeat biopsy and comprehensive immunohistochemical evaluation including ALK testing. This patient’s dramatic and durable response to first‑line brigatinib highlights the critical role of ALK‑driven signaling in a subset of aggressive PIMTs and supports the use of second‑generation ALK tyrosine kinase inhibitors as a rational therapeutic option when complete surgical resection is not feasible. Furthermore, the case underscores the need for systematic collection of clinical, molecular, and outcome data in ALK‑positive IMT to refine prognostication, guide selection and sequencing of ALK TKIs, and clarify the role of other modalities, alongside long‑term follow‑up to monitor for late progression or resistance.

Conclusion

PIMT is a rare disease with a nonspecific onset of symptoms that should always be considered in the differential diagnosis of primary lung lesions in children and young adults. To confirm the diagnosis, histopathologic examination is necessary. Surgical resection is preferred, and overall survival is good if complete. Targeted therapy may be considered in ALK- positive patients, and beyond that, more data is needed on the efficacy of other TKIs, chemotherapy, and immunotherapy. Summarizing IMT cases is critical. These data will not only help to better understand IMT, but will also inform a rational targeted therapy strategy. Long-term follow-up of these patients will continue to be necessary. Further clinical studies are warranted to validate these findings and optimize diagnostic and therapeutic strategies for IMT.

Abbreviations

ALK, Anaplastic-lymphoma kinase; IMT, Inflammatory myofibroblastoma; PIMT, Pulmonary-IMT; TKI, Tyrosine kinase-inhibitor; CT, Computed-tomography; ROS1, c-ros-1; NTRK, Neurotrophic-tyrosine-receptor-kinase; PDGFR, Platelet-derived-growth-factor receptor; IGF1R, Insulin-like-growth-factor-1-receptor.

Ethics Committee Approval

This study was approved by Clinical Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University ([2025B] IIT Ethics Approval No. 0918) and was performed according to the Good Clinical Practice Guidelines and the Helsinki Declaration. Institutional approval was obtained from the First Affiliated Hospital, College of Medicine, Zhejiang University for the publication of the case detail.

Consent to Publication

Informed consent for the publication of identifying information/images in an online open-access publication was obtained from the patient.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.