Inflammatory myofibroblastic tumor (IMT) is a rare, mesenchymal tumor that has an increased incidence in childhood. Tumors are usually isolated to the chest, abdomen, and retroperitoneum, but metastatic presentations can be seen. Presenting symptoms are nonspecific and include fever, weight loss, pain, shortness of breath, and cough. Approximately 85% of IMTs harbor actionable kinase fusions. The diagnosis can be delayed because of overlapping features with inflammatory disorders, such as elevated inflammatory markers, increased immunoglobin G levels, fever, weight loss, and morphologic similarity with nonmalignant conditions. We present a girl aged 11 years with a TFG-ROS1 fusion–positive tumor of the lung that was initially diagnosed as an immunoglobin G4–related inflammatory pseudotumor. She underwent complete left-sided pneumonectomy and later recurred with widely metastatic disease. We then report the case of a boy aged 9 years with widely metastatic TFG-ROS1 fusion–positive IMT with rapid molecular diagnosis. In both children, there was an excellent response to oral targeted therapy. These cases reveal that rapid molecular testing of inflammatory tumors is not only important for diagnosis but also reveals therapeutic opportunities. Targeted inhibitors produce significant radiologic responses, enabling potentially curative treatment approaches for metastatic ROS1 fusion IMT with previously limited treatment options. Primary care pediatricians and pediatric subspecialists have a crucial role in the early consultation of a pediatric oncology center experienced in molecular diagnostics to facilitate a comprehensive evaluation for children with inflammatory tumors.

Inflammatory myofibroblastic tumors (IMTs) mainly occur in children and young adults. It is a rare tumor, with only 100 to 200 new cases annually in the United States. Metastatic presentations can be seen but are not typical. The most common sites for IMTs are the lung, abdomen, and retroperitoneum.1  Histologically, IMTs consist of spindle cell–appearing fibroblasts and myofibroblasts with an inflammatory lymphoplasmocytic infiltrate, fibrosis, and calcification.1  Previously, surgical resection had been the only curative approach.1  Surgical resection may require extensive procedures associated with significant morbidity and mortality risks. In some cases, a complete surgical resection may not be feasible. In addition, recurrences have been described.1,2 

Recently, several groups identified actionable kinase fusions in IMTs.39  Receptor tyrosine kinases are gatekeepers that regulate cell growth by phosphorylation of signal proteins. In kinase fusions, the phosphorylation domain of a strictly regulated enzyme is fused to a second protein, which causes loss of its regulation, constitutive activation, and abnormal cell growth. Approximately 50% of IMTs contain anaplastic lymphoma kinase (ALK) fusions. PDGFRB, NTRK, ROS1, and RET fusions have also been described.39  Targeted therapies for many kinase fusions present in IMTs are available. A kinase inhibitor is a type of enzyme inhibitor that can block the action of dysregulated protein kinases and stop abnormal cell growth. Kinase inhibitors have revealed efficacy in IMTs in a small prospective study10  and several case series.3,7,8,11  Mosse et al report an overall response rate of 86% (95% confidence interval [CI], 57–98) in 14 patients with metastatic or inoperable ALK fusion–positive IMT treated with crizotinib.10  Lovely et al and Mai et al have both reported localized ROS1 fusion–positive IMT, with responses to ROS1 inhibitors.3,11  Successful medical treatment of hematogenous metastatic and intracranial metastatic ROS1 fusion–positive IMT has not been reported.

The rare incidence of IMTs and the diversity of the fusion kinases identified in IMTs represent challenges for the ability to prospectively study targeted therapy matched to the molecular aberrations. However, a proportion of adult NON–SMALL cell lung cancer has ROS1 fusions that drive proliferation. A prospective phase 1 expansion trial revealed excellent response to crizotinib in patients with metastatic or locally advanced disease.1216  The combined partial and complete response rate to crizotinib in this trial was 72% (95% CI, 58%–83%). These responses were durable, with median duration of response of 24.7 months (95% CI, 15.2–45.3 months).14 

A general principle of precision oncology is that the activity of a drug is determined primarily by the molecular aberration and, to a lesser extent, by the disease context. This appears to be particularly true when the molecular aberration is a kinase fusion, as revealed by a response rate of 75% to NTRK inhibitors in 17 different cancer types in patients aged 4 months to 76 years.17  Therefore, results of ROS1 inhibitor trials in adult malignancies can be used to inform selection of therapy for pediatric patients with kinase fusion–positive tumors.

A girl aged 11 years presented to an outside institution with fever, weight loss, and cough, and a chest radiograph revealed a unilateral lung mass. She appeared fatigued, and her examination was notable for decreased ipsilateral breath sounds. Laboratory workup revealed an elevated C-reactive protein (CRP) level (150 mg /L, normal <5 mg/L). Cross-sectional imaging of the chest, abdomen, and brain demonstrated no evidence of other sites of disease. A needle biopsy specimen of the lung mass was inconclusive. She underwent complete pneumonectomy of the affected lung. Pathology was notable for spindle cells, with a dense, mixed chronic inflammatory infiltrate. Morphologic findings were consistent with IMT or immunoglobin G4 (IgG4) disease. Immunohistochemistry results for ALK, ROS, and NTRK expression were negative, and IgG4 plasma cell infiltration was present. Further workup revealed an elevated serum IgG4 (309 mg/dL, normal up to 110 mg/dL). Despite second-opinion, expert pathology review, diagnostic uncertainty remained, with IMT and IgG4 disease being the leading possibilities. She received no medical treatment. Nine months later, surveillance imaging identified a new pancreatic mass and local recurrence in the lung cavity. Although IMT remained in the differential diagnosis, the location of the new mass in the pancreas, which is the most frequently involved organ in systemic IgG4 disease;18  the morphologic appearance; and immunohistochemistry results of the previous lung tumor led to a decision to treat for IgG4 disease.18  The patient was treated for ∼2 months with rituximab and glucocorticoids, with ongoing weight loss (Fig 1A), fatigue and cough. Inflammatory markers also remained elevated (CRP level 107 mg/L, erythrocyte sedimentation rate 130 mm/hour). She received treatment in several centers before a general pediatrician and pediatric rheumatology–initiated referral for pediatric oncology consultation. Approximately 1 year after initial presentation, review of the outside pathology material (Fig 1B) led to initiation of molecular testing on the previously resected lung tumor, which identified a TFG-ROS1 fusion using an RNA next-generation sequencing fusion panel (Fig 1C and Supplemental Information). A diagnosis of TFG-ROS1–fused IMT, involving exons 1 to 4 of TFG and exons 35 to 43 of ROS1 with intact kinase domain of ROS1, was rendered. Formal staging imaging revealed additional sites of disease, including brain metastasis and subcutaneous deposits. Repotrectinib has revealed activity in ROS1 fusion–positive lung cancer in early reports.19  Treatment with this investigational ROS1 inhibitor as part of a first in child phase 1 clinical trial (NCT04094610) was initiated. She remains on this therapy, with resolution of symptoms and a confirmed radiologic partial response (Fig 1D).

FIGURE 1

A, Growth chart notable for weight loss while receiving rituximab and steroids and catch-up weight after initiation of medical treatment. B, Histology of ROS1-fused IMT reveals fascicles of myofibroblastic cells with interspersed inflammation (left), and the tumor also reveals large foci of plasma cell–rich infiltrate (right): hematoxylin and eosin stain (×100 magnifications). C, Targeted RNA fusion panel sequencing reveals that exon 4 of TFG is fused with exon 35 of ROS1. The predicted TFG-ROS1 fusion joins the 5-ft portion of TFG to the 3-ft portion of ROS1, connecting the PB1 domain of TFG to the intracellular kinase domain of ROS1. D, Response of targeting the TFG-ROS1 fusion with the ROS inhibitor repotrectinib. Brain MRI (upper panel) and positron emission tomography–computed tomography imaging (lower panel) at the time of relapse, before the initiation of repotrectinib, reveals a large fluorodeoxyglucose-avid chest mass and abdominal mass (left), and imaging after 8 cycles of repotrectinib is notable for absence of any positron emission tomography–avid disease (right). A partial response of a representative brain lesion is shown. PB1, Phox and Bem1.

FIGURE 1

A, Growth chart notable for weight loss while receiving rituximab and steroids and catch-up weight after initiation of medical treatment. B, Histology of ROS1-fused IMT reveals fascicles of myofibroblastic cells with interspersed inflammation (left), and the tumor also reveals large foci of plasma cell–rich infiltrate (right): hematoxylin and eosin stain (×100 magnifications). C, Targeted RNA fusion panel sequencing reveals that exon 4 of TFG is fused with exon 35 of ROS1. The predicted TFG-ROS1 fusion joins the 5-ft portion of TFG to the 3-ft portion of ROS1, connecting the PB1 domain of TFG to the intracellular kinase domain of ROS1. D, Response of targeting the TFG-ROS1 fusion with the ROS inhibitor repotrectinib. Brain MRI (upper panel) and positron emission tomography–computed tomography imaging (lower panel) at the time of relapse, before the initiation of repotrectinib, reveals a large fluorodeoxyglucose-avid chest mass and abdominal mass (left), and imaging after 8 cycles of repotrectinib is notable for absence of any positron emission tomography–avid disease (right). A partial response of a representative brain lesion is shown. PB1, Phox and Bem1.

Close modal

A boy aged 9 years presented to the emergency department after a syncopal event and was found to have a large chest mass. The patient had been previously asymptomatic without pain, cough, or fever. In retrospect, however, he had been fatigued for several years and had lost weight, moving from the 75th percentile to the 10th percentile for weight in the year before presentation (Fig 2A). He was transferred to our center for further management of a large chest mass (13.2 × 13.2 × 15.7 cm). His physical examination was notable for a well-appearing but cachectic child with absent ipsilateral breath sounds. A perianal mass and a leg mass were palpable. Laboratory studies were notable for an elevated CRP level (68.8 mg/L) and erythrocyte sedimentation rate (120 mm/hour). Further staging evaluation revealed a brain metastasis. An interventional radiology-guided biopsy specimen of the chest mass was notable for myofibroblastic cell proliferation, with a lymphoplasmacytic inflammatory infiltrate and patchy calcification (Fig 2B). Within 5 days of presentation, molecular testing using the same fusion panel identified the presence of a TFG-ROS1 kinase rearrangement (Fig 1C and Supplemental Information). On the basis of this finding, he was treated with the ROS1/ALK/MET kinase inhibitor crizotinib (Fig 2C) and experienced rapid, symptomatic improvement, with a decrease in tumor burden (Fig 2D). Remaining brain, chest, and soft tissue masses were resected after 8 to 9 cycles, without significant associated morbidity. The resected tumors revealed treatment effect. He has tolerated therapy well, and the only side effect has been a mild gait abnormality, with a lower-leg MRI revealing abnormal bone signal suggestive of crizotinib osteitis. His ambulation normalized over time, and the pain resolved without a dose reduction of crizotinib. He continues on crizotinib >1 year after surgical resection, without evidence of recurrence.

FIGURE 2

A, Growth chart notable for weight loss, from the 75th percentile to the 10th percentile for weight in the year before presentation and catch-up weight gain after initiation of medical treatment with the ROS1 inhibitor crizotinib. B, Histology of ROS1-fused IMT reveals variably cellular myofibroblastic proliferation arranging in a vaguely fascicular pattern, with interspersed inflammation and foci of calcification; by immunohistochemistry tests, tumor cells are positive for SMA and ROS1 (insets): hematoxylin and eosin stain (×100 magnification; insets: ×400 magnification). C, Structure of human ROS1 kinase domain in complex with crizotinib. Image of 3ZBF (McTigue, M., Deng, Y., Liu, W., Brooun, A., Stewart, A. [2012]: Structure of Human ROS1 Kinase Domain in Complex with Crizotinib. DOI: 10.2210/pdb3ZBF/pdb, Awad MM, Katayama R, McTigue M, et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013;368[25]:2395) created with The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC. D, Response of targeting the TFG-ROS1 fusion with the ROS1 inhibitor crizotinib. Brain MRI (upper panel), positron emission tomography–computed tomography imaging (lower panel), and chest computed tomography (middle panel), before the initiation of crizotinib (left) and after 7 to 9 cycles of crizotinib (middle), revealing reduction in the tumor mass in the brain, lung, and perianal lesion. A complete remission after the surgical resection of the remaining masses is shown on the right.

FIGURE 2

A, Growth chart notable for weight loss, from the 75th percentile to the 10th percentile for weight in the year before presentation and catch-up weight gain after initiation of medical treatment with the ROS1 inhibitor crizotinib. B, Histology of ROS1-fused IMT reveals variably cellular myofibroblastic proliferation arranging in a vaguely fascicular pattern, with interspersed inflammation and foci of calcification; by immunohistochemistry tests, tumor cells are positive for SMA and ROS1 (insets): hematoxylin and eosin stain (×100 magnification; insets: ×400 magnification). C, Structure of human ROS1 kinase domain in complex with crizotinib. Image of 3ZBF (McTigue, M., Deng, Y., Liu, W., Brooun, A., Stewart, A. [2012]: Structure of Human ROS1 Kinase Domain in Complex with Crizotinib. DOI: 10.2210/pdb3ZBF/pdb, Awad MM, Katayama R, McTigue M, et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013;368[25]:2395) created with The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC. D, Response of targeting the TFG-ROS1 fusion with the ROS1 inhibitor crizotinib. Brain MRI (upper panel), positron emission tomography–computed tomography imaging (lower panel), and chest computed tomography (middle panel), before the initiation of crizotinib (left) and after 7 to 9 cycles of crizotinib (middle), revealing reduction in the tumor mass in the brain, lung, and perianal lesion. A complete remission after the surgical resection of the remaining masses is shown on the right.

Close modal

IMT is a rare disease that affects 100 to 200 children and young adults in the United States every year. Because of the presenting signs and symptoms with evidence of systemic inflammation,20  the initial evaluation may be managed by a primary care pediatrician who may refer to a pediatric surgeon or rheumatologist. It was previously assumed that surgery was the main therapeutic approach for IMT, whereas chemotherapy for patients with tumors that could not be resected revealed low efficacy.3  Recent advances in molecular diagnostics identified actionable fusions in 85% of IMTs.3  As revealed in both cases, molecular testing enabled initiation of effective medical therapy, with low morbidity. Patient 2 achieved partial remission after treatment with crizotinib for ROS1 fusion–positive, metastatic IMT, and surgical resection was performed once the lesions had a significant radiographic response. These cases represent the first report of successful treatment of hematogenous, metastatic, ROS1-fused IMT and further reveal efficacy of ROS1 inhibitors against intracranial lesions.

Molecular testing can additionally aid in diagnosis by increasing diagnostic confidence in cases with clinical and morphologic similarity with nonmalignant conditions. As outlined in case 1, even dedicated immunohistochemistry can fail to detect fusion-protein expression because of imperfect sensitivity.21  Additionally, although the most common fusion partners consist of ALK, ROS1, and NTRK, there are other possible kinase fusions, and consequently, molecular testing, which usually assessed multiple genes potentially involved in kinase fusions, is more efficient than serial immunohistochemistry staining.3 

The general pediatrician can play a key role in the definitive diagnosis by ensuring involvement of a provider with experience in molecular oncology. Molecular oncologic testing is available in specialized laboratories, and the optimization of modern assays for use with standard pathology tissues allows for testing on previously obtained biopsies. Generally, diagnostic results are available within days to weeks. However, variable insurance coverage determinations and variable knowledge about testing remain barriers to testing. Improved knowledge about the role of molecular testing during the workup of possible malignancy will enable improved care for children with IMT.

We report 2 cases of widely metastatic ROS1-rearranged IMT responsive to kinase fusion inhibition. Additional research is needed to determine the optimal duration of kinase inhibition therapy and the role and optimal timing of local control and long-term outcomes in metastatic IMT treated with kinase inhibitor therapy. Further studies are also needed to clarify the ideal ROS1 inhibitor for use at the time of presentation and in the event of resistance development. The role of pediatric general practitioners, subspecialists, surgeons, pathologists, and oncologists in facilitating molecular testing to enable diagnosis and precision therapy is crucial.

We thank Christopher B. Weldon, MD, PhD; Katie P. Fehnel, MD; Gary Griffieth, MD; and Ezra M. Cohen, MD, for insightful discussions.

Dr Wachter conceptualized and designed the study, drafted the figures, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Al-Ibraheemi and Hollowell provided the pathology slides, revised the manuscript, and critically reviewed the manuscript for important intellectual content; Drs Trissal, DuBois, and Collins drafted figures, edited the manuscript, and critically reviewed the manuscript for important intellectual content; Dr Church provided the molecular testing, wrote the supplemental method, provided part of the figures, and revised the manuscript; Dr Janeway conceptualized and designed the study, edited the initial manuscript multiple times, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Permission to publish this case as a separate case report was obtained by the study sponsor Turning Point Therapeutics, Inc. Permission for the publication of both cases was obtained per institutional guidelines.

FUNDING: No external funding.

This trial has been registered at www.clinicaltrials.gov (identifier NCT04094610).

CI

confidence interval

CRP

C-reactive protein

IgG4

immunoglobin G4

IMT

inflammatory myofibroblastic tumor

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr DuBois has received consulting fees from Bayer and Loxo Oncology and travel expenses from Loxo Oncology, Roche, and Salarius Pharmaceuticals. Dr Church has received consulting fees from Bayer. Dr Janeway has received consulting fees from Bayer and Ipsen and speaking honoraria from Foundation Medicine and Takeda; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr DuBois has received consulting fees from Bayer and Loxo Oncology and travel expenses from Loxo Oncology, Roche, and Salarius Pharmaceuticals. Dr Church has received consulting fees from Bayer. Dr Janeway has received consulting fees from Bayer and Ipsen and speaking honoraria from Foundation Medicine and Takeda; the other authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data