Inflammatory myofibroblastic tumor (IMT) is a rare soft tissue neoplasm containing myofibroblastic spindle cells with inflammatory cells.1 It usually arises in the lung, abdomen, or pelvis and affects primarily children and young adults.2 Symptoms of disease are often restricted to the involved organ, and 15% to 30% of patients present with fever, malaise, microcytic anemia, weight loss, thrombocytosis, elevated erythrocyte sedimentation rate, or polyclonal hypergammaglobulinemia.3
Surgery is the primary management for patients with localized IMT; however, there is no standard treatment for patients with advanced and/or unresectable IMT. At the molecular level, gene fusion is a feature of IMT and also a common molecular feature of soft tissue sarcoma. Almost half of IMT cases carry ALK gene rearrangement that can be treated using ALK inhibitors,4–6 but therapeutic options for ALK-negative tumors are limited. ALK-negative IMTs may be more aggressive, with a higher frequency of metastasis compared with ALK-positive IMTs.7 Recent studies have described novel fusions involving ROS1, NTRK, RET, and PDGFRβ genes in a subset of ALK-negative cases.8–10 Little is known on the genomic level about potential oncogenic drivers in this subset of IMTs. Given the rarity of IMT, few prospective studies focusing on its targeted therapy are available. This report presents a case of TFG-ROS1–positive IMT that developed in the abdominal cavity and shrank remarkably after treatment with ceritinib.
Case Description
On September 3, 2018, a woman aged 22 years with no relevant past medical history presented to a local hospital with multiple masses in the left abdominal cavity and retroperitoneum seen on CT scan, and polypoid hyperplasia in the large intestine seen on colonoscopy. PET scan showed enhanced FDG-avid uptake in the retroperitoneum, suggesting a malignant tumor in the abdomen. The patient was subsequently referred to our hospital, where she underwent gastrojejunostomy on October 8, 2018. Postoperative pathologic diagnosis was intermediate spindle cell tumor of omental nodules. Under a light microscope, the tumor was found to be composed of proliferating fusiform fibroblasts/myofibroblasts and collagen fibers; fibroblasts were displayed with the shapes of striate, star, and bundle; and the mesenchyme contained abundant lymphocytes and plasmocytes. Immunohistochemical (IHC) staining of CD34, SMA, Ki67, β-catenin, CR, IgG4, CD38, CK, EMA, calretinin, and desmin were positive, whereas ALK, DOG1, CD117, S100, CD30, HMB45, Melan-A, STAT6, IgG, Era, progesterone receptor, and caldesmon were negative. Based on her IHC results and the tumor characteristics seen on light microscopy, the patient was finally diagnosed with abdominal IMT.
On November 7, 2018, the patient was treated with cisplatin (40 mg/d intravenously) and methotrexate (25 mg/d intravenously) as adjuvant chemotherapy for 1 cycle. Meanwhile, next-generation sequencing (NGS) of the tumor tissue was performed at OrigiMed. A TFG-ROS1 fusion involving exons 1–4 of TFG and exons 35–43 of ROS1 was identified (Figure 1). The fusion retained the intact kinase domain of ROS1. During reexamination in December 2018, PET/CT scan (Figure 2A, B) showed enhanced hypermetabolic lesions in the retroperitoneum and mesenteric roots and the left lower abdomen. The patient withdrew from chemotherapy because of severe adverse effects and started ceritinib (450 mg/d) monotherapy on December 8, 2018. After 2.5 months of ceritinib treatment, PET/CT scan showed remarkable shrinkage and even disappearance of masses in the retroperitoneum and mesenteric roots and the left lower abdomen (Figure 2C, D). Clinical efficacy was evaluated as partial response. The patient developed vomiting and diarrhea after ceritinib treatment. These adverse effects disappeared after a ceritinib dose reduction to 300 mg/d beginning in June 2019. In August 2019, she restarted ceritinib at 450 mg/d, and no adverse effects occurred.
Genomic fusion of exons 1–4 of TGF to exons 35–43 of ROS1.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7360
Genomic fusion of exons 1–4 of TGF to exons 35–43 of ROS1.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7360
Genomic fusion of exons 1–4 of TGF to exons 35–43 of ROS1.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7360
PET/CT imaging showing enhanced hypermetabolic lesions in the (A) retroperitoneum and mesenteric roots and (B) left lower abdomen before ceritinib treatment, and remarkable shrinkage and even disappearance of masses in the (C) retroperitoneum and mesenteric roots and (D) left lower abdomen after 2.5 months of ceritinib treatment.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7360
PET/CT imaging showing enhanced hypermetabolic lesions in the (A) retroperitoneum and mesenteric roots and (B) left lower abdomen before ceritinib treatment, and remarkable shrinkage and even disappearance of masses in the (C) retroperitoneum and mesenteric roots and (D) left lower abdomen after 2.5 months of ceritinib treatment.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7360
PET/CT imaging showing enhanced hypermetabolic lesions in the (A) retroperitoneum and mesenteric roots and (B) left lower abdomen before ceritinib treatment, and remarkable shrinkage and even disappearance of masses in the (C) retroperitoneum and mesenteric roots and (D) left lower abdomen after 2.5 months of ceritinib treatment.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7360
Discussion
According to WHO classification, IMT is currently a distinctive neoplasm composed of myofibroblasts accompanied by an inflammatory infiltrate of lymphocytes, plasma cells, and/or eosinophils.11 Surgery is considered the main therapeutic approach for IMT, because other treatment approaches for patients with advanced and/or unresectable IMT are extremely limited. Importantly, IMT has drawn increasing attention because of its molecular characteristics and actionable targets reported in recent years. This report describes a woman aged 22 years who was diagnosed with ALK-negative abdominal IMT based on IHC results and tumor characteristics seen on light microscopy, and in whom NGS testing identified a TFG-ROS1 fusion. The patient achieved partial response after treatment with ceritinib. This report provides a new potential therapeutic option for some patients with ROS1 gene rearrangement of this tumor type.
ROS1 is a receptor tyrosine kinase involved in the regulation of several cellular processes, including proliferation, differentiation, apoptosis, and cell migration.12 Substantial evidence supports ROS1 as a key player in many solid tumors, including non–small cell lung cancer (NSCLC), cholangiocarcinoma, gastric adenocarcinoma, and colorectal cancer.13 ROS1 rearrangements create fusion proteins that result in constitutive activation of the tyrosine kinase and acceleration of cellular proliferation.14,15 ROS1 gene fusions were recently identified in a subset of ALK-negative IMT,8,16 suggesting a new diagnostic marker for this group of neoplasms. Thus far, only 2 ROS1 fusion partners, TFG and YWHAE, have been identified in IMTs, with TFG the most common partner.8,16,17 In our patient’s case, because complete tumor resection was not possible, tumor biopsies were subjected to NGS testing and a TFG-ROS1 fusion was identified. The chromosomal rearrangement was identified between regions 3p12 and 6q22, causing fusion between exon 4 of TFG and exon 35 of ROS1. This result is consistent with previous reports on TFG-ROS1 fusion, the breakpoints of which are located between exon 4 of TFG and exon 34 or 35 of ROS1, leading to constitutive activation of ROS1 that contains its intact kinase domain.8,18
The discovery of ROS1 fusions in patients with IMT has facilitated the clinical development of ROS1 inhibitors, including crizotinib and ceritinib. Crizotinib is a small molecule tyrosine kinase inhibitor (TKI) that was found to actively inhibit ALK, MET, and ROS1. Crizotinib was originally developed as an anti-MET molecule,19 but subsequently showed significant activity in ALK-driven tumors and was FDA-approved for ALK-positive advanced NSCLC.20 Crizotinib has also shown remarkable efficacy against ROS1-positive lung cancer and was the first TKI approved for ROS1-positive advanced NSCLC.21 A patient aged 14 years with pulmonary IMT with a TFG-ROS1 fusion achieved continuous remission22 and a boy aged 8 years with treatment-refractory ALK-negative IMT harboring a TFG-ROS1 fusion experienced a dramatic response after treatment with crizotinib.8 However, another study found that a patient aged 59 years with metastatic gastric IMT carrying a TFG-ROS1 fusion and treated with crizotinib showed a poor response.23
Ceritinib, a selective oral TKI of ALK, is similar in action to crizotinib without MET-inhibiting ability. It was FDA-approved for treatment of crizotinib-resistant ALK-positive NSCLC. In enzymatic assays, ceritinib showed 20 times greater potency than crizotinib against ALK.24 In addition, ceritinib has shown comparable activity to crizotinib against ROS1.25,26 In an open-label multicenter phase II study, ceritinib showed potent clinical activity in patients with NSCLC harboring ROS1 rearrangement, with a 62% objective response rate and 9.3 and 19.3 months of median progression-free survival among all patients and those who were crizotinib-naïve, respectively.27 Ceritinib has also shown clinical activity in patients with IMT. A male patient aged 32 years with an ALK-rearranged IMT showed partial response to ceritinib after failure of crizotinib,28 and another patient with a highly aggressive ALK-rearranged IMT arising in the pleural cavity showed a drastic response to 2 ALK inhibitors: ASP3026 and ceritinib.5 In our study, the patient began ceritinib therapy and achieved partial response with an excellent tolerance after 2.5 months. This is the first report of a patient with ROS1-rearranged IMT being treated successfully with ceritinib.
Conclusions
Because no standard treatment exists for patients with advanced and/or unresectable IMT, we hope that the identification of actionable genetic alterations will redefine management strategies for this disease. We identified a TFG-ROS1 fusion in a patient with IMT, who showed remarkable tumor shrinkage and achieved partial response after treatment with ceritinib. Our study provides the first report of a patient with ROS1-rearranged IMT being treated successfully with ceritinib. However, the response seen in this patient, although promising, requires further investigation in large clinical trials.
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