RESUMEN
Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate. Diagnostic challenges arise from the diverse pathological presentation, variable symptomatology, and lack of different imaging features. However, IMT is identified by the fusion of the anaplastic lymphoma kinase (ALK) gene, which is present in approximately 70% of cases, with various fusion partners, including ran-binding protein 2 (RANBP2), which allows confirmation of the diagnosis. While surgery is the preferred approach for localized tumors, the optimal long-term treatment for advanced or metastatic disease is difficult to define. Targeted therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in IMT. Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement. However, most patients face resistance and disease progression, requiring consideration of sequential treatments. Combining radiotherapy with targeted therapy appears to be beneficial in this indication. Early promising results have also been achieved with immunotherapy, indicating potential for combined therapy approaches. However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy.
Asunto(s)
Neoplasias de Tejido Muscular , Humanos , Neoplasias de Tejido Muscular/genética , Neoplasias de Tejido Muscular/diagnóstico , Neoplasias de Tejido Muscular/patología , Neoplasias de Tejido Muscular/terapia , Neoplasias de Tejido Muscular/tratamiento farmacológico , Quinasa de Linfoma Anaplásico/genética , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
INTRODUCTION: Inflammatory myofibroblastic tumor (IMT) is a rare invasive soft tissue tumor. Many IMTs are positive for anaplastic lymphoma kinase (ALK) with ALK gene fusion; other gene mutations have also been reported, which indicates a key role for genetic testing and the development of target therapy to optimize treatment strategies. PATIENT CONCERNS: We report 2 patients who obtained clinical benefits following targeted treatment with ensartinib. DIAGNOSIS: The first patient was diagnosed as IMT, with TFG-ROS1 fusion gene mutation. The second patient was IMT harboring the ALK-STRN fusion gene mutation. INTERVENTIONS: We performed gene testing for these 2 patients. According to the test result, both patients received ensartinib 225 mg QD as targeted therapy for a 30-day cycle. OUTCOMES: The first patient achieved partial remission and maintained a stable state for 14.7 months. The second patient was treated for 10 months and reached complete remission after 5 months and is currently still benefiting from treatment. Treatment-related side effects were mild in both patients. CONCLUSION: Our cases provided some new insights and approaches for the clinical diagnosis and treatment of IMT.
Asunto(s)
Neoplasias de Tejido Muscular , Humanos , Quinasa de Linfoma Anaplásico/genética , Antineoplásicos/uso terapéutico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Neoplasias de Tejido Muscular/genética , Neoplasias de Tejido Muscular/patología , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Inflammatory myofibroblastic tumors (IMTs) are mesenchymal solid tumors, in which anaplastic lymphoma kinase (ALK) gene rearrangement might be detected. A 48-year-old female presented with IMT of lung, treated with surgery. After a 39-month disease-free survival metastatic recurrence was occurred involving soft tissues both infra- and supradiaphragmatic regions. The biopsies obtained from metastatic regions confirmed the recurrence with ALK rearrangement in immunohistochemistry. Initial partial response observed early in treatment course remained as a stable disease with crizotinib treatment. Although an excellent outcome with overall survival of 57 months was observed in our case, there is not enough information about survivals with crizotinib and the treatment options beyond progression. Therefore, every individual case has a unique value paving the way for more effective treatment.
Asunto(s)
Antineoplásicos/uso terapéutico , Crizotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Quinasa de Linfoma Anaplásico/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Persona de Mediana Edad , Neoplasias de Tejido Muscular/genéticaRESUMEN
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.
Asunto(s)
Neoplasias Pulmonares/genética , Neoplasias de Tejido Muscular/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Proteínas/genética , Proteínas Proto-Oncogénicas/genética , Antineoplásicos Inmunológicos/uso terapéutico , Niño , Crizotinib/uso terapéutico , Diagnóstico Diferencial , Femenino , Glucocorticoides/uso terapéutico , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Inflamación/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Masculino , Terapia Molecular Dirigida/métodos , Recurrencia Local de Neoplasia , Neoplasias de Tejido Muscular/diagnóstico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Neoplasias de Tejido Muscular/cirugía , Neoplasias Pancreáticas/secundario , Granuloma de Células Plasmáticas del Pulmón/diagnóstico , Enfermedades Raras/diagnóstico , Enfermedades Raras/tratamiento farmacológico , Enfermedades Raras/genética , Enfermedades Raras/cirugía , Rituximab/uso terapéuticoRESUMEN
PURPOSE: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up. PATIENTS/METHODS: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful. RESULTS: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data. CONCLUSION: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses. CLINICAL TRIAL NUMBER: EORTC 90101, NCT01524926.
Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Crizotinib/uso terapéutico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Anciano , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Antineoplásicos/efectos adversos , Crizotinib/efectos adversos , Progresión de la Enfermedad , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias de Tejido Muscular/enzimología , Neoplasias de Tejido Muscular/genética , Neoplasias de Tejido Muscular/mortalidad , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Factores de Tiempo , Adulto JovenRESUMEN
Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor of intermediate malignant potential that predominantly affects children, adolescents and young adults. IMT has a predilection for the lung, abdomen, pelvis, and retroperitoneum, however, can affect any part of the body. IMT is typically localized, and multifocal or metastatic disease is uncommon. Complete surgical resection is the treatment of choice when feasible. There is no established standard of care for unresectable and advanced IMT. Approximately half of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, and fusions involving ROS1, PDGFRß, RET and NTRK have also been described. Given the molecular landscape of IMT, management of these tumors has evolved to include tyrosine kinase inhibitors and novel targeted therapeutics. This review highlights the molecular characteristics, evolution of targeted therapies and the remaining challenges in the management of IMT.
Asunto(s)
Neoplasias de Tejido Muscular , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Terapia Molecular Dirigida , Neoplasias de Tejido Muscular/diagnóstico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Neoplasias de Tejido Muscular/genética , Neoplasias de Tejido Muscular/cirugía , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Sulfonas/efectos adversos , Sulfonas/uso terapéutico , Resultado del TratamientoRESUMEN
Most inflammatory myofibroblastic tumors (IMTs) harbor ALK fusions but oncogene fusions involving ROS1, RET, NTRK, and PDGFR also occur. The recognition that most IMTs harbor receptor tyrosine kinase fusions has provided a rationale for the use of tyrosine kinase inhibitors to target these oncogenic drivers in advanced IMTs. Crizotinib has been effective in ALK and ROS1-positive IMTs but resistance eventually develops. Here we report the successful use of lorlatinib in a patient with heavily pretreated ROS1-positive IMT of the chest wall with acquired crizotinib-resistance and metastasis to the brain.
Asunto(s)
Aminopiridinas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/secundario , Lactamas/uso terapéutico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Neoplasias de Tejido Muscular/patología , Pirazoles/uso terapéutico , Neoplasias Torácicas/tratamiento farmacológico , Neoplasias Torácicas/patología , Adolescente , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Humanos , Masculino , Miofibroblastos/efectos de los fármacos , Miofibroblastos/patología , Neoplasias de Tejido Muscular/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/uso terapéutico , Proteínas/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias Torácicas/genéticaRESUMEN
Inflammatory myofibroblastic tumor (IMT) is a rare borderline malignancy, usually treated with surgery only. Exceedingly rare cases of inoperable, recurrent, or metastatic IMTs pose a therapeutic challenge. We report successful treatment of a 7-year-old girl with an inoperable anaplastic lymphoma kinase (ALK)-negative IMT of the tongue. The patient underwent various anti-inflammatory (steroids, nonsteroidal anti-inflammatory drugs, clarithromycin) and antiproliferative (chemotherapy) therapies to enable tumor regression and complete resection. Ultimately, next-generation sequencing of the tumor revealed a TFG-ROS-1 translocation, allowing for an off-label targeted therapy with crizotinib. Crizotinib treatment caused slight tumor regression but evident change of its structure, allowing for complete non-mutilating resection. Two histopathology examinations revealed complete disappearance of neoplastic cells following therapy. The patient remains disease-free 22 months after the delayed surgery. In children with inoperable ALK-negative IMTs, molecular testing must be performed to identify other targetable oncogenic fusions, including TFG-ROS1.
Asunto(s)
Antineoplásicos/uso terapéutico , Crizotinib/uso terapéutico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Neoplasias de la Lengua/tratamiento farmacológico , Quinasa de Linfoma Anaplásico/genética , Niño , Femenino , Humanos , Neoplasias de Tejido Muscular/genética , Neoplasias de Tejido Muscular/patología , Neoplasias de Tejido Muscular/cirugía , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/cirugíaRESUMEN
Myofibroblastic tumors are rare lesions which can affect any part of the body. Although benign, their mass effect causes symptoms that can become life-threatening. Supraglottic laryngeal involvement is extremely rare, with only 4 cases described in the English literature. Because the pathophysiology is unknown and the incidence is so low, there is no standardized therapeutic management, although for laryngeal tumors surgery has traditionally been the preferred initial option. Another less common option is intravenous and oral corticosteroid therapy, but this is usually reserved for myofibroblastic tumors in other head and neck sites that are more difficult to access surgically, or patients who cannot undergo surgery. These lesions have a very high tendency to recur, and morbidity rates are therefore also high. We present a case of supraglottic myofibroblastic tumor in which we elected high-dose corticosteroid therapy as the only form of treatment. With this new therapeutic approach, we avoided the undesirable effects of the usual type of surgery. At the 12-month follow-up, the patient is in complete remission.
Asunto(s)
Corticoesteroides/uso terapéutico , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Humanos , Neoplasias Laríngeas/patología , Laringe/patología , Neoplasias de Tejido Muscular/patología , Resultado del TratamientoRESUMEN
Inflammatory myofibroblastic tumors (IMTs) are rare in neonates. IMTs of the tongue are also very rare in infancy, with only 1 case reported in this age group. The mainstay of therapy has traditionally been surgery, which can be devastating to surrounding structures and negatively impact prognosis. Approximately 50% of IMTs harbor a translocation involving the anaplastic lymphoma kinase gene. We describe a case of IMT of the tongue in a neonate treated with debulking and an anaplastic lymphoma kinase inhibitor. The patient achieved complete response and remains disease-free 1.5 year following completion of therapy.
Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Neoplasias de Tejido Muscular/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Lengua/tratamiento farmacológico , Femenino , Humanos , Recién Nacido , Neoplasias de Tejido Muscular/patología , Neoplasias de la Lengua/patología , Resultado del TratamientoRESUMEN
An inflammatory myofibroblastic tumor (IMT) is a rare invasive soft tissue mass with intramuscular penetration that is primarily treated via a surgical procedure. However, with unclear boundaries and a high rate of relapse, there is no standard treatment for recurrence or unresectable tumors. It is noteworthy that approximately half of IMTs harbor genetic rearrangements of the anaplastic lymphoma kinase (ALK). ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. Here, we present a case of a 15-year-old patient with IMT around the hip. Next-generation sequencing (NGS) revealed an LRRFIP1-ALK fusion, which has not yet been reported in the literature. Crizotinib, an ALK inhibitor, was effective in the treatment of this patient, indicating that ALK inhibitors may be effective for IMT with LRRFIP1-ALK fusions. This report expands the list of gene fusions in IMTs and highlights a new target for treatment.
Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/genética , Crizotinib/uso terapéutico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Proteínas de Unión al ARN/genética , Adolescente , Fusión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Neoplasias de Tejido Muscular/genéticaRESUMEN
BACKGROUND: Crizotinib is a first-generation tyrosine kinase inhibitor used for anaplastic lymphoma kinase (ALK) positive cancers. Simple and complex renal cyst formation is a rare complication of crizotinib use that has been reported previously in the adult population. CASE: We report a case of a right renal mass in a 17-year-old with ALK-positive epithelioid inflammatory myofibroblastic sarcoma treated with Crizotinib. After cessation of Crizotinib and initiating Alectenib, a second generation ALK inhibitor, the mass decreased in size and the patient remained asymptomatic without evidence of recurrence at three months of follow-up.
Asunto(s)
Antineoplásicos/efectos adversos , Crizotinib/efectos adversos , Enfermedades Renales Quísticas/inducido químicamente , Adolescente , Antineoplásicos/uso terapéutico , Crizotinib/uso terapéutico , Humanos , Masculino , Neoplasias de Tejido Muscular/química , Neoplasias de Tejido Muscular/tratamiento farmacológico , Proteínas Tirosina Quinasas Receptoras/análisis , Sarcoma/química , Sarcoma/tratamiento farmacológicoRESUMEN
Inflammatory myofibroblastic tumors are rare tumors with an ALK (anaplastic lymphoma kinase) gene rearrangement in up to 65% of all cases. In our patient, the tumor was not primary resectable due to its extension. Under neoadjuvant treatment with the first generation ALK inhibitor crizotinib no tumor response was seen, but the following therapy with the next generation ALK inhibitor lorlatinib led to a rapid and deep response, enabling a complete tumor resection by partial cystectomy. Our case indicates that ALK positive inflammatory myofibroblastic tumors which do not respond to ALK inhibition with crizotinib can be successfully treated with newer agents.
Asunto(s)
Aminopiridinas/administración & dosificación , Quinasa de Linfoma Anaplásico/genética , Crizotinib/administración & dosificación , Fibronectinas/genética , Lactamas/administración & dosificación , Miofibroblastos/citología , Proteínas de Fusión Oncogénica/genética , Pirazoles/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Adulto , Quinasa de Linfoma Anaplásico/metabolismo , Antineoplásicos/administración & dosificación , Cistoscopía , Femenino , Fibronectinas/metabolismo , Fusión Génica , Humanos , Inflamación , Neoplasias de Tejido Muscular/tratamiento farmacológico , Neoplasias de Tejido Muscular/genética , Proteínas de Fusión Oncogénica/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Resultado del TratamientoRESUMEN
Oral inflammatory myofibroblastic tumor (IMT) is extremely rare and its manifestation as generalized gingival enlargement (GGE) has never been reported. We are reporting the case of 50-year-old female patient presenting with recurrent GGE for 4 years. Panoramic radiograph revealed severe bone loss in posterior sextants and root resorption in some teeth. Initial incisional biopsy was suggestive of chronic inflammatory infiltrate with fibrocollagenous tissue. Definitive treatment comprised of surgical excision of the enlarged gingiva with a tapering dose of steroid therapy. Histopathological and immunohistochemical examination from a repeat biopsy of deeper tissues was suggestive IMT. No recurrence was found at 2 years follow up. Recurrent GGE with advanced bone loss and external root resorption should raise the suspicion of a locally aggressive lesion. Dentists should be aware of oral IMT and include it in differential diagnosis of gingival enlargements for comprehensive management to avoid recurrence of the lesion.
Asunto(s)
Encía/patología , Inflamación , Recurrencia Local de Neoplasia , Neoplasias de Tejido Muscular/diagnóstico , Biopsia , Femenino , Técnicas Histológicas , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Esteroides/uso terapéutico , Resultado del TratamientoRESUMEN
Pulmonary inflammatory myofibroblastic tumor (IMT) is a rare tumor. Here, we report two cases of pulmonary IMT successfully treated with platinum and pemetrexed. The results from this study suggest that platinum-pemetrexed might be an effective therapy in patients with IMT, but requires further investigation.
Asunto(s)
Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias de Tejido Muscular/tratamiento farmacológico , Pemetrexed/uso terapéutico , Platino (Metal)/uso terapéutico , Biomarcadores de Tumor , Femenino , Humanos , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Neoplasias de Tejido Muscular/patología , Pemetrexed/farmacología , Platino (Metal)/farmacologíaRESUMEN
INTRODUCTION: We report the clinical findings and results of treatment in the cohort of patients with inflammatory myofibroblastic tumor (IMT) managed according to the European pediatric Soft Tissue Sarcoma Study Group (EpSSG) protocol from 2005 to 2016. METHODS: Patients (<25 years old) with IMT from 9 countries were prospectively registered via a web-based system. Their histology was reviewed by a national/international pathology panel. Immunohistochemistry for ALK assessment was mandatory. No adjuvant therapy was suggested for initially resected tumors. No specific systemic therapy was recommended for cases of unresectable disease. RESULTS: Among 80 cases of IMT registered, 20 were excluded because pathology review led to a revised diagnosis. Of the remaining 60 patients (median age 9.5 years), 59 had localized, and 1 had multifocal/metastatic disease. The lung was the primary site in 14 cases. IMT developed as a second tumor in 2 cases. Forty cases were ALK-positive, and 20 were ALK-negative. Five-year event-free survival (EFS) and overall survival (OS) were 82.9% and 98.1%, respectively. No clinical variables correlated statistically with the outcome: survival was the same for ALK-positive and ALK-negative cases. The overall response to systemic therapy was 64%: 8/10 cases responded to vinblastine-methotrexate chemotherapy, and 5/5 to ALK-inhibitors. CONCLUSIONS: This study demonstrated a good overall prognosis for IMT, even for initially unresectable disease and in ALK-negative cases. Chemotherapy is still a valid option for advanced disease. Larger studies involving both pediatric and adult patients are needed to clarify the role of ALK inhibitors.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inflamación/tratamiento farmacológico , Miofibroblastos/efectos de los fármacos , Neoplasias de Tejido Muscular/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Inflamación/patología , Masculino , Miofibroblastos/patología , Neoplasias de Tejido Muscular/patología , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Inflammatory myofibroblastic tumors arising in infants are rare, poorly investigated and mostly reported as isolated cases or as a part of larger series thus, their clinicopathological and molecular features are essentially unknown. Archival files from two large pediatric institutions and a tumor registry were queried for pediatric inflammatory myofibroblastic tumors. Available material from patients ≤12 months of age was reviewed. Additional immunostains (ALK-1, D240, WT1) and ALK-FISH studies were performed as needed. Targeted anchored multiplex PCR with next-generation sequencing was done in all cases. A total of 12 of 131 infantile cases (mean 5.5 months) were identified (M:F of 2:1). Anatomic locations included intestinal/mesenteric (n = 6), head/neck (n = 3), and viscera (n = 3). Half of tumors showed a hypocellular myxoid pattern, perivascular condensation, and prominent vasculature with vague glomeruloid structures present in four of them. The remaining cases exhibited a more cellular pattern with minimal myxoid component. ALK-1 immunohistochemistry was positive in most cases (11/12) with cytoplasmic-diffuse (n = 6), cytoplasmic-granular (n = 2), and dot-like (n = 3) staining patterns. ALK fusion partners identified in five cases included EML4, TPM4, RANBP2, and a novel KLC1. Three inflammatory myofibroblastic tumors showed fusions with other kinases including TFG-ROS1 and novel FN1-ROS1 and RBPMS-NTRK3 rearrangements. Favorable outcome was documented in most cases (10/11) with available follow-up (median 17 months) while three patients were successfully treated with crizotinib. In summary, infantile inflammatory myofibroblastic tumors are rare and can exhibit paucicellular, extensively myxoid/vascular morphology with peculiar immunophenotype mimicking other mesenchymal or vascular lesions. All tumors harbored kinase fusions involving ALK, ROS1, and NTRK3 including three novel fusion partners (KLC1, FN1, and RBPMS, respectively). A favorable response to crizotinib seen in three cases supports its potential use in infants as seen in older patients. Awareness of these unusual morphologic, immunophenotypic, and molecular features is critical for appropriate diagnosis and optimized targeted therapy.
Asunto(s)
Biomarcadores de Tumor/genética , Miofibroblastos/patología , Neoplasias de Tejido Muscular/genética , Neoplasias de Tejido Muscular/patología , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Crizotinib/uso terapéutico , Femenino , Fusión Génica , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Italia , Cinesinas , Masculino , Miofibroblastos/efectos de los fármacos , Miofibroblastos/enzimología , Neoplasias de Tejido Muscular/tratamiento farmacológico , Neoplasias de Tejido Muscular/enzimología , Fenotipo , Philadelphia , Inhibidores de Proteínas Quinasas/uso terapéutico , Sistema de Registros , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/enzimologíaRESUMEN
INTRODUCTION: Inflammatory myofibroblastic tumor is a rare disease which is typically seen in children and young adults. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in over-expression of anaplastic lymphoma kinase gene. Herein, we present two anaplastic lymphoma kinase-positive cases with long-term remission with crizotinib. We do not know how long these therapies need to be continued. CASE REPORTS: We present two cases of inflammatory myofibroblastic tumor treated with anaplastic lymphoma kinase inhibitor therapies: an 8-year-old Turkish boy and a 21-year-old Caucasian man. MANAGEMENT AND OUTCOME: Two cases, both with good tumor control under crizotinib, but one who progressed on drug holiday, responded again to the same drug, and had a very short period of response after restarting crizotinib. CONCLUSION: A molecular-targeted drug (anaplastic lymphoma kinase inhibitor) was found to be extremely effective as selective therapy for inflammatory myofibroblastic tumor with anaplastic lymphoma kinase translocation. Here, we want to emphasize the continuation of this treatment after achieving a good response until progression or a major side effect.
Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Antineoplásicos/administración & dosificación , Crizotinib/administración & dosificación , Neoplasias de Tejido Muscular/tratamiento farmacológico , Neoplasias de Tejido Muscular/genética , Translocación Genética/genética , Niño , Humanos , Masculino , Miositis/diagnóstico por imagen , Miositis/tratamiento farmacológico , Miositis/genética , Neoplasias de Tejido Muscular/diagnóstico por imagen , Inhibidores de Proteínas Quinasas/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
Inflammatory myofibroblastic tumor (IMT), a rare sarcoma, is primarily treated via resection of the mass. However, there is no standard treatment for recurrence or unresectable tumors. Almost 50% of IMTs carry ALK gene rearrangement that can be treated using ALK inhibitors, but therapeutic options for ALK-negative tumors are limited. This report describes a woman aged 22 years with unresectable ALK-negative IMT. Next-generation sequencing revealed a TFG-ROS1 fusion, and she had a partial response to the ROS1 inhibitor ceritinib. This report provides the first published demonstration of a patient with IMT with ROS1 fusion successfully treated using ceritinib. Our study suggests that targeting ROS1 fusions using the small molecule inhibitor shows promise as an effective therapy in patients with IMT carrying this genetic alteration, but this requires further investigation in large clinical trials.