RESUMO
Objective: The study was to assess whether tumour expressions of hypoxia-inducible factor (HIF)-1α, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX and vascular endothelial growth factor (VEGF) predict response to neo-adjuvant chemotherapy (naCHT) in children with inoperable rhabdomyosarcoma (RMS). Methods: Immunohistochemical expressions of hypoxia markers were determined semi-quantitatively in tumour tissue microarray of 46 patients with embryonal RMS (RME) and 20 with alveolar (RMA), treated with CWS protocols (1992-2013). Results: In paediatric RME, response to naCHT was influenced significantly by tumour expression of CA IX and GLUT-1. Patients with RMA with low expressions of analysed markers responded well to naCHT, while all poor-responders expressed highly hypoxia markers. Only 5.88% of RMA and 11.11% of RME tumours did not express any of the proteins. In both RME and RMA subgroups, most poor-responders demonstrated simultaneous high expression of ≥3 markers, while most patients expressing ≤2 markers responded well to naCHT. In the whole cohort, co-expression of ≥3 markers, was the only independent factor predicting poor-response to chemotherapy (odds ratio 14.706; 95% CI 1.72-125.75; p = 0.014). Conclusions: Immunohistochemical expression pattern of four endogenous markers of hypoxia, in tumour tissue at diagnosis, emerges as a promising tool to predict response to naCHT in children with inoperable RMS.
Assuntos
Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Anidrase Carbônica IX/genética , Transportador de Glucose Tipo 1/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Musculares/tratamento farmacológico , Rabdomiossarcoma Alveolar/tratamento farmacológico , Rabdomiossarcoma Embrionário/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/genética , Adolescente , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Biópsia , Anidrase Carbônica IX/metabolismo , Carboplatina/uso terapêutico , Quimioterapia Adjuvante/métodos , Criança , Pré-Escolar , Dactinomicina/uso terapêutico , Epirubicina/uso terapêutico , Feminino , Expressão Gênica , Transportador de Glucose Tipo 1/metabolismo , Humanos , Hipóxia/diagnóstico , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/mortalidade , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ifosfamida/uso terapêutico , Lactente , Recém-Nascido , Masculino , Neoplasias Musculares/diagnóstico , Neoplasias Musculares/genética , Neoplasias Musculares/mortalidade , Terapia Neoadjuvante/métodos , Prognóstico , Estudos Prospectivos , Rabdomiossarcoma Alveolar/diagnóstico , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/mortalidade , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is rare, aggressive soft tissue sarcoma which may affect children. OBJECTIVE: We aimed to assess prognostic significance of immunohistochemical (IHC) markers, osteopontin, fibronectin, survivin, cyclin D1 and p53, in pediatric MPNST. METHODS: A total of 26 pediatric MPNST patients were enrolled in the current study with a median follow-up of 51 months. IHC staining using commercially available monoclonal antibodies were employed to detect analyzed antigens on tissue microarrays. Eventually, all markers were subclassified to high (H) and low (L) expression categories in all analyzed tumors. RESULTS: High IHC expressions of survivin, cyclin D1, osteopontin, fibronectin, and p53 were detected in 18 (69.2%), 13 (50%), 16 (61.5%), 16 (61.5%), and 13 (50%) tumors, respectively. A significant correlation was demonstrated between cyclin D1 and osteopontin (p= 0.004). Both markers were associated with neurofibromatosis type 1 (NF1) status (p= 0.041 and p= 0.037, respectively). H-fibronectin was more prevalent in deeply located tumors (p= 0.046). None of the markers was associated with IRS stage, age at diagnosis, and tumor size. Univariate analysis identified IRS stage, regional lymph node metastases, NF1, and cyclin D1 as variables associated with overall survival (OS), whereas tumor depth, osteopontin, and cyclin D1 - for relapse-free survival (RFS). Subsequent multivariate analysis identified cyclin D1 and p53 as independent variables predicting RFS, whereas cyclin D1 and regional lymph nodes status were independent predictors for OS.
