Prognostički značaj angiogeneze i mikrosredine tumora na ishod lečenja bolesnika sa Hočkinovim limfomom

Abstract

Uvod: I pored značajnog napretka u lečenju bolesnika sa Hočkinovim limfomom (HL) poslednjih nekoliko decenija i dalje značajan broj bolesnika ima loš klinički tok i kratko preživljavanje. U poslednje vreme su vrlo atraktivna istraživanja angioegeneze i mikrosredine tumora u limfomima i njihov prognostički značaj. Cilj istraživanja: Cilj ovog istraživanja je ispitivanje prognostičkog značaja karakteristika mikrosredine tumora (broj makrofaga (TAM), FOXP3 limfocita, gustine krvnih sudova i nivo ekspresije faktora rasta vaskularnog endotela (VEGF)), rutinskih kliničkih i biohemijskih parametara, i određivanje profila bolesnika sa rizikom za loš ishod lečenja. Materijal i metode: Ova retrospektivna studija je obavljena na 84 bolesnika sa novodijagnostikovanim Hočkinovim limfomom. Demografski, patohistološki, klinički i biohemijski podaci su dobijeni iz medicinske dokumentacije. Karakteristike angiogeneze i mikrosredine tumora određivane su na preparatima tkiva dobijenih iz parafinskih kalupa limfnih žlezda iz kojih je postavljena dijagnoza. Rezultati: U univarijantnoj analizi pacijenti sa VEGF pozitivnošću, velikim brojem TAM, malim brojem FOXP3, bulky bolešću, B simptomima, SE>50 mm/h i visokim IPS skorom imali su značajno kraće ukupno preživljavanje (OS) (p=0.046, p=0.017, p=0.003, p=0.006, p=0.022, p=0.013, p=0.024, po redosledu). Multivarijantna analiza kao nezavisne faktore rizika za OS identifikovala je veliki broj TAM i mali broj FOXP3 u grupi biomarkera (p=0.034, p=0.006, po redosledu), dok među kliničkim i laboratorijskim parametrima bulky bolest (p=0.002) i visok IPS (p=0.004) su identifikovani. Na osnovu kumultivnog skora nepovoljnih prognoznih faktora za OS, dizajnirali smo prognozni model za identifikovanje pacijenata sa malim (0-1 faktor), srednjim (2 faktora) i visokim rizikom (3-4 faktora) za loš ishod (p=0.000), sa 5-godišnjim OS 100%, 75% i 50%. Zaključak: Kombinovanje bioloških sa poznatim kliničkim i laboratorijskim prognoznim faktorima može rezultirati boljom stratifikacijom rizika pacijenata sa HL.

Introduction: In spite of great progress in treatment of Hodgkin’s lymphoma (HL) in recent few decades, still there is a portion of patients who have bad clinical course of the disease and short survival. In the past few years, the researches regarding prognostic role of angiogenesis and the tumor microenvironment in lymphomas are very attractive. Aim: The aim of this research is to investigate prognostic significance of the characteristics of tumor microenvironment (number of macrophages (TAM), FOXP3 lymphocytes, the density of blood vessels and, the level of expression of vascular endothel growth factor (VEGF)), routine clinical and laboratory findings and, to determinate profile of patients with risk for poor outcome. Patients and methods: A retrospective study was performed on 84 newly diagnosed Hodgkin lymphoma patients. Demographic, pathohistological, clinical and laboratory findings were collected from medical records. The characteristics of angiogenesis and microenvironment were determined on tissue samples taken from paraffin embeded tissue blocks of lymph nodes from which the diagnosis was established. Results: In univariate analysis patients with VEGF positivity, high number of TAM, low number of FOXP3, bulky disease, B symptoms, ESR>50 mm/h and high IPS score had significantly shorter overall survival (OS) (p=0.046, p=0.017, p=0.003, p=0.006, p=0.022, p=0.013, p=0.024, respectively). Multivariate analysis as the independent risk factors for poor OS identified high number of TAM and low number of FOXP3 in the group of biomarkers (p=0.034, p=0.006, respectively), while between clinical and laboratory parameters bulky disease (p=0.002) and high IPS (p=0.004) were identified. Utilizing the cumulative score of unfavorable prognostic factors for OS, we developed prognostic model for identifying patients at low (0-1 factors), intermediate (2 factors) and high risk (3-4 factors) for poor outcome (p=0.000), with 5-years OS of 100%, 75% and 50%. Conclusion: Combining of biological with established clinical and laboratory prognostic factors could result in better risk stratification of patients with HL.