Prognostički značaj angiogeneze i ekspresije adhezivnih molekula stromalnih ćelija kod bolesnika sa folikularnim i difuznim B krupnoćelijskim limfomom

Abstract

Značaj tumorske mikrosredine limfoma je prepoznat upotrebom najsavremenijih tehnologija sa posledičnom analizom prognostičkog značaja ovih rezultata. Poznavanje tumorske mikrosredine difuznog B krupnoćelijskog limfoma (DBKL), folikularnog limfoma (FL), kao i genetske osnove primarnog DBKL centralnog nervnog sistema (DBKL CNS) kao posebnog podentiteta u okviru DBKL je još uvek nedovoljno. Cilj ove studije je bio analiza prognostičkog značaja kliničkih parametara, gustine krvnih sudova merene ekspresijom CD34 na endotelnim ćelijama u tumorskom tkivu, ekspresije CD44s kao adhezivnog molekula na stromalnim i tumorskim ćelijama, i ekspresije transkipcionog faktora FOXP1 na tumorskim ćelijama DBKL, primarnog DBKL CNS-a i FL. Metoda: Analizirana su 202 patohistološka uzorka fiksirana na formalinu i ukalupljena na parafinu (115 DLBCL/65 FL/22 primarni DLBCL CNS). Korišćenjem MiSeq i TruSeqAmplicon Cancer Panel-a (TSCAP) za 48 kancer-povezanih gena analizirano je 19 bolesnika sa primarnim DBKL CNS-a. Rezultati: Povoljan terapijski odgovor (kompletna/parcijalna remisija) je postignut kod 81.3% bolesnika sa DBKL, 81.8% sa primarnim DBKL CNS i 92.3% sa FL. Pored kliničkih parametara koji su pokazali uticaj na ukupno preživljavanje i preživljavanje bez pojave bolesti, utvrđen je značaj visoke gustine krvnih sudova kod bolesnika sa DBKL, a visoke ekspresije CD44s adhezivnog molekula na tumorskim ćelijama kod FL. Multivarijanta analiza je kod DBKL pokazala prognostički značaj na preživljavanje gustine krvnih sudova zajedno sa NCCN-IPI-jem (p=0.026, p<0.001), dok su se kod FL izdovojili FLIPI, pol, ALC/AMC (absolutni broj limfocita/ absolutni broj monocita u perifernoj krvi), gradus FL i visoka FOXP1 ekspresija (p=0.006, p=0.007, p=0.016, p=0.034, p=0.014) kao prognostički značajni markeri. Bolesnici sa primarnim DBKL CNS-a su imali bolje preživljavanje ukoliko je prethodno sprovedena kompletna tumorska resekcija (p=0.03)...

The significance of tumor immune microenvironment has been emphasized using the most advanced analysis, with consecutive attempts to reveal prognostic impact of this findings. Furthermore, the knowledge about tumor microenviroment of diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) as well as the genomic basis of primary central nervous system DLBCL (CNS DLBCL), as the special entity within DLBCL, is still insufficient. The aim of this study was to compare and define the prognostic significance of clinical parameters, microvessel density (MVD) in tumour tissue labelled with anti CD34 antibody on endothelial cells of tumour blood vessels, expression of CD44s as adhesive molecule on stromal and tumour cells, as well as transcription factor FOXP1 on tumor cells of DLBCL, primary CNS DLBCL and FL. Methods: A total of 202 formalin fixed, paraffin-embedded tumor samples (115 DLBCL/65 FL/22 primary CNS DLBCL) were evaluated. Using the MiSeq and TruSeqAmplicon Cancer Panel (TSCAP) for 48 cancer-related genes, 19 primary CNS DLBCL were investigated. Results: Overall response (complete/partial remission) was achieved in 81.3% DLBCL patients, 81.8% primary CNS DLBCL and 92.3% FL. Beside clinical parameters that were significant for overall survival (OS) and event free survival (EFS), high MVD in DLBCL correlated with poorer outcome, while in FL high CD44s expression correlated with inferior EFS and OS. In DLBCL, multivariate regression analysis showed that MVD along with NCCN-IPI (p=0.026, p<0.001) were the most important parameters that influenced survival, and in FL were as following: FLIPI, gender, ALC/AMC (absolute lymphocyte count/absolute monocyte count), FL histological grade and high FOXP1 expression (p=0.006, p=0.007, p=0.016, p=0.034, p=0.014, respectively). In primary CNS DLBCL complete tumor extirpation correlated previous to chemotherapy with favourable outcome (p=0.03)...