Prognostic significance of angiogenesis and tumor microenvironment on treatment outcome of Hodgkin lymphoma patients

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

Extramedullary plasmacytoma of the tongue base: A rare presentation of head and neck plasmacytoma

Introduction. Special entities like solitary bone plasmocytoma (SBP) or extramedullary plasmacytoma (EMP) can be found in a less than 5% of patients with plasma cell disorders. EMP of the tongue represents very rare localization of the head and neck plasmacytoma. Case report. We report a case of 78-years-old woman who developed EMP of the tongue base detected by the magnetic resonance imaging (MRI) of the head and neck region. Immunohistochemical profile of the tumor tissue biopsy (CD38, IgG, kappa positivity) indicated diagnosis of EMP. The diagnosis was established with additional staging which confirmed the absence of other manifestation of the disease. The patient was treated with 40 Gy of radiotherapy in 20 doses resulting in the achievement of the complete remission of the disease. This case was discussed with the reference to the literature. Conclusion. EMP of the tongue base is a very rare entity of plasma cell dyscrasias. Appropriate irradiation results in the achievement of a long-term remission and a potential cure of the disease

Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach

Prognostic significance of angiogenesis and tumor microenvironment on treatment outcome of Hodgkin lymphoma patients

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

Serbian lymphoma study group: Demografic characteristics of 257 patients with follicular lymphoma

Background/Aim. Follicular lymphoma (FL) is a B-cell tumor usually with indolent clinical course, yet in some cases the course of the disease can be very aggressive. The aim of the re-search was to determine distribution of patients into prognostic groups based on the International Prognostic Index (IPI) and Folicular Lymphoma International Prognostic Index (FLIPI) criteria, as well as to determine the importance of classifying patients into the prognostic groups, since this could potentially have the influence on selection of the treatment modality. Methods. The retrospective study was performed on 257 patients with follicular lymphoma diagnosed between January 2000 and April 2011. Results. Based on the IPI score, 153 (59.53%) patients had low risk, 57 (22.18%) low intermediate risk, 15 (5.84%) high intermediate risk, 9 (3.50%) high risk, whereas the classification of 23 patients diagnosed with FL remained with unknown risk according to the IPI. Based on the FLIPI prognostic index, 113 (43.97%) patients had low risk, 70 (27.24%) intermediate risk and 51 (19.84%) high risk, whereas the classification of 23 (8.95%) patients remained unknown. On the basis of the FLIPI 2 prognostic index, 48 (18.68%) patients had low risk, 145 (56.42%) intermediate risk and 41 (15.95%) high risk. The classification into prognostic groups for 23 (8.95%) patients remained unknown. According to the IPI, FLIPI and FLIPI 2 there were the patients that required treatment in all the risk groups. Conclusion. The FLIPI and FLIPI 2 effectively identify patients at high risk, thus helping in treatment decision for each single patient

Follicular lymphoma patients with a high FLIPI score and a high tumor burden: A risk stratification model

Background/Aim. The widely accepted Follicular Lymphoma International Prognostic Index (FLIPI) divides patients into three risk groups based on the score of adverse prognostic factors. The estimated 5-year survival in patients with a high FLIPI score is around 50%. The aim of this study was to analyse the prognostic value of clinical and laboratory parameters that are not included in the FLIPI and the New Prognostic Index for Follicular Lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project (FLIPI2) indices, in follicular lymphoma (FL) patients with a high FLIPI score and high tumor burden. Methods. The retrospective analysis included 57 newly diagnosed patients with FL, a high FLIPI score and a high tumor burden. All the patients were diagnosed and treated between April 2000 and June 2007 at the Clinic for Hematology, Clinical Center of Serbia, Belgrade. Results. The patients with a histological grade > 1, erythrocyte sedimentation rate (ESR) ± 45 mm/h and hypoalbuminemia had a significantly worse overall survival (p = 0.015; p = 0.001; p = 0.008, respectively), while there was a tendency toward worse overall survival in the patients with an Eastern Cooperative Oncology Group (ECOG) > 1 (p = 0.075). Multivariate Cox regression analysis identified a histological grade > 1, ESR ± 45 mm/h and hypoalbuminemia as independent risk factors for a poor outcome. Based on a cumulative score of unfavourable prognostic factors, patients who had 0 or 1 unfavourable factors had a significantly better 5-year overall survival compared to patients with 2 or 3 risk factors (75% vs 24.1%, p = 0.000). Conclusion. The obtained results suggest that from the examined prognostic parameters histological grade > 1, ESR ± 45 mm/h and hypoalbuminemia can contribute in defining patients who need more aggressive initial treatment approach, if two or three of these parameters are present on presentation

The Role of Lymphocyte to Monocyte Ratio, Microvessel Density and HiGH CD44 Tumor Cell Expression in Non Hodgkin Lymphomas

Prognostic significance of immune microenvironment has been emphasized using the most advanced analysis, with consecutive attempts to reveal prognostic impact of this findings. The aim of this study was to compare and define prognostic significance of clinical parameters, microvessel density (MVD) in tumour tissue and expression of CD44s as adhesive molecule on tumour cells in diffuse large B cell lymphoma-DLBCL, primary central nervous system DLBCL-CNS DLBCL and follicular lymphoma-FL. A total of 202 histopathological samples (115 DLBCL/65 FL/22 CNS DLBCL) were evaluated. Overall response (complete/partial remission) was achieved in 81.3 % DLBCL patients, 81.8 % primary CNS DLBCL and 92.3 % FL. Absolute lymphocyte count-ALC/Absolute monocyte count-AMC gt 2.6 in DLBCL and ALC/AMC a parts per thousand yenaEuro parts per thousand 4.7 in FL were associated with better event-free survival (EFS) and overall survival (OS) (p lt 0.05). In DLBCL, MVD gt 42 blood vessels/0.36 mm(2) correlated with primary resistant disease (p lt 0.0001), poorer EFS and OS (p = 0.014). High CD44s expression in FL correlated with inferior EFS and OS (p lt 0.01). In DLBCL, multivariate Cox regression analysis showed that ALC/AMC was independent parameter that affected OS (HR 3.27, 95 % CI 1.51-7.09, p = 0.003) along with the NCCN-IPI (HR 1.39, 95 % CI 1.08-1.79, p = 0.01). Furthermore, in FL, ALC/AMC mostly influenced OS (HR 5.21, 95 % CI 1.17-23.21, p = 0.03), followed with the FLIPI (HR 3.98, 95 % CI 1.06-14.95, p = 0.041). In DLBCL and FL, ALC/AMC is simple and robust tool that is, with current prognostic scores, able to define long-term survival and identify patients with inferior outcome. The introduction of immunochemotherapy might altered the prognostic significance of microenvionmental biomarkers (MVD and CD44s)