Microenvironment Related Prognostic Factors Associated With Hodgkin Lymphoma

Objective:Hodgkin’s lymphoma is the origin of malignant lymphoma with B cells, its incidence accounts for about 11% of all malignant lymphoma. Hodgkin’s lymphoma is characterized by the presence of Hodgkin Reed-Sternberg(HRS) cells,and the Hodgkin and Reed-Sternberg cells are embedded in a heterogeneous background of non-neoplastic bystanders. Hodgkin’s lymphoma has a good prognosis for most patients, with long-term remission greater than 80% following conventional chemotherapy or radiotherapy-based protocols. But a small proportion still experience relapsing or refractory disease which eventually leads to their death, and many long-term patients suffer the late effects of excessively toxic treatments. Therefore, it is very important to search for new prognostic factors to guide the treatment and prognosis.In recent years, the microenvironment becomes more and more attention in tumor invasion and metastasis, which is involved in a variety of malignant tumors,the occurrence and development, and has become a potential target for clinical treatment. AS we know the microenvironment of Hodgkin’s lymphoma is composed of a large number of inflammatory cells including macrophages, lymphocytes,eosinophils, mast cells, plasma cells, stromal cells, fibroblasts. Recently most researchers pay attention on T lymphocyte and tumor associated macrophage in the background of Hodgkin’s lymphoma cells. So we chose two T lymphocyte markers in the microenvironment: PD-1 and FOXP3, as well as a tumor associated macrophage marker CSF-1R.The current study retrospectively analysis clinical features, treatment outcomes,and relative prognostic factors in 86 Hodgkin’s lymphoma patients at the Tianjin Medical University Cancer Institute and Hospital, as well as Chinese PLA General Hospital.To conclude the clinical features and relative prognostic factors of Hodgkin’s lymphoma, and the aim of the study is to explore the relationship between the prognosis of the three types of microenvironment related prognostic factors and HL patients, in order to provide theoretical basis for the pathogenesis of the disease and clinical molecular targeted therapy.Methods:1. Between October 2004 and January 2013, 86 Hodgkin’s lymphoma patients(including 13 Nodular Lymphocyte predominant Hodgkin’s lymphoma and 73 Classical hodgkin lymphoma) were diagnosed with pathologically proven plasmacytoma at the Tianjin Medical University Cancer Institute and Hospital as well as Chinese PLA General Hospital. All the statistical tests were performed using SPSS Statistics 17.0 software. chi-square test, the Log-rank method were used to compare differences between groups, Kaplan-Metier curves were used for survival analysis, multivariate analysis with Cox regression, P<0.05 for the difference is statistically significant.2. 86 paraffin-embedded tissues were selected from 2004 to 2013 by surgery or biopsy pathology confirmed for Hodgkin’s lymphoma. The 5μm sections were cut for immunohistochemical staining including PD-1,FOXP3 and CSF-1R. We also set up the positive control and negative control. Collect the clinical pathological data, using SPSS17.0 software, chi-square test, Kaplan-Meier curves, Log-Rank test and Cox regression were used for statistical processing, P < 0.05 for the difference is statistically significant.Results:1. Retrospectively analyzed 86 cases of Hodgkin’s lymphoma1.1 86 Hodgkin’s lymphoma patients including 13 Nodular lymphocyte predominant Hodgkin’s lymphoma and 73 Classical Hodgkin’s lymphoma which including 37 Nodular sclerosis Hodgkin’s lymphoma,31 Mixed cellularity Hodgkin’s lymphoma,4 Lymphocyte depleted Hodgkin’s lymphoma,1 Lymphocyte predominant Hodgkin’s lymphoma.1.2 Hodgkin’s lymphoma patients most were youngsters and elderly persons,the median age of Hodgkin’s lymphoma patients was 31.5 years(ranged from 7 to 82years),and most patients were male, the rate is 1.6.1.3 For all of the 86 cases, 5-year overall survival was 75.6%, and 5-year progression-free survival was 54.2%1.4 Univariate analysis showed that for Hodgkin’s lymphoma patients, age ≧45years(P=0.017),B systems positive(P=0.015) were the significantly factor associated with shorter progression-free survival. Whereas age ≧ 45years(P<0.01),advanced stage III/IV(P=0.032),IPS﹥2 score(P=0.001), β2-MG levels high(P=0.014) were significant predictors of shorter overall survival.2. The immunohistochemical results and relative prognostic factors for Hodgkin’s lymphoma2.1 The expression of FOXP3 was negatively correlated with the prognosis of patients with Hodgkin’s lymphoma, high expressing of CSF-1R confers poor prognosis. While PD-1 expression has no any significantly association with overall survival and progression-free survival( P=0.624,P=0.105, respectively).Also we found Epstein-Barr virus has a significantly association with Hodgkin’s lymphoma patients’ s overall survival and progression-free survival( P=0.005,P=0.006,respectively) Multivariate analysis indicated that the expression of FOXP3 was independent factor for overall survival(HR=0.262,95%CI:0.108-0.634, P=0.002)、progression-free survival(HR=0.253,95%CI:0.114-0.561, P=0.001).Conclusion:1. FOXP3 was the independent prognostic factor of PFS and OS in patients with Hodgkin’s lymphoma, and CSF-1R was closely related to PFS in patients with Hodgkin’s lymphoma.2. The expression of FOXP3 and CSF-1R in the microenvironment of HL patients were related to the EBV infection.3. Low expression of FOXP3 combined with PD-1 positive or FOXP3 low expression combined with high expression of CSF-1R can be used as a biological indicator to judge the prognosis of Hodgkin’s lymphoma patients.