Significance Of EPAS1 In Sporadic Pheochromocytoma/Paragangliomas

Objective:The present study investigated the expression of Endothelial PAS domain protein 1(EPAS1)in benign and malignant sporadic pheochromocytoma/paragangliomas(PPGLs),and clarified its roles in the early diagnosis of malignant PPGLs.Method:The cohort consisted of 83 patients(50 benign patients and 33 malignant patients)confirmed as sporadic PPGLs by clinical-pathological diagnosis in the Affiliated Hospital of Qingdao University from January 2014 to December 2018,and 8cases of normal adrenal medullae were selected during the same period.According to the diagnostic principles and PASS scores in the expert consensus of PPGLs diagnosis and treatment in 2016,they are divided into benign and malignant groups.The clinical data,inspections,pathological parameters and other indicators between the benign and malignant groups were compared and analyzed.Immunohistochemical staining was used to detect the expression of EPAS1 in benign,malignant PPGLs and normal adrenal medulla tissues.Finally we compared the differences of EPAS1 expression levels among the three groups to explore the value of EPAS1 in the early diagnosis of malignant PPGLs.Result:1.Clinical data1.1 Comparing the clinical data of benign group and malignant group,the results show that the malignant patients'onset age were younger(48.29±16.76 years old vs 53.47±18.01 years old).At the same time,malignant group had lower BMI(22.25±2.89 kg/m~2vs 24.17±3.74 kg/m2),lower potassium(3.62±0.79 mmol/L vs 3.81±0.94 mmol/L)and higher CRP(5.74±4.89 mg/L vs1.25±2.41 mg/L)(P<0.05).1.2 64%of malignant tumors located outside the adrenal gland,which was significantly more than 32%of benign group(P<0.01).The average diameter of tumor in malignant group was remarkable larger than benign group(95.20±26.54mm vs 47.28±22.41mm).Ki67 in malignant group was also higher than benign group[5.00%(2.00,7.00)vs2.10%(1.00,5.00)],which was significantly higher than that in the benign group.1.3 There were no differences in gender,blood pressure,fasting plasma glucose(FPG),fasting insulin(FINS),serum total cholesterol(TC)level,triglyceride(TG)level,uric acid.Also there were no significant differences in hormone secretion levels such as plasma renin activity,aldosterone,cortisol and free CA leve in urine for 24 hours among the three groups.2.Immunohistochemical staining resultsThe result of EPAS1 immunohistochemical staining was negative in normal adrenal medullae.The positive staining rates in benign and malignant groups were 16%and 85%,respectively(P<0.01).36%,30%and 18%of malignant PPGLs recorded mild,moderate and strongly positive staining.In the benign group,there were 8 cases with mild to moderate staining.3.Correlation analysisImmunohistochemical staining intensity score of malignant PPGLs was positively correlated with tumor diameter(r=0.471,P<0.01),Ki67(r=0.323,P<0.01)and CRP(r=0.206,P<0.05),and negatively correlated with BMI(r=-0.168,P<0.05).With further analysis of 8 cases with positive staining in benign PPGLs group,immunohistochemical staining intensity score was positively correlated with Ki67(r=0.215,P<0.05),PASS score(r=0.197,P<0.05)and CRP(r=0.263,P<0.05),and the PASS scores of these 8 cases were all above 4 points.Conclusion:EPAS1 is highly expressed in malignant and aggressive PPGLs tumor tissues,and is positively correlated with tumor diameter and Ki67.Therefore EPAS1can be applied to early diagnose of benign and malignant PPGLs.Strong EPAS1 expression is correlated positively with CRP and negatively with BMI,which suggests that benign PPGLs with high CRP and low BMI may have a metastatic tendency and need a follow-up study.