The Diagnostic Value Of Combined Detection Of Human Epididymis Protein 4 With Serum CA125 In Ovarian Epithelial Cancer

Backgroud and PurposeOvarian cancer is one of a gynecological malignancy tumor, whose mortality rates are almost highest. And in recent years its incidence rise sigificantly. The new cases of ovarian cancer is about 190,000 and the number of deaths of them is about 114,000 in the whole word of each year.90% of ovarian cancers are epithelial ovarian cancer (hereinafter referred to as ovarian cancer). The 5-year survival rate in early-stage ovarian cancer can reach to 90% with currently available therapy. Unfortunately, only 15% to 20% of patients with advanced stage ovarian cancer will be cured, despite the continuous improvement of surgical treatment and chemotherapy. At present, only 25% of ovarian cancers are detected as early stage. So that more patients with ovarian cancer are diagnosed at an early stage is important in improving the overall survival. The cancer antigen 125 (CA125) is a kind of mucinous glycoprotein. Serum CA125 level has been widely used to clinical diagnosis of ovarian cancer and monitoring its recurrence around the world. But when it is used in the diagnosis of early stage ovarian cancer, the positive result only went to 40～50% of patients with early stage ovarian cancer. CA125 level can also be mildly elevated in many benign diseases in serum. The gene of human epididymis protein 4 (Human epididymis protein 4, HE4) encode the HE4 protein with the anti-protease activity, and its molecular weight is about 25kDa. HE4 gene is related to ovarian cancer was first reported in 1999 abroad. The HE4 level in ovarian cancer group was higher than the benign tumor and control group. This study adopt enzyme-linked immunosorhent method (ELISA) to detect the urine and serum levels of HE4 and serum CA125 in patients with different organizational nature. To explore the HE4 as a tumor marker joint detected with CA125, and the value of early diagnosis for ovarian cancer.Materials and methods1. Experimental samples:We selected 128 cases from patients admitted to the First Affiliated Hospital of Zhengzhou University during Jan.2010 to Jan.2011. They were divided into three groups by pathology, one group have 50 cases epithelial ovarian cancer patients, mean age (50.1±10.2) years old (according to FIGO (2000): 16 cases of the stages I/II period,34 cases of the stages III/IV period; according to the WHO histological classification:33 cases of the serous carcinoma,17 cases of the mucinous carcinoma). The other group have 38 benign ovarian tumor, and mean age was (45.0±17.3) years old, of which 25 cases were diagnosed as serous cystadenoma, 13 cases as mucinous cystadenoma. We selected 40 cases of normal women in control group from the First Affiliated Hospital of Zhengzhou University aged (46.4±10.7). Three groups have no significant difference in age and had no history of cancers, and never suffered radiotherapy and chemotherapy before surgery. And in addition to the control group, all patients were confirmed by postoperative pathology.We phlebotomized 5ml fasting blood from patients, before radiation and chemotherapy or other treatment. All specimens were saved in clean tubes, solidificated for 30 min at room temperature, and then centrifuged for 15 min by 3000r/min at 4℃. We got upper serum into the EP tube freeze-stored in-80℃refrigerator. Simultaneously, we collected 5ml fasting urine in the preoperative morning, got the upper urine into EP tube then frozed at-80℃for use after centrifuged for 5min. It is the same to the controls. It must be avoid specimens freezing and thawing repeatedly and inform patients before we aquired them. 2. Test methods:We detected the expression levels of HE4 in serum and urine and levels of CA125 in serum by Enzyme-linked immunosorbent assay (ELLSA). We regarded value of Serum CA125 more than 70pmol/L as positive.Warning value of urine HE4 was got from normal healthy women (X±1.96s), after calculation we took 6.51 pmol/L as on alert value and when the value is more than 6.51 pmol/L as positive. We took greater than 35kU/L of serum CA125 as positive.3. Statistical analysis:The data were analysised by SPSS 17.0 statistical package program. Comparison between the two groups with t-test, the multiple groups comparison with one-way analysis of variance. Counted datas were usedχ2 test the rate of usingχ2 test analysis. Simultaneously sensitivity (Se), spceificity (Sp) were analysised a=0.05 were deemed signifieant and P< 0.05 for differences with a statistical significance.Results1. HE4 levels in serum and urine of patients with ovarian cancer were (219.48±93.56) pmol/L and (21.37±12.40) pmol/L, respectively. HE4 levels in serum and urine of ovarian benign tumor were (68.78±24.71) pmol/L and (4.55±1.94) pmol/L and the quantitative values were (48.47±16.87) pmol/L and (4.06±1.25) pmol/L in nomal control group, respectively. Ovarian cancer group’s level is more than the other two group’s and there was significant difference between of them (P<0.05). There was no significant difference between patients with ovarian benign tumor and control group(P>0.05). Serum CA125 was (562.68±358.22) kU/L in ovarian cancer group, the difference were statistically when compared it to the levels of in benign tumor (31.64±18.5) kU/L and nomal control group (16.42±7.0) kU/L (P<0.05). There was no significant difference between patients with ovarian benign tumor and control group (P>0.05).2. HE4 levels in serum and urine were (189.48±32.02) pmol/L and (17.79±4.28) pmol/L of theⅠ～Ⅱstage ovarian cancer, and that ofⅢ～Ⅳstage ovarian cancer were (246.21±52.77) pmol/L and (25.52±9.04) pmol/L. There were no significant difference in two groups (P>0.05). The serum and urine HE4 levels in patients with ovarian serous cystadenocarcinoma were (289.28±64.05) pmol/L and (27.23+10.16) pmol/L, compared with (152.57±70.36) pmol/L and (15.12±7.42) pmol/L of mucinous ovarian cancer, and there has significant differerce in the two of them(P<0.05).3. The sensitivity of serum HE4 was 43.8% inⅠ～Ⅱstage ovarian cancer, and was 64.7% inⅢ～Ⅳstage. And the sensitivity of urine HE4 was 75.5% inⅠ～Ⅱstage ovarian cancer, compared with the 82.4% inⅢ～Ⅳstage. Both of the difference was not statistically significant (P>0.05). The sensitivity of serum and urine HE4 in ovarian serous cystadenocarcinoma were up to 72.7% and 90.3%, Which were 29.4% and 58.8% in ovarian mucinous cystadenocareinoma, all the difference have statistics significance(P<0.05). The sensitivity of serum CA125 was 56.3% inⅠ～Ⅱstage ovarian caneer, and that ofⅢ～Ⅳstage was up to 94.1%, the difference have statistics significance (P<0.05), while, there was also statistical difference about the sensitivity between the ovarian serouse cystadenocarcinoma and ovarian mucinous cystadenoeareinoma (P<0.05).4. The sensitivity and specificity of serum HE4 were 58.0%(29/50) and 87.2% (68/78) for diagnosis of ovarian cancer; The sensitivity and specificity of urinary HE4 were up to 80.0%(40/50) and 91.0%(71/78); The sensitivity and specificity of serum CA125 were 82.0%(41/50) and 70.5%(55/78). While combination of serum HE4 and CA125 and urinary HE4, the sensitivity and specificity were up to 94.0%(47/50) and 94.9%(74/78).Conclusion1. The sensitivity and specificity of the combination detection of serum HE4 and CA125 and urinary HE4 was higher than individual or single detection of them in diagnosis of ovarian cancer, which could improve the accuracy of the diagnosis to a large extent. Suggested that serum and urinary HE4 have important clinical signify-cance in diagnosis of ovarian cancer.2. The sensitivity of urinary HE4 betweenⅠ～Ⅱstage ovarian cancer andⅢ～Ⅳstage, has non-statistics significance difference. Suggest that urinary HE4 has a certain value for the early diagnosis of ovarian cancer, and with important significance in ovarian cancer screening.