Predictive values of human papillomavirus E6/E7 mRNA test in the prognosis of cervical epithelial neoplasm 1

doi:10.3877/cma.j.issn.1673-5250.2018.01.007

Objective

To evaluate the predictive values of human papilloma virus (HPV) E6/E7 mRNA test in the prognosis of patients with cervical intraepithelial neoplasia (CIN) 1.

Methods

From July 2013 to October 2014, a total of 107 cases of patients who were initially diagnosed as CIN1 by pathologic results of colposcopic cervical biopsy in Department of Gynecology, Yantaishan Hospital of Yantai were selected as research subjects. All subjects received cervical ThinPrep liquid-based cytology test (TCT), HPV DNA genotyping test and HPV E6/E7 mRNA test within one month prior to initial diagnosis of CIN1. Two-year follow-ups and once every six months were conducted on all subjects, including the re-examination of TCT, HPV DNA genotyping test and HPV E6/E7 mRNA test. And cervical biopsies were conducted on suspicious lesions. According to the results of TCT, HPV DNA genotyping test, HPV E6/E7 mRNA test and colposcopic cervical biopsy at the end of follow-up, all subjects were enrolled into negative group and continuous or progressive group, respectively. Chi-square test was used to compare the positive rates of HPV E6/E7 mRNA between two groups. Mann-Whitney U rank sum test was used to compare expression levels of HPV E6/E7 mRNA between two groups. The sensitivities and specificities of these three cervical screening methods in predicting the prognosis of CIN1 were calculated respectively. Then receiver operator characteristic (ROC) curve of HPV E6/E7 mRNA expression level in predicting the prognosis of CIN1 was drawn, and the area under ROC curve (ROC-AUC) was calculated.The optimal critical value of HPV E6/E7 mRNA expression level in predicting the prognosis of CIN1 was obtained when the Youden index reaching the maximum value.And its sensitivity and specificity were calculated. This study was approved by the Ethics Committee of Human Beings in Yantaishan Hospital of Yantai and informed consent of clinical research has been signed with every subject.

Results

①According to the results of TCT, HPV DNA genotyping test, HPV E6/E7 mRNA test and colposcopic cervical biopsy at the end of follow-up, all subjects were enrolled into negative group (n=63, the results of TCT, HPV DNA genotyping test and HPV E6/E7 mRNA test all were normal or the colposcopic cervical biopsy result was negative at the end of follow-up) and continuous or progressive group (n=44, the colposcopic cervical biopsy result was CIN1 or higher grade at the end of follow-up). There were no statistically significant differences between two groups in basic clinical data such as age and etc. (P>0.05). ②The positive rate of HPV E6/E7 mRNA and median expression level of HPV E6/E7 mRNA were 61.9% (39/63) and 3 738.4 copy/mL in continuous or progressive group, which were significantly higher than those in negative group (81.8%, 36/44) and 583.5 copy/mL, respectively), and both the differences were statistically significant (χ²=4.901, P=0.027; U=821.000, P<0.001). ③According to the results of two-year follow-up, the continuous or progressive rate of CIN in patients with HPV-16/18 positive was 50.8% (31/61), which was significantly higher than that in patients with HPV-16/18 negative (28.3%, 13/46), and the difference was statistically significant (χ²=5.512, P=0.019). The continuous or progressive rate of CIN in patients with HPV E6/E7 mRNA positive was 48.0% (36/75), which was significantly higher than that in patients with HPV E6/E7 mRNA negative (25.0%, 8/32), and the difference was statistically significant (χ²=4.901, P=0.027). The sensitivities of TCT, HPV DNA genotyping test and HPV E6/E7 mRNA qualitative test in predicting the prognosis of CIN1 were 50.0%, 70.5%, 81.8%, and the specificities were 66.7%, 52.4%, 38.1%, respectively. ④The results of ROC curve analysis of HPV E6/E7 mRNA expression level in predicting the prognosis of CIN1 showed that the ROC-AUC was 0.704 (95%CI: 0.601-0.806, P<0.001), and the optimal critical of value HPV E6/E7 mRNA expression level in predicting the prognosis of CIN1 was 2 724.0 copy/mL, and the sensitivity of HPV E6/E7 mRNA expression level in predicting continuous or progression of CIN was 54.5%, and the sensitivity was 81.0%.

Conclusions

The sensitive of HPV E6/E7 mRNA qualitative test in predicting the prognosis of CIN1 is relatively high, while the specificity of HPV E6/E7 mRNA quantitative test in predicting the prognosis of CIN1 is relatively high. HPV E6/E7 mRNA test may has clinical values in predicting the prognosis of patients with CIN1.

Key words: Cervical intraepithelial neoplasia, Human papillomavirus, Papillomavirus E7 proteins, Genotyping, Prognosis, Female

表1 2组患者确诊为CIN1时的HPV E6/E7 mRNA阳性率及其表达水平比较

组别	例数	HPV E6/E7 mRNA阳性[例数(%)]	HPV E6/E7 mRNA表达水平[copy/mL，M(P₂₅～P₇₅)]
转阴组	63	39(61.9)	583.5(0～2 148.3)
持续或进展组	44	36(81.8)	3 738.4(784.6～7 277.2)
检验值	?	χ²＝4.901	U＝821.000
P值	?	0.027	<0.001

表1 2组患者确诊为CIN1时的HPV E6/E7 mRNA阳性率及其表达水平比较

组别	例数	HPV E6/E7 mRNA阳性[例数(%)]	HPV E6/E7 mRNA表达水平[copy/mL，M(P₂₅～P₇₅)]
转阴组	63	39(61.9)	583.5(0～2 148.3)
持续或进展组	44	36(81.8)	3 738.4(784.6～7 277.2)
检验值	?	χ²＝4.901	U＝821.000
P值	?	0.027	<0.001

表2 不同宫颈病变筛查方法对CIN1患者预后的预测效果分析[例数(%)]

宫颈病变筛查方法		例数	CIN1预后情况		χ²值	P值
宫颈病变筛查方法		例数	持续或进展	转阴	χ²值	P值
TCT		?	?	?	2.994	0.084
?	阳性	43	22(51.2)	21(48.8)	?	?
?	阴性	64	22(34.4)	42(65.6)	?	?
HPV DNA基因		?	?	?	5.512	0.019
?	分型检测	?	?	?	?	?
?	HPV-16/18阳性	61	31(50.8)	30(49.2)	?	?
?	HPV-16/18阴性	46	13(28.3)	33(71.7)	?	?
HPV E6/E7		?	?	?	4.901	0.027
?	mRNA检测	?	?	?	?	?
?	阳性	75	36(48.0)	39(52.0)	?	?
?	阴性	32	8(25.0)	24(75.0)	?	?

表2 不同宫颈病变筛查方法对CIN1患者预后的预测效果分析[例数(%)]

宫颈病变筛查方法		例数	CIN1预后情况		χ²值	P值
宫颈病变筛查方法		例数	持续或进展	转阴	χ²值	P值
TCT		?	?	?	2.994	0.084
?	阳性	43	22(51.2)	21(48.8)	?	?
?	阴性	64	22(34.4)	42(65.6)	?	?
HPV DNA基因		?	?	?	5.512	0.019
?	分型检测	?	?	?	?	?
?	HPV-16/18阳性	61	31(50.8)	30(49.2)	?	?
?	HPV-16/18阴性	46	13(28.3)	33(71.7)	?	?
HPV E6/E7		?	?	?	4.901	0.027
?	mRNA检测	?	?	?	?	?
?	阳性	75	36(48.0)	39(52.0)	?	?
?	阴性	32	8(25.0)	24(75.0)	?	?

图1 HPV E6/E7 mRNA表达水平预测CIN1预后的ROC曲线

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