Meta-analysis Of Factors Associated With High-risk HPV-negative Cervical Cancer

Background:Cervical cancer is a serious gynecological cancer affecting women all over the world.In 2018,the number of cases worldwide reached nearly 570,000,including about311,000 deaths.The persistent infection of high-risk human papillomavirus(HR HPV)is an important factor in the development of cervical lesions.At present,many studies have proven that the infection rate of high-risk HPV in patients with cervical lesions less than 100%。there is a part of clinical high-risk HPV-negative cervical cancer patients,they may miss diagnosis because of the negative high-risk HPV,resulting in late disease diagnosis and poor prognosis and other serious consequences.High-risk HPV-negative cervical cancer is easy to be missed in routine screening,although the proportion of patients in this part is small,with the large population base in China,the number of patients with high-risk HPV-negative cervical cancer is enough for us to pay more attention to.Objective:The clinical and pathological characteristics of high-risk HPV-negative cervical cancer were comprehensively evaluated through Meta-analysis,aiming to provide evidence-based medical evidence for the causes,diagnosis,treatment and prognosis of high-risk HPV-negative cervical cancer,so as to reduce the rate of missed diagnosis,improve the positive detection rate and provide precise and individualized treatment for patients with HR HPV cervical cancer.Methods:The common Chinese and English databases such as Pub Med,Embase,Cochrane Library,Medline,Web of Science,Wanfang,CNKI,VIP,were used to search the literatures related to the factors of high-risk HPV-negative cervical cancer,and the retrieval strategy was developed by using the method of subject words plus free words.According to the inclusion and exclusion criteria,20 literatures,10 literatures in Chinese and 10 literatures in English were screened,with a total of 8887 cases.They were divided into two groups: the high-risk HPV-negative group(1275 cases)and the high-risk HPV-positive group(7612 cases).Factors included age,smoking history,maximum tumor diameter at diagnosis,pathological type,degree of histological differentiation,clinical stage,lymph node positivity,treatment regimen,5-year overall survival,and 5-year disease-free survival.Meta-analysis was performed using Rev Man5.3 to obtain the combined statistics and their 95% confidence intervals in each study.Results:1.HPV-negative cervical cancer general characteristics analysis:(1)age: in the average age,high-risk HPV-negative cervical cancer and high-risk HPV-positive cervical cancer comparison no statistical difference;In the age group of >45 years old,OR=1.59,95%CI[1.05,2.41],P <0.05,high-risk HPV-negative cervical cancer patients in the age group of >45 years old was 1.59 times of high-risk HPV-positive cervical cancer patients.(2)Smoking history: OR=0.27,95%CI [0.04,1.79],P > 0.05,no statistical difference.A history of smoking may be a risk factor for cervical cancer,independent of HPV classification,but the results are unreliable.(3)The maximum tumor diameter at diagnosis: MD=0.38,95%CI [0.06,0.71],P <0.05.Compared with high-risk HR HPV-positive cervical cancer,the maximum tumor diameter at diagnosis of high-risk HPV-negative cervical cancer was larger.2.Clinicopathological analysis of HPV-negative cervical cancer:(1)Pathological types: the prevalence of non-squamous cell carcinoma(OR=2.70,95%CI[1.88,3.88],P <0.00001)in high-risk HPV-negative cervical cancer was 2.70 times higher than in high-risk HPV-positive cervical cancer.The prevalence of adenocarcinoma was OR=2.95 95%CI [1.91,4.57],P <0.00001,and the prevalence of high-risk HPV-negative cervical cancer was 2.95 times than that of high-risk HPVpositive cervical cancer.(2)Clinical stage: clinical stage ≥ IB2:OR=1.61,95%CI[1.40,1.85],P <0.00001.The proportion of clinical stage ≥ IB2 in high-risk HPV-negative cervical cancer was 1.61 times that in high-risk HPV-positive cervical cancer.(3)The degree of tissue differentiation: high tissue differentiation,OR=0.57,95%CI[0.35,0.94],P <0.05;low tissue differentiation,OR=2.65 95%CI[1.60,4.38],P <0.05.The results showed that high tissue differentiation was more common in high-risk HPVpositive cervical cancer,and low tissue differentiation was more common in high-risk HPV-negative cervical cancer.(4)Positive rate of lymph node metastasis: OR=2.40,95%CI[1.64,3.51],P <0.00001.The positive rate of lymph node metastasis in high-risk HPV-negative cervical cancer was 2.40 times higher than that in high-risk HPV-positive cervical cancer.(5)Treatment plan: postoperative radiotherapy and chemotherapy:OR=1.13,95%CI[0.68,1.88],P > 0.05,no statistical difference.3.Prognostic analysis of HPV-negative cervical cancer:(1)5-year overall survival(OS): HR=3.86,95%CI[2.32,6.43],P <0.00001,5-year survival of high-risk HPV-negative cervical cancer was significantly lower than that of HR HPV-positive cervical cancer.(2)5-year disease-free survival(DFS): HR=4.67,95%CI[1.57,13.95],P <0.01.The 5-year disease-free survival of high-risk HPV-negative cervical cancer was significantly lower than that of high-risk HPV-positive cervical cancer.Conclusion:1.High-risk HPV-negative cervical cancer is more common in the higher age group(> 45 years old),and the maximum tumor diameter is larger at the time of diagnosis,resulting from that the diagnosis of HR HPV-negative cervical cancer is difficult and easy to missing diagnosis.2.Compared with high-risk HPV-positive cervical cancer,the high-risk HPVnegative cervical cancer has a later clinical stage,the positive rate of lymph node metastasis is high,the tissue is poorly differentiated,and the proportion of nonsquamous carcinoma and adenocarcinoma is high.These clinical and pathological characteristics may indicate that high-risk HPV-negative cervical cancer has a lower early diagnosis and a more severe disease at onset.3.Compared with high-risk HPV-positive cervical cancer,the 5-year overall survival and 5-year disease-free survival of HR HPV-negative cervical cancer patients were significantly increased,indicating that the prognosis of high-risk HPV-negative cervical cancer patients is poor,and further follow-up is needed to strengthen the postoperative follow-up to prevent tumor recurrence.No statistical difference in mean age,postoperative radiotherapy and chemotherapy.