In Situ Detection Of HPV16/18 In Cervical Lesions And Systematic Review Of HPV Vaccine Clinical Trials

Objective: To examine the cellular location of HPV16/18 subtypes in cervical epithelia and lesions,followed by a systematic review of the HPV vaccine clinical trials.Method:1.We searched literatures about the associations of cervical carcinoma and intraepithelial neoplasia with HPV using CNKI and Pub Med up to January2019,to characterize the HPV positivity based on different detection methods and cervical lesions according to the presence of illustrated histological images and the description of the location and distribution of positive cells.2.We collected the clinical information and paraffin blocks of the patients with cervical lesions from the department of pathology of our affiliated hospital from January 2005 to January 2019.HPV16/18 were detected in tissue sections by in situ hybridization（ISH）,in combination with H＆E stains and immunohistochemical stains to assess other pathological changes.The ISHstained HPV16/18 reactivity in normal and neoplastic cells was examined with light microscopy.3.We also searched Clinical Trials.gov up to January 2019 to address the demographic characteristics of all the clinical trials of HPV vaccines concerning the issues of placebo-controls and funding sources,and then divided into industry and non-industry groups.Result: 1.Few literatures showed any histopathological figures and descriptions of the HPV-positive cells.Majority claimed HPV positivity using extracted total DNA samples such as detected by PCR.Compared to ISH,PCR showed a significantly higher positive rate for HPV（p <0.001）.2.Among the 437 cases with different cervical lesions（intraepithelial neoplasia,287 cases;squamous carcinoma,75 cases adenocarcinoma,39 cases adensquamous carcinoma,36 cases）,82 were ISH-positive for HPV16/18 and mean age of these patients were 45.13±10.54 y.The HPV16/18 positivity was mainly shown in the nuclei of mature squamous cells rather than the basal layer cells,glandular cells,atypical cells and cancer cells.3.Among the 455 clinical trials of HPV vaccines,240 were industry-sponsored and completed in large proportions with control groups（p<0.001）.The controls were given aluminum-containing adjuvants rather than the saline placebo.Conclusions: 1.The ISH-detected HPV 16/18 reactivity was found in normal mature squamous epithelial cells rather than glandular epithelial cells,atypical cells,and neoplastic cells.Cervical cancer cells were rarely positive.2.The assays such as PCR using extracted HPV DNA samples was more sensitive than ISH,and could not locate the positive cells in situ.3.The published literatures reporting the relationship between HPV and cervical cancer rarely showed histopathological images and descriptions of HPV distribution and location.4.Very few clinical trials of HPV vaccines used the authentic placebo-saline as the control.Safety concerns of the aluminum-containing adjuvants warrant future examination.