Spontaneous Regression of High-Grade Cervical Dysplasia: Effects of Human Papillomavirus Type and HLA Phenotype

Abstract

Purpose: Persistent infection with oncogenic human papillomaviruses (HPV) plays a central etiologic role in the development of squamous carcinomas of the cervix and their precursor lesions, cervical intraepithelial neoplasias (CIN). We carried out a prospective observational cohort study evaluating known, quantifiable prognostic variables of clinical behavior in women with high-grade cervical lesions. Experimental Design: Our study cohort included healthy women with high-grade cervical lesions (CIN2/3) with residual visible lesions after colposcopically directed biopsy. We prospectively followed 100 women over 15 weeks before standard resection. HPV typing was done using PCR and a reverse line blot detection method. Results: The rate of spontaneous histologic regression, defined as (CIN1 or less at resection) was 28%. The overall rate of HPV infection was 100%. HPV16 was identified in 68% of the lesions. Women with HPV16 only were significantly less likely to regress, compared with women with HPV types other than HPV16 (odds ratio, 0.342; 95% confidence interval, 0.117-0.997; P = 0.049). In the cohort with HPV16 only, patients who had an HLA*A201 allele had similar outcomes to those who did not carryA201. However, among patients with HPV types other than HPV16, the HLA*A201 allele interaction was significant; patients with HLA*A201 were the least likely to resolve. Conclusions: CIN2/3 lesions associated with HPV16 alone are significantly less likely to resolve spontaneously than those caused by other types. Interactions among HPV type, HLA type, and regression rate support a role for HLA-restricted HPV-specific immune responses in determining disease outcome.Persistent infection with a high risk, or oncogenic type of human papillomavirus (HPV) is necessary but not sufficient for the development of most squamous carcinomas of the cervix and their precursor lesions, cervical intraepithelial neoplasia (CIN; ref. 1). CIN1, CIN2, and CIN3 lesions represent a spectrum of disease. Low-grade, or CIN1 lesions, represent a chronic HPV infection, in which HPV DNA is episomal and intact virion production and shedding occur. In women who are immunocompetent, many low-grade, or CIN1 lesions, will nonetheless eventually regress without intervention (1, 2). Reported rates of regression range up to 58% over 24 months (3). A very small percentage (f2%) will progress to high-grade lesions.In contrast, most high-grade, or CIN2/3 lesions are thought to be much more likely to persist than to regress. However, reported rates of spontaneous regression vary from 6% to 50%, depending on diagnostic criteria, and length of follow-up (4). The risk for progression to invasive cancer at 24 months in women with high-grade lesions is f1% to 2%.The mechanisms by which HPV-associated intraepithelial lesions resolve are not well understood. As a prelude to interventional clinical trials in women with biopsy-proven CIN2/3, we carried out a prospective observational cohort study evaluating known, quantifiable prognostic variables in immune ...

p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population

“…≥ CIN2 was used as secondary study endpoint, as the category of CIN2 reflects a heterogeneous disease, of which a substantial part results from productive high-risk HPV infections 1 and regresses spontaneously. 26,27 The study endpoint was based on the histological outcome of the colposcopy-directed biopsy or, if classified worse, on the histology result of the specimen excised by LLETZ, conization, or hysterectomy. For Pap cytology, Pap cytology combined with HPV16/18 genotyping and p16/Ki-67 dual-stained cytology, sensitivity, specificity, positive predictive value, and the complemented negative predictive value (a measure of disease risk after a negative result) for the detection of ≥ CIN3 and ≥ CIN2 were calculated with 95% confidence intervals (95% CIs).…”

Distribution and viral load of eight oncogenic types of human papillomavirus (HPV) and HPV 16 integration status in cervical intraepithelial neoplasia and carcinoma

“…HPV 16 type-specific persistent infection has been attributed partially to its oncogenic potency and proposed to be used as a reliable marker indepen- HPV genotyping M Guo et al dent of morphology for cervical precancerous lesion progression. 36,39,40 Although the mechanism that causes persistent infection of HPV 16 is not completely clear, it has been reported to be associated with viral integration into the human genome. 41,42 In contrast, the oncogenic HPV types, such as HPV 52 and 58, was reported significantly less likely to be integrated into the cells of cervical carcinoma.…”

Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III

“…Nearly all patients undergo timely treatment, only being observed if on a clinical trial. Prior studies have often combined cases of both CIN II and CIN III [28] or had a short observation period [29]. One clinical trial has reported the regression rate of CIN III in a treated versus placebo group [29] and evaluated the effects of oral supplementation of β-carotene on the regression of high-grade CIN.…”