High‐risk HPV testing in the management of atypical glandular cells: A systematic review and meta‐analysis

Abstract

Whereas the utility of high-risk HPV (hrHPV) testing is widely accepted in triage of women with atypical squamous lesions, its role in managing atypical glandular cells (AGC) is not fully elucidated. A systematic review and meta-analysis were performed to evaluate the accuracy of hrHPV testing in the management of women with AGC to detect underlying high-grade intraepithelial neoplasia or worse, and adenocarcinoma in situ or worse (AIS1). Additionally, the diagnosis of extra-cervical cancer was considered as an outcome in this review. A bibliographic database search (PubMed, EMBASE, CENTRAL) identified twelve eligible studies. The occurrence of cervical intraepithelial neoplasia grade two or worse including AIS1 (CIN21/AIS1), was 19.8% among women with AGC, and 55.7% among women with AGC and concurrent squamous lesions (atypical squamous cells of undetermined significance or worse, ASC-US1). The pooled sensitivity and specificity of hrHPV-testing with Hybrid Capture 2 (HC2) to detect CIN21/AIS1 in women with AGC was 90.0% (95% CI 5 85.1-93.4%) and 75.1% (95% CI 5 64.8-83.2%), respectively. Women who were hrHPV-negative, demonstrated an increased risk for extra-cervical malignancy (endometrium, fallopian tube, ovary). In women of 50y and older, a hrHPV-negative result was linked with a 18.0% chance of extra-cervical malignancy, while the chance of cervical pre-cancer and cancer was 0.4 and 0.0%, respectively. In conclusion, given the high risk of underlying CIN21/AIS1, women with AGC should be referred directly to colposcopy. However, hrHPV test results in combination with the age, appears to improve the diagnostic process by distinguishing the risk for cervical versus non-cervical lesions.

Atypical Glandular Cells: Interobserver Variability according to Clinical Management

“…Pirog et al [21] examined HPV in cervical AC by PCR methodology in 682 cases and found that "cervical AC, usual type" had the highest proportion of HPV-positive cases (71.8%), with HPV positivity for the rarer subtypes as follows: endometrioid (27.3%), serous (25%), and clear cell (20%) [21]. Ronco et al [22] found a clinically significant gain in detection of glandular lesions when adding HPV testing to cytology, while Verdoodt et al [23] in a meta-analysis found that reflex HPV testing was generally unnecessary as the pretest probability of finding a clinically relevant lesion was sufficient for the next clinical decisions [22,23]. In the present study we did not have HPV testing data available for most cases as in 2011 cotesting was less common than in current practice.…”

Significance of High-Risk Human Papillomavirus Testing for Atypical Glandular Cells on Cervical Cytology

“…Moreover, genotyping of hrHPVpositive ASC-US revealed a type-dependent, 10-fold range in 3-year risk of CIN3+, which suggests that genotyping of HPV might be useful for risk stratification of ASC-US [19]. A meta-analysis showed that hrHPV DNA test results, when combined with age, distinguish the risk for AGC lesions with cervical versus noncervical cytology, which improves the diagnostic process [17]. However, few studies have evaluated hrHPV genotype distribution in women with AGC.…”

“…Verdoodt et al [17] conducted a meta-analysis to examine the accuracy of hrHPV testing for identifying or excluding (pre)cancerous lesions of the uterine cervix and reported that 19.8% of women with AGC were classified as CIN2+/AIS+. The prevalence of CIN2+/AIS+ was 22-48% in previous studies examining 50-100 cases of AGC, whereas 1 Japanese study reported that 87.5% of women diagnosed with AGC were classified as CIN2+/AIS+ [18].…”

Clinical Significance of Endometrial Cells in Papanicolaou Smears of Women Attending an Organized Cervical Cancer Screening Program

“…Although the Bethesda System recommends reporting of EMC, the significance of these cells in detecting endometrial adenocarcinoma remains controversial [2,3,4,5,6,7]. While additional testing for high-risk human papilloma virus helps in detecting high-grade cervical squamous and glandular lesions, it cannot rule out an elevated risk of extracervical malignancy [8]. We performed a similar study, in which we investigated the clinical significance of ‘out-of-phase' normal EMC (nEMC), atypical EMC (aEMC) and aEMC favoring neoplasia/endometrial carcinoma in Pap smears from women attending an organized cervical cancer screening program.…”