Human papillomaviral load changes in low-grade squamous intraepithelial lesions of the uterine cervix

Abstract

To better predict risk of progression of low-grade squamous intraepithelial lesions (LSILs) of the uterine cervix in women with human papillomavirus (HPV) infections, 294 baseline cervical specimens from women with LSILs were evaluated. Specimens were tested for HPV DNA using hybrid capture 2 (HC2) and PCR-reverse line blotting. 65 LSILs with HPV DNA types 16, 18, 52, or 58 were examined for physical status, E2/E6 ratio and viral load at two time points, along with patient age. Women with LSILs whose viral loads increased between baseline and 6 month follow-up had a 45% risk of developing HSIL (OR ¼ 7.6, 95% CI ¼ 1.9 -29.4, Po0.01), as evaluated by real-time PCR and a 44% risk (OR ¼ 6.1, 95% CI ¼ 1. Human papillomavirus (HPV) plays an important role in the carcinogenesis of cervical cancer (Bosch et al, 1995;Walboomers et al, 1999). The most common oncogenic HPV type in preinvasive and cervical cancer is HPV 16, detectable in 21% of women with low-grade squamous intraepithelial lesions (LSILs) (Castle et al, 2005), in more than 50% of women with cervical intraepithelial neoplasia grade 3 (CIN 3), and women with cervical cancer in America and Europe (Bosch et al, 1995;Herrero et al, 2000; Munoz et al, 2003). HPV 18 causes 10 -15% of CIN 3 and cervical cancers (Bosch et al, 1995). In addition, HPV 18 also causes more than 35% of cervical adenocarcinomas, which are difficult to detect by current screening methods (Bosch et al, 1995). Additionally, HPV 52 and 58 are as prevalent as HPV 16 and 18 in patients with preinvasive and cervical cancer in Taiwan and Asian countries (Liaw et al, 1995;Huang et al, 1997;Ho et al, 2005Ho et al, , 2006. Approximately 50% of atypical squamous cells of undetermined significance (ASCUS) and 80% of LSILs are infected by oncogenic types of HPV (ALTS group, 2000;Solomon et al, 2001). HPV DNA testing for patients with ASCUS provides useful information and allows referral of patients for immediate colposcopy to detect highgrade squamous intraepithelial lesions (HSILs) and cancer (Solomon et al, 2001). In contrast, oncogenic HPV DNA testing is not informative for triage of patients with LSILs because a high percentage of LSIL patients are HPV positive (ALTS group, 2000). A repeat Pap smear in 3 -6 months or direct biopsy under colposcopy is generally used in clinical practice. Development of alternative triage strategies for women with LSILs would be valuable in distinguishing women with LSILs that have high probabilities of progression to HSILs from women with LSILs that have spontaneously regressed.As a result of the lack of sufficiently large prospective longitudinal follow-up studies and the different geographic distributions of HPV types, it has not been established how the risk of HSILs differs during transition by physical status of HPV 16, 18, 52, and 58 DNA (integrated versus episomal DNA) during longitudinal follow-up, viral loads (high vs low) and viral load change (increased vs not increased) between baseline and followup among women with LSILs. To examine this issue, we evalu...

Is Human Papillomavirus Viral Load a Clinically Useful Predictive Marker? A Longitudinal Study

“…Our use of serial sampling allowed us to overcome some of the methodologic limitations of previous studies that have reported an association between changes in HPV viral load and the acquisition or progression of cervical neoplasia. In these studies, viral load was measured at only two time points, with the sample taken at the time of diagnosis of cervical neoplasia used to provide the second of the two samples necessary to define the change in viral load (1,9). Observations on viral load made at or after the time of diagnosis of an event are uninformative with respect to determining the change in viral load necessary for that event to occur; an outcome cannot be attributed to a given level of exposure until that period of exposure has been completed (2).…”

Type‐specific human papillomavirus oncogene messenger RNA levels correlate with the severity of cervical neoplasia

“…The details of the real-time PCR procedure for HPV DNA viral load test and primer sequences were described previously. 11 Concentrations of HPV DNA were expressed as copies of HPV genome in 50 ng of cellular DNA.…”

“…About 3,800 bp length of the E6/E7/E1/E2 regions of HPV 6,11,16,18,31,33,39,45, 51, 52, 56, 58, 59 and 68 genomes from clinical samples were separately cloned into pGEM T-Easy vector (Promega) and sequenced by automated sequencing for verification of the sequences. All the type-specific primer pairs were checked by chessboard test to confirm their specificity.…”

“…1 In addition, HPV 52 and 58 are more prevalent in patients with preinvasive and cervical cancer in Taiwan and other Asian countries. [8][9][10][11][12][13][14][15] On the other hand, the occurrence of infection with HPV types 52 or 58 is relatively uncommon in cervical cancer in the Americas, Europe, Africa and …”

Human papillomavirus research on the prevention, diagnosis, and prognosis of cervical cancer in Taiwan

“…The authors concluded that evaluation of viral load changes (increased or not increased) through repeat HPV DNA testing could predict disease progression in LSIL cases with HPV types 16, 18, 52, and 58. (47) To determine the effects of age, Lin and associates analyzed 119 women over 50 years old with ASCUS or LSIL. Those who had positive HPV infections were at increased risk for developing ≥ CIN2.…”