Factors that favour a small proportion of HPV16 infections to progress to cancer are still poorly understood, but several studies have implicated a role of HPV16 genetic variation.
To evaluate the ...association between HPV16 genetic variants and cervical cancer risk, we designed a multicentre case-control study based on HPV16-positive cervical samples (1121 cervical cancer cases and 400 controls) from the International Agency for Research on Cancer biobank. By sequencing the E6 gene, HPV16 isolates were classified into variant lineages and the European (EUR)-lineage isolates were subclassified by the common polymorphism T350G.
Incidence of variant lineages differed between cases and controls in Europe/Central Asia (P=0.006, driven by an underrepresentation of African lineages in cases), and South/Central America (P=0.056, driven by an overrepresentation of Asian American/North American lineages in cases). EUR-350G isolates were significantly underrepresented in cervical cancer in East Asia (odds ratio (OR)=0.02 vs EUR-350T; 95% confidence interval (CI)=0.00-0.37) and Europe/Central Asia (OR=0.42; 95% CI=0.27-0.64), whereas the opposite was true in South/Central America (OR=4.69; 95% CI=2.07-10.66).
We observed that the distribution of HPV16 variants worldwide, and their relative risks for cervical cancer appear to be population-dependent.
Objective
To evaluate partial HPV16/18 genotyping as a possible biomarker to select women attending HPV‐based cervical cancer screening at higher risk to be referred to colposcopy.
Design
...Population‐based cohort study.
Setting
Organised cervical cancer screening programmes (Italy).
Population
Women with high‐risk HPV infection (period: 2015–2019).
Methods
We analysed the association between partial HPV16/18 genotyping, cytology triage and histologically confirmed diagnosis of high‐grade cervical intraepithelial neoplasia (CIN3+) lesions.
Main outcome measures
Detection rate (DR) and positive predictive value (PPV) for histologically confirmed CIN3+ (any episode in the 2 years after baseline); sensitivity for CIN3+ and number of colposcopies needed for lesion detection.
Results
The study included 145 437 women screened with HPV testing by the clinically validated COBAS 4800 HPV assay (Roche). Overall, 9601 (6.6%) women were HPV+ at baseline; HPV16 and HPV18 were present in 1865 and 594 samples, respectively. The cumulative (baseline plus 1‐year repeat) cytology positivity was 42.8% and high‐grade cytology was significantly higher (P < 0.0001) among women with HPV16 infection at baseline (15.2%). The cumulative CIN3+ DR for women with HPV16, HPV18 and other HPV‐type infections was 9.8%, 3.4% and 1.8%, respectively.
Conclusions
Partial HPV16 genotyping may play a role in triage, whereas HPV18 seems to behave much more similarly to the other HPV types and does not provide additional stratification. HPV16 genotyping combined with high‐grade cytology can be envisaged as a triage biomarker in cervical screening to maximise CIN3+ detection while minimising colposcopy at baseline or 1‐year repeat.
Tweetable
HPV16 genotyping combined with high‐grade cytology can be used as triage biomarker for CIN3+ in HPV‐positive women.
Tweetable
HPV16 genotyping combined with high‐grade cytology can be used as a triage biomarker for CIN3+ in HPV‐positive women.
Objective
To assess the 5‐year risk of high‐grade lesions in women with a transient high‐risk HPV infection.
Design
Population‐based cohort study.
Setting
HPV primary testing within population‐based ...organised cervical cancer screening programmes.
Population
Italian women enrolled in seven pilot projects and attending the second round.
Methods
On the basis of the cytology triage performed on HPV‐positive women, immediate colposcopy or HPV repeat at 12 months was recommended. Data were collected at the subsequent round 3–4 years after HPV infection clearance.
Main outcome measures
Rates of HPV infection, CIN2+ and CIN3+ detection at subsequent round after HPV clearance, and relative risks (RR) in comparison with HPV‐negative women (with 95% confidence interval).
Results
Data on 1230 women (1027 aged 25–64 years and 203 aged 35–64 years) have been analysed. Overall compliance with repeat HPV testing was 84%. In comparison with HPV‐negative women, those with a transient HPV infection had higher proportions of HPV positivity (15% versus 3.7%) and of CIN2+ lesions (0.87% versus 0.23%) in round two; most of these (7/10) were CIN2; no cancers were detected, and CIN3 occurred in 3/1230 (0.24%).
Conclusions
HPV‐based protocols for cervical cancer screening allow long intervals for HPV‐negative women; it is important to monitor the clinical outcome in the women with transient high‐risk HPV infection. CIN3 detection is similar to that observed in routine European cytology‐based screening programmes (CIN3+: 2.7‰); 5‐year intervals may provide reasonable protection but longer intervals are not recommended.
Tweetable
A screening interval of 5 years (but no longer) appears safe in women with transient HPV detection.
Tweetable
A screening interval of 5 years (but no longer) appears safe in women with transient HPV detection.
Objective
To compare the results from an initial negative human papillomavirus (HPV) test with re‐screening after 3 years in women attending two HPV‐based screening programmes.
Design
...Population‐based cohort study.
Setting
Two cervical service screening programmes in Italy.
Population
Women aged 25–64 years invited to screening from April 2009 to October 2015.
Methods
Eligible women were invited to undergo an HPV test. Those with a negative HPV test went on to the next screening round 3 years later. Cytology triage was performed for HPV+ (HPV by Hybrid Capture 2) samples, with immediate colposcopy (if abnormal) and HPV re‐testing 1 year later (if negative).
Main outcome measures
Participation rate, positivity at HPV and at triage, referral rate to colposcopy, positive predictive value for cervical intraepithelial neoplasia grade 2+ (CIN2+) at colposcopy, and detection rate for CIN2+.
Results
We present the results from 48 751 women at the first screening and 22 000 women at re‐screening 3 years later. The response rate was slightly higher at the second screening (74.5 versus 72.1% at the first screening; referral rate, RR 1.11; 95% confidence interval, 95% CI, 1.07–1.14). Compared with the first screening, we observed a significant reduction at the second screening in terms of HPV positivity (RR 0.55, 95% CI 0.51–0.60), referral rate to colposcopy (RR 0.47, 95% CI 0.41–0.53), CIN2+ detection rate (RR 0.24, 95% CI 0.13–0.39), and positive predictive value (PPV) for CIN2+ at colposcopy (RR 0.51, 95% CI 0.29–0.87).
Conclusions
The very low frequency of disease and inadequate PPV at colposcopy indicate that a 3‐year interval after a negative HPV test is too short.
Tweetable
Three years after a negative HPV the frequency of cervical disease is so low that re‐screening is inefficient.
Tweetable
After a negative HPV test the frequency of cervical disease is so low at 3 years that re‐screening is inefficient.
Objective
To present the results of the first 2 years of a human papillomavirus (HPV) test‐based screening programme outside the research context.
Design
Population‐based cohort study.
Setting
A ...cervical service screening programme in Italy.
Population
Women aged 25–64 years invited to screening from April 2009 to April 2011.
Methods
Eligible women were invited to undergo an HPV test: those with a negative HPV test went on to the next screening episode; those with a positive HPV went on to triage with a Pap smear. Women with positive cytology (i.e. positive for atypical squamous cells of undetermined significance or worse, ASC‐US+) were referred to colposcopy, whereas those with negative cytology were referred to repeat HPV testing 1 year later.
Main outcome measures
Participation rate, positivity at HPV and at triage, referral rate to colposcopy, positive predictive value for cervical intraepithelial neoplasia grade 2+ (CIN2+) at colposcopy, and detection rate for CIN2+.
Results
Participation increased compared with the previous Pap programme (60.6 versus 43.9%). The HPV positivity rate was 7.0; 39.6% of Pap smears were scored as positive, and therefore 2.8% of the women screened were referred for immediate colposcopy. The compliance of women who scored positive for HPV and negative for Pap for repeat HPV testing at 12 months was 78.6%, and the HPV positivity rate was 56.6%. The overall referral rate to colposcopy was 4.6%. The overall detection rate for CIN2+ was 4.5 versus 1.5% of the Pap programme (25–34 years, 8.2%; 35+ years, 3.6%).
Conclusions
Compared with the traditional Pap test, the HPV programme recorded a higher response to invitation and an increased DR for CIN2+. The most critical aspects were the reading of cytology in women that were positive for HPV and the increased workload at colposcopy.
Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is an entity with peculiar clinical and molecular characteristics, which mainly arises from the reticulated ...epithelium lining the crypts of the palatine tonsils and the base of the tongue. The only head and neck site with a definite etiological association between persistent high-risk (HR) HPV infection and development of SCC is the oropharynx. HPV-positive malignancies represent 5-20% of all HNSCCs and 40-90% of those arising from the oropharynx, with widely variable rates depending on the geographic area, population, relative prevalence of environment-related SCC and detection assay. HPV-16 is by far the most common HR HPV genotype detected in oropharyngeal SCC (OPSCC), and the only definitely carcinogenic genotype for the head and neck region. Patients with HPV-induced OPSCC are more likely to be middle-aged white men, non-smokers, non-drinkers or mild to moderate drinkers, with higher socioeconomic status and better performance status than subjects with HPV-unrelated SCC. HPV-induced HNSCCs are often described as non-keratinizing, poorly differentiated or basaloid carcinomas, and are diagnosed in earlier T-category with a trend for a more advanced N-category, with cystic degeneration, than the HPV-unrelated carcinomas. HPV positivity is associated with better response to treatment and modality-independent survival benefit. Treatment selection in HPV-related oropharyngeal carcinoma is becoming a critical issue, and although there is no evidence from randomized, controlled trials to support a treatment de-escalation in HPV-positive SCC, some investigators argue that intensive combined modality strategies may represent an overtreatment.
Objective To evaluate the clinical course of extensive anal condylomatosis in relation to treatment modalities, patient comorbidity and immune function, and associated papillomavirus (HPV) ...sequences.
Method Clinical data, treatment modalities and follow‐up were recorded and analysed in relation to host and viral type. Histology, immunohistochemistry and molecular analyses for HPV search and typing were performed on formalin‐fixed paraffin‐embedded samples.
Results Sixteen patients 14 males, median age 41.8 years (range 19–66) affected by extensive anal condylomatosis 10 Buschke‐Lowenstein Tumors (BLT) and 6 condylomatosis treated in three different Italian institutions were included. There was associated preoperative anal intraepithelial neoplasia grade 3 (AIN3) in one and invasive carcinoma in three patients. After radical resection (n = 16) recurrence occurred in 4/10 (40%) BLT patients. Malignancy before or after treatment developed in 5/16 (31.25%) patients. HPV sequences were present in all the samples of 15 evaluable patients (types 6 or 11, 9 patients; type 16, 6 patients). A statistically significant association was found between presence of HPV type 16 and both malignancy and recurrence. Viral variant L83V was present in 3/4 HPV 16 positive recurrent cases.
Conclusion Radical resection resulted in a favourable clinical course. Typing of HPV sequences in the management of patients affected by extensive anal condylomatosis may be useful.
Background In the first recruitment phase of a randomized trial of cervical cancer screening methods (New Technologies for Cervical Cancer Screening NTCC study), we compared screening with ...conventional cytology with screening by human papillomavirus (HPV) testing in combination with liquid-based cytology. HPV-positive women were directly referred to colposcopy if aged 35 or older; if younger, they were retested after 1 year. Methods In the second recruitment phase of NTCC, we randomly assigned women to conventional cytology (n = 24661) with referral to colposcopy if cytology indicated atypical squamous cells of undetermined significance or more severe abnormality or to testing for high-risk HPV DNA alone by Hybrid Capture 2 (n = 24535) with referral to colposcopy if the test was positive at a concentration of HPV DNA 1 pg/mL or greater. For the main endpoint of the study, histologic detection of cervical intraepithelial neoplasia of grade 2 or more (CIN2+), we calculated and compared sensitivity and positive predictive value (PPV) of the two screening methods using HPV DNA cutoffs of 1 pg/mL and 2 pg/mL. All statistical tests were two-sided. Results For women aged 35–60 years, the relative sensitivity of HPV testing for detection of CIN2+ at a cutoff of 1 pg/mL vs conventional cytology was 1.92 (95% CI = 1.28 to 2.87) and the relative PPV was 0.80 (95% CI = 0.55 to 1.18). At a cutoff of 2 pg/mL HPV DNA, the relative sensitivity was 1.81 (95% CI = 1.20 to 2.72) and the relative PPV was 0.99 (95% CI = 0.67 to 1.46). In this age group, there was no evidence of heterogeneity between study phases. Among women aged 25–34 years, the relative sensitivity for detection of CIN2+ of HPV testing at a cutoff of 1 pg/mL vs cytology was 3.50 (95% CI = 2.11 to 5.82), statistically significantly larger (P = .019) than that observed in phase 1 at this age (1.58; 95% CI = 1.03 to 2.44). Conclusions For women aged 35–60 years, HPV testing with a cutoff of 2 pg/mL achieves a substantial gain in sensitivity over cytology with only a small reduction in PPV. Among women aged 25–34 years, the large relative sensitivity of HPV testing compared with conventional cytology and the difference between relative sensitivity during phases 1 and 2 suggests that there is frequent regression of CIN2+ that are detected by direct referral of younger HPV-positive women to colposcopy. Thus, triage test or repeat testing is needed if HPV is to be used for primary testing in this context.
Objective
To assess the 5‐year risk of high‐grade lesions in women with a transient high‐risk
HPV
infection.
Design
Population‐based cohort study.
Setting
HPV
primary testing within population‐based ...organised cervical cancer screening programmes.
Population
Italian women enrolled in seven pilot projects and attending the second round.
Methods
On the basis of the cytology triage performed on
HPV
‐positive women, immediate colposcopy or
HPV
repeat at 12 months was recommended. Data were collected at the subsequent round 3–4 years after
HPV
infection clearance.
Main outcome measures
Rates of
HPV
infection,
CIN
2+ and
CIN
3+ detection at subsequent round after
HPV
clearance, and relative risks (
RR
) in comparison with
HPV
‐negative women (with 95% confidence interval).
Results
Data on 1230 women (1027 aged 25–64 years and 203 aged 35–64 years) have been analysed. Overall compliance with repeat
HPV
testing was 84%. In comparison with
HPV
‐negative women, those with a transient
HPV
infection had higher proportions of
HPV
positivity (15% versus 3.7%) and of
CIN
2+ lesions (0.87% versus 0.23%) in round two; most of these (7/10) were
CIN
2; no cancers were detected, and
CIN
3 occurred in 3/1230 (0.24%).
Conclusions
HPV
‐based protocols for cervical cancer screening allow long intervals for
HPV
‐negative women; it is important to monitor the clinical outcome in the women with transient high‐risk
HPV
infection.
CIN
3 detection is similar to that observed in routine European cytology‐based screening programmes (
CIN
3+: 2.7‰); 5‐year intervals may provide reasonable protection but longer intervals are not recommended.
Tweetable abstract
A screening interval of 5 years (but no longer) appears safe in women with transient
HPV
detection.
Tweetable abstract
A screening interval of 5 years (but no longer) appears safe in women with transient
HPV
detection.
Human papillomavirus (HPV) infection of the lower genital tract is now considered the most important factor in the initiation of neoplasia. Human immunodeficiency virus (HIV) infection appears to ...alter the natural history of HPV-associated oncogenesis, but its impact on gynaecology has only recently been defined; the Centers for Disease Control (CDC) designated moderate and severe cervical dysplasia as a category B defining condition, and invasive cervical cancer as a category C defining condition of AIDS in 1993. Anal HPV infection and anal squamous intra-epithelial lesions have been found to be highly prevalent among HIV-positive homosexual men, and recent preliminary data suggest a relatively high prevalence among HIV-positive women as well. Moreover, HPV infection and associated lesions are also observed in body sites other than the anogenital area, particularly the skin and the oral cavity.
PDF
