Self-sampling for high-risk human papillomavirus as a follow-up alternative after treatment of high-grade cervical intraepithelial neoplasia

Women treated for high-grade cervical-intraepithelial-neoplasia (CIN) require long-term follow-up with high-risk human-papillomavirus (HPV) testing. Self-sampling for HPV is well-accepted among these patients, but its role in follow-up for this group requires investigation. The present study examined how well HPV findings from self-sampled vaginal (VSS) and urine specimens correctly identified women from this cohort with recurrent CIN2+ compared with samples collected by clinicians. At 1st post-conization follow-up, 531 patients (99.8% participation) gave urine samples, performed VSS, underwent colposcopy with punch biopsy of visible lesions and clinician-collected cervical sampling for HPV analysis and liquid-based cytology. A total of 113 patients with positive HPV and/or abnormal cytology at 1st follow-up underwent 2nd follow-up. At 1st follow-up, all patients with recurrent CIN3 had positive HPV results by all methods. Clinician sampling and VSS revealed HPV16 positivity in 50% of recurrent cases and urine sampling revealed HPV16 positivity in 25% of recurrent cases. At 2nd follow-up, all 7 newly-detected CIN2/3 recurrences were associated with HPV positivity on VSS and clinician-samples. Only clinician-collected samples detected HPV positivity for two adenocarcinoma-in-situ recurrences, and both were HPV18 positive. A total of 77 patients had abnormal cytology at 1st follow-up, for which HPV positivity via VSS yielded highest sensitivity. The HPV findings were positive from VSS in 12 patients with high-grade squamous-intraepithelial-lesions (HSIL), and 11 patients with HSIL had positive HPV findings in clinician-collected and urine samples. All methods for assessing HPV presence yielded significant age-adjusted odds ratios for predicting abnormal lesions at 1st follow-up. For overall HPV results, Cohen''s kappa revealed substantial agreement between VSS and clinician sampling, and moderate agreement between urine and clinician sampling. Clinician sampling and VSS were highly concordant for HPV16. Insofar as the pathology was squamous (not glandular), VSS appeared as sensitive as clinician sampling for HPV in predicting outcome among the present cohort. Since VSS can be performed at home, this option can maximize participation in the required long-term follow-up for these women at high-risk.     

Prediction of high-grade cervical intraepithelial neoplasia in cytologically normal women by human papillomavirus testing

Human papillomavirus (HPV) testing has been suggested for primary screening of cervical cancer. Prediction of future high-grade cervical lesions is crucial for effectiveness and cost. We performed a case control study in a retrospective cohort of women with at least two cervical smears, all but the last one being negative, from the organized cervical screening programme in Florence, Italy. We searched for high-risk HPV in all previous, archival, smears from cases (new histologically confirmed cervical intraepithelial neoplasia (CIN) grade II or worse) and in one previous smear from each control (last smear cytologically normal, matched by age and interval (latency) from last smear). We applied polymerase chain reaction (PCR), and the b-globin gene was used as a DNA preservation marker. High-risk HPV was identified in 71/92 (77.17%) previous smears from 79 cases and 17/332 controls (5.12%). The odds ratio (OR) was 63.76 (95% CI 30.57-132.96). Among cases the proportion of HPV-positive smears declined slightly with increasing latency. Among cases, HPV was found in 81.24% (95% CI 69.93-88.96%) of smears with latency < 4 years and in 67.80% (95% CI 47.72-82.93%) of those taken at longer intervals, up to 6 years. These findings suggest that testing for high-risk HPV allows predicting 80% of CINII/III 3 years before the cytological diagnosis and two thirds 6 years before. They also suggest that testing women negative for high-risk HPV at longer interval and strictly following-up women who are HPV positive could be an effective strategy for cervical cancer screening.     

HPV检测与细胞学检查在宫颈癌前病变诊断中的比较

目的:探讨人乳头瘤状病毒DNA检测与细胞学检查在宫颈癌前病变早期诊断中的比较。方法:病例来源于我院门诊及住院病人,均已在普通门诊做巴氏涂片(采用TBS细胞分类法)和高危型HPV-DNA检测,任何一项检查异常均在阴道镜下行多点活检。巴氏涂片以≥ASCUS/AGUS为阳性,HPV-DNA≥1.0pg/ml,宫颈活检病理作为金标准,以≥CIN2为阳性。结果:高危型HPV-DNA检测的敏感性为97.3%;特异性为71.6%;巴氏涂片的敏感性为62.2%;特异性为83.8%;两者相比高危型HPV-DNA检测方法有较高的敏感度和阴性预测值。结论:HPV-DNA检测在宫颈癌前病变早期诊断中的敏感度和阴性预测值都很高,是一种有效的初筛手段。     

Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis

Objective

We conducted a pooled analysis of published studies to compare the performance of human papillomavirus (HPV) testing and cytology in detecting residual or recurrent diseases after treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3).

Methods

Source articles presenting data on posttreatment HPV testing were identified from the National Library of Medicine (PubMed) database. We included 5,319 cases from 33 articles published between 1996 and 2013.

Results

The pooled sensitivity of high-risk HPV testing (0.92; 95% confidence interval [CI], 0.90 to 0.94) for detecting posttreatment CIN 2 or worse (CIN 2+) was much higher than that of cytology (0.76; 95% CI, 0.71 to 0.80). Co-testing of HPV testing and cytology maximized the sensitivity (0.93; 95% CI, 0.87 to 0.96), while HPV genotyping (detection of the same genotype between pre- and posttreatments) did not improve the sensitivity (0.89; 95% CI, 0.82 to 0.94) compared with high-risk HPV testing alone. The specificity of high-risk HPV testing (0.83; 95% CI, 0.82 to 0.84) was similar to that of cytology (0.85; 95% CI, 0.84 to 0.87) and HPV genotyping (0.83; 95% CI, 0.81 to 0.85), while co-testing had reduced specificity (0.76; 95% CI, 0.75 to 0.78). For women with positive surgical margins, high-risk HPV testing provided remarkable risk discrimination between test-positives and test-negatives (absolute risk of residual CIN 2+ 74.4% [95% CI, 64.0 to 82.6] vs. 0.8% [95% CI, 0.15 to 4.6]; p<0.001).

Conclusion

Our findings recommend the addition of high-risk HPV testing, either alone or in conjunction with cytology, to posttreatment surveillance strategies. HPV testing can identify populations at greatest risk of posttreatment CIN 2+ lesions, especially among women with positive section margins.     

Difference in prevalence of human papillomavirus genotypes in cytomorphologically normal cervical smears is associated with a history of cervical intraepithelial neoplasia.

The prevalence of human papillomavirus (HPV) genotypes was investigated by the polymerase chain reaction (PCR) method in cytologically normal and abnormal cervical scrapes obtained from asymptomatic women (n = 1,346), participating in a triennial screening program for cervical cancer, and from a gynecological outpatient population (n = 593). In the symptom-free population oncogenic HPV types 16, 18, 31 and 33 were present in 1.5% of cytologically normal scrapes, while the overall HPV prevalence rate was 3.5%. Significantly, higher HPV prevalence rates of 7% (oncogenic HPV; p less than 0.01) and 14% (all HPV; p less than 0.01), respectively, were found in cytologically normal scrapes of the gynecologic outpatient population. It appeared that in this outpatient group 78% of the smears containing HPV 16 and 18 were associated with a history of cervical pathology, i.e. cervical intraepithelial neoplasia grade I to III. In smears with mild and severe dysplasia and smears suspected of carcinoma in situ from both populations, the overall HPV prevalence was 70%, 84% and 100%, respectively. In all squamous-cell carcinomas of the cervix (n = 50) HPV was detected. Frequencies of HPV 16 and 18 increased from 41% in mild dysplasia to 94% in cervical carcinomas. Since a low prevalence of HPV was found in cytomorphologically normal cervices of women without a clinicopathological history, the findings in this study suggest that HPV detection in population-based screening programs for cervical neoplasia can be an important tool in identifying women who are at risk of developing dysplasia and cervical cancer.     

Combined human papillomavirus DNA and human papillomavirus-like particle serologic assay to identify women at risk for high-grade cervical intraepithelial neoplasia

The objective of this study was to assess the utility of a second generation human papillomavirus (HPV) virus-like particle (VLP)-based ELISA as an adjunct to HPV DNA testing to identify women at risk for high-grade cervical intraepithelial neoplasia (CIN). Participants provided blood, cervical samples and interviewer-obtained questionnaire information. HPV VLPs for types 16, 18, 33, 45 and 52 were produced using a baculovirus expression system. These highly purified VLPs were used in a polymer-based ELISA test. Cases with biopsy-confirmed CIN (CIN I, n = 237; CIN II, n = 56; CIN III, n = 48) and controls (n = 351) with normal Pap smears were tested for HPV DNA by PCR and serologic response to multiple oncogenic HPV VLPs. 258/341 (76%) of cases and 230/351 (65.5%) of control patients had any type of HPV VLP antibody (OR = 1.63, 95% CI 1.16-2.30). More cases were seropositive than controls for each individual HPV type (p < 0.001 for HPV types 16, 18, 33 and 45; p = 0.06 for HPV 52). Reactivity to an increasing number of different HPV type-specific VLPs are associated with high-grade CIN independent of HPV DNA status. HPV VLP assays may be useful as an adjunct to HPV DNA testing in a subset of patients that needs to be defined by further studies.     

Risk for high-grade cervical intraepithelial neoplasia associated with variants of human papillomavirus types 16 and 18.

BACKGROUND: Although the variant lineages of human papillomavirus (HPV) types 16 and 18 are well established, their individual associations with high-grade cervical intraepithelial neoplasia (CIN) have not been extensively evaluated. METHODS: Study subjects were women participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study who were positive for HPV16 or HPV18 at enrollment. These women were followed every 6 months for 2 years. Viral isolates from enrollment samples were characterized by DNA sequencing and classified as variant lineages. RESULTS: Over a 2-year study period, CIN3 was histologically diagnosed in 291 of the 779 HPV16-positive women and 47 of the 275 HPV18-positive women. Among women without CIN2-3 at enrollment, the risk of subsequent CIN3 was 2.7-fold greater for those with HPV16 African-2 [95% confidence interval (95% CI), 1.0-7.0] and 3.1-fold greater for those with HPV16 Asian American (95% CI, 1.6-6.0), compared with European variants. Relative to infection with HPV18 African variants, the risk associating subsequent CIN3 was 3.8 (95% CI, 0.9-17.2) for infection with HPV18 European variants and 4.8 (95% CI, 1.0-23.6) for infection with HPV18 Asian American variants. Similar associations were observed when the 2-year prevalence of CIN3 was used as the end point. Further, for those with HPV16 European variants, the 2-year prevalence of CIN3 was higher in White women than in African American women (P = 0.01); this trend was reversed for those with HPV16 African-1 variants (P = 0.22). A similar pattern was present for infections with HPV18 European versus African variants. CONCLUSIONS: The lineages of HPV16 and HPV18 variants are associated with differing risks for high-grade CIN.     

The physical state of human papillomavirus 16 DNA in cervical carcinoma and cervical intraepithelial neoplasia

Cervical carcinomas and cervical intraepithelial neoplasias (CIN) were analyzed for the presence of human papillomavirus (HPV) DNA using Southern blot hybridization. Of the five HPV types examined (HPV types 6, 11, 16, 18, and 33), HPV 16 DNA was detected most frequently. In most HPV 16-positive carcinomas examined, HPV 16 DNA was present in an integrated state in cellular DNA with or without the coexistence of episomal species. In one case, however, only episomal species were detected. Among seven cases of HPV 16-positive CIN, four contained HPV 16 DNA only in the episomal state and the rest contained HPV 16 DNA only in the integrated state, but the coexistence of both states was not found. These results suggest that the integration of HPV 16 DNA is not necessary for cells to become malignant, although it is frequently associated with malignant cells.     

高危型人乳头瘤病毒检测对宫颈上皮内瘤样病变诊断价值的探讨

目的:探讨在ASC-H患者中检测HR-HPV DNA预测宫颈上皮内瘤样病变(CIN)和浸润癌的价值,为完善CIN和浸润癌的筛查方案提供依据.方法:研究宫颈薄层液基细胞学诊断为ASC-H的患者68例,均进行HR-HPV DNA检测并在阴道镜下行宫颈组织活检,综合评价HR-HPV预测高级别CIN的价值.结果:在ASC-H中CIN发生率为52.9％(36/68),CINⅡ及以上病变(CINⅡ、CINⅢ及浸润癌)发生率为33.8％(23/68); HR-HPV检测阳性率为70.6％(48/68),HR-HPV阳性组CINⅡ及以上病变发生率为47.9％(23/48),HR-HPV阴性组CINⅡ及以上病变发生率为0(0/20),两组比较差异有统计学意义,x2=14.797,P=0.001,HR-HPV诊断CINⅡ及以上病变的敏感度和特异度分别为100.0％和44.4％,阳性预测价值和阴性预测价值分别为47.9％和100.0％.结论:初步研究结果提示,HR-HPV阳性ASC-H患者应高度警惕CINⅡ及以上病变发生,建议立即行阴道镜检查;而HR-HPV阴性患者可不进行阴道镜检查.     

Chromosomal profiles of high-grade cervical intraepithelial neoplasia relate to duration of preceding high-risk human papillomavirus infection

High-grade cervical intraepithelial neoplasia (CIN2/3) represents a heterogeneous disease both with respect to clinical behavior and chromosomal aberrations detected. We hypothesized that the extent of chromosomal aberrations reflects the duration of their existence. Chromosomal profiles were determined of CIN3 of women with a known 5-year history of high-risk human papillomavirus virus (hrHPV) infection, in which duration of prior hrHPV infection was considered a proxy for duration of CIN3 existence. Eleven women had a <5 year preceding hrHPV infection (CIN3<5yrPHI) and 24 had a PHI lasting ≥5 years (CIN3≥5yrPHI). For comparison, six CIN3 adjacent to squamous cell carcinomas (CIN3-SCC), the corresponding SCCs, and six CIN1 were included. Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two clusters. One was characterized by a low number of chromosomal aberrations and included all CIN1, 81.8% of CIN3<5yrPHI and 33.3% of CIN3≥5yrPHI. Samples in the second cluster, displaying multiple aberrations, included 18.2% of CIN3<5yrPHI, 66.7% CIN3≥5yrPHI, all except one CIN3-SCC and all SCCs. The number of genomic aberrations increased according to lesion grade and also with longer duration of PHI. The increase in aberrations in CIN3≥5yrPHI compared to <5yrPHI was highly significant (p = 0.001), suggesting that CIN3≥5yrPHI represent more severe lesions. In conclusion, longer duration of preceding hrHPV infection is associated with an increased number of chromosomal aberrations. Hence, CIN3 with a longer duration of existence are likely more prone to have an increased short-term risk of cervical cancer.     

宫颈电圈切除术对重度宫颈上皮内瘤变的诊疗价值及高危型HPV检测的临床意义

目的探讨宫颈电圈切除术(LEEP)对重度宫颈上皮内瘤变(CINⅡ～Ⅲ)的诊疗价值,研究高危型人乳头瘤病毒(HPV)在重度CIN中的感染情况及对LEEP术预后的影响.方法对112例重度CIN患者行阴道镜活检及LEEP术治疗,并同时行高危型HPV的PCR检测,对其疗效及预后进行分析.结果在112例重度CIN患者中,CIN Ⅱ级67例,CIN Ⅲ级(包括原位癌)45例.LEEP术后随访,治愈98例,治愈率达87.5%;发现病变残留者14例(12.5%),复发者4例(3.6%).在所有患者中,92例高危型HPV检测阳性,总感染率为82.1%.CIN Ⅲ级患者HPV阳性率(93.3%)较CIN Ⅱ级患者(74.6%)显著升高(P<0.05).高危型HPV阳性组LEEP术后病变残留率或复发率与HPV阴性组比较,差异无显著性(10.9%比20.0%,或4.3%比0;P>0.05).因CIN残留或复发而再次行LEEP术的13例患者中,检测到12例(92.3%)仍有高危型HPV感染.结论 LEEP术是诊断和治疗重度CIN的有效且理想的方法.高危型HPV与重度CIN的发生有关.术前高危型HPV阳性与否似乎与LEEP术预后无关.     

Viral load as a predictor of the risk of cervical intraepithelial neoplasia

HPV infections are believed to be a necessary cause of cervical cancer. Viral burden, as a surrogate indicator for persistence, may help predict risk of subsequent SIL. We used results of HPV test and cytology data repeated every 4–6 months in 2,081 women participating in a longitudinal study of the natural history of HPV infection and cervical neoplasia in São Paulo, Brazil. Using the MY09/11 PCR protocol, 473 women were positive for HPV DNA during the first 2 visits. We retested all positive specimens by a quantitative, low‐stringency PCR method to measure viral burden in cervical cells. Mean viral loads and 95% CIs were calculated using log‐transformed data. RRs and 95% CIs of incident SIL were calculated by proportional hazards models, adjusting for age and HPV oncogenicity. The risk of incident lesions increased with viral load at enrollment. The mean number of viral copies/cell at enrollment was 2.6 for women with no incident lesions and increased (trend p = 0.003) to 15.1 for women developing 3 or more SIL events over 6 years of follow‐up. Compared to those with <1 copy per cell in specimens tested during the first 2 visits, RRs for incident SIL increased from 1.9 (95% CI 0.8–4.2) for those with 1–10 copies/cell to 4.5 (95% CI 1.9–10.7) for those with >1,000 copies/cell. The equivalent RR of HSIL for >1,000 copies/cell was 2.6 (95% CI 0.5–13.2). Viral burden appears to have an independent effect on SIL incidence. Measurement of viral load, as a surrogate for HPV persistence, may identify women at risk of developing cervical cancer precursors. © 2002 Wiley‐Liss, Inc.     

Human papillomavirus DNA in cervical intraepithelial neoplasia detected by in situ hybridisation

Human papillomavirus (HPV) infection was investigated by in situ hybridisation in histological sections from 38 women with abnormal Papanicolaou smears. 13 patients had condylomatous lesions without atypia, 15 cervical intraepithelial neoplasia (CIN) I, 4 CIN II, 3 CIN III and 2 carcinoma in situ (CIS). HPV DNA was detected in 29 cases (78%) (1 specimen was technically inadequate). HPV 16 and 18, and 31, 33 and 35 were both present (67%) in CIN III. HPV 6 and 11 were more frequent in CIN I (56%) and in condylomatous lesions (38%). 31% of the condylomatous lesions without atypia contained HPV 31, 33, and 35 and 31% of those with CIN I were infected with HPV 16 and 18. These data confirm the frequent association of HPV infection with cervical cancer and CIN, and indicate that in situ hybridisation can identify patients with specific types of HPV infection at risk for cervical cancer.     

Human papillomavirus status in the prediction of high-grade cervical intraepithelial neoplasia in patients with persistent low-grade cervical cytological abnormalities.

The role of human papillomavirus (HPV) detection in the management of patients with persistent low-grade (mild dyskaryosis or less) cervical cytological abnormalities is unclear. We have analysed cytological material from 167 such patients both cytologically and by non-isotopic in situ hybridisation (NISH) for HPV 16, 18, 31 and 33 and consensus primer polymerase chain reaction (PCR) amplification followed by both generic and specific typing for these HPV types. Cervical intraepithelial neoplasia (CIN) 2 or 3 was present in 40 of 167 patients (23.9%), and the positive predictive values (PPVs) for the presence of CIN 2 or 3, of moderate or severe dyskaryosis at repeat cytology and an HPV-positive NISH and generic PCR signal were 100%, 66% and 42% respectively. The corresponding sensitivities were 48%, 68% and 87%. Addition of cytology to molecular analysis improved both PPV and sensitivity, the best combination being NISH and cytopathology (PPV 71%, sensitivity 87%). These data demonstrate that the presence of CIN 2 or 3 in patients with mild cytological abnormalities can be predicted by molecular detection of HPV in some cases, particularly when combined with cytological analysis. However, the magnitude of this prediction is dependent on the population of patients studied, and the clinical role of this approach therefore remains to be defined.     

Epidemiological evidence of cervical intraepithelial neoplasia without the presence of human papillomavirus.

The aim of this paper was to provide epidemiological evidence to support the notion that cervical intraepithelial neoplasia (CIN) without human papillomavirus (HPV) is a true entity. If a diagnosis of HPV-negative cervical neoplasia is erroneous, one would not expect there to be any differences in risk factors between HPV-positive and HPV-negative patients. Patients at a gynaecological outpatient clinic of a university hospital [a total of 265 consecutive women with dyskaryotic cervical smears who were subsequently diagnosed with CIN I (n=37), CIN II (n=48) or CIN III (n=180)] completed a structured questionnaire regarding smoking habits and sexual history. Analysis of an endocervical swab for Chlamydia trachomatis, analysis of a cervical scrape for HPV, and morphological examination of cervical biopsy specimens were also performed. HPV was found in 205 (77.4%) out of the 265 women. Univariate analysis showed that current age (P=0.02), current smoking behaviour (P=0.002) and the number of sexual partners (P=0.02) were significantly associated with the presence of HPV. Age at first sexual intercourse, a past history of venereal disease or genital warts, and current infection with Chlamydia trachomatis were not associated with the presence of HPV. Using multivariate logistic regression analysis, the number of sexual partners and current smoking behaviour showed an independent significant association with HPV. HPV-negative and HPV-positive CIN patients differ with respect to the risk factors for HPV. These findings suggest that HPV-negative CIN is a separate true entity.     

Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer.

Forty anal paraffin-embedded tissue specimens from 24 subjects were studied for the presence of human papillomavirus (HPV) types 6, 11, 16, 18, 31, and 33, herpes simplex virus (HSV), Epstein-Barr virus, and cytomegalovirus DNA by using the polymerase chain reaction. These tissues ranged from histologically normal to invasive squamous cell carcinoma. HPV DNA was detected in the invasive anal cancer tissues of 11 of 13 subjects. HPV types were segregated by histopathological severity, with HPV 16 associated exclusively with high grade anal intraepithelial neoplasia and invasive cancer. HPV types 6 and 11 were associated with condyloma and low grade anal intraepithelial neoplasia. HPV DNA in situ hybridization studies confirmed the presence of HPV DNA in the invasive cancer tissues of 6 of 12 subjects. HPV DNA in these tissues was highly focal and primarily associated with invasive cell nests that demonstrated the greatest degree of squamous differentiation. HSV DNA was detected only in association with advanced disease, being found in the cancer tissues of 5 of 13 subjects, and in 3 of 4 subjects with high grade anal intraepithelial neoplasia, but was not detected by in situ hybridization. Epstein-Barr virus and cytomegalovirus DNA were not detected in the 40 tissue specimens. We conclude that HPV infection may play an important role in the pathogenesis of anal cancer. The association between HSV infection and high grade anal disease suggests that HSV infection may also play a role in disease progression.     

Value of cytologic Papanicolaou smears and polymerase chain reaction screening for human papillomavirus DNA in detecting anal intraepithelial neoplasia

BACKGROUND:

The performance of cytologic screening and its correlation with histology and polymerase chain reaction (PCR) detection of human papillomavirus (HPV) DNA have not been evaluated in populations with a low prevalence of anal intraepithelial neoplasia (AIN). The objective of the current study was to analyze the significance of abnormal smears relative to the histology and PCR detection of HPV DNA.

METHODS:

A cytologic smear and a viral sample were taken in 300 consecutive patients undergoing surgery (Milligan‐Morgan hemorrhoidectomy and/or fissurectomy) who gave their informed consent.

RESULTS:

The cytologic smear was normal in 216 of 290 patients (74.5%). Four high‐grade and 19 low‐grade intraepithelial neoplastic lesions were identified. In 5 patients, high‐grade lesions could not be excluded, 30 lesions were of undetermined significance, and there were 16 cellular modifications with a non‐neoplastic appearance. The PCR test for HPV was positive in 18.7% of patients, and a high‐risk genotype was identified in 63.6% of positive samples. Histologic examination of the surgical samples was normal in 92.3% of patients. The 23 AIN samples were distributed as follows: 13 grade 1 AIN (AIN1), 6 AIN2, and 4 AIN3. The sensitivity of cytologic smears and PCR for detecting AIN was 56% and 60.8%, respectively, and specificity was 77% and 84.5%, respectively. Combining the 2 tests increased sensitivity to 78% but decreased specificity to 68%.

CONCLUSIONS:

Compared with a large surgical sample, anal cytologic Papanicolaou smears and HPV PCR exhibited sensitivity and specificity that varied, depending on the risk of HPV infection and AIN. Positive HPV DNA screening increased with AIN grade, and high‐risk HPV testing was particularly helpful. Cancer 2012. © 2012 American Cancer Society.     

Insulin-like growth factor-I and risk of high-grade cervical intraepithelial neoplasia.

Insulin-like growth factors (IGF) and their binding proteins (IGFBP) have been implicated in the risk of several epithelial or glandular tumors, including prostate cancer, breast cancer, and colon cancer. Cervical cancer, which is also of epithelial origin, has been shown to overexpress receptors for IGF-I, and plasma levels of IGF-I have been positively associated with cervical cancer precursors in one epidemiologic study. In this case-control study, we investigated plasma levels of IGF-I and IGFBP-3 in relation to the risk of histologically confirmed high-grade cervical intraepithelial neoplasia (HGCIN) and the risk of human papillomavirus (HPV) infection. Included in this analysis were 329 cases and 621 controls recruited from clinics affiliated with two Montréal-area hospital centers. We observed a reduced risk of HGCIN for increasing levels of IGF-I, with an adjusted odds ratio (OR) of 0.40 (95% confidence interval, 0.19-0.87) for the highest quartile relative to the lowest quartile of IGF-I. No association was observed between IGFBP-3 levels and HGCIN. Among controls, IGF-I was associated with a decreased risk of being positive for HPV-16 or HPV-18, with an adjusted odds ratio of 0.20 (95% confidence interval, 0.05-0.87) for the highest quartile relative to the lowest quartile of IGF-I. There was no association observed between IGFBP-3 levels and HPV infection status. IGF-I-mediated effects seemed to predominate among women <30 years of age. In contrast to the previously reported study, our results suggest that levels of IGF-I in young women may be inversely associated with HGCIN, a precursor to cervical cancer.     

Human papillomavirus infection in women who develop high-grade cervical intraepithelial neoplasia or cervical cancer: a case-control study in the UK

Human papillomavirus (HPV) testing might identify older women who could be withdrawn from the cervical screening programme, or require less frequent screening. A case-control study using the United Kingdom cervical screening population was set up to help address this issue. Cases comprised 575 women who developed cervical intraepithelial neoplasia (CIN) grade 2 or worse over a 13-year period following a cytologically normal baseline smear, and were stratified by age group ('under 20', '20-39' and 40 years or over). Controls (n=601) were women who remained disease free over this interval and were the same age on average as cases. DNA was extracted from the baseline smears and tested for HPV by PCR using GP5+/6+ consensus primers. HPV+ samples were tested for HPV types 16 and 18 using specific PCR primers. In all, 27.0% of cases tested positive for HPV at baseline, compared with 15.4% of controls (odds ratio (OR)=2.00; 95% confidence interval (CI), 1.50-2.68). Among women aged 40 years or over, the OR for HPV 16 was 8.95 (95% CI, 2.63-30.4). These results support the need for further cervical screening of HPV- older women, as many of the cases were HPV- at baseline.