2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests

A group of 146 experts representing 29 organizations and professional societies met September 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. Recommendations for managing atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion (LSIL) are essentially unchanged. Changes were made for managing these conditions in adolescents for whom cytological follow-up for 2 years was approved. Recommendations for managing high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells (AGC) also underwent only minor modifications. More emphasis is placed on immediate screen-and-treat approaches for HSIL. Human papillomavirus (HPV) testing is incorporated into the management of AGC after their initial evaluation with colposcopy and endometrial sampling. The 2004 Interim Guidance for HPV testing as an adjunct to cervical cytology for screening in women 30 years of age and older was formally adopted with only very minor modifications.     

Diagnosing human papillomavirus of the female lower genital tract: failure of the Pap smear as a sole screening test

Of 197 patients referred for colposcopy who underwent repeat Pap smears and colposcopic biopsies (when indicated), histologic evidence of human papillomavirus (HPV) infection involving the endocervix, cervix, or vagina or all three sites was documented in 109 biopsies. Sixty-six (61%) had normal Pap smears at the time of colposcopy. Despite a specificity of 92% for detecting HPV, the Pap smear demonstrated a low sensitivity (39%), with a positive and negative predictive test value of 88% and 50%, respectively. In patients with biopsies revealing HPV infection without associated dysplasia, false negative Pap smears were found most often in women with strictly vaginal HPV (74%) (P less than 0.05), followed by those with coexistent cervical and vaginal HPV (65%), and then by those with solely cervical HPV (51%). We question the use of the Pap smear for the detection of lower genital tract HPV, particularly in patients with only vaginal involvement, especially when the smear is repeated at the time of colposcopy. Benefits and disadvantages of other screening tests for HPV are discussed.     

Cervical cancer prevention: the impact of HPV vaccination

Cervical cancer remains a critical public health problem that is second only to breast cancer in overall disease burden for women throughout the world. In spite of the success of cervical cancer screening, Pap cytology screening is yet to be effectively implemented or has failed to reduce cervical cancer rates to an appreciable extent. Screening appears to benefit only a small fraction of women although a much larger percentage endures the inconvenience of the Pap test in order to avoid cervical cancer. The establishment of Human Papillomavirus (HPV) infection as the necessary cause of cervical precancers and cancers provides a tremendous opportunity for cervical cancer prevention through vaccination. HPV 16 and 18 which cause 70% of cervical cancers worldwide. Thus a prophylactic vaccine to prevent HPV related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world with substantial benefits. Based on the induction of neutralizing antibodies by non infectious Virus Like Particles (VLP) of L1 capside protein, prophylactic HPV vaccines have consistently induced high titter of neutralizing antibodies with minimal side effects and induce more than 90% protection from persistent HPV 16-18 infection and HPV 16 and 18 associated high-grade Cervical Intraepithelial Neoplasia (CIN) in proof of concept efficacy trials. HPV 16-18 vaccination will prevent HPV16-18 incident infection, and subsequently decrease in 90% the frequency of abnormal Pap attributable to these types and in about 50% overall abnormal Pap. HPV vaccination will reduce the number of women who require colposcopy, biopsy and cervical treatment for precancerous cervical lesions. The level of protection from death due to cervical cancer could exceed 95%. Three large phases prophylactic HPV VLP trials are now in progress and will form the basis for licensing of candidate vaccines in 2006. HPV vaccination targeting young female adolescents, aged 11 to 16 years, with a catch-up of those aged 17-25 years, would be a strategy to be addressed. Cervical cancer screening strategies, that will be cost-effective for the proper surveillance of women protected by HPV vaccination, are under analysis.     

Role of human papilloma virus testing in cervical cancer prevention

A clear causal relationship has been established between human papilloma virus (HPV) infection and the development of cervical cancer. Genital HPV infection is currently the most common sexually transmitted disease worldwide. The recent 2001 American Society for Colposcopy and Cervical Pathology Consensus Guidelines have included HPV testing for management of women with cervical cytological abnormalities. Clinicians now face the challenge of deciding when to use HPV testing in follow-up of abnormal Pap tests. This article includes updates on HPV, cervical cancer screening, and HPV testing technology. Recommendations for integration of HPV testing into clinical practice are provided.     

A Study of Cervical Intraepithelial Neoplasia in Pregnancy

Objective

To find the incidence of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) in pregnant women and compare Pap smear with the HPV DNA test in detecting HPV infection.

Materials and Methods

Hundred antenatal women, irrespective of gestational age, were enrolled as subjects in this prospective pilot study for blood investigations, wet mount examination of cervical discharge, Pap smear, and high-risk HPV DNA detection of cervical scrape by PCR. Women showing abnormality in Pap smear and/or those who were high-risk HPV DNA positive were subjected to colposcopy.

Results

The incidence of HPV-positive pregnant women was 18 %. Koilocytosis on Pap smear was observed in six women. Three high-risk HPV DNA-positive women showed changes consistent with CIN 1 on colposcopy.

Conclusions

The HPV DNA test is the most sensitive and reliable in detecting HPV infection as compared to Pap smear, but considering the cost of PCR, Pap smear screening of all antenatal women was recommended.     

A study of women's knowledge regarding human papillomavirus infection, cervical cancer and human papillomavirus vaccines

AIMS: Human papillomavirus (HPV) infection is a common sexually transmitted viral infection and is associated with the development of cervical cancer. HPV vaccines are now undergoing phase 3 clinical trials in Australia. It is likely that an HPV vaccine will become licensed for use in the near future. METHODS: Ninety women aged 18-30 years from three different groups (those attending a dysplasia clinic, a local university health service and participants currently involved in a phase 3 HPV vaccine trial) completed a questionnaire assessing their knowledge base regarding HPV infection, cervical cancer, Pap tests and HPV vaccines. RESULTS: Respondents demonstrated good understanding of the Pap test and interpretation of an abnormal result. Most respondents (89%) had heard of HPV and attributed a number of different clinical symptoms to infection. For women who had not heard of an HPV vaccine, 79% of respondents stated that the most common resource they would use to obtain further information is their general practitioner. DISCUSSION: Many women do not understand the risk factors for HPV infection, the clinical problems it may cause and the potential long-term complications of infection. Few women have heard of a HPV vaccine, but most women surveyed would approach their general practitioner for more information if one became available. CONCLUSION: This study highlights the need for further education regarding HPV infection and the potential long-term complications such as cervical cancer. It also demonstrates that education of general practitioners regarding an HPV vaccine is essential, as this is the most likely resource women will use to obtain further information in the future.     

改良取样巴氏涂片在人群子宫颈癌筛查中的应用

目的：探讨改良取样巴氏涂片（Pap）在子宫颈癌筛查中的应用价值。方法：对500例30~59岁、3年内未行宫颈癌筛查的妇女行改良Pap、液基细胞学（LCT）和第二代杂交捕获实验（HC-Ⅱ）人乳头瘤病毒（HPV）检测,Pap采用液基细胞学刷取样,2种细胞学取样采用分配样本法。细胞学以无明确诊断意义不典型鳞状细胞（ASCUS）为阳性阈值,对任一细胞学结果或HPV检测阳性的妇女行阴道镜下宫颈多点活检,以病理诊断为金标准,评价2种细胞学方法筛查宫颈癌的价值。结果：宫颈细胞学筛查宫颈上皮内瘤样病变（CIN）Ⅱ以上病变以ASCUS为阳性阈值的筛查效率最高;改良Pap和LCT的筛查效率（ROC曲线下面积比较,Z ＝0.70,P ＞0.05）和不满意率（χ2＝0.343,P =0.558）差异无统计学意义;两种细胞学的诊断完全一致率为86.8%,宫颈癌和宫颈癌前病变级别越高,2种细胞学方法判读结果的一致性越好。结论：改良Pap经济有效,可广泛应用于人群子宫颈癌筛查。     

Knowledge and attitudes about human papillomavirus, Pap smears, and cervical cancer among young women in Brazil: implications for health education and prevention

The objective of the study was to assess knowledge and attitudes about human papillomavirus (HPV), cervical cancer, and Papanicolaou (Pap) smears among young women. A questionnaire was administered to 204 women aged 16-23 years, attending a public clinic. Data were gathered on sociodemographic characteristics, knowledge, and attitudes related to HPV. Overall, 92% of women reported current/previous sexual activity, 42% perceived themselves at high risk of acquiring a sexually transmitted disease, 67% did not know that HPV can cause cervical cancer/warts, and only 10% acknowledged that HPV might lead to cervical cancer. In general, women had a poor knowledge on HPV diagnosis/treatment, condyloma signs, and Pap smear test. The main reasons for not having a Pap smear test done before were embarrassment (63%) and fear of pain (61%). Knowledge of HPV infection and cervical cancer was low in this urban young population. Our findings recommend for greater HPV education of the public and health care practitioners.     

Comparison of three management strategies for patients with atypical squamous cells of undetermined significance, after six months delay: A three-year experience in an Iranian university hospital

Background: A Pap test result of atypical squamous cells of undetermined significance (ASCUS) presents a clinical challenge. Only 5–10% of women with ASCUS harbour serious cervical disease.
Methods: We screened 3619 women, who attended to Mirza Koochak Khan Hospital at Tehran University of Medical Sciences with Pap smears, of whom 100 returned with ASCUS. After six months, each subject underwent a standard cytology (conventional Pap smear), human papillomavirus (HPV) DNA testing (identifying high-risk HPV types with polymerase chain reaction) and colposcopy with multiple cervical biopsies.
Results: Mean age was 44.09 ± 8.6 years. The estimated prevalence of cervical intraepithelial neoplasia (CIN) II or higher was 4%. When histologically verified high-grade lesions (≥ CIN II) were observed, the relative sensitivity of HPV DNA testing was 100% compared with conventional Pap smear, which performed 75% versus 100% relative sensitivity, respectively, using cytological diagnosis high-grade squamous intraepithelial lesion, or low-grade squamous intraepithelial lesion (LSIL) as the cut-off. Negative and positive predictive values (NPV and PPV) of Pap test were 98.9% and 100%. The NPV and PPV of HPV DNA testing were 100%.
Conclusions: Although less complicated than colposcopy, the repeat Pap smear triage algorithm for ASCUS may underdiagnose some women with high-grade CIN, when compared with colposcopy. Considering the high sensitivity of HPV testing, it may be useful as an alternative to the current policy of six-month repeat cytology for women with ASCUS results.     

Adjunctive testing for cervical cancer in low resource settings with visual inspection, HPV, and the Pap smear.

OBJECTIVE: To test whether the performance of visual inspection using acetic acid (VIA) could be improved through adjunctive testing and to determine whether the combination of visual inspection of the cervix and HPV testing could prove useful for identifying those at highest risk of cervical precancer. METHODS: Between October 1995 and August 1997, 2199 women willing to be screened for cervical cancer in peri-urban clinics in Harare, Zimbabwe received VIA, Pap smear and HPV as screening tests. The presence or absence of (pre)cancer was confirmed via colposcopy with biopsy as indicated for >97% of all women. Computerized simulations of sequential testing scenarios provided estimates of the joint (net) test qualities of different paired combinations of the three tests and allowed for comparisons with the individual test qualities. RESULTS: Using HGSIL/CIN II-III as the reference threshold of disease, the net sensitivity and specificity of VIA and HPV when used sequentially were 63.6 and 81.9%, respectively, compared to 43.3 and 91%, respectively, when Pap smears were followed by HPV testing. VIA followed by the Pap smear yielded a net sensitivity of 37.5% and net specificity of 94.3%. CONCLUSIONS: For programs with limited resources but with the capacity for HPV testing, sequential testing involving the use of VIA followed by HPV could yield fewer false positives than the use of VIA alone at a cost of relatively few additional false negatives.     

Risk assessment to guide the prevention of cervical cancer

Advances in screening and diagnosis make it increasingly possible to prevent cervical cancer. However, if misused or poorly understood, these new tools will only increase costs and potentially harm patients without benefit. As a framework for standardized care that maximizes patient safety and well-being, we propose that a risk model be adopted to guide clinical management now and in the future. The model would use thresholds of increasing risk for cervical precancer and treatable cancer to guide clinical decision making for screening intensity, diagnostic evaluation, or treatment. Experts would decide on these risk thresholds and stratum based on the patient risk to benefit, independent of current (eg, cytology, carcinogenic HPV testing, and colposcopy) and future methods of measuring risk. A risk management model for cervical cancer prevention, based on appropriate clinical actions that correspond to risk stratum, can result in better allocation of resources to and increased safety for women at the greatest risk and increased well-being for women at the lowest risk.     

Cervical neoplasia in pregnancy. Part 1: screening and management of preinvasive disease

Cervical cancer screening is an essential component of prenatal care. The diagnosis and management of cervical intraepithelial neoplasia (CIN) during pregnancy are challenging, and sufficient information does not exist to allow for a definitive evidence-based approach. The American Society for Colposcopy and Cervical Pathology has recently published guidelines regarding the evaluation of abnormal Papanicolaou tests and the treatment of CIN in this setting. Many techniques traditionally recommended in the evaluation of abnormal cervical cytology and the treatment of CIN in the nonpregnant woman, such as colposcopy, cervical biopsy, and electrosurgical excision, can be applied to the pregnant patient with important exceptions. The vascular cervix associated with the gravid condition and the risk of premature pregnancy loss mandates deviation from existing consensus guidelines in screening for cervical cancer in pregnancy and treating associated CIN. In the present review, current guidelines regarding cervical cancer screening are reviewed, and data from studies of pregnant populations are summarized.     

2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ

A group of 146 experts representing 29 organizations and professional societies met Sept. 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. The management of low-grade cervical intraepithelial neoplasia (CIN) grade 1 has been modified significantly. Previously, management depended on whether colposcopy was satisfactory and treatment using ablative or excisional was acceptable for all women with CIN 1. In the new guidelines, cytological follow-up is the only recommended management option for women with CIN 1 who have low-grade referral cervical cytology, regardless of whether the colposcopic examination is satisfactory. Treatment is particularly discouraged in adolescents. The basic management of women in the general population with CIN 2,3 underwent only minor modifications, but options for the conservative management of adolescents with CIN 2,3 have been expanded. Moreover, management recommendations for women with biopsy-confirmed adenocarcinoma in situ are now included.     

内蒙古少数民族地区宫颈癌的筛查方法研究

目的探讨内蒙古少数民族聚居区宫颈癌及癌前病变适宜的筛查方法。方法2009年4月-8月对内蒙古自治区鄂尔多斯、兴安盟、通辽三个地区的2958名年龄30～59岁的已婚妇女进行了宫颈癌筛查。取宫颈脱落细胞,做人乳头瘤病毒（HPV-HC2）检测;同时用醋酸着色及碘着色（VIA/VILI）肉眼观察的方法进行筛查。对HPV-HC2阳性或VIA/VILI肉眼观察异常或两者均异常者,行阴道镜检查,在可疑处取宫颈组织活检,必要时行颈管诊刮术（ECC）;送组织病理学检查确诊。结果内蒙古鄂尔多斯、通辽、兴安盟三地区HPV总感染率为17.36%,中度及以上宫颈上皮内瘤样病变（≥CIN2）和宫颈癌的检出率为0.9%;应用HPV-HC2筛出阳性者最后确诊≥CIN2者27例,而用VIA/VILI仅确诊13例,漏诊14例。结论HPV检测结合醋酸、碘肉眼观察是宫颈癌筛查的有效方法。在内蒙等经济发展不均衡地区,可尝试采用HPV检测进行初筛,对HPV阳性患者用VIA＋VILI或者细胞学筛查的方法进行分流的筛查策略,降低漏诊率,也相对降低HPV阳性患者阴道镜的转诊率。     

21～24岁年轻女性子宫颈癌筛查建议及子宫颈病变的处理

21～24岁年轻女性子宫颈癌及癌前病变发生率较低,且该年龄段子宫颈病变逆转可能性大,因此对21～24岁年轻女性初级筛查建议采用单独子宫颈脱落细胞学检测;对于子宫颈细胞学筛查结果异常推荐随访为主;异常组织病理学趋于保守处理,根据病变级别和细胞学筛查结果实施分层管理,并采取子宫颈脱落细胞学、高危型HPV检测以及阴道镜检查随访。     

Abnormal cervical smears in adolescents: a ten-year comparative study of demographic criteria and management

OBJECTIVE: Comparison of the demographic criteria and management of adolescents and other age groups referred to a colposcopy clinic with abnormal smears. METHODS: Retrospective study of newly referred cases to a colposcopy clinic in a UK district general hospital between 1996 and 2005. RESULTS: Most of the sociodemographic and sexual factors associated with HPV infection and cervical cancer were more obvious among adolescents than older women. There was a comparable incidence of high-grade cervical lesions in the two groups. CONCLUSIONS: A policy is needed to deal with adolescents who are exposed to all the risk factors associated with the development of HPV infection and high-grade cervical lesions. This has become an important issue for discussion recently in the UK after raising the age of onset of cervical screening to 25.     

Shanxi Province Cervical Cancer Screening Study: a cross-sectional comparative trial of multiple techniques to detect cervical neoplasia

OBJECTIVE: The aim of this study was to design a cervical cancer screening algorithm for the developing world that is highly sensitive for cervical intraepithelial neoplasia (CIN) II, III, and cancer and highly specific for CIN II and III, making it possible to ablate the transformation zone without histologic confirmation. METHODS: In rural Shanxi Province, China, we examined 1997 women ages 35-45. Each subject underwent a self-test for intermediate and high-risk HPV (by HC-II assay), fluorescence spectroscopy, a liquid-based Pap (read manually and by computer and used as a direct test for HPV), a visual inspection (VIA) diagnosis, and colposcopy with multiple cervical biopsies. RESULTS: Mean age was 39.1 +/- 3.16 years, mean number of births was 2.6 +/- 0.93. Based on tests administered, 4.3% subjects had > or =CIN II. All subjects with > or =CIN II had either a ThinPrep Pap (> or =ASCUS) or a positive HPV direct test. The sensitivity and specificity for the detection of > or =CIN II were, respectively, 83 and 86% for the HPV self-test, 95 and 85% for the HPV direct test, 94 and 78% for the ThinPrep Pap (> or =ASCUS), 77 and 98% for the ThinPrep Pap (> or =HGSIL), 94 and 9% for fluorescence spectroscopy, 71 and 74% for VIA, and 81 and 77% for colposcopy. CONCLUSION: Based on these data and the existing healthcare infrastructure in China, we believe that further refinement of primary HPV screening using centralized labs is indicated. Self-testing in the local villages may be effective with improvements in the devices and techniques.     

A 6-Year Experience with Pap Smears in an Urban Adolescent Practice: The Scope and Burden of Abnormalities

Study ObjectiveTo determine the prevalence of cervical dysplasia and adherence to recommendations for referral/follow-up in a group of adolescent girls undergoing routine reproductive health care in a primary care setting.DesignRetrospective review of all screening Papanicolaou (Pap) smears performed between 12/99 and 12/05.SettingAn urban academic adolescent medicine practice in New York City.Participants824 sexually active adolescent girls.Main OutcomesCytology and cervical biopsy results and adherence to follow-up and colposcopy recommendations.ResultsAmong 824 adolescents ages 12–21 years (mean = 17) who underwent 1 to 6 screening Paps, 81% (n = 666) had normal Pap smears only and 19% (n = 158) had at least one abnormal Pap. Of the 1214 screening Pap smears reviewed, only one was suggestive of a high grade lesion, 85 (7%) revealed atypical squamous cells of undetermined significance (ASCUS), 81 (6.6%) showed low-grade squamous intraepithelial lesions (LGSIL), and the rest were normal. Fifteen percent of patients (n = 123) were referred for at least one colposcopy; only 72% (n = 88) complied. Biopsy identified 5 high-grade lesions; 3 patients required cervical Loop Electrosurgical Excision Procedures: Despite appropriate referrals and access to services, 32% of patients with ASCUS and 28% of patients with LGSIL lacked evidence of either follow-up Pap or colposcopy by the time of last review.ConclusionsHigh-grade lesions were rare in our sample, supporting new guidelines for less colposcopy in this age group. Although many adolescents were followed within primary care, achieving appropriate follow-up for those with cervical dysplasia was challenging and often unsuccessful.     

Guidelines for screening and treatment of cervical disease in the adolescent

BACKGROUND: The last decade has seen a significant increase in our knowledge of HPV infection and its natural history. The advent of liquid-based cytology and HPV testing has changed the way we approach patients with abnormal Pap tests. The objective is to summarize some of the key evidence that lead to the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for the management of abnormal cytology and histology and the American Cancer Society (ACS) cervical cancer screening guideline as they pertain to adolescents. METHODS: The critical publications responsible for the recent ASCCP guidelines as well as the ACS recommendations for cervical cancer screening were reviewed. RESULTS: Sexually active adolescents are frequently infected by HPV. The natural history of these infections is one with a high rate of resolution. The typical HPV infection will resolve in approximately one year. The ACS has recommended that Pap test screening begin at 21, or 3 years after the onset of sexual activity. The ASCCP guidelines for the management of CIN 1 conclude that observation is the preferred therapy. These recommendations reflect our improved understanding of the natural history of HPV infection. CONCLUSIONS: Adolescents frequently experience transient HPV infections. As our understanding of the natural history of these infections has improved major national organizations have changed the recommendations for the screening of cervical disease and treatment of low-grade cervical abnormalities. The health care community servicing adolescents should incorporate these recommendations into daily practice.