Much higher risk of premalignant and malignant cervical diseases in younger women positive for HPV16 than in older women positive for HPV16

Human papillomavirus (HPV), particularly HPV16, is strongly associated with premalignant lesions of the uterine cervix and cervical cancer. However, HPV infection is a common sexually transmitted disease and only a few women develop cervical cancer. Although the presence of HPV and abnormal cytology are independent risk factors for cervical diseases, implementing both tests on every woman is argued not to be recommended mainly in terms of cost-effectiveness. During a 20-month period between October, 1994, and May, 1996, cervical swabs from 207 women who were referred for colposcopy because of cervical dyskaryosis (Papanicolaou class IIIa or higher) were examined by PCR for the presence of HPV16. When these women were divided into two groups; i.e., group A consisting of women who were 44 years old or younger (n = 111), and group B consisting of women who were 45 years old or older (n = 96), the risk of having premalignant and malignant cervical diseases upon infection with HPV16 was approximately 8 times higher in group A than in group B. Thus, we conclude that HPV-testing should be implemented on every young woman with an abnormal Papanicolaou smear test.     

The early detection of cervical cancer. The current and changing landscape of cervical disease detection

Cervical cancer prevention has undergone dramatic changes over the past decade. With the introduction of human papillomavirus (HPV) vaccination, some countries have seen a dramatic decline in HPV‐mediated cervical disease. However, widespread implementation has been limited by economic considerations and the varying healthcare priorities of different countries, as well as by vaccine availability and, in some instances, vaccine hesitancy amongst the population/government. In this environment, it is clear that cervical screening will retain a critical role in the prevention of cervical cancer and will in due course need to adapt to the changing incidence of HPV‐associated neoplasia. Cervical screening has, for many years, been performed using Papanicolaou staining of cytology samples. As our understanding of the role of HPV in cervical cancer progression has advanced, and with the availability of sensitive detection systems, cervical screening now incorporates HPV testing. Although such tests improve disease detection, they are not specific, and cannot discriminate high‐grade from low‐grade disease. This has necessitated the development of effective triage approaches to stratify HPV‐positive women according to their risk of cancer progression. Although cytology triage remains the mainstay of screening, novel strategies under evaluation include DNA methylation, biomarker detection and the incorporation of artificial intelligence systems to detect cervical abnormalities. These tests, which can be partially anchored in a molecular understanding of HPV pathogenesis, will enhance the sensitivity of disease detection and improve patient outcomes. This review will provide insight on these innovative methodologies while explaining their scientific basis drawing from our understanding of HPV tumour biology.     

Cervical cytology quality assurance in Washington State.

The objectives of this study were to establish a profile of cervical cytology laboratories in Washington State, identify quality assurance problems amenable to correction through education or legislation, and describe differences between large and small cytology laboratories. All 43 Washington laboratories that perform cervical cytology were surveyed by mail during 1989. Completed surveys were returned by 37 (86%) of the laboratories. Nearly half (43%) of the respondents reported processing less than 10,000 Papanicolaou smears annually. Only one-third (35%) of the respondents reported participating in relevant proficiency programs. A proportion of smaller cytology laboratories were compensating their cytotechnologists on the basis of the number of slides read and allowing Papanicolaou smears to be read outside the confines of the laboratory. The results of this study suggest that cytotechnologists in some larger Washington laboratories have been exceeding work load limits recommended by professional associations. Recent legislation includes regulations that address cervical cytology quality assurance. However, continued efforts will need to be made to encourage voluntary adoption of quality control measures not addressed by this legislation.     

Comparison of conventional Papanicolaou smear and SurePath® liquid-based cytology in the Copenhagen population screening programme for cervical cancer

OBJECTIVE: To compare diagnostic performance of conventional Papanicolaou smear with SurePath liquid-based cytology in a population screening programme. METHODS: A retrospective comparison was performed on data from two 18-month periods of the screening programme for cervical cancer in the municipality of Copenhagen with conventional Papanicolaou technique (n = 82,116) and liquid-based cytology (n = 84,414). RESULTS: After the conversion to liquid-based cytology the percentage of unsatisfactory samples decreased from 2.3% to 0.3% (P < 0.001), whereas the number of normal cervical samples lacking an endocervical component increased from 8.5% to 8.9% (P < 0.005). The percentage of samples with atypical cells and cells suspicious for malignancy increased from 3% to 4.2% (P < 0.001) and from 1.9% to 2.4% (P < 0.001), respectively. The subsequent histological follow-up showed normal findings decreased from 70.5% to 68.9% and from 28.0% to 26.1%, respectively. However, in relation to the entire screening populations, there was an increase of normal findings from 2.12% to 2.89% after primary atypical diagnosis and from 0.53% to 0.62% after diagnosis of suspicious cells after conversion to the liquid-based technique. CONCLUSIONS: This study showed the number of unsatisfactory samples to be significantly reduced with the liquid-based technique. The data suggest that there is an increased detection rate of cervical precancerous lesions with liquid-based cytology, but the number of false positive tests is still high. The specificity of the two tests seems similar, but this cannot be ascertained exactly, because of the fact that follow-up of negative cases is unavailable.     

Organisation of cervical cytology screening in Croatia: past, present and future

This presentation highlights strengths and weaknesses of cervical cytology screening in Croatia, with particular reference to the opportunistic screening, the use of conventional Papanicolaou (Pap) test and the analysis of some organizational, educational and performance issues that are associated with it. Its aim is to propose measures to improve the efficacy of cervical cytology screening in order to reduce cervical cancer mortality. Currently, in excess of 450,000 Pap tests/ year are examined at 35 laboratories scattered throughout the country. All of these laboratories use standard operating procedures including internal and external quality control. They employ a total of 68 cytologists and 91 cytotechnologists. The sensitivity of cervical screening in Croatia is 90.0%, specificity 98.6%, positive predictive value 92.3%, negative predictive value 98.1% and overall diagnostic accuracy 97.2%. The high diagnostic accuracy of cervical cytology is attributed to the long-standing tradition of education and training of cytologists (postgraduate MSc course since 1967, independent residency since 1974) and cytotechnologists (since 1968). This tradition spanning more than half a century means that today in Croatia there is a developed network of cytology laboratories staffed by highly competent cytologists and trained cytotechnologists. The high accuracy of cancer detection through Pap tests provides strong evidence in support of cervical cytology screening remaining the basic method of prevention for cervical carcinoma. However, some modifications to the current situation are needed. These relate primarily to opportunistic screening. The current screening coverage rate is 68%, although there is capacity, which would allow for all women at risk, i.e. those aged 25-64, to be screened once in three years. The screening coverage relates mainly to those women visiting gynecological out patient clinics for unrelated conditions. A properly organized and controlled national screening programme should replace this. This should be accompanied by the introduction of alternative, highly sensitive methods of sample collection and preparation, such as are available through the introduction of new technologies, e.g. liquid based cytology.     

Clinical Implications of the Cervical Papanicolaou Test Results in the Management of Anal Warts in HIV-Infected Women

The Papanicolaou test (or Pap test) has long been used as a screening tool to detect cervical precancerous/cancerous lesions. However, studies on the use of this test to predict both the presence and change in size of genital warts are limited. We examined whether cervical Papanicolaou test results are associated with the size of the largest anal wart over time in HIV-infected women in an on-going cohort study in the US. A sample of 976 HIV-infected women included in a public dataset obtained from the Women’s Interagency HIV Study (WIHS) was selected for analysis. A linear mixed model was performed to determine the relationship between the size of anal warts and cervical Pap test results. About 32% of participants had abnormal cervical Pap test results at baseline. In the adjusted model, a woman with a result of Atypia Squamous Cell Undetermined Significance/Low-grade Squamous Intraepithelial Lesion (ASCUS/LSIL) had an anal wart, on average, 12.81 mm² larger than a woman with normal cervical cytology. The growth rate of the largest anal wart after each visit in a woman with ASCUS/LSIL was 1.56 mm² slower than that of a woman with normal cervical results. However, they were not significant (P = 0.54 and P = 0.82, respectively). This is the first study to examine the relationship between cervical Pap test results and anal wart development in HIV-infected women. Even though no association between the size of anal wart and cervical Pap test results was found, a screening program using anal cytology testing in HIV-infected women should be considered. Further studies in cost-effectiveness and efficacy of an anal cytology test screening program are warranted.     

Quality assurance activities of the College of American Pathologists

Since its inception, the College of American Pathologists (CAP) has played a fundamental and pivotal role in the development and execution of quality assurance programs for laboratories. Within the realm of anatomic pathology, operational programs include those in surgical pathology, immunohistochemistry and cytopathology. The emphasis of prior cytopathology programs on cervical cytology has now been expanded to include body fluids and fine needle aspiration material. CAP's role in the expansion of quality assurance programs in cytology may be enhanced in the future by intersociety cooperation with established cytology organizations and will also be influenced by and closely linked to the expansion of its quality assurance programs in surgical pathology. As for the Papanicolaou smear, it can no longer be regarded as the "Cinderella of cytology"; it is in fact the present-day cynosure in the laboratory. In recognition of this, CAP has undertaken efforts to help heighten public awareness about the value of Papanicolaou smear testing and is encouraging women to become more informed about the process involved in the examination of their smears.     

Cervical cancer screening in the Czech Republic

Cytological diagnosis of atypical cells of cervix uteri by the Papanicolaou method was introduced in the Czech Republic (CR) very early - in 1947. The first data on the incidence of cervical cancer in CR are available from 1960 when the rate was 32.3 cases/10(5) women. In 1966 the Czech National Health Law was passed that guaranteed women a yearly preventive examination by a gynaecologist including screening for cervical carcinoma that would be covered by the compulsory health insurance. Notwithstanding high frequency of screening visits and the fact that all women are eligible, the incidence of CC has not changed in the last 34 years. The reasons for this include the coverage of Czech women, which is estimated to be low (50% at the most), and that none of the cytology laboratories are accredited for screening, there are no national registries for any aspect of screening and there are no mechanisms for evaluation of the screening process. As a result, it is likely that the majority of cervical screening activity that is undertaken is ineffective and the implementation of an organised and quality controlled screening programme, in compliance with the recommendations of many European Institutions, is urgently required to ensure that Czech women are properly protected against this disease and that scarce healthcare resources are used in the most cost-effective manner.     

The century for cytopathology

By the end of the 19th century, exfoliated cancer cells had been described in all of the types of specimen in which we find them today. However, it was not until Drs. Papanicolaou and Traut published their account of the diagnosis of uterine cancer from exfoliated cells (1941 and 1943) that cytopathology acquired the momentum to develop into the powerful presence that it has in human medicine today. These and the subsequent publications by Papanicolaou stimulated the development and application of cytopathology worldwide, resulting in abundant literature on the subject and a galaxy of outstanding practitioners. The 1980s saw the development and widespread use of aspiration cytology. This was followed in the 1990s by the development of automated screening systems, marking the latest stage in the evolution of cytopathology. These and other events and achievements in cytopathology, from its meager beginnings in the early 20th century to its worldwide use and acceptance today, mark this century as the "century for cytopathology."     

Cervical cancer screening from the public health perspective

Many state health departments have a significant role in cervical cancer screening. Given that role, a group of public health personnel from eight southeastern states drafted a set of questions and quality assurance issues to be discussed with a laboratory under consideration as a contract provider of cytology services. The major points of concern included: (1) quality of laboratory services (accreditation, personnel, facilities and operational and quality control procedures); (2) quality of sampling (including techniques used and the training and monitoring of sample takers); (3) terminology for cytology reporting; and (4) protocols used for diagnostic evaluation of abnormal Papanicolaou smears.     

Improved rate of high-grade cervical intraepithelial neoplasia detection in human papillomavirus DNA hybrid capture testing

BACKGROUND: Numerous studies have established a link between human papillomavirus (HPV), squamous intraepithelial lesions (SIL) and carcinoma of the cervix. Testing for HPV DNA in addition to cytology in screening programs for cervical cancer has been suggested to increase detection rates. STUDY DESIGN: HPV DNA testing (performed by hybridization antibody capture assay I or II), cytology and biopsy (performed within 1 month of each other) were retrospectively reviewed for a series of 155 women. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HPV testing vs. cytology were calculated using biopsy as the gold standard. These values were also calculated in a subgroup of 37 individuals older than 35 years. RESULTS: The sensitivity, specificity, PPV and NPV of DNA hybrid capture HPV testing for detecting high-grade cervical intraepithelial neoplasia (CIN) were 86%, 44%, 26% and 93%, respectively. The respective values for cytology detection of high-grade CIN were 17%, 97%, 56% and 82%. CONCLUSION: HPV testing was significantly more sensitive for detecting high-grade CIN than cytology (86% vs. 17%). Our data support immediate colposcopy and biopsy, rather than follow-up Papanicolaou testing, if the test for HPV DNA is positive for an intermediate- to high-risk type.     

Quality assurance in cytopathology. Recommendations and ongoing quality assurance activities of the American Society of Clinical Pathologists

The recommendations and activities of the American Society of Clinical Pathologists (ASCP) pertaining to quality assurance in cytopathology are reviewed. To assure the early detection of cervical cancer, the ASCP recommends that all women who are, or have been, sexually active should have an annual Papanicolaou smear examination, the reasons for which are discussed. To assure the optimal quality in the evaluation of these smears, the ASCP recommends that the screening should be performed (1) in an accredited laboratory by certified cytotechnologists, (2) for whom realistic workloads have been established, (3) under the supervision of a pathologist adequately trained in cytology, (4) who will maintain an ongoing quality assurance program. In addition, (5) Papanicolaou smear evaluations should be available to all patients at a reasonable cost and (6) the financial incentives for the performance of low-quality screening should be eliminated. The society's quality assurance activities discussed include the Check Sample program, self-assessment examinations, meetings and publications; planned additions to this arena include a challenge exam and proficiency survey mechanisms.     

宫颈人乳头瘤病毒感染的药物治疗

宫颈癌是妇科三大恶性肿瘤之一。根据GLOBOCAN 2008数据统计,在中国女性所有恶性肿瘤中,发病比占6.3%,死亡比占4.6%。宫颈癌的发生与宫颈HPV感染存在密切关系。2012年NCCN指南提出30岁的女性推荐HPV DNA检查与细胞学检查结合用于宫颈癌的筛查。单纯HPV检测阳性时,患者可以选择继续观察随访。但事实上,妇科医生在临床诊疗过程中发现很多病人心理上无法接受对疾病不进行任何处理。而一些过度治疗方案包括LEEP,冷刀锥切,宫颈局部激光治疗等又有可能会造成宫颈机能不全,继发宫颈管狭窄,早产及低体重出生儿等不良结果。若积极处理的话有多种治疗方案可供选择。但是对于有生育要求的女性在治疗方案的选择上应该尤为慎重。本文对目前相关治疗方案的治疗效果及其能否阻止宫颈病变的进展等方面进行总结。旨在解决临床医生和患者共同关注的问题。     

Automation in cervical cytology: an overview.

Cancer of the uterine cervix is one of the more common female cancers and a major source of premature female mortality. UK deaths in 1987 exceeded 2000. To reduce these rates, national screening programmes have been introduced using the Papanicolaou method. In screening for cancer, the examination of specimens is an intensive and expensive task. Its high cost has led to a number of attempts to automate the process, either fully or partially. Over the last 30 years, various experimental prescreening systems have been developed for the diagnosis of cytological samples including the use of image processing techniques. This paper presents a historical overview of automation in cervical cytology and the status of current developments for automated cytological diagnosis.     

National registry of cervical cytologic diagnoses in The Netherlands

The national cervical cytology registry being developed in the Netherlands is described. A large-scale screening program for cervical cancer has been in effect since 1975 in the region of the cities of Nijmegen, Utrecht and Rotterdam. At the start of the pilot projects, laboratories agreed upon a uniform protocol for reporting cytologic findings and recommendations for follow-up examinations in cases of abnormalities. Based on the results of the three pilot projects, in 1985 the Dutch government decided to organize a nationwide screening program for cervical cancer. All pathology laboratories involved in this national screening program are using the same screening protocol and the same coding system for cytologic and histologic diagnoses. By the end of 1989, all pathology laboratories will be linked to a central pathology diagnosis data base (PALGA). Linkage of screening results to previous and follow-up cytologic and histologic findings will enable epidemiologic studies on a regional or national level. Each physician who has submitted specimens will, next to the cytology reports, periodically receive reviews of the number of smears submitted, the cellular composition (quality) of those smears and the follow-up findings. The execution of requests for follow-up examination will be supervised by the participating pathology laboratories. The national cervical cytology registry will enable registration of all relevant cytologic and histologic diagnoses in a uniform way, but will also establish a unique high-quality national data bank, which will be of great value in the analysis of the effectiveness of the national screening program for cervical cancer. It will enable measurement of the impact of various screening protocols and give insight into the behavior of cervical cancer and the progressive or regressive character of its early stages. It will also offer the opportunity to initiate and evaluate quality control protocols.     

Papanicolaou smears without endocervical cells. Are they inadequate?

The retrieval of columnar endocervical cells from the squamocolumnar junction has generally been considered to be a measure of the adequacy of a Papanicolaou smear; this implies that, if endocervical cells are absent from the smear, the examination for cervical cancer is less than optimal and should be repeated. A study was undertaken to determine if women with serial Papanicolaou smears without endocervical cells showed an increased rate of development of cervical atypia in subsequent smears. The smears of 18,914 women were evaluated for the presence or absence of endocervical cells and for the subsequent development of an abnormal smear over a four-year study period. No differences were found in the rates of atypia between women with and those without endocervical cells on serial Papanicolaou smears. Women with prior Papanicolaou smears without endocervical cells were much more likely to have a subsequent Papanicolaou smear without endocervical cells. Although no difference was found in the incidence of cervical atypia in the two groups during this short study period, these results should be considered to be preliminary.     

Clinical relevance of human papillomavirus testing in cytopathology

Cancer of the uterine cervix is the second most common cancer in women worldwide. Currently, cervical screening is based on cytology alone. Because infection with high-risk human papillomavirus types (hrHPVs) is a necessary cause of cervical cancer, it has been postulated that screening might become more efficient when it is based on combined cytology and hrHPV testing. In this review we will discuss the advantages of added HPV tests in cervical cancer screening, as a quality control for false-negative smears, in triage of women with equivocal smears, in follow-up of women treated for CIN3 or cervical cancer and for the detection of cervical adenocarcinoma.     

Cellular Differences Between True Negative and False Negative Papanicolaou Smears

A matched case-control study of 123 false negative Papanicolaou smears and 488 true negative Papanicolaou smears was undertaken to determine the association between the types of cells present on the smear and the correctness of the cytology report. the false negative slides were significantly more likely to include endocervical columnar cells than the true negative slides (odds ratio 1.90, 95% confidence interval (CI) 1.21–3.01). No statistically significant difference in metaplastic cell status was evident (odds ratio 1.48, 95% CI 0.95–2.30). When considered together, metaplastic and/or columnar cells were significantly more likely to be present in false negative smears than in true negative smears (odds ratio 1.87, 95% CI 1.13–3.08). the implications of these findings for improving the accuracy of cervical cytology for the detection of precancerous lesions are discussed.     

Cervical intraepithelial neoplasia III. An estimate of screening error rates and optimal screening interval

The detection rates of grade III cervical intraepithelial neoplasia (CIN III) in women at the initial and subsequent screenings were studied in Florence for the period 1979 to 1982 to assess the optimal interval between tests and the sensitivity of the screening (cytology plus advised colposcopy in cases with slightly abnormal Papanicolaou tests). The protective interval was calculated to be about three years. No differences in the risk of developing CIN III were observed between women with only an initial screening and women rescreened within the three-year interval. Screening sensitivity was calculated according to two different models: (1) when assumed to be a constant, the sensitivity of our cytologic-colposcopic screening was 0.71, with 0.64 for cytology alone; (2) when assumed to decrease in subsequent screening rounds, the sensitivity was calculated at 0.60 (0.50 in subsequent rounds), with 0.52 for cytology alone. The benefit of an early cytologic rescreening is discussed and compared to a wider use of colposcopy, which, with lower costs, permits a good sensitivity utilizing only one round of screening.     

Cytologic detection of cervical and endometrial carcinoma with other genital tract involvement

OBJECTIVE: To investigate the possibility of a correct cytologic diagnosis of cervical and endometrial carcinoma with other genital organ involvement. STUDY DESIGN: From uteri removed during hysterectomy due to cervical (33 cases) and endometrial (44 cases) cancer, samples were taken by cytobrush or spatula from the ectocervix, endocervix and endometrium of uteri opened longitudinally. Smears and cytosediments were stained by the Papanicolaou polychrome method. Moreover, acid beta-galactosidase activity was demonstrated in serial cytosediments by the indigogenic method of Lojda. From quenched tissue samples taken from the same sites as those for cytology, a series of cryostat sections was prepared and stained by hematoxylin and eosin or azure A, or subjected to the reaction for acid beta-galactosidase. RESULTS: In 17 of 33 patients with cervical cancer, the same type of cancer was also found in smears of the endocervix and endometrium. In six patients the type of cancer was different. Of 44 patients with endometrial cancer, 16 had an endocervical malignancy of the same type. In seven cases the type of cancer was different. The reaction for acid beta-galactosidase helped in the differentiation between squamous (negative reaction in cancer cells) and cylindrocellular (positive reaction) cancer in cytologic preparations. CONCLUSION: Before treatment, it is necessary to determine if there is involvement of the endocervix in endometrial cancer and of the endometrium in cervical cancer. Routine cytologic examination supplemented by the reaction for acid beta-galactosidase proved to be useful for this purpose.