The complex detection system leading to the discovery and treatment of precancerous lesions and early cancer of the uterine cervix is described in detail and discussed By far the most difficult and underestimated component of this system is the screening and interpretation of cervical (Papanicolaou) smears Cytologic case finding may fail because of inadequate samples, insufficient time devoted to screening, or human fatigue Other weak points of the system, such as an inadequate clinical component, inadequate patient compliance, poor reproducibility of diagnoses, and ineffective aftercare, are also described For example, obtaining a second smear to confirm or refute a diagnosis of cellular atypia is often a misleading practice Although this cancer detection system has been shown to be effective in reducing the rate of morbidity and mortality from invasive cervical cancer in appropriately screened populations, there is no evidence that the Papanicolaou test has succeeded anywhere in complete eradication of this theoretically preventable disease It is important to inform the public about the potential failures of the system and the reasons for them (JAMA1989;261:737-743)

https://jamanetwork.com/journals/JAMA/articlepdf/376198/jama_261_5_046.pdf

The Papanicolaou test for cervical cancer detection. A triumph and a tragedy.

THE INCIDENCE of and mortality from cervical cancer in the United States have decreased dramatically over the past 40 years, in part because of early diagnosis and treatment of cervical cancer precursor lesions. The success of cervical cytological screening has served as a model for early diagnosis of other types of cancer. Although numerous studies have shown that lack of cytological screening is a major risk factor for the development of invasive cervical cancer, 1-3 it is important to emphasize that none of the screening, diagnostic, or therapeutic techniques used in medicine are perfect. Accordingly, a few women will develop cervical cancer despite adherence to accepted screening protocols . In addition, problems inherent with sampling, interpretation, and effective clinical follow-up preclude total prevention of cervical cancer. In recent years it has become evident that the cost and morbidity associated with the detection and treatment of low-grade cervical lesions have escalated, probably

https://jamanetwork.com/journals/jama/articlepdf/375003/jama_271_23_037.pdf

Interim Guidelines for Management of Abnormal Cervical Cytology

Genital human papillomaviruses (HPV) are common sexually transmitted agents that induce a variety of proliferative genital lesions, including condylomata acuminata and benign cervical atypia. Infection by high-risk HPV types (most often HPV16 and HPV18) is by far the most significant risk factor for the development of cervical intraepithelial neoplasia (increased risk of 10-fold to 40-fold), which can progress to invasive cervical carcinomas (increased risk of 200-fold to 300-fold) (1-3). Infection by low-risk types (most often HPV6 and HPV11) is common, but lesions induced by these types are rarely associated with carcinogenic progression.

The identification of women who are at risk for developing cervical cancer has depended primarily on the use of the Papanicolaou (Pap) test, which detects cytologic abnormalities in cells from cervico-vaginal scrapes. In recent years, it has become evident that most of the cytologic changes represent manifestations of genital HPV infection. Although the Pap test is a very useful screening assay, it has a relatively high proportion of misdiagnosis and requires highly trained personnel to obtain and analyze the samples (4). Therefore, attempts have been made to devise assays to complement or partially replace Pap screening. Most of the ancillary assays are based on the direct detection of HPV nucleic acids in exfoliated cervico-vaginal cells and biopsy specimens. Two major shortcomings of the DNA-based assays are that they are beyond the scope of procedures currently in use in most clinical laboratories and, since the viral lesions are focal, they are subject to the same sampling errors as Pap smears (5).

A serologic assay for genital HPV infection may offer advantages over currently available HPV diagnostic methods, since it would measure systemic responses to a significant viral infection and could be performed by most clinical laboratories. In addition, an antibody test might be useful for evaluating past exposure to the viruses. Attempts to develop serologic assays for high-risk HPV infections, however, have thus far been relatively unsuccessful. Responses to nonstructural viral proteins appear to be low and show substantial variability, with no single protein eliciting a detectable response in more than a minority of HPV-infected people (6,7). Assays using bacterially produced LI major or L2 minor virion structural proteins have not shown a good association between serum reactivity and other measures of HPV infection (8). The latter finding may indicate that HPV infections that are localized to the genital mucosa do not regularly elicit a significant systemic immune response to the virion proteins. Alternatively, most of the immunogenic epitopes of HPV virions recognized during natural infection may not be displayed by the bacterially derived virion proteins, which are generally isolated as denatured proteins and lack eukaryotic specific modifications.

Humoral responses to native genital HPV virions have only been studied using virions of the low-risk HPV11 virions propagated in human tissues grown in immunologically impaired mice (9,10) because no efficient in vitro system exists for generating preparative amounts of native virions. However, we have reported (11) that the L1 virion proteins of bovine papillomavirus type 1 (BPV1) and HPV16 have the intrinsic capacity to self-assemble into virus-like particles when expressed in insect cells via recombinant baculoviruses. We have now used purified HPV16 L1 plus L2 virus-like particles (12) as the antigen to develop an enzyme-linked immunosorbent assay (ELISA). We have tested whether this assay can detect IgG anti-HPV16 virion antibodies in the sera of women who test positive for genital HPV16 infection by DNA-based methods.

/pdf/a-virus-like-particle-enzyme-linked-immunosorbent-assay-4hwxchabxt.pdf

A virus-like particle enzyme-linked immunosorbent assay detects serum antibodies in a majority of women infected with human papillomavirus type 16.

Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance.

Invasive cervical cancer is uncommon in the United States, with an incidence of 15,800 cases and 4800 deaths in 1995.1 This relatively low incidence is largely due to the effectiveness of screening programs that assess cervical cytology by Pap smear. On a global scale, however, cancer of the cervix is a major cause of death, especially in Third World countries, where such screening is often not routinely performed. Pap-smear screening is designed to detect precursor lesions in cervical epithelium, which may antedate the development of invasive cancer by several years. In contrast to other screening strategies, such as mammography, which . . .

Cancer of the Uterine Cervix

The significance of endocervical columnar cells as a high-quality parameter of cervical smears was studied. In a cohort of women with two successive screenings, the consistency of the cellular composition of the cervical smears and the relation between the cellular composition of the smears and the frequency of the diagnosis of abnormal epithelial changes was investigated. At the first screening, a significantly higher number of epithelial abnormalities was found in smears with endocervical columnar cells than in smears without endocervical columnar cells. A significantly higher number of abnormal epithelial changes was found on the second screening in smears from women whose smears from the first screening did not contain endocervical columnar cells than in smears from women whose smears from the first screening did contain endocervical columnar cells. The presence of endocervical cells should be considered a very important indicator of the quality of cervical smears. The chance of missing an abnormal epithelial change is increased in smears without endocervical columnar cells. When endocervical columnar cells are absent, the smear should be considered to be of unreliable quality and a repeat smear should be taken after a short interval, unless the absence of columnar cells can be satisfactorily explained.

Relationship between the diagnosis of epithelial abnormalities and the composition of cervical smears.

A total of 555 cervical smears, originally classified as Papanicolaou classes I and II, from women in whom three years later cytologic findings consistent with moderate dysplasia, severe dysplasia, carcinoma in situ and invasive cancer were diagnosed were reviewed in order to estimate the screening error. The initial diagnosis proved to be underestimated in 17.5% of the smears. The two diagnoses correlated in 70.2% of the smears while 12.3% of the smears that contained no abnormality were judged to be inadequate for making a diagnosis, probably representing sampling errors. Quality-control measures to reduce these errors are briefly summarized.

Screening errors in cervical cytologic screening.

Some of the achievements of cervical screening in the reduction of morbidity and mortality in different countries are briefly reviewed, along with a consideration of some of the aspects of cervical cancer screening programs. The latter include the organization of the program (e.g., whether it is organized by the national health authorities), the protection afforded by routine screening, the assurance of quality in cervical sampling and in the screening program, the screening interval, the age groups to be screened, the compliance of women to present themselves for screening and of health care personnel to provide appropriate follow-up and/or treatment for the lesions diagnosed, the problem of false positives and its relation to overdiagnosis and overtreatment and, finally, the cost effectiveness. It is concluded that a centrally organized and well supervised cervical screening program, cautiously executed and with all involved parties closely cooperating, can be a cost-effective means of combatting cervical cancer.

Cervical screening revisited.

OBJECTIVE: To test the effectiveness of the PAPNET testing system in identifying false negative smears, using archival cervical cytologic smears from women with histologically proven diagnoses of high grade lesions and carcinoma of the uterine cervix. STUDY DESIGN: Forty-six negative smears from women who developed a high grade cervical intraepithelial lesion (CIN 3) or carcinoma of the uterine cervix within three years were retrieved from the archives, plus 20 consecutive control smears for each case. The smears were analyzed with the PAPNET testing system, and the selected cells were reviewed by a cytotechnologist using a strict protocol. RESULTS: With the PAPNET testing system, 9 of 46 (20%) smears were positive. Seven were reclassified as low grade and two reclassified as high grade squamous intraepithelial lesion (SIL). One of the 31 initially positive smears in the control group of 920 smears was not recognized as such. In the control group of 889 negative smears, 14 newly identified positive cases (1.6%) were detected, all low grade SIL. CONCLUSION: The PAPNET testing system is a good tool for detecting false negative smears and, when used as an adjunct to conventional screening, can reduce the false negative rate.

Negative Cervical Smears Before CIN 3/Carcinoma

The influence of the day of the menstrual cycle and the method of contraception on the cellular composition of cervical smears was investigated. The percentage of unsatisfactory smears during the first four days of the cycle was understandably very high, leaving only 80% of the smears of sufficient quality for cytologic diagnosis. The percentage of smears of insufficient quality during the remainder of the cycle was significantly higher in women using oral hormonal contraceptives. The percentages of smears containing endocervical columnar cells, a criterion for judging smears to be of high quality, differed significantly among women using different modes of contraception. The highest percentage of smears without endocervical columnar cells was found in women using oral contraceptives; during the first half of the cycle in these women, smears were of higher quality than during the second half of the cycle. In women not practicing contraception or using nonhormonal methods of contraception, the differences in cellular composition during the cycle, though significant, were too small to be of practical importance. Women using oral contraceptives thus have an increased risk for a potential false-negative diagnosis because of the higher percentage of smears of unreliable quality taken in these women. In women using oral hormonal contraceptives, smears should be taken during the first half of the cycle because of the higher percentage of smears of high quality in that period.

Y. van der Graaf

Papers

Relationship between the diagnosis of epithelial abnormalities and the composition of cervical smears.

Screening errors in cervical cytologic screening.

Cervical screening revisited.

Negative Cervical Smears Before CIN 3/Carcinoma

Cellular composition of cervical smears in relation to the day of the menstrual cycle and the method of contraception.