Negative Papanicolaou Tests Research Articles

Serum Antibodies Against the E5 Oncoprotein from Human Papillomavirus Type 16 Are Inversely Associated with the Infection and the Degree of Cervical Lesions.

The humoral immune response against human papillomavirus (HPV) has been suggested as a source of biomarkers for the early detection of cervical cancer (CC). Therefore, we aimed to characterize the antibody response against HPV16 E5 in the natural history of cervical cancer and to determine its usefulness as a biomarker of HPV-associated cervical lesions. This study was conducted at the Cuautla General Hospital, Morelos, Mexico, with women (18 to 64 years) who agreed to participate. Samples were obtained from 335 women with cervical lesions and 150 women with negative Papanicolaou tests. HPV genotyping was performed by PCR and pyrosequencing, and anti-E5 antibodies were detected by slot blot. The overall anti-E5 antibodies prevalence in the study was 17.9%, with the higher prevalence observed in the no lesion (NL, 49.4%) group, and with a downward trend according to the degree of the cervical lesion, from cervical intraepithelial neoplasia-1 (CIN1, 32.2%) to CIN2 (11.5%) and CIN3/CC (6.9%). The logistic regression model showed negative associations of anti-E5 antibodies with CIN1 (OR = 0.38), CIN2 (OR = 0.42), and CIN3/CC (OR = 0.32) groups, being statistically significant. Contrast analysis showed an inverse relationship between anti-E5 antibodies with HPV DNA and the CIN1 (OR = 0.35), CIN2 (OR = 0.39), and CIN3/CC (OR = 0.31) groups. These results suggest that anti-E5 antibodies could be associated with clearance of infection in women without lesions and with CIN1 lesions since an inverse relationship was observed between the presence of HPV DNA and anti-E5 antibodies. In contrast, with progression from CIN2/CIN3 to CC, the relationship was reversed, as the anti-E5 antibodies disappeared, and the frequency of the viral genome increased.

Cervical Cancer Treatment Update: A Society of Gynecologic Oncology Clinical Practice Statement

ABSTRACT Despite increased screening and human papillomavirus (HPV) vaccination in high-income countries, cervical cancer represents the fourth most diagnosed cancer in women worldwide and the second highest cause of cancer mortality among women in low- and middle-income countries. This clinical practice statement describes therapies for cervical cancer by treatment setting, as well as quality of life, financial toxicity, and disparities associated with the disease. Persistent HPV infection, particularly types 16 and 18, are the main factor in the development of cervical cancer. High-risk HPV variants integrate HPV DNA into the host genome to upregulate two viral oncoproteins, E6 and E7, which in turn inhibit the tumor suppressor proteins p53 and Rb. Certain driver mutations including PIK3CA, KRAS, and EGFR are frequently seen in cervical cancer, however further research is needed to identify an actionable biomarker based on targetable oncogenic alterations. Locally advanced cervical cancer is defined as clinically visible tumor exceeding 4 cm or invading beyond the cervix, extending to the pelvic sidewalls, vagina, bladder, rectum, or involving pelvic and/or paraaortic lymph nodes. Standard treatment for locally advanced cervical cancer is external beam radiation therapy and concurrent weekly cisplatin. Standard treatment for advanced, recurrent, or metastatic cervical cancer is cisplatin, paclitaxel, and bevacizumab (possibly adding pembrolizumab). Several studies have shown that checkpoint inhibitors, when combined or sequenced with chemoradiation, may provide survival benefit in both locally advanced and recurrent/metastatic cervical cancer. Given these findings, immunotherapy should be incorporated in treatment of advanced or recurrent disease. Negative effects on quality of life (QOL) in patients with cervical cancer often begin in people who receive negative Papanicolaou test results or positive HPV DNA tests. Negative body image, self-esteem, and relationships with partners contribute to an overall decrease in QoL. Surgical, radiation-induced, and chemotherapy-induced treatment effects further impact survivors’ physical health, body-image, and sexual function. Economic burdens of cancer diagnosis and treatment may disproportionally affect cervical cancer patients due to the intensity of curative treatment, decreases in QoL and functional status, and unique population including younger patients, those with poor access to health care at baseline, and those who identify as racial or ethnic minorities.

Significant outcomes associated with high-risk human papillomavirus negative Papanicolaou tests.

The 2020 American Cancer Society guidelines preferred primary human papillomavirus (HPV) screening for cervical cancer prevention. Studies investigating the role of cytology in detection of cervical precancer/cancer have focused on high-grade squamous intraepithelial lesion (HSIL) or worse interpretations. Here, we have examined the significance of all those cytology results that require histologic follow-up as per the current management guidelines, regardless of the HPV test result. A database search (September 2010 to December 2019) retrieved cervical Papanicolaou tests with any of the following interpretations: ≥ atypical squamous cells - cannot exclude HSIL or low-grade squamous intraepithelial lesion, HSIL cannot be excluded, and ≥ atypical glandular cells, not otherwise specified and its subcategories. Of these, those with concurrent negative HPV test result were included for further analysis. For this cohort, relevant clinical history and histologic follow-up (within 1year) were recorded. The study cohort comprised 763 patients. Of them, 586 (76.8%) patients had histologic follow-up: 53 (9.0%) had ≥ HSIL/adenocarcinoma in situ; of which, 43 (81.1%) had prior abnormal cytology/histology/not otherwise specified history and/or HPV positivity, and 66 (11.3%) had HPV-unassociated neoplasia; of which, 60 (90.9%) had a known diagnosis or clinical signs/symptoms of the disease. With widespread adoption of risk-based approach to management, the role of cytology, by itself, will likely diminish in the detection of HPV-associated lesions. Additional data regarding the role of cytology in the screening of patients with no/unknown/limited history and in the detection/management of HPV-independent lesions may be helpful for designing future screening guidelines.

Rescreening Practices of Negative Papanicolaou Tests With Positive Human Papillomavirus Test Result.

The yield of the prospective rescreening process for "negative for intraepithelial lesion or malignancy" (NILM) Papanicolaou (Pap) tests is higher with the inclusion of a greater proportion of high-risk cases. One of the suggested criteria for classifying a Pap test finding as high risk is recent or concurrent high-risk human papillomavirus (HPV) positivity. To evaluate how the results of HPV testing have been incorporated in the prospective rescreening of NILM Pap tests across a wide range of laboratories. A questionnaire survey was sent to laboratories participating in the 2019 College of American Pathologists (CAP) Gynecologic Cytology (PAP Education) Program. Of the 1507 participating laboratories, 667 (44%) responded to the survey. Most laboratories (59.4%; 396 of 667) had not incorporated HPV test/genotyping results to select NILM Pap tests for rescreening. Amongst the remaining laboratories, for NILM HPV-positive Pap test results, 112 (16.8%) had a policy to rescreen by a cytotechnologist only, 51 (7.6%) by a pathologist only, and 86 (12.9%) by both. Of 264 laboratories, 181 (68.6%) reported the cytology upon availability of the HPV test result and completion of the secondary review. Of 661 laboratories, 145 (21.9%) included consensus-type recommendations in the cytology report for such Pap tests. This CAP survey provides significant information regarding the current trends in the use of HPV test results in prospective rescreening of NILM Pap tests. Future studies on quality improvement can further assist in the standardization of this process across different laboratories.

Cervical biopsy rates before and after the introduction of human papillomavirus type reporting in co-tests with negative cytology

In 2013, our laboratory introduced Roche cobas high-risk human papillomavirus (HRHPV) testing, which includes limited HPV genotype reporting. The shift from Hybrid Capture II (HC2) HPV testing to Roche led to an observed increase in biopsies for patients with negative Papanicolaou tests with positive HRHPV. We conducted a retrospective review of data from our facility to examine biopsies conducted on patients with negative Papanicolaou tests and positive HRHPV. We compared data from 2012 (HC2) to 2015 after implementation of Roche cobas platform. In 2012, 37 biopsies were performed on patients with negative Papanicolaou test and positive HRHPV, out of 82,721 Papanicolaou tests (0.045%). In 2015, the number of biopsies performed on patients with negative Papanicolaou test and positive HRHPV test was 281, out of 115,104 Papanicolaou tests (0.244%; P < 0.001). Of these, 141 had HPV type 16 or 18, and 140 had "other" HRHPV types. We observed an increased detection rate of high-grade squamous intraepithelial lesion (HSIL) or greater lesions (5.4% in 2012 to 8.9% in 2015), but it was not statistically significant (P = 0.398). Fifteen HSIL or greater lesions were found in women with types 16 or 18 (5.3%) and 10 were found in women with "other" HRHPV types (3.6%). The introduction of HRHPV testing with type reporting is associated with a marked increase in the number of women undergoing colposcopy and biopsy for HRHPV despite negative cytology. Half of these have a HRHPV type other than type 16 or 18, despite recommendations to repeat co-testing instead.

Weighty talks about wise choices

Weighty talks about wise choices

Co-testing in Women with Negative Papanicolaou Tests and High-Risk HPV Testing: A Large Single Institution Study with up to 4-year Follow-up

Co-testing in Women with Negative Papanicolaou Tests and High-Risk HPV Testing: A Large Single Institution Study with up to 4-year Follow-up

High-Risk HPV Testing in Women 30 Years or Older With Negative Papanicolaou Tests

Cervical screening with combined cytology and high-risk human papillomavirus (HR-HPV) detection has been approved for women 30 years or older. We investigated the clinical use of cotesting for women with negative Papanicolaou tests. Follow-up cytology, HR-HPV test, and biopsy findings were identified during an 18-month period. In 1 year, 2,719 cotests from 2,686 women were identified; 146 were positive for HR-HPV. Among women with positive HR-HPV testing, 120 had follow-up, including 70 with repeated cotesting, and 3 had high-grade dysplasia identified (2.5% of women with follow-up). In 1,334 women with initial double-negative cotest results who had repeated cytologic testing within 18 months, 2 high-grade dysplasias were found (0.1%). The vast majority of cotest results are double-negative. Among tests that show HR-HPV positivity, the prevalence of underlying high-grade dysplasia is low. About half of all women who undergo cotesting receive follow-up that is not in accord with published guidelines.

Adjunctive high-risk human papillomavirus DNA testing is a useful option for disease risk assessment in patients with negative Papanicolaou tests without an endocervical/transformation zone sample

Current guidelines recommend that women with negative Papanicolaou (Pap) test results and no endocervical/transformation zone (EC/TZ) sample return for screening within 12 months. For some women, this represents earlier follow-up than advocated in several routine screening guidelines. Controversy remains with regard to the correlation between sampling of the EC/TZ, Pap test quality, and disease risk assessment. A retrospective study was conducted reviewing the results from 143,438 liquid-based cervical Pap tests performed at a large academic women's hospital between July 2005 and December 2006. Vaginal Pap tests were excluded from the study. Women with any Pap result, women with low-grade squamous intraepithelial lesions (LSILs), and patients with high-grade squamous intraepithelial lesion (HSIL) Pap test results were stratified by 10-year age groups and according to the presence or absence of an EC/TZ sample (EC/TZS). Women with LSIL and HSIL Pap test results with and without an EC/TZS were also compared for rates of high-risk human papillomavirus (hrHPV) DNA detection. Of the total of 143,438 cervical Pap tests performed, 27,359 (19.1%) were reported to be lacking an EC/TZS. The absence of an EC/TZS was found to be highest in adolescents and in mature women aged >or=50 years. The overall detection rate of LSIL was 4.29% and that of HSIL was 0.64%. Both the LSIL and HSIL rates were found to be significantly higher in Pap tests with an EC/TZS compared with Pap tests without an EC/TZS (LSIL: 4.51% vs 3.37% and HSIL: 0.72% vs 0.29%). However, when women with LSILs and HSILs were divided into a group in which EC/TZS was present and a group in which EC/TZS was absent, no significant differences were found to be present with regard to hrHPV DNA rates between the 2 groups. Adjunctive hrHPV DNA testing is effective in stratifying risk for the presence of SIL in women with and without an EC/TZS. This finding is consistent with recently reported data from >9000 patients with negative Pap results, which found that hrHPV DNA-positive test rates are independent of the presence or absence of an EC/TZS. hrHPV DNA results provide a useful new optional adjunctive tool for the objective stratification of disease risk in women with negative Pap tests and no EC/TZS.

Risk of cervical cancer associated with extending the interval between cervical-cancer screenings.

Although contemporary guidelines suggest that the intervals between Papanicolaou tests can be extended to three years among low-risk women with previous negative tests, the excess risk of cervical cancer associated with less frequent than annual screening is uncertain. We determined the prevalence of biopsy-proven cervical neoplasia among 938,576 women younger than 65 years of age, stratified according to the number of previous consecutive negative Papanicolaou tests. Using a Markov model that estimates the rate at which dysplasia will progress to cancer, we estimated the risk of cancer within three years after one or more negative Papanicolaou tests, as well as the number of additional Papanicolaou tests and colposcopic examinations that would be required to avert one case of cancer given a particular interval between screenings. Among 31,728 women 30 to 64 years of age who had had three or more consecutive negative tests, the prevalence of biopsy-proven cervical intraepithelial neoplasia of grade 2 was 0.028 percent and the prevalence of grade 3 neoplasia was 0.019 percent; none of the women had invasive cervical cancer. According to our model, the estimated risk of cancer with annual Papanicolaou tests for three years was 2 in 100,000 among women 30 to 44 years of age, 1 in 100,000 among women 45 to 59 years of age, and 1 in 100,000 among women 60 to 64 years of age; these risks would be 5 in 100,000, 2 in 100,000, and 1 in 100,000, respectively, if screening were performed once three years after the last negative test. To avert one additional case of cancer by screening 100,000 women annually for three years rather than once three years after the last negative test, an average of 69,665 additional Papanicolaou tests and 3861 colposcopic examinations would be needed in women 30 to 44 years of age and an average of 209,324 additional Papanicolaou tests and 11,502 colposcopic examinations in women 45 to 59 years of age. As compared with annual screening for three years, screening performed once three years after the last negative test in women 30 to 64 years of age who have had three or more consecutive negative Papanicolaou tests is associated with an average excess risk of cervical cancer of approximately 3 in 100,000.

Review of Negative Papanicolaou Tests: Is the Retrospective 5-Year Review Necessary?

Review of Negative Papanicolaou Tests: Is the Retrospective 5-Year Review Necessary?

Adverse psychologic consequences of positive cYtologic cervical screening

Cervical cancer is still widely prevalent in the female population. This study explores the relationship of cervical cancer screening, positive versus negative Papanicolaou's test results, and psychologic status among lower-income minority women. All patients were interviewed 3 months after they had received initial test results. One hundred six women with normal Papanicolaou's test results were compared with 118 women who were referred for colposcopic examination for follow-up of positive test results. Women with positive PapanicoIaou's-test results showed statistically significant elevations in worries about cancer and impairments in mood, daily activities, sexual interest, and sleep patterns. More fine-grained analyses revealed that the effects of positive results were most pronounced among those women who did not comply with colposcopy (n = 53). These findings suggest that lack of compliance with follow-up may maintain high levels of uncertainty about disease and may interfere with successful psychologic adaptation. Health education targeted to psychologically vulnerable individuals may reduce psychologic distress and enhance compliance.

Clinical evaluation of norethindrone acetate in fertility control

A clinical evaluation of 300 Mexican women accumulating 5902 treatment cycles representing 454 woman-years with 4 mg norethindrone acetate and .05 mg ethinyl estradiol (Anovlar) is presented. Each woman was instructed to take 1 tablet daily for 20 consecutive days beginning on Cycle Day 5. Anovlar was virtually 100% effective. Unpleasant side effects were minimal and transient occurring principally in the first 3 cycles and disappearing rapidly thereafter. Acceptability was high in women of all social classes. Fertility was rapidly restored after discontinuing medication. Extensive laboratory tests confirm the harmlessness of this compound. Consistent negative Papanicolaou tests during long-term treatment with this compound as with other progestagen-estrogen compounds warrent further study to determine a possible anticarcinogenic effect.(AUTHORS MODIFIED)