Negative Pap Test Research Articles

Screening history of cervical cancers in Emilia-Romagna, Italy: defining priorities to improve cervical cancer screening.

Most invasive cervical cancers in industrialized countries are due to the lack of Pap test coverage, very few are due to screening failures. This study aimed at quantifying the proportion of invasive cancers occurring in nonscreened or underscreened women and that in women with a previous negative screening, that is, screening failure, during the first two screening rounds (1996-2002) and in the following rounds (2003-2008) in the Emilia-Romagna region. All cases of invasive cancers registered in the regional cancer registry between 1996 and 2008 were classified according to screening history through a record linkage with the screening programme registry. The incidence significantly decreased from 11.6/100 000 to 8.7/100 000; this decrease is due to a reduction in squamous cell cancers (annual percentage change -6.2; confidence interval: -7.8, -4.6) and advanced cancers (annual percentage change -6.6; confidence interval: -8.8, -4.3), whereas adenocarcinomas and microinvasive cancers were essentially stable. The proportion of cancers among women not yet invited and among nonresponders decreased over the two periods, from 45.5 to 33.3%. In contrast, the proportion of women with a previous negative Pap test less than 5 years and 5 years or more before cancer incidence increased from 5.7 to 13.3% and from 0.3 to 5.5%, respectively. Although nonattendance of the screening programme remains the main barrier to cervical cancer control, the introduction of a more sensitive test, such as the human papillomavirus DNA test, could significantly reduce the burden of disease.

Insulin-like growth factor II mRNA binding protein 3 (IMP3) expression in cervical intraepithelial neoplasia and its relationship with HIV-infection status.

Background Cervical cancer is preventable through screening, and HIV treatment guidelines recommend that all HIV-infected women receive cervical cancer twice during the year after HIV diagnosis and annually thereafter. Different immunohistochemical markers have been studied to highlight cervical intraepithelial lesions of low and high grade, the most widely used being p16. Recent studies have shown that insulin-like growth factor mRNA binding protein 3 (IMP3) plays a role in the development of invasive squamous cell carcinoma from cervical dysplasia, both in histology and in liquid-based cytology. We evaluated the clinical significance of the immunohistochemical expression of IMP3 and p16 in histological samples of cervical intraepithelial neoplasia from 56 samples of HIV-positive and 30 samples of HIV-negative patients. A significant difference was found in IMP3 and p16 protein expression between HIV-positive and HIV-negative specimens. All cases of HIV-positive low grade squamous intraepithelial neoplasia (L-SIL) with IMP3 expression progressed in high grade (H)-SIL. However, the HIV-positive patients with IMP3-negative L-SIL remained stable or had a negative follow up. The L-SIL of HIV-negative patients with IMP3 protein expression had an uneventful follow up. IMP3-positive H-SIL recurred with low- or high-grade dysplasia during follow up after conisation in both populations. All IMP3-negative L-SIL and H-SIL had negative pap tests at follow up. In HIV-positive cases, IMP3 showed a higher sensitivity than p16 in identifying patients at risk of progression and recurrence.

Abstract B92: HPV and Pap test results among low-income, underserved women: Providing insights into management strategies

Abstract Objective: Human papillomavirus (HPV) DNA testing combined with cytology (co-testing) has been recommended as a primary cervical cancer screening strategy and will be covered as a preventive service by the Affordable Care Act (ACA). Women with discordant results (HPV positive/cytology negative) present significant management challenges and result in additional costs due to follow-up visits and testing required. The frequency of discordant results in insured populations is at a level that does not negate the benefit of co-testing. However, it is unknown if the frequency of discordant results would be the same for underserved women, who may have more risk factors for HPV infection and cancer precursors. Methods: The Centers for Disease Control and Prevention's Cervical Cancer (Cx3) Study was conducted at 15 clinics in 6 Federally Qualified Health Centers (FQHCs) across Illinois. Providers at these clinics were given the option of co-testing for routine cervical cancer screening. Clinical high-risk HPV testing was performed using the FDA approved Hybrid Capture 2 assay (HC2: Qiagen). An additional research test to determine type-specific HPV results was performed on residual extracts. Results: Testing was completed on 2246 underserved women, mean age 45.1 years. The HPV test was positive in 7.2% and cytology abnormalities were detected in 6.0% with discordant results in 4.9% of women. The percentage of HPV positive tests decreased with age, from 10.3% among 30-39 year olds to 4.5% among 50-60 year olds. Among women with negative normal Pap test results who where high risk positive, 14% of the women were positive for HPV 16/18 while the remaining were positive for other high risk types. Conclusion: The rate of discordant co-testing in this study of underserved women was similar to those reported throughout the U.S. in different populations, including those who are insured. Similarly, the lower percentage of discordant results and those positive for HPV 16/18 may favor a more conservative management strategy than an aggressive strategy of immediate colposcopy. Citation Format: Mona Saraiya, Vicki Benard, April Greek, Martin Steinau, Sonya Patel, Diane Manninen, George Sawaya, Stuart Massad, Elizabeth Unger. HPV and Pap test results among low-income, underserved women: Providing insights into management strategies. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B92. doi:10.1158/1538-7755.DISP13-B92

The low risk of precancer after a screening result of human papillomavirus-negative/atypical squamous cells of undetermined significance papanicolaou and implications for clinical management.

Different US practice guidelines have conflicting recommendations for when women should return after a screening result of human papillomavirus (HPV)-negative with an equivocal Papanicolaou (Pap) result of atypical squamous cells of undetermined significance (ASC-US) (ie, return in either 3 or 5 years). One way to determine management is to compare the risk of precancer/cancer after an HPV-negative/ASC-US result with the risks after other negative screening results. For example, if the risk after an HPV-negative/ASC-US result was similar to the risk after a negative Pap test, a 3-year return would be preferred because guidelines agree that women with negative Pap test results should return in 3 years. Alternatively, if the risk after an HPV-negative/ASC-US result is similar to that after a cotest-negative result (HPV negative/Pap test negative), a 5-year return would be preferred because guidelines agree that women testing cotest negative should return in 5 years. The authors compared risks of cervical intraepithelial neoplasia of grade 3 or higher (CIN3+) and cervical cancer among women aged 30 years to 64 years at Kaiser Permanente Northern California with the following test results from 2003 through 2012: 17,191 women testing HPV negative/ASC-US; 980,268 women testing Pap test negative (regardless of HPV result); and 892,882 women testing cotest negative. The 5-year CIN3+ and cancer risks after an HPV-negative/ASC-US result were closer to the risks after a negative Pap test result (CIN3+: 0.48% vs 0.31% [P =.0019]; and cancer: 0.043% vs 0.031% [P =.4]) than after a negative cotest (CIN3+: 0.48% vs 0.11% [P<.0001]; and cancer: 0.043% vs 0.014% [P =.016]). Women testing HPV negative/ASC-US were found to have precancer/cancer risks that were more closely aligned with women with negative Pap test results, suggesting that women testing HPV negative/ASC-US should be managed similarly to women testing negative on Pap tests with a 3-year return for screening.

Does total manual rescreening of negative pap tests screened by the thinprep imaging system add any value?

We compared the performance of utilizing the ThinPrep® Imaging System (TIS) according to the manufacturer's directions to screening with the TIS plus total manual rescreening in Pap tests that were initially diagnosed as NIL to determine whether manual rescreening decreases the false-negative rate for epithelial lesions. Three thousand three hundred forty cases were diagnosed as NIL on the 22 fields of view selected by the TIS and subsequently manually rescreened by the same cytotechnologist. Six hundred seventy-four cases were sent to a cytopathologist for final diagnosis based on review criteria. Biopsy follow-up and Human Papilloma Virus (HPV) test results were noted if available for cases with a diagnosis of ASCUS or above. Three thousand one hundred fifty-nine (94.6%) were confirmed NIL and 181 cases were diagnosed as abnormal on manual rescreen. There were 147 ASCUS, 6 ASCH, 9 AGC, 19 LSIL, and 0 HSIL cases. The overall false-negative rate of screening for atypia/SIL with the TIS was 5.4%. Of the 147 cases with HPV results, 43 (29%) were positive. Only 1 cervical intraepithelial neoplasia 2 was found on biopsy follow-up, in a case of ASCUS with a positive HPV. Based on our data, the TIS for screening of Pap tests is reliable in NIL cases as compared to total manual rescreening. The majority of the false-negative cases were diagnosed as ASCUS on subsequent review, with 0 HSIL cases. Our results confirm that the TIS is highly accurate in excluding HSIL, negating the need for total manual rescreening of NIL Pap tests.

Cervical Cancer Rates After the Transition From Annual Pap to 3-Year HPV and Pap

Kaiser Permanente Northern California (KPNC) introduced 3-year Pap and human papillomavirus DNA cotesting for cervical cancer screening in women 30 years or older in 2003 to 2004. Patient and provider willingness to extend screening intervals and the impact on annual cervical cancer incidence after interval extension are evaluated. Age-adjusted cervical cancer rates and screening intervals were calculated from KPNC Regional Laboratory databases and Northern California Cancer Registry from 2000 to 2009. The median screening interval between negative cotests was 36 months compared to the 16 months after a negative Pap test alone before the implementation of cotesting. The age-adjusted invasive cancer rate was 6.5 per 100,000 women in 2000 and 6.3 in 2009; there was no difference in the rates of cervical cancer in women 30 years or older from 2000 to 2009 (p(trend) = .7). Patients and providers were compliant with the extension of screening intervals with cotesting. Cervical cancer rates remained constant during the 10-year study period despite extending screening intervals after a negative cotest.

The importance of HPV testing in cervical cancer prevention

Introduction: Cervical cancer is second most common malignant tumor of female reproductive system in the world. HPV infection is present in 99% of cases, therefore very important in its development.Material and method: Our research was conducted in Primary health care center for women in Podgorica and included 100 women aged 20-60. During the examination PAP testing and colposcopy were performed to every participant. HPV mRNA detection test with differentiation of types 16, 18, 31, 35, 55 was done in cases of abnormal PAP test result, or suspected clinical or colposcopic examination accompanied by normal PAP test.Results: PAP testing showed II group in 72 patients, IIIa in 19 and IIIb in 3. HPV testing was performed in 26 patients (in which 4 with PAP II result). It was positive for presence of high-oncogenic types in 15 patients (57,69%) and negative in 11 (42,31%). In patients with detected lesion by examination or colposcopy, we performed biopsy. Results showed CIN I in 1 patient, CIN II in 2, CIN III in 5 and invasive carcinoma in 1 patient.Conclusion: Our research showed great importance of HPV testing in patients with false negative PAP tests; its importance as diagnostic marker in prognosis of illness, as well as the fact that HPV testing, as basic one, without examination and PAP testing, doesn’t make sense as it would increase the number of false negative results.

Evaluación de un nuevo protocolo de cribado de cáncer cervical con citología convencional y test del virus del papiloma humano

ObjectiveTo compare the effectiveness of cervical cancer screening using cytology plus the high risk human papillomavirus (HR-HPV) DNA test in 2011 versus cytology alone in 2010. MethodScreening was performed in primary care. The target population in the Barbastro sector consisted of 26,936 women (aged 25 to 65 years). The HPV test was performed with hybrid capture (HC2) and the PCR cobas® system in women between the ages of 30 and 65 years. Women with negative Pap and HPV test results underwent a 5-year recheck as per the latest protocol of Spanish Society of Obstetrics and Gynecology (SEGO, 2010). ResultsA total of 4,770 Pap tests were received in 2010 and 5,241 in 2011 with coverage between 36.8 and 46.8%; 784 HPV tests were carried out in 2010 and 3,560 in 2011, with positive results in 10.58% the first year and in 7.5% the second year. Eighteen new cases of cervical intraepithelial neoplasia grades 2/3 were diagnosed in 2010 and 35 in 2011, along with 3 invasive carcinomas each year (in 2011, 3 microinvasive carcinomas). ConclusionsThe implementation of HPV testing in primary screening for cervical cancer increased the number of pre-invasive lesions detected by 98% in the year of its introduction. Primary Care involvement allows screening for cervical cancer to be performed without additional costs.

Utility of HPV Cotesting in the Management of Women with Negative Pap Tests

Utility of HPV Cotesting in the Management of Women with Negative Pap Tests

Cervical Screening Test Results Associated With 265 Histopathologic Diagnoses of Cervical Glandular Neoplasia

To document screening test histories of women with histopathologic cervical glandular neoplasia (CGN) in a large integrated health system using new methods of cervical screening. Cervical screening test results were reviewed for 265 patients with histopathologic diagnoses of CGN, including 168 adenocarcinoma in situ, 80 invasive cervical adenocarcinoma, and 17 invasive cervical adenosquamous carcinoma cases. Among 222 cases with known triggers of diagnostic studies, 211 (95%) had recent abnormal Papanicolaou (Pap) test results. Glandular cell abnormalities were the most common recent abnormal Pap test finding in 130 (61.6%) of 211; squamous cell abnormalities alone were documented in 81 (38.4%) of 211, reflecting coexisting cervical intraepithelial neoplasia (CIN) in 60% of CGN cases. Among 114 CGN cases with additional Pap tests more than 4 months to 3 years before CGN diagnosis, 70 (61.4%) had only earlier negative Pap test results. Among 72 CGN cases with recent human papillomavirus (HPV) test results, 70 (97.2%) tested HPV positive. Among 29 CGN cases with HPV test results more than 4 months to 3 years before CGN diagnosis, 25 (86.2%) tested HPV positive. Conservative cytologic screening practices and HPV cotesting can facilitate early diagnoses of CGN.

Five-Year Risk of Recurrence After Treatment of CIN 2, CIN 3, or AIS

After excisional treatment, cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) can recur. It is not clear how many negative posttreatment Pap or cotest results are needed to ensure adequate safety against CIN 2+ before returning to extended retesting intervals. We observed 5-year risks of CIN 2+ for 3 follow-up management strategies after treatment (Pap-alone, human papillomavirus [HPV]-alone, and HPV/Pap cotesting) for 3,273 women aged 25 years and older who were treated for CIN 2, CIN 3, or adenocarcinoma in situ (AIS) between 2003 and 2010 at Kaiser Permanente Northern California. Five-year risks of recurrent CIN 2+ after treatment varied both by antecedent screening test result and the histology of the treated lesion. The risk ranged from 5% for CIN 2 preceded by HPV-positive/atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion to 16% for CIN 3/AIS preceded by atypical glandular cells (AGC)/atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion (ASC-H)/high-grade squamous intraepithelial lesion or worse (HSIL+) (p < .0001). However, after posttreatment negative tests, risks were lowered and similar regardless of antecedent screening test and histology of treated disease. The 5-year recurrent CIN 2+ risk after a negative posttreatment cotest (2.4%) was lower than that following a negative HPV test (3.7%, p = .3) or negative Pap result (4.2%, p = .1). Two negative posttreatment tests of each kind conferred slightly lower 5-year CIN 2+ risk than one (2 negative Pap tests vs. 1, 2.7% vs 4.2%, p = .2; 2 negative HPV tests vs. 1, 2.7% vs 3.7%, p = .7; 2 negative cotests vs. 1, 1.5% vs 2.4%, p = .8). The 5-year CIN 2+ risk after 2 negative cotests of 1.5% (95% confidence interval = 0.3%-7.2%) approached the 0.68% risk after a negative Pap test during routine screening. Women with antecedent AGC/ASC-H/HSIL+ Pap results or those treated for CIN 3/AIS had a substantial risk of developing CIN 2+ posttreatment. On the basis of the principle of "equal management of equal risks," after negative test results posttreatment, no subgroup of women achieved risk sufficiently low to return to 5-year routine screening. However, negative cotests after treatment provided more reassurance against recurrent CIN 2+ than either negative Pap tests or HPV tests alone.

Screening History Preceding a Diagnosis of Cervical Cancer in Women Age 65 and Older

Abstract Objective To characterize the antecedent screening of women 65years of age and older diagnosed with cervical cancer. Methods Screening histories of women 65years of age and older who were diagnosed with cervical cancer between 2003 and 2008 were examined utilizing the organization's databases and the regional Cancer Registry. Stopping screening was recommended at age 65 for members who had either 3 consecutive negative Paps or a single negative Pap plus HPV test (cotest). Results From 2003 through 2008 there were 56 Kaiser Permanente Northern California members 65years of age and older diagnosed with cervical cancer. During the same time period there were 1,323,100 woman-years of membership in women age 65 and older. The risk of invasive cancer among women age 65 and older was 4.2/100,000/year in 2003–2008. 33 of 56 (59%) had one or more Pap smears prior to diagnosis. Of the 33, 14 women (25%) had 3 consecutive negative Pap smears prior to diagnosis. Three of 46,401 women with 1 or more negative cotests at age 65 and older were subsequently diagnosed with invasive cancer during 132,639 women-years of follow-up (2.3/100,000/year). Conclusions Most cervical cancers diagnosed at age 65 and older occur in women who have not met our criteria for stopping screening. A few cancers will continue to occur at age 65 and older despite multiple negative tests, as is true in other age groups. We currently have no evidence that these cancers would be prevented with continued screening at ages 65 and older.

Comparison of Hybrid Capture II, Linear Array, and a Bead-Based Multiplex Genotyping Assay for Detection of Human Papillomavirus in Women with Negative Pap Test Results and Atypical Squamous Cells of Undetermined Significance

Many methods with different levels of analytical sensitivity and clinical specificity have been developed to detect the presence of high-risk (HR) types of the human papillomavirus (HPV) in cervical samples. The Hybrid Capture II (HC-II) assay is broadly used for primary screening. In addition, several HPV genotyping assays, based on PCR methods, display higher sensitivity than the HC-II and are also used in screening programs. We evaluated the performance of three HPV DNA tests, namely, the HC-II, the Linear Array (LA) HPV genotyping assay, and an HPV type-specific E7 PCR bead-based multiplex genotyping assay (TS-MPG) that is a laboratory-developed method for the detection of HPV, in 94 women with atypical squamous cells of undetermined significance (ASC-US) and in cytological samples from 86 women with a negative Pap test. The HPV prevalence with the TS-MPG assay was increased compared to the prevalence with the LA and HC-II assays. The HPV DNA prevalence in women with ASC-US was greater with the TS-MPG assay (46.2%) than with the LA (36.3%) and HC-II (29.7%) assays. The HPV DNA prevalence in the control group was greater with the TS-MPG assay (32.1%) than with the LA assay (10.7%). Two women with ASC-US who were HPV DNA negative by the HC-II and positive by the TS-MPG or/and LA assays had lesions that progressed to low-grade squamous intraepithelial and high-grade squamous intraepithelial lesions. This study shows that the TS-MPG assay exhibited higher analytical sensitivity than the LA and HC-II assays for the detection of HPV DNA, which reduces the potential to incorrectly identify a woman's HPV infection status.

Negative Predictive Value of Pap Testing

To estimate the accuracy of Pap testing for women who are human immunodeficiency virus (HIV)-seropositive, with a focus on negative predictive value. Participants in the Women's Interagency HIV Study were monitored with conventional Pap tests every 6 months. After excluding those with abnormal Pap test results before study, cervical disease, or hysterectomy, women with negative enrollment Pap test results were monitored for development of precancer within 15 or 39 months, defined as a Pap test result read as high-grade squamous intraepithelial lesion, atypical glandular cells favor neoplasia, or adenocarcinoma in situ, or a cervical biopsy read as cervical intraepithelial neoplasia 2 or worse. Correlations between one or more consecutive negative Pap test results and subsequent precancer were assessed using Cox proportional hazards models. Among 942 HIV-infected women with negative baseline Pap test results, eight (1%) developed precancer within 15 months and 40 (4%) within 39 months. After three consecutive negative Pap test results, precancer was rare, with no cases within 15 months and 10 of 539 (2%) within 39 months. No women developed precancer or cancer within 39 months after 10 consecutive negative Pap test results. Risks for precancer within 15 months after negative Pap test result included current smoking (adjusted hazard ratio [HR] 1.5, 95% confidence interval [CI] 1.2-2.0 compared with nonsmokers), younger age (adjusted HR 1.5, 95% CI 1.1-2.1 for women aged younger than 31 years compared with older than 45 years), and lower CD4 count (adjusted HR 11.8, 95% CI 1.3-2.3 for CD4 200-500/microliter, adjusted HR 2.2, 95% CI 1.6-2.9 for CD4 less than 200/microliter, compared with CD4 more than 500/microliter). Annual Pap testing appears safe for women infected with HIV; for those with serial negative tests, longer intervals are appropriate. II.

Follow-up Findings in Women Aged 30 or Older With a Positive High-Risk Human Papillomavirus Test and a Negative Pap Test

Follow-up Findings in Women Aged 30 or Older With a Positive High-Risk Human Papillomavirus Test and a Negative Pap Test

Screening history preceding a diagnosis of cervical cancer in women age 65 and older

ObjectiveTo characterize the antecedent screening of women 65years of age and older diagnosed with cervical cancer. MethodsScreening histories of women 65years of age and older who were diagnosed with cervical cancer between 2003 and 2008 were examined utilizing the organization's databases and the regional Cancer Registry. Stopping screening was recommended at age 65 for members who had either 3 consecutive negative Paps or a single negative Pap plus HPV test (“cotest”). ResultsFrom 2003 through 2008 there were 56 Kaiser Permanente Northern California members 65years of age and older diagnosed with cervical cancer. During the same time period there were 1,323,100 woman-years of membership in women age 65 and older. The risk of invasive cancer among women age 65 and older was 4.2/100,000/year in 2003–2008. 33 of 56 (59%) had one or more Pap smears prior to diagnosis. Of the 33, 14 women (25%) had 3 consecutive negative Pap smears prior to diagnosis. Three of 46,401 women with 1 or more negative cotests at age 65 and older were subsequently diagnosed with invasive cancer during 132,639 women-years of follow-up (2.3/100,000/year). ConclusionsMost cervical cancers diagnosed at age 65 and older occur in women who have not met our criteria for stopping screening. A few cancers will continue to occur at age 65 and older despite multiple negative tests, as is true in other age groups. We currently have no evidence that these cancers would be prevented with continued screening at ages 65 and older.

Safe to Wait 3 Years After Negative HPV and Pap Tests

Safe to Wait 3 Years After Negative HPV and Pap Tests

Prevalence of High-Risk Human Papillomavirus in Women With Abnormal and Normal Vaginal ThinPrep Papanicolaou Cytology

The significance of high-risk HPV (hrHPV) testing in the management of women with abnormal cervical Pap tests is well known. However, the data about the hrHPV detection and its significance in abnormal vaginal specimens are very limited. The purpose of this study was to assess the prevalence of hrHPV in women with abnormal vaginal smears. Our Copath database system was searched to retrieve all the vaginal Pap tests with adjunctive HC2 hrHPV DNA test performed between July 1, 2005, and July 30, 2009. The results of hrHPV were reviewed in different TBS 2001 categories, in different age groups, and in white and African American women. During the study period, there were 1,320 vaginal ThinPrep Pap tests with adjunctive HC2 hrHPV, reported as atypical squamous cells of undetermined significance (n = 1,125), atypical squamous cells cannot rule out high grade (n = 36), low-grade squamous intraepithelial lesion (n = 148), and high-grade squamous intraepithelial lesion (n = 11). A positive hrHPV DNA result was obtained in a total of 387 cases (29.3%), which included 244 atypical squamous cells of undetermined significance (21.7%), 21 atypical squamous cells cannot rule out high-grade (58.3%), 113 low-grade squamous intraepithelial lesion (76.4%), and 9 high-grade squamous intraepithelial lesions (81.8%). Mean age was 56.5 years (range = 17-93 y). High-risk HPV-positive rate was 34.5% versus 24.9% in women aged 54 years or younger compared with those aged ≥ 55 years or older (p < .001) and 45.1% versus 27.3% in African American women compared with white women (p < .001). High-risk HPV DNA-positive rate was 2.6% among the 1,572 women with negative vaginal Pap tests. Our results show that prevalence of hrHPV in abnormal vaginal smears parallels that of cervical smears with equivalent degree of abnormality. The suggestion of reflex hrHPV testing as a tool in formulating the management plan for women with abnormal vaginal smears needs further attention.

Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice

ObjectiveTo characterize the cervical cancers diagnosed following a Pap-negative, high risk human papillomavirus (HPV)-positive (Pap−/HPV+) screen in routine clinical practice. MethodsUsing data from Kaiser Permanente Northern California, we investigated the cases of cervical cancer diagnosed between January, 2003 and January, 2009 following Pap−/HPV+ screen. Two cervical specimens were routinely collected for cervical cancer screening, one for conventional cytology and the other for high risk HPV testing using Hybrid Capture 2 (Qiagen). ResultsForty-four women (median age at diagnosis=44years) were diagnosed with primary invasive cervical cancer with a recent history of one or more Pap−/HPV+ screens. Twenty-six women had one Pap−/HPV+ screen preceding the diagnosis of cancer, 15 had two, and three had three. There were 16 squamous cancers, one small cell cancer, 24 adenocarcinomas, 2 adenosquamous carcinomas, and one case with separate invasive squamous and adenocarcinoma. FIGO Stage was IA in 11 women, IB in 31 women and IIA in 2 women. Treatment included a pelvic node dissection in 30, 2 (6.7%) of whom had positive nodes. ConclusionsHPV testing contributes to early cervical cancer diagnosis detection in women with negative Pap tests. Most women in this cohort have early stage, node negative, treatable and potentially curable disease. Adenocarcinoma predominated as might be expected because cytology misses these cancers and their precursors. The majority of cancers were diagnosed following a single Pap−/HPV+ screen, suggesting that effective triage to colposcopy of women with a Pap−/HPV+ screen would be preferable to retesting in one year as currently recommended.

The Changing Face of Cervical Cancer Screening in the United States

With the introduction of widespread Pap smear screening starting in the 1940s, the United States has seen at least a 50% reduction in the incidence and mortality of invasive cervical cancer. In light of the ease of sampling, the long pre-malignant phase of cervical cancer, and well-tolerated treatment options for pre-invasive disease, cervical cancer screening has served as a model for screening for other malignancies. For some women, it also serves as the cornerstone for annual routine visits with gynecologists. Both patients and gynecologists have been taught that a yearly Pap test is important, and it can serve as the backbone of care. Unfortunately, however, access to screening and treatment for cervical cancer continues to be an issue for some women in the United States. Approximately 60% of women with invasive cancer had not undergone a Pap test in the 5 years preceding their diagnosis or have never undergone a Pap test. 1 The long history of Pap tests has also taught us a number of lessons. We have learned that cytologic screening is hardly perfect. In a study by Nanda et al. 2 the sensitivity of a single test was 51%, and this was subsequently confirmed in a pooled analysis of European and Canadian studies by Cuzick et al. 3 One way to compensate for this poor sensitivity is by using serial screening; the sensitivity of cytology increases to 76% with 2 consecutive annual Pap tests and 88% with 3 consecutive tests. Just adding tests and procedures, however, is not always the answer, and most recently the pendulum has swung in the other direction. We now understand the risk of overtreating pre-invasive disease and the potential impact of overtreatment on preterm labor and neonatal morbidity and mortality. In many adolescents and young women, abnormal Pap tests and underlying disease will resolve spontaneously. Therefore, in 2009, the American College of Obstetricians and Gynecologists recommended that screening for cervical cancer start at age 21. 4 Another lesson learned is the role of human papillomavirus (HPV) in cervical cancer. High-risk (HR) HPV DNA testing has become a mainstay of cervical cancer screening over the past 10 years. Experts now recognize that more than 99% of all invasive cervical cancers are associated with 14 different HR HPV types. Currently, HR HPV testing is recommended for women with equivocal Pap tests (ASC-US) and atypical glandular Pap tests (AGC). Most importantly, it is also widely recommended in conjunction with Pap testing in women older than 30 years of age. In keeping with the lesson of not overtreating and overscreening, after negative Pap and HPV test results, an individual woman can increase her screening interval to every 3 years. Another benefit of HR HPV testing is its much higher sensitivity than Pap testing (96% vs. 53% in pooled estimates). Since 2005, 7 randomized controlled trials 5–11 have been published that evaluated HPV testing in the screening setting. These studies have largely shown improvements in the detection of pre-invasive lesions either alone or in conjunction with Pap testing. Of particular note, a recently published trial from Finland showed