Abstract
Purpose
This study has two aims: determine the prevalence of CIN3+ in patients with discordant cotesting, defined as negative cytology and positive human papillomavirus (HPV) testing, and identify factors (including HPV strain) associated with CIN3+, defined as cervical intraepithelial neoplasia (CIN) 3 or cancer within this population.
Methods
We conducted a retrospective chart review of women age 30–65 with intact cervices who had discordant cotesting results between January 1, 2013, and September 1, 2018, at an academic medical center. We used the t test for continuous variables and the chi-square test for categorical variables to compare women with and without CIN3+. To identify factors associated with CIN3+, we performed univariate and multivariate logistic regression.
Results
The primary outcome was the prevalence of CIN3+ based on pathologic diagnosis following biopsy or excisional procedure. Among 375 patients with discordant cotesting, the mean age was 43.8 years, 58.4% were parous, and 84.8% were white. Overall, 43/375 (12.0%) had CIN3+ and 7/375 (1.9%) had AIS. On logistic regression, only parity ≥ 1 (p = 0.04, adjusted OR = 2.23, CI = 1.06–4.68) was significantly associated with CIN3+. HPV-18 was less likely to be associated with CIN3+ (p = 0.02, adjusted OR 0.08, CI 0.01–0.65) but was present in 43% of AIS cases. HPV16 and other HR-HPV strains were highly associated with CIN3+.
Conclusions
Women with discordant cotesting are at significant risk for CIN3+. We recommend that biopsy be performed at the time of indicated colposcopy for all patients with discordant cotesting to assess for high-grade dysplasia.
Keywords: Cytology, HPV, Colposcopy, High-grade dysplasia, Discordant cotesting
INTRODUCTION
Current screening recommendations for cervical dysplasia commonly involve concurrent Pap smear and human papillomavirus (HPV) testing. The American Society for Colposcopy and Cervical Pathology (ASCCP) provides algorithms for managing results. With discordant cotesting (negative cytology with positive high-risk HPV infection), ASCCP recommends HPV genotyping. If the HPV genotyping is positive for HPV-16 or HPV-18, a colposcopy is recommended. If HPV genotyping is unavailable or is negative for HR-HPV (high-risk human papillomavirus) subtypes 16 and 18, ASCCP recommends a repeat cotesting in 12 months followed by a colposcopy for persistently positive HPV or cytologic abnormalities [1].
Recent data suggest the importance of HPV as a marker for high-grade dysplasia (cervical intraepithelial neoplasia [CIN] grade 2 or 3) or invasive cervical carcinoma. When HPV primary screening was compared to cotesting, it was found to be comparable with higher sensitivity, while cytology had higher specificity [2]. Positive HPV is more predictive of precancers and cancers than cytology alone [3]. Persistent HPV infection has been shown to be related to increased rates of both low-grade and high-grade lesions in patients who initially had negative cytology [4]. One study showed that the negative predictive value of colposcopy in HPV+ women is similar if they are referred based on cytology, HPV genotyping, or prior HPV result alone [5]. Cytology is also prone to interobserver variability. A 2001 comparison of cytology and colposcopy-guided biopsy found that only 35% of samples had exact correspondence and 31% had a more severe lesion on biopsy when compared with cytology [6]. A similar comparison of lesions with atypical squamous cells of undetermined significance (ASCUS) or low-grade dysplasia by cytology and biopsy found poor reproducibility among all grades of dysplasia but worse in ASCUS samples [7].
When comparing risks, one study showed the 1-year risk of developing CIN3+ was similar between NILM/HPV16+ (13.95%) and LSIL/HPV16+ (11.45%) [8]. This is in accordance with ASCCP’s recommendation for colposcopy with any HPV-16+ result. ASCCP does not specify if biopsies should be taken, but improved rates of detection of CIN2+ have been noted when targeted biopsies are performed of lesions appearing to be low-grade on colposcopic impression [9] or in patients who are HPV+ [10]. For patients with discordant cotesting, the risk of CIN3+ stratified by HPV strain has not been examined. Therefore, the goal of this study is to determine the prevalence of CIN3+ in patients with discordant cotesting stratified by HPV strain and identify factors associated with CIN3+.
METHODS
We conducted a retrospective review of women age 30–65 with intact cervices who underwent cervical cancer screenings with negative cytology and positive HPV testing between January 1, 2013, and September 1, 2018, at a single academic institution in the Midwest. Women who did not have confirmed pathology from colposcopy-guided biopsy, loop-electrocautery excision procedure (LEEP), cold knife conization (CKC), or hysterectomy were excluded from primary analysis but were compared to women who did have final confirmed pathology to identify any differences between these two groups. Patients with both cytology and HPV status were identified using Current Procedural Terminology (CPT) codes and chart review confirmed presence or absence of their pathology report. The Health Sciences Minimal Risk Institutional Review Board (MR-IRB) at the University of Wisconsin (#2018–1135) approved this study.
Descriptive analyses were used to characterize the sample for whom pathology results were available and to compare patients with benign, CIN1, or CIN2 pathology to those with CIN3+ pathology and AIS pathology. The t test was used to compare continuous variables (age, body mass index [BMI], and parity), and the chi-square test was used to compare categorical variables. Final pathology results of NILM, CIN1, and CIN2 were grouped together. CIN2 was grouped with NILM and CIN1 due to the high rates of regression of CIN2, especially in young women [11, 12]. Final pathology results of CIN3 and invasive carcinoma were grouped together as CIN3 is a proxy for those patients who are at high risk of developing cervical cancer. Final pathology of AIS was analyzed separately from CIN3+. Patients underwent additional procedures (LEEP, CKC, or hysterectomy) based on ASCCP guidelines and/or concurrent medical conditions (i.e abnormal uterine bleeding resulting in hysterectomy unrelated to cervical dysplasia). When multiple pathologic specimens were available in the medical record at the time of chart review, the highest grade dysplasia was used for classification purposes. We compared patients who underwent colposcopy without biopsies to patients who underwent colposcopy with biopsies.
Prior Pap history reflects any prior abnormal Pap smear in the patient’s history, with the highest-grade cytology result noted. Prior procedure reflects any prior colposcopy, loop electrocautery excisional procedure (LEEP), or cold knife conization (CKC), with the most significant procedure noted.
A k-proportions test was used to compare the proportions of patients with benign, CIN1-CIN2, CIN3, and cancerous biopsies by HPV strain (HPV-16, HPV-18, or other high-risk HPV strain).
Univariate and multivariate logistic regressions were performed to identify factors associated with high-grade dysplasia using Stata/SE 16.0 (StataCorp. 2019. College Station, TX, USA.). For logistic regression, race was categorized as white, black, Hispanic, or other; insurance status was categorized as private, Medicaid/Medicare, or other; and parity was classified as P0 or P1+.
Alpha of 0.05 was considered significant for all analyses.
RESULTS
The study participants are described in Figure 1. Of all patients who had discordant cotesting, 26.9% underwent colposcopy with biopsy and were included in the primary analysis. 3.7% underwent colposcopy without biopsy; these patients were compared to those who underwent colposcopic biopsy. The patients who underwent colposcopy without biopsy were generally noted to have normal colposcopy findings. Notably, 14.5% of patients should have received colposcopy but did not due to inappropriate provider recommendation and loss to follow up.
Figure 1.
Study participants.
Table 1 describes the sample of women who had discordant cotesting, stratified by whether they received a biopsy. Those patients who did not have pathology results (no biopsy performed at the time of colposcopy) are compared with all patients who did have pathology results (biopsy performed at the time of colposcopy or excisional pathology). The patients who underwent colposcopy without biopsy were similar to those who did have colposcopic biopsies; the two groups did not differ by age, race, parity, smoking status, immunosuppression, prior procedures, or HPV subtype. They were less likely to have Medicaid, less likely to have had a prior negative for intraepithelial lesion or malignancy (NILM)/HPV+ Pap smear, and more likely to have had prior appropriate cervical dysplasia screening.
Table 1.
Sample Description: Women with Discordant Co-Testing, Stratified by Biopsy or No Biopsy
| Colposcopy without biopsy N = 52 (12.2%) |
Colposcopy with biopsy N = 375 (87.8%) |
|
|---|---|---|
| Age in years (mean +/− SD) | 43.3 +/− 10.3 | 43.8 +/− 9.9 |
| Race (%) | ||
| White | 45 (86.5) | 318 (84.8) |
| Black | 3 (5.8) | 19 (5.1) |
| Asian | 2 (3.8) | 13 (3.5) |
| Hispanic | 1 (1.9) | 21 (5.6) |
| Native American | 0 (0) | 1 (0.3) |
| Multiracial / Other | 1 (1.9) | 3 (0.8) |
| Insurance (%) | ||
| Private | 48 (92.3) | 308 (82.1) |
| Medicaid | 0 (0) | 34 (9.1) * |
| Medicare | 1 (1.9) | 16 (4.3) |
| Unknown | 3 (5.8) | 17 (4.5) |
| BMI (mean +/− SD) | 27.6 +/− 5.8 | 28.7 +/− 7.2 |
| Parity (%) | ||
| P0 | 21 (40.4) | 156 (41.6) |
| P1 | 11 (21.2) | 68 (18.1) |
| P2+ | 20 (38.5) | 151 (40.3) |
| Smoking (%) | 4 (7.7) | 48 (12.8) |
| Immunosuppressed (%) | 0 (0) | 3 (0.8) |
| Prior pap (%) | ||
| Benign | 26 (50.0) | 157 (41.9) |
| NILM/HPV+ | 0 (0) | 46 (12.3) * |
| LSIL | 5 (9.6) | 28 (7.5) |
| ASCUS | 13 (25.0) | 87 (23.2) |
| HSIL | 2 (3.8) | 18 (4.8) |
| Unknown | 6 (11.5) | 39 (10.4) |
| Prior procedure (%) | ||
| None | 37 (71.2) | 289 (77.1) |
| Colposcopy | 7 (13.5) | 50 (13.3) |
| LEEP / CKC | 8 (15.4) | 36 (9.6) |
| Screening guidelines (%) | ||
| Inappropriate | 2 (3.8) | 59 (15.7) * |
| Appropriate | 44 (84.6) | 266 (70.9) * |
| Unknown | 6 (11.5) | 50 (13.3) |
| HPV strain (%) | ||
| HPV 16 | 16 (30.8) | 142 (37.9) |
| HPV 18 | 10 (19.2) | 72 (19.2) |
| HPV HR other | 26 (50.0) | 158 (42.1) |
Table 2 describes the sample of women who had discordant cotesting and received a colposcopic biopsy, stratified by their final pathology results. The pathology results were stratified into benign/CIN1-CIN2, CIN3+, and AIS. Overall, 12% of patients with discordant cotesting had final pathology consistent with CIN3+ and 1.9% had AIS. Patients with CIN3+ were less likely than patients with benign/CIN1-CIN2 to be nulliparous and more likely to to have a prior NILM/HPV+ pap smear. They were also less likely to be positive for HPV18 compared with other strains. Patients with AIS were younger than patients with benign/CIN1-CIN2 and were less likely to be positive for non-16/18 strains of HPV. Only 3 patients in the entire sample had documented immunosuppression and all were in the benign/CIN1-CIN2 group. Therefore, we excluded immunosuppression from subsequent analyses.
Table 2.
Sample Description: Women with Discordant Co-Testing, Stratified by Final Pathology Result
| Final pathology benign, CIN1-CIN2 N = 323 (86.1%) |
Final pathology CIN3+ N = 45 (12.0%) |
Final pathology AIS N = 7 (1.9%) |
|
|---|---|---|---|
| Age in years (mean +/− SD) | 44.0 +/− 9.8 | 43.4 +/− 10.2 | 34.4 +/− 4.8 |
| Race (%) | |||
| White | 272 (84.2) | 40 (88.9) | 6 (85.7) |
| Black | 18 (5.6) | 1 (2.2) | 0 (0) |
| Asian | 10 (3.1) | 2 (4.4) | 1 (14.3) |
| Hispanic | 20 (6.2) | 1 (2.2) | 0 (0) |
| Native American | 1 (0.3) | 0 (0) | 0 (0) |
| Multiracial / Other | 2 (0.6) | 1 (2.2) | 0 (0) |
| Insurance (%) | |||
| Private | 264 (81.7) | 38 (84.4) | 6 (85.7) |
| Medicaid | 30 (9.3) | 3 (6.7) | 1 (14.3) |
| Medicare | 14 (4.3) | 2 (4.4) | 0 (0) |
| Unknown | 15 (4.6) | 2 (4.4) | 0 (0) |
| BMI (mean +/− SD) | 28.7 +/− 7.3 | 30.2 +/− 6.6 | 27.1 +/− 8.1 |
| Parity (%) | |||
| P0 | 142 (44.0) | 12 (26.7) * | 2 (28.6) |
| P1 | 56 (17.3) | 10 (22.2) | 2 (28.6) |
| P2+ | 125 (38.7) | 23 (51.1) | 3 (42.9) |
| Smoking (%) | 44 (13.6) | 3 (6.7) | 1 (14.3) |
| Immunosuppressed (%) | 3 (0.9) | 0 (0) | 0 (0) |
| Prior pap (%) | |||
| Benign | 139 (43.0) | 13 (28.9) | 5 (71.4) |
| NILM/HPV+ | 33 (10.2) | 13 (28.9) *** | 0 (0) |
| LSIL | 26 (8.0) | 2 (4.4) | 0 (0) |
| ASCUS | 73 (22.6) | 14 (31.1) | 0 (0) |
| HSIL | 17 (5.3) | 1 (2.2) | 0 (0) |
| Unknown | 35 (10.8) | 2 (4.4) | 2 (28.6) |
| Prior procedure (%) | |||
| None | 245 (75.9) | 37 (82.2) | 7 (100) |
| Colposcopy | 46 (14.2) | 4 (8.9) | 0 (0) |
| LEEP / CKC | 32 (9.9) | 4 (8.9) | 0 (0) |
| Screening guidelines (%) | |||
| Inappropriate | 52 (16.1) | 7 (15.6) | 0 (0) |
| Appropriate | 227 (70.3) | 34 (75.6) | 5 (71.4) |
| Unknown | 44 (13.6) | 4 (8.9) | 2 (28.6) |
| HPV strain (%) | |||
| HPV 16 | 117 (36.2) | 21 (46.7) | 4 (57.1) |
| HPV 18 | 68 (21.1) | 1 (2.2) ** | 3 (42.9) |
| HPV HR Other | 135 (41.8) | 23 (51.1) | 0 (0) * |
Table 3 presents pathology results stratified by HPV strain. For this analysis, pathology results were stratified into four categories: benign, CIN1-CIN2, CIN3+, and AIS. One patient was found to have invasive squamous cell carcinoma of the cervix, which was FIGO stage IVB with no prior abnormal pap smears and appropriate screening. Seven patients were found to have adenocarcinoma in situ. Patients with HPV-16 and other HR-HPV strains were more likely to have CIN3+ for their final pathology compared with patients with HPV-18 (p = 0.008). There was no statistical difference between HPV strains among patients with AIS.
Table 3.
Pathology Results by HPV Strain
| HPV Strain | Benign | CIN1-CIN2 | CIN3+ | AIS | Total | ||||
|---|---|---|---|---|---|---|---|---|---|
| HPV 16 | 96 | 67.6% | 21 | 14.8% | 21 | 14.7% | 4 | 2.8% | 142 |
| HPV 18 | 55 | 76.4% | 13 | 18.1% | 1 | 1.4% | 3 | 4.2% | 72 |
| HPV HR Other | 106 | 67.1% | 29 | 18.4% | 23 | 14.6% | 0 | 0% | 158 |
| HPV pos, unknown genotype | 5 | 83.3% | 0 | 0% | 1 | 16.7% | 0 | 0% | 6 |
Three patients were positive for both HPV16 and HPV18 and were counted in both categories. Six patients were HPV positive but did not have genotyping completed.
To identify factors associated with CIN3+, we performed both univariate and multivariate logistic regressions (Table 4). We looked at groups of variables including HPV strain, screening history, demographic information, and finally a full multivariate analysis. Parity of P≥1 was found to be statistically significant for all analyses (p = 0.04, adjusted OR = 2.23, CI = 1.06–4.68) and as above HPV-18 was less likely to be associated with CIN3+ (p = 0.02, adjusted OR 0.08, CI = 0.01 – 0.65). An increasing BMI was slightly associated with CIN3+ in the multivariate analyses but not in the univariate analysis.
Table 4.
Univariate and multivariate logistic regression comparing benign/CIN1–2 group and CIN3+ group
| Variable | Univariate | Multivariate HPV | Multivariate Screening | Multivariate Demographics | Multivariate Final | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | |
| HPV-16 | 1.54 | 0.82 – 2.89 | 1.12 | 0.59 – 2.13 | 1.01 | 0.51 – 2.02 | ||||
| HPV-18 | 0.09 ** | 0.01 – 0.63 | 0.09 ** | 0.01 – 0.67 | 0.08 ** | 0.01 – 0.65 | ||||
| HPV-HR Other | 1.46 | 0.78 – 2.72 | ||||||||
| Prior Pap ASCUS or HSIL | 1.29 | 0.67 – 2.52 | 1.67 | 0.79 – 3.58 | 1.28 | 0.56 – 2.91 | ||||
| Prior Procedure | ||||||||||
| Colposcopy | 0.58 | 0.20 – 1.69 | 0.42 | 0.13 – 1.36 | 0.49 | 0.15 – 1.66 | ||||
| LEEP/CKC | 0.83 | 0.28 – 2.48 | 0.65 | 0.20 – 2.06 | 0.65 | 0.19 – 2.19 | ||||
| Prior Screening Adequate | 0.87 | 0.48 – 1.54 | 0.90 | 0.50 – 1.62 | 0.81 | 0.43 – 1.56 | ||||
| Age | 0.99 | 0.96 – 1.03 | 0.99 | 0.96 – 1.02 | 0.99 | 0.96 – 1.02 | ||||
| Race | ||||||||||
| Black | 0.38 | 0.05 – 2.91 | 0.27 | 0.03 – 2.35 | 0.30 | 0.03 – 2.86 | ||||
| Hispanic | 0.34 | 0.04 – 2.60 | 0.28 | 0.04 – 2.23 | 0.32 | 0.04 – 2.67 | ||||
| Other | 1.57 | 0.43 – 5.75 | 1.86 | 0.47 – 7.26 | 1.84 | 0.44 – 7.78 | ||||
| Medicaid/Medicare | 0.82 | 0.35 – 1.94 | 1.01 | 0.40 – 2.52 | 1.00 | 0.38 – 2.61 | ||||
| BMI | 1.03 | 0.99 – 1.07 | 1.04 * | 1.00 – 1.09 | 1.05 * | 1.00 – 1.10 | ||||
| Parity ≥1 | 2.16 ** | 1.08 – 4.33 | 2.38 ** | 1.16 – 4.89 | 2.23 ** | 1.06 – 4.68 | ||||
| Smoking | 0.45 | 0.13 – 1.52 | 0.46 | 0.13 – 1.59 | 0.50 | 0.14 – 1.79 | ||||
DISCUSSION
Our results show that 12.0% of patients with discordant cotesting have CIN3+ and an additional 1.9% have AIS. Of different strains of HPV, HPV18 was significantly less likely to be associated with CIN3+ compared with HPV16 and other HR-HPV strains. HPV16 and HPV18 were equally likely to be associated with AIS.
Among HPV16 cases, 14.7% had CIN3+, which is comparable to the 13.9% identified by Castle, et al [8]. Of all NILM/HPV+ cases, however, 12.0% had CIN3+, which is significantly higher than the 5.9% identified by Castle et al and is primarily driven by the high proportion of CIN3+ among patients with other HR-HPV strains. This increase in CIN3+ caused by other HR-HPV strains may be a regional difference, as our study was conducted at a single institution in the Midwest. The relationship between other HR-HPV strains and CIN3+ may also be related to the persistence of HPV rather than the specific strain of HPV as these patients only underwent colopscopic biopsy after at least two NILM/HPV+ results. The most common inappropriate screening identified in this study (excluding patients who were lost to follow up) was persistent NILM/HPV+ (negative 16/18) with provider recommendation for repeat screening in 1 year rather than recommendation for colposcopy after the second consecutive result.
Our results also found that 1.9% of NILM/HPV+ patients have AIS. The incidence of AIS is 6.6 per 100,000 and has been increasing in the population aged > 30, which was our patient population, despite decreases in younger women aged 21–24 [13, 14]. In our sample, 57% of the AIS cases were attributable to HPV16 and 43% were attributable to HPV18, with no other HR-HPV strains identified, though the sample size of AIS pathology was low. These data are consistent with prior data examining rates of HPV strains in AIS vs CIN3+ [13, 14], which have found 38–50% of AIS to be associated with HPV18 compared with 8% of CIN3+.
Our data showed that HPV-18 was less likely to be associated with CIN3+ compared with either HPV16 or other HR-HPV strains but was equally likely to be associated with AIS compared with HPV16. The current ASCCP guidelines [15] for management of discordant cotesting is predicated on the ability of high-risk HPV strain to predict CIN3+ requiring excisional procedure or other treatment, but our data suggests that high risk HPV strains besides HPV-16/18 are also predictive of CIN3+ despite negative cytology. This data further suggests that our ability to predict which patient-specific factors increase the risk of CIN3+ is limited. The primary factor identified as a predictor of CIN3+ on multivariate logistic regression was parity. Though parity may be a loose proxy for more sexual partners, the number of sexual partners and history of other STIs was not included in this analysis.
Our data set shows a large proportion of patients with negative cytology who ultimately have CIN3+ including among patients with HPV strains other than 16/18. This is consistent with existing data [8] that cytology is a poor representation of pathology while HPV is independently suggestive of high-grade dysplasia. In our data set, persistent infection with non-HPV-16/18 is significantly associated with CIN3+, though is less likely to be associated with AIS. This data would support the use of HPV as a primary screening tool for high-grade dysplasia. For patients for whom colposcopy is indicated (cytology negative/HR-HPV+ or persistent cytology negative/HPV+), we recommend consideration of routine biopsy in the setting of discordant cotesting because a large proportion of these patients will have CIN3+ even among patients who do not have HPV-16/18. Additionally, given that AIS was identified in 1.9% of patients in this sample, a biopsy would provide early identification of these patients who would warrant an excisional procedure.
The strengths of this study are its broad inclusion criteria and inclusion of multiple possible confounding variables in logistic regression. The limitations of this study are its retrospective nature including that not all patients who warranted colposcopy underwent the procedure (14.5%) and not all who had colposcopy had simultaneous biopsies for pathologic confirmation (3.7%). Analysis of the patients who underwent colposcopy without biopsy indicates no demographic differences between them and the cohort who had biopsies; however, patients who did not have colposcopic biopsies were more likely to have had prior appropriate cervical dysplasia screening and less likely to have had a prior NILM/HPV+ Pap smear, which may explain why their providers opted not to perform biopsies at the time of colposcopy. A prospective approach would allow for confirmation that there is no difference at the time of colposcopic impression. The number of biopsies collected was not taken into consideration for this study; data suggests that more biopsies improves the ability to detect abnormalities [16].
CONCLUSION
The results of this study suggest that the prevalence of CIN3+ among patients with discordant cotesting is 12%. However, non-16/18 HR-HPV strains were also a significant risk factor for CIN3+. This suggests that for indicated colposcopy in the setting of discordant cotesting, biopsy should be strongly considered in order to assess for high-grade dysplasia. Future research could include prospective studies to include genotyping beyond HPV-16/18, inclusion of HPV vaccination status as a factor, and examination of biopsy results of patients who undergo immediate colposcopy following NILM/HPV+ results.
Acknowledgements:
The project described was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR002373. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funding
There was no external funding source for this study.
LIST OF ABBREVIATIONS
- AIS
Adenocarcinoma in situ
- ASCCP
American Society for Colposcopy and Cervical Pathology
- ASCUS
Atypical squamous cells of undetermined significance
- ASC
Atypical squamous cells
- BMI
Body mass index
- CIN
Cervical intraepithelial neoplasia
- CKC
Cold knife conization
- CPT
Current Procedural Terminology
- HPV
Human papillomavirus
- HR-HPV
High-risk Human papillomavirus (HPV 16/18)
- HSIL
High-grade squamous intraepithelial lesion
- LEEP
Loop electrocautery excisional procedure
- LSIL
Low-grade squamous intraepithelial lesion
- NILM
Negative for intraepithelial lesion or malignancy
- SCC
Squamous cell carcinoma
Footnotes
Disclosure of financial support: None
Conflict of interest: There are no conflicts of interest.
IRB status: Approved by University of Wisconsin with IRB number 2018-1135
DECLARATIONS
Availability of Data and Material Data can be made available upon request.
Code Availability Not applicable.
COMPLIANCE WITH ETHICAL STANDARDS
This study was approved by the University of Wisconsin with IRB number 2018-1135. There was no funding source for this project. Neither author has any conflicts of interest. Informed consent was exempted by the IRB and therefore was not obtained.
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