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Diagnosis of Cervical Precancers by Endocervical Curettage at Colposcopy of Women With Abnormal Cervical Cytology

Liu, Angela Hui-Chia MD; Walker, Joan MD; Gage, Julia C. PhD, MPH; Gold, Michael A. MD; Zuna, Rosemary MD; Dunn, S. Terence PhD; Schiffman, Mark MD; Wentzensen, Nicolas MD, PhD

doi: 10.1097/AOG.0000000000002330
Contents: Dysplasia: Original Research
ABOG MOC II

OBJECTIVE: To evaluate the performance of routine endocervical curettage (ECC) for diagnosing high-grade cervical intraepithelial neoplasia (CIN) 2 or worse and additional precancers not otherwise detected by ectocervical biopsies.

METHODS: In a secondary analysis of the Biopsy Study, a cross-sectional study conducted between 2009 and 2012 at the University of Oklahoma Health and Sciences Center that found an incremental increase in detection of cervical precancers by multiple biopsies at colposcopy, ECC was performed in most women aged 30 years or older. Cervical intraepithelial neoplasia 2 or worse yield by ECC alone was evaluated in analyses stratified by cervical cytology (atypical squamous cells of undetermined significance [ASC-US] or low-grade squamous intraepithelial lesions [LSIL] compared with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions [ASC-H] or high-grade squamous intraepithelial lesions [HSIL] or worse), colposcopic impression (less than high-grade compared with high-grade), human papillomavirus (HPV)-16 infection status, whether the examination was satisfactory, and by ECC indications per the current guidelines for cervical cancer screening. The diagnostic value of ECC for detecting additional disease was evaluated by the number of lesion-directed ectocervical biopsies.

RESULTS: Of the 204 women aged 30 years or older, 181 (88.7%) underwent ECC. Overall ECC detected 14.4% CIN 2 or worse (95% CI 10.0–20.2%). Endocervical curettage was more likely to find disease in the endocervix among women with high-grade cytology, positive HPV-16 infection, or high-grade colposcopic impressions (respective P values <.05). Among women with ASC-US or LSIL cytology, those with an unsatisfactory examination had a 13.0% CIN 2 or worse yield on ECC (95% CI 6.1–25.7); when colposcopic examination was normal or satisfactory with visible abnormal lesions, ECC detected less than 5% CIN 2 or worse in the endocervix. An ASC-H or HSIL or worse cytology was associated with a CIN 2 or worse yield of 25.8% by ECC (95% CI 16.6–37.9%). However, ECC found only 3.9% (95% CI 1.9–7.8%) additional CIN 2 or worse beyond the cumulative disease detected by up to four biopsies of visible acetowhite ectocervical lesions. Additional CIN 2 or worse yield by ECC increased when fewer lesion-directed biopsies were taken (P<.05).

CONCLUSION: The additional yield of CIN 2 or worse by ECC in a colposcopy with up to four ectocervical biopsies was low. Based on our findings, we recommend routine ECC be performed in women aged 45 years old or older with HPV-16 infection and in any woman aged 30 years or older with HSIL or worse or ASC-H cytology, high-grade colposcopic impression, or ASC-US or LSIL cytology and an unsatisfactory examination.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00339989.

In a U.S. cohort of women undergoing colposcopy for abnormal cervical cytology, endocervical curettage found only 3.9% of otherwise undetected grade II or worse cervical intraepithelial neoplasia.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland; the University of Oklahoma Health Sciences Center, Oklahoma City, and Oklahoma Cancer Specialists and Research Institute and University of Oklahoma School of Community Medicine, Tulsa, Oklahoma.

Corresponding author: Angela Hui-Chia Liu, MD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Room 7E-216, Rockville, MD 20850; email: angela.liu@nih.gov.

Supported by the Intramural Research Program of the National Cancer Institute.

Financial Disclosure The authors did not report any potential conflicts of interest.

Each author has indicated that he or she has met the journal's requirements for authorship.

Endocervical curettage (ECC) has been increasingly incorporated in the colposcopy–biopsy examination for a subset of approximately 3 million women undergoing colposcopic evaluation each year in the United States.1–3 for abnormal screening cytology. Cervical colposcopy has limitations related to the reproducibility of colposcopic impression and biopsy placement.4,5 Some studies have suggested that colposcopic biopsy can fail to detect 30–50% of prevalent high-grade cervical precancers.6,7 To improve the accuracy of the overall cervical colposcopy–biopsy examination, taking multiple lesion-directed biopsies and ECC have both been proposed.6,8–10

However, the specific indications for ECC remain debated.11 Besides the clear contraindication in pregnancy, there is wide agreement on the greater benefits of performing ECC in older women, in whom the squamocolumnar junction is more difficult to visualize entirely,8 yet the age cutoff to begin performing ECC differs between or is not stated in various management guidelines.12 The evidence for identifying women most likely to benefit from endocervical sampling based on cytology and colposcopic abnormalities has also been inconclusive as a result of biased selection of women undergoing the procedure.8,13–16 Studies on routine ECC are heterogeneous in methodologies and designs and report a wide range of cervical intraepithelial neoplasia (CIN) 2 or worse yield from 1.0% to 15%.3,11,17–19

To address selection bias related to cytology and colposcopic findings, we designed an ancillary analysis of the Biopsy Study20 to evaluate detection of cervical precancers by routine endocervical sampling in women 30 years or older. Using a highly standardized multiple-biopsy colposcopy protocol, we also compared the additional precancer yield by ECC over additional ectocervical biopsies.

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MATERIALS AND METHODS

In a secondary analysis, women aged 30 years or older underwent routine endocervical sampling in the Biopsy Study, a cross-sectional study that evaluated the incremental benefit of multiple biopsies at colposcopy.20 Of the 2,270 women referred to the colposcopy clinic at the University of Oklahoma Health Sciences Center between February 2009 and September 2012 for abnormal cervical screening results or treatment of previously diagnosed disease, 690 of 1,373 (50.3%) eligible women agreed to participate in the study. The remaining 897 women were excluded by a history of previous surgery, chemotherapy, or radiation treatment for cervical disease or neoplasia; pregnancy; or known human immunodeficiency virus infection.20 All women aged 30 years or older enrolled in the Biopsy Study (age range 18–76 years, median age 26 years) were supposed to undergo endocervical sampling to avoid selection biases by cervical cytology or colposcopic findings. Women younger than 30 years old received ECC for the following indications: discrepancy between colposcopic findings and high-grade squamous intraepithelial lesion (HSIL) referral cytology, unsatisfactory examination, or atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) cytology. Institutional review boards at both the University of Oklahoma Health Sciences Center and the National Cancer Institute approved the study.

Community-based referral for colposcopy was based on the 2007 American Society for Colposcopy and Cervical Pathology guidelines.2 Each of the six participating colposcopists performed between 60 and 179 colposcopic examinations in the study. Cervical samples were collected using a Wallach broom and transferred to PreservCyt solution for cytology and human papillomavirus (HPV) testing. After the cervix was assessed with 5% acetic acid application, each distinct area of acetowhite cervical epithelium in the transformation zone was sampled as a lesion-directed biopsy using sharp Tischler or Baby-Tischler biopsy forceps. A single random biopsy of normal-appearing cervical epithelium in any quadrant of the cervix was added if fewer than four lesion-directed biopsies were taken. Cervical specimens were placed into separate labeled containers with 10% buffered formalin. Each biopsy was ranked by the severity of colposcopic impression at the time of examination, stained with hematoxylin and eosin, and evaluated independently by a study pathologist for clinical management. In addition, p16 staining was performed to establish biomarker-adjudicated CIN endpoints for each cervical biopsy.21

To assess the endocervix, a sharp Kevorkian curette without a basket was placed inside the endocervical canal. Gentle pressure was applied at its tip, and the curette was moved back and forth along the length of the endocervix while being rotated in a circular fashion to sample the entire circumference of the canal. The extension of sampling to lesions external to the cervical os was avoided during the procedure to minimize contamination with ectocervical tissue. A rapid spinning motion was exerted when removing the curette from the endocervical canal, trapping all tissue and cellular materials in the curette chamber. To retrieve any remaining curettage material, a Singly or Campion forceps could be introduced into the canal. In women with severe cervical stenosis, a Cytobrush or Wallach broom was used to provide specimens to evaluate the endocervical canal.

Community-based referral cytology was reported using the Bethesda nomenclature.22 Women were referred with one of the following diagnoses: atypical squamous cells of undermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells, favor high-grade (ASC-H), HSIL, AGC, AIS, and squamous cell carcinoma.22 Human papillomavirus genotyping was performed using the Linear Array HPV Genotyping Test according to the manufacturer's instructions with slight modifications.23,24

Histologic endpoints were defined according to the Lower Anogenital Squamous Terminology criteria25: all CIN 3– and p16–positive CIN 2 biopsies were grouped as high-grade cervical precancers. Endocervical curettage samples did not yield sufficient specimens to perform p16 adjudication. Cervical intraepithelial neoplasia 2 or worse on ECC defined the precancer yield by routine endocervical sampling. Additional precancer yield by ECC was defined as CIN 2 or worse not otherwise found on biopsies of ectocervical lesions.

As previously reported, the main analyses of the Biopsy Study found a 25% increase in detection of precancers between the first and second lesion-directed biopsy (60.6–85.6%) and a 10% increase between the second and third lesion-directed biopsy (85.6–95.6%). This incremental increase in sensitivity by multiple biopsies was observed in all subgroups of patient characteristics.20 In the current analysis, we first evaluated the overall yield of high-grade precancers on ECC and stratified by age, referral cytology (ASC-US or LSIL compared with ASC-H or HSIL or worse), HPV-16 infection status, adequacy of squamocolumnar junction visualization (satisfactory compared with unsatisfactory colposcopy), or colposcopic impression (less than high-grade compared with high-grade). Women missing any of the information were not included in the respective stratified analyses. Cervical intraepithelial neoplasia 2 or worse yield by ECC was also estimated based on indications in the current U.S. management guidelines for cervical cancer screening.11 Specifically, we assessed the recommendations to perform ECC 1) routinely in nonpregnant women with ASC-H or HSIL or worse cytology undergoing colposcopy and 2) selectively in women with ASC-US or LSIL cytology who had a normal colposcopy, unsatisfactory examination, or a satisfactory examination and visible colposcopic lesions. We evaluated the additional CIN 2 or worse yield in ECC by varying the number of ectocervical biopsies (from only one biopsy of the most severe colposcopic lesion to up to four acetowhite lesions), which changes the cumulative disease found on the ectocervix. All analyses were performed with the statistical programming language R-3.1.2 in the open-source integrated development environment of RStudio.

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RESULTS

Of 204 women aged 30 years or older enrolled in the Biopsy Study, 181 received an ECC procedure (88.7%). Among 477 women younger than 30 years old, 100 had ECC (21.0%) for discrepancy between normal colposcopy and HSIL referral cytology, an unsatisfactory colposcopy, or AGC or AIS cytology results (data not shown). We compared characteristics between 23 women aged 30 years or older who did not receive ECC and the majority of 181 who did. Women without an ECC were more likely to have a satisfactory examination (78.3% compared with 58.0%, χ2 P<.05), but did not differ from those who received an ECC by the prevalence of HPV infection and types, cervical cytology, or colposcopic impression (Table 1). Of the 181 ECC samples, 144 were normal (79.6%, 95% CI 73.1–84.8%); five showed atypical metaplasia (2.8%, 95% CI 1.2–6.3%); six showed CIN 1 (3.3%, 95% CI 1.5–7.0%); 14 showed CIN 2 (7.7%, 95% CI 4.7–12.6%); and 16 showed CIN 3 or worse (8.8%, 95% CI 5.5–13.9%). Seven of the 23 women who met the age criterion but did not receive ECC were diagnosed with CIN 2 or worse on ectocervical biopsies.

Table 1

Table 1

We evaluated the diagnostic yield of CIN 2 or worse based on routine endocervical curettage. Age stratification by 10-year increments showed overall higher CIN 2 or worse yield by ECC with increasing age. Of 99 women 20–29 years old who received ECC for specific indications other than age, 10 (10.1%, 95% CI 5.6–17.6%) showed CIN 2 or worse in the endocervix. Routine ECC found 11.9% CIN 2 or worse (95% CI 7.1–19.4%) among 30- to 39-year-old women, 18.0% among 40- to 49-year-old women (95% CI 9.8–30.8%), 14.3% among 50- to 59-year-old women (95% CI 4.0–40.0%), and 25% (95% CI 9.7–70.0%) among 60- to 69-year-old women (χ2 test for trend; P=.55; Table 2). To avoid selection bias related to cervical cytology and colposcopic examination findings in the youngest age group, further analyses were restricted to the 181 women aged 30 years or older who met age eligibility for endocervical sampling at colposcopy.

Table 2

Table 2

The ECC found CIN 2 or worse among 26 of 181 women (14.4%; 95% CI 10.0–20.2%) 30 years old or older. Cervical intraepithelial neoplasia 2 or worse yield by ECC was significantly higher among women with an ASC-H or HSIL or worse (includes AGC, AIS, and squamous cell carcinoma) cervical cytology (27.1%) compared with 7.3% in women with ASC-US or LSIL cytology (P<.05), positive HPV-16 infection (24.4% compared with 11.5% in women without HPV-16 infection, P<.05), or high-grade colposcopic impression (26.8% compared with 8.0% in women with less than high-grade impression, P<.05) and nonsignificantly higher among women with inadequate colposcopies (20.3% of 74 women with an unsatisfactory examination compared with 10.5% of 105 women with a satisfactory examination, P=.07) (Table 3). Our study population (women who qualified for an ECC procedure at colposcopy based on age of 30 years old or older) was relatively young; only 22.1% were 45 years old or older. Statistical power was limited to detect unique findings in women 45 years of age or older, but similar trends among women 30–44 years old held in this age group, except for the association between endocervical involvement and HPV-16 positivity (Table 4).

Table 3

Table 3

Table 4

Table 4

We stratified women based on the indications for ECC in the current U.S. management guideline for cervical cancer screening (Table 5). Among women with ASC-US or LSIL cytology, endocervical sampling is preferred when the colposcopic examination is normal or unsatisfactory and is acceptable when the examination is satisfactory with visible colposcopic lesions. Among women with ASC-US or LSIL cytology, ECC found CIN 2 or worse in 4.3% of normal examinations (95% CI 0.8–21.0%), 13.0% of unsatisfactory examinations (95% CI 6.1–25.7%), and 1.9% of satisfactory examinations with positive findings on the ectocervix (95% CI 0.3–10.0%). The indication for performing ECC in all nonpregnant women with ASC-H or HSIL referral cytology was associated with a 25.8% CIN 2 or worse yield in the endocervix (95% CI 16.6–37.9%). The number of additional CIN 2 or worse by ECC not otherwise found on ectocervical biopsies was too few for analyses in these strata (data not shown).

Table 5

Table 5

We also evaluated the utility of ECC for diagnosing precancers otherwise missed on ectocervical biopsies. Endocervical sampling showed a CIN 2 or worse yield of 14.4% (95% CI 10.0–20.2%) when no lesion-directed ectocervical biopsies were taken. In the multiple-biopsy colposcopy protocol, cumulative CIN 2 or worse yield on the ectocervix increased with the number of lesion-directed biopsies. Sampling the worst-appearing lesion found CIN 2 or worse in 21.0% of examinations, and adding one, two, or three additional colposcopic biopsies showed 27.6%, 29.3%, and 29.8% CIN 2 or worse, respectively. Additional yield of CIN 2 or worse by ECC (gain over ectocervical biopsies) decreased from 7.7% to 5.0%, 4.4%, and 3.9% with the incremental increase in detection of precancer by each successive lesion-directed colposcopic biopsy of the ectocervix (χ2 test for trend; P<.05; Table 6).

Table 6

Table 6

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DISCUSSION

Detecting endocervical disease on ECC during colposcopy can increase the sensitivity of colposcopy and biopsy and inform the method of treatment. However, there is controversy about when endocervical sampling should be performed. In the Biopsy Study,20 selecting for the ECC procedure by age alone affirmed previously reported associations between diagnosing cervical precancers on routine ECC and high-grade colposcopic impression and ASC-H or HSIL or worse cytology. For the first time, we described an association between HPV-16 infection and positive ECC among women 45 years old or older (Tables 3 and 4). Unconstrained by selection biases, our findings support the following ECC indications in the current cervical cancer screening guidelines: 1) ASC-H or HSIL or worse cytology and 2) ASC-US or LSIL cytology with unsatisfactory colposcopy. Using a multiple-biopsy colposcopy protocol, we showed that detection of additional CIN 2 or worse by ECC substantially decreases with increasing number of ectocervical biopsies (Table 6).

Considerations for the risk of finding precancers in the endocervix differ by age. In contrast to previous research, we showed that ECC did not yield significantly more disease in unsatisfactory examinations in women 30–44 years old (Table 4). This suggests that for younger women, incomplete visualization of the squamocolumnar junction can be related more to the colposcopist's technique and does not necessarily raise concern for missed disease in the endocervix. Examination technique may attribute less to the incomplete visualization of the squamocolumnar junction in older women, which recedes into the endocervix with postmenopausal decrease of estrogen level. However, our finding of 10.1% CIN 2 or worse yield on ECC in women 20–29 years old implicates that AGC or AIS cytology, unsatisfactory examination as well as discrepancy between HSIL cytology and normal examination remain important considerations for performing ECC in young women. Human papillomavirus-16 positivity in women 45 years old or older should particularly raise concern for persistent oncogenic infection and trigger endocervical sampling at colposcopy. Based on a woman's age, it is important to distinguish the different sets of examination technique and biological factors associated with the risk of endocervical disease.

Given acetowhitening is highly sensitive for the detection of cervical precancers,26 the additional yield of CIN 2 or worse by ECC was less than 10% in our study even when the worst-appearing colposcopic lesion was the only ectocervical biopsy taken. The detection of additional precancers by ECC may appear greater in studies that used biopsy protocols targeting less sensitive lesion characteristics such as mosaicism or punctation. This relationship of ECC yield to biopsy protocols may in part explain the heterogeneity of previous findings regarding yield of ECC in different studies.

Furthermore, presence of endocervical disease may be important in guiding the decision between ablation and excisional treatment. The current U.S. management guideline recommends against ablation in women with significant endocervical disease.12 Our results showed that an unsatisfactory examination in women with low-grade or equivocal cytology warrants endocervical sampling, which may indicate excision rather than ablation therapy in approximately one of every seven or eight women. A high-grade cytology is associated with endocervical disease in approximately one of every four women and also supports performing ECC.

Given the relatively young colposcopy population, the number of women aged 30 years or older was small and limited the statistical power of some of our stratified analyses. The prevalence of HPV-18 infection was low, preventing analyses of the association between HPV-18 infection and endocervical involvement of cervical precancers (data not shown). Human papillomavirus genotyping was performed as part of the research protocol at colposcopy and further analysis of population screened by cytology–HPV contesting is necessary for evaluating ECC in women with normal cytology and high-risk HPV types. Because women younger than 30 years old had to have specific indications for ECC, we were not able to fully evaluate clinical predictors for performing endocervical sampling in this age group. A larger sample size would be needed to calculate more accurately the number needed to treat. Prospective concordance analyses between the histology of excision treatment specimen and ECC performed at colposcopy will better assess the accuracy of the endocervical sampling technique used in this study.

Our study addresses important questions about the role of ECC in colposcopic diagnosis and treatment of cervical precancers. Importantly, not every woman benefitted from the ECC procedure equally. By refining the selection of women for ECC, young women with unsatisfactory examination may be spared a painful procedure, high-risk women with positive ECC will receive appropriate excision treatment to confirm the margin status and minimize missed disease or recurrence, and obstetric complication can be avoided in women with low-grade cytology and intermediate risk of precancers in the endocervix.

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