Abstract
Objective
Assessment of cytology and biopsy results preceding cervical excisional treatment and their association with excisional histology, to evaluate compliance with treatment recommendations and the potential effect of revisions in cervical histology terminology and usage.
Design
Data from a unique statewide population-based screening registry was used to describe the use and histologic outcomes of cervical excisional procedures in the year following an abnormal cervical screening cytology.
Results
From 2007 to 2011, LEEP rates decreased 87%, 45%, and 16% for women aged 15–20, 21–24, and 25–29 years, respectively. Reductions were attributable to an overall decline in cervical screening and colposcopy, and a decrease in LEEP following a diagnosis of less than cervical intraepithelial neoplasia grade 2 (<CIN2) or CIN2 histology preceded by any abnormal cytology other than high-grade squamous intraepithelial lesion (<HSIL). LEEP rates did not change significantly (p > 0.7) for women aged 30–39 years. Irrespective of age, CIN2 was the most common histologic antecedent of excisional treatment (42%), with most (80%) preceded by <HSIL cytology.
Conclusion
Cervical excisions are an unavoidable consequence of cervical screening. Adherence to treatment guidelines stipulating conservative follow-up of young women with biopsies ≤CIN2 could significantly decrease the number of excisional procedures and associated harms. This opportunity will be lost if cervical intraepithelial neoplasia grade 3 (CIN3) and some or all of CIN2 are merged into a single histologic category, as has been recently recommended in the United States.
Keywords: cervical screening, colposcopy, loop electrosurgical excision procedure (LEEP), cervical intraepithelial neoplasia grades 2 and 3 (CIN2 and CIN3), adherence to cervical treatment guidelines, effectiveness and harms of cervical screening
Introduction
In March 2012, the United States Preventive Services Task Force (USPSTF), the American Cancer Society (ACS), the American Society for Colposcopy and Clinical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) released new guidelines recommending cervical screening at three-year intervals starting at age 21, with the option to substitute cytology plus human papillomavirus (HPV) DNA testing (“cotesting”) at five-year intervals starting at the age of 30. The cotesting regimen was preferred for women age 30 and above by all groups except the USPSTF.1,2
These recommendations, and the trend towards less screening over a woman’s lifetime that has been the focus of guideline changes over the past decade, are driven by the recognition that screening is not without harms and that many if not most of the lesions treated as a consequence of screening would not have progressed to cancer.3,4 Sasieni et al. showed that screening women 20–24 years old has no effect on cervical cancer incidence up to age 30.6 For women aged 13–25 years in Kaiser Northern California, 68% of cervical intraepithelial neoplasia grade 2 (CIN2) resolves spontaneously within three years, supporting the recommendation that observation is preferred over treatment in young women.7,8
Concerns have been raised about risks of preterm birth, premature rupture of membranes, low birth-weight, and cesarean section following cervical excisional treatment.9–11 In addition, the discomfort, anxiety, and negative impact on sexual function that have been associated with excisional treatment are of concern in circumstances where treatment may not contribute to cancer prevention. The risk/benefit calculation for treatment is least favorable in young women, prompting the June, 2009, Practice Improvement in Cervical Screening and Management (PICSM) symposium and, subsequently, the American College of Obstetrics and Gynecology (ACOG) to recommend discontinuing cervical screening in women younger than age 21.5 Despite the low risk for cervical precancer (cervical intraepithelial neoplasia grade 3; CIN3) and cervical cancer in young women and the potential harms of excisional procedures, studies involving provider responses to hypothetical clinical scenarios suggest major deviations in cervical screening practice from clinical practice recommendations, with reflex HPV testing done for high-grade cytology, testing for low-risk HPV, and screening annually with all tests regardless of the clinical situation as the most common preference of survey respondents.12–15
Prior to this assessment, the association of cervical screening and excisional treatment has never been investigated in actual practice in the United States (US), and modeling studies are hampered by the assumption that clinical practice guidelines are followed, which the investigations of screening practices cited above suggest may be significantly inaccurate. It is also recognized that self-selection by respondents to studies of clinical vignettes may not produce a representative sample of care providers, and thereby reflect an imperfect view of provider compliance with guideline recommendations. Using data from a population-based statewide surveillance program, we sought to quantify the utilization of excisional treatment associated with cervical screening by age, to infer the actual indications for excisional treatment from the antecedent cytology and biopsy diagnoses, and to examine the diagnostic yield of CIN3+ associated with different combinations of antecedent test results.
Materials and Methods
The New Mexico HPV Pap Registry (NMHPVPR) is located at the University of New Mexico and acts as a designee of the New Mexico Department of Health (NMDOH). The NMHPVPR operates under New Mexico Administrative Code (NMAC) 7.4.3, which specifies the list of Notifiable Diseases and Conditions for the state of New Mexico. In 2006, with the intention of monitoring cervical screening practices and outcomes and the impact of HPV vaccination, NMAC 7.4.3 specified that laboratories must report to the NMHPVPR all cervical or vaginal cytology, cervical pathology, and HPV tests performed on women residing in New Mexico. NMAC 7.4.3 was updated in 2009 to include vulvar and vaginal pathology (http://nmhealth.org/ERD/healthdata/documents/NotifiableDiseasesConditions022912final.pdf). Ongoing evaluations of cervical screening, diagnosis and treatment by the NMHPVPR have been reviewed and approved under exempt status by the University of New Mexico Human Research Review Committee.
In this analysis we used the NMHPVPR database to investigate the use of cervical excisional treatment over the period of 2007 through 2011 in New Mexico among women aged 15–39 years. The majority (80%) of cervical excisional procedures in which the method of excision was described were identified as Loop Electrosurgical Excision Procedure (LEEP). When not identified as LEEP, excisional procedures were generally identified only as cone biopsy (without specifying the excisional method), or infrequently as cold knife conization. Therefore, we elected not to attempt to stratify cervical excisional procedures by method of excision. Hysterectomy and the rarely used trachelectomy were not included as excisional treatment for the purposes of this analysis.
We evaluated the use of cervical excisional treatment by considering the likelihood that a woman would undergo excision within one year of an abnormal screening cervical cytology test with a result of atypical cells of unknown significance (ASC-US) or worse. We defined a screening cervical cytology test as one without any prior cervical cytology within 10 months (300 days) based on our earlier published findings.16 We further restricted this analysis to those screening cytology tests without any preceding abnormal cervical cytology or histology within 15 months, and without any prior excisional procedure in the database. If a woman had more than one such cervical cytology test during the period of 2007–2010 we chose the earliest and refer to this as the “index” screening cytology exam. A total of 39,804 abnormal index screening cytology exams were identified, as were 2,236 excisional procedures in the year following these index screens.
We calculated the proportion of women undergoing excisional treatment within one year of the abnormal index screening cytology within strata defined by the cytologic result of the index screen and the histologic result of the follow-up cervical biopsy or endocervical curettage (ECC). Abnormal cytologic results were classified as ASC-US [negative for high-risk HPV or HPV status unknown], ASC-US + [positive for high-risk HPV; high risk HPV types are based on Hybrid Capture 2 (Germantown, MD, USA) clinical HPV assay results which detect HPV types, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68], low-grade intraepithelial lesion (LSIL), atypical squamous cells-cannot rule out high-grade (ASC-H), atypical glandular cells (AGC), and high-grade intraepithelial lesion (HSIL) and less than HSIL (<HSIL) which included ASC-US, ASC-US+, LSIL, ASC-H, and AGC. Cytologic results of carcinoma were classified as HSIL. The HPV status of ASC-US results was determined by linking the index cytology with a separate database of HPV tests.
Cervical biopsy results were classified as negative, cervical intraepithelial neoplasia grades 1, 2 and 3 (CIN1, CIN2, CIN3), carcinoma in situ (CIS), adenocarcinoma in situ (AIS), and cancer. The histologic interpretation CIN1-2 is included with CIN2, and CIN2-3 is included with CIN3. This is believed to represent current clinical practice, provides the most charitable view of the indications for excisional treatment, and recognizes the reported irreproducibility of these histologic designations, though it is understood that there is, at present, no published data about subsequent cancer risk to validate these choices.
We also computed population rates of cervical excision for the period 2007–2011. These rates were computed as the number of women treated in a given calendar year per 10,000 women in the population and also per 10,000 women receiving a screening cervical cytology test. New Mexico population counts are US Census estimates (www.census.gov). Using the 2007–2010 Centers for Disease Control bridged-race population files, 42.2% of NM women were non-Hispanic white, 42.2% were Hispanic white, 3.0% were African American, 10.5% were American Indian, and 1.9% were Asian.
Data analysis was conducted using SAS version 9.3. Confidence intervals for population excisional treatment rates are based on normal approximation and all confidence intervals for proportions are exact. Significance testing with the Cochran-Armitage test of linear trend was employed to discern changes over time.
Results
The rate of excisional treatment for cervical abnormalities decreased in New Mexico over the period 2007–2011 for women < 30 years of age (Table 1). The decrease was greatest for women aged 15–20 years, where the excision rate declined by 87%. The excision rate in women aged 21–24 years decreased by 45%, and in women aged 25–29 years by 16%. Excision rates did not change significantly (p > 0.7) for women aged 30–39 years. Although screening rates declined over this period, excisional rates per 10,000 women screened also decreased significantly (p < 0.0001) for women aged 15–24 years.
Table 1.
Cervical excision (LEEP) rates in New Mexico for women 15–39 years old, 2007–2011*
| Age | Year | LEEPs | LEEPs per 10,000 women | LEEPs per 10,000 women screened | ||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Women | Rate | (95% CI) | Women screened | Rate | (95% CI) | |||
| 15–20 y | 2007 | 158 | 87,944 | 18·0 | (15·2–20·8) | 21,068 | 75·0 | (63·3–86·7) |
| 2008 | 118 | 87,830 | 13·4 | (11·0–15·9) | 19,735 | 59·8 | (49·0–70·6) | |
| 2009 | 77 | 87,679 | 8·8 | (6·8–10·7) | 17,902 | 43·0 | (33·4–52·6) | |
| 2010 | 29 | 87,610 | 3·3 | (2·1–4·5) | 11,261 | 25·8 | (16·4–35·1) | |
| 2011 | 20 | 85,420 | 2·3 | (1·3–3·4) | 7,288 | 27·4 | (15·4–39·5) | |
| p < 0·0001 | p < 0·0001 | |||||||
| 21–24 y | 2007 | 278 | 54,696 | 50·8 | (44·9–56·8) | 24,272 | 114·5 | (101·1–128·0) |
| 2008 | 240 | 54,824 | 43·8 | (38·2–49·3) | 23,745 | 101·1 | (88·3–113·9) | |
| 2009 | 265 | 54,825 | 48·3 | (42·5–54·2) | 22,827 | 116·1 | (102·1–130·1) | |
| 2010 | 180 | 54,941 | 32·8 | (28·0–37·5) | 21,494 | 83·7 | (71·5–96·0) | |
| 2011 | 160 | 56,925 | 28·1 | (23·8–32·5) | 20,550 | 77·9 | (65·8–89·9) | |
| p < 0·0001 | p < 0·0001 | |||||||
| 25–29 y | 2007 | 270 | 66,629 | 40·5 | (35·7–45·4) | 28,780 | 93·8 | (82·6–105·0) |
| 2008 | 301 | 67,363 | 44·7 | (39·6–49·7) | 29,080 | 103·5 | (91·8–115·2) | |
| 2009 | 329 | 67,971 | 48·4 | (43·2–53·6) | 28,457 | 115·6 | (103·1–128·1) | |
| 2010 | 266 | 68,306 | 38·9 | (34·3–43·6) | 26,888 | 98·9 | (87·0–110·8) | |
| 2011 | 236 | 69,169 | 34·1 | (29·8–38·5) | 25,673 | 91·9 | (80·2–103·7) | |
| p = 0·02 | p = 0·7 | |||||||
| 30–34 y | 2007 | 185 | 58,603 | 31·6 | (27·0–36·1) | 24,438 | 75·7 | (64·8–86·6) |
| 2008 | 203 | 59,205 | 34·3 | (29·6–39·0) | 24,502 | 82·9 | (71·5–94·2) | |
| 2009 | 200 | 61,055 | 32·8 | (28·2–37·3) | 24,026 | 83·2 | (71·7–94·8) | |
| 2010 | 190 | 63,234 | 30·0 | (25·8–34·3) | 23,554 | 80·7 | (69·2–92·1) | |
| 2011 | 210 | 64,717 | 32·4 | (28·1–36·8) | 22,392 | 93·8 | (81·1–106·5) | |
| p = 0·7 | p = 0·07 | |||||||
| 35–39 y | 2007 | 130 | 62,665 | 20·7 | (17·2–24·3) | 23,170 | 56·1 | (46·5–65·8) |
| 2008 | 132 | 62,543 | 21·1 | (17·5–24·7) | 22,936 | 57·6 | (47·7–67·4) | |
| 2009 | 127 | 62,645 | 20·3 | (16·7–23·8) | 22,293 | 57·0 | (47·1–66·9) | |
| 2010 | 113 | 61,762 | 18·3 | (14·9–21·7) | 20,366 | 55·5 | (45·3–65·7) | |
| 2011 | 129 | 60,634 | 21·3 | (17·6–24·9) | 19,013 | 67·8 | (56·1–79·6) | |
| p = 0·8 | p = 0·2 | |||||||
| Total | 2007 | 1,021 | 330,537 | 30·9 | (29·0–32·8) | 121,728 | 83·9 | (78·7–89·0) |
| 2008 | 994 | 331,765 | 30·0 | (28·1–31·8) | 119,998 | 82·8 | (77·7–88·0) | |
| 2009 | 998 | 334,175 | 29·9 | (28·0–31·7) | 115,505 | 86·4 | (81·0–91·8) | |
| 2010 | 778 | 335,853 | 23·2 | (21·5–24·8) | 103,563 | 75·1 | (69·8–80·4) | |
| 2011 | 755 | 336,865 | 22·4 | (20·8–24·0) | 94,916 | 79·5 | (73·9–85·2) | |
| p < 0·0001 | p < 0·06 | |||||||
p-values are for test of trend in rates over the five year period.
Table 2 gives the number of abnormal index cervical cytology tests by age and result, and shows the follow-up over a period of 12 months. Follow-up has been classified hierarchically as colposcopy with cervical biopsy and/or ECC, else other gynecologic procedure, else follow-up cytology only, else no-follow-up. Other gynecologic procedures include endometrial biopsies, vaginal and vulvar biopsies, and hysterectomies. A small percent (6.6%) of women who underwent excision and had no cervical biopsy or ECC prior to the excision are included in the colposcopic biopsy follow-up category, given that they received histologic evaluation of their cytologic abnormalities. Colposcopies without biopsy or ECC are not reported to the NMHPVPR.
Table 2.
One year follow-up of abnormal index cervical screen*
| Colposcopy with cervical biopsy/ECC | Other gynecologic procedure | Follow-up cytology only | No follow-up | ||||
|---|---|---|---|---|---|---|---|
|
| |||||||
| Ages | Cytology | n | % | % | % | % | % |
| 15–20 y | ASC-US | 2,329 | 23·9 | 5·4 | 0·1 | 25·3 | 69·2 |
| ASC-US+ | 2,643 | 27·2 | 28·8 | 0·3 | 22·0 | 49·0 | |
| LSIL | 4,160 | 42·7 | 35·6 | 0·4 | 18·9 | 45·1 | |
| ASC-H | 316 | 3·2 | 49·7 | 0·0 | 16·8 | 33·5 | |
| HSIL | 234 | 2·4 | 73·5 | 0·0 | 10·3 | 16·2 | |
| AGC | 49 | 0·5 | 55·1 | 0·0 | 12·2 | 32·7 | |
| 21–24 y | ASC-US | 2,759 | 27·1 | 8·3 | 0·6 | 29·1 | 62·1 |
| ASC-US+ | 2,839 | 27·9 | 50·8 | 0·3 | 16·3 | 32·6 | |
| LSIL | 3,641 | 35·8 | 54·2 | 0·4 | 15·7 | 29·8 | |
| ASC-H | 441 | 4·3 | 57·8 | 1·1 | 12·7 | 28·3 | |
| HSIL | 383 | 3·8 | 73·4 | 0·3 | 8·1 | 18·3 | |
| AGC | 104 | 1·0 | 53·8 | 1·0 | 18·3 | 26·9 | |
| 25–29 y | ASC-US | 3,012 | 33·1 | 7·0 | 1·3 | 27·7 | 63·9 |
| ASC-US+ | 2,303 | 25·3 | 58·0 | 0·3 | 15·7 | 26·0 | |
| LSIL | 2,707 | 29·7 | 58·6 | 0·7 | 13·6 | 27·1 | |
| ASC-H | 444 | 4·9 | 65·8 | 0·7 | 10·1 | 23·4 | |
| HSIL | 464 | 5·1 | 77·8 | 0·4 | 6·3 | 15·5 | |
| AGC | 171 | 1·9 | 56·1 | 0·6 | 11·7 | 31·6 | |
| 30–34 y | ASC-US | 2,552 | 41·9 | 7·0 | 2·5 | 25·5 | 65·0 |
| ASC-US+ | 1,268 | 20·8 | 64·4 | 1·0 | 10·9 | 23·7 | |
| LSIL | 1,444 | 23·7 | 62·5 | 0·6 | 12·8 | 24·1 | |
| ASC-H | 323 | 5·3 | 68·4 | 0·3 | 12·1 | 19·2 | |
| HSIL | 306 | 5·0 | 76·1 | 1·0 | 6·2 | 16·7 | |
| AGC | 196 | 3·2 | 60·2 | 3·6 | 11·7 | 24·5 | |
| 35–39 y | ASC-US | 2,331 | 49·4 | 5·9 | 3·7 | 23·6 | 66·8 |
| ASC-US+ | 802 | 17·0 | 64·1 | 2·1 | 12·3 | 21·4 | |
| LSIL | 923 | 19·6 | 63·8 | 1·7 | 11·9 | 22·5 | |
| ASC-H | 226 | 4·8 | 73·5 | 2·2 | 9·7 | 14·6 | |
| HSIL | 224 | 4·7 | 79·5 | 2·2 | 4·5 | 13·8 | |
| AGC | 210 | 4·5 | 67·1 | 5·2 | 8·6 | 19·0 | |
| Total | ASC-US | 12,983 | 32·6 | 6·8 | 1·6 | 26·4 | 65·2 |
| ASC-US+ | 9,855 | 24·8 | 49·4 | 0·5 | 16·7 | 33·4 | |
| LSIL | 12,875 | 32·3 | 50·7 | 0·6 | 15·7 | 33·0 | |
| ASC-H | 1,750 | 4·4 | 62·3 | 0·8 | 12·3 | 24·6 | |
| HSIL | 1,611 | 4·0 | 76·0 | 0·7 | 7·0 | 16·3 | |
| AGC | 730 | 1·8 | 60·0 | 2·7 | 11·8 | 25·5 | |
Follow-up classification is hierarchical: colposcopy with cervical biopsy or endocervical curettage (ECC), else other gynecologic procedure, else follow-up cytology, else no follow-up. Colposcopy without biopsy or curettage is not ascertained by the New Mexico HPV Pap Registry (NMHPVPR). Women with LEEP and no preceding colposcopy are included in the colposcopy category. Other gynecologic procedures include endometrial, vaginal, and vulvar biopsies and hysterectomies. Follow-up cytology is defined as cervical cytology within 300 days of the index cytology. Cytologic results are as follows: atypical squamous cells of unknown significance (ASC-US) is negative for high-risk human papillomavirus (HPV) or HPV status unknown, ASC-US + is positive for high-risk HPV defined as positive for one or more HPV types including, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68, low-grade intraepithelial lesion (LSIL), atypical squamous cells-cannot rule out high-grade (ASC-H), atypical glandular cells (AGC), and high-grade intraepithelial lesion (HSIL)
Follow-up with colposcopy and cervical biopsy/ECC increases with age for all categories of cytologic result except for ASC-US [HPV negative or unknown] and HSIL (Figure 1). Follow-up by only repeat cytology after an abnormal cytology of LSIL or worse was more common among younger women. Notably, 10.3% of women aged 15–20 years with HSIL cytology were followed only by repeat cytology compared to 4.5% of women aged 35–39 years. Similarly, lack of follow-up of any kind was more common among younger women, particularly among those with LSIL or ASC-H cytology. There was little change between 2007 and 2010 in the percent of women with ASC-US+ or worse cytology receiving follow-up colposcopy with biopsy, except for women 15–20 years of age (Figure 2A). In this age group, follow-up with colposcopy and biopsy decreased significantly from 46% in 2007 to 26% in 2010 (p<0.0001). The proportion of women aged <21 years with preceding abnormal cytology was as expected and was similar to that observed for other age groups. For the period of 2007–2011, 43.8% of women aged 15–20 years had a prior cytology within 3 years of the screening cytology and 8.2% had a prior abnormal cytology within 3 years. For the more recent period of 2009–2011, 48.6% had a prior cytology within 3 years of the screening cytology and 10.0% had a prior abnormal cytology within 3 years.
Figure 1.
(A) Percent of women with colposcopic biopsy or endocervical curettage (ECC) within 12 months of abnormal index screening cytology by age of woman and result of cytology. Cytology results are classified as ASC-US [atypical squamous cells of undetermined significance, negative for high-risk human papillomavirus (HPV) or HPV status unknown], ASC-US+ [ASC-US, positive for high-risk HPV], LSIL [low-grade squamous intraepithelial lesion], ASC-H [atypical squamous cells-cannot rule out high-grade], and HSIL [high-grade squamous intraepithelial lesion].
Figure 2.
(A). Percent of women with colposcopic biopsy or endocervical curettage (ECC) within 12 month of index screening cytology with result of ASC-US+ [atypical squamous cells of unknown significance, high-risk human papillomavirus (HPV) positive] or more severe by age of woman and year of cytology. (B). Percent of women receiving excisional treatment (LEEP) following colposcopic biopsy or endocervical curettage (ECC) with diagnosis of negative, cervical intraepithelial neoplasia grade 1 (CIN1), or cervical intraepithelial neoplasia grade 2 (CIN2) accompanied by less than high-grade squamous intraepithelial lesion (<HSIL) cytology. (C). Percent of excisional treatment (LEEP) with diagnosis of CIN3+ [CIN grade 3 or worse] by age of women and year of biopsy.
Table 3 displays the likelihood, by age category and overall (ages 15–39 years), that a woman with a specific cervical cytology and histology result will undergo a cervical excisonal procedure in the following 12 months. As expected, excisional treatment increased with severity of the preceding cervical histology. The cytology result had no significant effect on the likelihood of excisional treatment for CIN2 and CIN3+ histology, but was a significant factor for CIN1 and negative histology. Excisional treatment increased with age in all categories. Table 3 reveals the importance of the combination of a CIN2 biopsy and a cytology result less than HSIL (<HSIL) as an indication for excision. The likelihood of excision following this combination of histology and cytology results increased from 32.6% at age 15–20 years to 67.8% at age 35–39 years, and preceded fully one-third (746 of 2,236) of all excisional procedures in women aged 15–39 years. Independent of the associated cytology result, CIN2 was the most common histologic antecedent of excisional treatment, preceding 41.8% (935 of 2,236) of all excisional treatments. For women with CIN2 biopsy, 7.4% had a prior abnormal cytology within 3 years. The rate of excisional treatment for these women was 56.9% compared to 46.5% for women without prior abnormal cytology. Very few of these women had persistent CIN. For the period of 2007–2010, 32 of the 1,968 women with CIN2 had CIN1 or greater on a prior biopsy within 3 years. When restricting to the more recent period of 2009–2010, 9 of 861 women with CIN2 had a CIN1 or greater result on a prior biopsy within 3 years. The median length of follow-up for women with CIN2 was 316 days and 90% were in the range of 62 to 350 days. For comparison, the median number of days between a CIN2 biopsy and excisional treatment was 43 days.
Table 3.
LEEP within one year of abnormal index screen by cytological result and result of follow-up cervical biopsy*
| Age | Histology | Cytology | Screens | LEEP | CIN3+ yield | ||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| n | % | (95% CI) | n | % | (95% CI) | ||||
| 15–20 y | CIN3+ | HSIL | 38 | 20 | 52·6 | (35·8–69·0) | 11 | 55·0 | (31·5–76·9) |
| <HSIL | 88 | 46 | 52·3 | (41·4–63·0) | 17 | 37·0 | (23·2–52·5) | ||
| CIN2 | HSIL | 72 | 21 | 29·2 | (19·0–41·1) | 4 | 19·0 | (5·4–41·9) | |
| <HSIL | 261 | 85 | 32·6 | (26·9–38·6) | 16 | 18·8 | (11·2–28·8) | ||
| CIN1 | HSIL | 72 | 8 | 11·1 | (4·9–20·7) | 0 | 0·0 | (0·0–36·9) | |
| <HSIL | 1,401 | 25 | 1·8 | (1·2–2·6) | 1 | 4·0 | (0·1–20·4) | ||
| Negative | HSIL | 36 | 2 | 5·6 | (0·7–18·7) | 0 | 0·0 | (0·0–84·2) | |
| <HSIL | 725 | 2 | 0·3 | (0·0–1·0) | 0 | 0·0 | (0·0–84·2) | ||
| No biopsy | HSIL | 92 | 4 | 4·3 | (1·2–10·8) | 1 | 25·0 | (0·6–80·6) | |
| <HSIL | 6,946 | 13 | 0·2 | (0·1–0·3) | 2 | 15·4 | (1·9–45·4) | ||
| 21–24 y | CIN3+ | HSIL | 105 | 59 | 56·2 | (46·2–65·9) | 49 | 83·1 | (71·0–91·6) |
| <HSIL | 178 | 120 | 67·4 | (60·0–74·2) | 64 | 53·3 | (44·0–62·5) | ||
| CIN2 | HSIL | 98 | 47 | 48·0 | (37·8–58·3) | 14 | 29·8 | (17·3–44·9) | |
| <HSIL | 503 | 219 | 43·5 | (39·2–48·0) | 39 | 17·8 | (13·0–23·5) | ||
| CIN1 | HSIL | 84 | 12 | 14·3 | (7·6–23·6) | 2 | 16·7 | (2·1–48·4) | |
| <HSIL | 1,989 | 34 | 1·7 | (1·2–2·4) | 0 | 0·0 | (0·0–10·3) | ||
| Negative | HSIL | 51 | 10 | 19·6 | (9·8–33·1) | 4 | 40·0 | (12·2–73·8) | |
| <HSIL | 1,188 | 4 | 0·3 | (0·1–0·9) | 0 | 0·0 | (0·0–60·2) | ||
| No biopsy | HSIL | 129 | 8 | 6·2 | (2·7–11·9) | 4 | 50·0 | (15·7–84·3) | |
| <HSIL | 5,842 | 18 | 0·3 | (0·2–0·5) | 3 | 16·7 | (3·6–41·4) | ||
| 25–29 y | CIN3+ | HSIL | 155 | 94 | 60·6 | (52·5–68·4) | 77 | 81·9 | (72·6–89·1) |
| <HSIL | 217 | 141 | 65·0 | (58·2–71·3) | 69 | 48·9 | (40·4–57·5) | ||
| CIN2 | HSIL | 123 | 67 | 54·5 | (45·2–63·5) | 20 | 29·9 | (19·3–42·3) | |
| <HSIL | 456 | 234 | 51·3 | (46·6–56·0) | 37 | 15·8 | (11·4–21·1) | ||
| CIN1 | HSIL | 87 | 20 | 23·0 | (14·6–33·2) | 5 | 25·0 | (8·7–49·1) | |
| <HSIL | 1,562 | 64 | 4·1 | (3·2–5·2) | 7 | 10·9 | (4·5–21·2) | ||
| Negative | HSIL | 45 | 11 | 24·4 | (12·9–39·5) | 4 | 36·4 | (10·9–69·2) | |
| <HSIL | 1,174 | 6 | 0·5 | (0·2–1·1) | 3 | 50·0 | (11·8–88·2) | ||
| No biopsy | HSIL | 141 | 21 | 14·9 | (9·5–21·9) | 12 | 57·1 | (34·0–78·2) | |
| <HSIL | 5,141 | 24 | 0·5 | (0·3–0·7) | 5 | 20·8 | (7·1–42·2) | ||
| 30–34 y | CIN3+ | HSIL | 121 | 77 | 63·6 | (54·4–72·2) | 61 | 79·2 | (68·5–87·6) |
| <HSIL | 156 | 112 | 71·8 | (64·0–78·7) | 67 | 59·8 | (50·1–69·0) | ||
| CIN2 | HSIL | 59 | 33 | 55·9 | (42·4–68·8) | 15 | 45·5 | (28·1–63·6) | |
| <HSIL | 242 | 126 | 52·1 | (45·6–58·5) | 24 | 19·0 | (12·6–27·0) | ||
| CIN1 | HSIL | 35 | 8 | 22·9 | (10·4–40·1) | 0 | 0·0 | (0·0–36·9) | |
| <HSIL | 968 | 53 | 5·5 | (4·1–7·1) | 3 | 5·7 | (1·2–15·7) | ||
| Negative | HSIL | 28 | 9 | 32·1 | (15·9–52·4) | 5 | 55·6 | (21·2–86·3) | |
| <HSIL | 819 | 7 | 0·9 | (0·3–1·8) | 1 | 14·3 | (0·4–57·9) | ||
| No biopsy | HSIL | 99 | 13 | 13·1 | (7·2–21·4) | 8 | 61·5 | (31·6–86·1) | |
| <HSIL | 3,562 | 17 | 0·5 | (0·3–0·8) | 5 | 29·4 | (10·3–56·0) | ||
| 35–39 y | CIN3+ | HSIL | 89 | 55 | 61·8 | (50·9–71·9) | 42 | 76·4 | (63·0–86·8) |
| <HSIL | 119 | 73 | 61·3 | (52·0––70·1) | 48 | 65·8 | (53·7–76·5) | ||
| CIN2 | HSIL | 43 | 21 | 48·8 | (33·3–64·5) | 6 | 28·6 | (11·3––52·2) | |
| <HSIL | 121 | 82 | 67·8 | (58·7–76·0) | 15 | 18·3 | (10·6–28·4) | ||
| CIN1 | HSIL | 22 | 6 | 27·3 | (10·7–50·2) | 3 | 50·0 | (11·8–88·2) | |
| <HSIL | 602 | 48 | 8·0 | (5·9–10·4) | 2 | 4·2 | (0·5–14·3) | ||
| Negative | HSIL | 31 | 14 | 45·2 | (27·3––64·0) | 4 | 28·6 | (8·4–58·1) | |
| <HSIL | 654 | 9 | 1·4 | (0·6–2·6) | 0 | 0·0 | (0·0–33·6) | ||
| No biopsy | HSIL | 66 | 14 | 21·2 | (12·1–33·0) | 10 | 71·4 | (41·9–91·6) | |
| <HSIL | 2,969 | 20 | 0·7 | (0·4–1·0) | 6 | 30·0 | (11·9–54·3) | ||
| Total | CIN3+ | HSIL | 508 | 305 | 60·0 | (55·6–64·3) | 240 | 78·7 | (73·7–83·1) |
| <HSIL | 758 | 492 | 64·9 | (61·4–68·3) | 265 | 53·9 | (49·3–58·3) | ||
| CIN2 | HSIL | 395 | 189 | 47·8 | (42·8–52·9) | 59 | 31·2 | (24·7–38·3) | |
| <HSIL | 1,583 | 746 | 47·1 | (44·6–49·6) | 131 | 17·6 | (14·9–20·5) | ||
| CIN1 | HSIL | 300 | 54 | 18·0 | (13·8–22·8) | 10 | 18·5 | (9·3–31·4) | |
| <HSIL | 6,522 | 224 | 3·4 | (3·0–3·9) | 13 | 5·8 | (3·1–9·7) | ||
| Negative | HSIL | 191 | 46 | 24·1 | (18·2–30·8) | 17 | 37·0 | (23·2–52·5) | |
| <HSIL | 4,560 | 28 | 0·6 | (0·4–0·9) | 4 | 14·3 | (4·0–32·7) | ||
| No biopsy | HSIL | 527 | 60 | 11·4 | (8·8–14·4) | 35 | 58·3 | (44·9–70·9) | |
| <HSIL | 24,460 | 92 | 0·4 | (0·3–0·5) | 21 | 22·8 | (14·7–32·8) | ||
Histology result is the most severe diagnosis from any cervical biopsy or ECC done after the index cytology and before the LEEP. Cytology result is the most severe diagnosis from the index cytology and any follow-up cytology done before LEEP. Cervical intraepithelial neoplasia grade 3 (CIN3+) includes CIN3, CIN grade 2–3 (CIN2-3), carcinoma in situ (CIS), adenocarcinoma in situ (AIS), and cancer; Cervical Intraepithelial neoplasia grade 2 (CIN2) includes CIN2 and CIN grade (1–2); abbreviations for cytologic results are as outlined in Table 2, less than high-grade squamous intraepithelial lesions (<HSIL) cytology includes ASC-US, ASC-US+, LSIL, ASC-H, and AGC.
Although LEEPS performed within one year of the index cytology accounted for the majority (70%), some women received LEEP treatment more than one year after the index cytology. In the second year following the index cytology, the percent of women receiving LEEP increased from 35·2% at 12 months to 39% at 24 months for HSIL cytology, from 17·9% to 21·1% for ASC-H, from 5·3% to 6·7% for ASC-US+ [high-risk HPV positive] and LSIL combined, from 9·6% to 11·2% for AGC, and from 0·5% to 1·1% for ASC-US [high-risk HPV negative or unknown].
Histology results of CIN2-3 (n=317), which are combined with CIN3+ in Table 3, were followed by excision in 60.3% of cases, which was similar to that for CIN3+ excluding CIN2-3 (64.0 %). The percent of excisions that were diagnosed as CIN3+ was also similar (55.5% for CIN2-3 vs. 64.5% for CIN3+ excluding CIN2-3).
The percentage of excisional specimens with CIN3 or greater histology (“CIN3+ yield”) is also reported in Table 3. CIN3+ yield increased not only with the severity of the preceding histology, but also with the severity of the preceding cytology. With few exceptions CIN3+ yield from excision was significantly greater when preceded by HSIL cytology than by <HSIL cytology.
Time trends in use of excision over the period 2007–2010 are shown in Table 4 and Figure 2B, stratified by age and preceding cytology/histology. The overall use of excision decreased for women aged 15–24 years but was limited to those with <HSIL cytology and/or biopsy results <CIN2. Among women aged 25–39 years, the reduction in use of excision was seen only for those with <HSIL cytology. Because of the decrease in screening at all ages and decrease in referral to colposcopy, the absolute number of excisions decreased in all categories and age groups. Notably the proportion of LEEPs that were CIN3+ increased from 10·3% to 52·4% (p<0·0001) in women aged 15–20 years but this proportion remained unchanged in older women (Figure 2C).
Table 4.
Time trends in percent of abnormal index cytology followed by a LEEP within one year*
| Histology | Cytology | Year | 15–24 y | 25–39 y | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| LEEPs | LEEPs | |||||||||
| Screens | N | % | (95% CI) | Screens | N | % | (95% CI) | |||
| CIN3+ | HSIL | 2007 | 37 | 20 | 54·1 | (36·9–70·5) | 98 | 72 | 73·5 | (63·6–81·9) |
| 2008 | 48 | 30 | 62·5 | (47·4–76·0) | 98 | 59 | 60·2 | (49·8–70·0) | ||
| 2009 | 31 | 15 | 48·4 | (30·2–66·9) | 92 | 49 | 53·3 | (42·6–63·7) | ||
| 2010 | 27 | 14 | 51·9 | (31·9–71·3) | 77 | 46 | 59·7 | (47·9–70·8) | ||
| <HSIL | 2007 | 76 | 46 | 60·5 | (48·6–71·6) | 101 | 70 | 69·3 | (59·3–78·1) | |
| 2008 | 70 | 50 | 71·4 | (59·4–81·6) | 129 | 81 | 62·8 | (53·8–71·1) | ||
| 2009 | 70 | 38 | 54·3 | (41·9–66·3) | 128 | 91 | 71·1 | (62·4–78·8) | ||
| 2010 | 50 | 32 | 64·0 | (49·2–77·1) | 134 | 84 | 62·7 | (53·9–70·9) | ||
| CIN2 | HSIL | 2007 | 63 | 21 | 33·3 | (22·0–46·3) | 59 | 32 | 54·2 | (40·8–67·3) |
| 2008 | 50 | 25 | 50·0 | (35·5–64·5) | 65 | 43 | 66·2 | (53·4–77·4) | ||
| 2009 | 28 | 10 | 35·7 | (18·6–55·9) | 63 | 30 | 47·6 | (34·9–60·6) | ||
| 2010 | 29 | 12 | 41·4 | (23·5–61·1) | 38 | 16 | 42·1 | (26·3–59·2) | ||
| <HSIL | 2007 | 237 | 100 | 42·2 | (35·8–48·8) | 213 | 117 | 54·9 | (48·0–61·7) | |
| 2008 | 229 | 101 | 44·1 | (37·6–50·8) | 201 | 121 | 60·2 | (53·1–67·0) | ||
| 2009 | 166 | 67 | 40·4 | (32·8–48·2) | 202 | 110 | 54·5 | (47·3–61·5) | ||
| 2010 | 132 | 36 | 27·3 | (19·9–35·7) | 203 | 94 | 46·3 | (39·3–53·4) | ||
| CIN1, Negative, no biopsy | HSIL | 2007 | 167 | 21 | 12·6 | (8·0–18·6) | 172 | 33 | 19·2 | (13·6–25·9) |
| 2008 | 123 | 11 | 8·9 | (4·5–15·4) | 141 | 33 | 23·4 | (16·7–31·3) | ||
| 2009 | 103 | 9 | 8·7 | (4·1–15·9) | 134 | 28 | 20·9 | (14·4–28·8) | ||
| 2010 | 71 | 3 | 4·2 | (0·9–11·9) | 107 | 22 | 20·6 | (13·4–29·5) | ||
| <HSIL | 2007 | 5,122 | 32 | 0·6 | (0·4–0·9) | 4,686 | 97 | 2·1 | (1·7–2·5) | |
| 2008 | 4,843 | 35 | 0·7 | (0·5–1·0) | 4,411 | 72 | 1·6 | (1·3–2·1) | ||
| 2009 | 4,613 | 16 | 0·3 | (0·2–0·6) | 4,376 | 43 | 1·0 | (0·7–1·3) | ||
| 2010 | 3,513 | 13 | 0·4 | (0·2–0·6) | 3,978 | 36 | 0·9 | (0·6–1·3) | ||
Histology result is the most severe diagnosis from any cervical biopsy or ECC done after the index cytology and before the LEEP. Cytology result is the most severe diagnosis from the index cytology and any follow-up cytology done before LEEP. Abbreviations are as detailed for Table 3, CIN3+ includes CIN3, CIN2-3, CIS, AIS, and cancer; CIN2 includes CIN2 and CIN1-2; <HSIL cytology includes ASC-US, ASC-US+, LSIL, ASC-H, and AGC.
Comment
Taken together, these data show some grounds for optimism about the effect of clinical practice guidelines on the care provided to young women. The decrease in cervical screening from 2009 to 2011 and the 87% decrease in excisions performed per 10,000 women aged 15–20 years are encouraging, as is the 45% reduction in LEEPs in women aged 21–24 years. Furthermore, follow-up of abnormal screens with colposcopy and biopsy in women aged 15–20 years declined by more than 40% from 2007 to 2010. Also reassuring is the reduction in the use of excision following biopsies of <CIN2, and biopsies of CIN2 with <HSIL cytology in women aged 15–24 years. Longitudinal follow-up of the New Mexico population through the NMHPVPR provides a unique opportunity to evaluate real world clinical practice versus cervical screening guidelines and to measure the impact on population-based disease outcomes. These data will become increasingly important to estimating the impact and effectiveness of HPV vaccination given the concurrent changing landscape of cervical screening in the United States must be considered.
Despite the documented progress, screening and treatment of women below the age of 21 years continues to occur. Adherence to current US cervical screening guidelines would eliminate screening in these women, and would eliminate most excisional procedures in the event that screening was undertaken. While the benefit of cervical screening at age 21–24 years is difficult to demonstrate, the negative consequences in terms of the number of excisional procedures performed are measurable. Moscicki et al reported that 68% of CIN2 diagnosed in the community hospital setting at ages 13–25 years remits spontaneously in a 36 month period which is consistent with reports from the ALTS experience. 7,17 Although it is recognized that the diagnosis of individual cases of CIN2 is poorly reproducible,18 from the population perspective the distinction of CIN2 from CIN3 appears to confer significantly different risk of the presence of CIN3+ on LEEP histology and, therefore, to have potential clinical benefits, particularly for the purpose of avoiding overtreatment of younger women.
The observation concerning the importance of CIN2 as an antecedent to excision is accentuated by the recognition that our analyses did not include the diagnosis of CIN2-3 within the CIN2 category, despite the fact that observation in place of treatment is also regarded as an option for “adolescents and young women” with CIN2-3. 19 While a minority of the CIN2 were associated with HSIL cytology, the fact that almost half of excisions in women 15–39 years (1,090 of 2,236) were preceded by <HSIL cytology and biopsies of ≤CIN2, suggests that there is an opportunity to significantly decrease the harms of screening but only if the current distinctions of CIN2 and CIN3 diagnostic categories are fully maintained versus grouping as “high-grade” histology not otherwise specified.
In contrast, the potential grouping of CIN2 and <CIN2 biopsies together as “low-grade” is supported by the observation that low versus high grade cytology differentiates the risk of finding CIN3+ on LEEP histology more effectively than CIN2 versus <CIN2 on biopsy. A biopsy of <CIN2 and HSIL cytology carries as much risk as CIN2 and HSIL cytology. These observations are consistent with the recent recognition of the imperfect sensitivity of colposcopy20,21 and suggestions for improvement.22–23 Furthermore, the unsurprising demonstration that the grade of the antecedent cytology effectively predicts risk of CIN3+ in women with CIN2 provides a method of discerning the potential benefit of excisional treatment without requiring additional testing, and should be considered in the evolution of clinical guidelines to promote conservative management of young women with biopsies less than CIN3 following cytology less severe than HSIL.
The strengths of these observations lie in their completeness, data quality, longitudinal nature, and scope. Colposcopies without biopsy, and cervical treatment by methods that do not produce a histologic specimen (cryotherapy and laser ablation, for example) are not reported to the NMHPVPR, which limits assessment of the completeness of follow-up and treatment of abnormal test results. An additional weakness is the geographical restriction to New Mexico, which may not reflect clinical practice elsewhere in the US. In the absence of any other data sources about actual fee-for-service clinical practice in the United States, assertions about generalizability cannot be made or refuted. The development of programs similar to the NMHPVPR in other states should be a priority, and would serve to inform provider education, assessment of the “real world” risks and benefits of screening, and conceivably influence reimbursement policy.
The NMHPVPR data presented here does provide guidance about cervical excision as a consequence of cervical screening at different ages. If screening is going to continue in the US at ages <25 years, then these data show that a significant number of the excisions in the younger age groups could be avoided, a benefit of optimal adherence to current clinical practice guidelines. Importantly these data also suggest that the proposal for changes regarding categories for cervical histology that equate CIN3 with all or part of CIN224 obviates the ability to manage CIN3 differently than CIN2 or CIN2/3. The newly recommended use of p16 to in effect predict risk and clinical course does not resolve this issue, as there is no data on natural history and disease outcomes stratified by p16 status, and much of the p16 positive CIN2 must also be regressive based on the high rates of regression observed in CIN2 unqualified by p16 testing.7,18 If these recommendations are implemented (i.e., CIN2 and CIN3 are grouped as “high-grade” without the optional specification of CIN grade), then reduction of the potential harms associated with screening women in their childbearing years can only be realized by decreasing screening itself, rather than encouraging more appropriate responses to the lesser histologic abnormalities that precede the majority of LEEPs in the youngest women.
RESEARCH HIGLIGHTS.
A biopsy of <CIN2 with HSIL cytology carried as much risk for CIN3+ on LEEP as did CIN2 with HSIL cytology.
CIN2 and cytology <HSIL preceded more LEEPs than any other combination in every age group studied.
The opportunity to reduce excisional harm will be lost if CIN3 and CIN2 are merged into a single histologic category.
Acknowledgments
Evaluations reported in this publication were funded by the U.S. National Institute of Allergy And Infectious Diseases (NIAID) and the U.S. National Cancer Institute (NCI) under cooperative agreements U19AI084081 and U54CA164336 to CMW. The NIAID and NCI had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. National Institutes of Health. The authors had full access to the data and had final responsibility for the decision to submit for publication. The authors (WC, WCH, HD, MR, JC and CMW) had access to the data, reviewed, provided input and approved the final manuscript submitted for publication. Walter Kinney MD and Cosette Wheeler PhD created the concept of the manuscript. Walter Kinney MD and Helen Dinkelspiel MD wrote the manuscript that was reviewed and modified by all authors. William C. Hunt performed the data extraction and analyses. Members of the New Mexico HPV Pap Registry (NMHPVPR) Steering Committee gave input to the manuscript concepts and supported the directions of the NMHPVPR including the evaluations presented in this manuscript. The NMHPVPR Steering members participating are as follows: Nancy E. Joste, MD, University of New Mexico Health Sciences Center and Tricore Reference Laboratories, Albuquerque, New Mexico; Walter Kinney, MD, Kaiser Permanente Northern California; Cosette M. Wheeler, PhD, University of New Mexico Health Sciences Center; William C. Hunt, MS, University of New Mexico Health Sciences Center; Deborah Thompson, MD MSPH, New Mexico Department of Health; Susan Baum, MD MPH, New Mexico Department of Health; Linda Gorgos, MD MSc, former Medical director of the Infectious Disease Bureau, New Mexico Department of Health, Alan Waxman, MD MPH, University of New Mexico Health Sciences Center; David Espey MD, US Centers for Disease Control and Prevention; Jane McGrath MD, University of New Mexico Health Sciences Center; Steven Jenison, MD, Community Member; Mark Schiffman, MD MPH, US National Cancer Institute; Philip Castle, PhD MPH, Albert Einstein College of Medicine; Vicki Benard, PhD, US Centers for Disease Control and Prevention; Debbie Saslow, PhD, American Cancer Society; Jane J. Kim PhD, Harvard School of Public Health; Mark H. Stoler MD, University of Virginia; Jack Cuzick, PhD, Wolfson Institute of Preventive Medicine, London; Giovanna Rossi Pressley, MSc, Collective Action Strategies, and RWJF Center for Health Policy at University of New Mexico and Kevin English, RPh MPH, Albuquerque Area Southwest Tribal Epidemiology Center (AASTEC). No compensation was received for contributions to this manuscript by any named authors or by the NMHPVPR Steering Committee members.
Footnotes
Conflicts of Interest Statement
The authors report no conflicts of interest.
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