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Thank laurelshihxbl for 翻译 of the AGC abstract:
verification bias:
Example: We perform Pap screening test with biopsy follow up. 10% women with LSIL Pap have or develope CIN 2/3. Then we conclude the risk of women with LSIL Pap for CIN 2/3 is 10%. However, women with normal Pap also can develop CIN 2/3 in study period. Rare studies can include a control group----to do the cervical biopsy for the women with negative Pap. True risk for LSIL-CIN 2/3 may be less than 10%.
This is called verification bias.
In fact the only study in which the control group of women with negative Pap had colposcopic examination was performed in Shanxi, China several years ago. This is called verification bias-adjusted.
In our AGC study, we added the data about hysterctomy specimens. We calculated the AGC rate in all women with hysterectomy (cervical tissue were examined). This data avioided verification bias-----called verification bias- adjusted.
It is a very complicated concept. I am not sure if I explain it clearly.
2008 USCAP abstract (is working for paper)
Follow-up outcomes of cytological and histological abnormalities among women with negative computer-imaged liquid-based Pap and positive HPV DNA test results
C Zhao, RM Austin
Department of Pathology,
Background:
Limited data from the U.S. and overseas has been reported on the natural history of high risk(hr) HPV DNA positive women screened with negative conventional Pap smear results, but no reports have documented follow-up of cytology negative- HPV positive women routinely screened with newer methods of liquid-based cytology (LBC), computer-assisted screening, and HPV reflex or co-testing. The purpose of this study was to document the development of cytological and histological abnormalities among several hundred women who tested hrHPV DNA positive along with negative computer-imaged liquid-based Pap co-test results (DNAwithPap).
Design:
The computerized hospital records of MWH were searched for patients reported as negative on ThinPrep Imaging System (TIS)-imaged ThinPrep Pap tests (TPPT) who also had positive Hybrid Capture 2 (HC2) hrHPV DNAwithPap co-test results over a 30 month span between July 2005 and December 2007. Cytologic and histologic follow-up outcomes were analyzed.
Results:
During the study period 402 women with negative TPPT and concurrent positive HC2 hrHPV DNA test results had documented cytologic and/or histologic follow-up. Histologic follow-up included 111 women who underwent cervical biopsy with or without ECC and 39 who underwent ECC alone. The mean age was 41.6 years (15-84 years). The average follow-up period was 13 months, ranging from 1 to 35 months (mean 10.6 m). Follow-up results documented that 8 of 402 (2.0%) women had tissue diagnoses of intraepithelial neoplasia 2+, including, four CIN2, 2 CIN3, one VAIN3, and one case of AIS on biopsy and microinvasive endocervical adenocarcinoma on subsequent conization. CIN1 or LSIL were confirmed in 61 (15.2%) and 82 (20.4%) had follow-up ASC-US Pap test results without biopsy findings of CIN1+. All CIN 2+ and 50 of 61 CIN 1 lesions were diagnosed based on histology. The interval between positive HPV and negative TPPT findings and an initial diagnosis of CIN 2+ ranged from 1 month to 19 months (median 14 months).
Conclusion:
CIN3, often proposed as a surrogate for invasive cervical cancer in cervical screening trials, was detected on initial follow-up (average 13 months) in 2 of 402 women (0.5%) with negative computer-imaged TPPT and positive HPV co-test results. Inclusion of two additional cases of histologically detected CIN2, one VAIN3, and one case of AIS with microinvasive endocervical adenocarcinoma potentially alters the risk profile of this cohort of over 400 cytology negative HPV positive patients. Additional natural history studies are needed on cytology negative HPV positive women routinely screened with modern methods which are now prevalent in the
Table 1
Cytologic and histologic follow-up results among 402 women with positive HPV tests and negative Pap tests
Follow-up |
No. |
% |
Negative |
251 |
62.4 |
ASC-US |
82 |
20.4 |
CIN 1/LSIL |
61 |
15.2 |
CIN 2 |
4 |
1.0 |
CIN3 |
2 |
0.5 |
VAIN3/AIS |
2 |
0.5 |
The previous history of cytological and histological abnormalities among women with negative computer-imaged liquid-based Pap and positive HPV DNA test results
Anisa Kanbour, MD, Shuping Zhao, MD/PhD, Amal Kanbour-Shakir, MD/PhD, Chengquan Zhao Zhao, MD.
Abstract:
Introduction:
No reports have documented the previous Pap test history for women with cytology negative- HPV positive testing results with methods of liquid-based cytology (LBC), computer-assisted screening, and HPV co-testing. The purpose of this study was to document the abnormal cytology and/or positive HPV testing results among women who tested hrHPV DNA positive along with negative computer-imaged liquid-based Pap co-test results.
Materials and methods:
The computerized hospital records of MWH were searched for patients reported as negative on ThinPrep Imaging System (TIS)-imaged ThinPrep Pap tests (TPPT) who also had positive Hybrid Capture 2 (HC2) hrHPV DNAwithPap co-test results between January 2008 and June 2008. The previous Pap cytology and HPV testing results for these women were analyzed. For women has two or more abnormal Pap tests or biopsy results, only the most abnormal diagnosis was recorded.
Results:
During the study period 202 women had negative TPPT and concurrent positive HC2 hrHPV DNA test results. 71 women showed no previous Pap tests and HPV testing in our files. 131 women had documented previous cytologic and/or HPV testing, or cervical biopsy results. Among these women, 55 (42%) showed normal Pap test and/or negative HPV testing history, 76 (58.0%) had at least one time of abnormal Pap tests or biopsy or Positive HPV testing results previously (Table 1).The interval between an initial abnormal Pap test and current positive HPV and negative TPPT findings ranged from 6 month to 13 years with average of 2.9 years. 71 of 76 cases (93.4%) had the first atypical Pap tests within 5 years.
Conclusion:
Our study indicates that more than half of the women (58%) with negative computer-imaged TPPT and positive HPV co-test results had previous abnormal Pap test or positive HPV testing history. HPV positivity predicts subsequent infection even though the risk of developing high grade dysplasia in women with negative Pap and positive HPV testing is very low. The previous Pap test, cervical biopsy, and HPV testing result should be considered for the risk assessment for cytology negative HPV positive women.
Cytologic and histologic abnormalities among 202 women with positive HPV tests and negative Pap test | ||
Previous history |
No. |
% |
No history |
71 |
35.1 |
Negative |
55 |
27.2 |
ASC-US |
44 |
21.8 |
CIN 1/LSIL |
24* |
11.9 |
CIN 2 |
2 |
1.0 |
Pap-HPV+ |
6 |
3.0 |
Total HPV+ |
47 |
23.3 |
Histological Follow-up Findings in Adolescents with HSIL Cytology Results
Magee Womens Hospital, UPMC,
Abstract:
Introduction:
The incidence of cervical intraepithelial lesions is increased in adolescents and reflects the high prevalence of hrHPV infection in this special population. Recent follow-up guidelines emphasize conservative follow-up options. Furthermore, data from cohort studies suggest that regression of both low grade and high grade CIN are quite frequent in very young women. In this study we analyzed histological follow-up data for adolescent women who had HSIL cytology reports. We also assessed the effect of presence or absence of an adequate TZ/ECS in liquid-based Pap tests on the follow-up biopsy diagnoses.
Materials and methods:
The computerized records of a large academic women’s hospital were searched for cases reported as HSIL on TPPT in women age 20 or younger over a 6 year span between January 2002 and December, 2007. Histologic and Pap follow-up results, variations among age groups of adolescent women, and impact of presence or absence of TZ/ECS in Pap test were analyzed. Chi-Square test analysis was performed using SAS 9.1 System.
Results:
During the study period a total of 474 women age 20 or younger had HSIL Pap test results. 335 adolescent women with at least one cervical biopsy with or without endocervical curettage were included in the analysis. The average age was 18.6 years (13-20 years). The average follow-up period was 24 months (0 to 75 months) with a median of 22 months. The overall histologic CIN2/3 and detection rate was 44.2% and 47.8% for CIN1. The average period between the HSIL Pap test and an initial diagnosis of CIN2/3 was 5 months (0-62 months) with a median 2 months. The rates for histologic documentation of CIN in women age 19-20 compared to younger women were not statistically different. Detailed histologic findings are shown in Table 1. No invasive carcinomas or adenocarcinoma in situ cases were identified in this series of adolescents. The percentage of CIN 2/3 diagnosed on histologic follow up was not statistically significantly different when comparing women with and without a TZ/ECS in their preceding HSIL Pap tests (44.5% vs. 38.9%, p=0.642).
Conclusion:
Less than half of adolescent patients with HSIL cytology results had documented histologic CIN2/3 over an average follow-up period of 24 months, and no cases of invasive carcinoma were identified. CIN1 histologic follow-up findings were as common as CIN2/3 findings, likely reflecting both the increased likelihood of HSIL regression in younger women as well as the challenges of precise cytologic and histologic classification. High rates of hrHPV infection, only moderate rates of histologic CIN2/3 following HSIL cytology, and absence of invasive carcinoma all mark the adolescent group as a unique subset of patients deserving further study. Identification of additional biomarkers for HSIL progression would be useful.
Histologic Follow-up Finding in Adolescent Women with HSIL Cytology | ||||
Age (y) |
F/U No |
Negative (%) |
CIN 1 (%) |
CIN 2/3 (%) |
19-20 |
199 |
13 (6.5) |
94 (47.2) |
92 (46.2) |
<19 |
136 |
14 (10.3) |
66 (48.5) |
56 (41.2) |
Total |
335 |
27 (8.1) |
160 (47.8) |
148 (44.2) |
CAP Nov. 2009 abstract (will work on paper soon)
Significance of hrHPV Testing in Women Age 50 Years or Older with LSIL and HSIL Cytology
Chengquan Zhao, MD (zhaoc@upmc.edu); Amer Heider, MD; R Mashall Austin, MD/PhD. Department of Pathology, Magee Womens Hospital, UPMC, Pittsburgh, Pa.
Abstract:
Context:
Older women are considered a “special population”. 2006 ASCCP Guidelines support reflex hrHPV testing as an option for postmenopausal women with LSIL. The data of hrHPV infection and its association to histologic CIN 2/3 in older women with LSIL and HSIL cytology are limited.
Design:
A computer-based search of Copath files of Magee-Womens Hospital, UPMC was carried out between July 1, 2005 and June 30, 2008 to retrieve women aged 50 years or above reported as LSIL or HSIL cytology who also were tested for hrHPV DNA (HC2). The HPV testing result, Pap and histologic follow up results were recorded.
Results:
hrHPV DNA was detected in 25 of 28 (89.3%) women age 50 or older with HSIL cytology, and in 154 of 217 (71.0%) women age 50 or older with LSIL cytology. The average interval between SIL cytology and an initial diagnosis of CIN 2/3 was 2.6 months (0 to 22 months) in women with HSIL cytology, and was 10.4 months (0-35 months) in women with LSIL cytology.The histologic findings are listed in the Table 1.
Histologic CIN Lesions between hrHPV Positive and Negative Testing Results in Older Women with LSIL and HSIL Cytology
hrHPV Positive | hrHPV Negative | |||||||
F/U No | CIN 1 (%) |
CIN 2 (%) |
CIN 3 (%) |
F/U No | CIN 1 (%) |
CIN 2 (%) |
CIN 3 (%) | |
HSIL | 21 | 2 (9.5) |
9 (42.9) |
10 (47.6) |
3 | 0 | 1 (33.3) |
1 (33.3) |
LSIL | 82 | 48 (58.5) |
6 (7.3) |
2 (2.4) |
24 | 11 (45.8) |
0 | 0 |
Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213-3180, USA.
OBJECTIVE: Sampling of the transformation zone (TZ) and endocervical cells (EC) has been widely regarded as a quality indicator in cervical screening programs; however, the significance of a TZ/EC sample (TZ/ECS) in promoting disease detection remains a matter of controversy. Because little data are available on the relationship between TZ/EC sampling and HPV DNA test results, we examined whether or not there is a measurable association between high-risk human papillomavirus (hrHPV) DNA test results and TZ/EC sampling in several thousand women screened in a large academic women's hospital laboratory. METHODS: 9035 ThinPrep Pap tests (TPPT) reported as negative, LSIL, or HSIL and which also had Hybrid capture 2 (HC2) hrHPV DNA testing over an 18 month period between July 1, 2005 and December 31, 2006 were documented. 8415 negative, 526 LSIL, and 84 HSIL TPPT were included in the study. The age of patients, the presence or absence of a TZ/ECS, and hrHPV DNA test results were noted from CoPath data files. Patients were stratified into 10 year age groups for data analysis. RESULTS: An identical 2.8% of Pap negative patients were hrHPV DNA positive in both the 6709 cytology negative patients with a TZ/ECS and the 1706 cytology negative patients without a TZ/ECS. Neither were statistically significant differences noted for hrHPV DNA prevalence in patients with SIL Pap test results from women with and without a TZ/ECS. CONCLUSIONS: HC2 hrHPV DNA detection in TPPT vials is independent of cytologic sampling of the transformation zone. hrHPV DNA results provide for the first time an available objective basis for risk assessment of patients with no TZ/ECS. The observation that hrHPV DNA test status is independent of presence or absence of a TZ/ECS is consistent with longitudinal studies of Pap negative women with no TZ/ECS which have not found increased disease on follow-up.
Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA. zhaoc@UPMC.edu
BACKGROUND: The prevalence of high-risk Human Papillomavirus DNA (hrHPV DNA) in women with negative Papanicolaou (Pap) test results provides a measure of residual risk for cervical neoplasia after cytology screening. The purpose of this study was to document the prevalence of hrHPV DNA in several thousand women ages > or =30 years with negative ThinPrep Imaging System (TIS)-imaged Pap test results in a large academic hospital cytology laboratory. METHODS: All cytology-negative TIS-imaged ThinPrep Pap tests (TPPT) with hrHPV DNA tests that were performed by the United States Food and Drug Administration (FDA)-approved Hybrid Capture 2 (HC2) method from May 1, 2005 to November 20, 2006 were identified and reviewed. Imaged-negative Pap test slides associated with a positive hrHPV DNA test result were rescreened manually. Variation in hrHPV DNA prevalence was assessed for different age and ethnic groups. RESULTS: Of 8070 imaged cytology-negative TPPT from women ages 11 to 90 years, hrHPV DNA test results were also available. Among 7426 women ages > or =30 years with a cytology-negative, TIS-imaged, Pap test, a significant age-associated decline in hrHPV DNA prevalence was noted, 3.4% in 3050 women ages 30-45 years, 2.4% in 7426 women ages 30-90 years, and 1.8% in 5491 women ages 40-90 years. The hrHPV DNA-positive rate was 2.3% in 6012 imaged cytology-negative white women and 4.1% in 739 imaged cytology-negative black women. CONCLUSIONS: Very low HC2 hrHPV DNA rates in 7426 women ages > or =30 years with cytology-negative, TIS-imaged, ThinPrep, Pap tests were similar to recently published data from 1 other academic center and lower than rates reported in previous studies on cytology-negative North American or European women screened manually with conventional or liquid-based Pap tests. These data may impact assessments of how best to combine cytology and HPV testing.
TABLE 1
Age-Associated Absence of an EC/TZS in 10 Year Age Intervals (All TBS 2001 Pap Result Categories Included)
Age group |
Total No. |
TZ/ECS absent |
% |
95% CI |
P value |
10-19 |
7193 |
1239 |
20.81 |
19.87-21.75 |
0.0011 |
20-29 |
35906 |
5858 |
16.32 |
15.94-16.70 |
0.0209 |
30-39 |
29628 |
4614 |
15.57 |
15.16-15.98 |
Reference |
40-49 |
31416 |
4870 |
15.50 |
15.10-15.90 |
0.8076 |
50-59 |
26765 |
6554 |
24.49 |
23.97-25.01 |
<1x10-4 |
60-69 |
12530 |
4224 |
33.71 |
32.88-34.54 |
<1x10-4 |
All |
143438 |
27359 |
19.07 |
18.87-19.27 |
|
EC/ TZS indicates endocervical/ transformation zone sample.
P value was calculated by comparing each group with reference group.
TABLE 2
Comparison of LSIL Prevalence in Women with and without an EC/TZS (10 Year Age Intervals)
Age group |
EC/TZS present |
EC/TZS absent |
P value | ||||||
Total No |
LSIL No |
% |
95% CI |
Total No |
LSIL No |
% |
95% CI | ||
10-19 |
5954 |
849 |
14.26 |
13.37-15.15 |
1239 |
129 |
10.41 |
8.71-12.11 |
3x10-4 |
20-29 |
30048 |
2665 |
8.87 |
8.55-9.19 |
5858 |
490 |
8.36 |
7.65-9.07 |
0.212 |
30-39 |
25014 |
811 |
3.24 |
3.02-3.46 |
4614 |
108 |
2.34 |
1.90-2.78 |
0.001 |
40-49 |
26546 |
577 |
2.17 |
1.99-2.35 |
4870 |
95 |
1.95 |
1.56-2.34 |
0.323 |
50-59 |
20211 |
256 |
1.27 |
1.12-1.42 |
6554 |
77 |
1.18 |
0.92-1.44 |
0.560 |
60-69 |
8306 |
75 |
0.90 |
0.70-1.10 |
4224 |
23 |
0.55 |
0.37-0.83 |
0.031 |
All |
116079 |
5233 |
4.51 |
4.39-4.63 |
27359 |
922 |
3.37 |
3.16-3.58 |
<1x10-4 |
LSIL indicates low grade squamous intraepithelial lesion; EC/TZS, endocervical/ transformation zone sample; TPPT, ThinPrep Pap test.
TABLE 3
Comparison of HSIL Prevalence in Women with and without an TZ/ECS (10 Year Age Intervals)
Age group |
EC/TZS present |
EC/TZS absent |
P value | ||||||
Total No |
HSIL No |
% |
95% CI |
Total No |
HSIL No |
% |
95% CI | ||
10-19 |
5954 |
82 |
1.38 |
1.08-1.68 |
1239 |
8 |
0.65 |
0.20-1.10 |
0.035 |
20-29 |
30048 |
429 |
1.43 |
1.30-1.56 |
5858 |
32 |
0.55 |
0.36-0.74 |
<1x10-4 |
30-39 |
25014 |
199 |
0.80 |
0.69-0.91 |
4614 |
19 |
0.41 |
0.18-0.61 |
0.005 |
40-49 |
26546 |
79 |
0.30 |
0.23-0.37 |
4870 |
7 |
0.14 |
0.04-0.25 |
0.059 |
50-59 |
20211 |
36 |
0.18 |
0.12-0.24 |
6554 |
8 |
0.12 |
0.04-0.20 |
0.330 |
60-69 |
8306 |
12 |
0.15 |
0.06-0.22 |
4224 |
5 |
0.12 |
0.02-0.22 |
0.708 |
All |
116079 |
837 |
0.72 |
0.67-0.77 |
27359 |
79 |
0.29 |
0.23-0.35 |
<1x10-4 |
HSIL indicates high grade squamous intraepithelial lesion; EC/TZS, endocervical/ transformation zone sample; TPPT, ThinPrep Pap test.
TABLE 4
hrHPV DNA Detection Rates in 526 Women with LSIL with and without an EC/TZ (10 Year Age Intervals)
Age group |
EC/TZS present |
EC/TZS absent |
P value* |
Total No |
EC/TZS present |
% | ||||||
HPV tested |
Positive |
% |
95% CI |
HPV tested |
Positive |
% |
95% CI | |||||
10-19 |
36 |
32 |
88.9 |
78.6-99.2 |
5 |
4 |
80.0 |
44.9-100.0 |
0.4969 |
41 |
36 |
87.8 |
20-29 |
169 |
149 |
88.2 |
83.3-93.1 |
37 |
27 |
73.0 |
58.7-87.3 |
0.0357 |
206 |
169 |
82.0 |
30-39 |
101 |
80 |
79.2 |
71.3-87.1 |
15 |
10 |
66.7 |
42.8-90.6 |
0.3213 |
116 |
101 |
87.1 |
40-49 |
79 |
52 |
65.8 |
55.3-76.3 |
13 |
10 |
76.9 |
54.0-99.8 |
0.5352 |
92 |
79 |
85.9 |
50-59 |
38 |
26 |
68.4 |
53.6-83.2 |
13 |
8 |
61.5 |
35.0-88.0 |
0.7379 |
51 |
38 |
74.5 |
60-69 |
14 |
11 |
78.6 |
57.1-100.0 |
6 |
5 |
83.3 |
53.5-100.0 |
1.0000 |
20 |
14 |
70.0 |
All |
437 |
350 |
80.1 |
76.4-83.8 |
89 |
64 |
71.9 |
62.6-81.2 |
0.0898 |
526 |
437 |
83.1 |
LSIL indicates low grade squamous intraepithelial lesion; EC/TZS, endocervical/ transformation zone sample; TPPT, ThinPrep Pap test, hrHPV, high risk human papillomavirus.
*P value was calculated by Fishers’ exact test.
TABLE 5
hrHPV DNA Detection Rates in 133 Women with HSIL with and without TZ/ECS (10 year age intervals)
Age group |
EC/TZS present |
EC/TZS absent |
P value* |
Total No |
EC/TZS present |
% | ||||||
HPV tested |
Positive |
% |
95% CI |
HPV tested |
Positive |
% |
95% CI | |||||
10- |
9 |
9 |
100 |
100-100 |
0 |
|
|
|
- |
9 |
9 |
100.0 |
20- |
42 |
41 |
97.6 |
93.0-100 |
4 |
4 |
100 |
100-100 |
1.0000 |
46 |
42 |
91.3 |
30- |
46 |
41 |
89.1 |
80.1-98.1 |
2 |
2 |
100 |
100-100 |
1.0000 |
48 |
46 |
95.8 |
40- |
14 |
13 |
92.9 |
79.5-100 |
0 |
|
|
|
- |
14 |
14 |
100.0 |
50- |
8 |
6 |
75.0 |
45.0-100 |
1 |
1 |
100 |
100-100 |
1.0000 |
9 |
8 |
88.9 |
60- |
4 |
3 |
75.0 |
32.6-100 |
3 |
2 |
66.7 |
13.4-100 |
1.0000 |
7 |
4 |
57.1 |
All |
123 |
113 |
91.9 |
87.1-96.7 |
10 |
9 |
90.0 |
71.4-100 |
0.5916 |
133 |
123 |
92.5 |
Cancer. 2008 Aug 25;114(4):242-8.
Adjunctive high-risk human papillomavirus DNA testing is a useful option for disease risk assessment in patients with negative Papanicolaou tests without an endocervical/transformation zone sample.
Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213, USA. zhaoc@UPMC.edu
BACKGROUND: Current guidelines recommend that women with negative Papanicolaou (Pap) test results and no endocervical/transformation zone (EC/TZ) sample return for screening within 12 months. For some women, this represents earlier follow-up than advocated in several routine screening guidelines. Controversy remains with regard to the correlation between sampling of the EC/TZ, Pap test quality, and disease risk assessment. METHODS: A retrospective study was conducted reviewing the results from 143,438 liquid-based cervical Pap tests performed at a large academic women's hospital between July 2005 and December 2006. Vaginal Pap tests were excluded from the study. Women with any Pap result, women with low-grade squamous intraepithelial lesions (LSILs), and patients with high-grade squamous intraepithelial lesion (HSIL) Pap test results were stratified by 10-year age groups and according to the presence or absence of an EC/TZ sample (EC/TZS). Women with LSIL and HSIL Pap test results with and without an EC/TZS were also compared for rates of high-risk human papillomavirus (hrHPV) DNA detection. RESULTS: Of the total of 143,438 cervical Pap tests performed, 27,359 (19.1%) were reported to be lacking an EC/TZS. The absence of an EC/TZS was found to be highest in adolescents and in mature women aged >or=50 years. The overall detection rate of LSIL was 4.29% and that of HSIL was 0.64%. Both the LSIL and HSIL rates were found to be significantly higher in Pap tests with an EC/TZS compared with Pap tests without an EC/TZS (LSIL: 4.51% vs 3.37% and HSIL: 0.72% vs 0.29%). However, when women with LSILs and HSILs were divided into a group in which EC/TZS was present and a group in which EC/TZS was absent, no significant differences were found to be present with regard to hrHPV DNA rates between the 2 groups. CONCLUSIONS: Adjunctive hrHPV DNA testing is effective in stratifying risk for the presence of SIL in women with and without an EC/TZS. This finding is consistent with recently reported data from >9000 patients with negative Pap results, which found that hrHPV DNA-positive test rates are independent of the presence or absence of an EC/TZS. hrHPV DNA results provide a useful new optional adjunctive tool for the objective stratification of disease risk in women with negative Pap tests and no EC/TZS. (c) 2008 American Cancer Society.
The significance of high-risk human papillomavirus testing in women with LSIL Pap test
Amer Heider, RM
From the Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA 15213
The authors have no relevant financial interest in the products or companies described in this article.
Presented orally at the 2009 USCAP Annual Meeting,
*Reprints: Chengquan Zhao MD, Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213 (e-mail: zhaoc@upmc.edu)
Background:
High risk (hr) HPV infection has been recognized as the primary risk factor for cervical carcinoma. Based primarily on ALTS data and American Society for Colposcopy and Cervical Pathology (ASCCP) Guidelines, LSIL cytology is most often managed with colposcopic evaluation. 2006 ASCCP Guidelines support reflex hrHPV testing as an acceptable option for postmenopausal women with LSIL. Data on the efficacy of hrHPV triage and histologic follow-up of women with LSIL and HPV test results in different age groups remain limited.
Design:
A computer-based search of Copath files of Magee-Womens Hospital of University of
Results: 719 women with LSIL cytology and hrHPV DNA testing who had at least one subsequent cervical biopsy during the study period were included. The histologic procedures included 98 LEEP/Cone biopsies and 10 hystectomies. The average follow-up period was 11 months, ranging from 0 to 35 months with a median 10.4 months. The interval between LSIL cytology and the initial diagnosis of CIN 2/3 ranged from 1 month to 29 months with a median 2.5 months (mean 6.9 months). Either CIN 2/3 or CIN 1 were identified on histologic follow up in a significant greater proportion of LSIL women with positive hrHPV results than in LSIL women with negative hrHPV testing (p=0.002 for CIN 2/3; p<0.001 for CIN 1). Detailed histologic findings are shown in Table 1. No CIN 2/3 was reported in women age 50 years or older with negative hrHPV test results. The percentage of CIN diagnosed on histologic follow up was not statistically significant between women with and without a TZ/ECS in their preceding LSIL cytology samples.
Conclusion:
The absence of histologic CIN2/3 in women 50 years and older with hrHPV negative LSIL in this series supports that triage using hrHPV testing may be an efficient alternative to colposcopy in postmenopausal women with LSIL cytology in 2006 ASCCP consensus guidelines for the management of women with abnormal cervical cancer screening tests. hrHPV DNA results also help to stratify risk for underlying CIN2/3 in younger women and deserves further investigation along with other biomarkers for cervical carcinogenesis.
Comparison of Age-Specific hrHPV Prevalence among Women with LSIL TPPT with and without TZ/ECS (10-Year Intervals)
Age group |
Tested No |
Positive No |
% (95% CI) |
TZ/ECS present |
TZ/ECS absent |
P | ||||
Tested No |
Positive No |
% (95% CI) |
Tested No |
Positive No |
% (95% CI) | |||||
10- |
99 |
91 |
92.0 |
86 |
79
|
91.9 |
13 |
12 |
92.3 |
1.0* |
20 |
456 |
402 |
88.2 |
382
|
342 |
89.5 |
74 |
60 |
81.1 |
0.049 |
30- |
326 |
261 |
80.1 |
281
|
228 |
81.1 |
45 |
33 |
73.3 |
0.498 |
40 |
271 |
189 |
69.7 |
232
|
160 |
69.0 |
39 |
29 |
74.4 |
0.498 |
50- |
142 |
96 |
67.6 |
103
|
69 |
67.0 |
39 |
27 |
69.2 |
0.799 |
60- |
49 |
39 |
79.6 |
36
|
29 |
80.5 |
13 |
10 |
76.9 |
1.0 * |
≥70- |
8 |
5 |
62.5 |
4 |
1 |
25.0
|
4 |
4 |
100.0 |
0.143* |
Total |
1351
|
1083 |
80.2 |
1124 |
908 |
80.8 |
227 |
175 |
77.1 |
0.185 |
Comparison of Histologic CIN between hrHPV Positive and Negative TPPT in LSIL Women Stratified by Ages
Age |
Total |
hrHPV Positive |
hrHPV Negative | ||||||
F/U No |
CIN 2/3 (%) |
CIN 1 (%) |
F/U No |
CIN 2/3 (%) |
CIN 1 (%) |
F/U No |
CIN 2/3 (%) |
CIN 1 (%) | |
10-19 |
44 |
6 (13.6) |
29 (65.9) |
40 |
6 (15.0) |
26 (65.0) |
4 |
0 (0.0) |
3 (75.0) |
20-29 |
234 |
24 (10.3) |
141 (60.3) |
211 |
23 (10.9) |
128 (60.7) |
23 |
1 (4.3) |
13 (56.5) |
30-39 |
189 |
31 (16.4) |
94 (49.7) |
164 |
30 (18.3) |
84 (51.2) |
25 |
1 (4.0) |
10 (40.0) |
40-49 |
156 |
24 (15.4) |
82 52.6) |
124 |
22* (17.7) |
75 (60.5) |
32 |
2 (6.3) |
7 (21.9) |
50-59 |
67 |
3 (4.5) |
40 (59.7) |
48 |
3 (6.3) |
31 (64.6) |
19 |
0 (0.0) |
9 (47.4) |
≥60 |
29 |
5 (17.2) |
15 (51.7) |
25 |
5 (20.0) |
13 (52.0) |
4 |
0 (0.0) |
2 (50.0) |
Total |
719 |
93 (12.9) |
401 (55.8) |
612 |
89 (14.6) |
357 (58.3) |
107 |
4 (3.7) |
44 (41.1) |
Arch Pathol Lab Med. 2009. In press.
Follow-Up Findings in Women with HPV-Positive ASC-US Screening Test Results in a Large
Henry Armah MD, PhD; R. Marshall Austin MD; PhD, David Dabbs MD; Chengquan Zhao* MD
From the Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA 15213
The authors have no relevant financial interest in the products or companies described in this article.
Presented orally at the 2008 USCAP Annual Meeting,
Reprints: Chengquan Zhao MD, Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213 (e-mail: zhaoc@upmc.edu)
ABSTRACT
Context.- Reflex HPV testing has been designated in consensus guidelines as “preferred” for women with ASC-US liquid-based cytology (LBC) results, and colposcopy is currently recommended for patients with HPV-positive ASCUS results. Data from large clinical practices utilizing newer screening methods and current cytology terminology remain limited.
Objectives.-We analyzed data from patients with ASCUS LBC and positive HPV test results. We also assessed the impact of the presence or absence of an endocervical cell/transformation zone sample (EC/TZS) on biopsy diagnoses.
Design.-The information system of a large women’s hospital serving an older than average population was searched over a 21 month period between July 1, 2005 and March 31, 2007 for HPV positive cases interpreted as ASC-US (Bethesda System 2001) utilizing computer-imaged LBC. Histologic diagnoses, patient ages, and presence or absence of an EC/TZS were analyzed. The average follow-up period was 7.5 months.
Results.- Among 4,273 women with HPV positive ASC-US results the cumulative cervical intraepithelial neoplasia 2 or 3 (CIN 2/3) and CIN 1 rates for 2,192 women with available biopsies were 5.1% and 43.6%, respectively. CIN2 /3 and CIN1 rates for women with HPV-positive ASC-US results were not significantly different for women with and without an EC/TZS.
Conclusions.- The risk of CIN2/3 in the study population was significantly lower than reported in widely cited trial data. Neither presence or absence of an EC/TZS nor the age of the patient had a statistically significant impact on the likelihood of biopsy diagnoses of CIN 2/3 and CIN1 in patients with HPV-positive ASC-US test results.
Table 2. Histologic Follow up Results in Women with Positive hrHPV and ASC-US TPPT Stratified by Age (10-Year Interval)
Age F/U No CIN 2/3 CIN 1 No (%) 95% CI P* No (%) % P* 10-19 302 15 (5.0) 2.5-7.5 .94 121 (40.1) 34.6-45.6 .25 20-29 1268 69 (5.4) 4.2-6.6 .63 577 (45.5) 42.8-48.2 .27 30-39 352 16 (4.6) 2.4-6.8 .68 155 (44.0) 38.1-49.2 .87 40-49 176 8 (4.6) 1.5-7.7 .76 66 (37.5) 30.4-44.7 .12 50-59 75 3 (4.0) 0-8.4 >.998224; 28 (37.3) 26.4-48.2 .28 60-69 19 0 .628224; 8 (42.1) 19.9-64.3 .90 Total 2192 111 (5.1) 4.2-6.0 955 (43.6) 41.5-45.7 * P values were obtained by comparing each age group with total average %. 8224; Fisher’s exact test hrHPV indicates high risk human papillomavirus; ASC-US, atypical squamous cells, undetermined significant; TPPT, ThinPrep Pap test; F/U, follow-up; CIN, cervical intraepithelial lesion, No, number.
Arch Pathol Lab Med. 2009. In press.
Clinical Utility of Adjunctive High Risk HPV DNA Testing in Women with Pap Test findings of Atypical Glandular Cells
From the Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA 15213
The authors have no relevant financial interest in the products or companies described in this article.
Some of the data was presented as a poster at the USCAP Annual Meeting,
Reprints: Chengquan Zhao, MD, Department of Pathology, Magee-Womens Hospital University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213 (e-mail: zhaoc@upmc.edu)
Context.- Atypical glandular cell (AGC) Pap interpretations are challenging. Most biopsy findings are benign, but AGC results may also reflect highly significant noninvasive neoplastic and malignant histologic outcomes. High risk human papillomavirus (hrHPV) test use with AGC Pap results is evolving.
Objectives.- This study was conducted to further evaluate the utility and limitations of hrHPV testing with AGC Paps.
Design - Hospital records were searched for AGC Pap tests from 6/1/2005 to 8/31/2007. Cases of AGC with hrHPV test and histopathologic follow-up were included.
Results - 662 women with AGC Pap results and follow-up were analyzed; hrHPV results were available in 309 of 662 and were positive in 75. Among the 75 with hrHPV-positive AGC results, 13 had cervical intraepithelial neoplasia (CIN) 2/3, 10 had adenocarcinoma (AIS), and 3 had cervical invasive adenocarcinoma, whereas for 234 women with hrHPV-negative results, 1 had CIN 2/3, 1 had AIS, 1 each had cervical adenocarcinoma and ovarian carcinoma, and 8 had endometrial carcinoma.
Conclusions.- hrHPV-positive AGC results were most strongly associated with CIN2/3 and AIS in women younger than 50. hrHPV positive AGC results were also present in all three cases of invasive cervical adenocarcinoma in women under 50. Of note, hrHPV-negative AGC results were present in ten of thirteen (76.9%) of carcinomas detected after AGC Pap tests, all in women 40 or older- 8 endometrial adenocarcinomas, 1 ovarian carcinoma, and 1 cervical adenosquamous carcinoma in a woman in her 50s. hrHPV testing after AGC Pap findings was most helpful in detection of CIN2/3 and AIS and invasive cervical adenocarcinomas in women younger than 50.
Table 1.
Correlation of the AGC Subcategories for 309 Cases with hrHPV DNA testing and Histologic Diagnoses of Neoplastic or Malignant Lesions on Surgical Pathology Follow-up
Cytologic Result
|
AGC/ASC-US (n=97) |
AGC/ASC-H (n=29) |
AGC/HSIL (n=4) |
AGC-EM (n=19) |
AGC-EC (n=75) |
AGC-NOS (n=85) |
Total (n=309) | |||||||
Age (years) |
45.1 (19-84) |
41.5 (21-76) |
34.4 (24-45) |
52.2 (42-77) |
38.7 (19-72) |
46.3 (27-84) |
43.9 (19-84) | |||||||
Histologic diagnosis
|
HPV+ n=17 (%) |
HPV- n=80 (%) |
HPV+ n=12 (%) |
HPV- n=17 (%) |
HPV+ n=3 (%) |
HPV- n=1 (%) |
HPV+ n=1 (%) |
HPV- n=18 (%) |
HPV+ n=28 (%) |
HPV- n=47 (%) |
HPV+ n=14 (%) |
HPV- n=71 (%) |
HPV+ n=75 (%) |
HPV- n=234 (%) |
Squamous cell Cervical Intaepithelieal Neoplasia |
10 (58.8) |
10 (12.5) |
4 (33.3) |
5 (29.4) |
3 (100) |
1 (100) |
0 |
1 (5.6) |
15 (53.6) |
12 (25.5) |
7 (50.0) |
3 (4.2) |
39 (52.0) |
32 (13.7) |
CIN2/3
|
3* |
|
2* |
|
2* |
1 |
|
|
4* |
|
2 |
|
13 |
1 |
CIN1
|
7 |
10 |
2 |
5 |
1 |
|
|
1 |
11 |
12 |
5 |
3 |
26 |
31 |
Glandular cell Cervical Neoplasia |
1 (5.9) |
0 |
2 (16.7) |
1 (5.9) |
1 (33.3) |
0 |
0 |
0 |
7 (25.0) |
0 |
2 (14.3) |
0 |
13 (17.3) |
1 (0.4) |
Invasive Cervical Carcinoma |
|
|
|
1‡ |
|
|
|
|
3 |
|
|
|
3 |
1 |
AIS
|
1* |
|
2* |
|
1* |
|
|
|
4* |
|
2 |
|
10 |
|
Endometrial Neoplasia |
0 |
6 (7.5) |
0 |
0 |
0 |
0 |
0 |
4 (22.2) |
0 |
1 (2.1) |
0 |
4 (5.6) |
0 |
15 (6.4) |
Endometrial carcinoma |
|
3 |
|
|
|
|
|
1 |
|
|
|
4 |
|
8† |
Endometrial hyperplasia |
|
3 |
|
|
|
|
|
3 |
|
1 |
|
|
|
7 |
Ovarian Neoplasia
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.1) |
0 |
0 |
0 |
1 (0.4) |
Serous carcinoma
|
|
|
|
|
|
|
|
|
|
1 |
|
|
|
1 |
Table 2
Age and Subsequent Significant Histologic Diagnoses in Women with AGC Paps and hrHPV Test Results
Histologic diagnoses
|
<40 years |
≥40 to <50 years |
≥50 years |
Total | ||||
HPV+ (n=41) |
HPV- (n=64) |
HPV+ (n=19) |
HPV- (n=108) |
HPV+ (n=15) |
HPV- (n=62) |
HPV+ (n=75) |
HPV- (n=234) | |
CIN2/3
|
10* (24.4%) |
1 (1.6%) |
2† (10.5%) |
0 |
1 (6.7%) |
0 |
13 (17.3%) |
1 (0.4%) |
Invasive carcinoma |
2 (4.9%) |
0 |
1 (5.3%) |
0 |
0 |
1 (1.6%) |
3 (4.0%) |
1 (0.4%) |
AIS
|
4* (9.8%) |
0 |
6† (31.6%) |
0 |
0 |
0 |
10 (13.3%) |
|
Endometrial carcinoma |
0 |
0 |
0 |
2 (1.9%) |
0 |
6 (9.7%) |
0 |
8 (3.4%) |
CAH |
0 |
0 |
0 |
2 (1.9%) |
0 |
3 (4.8%) |
0 |
5 (2.1%) |
Metastatic carcinoma |
0 |
0 |
0 |
1 (0.9%) |
0 |
0 |
0 |
1 (0.4%) |
Total |
13 (31.7%) |
1 (1.6%) |
8 (42.1%) |
5 (4.6%) |
1 (6.7%) |
10 (16.1%) |
22 (29.3%) |
16 (6.8%) |
* 3 cases with both AIS and CIN 2/3
† 1 case with both AIS and CIN 2/3
Total 4 cases with AIS and CIN 2/3, all HPV+
Table 6.
Accumulated Data on ASC-H Prevalence in Women with LBC Pap Test (Literature review)
Total No. |
Positive No. |
% |
Reference |
10745 |
36 |
0.34 |
Lee4 |
107021 |
257 |
0.24 |
Taraif5 |
20354 |
222 |
1.09 |
Geisinger6 |
29475 |
60 |
0.22 |
Gupta7 |
83667 |
488 |
0.58 |
McHale8 |
119659 |
377 |
0.32 |
Wu9 |
60390 |
414 |
0.69 |
Duncan10 |
30658 |
96 |
0.31 |
Srodon11 |
76675 |
223 |
0.29 |
Stany12 |
152495 |
800 |
0.52 |
Saad13 |
9214 |
25 |
0.27 |
Selvaggi14 |
77979 |
255 |
0.33 |
Shidham15 |
778332 |
3253 |
0.42 |
In total |
270,338 |
1,619 |
0.60 |
Current study |
122 Lab, Mean (ThinPrep Pap) |
|
0.57 |
Davey17 |
ASC-H indicates atypical squamous cells, cannot exclude high grade squamous intraepithelial lesion; LBC, liquid-based cytology; Lab, laboratories.
Table 7.
Accumulated Data on HC2 hrHPV Positive Rates in Women with ASC-H LBC Results and Histopathological Follow-up (Literature Review)
hrHPV test |
Histologic CIN 2/3 |
Panel review/ Reclassi- fication |
Year of publica -tion |
Reference | |||||||
hrHPV positive |
hrHPV negative | ||||||||||
Tested No. |
Positive No. |
% |
Tested No. |
CIN 2/3 No. |
% |
Tested No. |
CIN 2/3 No. |
% | |||
23 |
17 |
73.9 |
|
|
|
|
|
|
yes |
2005 |
Duncan10 |
110 |
92 |
83.6 |
92 |
54 |
58.7 |
18 |
2 |
11.1 |
yes |
2001 2006 |
Sherman2, 18 |
48 |
38 |
79.2 |
38 |
22 |
57.9 |
10 |
0 |
0 |
yes |
2005 |
Liman19 |
101 |
82 |
81.2 |
33 |
16 |
48.5 |
9 |
0 |
0 |
yes |
2007 |
Nguyen33 |
96 |
64 |
66.7 |
45 |
18 |
40.0 |
12 |
1 |
4.5 |
no |
2006 |
Srodon11 |
95 |
54 |
56.8 |
31 |
13 |
41.9 |
13 |
1 |
7.7 |
no |
2007 |
Reid20 |
88 |
59 |
67.0 |
35 |
15 |
42.9 |
7 |
0 |
0 |
no |
2006 |
Wu9 |
16 |
6 |
37.5 |
|
|
|
|
|
|
no |
2004 |
Rowe21 |
48 |
16 |
33.3 |
10 |
3 |
30.0 |
6 |
0 |
0 |
no |
2005 |
Palma22 |
33 |
21 |
63.6 |
15 |
4 |
26.7 |
4 |
0 |
0 |
no |
2006 |
Chivukula24 |
73 |
43 |
58.9 |
43 |
14 |
32.6 |
30 |
1 |
3.3 |
no |
2007 |
Owens25 |
109 |
58 |
53.2 |
58 |
19 |
32.8 |
51 |
1 |
2.0 |
no |
2007 |
You26 |
88 |
60 |
68.2 |
60 |
15 |
25.0 |
28 |
0 |
0 |
no |
2004 |
El-Fakhara 28 |
40 |
21 |
52.5 |
21 |
11 |
52.4 |
13 |
1 |
7.7 |
no |
2004 |
Hoschar 29 |
257 |
151 |
58.8 |
87 |
33 |
37.9 |
|
|
|
no |
2005 |
Taraif 5 |
187 |
86 |
46.0 |
|
|
|
|
|
|
no |
2006 |
O’Brien30 |
209 |
105 |
50.2 |
|
|
|
|
|
|
no |
2007 |
Howard31 |
138 |
53 |
38.4 |
36 |
11 |
30.6 |
45 |
2 |
4.4 |
no |
2006 |
Christal32 |
115 |
54 |
47.0 |
54 |
23 |
42.6 |
19 |
4 |
21.1 |
no |
2007 |
Sullivan34 |
1874 |
1080 |
57.6 |
658 |
271 |
41.2 |
265 |
13 |
4.9 |
|
|
In total |
1187 |
589 |
49.6 |
257 |
84 |
32.7 |
248 |
3 |
1.2 |
no |
2008 |
Current |
hrHPV indicates high risk human papillomavirus; HC 2, Hybrid Capture 2; ASC-H, atypical squamous cells, cannot exclude high grade squamous intraepithelial lesion; TPPT, ThinPrep Pap tests; CIN 1, cervical intraepithelial neoplasm 1; CIN 2/3, cervical intraepithelial neoplasm 2 or 3; F/U, follow-up; LBC, liquid-based cytology.