Please share your oppinion:

请分享你的观点

Recently I noticed this topic in another cytology website in China. Let us have a discussion here.

最近我在另一个中国的细胞学网站中注意到这个主题。让我们一起在这里讨论。

1. Are all cervical carcinoma related to HPV infection?

所有的宫颈癌都是由HPV导致的吗？

2. When the women or who should have high risk HPV (hrHPV) testing?

那些女性需要或者什么时候做高危HPV检测呢？

3. What methods to detect hrHPV do you used in your hospitals?

你们医院用的是那种方法检测高危HPV？

4. What should the women do if she has positive hrHPV result?

如果她的高危HPV的结果是阳性的，她们该怎么办？

5. hrHPV testing should be performed for women with AGC?

细胞学结果为AGC的女性应该进行高危的HPV检测吗？

6. Any question, experience or oppinion you have, please share or discuss.

所有以上问题，就你个人的观点或经验来分享和讨论吧。

We as pathologists should know some basic information about HPV even though HPV testing might not be oerformed in your hospital, or the patients might not be able to pay for the test.

 即使HPV检测在你们医院没有开展或病人没有经济能力支付这项检测。我们做为病理学医生应该知道一些关于HPV的基本知识。 

Now relative numbers of  people  support HPV testing as primary screening. I share you a paper here, even though I do not agree the strategy.

cz

 J Natl Cancer Inst. 2009 Jan 21;101(2):88-99. Epub 2009 Jan 13. onmouseout="PopUpMenu2_Hide();" href="javascript：PopUpMenu2_Set(Menu19141778);" target="_self">Links

目前国内有的在做FISH检测，可以预测出具体某个CIN1的病例发展到CIN3-浸润癌的风险大小。但是价格太昂贵了……

I doubt it. Do not trust the adventisment from companis. We need to see the solid and large research and clinical trial data.

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, Magee-Womens Hospital (MWH) of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

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 U.S. The potential benefits of routinely combining LBC and HPV co-testing for enhanced detection of endocervical neoplasia deserves special study, given the limited reported success of screening in this area to date.         

Table 1

Cytologic and histologic follow-up results among 402 women with positive HPV tests and negative Pap tests

 High Risk HPV DNA Detection RATES in over 26,000  

  CYTOLOGY NEGATIVE IMAGED LIQUID-BASED PAP TEST SAMPLES

Chengquan Zhao, MD., and R. Marshall Austin, MD, PhD

Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA

INTRODUCTION: Detection rates for high risk HPV (hrHPV) DNA by Hybrid Capture 2 (HC2) vary significantly between different countries and regions, in different local populations and age groups, and based on the frequency and methods of cytologic screening and treatment. Although a single hrHPV DNA test result has low positive predictive value for subsequent development of cervical precancer or cancer, hrHPV DNA testing provides an objective measure of relative risk for cervical neoplasia after screening in different populations. The purpose of this study was to document detection rates of hrHPV DNA in a large, low risk, older than average U.S. population. hrHPV DNA tests results were available from over 26,000 samples with companion negative ThinPrep Imaging System (TIS)-imaged ThinPrep Pap test (TPPT) results.

MATERIALS AND METHODS: A computer-based search of Copath files of Magee-Womens Hospital (MWH) of University of Pittsburgh Medical Center (UPMC) was carried out over a 30 month period between July 1, 2005 and December 31, 2007 to retrieve women with ThinPrep Pap Test (TPPT) reported as negative for intraepithelial lesion or malignancy who also were tested for hrHPV DNA. All TPPT were processed in the pathology laboratory at MWH and prepared using an automated processor (ThinPrep 3000) and imaged using the ThinPrep Imaging System (TIS). Vaginal Pap tests were excluded from this study. hrHPV DNA testing was ordered by clinicians according to several ordering options as follows: reflex triggered by indeterminate abnormal atypical squamous cell (ASC) Pap test results, co-testing with Pap tests in women 30 and over (DNAwithPap), and co-testing regardless of age or Pap test results. If hrHPV DNA was detected in negative Pap tests, the Pap test slides were routinely manually rescreened by the screening cytotechnologist, referred for further manual rescreening by a quality-assurance cytotechnologist, and then also reviewed by a pathologist. hrHPV DNA detection was performed by the FDA-approved Hybrid Capture II (HC2) method. hrHPV detection rates were compared between women with either presence or absence of an transformation zone/endocervical cell sample (EC/TZS). 95% confidence intervals (95% CI) for the different frequencies of hrHPV DNA detection were obtained by a Wald test. Comparisons of hrHPV detection rates between women with and without an EC/TZS were performed by Chi-square test or Fisher’s exact test for small number using SAS 9.1 system (SAS Institute Inc., Cary, NC). P values of <0.05 were considered statistically significant.

RESULTS: A total of 26558 cytology negative TPPT also underwent hrHPV DNA testing. The age-specific hrHPV prevalence with 10-year intervals and comparison of hrHPV rates between TZ/ECS presence and absence are listed in table 1. hrHPV positive detection was significantly higher in women younger than 30, and sharply declined in women 30-39 years of age (p<1x10^-4). Declining hrHPV DNA detection rates continued in the 40-49 year age group (age 30-39 vs 40-49; 2.8% vs. 1.7%, p<1x10^-4) and then levelled off. No statistically significant difference of hrHPV prevalence was present between women with and without a TZ/ECS except for age 40-49 year in which hrHPV rate was slightly higher in TZ/ECS absent group than that in TZ/ECS present group. The total number of negative Pap tests with hrHPV DNA testing significantly increased for the women age 30 and over in 2007 [2007 (12 months) vs. July 2005-December 2006 (18 months), 17256 vs. 8003], reflecting increased physician orders for DNAwithPap co-testing in women 30 and older.

CONCLUSION: This is the largest study to date documenting hrHPV DNA detection rates in women screened as cytology negative with imaged LBC methods now representing a major portion of the U.S. cervical cytology market. Findings of very low rates of hrHPV DNA detection in 490 (1.9%) of 25,259 cytology negative women 30 and older extends similar previously reported findings in smaller study populations. Because hrHPV DNA testing provides an objective measure of relative risk for cervical neoplasia after screening, these data are relevant to discussions on how best to combine cytology and HPV testing in screening low risk populations. 

TABLE 1

Comparison of Age-Specific hrHPV Prevalence among Women with Negative TPPT with and without TZ/ECS (10-Year Intervals)

*Fisher’s exact test

hrHPV indicates high-risk human papillomavirus; TPPT, ThinPrep Pap Test; TZ/ECS, transformation zone/endocervical cell sample; CI, confidence interval.

Table 2

Comparison of hrHPV DNA positive rates between women ages ≥30 years and younger women with imaged negative TPPT

 Agree with above.

Now in the USA a group of people are trying hard to recommend high risk HPV testing for all women 30 and older. Of cause Diagen (company to produce HC2 HPV testing , only one method FDA approved for Pap HPV testing) will be very happy, but the companies to make LBC test will not be happy.

I still think the best way is to combine cytology and HPV testing in screening---screening with cytology, HPV test for atypical squamous cell, atypical glandular cells.

I can share two of my recent abstracts in ASC and USCAP meeting below. I am working for the papers for these two studies.

Women with negative Pap have very low HPV infection rate in our study. It depends on the populations, cities, contries. 

Thank you, Dr. wq-9603. I noticed that you have many good comments in this website.

Could you explain more to your statement above.

 Recently I contacted a Professor of gynecologist in a medical school hospital in China and know that all women with atypical Pap including LSIL and HSIL would have HPV testing in her hospital. Do you think this is standard patient care? If not, do you know why?

Some people told me that in China the adventisment said: HPV testing can detect cervical cancer and all women who have sexual activity should have HPV testing.

Do you think it is true? why?

 I hope these kinds of trials will not be performed in China. The companies and researchers like the population in China, contrysides. We welcome some good trials and should against some trials with final purpose.

我希望这种类型的实验不要在中国进行。这些公司和研究机构看中的是中国农村广大的人口。我们欢迎一些好的科研实验和反对一些操控最终目标的科研实验。

 The above paper was out just in April 1. Dr. Austin (did the main work) and I analysed their data in details and noted that the authors manipulated the data and obtained the conclusion that one HPV screening is better than one cytology screening.  We think it is abiase. The paper is agaist Pap cytology.

In fact, the study acknowledged that the positive predictive value (PPV) for detecting CIN 2-3 was 19.3% in the cytologic-testing group, higher than 11.3% in the HPV-testing group, and study results indicate that essentially the same numbers of cervical cancers were detected after positive screening test results in the cytology arm (88) as in the HPV arm (87). Cervical cancer detection rates were 0.344% in the cytologic-testing group and 0.321% in the HPV-testing group. However the authors can obtain different conclusion based on the results.

Now most large studies are company related or finally related. We write a commentary titled as " Test group biases and ethical issues mar New England Journal of Medicine articles promoting HPV screening for cervical cancer in rural India" to this paper and sent to CytoJournal (online journal) today. Hope it can be released quickly.

 Thank Dr. Chen's input.

I really do not agree with Dr. Stoler oppinion. He is one of the HPV screening advancers in the US.

如果细胞学为明确病变（HSIL或LSIL），或活检也能明确诊断，则不需要检测HPV。

You are right.

More than 80% LSIL and more than 90% (aaverage 95%) HSIL cases are high risk HPV positive detected by HC2. This is why HPV testing should not be done for these women. I know some medical school hospitals in China detect HPV for all women with abnormal Pap including LSIL and HSIL. This really wastes patients' money. I feel pain for these women especially for those who pay their own money for the testing. As pathologists we need to let clinical physicians know that. We have the responsibility.

By the way, how much for one convention Pap, LBC, and HC2 HPV testing?

 Thank   法师 for your considerate statement. I appreciate the way you share your oppinion. Wish more pathologists could do the same as our   法师 did. it is good part of internet that every one can share your own oppinion. By communication and discussion we can learn from each other and know somethings in details.

What are your oppinion? Do you agree with 法师 ?

 Agree with Dr. Yu. People think almost all cervical squamous cell ca and endocervical ca are related to HPV infection. A few scc and relative percentage of adenocarcinoma are HPV negative even using PCR test. Two possibilities: 1) rare cases may not caused by HPV, 2) some studies indicated the HPV genes lost in some invasive cancer cases.

As Dr. Yu mentioned that relative % of vagina and anal scc are not related with HPV infection.