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。 

 宫颈癌作为目前唯一的病因明确的人类恶性肿瘤，使其具有了可能通过筛查而减少的甚或消失的疾病。因此，筛查的意义毋庸置疑。PAP smear 在目前的客观条件下具有现实的意义。但PAP smear有一个致命的弱点：对于形态学的方法而言，所要求的条件太高，即在诊断环节的人员必须是专业的人员。对于庞大人群的普查而言，至少在中国是无法实现的。如果不能做到所有人群的普查，其意义有限。

其次，HPV做为宫颈癌发生的必要条件，理论上应该是没有HPV就没有宫颈癌，因此检测HPV的感染十分必要。个人认为，HPV检测后可以指导细胞学检测的计划，虽然目前人类对于病毒没有有效的手段阻止。

对于HPV检测后所带来的一系列问题，其实对于每个疾病都会遇到不同程度的这样那样的问题。所以现代医学已经从单纯的生物模式逐渐在向社会－心理－生物模式转变，更加重视心理健康和社会影响。其实对于疾病的预防，我认为除了对于疾病的早期发现外，更重要的还有一点是健康知识的传播，大众健康意识的培养。

“廉价的病例”，我不感苟同。中国人口众多，疾病谱完全，可是为什么疾病的命名鲜见中国人呢？这么多的新技术不断被发明、使用，可是我们自己为什么还以FDA马首是瞻呢？以WHO唯命是从呢？我们有那么多的科研者，那么多的高头衔的人，为什么总是在卖别人的成果呢？我们自己不能够有新的发现、新的技术，我们有必要阻止别人做吗？科学应该是无国界的，所谓的廉价的病例，不一样给这些廉价的病例带来了一定的好处吗？如果我们自己的技术要做实验的话，还是“廉价的病例”吗？

作为筛查技术，应该具备：操作简单，费用低廉的可行性条件。因此随着对HPV检测手段的发展，最终应该是HPV检测技术取代PAP smear 技术。

纯属个人观点。

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. 

 看到大家讨论现在，貌似HPV仅仅是预测宫颈癌的发病风险，很想知道即使检测出高危阳性，除了随访还有更好的治疗方法吗？HPV感染可以是一过性的，其治疗价值？既然是随访，用细胞学更准确有效又不增加病者负担，岂不是更有实际意义？

难道检测HPV像大家在开展液基细胞一样仅仅是诱惑而已吗？

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 guess that HPV DNA test may be more profitable for the hospitals than the Pap test. Is that the case in China?

I just would like to make few comments. When we talk about HPV positive, AGE is a big factor, as Dr. Yu's previous post, in older women, HPV has a very high positive predictive valure for cervical squamous dysplasia, on the other hand, in younger (<30 years old) women, its PPV is poor. So, doing HPV DNA test as the primary screen NOW in all women age groups is not cost effective.

What if in the near future, a very cheap and good HPV test method is developed, in stead of 320 CNY, it lowers down to 40 CNY, is Pap test at that time threatened?

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。