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。 

 What is careHPV

I copied the method description from the Lancer oncolgy paper:

CareHPV and HC2

The careHPV test is broadly based on the HC2 test with some important differences. The assay time is 2·5 h or less, compared with up to 6 h for HC2. The careHPV collection medium, unlike other collection media, contains no toxic chaotropic salts, but rather contains non-toxic surfactants and is specifically formulated for solubilisation of cervical specimens from the collection brush without any requirement for extended mechanical shaking. The capture microplates in HC2 are replaced by magnetic beads coated by a monoclonal antibody with high affinity to RNA-DNA hybrids. Furthermore, the temperatures of some steps in the careHPV assay are increased to decrease the overall assay time by more than 2 h. The principle of the assay is as follows: target HPV DNA from lysed cells is denatured and hybridised to full-length complementary RNA, then captured by monoclonal antibodies coated on paramagnetic beads. The captured hybrids on the beads are detected by antihybrid monoclonal antibody conjugated to calf intestine alkaline phosphatase, which reacts with an added chemiluminescent substrate to produce light in proportion to the number of bound alkaline phosphatase molecules along the hundreds of antigenic binding sites per target molecule. Specimen test findings are expressed in relative light units (RLU) and compared with the mean RLU from a minimum positive control set at 1 pg/mL of HPV-16 DNA (expressed numerically as the cutoff) resulting in a ratio, the RLU/cut-off, the proportion of which is indicative of clinical positivity. Because the output signals of both HC2 and the new careHPV test are quite linear over a broad range around the cut-off-point ratio (RLU/cutoff) of 1·0, there is the possibility to vary the cut-point by adjusting the calculations to indicate specimen positives at lower or higher values than the value of positive controls, thus a cut-point of 0·5 reflects an assay that can score 0·5 pg/mL of HPV-16 DNA as positive.

 I think this is great we can do the cooperation with some companies or experts from other countries, or founding to do basic search or clinical trials to develpe or confirm the new, low price HPV detection method for the people in China and the world.

英国《柳叶刀—肿瘤学》（The Lancet Oncology）杂志9月22日在线发表中国医学科学院肿瘤研究所、中国癌症基金会、江西省妇幼保健院等单位共同完成的一项最新研究成果。研究人员第一次在世界上验证了人乳头瘤病毒快速检测技术（care HPV）能够准确、快速地发现子宫颈癌及癌前病变，

From the Chinese News  (floor 67).

If you read above story about the study in China and if you are a true medical doctor or scentific researcher, you know 1) this study is not a true Chinese new research achievement  2) HPV testing (careHPV ,even HC2) cannot (能够)准确、快速地发现子宫颈癌及癌前病变.

 Today i read the full paper careHPV in China

 In India they had very large numbers of women for study, 161845. HC2 was used foe HPV testing. The results indicated the HPV testing was more senstive for detecting high grade dysplasia and cancer than visual inspection with acetic acid (VIA). I can not see HPV testing is better than LBC even though the paper mentioned yes (New Egl J Med april 2009). See above floor 39-40.

Now we see the study in China. I have not the time to read the entire paper yet (paper in hospital computer). We know about 2000 women detected with care HPV, HC2, VIA, LBC, colposcopy.

from the abstract:

 the careHPV test was done locally by use of self-obtained vaginal and provider-obtained cervical specimens from a screening population-based set of 2530 women aged 30 to 54 years in Shanxi province, China. All women were assessed by visual inspection with acetic acid (VIA), Digene High-Risk HPV HC2 DNA Test (HC2), liquid-based cytology, and colposcopy with directed biopsy and endocervical curettage as necessary.

Do you think the normal women will agree to have colposcopy for these kinds of trials  in the USA?

the sensitivities and specificities of care HPV to detect cin2+  was better than VIA. I can not see care HPV is better than LBC in the study. Of cause we know care HPV will not be or cannot be more sensitiv and specific than HC2.

 In fact I never pay attention to care HPV until today.

Now we know HC2 and care HPV are the products from the same company, Qiagen.

HC2 testing is widely used in the USA and other western countries for women with abnormal Pap and is recommended for women age 30 and old along with Pap test by FDA (see above 77).

Qiagen has not had care HPV in marketing yet. The compay had  the first clinical trial  for about 2000 Chinese women in two county hospitals rural areas in Shanxi, China.

HC2 detrect 13 high risk HPV and care HPV detecte 14 high risk HPV. I do not know the detailed priniciple for care HPV testing. However we know it is easy, cheap, and fast (mentioned by the paper). The purpose of the new product is mainly for use in the rural areas in other words for the people who do not have enough money for medical care. Logically we will know the sensitivity, and specificity of care HPV will be lower than HC2 (remmber the products of the same company). Otherwise this care HPV can be used in the USA or other western countries, in stead of current HC2. If you do the ggogle serach for care HPv, only very few reports can be found (I pasted above).

 Ok, I want to finish the discussion today.

A few mian points

1. Care HPV is still in the testing stage. No product commercially is available.

2. Care HPV may be cheaper, fast and easy to be used baed on the paper.

3. Purpose of this product is for rural areas, in other words for people who cannot have enough money for medical care or not rich people ( I do not like to use the word poor).

4. Both care HPV and HC2 are the products of QIAGEN. Care HPV cannot be or will not be more sensitive or specific than HC2.

5. Some companies are trying to produce kit for detecting HPV16/18, main types of HPV for cervical cancer. 6. In term of my knowledge I do not know any  HPV detecting method can detect cervical cancer.

Ok, Thank you for reading.

 Now we can see a few points in the news from China (floor 67 from o164) I do not know where was the news published.

子宫颈癌快速筛查技术----care HPV技术有望极大减轻发展中国家子宫颈癌疾病负担

研究人员第一次在世界上验证了人乳头瘤病毒快速检测技术（care HPV）能够准确、快速地发现子宫颈癌及癌前病变.

夸大，吓人: It is just kind of cheaper HPV testing. We know almost cervical squamoust ca and most adenocarcinoma are caused by HPV or related to HPV. High risk HPV infection does not mean cancer. Most women with HPV infection will not develope high grade dysplasia or cancer.

HC2 has been used for many years.

英国《柳叶刀—肿瘤学》（The Lancet Oncology）杂志9月22日在线发表中国医学科学院肿瘤研究所、中国癌症基金会、江西省妇幼保健院等单位共同完成的一项最新研究成果。研究人员第一次在世界上验证了人乳头瘤病毒快速检测技术（care HPV）能够准确、快速地发现子宫颈癌及癌前病变，这一检测技术不仅只需两个多小时就能得出结果，而且费用也只有目前高收入发达国家与地区所使用检测方法的1/10。

You read the paper carefully you will know the senior author is not Chinese.

Check 82 floor:

Attila Lorincz, PhD, senior author of the study and a professor of molecular epidemiology at Barts and the London School of Medicine, as well as London's Queen Mary College.

The first published study of patient outcomes with Qiagen's Care HPV test, developed with support from Path, appears in the October issue of Lancet Oncology (82 floor).

From abroad news you will see no people will think this is a great search study  or breaking news done by Chinese researchers or scientistis. People know that the truth is that some companies, 基金会 cooperated with Chinese medical people, researchers, pathologists to do some clinical trials in rural areas in China or India.

The News abroad only mentioned that QIAGEN companony with Path had the first trial about care HPV in rural areas in China.No one mentioned that this was a trial by Chinese researchers.

It is good some companies or institute can help our Chinese people or do some clinical trials in China.

If some effective and cheaper HPV detection methods can be used in rural areas in China, I am very happy to see it. I am not against HPV testing. In fact we use a lot of HPV testing testing in our clincal practice.

More news about careHPV test in China.

HPV Test For Rural Areas Major Breakthrough

The news provided by Qiagen:

HPV test provides accurate front-line screening

A Qiagen product story

 http://www.thehpvtest.com/About-the-digene-HPV-Test/HPV-Testing-in-the-News.html

Diagen or Qiagen HPVtest.com

They listed the large good news for HPV testing. I did not notice the study in China.

 March 2000:

FDA approved HC2 test for women with abnormal Pap test.

March 2003:

FDA approved to allow HC2 test to be used for screening, in conjunction with the Pap test, of women over age 30 for HPV infection. It should be used along with the Pap test, a complete medical history and an evaluation of other risk factors to help physicians determine what kind of follow-up is necessary.

Below for detailded FDA news.

FDA News

FDA Approves Expanded Use of HPV Test

The Food and Drug Administration (FDA) today approved expanded use of a laboratory test to detect the presence in women of human papillomavirus (HPV), one of the most common sexually transmitted infections.

There are more than 100 types of HPVs. The test, the HC2 High-Risk HPV DNA Test, manufactured by Digene Corp., of Gaithersburg, Md., can identify 13 of the high-risk types associated with the development of cervical cancer. The HPV DNA test does not test for cancer, but for the HPV viruses that can cause cell changes in the cervix. If left untreated, these changes can eventually lead to cancer in some women.

FDA initially approved the HPV DNA test in March 2000 for testing women who had abnormal Pap test results to determine whether they needed to be referred for further examination. The new indication allows the test to be used for screening, in conjunction with the Pap test, of women over age 30 for HPV infection. It should be used along with the Pap test, a complete medical history and an evaluation of other risk factors to help physicians determine what kind of follow-up is necessary.

“Knowing whether or not a woman is infected with high-risk HPV is added information that will help physicians detect and treat early cell changes that might eventually lead to cervical cancer,” said FDA Commissioner Mark B. McClellan, M.D., Ph.D. “FDA is committed to bringing safe and effective new technologies to the market quickly.”

Up to 20 percent of the sexually active U.S. population is believed to be infected with HPV at any one time. Most women who become infected with HPV are able to eradicate the virus and suffer no apparent long-term consequences to their health. But a few women develop a persistent infection that can eventually lead to pre-cancerous changes in the cervix.

The HPV DNA test, like the Pap test, is performed by collecting cells from the cervix and then sending them to a laboratory for analysis. The test detects high-risk types of HPV in cell DNA even before there are any conclusive visible changes to the cervical cells.

Women who have normal Pap test results and no HPV infection are at very low risk (0.2%) for developing cervical cancer. Women who have an abnormal Pap test and a positive HPV test are at higher risk (6%-7% or greater) of developing cervical cancer if not treated.

FDA approved the expanded use of the test based on published literature describing studies of a cross section of women with normal and abnormal Pap test results who tested positive or negative for high-risk types of HPV. FDA also took into account additional input from professional societies, FDA advisory panel members and other interested parties in arriving at a decision.

The HPV DNA test is not intended to substitute for regular Pap screening. Nor is it intended to screen women under 30 who have normal Pap tests. Although the rate of HPV infection in this group is high, most infections are short-lived and not associated with cervical cancer.

Some 50 million women get Pap tests annually in the United States. According to the American Cancer Society, in 2003, 12,200 women will be diagnosed with cervical cancer and 4,100 will die from the disease. With proper screening, cervical cancer is avoidable and, if caught early, curable.

 HC2 is the product of Digen.

In 2007

Corporate History — Milestones and Highlights

QIAGEN was founded 1984 as a spin-off at the University of Düsseldorf. Since then the company has continuously developed and turned into what is today the world's leading provider for innovative sample and assay technologies for research in molecular diagnostics, applied testing, pharma and academic research.

A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China.

Cancer Institute, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.

BACKGROUND: A new test (careHPV; QIAGEN, Gaithersburg, MD, USA) has been developed to detect 14 high-risk types of carcinogenic human papillomavirus (HPV) in about 2.5 h, to screen women in developing regions for cervical intraepithelial neoplasia (CIN). We did a cross-sectional study to assess the clinical accuracy of careHPV as a rapid screening test in two county hospitals in rural China. METHODS: From May 10 to June 15, 2007, the careHPV test was done locally by use of self-obtained vaginal and provider-obtained cervical specimens from a screening population-based set of 2530 women aged 30 to 54 years in Shanxi province, China. All women were assessed by visual inspection with acetic acid (VIA), Digene High-Risk HPV HC2 DNA Test (HC2), liquid-based cytology, and colposcopy with directed biopsy and endocervical curettage as necessary. In 2388 women with complete data, 441 women with negative colposcopy, but unsatisfactory or abnormal cytology or who were positive on HC2 or the new careHPV test, were recalled for a second colposcopy, four-quadrant cervical biopsies, and endocervical curettage. An absence of independence between the tests was not adjusted for and the Bonferroni correction was used for multiple comparisons. FINDINGS: Complete data were available for 2388 (94.4%) women. 70 women had CIN2+ (moderate or severe CIN or cancer), of whom 23 had CIN3+. By use of CIN2+ as the reference standard and area-under-the-curve analysis with a two-sided alpha error level of 0.0083, the sensitivities and specificities of the careHPV test for a cut-off ratio cut-point of 0.5 relative light units, were 90.0% (95% CI 83.0-97.0) and 84.2% (82.7-85.7), respectively, on cervical specimens, and 81.4% (72.3-90.5) and 82.4% (80.8-83.9), respectively, on vaginal specimens (areas under the curve not significantly different, p=0.0596), compared with 41.4% (29.9-53.0) and 94.5% (93.6-95.4) for VIA (areas under the curve significantly different, p=0.0001 and p=0.0031, for cervical and vaginal-specimen comparisons for the careHPV test, respectively). The sensitivity and specificity of HC2 for cervical specimens were 97.1% (93.2-100) and 85.6% (84.2-87.1), respectively (areas under the curve not significantly different from the careHPV test on cervical specimens, p=0.0163). INTERPRETATION: The careHPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions.

 Your comment is excellent. I like these kinds of discussion.

作为一个宫颈癌筛查的志愿者，我只希望有更好的方法能够汇集所有的女性，不论地位高低，不论贫穷与富有。This is great. Wish there are more people like you in China.

I feel bad for our Chinese people when I heard many things in China, for example, open biopsy with frozen for breast masses, frozen fro breast margins, uterine fibroid with frozen, CIN1, 2, 3 for hystectomy et al.

News reports often 夸大事实 in China and all other countries. I will do a little serach about careHPV.

By the way I just an associate professor of pathology, not a professor. I am more happy if people call me Dr. zhao, or zhao, or Cheng (chengquan is too difficult for American, so I ask then to call me cheng).

 为比较不同子宫颈癌筛查方法的灵敏度、特异度和成本效益，探索适于我国不同地区资源条件和人群风险度的合理的筛查方案，提高我国妇女子宫颈癌的防治水平，1999年我们开展了“中国山西子宫颈癌筛查方法的研究”。该研究也表明，HPV由于其高敏感度和高重复性，可用于子宫颈癌初筛；薄层液基细胞学和hc2是目前最有效的子宫颈癌初筛手段可用于子宫颈癌的早诊早治。此项研究结果在2000年法国巴黎举行的欧洲生殖道感染与肿瘤大会上报告并获得欧罗金国际奖。美国药品与食品监督管理局（FDA）根据此结果，首次批准可用检测HPV病毒的hc2技术来发现子宫颈癌与癌前病变。该技术迅速被发达国家与地区采用，挽救了无数妇女的生命。 

 From above 子宫颈癌快速筛查技术----care HPV技术有望极大减轻发展中国家子宫颈癌疾病负担

I do not know the story in details, but I am sure it is not true. FDA approved HPV based on the one study in China?????? Maybe my chinese is bad and I misunderstand the meaning above.

 一位教授提到WHO在写宫颈癌防治手册（大概是这个计划吧）时，没有中国关于这方面的可信资料；另一位教授提到关于乳腺癌细胞学的文献好像只有阚秀教授发表在国内杂志上，国际杂志上找不到中国人发表的相关文献。我们应该做什么呢？我们应该怎么做呢？

In fact above was that I gave a talk about breast FNA and core biopsy for diagnosis of breast lesion in cytpathology meeting in Guangzou in the end of March. I chose this topic because I knew that we still use the open biopsy with frozen for breast mass lesions in a lot of hospitals in China. I found rare related papers published in english journal from China even though FNA for breast lesions are used in some large hospitals in China even in 1970th, 1980th.

 Anyway hope most of Chinese women will have cervical screening test because cervical cancer is a preventable cancer. Wish our China becomes stronger and stronger in all areas including medicine and pathology.

Thank Dr. lingxg again for your discussion. Welcome you visit here more often if you have time.

cz

 Thank Dr. lingxg .

This is very considerable and comprehensive discussion.  I like it.

I do not agree the term 廉价的病例 also. Some large clinical trials like to be perfomed in India, China or Aferia. There are several reasons I think, including population base and the selection of the control groups. 

For example:  HPV screeining  paper (above) just was published in New Engl J Med. 31,488 women were selected as control group without screening. This kinds of clinical trials will not be permitted to have in the usa or most european countries.

可是我们自己为什么还以FDA马首是瞻呢. Sure it is not necessary. FDA makes the rule for USA, not for other countries.

以WHO唯命是从呢？WHO is an international organization. We do not need to do all things as WHO suggested.  But medicine needs some standard for example, classification, terminology in the world for communication and patient care. If we have good system in China which can be used in all hospitals in China, this is good.

 In the USA there are big fight for primary cervical lesion screening, Pap test vs. HPV testing for all women older than 30, as Dr.  陈隆文 mentioned above. I still favor Pap test as primary screening method and reflex HPV testing for atypical squamous cells, AGC, or older women with LSIL in the USA. With the wide use of HPV vaccine for young girls, I agree screening approach may be change in the future.

From this web, I know the HPV testing is more than 300 RMB in China. This is too expensive for a lot of people in China.

If we have our own HPV testing method with good quality I think it will be much cheapter.

In China there should be more women with screening, even the conventional Pap (25 RMB, see above).

In fact many countries still use conventional Pap tests. I got the information from ThinPap company and psted in another topic.

UK and Ireland 100% LBC, 67% TPPT, 33% SP

 （英国和爱尔兰100%液基细胞学，67% TPPT, 33% SP）

Benelux 60% LBC, 55% TPPT, rest mainly SP 

 （英国和爱尔兰100%液基细胞学，67% TPPT, 33% SP）

Benelux 60% LBC, 55% TPPT, rest mainly SP 

（Benelux 60%液基细胞学，55%TPPT，余下主要是SP） 

Suisse 75% LBC, 60% TPPT, rest mainly SP 

 （瑞士75%液基细胞学，60% TPPT，余下主要是SP）

German 10% LBC, 60% TPPT 

 (德国10%液基细胞学，60%TPPT）

Nordic 15% LBC, 80% TPPT

（北欧15%液基细胞学，80%TPPT） 

Australia: 100% Conventional with 25 % of women paying for an additional TPPT

 （澳大利亚100%传统涂片和25%自费加做TPPT）

NZ- 60% conventional 25 % TPPT and 15% other LBC

（新西兰60%传统涂片、25%TPPT和15%的其他液基细胞学） 

For China we do not have what we would consider reliable market share data.

 （对于中国，我们没有可靠的市场份额数据。）

from

Jeff Keene, Director Global Communications and Payer Relations,Hologic/Cytyc Corp

（Jeff Keene是赛迪公司全球联络部主任和付款联系人）