Albert Singer教授访谈：阴道镜宫颈癌检查和阴道镜微创手术的应用

Albert Singer 教授

1 Chinese obstetrics and gynecology online:Dear Professor Singer, thank you so much for accepting our interview with Chinese Obstetrics and Gynecology online, nowdays HPV vaccine has become the primary prevention of cervical cancer, could you talk about HPV vaccine and the progress in diagnosis and treatment of cervical cancer internationally?

1 中国妇产科在线：教授您好，非常感谢您能接受我们中国妇产科在线的采访，目前认为HPV疫苗作为宫颈癌的一级预防措施受到了广泛关注，能不能请您谈一下您对HPV疫苗的看法?

Answer: HPV vaccine is one of the first vaccines developed specifically against cancer. Now we recognize that human papillomavirus(HPV) in lower genital tract also took up to 20-30% oral cancers, anal cancers, 60% of oropharyngeal cancers (cancers of the back of the throat, including the base of the tongue and tonsils).The vaccine was developed  in Cambridge, England by Australian Professor Ian Frazer. Now 10 years has passed since the vaccine was developed. There are antibodies against different types of HPV. The main forms of HPV that cause malignancy are type 16 and 18. Now there are 2 vaccines that been developed specifically against those 2 types, one is from Merck' in United States it was called Gardasil. It was developed 10 years ago against type 16 and 18. Gardasil includes type 6 and 11 specifically related to the development of warts. The second vaccine is called Cervarix by the GSK company, is against type 16 and 18. Many trials done by both company showed an effect against at least 70% of the types that caused those cancers. Within the last 12 months, Gardasil has now been increased to 9 viral types not only 16, 18 but 7 other types against cervical cancer that will increase the effect up to 92%,; certainly superior to what it exist in its competitive vaccine Cervarix. It seems the Cervarix produces more local reactions than the Gardasil. There is no significant evidence that serious medical conditions are caused by the vaccines. There are many reports which suggest this is the one of the safest vaccines and also  has been more supervised than any other vaccine. Their side effects are minor and are mainly at injection sites .There seems to be no effect on pregnancy . The routine has been to give 3 intramuscular injections over one year to adolescent or teenage girls in the United Kindom-countries starting 12 to 18. In Australia, the vaccine has been  given longest: now since 2007  it goes from age 12 to 26, with  the vaccine dosage standard at 3 injections. The WHO has now accepted evidence for the 2 vaccine injections in 12 months.. In Australia there is already evidence that number cases of high-grade squamous intraepithelial lesion (HSIL) has  reduced and  already 3 years ago already showed the number of man and woman with genital warts decreasing at a very significant rate. Finally the vaccine has now been extended to boys in Australia in the age from 12 to 18, and the main reason for that is to prevent man from getting both anal cancers and oropharyngeal cancers. Anal cancers mainly occurred in man who has sex with man( homosexually ).This program started in Australia 18 months ago.

　　Finally it would seem that efficacy of the vaccines will last at least a minimum of 10 years, but more studies are needed to evaluate how long the effect will last. 

Albert 教授：在历史上发展人乳头状瘤病毒疫苗是第一种针对癌症的疫苗。现在我们认识到，下生殖道的人类乳头状瘤病毒，口腔癌的发病中也高达20-30%，肛门、直肠癌、口咽癌（咽后壁的癌症，包括生长在舌根和扁桃体基底部的肿瘤）的达60%。该疫苗是由英国剑桥大学的澳大利亚教授伊恩弗雷泽10年前研发的，有针对不同类型别的HPV抗体。HPV16，18型是引起恶性肿瘤的最主要的型别。现已研发出专门针对这2种型别的2种疫苗上市，分别是10年前默沙东(Merck)药厂研制的子宫颈癌疫苗加卫苗(Gardasil)，抗16 18型，现在又增加了6， 11型等9种型别的和疣相关的HPV。另一种疫苗是由葛兰素史克(GlaxoSmithKline GSK)药厂生产研发的子宫颈癌疫苗卉妍康苗（Cervarix），预防16和18型。这2家公司的大量实验都表明至少对70%的上文提到的癌症类型有良好效果。在过去的12个月内，Gardasil的宫颈癌预防型别已经增加到了9种，不仅仅是16,18还包括其它7种型别，其预防效果高达92%，比它的竞争对象卉妍康疫苗（Cervarix）要优越很多，但从局部反应来看，卉妍康疫苗（Cervarix）比加卫苗(Gardasil)产生更多的局部反应。没有明显的证据这些疫苗可能会影响人体，但它也存在一些异常的报告，但只有一例是发生在过去的一个月内，这表明到目前为止还是一个最安全的疫苗，并且它比其它任何疫苗监管的到位些，它几乎不会影响到怀孕，在孕期被认为是一种安全的疫苗。在联合国的国家，从12到18岁的青少年或少女1年内常规给予3次肌肉注射。在澳大利亚，这种疫苗接种的时间是最长的，从12到26。该注射疫苗的有3种剂量标准。去年WHO认可了这2种注射疫苗，3到4周前英国宣布认可了一种混合注射制剂。在澳大利亚，刊登在柳叶刀杂志上的一篇文章已经有证据表明，高级别宫颈癌病例数（HSIL指的是宫颈细胞鳞状上皮内高度病变）正在减少，3年前已显示出男性和女性患生殖器疣的数量在显著的下降。如今疫苗现在已经扩展到澳大利亚的12到18的男孩中，主要是防止肛门癌和口咽癌。男性肛门癌主要发生在和男同性恋，所以这个项目18个月前在澳大利亚启动了，但似乎最少需要10年的研究才能评估其效果可以持续多久。

2 Chinese obstetrics and gynecology online:Can you introduce updates in diagnosis and treatment of cervical cancer internationally?

２ 中国妇产科在线：目前国际上宫颈癌的诊治方面有哪些进展呢？

 Answer: Significant developments in regard to diagnosis and subsequent treatment will only come from the introduction of HPV-DNA screening. Cytology has an average sensitivity of 65-70% while the  HPV DNA test is probably 97-8%  The negative predictive rate is 99%And it is certainly cheaper to do and just need one doctor to take a swab .There are however many studies showing the positive predicted value is only 16%. That means that 1 in 6 women positive with  HPV have cervical precancer, the other 5 have infection. If the infection persists over many years  then eventually 1 or 3 will get precancer .It also means that positive HPV women have to be either sent to colposcopy or tested by bio-markers such as p16. to find the one in six with CIN
For high grade disease (CIN 2/3) the most popular form of treatment is to use loop excision procedure. Most will be done in the outpatients department under local anaesthesia  with cure rates of 95%. In the developing world, it seem the use of cold coagulation would be highly effective treatment producing destruction to 6-7mm and giving a cure rate similar to loop excision.

Albert 教授：宫颈癌的诊治进展要涉及到HPV-DNA筛查，细胞学筛查的平均敏感约为65-70% 加上HPV筛查其准确性可能达到99.5%。细胞学筛查很便宜并且只需要一个医生用一个棉签就可以完成了，但许多研究者报道其阳性预测值却仅为60%，这就意味着每6个HPV阳性患者中就有1个是宫颈癌前病变，其他5人可能由感染引起，如果这种感染持续存在，则最终会有1到3个人会得病。同时这些HPV阳性的妇女会被接受阴道镜检查治疗或者p16标记物治疗。高级别病变的局部高频电波破坏治疗中最流行的治疗方式是使用宫颈环形电切术利普刀，大部分手术可以在门诊部完成，像这样使用凝固的治疗方法在发展中国家，很多临床试验都证明非常有效，另一个发展则是关于这方面的培训。

3 Chinese obstetrics and gynecology online: Could there be any medicine to treat persistent HPV infection?

３ 中国妇产科在线：：存在治疗人类乳头状瘤病毒持续感染的药物吗？

Answer: No. HPV is a virus infection, and 80% of sexually active women will come across it   in their life time .The vast majority about 90% will clear it within 12 to15 months from their body. We know that  when immunity is poor such as in women with HIV,  or were the immune system is deficient then these  conditions will contribute to persistent infection. Normal young woman will get rid of the virus just living a healthy life style, like reduction in smoking and alcohol. Enough sleep and exercise which will be good for the immune system will certainly allow women to clear the virus , and there is no therapeutic product that will clear HPV, if there is, I believe that will be  a form of unproven medicine.

Albert 教授：目前还不存在这样的药物。HPV是一种病毒感染，80%性活跃的妇女在她们的一生中都有可能感染这种病毒。绝大部分（约为90%）的人会在感染后的12 到15个月内自动将它从肌体内清除。我们知道免疫能力差，如免疫抑制者如感染HIV的妇女，系统免疫功能缺陷的条件下可能会导致持续感染，而正常的年轻女子会自动清除病毒。健康的生活方式，如减少吸烟和饮酒，足够的睡眠和锻炼，一定会帮助女性免疫系统很好的清除肌体内病毒。目前不存在任何一种治疗性的药物可以清除HPV，如果有我相信它一定会是药物界的奇迹。

4 Chinese obstetrics and gynecology online: At present, colposcopic examination has become a common method in the diagnosis of cervical precancer.  However, in CIN 1, there may be some divergence. Can you please talk about what we should pay attention in the colposcopic examination? Are there any skills?

４ 中国妇产科在线：目前阴道镜检查宫颈癌前病变已经成为临床上常用方法，但是如CIN I   级，在诊断过程中可能会出现一些分歧，能不能请您谈一下阴道镜检查宫颈癌前病变中应该注意哪些方面，又有哪些技巧呢？

Answer: Colposcopy is used as a bionocular devicewith magnification .However recently  a monocular device weighing only 450 grams with the latest lense and lighting system is poised to transform colposcopy .It has a smart phone attachment which can record with photographs and video the cervical epithelium and images are able to transmitted outside the clinic.all the data is stored in the cloud  Premalignant disease, usually includes low grade. CIN 1 but it  is most likely that it is no more than a reversible HPV condition, found  in association with high grade disease  the so called CIN 2 and 3. We know for sure if we left CIN 2 and 3, it will go on cancer about 30% for cases over 30 years. Finding CIN 1 is by biopsies. CIN 1 should be left unless  it persists for over 2 years and cause emotional distress to the woman. It usually can be easily removed, but just getting a diagnosis of CIN 1 does not warrent intervention.
 Colposcopy and cytology are subjective observations. There are a number of studies which  show that the diagnosis of CIN 1 on one day can be completely misinterpreted the next day. It is well known that 30% of low grade lesion like CIN 1, when reexamined are  usually down grade to just HPV infection.

Albert 教授：目前阴道镜是作为一种单眼装置用来观察和检查子宫颈的医疗设备，它甚至可以用来区分癌前疾病和临床癌症。如果是癌前疾病，它检查到的级别通常会比较低危。CIN1（轻度上皮内瘤变）是一种可逆的HPV感染，但发现有时候它会和高级别病变（CIN2、 CIN3）联系在一起。我们知道如果放置CIN2、 CIN3不进行干预，任由其发展，那么在30年内将会有30%的病例发生癌变。发现CIN 1最主要的办法就是宫颈活检采样，采样时，我们通常会取3活检标本，病理会回报为衰退性改变，炎性改变或免疫反应性改变。只有当CIN1持续两年感染或者它对女性造成了情绪压抑的困扰时才需要给予治疗，通常我们的肌体可以很容易的将其清除，但单独诊断为CIN 1不需要任何干预治疗。从我个人的观点，我认为阴道镜检查和细胞学检查是主观的观察，有许多前人的研究显示今天诊断为CIN 1到了第二天可以是一个完全不一样的诊断。众所周知，30%的低级别病变如CIN 1，复查时通常下降低程度到只是HPV感染。如此所见相同的情况也可以发生在进行阴道镜检查时，因此它需要对检查实施者进行专业技术的培训。

5 Chinese obstetrics and gynecology online: Excision procedure like LOOP or LEEP certainly have  been recognized by most medical workers and patients as highly effective , but with the rapid growth of colposcopy has also raised some questions about long term effects on the cervix and consequences for future pregnancies   so what do you think we should do to perform the surgeries better  and prevent these complications?

５ 中国妇产科在线：阴道镜手术作为一项微创手术已经得到了广大患者及医疗工作者的认可，但是阴道镜手术量的过快增长也带来了一些问题，您认为如何合理规范的利用阴道镜手术呢？

Answer: The increasing evidence that excision procedure like LOOP or LEEP certainly can have an affect of obstetric morbidity. In 2006 paper in Lancet showed that  excision techniques used on the cervical, like cold knife  conisation or LEEP or electro- coagulation will  be associated with increasing rates  premature delivery, premature rupture of membrane, increase in the number of baby going to the neonatal intensive care wards , So we  now realize for the first time that these operations were not without their problems. In the last 9 years we  have become more aware  of the problems associated with the mechanical remove of  part of the cervical. It seems once of the 10mm of the cervical tissue is  removed  that this will increase the  obstetrical mobidity, .However we now realize there are other facts involved in increasing this morbidity and not all are of a mechanical nature  Years ago  it was realized that women having a premature delivery have a certain life style which is very similar to the life style of many woman who have cervical precancer and the treatment, , Malnutrition,in those women will have also an associated  increased risk of abnormal cytology, as well as vaginal infection and a change in the vaginal biome..We therefore have a mix of the social factor with  the mechanical ones. In the last 2 years there is a big work done about the microbiome (as mentioned above ) of the vaginal, i bacteria 

　　So it is probably a combination of all thEse factors, but the major one seem to be a mechanical removal of more than 10 mm of the end of the cervical..It is  most important  for these women to recognize there is increasing risk of mobidity  in a pregnancy after  a loop excision and to undertake ultrasonic vaginal screening  to  determine the length of the cervix from very early in pregnancy. The important thing is to balance up the mobidity against the potential mortality of leaving a woman who is undertreated for a treatable premalignant lesion.

Albert 教授：在阴道镜下不能对宫颈进行治疗，我认为你想问的问题可能是：越来越多的证据研究表明像环切除术或LEEP术可能会给妇女带来产科相关的宫颈过度活动症。2006发表在柳叶刀杂志上的关于宫颈切除的技术，如冷刀或电凝术会增加早产、胎膜早破甚至增加新生儿去新生儿重症监护室的数量，所以我们第一次认识到这些操作并不是没有副作用的。在过去的9年里，我们越来越意识到机械性的去除宫颈，对宫颈的切除超过10mm将会增加宫颈过度活动症的风险，但现在我们也意识到这可能还有其他的因素也参与了它的发生。4年前有过流产史的妇女的生活方式和许多有过宫颈癌前病变和治疗的生活方式非常相似，如性伙伴数目较多、营养不良，这些妇女发生细胞学结果异常的风险较高，所以当发生症状时你必须综合考虑社会因素还是机械性因素的反应。在过去的2年里，一个规模较大的针对阴道微生态的研究显示，似乎局部细菌差异的改变也参与了该症状的发生，因此其发生可能是这一系列因素的综合原因，但最主要的似乎是由于机械性的去除宫颈末端深度大于10mm。这些妇女最应该关注的是，首先要认识到它有增加宫颈过度活动症的风险，并且要在怀孕的早期就进行阴道超声筛查，确定宫颈的长度。但对于医生来说最重要的是要权衡宫颈过度活动症给女性带来的风险和由于对病灶不进行治疗而导致癌前病变潜在的死亡率增加的后果。

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