Team:ZJU-China/Background
HPV & Cervical Cancer
In the past 10 years, the war between humans and viruses has become more and more fierce. In an annual review released by WHO in 2018, the need to develop a better and more thorough diagnostic tools for screening the epidemic diseases, especially those caused by viruses was emphasized.
Undoubtfully, High-risk Human papillomavirus (HPV) is one of those threatened viruses because of its evil “witchcrafts” to cause Cervical Cancer (CC) in women.[1] Nowadays, CC is the most or second most common cancer among women in developing countries (157/100,000 women).[2] For example, In Africa and Central America, CC is the deadliest cancer every year. In 2018, approximately 311,000 women died from CC; more than 85% of these deaths occurring in low- and middle-income countries (WHO, 2019). Patients suffer from foul-smell discharge, vaginal discomfort, swelling of legs or vaginal bleeding. Even those who get cured by surgery will lose fertility in most cases, which will surely bring great pain not only to patients, but a family.
Only to make things worse, unlike the infection of low-risk types which will induce obvious but non-lethal symptoms such as flat wart, condyloma acuminate or toe wart, high-risk HPV infection of the reproductive system does not cause any visible symptoms. That means if you do not get HPV infection screening regularly, you may never find you were infected until it is too late (after you get CC). What’s more, contrary to traditional beliefs, HPV does not only infect women, and its infection is not limited to the reproductive organs. The infection of the malignant strain may develop into systemic infection (Figure 1). Many smokers suffer from head and neck cancer due to HPV infection of their mouth.
Figure 1. An Indonesian man known as “tree man” due to the scaly warts covering his body. These warts are all caused by HPV.
Pictures from Ardiles Rante & HKV / Barcroft Media.
HPV & CC in China
Just like many other developing countries’, Chinese women suffer from CC and other diseases brought about by HPV. In China, the infection rate of HPV is up to 21.7%, and the highest infection rate among women aged 15-19 years is 30.55%. In 2013, nearly 277 Chinese women were diagnosed with CC per day. About 48,000 Chinese women die from it annually (HPV Information Centre).
According to WHO, CC control includes primary prevention (vaccination against HPV), secondary prevention (screening and treatment of pre-cancerous lesions), and tertiary prevention (diagnosis and treatment of invasive CC).
Unfortunately, until now, Chinese domestic 9-valent HPV vaccine is still in the process of clinical trials and China holds an extremely rigorous attitude to imported HPV vaccines. So that the supply of 9-valent vaccines become so limited that China has to ban the 9-valent vaccine for men, and women also need to "queue up" for the vaccine. Therefore, many people lose chance to get primary prevention for themselves, which makes secondary and tertiary prevention more important in our country.
CC has a long pre-invasive phase, that means, in theory, the earlier you find it, the more likely you are to be cured. Many researchers approve of this statement after they found the close relationship between the decline of incidence and mortality of CC in developed countries with the discovery of the “Pap test” (a screening method) in the 1940s. After Thinprep cytologic test (TCT) was approved by FDA in 1996, the incidence of CC further decreased in countries introduced this method. It seems that screening is of great importance in the prevention of CC. Considering this, China introduced TCT in 1999 and emphasize that the CC regular screening ratio should reach 80% by 2020 in The implementation of the Program of China's Women Development (2011- 2020).
However, TCT seems to lost its “magic” in China. Based on data collect by the National Central Cancer Registry (NCCR), the incidence and ASRIC of CC continued to increase between 2009 to 2014 (figure. 2A), the WHO’s statistics also show the same results (figure. 2B). In light of our questionnaire and a survey done by Women’s Hospital School of Medicine Zhejiang University, the CC regular screening ratio (between 20%-30%) is much lower than our set aim (80%) in Zhejiang Province, one of the most developed provinces in China, suggested an even lower screening ratio nationwide. Click to see the questionnaire results.
Figure 2. Incidence of Cervical Cancer in China over time.
(A) Incidence of Cervical Cancer in China from 1998 to 2012, data from WHO CI5. Only five regions in China were involved, they are Shanghai, Jiashan, Zhongshan, Harbin and Hong Kong. population.
(B) Incidence of Cervical Cancer in China from 2009 to 2012, data from National Central Cancer Registry (NCCR).[3-8] The whole country is involved.
*ASRIW: Age-standardized rate of incidence by the world standard.
*ASRIC: Age-standardized rate of incidence by the Chinese standard population in 2000.
Existing methods for CC detection
Existing CC detection is based on cytological evidence, the classic method is called “Pap test”, a kind of cytologic test which involves scraping a small amount of cervical epithelial cells, smears and microscopic examination to determine the condition. Newer technology such as TCT significantly improves the sensitivity and specificity, but still need doctors to judge the progress of CC. However, the invasive sampling which is needed in TCT hesitate many women. Besides, the number of doctors is limited and they need time to check every cell smear, it limits the number of people furthermore, this method involves subjective assessments which can be influenced by intraindividual and interindividual variability. Due to it, cytologic test can never be a good method in wide-range screening.
Nowadays, the most common way used for CC wide-range screening is HPV infection detection based on DNA probe or PCR.
There are also many problems with this method:
(1) Invasive sampling (Figure 3) is still in need, which will not only cause physical pain, but bring psychological challenges to many patients such as in China, where women are more conservative and reserved than in western countries.
Figure 3. Invasive sampling for Cervical Cancer detection.
Pictures from U.S. NATIONAL CANCER INSTITUTION
(2) Invasive sampling, PCR technology as well as DNA probe testing all requires special equipment and professionally trained testing personnel, which is complicated. For women in remote areas, they often cannot find a place for the screening.
(3) The price for HPV detection is pretty high. According to our investigation, the price ranged from 200 to 580 yuan (30-82 dollars). Many people also said that they can’t afford it in the questionnaire.
(4) Time-consuming, many urban women get involved with their work and have no time to go to the hospital for a detection deliberately.
(5) Many vaginal infections may cause vaginal swelling and inflammation. For these patients, invasive sampling is not considered medically acceptable, because they may aggravate the condition.
All these problems become obstructions for Chinese women to do HPV detection regularly based on our survey. Therefore, there is an urgent need to develop novel nucleic acid detection technologies with high sensitivity (for early screening, specificity is not very important), low price and extreme convenience. That’s where we got to start our project and we do hope our devotion can make differences.
Reference
[1] Chetty, R. 70 years of the JCP-highly cited papers: The causal relation between human papillomavirus and cervical cancer. Journal of Clinical Pathology 70, 997, doi:10.1136/jclinpath-2017-204867 (2017).
[2] WHO. IARC handbooks of cancer prevention. Volume 10: Cervix cancer screening. Vol. 10 (2005).
[3] Chen, W., Zheng, R., Zeng, H., Zhang, S. & He, J. Annual report on status of cancer in China, 2011. Chin J Cancer Res 27, 2-12, doi:10.3978/j.issn.1000-9604.2015.01.06 (2015).
[4] Chen, W. et al. Cancer incidence and mortality in China, 2014. Chin J Cancer Res 30, 1-12, doi:10.21147/j.issn.1000-9604.2018.01.01 (2018).
[5] Song, B. et al. Incidence and mortality of cervical cancer in China, 2013. Chin J Cancer Res 29, 471-476, doi:10.21147/j.issn.1000-9604.2017.06.01 (2017).
[6] Chen, W. et al. National cancer incidence and mortality in China, 2012. Chin J Cancer Res 28, 1-11, doi:10.3978/j.issn.1000-9604.2016.02.08 (2016).
[7] Chen, W. et al. Report of cancer incidence and mortality in China, 2010. Ann Transl Med 2, 61-61, doi:10.3978/j.issn.2305-5839.2014.04.05 (2014).
[8] Chen, W. et al. Report of incidence and mortality in China cancer registries, 2009. Chin J Cancer Res 25, 10-21, doi:10.3978/j.issn.1000-9604.2012.12.04 (2013).
