Dual P16/Ki67 staining may help identify women with low grade cytology who are likely to progress to cervical cancer.
Amber Joyner BSc (Hons) LIBMS
The Royal Sussex County Hospital, Brighton in collaboration with Roche Tissue Diagnostics, Burgess Hill.
Supervisor: Gary Robinson
This dissertation is submitted in partial fulfilment of the project requirements for the M.S.c:
Clinical Sciences
May 2015
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Dual P16/Ki67 staining may help identify women with low grade
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It is widely accepted that HPV subtypes 16 and 18 are responsible for around 70% of cases of cervical cancer (2, 3), however, with the advent of the current quadrivalent vaccine it is expected that the number of HPV 16 and 18 infections will reduce in the coming years.
The high numbers of patients testing positive for oHPV has been noted at this centre, resulting in large numbers of colposcopy referrals. The gov.uk website publishes the National Schedule of Reference Costs every year which lists the number of patients who attend for procedures, the unit costs for these procedures and the total cost for these procedures for that year. In 2013-2014 a total of 230, 038 women attended diagnostic colposcopies across all NHS Trusts and Foundation Trusts costing a total of £28,179,422(4).
This study aimed to determine if it is possible to more accurately identify women who are most likely to develop high grade dyskaryosis or invasive cervical cancer, and send only those for treatment, thus streamlining the current protocol by using immunostaining during the screening process.
P16 and Ki67
Cell cycle control in mammalian cells is a complex mechanism and is regulated by cyclin-dependent kinases (CDKs) and their activating co-enzyme cyclins (A, B, D, and E).
P16INK4a (P16) is a tumour suppressor protein and
Cervical cancer is when there are malignant cells present in the cervix; it is developed in the lining of the cervix. A cervix is a narrow opening located at the bottom of the uterus that leads into the vagina. Cervical cancer mostly affects women between the ages of 40 and 55. This cancer can be prevented by screening for precancerous cells, and it can also be cured if it is detected at an early stage. Over the past few decades the number of cervical cancer cases has declined dramatically due to a more widespread screening of the disease. Today, it is estimated that 10,000 new
We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011). Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer.More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review.
The U.S. Preventative Services Task Force (USPSTF) recommends cervical cancer screening with cytology testing (also known as a Pap Smear) every three years in women ages 21 to 65 (U.S. Preventative Services Task Force [USPSTF], 2016a). The USPSTF has graded this recommendation with an “A” indicating that they have a high level of certainty that the screening will prove to be beneficial, rather than harmful to the patient (USPSTF, 2016a). However, if this patient would prefer to receive cervical cancer screening every five years, the USPSTF also has a high level of certainty that this will prove to beneficial rather than harmful if human papillomavirus (HPV) and cytology are both performed during this screening (USPSTF, 2016a). The
Prophylactic vaccination against high risk human papilloma virus 16 and 18 represents an exciting means of protection against HPV related malignancy. However, this strategy alone, even if there is a level of cross protection against other oncogenic viruses, cannot completely prevent cervical cancer. In some countries cervical screening programs have reduced the incidence of invasive cervical cancer by up to 80 percent although this decline has now reached a plateau with current cancers occurring in patients who have failed to attend for screening or where the sensitivity of the tests have proved inadequate. Cervical screening is inevitably associated with significant anxiety for the many women who require investigation and treatment following abnormal cervical cytology. However, it is vitally important to stress the need for continued cervical screening to complement vaccination in order to optimize prevention in vaccines and prevent cervical cancer in older women where the value of vaccination is currently unclear. It is likely that vaccination will ultimately change the natural history of HPV disease by reducing the influence of the highly oncogenic types HPV 16 and 18. In the long term this is likely to lead to an increase in recommended screening intervals. HPV vaccination may also reduce
The symptoms of cervical cancer are not always obvious thus the introduction of NHS cervical screening programme. The aim of the NHS Cervical Screening Programme is prevent the number women who die from cervical cancer each year due to not having early diagnoses. Since the introduction of the programme, a report was done between the NHS Cervical Screening Programme and Trent Cancer Registry it found that “Incidence and mortality rates in England have fallen considerably over the past 20 years. During this period, incidence rates decreased by over a third and mortality rates reduced by 60%. Survival, following a diagnosis of cervical cancer has improved in England since the 1980’s from the 83% to 88%”. (NHS, 2012, pp. P10-11).
Almost all cervical carcinomas are caused by Human papillomavirus (HPV). Cervical cancer can be a life-threating disease. However, over recent years the occurrence of cervical cancer has declined as well as the chance of dying from it. A huge contributing factor to this decline is the importance of a regular pap smear. A pap smear can find cervical pre-cancer before it turns into cancer. Recently, a vaccine for HPV, has been on the market, which provides close to a 100% protection against pre-cancer and general warts. HPV and cervical cancer are two disease that are closely related. However, each disease effects not only similar populations, but also different populations, as well as having its own signs and symptoms, detection procedures,
In addition, the immune system of most women will usually suppress or eliminate HPVs. This is very important because only an ongoing persistent infection has the potential to lead to cervical cancer (HPV). Eleven thousand cases of this kind of cancer were confirmed in 2007 in the United States; the amount undiagnosed is still unclear but believed to be in the tens of thousands. But to give some perspective of the problem you need to understand its effects on a global level. On the world wide scale cervical cancer strikes nearly half a million women each year, claiming more than a quarter of a million lives. “High risk” HPV types 16 and 18 are implicated in Seventy percent of cervical cancers and are hence selected for vaccine targets (The HPV).
Cervical cancer is the leading cause of cancerous death, in women, since 1950. Approximately 200,000 cervical cancer patients die each year in developing countries. Strains like HPV 16 and 18 cause about 70% of cervical cancer in women– one of the top causes of death in the world (WebMD, 2010, p.1). In the Unites States, about 10,000 women acquire the disease and 3,700 die annually Human Papilloma Virus (HPV) is directly associated as a cause of cervical cancer. This virus affects the skin and genital area and, in some cases, it can also infect the throat and mouth. Since the HPV is passed from one person to another through skin-to-skin or sexual contact, sexually active people are more prone to this virus. Merck
Approximately 500,000 new cases of cervical cancer occur each year worldwide, 260,000 of which are fatal. In the U.S., it is estimated that there were over 9,700 cases of cervical cancer in 2006, and of these 3,700 resulted in deaths”. Vaccinations are one of the most successful public health approaches to preventing and controlling infectious diseases. According to the CDC Advisory Committee on Immunization Practices the vaccine has been proven to be virtually 100% effective against the two types of HPV that are responsible for some 70% of cervical cancers.
Beginning since 2012, U.S. Preventive Services Task Force (USPSTF) has reduced the frequency for Cervical Cancer Screenings, and begins to continue with reducing recommendation as described in Kaiser’s article “Prevention Experts Propose Easing Advice on Number of Cervical Cancer Screenings.” This reduction came in 2013, 11,955 women were diagnosed with Cervical Cancer (Fowler, Saraiya, Moskosky, Miller, Gable & Mautone-Smith, 2017). The determination of which testing, Pap Smear or HPV Co- Testing, is based on the patient education, and future desire of pregnancy. Predominantly most cervical cancers are due to the lack of screening (Andrews, 2017). A plan based on education and notification would be more beneficial than a continued over
Among the many arguments for mandatory HPV vaccination, the foremost is that it is an important medical achievement and a major public health milestone. This vaccine has proven to be one-hundred percent effective in preventing the 4 HPV strains that are responsible for seventy percent of cervical cancers and ninety percent of genital warts. In addition, no serious side effects have been identified. Because this vaccine is a preventive measure, administration before onset of sexual activity is ideal; however, even females who have been sexually active can still benefit from this vaccination (Perkins et al., 2010). Nationally and internationally, the HPV vaccine will significantly reduce disease burden by reducing monetary and psychological costs of invasive procedures that remove precancerous and cancerous lesions. By combining vaccination with routine Pap smear screening, these public health efforts have the remarkable opportunity to eradicate cervical cancer (Ramet et al., 2011).
Castle and colleagues did a study to determine the appropriate age for HPV vaccination. They stated that in the United States cervical cancer screening program has achieved 75% reduction in incidence of the cervical cancer and HPV vaccine will only reduce additional cancer cases and other HPV related sequelae such as carcinoma intraepithelial neoplasia (CIN) 2 and CIN 3. These are the precancerous lesions. The vaccine will be effective only for those who are never exposed to HPV infection. It will have no use for those who are already infected or exposed.. According to the study the median age for CIN 2/3 lesion was between the ages 25 to 30. If the time since acquiring infection and development of CIN 2/3 is on average 5 to 10 years, HPV vaccine will prevent CIN 2/3 only if given to women before age of 26 years with best results if given before 18 years of age (Castle, et
Cervical Cancer Early Detection Program Journal of Women’s Health 20(10):1479-84 doi: 10.1089/jwh.2010.2530. Epub 2011 Jul 20
In the United States, it is one of the eight-most common cancer of women. According to researches, the data shows that Hispanic women are significantly more likely to be diagnosed with cervical cancer than the general population and their median age at diagnosis is 48. In 1998, about 12,800 women were diagnosed in the US and about 4,800 died. Among cancers of the female reproductive tract, it is less common than endometrial cancer and ovarian cancer. The rates of new cases in the United States was 7 per 100,000 women in 2004. Cervical cancer deaths decreased by approximately 74% in the
Cervical cancer is second among the most common cancer that affects women globally. The challenge towards the measures taken to reduce the disease among women is the lack of proper information on the link between the disease itself and the leading cause of it. The disease can be reduced by limiting sexual partners and practicing safe sex, which are challenging and difficult to promote. Therefore, one of the effective ways towards reducing the various cases of cervical cancer is through the HPV vaccination. Most women do not have the information on the connection between cervical cancer and HPV. Consequently, there is the uncertainty among women