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
You may be screened for cervical cancer more often if you have risk factors for cervical cancer
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
Human Papilloma Virus (HPV) is a double stranded DNA virus. There are many genotypes HPV and some of them are oncogenic. They have envelope proteins E6 and E7 on their cell wall which are associated to initiate cancer. Anogenital lesions associated to HPV are divided into ‘low-risk’ types (6, 11, 34, 40, 42, and 43) and ‘high risk’ types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, and 82). Most of the low risk HPV infections are asymptomatic and are not fatal, however infection to high risk HPV such as type 16 and 18 may cause cervical, anal, vaginal, vulvar and penile cancer (Centre of Disease Control, 2012). Low risk HPV generally cause warts on the skin surface which rarely develop into malignancy. Type 16 and 18 both were originally isolated from cervical carcinomas of human body. More than 70% of human cervical is due to the infection of either HPV 16 or 18. According to CDC, in 2008 it was estimated 11,070 cases of cervical cancer in United States and about 3,870 deaths due to cervical cancer. Higher percentage of HPV persistent infection occurs by HPV-16 and the risk of getting cervical cancer due the progression of disease is higher for HPV 16 and 18 and 45 (Tino F. Schwarz, 2008).
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,
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
According to the Centers for Disease Control and Prevention (CDC), Human papillomavirus (HPV) infects roughly 20 million individuals in the United States with 6.1 million new cases each year. There is no cure for HPV, only treatment for associated health problems. There are more than 30 strains of HPV that affect more than half of sexually active individuals in their lifetime. Public health risks involve several types of HPV leading to precancerous lesions and causing 70% of cervical cancer. Cervical cancer, the second most common cancer, affects many women globally. In the United States, nearly 10,000 women are diagnosed with cervical cancer annually and 3,700 of those women die. It has been reported by American Cancer Society that with early
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 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 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