• 1.
  

  a) F b) F c) F d) F e) T

Cost-effectiveness analyses have shown that screening annually is associated with high incremental cost-effectiveness ratios across a variety of settings and countries. This is because, compared with screening at less frequent intervals, screening annually detects a small additional amount of cervical intraepithelial neoplasia and cancer for a high number of additional tests and procedures.

• 2.
  

  a) T b) F c) T d) F e) F

Randomised-controlled trials and meta-analyses have shown that cytology-based screening detects about 50–70% of prevalent high-grade lesions. In addition, cytology has been shown to have only moderate reproducibility when comparing clinic-based diagnoses to that obtained from an expert panel of pathologists.

• 3.
  

  a) F b) T c) F d) F e) F

Only vaccination coverage has actually proved to be lower than when modelled of the parameters above.

• 4.
  

  a) F b) F c) T d) F e) F

Owing to the rapid natural history of ovarian cancer, even a perfectly sensitive screening test may not optimally reduce mortality from this disease. Simulation models indicate that increasing the frequency of screening may have a greater effect on reducing mortality than improving the sensitivity of an annual screening test. Unfortunately, increasing the frequency of a screening test also seems to have a negative effect on its cost-effectiveness. Using sequential screening tests rather than single ones may improve sensitivity for detecting the disease but does not per se equate to an improved outcome.

• 5.
  

  a) F b) T c) F d) F e) F

In order for screening to be effective, the disease needs sufficient incidence, and there should be a tool that can detect a premalignant state in order to provide effective treatment before the malignancy develops. Vulvar squamous cell carcinoma is rare, and evidence that screening increases early detection of cancer or associated premalignant conditions is lacking. Between 60 and 80% of VSCC are not dependent on the human papilloma virus and are associated with differentiated VIN or lichen sclerosus. Evidence is increasing that associated skin changes adjacent to VSCC, previously diagnosed as lichen sclerosus, are in fact differentiated VIN on review. The incidence of differentiated VIN is increasing. It is likely, however, to be a reflection of increased awareness and a higher biopsy rate, rather than a true increase in incidence of disease. Differentiated VIN has a high risk of malignant progression compared with usual type VIN. Tumours associated with human papilloma virus (HPV) tend to occur in younger women and have a better prognosis. In a recent analysis of VSCC, 96% of tumours associated with usual type VIN were HPV positive, compared with 10% of tumours associated with differentiated VIN. The disease-specific survival was significantly better in tumours associated with positive HPV tests and usual type VIN compared with negative HPV tests and differentiated VIN. Surprisingly, however, the worst survival was in a small subset of women with tumours associated with differentiated VIN that were HPV positive. Women with VSCC associated with usual type VIN tend to be younger, whereas women with VSCC with lichen sclerosus and differentiated VIN tend to be older. The incidence of women under 50 years developing VSCC has increased over the past 30 years from 2–21% of all VSCC. It is thought that this is caused by the increased incidence of usual type VIN, which has increased by 400% in the same time period. Differentiated VIN has a greater malignant potential than usual type VIN, but the mechanism of this is unknown. Studies have shown an association of up to 85% between differentiated VIN and VSCC. In a study assessing the development of VSCC more than 6 months after a biopsy showing differentiated VIN, 32.8% of women developed a cancer compared with only 5.7% of usual type VIN, producing a 5.6-fold increased risk of progression with differentiated VIN. The malignant potential of usual type VIN is thought to be 3–9% if the disease is treated, but if usual type VIN is untreated, the risk of progression has been reported to increase to 87%. Tumours associated with differentiated VIN are three times more likely to recur than tumours associated with usual type VIN.

• 6.
  

  a) T b) F c) T d) F e) T

The use of vulval cytology may provide an adjunct as a diagnostic tool, but is not an effective screening tool in the general population. The use of staining methods, such as acetic acid and toluidine blue, may help delineate vulval lesions, but is also not an effective method of screening, as 30% of normal vulvas have been shown to uptake aceto-white. The incidence of differentiated VIN is increasing. It is likely, however, to be a reflection of increased awareness and a higher biopsy rate, rather than a true increase in incidence of disease. Women with VSCC who are HPV negative have an increased risk of metastatic disease, and women with VSCC arising on a background of differentiated VIN have a three-fold greater risk of recurrence compared with women with VSCC associated with usual type VIN. This risk is potentiated further by the presence of lichen sclerosus.

• 7.
  

  a) T b) T c) F d) T e) T

The age-specific incident rate of cervical cancer worldwide is indeed 15 per 100,000 women with the lowest burden of cervical cancer in the world in Australia and New Zealand and highest in East Africa. Breast, lung and colon cancer all have higher rates of disease specific death. Cervical cancer incidence is inversely proportional to the existence of screening programmes.

• 8.
  

  a) T b) F c) T d) T e) T

All successful screening programmes, regardless of disease, are dependent upon high coverage, defined target groups, and high quality functional systems. Screening younger women can result in more harm than good due to high rates of false positives.

• 9.
  

  a) T b) T c) T d) F e) F

• 10.
  

  a) F b) T c) F d) F e) T

• 11.
  

  a) T b) F c) F d) F e) T

Visual inspection with acetic acid has been shown to be as sensitive as cytology and have a high negative predictive value but low positive predictive value. It is a diagnostic test only and not therapeutic. Quality control is difficult as it is very operator dependent.

• 12.
  

  a) F b) T c) T d) T e) T

Cost per se it is not a major barrier but the infrastructure invariably is. One-off or very infrequent testing will lead to poor sensitivity as interval cancers are inevitable. There is no point screening also if colposcopy and treatment are not available and many developing countries do indeed have many competing health needs

• 13.
  

  a) T b) T c) F d) F e) T

Advantages of testing for high-risk human papillomavirus DNA types indeed include its objectivity, high sensitivity and very high negative predictability and triaging women into those truly at higher risk of developing cervical intraepithelial neoplasia. The cost is not low though it is reducing over time.

• 14.
  

  a) F b) T c) T d) F e) T

High quality tests that can be used locally and out-with technical settings are ideal.

• 15.
  

  a) T b) F c) F d) T e) T

In case of cervical cytology, a good sample quality is essential, comprising ecto-and endocervical cells. Errors in sampling and preparation of slide might occur in conventional cytology. Collection of a sample for HPV DNA testing is simple. The HPV tests detect genetic material of HPV by DNA/RNA estimation techniques even from self-collected samples and residual material of sample collected for cytology. Unlike Pap smears, the HPV test does not depend on cell morphology. It is based on detection of HPV DNA. The interpretation of the HPV test is objective. The screening tests are quantitative or semi-quantitative assays that detect the DNA of the targeted HPV types using different probes. A Pap smear is subjective since it is read and interpreted by a cyto-pathologist. The absence of errors in sampling, preparation and interpretation means that the HPV test does not need to be repeated frequently. HPV DNA testing is more sensitive than cytology. Primary screening with HC2 detects more than 90% of all CIN2, CIN3 or cancer cases.

• 16.
  

  a) T b) F c) T d) T e) T

The sensitivity of HPV testing remains constant irrespective of age as it detects women with active HPV infection, whereas the specificity increases with age because of its transient nature. Younger women mostly clear the infection spontaneously. In the older age group, the presence of HPV persistent infections is more likely. The positive predictive value of both HPV testing and cytology is higher in the younger age group because of a high prevalence of CIN 2+ lesions in this age group. The negative predictive value of HPV testing has been reported to be as high as 97-99%. If the test result is negative, there is no need to repeat the test for 3 years. If this is combined with cytology, the screening interval can be increased to 5-8 years.

• 17.
  

  a) F b) F c) F d) F e) T

Women aged 30-60 years negative on both tests can be recalled after 3-5 years because of the high negative predictive value. Women with negative HPV and borderline cytology are recalled after 3-5 years for repeat HPV testing. Women with positive HPV and borderline or normal cytology are again called for HPV testing and cytology after 12 months because they are at increased risk of developing an abnormal smear within the next 5 years. Women with HSIL cytology should be referred for colposcopy and directed biopsy. The ALTS trial found that LSIL is associated with a 25% risk of histologic CIN2 or 3. Therefore, these patients should be evaluated with colposcopy even after a single LSIL report.

• 18.
  

  a) F b) T c) T d) T e) F

Probe B of Hybrid Capture2, approved by the FDA in 2000, detects 13 high risk HPV types and probe A detects 5 low risk types. HC2’s high risk probe may cross react with HPV types 53, 66, 67, 73, that are not present in the probe mix and this cross reaction could lead to false positive results decreasing the test specificity. Cervista HR HPV, approved by FDA in 2009, detects 14 high-risk HPV types, 13 of which are the same as in HC2 with an additional HPV type 66. Recently there have been assays that use transcription mediated amplification to detect the E6/E7 mRNA transcripts of 14 high-risk HPV types. The viral mRNA is detected by using reverse transcriptase PCR or by nucleic acid sequence based amplification (NASBA). By decreasing the threshold of a test, greater numbers of women would be reported positive and this will increase the sensitivity of the test.

• 19.
  

  a) F b) F c) T d) F e) F

The most important pre-requisite for VIA is a fully visible TZ hence why it is not appropriate for postmenopausal women. Women under 25 will also have a high rate of abnormality for little gain due to transient HPV infections.

• 20.
  

  a) T b) F c) F d) F e) F

• 21.
  

  a) F b) F c) F d) T e) F

• 22.
  

  a) F b) T c) F d) F e) F

• 23.
  

  a) F b) F c) T d) F e) F

• 24.
  

  a) T b) F c) F d) T e) F

p16 is a tumour suppressor marker associated with transforming HPV infections. It acts as an HPV diagnostic by indicating viral activity. In a normal cell, p16 acts to block cyclin-dependent kinases (CDK) 4/6. Increased production of oncogenes E6 and E7 occurs during HPV transformation and integration into the host cell. These viral proteins disrupt cell–cycle regulation through an incompletely understood mechanism mediated by inhibition of p53, pRb, and other key host proteins. E7 disrupts retinoblastoma protein by interrupting its binding to E2F transcription factor. Cell–cycle progression results from the interaction. In the normal cell, this cell–cycle progression is usually activated by CDK 4/6 and the host cells express p16 to counteract the irregular cell–cycle progression. Because cell–cycle activation is being caused by E7, however, and not by CDK 4/6, p16 has no effect on the cell–cycle activation. The resultant increased production of p16 may be detected through cellular immuno-staining. CDC6 is a protein marker that reflects cell proliferation. This protein is present in normal cells only during the activation of the cell cycle and helps form pre-replicative DNA complexes during the G1 phase. It is absent from the cell during quiescence and differentiation. Dysplastic cells have unregulated cell cycles and, as a result, CDC6 reflects cell proliferation. Studies on CDC6 indicate that it may be a biomarker of high-grade and invasive lesions of the cervix, with limited use in low-grade dysplasia. TERC is a biomarker that identifies epigenetic changes in the host cell. Most cervical cancers have an extra copy of the long arm of chromosome 3 and, as a result, show amplification of TERC (present on chromosome band 3q26), which seems to play a key role in progression from low-grade dysplasia to cancer. Many studies indicate that TERC identification may become a useful screening tool for cervical cancer. The careHPV™ assay (QIAGEN, Gaithersburg, MD, USA) uses a signal-amplification assay that detects 14 different high-risk HPV DNA types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), requires only 25 x 50 cm of work space, does not require electricity or running water, and takes about 2.5 h to carry out. This assay time of 2.5 h, compared with the approximate 6 h required for HC2 high-risk HPV testing, allows for evaluation and treatment the same day if needed.

• 25.
  

  a) T b) F c) T d) F e) F

The careHPV™ test is a type of HPV diagnostic assay that has great potential for use in low-resource settings. It uses a signal-amplification assay that detects 14 different high-risk HPV DNA types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). Most importantly, for use in low-resource settings, it requires only 25 x 50 cm of work space, does not require electricity or running water, and takes about 2.5 h to carry out. This assay time of 2.5 h allows for concurrent use with same day screen and treat programmes, currently in place in low-resource settings. TERC is a biomarker that identifies epigenetic changes in the host cell. While it may be a useful screening tool in high-resource settings, its current use in low-resource settings is limited by the costs associated with the assay. TERC requires the use of fluorescence in-situ hybridisation which is expensive and requires specialised laboratory training to run the assay. The E6 strip test is an HPV integration biomarker that shows great potential for usage in low-resource settings. It detects the HPV-E6 onco-protein of HPV type 16, 18 and 45. Studies show a good correlation between a positive HPV E6 test and CIN3+. This test shows incredible promise for application in low-resource settings as it takes a little over 1 h to carry out. HPV mRNA assays provide functional information about the transcription activity of the virus by evaluating the activity of E6 and E7. Their current use in low-resource setting is limited owing to the costs and materials necessary to run the assays. E2F transcription factor assays are expensive also.

• 26.
  

  a) T b) F c) T d) F e) T

To qualify for mass screening, a disease should have a high incidence and a high mortality, the disease should be preceded by a treatable precursor; a screening test should be available that is accurate (high sensitivity and a fair specificity), and is patient friendly and affordable.

• 27.
  

  a) F b) T c) F d) F e) T

Ovarian cancer screening has not been proven to improve ovarian cancer-specific survival in this subgroup. Ovarian cancer screening indeed has better sensitivity when CA125 is combined with TV ultrasound than with either modality alone. Testing negative for a BRCA mutation in the absence of a known mutation in the family is considered ‘uninformative’, because other genetic factors may play a role. Combined contraceptives decrease ovarian cancer risk and are not considered contraindicated in women or suspected members who are BRCA positive. The effect of lower dose combined oral contraceptives on breast cancer risk in this subgroup is not very clear. The progestogen-releasing intrauterine system has been shown not to increase breast cancer risk. Generally, the systemic levels of progestogen are low and considered safe or irrelevant.

• 28.
  

  a) F b) T c) F d) T e) F

Endometrial cancer is the most common related cancer in women from hereditary non-polyposis colon cancer families (HNPCC), and screening or prevention is absolutely indicated. Hysterectomy (with salpingo-oophorectomy) is under-utilised at the time of initial surgery as preventative surgery can prevent secondary malignancies. Genetic knowledge and testing for this syndrome is scarce, expensive and not widely available. The syndrome is hugely under-diagnosed. Screening in women with HNPCC should focus on pelvic and gynaecologic disease as well as colorectal cancer risk. Screening for endometrial cancer has not been shown to improve the survival from endometrial cancer.

• 29.
  

  a) F b) T c) F d) F e) T

Breast cancer has been shown to occur in a younger cohort of patients in developing countries. This is thought to reflect primarily different population age distribution and life expectancy, rather than intrinsically different cancer behaviour. Due to higher rates of cervical cancer and lower life expectancy the breast cancer:cervical cancer ratio is indeed reduced in the developing world.

• 30.
  

  a) T b) F c) T d) F e) F

Some of the mammographic trials have shown a reduction of breast cancer specific mortality of 30%. It is unlikely to ever be cost effective in developing countries and has been shown to increase biopsy rates. Radiation exposure from mammographic screening is not thought to confer any health risks.