1. (a) F (b) F (c) T (d) F (e) F

Papillomaviruses are species-specific, so HPV only infects humans; rabbits may be infected by a type of papillomavirus called cottontail rabbit papillomavirus. The relevance of this is that laboratory animals such as rodents cannot be infected with HPV for research purposes. Multiple types of HPV (over 200) are thought to be in existence. The definition of a new HPV type depends on a difference in the DNA sequence of a particular HPV gene of at least 10%. Acquisition of HPV in women is common with the onset of sexual intercourse. Cross-sectional prevalence studies in student-age women (late teens, early twenties) have shown rates exceeding 50%. Most of these infections are transient, and will be cleared by immunological mechanisms. There is no evidence that genital warts are pre-malignant and pre-dispose to cervical cancer. The viruses that cause genital warts and cervical cancer are genetically distinct; their biological behaviour is different, and those causing warts have no oncogenic potential. HPV viral types are stable, and there is no evidence that they mutate.

2. (a) T (b) F (c) F (d) F (e) F

The vaccine Gardasil generates immune responses against HPV types 6, 11, 16 and 18 (i.e. it is quadrivalent). The vaccine Cervarix (used in the UK HPV vaccination programme) is effective only against HPV types 16 and 18 (i.e. it is bivalent). The vaccines do not have to be given before the onset of sexual activity; but, once infection with a particular HPV type has occurred, the vaccine is no longer effective for generating protective immunity against that type. Therefore, it is preferable to immunise before the risk of HPV acquisition arises. Children and young teenagers also mount more effective immunological memory responses than older people. There is absolutely no risk that the vaccines can cause cervical cancer. The vaccines do not contain any HPV DNA, and therefore are not associated in any way with the oncogenic HPV proteins that cause malignant transformation of cervical epithelial cells. The vaccines against HPVs 16 and 18 are extremely efficacious in preventing the development of cervical pre-malignant lesions caused by these viruses. Despite being vaccinated against HPV types 16 and 18, these women should continue screening as per the recommendations of their local programme. HPV16 and 18 cause only about 70% of cervical cancers; nearly 30% are caused by other HPV types for which no vaccines are yet available. Therefore, screening to detect these cancers is mandatory in order to reduce their incidence and mortality.

3. (a) F (b) F (c) T (d) T (e) F

Although the risk of HPV acquisition increases with number of partners, a high-risk HPV type may be acquired at the first (or only) sexual contact; healthcare workers should be clear about this and should convey the message explicitly to anxious women, girls or their guardians. Cervical cancer should not be viewed as a disease associated with promiscuity, and women with HPV infection should not be made to feel stigmatised. At the present time, publically funded HPV vaccination programmes are confined to women. But, as men carry and transmit the virus, and as men develop HPV-induced malignancies themselves, there may well come a time when vaccination of boys and men becomes a cost-effective intervention. The phase III trials of both Gardasil and Cervarix involved vaccination of several thousand women. The incidence of side-effects did not differ between the vaccine and placebo arms of the studies. The virus-like particles are produced either by yeast cells (Gardasil) or insect cell lines (Cervarix). Certain viral vaccines are grown in chicken eggs and may be contraindicated in those with egg allergy; this does not pertain to either of the HPV vaccines. The existing vaccines are prophylactic and have no known therapeutic benefit. There is no evidence that either product positively affects dyskaryotic cells or pre-existing cervical dysplasia.

4. (a) T (b) F (c) F (d) F (e) T

Both cervicography and acetic acid application with visual inspection focus on identifying an acetowhite area on the ectocervix around the external os. b, c and d would not be considered appropriate for screening

5. (a) F (b) F (c) F (d) T (e) T

With a low specificity, the false–positives increase. The difference between a high sensitivity and positive predictive value remain fairly constant with a slight decrease in sensitivity.

6. (a) F (b) F (c) T (d) T (e) F

Rare events are missed more easily. Therefore, if the disease is rare, the identification of abnormal cells on a Pap test will become less accurate.

7. (a) T (b) T (c) T (d) T (e) T

All these answers are important and integral questions in justifying a screening programme.

8. (a) F (b) T (c) F (d) F (e) F

It is a well-established principle of population screening that the primary objective is to achieve adequate coverage, usually taken to be at least 80%, and only when that has been achieved is consideration given to the age range to be screened and frequency of screening. This is further supported by the frequent clinical observation that many women who develop cervical cancer have not participated in a screening programme. Women who are HIV positive should be screened annually as they are recognised to have a higher incidence of cervical neoplasia. It has not been possible to define ‘at risk’ groups using socio-sexual parameters, such as smoking habits or sexual behaviour. Although cytology-based screening programmes were originally established in the mid-20th Century to prevent cervical squamous carcinoma, the histological type most prevalent at that time, there is now good evidence that screening has had a significant effect on the incidence of adenocarcinoma and adeno-squamous carcinoma. Meta-analysis of studies comparing conventional cytology with histology tests has shown that cytology tests are only moderately accurate and do not achieve concurrent high sensitivity and specificity. Improvement in sensitivity (fewer false negative tests) is accompanied by loss of specificity (more false positive tests) and vice versa. A systematic review of studies that compared cytology screening by any method (conventional, computer aided, or liquid based) with a concurrent reference standard (histology, colposcopy of cytology) found that, in the 12 studies with the least biased estimates, sensitivity ranged from 30–87%, and specificity from 86–100%.

9. (a) T (b) F (c) T (d) F (e) T

Liquid-based cytology samples are obtained from the cervix using plastic devices, either a cervical broom or combined plastic spatula and cervical brush, and placed in preservative liquid for transport to the laboratory where they are processed to produce slide preparations, in contrast to conventional Papanicolaou smears where cells were obtained with a wooden or plastic spatula and then spread on a slide before immersion in alcohol for fixation. The liquid-based cytology pilot studies in the NHS Cervical Screening Programme showed a significant reduction in consultation time compared with a conventional Papanicolaou smear. Arbyn et al. have recently reported in a systematic review and meta-analysis that liquid-based cervical cytology is neither more sensitive nor more specific for detecting high-grade cervical intraepithelial neoplasia compared with the conventional Pap test. Also, the specificity, considering high-grade and low-grade squamous intraepithelial lesions as cut-off, was similar in conventional and liquid cytology, but lower for liquid-based cytology when the presence of atypical squamous cells of undetermined significance (borderline nuclear changes) was the cut-off. Although many studies have reported a decrease in the number of inadequate (unsatisfactory) samples with liquid-based cytology compared with conventional Papanicolaou smears, robust criteria have not been determined for the threshold of cellularity, which will minimise the risk of false negative reports in liquid-based cytology. This is the aim of a study currently in progress in the UK. The first part of the study is complete and has surveyed current practice in laboratories using liquid-based cytology for cervical screening to establish the cellularity of a large cohort of samples reported as inadequate, negative or abnormal. The second part of the study will evaluate the ability of screening staff to detect abnormalities of differing type and relative abundance, and these will be presented to a large number of laboratories for independent evaluation. The final results are expected in 2012. Evidence is accumulating that liquid-based cytology specimens are easier and quicker to examine in the laboratory because of a better distribution of the epithelial cells, improved preservation of cell morphology, and absence of obscuring factors such as blood, inflammatory cells and mucus.

10. (a) T (b) T (c) F (d) T (e) F

Both of the first two options are acceptable according to UK and USA guidance, unless the cytology report specifies that high-grade dyskaryosis or high-grade squamous epithelial lesion cannot be excluded (ASCH), in which case immediate referral for colposcopy is recommended. Women with borderline nuclear changes/atypical squamous cells should have at least two consecutive negative cytology tests before returning to routine screening. Human papillomavirus (HPV) testing to manage all women with low-grade cytological abnormality was shown to be cost-effective, feasible and acceptable to women within the NHS Cervical Screening Programme pilot evaluation of liquid-based cytology. The positive predictive value for the colposcopic diagnosis of CIN 2 or worse was 15–20%, and higher in women under 35 years. Testing for HPV DNA is the preferred approach for management of atypical squamous cells in the USA when liquid-based cytology is used for screening and will shortly introduced in the UK. The negative predictive value of a negative test for high-risk HPV types is such that women with a low-grade cytological abnormality and negative HPV test can be safely returned to routine screening.

11. (a) F (b) T (c) F (d) T (e) F

A principal driver for the development of liquid-based cytology was to produce slides consisting of a monolayer or near-monolayer of cells with clearly defined boundaries, largely devoid of obscuring blood, inflammatory cells or mucus, readily amenable to computerised image analysis; the BD FocalPoint™ Slide Profiler has been approved for primary cervical screening by the FDA for both conventional and SurePath LBC preparations. Although previous studies of automated screening had reported increased productivity with improved disease detection, a number had methodological weaknesses, and systematic reviews from New Zealand and the UK concluded that they were not of sufficiently good quality for reliable conclusions to be drawn. The UK Manual Assessment Versus Automated Reading In Cytology (MAVARIC) study has recently reported that automation-assisted reading is 8% less sensitive but 0·6% more specific than manual reading for the detection of CIN 2 or worse and that the inferior sensitivity of automation assisted reading combined with an inconsequential increase in specificity suggests that automation assisted reading cannot be recommended currently for primary cervical screening. As in both automated screening systems fields of view (FOVs) containing abnormal cells are presented for examination by laboratory screening staff, their interpretative skills will be maintained, although identification (primary screening) skills may be lost. Both systems increase laboratory productivity by directing the laboratory screening staff to the FOVs on a slide, thereby dramatically reducing the amount of time required to screen a slide, and can process specimens 24-h per day. In addition the BD FocalPoint™ Slide Profiler typically permits about 25% of a population of routine cervical screening samples to be archived with no need for human microscopic review. As the prevalence of abnormality progressively decreases in populations vaccinated against human papillomavirus, the FocalPoint™ Slide Profiler may be valuable as it permits a proportion of the workload containing normal samples to be archived with no need for human microscopic review, leaving the rest of the workload in which there will be a relatively high proportion of abnormal samples for detailed microscopic examination. However, this requires further investigation.

12. (a) T (b) F (c) T (d) F (e)

In the most recent retrospective analysis of more than 20,000 invasive cervical cancer cases obtained from 38 countries worldwide, 71% of these were associated with HPV16 an HPV18. HPV vaccination is used as primary prevention of cervical intraepithelial neoplasia, not for treatment. Twelve per cent of oro-pharangeal cancers are attributed to HPV. The International Agency of Research in Cancer has estimated that new cases of cervical cancer are expected to be more than 700,000 by 2025. The safety of HPV vaccination has been reassuring. Post-marketing surveillance carried out for the quadrivalent vaccine shows that the most common side-effects are pain at site of injection.

13. (a) T (b) F (c) F (d) F (e) F

As 90% of anal cancers are attributed to oncogenic HPV, the Food and Drug Administration recently approved the use of the quadrivalent vaccine as primary prevention for anal cancers. Numerous developed countries that already have effective cervical screening programmes (e.g. UK, Netherlands, Austria and Denmark), and which have significantly reduced the incidence of cervical cancer, have also introduced HPV vaccination. Cost-effective analysis supports this. Such a programme does not exist in the USA. The uptake of vaccination among adolescent girls is just above 10%. The WHO recommends that routine HPV vaccination should be included in national immunisation programmes, provided that prevention of cervical cancer or other HPV-related diseases, or both, constitutes a public health priority; vaccine introduction is feasible; sustainable financing can be secured; and the cost-effectiveness of vaccination strategies in the country or region is considered. In most countries where parents are the legal guardians, permission is required before vaccinating their child or children. In British Columbia, the uptake has not been as high as expected because of parental concerns about safety of the vaccines.

14. (a) F (b) F (c) T (d) F (e) T

Cytology is widely used in the developed world and in less-developed regions such as Latin America and the Caribbean. Cytology is currently being used as the primary screening test. In some countries and only recently, HPV testing is being used to triage women with borderline and mild dyskaryosis (ASCUS and low-grade squamous intraepithelial dysplasia). It is well known that cytology based screening programmes, where the quality of cytology can be guaranteed have prevented many cases of cervical cancer. Cervical cytology cannot discriminate between HPV types. Only HPV DNA (or mRNA) techniques can be used for HPV typing. Cervical cytology is used to follow women who have been treated.

15. (a) F (b) T (c) T (d) T (e) F

HPV testing is more sensitive than cytology but less specific. New HPV assays have improved specificity but have not been better than cytology specificity so far. HPV testing by HC-II or PCR techniques have shown substantially better sensitivity to detect high-grade cervical lesions than cytology. HPV testing is objective and does not depend on human judgment. It has been shown that a negative HPV test has a long term protective value, i.e. women who test negative for HPV are at less risk of developing cervical cancer for up to 10 years than those who have normal cytology. HPV testing is probably the most appropriate technique to use on vaccinated women in the future, but it is not true that cytology “does not work”.

16. (a) F (b) F (c) T (d) F (e) F

Since the current vaccines are not suitable for women already in their twenties, these women will need screening for the foreseeable future. Additionally the current vaccines offer less protection against cervical cancer than regular screening. There is no evidence that the sensitivity of cytology to detect CIN2/3 depends on the HPV type that has caused the lesion, hence the sensitivity for non-16/18 lesions will not be very different. It is possible that the quality of cytology will decrease if the prevalence of disease is lower but that is purely speculative. The PPV depends on the prevalence of the disease. If the prevalence is decreased (by vaccination) the PPV will decrease. The reverse is true for d as due to the fact that there are a number of causes of low-grade cytological abnormalities, vaccination will reduce them by a small proportion than it will high-grade abnormalities that are more likely to be caused by HPV16 or 18. Although it would be a good idea to continue screening, even without screening vaccination of women prior to exposure to HPV should reduce their risk of cervical cancer by at least 70%.

17. (a) F (b) F (c) T (d) F (e) F

HPV positive women should be either triaged with a second test or followed-up with a second HPV test 12–18 months later, in order to only refer to colposcopy and adequate treatment those at high risk of developing high-grade cervical disease. It is safe to screen HPV negative women every five years but clinical management of HPV positive ideally should be decided after triage with a second test. Management will be based on the second test result. If a triage test is not available, women should be offered a second HPV test at least 12 months later, and if the HPV infection persists, be referred to colposcopy. Currently, prophylactic vaccines do not offer protection to women already infected with HPV16 and HPV18. Women positive for HPV16 and/or of HPV18 are at high risk of high-grade disease and should probably be referred to colposcopy.

18. (a) F (b) F (c) F (d) T (e) F

According to current guidelines, CIN1 should not be treated invasively. The risk of progression is very low and surgical treatment will increase morbidity without any benefit for most women with CIN1. The TOMBOLA trials showed that immediate excisional treatment resulted in unnecessary treatment of women without any cervical atypia. The most cost-efficient management is observational treatment with colposcopic assessment of women with persisting or progressing atypical Pap results. During pregnancy, CIN should not be treated surgically when invasive disease is excluded. Large loop excision of the transformation zone (LLETZ) and conisation of the pregnant cervix are associated with a high rate of obstetrical complication, whereas the risk of malignant progression is low. In women with high-grade squamous intraepithelial lesion (HSIL), the risk of CIN2 and 3 is high, and 1–2% will have already invasive disease. Therefore, according to current guidelines, a diagnostic excision is indicated in these women even if the corresponding biopsies show only CIN1. Frank invasive cancer will be classified at least as FIGO stage Ib1. The clinical diagnosis may be confirmed by excisional or punch biopsies, but patients are in need of stage-adapted oncologic treatment.

19. (a) T (b) F (c) F (d) F (e) F

The randomised-controlled TOMBOLA trials confirmed that cytological surveillance of LSIL results is safe and reduces the number of referrals. In women with LSIL referred to colposcopy, immediate LLETZ was no better than targeted biopsies in detecting CIN2 or CIN3 lesions, but resulted in unnecessary treatment of women without any degree of atypia on histology. Colposcopical management needs to be based on a conclusion of screening results, type of transformation zone, colposcopy findings and histological assessment with biopsies. Colposcopists must be aware that CIN 2 and 3 may be missed by targeted biopsies but, in women with LSIL results this risk seems to be negligble. The TOMBOLA trials showed that a management based on targeted biopsies taken by experienced colposcopists was as good as immediate LLETZ in detecting CIN3 but achieved this with less morbidity and costs. The TOMBOLA trials demonstrated with a high level of evidence that immediate LLETZ is less cost-efficient than colposcopy with targeted biopsies in women with LSIL results. HPV testing and cytology are screening and triage tests, and should function as a filter to select the minority of women who need to be transferred to colposcopy. Although HPV testing is efficient in triaging borderline/ASCUS results it is of little help in managing LSIL. Almost 80% of LSIL were associated with high-risk HPV in meta-analyses. Compared with other HPV types, infections with HPV types 16 and 18 and associated lesions are more likely to progress. Therefore, HPV genotyping may be used for some well-defined individual decisions in women with persisting CIN1 or young women with CIN2, but there is insufficient evidence to base indications for invasive treatment on HPV genotyping without histological assessment. HPV testing is more sensitive in detecting CIN2 and 3 than cytology. The reason not to use HPV testing in this setting is that most LSIL will be associated with HPV.

20. (a) F (b) T (c) F (d) F (e) F

Cryotherapy carries a significantly increased risk for the development of subsequent cervical cancer compared with excisional methods of treatment and should not be used routinely for the treatment of CIN3. LLETZ and laser conisation were associated with less obstetrical complications than cold-knife conisation in two meta-analyses. The efficacy of LLETZ and laser conisation in controlling CIN and preventing cervical cancer was at least as good as cold-knife conisation in cohort studies and systematic reviews. Cold-knife conisation is associated with a significant increase in acute complications, such as severe bleeding and late obstetrical complications, and increased perinatal mortality, and therefore should no longer be used. In experienced, hands LLETZ and laser conisation specimens will show minimal thermonecrosis of 0.2–0.6 mm that marks the definite resection margins and do not disturb histo-pathological evaluation. Type 3 transformation zones spread into the deep endocervix. The squamous columnar junction is invisible. LLETZ can be used to treat CIN3 in type 3 transformation zones but it is ideal for treating CIN3 in type 1 and type 2 transformation zones. CIN3 lesions should not be treated in pregnant women.

21. (a) F (b) F (c) T (d) F (e) T

CIN1 should not be treated immediately. A number of RCTs have shown that observational management reduces the number of unnecessary treatments and costs. ASCUS, borderline and LSIL results should not be treated immediately. The TOMBOLA and other RCTs have confirmed that such an approach causes significant over-treatment, morbidity and costs. Most guidelines recommend invasive treatment of HSIL because it is associated with CIN2+ in most cases. Therefore, even in the case of normal colposcopy findings, the risk of underlying CIN2+ is high and women benefit from excision of the transformation zone with exceptions of pregnant and very young women. Primary screening with HPV testing will detect CIN3+ lesions in women with normal cytology. Until now, however, we do not have sufficient data to identify women who might benefit from immediate treatment in HPV screening concepts and therefore no evidence-based guidelines exist. As the positive predictive value of colposcopy for CIN3 is 65–80%, the recommended pathway in HPV screening pilot projects is colposcopy with biopsies even in women who are HPV positive with signs of high-grade lesions. CIN3 must be treated and this can be done immediately.

22. (a) F (b) F (c) T (d) F (e) F

One paper alludes to a higher rate of preterm delivery even in the presence of an abnormal cytology. Currently, there is no evidence that colposcopic assessment of the cervix results in miscarriage or earlier labour. It is a safe procedure in pregnancy. Its value, however, is questioned as it is unusual to treat high-grade CIN in pregnancy, and assessment can be difficult. UK practice tends not to take punch biopsies in pregnancy; however, in rare occasions, they may aid management. Published data show their use to be safe, although there is an increased risk of vaginal bleeding. Pragmatically, therefore, it may be safer to admit the pregnant woman for a small diagnostic biopsy in theatre. Evidence suggests that CIN does not progress in pregnancy, hence the rationale for conservative management. Few studies show regression of CIN 1 in pregnancy and even small volume high-grade disease. Women with CIN in pregnancy should be seen for colposcopic review at 12 weeks postpartum.

23. (a) F (b) F (c) F (d) T (e) T

The studies evaluating the use of ART in HIV-positive women with CIN are conflicting. Overall, it is felt if the CD4 count is kept high (> 500) with an undetectable viral load, then the likelihood of regression increases. The recent studies make the situation unclear. Evidence shows an increase in the risk or multifocal disease as women live longer with a chronic illness.

24. (a) F (b) T (c) F (d) F (e) T

The prevalence of HPV in the menopause is low, although it increases significantly if the woman has two or more sexual partners. At present, it is unclear whether this is because of new infection or the return of previous infection as one’s innate immunity decreases. At least one-third of women over the age of 40 years have an unsatisfactory colposcopy. CIN requires excision/conisation even in menopausal women as the first line procedure to exclude an underlying cervical cancer. Hysterectomy is contra-indicated until cancer is excluded, as one may inadvertently perform the wrong procedure and so compromise her further management. Common practice is to prescribe HRT for anything between 2–12 months. The only published study advocates giving HRT for 12 months to prevent cervical stenosis.

25. (a) T (b) T (c) T (d) F (e) F

Smoking is a significant risk factor for developing cervical cancer and pre-cancer. It is believed that cigarette smoking may exert its role in cervical carcinogenesis through immune suppression. The cervical mucosa is well equipped with an extensive network of Langerhans cells and T lymphocytes. These cells are depleted in cervical epithelium with HPV infection and neoplasia, and this phenomenon is more marked among women who smoke. Local immunosuppression permits a persistent HPV infection for a sustained period, allowing its carcinogenic effect to be expressed. Age is also a significant risk factor for developing cervical cancer. Women over 30 years of age are at an increased risk compared with women aged 30 years or younger. HPV is the single most important aetiological agent in the development of squamous and adenocarcinomas of the cervix. Over 100 HPV types have been identified, of which 40 types have been shown to infect the genital tract. Of these, up to 15 have been designated high-risk HPV types, owing to their role in cervical cancer. HPV16 followed by HPV18 are the most frequently detected HPV types in squamous cell carcinomas of the cervix, whereas HPV18 is more strongly associated with adenocarcinoma of the cervix. Although some genetic factors are associated with developing cervical cancer, these are not hereditary factors and no link has been made with familial breast cancer.

26. (a) F (b) T (c) T (d) T (e) F

CIN is a common lesion and is generally asymptomatic and can occur over a long period of 10–20 years. Not all cases of CIN will progress to develop into an invasive cancer. In particular, with early CIN lesions (CIN1 and 2), the progression rates to high-grade lesions are 9–22% and the rates to invasive cancer are 1–5%. In general, there is poor inter-observer agreement between pathologists in diagnosing CIN. Histological diagnosis of CIN is complicated by a variety of cellular changes associated with inflammation, pregnancy, atrophy, or both. These changes may mimic pre-cancerous cervical lesions, thereby making traditional cervical histology approaches subjective and prone to variability. In particular, the differential diagnosis between immature squamous metaplasia and CIN1 and 2, or between low-grade (CIN1) and high-grade (CIN2 and 3) lesions, tend to be difficult. The more severe grades of CIN are likely to have a thicker epithelium composed of undifferentiated cells with a narrow layer of mature undifferentiated cells on the surface. In CIN1, the undifferentiated cells are confined to the lower layer of the epithelium, whereas in CIN3, differentiation and stratification may be totally absent or only present in the superficial quarter of the epithelium. Nuclear abnormalities can be seen throughout the thickness of the epithelium. p16 ^INK4a can be used as a surrogate marker of active high-risk HPV infection. Over-expression of p16 ^INK4a has been demonstrated in CIN and cervical cancer, which increases with increasing grade of disease. p16 ^INK4a has also been described as a marker of progression as its over-expression is strongly associated with histologically confirmed CIN2 + lesions. If untreated, the percentage of CIN3 lesions that are likely to progress to an invasive cancer is likely to be close to 70%, over a lengthy period of time.

27. (a) F (b) T (c) F (d) F (e) T

Ki-67 is a cellular marker for proliferation that is expressed at all stages during the cell cycle except G0. Although Ki-67 has been used as a marker of cellular proliferation and as an aid for grading CIN, it is not thought to be involved specifically in the cervical carcinogenic process. p16 ^INK4a is a cyclin-dependent kinase inhibitor ((DK4/6) involved in cell– cycle regulation, through the retinoblastoma gene complex. Cellular levels of p16 ^INK4a protein are generally low, but it has been found to be up-regulated in HPV-infected cervical cells owing to inactivation of the Rb complex by HPV E7 onco-protein. E7 disrupts the protein of retinoblastoma from its binding to E2F transcription factor, and thereby promotes cell–cycle progression. It can therefore be used as a surrogate marker of HPV infection. p16 ^INK4a does mark non-dysplastic cells. In particular, endometrial, metaplastic and endocervical cells, as well as tubo-endometrioid metaplasia, have all been observed to stain positive for p16 ^INK4a . Trained cytologists and histopathologists should be adept at distinguishing between benign cells and abnormal cells to accurately interpret p16 ^INK4a immune-staining. Given the high prevalence of HPV DNA in the normal screening population, HPV DNA testing is not a very specific marker for detecting high-grade cervical disease. On the other hand, it has a good negative predictive value for patients negative for HPV who are at very low risk of developing disease. HPV types 16 and 18 are among the highest risk types for developing cervical cancer. Therefore, specific genotyping for the high-risk types is useful for distinguishing between low- and high-risk HPV positive CIN cases, which are more likely to progress to a high-grade lesion.

28. (a) T (b) F (c) T (d) T (e) F

Using a systematic approach to the colposcopic examination aids diagnostic accuracy and assists in selecting appropriate management. The use of a colposcopic grading system is helpful. The presence or absence of nabothian follicles helps in identifying the transformation zone where metaplasia will have taken place to replace columnar with squamous epithelium. The nature of the cervical mucus is not important for diagnostic purposes, although examination mid-cycle is preferred as the mucus is clear and not tenacious.

29. (a) F (b) F (c) T (d) F (e) T

Colposcopy has higher diagnostic accuracy for high-grade abnormalities compared with low-grade lesions. Reliance on a single punch biopsy for diagnostic purposes is fraught with potential error, leading to inappropriate management for women presenting with cytological abnormalities. Women can have significant adverse emotions when referred for colposcopy, and measures should be in place to try and alleviate this effect. Quality assurance of the training and practice of colposcopy is essential to maintain a service that is ‘fit for purpose’. There is general international agreement as to the constituent parts of a training programme.

30. (a) T (b) T (c) T (d) T (e) T

Detection of high-risk HPV DNA is potentially useful in four clinical applications: (1) as a primary screening test (solely or in combination with cytology) to detect cervical cancer precursors; (2) as triage test to select which women who have minor cytological abnormalities are in need of referral for colposcopy; (3) in the continuing management of women referred for colposcopy for whom no high-grade lesion is found; and (4) as a follow-up ‘test of cure’ for women treated for high-grade intraepithelial lesion to identify women who required continued surveillance.