Cervical screening

Cervical screening is a way of preventing cervical cancer from developing, and diagnosing the disease at an early stage. In the USA, cervical screening is usually performed using the Pap test (or 'smear test'),^[1] though the UK screening programmes changed the screening method to liquid-based cytology in 2008.^[2]

Screening tests look for pre-cancerous changes in the cervix that could develop into cervical cancer. If the abnormal tissue or cells can be removed, then the disease can be prevented from developing and causing problems. The tests can also diagnose the disease by identifying cancer cells that are already present.

Types of screening

Conventional cytology

Main article: Pap test

In the conventional Pap smear, the physician collecting the cells smears them on a microscope slide and applies a fixative. In general, the slide is sent to a laboratory for evaluation.

Studies of the accuracy of conventional cytology report:^[3]

• sensitivity 72%
• specificity 94%

Liquid-based monolayer cytology

Since the mid-1990s, techniques based on placing the sample into a vial containing a liquid medium that preserves the cells have been increasingly used. Two of the types are Sure-Path (TriPath Imaging) and Thin-Prep (Cytyc Corp). The media are primarily ethanol-based for Sure-Path and methanol for ThinPrep. Once placed into the vial, the sample is processed at the laboratory into a cell thin-layer, stained, and examined by light microscopy. The liquid sample has the advantage of being suitable for high-risk HPV testing and may reduce unsatisfactory specimens from 4.1% to 2.6%.^[4] Proper sample acquisition is crucial to the accuracy of the test, as a cell that is not in the sample cannot be evaluated.

Studies of the accuracy of liquid based monolayer cytology report:

• sensitivity 61%^[5] to 66%,^[3] (although some studies report increased sensitivity from liquid-based smears^[4])
• specificity 82%^[5] to 91%^[3]

Human papillomavirus testing

Human papillomavirus (HPV) infection is a cause of nearly all cases of cervical cancer.^[6] Most women will successfully clear HPV infections within 18 months. Those that have a prolonged infection with a high-risk type^[7] (e.g. types 16, 18, 31, 45) are more likely to develop Cervical Intraepithelial Neoplasia, due to the effects that HPV has on DNA.

Studies of the accuracy of HPV testing report:

• sensitivity 88% to 91% (for detecting CIN 3 or higher)^[5] to 97% (for detecting CIN2+)^[8]
• specificity 73% to 79% (for detecting CIN 3 or higher)^[5] to 93% (for detecting CIN2+)^[8]

By adding the more sensitive HPV Test, the specificity may decline. However, the drop in specificity is not definite.^[9] If the specificity does decline, the result is increased numbers of false positive tests and, for many women that did not have disease, an increased risk for colposcopy^[10] and treatment. A worthwhile screening test requires a balance between the sensitivity and specificity to ensure that those having a disease are correctly identified as having it and those without the disease are not identified as having it.

Regarding the role of HPV testing, randomized controlled trials have compared HPV to colposcopy. HPV testing appears as sensitive as immediate colposcopy while reducing the number of colposcopies needed.^[11] Randomized controlled trial have suggested that HPV testing could follow abnormal cytology^[5] or could precede cervical cytology examination.^[8]

A study published in April 2007 suggested that the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women that had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."^[12]

HPV testing can reduce the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cervical cancer detected by subsequent screening tests among women 32–38 years old according to a randomized controlled trial.^[13] The relative risk reduction was 41.3%. For patients at similar risk to those in this study (63.0% had CIN 2-3 or cancer), this leads to an absolute risk reduction of 26%. 3.8 patients must be treated for one to benefit (number needed to treat = 3.8). Click here to adjust these results for patients at higher or lower risk of CIN 2-3.

Testing in resource-poor areas

Many resource-poor areas cannot provide regular screening, and must rely on infrequent screening. A study of cervical cancer screening of 131,746 women in rural India found that a single DNA test reduced the number of advanced cervical cancers and deaths over 8 years, while a single acetic acid examination or a single Pap screening did not. However, the DNA test cost US $30–40, which was unaffordable in many regions, it is time-consuming, and requires a sophisticated laboratory infrastructure. A simple, affordable, and accurate test is being evaluated in China and other countries.^[14][15][16] The new test may become available on the market in 2010 at significantly lower cost than current tests.

With HPV testing, there was a 50 percent reduction ^[17][18] in the number of deaths from cervical cancer compared to unscreened women. Compared to other methods, the research showed the HPV testing reported the fewest false negatives.^[19]

Other options

The Bill and Melinda Gates Foundation has funded an eight-year study of a DNA test for the virus that causes cervical cancer. The test manufactured by Qiagen for a low cost per test with results available in only a few hours may allow reduction in use of annual Pap smears. The test has been shown to work "acceptably well" on women who take the swabs themselves rather than allowing a physician to test. This may improve the chances of early diagnosis for women who are unwilling to be screened due to discomfort or modesty.^[20]

Visual inspection to detect pre-cancer or cancer

In areas where Pap smear screening is not available or affordable, other methods of testing have been evaluated.

Visual inspection of the cervix, using acetic acid (white vinegar; VIA) or Lugol’s iodine (VILI) to highlight precancerous lesions so they can be viewed with the "naked eye", shifts the identification of precancer from the laboratory to the clinic. Such procedures eliminate the need for laboratories and transport of specimens, require very little equipment and provide women with immediate test results. A range of medical professionals—doctors, nurses, or professional midwives—can effectively perform the procedure, provided they receive adequate training and supervision. As a screening test, VIA may perform as well as or better than cervical cytology in accurately identifying pre-cancerous lesions.^[21] This has been demonstrated in various studies where trained physicians and mid-level providers correctly identified between 45% and 79% of women at high risk of developing cervical cancer.^[22] By comparison, the sensitivity of cytology has been shown to be between 47 and 62%. Cytology provides higher specificity (fewer false positives) than VIA. Like cytology, one of the limitations of VIA is that results are highly dependent on the accuracy of an individual's interpretation. This means that initial training and on-going quality control are of paramount importance. Increased false positives are particularly important in a screen-and-treat setting, since over-treatment and resulting impairment of fertility is more likely.

VIA can offer significant advantages over Pap in low-resource settings, particularly in terms of increased screening coverage, improved follow-up care and overall program quality. Due to the need for fewer specialized personnel and less infrastructure, training, and equipment, with VIA public health systems can offer cervical cancer screening in more remote (and less equipped) health care settings and can achieve higher coverage. Furthermore, providers can share the results of VIA with patients immediately, making it possible to screen and treat women during the same visit. This helps ensure that follow-up care can be provided on the spot and reduces the number of women who may miss out on treatment because they are not able to return to the clinic at another time. In a "screen and treat" project in Peru, for example, only 9% of women who screened positive failed to receive treatment in the single-visit approach, compared with 44% of women who were lost to treatment using a multi-visit model.^[23]

VIA has successfully been paired with cryotherapy, a relatively simple and inexpensive method of treating cervical lesions that can be performed by primary care physicians and mid-level providers.^[24]

How women are screened

The procedures for testing women using Pap smear, liquid-based cytology, or HPV testing are similar. A sample of cells is collected from the cervix using a spatula or small brush. The cells are then checked for any abnormalities.

To take the sample of cells, the doctor or nurse puts an instrument called a speculum inside the vagina. The speculum has two arms that spread the sides of the vagina apart so that the doctor or nurse can see the cervix. Then they scrape the surface of the cervix with a spatula or small brush. This collects a sample of cells from the outer layer of the cervix.

With a Pap smear, cells collected using a spatula are smeared onto a slide for examination under a microscope. In liquid-based cytology, a sample of cells is taken using a small brush. The cells are put it into a pot of liquid, and analysed for abnormalities. Cervical cells to be tested for HPV are collected in a similar way.

How abnormal cells are removed

Women may be told that they have CIN (cervical intraepithelial neoplasia), or CIS (carcinoma in situ) - these terms describe different levels of abnormality found in the cervical cells. Abnormal cells can be removed or destroyed using one of several different procedures.

Laser ablation and cryotherapy treat just the part of the cervix that contains abnormal cells. Laser ablation uses a laser to burn away the abnormal cells, while cryotherapy uses a cold probe to freeze the cells away. These procedures allow normal cells to grow back in their place. The loop electrical excision procedure (called LLETZ or 'large loop excision of the transformation zone' in the UK), cervical conization (or cone biopsy) and hysterectomy remove the whole area containing the cells that could become pre-cancerous or develop into cervical cancer.

References

1. ^ Screening: Cervical cancer, US Preventive Services Task Force (accessed 28/01/2011)
2. ^ Liquid Based Cytology (LBC), NHS cervical screening programme (accessed 28/03/2011)
3. ^ ^{a b c} Coste J, Cochand-Priollet B, de Cremoux P, et al. (2003). "Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening". BMJ 326 (7392): 733. doi:10.1136/bmj.326.7392.733. PMC 152633. PMID 12676841. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=152633.  ACP Journal Club
4. ^ ^{a b} Ronco G, Cuzick J, Pierotti P, et al. (2007). "Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening randomised controlled trial". BMJ 335 (7609): 28. doi:10.1136/bmj.39196.740995.BE. PMC 1910655. PMID 17517761. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1910655. 
5. ^ ^{a b c d e} Kulasingam SL, Hughes JP, Kiviat NB, et al. (2002). "Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral". JAMA 288 (14): 1749–57. doi:10.1001/jama.288.14.1749. PMID 12365959. 
6. ^ Walboomers JM, Jacobs MV, Manos MM (1999). "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide". J. Pathol. 189 (1): 12–9. doi:10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F. PMID 10451482. 
7. ^ Cuschieri KS, Cubie HA, Whitley MW, et al. (2005). "Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study". J. Clin. Pathol. 58 (9): 946–50. doi:10.1136/jcp.2004.022863. PMC 1770812. PMID 16126875. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1770812. 
8. ^ ^{a b c} Cuzick J, Szarewski A, Cubie H, et al. (2003). "Management of women who test positive for high-risk types of human papillomavirus: the HART study". Lancet 362 (9399): 1871–6. doi:10.1016/S0140-6736(03)14955-0. PMID 14667741. 
9. ^ Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J (2004). "Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia". J. Natl. Cancer Inst. 96 (4): 280–93. doi:10.1093/jnci/djh037. PMID 14970277. 
10. ^ Colposcopy and Treatment of Cervical Intraepithelial Neoplasia: A Beginner's Manual
11. ^ ASCUS-LSIL Traige Study (ALTS) Group. (2003). "Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance". Am. J. Obstet. Gynecol. 188 (6): 1383–92. PMID 12824967. 
12. ^ [1], J Inflamm 2007;4.
13. ^ Naucler P, Ryd W, Törnberg S, et al (2007). "Human papillomavirus and Papanicolaou tests to screen for cervical cancer". N. Engl. J. Med. 357 (16): 1589–97. doi:10.1056/NEJMoa073204. PMID 17942872. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17942872&promo=ONFLNS19. 
14. ^ "New England Journal of Medicine, HPV Screening for Cervical Cancer in Rural India". Content.nejm.org. 1970-01-01. http://content.nejm.org/cgi/content/full/360/14/1385. Retrieved 2010-08-29. 
15. ^ Emery, Gene. "Reuters- QIAGEN virus test cuts death from cervical cancer". Reuters.com. http://www.reuters.com/article/healthNews/idUSTRE5307XP20090401. Retrieved 2010-08-29. 
16. ^ Donald G. McNeil Jr. (April 6, 2009). "New DNA Test Outperforms the Pap Smear". The New York Times. http://www.nytimes.com/2009/04/07/health/07virus.html. 
17. ^ Chase, Marilyn (2009-04-01). "Bloomberg - Cervical cancer deaths halved by HPV Test, Treatment". Bloomberg.com. http://www.bloomberg.com/apps/news?pid=20601124&sid=asRUT4ihBQDw. Retrieved 2010-08-29. 
18. ^ Sarah Boseley, health editor. "The Guardian - NHS under pressure for new cervical cancer test provision". Guardian. http://www.guardian.co.uk/science/2009/apr/02/cervical-cancer-india-test-smear. Retrieved 2010-08-29. 
19. ^ Sharples, Tiffany (2009-04-02). "Time - HPV Test Screens Best for Cervical Cancer". Time.com. http://www.time.com/time/health/article/0,8599,1889078,00.html. Retrieved 2010-08-29. 
20. ^ McNeil Jr, Donald G. (2009-04-07). "DNA Test Outperforms Pap Smear". The New York Times. http://www.nytimes.com/2009/04/07/health/07virus.html?_r=2&em. Retrieved 2010-05-21. 
21. ^ Sherris J, Wittet S, Kleine A, et al. (September 2009). "Evidence-based, alternative cervical cancer screening approaches in low-resource settings". Int Perspect Sex Reprod Health 35 (3): 147–54. doi:10.1363/ifpp.35.147.09. PMID 19805020. 
22. ^ Sankaranarayanan, R; Gaffikin, L; Jacob, M; Sellors, J; Robles, S (2005). "A critical assessment of screening methods for cervical neoplasia". International Journal of Gynecology & Obstetrics 89: S4–S12. doi:10.1016/j.ijgo.2005.01.009. ISSN 00207292. 
23. ^ Luciani S, Winkler J. Cervical Cancer prevention in Peru: Lessons learned from the TATI demonstration project. Washington, DC: Pan American Health Organization; 2006.
24. ^ Gage, J (2003). "Follow-up care of women with an abnormal cytology in a low-resource setting". Cancer Detection and Prevention 27 (6): 466–471. doi:10.1016/j.cdp.2003.09.004. ISSN 0361090X.