cervical screening

Cervical screening is the process of detecting and removing abnormal tissue or cells in the cervix before cervical cancer develops. By aiming to detect and treat cervical neoplasia early on, cervical screening aims at secondary prevention of cervical cancer. Primary prevention of cervical cancer is vaccination against HPV. Several screening methods for cervical cancer are the Pap test (also known as Pap smear or conventional cytology), liquid-based cytology, the HPV DNA testing and the visual inspection with acetic acid. Pap test and liquid-based cytology have been effective in diminishing incidence and mortality rates of cervical cancer in developed countries but not in developing countries. Prospective screening methods that can be used in low-resource areas in developing countries are the HPV DNA testing and the visual inspection. There are wide disparities in cervical screening rates and outcomes, with about 90% of deaths from cervical cancer in 2018 occurring in low and middle-income countries. To help coordinate resources to address this gap, the World Health Organization in 2020 adopted the Global Strategy for Cervical Cancer Elimination. This created the goal of vaccinating 90% of women against HPV by age 15, screening 70% of women by age 35 and again by age 45, and treating and managing 90% of patients with pre-cancer and invasive cancer, respectively.

Recommendations

Different countries have different cervical screening recommendations.
* In Europe, most countries suggest or offer screening between the ages of 25 to 64. According to the 2015 European guidelines for cervical cancer screening, routine HPV primary screening should not begin under 30 years of age. Primary testing for oncogenic HPV can be used in a population-based programme for cervical cancer screening. In England, the NHS cervical screening programme is available to women aged 25 to 64; women aged 25 to 49 receive an invitation every 3 years and women aged 50 to 64 receive an invitation every 5 years to undergo HPV testing. If there is a positive HPV test result, then patients undergo further cytology (Pap smear).
* In the United States, screening is recommended for women between ages 21–65, regardless of age at sexual initiation or other high-risk behaviors. For healthy women aged 21–29 who have never had an abnormal Pap smear, cervical cancer screening with cervical cytology (Pap smear) should occur every 3 years, regardless of HPV vaccination status. The preferred screening for women aged 30–65 is "co-testing", which includes a combination of cervical cytology screening and HPV testing, every 5 years. However, it is acceptable to screen this age group with a Pap smear alone every 3 years or with an FDA-approved primary high risk HPV test every 5 years. In women over the age of 65, screening for cervical cancer may be discontinued in the absence of abnormal screening results within the prior 10 years and no history of high-grade lesions. Management of screening results is based on recommendations by the American College of Obstetricians and Gynecologists and other professional organizations.
* In Australia, screening is offered to women aged 18–70, every two years. This is by Pap smear, and regardless of sexual history. In Canada, where screening programmes are arranged at provincial level, the general recommendation is not to begin routine screening until the age of 25 in the absence of specific reasons to, then to screen every three years until the age of 69. In Ontario, "The Ontario Cervical Screening Program recommends that women who are or have been sexually active have a Pap test every 3 years starting at age 21."
* In Thailand, the Ministry of Public Health recommends women from age 30-60 receive primary HPV testing every 5 years. Based on the results of the test, those with higher risk strains of HPV will be referred for colposcopy, while those with lower risk strains will be referred for cytology.
* In low-resource countries, decisions regarding cervical screening are made based upon available resources and thus it is often not possible to offer cervical screening as frequently. The greatest impact on cervical cancer reduction appears to result from screening women aged 30 to 39 years, so resources may be directed to that age group.

Screening process

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 health care clinician inserts an instrument, called a speculum, inside the vagina. The speculum has two arms that spread the walls of the vagina apart in order to 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 into a container of liquid, and analysed for abnormalities. Cervical cells to be tested for HPV are collected in a similar way.

Removal of abnormal cells

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, with 3 classes of CIN: I, II and III in ordering of increasing stage/severity. 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.

Types of screening

There are a number of different types of screening method available. In the United States, cervical screening is usually performed using the Pap test (or 'smear test'), though the UK screening programmes changed the screening method to liquid-based cytology in 2008.

Conventional cytology

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:ACP Journal Club
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* sensitivity 50%
* 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%. 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% to 66%, (although some studies report increased sensitivity from liquid-based smears)
* specificity 82% to 91%

Human papillomavirus testing

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

In 1995, British researchers Anne Szarewski and Jack Cuzick showed that testing for the presence of HPV DNA in cells taken during cervical screening would pick up cases of pre-cancer that were missed by the routine test.

In 2022, the European Commission's Scientific Advice Mechanism recommended replacing cytology (smear tests) with HPV testing as a first line of screening. The scientists concluded that this change, combined with widespread HPV vaccination, could eliminate cervical cancer in Europe.

The English National Health Service now includes "HPV triage" in its screening programme. This means that if initial screening test shows borderline results or low-grade abnormal cells, a further test for HPV is made on the sample. If this shows HPV is present, the patient is called for a further examination, but if no HPV is present the patient resumes the usual screening schedule as if no abnormalities had been found.

Studies of the accuracy of HPV testing report:
* sensitivity 88% to 91% (for detecting CIN 3 or higher) to 97% (for detecting CIN2+)
* specificity 73% to 79% (for detecting CIN 3 or higher) to 93% (for detecting CIN2+)

By adding the more sensitive HPV test, the specificity may decline. 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, an invasive procedure and unnecessary 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. Randomized controlled trials have suggested that HPV testing could follow abnormal cytology or could precede cervical cytology examination.

A study published in 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."

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. 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). One promising prospect in HPV testing is possibility to self-sampling. HPV testing on a self-sample can today be suggested as an additional strategy to reach women not participating in the regular screening programme and in future as a possible screening strategy.

Co-testing

A newer approach to screening is known as co-testing, in which individuals can receive both high risk HPV testing and cytology. These results can be utilized to calculate the patient's immediate risk for cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). In the United States, several physician organizations such as the American College of Obstetricians and Gynecologists created management guidelines based on the immediate CIN3+ risk over 5 years, instead of the test results themselves. This risk guides clinical decisions, with a risk ≥ 4% leading to more frequent screening, colposcopy, and treatment. Risk ≤ 4% leads to a recommendation of shorter screening intervals. If the risk is low enough, the patient can return to a routine screening interval. Management guidelines are summarized below:

Testing in resource-poor areas

Many resource-poor areas cannot provide regular screening or are unable to offer cytology-based screening. These areas must rely on infrequent screening, or alternative methods screening such as HPV testing or, when that is not available, visual inspection with acetic acid followed by treatment with cryotherapy. 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. 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 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. The WHO recommends HPV testing with treatment for women with positive test results.

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. This method is also referred to as direct visual inspection or cervicoscopy. 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. 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. Though VIA has limited specificity and low positive predictive value (~10%), it is economical, requires little equipment, and provides immediate results. 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.

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.

Emerging technologies

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.

VIA, one of the alternative approaches to conventional testing, has shown to have a low specificity compared to cytology and a high rate of false positives in several studies. Entities such as inflammation, cervical condyloma and leukoplakia can give false positive results of VIA test. There is no permanent record of the test to be reviewed later. Between community centers high variability has been observed, and even in a study of Nigeria of 2013 VIA was not reproducible nor sensitive; this led to discouraging the method in that country.

In addition, p16/Ki-67 are emerging biomarkers that have been used as a triage method for HPV-positive patients. In studies conducted so far, p16/Ki-67 dual staining had a higher sensitivity and specificity compared to cytology. Using these biomarkers may help in reducing the number of false-positive tests and unnecessary examinations.

Assessing DNA methylation patterns in individuals with HPV is also an emerging screening method. There are about 80 methylation patterns that can serve as potential biomarkers for cervical cancer. Molecular testing of DNA methylation patterns is more objective than cytology testing and can be automated, requiring less training with more precision.

See also

* CervicalCheck

References

{{Female genital procedures

Cancer screening
Gynaecological cancer
Papillomavirus-associated diseases
Infectious causes of cancer