INTRODUCTION — Cervical cancer is the fourth most common malignancy among females globally and the leading cause of mortality among gynecologic malignancies [1]. Effective strategies for cervical cancer screening and treatment of cervical intraepithelial neoplasia, a precursor to cancer, have been in place for more than 70 years and, where applied, have dramatically reduced the incidence of and mortality from this disease [2,3].

However, standard strategies such as cervical cytology, human papillomavirus testing, and colposcopy are often not possible in resource-limited settings due to economic and other infrastructure issues. Health care resources and disease burden vary among and within countries, making it difficult to draw general conclusions regarding screening strategies for the entire resource-limited world. Addressing individual countries is beyond the scope of this topic review. Therefore, cervical cancer screening in health care systems in which cytology or colposcopy is not feasible will be reviewed here.

The general approach to and tests used for cervical cancer screening are discussed separately. (See "Screening for cervical cancer in resource-rich settings" and "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing" and "Cervical cancer screening tests: Visual inspection methods".)

EPIDEMIOLOGY — Worldwide, cervical cancer is the fourth most common cancer in women after breast, colon, and lung cancers [4]. In 2020, an estimated 604,127 new cases of cervical cancer were diagnosed, and 341,831 deaths occurred, although incidence and mortality varied widely geographically [1]. Over 85 percent of new cases are diagnosed in resource-limited countries, and in most of these countries, it is the most common cancer in females after breast cancer [1]. The following links provide global rates of cervical cancer from the International Agency of Research on Cancer GLOBOCAN database: incidence and mortality [5].

RATIONALE — In countries that have introduced successful cervical cancer screening programs, cervical cancer has become a relatively rare disease. In most resource-rich countries, the age-standardized incidence rate (ASIR) for cervical cancer is less than 10/100,000, whereas in resource-limited countries, the ASIR of cervical cancer ranges from 25 to 55/100,000 [6].

Cervical cancer screening and human papillomavirus (HPV) vaccination are both used to decrease the risk of cervical cancer. In resource-limited settings, expert groups recommend that public health efforts focus primarily on vaccinating young females, the group in which the absolute benefit of HPV vaccination is the highest. In a modeling study in 78 low-income and lower middle-income countries, HPV vaccination of girls had minimal predicted impact on cervical cancer mortality, but vaccination in addition to twice-lifetime Pap smear screening and scaled up cancer treatment was projected to decrease the mortality from cervical cancer by approximately 33 percent by the year 2030 and 99 percent by the year 2120 [7,8]. HPV vaccines are discussed in detail separately. (See "Human papillomavirus vaccination".)

BARRIERS TO CERVICAL CANCER SCREENING — Barriers to implementing programs for cervical cancer prevention include competing health care demands and economic, social, and political issues [9].

The principal health care issues that compete with cervical cancer prevention are maternal and infant mortality and infectious diseases (eg, tuberculosis, malaria, and HIV infection). The challenges facing health care systems worldwide are illustrated by the following: In 2002, there were 510,000 deaths (0.9 percent of the total deaths) attributed to maternal conditions and 2,464,000 deaths (4.3 percent of total deaths) due to perinatal conditions worldwide. Although cervical cancer is prevalent, it caused fewer deaths (239,000 deaths; 0.4 percent of total deaths) [10]. HIV infection is particularly important, since it is not only a competing health priority in some regions but also exacerbates cervical neoplasia. In addition, with the scarcity of health care resources, existing health care services tend to focus on curative, rather than preventive, health care. (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states".)

Economic factors also present an obstacle to screening. Resource-limited countries account for 84 percent of the global population, 90 percent of the disease burden, 20 percent of gross domestic product, but only 12 percent of health spending [11]. The disparity in per capita expenditure on health in resource-rich versus resource-limited countries is stark. Yearly per capita expenditure on health in the United States in 2006 was $5711, $3809 in Switzerland, and $2389 in the United Kingdom. By contrast, in resource-limited countries, annual per capita expenditures ranged from $14 in the Democratic Republic of Congo to $64 in Nepal [12]. Standard cervical cancer screening methods, such as cytology or colposcopy, are costly and are not affordable considering the per capita expenditure on health in these countries. One study estimated that 63 percent of females in resource-rich countries receive cervical cancer screening, with an upper range of 80 to 90 percent [13]. The comparative figure in resource-limited countries is 19 percent, ranging from 1 percent in Bangladesh, Ethiopia, and Myanmar to 73 percent in Brazil.

Social and political conditions in resource-limited settings often impede cervical cancer screening programs. Reliable and affordable modes of communication and transportation are often lacking. Therefore, patients are often not able to travel to a screening site for an initial or follow-up visit or to receive results in a timely manner. Education and literacy also make an impact. Patients in resource-limited countries may be illiterate or may use a local dialect that differs from the national language. Thus, they may not be able to read written results. Also, patients are likely to be uninformed about interventions such as cervical cancer screening, and thus, there is no public demand and no political motivation to establish screening programs. War and civil strife are endemic in many resource-limited countries and are additional factors that may have devastating consequences for health care infrastructure.

APPROACH TO CERVICAL CANCER SCREENING — Cytologic screening with or without human papillomavirus (HPV) DNA testing has led to vast improvements in prevention and early detection of cervical cancer. Evidence of the effectiveness of this approach has led to the adoption of cervical cytology screening in all resource-rich and some resource-limited nations.

General principles — The standard approach to cervical cancer screening in resource-rich settings is to use cytology, typically in some combination with HPV testing, followed with colposcopy, and then treatment based on the results of colposcopic diagnosis. This approach requires three visits with communication of test results after each step.

Unfortunately, due to the barriers discussed above, the success of the approach used in resource-rich countries has not been replicated in resource-limited countries. Cytology-based screening programs require a relatively sophisticated and costly infrastructure, including highly trained personnel, built-in quality control, ongoing training of staff, adequately equipped laboratories, and functional referral systems to communicate results of the test to patients. HPV testing is costly; currently laboratory based; and, when used as a triage test, adds an extra processing step to cervical cytology. Patients, in turn, need to be able to return for further testing if indicated. Additionally, colposcopy requires a level of clinical expertise typically found only in tertiary health care facilities, if available at all, and histology requires a laboratory infrastructure and trained pathologists, all of which are in short supply in resource-limited countries. (See 'Barriers to cervical cancer screening' above.)

Creating a functional cervical cancer screening program in a resource-limited setting must include consideration of the screening test and its characteristics and also address the limitation of health care access and infrastructure. Ideal characteristics of a cervical cancer screening test used in such settings include:

●Can be performed in a primary health care facility

●Can be performed by trained nurses or paramedical staff, particularly where there are few or no clinicians

●Requires little technology and staff training to perform, process, and interpret

●Test results should either be immediate (eg, visual screening methods such as visual inspection with acetic acid [VIA]) or be available within several hours or days (eg, rapid-result HPV testing, also known as point-of-care testing)

Performing screening and treatment at the same visit, thereby eliminating the intermediate steps of colposcopy and histologic sampling, is another strategy that can avoid patient noncompliance with follow-up and reduce infrastructure requirements and therefore the overall costs of cervical cancer prevention. (See 'Screen and treat protocols' below.)

Screening frequency and patient age — Patients in resource-rich countries are often screened for cervical cancer every one to three years. However, this screening frequency is not possible in most resource-limited settings. Decisions regarding screening frequency must be made based upon available resources. In programs in which patients will receive screening only once or twice in a lifetime, screening should focus on the age range that will result in the largest reduction in cervical cancer incidence and mortality.

The greatest impact on cervical cancer reduction appears to result from screening patients aged 30 to 39 years. This is supported by a subgroup analysis from a randomized trial in which over 80,000 patients aged 30 to 59 in India were assigned to either VIA screening or cervical cancer health education [14]. At seven-year follow-up, patients in the screening group showed a significant decrease in age-standardized rates of cervical cancer incidence (25 percent) and mortality (35 percent); these decreases were greater in patients aged 30 to 39 (incidence: 38 percent; mortality: 66 percent) compared with other age ranges (40 to 49 years: 18 and 45 percent; 50 to 59 years: 24 and 1 percent).

Optimal screening frequency and patient age have also been calculated using modeling studies, since longitudinal clinical data are not available. One such modeling study used clinical data from India, Thailand, Kenya, South Africa, and Peru to evaluate cervical cancer screening in patients once in a lifetime at the age of 35 years [15]. Within these parameters, screening with VIA or HPV testing would reduce the lifetime risk of cervical cancer by 25 to 36 percent and cost less than USD $500 per year of life saved. Costs of the various protocols varied from country to country.

By contrast, using cytology as the screening method in the United States, one study estimated that, compared with no screening, screening every three years costs $22,000 per year of life gained [16]. Increasing the frequency of screening to every two years would cost $440,000 for every additional year of life gained, whereas annual screening would cost $1.8 million for each additional year.

Challenges to evaluating screening tests — Determination of the performance of a screening test depends on the reference standard used. The gold standard typically used for cervical cancer screening tests is colposcopic-directed biopsy (biopsy of areas with suspicious colposcopic findings). Use of this standard tends to overestimate sensitivity, since false-negative colposcopy will result in missing some cervical neoplasia. Few studies use random cervical biopsies as the reference standard [17].

VISUAL INSPECTION METHODS — Historically, visual inspection of the cervix without magnification was the first method of screening of the cervix. It was introduced in the 1930s by Schiller, who used Lugol iodine to stain the cervix [18]. It was, however, soon realized that this method of screening had a low specificity, and Schiller's test, as it was known, was rapidly replaced when cervical cytology became available.

In contrast with colposcopy, visual inspection of the cervix is performed using the naked eye. Visual inspection with acetic acid (VIA) is also referred to as direct visual inspection or cervicoscopy. This technique has reemerged as a screening tool for resource-limited settings because, despite its limited specificity and low positive predictive value (around 10 percent), it is economical, requires little equipment, and provides immediate results [19]. Visual inspection can be performed with acetic acid (VIA) or Lugol iodine (VILI).

Primary care clinicians or midlevel providers can be trained to perform visual inspection within a relatively short period of time; however, due to the subjective nature of the test, it is difficult to standardize quality control. Improved training and quality control may be obtained by utilizing smartphone technology (smartphone VIA [S-VIA]) and allowing remote expert reviewers to view cervical images and provide diagnostic and management feedback [20]. The technique for performing these tests is discussed separately. (See "Cervical cancer screening tests: Visual inspection methods".)

Visual inspection with acetic acid — Use of VIA screening followed by treatment reduces the rate of cervical cancer compared with no screening. This was illustrated by two large randomized trials:

●In one trial, clinics serving over 80,000 patients aged 30 to 59 years in India were assigned to either VIA screening or cervical cancer health education [14]. Patients with positive screening tests were further evaluated with colposcopy and directed biopsy, and those with cervical intraepithelial neoplasia (CIN) were treated with cryotherapy or excision. At seven-year follow-up, patients in the screening group versus the health education group showed a significant decrease in age-standardized rates of cervical cancer incidence (75 versus 99 per 100,000 person-years) and mortality (40 versus 57 per 100,000 person-years).

●Similarly, another trial included over 150,000 patients aged 35 to 64 years in India who were assigned to either VIA screening or cancer education, performed by public health workers [21]. The incidence of invasive cervical cancer was 26.74 per 100,000 in the screening group and 27.49 per 100,000 in the control group. At 12-year follow-up, the screening group showed a 31 percent reduction in cervical cancer mortality. A 7 percent reduction was also observed in all-cause mortality.

The sensitivity and specificity of VIA in resource-limited countries for detection of CIN or cervical cancer have been evaluated in multiple observational studies [19,22-31]. The highest quality data are reported in a meta-analysis of 11 studies with over 58,000 patients aged 25 to 64 years in India and Africa. Each patient underwent VIA and one or more other screening tests; the reference standard was colposcopic-directed biopsy performed in all patients [31]. For detection of CIN 2 or a more severe abnormality (CIN 2+), VIA had a sensitivity and specificity of 79 and 85 percent, respectively. The diagnostic accuracy of S-VIA has also been evaluated. In a meta-analysis including eight prospective studies with over 680 patients, S-VIA for the diagnosis of CIN 2+ had a sensitivity and specificity of 75 and 62 percent, respectively [32].

The World Health Organization published the results of a demonstration project from 2005 to 2009 to use VIA screening in 19,759 patients in six African countries [33]. VIA was positive in 10.1 percent of patients, and 87.7 percent of VIA-positive cases were eligible for cryotherapy. Thirty-nine percent of patients accepted treatment on the same day, but there was high loss to follow-up for those diagnosed with high-grade precursors and cervical cancer. A total of 326 patients had a "suspicious for cancer" diagnosis; only 77 out of 96 investigated were finally treated, almost all with radiation, with the rest of the patients lost to follow-up.

At best, VIA screening offers an interim approach to establish a screening culture and infrastructure in resource-limited settings until an affordable human papillomavirus test can be introduced. Inherent in any screening strategy are the tradeoffs between the characteristics of the test (ie, sensitivity to maximize precursors detected and specificity to minimize overtreatment) and programmatic issues such as population coverage and the necessary diagnostic and treatment procedures, costs, and quality control.

An aspect of the single-visit approach that has not been well evaluated is the impact of point-of-care testing at a primary care level. The single-visit approach does not obviate the need for counseling or careful explanation for follow-up and requires additional work on already overloaded health care workers and fragile health systems. Careful evaluation and planning are needed to plan how to integrate this approach with other interventions for patients' and general health.

Coexisting vaginal or cervical infection with Trichomonas vaginalis, Chlamydia trachomatis, or Neisseria gonorrhoeae did not alter the sensitivity or specificity of VIA for CIN2+ in a cross-sectional study of 2754 patients in South Africa [29]. However, there was a significant decrease in VIA specificity in patients with HIV infection.

VIA with magnification — The addition of magnification to VIA (VIAM) does not improve the detection of CIN or cervical cancer over VIA with the naked eye. This was best illustrated by a meta-analysis of three studies that included over 18,000 patients aged 25 to 65 years who were evaluated with both VIA and VIAM; colposcopy with directed cervical biopsy was used as the reference standard [34]. For detection of CIN2+, there were no significant differences in the sensitivity and specificity for VIA (60 and 87 percent) versus VIAM (64 and 87 percent).

Visual inspection with Lugol iodine — VILI is more sensitive than VIA but equally specific. It is, however, used less commonly than VIA [31,35]. In our experience, VIA allows a more nuanced and more detailed analysis of the dysplastic area. In the meta-analysis of 11 studies described in a preceding section, patients were evaluated with both VIA and VILI in 10 studies [31]. For detection of CIN 2+, the sensitivity and specificity for VILI were 91 and 85 percent (compared with 79 and 85 percent for VIA). (See 'Visual inspection with acetic acid' above.)

HPV TESTING — Human papillomavirus (HPV) testing used alone or in combination with visual inspection with acetic acid (VIA) has the potential to improve cervical cancer screening in resource-limited settings. Unfortunately, it is not feasible to use the current laboratory-based HPV tests used in resource-rich countries due to expense, the infrastructure required for processing, and the waiting time for results, although new HPV tests capable of giving a result within one hour are currently being developed and tested. These tests include the Xpert HPV (Cepheid), which uses polymerase chain reaction (PCR) technology to detect 14 high-risk types of HPV. The test identifies all high-risk HPV types and determines the presence of HPV 16 and other combinations of high-risk genotypes. It gives a result within one hour and is uniquely positioned to provide screening and treatment in one visit without the complexity of a laboratory-based test. The manufacturer has implemented point-of-care tuberculosis testing using similar technology (GeneXpert) in sub-Saharan Africa.

Additional advantages of Xpert HPV are that the test can be performed on site and batched so that each cartridge can be inserted into the machine singularly, rather than having to fill 80 or more wells to run samples simultaneously. It can be performed by an individual who is trained but not as a fully credentialed laboratory assistant. Our group has used this test in over 4000 patients (HIV positive and HIV negative) and shown that it enables the provider to increase the specificity of HPV DNA testing in HIV-positive patients from approximately 63 to over 80 percent, thus reducing over treatment [36].

This section will focus on the clinical utility of HPV DNA testing in resource-limited settings. The general use of HPV DNA testing for cervical cancer screening is discussed in detail separately. (See "Screening for cervical cancer in resource-rich settings".)

HPV testing reduces cervical cancer mortality in resource-limited settings and is superior to VIA or cervical cytology. This was illustrated in a randomized trial of 131,746 patients aged 30 to 59 years in rural India that compared a single lifetime screening with one of three screening modalities with standard care; the screening modalities were HPV testing using the Hybrid Capture II test (HC2), cervical cytology, or VIA [37]. At eight-year follow-up, patients who received HPV testing versus standard care had a 50 percent reduction in stage II or higher cervical cancer (15 versus 33 per 100,000 person-years) and cervical cancer mortality (13 versus 26 per 100,000 person-years). For the groups screened by cytology or VIA, rates of stage II or higher cervical cancer (VIA: 32 per 100,000 person-years; cytology: 23 per 100,000 person-years) or cervical cancer mortality (VIA: 21 per 100,000 person-years; cytology: 21 per 100,000 person-years) did not differ significantly compared with standard care but were significantly higher than patients in the HPV testing group. This result for VIA differed from the finding of the trial in 80,000 patients described above; the authors attributed this difference to a higher rate of treatment in that trial. (See 'Visual inspection with acetic acid' above.)

Rapid-result HPV test — While these results are promising, the HPV tests (eg, HC2) used in resource-rich countries are prohibitively expensive for resource-limited settings (in the United States, the cost per test is approximately USD $50 to $100), and the waiting time for a result of one or more days [38] is an additional impediment to patient follow-up. However, there are data emerging regarding a careHPV test that is affordable, gives results quickly, and is portable. Each test will cost less than USD $5, the processing kit has its own reagents and water supply and can be run using batteries, and the result is available within 2.5 hours [39]. The new test detects 14 high-risk types of HPV, similar to the 14 or 18 types detected by the tests used in resource-rich countries. This test is not yet commercially available.

The rapid-result HPV test appears to perform as well for the detection of high-grade cervical neoplasia as standard HPV testing and to be superior to VIA. The single study that has evaluated the rapid-result test was a cross-sectional study of 2388 patients in China aged 30 to 54 [40]. Each patient was assessed using a self-collected vaginal specimen (for careHPV testing), VIA, and a provider-collected cervical specimen (for careHPV, HC2, and cervical cytology); colposcopic-directed biopsy was performed in all patients and used as the reference standard. HC2 testing showed no significant difference in detection of cervical intraepithelial neoplasia (CIN2+) versus provider-collected careHPV but was superior to self-collected careHPV (sensitivity and specificity, HC2: 97 and 86 percent; provider-careHPV: 90 and 84 percent; self-careHPV: 81 and 82 percent). On the other hand, VIA was inferior to either a provider-collected or self-collected careHPV for detecting CIN2+ (sensitivity and specificity, VIA: 41 and 95 percent). Direct comparison of collection method for careHPV revealed no significant difference in CIN2+ detection between provider- and self-collected samples.

These data are promising and indicate that rapid-result HPV testing may be suitable for performing screening and treatment on the same day in resource-limited settings; however, the newer PCR GeneXpert tests are likely to be more efficient and effective.

Increasing HPV test specificity — HPV testing has a high sensitivity but a low specificity. Specificity takes on added importance in resource-limited settings whether follow-up for a positive test is further evaluated or immediately treated. Additional costs are incurred when patients with false-positive screening tests are referred for a costly test like colposcopy. Also, where treatment is performed based on a screening test, low test specificity may result in large numbers of patients being treated unnecessarily.

One approach to the low specificity of HPV testing is to change the definition of a positive test. In the case of HPV testing, the definition of a positive test can be varied by changing the positivity threshold (expressed as the ratio of light emission, ie, relative light units [RLU] per positive control specimen [PC]). As for most tests, increasing the specificity results in a decrease in sensitivity. This was illustrated in a study of over 2900 patients in South Africa in which detection of CIN2+ by HC2 at a threshold of >1 RLU/PC (the typical standard) had a sensitivity of 88 percent and specificity of 82 percent, while a threshold of >8 RLU/PC had a sensitivity of 79 percent and specificity of 90 percent [41].

Self-collected samples — For patients who do not have access to a speculum examination or who are reluctant to undergo a pelvic examination, self-collected vaginal samples can be used for HPV testing [42]. Patients can collect samples from the vagina using a tampon, Dacron or cotton swab, cytobrush, or cervicovaginal lavage. Self-collection can be performed under supervision at a clinic or at home. If a patient collects a sample at home, it is then placed in a collection tube with a transport medium and brought back to the clinic for processing.

Self-collected samples appear to be acceptable to patients and as effective at detecting high-grade CIN as clinic screening methods.

HPV test self-collection was compared with clinician collection in a Dutch randomized trial that included 16,410 patients aged 29 to 61 years. Self-collected HPV testing (with a cervical brush) was compared with cervical cytology performed at a clinic in a randomized trial of 12,330 patients in Mexico [43]. The acceptability of self-collected HPV testing was high; 98 percent of patients in the HPV testing group agreed to collect the sample and performed the testing, while 89 percent of those scheduled for a Pap test had the test performed. HPV testing had a higher sensitivity for detection of CIN2+ (relative sensitivity 2.9, 95% CI 2.0-4.1) and for invasive cancer (3.6, 95% CI 1.6-7.9). The disadvantage of HPV testing was that more patients underwent colposcopy and ultimately had negative findings: 28 percent in the HPV testing group compared with none in the cytology group. For CIN2+, the positive predictive value of HPV testing was 12.2 percent compared with 90.5 percent for cytology.

In a meta-analysis including 56 accuracy studies and 25 randomized trials, self-collected compared with clinician-collected samples had similar absolute pooled sensitivity (96 percent) when high-risk HPV (hrHPV) assays for CIN2+ based on polymerase chain reaction were used [44]. In addition, patients receiving a self-sampling kit rather than a reminder letter to attend a clinician-screening appointment had higher response rates (pooled relative participation rate of 2.3, 95% CI 1.9-2.9); however, response rates were highly variable among different settings.

Further study is needed to determine the best method of self-collection (eg, swab, cervical brush, tampon). This question was addressed in an earlier meta-analysis, which included 12 of the same studies as the analysis described above and used clinician-collected HPV samples as a reference standard [45]. For seven studies that used a Dacron or cotton swab or a cytobrush, the pooled sensitivity and specificity for HPV detection was 78 and 90 percent. For three studies in which a tampon was used, the results are reported as a range of sensitivities (67 to 94 percent) and specificities (80 to 100 percent). These data do not allow comparison among the methods.

Given these data, self-collection appears to be a useful method for HPV testing in patients who do not have access to a speculum examination.

COMBINING TWO SCREENING TESTS — Combining two screening tests (eg, visual inspection with acetic acid [VIA] and human papillomavirus [HPV] testing) is one approach to balancing the strengths and weaknesses of each test. Two-test strategies can be either: additive, with screen-positive defined as an abnormal result on either test; or sequential, in which only patients with an abnormal result on the first test undergo a second test and only those who are also positive on the second test would receive treatment [46]. The goal is to maximize screening performance by combining a test with high sensitivity (eg, VIA) with another test with high specificity (eg, HPV testing with use of a high threshold for positivity). (See 'Increasing HPV test specificity' above.)

Use of a two-test approach to screening increased specificity but decreased sensitivity in a prospective observational study of 1266 South African patients aged 35 to 65 years. Each patient underwent screening with Hybrid Capture I HPV testing and VIA; VIA with magnification (VIAM), cervicography (a photograph of the cervix after application of acetic acid), and cytology were also performed. Patients with abnormal results on any of the screening tests underwent colposcopy at a follow-up visit [47]. Based on study results, use of VIA or HPV alone would result in a missed diagnosis of cervical intraepithelial neoplasia (CIN2+) in 6 or 8 per 1000 females screened, respectively, while 180 or 131 per 1000 would receive unnecessary treatment. Sequential use of VIA followed by HPV would result in a missed CIN2+ diagnosis in 13 per 1000 females screened, while 41 per 1000 would receive unnecessary treatment.

Given these results, it appears that it is preferable to use a combination of the two screening tests rather than either test alone. The number of missed diagnoses is notable but does not outweigh the large decrease in the number of patients who would receive unnecessary treatment. Complications are rare with cryotherapy, the predominant method of treatment for CIN used in resource-limited settings. However, unnecessary treatment also incurs costs, which may reduce the number of total patients who can be screened within a particular program. (See "Cervical intraepithelial neoplasia: Ablative therapies".)

SCREEN AND TREAT PROTOCOLS — A screening test followed in the same visit by treatment of positive results is referred to as a "screen and treat" or "see and treat" protocol. This approach is only possible with screening tests that produce immediate results (eg, visual inspection, rapid-result human papillomavirus [HPV] testing).

One-visit protocols eliminate communication difficulties involved in delivering and interpreting written results for patients as well as the issue of noncompliance with follow-up, in contrast with protocols that require two visits (screening followed by treatment) or three visits (screening followed by colposcopy followed by treatment).

Treatment method — The treatment method used in most resource-limited settings is cryotherapy rather than loop electrosurgical excision procedure (LEEP) or cold-knife conization. Cryotherapy is generally easier and cheaper to perform at a primary care level. A handheld portable device is available for cryotherapy. Cryotherapy does not require local anesthetic, and complications, such as damage to contiguous organs, are less likely. The World Health Organization (WHO) evaluated cryotherapy in a systematic review and recommended cryotherapy in settings where LEEP is not available [48]. Similarly, they recommended LEEP rather than cryotherapy in HIV-positive patients. A major advantage of cryotherapy is that it can be performed by non-clinicians in a primary care setting, and it is also suitable for a "screen and treat" approach. This method of treating cervical cancer precursors is effective and may well make treating patients in resource-limited settings more accessible with much greater coverage of the target population. Another innovation is the use of thermocoagulation, which has been used in some settings for the past 20 to 30 years. Due mostly to the complications of acquiring gas in resource-limited settings, the thermocoagulator has been reintroduced. The probe heats up to 100°C and causes necrosis of the transformation zone. Results of randomized controlled trials are pending.

One-visit protocols — The ability of screen and treat protocols, specifically with use of HPV testing, to reduce the rate of high-grade cervical intraepithelial neoplasia (CIN) or cancer was demonstrated in a randomized trial of 6555 previously unscreened patients in South Africa, aged 35 to 65 years [49]. All patients were screened with visual inspection with acetic acid (VIA), Hybrid Capture II (HC2) HPV testing, and cytology and were assigned to one of three groups: VIA screen-positive followed by cryotherapy, HPV screen-positive followed by cryotherapy, or no further evaluation or treatment for six months. All patients also underwent HIV testing. At six-month follow-up, colposcopy with directed biopsy was performed in all patients and CIN2+ was found in significantly fewer patients in both the VIA and HPV screen and treat groups (2.2 and 0.8 percent, respectively) versus the delayed group (3.6 percent). This difference persisted in a subset of 2708 patients who were evaluated at 12 months, with a rate of CIN2+ for VIA and HPV versus the delayed group of 2.9 and 1.4 percent versus 5.4 percent. At 36 months, based on data from 3639 patients, the cumulative rate of CIN2+ detection continued to be lower in the VIA and treat group (3.8 percent) and HPV and treat group (1.5 percent) than in the delayed group (5.6 percent) [50].

Treatment based on results of screening tests with low specificity, such as VIA or HPV testing, will result in some patients receiving unnecessary treatment. However, cryotherapy, until recently the preferred treatment in resource-limited settings, has a low complication rate [51,52]. In this trial, adverse effects reported by patients who underwent cryotherapy included vaginal discharge (78 percent), abdominal pain (30 percent), and abnormal bleeding (14 percent); only one patient had bleeding that required hospitalization [49]. Patients who underwent cryotherapy had more unscheduled visits during the study period than those who did not (1.0 versus 0.5 percent).

This study is limited by the protocol used, since screening was followed two to six days later by treatment in the screen and treat groups, while a one-visit approach is generally an important component of screen and treat protocols. In fact, 82 patients did not return after the initial screening visit.

In a WHO demonstration project from 2005 to 2009 in 19,759 patients in six African countries that included VIA screening followed by treatment with cryotherapy if positive, 39.1 percent of patients were screened and treated on the same day [33].

Cost-effectiveness is also more likely to be improved with one-visit screen and treat protocols than those requiring two or more visits. The data regarding cost derive from studies based on mathematical modeling rather than clinical studies. In one such report, based on a theoretical cohort of previously unscreened 30-year-old Black females from South Africa, a single visit in which screen-positive VIA or HPV testing is coupled with cryotherapy would be more cost-effective than two-visit protocols with HPV or cytology (lifetime cost per patient USD $39 to 41 versus $42 to 44) [46].

The WHO has published guidelines for clinical settings regarding the screen and treat approach [53]. In general, in the guidelines, use of an HPV test as the screening test is preferred if feasible. If HPV testing is not available, VIA is advised rather than cervical cytology followed by colposcopy (with or without biopsy). HPV testing may be combined with VIA (algorithm 1).

In the past five years, thermocoagulation has become more popular than cryotherapy as an ablative method of treating screen-positive patients. The Department of Reproductive Health and Research at the WHO released guidelines for the use of thermocoagulation (WHO February, 2019) that acknowledge that a major disadvantage of cryotherapy is the need for gas (either nitrous oxide or carbon dioxide) [54]. By comparison, thermocoagulation is a simple method of treatment, lightweight and easily portable, and treatment is based on 20 to 40 seconds at 100°C, leading to epithelial and stromal destruction of the lesion.

New innovations — The use of optical devices to either triage HPV testing or to use as a primary screening test is a new approach under evaluation. These devices use the technology included in smart phones and are able to take pictures of the cervix and to store data. Essentially, a mobile phone is used as a colposcopist aid. Ultimately, these devices will rely on artificial intelligence (AI). The use of AI to interpret cytology specimens has also been described [55].

Two-visit protocols — Two-visit protocols typically include a first visit with cervical cytology followed by a second visit with colposcopy and treatment based on colposcopic impression. Overtreatment, defined as treatment of lesions that are actually low grade, is an important concern, as with one-visit protocols.

It appears that the risk of overtreatment of CIN increases when there is a discrepancy between cervical cytology and colposcopic impression and with treatment in the presence of a low-grade colposcopic appearance. A meta-analysis was performed of 13 studies including 4611 patients who were managed with a see and treat approach, cervical cytology, and then colposcopy and treatment (with a LEEP) [56]. This analysis is relevant mainly to resource-rich settings since it evaluated use of cervical cytology and colposcopy, which may not be available in resource-limited settings, and LEEP is not the preferred treatment method in resource-limited settings based on cost and risk of complications. The analysis found the following overtreatment rates for differing combinations of cytology and colposcopic impression: high-grade cytology and high-grade colposcopic impression (11.6 percent), high-grade and low-grade (29.3 percent), low-grade and high-grade (46.4 percent), and low-grade and low-grade (72.9 percent). The rate for patients with both high-grade cytology and colposcopic impression is comparable to the overtreatment rate (11 to 35 percent) for a three-visit protocol (cytology, colposcopy and biopsy, then treatment). Thus, for patients with a discrepancy between cervical cytology results and colposcopic impression, with a low-grade colposcopic impression, and who are able to comply with a three-visit protocol, biopsy and treatment only for a histologic result of cervical intraepithelial lesion 2 or 3 is prudent. This is particularly true for patients who plan future pregnancy and when LEEP or cold-knife cone is the treatment mode, since these may result in adverse obstetric outcomes. (See "Reproductive effects of cervical excisional and ablative procedures".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical cancer screening, prevention, and management".)

SUMMARY AND RECOMMENDATIONS

●Cervical cancer is the most common malignancy among females in resource-limited settings, and more than 85 percent of worldwide cervical cancer deaths occur in these settings. (See 'Epidemiology' above.)

●Cervical cancer screening strategies, such as cervical cytology and colposcopy, are not feasible in many resource-limited settings due to economic, social, and political issues. (See 'Barriers to cervical cancer screening' above.)

●Strategies for cervical cancer screening in resource-limited settings include use of tests that are performed in a primary care facility by trained nurses or paramedical staff; require little equipment, technology, and staff training to perform, process, and interpret; and provide immediate results. (See 'General principles' above.)

●For patients in whom cervical cancer screening will be performed once in a lifetime, we suggest screening between the ages of 30 and 39 years rather than other age ranges (Grade 2B). (See 'Screening frequency and patient age' above.)

●For patients who are able to access a screening program that involves two or more visits, we suggest human papillomavirus (HPV) testing and visual inspection used in a sequential combination rather than either test alone (Grade 2C). If one test is used, we suggest HPV testing rather than visual inspection (Grade 2B). (See 'Visual inspection methods' above and 'HPV testing' above and 'Combining two screening tests' above.)

●Visual inspection is the only method available for patients who are only able to access a screening program for one visit. The preferred algorithm is to use point-of-care testing as the screening test, followed by cytology. (See 'Visual inspection methods' above and 'HPV testing' above.)

●For patients screened using HPV testing who do not have access to a speculum examination, we suggest self-collection of vaginal samples rather than clinician-collected samples (Grade 2B). There is insufficient evidence regarding the best method for self-collection (eg, swab, cytobrush, cervicovaginal lavage). (See 'Self-collected samples' above.)

●For patients screened using visual inspection, we suggest visual inspection with acetic acid (VIA) rather than visual inspection with Lugol iodine (VILI) (Grade 2C). We suggest visual inspection with the naked eye rather than with magnification (Grade 2C). (See 'Visual inspection with Lugol iodine' above and 'VIA with magnification' above.)

●Screen and treat protocols, in which a screening test is followed in the same visit by treatment of patients with positive results, eliminate communication difficulties involved in delivering and interpreting written results for patients as well as the issue of noncompliance with follow-up. (See 'Screen and treat protocols' above.)