Screening for cervical cancer in resource-limited settings

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 (CIN), 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].

While most resource-rich countries have adopted standard cervical cancer screening strategies, such strategies (eg, cervical cytology, human papillomavirus [HPV] testing, colposcopy) are often not possible in resource-limited settings due to economic and other infrastructure limitations. 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 standard strategies are 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".)

●(See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing".)

●(See "Cervical cancer screening tests: Visual inspection methods".)

EPIDEMIOLOGY — Worldwide, cervical cancer is the fourth most common cancer in females after breast, colon, and lung cancers [1]. The majority (over 85 percent) of new cases are diagnosed in resource-limited countries. In such countries, cervical cancer is the second most common cancer (after breast cancer) in females. In countries that have introduced successful cervical cancer screening programs, the incidence of cervical cancer has declined dramatically. 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 [4]. The following links provide global rates of cervical cancer from the International Agency of Research on Cancer GLOBOCAN database: incidence and mortality [5].

In August 2020 the World Health Organization (WHO) launched the global strategy to accelerate the elimination of cervical cancer as a public health problem [6]. The strategy proposed an incidence threshold of four per 100,000 women-years for elimination of cervical cancer as a public health problem. In addition, the following targets must be met by 2030 for countries to be on the path towards cervical cancer elimination:

●Fully vaccinate 90 percent of females by age 15 years.

●Screen 70 percent of females with a high-performance test by age 35 and again at age 45.

●Treat 90 percent of females identified with cervical disease (including precancers and cancers).

If these targets are reached, mathematical modelling estimates that over 62 million cervical cancer deaths will be averted by 2120.

BARRIERS — Barriers to implementing programs for cervical cancer prevention include competing health care demands and economic, social, and political issues [7].

●Competing health demands – Health care issues that compete with cervical cancer prevention include maternal and infant mortality and infectious diseases. For example, in 2020, the COVID-19 pandemic diverted resources away from cervical cancer screening. In addition, while there were approximately 342,000 deaths attributed to cervical cancer worldwide in 2020 [1], more than 2.4 million children died within the first month of life, and there were an estimated 1.5 million new cases of human immunodeficiency virus (HIV), 10 million new cases of tuberculosis, and 241 million cases of malaria [8]. HIV infection is particularly important, as it is not only a competing health priority in some regions but also exacerbates cervical neoplasia through increased incidence of oncogenic human papillomavirus (HPV) infection. (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states".)

With the scarcity of health care resources, existing health care services also tend to focus on urgent medical needs and curative, rather than preventive, health care.

●Economic factors – 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, and 20 percent of gross domestic product, but only 12 percent of health spending [9]. The disparity in per capita expenditure on health in resource-rich versus resource-limited countries is stark. In 2019, the yearly per capita expenditure on health was $10,921 in the United States, $9666 in Switzerland, and $6003 in Denmark. By contrast annual per capita health expenditure ranged from $21 in the Democratic Republic of Congo, to $46 in Bangladesh, and $64 in India [10]. Standard cervical cancer screening methods, such as HPV testing, cytology, or colposcopy, are costly and are not affordable considering the per capita expenditure on health in these countries.

●Social and political issues – 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 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 such 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.

●Other – Other barriers include the lack of the following: medical insurance programs, medical equipment and supplies (eg, Pap spatulas and brushes, liquid fixative solutions, sterilization equipment), and trained cytopathologists or pathologists.

These barriers result in lower rates of cervical cancer screening. In one retrospective study, the estimated number of females in resource-rich countries receiving cervical cancer screening was 63 percent (upper range: 80 to 90 percent) [11]. The comparative figure in resource-limited countries was 19 percent, ranging from 1 percent in Bangladesh, Ethiopia, and Myanmar to 73 percent in Brazil.

SCREENING AGE AND FREQUENCY — While patients in resource-rich countries are often screened for cervical cancer starting at the age of 21 or 25 years and are screened every three to five years, these screening ages and frequencies are not possible in most resource-limited setting and decisions regarding screening age and frequency must be made based on available resources. (See "Screening for cervical cancer in resource-rich settings", section on 'Screening in average-risk patients'.)

The World Health Organization (WHO) recommends initiation of cervical cancer screening for most patients at the age of 30 years with repeat testing every three to ten years (depending on test used); screening can be discontinued at the age of 50 years if last two consecutive screening results are negative [12]. Screening recommendations are different for patients with HIV. (See 'Patients with HIV' below.)

However, for many patients in resource-limited settings, screening only occurs once or twice in a lifetime. For such patients, screening between the ages of 30 to 39 years appears to result in the largest reduction in cervical cancer incidence and mortality. 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 visual inspection with acetic acid (VIA) screening or cervical cancer health education [13]. At seven-year follow-up, patients in the screening group had a 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 [14]. Within these parameters, screening with VIA or human papillomavirus (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 [15]. 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.

SCREEN-AND-TREAT PROTOCOLS — "Screen-and-treat" (also referred to as "see-and-treat" or "one-visit") protocols include a screening test followed in the same visit by treatment of positive results. This approach is only possible in settings where screening tests that produce immediate results (ie, point of care, rapid-result human papillomavirus [HPV] testing and/or visual inspection with acetic acid [VIA]) are available.

Advantages and disadvantages

●Advantages – Screen-and-treat protocols:

•Provide immediate results (eg, VIA) or results within several hours (eg, rapid-result HPV testing) and eliminates intermediate steps (eg, colposcopy, histologic sampling).

•Eliminate communication difficulties involved in delivering and interpreting written results for patients as well as the issue of noncompliance with follow-up.

•Can be performed by trained nurses or paramedical staff, particularly where there are few or no clinicians, and be performed in a primary health care facility.

•Reduce the rate of high-grade cervical intraepithelial neoplasia (CIN) or cancer. In a randomized trial of 6555 previously unscreened patients (aged 35 to 65 years) in South Africa, all patients were screened with 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 [16]. 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 fewer patients in both the VIA (2.2 percent) and HPV (0.8 percent) screen and treat groups compared with the delayed group (3.6 percent). This difference persisted at 12 and 36 months [17].

•Are feasible and accepted by patients. In a World Health Organization (WHO) demonstration project from 2005 to 2009 including approximately 19,600 patients in six African countries that included VIA screening followed by treatment with cryotherapy if positive, 39 percent of patients were screened and treated on the same day; the majority of patients (63 percent) received cryotherapy within one week of initial screening [18]. Patients with lesions suspicious for cancer and those who were ineligible for cryotherapy (eg, extension of lesion to the vaginal wall) were referred to a higher-level health facility. The VIA and cryotherapy procedures were well tolerated, and patients’ acceptability was high.

•Are more cost-effective than protocols 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 patients 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) [19].

●Disadvantages – An aspect of the screen and treat 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 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 aspects of general health visits.

Furthermore, treatment based on results of screening tests with low specificity, such as HPV testing and VIA, will result in some patients receiving unnecessary treatment. (See 'Role of combining two screening tests' below and 'Multi-visit protocols' below.).

Preferred: HPV testing — For patients undergoing cervical cancer screening using a screen-and-treat protocol, we suggest human papillomavirus (HPV) testing rather than visual inspection (algorithm 1). This is consistent with the WHO which recommends using HPV deoxyribonucleic acid (DNA) testing as the primary screening test rather than other methods for screening of patients in resource-limited settings [12]. HPV testing is repeated every five to ten years; sampling may be through a provider or self-sampling. (See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing", section on 'Cervical testing'.)

Rapid-result HPV tests — Human papillomavirus (HPV) tests capable of providing a rapid result include Xpert HPV (Cepheid) and careHPV (Qiagen) (table 1). These tests appear to perform as well for the detection of high-grade CIN as standard HPV testing and be superior to VIA.

●Xpert HPV – Xpert HPV uses polymerase chain reaction (PCR) technology to detect 14 high-risk types of HPV, including HPV 16 and 18/45. It gives a result within one hour and is uniquely positioned to provide screening and treatment in one visit. 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. In one prospective study including 1121 patients (ages 30 to 65 years and over half of whom were living with HIV), cervical samples were collected for Xpert HPV testing, and all patients underwent colposcopy and histological sampling with consensus pathology review. Modifying cycle thresholds of the Xpert HPV assay allowed specificity to improve (from 63 to >80 percent) without loss of sensitivity. Improved specificity results in lower rates of overtreatment, an important consideration for use of HPV DNA testing. [20]. This is discussed in more detail below. (See 'Increasing HPV test specificity' below.)

In a prospective study of 4285 patients in Papua New Guinea of whom 15 percent tested positive for oncogenic HPV types using the Xpert HPV test, sensitivity to detect HSIL or worse was 85 percent with specificity of 90 percent [21]. Almost all (94 percent) of the patients with HPV positive disease were treated with same-day thermal ablation; up to three months posttreatment there were no serious adverse events and patients reported mild adverse symptoms posttreatment which resolved in all cases.

●careHPV – careHPV uses PCR technology to detect 14 high-risk types of HPV, similar to the 14 types detected by the tests used in resource-rich countries. It is affordable (each test costs less than USD $5), gives results quickly (within 2.5 hours), and is portable; the processing kit has its own reagents and water supply and can be run using batteries [22].

In a cross-sectional study of 2388 patients (ages 30 to 54) in China assessing the clinical accuracy of careHPV, each patient was assessed with 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 [23]. Provider-collected and self-collected careHPV resulted in similar or lower detection rates of CIN2+ compared with HC2 (sensitivity and specificity, provider-careHPV: 90 and 84 percent; self-careHPV: 81 and 82 percent; HC2: 97 and 86 percent). By contrast, VIA was inferior to either provider-collected or self-collected careHPV for detecting CIN2+ (sensitivity and specificity, VIA: 41 and 95 percent). Direct comparison of collection method for careHPV (provider- and self-collected sampled) revealed similar CIN2+ detection between groups.

Efficacy — 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 HC2, cervical cytology, or VIA [24]. 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) were similar compared with standard care but were higher than patients in the HPV testing group. This result for VIA differed from the finding of the trial in 80,000 patients described below (see 'Acetic acid' below); the authors attributed this difference to a higher rate of treatment in that trial.

The use of standard HPV tests (ie, nonrapid-result HPV testing) is discussed in more detail below. (See 'Multi-visit protocols' below.)

Increasing HPV test specificity — Human papillomavirus (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 or relative light units [RLU] per positive control specimen [PC]). As for most tests, increasing the specificity results in a decrease in sensitivity. 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 [25].

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 [26]. 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 provider-collected screening methods. In a randomized trial of 12,330 patients in Mexico, patients underwent either self-collection of HPV samples (with a cervical brush) or cervical cytology performed at a clinic [27]. 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 2-4.1) 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.

Similarly, 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 [28]. 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). In an earlier meta-analysis, which included 12 studies also used in the meta-analysis described above [28], self-collection methods were compared with clinician-collected HPV samples [29]. Seven studies used a Dacron or cotton swab or a cytobrush, for which the pooled sensitivity and specificity for HPV detection was 78 and 90 percent. For three studies in which a tampon was used, the sensitivities and specificities ranged from 67 to 94 percent and 80 to 100 percent, respectively. These data, unfortunately, do not allow comparison among the methods.

Alternate: Visual inspection methods — Visual inspection of the cervix with the naked eye (also referred to as direct visual inspection or cervicoscopy) every three years is an alternate approach to cervical cancer screening in resource-limited settings when an affordable HPV rapid-result test in not available. It can be performed with acetic acid (VIA), Lugol iodine (visual inspection with Lugol iodine [VILI]), and with or without magnification (VIA with or without magnification [VIAM]).

Visual inspection screening was the first method of screening of the cervix [30], but was rapidly replaced in resource-rich settings when cervical cytology became available. However, it has reemerged as a screening tool in 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 [31]. Primary care clinicians or midlevel providers can also 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 [32]. (See 'New innovations' below.)

The technique for performing these tests is discussed separately. (See "Cervical cancer screening tests: Visual inspection methods".)

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

●In one trial including over 80,000 patients in India discussed above (see 'Screening age and frequency' above), patients undergoing VIA screening compared with health education had lower 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) at seven-years of follow-up [13].

●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 [33]. The incidence of invasive cervical cancer was 26.7 per 100,000 in the screening group and 27.5 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 also been evaluated in multiple observational studies [31,34-43]. In a meta-analysis of 11 studies with over 58,000 patients (ages 25 to 64 years) in India and Africa who underwent VIA and one or more other screening test(s), the sensitivity and specificity for detection of a CIN2+ was 39 and 85 percent, respectively; the reference standard was colposcopic-directed biopsy performed in all patients [43]. 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 [41]. However, there was a significant decrease in VIA specificity in patients with HIV infection. (See 'Patients with HIV' below.)

Other

●Lugol — VILI is more sensitive than VIA but equally specific. It is, however, used less commonly than VIA [43,44], and in our experience, VIA allows for a more nuanced and detailed analysis of the dysplastic area.

In the meta-analysis of 11 studies described above (see 'Acetic acid' above), patients were evaluated with both VIA and VILI in 10 studies [43]. For detection of CIN2+, the sensitivity and specificity were higher for VILI compared with VIA (VILA: 91 and 85 percent; VIA: 79 and 85 percent). (See 'Acetic acid' above.)

●Magnification – The addition of magnification to VIA (VIAM) does not improve the detection of CIN or cervical cancer over VIA. In 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, the sensitivity and specificity for detection of CIN2+ were similar between groups); colposcopy with directed cervical biopsy was used as the reference standard [45].

Role of combining two screening tests — Combining two screening tests (eg, HPV followed by VIA or cytology) has also been described as is the preferred screening test in resource-limited settings for patients with HIV (see 'Patients with HIV' below), but not for the general population [12].

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 [19].

Use of a two-test approach decreases the number of patients receiving unnecessary treatment. In a prospective study of 1266 South African patients (ages 35 to 65 years), patients underwent sequential screening with Hybrid Capture I HPV testing and VIA; VIAM, cervicography (a photograph of the cervix after application of acetic acid), and cytology were also performed [46]. Patients with abnormal results on any of the screening tests underwent colposcopy at a follow-up visit. Sequential screening resulted in lower rates of unnecessary treatment (22 to 41 patients without disease/1000 patients screened) compared with either VIA (182/1000) or HPV alone (137/1000).

A disadvantage of this approach is that more patients are lost to follow-up than with single-test screen-and-treat protocols.

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 (smartphone VIA [S-VIA]) 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) but clinical validation is awaited as algorithms are tested and developed. The use of AI to interpret cytology specimens has also been described [47].

The diagnostic accuracy of S-VIA has been evaluated. In a meta-analysis including eight prospective studies with over 680 patients, S-VIA for the diagnosis of CIN2+ had a sensitivity and specificity of 75 and 62 percent, respectively [48].

MULTI-VISIT PROTOCOLS — Multi-visit protocols include a screening test followed by a second (or more) visit based on results from the screening test. This approach requires communication of test results to the patient after each step. Two-visit protocols typically include a first visit with cervical cytology or human papillomavirus (HPV) testing followed by a second visit with colposcopy and treatment based on colposcopic impression. The three-visit protocol is the standard approach to cervical cancer screening in resource-rich settings; this approach typically includes HPV testing and/or cytology, followed by colposcopy, and then treatment based on the results of colposcopic biopsies. (See "Screening for cervical cancer in resource-rich settings".)

Unfortunately, due to the barriers discussed above (see 'Barriers' above), the success of the multi-visit protocol approach used in resource-rich countries has not been replicated in resource-limited countries.

●HPV testing – Use of standard HPV tests (eg, Hybrid Capture II [HC2]) in resource-rich countries is not feasible in resource-limited settings. They are prohibitively expensive for resource-limited settings (in the United States the cost per test is approximately USD $50 to $100), the waiting time for a result of one or more days is an additional impediment to patient follow-up [49], and the infrastructure required for specimen processing is not available.

●Cytology – Cytology-based screening programs also 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.

●Colposcopy – An abnormal HPV or cytology result is followed by colposcopy, which 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.

Overtreatment, defined as treatment of lesions that are actually low grade, is an important concern with multi-visit protocols, as with one-visit protocols (see 'Role of combining two screening tests' above). The risk of overtreatment also appears to increase when there is a discrepancy between cervical cytology and colposcopic impression and with treatment in the presence of a low-grade colposcopic appearance. In a meta-analysis of 13 studies including 4611 patients managed with cervical cytology followed by colposcopy and treatment (with loop electrosurgical excision procedure [LEEP]), overtreatment rates for differing combinations of cytology and colposcopic impression were as follows: 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) [50]. 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 such treatments may result in adverse obstetric outcomes. (See "Reproductive effects of cervical excisional and ablative procedures".)

TREATMENT — Cervical intraepithelial neoplasia (CIN) is treated with excisional (eg, loop electrosurgical excision procedure [LEEP], cold knife conization) and ablative (eg, cryotherapy, CO₂ laser ablation, thermal ablation) techniques.

The World Health Organization (WHO) recommends LEEP over cryotherapy in settings where LEEP is available [51]. (See "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment", section on 'Choosing the treatment approach'.)

However, in most resource-limited settings, cryotherapy rather than LEEP is often the preferred treatment as it is generally easier and cheaper to perform in a primary care setting, and a handheld portable device is available. Cryotherapy also does not require local anesthetic, and complication rates are low [52,53]. In the randomized trial discussed above (see 'Advantages and disadvantages' above), 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 [16]. Patients who underwent cryotherapy had more unscheduled visits during the study period than those who did not (1 versus 0.5 percent). This study was 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 completed in one day. In fact, in this trial, 82 patients did not return after the initial screening visit.

Since 2018, thermal ablation (also called cold coagulation or thermocoagulation) has regained popularity as a method of ablating the transformation zone due to the difficulty of acquiring gas (which is required for cryotherapy) in resource-limited settings. The WHO endorsed the use of such devices for the treatment of precancerous cervical lesions in 2019 [54]. Thermal ablation devices can be efficient and economical as modern devices are portable, battery-operated, and use reusable metallic probes. (See "Cervical intraepithelial neoplasia: Ablative therapies", section on 'Thermal ablation (cold coagulation)'.)

Further discussed regarding complications after such procedures is presented separately. (See "Cervical intraepithelial neoplasia: Ablative therapies", section on 'Adverse effects and complications'.)

SPECIAL CONSIDERATIONS

Importance of HPV vaccination — Human papillomavirus (HPV) vaccination should be used together with cervical cancer screening 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 young females 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 [55,56]. HPV vaccines are discussed in detail separately. (See "Human papillomavirus vaccination".)

Pregnant patients — In general, screening of pregnant patients in resource-limited settings is not recommended, particularly after 20 weeks of gestation. Quality of cytology is impaired due to the high levels of progestogen in pregnant patients, which renders endocervical secretions more viscid and limits exfoliative cytology [57,58]. Furthermore, in such settings, pregnant patients often initiate care late and follow-up post screening is poor.

However, if performed and cytology shows a precancerous abnormality, colposcopy is recommended to exclude evidence of microinvasion. However, histological sampling of the cervix should only be performed if a lesion is present that appears to be high-grade. Otherwise, further follow-up can be delayed until postpartum. (See "Cervical cancer screening: Risk assessment, evaluation, and management after screening", section on 'Pregnant patients' and "Cervical intraepithelial neoplasia: Management", section on 'Pregnant patients'.)

A treatment procedure is only performed in pregnancy if invasive cancer is suspected. (See "Cervical cancer in pregnancy", section on 'Indications for and performance of conization'.)

The author could not find any published studies of HPV DNA testing as a screening test in pregnant patients.

Patients with HIV — Patients with human immunodeficiency virus (HIV) are at an increased risk for cervical intraepithelial neoplasia (CIN) and cervical cancer. Thus, for such patients, the World Health Organization (WHO) recommends using HPV DNA testing followed by HPV 16/18 genotyping, visual inspection with acetic acid (VIA), cytology, or colposcopy [12] (see 'Role of combining two screening tests' above). The choice of triage tests depends on available resources.

Furthermore, screening for patients with HIV starts sooner and is more frequent than patients without HIV in resource-limited settings, and should be initiated at age 25 (rather than 30) years and repeated every three to five (rather than five to ten) years [12].

Treatment of CIN is similar to that of patients without HIV and is discussed above. (See 'Treatment' above.)

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

●Epidemiology – Cervical cancer is the fourth most common cancer in females worldwide; the majority (85 percent) of new cases are diagnosed in resource-limited countries. (See 'Epidemiology' above.)

●Barriers – Barriers to implementing programs for cervical cancer prevention include competing health care demands and economic, social, and political issues. (See 'Barriers' above.)

●Screening age and frequency

•For patients in whom cervical cancer screening will be performed once or twice in a lifetime, we initiate screening between the ages of 30 and 39 years rather than other age ranges. Screening between these ages appears to result in the largest reduction in cervical cancer incidence and mortality. (See 'Screening age and frequency' above.)

•For patients in whom more frequent testing can be performed, we initiate screening at age 30 years and repeat testing every three to ten years (depending on test used) until age 50 years. (See 'Screening age and frequency' above.)

●Screen-and-treat protocols – Screen-and-treat protocols include a screening test followed in the same visit by treatment of positive results. This approach is only possible in settings where tests that produce immediate results (ie, rapid-result human papillomavirus [HPV] testing, visual inspection) are available. Such protocols eliminate communication difficulties involved in delivering and interpreting written results as well as the issue of noncompliance with follow-up. (See 'Screen-and-treat protocols' above and 'Advantages and disadvantages' above.)

•Rapid-result HPV – For patients undergoing a screen-and-treat protocol, we prefer HPV testing rather than visual inspection (algorithm 1). This is consistent with the World Health Organization (WHO) recommendations. Rapid-result HPV tests include Xpert HPV (Cepheid) and careHPV (Qiagen) (table 1); screening with these tests is repeated every five to ten years. (See 'Preferred: HPV testing' above.)

For patients screened using HPV testing who do not have access to a speculum examination or who are reluctant to undergo a pelvic examination, self-collection of vaginal samples rather than clinician-collected samples is a reasonable option. There is insufficient evidence regarding the best method for self-collection (eg, swab, cytobrush, cervicovaginal lavage). (See 'Self-collected samples' above.)

•Visual inspection – Visual inspection of the cervix every three years is an alternate approach to cervical cancer screening when an affordable HPV rapid-result test in not available. (See 'Alternate: Visual inspection methods' above.)

For patients screened using visual inspection, we prefer visual inspection with acetic acid (VIA) rather than with Lugol iodine (visual inspection with Lugol iodine [VILI]) or magnification (VIA with or without magnification [VIAM]). In our experience, VIA allows for a more nuanced and detailed analysis of the dysplastic area. (See 'Alternate: Visual inspection methods' above.)

●Multi-visit protocols – Unfortunately, due to the barriers discussed above, the multi-visit protocol approach used in resource-rich countries has not been replicated in resource-limited countries and is unavailable to most patients. (See 'Multi-visit protocols' above.)

●Treatment – Cervical intraepithelial neoplasia (CIN) can be treated with excisional (eg, loop electrosurgical excision procedure [LEEP]) and ablative (eg, cryotherapy) techniques. While LEEP is the preferred treatment option, cryotherapy is more commonly performed given the resources available in resource-limited settings. (See 'Treatment' above.)

●HPV vaccination – HPV vaccination should be used together with cervical cancer screening to decrease the risk of cervical cancer. (See 'Importance of HPV vaccination' above.)

●Special populations – Pregnant patients and patients with HIV are managed differently than nonpregnant patients without HIV. (See 'Pregnant patients' above and 'Patients with HIV' above.)