Screening technologies for cervical cancer: Overview

Screening target age and screening interval

Cancer screening aims to detect preclinical disease in an apparently healthy population through systematic administration of a simple and safe test to all men/women belonging to a specified target age group. Since the primary objective of cervical cancer screening is to detect the premalignant lesions (known as cervical intraepithelial neoplasia [CIN]), World Health Organization (WHO) recommended screening of women between 30 and 49 years of age.^[1] At this age, the women have the highest possibility of harboring the CIN 2 and CIN 3 lesions that are considered as true cervical cancer precursors or high grade lesions. Screening at younger age detects large number of low grade lesions that regress of their own and the women are subjected to unnecessary biopsies and treatment. However, screening of HIV positive women should be initiated whenever they are sexually active. The upper age range can be extended to 55–60 years age if resources permit. The frequency of screening in the screen negative women depends on the screening test being used and the resources available within the program. Too frequent screening should be avoided and the minimum interval between two rounds of screening should be 5 years. Programs with limited resources can extend the interval to 10 years, if a highly sensitive screening test (such as HPV DNA test) with very low possibility of missing cases can be used. Even once a lifetime screening around the age of 40 years can reduce cervical cancer incidence by 30%.^[2] Achieving high coverage (>70%) of the target population rather than frequent screening is the most important determinant of success of the screening program.

Confirmation of diagnosis of screen positive women

Administering the screening test is only a component of cervical cancer screening that involves community mobilization to motivate large number of women to participate, training of all levels of service providers, ensuring further assessment of screen positive women and ensuring appropriate treatment, and follow-up of the screen detected abnormalities. It is extremely important to ensure appropriate investigations of the screen positive women to establish the disease and treatment of the screen detected cases of CIN and cancer. Traditionally, colposcopy followed by directed biopsies have been used to confirm diagnosis in the screen positive women and subsequent treatment decisions were made on the basis of histology report. However, this multiple visit approach (at least three) is very inconvenient for the women and the compliance is often poor. Several alternate strategies have been recommended and adopted to reduce the number of visits and improve compliance of the women. The positive predictive value of colposcopy is reasonably high to detect CIN 2/CIN 3 disease and treatment can be done on the basis of colposcopy diagnosis alone. Such strategy of “colposcopy and treat, also known as see and treat” improves compliance to treatment and is convenient to the women though some over-treatment is unavoidable. Over-treatment is acceptable as the treatment methods are simple and safe and the treated women with negative histology will require less intensive follow-up. In more basic settings where organizing colposcopy and histopathology is challenging, a more simpler approach like direct treatment of the screen positive women (“screen and treat”) is also recommended.^[1] This will be further discussed in the subsequent sections.

A second screening test is sometimes recommended for the women positive on the primary screening test. The second test is called triaging test and the women positive on both the tests are only referred for colposcopy. Such triaging strategy is used if the primary screening test is less specific and/or if the colposcopy services are insufficient and expensive.

Treatment of women with premalignant disease

To achieve desired effectiveness of program to reduce cervical cancer burden, the screen detected CIN 2/CIN 3 lesions must be treated appropriately. CIN lesions can be treated by ablation or by excision. Ablative techniques are simpler, less expensive, can be performed by trained nonclinicians and have very low complication rates. Two different ablative techniques are available – Cryotherapy and Thermocoagulation; both of them are equally effective and safe even when performed by nurses.^[3] A major advantage of ablative therapies is that the treatment can be done in primary care or secondary care settings. The excision methods of treatment include large loop excision of transformation zone (LLETZ) and cold knife conization (CKC). In both the techniques, the entire transformation zone (TZ) is excised and submitted for histopathological evaluation. While LLETZ is much simpler, requires local anesthesia only and has low complication rate, CKC has to be done under regional or general anesthesia, requires higher level of technical expertise and has higher complication rates.

All the screen positive women need to be assessed for suitability of treatment by ablative techniques using the following criteria (with colposcopy or with naked eye after application of 3–5% acetic acid):

• Squamocolumnar junction (SCJ) is fully visible

• Type 1 TZ

• Lesion occupying <75% of cervix

• Lesion not extending to endocervix or vagina

• There is no suspicion of invasive or glandular disease.

If suitable, the lesions may be treated by Cryotherapy or Thermocoagulation without waiting for histopathological verification. Only the women with lesions not suitable for Cryotherapy should be referred for treatment by exciscion.^[4]

Follow-up of the women after treatment is also important. Women treated for CIN 2 or CIN 3 have much higher risk of developing cervical cancer even after 10 years of treatment compared to the normal women.^[5] Post-treatment initial follow-up should be done after 1 year either by the screening test or by colposcopy. The protocol for subsequent checkups varies from program to program. Usually, the women are sent back to routine screening if they are normal on 2–3 consecutive rounds of yearly screening.

Cytology

The most widely used cervical screening test is cytology. High-income countries have integrated cytology screening services in medical and public health services and have achieved high coverage through better program organization. This has resulted in substantial declines in cervical cancer incidence and mortality over time.^[6] Some of the middle-income countries in South and Central America and in Asia also implemented population-based cervical cancer screening using cytology for a few decades. However, these programs were largely ineffective in reducing cervical cancer burden due to poor coverage with screening, treatment and follow-up care and lack of quality assurance.^[7] Majority of the low middle income countries (LMICs) have neither initiated nor have the capacity to initiate and sustain quality assured cytology screening programs in their underdeveloped and fragmented health services with several competing priorities, lack of resources, and trained manpower. Cytology needs good quality laboratory infrastructure, rigorous monitoring and supervision, highly skilled technicians or pathologists and a good system of recalling the screen positives. All these are very challenging to implement in the low resourced countries.

Cytology results are most widely reported using The Bethesda system (TBS); the major categories of 2014 TBS is given in [Table 1].^[8] The threshold for positive cytology for referral for triaging/diagnostic investigations such as colposcopy may be at atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) in various settings. All women with atypical squamous cells, cannot rule out high-grade squamous intraepithelial lesion (ASC-H), LSIL or high-grade squamous intraepithelial lesion (HSIL) report on cytology must have further evaluation with colposcopy. The management options for ASCUS smears are either repeat smear after 6 months or HPV test (triaging) or direct colposcopy.

Cytology smears are prepared by spreading the cervical cell specimen collected using a spatula and cervical brush on to a glass slide which is then fixed and stained using Papanicolaou (PAP) staining. Cytology is a highly subjective and provider dependent test with varying performance between laboratories and cytologists reading the smears.

High frequency of cervical inflammation in developing countries contributes to significant amount of inflammatory debris in PAP smear, posing major challenges in interpretation and reporting. The high false negative rate (14–33%) is largely due to limitations of sampling and smear preparation. Quality assurance in preparing, fixing, staining, reading and reporting the smears is critical for accurate results. The sensitivity and specificity of a single, quality assured PAP smear to detect CIN 2+ lesions is around 60– 95%, respectively.^[9,10]

Visual screening tests

VIA involves naked eye visualization of the cervix 1 min after the application of 3–5% dilute acetic acid under bright light. Test results are reported as negative, positive or suspicious of invasive cancer and their criteria^[18] are given in the [Table 3].

A positive test is defined by the appearance of well-delineated, dense acetowhite area abutting the SCJ in the TZ of the cervix. It is a suitable test in premenopausal women under 50 years of age when the TZ is fully visualized on the ectocervix. Interpretation of test is difficult in postmenopausal and older women. VIA is not ideal for women above 50 years of age or when the SCJ is not fully visible. [Figure 1] shows images of cervix for different VIA outcome categories.

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Figure 1:

Visual inspection on acetic acid outcome categories. (a) VIA – Negative, (b) VIA – Positive, (c) VIA - Suspicious of invasive cancer.

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VIA is a simple, feasible and affordable point of care test, providing immediate results enabling diagnosis and/or treatment to be carried out in the same visit for screen positive women. Wide range of health professionals including doctors, nurses, midwives and primary health care workers can be trained to perform VIA after a short period of training. The infrastructural need is minimal and the consumables are universally available.

VIA has been extensively evaluated in a variety of settings. Although the pooled sensitivity and specificity of VIA to detect CIN 2 + lesions were 80–92%, respectively, in a pooled analysis,^[19] these values varied widely in different settings due to the subjective and provider dependent nature of the test, varying quality of reference standard investigations and differing age groups included in the studies. VIA also suffers from high false positive rates.

VIA screening was followed by a 31% reduction in cervical cancer mortality in a randomized trial in Mumbai^[5] In a randomized trial in South India, VIA screening was associated with 25% decline in cervical cancer incidence and 35% reduction in mortality.^[20] This evidence culminated in the launching of a population based VIA screening program in the state of Tamil Nadu in India. Large number of nurses have been trained in providing VIA throughout the primary health centers in the state and 55% of targeted 15 million have been screened through the first round of a VIA screening program during 2012–2014.

The visual tests seem to perform better in HIV-infected women than in the general population due to the increased prevalence of large high-grade lesions.^[21,22]

The safety, acceptability and effectiveness of a single visit “screen and treat” approach (SVA) in which VIA positive women eligible for cryotherapy, are treated in the same sitting has been well established.^[23-25] Women with precancerous lesions not eligible for Cryotherapy may be referred for loop electrosurgical excision procedure for diagnosis and treatment. The SVA paradigm represents a major innovation for scaling up cervical cancer screening in LMICs and has been adopted by many countries in subSaharan Africa and Asia.^[26] Primary care practitioners should utilize every opportunity in routine health care interactions to screen women aged 30 years and above with VIA and investigate and treat screen positive women.

Despite all its limitations, implementing VIA screening in low-income countries provides a realistic approach to build up infrastructure and human resources that may facilitate the introduction of affordable HPV screening in future.

Visual inspection after application of Lugol’s iodine (VILI) is another simple inexpensive visual screening technique. The test relies on identification of Iodine negative areas on the cervix after application of Lugol’s Iodine [Figure 2]. VILI has not been widely evaluated and has high false positivity. The consumables are expensive and are not readily available. The test is not yet recommended by WHO for routine screening.

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Figure 2:

Bright yellow Iodine negative area after application of Lugol’s Iodine.

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Management of women with positive screening tests

The ultimate aim of cervical cancer screening is to reduce the disease burden by detecting the precancerous lesions early and managing them appropriately.

Management of women positive on HPV test

There is no single definitive strategy for management of HPV positive women. The management approaches generally depend on factors such as available resources, logistics, and program guidelines. As cervical cancer is a rare outcome of high risk-HPV infections, management strategies are based on assessment of risk thresholds that identifies the small percentage of women who are likely to develop cervical precancer or cancer. To allow risk stratification and subsequent identification of at-risk women, additional tests (Triage tests) are indicated depending on availability of the tests and feasibility of doing it. Triage tests like Cytology, HPV genotyping for HPV 16/18, test for E6/E7 mRNA, p16/Ki-67 dual staining and VIA may be used for risk-based management.

As majority of the HPV infections are transient, most of the HPV positive women will not have any clinically detectable disease on colposcopy. Referral of all HPV positive women for colposcopy will lead to over burdening of the system, particularly in context of LMICs with limited colposcopy facility. This approach is also likely to increase the cost of public health programs and should be considered for situations where performing triage tests are not feasible or ensuring follow-up of positive women is challenging.

Direct treatment of HPV positive women has been widely promoted, especially in LMICs, to ensure a linkage between screening and treatment and minimize loss to follow-up. In settings where colposcopy and histopathology services are not available, the WHO recommendation of “screen and treat” strategy has strongly encouraged treatment of HPV positive women by ablative treatment methods such as cryotherapy, provided the lesion suits the eligibility criteria for ablation.^[4] Various management strategies for HPV positive women is summarized in [Figure 3].

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Figure 3:

Flowchart on management of women positive on HPV test.

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Management of women positive on VIA test

VIA is a real time test that allows for taking treatment decisions in the same sitting as screening. In the context of LMICs where there is no or limited facility for colposcopy and histology, the WHO guidelines for “screen and treat” strategies recommend immediate treatment of VIA positive cases by ablative method if the lesion characteristic fulfills the criteria for ablative treatment.^[4] In situations where Colposcopy and biopsy facilities are available, the VIA positive women can be referred for evaluation by Colposcopy. Treatment can be done either in the same sitting as Colposcopy (“See and treat”) or based on histopathology report. The management options for VIA positive women are given in [Figure 4].

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Figure 4:

Flowchart on management of women positive on VIA test.

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Management of women with cytological abnormalities

The management options for women with cytological abnormalities are presented in [Figure 5] and discussed in details in the chapter “Role of colposcopy in management of women with abnormal cytology.”

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Figure 5:

Flowchart on management of women with cytological abnormalities.

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