|
 
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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 13
| Issue : 2 | Page : 81-88 |
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Cervical cytology and HPV in cervical cancer screening: Current and future perspectives
Pooja Bakshi, Poojan Agarwal, Gunjan Mangla
Department of Cytopathology, Sir Ganga Ram Hospital, New Delhi, India
| Date of Submission | 03-Feb-2023 |
| Date of Decision | 18-Mar-2023 |
| Date of Acceptance | 21-Mar-2023 |
| Date of Web Publication | 28-Apr-2023 |
Correspondence Address:
Dr. Pooja Bakshi
Department of Cytopathology, Sir Ganga Ram Hospital, New Delhi
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/cmrp.cmrp_29_23
Cervical cancer remains a health burden in our country and is the 2nd most common cancer in Indian women. Effective screening can reduce the incidence as well as the morbidity and mortality of this disease. Cervical cytology and the more recent human papilloma virus (HPV) DNA test are the two main pillars of screening. Liquid based cytology has improved the cytological preparations and has shown certain advantages while advancements in molecular techniques for detection of high-risk HPV DNA/RNA has opened up new frontiers. These technological advancements have led to the changes in screening practices and paradigms and are evolving at a rapid pace. This article gives an overview of the screening modalities currently available, the technological advancements, recent updates of the screening guidelines and the future directions.
Keywords: Cervical cancer screening, genotyping, high risk human papilloma virus, human papilloma virus testing, liquid based cytology
How to cite this article:
Bakshi P, Agarwal P, Mangla G. Cervical cytology and HPV in cervical cancer screening: Current and future perspectives. Curr Med Res Pract 2023;13:81-8 |
How to cite this URL:
Bakshi P, Agarwal P, Mangla G. Cervical cytology and HPV in cervical cancer screening: Current and future perspectives. Curr Med Res Pract [serial online] 2023 [cited 2023 May 30];13:81-8. Available from: http://www.cmrpjournal.org/text.asp?2023/13/2/81/375232 |
| Introduction | |  |
Cervical cancer is a significant public health burden in the developing world and a major cause of mortality and morbidity among women. It is the 2nd most common cancer in Indian women and 4th most common cancer in women globally.[1] The WHO in 2020 announced a global call for action to eliminate cervical cancer and outlined three pillars to achieve this target: Vaccination of 90% of girls with human papilloma virus (HPV) vaccine by age 15; screening of 70% of women with a high performance test at least twice in a lifetime; treatment of 90% of women with pre-cancer and invasive cancer.[2]
Cervical cancer is preventable and curable as long as it is detected early and managed effectively. Countries which introduced an organized cervical cancer screening programme have shown marked reduction in the incidence and mortality of the disease.[3] The latent period of many years between initial infection with high-risk HPV and development of cervical cancer gives a long window period for the detection of pre-invasive lesions which can be treated effectively, hence, preventing progress to invasive cancer. This forms the basis of all screening strategies employed in cervical cancer. The emergence of new technologies has led to the rapid changes in the screening practices. This article reviews the technological advancements, the new screening recommendations incorporating these technologies, the current role and interplay of cytology and HPV testing and the future directions.
| Cervical Cancer Screening Modalities | | |
Cervical cytology
Conventional pap smear/liquid-based cytology (LBC).
Human papilloma virus testing
Primary screening/Co-test with cytology.
Visual inspection with acetic acid/Visual inspection with Lugol's iodine VIA/VILI
Visual inspection with acetic acid/Lugol's iodine (used in limited-resource settings).
| Cervical Cytology | | |
Cervical smear also known as Pap test is acknowledged as the most successful mass screening programme worldwide. First introduced by George Papanicolaou and Traut, this test involves collection of cells from the ectocervix, transformation zone and endocervix by use of a spatula/brush followed by staining and examination of cells under the microscope to detect the dysplastic cells.[4] Various collection devices such as Ayre's spatula, extended tip spatula, endocervical brush and the broom like Cervex brush can be used to collect cells.
Preparation methods
Two types of preparations can be made: Conventional Pap smear or LBC.
Conventional Pap smear
The material collected is smeared in a linear or circular fashion onto the central 2/3rd area of a glass slide and is immediately wet fixed with 95% ethyl alcohol in a Coplin jar or by a spray fixative and sent to the lab.
Some of the limitations of the conventional preparation are that 80% of cells get discarded with the brush/spatula and diagnostic cells may not be transferred onto the slide, obscuration of cells by blood, mucus and inflammatory cells, inconsistent preparations, delayed fixation causing air drying artefacts and high unsatisfactory rates.
LBC introduced in 1996 addressed these preparatory issues of conventional Pap smear and there has been a shift globally to liquid based Pap test.
Liquid based cytology
It is based on a two-step procedure of rinsing the sample in an alcohol based fixative solution forming a cell suspension followed by automated processing in laboratory to obtain a thin monolayered preparation. A broom type sampling device like the Cervex brush is inserted into the endocervical canal and rotated 2–5 times in a clockwise direction and then rinsed in the liquid fixative, i.e. liquid Pap test [Figure 1]. The LBC systems most commonly used are: | Figure 1: (a) Rovers Cervex-Brush® and SurePath LBC vials (b) Liquid based cytology slides: Thin monolayered circular preparation. (c) NILM, Pap stain, ×100 (d) LSIL, Pap stain, ×200 (e) HSIL, Pap stain, ×400 (f) Squamous cell carcinoma, Pap stain, ×200 (g) Graph depicting run of controls on Roche Cobas® 4800 for High risk HPV-DNA testing. LBC: Liquid-based cytology, NILM: Negative for intraepithelial lesion or malignancy, LSIL: Low-grade squamous intraepithelial lesion, HSIL: High-grade squamous intraepithelial lesion, HPV: Human papilloma virus
Click here to view |
Sure path Pap test (BD)
The brush used has a detachable head which is dropped into a vial containing the Sure Path fixative, thus capturing the entire sample. The vial is sent to the lab for processing. It uses a density gradient sedimentation process where cell enrichment process occurs with removal of blood, mucus and inflammatory cells. This is followed by centrifugation to generate a pellet which is then applied to the slide on settling chambers to prepare monolayered smears. Papanicolaou staining is done for the analysis. It is an automated process.[5],[6]
Thin Prep Pap test (Hologic)
The brush is swirled and rinsed into the PreservCyt solution and then discarded. A monolayered smear is prepared in laboratory by liquid-based cell filtration process whereby the sample is dispersed, randomised and filtered using vacuum and a patented membrane technology.[6]
Other LBC systems include the indigenous low cost EziPrep (LBC India) and Liqui-Prep (China).
| Advantages of Liquid Based Cytology Over Conventional Pap Smear | | |
Advantages to the gynaecologist/smear taker: Better collection device with better harvest of cells, smear preparation is not required at the collection site, vial is easily and safely transportable and significantly decreased inadequacy rates.[7]
Advantages to the pathologist: Standardised uniform monolayered smears, removal of obscuring blood, mucus and inflammation giving a clean background, better visualisation of cells, higher detection rates of low grade and high grade squamous intraepithelial lesions (HSIL), amenable to automation to handle large sample volumes and sample can be stored for 6 months in refrigerator.
One big advantage is that LBC sample enables molecular testing on the same sample like the HPV test or other ancillary tests and patient need not be recalled.
Reporting of cervical cytology
The Bethesda System standardised reporting of cervical cytology with latest modifications in 2014 emphasising on communication of clinically relevant information and clear guidelines on the management.[8]
An adequate specimen requires at least 5000 well visualised squamous cells which can be reduced to 2000 cells in atrophic, post hysterectomy (vault) and post-therapy smears.
The diagnostic categories include
Negative for intraepithelial lesion or malignancy, atypical squamous cells of undetermined significance (ASC-US), ASC cannot exclude HSIL (ASC-H), low grade squamous intraepithelial lesion (LSIL), HSIL, squamous cell carcinoma and glandular abnormalities [Figure 1]. LSIL encompass HPV changes/cervical intraepithelial neoplasia 1 (CIN1). HSIL encompass CIN2, CIN3 and carcinoma in situ.
Implications of the cytology categories
Low grade lesions (CIN1) at 6 months follow up have shown regression in 50% of patients, persistence in 35% and progression to high grade in 7% indicating the low potential for progression.[9] The high-grade lesions show higher potential for progression. In a meta-analysis of 36 studies, CIN 2 at 24 months follow-up showed regression in 50% of the patients, persistence in 32% and progression to CIN 3+ in 18% of patients. In women below 30 years, the regression rate was higher at 60%. In CIN 3, 12%–40% progress to invasive cancer if untreated. Estimated 5-year CIN3+ risk after a negative cytology result ranged from 0.33% to 0.52% in various mass screening studies.[10],[11]
Sensitivity and specificity of cervical cytology in the detection of cervical intraepithelial neoplasia 2+ lesions of cervix
Pap test-based organised screening programmes have markedly lowered the incidence and mortality of cervical cancer worldwide.[3],[12] The sensitivity of cervical cytology varies widely from 39% to 88% and reflects the variability of expertise, training, infrastructure as well as limitations of the test. The specificity, however, is constantly high in the detection of CIN2+ lesions of cervix and is reported to be 95%–99%.[13],[14],[15]
| High Risk Human Papilloma Virus Testing | | |
Human papilloma virus and cervical cancer
Harold zur Hausen, a German virologist, first introduced the relation between genital HPV infections and cervical cancer.[16] Since then, HPV is now established as a necessary causative factor in cervical carcinoma and is associated with 95% of cervical squamous cell carcinomas and 75%–85% of cervical adenocarcinomas.[17]
HPV infections are common among young women and approximately 90% are transient with clearance of infection by innate immunity in 12–24 months. Persistent infection by high-risk HPV is a major risk factor for the development of CIN and progression to invasive cancer. However, it takes 15–20 years for carcinoma to develop.[18] [Figure 2] illustrates the natural history of HPV infection.
There are more than 150 serotypes of HPV and are classified as low risk, intermediate risk and high risk types based on their potential to cause anogenital cancers. The high-risk HPV (HR-HPV) includes HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 are the ones associated with cervical neoplasia.[19] Persistent infection with HR-HPV can trigger E6 and E7 oncogene deregulation leading to integration of HPV DNA into the host genome. This leads to the accumulation of chromosomal damages and genome destabilisation in the infected cells. The detection of high-risk HPV in a woman helps to strategise women into those at risk and requiring further intervention.
Human papilloma virus testing
The strong causal relationship between HPV and cervical cancer stimulated the development of molecular techniques for the detection of high-risk HPV DNA/RNA and opened up new frontiers in cervical cancer screening. Numerous tests and assays are now available, several of which have been commercialised. They can be divided into three categories, i.e. nucleic acid hybridisation assays, signal amplification assays and target amplification assays. Most of these detect 14 h-HPV with/without genotyping. US FDA has currently approved five HPV assays and a summary of this is outlined in [Table 1].[18],[20],[21],[22],[23],[24] They have shown comparable sensitivities for the detection of CIN.
The other PCR-based assays for HPV detection and genotyping include linear array HPV, INNO-LIPA HPV test, CLART human papillomavirus 2 and PapilloCheck assay.[25] Sequencing can be used for more extensive genotyping, however, is expensive, time-consuming and currently limited to research work.
Point-of-care HPV testing: The implementation of primary HPV screening in low- and middle-income countries needs affordable and point-of-care HPV test. Care HPV (Qiagen), Gene Xpert (Sunnyvale, CA, USA) and a portable battery operated device called True Nat have been evaluated and their performance has been shown to be comparable with gold standard tests. However, the cost needs to be reduced to make them affordable.[26],[27],[28]
The sensitivity and specificity of human papilloma virus test for the detection of cervical intraepithelial neoplasia 2+
The sensitivity of HPV test is higher than cytology and ranges from 90% to 97% in various studies offering an opportunity to improve the effectiveness of screening. It is an automated test and gives objective and reproducible results. As the negative predictive value is high, a negative result is more reassuring. The screening interval can also be prolonged to 5 years with the incorporation of HPV test. The specificity, however, is slightly lower than cytology and ranges from 85% to 95%.[29],[30],[31]
Limitations of HPV-based screening include high cost of test and equipment, need for a modern laboratory infrastructure and time taken for results leading to multiple visits and loss of follow up. The high false-positive rates for HPV testing in young women limit the clinical effectiveness of primary HPV screening under the age of 30 years
| Role of Cervical Cytology and Human Papilloma Virus Testing in Cervical Cancer Screening– The Old and the New | | |
Gradually, there has been a shift from only cytology-based screening to co-testing with cytology and HPV and more recently primary HPV screening [Figure 3]. | Figure 3: Role of cervical cytology and Human Papilloma Virus testing in cervical cancer screening
Click here to view |
Cytology-based screening
It has been the backbone of cervical cancer screening for decades. Pap test is done at 3 yearly intervals. Currently, this is preferred for women 21–29 years of age. For women more than 30 years of age, addition of HPV test is recommended. Women with ASC-US/LSIL on cytology can be triaged with HPV test or co-test can be done.
Co-testing (cytology and human papilloma virus test)
Cytology and HPV test are simultaneously done in same sample. Combining a test with high sensitivity, i.e. HPV test and a test with high specificity, i.e. cytology gives a high negative predictive value for CIN (99%–100%) and allows more precise risk-based management.[13] For example, the immediate risk of CIN3+ in patients with HPV16+ and HSIL cytology exceeds treatment threshold of 60%, and hence, expedited treatment in the form of excisional procedure is preferred.[32] Co-testing has been successfully implemented into practice in the United States in the past decade and data have shown a continued decline in cervical cancer rates.[33] The recommended frequency is every 5 years.
Primary human papilloma virus screening
The most recent suggested approach is primary HPV screening where hr-HPV test is used as a standalone primary screen due to the high sensitivity of the test. Longitudinal follow-up studies and randomised trials have shown that HPV primary screening is more sensitive than cytology alone and identifies CIN3+ earlier.[34],[35] The limitations are false-positive results and unnecessary referrals for colposcopy and limited availability of validated and affordable HPV assays.
Currently only cobas® HPV test (Roche) and the Onclarity HPV test (BD) are US FDA approved for primary HPV screening in patients 25 years or older.[20] Point-of-care HPV testing (Care HPV, Gene Xpert) in limited-resource setting needs evaluation. HPV-positive women can then undergo reflex triage with cytology, partial genotyping or VIA.
Various studies such as the Joint European Cohort study have analysed the overall long term predictive values of cytology and HPV testing in cervical cancer screening.[11] In this study, the positive predictive value for future CIN3+ was highest among women with abnormal cytology and positive HPV test at baseline (cytology+/HPV+) with a cumulative incidence rate of 34%. Women with both normal cytology and negative HPV test (cytology−/HPV−) had the lowest risk of future CIN3+ with a cumulative incidence rate of 0.28%.
Changing guidelines
In 2018, the USPSTF recommendation was updated to include primary HPV screening alone in women aged 30–65 years at 5-year interval as a screening option. Co-testing and cytology alone are the other options recommended.[36] This was subsequently also endorsed by American Cancer Society in 2020.[37] The WHO in its new guidelines of 2021 recommends an HPV DNA based test as the preferred method of screening in women more than 30 years of age. Primary HPV screening is set to become the preferred screening modality in this decade.
Risk based management guidelines from American society of colposcopy and cervical pathology (ASCCP) in 2019 have suggested clinical action thresholds with recommendation of colposcopy for any combination of history and test results yielding a 4% or greater risk of immediate CIN3+. Expedited treatment is added if immediate risk is more than 25%. If immediate risk is below 4%, the 5 year CIN3+ risk is examined to determine if patient should return in 1,3 or 5 years for surveillance.[38]
Human papilloma virus genotyping: The new kid on the horizon
Advanced molecular techniques now allow precise detection of individual HPV genotypes. HPV 16 and 18 cause approximately 70% of cervical cancers; hence, detection of these genotypes puts the woman in a higher risk category and requires immediate further action of colposcopy and biopsy. Those with lower risk can be followed up with retesting at a defined interval.[32]
The first large-scale implementation of HPV genotype information was the use of individual qualitative reporting of HPV genotypes 16 or 18 (with or without 45) as positive or negative in cervical cancer screening with the remaining high-risk HPV genotypes as a pooled result. This was termed as partial (or limited) genotyping.[39] HPV 16/18 genotyping increased the positive predictive value in triage of ASCUS/LSIL cytology.[40],[41] It can be used for triage of positive results in primary HPV screening as well.
The ARTISTIC study on cervical screening (UK) demonstrated that women who were HPV 16 positive at entry had a cumulative 6-year CIN 3 or worse rate of 30.4%, compared with 25.9% for 16/18 positive, 10.7% for non-HPV 16/18 but 31/33/45/52/58 positive, 2.7% for non-HPV 16/18 but 35/39/51/56/59/66/68 positive and 0.3% for HPV negative.[42]
Human papillomavirus 16 and 18 genotypes are associated with a significantly greater cumulative rate of CIN 3 or worse.
Full genotyping requires the assay to report all high-risk genotypes, individually and is currently used in research only.
| Upcoming Tests in Near Future | | |
Emerging biomarkers
One of the most established biomarkers is p16INK4a (p16), a cyclin-dependent kinase inhibitor and essentially a regulator of cell cycling. The application of Ki67, a proliferation marker, in a dual stain p16/Ki67 has been proposed to enhance the analytical specificity of p16. It has shown utility as a triage tool in studies.[43]
Other cellular markers indicative of HPV-associated neoplasia include Topoisomerase IIa (TOP2A), minichromosone maintenance proteins (MCMs), MYBL2 and Survivin.[44]
There has been renewed interest in methylation as a biomarker of significant infection and disease. Methylated target host genes or methylated viral genome can be used to triage HPV-positive cases. HPV genome methylation, especially in the E2, L2, and L1 regions, can be used to differentiate the transient and pre-cancerous infections.[45]
Human papilloma virus self-sampling
The use of HPV self-sampling has the potential to address many religious and attitude barriers to screening as well as has the potential to reach women in remote areas increasing the screening coverage. Self-taken samples usually comprise of vaginal swabs taken by the woman herself in her privacy which are then placed in a suitable transport medium. The Evalyn brush (Rovers), Viba brush (Rovers) and FLOQSwab (Copan) are some of the self-sampling devices in use. Various surveys have shown high acceptance by women and studies have shown good agreement between self-samples and provider collected samples in HPV testing.[46],[47],[48],[49]
Screening guidelines in India
India does not yet have an organised cervical cancer mass screening programme. It is mostly opportunistic based screening.
FOGSI (Federation of Obstetric and Gynaecological Societies of India) has outlined good clinical practice recommendations for cervical cancer screening in India based on the global guidelines and has modified them for good resource settings and low resource settings.[50] It recognizes that primary HPV testing, cytology, co-test and VIA are all valid options [Table 2]. It recommends increased frequency of screening in immunocompromised women, every 2–3 years. HPV testing has also been used in post treatment follow up as test of cure.[50] | Table 2: Federation of Obstetric and Gynaecological Societies of India recommendations for cervical cancer screening in India*
Click here to view |
Impact of human papilloma virus Vaccination on screening
With the emergence of HPV vaccines, primary prevention is now possible. The preferred target age group is 9–14 years, where two doses are administered at an interval of 6 months. Bivalent, quadrivalent and the more recent-nonavalent vaccines are available.
The data available on comparison of various tests and algorithms for screening are essentially based on non-immunised population. It is likely that the positive predictive value of existing HPV tests may be affected if the incidence of HPV 16 and 18 is reduced by vaccination. Non-HPV 16/18 types may become increasingly unmasked.[51] As the first vaccinated population enters screening age, data from them needs to be analysed to address these issues.
It is also important to educate the women and emphasize that screening must continue even after vaccination.
| Conclusion | | |
Cervical cancer screening programme with cytology (Pap smear) at the forefront has been recognized as a public health success in the past few decades and has greatly reduced the mortality and morbidity of the disease. The advent of new technologies like LBC has changed laboratory practices while molecular advancements, specifically detection of high risk HPV DNA/mRNA has opened up new frontiers and exciting possibilities. Currently, the incorporation of high-risk HPV testing in screening has already been implemented in the developed world and is rapidly moving towards primary HPV screening in near future. There are rapid advancements in this field in search of affordable, sensitive and precise tools.
Awareness of the updates and technologies available can help to establish screening practices as per the infrastructure and resources available to an establishment. In India, spreading awareness of cervical cancer screening coupled with an effective and accessible screening programme is the need of the hour to reduce the burden of this preventable disease.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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