Screening for Cervical Precancer in India

Dr. Dinesh Gupta is a technopreneur in healthcare committed to promote advanced cancer diagnostics at affordable costs to many. A molecular biochemist by training Dr Gupta is engaged in early detection and prevention of cervical, breast cancer and sexually transmittable infections as a national expert. He launched molecular HPV and LBC testing procedures in India.

Currently, heading CureHealth Diagnostics, a joint venturecancer diagnostic laboratory with the US partners. He is also an honorary molecular diagnostics expert at CR Wadia Preventive Oncology Center, Thane Municipal Corporation (TMC), Thane and at the helm of a TMC endeavor on cervical and breast cancer screening program covering nearly half a million women in Thane, Maharashtra in next 5 years.

Cervical cancer is a totally preventable cancer if women subject to screening once in five to seven years after the age of 30 years or post their sexual debut, whichever is early. It is a leading cause of cancer deaths in women in India, almost parallel to breast cancer. The most significant primary factor for cervical cancer is persistent or long term infection due to the oncogenic types of human papillomavirus (HPV). HPV is the most common sexually transmittable infection that many women would acquire sometimes in their life. Cervical pre-cancer is a clinically detectable stage by advanced mRNA testing followed by colposcopy and that can be treated by simple and inexpensive outpatient procedures that does not require hospitalization too. The national healthcare policy makers need to realize that providing a health insurance cover for screening for cervical precancer would actually save cost on national exchequerthousand folds to treat this cancer, thanks to the people centric governance in the rising India.

Major considerations behind cancer screening tests

The latest cancer mortality rates in the western world show reduction in cancer-related deaths. A high percentage of cancer patients now show a better 10-year survival rates than the past decade, thanks to their organized healthcare governance, advent and acceptance of newer diagnostic and therapeutic modalities, and consciously aware population at large. On one hand they have some cancers continuing to be chronic and lifelong conditions;cervical cancer is seen providing a greater relief towards overall reduction in cancer-related mortalities. The irrefutable role till lately was being played by a single most important test, the Pap Test (Papanicolaoutest or PapCytologyscreening test). During past 5 to 6 decades of its clinical practice Cytology wasthe most effective and most economical screening test for cervical cancer.

But why this did not do any good for the countries where there is no screening practice in place, is anybody’s guess!

With the advent of modern molecular era, for instance, an introduction of HPV testing in cervical screening, a definition of a cancer screening test is getting changed on its qualification criteria. By and large, a cancer screening test must have to be clinically very effective, measured in terms of the “test sensitivity, and the “test specificity”, that gives rise to better disease predictability for a disease prevalent in a given population, which in turn, is measured by positive and negative predictive values (PPV and NPV resp). Since the screening involves bigger population coverage in order to be effective, the screening test must also be affordable by most if not all, must have a high degree of reproducibility, must have an objectively quantifiable results and finally, that it must not have to be repeated too very often!

The Pap Cytology camecloser on only half of the criteria. No wonder, why this test did not evoke much response in the resource poor countries. While it has a high specificityof above 98%, it is known to have poor sensitivityto under 50%,or even worse in most resourcepoor population settings such as in India.A Cytology sensitivity at about 50% means that every other women with cervicallesions will stand a chance of being called as (false) negative, apart from missing disease in the otherwise healthy population. An inclusion of liquid based cytology (LBC)in place of PapCytology added some advantage, by only marginally improving the sensitivity. Higher the sensitivity for a given test, means higher the chances that a true disease will not be missed at screening, or give a false negative reaction; while higher the specificity, means higher are the chances that a true healthy (for a given disease) individuals will not be overcalled as having a disease, or give a false positive reaction. For any given clinical test, attempts to increase sensitivity would imply commensurate decrease in the specificity, and conversely, improving specificity would necessarily bring down the sensitivity. The improved sensitivity for Pap Cytology was only obtainable by repetitive testing annually, as was the practice in the west to bring some meaning to screening program, but proved a major limitation for less resourceful countries.

Given this poor sensitivity, the Pap Cytologytherefore had to be repeated annually to attain its sensitivity to correctly pick up precursor lesions in the screening population, identifiable when the dominant changes in cellular morphology have only begun to be observed. Several studies from the organized screening programs showed the LBC did not substantially alter the detection rate of high grade precancer disease (CIN 2/3) than only improving on “unsatisfactory” category of smears that often was a major gray area from the interpretation of conventional Cytology.

Changing gears!

A paradigm shift came in the screening for cervical cancer when testing for HPV DNA was added to the Pap Cytology. The poor sensitivity on Pap Cytology that only was marginally bettered by LBC, was greatly supplemented by an excellent clinical sensitivity of HPV DNA to almost 95% or above. The retrospective studies had shown that almost 99.8% of cervical cancers were attributable to the persistent infections due to one or more of 15 high risk HPV types. The mounting evidences during past decade led to the new clinical guidelines in 2012 by way of adding HPV to Cytology to increase sensitivity so as to reduce screening intervals from annual to tri-annual or even once in five years. Thus the screened negative women did not have to return for rescreening annually. Theoretically, better sensitivity by DNA with Pap Cytologyco-testing should also have given us with better positive disease predictability or positive predictive value (PPV) when it came to applying such a test for routine clinical use for symptomatic outpatients. Unfortunately it did not happen due to the fact that

many women in their 30s and 40s though remained persistently infected with HPV, identifiable by a DNA positive test, but without a clinical disease, only a small percentage of them progressed to aggressive form of precancer or early invasive disease in their 50s or 60s.HPV is largely a sexually transmitted virus and almost 80-90% of sexually active women have a chance to be infected with it sometimes in their lifespan. Given the fact that almost 80% of these women will clear this virus in 12 to 24 months of first infected, it still leaves a plethora of 20% who persistently may remain infected and thus may have a chance of reporting positive HPV DNA tests in screening set up, despite clinically being asymptomatic. In the clinical setting, this situation necessitates subjecting them to triaging by sequential tests such as HPV genotyping or frequently repeating Pap Cytology, histopathology or even other cancer biomarkers of lesser significance for staging the malignancy when presented to the clinicians with mild symptoms such as pelvic or chronic vulvarpain, abnormal bleeding, discharge, cervicitis, vaginitis or simply inflammatory conditions such as long term oral contraceptive use.In fact chronic vulvar pain is a major health concern for peri- or post-menopausal women[1] which, if compounded by persistent HPV infection, becomes challenge to correctly prognose the illness. Often, this tantamount to variety of undue patient anxieties and prognostic inaccuracies for a clinician.

The biggest advantage of HPV DNA testing is in its unmatched negative disease prediction or NPV; in that if an HPV DNA test is negative a woman does not need to return to rescreening for at least next 5years. This saves a larger burden of screening millions of women annually in the more organized countries and actually saving them millions of dollars for their national health GDP. For resource poor countries, however, this leaves a “clinical gap” between high specificity and very poor sensitivity of Pap Cytology versus high sensitivity and poor specificity of HPV DNA tests, even when following a co-testing strategy. Progressively, many western countries have begun to implement “HPV First” strategy, even without Pap Cytology in the first place. Also, efforts were directed towards applying a better molecular test having a superior specificity for detecting high grade precancer lesions withequal sensitivity of a DNA test.

HPV E6/E7 mRNA (or HPV mRNA) test was thus evolved, that filled the much needed “clinical gap”. It is a first fully quantitative and objective test that has high specificity of above 90% for detecting high grade precancer lesions with equal sensitivity as that of DNA tests. Studies have proved that HPV mRNA testing has a high concordance with histopathologic findings for high grade precancer too, identified as CIN2/3.

It is often said and widely believed that Pap test is by far a cheaper test, and hence better affordable. This has proven to be a myth through a number of cost effectiveness studies in the west. For instance, a cost of running a successful Pap Cytology based screening program in the US costs their healthcare a several billion dollars for its nearly 55 million beneficiaries. Yet, it needed to be performed annually. Triaging by HPV testing actually saved them a huge cost burden by shifting annual screening to once in five years. In fact, it amounted to co-testing with HPV for women above 30 years of age, as stipulated in the latest US-consensus guidelines (NCI/ASCCP/ACOG/ASCP) in 2012[2]. Further attempts are being made to see if theCytology with HPV co-testing could prolong screening interval to 9 years[3]. Though rather expensive way of learning, it proves Cytology as a spot-test has a very limited clinical use as a comprehensive screening program towards detecting a true disease in the given population. A woman subjecting herself for a screening by Pap Cytology test in the routine clinical practice must continue to do so at least once in five years between 30 to 60 years even if she continues to report normal findings, in order to bring some utility to Pap Cytology test.

The other important criterion of a screening test is in its ability to produce uniform results when performed repeatedly or even by different set of technical experts. Pap Cytology continues to be very subjective with very poor concordance between any two observer interpretations. Studies show that the liquid cytology only marginally improves its sensitivity though it reports far lesser number of “unsatisfactory” categories of slides.With the Pap Cytology method, cells can be obscured by blood, mucus, and inflammation as against the LBC method preserves the cells and minimizes cell overlap, blood, mucus, and inflammation for better visualization and interpretation. With the introduction of LBC in the UK a decade ago, a clear reduction in the reported rate of inadequatesmears was seen from 9% to less than 2%. Changes in reporting ofsmears lacking evidence of transformation zone sampling also had an effect onthe inadequate rate[4].

Cervical screening made easy

Inclusion of HPV testing has offered a big opportunity to cover a vast majority of population under a screening program at a relative ease, to be able to appreciate valuable gains such as quantitative reduction in mortality and morbidity rates. All that is needed for an HPV test is a tissue scraping from cervical opening in to vaginal vault with a brush like device having a long stalk. A cervical region harbors exfoliative cells those that are shed periodically with each menstrual cycle otherwise. The area between the cervical canal and cervical opening is a primary site of HPV infections and collecting exfoliative cells using a cervi-brush by a trained nursing staff is easy and simple, that does not cause any discomfiture to a woman. Alternatively, a woman may collect her own sample herself in the privacy of her home by following three simple steps to insert a cervi-brush till it finds a resistance in the vaginal vault, rotating the brush 4 to 5 turns over the cervical opening and taking the brush out with little care to collect the specimen in to the bottle that contains specimen preservative fluid. A brush and a fluid kit can be supplied by the nearest pathology lab where a properly labeled bottle with a woman’s name or ID could be simply sent. This self-collection of specimen is actually seen as a very powerful and effective means to bring a far large population under screening coverage. It is hoped that a self-sampling kit for HPV testing and a HPV test strip much like a routine pregnancy test strip may be available at the pharmacy outlets in the near future.

India marching towards cervical cancer prevention

Therefore where does India go from here in terms of seeing a successful cervical screening program? We perhaps need to normalize cervical cancer scenario in India sooner. According to WHO 2012 statistics, India sees 122,844 new cases of cervical cancer annually and is likely to increase to 148,624 by 2020, showing 21% rise in the incidence. A corresponding mortality rate is likely to increase by29% from the present number of 71,400 annual deaths. What is more concerning is nearly 35% increase in the incidence among women of 65 years or older by 2020!It is therefore very heartening to note that some of the state healthcare departments in India, such as in Tamil Nadu and Sikkim have taken up to the visual inspection (VIA) based screening programs, and parts of Maharashtra (Thane Municipal Corporation) have lately initiated a holistic VIA/Colposcopy/HPV mRNA/ HPV DNA based community screening program with an aim to provide complete treatment to women detected with high grade precursor lesions at screening.

The focus of the Thane program is to screen nearly half a million women population falling in the desired age group over a span of next 5 years. Thane is fast emerging as the best smart-city for the state of Maharashtra and theThane Municipal Corporation’s endeavor to cover the entire metropolitan population by five mobile camp vans laced with visual examination aid, colposcopy machine, and fully trained clinical and nursing staff will cover every single adult woman in the next five years. This is a very bold step to set an example for rest of the country.

The earlier studies in Tamil Nadu hadestablished nearly a 25% and 35% decline in cervical cancer incidence and mortality rates[5,6] and results of otherongoing programs are going to set up a cultural trend in the entire country in the years to follow, to see India wins over cervical cancer with thumping applaud by 2040; thanks to the newer molecular diagnostic approaches with superior specificity e.g. HPV E6/E7 mRNA, p16 IHC or ki67 markers, therapeutic interventional methodologies, vastly talented clinical excellence and conscious healthcare governance conceding to screening success to gain the huge mandate for women of India.

Concurrent mission!

Along the side lines of population based screening programs what India needs is a supportive and stronger advocacy program. The awareness about breast cancer early detection and prevention has been seen to be far better than cervical cancer, primarily owing to social taboo associated with lower genital tract diseases. This perspective needs to change. Cervical cancer is now fully preventable cancer, if detected correctly in its precancer stage and every single woman of this country need to know and be able to freely talk about it. The social and news media have lately been playing a significant role in mobilizing a mass mindset. A celebrity endorsement will certainly step up acceptance for screening. Australia became the first country to have introduced HPV vaccination in the national immunization plan in 2006 when the then prime minister John Howard’s wife was detected with cervical cancer and thus became a champion of the awareness cause. The Australian first lady, Janette Howard was treated for cervical cancer in 1996 and took up to immunizing adolescent girls no sooner the HPV vaccination became available in 2006[7].

The next step would be the role of healthcare insurance sector to consider providing reimbursement on at least 5-yearly screening using HPV and Pap Cytology co-testing through their products aimed at women’s health. A one-time reimbursement on HPV and Pap Cytology co-testing may cost under Rs 3000 once in 5 to 7 years but would fetch at least five times annual subscription and considering 100% compliance insurance sector stands to benefit out of such a product, still save few lacs of rupees of treatment cost reimbursements on patients progressing to invasive stages of cancer. On the other hand, what a boon it may be for the larger section of unorganized private sector women of modern India!

Our healthcare insurance sector is largely curative and hospitalization oriented for any reimbursement. For the first time for any cancer, we have a strong evidence of long term prognostic value resulting in to quantifiable economic benefits to insurance providers as well. Not only the cost of treatment for cervical precancer is far lower than frank cancer, but largely reduced number of cases still progressing to the invasive cancer stages would mean greater saving on insurance incomes. In addition, the insurance sector gains enormously by reaching out to our women folks who have remained a low family priority when it comes to the better family health. A market survey report suggests if only 10% of the 150 million target women (other than otherwise insured through their government or private sector employment) between the age group of 30 to 60 are reimbursed for cervical screening once in five years, it would fetch additional annual revenue of 5,500 million rupees at only a rupee-a-day subscription, while reimbursing the costs of screening only once in five years, considering 100% compliance of insurance claimants! While few states are pushing forward the cervical screening in their earnest endeavor to its women, can our union governance push for this dormant aspect of our healthcare system?

Take-home massage

Cervical cancer is fully preventable cancer if detected early and correctly. Hence screening is very important and each woman should subject herself for clinical pelvic examination at least once in five years, just as clinical breast examination to prevent breast cancer.

Testing for HPV has a better long-term predictive value and the specificity for HPV test improves with the age of a woman.

Women are encouraged to discuss their lower genital health more freely with their doctors, among friends or even with family members. Awareness is a boon and ignorance is a bane for many cancers. A socially and economically empowered woman of modern India must be ‘aware’ and share her knowledge to those who may be less privileged.

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