Medicosnext
Interaction on cervical cancer, Oct 2, 2019
Participating experts
Subject presentation: Dr. Sunila Shakya, Asst Prof. MBBS, MD, PhD
Jyoti Acharya, M.Sc. MLT Microbiology, K-Lab
Dr. Rupa Jha, MBBS, MD (Obstetrics and Gynecology)
Dr. Bibhuti Shahi, MBBS, MD (Obstetrics and Gynecology)
Mr. Sushil Thapa, MD, Dignotech
Dr. Sunila Shakya did her MBBS from Bangladesh and MD in OBGYN from Kathmandu University. She started minimal invasive surgery in gynecology at Dhulikhel Hospital in 2002 after competing her training in Austria. She earned her PhD degree from NTNU, Norway. Besides her clinical service as a senior consultant at Kathmandu University Hospital (KUH) and academician at KUSMS, she is currently leading Colposcopy and Dysplasia Unit and Hospital- and Community-based Cervical Cancer and STI Prevention Program at KUH. As an expert and a national resource person, she is involved in leading trainings and organizing international level pre-congress workshops on colposcopy and cervical cancer prevention in Nepal.
Jyoti Acharya is Joint-chief Medical Microbiologist at National Public Health Laboratory. An experienced technical director with a demonstrated history of working in the hospital and health care industry, she is skilled in molecular diagnostics, ELISA, laboratory skills, bacteriology, parasitology, and infectious diseases. She has an MSc.MLT Microbiology, focused on medical microbiology and bacteriology, from IOM TUTH.
Dr. Rupa Jha, MBBS, MD (Obstetrics and Gynecology), is associated with Green City Hospital,
Basundhara, for the last five years. Previously, she worked as a lecturer in People’s Dental College and Hospital.
Dr. Bibhuti Shahi, MBBS, MD (Obstetrics and Gynecology), is associated with Sukhi Pariwar Clinic,
Infertility Care & Women Health Care Center, Kathmandu. She has received special training in
gynecological laparoscopic surgery, colposcopy, screening and management of cervical pre-cancer, and minimally invasive gynecological surgery.
Cervical cancer is the cancer of the lower one-third of the uterus. Worldwide, it is the fourth most common cause of cancer among women, after breast, lung, and colorectal cancers, with nearly 570,000 new cases and 9.8 million deaths in 2018. Nearly 90 percent of all cervical cancer deaths are reported in the developing countries, of which one-third occurs in India, Bangladesh, Nepal, and Sri Lanka.
It usually occurs during midlife (30s to mid 40s). This is the time when women have just finished raising their kids and moving up in their careers. Despite being preventable, many women are still dying in the prime of their lives, and it is the most neglected tragedy of our times, says Dr. Sunila Shakya, MD, PhD (HPV infection and Cervical Cancer), and Asst. Professor, KUH.
According to current estimates, every year, 2,942 women are diagnosed with cervical cancer and 1,928 die from the disease in Nepal. As per the hospital-based cancer registry of Nepal, cervical cancer ranks as the 1st most frequent gynecological cancer among women between 15 and 44 years of age.
“But, the true incidence and mortality rate might be higher than what is estimated,” she states. “We assume it is higher because we don’t have organized cervical cancer-screening programs covering all eligible women across the country. These data are not from population-based cancer registry, because we do not yet have such fully functional registry in Nepal. There are hospital-based registries that only list women who have been diagnosed there. We don’t know what’s happening in the community. Many women die before they reach hospital, and we do not know how many women have precancerous lesions that are likely to develop into cervical cancer. Therefore, we don’t have data on the true incidence and mortality rate.”
In Nepal, there is a lack of awareness on cervical cancer prevention and its screening. Very few women go to hospital just for screening. Either the doctor offers them screening service or refers them to screening clinics when they are in the hospital for other gynecological or health problems, or a few more get screened through health-camps organized by NGOs, INGOs, and hospitals. The data shows that such opportunistic screening has covered only about 2.8 percent of eligible women. Over the last few years, the number of screened women might have slightly increased through these opportunistic screening, as more screening camps were held in both rural areas and cities, Dr. Shakya informs.
What causes cervical cancer?
In 2008, it was declared that human papillomavirus (HPV) virtually caused almost all types of cervical cancers. After this lab discovery by Harald Zur Hausen, who had won the Nobel Prize, HPV vaccines were developed, and HPV test was recommended as primary test for cervical cancer screening. HPV is a DNA virus. There are over 200 genotypes of Papilloma virus, and the characterization of new HPV types is ongoing. Among these HPV genotypes, 40 different types infect the ano-genital region. Almost all squamous cell carcinoma and adeno-carcinoma are caused by cervical HPV infection, says Dr. Shakya.
These HPVs are broadly classified into two groups: high-risk (HR) HPVs (carcinogenic: those with the potential to cause cancer) and low-risk (LR) HPVs.
World Health Organization further classifies the carcinogenic HPVs into three groups. The first and second groups are responsible for almost all kinds of cervical cancer, so they are considered HR HPVs. Among them, HPV-16 and HPV-18 account for about 70 percent of cervical cancer.
The LR HPVs that do not cause cancer are still problematic. For example, genital warts, caused by HPV-6 and -11, although not life threatening, are a big social problem. They look ugly and are highly contagious, causing extreme psychological distress and embarrassment for many couples. There are many cases where people have broken their relationships because of genital warts, the doctor says.
A meta-analysis of HPV infection was conducted among one million women with healthy cervix (normal cytology in screening) in different world regions in 2010. The study revealed that, on an average, 11.5 percent of these women with normal cervix (nothing wrong at the cellular level) were harboring HPV. The highest prevalence was in the Caribbean at 35.4 percent, and lowest was in Western Asia at 1.7 percent. The prevalence in South East Asia was at 14 percent.
In the first largest population-based study of HPV prevalence conducted in five villages in Kavre District in Nepal, the prevalence of HPV infection was found at 14.4 percent. The prevalence of high-risk and low-risk types from the study was 7.9 % and 6.5%, respectively.
The five most common HR types were HPV-18 (2.3%), 51 (1.2%), 59 (1.1%), 31 (0.9%), and 16 (0.8%). The prevalence of each of the other HR types (HPV-33, 39, 45, 52, 56, 58, and 68) was <1%. HR HPV-35 infection was not detected among any of the women. Among LR types, HPV-53 was most common (3.5%). Twenty-nine (2.2%) women had infection with multiple HPV types.
The study was conducted from February 2012 to May 2013 among 1,360 women. Around 2,416 women were eligible for screening, of which 1,498 showed up, and a valid HPV and cytology result was obtained for 1,289 women.
The prevalence of high-risk types in women with and without abnormal cytology was 8.3 % and 7.7%, respectively. HR HPV infection was associated with smoking, formal education, and being married to a husband with at least one previous marriage.
Why is HPV so prevalent?
HPV is transmitted by direct skin to skin, skin to mucosa, or mucosa to mucosa contacts. It is the most common sexually transmitted infection (STI) globally. While consistent use of condoms is recommended to prevent STIs, they don’t assure full protection against HPV infection, as HPV can infect areas that are not covered by the condoms. But, condoms do play a role in preventing cervical cancer, Dr. Shakya informs. Acquisition of other STIs, along with HR HPV, increases the risk for cervical cancer, so even though condoms don’t assure prevention from HPV infection, they prevent cervical cancer by preventing other STIs. The other modes of transmission are: vertical transmission, if the woman has HPV infection during delivery, which is spread in the form of recurrent juvenile respiratory papillomatosis; oral sex; and possibility of transmission through contamination of formites.
Age-wise variation in HPV infection, its clearance and persistence
“HPV is more prevalent around the age of sexual debut. About 90 percent of time women acquire HPV during their first sexual intercourse. The prevalence is higher during the 20s, and then it declines over the years,” states Dr. Shakya. She further adds that, in most of the Asian countries, the prevalence is similar in the all age groups, and that coincides in her study from Nepal. Anyone who has had sex is at risk of harboring HPV at some stage. There is no proven treatment for HPV infection, and research is still being done for medications for HPV clearance. But, interestingly, in about 80 to 90 percent of the infected cases, it clears up on its own within 1-2 years of acquisition by the body’s own defense mechanism. This is also one of the reasons why HPV prevalence is higher among younger population, then slows down gradually. However, in a small number (about 5 to 10 percent) the infection persists and progresses to precancerous changes in the cervix, which if not treated, develops into cervical cancer. It takes about months to 20 years for cervical HR HPV infection to develop into cancer. There are certain factors in presence of which the body’s own immunity fails to clear the infection. The factors that help in persistence of the infection are other risk factors or co-factors in causing the cancer, the doctor says.
What are the factors that help in persistence of HR HPV infection?
One of the major risk factors is having HR HPV along with other STIs. The most important STIs that act as the cofactors are chlamydia and HIV infection. The risk carried by gonorrhea, herpes, and trichomoniasis is still being studied. Other cofactors are having multiple sexual partners, smoking, immune-suppression, and sexual debut at a very young age, and low birth spacing. The prolonged use of contraceptive pills for more than 5 to 7 years is also suspected as a cofactor and is currently being studied, Dr. Shakya informs.
She says that the risk of persistence of HR HPV infection is more in the person with infection with multiple HR-types than the one with a single infection. Similarly, in a couple where both the individuals have multiple sexual partners, they will have higher persistence rate. Previously, it was believed that multi-parity or less birth spacing could cause cervical cancer. Dr. Shakya says that, while it’s true people with lots of children have cervical cancer, it is not the primary cause; it is one of the co-factors or risk factors for cervical cancer.
How HPV causes cervical cancer?
“HPV has a special characteristic,” says Dr. Shakya. “It infects only epithelial cells of the skin and mucosa and results in wide spectrum of benign and malignant diseases over the skin and mucosa of oropharyngeal and anogenital regions. HR- HPVs account for 40-45 percent of cancer in the oral and pharyngeal region, and up to 88 percent of cancer in the anogenital region such as vulva, vagina, and cervix in females; and penile, scrotal cancer in males; and anal cancer in both the sexes.” As HPV is a papillary virus, it causes papillary growth everywhere it infects, such as in the skin, where it causes warts that are mostly benign and rarely malignant. In neonates and newborns, it causes papillary growth in the oropharyngeal region that might lead to recurrent papillary growth in adults.
“Within the epithelium, HPV infects the basal cells in the specific area in the cervix called ‘transformation zone’. Through micro ulceration or micro abrasion of surface epithelium, the virus get access to the basal layer cells,” says Dr. Shakya.
Once the HR HPV gets into the basal cells, it is followed by a series of cellular dysplasia resulting in low and high-grade precancerous lesions. “A very few low-grade, and most of the high-grade, precancerous lesions progress to cervical cancer. When the cells are normally desquamated, infectious virion particles are released. These virion particles can be detected by HPV-testing, while precancerous changes in the cells can be detected by cytology test,” Dr. Shakya informs.
According to her, the precancerous changes are classified into high-grade (cervical intraepithelial neoplasia, CIN 2 and 3) and low-grade (CIN 1) lesions depending on the epithelial layers involved in dysplasia. The main purpose of cytology-based screening, such as Pap test or liquid-base cytology, is to detect these precancerous cellular changes in the cervical epithelium.
“Majority of this CIN 3 disease progress to cervical cancer if it is not timely detected and not treated appropriately and adequately, otherwise, they advance beyond basement membrane on which the basal epithelium rests and progress into invasive cancer,” says the doctor. She further explains that most of the low-grade lesions of CIN 1 simply indicate HPV infection and do not progress to high-grade lesion or cervical cancer, rather they resolve simultaneously. Therefore, women with low-grade lesions are not at high risk for cervical cancer and therefore do not need immediate treatment, but need further reflex testing or close follow up. “Additionally, while evaluating woman with precancerous lesions, we need to take into consideration the existing co-factors that she is living with, such as: multiple sex partners, STIs, including HIV infection, smoking history, immune-suppressants, and steroids,” she says.
Primary prevention
Vaccines against HR HPV are the primary prevention method for cervical cancer. Young boys and girls are vaccinated before their sexual debut to prevent HR HPV infection. HPV vaccine is recommended at age 9 years onwards before sexual debut. As these vaccines are designed to prevent initial HPV infection, they will not clear an existing HPV infection, so it is best and more effective to be vaccinated before the initiation of sexual activity, and HPV testing is not recommended before vaccination, says Dr. Shakya.
There are three types of FDA-approved vaccines for preventing cervical cancer
1. Bivalent vaccines: HPV-16 and -18
2. Quadrivalent vaccines: HPV-16, -18 and HPV-6 and -11(genital warts)
3. Nonavalent vaccines: HPV-16, -18, HPV- 31, – 33, – 45, – 52,- 58 and HPV-6 and -11.
All three vaccines (bivalent, quadrivalent, and nonavalent) are effective in preventing infection against HPV-16 and -18 that are responsible for 70 percent of cervical cancer. Additionally, nonavalent vaccine offers protection against five HR HPVs, and quadrivalent and nonavalent vaccines cover two more low-risk HPVs (HPV-6 and -11) that cause genital warts.
“However, even if one is vaccinated against HR HPVs, irrespective of which one of the approved vaccines was used, screening is still necessary, because it doesn’t cover all the HR HPVs causing cancer,” Dr. Shakya says. “HPV vaccination will not eradicate cervical cancer, but eliminate the disease by lowering its incidence. Australia will be the first country to eliminate cervical cancer by 2035. It is one of the first countries to start HPV vaccination to school-going boys and girls in 2007,” she adds.
HPV vaccination has been introduced in the national cervical cancer program in 81 countries. In Nepal, the government has recently announced its introduction, but has not said when it will begin. The policy makers do not seem to have any strategic plans yet, says Dr. Shakya.
How effective is the HPV vaccine?
According to a recent research paper by WHO, all the three FDA-approved vaccines are highly effective against cervical cancer. The study found that the antibodies produced against the HPV -16 and -18 after 3 doses of bivalent vaccine had sustained up to 8.5 years and 9.5 years, respectively, and with nonavalent vaccine, it was 5 years. However, it is not yet known if the booster dose is required after completion of vaccination. According to Dr. Shakya, the study regarding the vaccine dose and its efficacy and potency is still ongoing.
Secondary prevention
Screening is an important secondary prevention strategy. It detects the disease at a stage when treatment is highly effective to prevent cervical cancer. WHO recommends three different types of screening tests: 1) HR HPV testing, 2) visual inspection with acetic acid (VIA), and 3) cytology-based tests: Pap test and liquid-based cytology (LBC).
HPV test detects whether one is harboring HR HPV, while cytology-based test will look at any precancerous changes at the cellular level and will also determine if it is low or high-grade precancerous lesions. VIA test is based on whitish discoloration on the surface of cervix after the application of acid as viewed with the naked eyes under a good white-light source. Among these currently available screening tests, one of the benefits of HPV testing is that there is possibility of self collection of sample by women themselves, which might increase screening uptake, as in our context majority of women refuse screening because they feel ashamed to undergo gynecological examination,” says Dr. Shakya.
What is the recommended guideline in Nepal?
We need a kind of test that is simple and affordable, which gives quick result without compromising the accuracy of result, so that treatment can be done on the same day of screening if the test is positive. This is called see-and-treat approach, as recommended by WHO, says Dr. Shakya.
The National Guideline for Cervical Cancer Screening and Prevention in Nepal-2010, has recommended VIA as primary screening test for women between 30-65 years of age, with screening interval of five years. Pap test can be used where infrastructures are available.
Cytology-based test (conventional Pap test and liquid based cytology) smear has been the standard screening test for cervical cancer for many decades, and has dramatically reduced the cervical cancer incidence and mortality in industrialized countries over several decades. However, cytology-based test failed to do so in low- and middle-income countries due to lack of quality-assured infrastructure. Therefore, in low resource settings, VIA test has been recommended as a viable alternative to cytology for many years.
“Sometimes, even the gold standard test fails to work in all places. Pap smears, though a standard screening test, is not an ideal test in our context. In cytology-based test, the samples should be taken properly from the correct site in the cervix by a trained person, and cytology should be read and reported by trained, qualified, and experienced cytologist/cyto-pathologist. A lot of errors can happen at every step, from sample collection to transfer to staining to reading. One of the biggest challenges of cytology screening is that it is a more time consuming procedure, from screening to reporting. It takes a few days to a week to get the cytology result. So, there are high chances for lost-to-follow-up cases. It is especially problematic when the result is positive,” says Dr. Shakya.
According to her, many scientific evidences, including result from ATHENA study, have shown that HR HPV testing with focus on HPV-16 and -18 is a more accurate test to speed up the process of diagnosing high-grade lesions. Many countries have switched to HR HPV primary screening in their national screening programs. “Recently, WHO has also recommended using HPV as primary cervical screening test when and wherever feasible. Therefore, if we do not want to delay in detection of high-grade lesions and offer timely treatment, we should also think about how to incorporate HPV as a primary screening test in cervical cancer prevention program in Nepal,” says Dr. Shakya.
