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Cervical cancer is not the most common cancer detected in Irish women. It is in fact only the 9th most common, with skin, breast, bowel, and lung cancer being far more common, but it is a special cancer in that it is almost always preventable.
Around 300 new cases of cervical cancer are reported in this country each year (mainly in women in the over 40 years age group) but it may also affect young women. It is in fact the commonest gynaecological cancer detected in young women. Sadly, almost 100 deaths are attributed to cervical cancer each year in Ireland and this number has continued to rise in spite of free screening. Tragically, most of these deaths are completely avoidable.
Squamous cell carcinoma is identified in 85 per cent of cases of cervical cancer with the remainder being made up of adenocarcinoma and lymphoma predominately. The vast majority (>99 per cent) of cervical cancers, when examined, contain the DNA of one of the high risk or oncogenic human papillomavirus (HPV) subtypes. These viruses are frequently spread from individual to individual through sexual contact. Cervical cancer is uncommon in women who have never been sexually active.
The HPV virus is a double stranded DNA virus of which more than 130 serotypes have been identified. They are a very complex group of human pathogenic viruses. Over 40 of them are known to infect the genital mucosa.
The lower-risk subtypes like HPV 6 and 11 do not integrate into the nuclei of the human epithelial cells and so are only linked to the mainly harmless genital epithelial proliferative infection we call genital warts or condyloma acuminata.
At least 75 per cent of sexually active men and women will be exposed to oncogenic HPV strains but very few will develop cancers
However, the high-risk or oncogenic subtypes like 16, 18, 31, and 33 (as well as 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) are believed to integrate their viral DNA with that of their human host’s and may initiate changes which lead to impaired function of tumour suppressor genes, genomic instability, and cell immortalisation. The overwhelming majority – 99 per cent – of cervical cancers are caused by these high-risk HPV subtypes.
Preventing HPV infection
The HPV school vaccination programme began in Ireland in 2010. It offers the quadrivalent Gardasil vaccine. It is a quadrivalent vaccine in that it offers protection against the four most common strains of HPV: the genital warts/ non-oncogenic HPVs 6 and 11 and the oncogenic HPVs 16 and 18.
Young girls in their first year of secondary school are offered the vaccine free of charge. This young age group was chosen as the vaccine is most effective if given before sexual activity occurs and a superior immune response has been demonstrated in children of this age.
It is not yet offered to boys in Ireland under the public school vaccination programme but this may happen in due course.
Gardasil is recommended to be given at zero, two and six months by IM injection and its uptake has been very high in this country, with over 580,000 doses of Gardasil having been administered in Ireland as of January 2016.
Figure 1: Process fowchart for HPV reflex testing (HPV triage)
Is the HPV vaccine safe?
Adverse events are rare but are usually confined to local irritation and syncope (as with many vaccines). There is concern among some parents that the Gardasil vaccine is linked to a variety of complaints such as headache, sore throat, joint and/or muscle pains, memory impairment, menstrual problems, seizures, autoimmune illnesses, chronic fatigue, depression, and psychiatric illnesses. A support group for girls whose parents believe that their daughters may have been injured by the vaccine has been set up (www.regret.ie), but medical data does not support the theory that the vaccine is causally related to these adverse events.
The World Health Organisation Global Advisory Committee for Vaccine Safety (GACVS) has reviewed the evidence on the safety of Gardasil vaccine and concluded in December 2015 that Gardasil continues to have an excellent safety profile. In November 2015 the European Medicines Agency (EMA) reported on a review of HPV vaccines. This report found no evidence linking the vaccine to chronic fatigue-like conditions.
In January 2016, the European Commission endorsed the conclusion of the EMA; that there is no need to change the summary of product characteristics for Gardasil vaccine. Worried parents can be referred to the HSE’s vaccine website (www.hpv.ie) or the Centre for Disease Control’s (CDC’s)HPV vaccine safety page: www.cdc.gov/hpv/parents/vaccinesafety.html.
At least 75 per cent of sexually active men and women will be exposed to oncogenic HPV strains but very few will develop cancers.
Malignant transformation, if it occurs at all, tends to happen slowly after a long latency period and in only a small number of HPV-positive individuals.
This means that while infection with an oncogenic HPV is necessary for the development of HPV-associated cancers, it is not the only factor.
Host and environmental factors play a role in potential malignant change. Cigarette smoking, immune suppression, multiparity, co-infection with chlamydia, folic acid deficiency, and the use of oral contraceptives, et al, have all been identified as possible environmental co-factors for malignant change.
HIV-infected women are five times more likely than HIV-negative women to develop cervical neoplasia.
Is HPV a sexually transmitted infection (STI)?
The CDC lists HPV as the most prevalent STI in the USA but genital HPV is transmitted through skin-to-skin contact. So, while it may be spread by penetrative sex, this is not necessary for transmission. Additionally, condoms will not provide full protection from HPV if genital-to-genital contact has occurred before the condom is applied.
HPV infection, per se, is not routinely tested for in Ireland within an STI screen nor is it in itself on the list of notifiable STIs in this country (although genital warts are on the notifiable list).
It is true though that the more sexual contacts a woman has, the more likely she is to meet a partner with an oncogenic HPV infection, but reporting and contact tracing does not apply to women found to be positive for HPV.
Detecting HPV cervical changes
As said previously, not everyone exposed to a high-risk HPV gets cancer. In fact, more than 80 per cent of exposed individuals clear the virus within 18 months of their first exposure without any negative health impact but in the 20 per cent of exposed women in whom the HPV persists, the risk of cervical cancer is increased.
The cellular changes that occasionally result from persistent HPV infection are found at the squamocolumnar junction of the cervix. This area is known as the transformation zone (TZ).
The cells at the TZ are always changing and so are vulnerable to dysplasia.
Sampling the TZ
In 1933 a Greek-born and educated obstetrician gynaecologist working in Cornell University Medical School in New York, US, named Dr George N Papanicolaou, published a monograph entitled The Sexual Cycle of the Human Female as Revealed by the Vaginal Smear. Dr Pap (as he was known) continued researching vaginal cytology and cancer detection. In 1943, with his colleague Dr Herbert Traut, they validated the diagnostic potential of the vaginal smear and published their findings and conclusions (Diagnosis of Uterine Cancer by the Vaginal Smear). Thus the ‘pap smear’ was born and by the 1960s cervical cancer had gone from the number one gynaecological cancer in the USA to number three.
Dr Pap originally used a flat, wooden (Ayer’s) spatula to gently scrape mucus and cells from the transformation zone of the cervix and ‘smear’ them onto a glass slide. This often caused the cervix to bleed. The slide was then sprayed with alcohol to fix the cells.
They were sent to the lab for microscopic examination but if the material was clumped or if there was a lot of blood cells on the slide it would obscure the microscopic appearances and the smear would be reported as ‘unsatisfactory’. A repeat smear test was necessary and this happened in almost 33 per cent of samples in some areas, causing unnecessary concerns among the patients as well as additional workload for the doctors.
Modern smears and screening
In recent times, the soft nylon bristled brush has been adopted to gently sample the TZ. This causes much less contact bleeding. The brush is then swirled with its gathered cells and mucus into a bottle of preservative. The sample is posted to the lab where a machine filters the sample to separate out the cervical cells from mucus, blood, and any other extraneous material that might have gotten on to the brush. The remaining cells are prepared on a slide and examined. Unsatisfactory smears are much rarer now as a result. A computerised pre-processing of the sample will ‘red flag’ samples with possible dysplastic changes. The solution can be retained and tested for HPV.
Since April 2015 CervicalCheck has been automatically performing HPV testing as an adjunct when low-grade abnormalities (ASCUS or LSIL) are detected on cytology
Visualisation of the cervix is essential to good smear taking. Established cervical cancer may be evident on inspection and any suspicious appearance warrants immediate and urgent referral to colposcopy without waiting for the smear result to return. In fact in many cases of clinically evident cervical cancer the smear result has been negative. This is because the smear test is not as sensitive a diagnostic tool for malignancy as it is for pre-malignancy (nor do smears diagnose STIs, thrush, or any other vaginal complaints, as some women believe to be the case).
Managing abnormal smears
In general low-grade dysplasia rarely progresses to cancer so we usually reassure the patient and repeat the smear in six months.
Recurrent, or persistent low-grade dysplasia, does warrant referral for closer inspection via colposcopy, especially if the patient is also HPV-positive. When higher-grade dysplastic changes are identified there is a recommendation for colposcopic review in all cases.
The Bethesda reporting system replaced the previous WHO system of negative, borderline cellular changes, CIN I, CIN II, and CIN III.
- Now possible smear test results will be one of the following:
- Negative for intraepithelial lesion or malignancy;
- Atypical squamous cells (ASC) of undetermined significance (ASC-US), cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H);
- Low-grade squamous intraepithelial lesion (LSIL) encompassing: HPV/mild dysplasia/cervical intraepithelial neoplasia (CIN) 1;
- HSIL encompassing: moderate and severe dysplasia, carcinoma in situ; CIN 2 and CIN 3;
- Squamous cell carcinoma adenocarcinoma, as well as a variety of other less common anomalies that can be identified in the sample.
The national cervical cancer screening programme (www.cervicalcheck.ie), delivered through the HSE’s National Screening Service, has vastly improved access to smear testing in Ireland. A woman can book a smear test for free from any registered GP or nurse as long as she is eligible.The smear test schedule includes women from 25 years to 60 years.
Samples are sent by post for assessment and results typically are back in a matter of weeks. Follow-up recommendations from the lab are on the test result sheet.
Since April 2015 CervicalCheck has been automatically performing HPV testing as an adjunct when low-grade abnormalities (ASCUS or LSIL) are detected on cytology. The added information provided by this reflex HPV test is used to determine the recall recommendation for these women.
Women who test negative for oncogenic HPV will be given a recommendation of routine recall (either three years or five years depending on their age), as they are low-risk for developing high-grade CIN in those intervals. Women who test positive for oncogenic HPV will be given a recommendation of ‘refer to colposcopy’.
Oncogenic HPV testing when low grade CIN is found has greatly aided screening in that it reduces unnecessary repeat smear tests for women who are HPV negative, it expedites referral to colposcopy for HPV-positive women and it should reassure those women who are HPV-negative that the cellular abnormalities in the smear test are not considered clinically significant.
In addition, women who are on annual surveillance post-colposcopy treatment can return to routine recall if their smear test shows a low-grade abnormality and tests negative for HPV.
Some women prefer more frequent smear testing. Sometimes they come from a country where annual testing is the norm and prefer to continue on this schedule; sometimes they need a recent smear test prior to fertility treatments. In these situations, CervicalCheck will not accept their samples and one of the private labs must be used to offer testing.
Reassuring the patient
It is important to be clear about HPV prevalence, the significance of an abnormal smear and the significance of persistent HPV infection when discussing the smear test result with a patient so she feels informed and reassured.
It is also important to encourage women to avail of the free smear test, as unfortunately many of the most at-risk people are reluctant to present for health checks.
References available on request