HPV Testing and Cervical Screening

The introduction of HPV testing as the primary screening method in our CervicalCheck programme is based on substantial evidence linking high-risk human papillomavirus (hrHPV) infections to the development of cervical cancer. According to the World Health Organization (WHO), over 90% of cervical cancer cases are due to chronic infection with one or more of the high-risk oncogenic types of HPV. Read more in the WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention

The 2017 Health Technology Assessment (HTA) conducted by the Health Information and Quality Authority (HIQA) in Ireland recommended the adoption of HPV testing as the primary screening method for several key reasons:

1. Increased sensitivity: HPV testing is significantly more sensitive than cytology (smear) tests. This means that HPV testing is more effective at detecting women who are at risk of developing cervical cancer, as it reduces the likelihood of receiving a false negative result. In other words, fewer cases of cervical abnormalities go undetected with HPV testing.
2. Improved early detection: Since HPV is the primary cause of cervical cancer, detecting the presence of high-risk HPV types allows for earlier intervention and treatment, potentially preventing the progression to cancer.
3. Good specificity when triaged with cytology: While HPV testing is more sensitive, it can also result in more false positives compared to cytology. To address this, women who test positive for HPV undergo a follow-up cytology test (reflex testing) to identify those at higher risk of precancerous abnormalities and early-stage invasive cervical cancer. This approach ensures that women who need further investigation and treatment are identified and referred to colposcopy. Cytology triage reduces but does not eliminate false positives.

In summary, HPV testing is the primary screening method in Ireland's CervicalCheck programme because it is better at identifying the risk of developing abnormal cells that could become cancerous through earlier and more accurate detection of high-risk cases, thereby improving overall outcomes for women. For further information, please download the HIQA Health technology assessment of HPV testing for cervical cancer screening

Click to read Cervical cancer elimination initiative.

1. Higher sensitivity: HPV testing is more sensitive than cytology screening. Sensitivity refers to the ability of a test to accurately detect an underlying condition. Due to its higher sensitivity, HPV testing is more effective at detecting precancerous lesions when used in combination with reflex cytology testing. Cytology sensitivity is 15/20 (75%) whereas HPV sensitivity is 18/20 -90%
2. High negative predictive value: One significant advantage of HPV testing is its high negative predictive value, meaning that if a woman tests negative for HPV, she is at low risk of developing cervical precancer. This high negative predictive value allows for longer intervals between screenings—up to 5 years for many women.

However, it's important to note that while HPV testing is more sensitive, it is less specific than cytology. This means it may detect women with transient HPV infections that might not have caused any cellular changes. Therefore, a triage cytology test is necessary to distinguish between transient HPV, which is less likely to cause harm, and persistent/high risk HPV, which poses a higher risk of leading to precancerous changes or cervical cancer.

To summarise:“On average, out of every 1,000 women screened, around 20 will have abnormal (precancerous) cervical cells. With the old cytology-based screening test, 15 of these 20 women would be identified. With the new HPV cervical screening test, around 18 of these 20 women will be identified." (HIQA, 2017)

The introduction of HPV primary screening does not change how a cervical screening sample is taken from a woman. The sample is taken by visualising the entire cervix and collecting cells from the transformation zone. Once collected, the sample is sent to a laboratory for analysis to test for the presence of high-risk HPV.

CervicalCheck uses a HPV test that is validated for primary cervical screening and adheres to international standards. It's important to note that the HPV test is a measure of the risk of developing abnormal cell changes and cancer, rather than an indicator of disease. The test simply determines the presence or absence of HPV DNA above a certain threshold.

When determining the outcome of the test, the laboratory specifically looks for the 14 high-risk/oncogenic subtypes of HPV, which include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. The results will be reported as either 'HPV detected' or 'HPV not detected.'

If the sample cannot be processed the result will be reported as ‘test not processed’ or ‘inadequate/indeterminate’ depending on the root cause.

Read the HPV Primary Screening Algorithm.

Reflex cytology is performed on a HPV-detected sample to identify abnormal cell changes in the cervix. Although HPV testing is highly sensitive and effective at detecting the virus, it has low specificity, meaning that many individuals may test positive for HPV even though only a small proportion will develop cytological changes that require treatment. Without cytology triage, relying solely on HPV testing could result in numerous false positives, leading to unnecessary investigations.

The addition of the cytology triage test helps distinguish between those who are at sufficient risk to require further assessment, such as colposcopy (i.e., individuals with both HPV detection and cytological abnormalities or those with persistent HPV infection). This approach increases the overall specificity of the screening process, reducing the number of false positives and ensuring that only women at higher risk of developing cervical cancer receive the necessary follow-up. Reflex cytology, therefore, helps to minimise the risk of both over-investigation and under-investigation, protecting women from unnecessary procedures while ensuring those who need further care are accurately identified.

When HPV is detected, a slide is made using the cervical sample to screen for any cytological (cell) changes. These changes can indicate whether the HPV infection is causing abnormalities that may lead to cervical cancer. The cytological changes are graded as follows:

• Normal: The cells appear normal with no signs of abnormality.
• ASC-US: Atypical squamous cells of undetermined significance, where some cells don't look entirely normal but it's unclear if they're abnormal.
• LSIL: Low-grade squamous intraepithelial lesion, indicating mild abnormalities often associated with transient HPV infections.[NR1] 
• HSIL: High-grade squamous intraepithelial lesion, indicating more severe abnormalities that could progress to cancer if left untreated.

In addition to these, glandular abnormalities are also assessed, as they can indicate changes in the glandular cells of the cervix, which may also be a sign of precancerous conditions or cancer.

Reflex cytology is crucial because it helps to identify the specific nature and severity of cell changes in women with HPV, guiding appropriate follow-up and treatment.

If hrHPV is not detected, cytology screening of the cells is not required because the risk of developing cancer is low. The test result is sent directly to the woman’s GP, along with a management recommendation to repeat the test in 3 to 5 years, depending on her age. CervicalCheck is responsible for issuing the result letter to the woman. If a woman has certain risk factors, such as undergoing renal dialysis, being pre- or post-transplant, or living with HIV, this medical information must be indicated on the cervical screening form, and she will be recalled for screening in 1 year.

For samples that are taken in colposcopy, the lab will issue the result back to the colposcopy unit. The programme does not write to the woman in this instance as she is under the care of the colposcopy unit.

HPV regression refers to the body’s ability to clear HPV infection or its related cellular changes (like CIN) without medical treatment. Many HPV-related cervical abnormalities resolve spontaneously over time, especially low-grade lesions. Not all abnormalities that are identified at colposcopy are treated because most abnormalities have a chance of spontaneous regression. In particular, low grade abnormalities such as ASCUS and LSIL have a high chance of regression. More recently, conservative management has been advocated for CIN2 due to the low rate of progression to invasive cancer and the risks involved with excisional treatments. (Nygard 2003).

No. Most do not. Many cervical abnormalities identified at colposcopy, particularly low-grade changes, regress naturally. Treatment is not always necessary, especially when the risk of progression is low. Colposcopy helps confirm if any cervical abnormality is present. Not all abnormalities seen at colposcopy require treatment—especially when the likelihood of regression is high.

Yes, primary HPV testing is highly effective in detecting high-risk HPV types that are linked to around 99% of squamous cell cervical cancers. However, there are some types of cervical cancers that are less likely to be detected by HPV screening.

While approximately 90% of all cervical cancers are related to HPV, some cancers are not associated with HPV (HPV independent cancers) and may not be reliably detected through HPV screening alone. Other types of cervical cancer, such as adenocarcinoma or glandular carcinoma, are less likely to be associated with HPV. Overall, it is estimated that over 90% of all cervical cancers are HPV-related.

HPV-independent cancers are sometimes identified through other means, such as visual examination of the cervix or when a woman presents with symptoms. It is important that any woman that presents with unexplained vaginal bleeding has a pelvic examination as well as a speculum examination. HPV screening remains a crucial tool in reducing the incidence of the most common forms of cervical cancer and improving overall health outcomes.

In 2020, the WHO updated the Female Genital Tumours classification (5th edition) and included the following cervical cancers which are HPV-independent: villoglandular variant, intestinal adenocarcinoma, signet-ring /stratified mucin-producing adenocarcinoma, clear cell/mesonephric/endometroid adenocarcinoma.

No, the genotype specific hrHPV result is not available at present. Like other organised cervical screening programmes in England, Scotland, Wales and Northern Ireland, our guidelines recommend management based on a hrHPV positive result and the cytology result. However, the CervicalCheck senior leadership team regularly reviews the evidence for the utility of genotype information for cervical screening. Partial genotyping is currently used in other countries such as Australia, Sweden and the Netherlands.

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Yes, women who are vaccinated against HPV should still attend cervical screening. In Ireland, the HPV nonvalent vaccine (Gardasil 9®) protects against 7 of the 14 high-risk HPV (hrHPV) subtypes that are tested for in cervical screening. The earlier quadrivalent vaccine protected against 2 of these subtypes, while both vaccines also protect against HPV types 6 and 11, which cause anogenital warts.

Even if a woman has been vaccinated against 7 HPV subtypes with Gardasil 9®, she can still be infected with the remaining 7 hrHPV subtypes that CervicalCheck tests for. Therefore, it is recommended that vaccinated women continue to participate in the cervical screening programme. It’s important for them to understand that they may still receive a HPV-positive test result, which does not mean the vaccine has failed. Regular screening remains essential.

In Ireland, the HPV vaccine is provided free of charge to young people in their first year of secondary school. Get information on the HPV vaccine.

Cervical screening is designed for well women who do not have symptoms of disease. For women with a previous diagnosis of cervical cancer, follow-up is managed according to specific best practice guidelines set by their treating gynaecologist. Testing after a cancer diagnosis is considered surveillance rather than screening because women with a previous diagnosis have a higher risk of future disease than the general population.  Surveillance should be carried out through specialised follow-up pathways rather than routine screening pathways.