Human papillomavirus (HPV) is the leading cause of cervical cancer. In this short post, which coincides with Cervical Cancer Prevention Week (23-29 January 2023), find out more about how HPV can cause cancer, the significance of different HPV subtypes in the development of cervical cancer, and the importance of cervical screening as one intervention to reduce new cases and deaths from the disease.
Human Papillomavirus (HPV) [pappy (rhymes with snappy)–loma (rhymes with Homer)] stems from two words: ‘papilla’ from the Latin word for nipple and ‘oma’ from the Greek for tumour, reflecting the appearance of certain clinical manifestations of HPV infection.
HPV is a common group of viruses; there are >200 different subtypes of HPV. Each HPV subtype has an affinity for cutaneous or mucosal epithelial cells. Some subtypes have a predisposition to infect cutaneous epithelial cells of the skin, others infect mucosal epithelial cells lining of the mouth, throat, and respiratory tract. There are over 30 HPV subtypes that are sexually transmitted; these cause infection of anogenital mucosal epithelial cells.
Infection of cervical mucosal epithelial cells with certain subtypes of HPV is the leading cause of cervical cancer (>95% cases).
Encounters with HPV
Infection with HPV is very common; however, most infections are asymptomatic and self-limiting. Thanks to our immune system, the majority of HPV infections resolve without any lasting side effects.
In a small proportion of cases (~10%), the immune system does not clear the infection and HPV remains. It is this persistence of HPV in cervical epithelial cells over many years (typically 15-20 years) that may lead to the development of abnormal cells that form precancerous lesions. If these lesions are left untreated there is a higher risk of developing invasive cervical cancer.
How does HPV cause cervical cancer?
All viruses need living cells to replicate; viruses take over a cell’s machinery in order to reproduce and spread.
In healthy cervical cells, the cell cycle is tightly regulated by two ‘good guy’ regulatory proteins (p53 and pRB) that keep cell replication in check and send any unhealthy or damaged cells to be destroyed. When p53 and pRB are functioning, cells grow, multiply, and die at a controlled rate.
When the immune system has not cleared the infection, the persistent presence of some HPV subtypes in cervical cells can disrupt the healthy cell regulatory processes. Two ‘bad guy’ HPV proteins (E6 and E7) interact with the ‘good guy’ proteins and stop them from functioning properly (Burd, 2003).
In this simplified scenario, HPV infected cells continue to replicate in an uncontrolled manner, there is no quality control of the health of the cells and the DNA therein. Abnormal cells develop and proliferate unchecked. Over time, this unregulated growth causes a mass of cells to form, known as a tumour.
The significance of HPV subtypes
Based on their association with the development of cancer, HPV subtypes may be classified as ‘high-risk’ or ‘low-risk’ types (Green Book).
The WHO International Agency for Research on Cancer (IARC) lists the following 12 HPV subtypes as high-risk (carcinogenic to humans): 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, whereas HPV subtypes 6, 11 are considered low-risk.
Below are some facts about high-risk HPV subtypes:
- The distribution of high-risk HPV subtypes varies geographically (IARC HPV Monograph)
- In Europe, HPV-16 and HPV-18, are responsible for >70% HPV-related cervical cancer (Cancer Research UK)
- HPV 16 is uniquely carcinogenic
- HPV-31, 33, 35, 52 and 58 are HPV-16 related subtypes, whereas HPV-39, 45, and 59 are HPV-18 related subtypes.
- HPV viral load correlates with disease severity. HPV-16 can reach higher viral loads than other subtypes (Burd, 2003).
Global burden of disease
Cervical cancer is the fourth leading cause of death from cancer worldwide in women. In 2020, >600,000 new cases were diagnosed and >340,000 women died from the disease (WHO factsheet).
The highest burden of disease is found in low- and middle-income countries where >90% cases of cervical cancer occur. In 2019, 38% (217 390/565 541) of new cases occurred in China (n=109 759), India (n=84 981) and Brazil (n=22 650) (Yang et al., 2022).
These statistics don’t have to paint the final picture. With the introduction of HPV vaccination, screening programmes, and treatment of early cellular changes, cervical cancer is largely a preventable disease.
In November 2020, WHO launched the Global Strategy to Accelerate the Elimination of Cervical Cancer. Adopted by the World Health Assembly, 194 countries have pledged to commit resources to three key interventions: vaccination, screening, and treatment. WHO predict that: “Successful implementation of all three could reduce more than 40% of new cases of the disease and 5 million related deaths by 2050.”
There is no blood test for HPV (NHS website) and in the absence of overt symptoms that may indicate advanced disease, development of HPV-related precancerous lesions and cervical cancer are difficult to diagnose clinically. That’s where cervical screening comes in.
Cervical screening involves taking a sample of cells from the lining of the cervix, the purpose of which is to detect and remove precancerous cells early before they develop into cancer.
The sample of cells can be tested in at least one of four ways:
- By conventional cytology methods. The cervical sample is added to the surface of a microscope slide and cells are scanned for abnormalities by a skilled operator.
- Using liquid-based cytology. Cervical samples are collected in a liquid, which is filtered before a random sample of cells is added to a microscope slide. The slide can be scanned in a semi-automated way to increase sample throughput. These liquid-based samples can also be tested for high-risk HPV without the need for additional samples.
- Detection of HPV DNA and differentiation between high-risk and low-risk subtypes.
- VIA (Visual inspection with Acetic Acid) and now VIA augmented with AI interpreted image analysis following image capture post Acetic Acid flush, in low income settings.
Implementation of primary screening by detection of high-risk HPV DNA is being rolled out across the NHS Cervical Screening Programme. This screening approach has increased sensitivity of disease detection, a high negative predictive value and a low false negative rate (UKHSA).
Primary screening by detection of high-risk HPV DNA offers the following benefits:
- improvements in patient triage
- reduced frequency of cervical screening in HPV-negative patients
- reduced need for invasive colposcopy in low-risk patients
- targeted follow up of HPV-positive patients
Currently, many countries don’t have the resource or infrastructure to support reliable access to life-saving HPV vaccination, cervical screening, and appropriate treatment programmes. This needs to change if the objectives of the WHO Global Strategy are to be realised by 2050.
In terms of accessible cervical screening, detection, and differentiation of high-risk HPV subtypes at the point-of-need is a sustainable solution for those regions lacking high-quality centralised HPV DNA testing.
At QuantuMDx we believe that quality diagnostic testing should be available for everyone. Together with our partners Sansure, we are working to create equal access to HPV testing, making a difference to women’s health across the globe.
The following resources offer further information about cervical cancer:
- NHS (UK): Cervical Cancer – overview
- Cancer Research UK: Cervical Cancer – resources and support
- Centers for Disease Control and Prevention CDC (USA): Basic Information About Cervical Cancer
- National Cervical Cancer Coalition (USA): HPV and Cervical Cancer