Cervical Cancer Causes

Overview

Cervical cancer is defined as cancer that starts in the cells of the cervix, the lower and narrow part of the uterus. Cervical cancer typically develops slowly due to dysplasia - the appearance of abnormal cells in the cervical tissue - before cancer emerges in the cervix. If not removed or destroyed, these abnormal cells become cancerous cells, growing and spreading deeper into the cervix. 

There are two main types of cervical cancer:

  • Squamous cell carcinoma (SCC) - SCC arises from squamous cells in the ectocervix, the outer part of the cervix. SCC is the most common type of cervical cancer, accounting for up to 90% of cases 
  • Adenocarcinoma - Adenocarcinoma develops in the glandular cells of the endocervix, the inner part of the cervix connecting the vagina to the uterus

Very rarely, cervical cancer may have features of both SCC and adenocarcinoma and is referred to as mixed carcinoma or adenosquamous carcinoma

Cervical cancer can arise in anyone with a cervix and mostly occurs in people under the age of 45. Globally, cervical cancer is the fourth most common cancer in individuals assigned female at birth (AFAB). Its incidence and mortality rate is highest in low- and middle-income countries, such as countries in sub-Saharan Africa, South-East Asia, and Central America. This is due to limited access to preventative measures and healthcare services in those countries.

Cervical cancer is most common in the younger population. In the UK, most cervical cancer diagnoses are in individuals AFAB between 30-34 years old.

Understanding the causes of cervical cancer is vital in reducing its incidence and improving treatment outcomes. This article will explore the primary causes of cervical cancer, additional risk factors, and common preventative measures that can be adopted. 

Causes of cervical cancer

Human papillomavirus (HPV) infection

The human papillomavirus (HPV) infection is the primary cause of cervical cancer worldwide, accounting for approximately 99.7% of cases.1 HPV is classified as a deoxyribonucleic acid (DNA) virus that infects the mucocutaneous epithelium with infections causing genital warts or anogenital lesions in the cervix, vulva, vagina and anus.2 

HPV can also affect various parts of the body, with over 100 strains potentially causing warts on your face, hands and feet. As a common viral infection of the reproductive system, HPV has an estimated 30 strains targeting the genital area and approximately 15 strains causing cervical cancer.1 

HPV is a sexually transmitted infection (STI) with a common misconception being that transmission strictly involves penetrative intercourse. However, skin-to-skin contact during sexual intercourse is a well-established method of transmission, including any contact of the genital areas and vaginal, anal or oral intercourse.1 Due to this, almost 70% of sexually active people will be infected on at least one occasion by HPV during their lifetime, without symptoms. However, most HPV infections are cleared by the body’s immune system within a year or two and therefore do not pose a cause for concern for most people.

HPV can be categorised into two types based on its association with cancer3

In some cases, HPV infections are not successfully controlled by the immune system and can last for years following persistent HR-HPV infection. 

HPV can progress into cancer through infection and viral integration with the DNA of the host cell Persistent HR-HPV leads to a disrupted cell cycle, accumulation of genetic damage, and uncontrolled cell division.1 This causes normal cells to develop into abnormal cancerous cells. In cervical cancer, certain strains are attributed to causing cervical dysplasia and lesions. These include HR-HPV types 16 and 18.3

HPV risk factors

Developing HPV is common between the ages of 18-30. On the other hand, developing cervical cancer is most common in those over the age of 35, indicating the slow progression from infection, which must occur at a young age, to cancer.3 Studies have shown that it typically takes 15-20 years for abnormal cells to become cancerous.

Factors that increase your risk of becoming infected with HPV and thus cervical cancer can include1:

  • Having multiple sexual partners at any time
  • Having a partner who previously had multiple sexual partners
  • Having a partner with cervical or penile cancer
  • Sexual activity at an early age
  • A history of other STIs
  • Lack of use of barrier contraception

There is no treatment for HPV, highlighting the need to prevent its risk factors.

Cervical cancer risk factors 

A weakened immune system

Those with a weakened immune system are at a higher risk of developing cervical cancer. This is due to the body’s inability to fight off an HPV infection, causing it to persist and progress into cancer in those who are immunocompromised.1 Immunosuppression that can lead to cervical cancer may be caused by: 

  • Suffering from a disease, such as the human immunodeficiency virus (HIV) weakens your immune system. HIV infection is a major risk factor in acquiring HPV and the development of precancerous lesions, which progress to cervical cancer. Persistent infection with HPV is associated with an advanced HIV infection due to a weakened immune system, and individuals AFAB are three times more likely to be diagnosed with cervical cancer4
  • Medications can suppress an immune response. Immunosuppressive drugs cause the immune system to detect and destroy cancer cells or fight off cancer-causing infections less efficiently. These medications may be taken by individuals who have undergone an organ transplant to prevent organ rejection, to treat autoimmune diseases, or treat cancer1

Smoking 

Both active and passive smoking of tobacco increases the risk of developing precancerous lesions and therefore cervical cancer. Cigarettes contain high concentrations of nicotine and other cancer-causing substances, called carcinogens, that may damage the genes of cervical cells and lead to pre-cancer.5 

Smoking weakens the immune system and research suggests that tobacco found in cigarettes causes mutations in the cervical cells which can lead to cancer.1 A suppressed immune system means that people are more likely to be affected by HPV as the virus cannot be fought off by an immune response.

The risk of developing cervical cancer increases the more a person smokes or is exposed to passive smoking.

Oral-contraceptives 

Long-term use of oral contraceptives, particularly combined oral contraceptives (COC), might increase the risk of developing cervical cancer. This is because they can alter the susceptibility of cervical cells to persistent infection with HR-HPV. 

The exact mechanism by which this occurs/happens as to how this happens is not clearly understood. However, some studies have shown that the interaction between synthetic hormones in COC, such as oestrogen and progestogens, and hormone receptors in cervical tissue influence HPV infection. This allows viral DNA to transform into abnormal cells and induce cancer. They have also demonstrated a higher risk of cervical lesions with the use of COC in those with HR-HPV, indicating the interaction between these contraceptives and HPV infection.6

Birth history

Those with a high parity (number of full-term pregnancies) have an increased risk of developing cervical cancer compared to those with a low parity.7 High parity is defined as having 5 or more full-term pregnancies, whereas low parity is classified as less than 5 pregnancies. 

Possible reasons for this are linked to: 

  • Local tissue damage occurs during vaginal delivery or cellular oxidative stress which increases the likelihood of DNA damage and HPV integration into cells. This results in a high detection rate of HPV in pregnant people1,7
  • Increased hormone levels and impaired immune response of pregnancies1 

Prevention of cervical cancer

Cervical cancer cannot always be prevented. However, adopting preventative measures is vital in lowering your chances of developing cervical cancer and ensuring a decreased prevalence worldwide. 

Preventative measures can include: 

  • HPV vaccine - Vaccination against HPV infection is a major prevention strategy against cervical cancer. In the UK, all children aged 12-13 are offered the Gardasil 9 HPV vaccine on the NHS prior to their first sexual encounter8
  • Cervical cancer screening - Anyone with a cervix between 25-64 years of age is eligible for regular cervical screening to check the health of the cervix. During the test, a sample is taken to test for HR-HPV; if it is found to be present, it is further examined for abnormal changes to cells in the cervix. This allows for treatment before the cells turn cancerous1,8 
  • Use of barrier protection can prevent HPV transmission. However, it is important to note that barrier protection does not completely prevent HPV exposure 
  • Quit smoking 
  • Eating a balanced diet to support and strengthen your immune system to fight off infections
  • Education about safe sexual practice in schools, including the importance of delayed onset of sexual activity, use of barrier contraception and the implications of smoking1

Summary

  • The primary cause of cervical cancer is sexually transmitted HPV infection, attributed to 99.7% of cervical cancer cases
  • HPV is transmitted via skin-to-skin contact during sexual intercourse and most sexually active people will be infected during their lifetime, without any symptoms
  • HPV progresses into cancer by viral integration of cells, leading to the accumulation of genetic damage and uncontrolled cell division. This causes normal cells in the cervix to develop into cancerous cells 
  • Having multiple sexual partners, sexual activity at an early age, lack of barrier contraception and a history of other STIs can increase your risk of developing HPV
  • Additional factors that can cause cervical cancer include having a weakened immune system, smoking, using oral contraceptives and high-parity
  • Timely preventative measures should be taken, such as the HPV vaccine, regular cervical screening, use of barrier contraception and quitting smoking

References

  1. OKUNADE KS. Human Papillomavirus and Cervical Cancer. J Obstet Gynaecol [Internet]. 2020 [cited 2024 May 28]; 40(5):602–8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062568/
  2. Graham SV. The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review. Clinical Science [Internet]. 2017 [cited 2024 May 28]; 131(17):2201–21. Available from: https://portlandpress.com/clinsci/article/131/17/2201/71573/The-human-papillomavirus-replication-cycle-and-its
  3. Oyouni AAA. Human papillomavirus in cancer: Infection, disease transmission, and progress in vaccines. Journal of Infection and Public Health [Internet]. 2023 [cited 2024 May 28]; 16(4):626–31. Available from: https://www.sciencedirect.com/science/article/pii/S1876034123000564
  4. Trejo MJ, Soliman AS, Chen Y, Kalima M, Chuba A, Chama E, et al. Effects of HIV infection on metastatic cervical cancer and age at diagnosis among patients in Lusaka, Zambia. Int J Gynaecol Obstet [Internet]. 2022 [cited 2024 May 29]; 156(3):521–8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669036/
  5. Castle PE. How Does Tobacco Smoke Contribute to Cervical Carcinogenesis? J Virol [Internet]. 2008 [cited 2024 May 28]; 82(12):6084–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395121/
  6. Bovo AC, Pedrão PG, Guimarães YM, Godoy LR, Resende JCP, Longatto-Filho A, et al. Combined Oral Contraceptive Use and the Risk of Cervical Cancer: Literature Review. Rev Bras Ginecol Obstet [Internet]. 2023 [cited 2024 May 29]; 45(12):e818–24. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10748515/
  7. Tekalegn Y, Sahiledengle B, Woldeyohannes D, Atlaw D, Degno S, Desta F, et al. High parity is associated with increased risk of cervical cancer: Systematic review and meta-analysis of case–control studies. Womens Health (Lond) [Internet]. 2022 [cited 2024 May 29]; 18:17455065221075904. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819811/
  8. Sundström K, Elfström KM. Advances in cervical cancer prevention: Efficacy, effectiveness, elimination? PLoS Med [Internet]. 2020 [cited 2024 May 29]; 17(1):e1003035. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986699/.

Reema Devlia

Master of Science - MSc Pharmaceutical Technology, King’s College London

Reema is a MSc Pharmaceutical Technology and BSc Chemistry graduate with an in-depth knowledge of solid and liquid dosage form design and regulatory affairs, alongside a proven strong background in scientific writing, literature searches and reviews. She also has experience in pharmaceutical sales, where she provided technical information relating to pharmaceutical ingredients and fulfilled regulatory requests to support customer end use and strengthen client relations.

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