JAMA: Over 90% of Cervical Cancer Can Be Prevented!

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JAMA: Over 90% of Cervical Cancer Can Be Prevented!

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JAMA: Over 90% of Cervical Cancer Can Be Prevented! Highlights of 6 Clinical Advances in Cervical Cancer Screening.

Cervical cancer is one of the common malignant tumors in gynecology, with an incidence second only to breast cancer.

The median age of onset for cervical cancer patients is 51 years, with the highest prevalence between the ages of 40 and 50, and another peak appearing between 60 and 70 years.

In recent years, the average age of onset has gradually decreased, indicating a trend towards younger ages.

In 2020, the World Health Organization (WHO) released the “Global Strategy to Accelerate the Elimination of Cervical Cancer,” which received responses and support from multiple countries worldwide.

Recently, the Journal of the American Medical Association (JAMA) published a review of cervical cancer screening, detailing the pathological mechanisms of human papillomavirus (HPV) in cervical cancer, high-risk factors for HPV infection leading to cancer, HPV vaccination, screening recommendations, handling of abnormal results, treatment, and prognosis of cervical cancer. The aim is to provide reference for clinical prevention of cervical cancer.

HPV and Cervical Cancer

It is now clear that persistent infection with high-risk HPV is a necessary factor in the occurrence of cervical cancer and precancerous lesions. The intersection of squamous and columnar epithelia in the cervix is particularly susceptible to the carcinogenic effects of HPV, and cervical cancer lesions usually occur at this junction. In addition, new evidence suggests that reserve cells are prone to malignancy and serve as a “latent site” for HPV infection.

HPV Evolution and Carcinogenicity

HPV is a large virus “family” that can be classified into genera, species, types, variant lineages, and sublineages based on genetic differences. The major cause of cervical cancer is alpha-HPV, which is further divided into species such as alpha-1, alpha-2, …, alpha-14. Among these, alpha-9, alpha-7, alpha-5, and alpha-6 species contain carcinogenic HPV genotypes, known as “high-risk types.” HPV-16 in the alpha-9 species is the most carcinogenic, being associated with over 60% of cervical squamous cell carcinoma, adenocarcinoma, oropharyngeal cancer, and other genital cancers. Other alpha-9 species’ HPV genotypes have a moderate risk of carcinogenesis. HPV-18 and HPV-45 in the alpha-7 species are associated with squamous cell carcinoma and adenocarcinoma.

The risk of carcinogenesis is lower for HPV-39, HPV-59, HPV-68 in the alpha-7 species, HPV-51 in the alpha-5 species, and HPV-56 in the alpha-6 species. Low-risk HPV genotypes are not associated with an increased risk of cervical cancer, and their detection results have no significant value in cancer screening and prevention.

HPV Infection Active Phase and Latent Phase

Any new HPV infection, regardless of the genotype, is considered an active HPV infection capable of producing new virus copies. During this period, the cervix may show no or slight changes, and pathological examination of cervical cells may reveal suspicious or mild abnormalities, but generally no precancerous lesions. Due to the action of the immune system and other factors, most infections will naturally disappear within 12 to 24 months, with 80% of female HPV infections being transient. Although research suggests that immunity can be acquired after natural infection, the understanding of this aspect is limited. However, it is clear that immunity obtained through HPV vaccination can last for at least 15 years.

HPV infection can persist in basal cervical cells and replicate slowly, a process referred to as “latent infection.” During latent infection, HPV testing results for cervical-vaginal specimens are negative, and the risk of cancer is lowest.

The recurrence rate of HPV infection within 5 years is as high as 15%, so a positive HPV test result can indicate either a new infection or a recurrence of an old infection. However, whether it is a new or recurrent infection, the risk of progressing to precancerous lesions within 5 years is approximately 3%, making it unnecessary to distinguish between the two.

Persistent HPV Infection and Progression to Precancerous Lesions

Persistent HPV infection is a necessary factor in the occurrence of cervical cancer and precancerous lesions. “Precancerous lesions” refer to the changes from infected cells undergoing replicative infection to clonal growth. Currently, several biomarkers related to precancerous lesions have been identified, such as viral and host DNA methylation observed during the transition from replicative infection to cancer. The U.S. Food and Drug Administration (FDA) has approved a technique for detecting cell transformation—the p16/Ki67 dual-staining technique. The co-expression of p16 and Ki67 indicates that HPV infection can cause cell transformation.

Invasion: Squamous Cell Carcinoma and Adenocarcinoma

The HPV genotype determines the likelihood of progression to precancerous lesions and cancer after HPV infection, with HPV-16 having the highest risk of carcinogenesis. Adenocarcinoma is an endocervical glandular cell carcinoma, and almost all adenocarcinomas are caused by HPV-16, HPV-18, and HPV-45. The pathophysiology of adenocarcinoma is different from that of squamous cell carcinoma, which originates from the squamous cells of the surface epithelium.

Due to the possibility of missing adenocarcinoma precancerous lesions in screening and colposcopy, the detection rate and treatment rate of adenocarcinoma precancerous lesions are lower than those of squamous cell carcinoma. In terms of screening and preventing cancer, the effectiveness is not as good as squamous cell carcinoma.

High-Risk Factors for HPV Infection Leading to Carcinogenesis

In the course of their lifetime, women have a probability of over 70% of contracting high-risk HPV, but only less than 10% of women will eventually develop cervical cancer or cervical intraepithelial neoplasia. This is because, in addition to persistent high-risk HPV infection, other factors need to be involved and act together to eventually cause cervical cancer. The risk factors for cervical cancer can be divided into two categories: 1) biological factors, namely persistent high-risk HPV infection; 2) external behavioral risk factors.

Since HPV is mainly transmitted sexually, factors that may increase the risk of HPV infection, such as poor sexual hygiene and multiple sexual partners, may increase the risk of HPV infection, thereby increasing the risk of cervical cancer. According to statistics, most sexually active individuals will have an HPV infection in their lifetime, but the specific percentage is not clear.

The “Cervical Cancer Diagnosis and Treatment Guidelines (2022 Edition)” pointed out that factors such as menstrual and pregnancy-related factors, smoking, oral contraceptives, autoimmune diseases, or long-term immunosuppressive agents, malnutrition/nutritional imbalances, etc., may also increase the risk of carcinogenesis.

HPV Vaccination

Vaccination against HPV helps prevent HPV infection, precancerous lesions, and cancer. Current guidelines recommend that all children, regardless of gender, can receive the vaccine at the age of 9, with a 6-12 month interval for 2 doses of the HPV vaccine before the age of 13. Individuals aged 13 to 26 who have not been vaccinated should receive the vaccine. For individuals aged 15 and above starting the vaccine, it is recommended to receive 3 doses.

The vaccine primarily works as a preventive measure, so the effectiveness of the vaccine decreases after the first sexual encounter. Most studies show that the greatest benefits of vaccination are obtained before the age of 14, and with increasing age, the effectiveness of vaccination gradually decreases. Individuals aged 27 to 45 are advised to make joint decisions with clinical physicians before getting vaccinated.

Cervical Cancer Screening Recommendations

Effective screening and treatment of precancerous lesions can reduce the lifetime risk of cervical cancer to below 0.5%. It is recommended for asymptomatic individuals to undergo regular screening to diagnose and treat precancerous lesions early, preventing the occurrence of cervical cancer. It is important to note that screening is only applicable to asymptomatic individuals. If symptoms of cervical cancer, such as irregular bleeding, pain, or vaginal discharge, are present, relevant assessments, including pelvic examination and cervical cytology, should be conducted.

Screening Considerations

Effective cervical cancer screening includes the following steps:

1. Evaluate the need for screening, and only conduct screening when there are indications.

2. Use HPV testing (with or without cytology) for screening. The sensitivity of cytology for detecting precancerous lesions is 50%-70%, while HPV testing has a sensitivity of over 90%. Therefore, compared to cytology alone, a negative HPV test result more effectively indicates the absence of precancerous lesions. If subsequent HPV screening results are consistently negative, the risk of cancer continues to decrease. Additionally, 97% of precancerous lesion patients have positive HPV test results. From this perspective, the additional benefits of simultaneous HPV and cytology testing are limited.

Screening Ages

The risk of developing cervical cancer begins to increase around the age of 30. Therefore, individuals aged 25 to 65 with a cervix should undergo screening at least every 5 years.

The U.S. Preventive Services Task Force recommends: individuals aged 21 to 29 should undergo screening using cytology alone; individuals aged 30 to 65 can undergo cytology alone or cytology combined with HPV testing.

The latest guidelines from the American Cancer Society recommend: individuals aged 25 to 65 should undergo HPV testing alone every 5 years.

Monitoring or High-Risk Populations

Typically, about 20% of individuals in the general population screened belong to the high-risk screening population. They have a history of abnormal results, a history of precancerous lesions, or use immunosuppressive agents and need to be screened every 1 to 3 years.

Stopping Screening

Screening is not recommended for the following asymptomatic patients: 1) age <21; 2) those without a cervix (e.g., after hysterectomy), unless previously diagnosed with cervical cancer or precancerous lesions; 3) age >65 who meet the criteria for stopping screening.

What to Do if Cervical Cancer Screening Results Are Abnormal?

Cervical intraepithelial lesions include:

• Low-grade squamous intraepithelial lesion (LSIL), i.e., cervical intraepithelial neoplasia grade 1 (CIN1).
• High-grade squamous intraepithelial lesion (HSIL), including cervical intraepithelial neoplasia grades 2 and 3 (CIN2 and CIN3).
• High-grade glandular intraepithelial lesion (HG-CGIN), also known as adenocarcinoma in situ (AIS).

HSIL and AIS are precancerous lesions of cervical cancer. Risk assessment of precancerous lesions helps clinical doctors determine the next management strategy for patients with current or past abnormal screening results. Following the “equal risk, equal management” principle, the American Society for Colposcopy and Cervical Pathology (ASCCP) recommends using CIN3 and higher lesion risk as the main clinical endpoint to determine whether an individual needs colposcopy or can safely undergo repeat HPV testing or combined testing within 1, 3, or 5 years.

In addition, for patients with abnormal screening results, additional evaluations such as colposcopy and pathological biopsy may be required to clarify precancerous lesions and take timely treatment measures to prevent cancer development.

Cervical Cancer Treatment and Prognosis

The treatment of precancerous lesions involves eliminating lesions detected during colposcopy, and it may also be necessary to remove or eliminate the entire junction between squamous and columnar epithelia to eliminate most of the HPV-infected cells that have undergone precancerous transformation, reducing the risk of cervical cancer. Treatment methods include excision, ablation, etc.

After excision or ablation, the short-term recurrence risks of CIN3 at 6 months are 1.6% and 2.9%, respectively, and at 12 months, the risks increase to 3.2% and 7.2%. In the decades following the treatment of precancerous lesions, the risk of invasive cancer remains elevated, especially in patients aged 50 and older. Therefore, guidelines recommend screening every 3 years until the age of 65, and at least 25 years after treatment, as long as the patient is healthy, they can choose to continue treatment.

Conclusion

In the United States, approximately 100,000 people undergo treatment for precancerous lesions of cervical cancer each year to prevent the occurrence of cervical cancer. Individuals with a cervix should undergo HPV testing, and if the result is positive, cytology testing and clarification of the HPV genotype are needed to assess the risk of precancerous lesions and determine whether colposcopy and treatment are needed. Vaccination against HPV during adolescence helps prevent over 90% of precancerous lesions and cancer of the cervix from occurring.

JAMA: Over 90% of Cervical Cancer Can Be Prevented!

References:

[1]Perkins RB, Wentzensen N, Guido RS, et al. Cervical Cancer Screening: A Review. JAMA. 2023 Aug 8;330(6):547-558. doi: 10.1001/jama.2023.13174. PMID: 37552298.

(source:internet, reference only)

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