Which of the high-risk HPV types except HPV16 and HPV18 are more determinant for ≥CIN2 pathology?

Abstract

AimOur study aimed to analyze the single “other high-risk HPV type” and its relationship to the final pathology results.MethodsThe study was conducted retrospectively, and data was collected from a specialized outpatient clinic for gynecologic oncology colposcopy unit. We analyzed data from 3546 patients who tested high-risk HPV positive and underwent colposcopic examination from September 2019 to December 2022. The study included 333 patients, each with a single “other high-risk HPV type” positive.ResultsA total of 333 patients with a median age of 43 years (range, 22–66 years) were analysed. In study cohort 68 (20.4%) patients were HPV 31, 19 (5.7%) patients were HPV 33, 19 (5.7%) patients were HPV 35, 24 (7.2%) patients were HPV 39, 22 (6.6%) patients were HPV 45, 39 (11.7%) patients were HPV 51, 40 (12%) patients were HPV 52, 41 (12.3%) patients were HPV 56, 15 (4.5%) patients were HPV 58, 18 (5.4%) patients were HPV 59, and 28 (8.4%) patients were HPV 68. Final pathologic results were benign in 168 (50.5%) patients, LSIL in 139 (41.7%) patients, HSIL (CIN 2) in 16 (4.8%) patients, HSIL (CIN 3) in 8 (2.4%) patients, HSIL (undefined) in 1 (0.3%) patient, and cancer in 1 (0.3%) patient. There was no statistically significant correlation observed between the type of HPV and the presence of a ≥CIN2 lesion. Patients who tested positive for the single HPV 33 type had a higher prevalence of ≥CIN2 lesions.ConclusionIn summary, other high-risk HPV types can serve as a criterion for referring high-risk HPV positive patients to colposcopy. Patients with HPV 33 positive test results need to be managed more carefully.

Keywords

Introduction

According to GLOBOCAN 2022, cervical cancer is the most common gynecologic cancer in women worldwide.¹ The vast majority of cervical cancer cases are linked to long-lasting infection by one of 13 high-risk human papillomavirus (HPV) genotypes: HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.^2-4 The intermediate-risk group consists of HPV26, 66, 53, 73, and 82.⁵ Types other than HPV16 and 18 are defined as “other high-risk HPV types.”
The use of primary HPV testing for cervical cancer screening is being increasingly accepted as the preferred method in many countries.⁵ Testing for HPV has a higher sensitivity for identifying cervical intraepithelial neoplasia (CIN) grade 2–3 and above lesions.^6-9 Since a negative HPV test provides greater certainty that CIN3 is not present, it allows for a longer interval of five years between routine screenings compared to the currently recommended three-year interval for cytology-based screening alone.^10-11
Although the majority of cases classified as ≥CIN2 and ≥CIN3 are linked to an HPV infection, it is important to note that most HPV infections are temporary and eliminated without progressing to ≥CIN2.¹² Therefore, it is neither advantageous nor practical to refer all women who test positive for HPV to immediate colposcopy. Instead, HPV primary screening should be accompanied by an efficient triage system to accurately identify those individuals who are most likely to develop high-grade cervical disease.⁵
Identifying HPV16 and 18, which are responsible for 60–70% of cervical cancer cases, can enhance the assessment of risk for severe cervical disease and provide a valid reason for performing colposcopy.¹³ Traditionally, when any of the other high-risk HPV genotypes are detected, cytology triage is used to manage the positive high-risk HPV result.^13-14 A limited number of studies have classified other high-risk HPV types and included the final pathology results of these types. The present study analyzes data from patients with a single “other high-risk” type of HPV and examines its relationship to the final pathology results.

Materials and Methods

The study was conducted retrospectively, and data were collected from the colposcopy unit of a specialized outpatient clinic for gynecologic oncology. We analyzed data from 3,546 patients who tested positive for high-risk HPV and underwent colposcopic examination between September 2019 and December 2022. The study ultimately included 333 patients who were positive for a single other high-risk HPV type. It excluded individuals who were infected with HPV16 or HPV18, pregnant women, individuals infected with intermediate or low-risk types of HPV, and individuals infected with more than one other high-risk HPV type. The research protocol was approved by the clinical ethics committee of Ankara Bilkent City Hospital (Approval number: 2-24-308).
In our hospital, we use liquid-based systems for cytology and testing for HPV (Max-prep® system, Corebiotech Co., Ltd., Korea; NOVAprep® system, Novaprep, Inc., Russia). For the extraction of HPV DNA, the QIAsymphony® Digital Signal Processing Virus/Pathogen Midi kit was utilized. The obtained DNA was subsequently identified and categorized using the QIAscreen HPV PCR kit (Qiagen Inc., Germany).
Conization was performed on patients with high-grade squamous intraepithelial lesion (HSIL), microinvasive cancer, adenocarcinoma in situ (AIS) (as detected by colposcopic biopsy), or a discrepancy between biopsy and clinical evaluation. The highest-grade lesion from smear, cervical biopsy, conization, or hysterectomy was considered the final pathology result. Table 1 shows the process for defining the final pathology. The final pathology was classified as ≥CIN2; CIN2/CIN3, adenocarcinoma in situ, microinvasive cancer, or cervical cancer. All colposcopic exams and conization procedures were performed by gynecologic oncologists, and the surgical specimens were assessed by gynecologic pathologists with expertise in the profession.Ethical ApprovalThis study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 26.06.2024, Decision No: 308).Statistical AnalysisThe statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS version 20.0, IBM, Chicago, IL, USA). Descriptive values are represented by the arithmetic mean plus or minus the standard deviation, the median, and the percentage.Reporting GuidelinesThis study was reported according to the STROBE guidelines.

Results

Data were analyzed from 333 patients with a median age of 43 years (range 22–66 years). The study cohort consisted of 68 (20.4%) patients with HPV31, 19 (5.7%) patients with HPV33, 19 (5.7%) patients with HPV35, 24 (7.2%) patients with HPV39, 22 (6.6%) patients with HPV45, 39 (11.7%) patients with HPV51, 40 (12%) patients with HPV52, 41 (12.3%) patients with HPV56, 15 (4.5%) patients with HPV58, 18 (5.4%) patients with HPV59, and 28 (8.4%) patients with HPV68. The final pathologic results were benign in 168 (50.5%) cases, low-grade squamous intraepithelial lesion (LSIL) in 139 (41.7%) cases, HSIL (CIN 2) in 16 (4.8%) cases, HSIL (CIN 3) in 8 (2.4%) cases, HSIL (undefined) in 1 (0.3%) case, and cancer in 1 (0.3%) case. Table 2 contains information on patient ages, HPV types, and final pathologic results.
Table 3 presents the relationship between the HPV type and the final pathologic results. No statistically significant correlation was observed between HPV type and the presence of a ≥CIN2 lesion. ≥CIN2 lesions were present in 5 (7.4%) patients with HPV31, 4 (21.1%) patients with HPV33, 2 (10.5%) patients with HPV35, 4 (16.7%) patients with HPV39, 1 (4.5%) patient with HPV45, 2 (5.1%) patients with HPV51, 4 (10%) patients with HPV52, 1 (2.4%) patient with HPV56, 2 (13.3%) patients with HPV58, and 1 (3.6%) patient with HPV68. Notably, none of the patients who were positive for HPV59 had a ≥CIN2 lesion.
The smear result of the patient diagnosed with cervical cancer showed atypical squamous cells undetermined significance (ASCUS) and HPV31 positivity. The result of the patient’s colposcopic biopsy was squamous cell carcinoma.

Discussion

In our study, a benign final pathology result was the most common, while 7.8% of the patients had ≥CIN2 lesions. No statistically significant correlation was found between HPV type and the presence of a ≥CIN2 lesion. However, there was a higher prevalence of ≥CIN2 lesions among patients who tested positive for the single HPV33 type.
In a study by Zhao et al., which included 1,274 patients who tested positive for high-risk HPV, the distribution of single infections of other high-risk HPV types was as follows: 6.83% HPV31, 11.79% HPV33, 1.10% HPV35, 6.43% HPV39, 2.10% HPV45, 8.02% HPV51, 15.26% HPV52, 9.05% HPV56, 13.18% HPV58, 2.58% HPV59, and 1.44% HPV68.¹⁵ The same study examined the number of patients who were positive for a single “other” type of HPV who also had a ≥CIN2 lesion. According to the results, these lesions were present in 12.50% of the patients with HPV33, 3.13% of the patients with HPV35, 3.13% of the patients with HPV45, 6.62% of the patients with HPV51, 6.25% of the patients with HPV52, 3.13% of the patients with HPV56, 9.90% of the patients with HPV58, and 3.13% of the patients with HPV59.¹⁵
A study by Wheeler et al., which included 47,541 HPV-positive women, similarly examined the prevalence of ≥CIN2 lesions among patients with a single “other” type of HPV. The study found that these lesions were present in 10.4% of the HPV31 cases, 16.1% of the HPV33 cases, 4.4% of the HPV35 cases, 2.0% of the HPV39 cases, 3.8% of the HPV45 cases, 2.7% of the HPV51 cases, 3.3% of the HPV52 cases, 0.8% of the HPV56 cases, 0.6% of the HPV58 cases, 1.9% of the HPV59 cases, and 0.6% of the HPV68 cases.¹⁶
In our study, the prevalence of ≥CIN2 lesions in patients who were positive for a single “other” type of HPV was as follows: 7.4% for HPV31, 21.1% for HPV33, 10.5% for HPV35, 16.7% for HPV39, 4.5% for HPV45, 5.1% for HPV51, 10.0% for HPV52, 2.4% for HPV56, and 13.3% for HPV58. Similarly to Zhao et al. and Wheeler et al., we found that ≥CIN2 lesions were most common in patients with single-type HPV33 in our study.

Limitations

This study has some limitations. First, the retrospective study design is our study’s most significant limitation. Second, the presented results are not based on population-based screening and therefore do not reflect the country as a whole. The strengths of our study are that all colposcopy and excisional procedures were performed by gynecological oncology specialists, the same clinic followed up with the patients, and the patient samples were examined by pathologists who have expertise in gynecological pathology.

Conclusion

In summary, testing positive for another high-risk HPV type can serve as a criterion for referring patients who test positive for high-risk HPV to colposcopy. Patients who test positive for HPV33 need to be managed more carefully. It is necessary for further studies to elucidate the association between high-risk HPV infections and long-term risk of cervical lesions.

Declarations

Abbreviations

References

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