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- Springer Journals
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- Copyright © The Author(s) 2023
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- 10.1186/s13027-023-00510-1
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Abstract
Background With HPV screening the specificity of screening positives has decreased, even with a cytological triage test. Increases in colposcopies and detection of benign or low-grade dysplasia are reported, not least in older women. These results highlight the necessity to find other triage tests in HPV screening strategies, so that women can be more accurately selected for colposcopy, thus minimizing the clinically irrelevant findings. Methods The study included 55- to 59-year-old women who exited the screening with normal cytology, but later in a follow-up test were positive for the HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 and had a cervical cone biopsy done. To model a screening situation with hrHPV-positive women, three different triage strategies, namely, cytology, genotyping and methylation, were performed. The study considered the effect of direct referral to colposcopy for HPV genotypes 16, 18, 31, 33, 45, 52 and 58, and methylation for FAM19A4 and hsa-mir124-2 and/or any form of abnormal cytology. Results Seven out of 49 women aged 55–59 years with hrHPV had a cone biopsy with high-grade squamous intraepithelial lesion. No triage method found all cases, and when comparing positive and negative predictive value and false negative rate, cytology showed better results than genotyping and methylation. Conclusion This study does not support a switch in triage strategies from cytology to hrHPV genotyping and methylation for women above 55 years of age yet, but demonstrates the need for more evidence on molecular triage strategies. Keywords Cervical screening, Cytology, DNA methylation, Genotyping, Human papillomavirus Introduction Where cervical screening programmes are implemented cervical cancer is reduced, since cervical cancer is largely preventable through local treatment of screen-detected cervical precursor lesions, cervical intraepithelial neopla- sia [1]. Cervical cancer is caused by a persistent infection of certain types of human papilloma virus (HPV) [2]. In *Correspondence: several countries a shift is ongoing where HPV testing is Lovisa Bergengren replacing cytology in the screening programmes, as this lovisa.bergengren@regionorebrolan.se 1 offers greater protection against cervical cancer [ 3, 4] as School of Health Sciences, Örebro University, Örebro, Sweden Department of Laboratory Medicine, Faculty of Medicine and Health, well as allowing longer screening intervals [5, 6]. Never- Örebro University, Örebro, Sweden theless, HPV is a common infection; estimates show that Department of Women’s Health, Faculty of Medicine and Health, Örebro about 10% [7, 8] of the female population at screening University, Örebro, Sweden © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Helenius et al. Infectious Agents and Cancer (2023) 18:31 Page 2 of 6 age are carriers of the virus, although exact figures differ dysplasia and cervical cancer [22] and could therefore between continents, age groups and populations. possibly be used for triaging in the screening. Methyla- The HPV test has high sensitivity but lower specific - tion of promoters in the human genes FAM19A4, which ity to detect high-grade squamous intraepithelial lesion perform immunomodulation and influence macrophage (HSIL), compared to cytology. This is due to the fact activity, and mir124-2, which act as a tumour suppressor, that HPV infections most often are transient, and only a have shown high reproducibility and good correlation to minor proportion become persistent and cause dyspla- CIN3 and cervical cancer [23, 24]. FAM19A4/miR124-2 sia and cancer [4, 9]. Studies show that some HPV geno- methylation analysis has also shown equal sensitivity for types are more common as an infection but not as likely CIN3 + and similar negative predictive value (NPV) as to cause cancer, while other genotypes are more rare cytology [25]. Bimolecular tests to identify hypermethyl- but dominate in cervical cancer development [10, 11]. ated FAM19A4 and mir-124-2 have been suggested as a To increase the specificity in the screening, the primary way to increase the specificity in a screening programme HPV test is followed by a secondary method for triag- with HPV [23, 24]. ing. Today, the most commonly used method of triage Studies on screening programmes with HPV as pri- is cytology. Increases in colposcopies and in detection mary test and different molecular strategies are few. of benign or low-grade dysplasia with HPV screening Older women in these studies need special attention, compared to cytology screening are reported from the since in this age cohort colposcopies are more often Netherlands among other countries, even though triage inconclusive, cytology is not as reliable and whether reac- is implemented [1, 12, 13]. This lower specificity of the tivation of persistent infections – so-called latent infec- HPV test dictates the necessity of use of other triage tests tions – develop in the same pattern as newly acquired in current HPV screening strategies, which can select infections is not clearly established. Methylation and women for colposcopy more accurately [5] and thus min- genotyping are objective methods compared to cytology. imize the clinically irrelevant findings. They show promising results in increasing the specificity Cytology as a triage method has shown limited value in HPV screening in the same way as cytology, and are due to its poor sensitivity, not least among the older age appealing, as they can be used on self-samples [25, 26]. cohorts in the screening [14, 15]. The presence of a group The aim of this study was to evaluate triage strategies of women with HPV-positive, cytology-negative tests in such as cytology, genotyping and FAM19A4/miR124-2, the screening presents a challenge, and so far, the retest- among HPV-positive women 55–59 years of age. ing intervals for this group is under careful consideration. Cytology is still not optimal, due to the risk of missing Material and method women with HSILs [16]. In addition, many cytological The study cohort used in this study has previously been HSILs will regress, as this has been shown to be a hetero- published [14]. Briefly, women between 55 and 59 years geneous group with many cases regressing spontaneously old who exited the cervical screening programme with without treatment [17]. Methods for triaging women in normal cytology 2012–2014, in total 2973 women, were the screening programme are in great need, not least invited to participate in that previous study. The bio - among women exiting the screening programme. banked liquid-based cytology samples [27] were analysed Genotyping of HPV could be an alternative triage for HPV with a DNA-based assay detecting 35 HPV gen- method in the screening programme, since there is a dif- otypes, both low-risk HPV (lrHPV) and hrHPV, n = 2031. ference in cancer risk between genotypes, where HPV 16 The current study includes women who participated in and 18 genotypes are the most common in cervical can- the former study and who were positive for the HPV gen- cer [18–20]. A long-term Swedish cohort study shows dif- otypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and ference in the oncogenic potential of several HPV types 68 in the follow-up test, and had a cervical cone biopsy [11], with HPV 16, 18, 31 and 33 having the highest risk done at the clinical follow-up. To model a real-life screen- of developing histologically confirmed HSIL (CIN 3 +), ing situation with hrHPV-positive women, simulation of followed by HPV 35, 45, 52 and 58 as intermediate risk three different triage strategies – cytology, genotyping and HPV 39, 51, 56, 59, 66 and 68 as lowest risk among and methylation – was performed. The study model con - high-risk HPV (hrHPV). With minor disparity, this has sidered the effect of direct referral to colposcopy for HPV been confirmed in a meta-analysis from 2020 [ 21]. Data genotypes 16, 18, 31, 33, 45, 52 and 58 [21], methylation from Sweden also show that HPV 16, 18, 31, 33, 45 and positives and/or any form of abnormal cytology. 52 were found in 83.6% of all cervical cancers in Sweden, This study was approved by the regional ethical com - and the rest of the genotypes included in screening added mittee board in Uppsala, Sweden (D-nr. 2014/121). only 2.6% of the cancers [10]. ThinPrep cytology slides were assessed by one experi - Hypermethylation of certain sites in the human enced and certified cytotechnician and classified accord - genome have been associated with high-grade cervical ing to the international Bethesda classification system Helenius et al. Infectious Agents and Cancer (2023) 18:31 Page 3 of 6 [28] with atypical squamous cells of undetermined sig- A total of seven HSILs were found in this mate- nificance (ASC-US); atypical squamous cells, cannot rial where no method alone detected all of the cases. exclude high-grade lesion (ASC-H); low-grade squamous Of these, only three were found by all triage methods. intraepithelial lesion (LSIL); HSIL; squamous cell carci- Among the 49 women with a positive HPV-test, nine noma; atypical glandular cells (AGC); adenocarcinoma LSILs were detected. Cytology detected none, methyla- in situ (AIS); or adenocarcinoma. Concerning histopa- tion six and with genotyping including HPV 16, 18, 31, thology, cone specimens were formalin fixed and paraf - 33, 45, 52 and 58 four cases were found. When includ- fin embedded, and thereafter slides were cut at 4 μm ing all 14 genotypes, all nine cases were detected and of and stained with haematoxylin and eosin and evaluated them two were methylation negative and all had normal according to present WHO classification [ 29], by either cytology. of two senior pathologists. DNA was extracted from liquid-based cytology sam- Discussion and conclusion ples using QiaAmp DNA mini kit (Qiagen, Hilden, To further develop the HPV-based cervical screening, Germany) [30]. HPV detection and genotyping was per- future steps could include vaginal self-sampling followed formed with CLART (Genomica, Madrid, Spain) accord- by molecular triage using broad genotyping and methyla- ing to the manufacturer’s instructions. CLART is a test tion for risk stratification. In an attempt to address this that detects 35 different HPV genotypes. question in a pilot strategy, we used a cohort of samples For methylation analysis the QIAsure Methylation including women 55–59 years of age in 2012–2014 who Test Kit (Qiagen, Hilden, Germany) detecting promoter exited the screening programme with a normal cytology hypermethylation of the genes FAM19A4 and hsa- and had a positive follow-up sample including HPV gen- mir124-2 was used. Extracted DNA was subjected to otypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and bisulphite treatment with EZ DNA Methylation-Goldkit 68, as well as a clinical follow up with histological cone (Zymo Research, Irvine, CA, USA). Detection of hyper- biopsy [14]. The aim of the study was to compare triage methylation in any of the two genes resulted in a positive with cytology, HPV genotyping and methylation on the test result. HPV positive samples in women age 55–59 years. Previous studies show that methylation is non-inferior Data and statistical analysis to cytology triage [25, 31], but some data also indicate Excel 2010 (Microsoft, Redmond, WA, USA) was used that methylation increases spontaneously with age [32, for data collection and evaluation. The performance was 33]; this must be further investigated before being intro- evaluated for three screening strategies: cytology, HPV duced in the screening for all age groups. For the age 16/18/31/33/45/51/58 genotyping and FAM 19A4/has- group in the current study, as well as in older cohorts, mir124-2 methylation. Positive predictive value (PPV) cytology has shown to be inferior in detecting HSIL [14, and negative predictive value (NPV) were calculated for 16, 34], and in this study, methylation as a triage test is comparison of the accuracy of the test results between no better than cytology. The NPV as well as the PPV for the triage methods. Further analysis of the false negative ≥ HSIL were lower in the methylation triage, 0.85 and rate (FNR) was done for comparing the triage methods’ 0.14, compared to the cytology triage, 0.95 and 0.42, likelihood of improperly indicating no presence of dys- respectively. This applies both for ≥ LSIL and for ≥ HSIL. plasia. Absolute HSIL risk was calculated for the different The NPV of hrHPV-positive, methylation-negative screening strategies. samples was 93% for ≥ CIN2 in the article by Bonde et al. [31], whereas in our material the NPV was only 85% for Results this group. Here, the sample size is, however, very lim- The study population consisted of 49 hrHPV-positive ited, but still the possibility that methylation is not equal women from a study of women exiting the screening pro- in different age groups could be a reason for the results gramme [14]. in our study [33]. It is suggested that DNA methylation Of the women included in this study protocol, 49 were varies due to a number of factors, including age and dis- hrHPV-positive for HPV 16, 18, 31, 33, 35, 39, 45, 51, ease status. Increased methylation in CpG sites, related 52, 56, 58, 59, 66 and/or 68 and had a cone biopsy done. to older age, have been shown in different species and The screening samples were genotyped and analysed for is thought to be an example of methylation drift. Other cytology and methylation (Fig. 1). sites may simultaneously be hypomethylated. Findings Abnormal cytology was found in 12/49 samples, gen- may also differ between tissue types and contributing otypes resulting in direct colposcopy were detected in factors to methylation changes may as well be found in 30/49 samples and methylation positivity was found in altered expression of enzymes responsible for adding 35/48 samples; one sample had too little material to anal- methylation groups (methyltransferases). The exact bio - yse after storage in the biobank (Fig. 1; Table 1). logical function of age-increased hypermethylation in Helenius et al. Infectious Agents and Cancer (2023) 18:31 Page 4 of 6 Fig. 1 Flowchart of study design and results of the triage methods cytology, genotyping and methylation Table 1 Results from triaging with cytology, genotyping and methylation Triage test hrHPV Triage test Normal LSIL NPV PPV FNR HSIL NPV PPV FNR pos, n pos, n histo, n histo, n ≥LSIL ≥LSIL ≥LSIL histo, n ≥HSIL ≥HSIL ≥HSIL Cytology 49 12 7 0 0.73 0.42 67 5 0.95 0.42 29 Genotyping 49 30 20 4 0.74 0.33 33 6 0.95 0.2 14 Methylation 48 35 24 6 0.69 0.31 27 5 0.85 0.14 29 Abbreviations: hrHPV, high-risk HPV; histo, histology; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; NPV, negative predictive value; PPV, positive predictive value; FNR, false negative rate. genes investigated here such asFAM19A4/miR124-2, continuous work on the subject. With that in mind, a involved in immunomodulation and tumour suppressor, limitation in this study is the few histological HSILs in is however yet to be determined [35]. this study population. This illustrates the need of studies Concerning genotyping in screening, a meta-analysis on triage strategies that discriminate different age groups was published in 2020 [19] with results showing high and individualize risk stratification, as well as the need to and moderate risk for 16, 18, 31, 33, 45, 52 and 58, which further investigate the use of combinations of different was used in the triage setting in our study. HPV positivity molecular tests. for other than these HPVs showed to be non-inferior to negative cytology in detecting HSIL in this current study Conclusion population with an NPV of 95%, but with a better FNR This study does not support a transition to extended than cytology. genotyping and DNA methylation with these methods at This study has not explored a risk stratification with a this time. Rather, it supports the need for further studies combination of different triage methods, due to the small with larger cohorts, other methylation methods as well as study population, but that would be the natural step in prospective studies that demonstrate real-life outcomes. Helenius et al. Infectious Agents and Cancer (2023) 18:31 Page 5 of 6 List of Abbreviations Gynaecologic Oncology (ESGO) and the European Federation of Colposcopy AGC Atypical glandular cells (EFC). Br J Cancer. 2020;123(4):510–7. AIS Adenocarcinoma in situ 6. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary ASC-H A typical squamous cells cannot exclude high-grade lesion cervical cancer screening with human papillomavirus: end of study results ASC-US Atypical squamous cells of undetermined significance from the ATHENA study using HPV as the first-line screening test. Gynecol FNR False negative rate Oncol. 2015;136(2):189–97. HPV Human papilloma virus 7. de Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L, Munoz N, et al. World - hrHPV High-risk human papilloma virus wide prevalence and genotype distribution of cervical human papillomavirus HSIL High-grade squamous intraepithelial lesion DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. lrHPV Low-risk human papilloma virus 2007;7(7):453–9. LSIL Low-grade squamous intraepithelial lesion 8. Bruni L, Diaz M, Castellsague X, Ferrer E, Bosch FX, de Sanjose S. 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Meth- ylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: a large european multicenter study. Publisher’s Note Int J Cancer. 2021;148(2):396–405. Springer Nature remains neutral with regard to jurisdictional claims in 32. Luttmer R, De Strooper LM, Berkhof J, Snijders PJ, Dijkstra MG, Uijterwaal published maps and institutional affiliations. MH, et al. Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer
Journal
Infectious Agents and Cancer – Springer Journals
Published: May 23, 2023
Keywords: Cervical screening; Cytology; DNA methylation; Genotyping; Human papillomavirus