High-risk Human Papillomavirus Testing for Triage of Women with Previous Cytological Abnormalities from the Vale do Ribeira Region

Abstract

Objective To evaluate the performance of the hybrid capture 2 (HC2) high-risk papillomavirus (hrHPV) assay and cytological test in women with previous abnormalities, to detect cervical intraepithelial neoplasia grade 2 or worse (≥ CIN 2).

Methods A cytological test and HC2 (Qiagen, Gaithersburg, Maryland, EUA) for hrHPV were conducted in 359 liquid-based (Sure Path, Becton Dickinson, TriPath Imaging, Burlington, NC, USA) samples collected from women from the Vale do Ribeira Region, during July 2013 and September 2015 with previous cytology classified as atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions (ASC-H), and atypical glandular cells (AGC). The histopathological examination was conducted in 179 women. The performance evaluations were calculated using the “exact” Clopper-Pearson 95% confidence interval (CI) test by MEDCALC (Medcalc Software Ltd, Ostend, Belgium).

Results The ≥ CIN 2 frequency was 11.7% (21/179). The HC2 for hrHPV and repeat cytology to detect ≥ CIN 2 obtained, respectively, a sensitivity of 90.5% (95%CI = 69.6–98.8) and 90.5%, (95%CI = 69.6–98.8), a specificity of 65.8% (95% CI = 57.9–73.2) and 43.7% (95%CI = 35.8–51.8), a positive predictive value of 26.0% (95% CI = 21.4–31.3) and 17.6%, (95%CI = 14.9–20.6), and a negative predictive value of 98.1% (95%CI = 93.3–99.5) and 97.2% (95% CI = 90.1–99.2).

Conclusion Hybrid capture 2 for hrHPV improves the performance of the detection of ≥ CIN 2, without compromising sensitivity, and provides a greater safety margin to return to the triennial screening of women undergoing follow-up due to previous abnormalities, without underlying ≥ CIN 2.

Resumo

Objetivo Avaliar o desempenho da captura híbrida 2 (CH2) para papilomavírus humano de alto risco (HPVar) e repetição do exame citopatológico em mulheres com anormalidades em citologia anterior, para detectar neoplasia intraepitelial cervical grau 2 ou pior (≥ NIC 2).

Métodos Foi realizado exame citopatológico e CH2 para HPVar (Qiagen, Gaithersburg, Maryland, EUA) em 359 amostras em meio líquido (Sure Path, Becton Dickinson, TriPath Imaging, Burlington, NC, USA) coletadas de mulheres da região do Vale do Ribeira, durante julho de 2013 e setembro de 2015 com citologia anterior classificada como células escamosas atípicas de significado indeterminado (ASC-US), lesão intraepitelial de baixo grau (LSIL), células escamosas atípicas, não podendo excluir lesão de alto grau (ASC-H) e células glandulares atípicas (AGC). O exame histopatológico foi realizado em 179 mulheres. As avaliações de desempenho foram calculadas usando o teste de intervalo de confiança (IC) “exato” de Clopper-Pearson de 95% pelo software MEDCALC (Medcalc Software Ltd, Ostend, Bélgica).

Resultados A frequência de ≥ NIC 2 foi 11,7% (21/179). A CH2 para o HPVar e a citologia de repetição para a detecção ≥ NIC 2 obteve, respectivamente, sensibilidade de 90.5% (IC 95% = 69,6–98,8) e 90,5% (IC 95% = 69,6–98,8), especificidade de 65,8% (IC 95% = 57,9–73,2) e 43,7%, (IC 95% = 35,8–51,8), valor preditivo positivo de 26,0% (IC 95% = 21,4–31,3) e 17,6%, (IC95% = 14,9–20,6), e valor preditivo negativo de 98,1% (IC 95% = 93,3–99,5) e 97,2%, (IC 95% = 90,1–99,2).

Conclusão No geral, a CH2 para HPVar aprimora o desempenho para detecção de ≥ NIC 2, sem comprometer a sensibilidade e proporciona maior margem de segurança do retorno ao rastreio trienal de mulheres com anormalidades citológicas prévias, sem ≥ NIC 2 subjacente.

Keywords

human papillomavirus - screening - cervical cancer - papanicolaou test

Palavras-chave

papilomavírus humano - rastreamento - câncer do colo do útero - papanicolaou

Contributions

Lorente S.: conception and design, acquisition, analysis and interpretation of data and drafting of the article. Fernandes N. C. C. A.: conception and design, analysis and interpretation of data, critical review of the article and final approval of the version to be published. Etlinger-Colonelli D.: conception and design, analysis and interpretation of data and critical review of the article and final approval of the version to be published. Réssio R. A.: conception and design, analysis and interpretation of data, critical review of the article and final approval of the version to be published. Oliveira S. M. P.: conception and design, critical review of the article, and final approval of the version to be published. Catarino R. M.: conception, design, critical review of the article and final approval of the version to be published.

• References

• 1 Ministério da Saúde. Instituto Nacional de Câncer [Internet]. Câncer do colo do útero. Rio de Janeiro: INCA; 2018 [cited 2018 Apr 2]. Available from: https://www.inca.gov.br/tipos-de-cancer/cancer-do-colo-do-utero
• 2 Arbyn M, Sasieni P, Meijer CJLM, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine 2006; 24 (Suppl. 03) (S3): 78-89 . Doi: 10.1016/j.vaccine.2006.05.117
• 3 Rijkaart DC, Berkhof J, Rozendaal L, van Kemenade FJ, Bulkmans NWJ, Heideman DAM. , et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol 2012; 13 (01) 78-88 . Doi: 10.1016/S1470-2045(11)70296-0
• 4 Richardson LA, El-Zein M, Ramanakumar AV, Ratnam S, Sangwa-Lugoma G, Longatto-Filho A. , et al; PEACHS (Pap Efficacy After Cervical HPV Status) Study Consortium. HPV DNA testing with cytology triage in cervical cancer screening: Influence of revealing HPV infection status. Cancer Cytopathol 2015; 123 (12) 745-754 . Doi: 10.1002/cncy.21596
• 5 Ministério da Saúde. Instituto Nacional de Câncer José Alencar Gomes da Silva. Coordenação de Prevenção e Vigilância. Divisão de Detecção Precoce e Apoio à Organização de Rede [Internet]. Diretrizes brasileiras para o rastreamento do câncer do colo do útero. 2a ed. Rio de Janeiro: INCA; 2016 [cited 2018 Apr 12]. Available from: https://www.inca.gov.br/sites/ufu.sti.inca.local/files//media/document//diretrizesparaorastreamentodocancerdocolodoutero_2016_corrigido.pdf
• 6 Kyrgiou M, Kalliala I, Mitra A, Ng KYB, Raglan O, Fotopoulou C. , et al. Immediate referral to colposcopy versus cytological surveillance for low-grade cervical cytological abnormalities in the absence of HPV test: A systematic review and a meta-analysis of the literature. Int J Cancer 2017; 140 (01) 216-223 . Doi: 10.1002/ijc.30419
• 7 Xu L, Verdoodt F, Wentzensen N, Bergeron C, Arbyn M. Triage of ASC-H: A meta-analysis of the accuracy of high-risk HPV testing and other markers to detect cervical precancer. Cancer Cytopathol 2016; 124 (04) 261-272 . Doi: 10.1002/cncy.21661
• 8 Cuzick J, Clavel C, Petry KU, Meijer CJLM, Hoyer H, Ratnam S. , et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006; 119 (05) 1095-1101 . Doi: 10.1002/ijc.21955
• 9 Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Palma PD, Mistro AD. , et al; New Technologies for Cervical Cancer screening (NTCC) Working Group. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 2010; 11 (03) 249-257 . Doi: 10.1016/S1470-2045(09)70360-2
• 10 Luttmer R, De Strooper LMA, Steenbergen RDM, Berkhof J, Snijders PJF, Heideman DAM, Meijer CJLM. , et al. Management of high-risk HPV-positive women for detection of cervical (pre)cancer. Expert Rev Mol Diagn 2016; 16 (09) 961-974 . Doi: 10.1080/14737159.2016.1217157
• 11 Arbyn M, Ronco G, Anttila A, Meijer CJLM, Poljak M, Ogilvie G. , et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 2012; 30 (Suppl. 05) F88-F99 . Doi: 10.1016/j.vaccine.2012.06.095
• 12 Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J. Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst 2004; 96 (04) 280-293 . Doi: 10.1093/jnci/djh037
• 13 Zhao C, Moriarty AT, Ghofrani M, Husain M, Tambouret RH, Laucirica R. , et al. Human papillomavirus testing and reporting rates in 2012: results of a College of American Pathologists national survey. Arch Pathol Lab Med 2015; 139 (06) 757-761 . Doi: 10.5858/arpa.2014-0393-CP
• 14 Ginsburg O, Bray F, Coleman MP, Vanderpuye V, Eniu A, Kotha SR. , et al. The global burden of women's cancers: a grand challenge in global health. Lancet 2017; 389 (10071): 847-860 . Doi: 10.1016/S0140-6736(16)31392-7
• 15 Silva BP, Stockmann D, Lúcio DdeS, Henna E, Rocha MCP, Junqueira FM. Expanding health access in the more vulnerable region in the state of São Paulo, Brazil: is this a reflection of the Mais Médicos (More Doctors) Program?. Cien Saude Colet 2016; 21 (09) 2899-2906 . Doi: 10.1590/1413-81232015219.15552016
• 16 Ministério do Desenvolvimento Agrário. Sistema de Informações Territoriais [Internet]. Composição Municipal do Território Vale do Ribeira - SP. 2018 [cited 2018 Apr 10]. Available from: http://sit.mda.gov.br/download.php?ac=verMunTR&m=3542602
• 17 MEDCALC®: easy-to-use statistical software [Internet]. 2018 [cited 2018 Apr 10]. Available from: https://www.medcalc.org/calc/diagnostic_test.php
• 18 Mercaldo ND, Lau KF, Zhou XH. Confidence intervals for predictive values with an emphasis to case-control studies. Stat Med 2007; 26 (10) 2170-2183 . Doi: 10.1002/sim.2677
• 19 Koliopoulos G, Nyaga VN, Santesso N, Bryant A, Martin-Hirsch PPL, Mustafa RA. , et al. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane Database Syst Rev 2017; 8: CD008587 . Doi: 10.1002/14651858.CD008587.pub2
• 20 Arbyn M, Roelens J, Simoens C, Buntix F, Paraskevaidis E, Martin-Hirsch PPL, Prendiville WJ. , et al. Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions. Cochrane Database Syst Rev 2013; (03) CD008054 . Doi: 10.1002/14651858.CD008054.pub2
• 21 Cotton S, Sharp L, Little J, Cruickshank M, Seth R, Smart L. , et al; Trial Of Management of Borderline and Other Low-grade Abnormal Smears Group. The role of human papillomavirus testing in the management of women with low-grade abnormalities: multicentre randomised controlled trial. BJOG 2010; 117 (06) 645-659 . Doi: 10.1111/j.1471-0528.2010.02519.x
• 22 Catteau X, Simon P, Noël JC. Evaluation of the oncogenic human papillomavirus DNA test with liquid-based cytology in primary cervical cancer screening and the importance of the ASC/SIL ratio: a Belgian study. ISRN Obstet Gynecol 2014; 2014: 536495 . Doi: 10.1155/2014/536495
• 23 Khunamornpong S, Settakorn J, Sukpan K, Srisomboon J, Suprasert P, Siriaunkgul S. Performance of HPV DNA testing with hybrid capture 2 in triaging women with minor cervical cytologic abnormalities (ASC-US/LSIL) in Northern Thailand. Asian Pac J Cancer Prev 2014; 15 (24) 10961-10966
• 24 Bentley E, Cotton SC, Cruickshank ME. , et al; Trial of Management of Borderline and Other Low-Grade Abnormal Smears (TOMBOLA) Group. Refining the management of low-grade cervical abnormalities in the UK National Health Service and defining the potential for human papillomavirus testing: a commentary on emerging evidence. J Low Genit Tract Dis 2006; 10 (01) 26-38 . Doi: 10.1097/01.lgt.0000192695.93172.75
• 25 Ciavattini A, Clemente N, Tsiroglou D. , et al. Follow up in women with biopsy diagnosis of cervical low-grade squamous intraepithelial lesion (LSIL): how long should it be?. Arch Gynecol Obstet 2017; 295 (04) 997-1003 . Doi: 10.1007/s00404-017-4335-7
• 26 Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M. , et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol 2013; 121 (04) 829-846 . Doi: 10.1097/AOG.0b013e3182883a34
• 27 Sundström K, Lu D, Elfström KM, Wang J, Andrae B, Dillner J, Sparén P. Follow-up of women with cervical cytological abnormalities showing atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion: a nationwide cohort study. Am J Obstet Gynecol 2017; 216 (01) 48.e1-48.e15 . Doi: 10.1016/j.ajog.2016.07.042
• 28 The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. J Natl Cancer Inst 2000; 92 (05) 397-402
• 29 Davey DD, Greenspan DL, Kurtycz DFI, Husain M, Austin RM. Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion: review of ancillary testing modalities and implications for follow-up. J Low Genit Tract Dis 2010; 14 (03) 206-214 . Doi: 10.1097/LGT.0b013e3181ca66a6
• 30 Oliveira GG, Oliveira JMDSC, Eleutério RMN, Barbosa RCC, Almeida PRC, Eleutério Jr J. Atypical Squamous cells: cytopathological findings and correlation with hpv genotype and histopathology. Acta Cytol 2018; 62 (5-6): 386-392 . Doi: 10.1159/000489386
• 31 Noël JC, Simon P. Limitations on the detection rate of high-risk HPV by hybrid capture 2 methodology in high grade intraepithelial (HSIL) or atypical squamous cells-cannot exclude HSIL (ASC-H) cytological lesions with proved CIN2. Anal Cell Pathol (Amst) 2015; 2015: 746502 . Doi: 10.1155/2015/746502
• 32 Irvin W, Evans SR, Andersen W, Jazaeri A, Taylor P, Stoler M. , et al. The utility of HPV DNA triage in the management of cytological AGC. Am J Obstet Gynecol 2005; 193 (02) 559-565 , discussion 565–567. Doi: 10.1016/j.ajog.2005.03.044
• 33 Verdoodt F, Jiang X, Williams M, Schnatz PF, Arbyn M. High-risk HPV testing in the management of atypical glandular cells: A systematic review and meta-analysis. Int J Cancer 2016; 138 (02) 303-310 . Doi: 10.1002/ijc.29424
• 34 Kim MK, Lee YK, Hong SR, Lim KT. Clinicopathological significance of atypical glandular cells on cervicovaginal Pap smears. Diagn Cytopathol 2017; 45 (10) 867-872 . Doi: 10.1002/dc.23777
• 35 Norman I, Hjerpe A, Dillner J. Risk of high-grade lesions after atypical glandular cells in cervical screening: a population-based cohort study. BMJ Open 2017; 7 (12) e017070 . Doi: 10.1136/bmjopen-2017-017070
• 36 Chummun K, Fitzpatrick M, Lenehan P, Boylan P, Mooney E, Flannelly G. Diagnostic and therapeutic dilemma associated with atypical glandular cells on liquid-based cervical cytology. Cytopathology 2012; 23 (06) 378-382 . Doi: 10.1111/j.1365-2303.2012.00981.x