Role of Dual-Staining p16/Ki-67 in the Management of Patients under 30 Years with ASC-US/L-SIL
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Selection and Inclusion Criteria
2.2. Cervical Cytology, Colposcopy and Biopsy
2.3. HPV Testing
2.4. Dual-Staining p16/Ki-67
2.5. Statistical Analysis
3. Results
3.1. Demographics
3.2. Colposcopy
3.3. HPV Infection
3.4. Dual-Staining
3.5. Histopathology
- In total, 36 patients had positive HR-HPV infection: 17 patients CIN I, 8 patients CIN II, 8 patients CIN III, and 2 patients with in situ carcinoma.
- In total, 31 patients had a positive dual-staining test: 2 patients CIN I, 16 patients CIN II, 10 patients CIN III, and 2 patients had in situ carcinoma.
- In total, 19 patients had HR-HPV and positive dual-staining: 2 patients CIN I, 7 patients CIN II, 8 patients CIN III, and 2 patients in situ carcinoma.
- In total, 26 patients had an abnormal colposcopy and HR-HPV: 13 patients CIN I, 7 patients CIN II, and 6 patients CIN III.
- In total, 24 patients had an abnormal colposcopy and positive dual-staining: 1 patient CIN I, 15 patients CIN II, and 8 patients CIN III.
- In total, 4 patients had a normal colposcopy and positive dual-staining: 1 patient CIN I, 1 patient CIN II, and 2 patients CIN III.
- In total, 5 patients had negative HPV and positive dual-staining: 4 patients with CIN II and 1 patient with CIN III.
- In total, 26 patients had positive HPV and negative dual-staining: 24 patients CIN I and 2 patients CIN II.
- In total, 16 patients had positive HR-HPV and negative dual-staining: 15 patients CIN I and 1 patient CIN II.
4. Discussion
4.1. Screening for Cervical Cancer by Cervical Cytology and Co-Testing
4.2. Age and HPV
4.3. HR-HPV Testing
4.4. Studies Regarding the Distribution of HPV Infection
4.5. Dual-Staining p16/Ki-67
4.6. Triaging HPV-Positive Women with Normal Cytology by p16/Ki-67 Dual-Staining Cytology Testing
4.7. Impact of Overtreatment
4.8. Persistence of Positive Dual-Staining after Conization
4.9. Strengths and Limitations of the Study
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ASC-US | Atypical squamous cells of undetermined significance |
L-SIL | Low-grade squamous intraepithelial lesion |
LEEP | loop electrosurgical excision procedure |
PAP | cervical cytology, Papanicolau test |
HPV | human papilloma virus |
CIN | cervical intraepithelial neoplasia |
HR-HPV | high-risk human papilloma virus |
CIS | in situ carcinoma |
DS | dual-staining p16/Ki-67 |
IFCPC | International Federation for Cervical Pathology and Colposcopy |
RCT | randomized control trial |
References
- Sawaya, G.F.; Grimes, D.A. New technologies in cervical cytology screening: A word of caution. Obstet. Gynecol. 1999, 94, 307–310. [Google Scholar] [CrossRef]
- Saslow, D.; Solomon, D.; Lawson, H.W.; Killackey, M.; Kulasingam, S.L.; Cain, J. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am. J. Clin. Pathol. 2012, 137, 516–542. [Google Scholar] [CrossRef]
- Massad, L.S.; Einstein, M.H.; Huh, W.K.; Katki, H.A.; Kinney, W.K.; Schiffman, M.; Solomon, D.; Wentzensen, N.; Lawson, H.W. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet. Gynecol. 2013, 121, 829–846. [Google Scholar] [CrossRef] [Green Version]
- Bansal, N.; Wright, J.D.; Cohen, C.J.; Herzog, T.J. Natural history of established low grade cervical intraepithelial (CIN 1) lesions. Anticancer Res. 2008, 28, 1763–1766. [Google Scholar] [PubMed]
- Vrdoljak-Mozetič, D.; Krašević, M.; Verša Ostojić, D.; Štemberger-Papić, S.; Rubeša-Mihaljević, R.; Bubonja-Šonje, M. HPV16 genotype, p16/Ki-67 dual staining and koilocytic morphology as potential predictors of the clinical outcome for cervical low-grade squamous intraepithelial lesions. Cytopathology 2015, 26, 10–18. [Google Scholar] [CrossRef] [PubMed]
- Palla, V.V.; Karaolanis, G.; Moris, D.; Antsaklis, A. Sentinel lymph node biopsy in uterine cervical cancer patients: Ready for clinical use? A review of the literature. ISRN Surg. 2014, 2014, 841618. [Google Scholar] [CrossRef] [Green Version]
- Allia, E.; Ronco, G.; Coccia, A.; Luparia, P.; Macrì, L.; Fiorito, C.; Maletta, F.; Deambrogio, C.; Tunesi, S.; De Marco, L.; et al. Interpretation of p16(INK4a) /Ki-67 dual immunostaining for the triage of human papillomavirus-positive women by experts and nonexperts in cervical cytology. Cancer Cytopathol. 2015, 123, 212–218. [Google Scholar] [CrossRef]
- Wentzensen, N.; Schwartz, L.; Zuna, R.E.; Smith, K.; Mathews, C.; Gold, M.A.; Allen, R.A.; Zhang, R.; Dunn, S.T.; Walker, J.L.; et al. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin. Cancer Res. J. Am. Assoc. Cancer Res. 2012, 18, 4154–4162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bergeron, C.; Ikenberg, H.; Sideri, M.; Denton, K.; Bogers, J.; Schmidt, D.; Alameda, F.; Keller, T.; Rehm, S.; Ridder, R.; et al. Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results. Cancer Cytopathol. 2015, 123, 373–381. [Google Scholar] [CrossRef]
- Possati-Resende, J.C.; Fregnani, J.H.T.G.; Kerr, L.M.; Mauad, E.C.; Longatto-Filho, A.; Scapulatempo-Neto, C. The Accuracy of p16/Ki-67 and HPV Test in the Detection of CIN2/3 in Women Diagnosed with ASC-US or LSIL. PLoS ONE 2015, 10, e0134445. [Google Scholar] [CrossRef]
- Baena, A.; Guevara, E.; Almonte, M.; Arias-Stella, J.; Sasieni, P.; Sanchez, G.I. Factors related to inter-observer reproducibility of conventional Pap smear cytology: A multilevel analysis of smear and laboratory characteristics. Cytopathology 2017, 28, 192–202. [Google Scholar] [CrossRef] [PubMed]
- Stoler, M.H.; Baker, E.; Boyle, S.; Aslam, S.; Ridder, R.; Huh, W.K.; Wright, T.C., Jr. Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki-67 dual-stained cytology—Retrospective insights from ATHENA. Int. J. Cancer 2019, 146, 2599–2607. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grenko, R.T.; Abendroth, C.S.; Frauenhoffer, E.E.; Ruggiero, F.M.; Zaino, R.J. Variance in the interpretation of cervical biopsy specimens obtained for atypical squamous cells of undetermined significance. Am. J. Clin. Pathol. 2000, 114, 735–740. [Google Scholar] [CrossRef]
- Ronco, G.; Dillner, J.; Elfström, K.M.; Tunesi, S.; Snijders, P.J.F.; Arbyn, M.; Kitchener, H.; Segnan, N.; Gilham, C.; Giorgi-Rossi, P.; et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: Follow-up of four European randomised controlled trials. Lancet 2014, 383, 524–532. [Google Scholar] [CrossRef]
- Bulkmans, N.W.J.; Rozendaal, L.; Snijders, P.J.F.; Voorhorst, F.J.; Boeke, A.J.P.; Zandwijken, G.R.; van Kemenade, F.J.; Verheijen, R.H.; v Groningen, K.; Boon, M.E.; et al. POBASCAM, a population-based randomized controlled trial for implementation of high-risk HPV testing in cervical screening: Design, methods and baseline data of 44,102 women. Int. J. Cancer. 2004, 110, 94–101. [Google Scholar] [CrossRef]
- Kitchener, H.C.; Almonte, M.; Gilham, C.; Dowie, R.; Stoykova, B.; Sargent, A.; Roberts, C.; Desai, M.; Peto, J.; ARTISTIC Trial Study Group. ARTISTIC: A randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Health Technol. Assess. 2009, 13, 1–150. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bulk, S.; Bulkmans, N.W.J.; Berkhof, J.; Rozendaal, L.; Boeke, A.J.P.; Verheijen, R.H.M.; Snijders, P.J.; Meijer, C.J. Risk of high-grade cervical intra-epithelial neoplasia based on cytology and high-risk HPV testing at baseline and at 6-months. Int. J. Cancer 2007, 121, 361–367. [Google Scholar] [CrossRef]
- Leinonen, M.; Nieminen, P.; Kotaniemi-Talonen, L.; Malila, N.; Tarkkanen, J.; Laurila, P.; Anttila, A. Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J. Natl. Cancer Inst. 2009, 101, 1612–1623. [Google Scholar] [CrossRef]
- Naucler, P.; Ryd, W.; Törnberg, S.; Strand, A.; Wadell, G.; Elfgren, K.; Rådberg, T.; Strander, B.; Johansson, B.; Forslund, O.; et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N. Engl. J. Med. 2007, 357, 1589–1597. [Google Scholar] [CrossRef] [PubMed]
- Naucler, P.; Ryd, W.; Törnberg, S.; Strand, A.; Wadell, G.; Elfgren, K.; Rådberg, T.; Strander, B.; Forslund, O.; Hansson, B.G.; et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J. Natl. Cancer Inst. 2009, 101, 88–99. [Google Scholar] [CrossRef] [Green Version]
- Rijkaart, D.C.; Berkhof, J.; van Kemenade, F.J.; Coupe, V.M.H.; Rozendaal, L.; Heideman, D.A.M.; Verheijen, R.H.; Bulk, S.; Verweij, W.; Snijders, P.J.; et al. HPV DNA testing in population-based cervical screening (VUSA-Screen study): Results and implications. Br. J. Cancer 2012, 106, 975–981. [Google Scholar] [CrossRef] [PubMed]
- Ronco, G.; Giorgi-Rossi, P.; Carozzi, F.; Confortini, M.; Dalla Palma, P.; Del Mistro, A.; Ghiringhello, B.; Girlando, S.; Gillio-Tos, A.; De Marco, L.; et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: A randomised controlled trial. Lancet Oncol. 2010, 11, 249–257. [Google Scholar] [CrossRef]
- Ronco, G.; Giorgi-Rossi, P.; Carozzi, F.; Dalla Palma, P.; Del Mistro, A.; De Marco, L.; De Lillo, M.; Naldoni, C.; Pierotti, P.; Rizzolo, R.; et al. Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: Results at recruitment for a randomised controlled trial. Lancet Oncol. 2006, 7, 547–555. [Google Scholar] [CrossRef]
- Davies, P.; Arbyn, M.; Dillner, J.; Kitchener, H.C.; Meijer, C.J.L.M.; Ronco, G.; Hakama, M. A report on the current status of European research on the use of human papillomavirus testing for primary cervical cancer screening. Int. J. Cancer 2006, 118, 791–796. [Google Scholar] [CrossRef] [PubMed]
- Ronco, G.; Giorgi-Rossi, P.; Carozzi, F.; Confortini, M.; Dalla Palma, P.; Del Mistro, A.; Gillio-Tos, A.; Minucci, D.; Naldoni, C.; Rizzolo, R.; et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test. J. Natl. Cancer Inst. 2008, 100, 492–501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mayrand, M.H.; Duarte-Franco, E.; Rodrigues, I.; Walter, S.D.; Hanley, J.; Ferenczy, A.; Ratnam, S.; Coutlée, F.; Franco, E.L.; Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N. Engl. J. Med. 2007, 357, 1579–1588. [Google Scholar] [CrossRef] [Green Version]
- Sankaranarayanan, R.; Nene, B.M.; Dinshaw, K.A.; Mahe, C.; Jayant, K.; Shastri, S.S.; Malvi, S.G.; Chinoy, R.; Kelkar, R.; Budukh, A.M.; et al. A cluster randomized controlled trial of visual, cytology and human papillomavirus screening for cancer of the cervix in rural India. Int. J. Cancer 2005, 116, 617–623. [Google Scholar] [CrossRef]
- Perkins, R.B.; Guido, R.S.; Castle, P.E.; Chelmow, D.; Einstein, M.H.; Garcia, F.; Huh, W.K.; Kim, J.J.; Moscicki, A.B.; Nayar, R.; et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J. Low. Genit. Tract Dis. 2020, 24, 102–131. [Google Scholar] [CrossRef] [Green Version]
- American College of Obstetricians and Gynecologists. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention. Obstet. Gynecol. 2016, 128, e111–e130. [Google Scholar]
- US Preventive Services Task Force; Curry, S.J.; Krist, A.H.; Owens, D.K.; Barry, M.J.; Caughey, A.B.; Davidson, K.W.; Doubeni, C.A.; Epling, J.W., Jr.; Kemper, A.R.; et al. Force USPST. Screening for Cervical Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2018, 320, 674–686. [Google Scholar] [CrossRef] [Green Version]
- Maver, P.J.; Poljak, M. Primary HPV-based cervical cancer screening in Europe: Implementation status, challenges, and future plans. Clin. Microbiol. Infect. 2020, 26, 579–583. [Google Scholar] [CrossRef] [PubMed]
- Marth, C.; Landoni, F.; Mahner, S.; McCormack, M.; Gonzalez-Martin, A.; Colombo, N. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. J. Eur. Soc. Med. Oncol. 2017, 28, 72–83. [Google Scholar] [CrossRef] [PubMed]
- Einstein, M.H.; Garcia, F.A.R.; Mitchell, A.L.; Day, S.P. Age-stratified performance of the Cervista HPV 16/18 genotyping test in women with ASC-US cytology. Cancer Epidemiol. Prev. Biomark. 2011, 20, 1185–1189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sherman, M.E.; Schiffman, M.; Cox, J.T. Effects of age and human papilloma viral load on colposcopy triage: Data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J. Natl. Cancer Inst. 2002, 94, 102–107. [Google Scholar] [CrossRef] [Green Version]
- Stoler, M.H.; Wright, T.C.J.; Sharma, A.; Apple, R.; Gutekunst, K.; Wright, T.L. High-risk human papillomavirus testing in women with ASC-US cytology: Results from the ATHENA HPV study. Am. J. Clin. Pathol. 2011, 135, 468–475. [Google Scholar] [CrossRef] [Green Version]
- Wright, T.C.; Stoler, M.H.; Behrens, C.M.; Sharma, A.; Zhang, G.; Wright, T.L. Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test. Gynecol. Oncol. 2015, 136, 189–197. [Google Scholar] [CrossRef] [Green Version]
- Rijkaart, D.C.; Berkhof, J.; Rozendaal, L.; van Kemenade, F.J.; Bulkmans, N.W.J.; Heideman, D.A.M.; Kenter, G.G.; Cuzick, J.; Snijders, P.J.; Meijer, C.J. 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, 78–88. [Google Scholar] [CrossRef]
- Thrall, M.J.; Smith, D.A.; Mody, D.R. Women > or =30 years of age with low grade squamous intraepithelial lesion (LSIL) have low positivity rates when cotested for high-risk human papillomavirus: Should we reconsider HPV triage for LSIL in older women? Diagn. Cytopathol. 2010, 38, 407–412. [Google Scholar] [CrossRef]
- Arbyn, M.; Martin-Hirsch, P.; Buntinx, F.; Van Ranst, M.; Paraskevaidis, E.; Dillner, J. Triage of women with equivocal or low-grade cervical cytology results: A meta-analysis of the HPV test positivity rate. J. Cell. Mol. Med. 2009, 13, 648–659. [Google Scholar] [CrossRef] [Green Version]
- Meijer, C.J.L.M.; Berkhof, J.; Castle, P.E.; Hesselink, A.T.; Franco, E.L.; Ronco, G.; Arbyn, M.; Bosch, F.X.; Cuzick, J.; Dillner, J.; et al. Guidelines for human papillomavirus DNA test requirements for primary cervical cancer screening in women 30 years and older. Int. J. Cancer 2009, 124, 516–520. [Google Scholar] [CrossRef] [Green Version]
- Evans, M.F.; Adamson, C.S.C.; Papillo, J.L.; St John, T.L.; Leiman, G.; Cooper, K. Distribution of human papillomavirus types in ThinPrep Papanicolaou tests classified according to the Bethesda 2001 terminology and correlations with patient age and biopsy outcomes. Cancer 2006, 106, 1054–1064. [Google Scholar] [CrossRef] [PubMed]
- Zuna, R.E.; Wang, S.S.; Rosenthal, D.L.; Jeronimo, J.; Schiffman, M.; Solomon, D. Determinants of human papillomavirus-negative, low-grade squamous intraepithelial lesions in the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions triage study (ALTS). Cancer 2005, 105, 253–262. [Google Scholar] [CrossRef] [PubMed]
- Tsoumpou, I.; Arbyn, M.; Kyrgiou, M.; Wentzensen, N.; Koliopoulos, G.; Martin-Hirsch, P.; Malamou-Mitsi, V.; Paraskevaidis, E. p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: A systematic review and meta-analysis. Cancer Treat. Rev. 2009, 35, 210–220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- von Knebel Doeberitz, M. New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur. J. Cancer 2002, 38, 2229–2242. [Google Scholar] [CrossRef]
- von Knebel Doeberitz, M.; Vinokurova, S. Host factors in HPV-related carcinogenesis: Cellular mechanisms controlling HPV infections. Arch. Med. Res. 2009, 40, 435–442. [Google Scholar] [CrossRef]
- Agoff, S.N.; Lin, P.; Morihara, J.; Mao, C.; Kiviat, N.B.; Koutsky, L.A. p16(INK4a) expression correlates with degree of cervical neoplasia: A comparison with Ki-67 expression and detection of high-risk HPV types. Mod. Pathol. 2003, 16, 665–673. [Google Scholar] [CrossRef] [Green Version]
- Hitchcock, C.L. Ki-67 staining as a means to simplify analysis of tumor cell proliferation. Am. J. Clin. Pathol. 1991, 96, 444–447. [Google Scholar] [CrossRef] [Green Version]
- Cina, S.J.; Richardson, M.S.; Austin, R.M.; Kurman, R.J. Immunohistochemical staining for Ki-67 antigen, carcinoembryonic antigen, and p53 in the differential diagnosis of glandular lesions of the cervix. Mod. Pathol. 1997, 10, 176–180. [Google Scholar]
- Pinto, A.P.; Schlecht, N.F.; Woo, T.Y.C.; Crum, C.P.; Cibas, E.S. Biomarker (ProEx C, p16(INK4A), and MiB-1) distinction of high-grade squamous intraepithelial lesion from its mimics. Mod. Pathol. 2008, 21, 1067–1074. [Google Scholar] [CrossRef] [Green Version]
- Lim, S.; Lee, M.J.; Cho, I.; Hong, R.; Lim, S.C. Efficacy of p16 and Ki-67 immunostaining in the detection of squamous intraepithelial lesions in a high-risk HPV group. Oncol. Lett. 2016, 11, 1447–1452. [Google Scholar] [CrossRef] [Green Version]
- Bergeron, C.; Ordi, J.; Schmidt, D.; Trunk, M.J.; Keller, T.; Ridder, R. Conjunctive p16INK4a testing significantly increases accuracy in diagnosing high-grade cervical intraepithelial neoplasia. Am. J. Clin. Pathol. 2010, 133, 395–406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kotaniemi-Talonen, L.; Nieminen, P.; Anttila, A.; Hakama, M. Routine cervical screening with primary HPV testing and cytology triage protocol in a randomised setting. Br. J. Cancer 2005, 93, 862–867. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Qiao, X.; Bhuiya, T.A.; Spitzer, M. Differentiating high-grade cervical intraepithelial lesion from atrophy in postmenopausal women using Ki-67, cyclin E, and p16 immunohistochemical analysis. J. Low. Genit. Tract Dis. 2005, 9, 100–107. [Google Scholar] [CrossRef] [PubMed]
- Uijterwaal, M.H.; Polman, N.J.; Witte, B.I.; van Kemenade, F.J.; Rijkaart, D.; Berkhof, J.; Balfoort-van der Meij, G.A.; Ridder, R.; Snijders, P.J.; Meijer, C.J. Triaging HPV-positive women with normal cytology by p16/Ki-67 dual-stained cytology testing: Baseline and longitudinal data. Int. J. Cancer 2015, 136, 2361–2368. [Google Scholar] [CrossRef]
- Sawaya, G.F.; Kuppermann, M. Identifying a “range of reasonable options” for cervical cancer screening. Obstet. Gynecol. 2015, 125, 308–310. [Google Scholar] [CrossRef] [PubMed]
- Sharp, L.; Cotton, S.; Cruickshank, M.; Gray, N.M.; Harrild, K.; Smart, L.; Walker, L.G.; Little, J.; TOMBOLA Group. The unintended consequences of cervical screening: Distress in women undergoing cytologic surveillance. J. Low. Genit. Tract Dis. 2014, 18, 142–150. [Google Scholar] [CrossRef] [Green Version]
- Sutthichon, P.; Kietpeerakool, C. Perioperative complications of an outpatient loop electrosurgical excision procedure: A review of 857 consecutive cases. Asian Pac. J. Cancer Prev. 2009, 10, 351–354. [Google Scholar]
- Kyrgiou, M.; Koliopoulos, G.; Martin-Hirsch, P.; Arbyn, M.; Prendiville, W.; Paraskevaidis, E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: Systematic review and meta-analysis. Lancet 2006, 367, 489–498. [Google Scholar] [CrossRef]
- Hoyer, H.; Mehlhorn, G.; Scheungraber, C.; Hagemann, I.; Hirchenhain, C.; Woelber, L.; Stolte, C.; Hampl, M.; Scherbring, S.; Denecke, A.; et al. Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance. Cancers 2021, 13, 3309. [Google Scholar] [CrossRef]
- Liu, W.; Gong, J.; Xu, H.; Zhang, D.; Xia, N.; Li, H.; Song, K.; Lv, T.; Chen, Y.; Diao, Y.; et al. Good performance of p16/Ki-67 dual-stain cytology for detection and post-treatment surveillance of high-grade CIN/VAIN in a prospective, cross-sectional study. Diagn. Cytopathol. 2020, 48, 635–644. [Google Scholar] [CrossRef]
- Polman, N.J.; Uijterwaal, M.H.; Witte, B.I.; Berkhof, J.; van Kemenade, F.J.; Spruijt, J.W.M.; van Baal, W.M.; Graziosi, P.G.; van Dijken, D.K.; Verheijen, R.H.; et al. Good performance of p16/ki-67 dual-stained cytology for surveillance of women treated for high-grade CIN. Int. J. Cancer 2017, 140, 423–430. [Google Scholar] [CrossRef] [PubMed]
bcHR-HPV | ||||
---|---|---|---|---|
Factor | Group | 0 (n = 24) | 1 (n = 36) | p Value (a) |
ac6moHR-HPV (a) | 0 | 24 (100%) | 16 (44.4%) | <0.001 ** |
1 | 0 | 20 (55.6) | ||
ac12moHR-HPV (a) | 0 | 24 (100%) | 30 (83.3%) | 0.072 |
1 | 0 | 6 (16.7%) |
bcDS | ||||
---|---|---|---|---|
Factor | Group | 0 (n = 29) | 1 (n = 31) | p Value (a) |
ac6moDS (a) | 0 | 26 (89.7%) | 28 (90.3%) | 1 |
1 | 3 (10.3%) | 3 (9.7%) | ||
ac12moDS (a) | 0 | 29 (100%) | 29 (93.5%) | 0.492 |
1 | 0 | 2 (6.5%) |
(a). Crosstabulation of CIN2+ and Colposcopy, Dual-Staining p16/Ki-67, HPV, and HR-HPV (Total Number and Separate for Each Strain). | ||||
ConCIN2+ | ||||
Factor | Group | 0 (n = 29) | 1 (n = 31) | pValue (a) |
Abnormal colposcopy (a) | 0 | 4 (13.8%) | 5 (16.1%) | 1 |
1 | 25 (86.2%) | 26 (83.9%) | ||
DS (a) | 0 | 27 (93.1%) | 2 (6.5%) | <0.001 ** |
1 | 2 (6.9%) | 29 (93.5%) | ||
HPV (a) | 0 | 3 (10.3%) | 5 (16.1%) | 0.708 |
1 | 26 (89.7%) | 26 (83.9%) | ||
HPV-16 (a) | 0 | 21 (72.4%) | 17 (54.8%) | 0.188 |
1 | 8 (27.6%) | 14 (45.2%) | ||
HPV-18 (a) | 0 | 21 (72.4%) | 24 (77.4%) | 0.769 |
1 | 8 (27.6%) | 7 (22.6%) | ||
HPV-31 (a) | 0 | 28 (96.6%) | 31 (100%) | 0.483 |
1 | 1 (3.4%) | 0 | ||
HPV-33 (a) | 0 | 27 (93.1%) | 28 (90.3%) | 1 |
1 | 2 (6.9%) | 3 (9.7%) | ||
HPV-35 (a) | 0 | 28 (96.6%) | 29 (93.5%) | 1 |
1 | 1 (3.4%) | 2 (6.5%) | ||
HPV-39 (a) | 0 | 27 (93.1%) | 30 (96.8%) | 0.606 |
1 | 2 (6.9%) | 1 (3.2%) | ||
HPV-51 (a) | 0 | 25 (86.2%) | 30 (96.8%) | 0.188 |
1 | 4 (13.8%) | 1 (3.2%) | ||
HPV-53 (a) | 0 | 29 (100%) | 30 (96.8%) | 1 |
1 | 0 | 1 (3.2%) | ||
HPV-56 (a) | 0 | 26 (89.7%) | 29 (93.5%) | 0.666 |
1 | 3 (10.3%) | 2 (6.5%) | ||
HPV58 (a) | 0 | 28 (96.6%) | 31 (100.0%) | 0.483 |
1 | 1 (3.4%) | 0 (0.0%) | ||
HPV68 (a) | 0 | 28 (96.6%) | 30 (96.8%) | 1 |
1 | 1 (3.4%) | 1 (3.2%) | ||
HR-HPV (a) | 0 | 12 (41.4%) | 12 (38.7 | 1 |
1 | 17 (58.6%) | 19 (61.3%) | ||
(b). Crosstabulation of CIN2+ and ASC-US, L-SIL, co-infection (i.e., more than one strain of HR-HPV present), and dual-staining on the conization piece (conization DS). | ||||
ConCIN2+ | ||||
Factor | Group | 0 (n = 29) | 1 (n = 31) | pValue (a) |
ASC-US (a) | 0 | 20 (69.0%) | 17 (54.8%) | 0.298 |
1 | 9 (31.0%) | 14 (45.2%) | ||
L-SIL (a) | 0 | 9 (31.0%) | 14 (45.2%) | 0.298 |
1 | 20 (69.0%) | 17 (54.8%) | ||
Co-infection (a) | 0 | 17 (58.6%) | 18 (58.1%) | 1 |
1 | 12 (41.4%) | 13 (41.9%) | ||
Conization DS (a) | 0 | 27 (93.1%) | 6 (19.4%) | <0.001 ** |
1 | 2 (6.9%) | 25 (80.6%) |
Diagnostic Test | Sensitivity (95% CI) | Specificity (95% CI) | ||||
---|---|---|---|---|---|---|
All | ASC-US | L-SIL | All | ASC-US | L-SIL | |
n = 60 | n = 23 | n = 37 | n = 60 | n = 23 | n = 37 | |
HR-HPV | 0.61 (0.42, 0.78) | 0.43 (0.18, 0.71) | 0.76 (0.50, 0.93) | 0.41 (0.24, 0.61) | 0.22 (0.03, 0.60) | 0.50 (0.27, 0.73) |
Colposcopy | 0.52 (0.38, 0.65) | 0.79 (0.49, 0.95) | 0.88 (0.64, 0.99) | 0.14 (0.04, 0.32) | 0.11 (0.00, 0.48) | 0.15 (0.03, 0.38) |
p16/Ki-67 | 0.94 (0.79, 0.99) | 0.93 (0.66, 1.00) | 0.94 (0.71, 1.00) | 0.93 (0.77, 0.99) | 1.00 (0.66, 1.00) | 0.90 (0.68, 0.99) |
combA | 0.45 (0.27, 0.64) | 0.21 (0.05, 0.51) | 0.65 (0.38, 0.86) | 0.55 (0.36, 0.74) | 0.33 (0.07, 0.70) | 0.65 (0.41, 0.85) |
combB | 0.58 (0.39, 0.75) | 0.43 (0.18, 0.71) | 0.71 (0.44, 0.90) | 0.93 (0.77, 0.99) | 1.00 (0.66, 1.00) | 0.90 (0.68, 0.99) |
combC | 0.77 (0.59, 0.90) | 0.71 (0.42, 0.92) | 0.82 (0.57, 0.96) | 0.97 (0.82, 1.00) | 1.00 (0.66, 1.00) | 0.95 (0.75, 1.00) |
combD | 0.42 (0.25, 0.61) | 0.21 (0.05, 0.51) | 0.59 (0.33, 0.82) | 0.97 (0.82, 1.00) | 1.00 (0.66, 1.00) | 0.95 (0.75, 1.00) |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Secosan, C.; Pasquini, A.; Zahoi, D.; Motoc, A.; Lungeanu, D.; Balint, O.; Ilian, A.; Balulescu, L.; Grigoras, D.; Pirtea, L. Role of Dual-Staining p16/Ki-67 in the Management of Patients under 30 Years with ASC-US/L-SIL. Diagnostics 2022, 12, 403. https://doi.org/10.3390/diagnostics12020403
Secosan C, Pasquini A, Zahoi D, Motoc A, Lungeanu D, Balint O, Ilian A, Balulescu L, Grigoras D, Pirtea L. Role of Dual-Staining p16/Ki-67 in the Management of Patients under 30 Years with ASC-US/L-SIL. Diagnostics. 2022; 12(2):403. https://doi.org/10.3390/diagnostics12020403
Chicago/Turabian StyleSecosan, Cristina, Andrea Pasquini, Delia Zahoi, Andrei Motoc, Diana Lungeanu, Oana Balint, Aurora Ilian, Ligia Balulescu, Dorin Grigoras, and Laurentiu Pirtea. 2022. "Role of Dual-Staining p16/Ki-67 in the Management of Patients under 30 Years with ASC-US/L-SIL" Diagnostics 12, no. 2: 403. https://doi.org/10.3390/diagnostics12020403