doktorska disertacija
Uršula Salobir Gajšek (Author), Alenka Repše-Fokter (Mentor), Iztok Takač (Co-mentor)

Abstract

Raka materničnega vratu (RMV) lahko preprečimo z odkrivanjem in zdravljenjem predrakavih sprememb. Za nastanek RMV je ključna okužba z visokotveganimi genotipi humanih papilomavirusov (HPV). Bris materničnega vratu (BMV) za citološko analizo – test PAP in na viruse HPV – test HPV, kolposkopija in histološka verifikacija spremembe na MV so metode diagnosticiranja intraepitelijske lezije visoke stopnje MV (CIN2+) in RMV. Uvedba testa HPV v presejalne programe zahteva triažo HPV pozitivnih žensk. Pomembno je ločiti ženske z velikim tveganjem za razvoj CIN2+ in RMV od žensk z minimalnim tveganjem. Ker se poteka okužbe ne da predvideti, je potrebna vključitev dodatnih bioloških označevalcev. Eden od takih testov je dvojno imunocitokemično barvanje p16/Ki-67 (test p16/Ki-67). Izziv je odkritje CIN2+ in zgodnjih oblik RMV z optimalnim številom postopkov in vrnitev ženske v redno presejanje. Namen raziskave je bila opredelitev pomena testa p16/Ki-67 v odkrivanju CIN2+, določitev pomena števila pozitivnih celic v BMV pri diagnosticiranju CIN2+ pri ženskah, obravnavanih v kolposkopski ambulanti. Želeli smo ugotoviti, ali lahko test p16/Ki-67 zmanjša število kolposkopij in spremeni klinično obravnavo žensk. Raziskava je bila razdeljena na prospektivi in retrospektivi del. Vključili smo 174 žensk, iz nadzorovane randomizirane raziskave Test HPV doma , ki je v okviru Državnega presejalnega programa ZORA, potekala od avgusta 2013 do julija 2016. Pri vseh ženskah smo naredili ginekološki pregled, odvzeli BMV, opravili kolposkopijo in po potrebi naredili biopsijo. V retrospektivnem delu smo v raziskavo vključili 169 žensk z izvidom BMV APC-VS izmed 77.430 BMV iz rednega presejalnega programa od 1. oktobra 2011 do 1. oktobra 2013. Za vse ženske smo pridobili histološki izvid biopsije in/ali rezultate enoletnega citološkega sledenja z BMV. V prospektivnem delu smo analizirali rezultate testa p16/Ki-67 BMV in število pozitivno obarvanih celic. Opredelili občutljivost, specifičnost, pozitivno napovedno vrednost (PNV), negativno napovedno vrednost (NNV) testa p16/Ki-67 v odkrivanju CIN2+, opredelili tveganje za CIN2+ glede na število pozitivno obarvanih celic. V retrospektivnem delu smo opredelili občutljivost, specifičnost, PNV in NNV testa p16/Ki67 v odkrivanju CIN2+. Za celotno populacijo 343 žensk smo opredelili pomen testa p16/Ki-67 v odkrivanju CIN2+, določili diagnostični pomen testa glede na starost žensk in vpliv na delež kolposkopij. V prospektivnem delu je imelo 42 od 174 žensk (24,1%) histološki izvid CIN2+. Dokazali smo, da se tveganje za CIN2+ povečuje s številom pozitivno obarvanih celic v BMV (p ˂ 0,001). Skupna občutljivost testa za odkrivanje CIN2+ je bila 88,1%, specifičnost 65,2%, PNV je bila 44,6% in NNV 94,5%. V retrospektivnem delu raziskave je 97 žensk od 169 (57,4%) imelo izvid CIN2+. Skupna občutljivost testa p16/Ki-67 za odkrivanje CIN2+ je bila 94,8%, specifičnost 72,2%, PNV 82,1% in NNV 91,2%. V celotni populaciji 343 žensk je imelo 139 žensk (40,5%) izvid CIN2+. Skupna občutljivost testa p16/Ki-67 za odkrivanje CIN2+ je bila 92,8%, specifičnost 67,6%, PNV 66,1% in NNV 93,2%. Primerjava občutljivosti in specifičnosti testa p16/Ki-67 s testom PAP APC-N+ v odkrivanju CIN2+ ni pokazala statistično pomembne razlike. Statistično pomembna razlika je bila v PNV (p < 0,05) in NNV (p < 0,05), test p16/Ki-67 je bil zaneslivejši. Analiza razlik v občutljivosti in specifičnosti testa p16/Ki-67 v odkrivanju CIN2+ v posameznih starostnih skupinah v raziskavi ni pokazala statistično pomembnih razlik. Statistično pomembno razliko smo zaznali v NNV testa p16/Ki-67 (p < 0,05) pri ženskah, mlajših od 30 let, in ženskah starejših od 30 let.V raziskavi smo dokazali, da test p16/Ki-67 kot triažni test za kolposkopijo zmanjša število potrebnih kolposkopij za dokaz enega primera CIN2+ in lahko zmanjša število napotitev na kolposkopijo. Ob tem nismo ugotovili statistično pomembne manjše občutljivosti tega testa v primerjavi s testom PAP.

Keywords

citologija materničnega vratu;intraepitelijska lezija visoke stopnje;imunocitokemično dvojno barvanje p16/Ki-67 - test p16/Ki-67;

Data

Language: Slovenian
Year of publishing:
Typology: 2.08 - Doctoral Dissertation
Organization: UM MF - Faculty of Medicine
Publisher: S. Salobir Gajšek]
UDC: 618.146-006-076.5:576/577.2.083(043.3)
COBISS: 145218563 Link will open in a new window
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Other data

Secondary language: English
Secondary title: Evaluation of p16/ki-67 dual-stained cytology on clinical evaluation and treatment of women with pathological pap smear of the cervix uteri
Secondary abstract: Cervical cancer (CC) can be prevented by detecting and treating precancerous lesions. High-risk human papillomavirus (hrHPV) infection is confirmed to be the essential etiological agent of CC development.The introduction of the HPV test in screening programs requires the triage of HPV-positive women. How to distinguish between HPV-positive women at high risk for developing CIN2+ and CC from women at minimal risk. The aim of our study was to confirm the diagnostic accuracy of p16/Ki-67 DS in cervical cytology and the number of positive p16/Ki-67 cells to diagnose CIN2+ in the population that underwent colposcopy. We also wanted to determine whether the p16/Ki-67 DS could reduce referrals for colposcopy and change the clinical practice in the management of women. The research was divided into two parts, prospective and retrospective. In the prospective part of the research, we performed an analysis on a subset cohort of 174 women enrolled within a large-scale randomised controlled HPV self-sampling project organised as part of the population-based Cervical Cancer Screening Programme ZORA in Slovenia in the period from August 2013 to July 2016. We did a gynecological examination, cervical smear for cytologic examination, colposcopy, and colposcopy-guided biopsy if necessary. In the retrospective part of the study, we included 169 women with PAP cytology ASC-H from 77,430 women from the regular screening program from October 1, 2011 to October 1, 2013. For all women, we obtained histological biopsy and / or cytological one year follow-up. In the prospective part of the study, we analyzed the p16/Ki-67 DS cervical cytology and the number of p16/Ki-67 positive cells determined. We determined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the p16/Ki-67 DS for detection of CIN2+. In the retrospective part of the study, we also defined the sensitivity, specificity, PPV, and NPV of the p16/Ki-67 DS for CIN2 + detection. Finally, we defined the significance of the p16/Ki-67 DS for detection of CIN2+ for the entire population of 343 women and determined the diagnostic accuracy of p16/Ki-67 DS with respect to age and its influence on reduction of unnecessary colposcopy referrals. In the prospective part of the study, 42 of 174 women (24.1%) had histologically confirmed CIN2+. The risk for CIN2+ was increasing with the number of positive cells (p˂0.001). The sensitivity of p16/Ki-67 DS for detection of CIN2+ 88.1%, specificity 65.2%, PPV 44.6%, NPV 94.5%. In retrospective part of the study, 97 of 174 women (57.4%) had histologically confirmed CIN2+. The sensitivity of p16/Ki-67 DS for detection of CIN2+ 94.8%, specificity 72.2%, PPV 82.2%, NPV 91.2%. In the total population of 343 women, 139 (40.5%) had histologically confirmed CIN2+. The sensitivity of p16/Ki-67 DS for detection of CIN2+ 92.8%, specificity 67.6%, PPV 66.1%, NPV 93.2%. Comparison of clinical utility of p16/Ki-67 DS with cytology ASCUS+ (atypical squamous cells of undeterminated significance) in sensitivity and specificity for detection of CIN2+ between tests was not statistically significant, and difference between tests in PPV (p<0.05) and NPV (p<0.05) was statistically significant, p16/Ki-67 DS was better. Analysis of differences in the sensitivity and specificity of the p16/Ki-67 DS for detection of CIN2+ between age groups in our study was not statistically significant, a statistically significant difference was detected in the NPV p16/Ki-67 DS (p<0.05) between age under 30 and over 30 years. In the study, we demonstrated that dual immunocytochemical staining p16/Ki-67 as a triage test for colposcopy reduces the number of colposcopies required to detect a single case of CIN2+ and reduce referrals for colposcopy. At the same time, we did not find a statistically significant decrease in the sensitivity of the p16/Ki-67 DS compared to PAP cytology.
Secondary keywords: cervical cytology;high-grade dysplasia;p16/Ki-67 immunostaining;
Type (COBISS): Dissertation
Thesis comment: Univ. v Mariboru, Medicinska fak.
Pages: XI, 75 str.
ID: 13765336