Dissertation committee:
Γοργούλης Βασίλειος, Καθηγητής, Τμήμα Ιατρικής, ΕΚΠΑ
Ροδολάκης Αλέξανδρος, Καθηγητής, Τμήμα Ιατρικής, ΕΚΠΑ
Δασκαλάκης Γεώργιος, Καθηγητής, Τμήμα Ιατρικής, ΕΚΠΑ
Παππά Καλλιόπη, Καθηγήτρια, Τμήμα Ιατρικής, ΕΚΠΑ
Θωμάκος Νικόλαος, Αναπληρωτής Καθηγητής, Τμήμα Ιατρικής, ΕΚΠΑ
Βραχνής Νικόλαος, Αναπληρωτής Καθηγητής, Τμήμα Ιατρικής, ΕΚΠΑ
Παπαπαναγιώτου Αγγελική, Αναπληρώτρια Καθηγήτρια, Τμήμα Ιατρικής, ΕΚΠΑ
Summary:
Introduction: Cervical cancer (CxCa), although preventable, remains a global health problem despite the availability of effective screening methods. The World Health Organization in 2020 announced the strategy to eliminate cervical cancer by 2030 based on three targets. Specifically, vaccinating 90% of young girls, screening 70% of eligible women twice in their lifetime, and treating 90% of precancerous lesions or invasive cancer.
For decades, regular Pap smear testing has contributed to substantial reductions in Cervical Cancer morbidity and mortality. On the other hand, the causal relationship between the infection with high-risk type of human papillomavirus (HR-HPV) and the development of cervical cancer has led to the introduction of HPV testing into organized population control programs. However, it is a fact that it is impossible and at the same time ineffective to refer all HPV positive women to colposcopy, as a high percentage of HPV infections will regress spontaneously. Therefore, it is imperative to find suitable screening tests for the early detection of HR-HPV positive women who have an increased likelihood of developing cervical high-grade lesions or CxCa. In search of an objective biomarker with high clinical performance, evidence in the recent literature has showed that dual immunocytochemical staining (p16/Ki-67 dual-stain) may be a reliable triage screening test.
Aim: The present doctoral thesis aimed to initially evaluate the diagnostic accuracy ofp16/Ki-67 dual-stain, as a triage method for detecting underlying cervical intraepithelial neoplasia grade 2 or worse (CIN2+). In addition, the suitability of the biomarker as a triage test was investigated in existing primary screening strategies for the most effective management of women with mild and equivocal cytological findings or HR-HPV positive.
Materials and Method: According to the study design, women aged 20 to 60 years old who proceeded to the Clinic of Cervical Pathology and Colposcopy of the General Hospital of Athens «Alexandra», for their annual cytology-based primary screening examination, were recruited. The final study cohort comprised of 759 cases with negative, equivocal, or low-grade cytological findings. Each liquid-based cytology sample was tested for HPV DNA detection and dual-stained cytology (p16/Ki-67 dual-stain). Patients were subsequently referred to colposcopy with cervical biopsy for histological diagnosis. Women with CIN2+ histologic evaluations were managed accordingly to their individual medical history and the national guidelines while patients with negative results or Results: The main findings of the study were the following: regarding the prevalence of high-risk (HR-HPV) types of the virus in the study population, HPV16 was the predominant genotype with a prevalence of 17.4%, followed by HPV31 and HPV51 (9.9% and 7.6%, respectively). Infection by HPV18 and HPV16 has been a stronger risk factor for the development of CIN2+ lesions with OR: 53.16 and OR: 11.31, respectively compared to the other HR-HPV types. HR-HPV and p16/Ki-67 dual-stain positivity rates increased with histopathological lesions severity. Specifically, HR-HPV rates increased as dysplasia deteriorated from 37.6% in No CIN, to 62.5% in CIN1 cases through 98.7% in CIN2+ lesions. In addition, dual stain cytology rates were higher from 0% in No CIN, to 1.6% in CIN1 through 97.3% in CIN2+ histological evaluations. Concerning the clinical efficiency analysis of the diagnostic methods our findings, similar to other published studies, illustrated that both p16/Ki-67 dual-stained cytology and HR-HPV test presented similar high sensitivity of 97.3% and 98.7%, respectively. However, p16/Ki-67 dual-stain provided higher specificity values of 99.3% superior to that of the HR-HPV test (52.2%,) with statistical significance (p <0.005). Furthermore, considering the ASCCP primary screening guidelines of referring for colposcopy women tested positive for HPV16/18 or for the rest 12 HR-HPV types with positive cytology results of ASCUS or higher, we studied and evaluated different screening scenarios according to colposcopy referrals. Concerning the population of the study, the ASCCP algorithm would require 352 colposcopies to detect 147 out of 149 actual CIN2+ cases (2.4 colposcopies/CIN2+ case). Interestingly, the implementation of p16/Ki-67 dual-stain as a triage method in the ASCCP guideline as well as in different existing screening strategies has led to a decrease in the number of colposcopies to detect CIN2+ cases, resulting in a ratio of 1.0 colposcopy needed per CIN2+ incident.
Conclusions: As a conclusion, the results of this doctoral thesis demonstrate the clinical utility of p16/Ki-67 dual-stained cytology as a triage method for the effective management of women with mild cervical abnormalities. p16/Ki-67 dual-stain in accordance with other studies is an objective biomarker with equal high sensitivity and significantly higher specificity versus HR-HPV test for CIN2+ detection. In addition, the findings support the use of dual stained cytology as a triage test in existing screening strategies by minimizing references for colposcopy. Especially in countries, such as Greece, with mainly opportunistic screening, based on cytological examination, the implementation of p16/Ki-67 dual-stain, could provide accuracy and financial benefits for the healthcare system.
Keywords:
Cervical cancer, Human papillomavirus (HPV), p16/Ki-67 dual-stained cytology, Primary screening, Risk stratification
