Predictive value of p16INK4a, Ki‑67 and ProExC immuno‑qualitative features in LSIL progression into HSIL

Abstract

The current nested case-control study was conducted to explore the prognostic value of cyclin-dependent kinase inhibitor 2A (p16 INK4a), marker of proliferation Ki-67 (Ki-67) and immunohistochemical cocktail containing antibodies directed against topoisomerase IIα (TOP2A) and minichromosome maintenance 2 (MCM2) proteins (ProExC) immuno-qualitative features to predict low-grade squamous intraepithelial lesion (LSIL) progression. A total of 92 LSIL patients were followed-up for 2 years, where those with high-grade squamous intraepithelial lesion (HSIL) or persistent LSIL were designated as the case group and those who spontaneously regressed were designated as the control group. The infection status of human papillomavirus (HPV) was evaluated using flow-through hybridization and gene chip, whilst the expression of p16 INK4a , Ki-67 and ProExC were tested in LSIL patient biopsies by immunohistochemistry. All data were collected at the beginning of the follow-up and patient outcomes were diagnosed by histopathological examination. To analyze the risk factors for LSIL progression, sensitivity, specificity, positive-negative predictive value (PPV-NPV), positive-negative likelihood ratio (PLR-NLR), Youden's index (YI) and multinomial logistic regression analysis was performed. The expression rates of p16 INK4a , Ki-67, and ProExC were found to be higher in the progression group compared with those in the persistence and regression groups. Only p16 INK4a expression significantly associated with high-risk HPV infection. With respect to predicting HSIL, p16 INK4a staining was the most sensitive but Ki-67 staining was found to be the most specific. YI was the highest (42.1%) for p16 INK4a expression in the present study, followed by ProExC (39.5%) and Ki-67 (28.3%). However, the expression of ProExC was found to be an independent risk factor for LSIL progression into HSIL. In conclusion, whilst immunohistochemical staining for p16 INK4a , Ki-67, and ProExC can be used to predict HSIL progression, only ProExC expression can be applied an independent risk factor for LSIL progression.

Expression analysis of p16 and TOP2A protein biomarkers in cervical cancer lesions and their correlation with clinico-histopathological characteristics in a referral hospital, Tanzania

“…Several histological studies have reported the application of most common cellular biomarkers, including Ki-67, cyclin-dependent kinase inhibitor (p16), and ProEx C [topoisomerase II-alpha (TOP2A) and minichromosomal maintenance-2 (MCM2)] in the early diagnosis of cervical cancer [ 14 – 17 ]. Recently, Ki-67 has been demonstrated to be an important cell proliferation biomarker for malignant lesions among women in Tanzania [ 18 , 19 ].…”

“…However, several cancer biomarkers, especially when applied individually, may not detect cervical cancer as it develops, making them unsuitable for early diagnosis of cervical cancer [ 16 , 20 , 21 ]. However, a combination of biomarkers may improve the sensitivity and specificity of cancer detection in discriminating altered cells from normal cells across age groups [ 14 , 15 , 21 – 23 ]. During the pathogenesis of cervical cancer, the expression of E7 viral oncoprotein inactivates retinoblastoma proteins (pRb), which consequently increases the E2F activation factors in the cell, which leads to increased p16 in the S-phase of the cell cycle.…”

“…Likewise, the TOP2A gene encodes for DNA topoisomerase, a nucleic enzyme responsible for unwinding supercoiled DNA strands during its replication in the S-phase of the cell cycle [ 22 , 24 ]. Expression levels of p16 and TOP2A biomarkers have been reported for early diagnosis of cervical cancer in high-resource countries, [ 14 , 15 , 22 , 25 ] which necessitates the need for their feasibility study in low-resource settings.…”

Predictive Value of Marker of Proliferation Ki-67 and Cell Cycle Dependent Protein kinase Inhibitor P16INK4a in Cervical Biopsy to Determine Its Biological Behaviour

“…(Quin Shi et al, 2019) which is similar to the present study. Ding et al, (2020) reported the importance of both P16 INK4a and Ki-67 immunostaining in the LSIL category to predict the outcome in future as their study provides new insight into identifying LSIL patients at a higher risk of malignant progression, potentially facilitating more cost-effective and efficient interventions (Ding et al, 2020). The limitation of our study is the small sample size.…”

Cervical cancer risk profiling: molecular biomarkers predicting the outcome of hrHPV infection

“…Additionally, Ding et al recently demonstrated that women with an initial diagnosis of LSIL by ProEx™ C immunostaining have a higher risk of developing HSIL in the next two years. They showed that this test might achieve a sensitivity of 75.0%, specificity of 64.5%, PPV of 30.8%, and NPV of 92.40% in LSIL lesions that may progress to HSIL [142]. Therefore, these overall results suggest that TOP2A/MCM2 biomarkers have excellent performance for both low and highgrade lesions.…”