The Role of p16/Ki-67 Immunostaining, hTERC Amplification and Fibronectin in Predicting Cervical Cancer Progression: A Systematic Review

Abstract

Human papillomaviruses (HPVs) are common sexually transmitted infectious agents responsible for several anogenital and head and neck cancers. Cervical cancer (CC) is the fourth leading cause of death in women with cancer. The progression of a persistent HPV infection to cancer takes 15–20 years and can be preventable through screening. Cervical cytology (Pap smear) is the standard screening test for CC and precancerous lesions. For ASC-US and ASC-H lesions, a combination of Pap smear and HR-HPV analysis is recommended as a triage step before colposcopy. However, these tests cannot predict progression to CC. For this purpose, we summarized current scientific data on the role of p16/Ki-67 immunohistostaining, telomerase and fibronectin in predicting progression to CC. p16 and p16/Ki-67 dual staining (DS) were more specific than HR-HPV DNA testing for the detection of CIN2+/CIN3+ in women with ASC-US and LSIL. Similarly, hTERC FISH analysis significantly improved the specificity and positive predictive value of HPV DNA testing in differentiating CIN2+ from CIN2 cytological samples. In conclusion, p16 IHC, p16/Ki-67 DS and hTERC FISH amplification are all valid adjunctive biomarkers which significantly increase the sensitivity and specificity of cervical dysplasia diagnosis, especially when combined with HPV DNA testing. However, considering the global socioeconomic background, we can postulate that p16 and p16/ Ki-67 IHC can be used as a next step after positive cytology for ASC-US or LSIL specimens in low-income countries, instead of HPV DNA testing. Alternatively, if HPV DNA testing is covered by insurance, p16 or p16/Ki-67 DS and HPV DNA co-testing can be performed. In middle- and high-income countries, hTERC amplification can be performed as an adjunctive test to HPV DNA testing in women with ASC-US and LSIL.

False-Positive Atypical Endocervical Cells in Conventional Pap Smears: Cyto-Histological Correlation and Analysis

“…Meanwhile, hrHPV-positive cases are problematic and will continue to be a source of overdiagnoses and added costly diagnostic procedures until more specific biomarkers are introduced. Among liquid-based cervical cytological samples with mild squamous atypia, the use of p16/Ki-67 dual stain has been shown to be more specific than the hrHPV testing and cytology in detecting HSILs and carcinomas [61, 62]. Although the data are still limited, the p16/Ki-67 dual stain also appears to be useful in the diagnosis of endocervical glandular atypia [62].…”

The potential and promise for clinical application of adoptive T cell therapy in cancer

“…Furthermore, a study found that modifying CAR-T cells to secrete heparinase enzyme could destroy the tumor matrix and improve tumor infiltration while increasing anticancer efficacy [ 160 ]. Fibronectin, an essential scaffold of the ECM, acted as a barrier between T cells and tumor cells, significantly affecting T cell infiltration [ 161 ]. Extra domain A (EDA) and extra domain B (EDB), two selectively spliced fibronectin exons, are overexpressed in most cancers but barely expressed in healthy tissues [ 162 ].…”

Enhancing Cervical Cancer Screening: Review of p16/Ki-67 Dual Staining as a Promising Triage Strategy

“…The most striking advantage of p16/Ki-67 dual staining is its heightened sensitivity for detecting CIN2+ or CIN3+ lesions, which are precursors of cervical cancer [61,64,67]. Studies have consistently indicated that the sensitivity of dual staining is markedly higher than that of traditional cytology.…”