Diagnostic value of p16 and Ki-67 expression in cervical glandular intraepithelial disease: A review

The development of neoplasia is associated with abnormalities in cell cycle control and in the mechanisms of apoptosis. The cell cycle is the set of phases through which the cell passes from its origin to its duplication. This sequence of phases, with their respective checkpoints, allows the cell to complete its normal cycle, while maintaining the integrity of its genoma [1]. Progression through the cell cycle is controlled by proteins called cyclin dependent kinases (CDKs) and their inhibition controlled by CDK inhibitors (CDKis). Cell division stimulating genes are proto-oncogenes and cycle-blocking genes are tumor suppressor genes. Mutations in these genes lead to the loss of normal cell cycle controlling mechanisms [1].

Genes that control life span or program cell death also directly intervene in tumor genesis [1]. All cells carry control programs of their lifetime, among these mechanisms, apoptosis provides a quickly elimination of unnecessary or dangerous cells [1]. Telomerase deserves to be highlighted as a gene that determines cell life and death. Its normal function protects the chromosome, allowing repair of eventual damages and stabilizing the genome [1].

Molecular markers enter this scenario as a diagnosis, prognostic and therapeutic perspective. By understanding the mechanism of action of the genes involved in tumor genesis, it is possible to intervene deactivating inappropriately activating oncogenesis, inducing defective cells to apoptosis, preventing proliferation and metastasis [1].

P16 is a regulatory protein of the cell cycle. Its main function is the inhibition of cyclin-dependent kinases (CDK4 and CDK6) that are needed to phosphorylate the retinoblastoma protein (pRb). It is a marker of the oncogenic activity of the HPV E7 protein, which has the ability to bind to pRb leading to rapid cell cycle progression with loss of control over DNA integrity. This binding to pRb releases p16 production from its negative feedback control, with its levels increasing in the cell, in an attempt to inhibit this uncontrolled proliferation. Therefore, abnormal p16 expression is a marker of pRb E7 mediated inactivation and can be used as an indicator of high risk HPV with transformation potential [3], [14]. P16 indicates much more than the presence of a high-risk virus [12]. High-risk HPV can be present without anything happening, p16 is a sensitive and specific marker of potentially transforming lesions.

Through immunohistochemistry, p16 can be observed as cytoplasmic and/or nuclear staining. Mutations in this protein and/or its inactivation have been demonstrated in numerous cancers [7].

The importance of p16 in squamous intraepithelial lesions is well established. Based on LAST recommendations, p16 immunohistochemistry is a sensitive and specific method for diagnosing HPV DNA positive cervical squamous intraepithelial lesions [14] and it is well defined that p16 overexpression is associated with carcinoma.

HPV-induced cervical glandular lesions are almost invariably p16 positive [3], however, there is still no consensus on the use of the biomarker in these lesions [12]. Some benign conditions also present overexpression of p16, such as endocervical tubal metaplasia and endometrial glands.

Ki-67 is a nuclear protein. It is considered a marker of cell proliferation and is expressed in all phases of cell division [9]. The immunostaining of ki-67 in the squamous epithelium of the normal uterine cervix is restricted to the basal layers, as they are in constant renewal, in these layers there will always be cells in mitosis and marking for Ki-67. When this labeling is detected in other layers of the epithelium, it can be suggested that there is deregulation of the cell cycle.

Ki-67 was one of the first markers used in an attempt to better define glandular lesions. Studies show an increased expression in adenocarcinomas but it is not a specific marker of neoplastic diseases, it also has expression in non-neoplastic conditions [2].

The incidence of adenocarcinoma has been increasing every year, it affects young women and the diagnosis of glandular lesions has many limitations. Unlike squamous lesions, the cytological criterias for identifying glandular neoplasms are not well established and colposcopic changes are not very clear. In addition to technical difficulties, there is great inter-observer variability and many benign situations that mimic glandular diseases, like inflammatory processes, response to irradiation, microglandular hyperplasia and tubo endometrioid metaplasia. Therefore, there is a great need for more specific methods to improve the diagnosis of glandular lesions in screening programs, allowing potential intervention in precursor lesions before they become invasive, and also reducing the number of unnecessary surgeries in benign glandular pathologies that mimic diseases.

Immunohistochemistry is a valuable adjunct while performing cervical histopathology, it can aid to distinguish cervical glandular dysplasia and adenocarcinoma from reactive changes [6]. Biomarkers can be used in both biopsy specimens and cytology smears. Proteins that regulate the cell cycle generally exhibit aberrant patterns of expression in cervical squamous neoplasms, but there are few studies of these markers in adenocarcinomas [10].

This review aims to evaluate the scientific data related to the use of p16 and Ki-67 as auxiliary tools in the diagnosis of glandular diseases.

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