J Pathol Transl Med.  2021 Mar;55(2):102-111. 10.4132/jptm.2020.10.22.

The prognostic significance of p16 expression pattern in diffuse gliomas

• Park JW
• Kang J
• Lim KY
• Kim H
• Kim SI
• Won JK
• Park CK
• Park SH

• KMID: 2513895
• DOI: http://doi.org/10.4132/jptm.2020.10.22

Abstract

Background
CDKN2A is a tumor suppressor gene that encodes the cell cycle inhibitor protein p16. Homozygous deletion of the CDKN2A gene has been associated with shortened survival in isocitrate dehydrogenase (IDH)–mutant gliomas. This study aimed to analyze the prognostic value of p16 and to evaluate whether p16 immunohistochemical staining could be used as a prognostic marker to replace CDKN2A genotyping in diffuse gliomas.
Methods
p16 immunohistochemistry was performed on tissue microarrays of 326 diffuse gliomas with diagnoses that reflected IDH-mutations and 1p/19q codeletion status. The results were divided into three groups (negative, focal expression, overexpression) according to the presence and degree of p16 expression. Survival analysis was performed to assess the prognostic value of p16 expression.
Results
A loss of p16 expression predicted a significantly worse outcome in all glioma patients (n=326, p<.001), in the IDH-mutant glioma patients (n=103, p=.010), and in the IDH-mutant astrocytoma patients (n=73, p=.032). However, loss of p16 expression did not predict the outcome in the IDH-wildtype glioma patients (n=223, p=.121) or in the oligodendroglial tumor patients with the IDH-mutation and 1p/19q codeletion (n=30, p=.457). Multivariate analysis showed the association was still significant in the IDH-mutant glioma patients (p=.008; hazard ratio [HR], 2.637; 95% confidence interval [CI], 1.295 to 5.372) and in the IDH-mutant astrocytoma patients (p=.001; HR, 3.586; 95% CI, 1.649 to 7.801). Interestingly, patients who presented with tumors with p16 overexpression also had shorter survival times than did patients with tumors with p16 focal expression in the whole glioma (p< .001) and in IDH-mutant glioma groups. (p=.046).
Conclusions
This study suggests that detection of p16 expression by immunohistochemistry can be used as a useful surrogate test to predict prognosis, especially in IDH-mutant astrocytoma patients.

Keyword

Glioma; p16; Immunohistochemistry; Prognosis

Figure

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  Fig. 1 Representative images of p16 immunohistochemical staining. If immunopositive cells were absent or made up < 1% of cells, the tumor was classified as having a loss of expression (A). Conversely, tumors with > 1% of immunopositivity were considered to have retained expression, which was further subdivided into focal expression (B, C) or overexpression (D) according to the degree of p16 expression on a 50% basis. B and C show the range of focal expression.

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  Fig. 2 Ki-67 labeling index according to p16 expression status (A) and the degree of p16 expression (B). IHC, immunohistochemistry.

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  Fig. 3 Kaplan-Meier curves for overall survival according to p16 expression status: (A) whole gliomas, (B) IDH-mutant gliomas including oligodendrogliomas, (C) IDH-wildtype astrocytomas, and (D) IDH-mutant astrocytomas. IDH, isocitrate dehydrogenase; IHC, immunohistochemistry.

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  Fig. 4 Kaplan-Meier curves for overall survival according to the degree of p16 expression: (A) whole gliomas, (B) IDH-mutant gliomas including oligodendrogliomas, (C) IDH-wildtype astrocytomas, and (D) IDH-mutant astrocytomas. IHC, immunohistochemistry; IDH, isocitrate dehydrogenase.

Reference

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