Immunohistochemical Staining Patterns of p53 Can Serve as a Surrogate Marker for TP53 Mutations in Ovarian Carcinoma

An Immunohistochemical and Nucleotide Sequencing Analysis

Anna Yemelyanova; Russell Vang; Malti Kshirsagar; Dan Lu; Morgan A Marks; Ie Ming Shih; Robert J Kurman


Mod Pathol. 2011;24(9):1248-1253. 

In This Article

Abstract and Introduction


Immunohistochemical staining for p53 is used as a surrogate for mutational analysis in the diagnostic workup of carcinomas of multiple sites including ovarian cancers. Strong and diffuse immunoexpression of p53 is generally interpreted as likely indicating a TP53 gene mutation. The immunoprofile that correlates with wild-type TP53, however, is not as clear. In particular, the significance of completely negative immunostaining is controversial. The aim of this study was to clarify the relationship of the immunohistochemical expression of p53 with the mutational status of the TP53 gene in ovarian cancer. A total of 57 ovarian carcinomas (43 high-grade serous ovarian/peritoneal carcinomas, 2 malignant mesodermal mixed tumors (carcinosarcomas), 2 low-grade serous carcinomas, 4 clear cell carcinomas, 1 well-differentiated endometrioid carcinoma, and 5 carcinomas with mixed epithelial differentiation) were analyzed for TP53 mutations by nucleotide sequencing (exons 4–9), and subjected to immunohistochemical analysis of p53 expression. Thirty six tumors contained functional mutations and 13 had wild type TP53. Five tumors were found to harbor known TP53 polymorphism and changes in the intron region were detected in three. Tumors with wild-type TP53 displayed a wide range of immunolabeling patterns, with the most common pattern showing ≤10% of positive cells in 6 cases (46%). Mutant TP53 was associated with 60–100% positive cells in 23 cases (64% of cases). This pattern of staining was also seen in three cases with wild-type TP53. Tumors that were completely negative (0% cells staining) had a mutation of TP53 in 65% of cases and wild-type TP53 in 11%. Combining two immunohistochemical labeling patterns associated with TP53 mutations (0% and 60–100% positive cells), correctly identified a mutation in 94% of cases (P<0.001). Immunohistochemical analysis can be used as a robust method for inferring the presence of a TP53 mutation in ovarian carcinomas. In addition to a strong and diffuse pattern of p53 expression (in greater than 60% of cells), complete absence of p53 immunoexpression is commonly associated with a TP53 mutation. Accordingly, this latter pattern, unlike low-level expression (10–50% cells), should not be construed as indicative of wild-type TP53.


Mutations of the TP53 gene are the most common and most frequently studied molecular alterations in human cancer.[1–3] Many studies have investigated their significance in diagnosis, prognosis, and treatment in tumors of various sites. For example, the presence of a TP53 mutation in colorectal, lung, prostate, and breast carcinomas has been shown to be a poor prognostic factor, and for the tumors of other sites a TP53 mutation has been associated with chemoresistance in some studies.[4–9] Accordingly, detection of a TP53 mutation has taken on considerable importance in clinical practice.

While nucleotide sequencing is the most reliable technique to detect gene mutation, it is labor intensive, time consuming, and therefore, currently has limited application in clinical pathology practice. Immunohistochemical analysis of p53 expression is therefore commonly used as a surrogate for mutational analysis.[10–13] It has been generally accepted that wild-type p53 protein is relatively unstable and has a short half-life, which makes it undetectable by immunohistochemistry.[14] In contrast, mutant p53 has a much longer half-life, and therefore, accumulates in the nucleus creating a stable target for immunohistochemical detection.[15,16] Although some studies have described immunohistochemical overexpression of wild-type p53, suggesting abnormal stability of non-mutant protein due to impaired degradation under cellular stress, strong and diffuse immunolabeling is generally regarded as indicative of a missense mutation of TP53.[1,7,17] It has been proposed, but not as well appreciated that complete lack of immunohistochemical expression may be a result of a nonsense mutation leading to formation of a truncated, non-immunoreactive protein.[18–20] In view of these different patterns of immunoexpression associated with mutant TP53, it is therefore not surprising that studies correlating TP53 gene status and/or p53 overexpression with clinical outcome and response to chemotherapy in ovarian/pelvic serous carcinoma have reported conflicting results.[10,12,19,21–27] Some of the studies that focused on ovarian high-grade serous carcinomas failed to demonstrate correlation between TP53 mutation and survival that to some extent have been related to the fact that TP53 mutation is an early event in high-grade serous carcinogenesis with near ubiquitous occurrence.[21,25,28,29] In addition, accurate pathological classification of ovarian carcinoma is frequently lacking in many reports as evidenced by the use of the all encompassing diagnosis 'ovarian cancer', without segregating tumors by histological type. Particularly pertinent to the current study has been a failure to use a consistent definition of what constitutes p53 overexpression. Some studies have simply used a cuff-off of as little as 10% of positive cells staining, whereas other have employed complicated scoring systems, which take into account both the quantity of positive cells, as well as the staining intensity.[22,25,27,30,31] In addition to the lack of uniform scoring systems, variations in immunohistochemical protocols make data from different studies difficult to compare and interpret. The aim of this study was to correlate immunohistochemical staining patterns of p53 expression in ovarian carcinomas with mutational analysis in order to establish practical immunohistochemical cut-points, which can be used to infer the presence of a TP53 mutation.


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