Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis

Abstract

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 r10% 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 wildtype 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 (Po0.001). 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.

The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumors

“…Defining TP53 positivity by an arbitrary cutoff such as 10% makes no sense considering the biological (ie, mutational) correlate for the aberrant or 'all or nothing' staining pattern. 23,26,28 It has been previously shown that diffuse strong TP53 overexpression in at least 50-60% of the tumor Complete absence of staining indicates null mutation, in which a deleterious mutation leads to mRNA, which is degraded by nonsense-mediated decay. 26 Further studies to confirm these associations are warranted.…”

“…As previously shown, the TP53-staining patterns correlate with the mutational status of TP53 ( Figure 1). 23,26 Complete absence of TP53 indicates TP53 null mutation, whereas TP53 overexpression is indicative of TP53 missense mutation, and any staining pattern in between suggests wild-type TP53. The two extreme staining patterns ('all or nothing') are combined as aberrant expression, suggesting any type of TP53 mutation.…”

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

“…Absence of p53 nuclear reactivity or nuclear reactivity in ≥ 60% of tumor cells was considered to be an abnormal pattern and suggestive of TP53 mutation. 24 For cases represented by more than one tumor core, absence of p53 nuclear reactivity in all cores or ≥ 60% nuclear reactivity in any core was considered an abnormal pattern.…”

Diagnostic and Prognostic Significance of p16, p53, and bcl-2 Expressions and Ki-67 Proliferation Index in Benign and Malignant Uterine Smooth Muscle Tumors

“…Mota et al (23) investigated the presence of p53 mutations in high-grade serous ovarian carcinomas and reported that the most common p53 mutations were missense mutations; tumors with these mutations had strong and diffuse immunohistochemical p53 positivity. However, the authors defined these tumors as TP53 null cell tumors in the presence of somatic (nonsense, frameshift, and splice junction) p53 mutations, accounting for 30% of all cases, and reported the complete absence of p53 expression by immunohistochemistry in these tumors (23,24); moreover, cases with p53 null mutations had a worse clinical course. In our study, p53 overexpression was found to be statistically significant in the distinction of LMS from benign tumors (p=0.006).…”