TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma--evidence supporting the clonal relationship of the two lesions

Abstract

Serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of ovarian, tubal and 'primary peritoneal' (pelvic) high-grade serous carcinoma (HGSC). As somatic mutation of TP53 is the most common molecular genetic change of ovarian HGSC, occurring in more than 95% of cases, we undertook a mutational analysis of 29 pelvic HGSCs that had concurrent STICs to demonstrate the clonal relationship of STICs and HGSCs. In addition, we correlated the mutational data with p53 immunostaining to determine the role of p53 immunoreactivity as a surrogate for TP53 mutations in histological diagnosis. Somatic TP53 mutations were detected in all 29 HGSCs analysed and the identical mutations were detected in 27 of 29 pairs of STICs and concurrent HGSCs. Missense mutations were observed in 61% of STICs and frameshift/splicing junction/nonsense mutations in 39%. Interestingly, there were two HGSCs with two distinctly different TP53 mutations each, but only one of the mutations was detected in the concurrent STICs. Missense mutations were associated with intense and diffuse (≥ 60%) p53 nuclear immunoreactivity, while most of the null mutations were associated with complete loss of p53 staining (p < 0.0001). Overall, this p53 staining pattern yielded a sensitivity of 87% and a specificity of 100% in detecting TP53 missense mutations. In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histological diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation, whereas complete absence of staining correlates with null mutations.

Figure 1

p53 immunoreactivity in representative normal Fallopian tubes and serous tubal intraepithelial carcinomas (STICs). (A) Normal Fallopian tube epithelium is negative for p53. (B) Normal Fallopian tube epithelium shows only single nuclei weakly positive for p53. This pattern is related to normal functional activation of wild-type p53 following a cellular stress. (C) An example of a STIC with a missense mutation of TP53 demonstrates intense and diffuse p53 positivity, while the adjacent normal-appearing Fallopian tube is negative for p53 staining (*, STIC cells). (D) Another STIC with a TP53 null mutation shows lack of nuclear p53 immunoreactivity (*, STIC cells).

Figure 2

Histological appearance, p53 staining, and TP53 mutation status in lesions of case 29. (A) Low magnification of a haematoxylin and eosin-stained section shows a segment of Fallopian tube and paratubal soft tissue containing multiple foci of high-grade serous carcinoma and serous tubal intraepithelial carcinomas (STICs). (B) The high-grade serous carcinoma is diffusely and intensely positive for p53. (C) High-grade serous carcinoma from another region is completely negative for p53. (D, E) Two discrete STICs are negative for p53.