[1073] Correlation of Immunohistochemistry and Mutation Status of PTEN in Endometrial Carcinoma

B Djordjevic, B Hennessy, R Broaddus. M.D. Anderson Cancer Center, Houston, TX

Background: PTEN is a tumor suppressor that negatively regulates the PI3K signaling pathway, which has been implicated in the pathogenesis of endometrial carcinoma, with PTEN mutations occurring at high frequency. With the advent of targeted therapy and PI3K inhibitors entering clinical trials, gynecologic pathologists must accurately identify endometrial cancer patients that may benefit from these new treatments. However, PTEN mutations are highly variable in type, and their detection necessitates the use of full-length sequencing, which cannot be feasibly employed in routine clinical practice. The aim of this study was to evaluate the fidelity of immunohistochemistry (IHC) for PTEN as a surrogate for assessment of PTEN mutation status.
Design: A cohort of 156 tumors comprised of 101 endometrioid and 55 non-endometrioid cases was subjected to full-length PTEN sequencing to detect mutations as well as PTEN IHC analysis. The antibody was previously validated on cancer cell lines known to be PTEN positive or negative. IHC staining was scored as positive (>90% of tumor with diffuse cytoplasmic staining), negative (0% of tumor cells staining) and heterogeneous (distinct positive and negative foci). Adjacent normal tissue was used as an internal positive control.
Results: PTEN mutation status and immunohistochemistry are summarized in the table below.

IHC	Mutation Detected	Mutation Not Detected	Total
Negative	25 (68%)	45 (38%)	70 (45%)
Heterogenous	6 (16%)	21 (18%)	27 (17%)
Positive	6 (16%)	53 (44%)	59 (38%)
Total	37	119	156

In 56% of cases in which mutations were not detected, IHC identified PTEN protein loss (negative and heterogeneous groups). In the group with a detected mutation, IHC showed a strong PTEN signal in 16% of cases. All of these cases were heterozygous at the mutation locus. By histotype, IHC detected PTEN protein loss in a substantially higher percentage of non-endometrioid tumors than did PTEN mutational analysis (41% vs. 13%) and a dramatically higher percentage of endometrioid tumors (75% vs. 29%).
Conclusions: The assessment of PTEN status by sequencing may under-estimate the number of women with endometrial cancer potentially eligible for targeted therapy using PI3K inhibitors. IHC detects more cases with PTEN loss than does PTEN full-length sequencing in addition to being less costly and labor intensive. As such, PTEN IHC represents a useful tool for the gynecologic pathologist.
Category: Gynecologic & Obstetrics

Monday, March 22, 2010 9:30 AM

Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 151, Monday Morning