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PI3K Pathway Effectors pAKT and FOXO1 as Novel Markers of Endometrioid Intraepithelial Neoplasia

Strickland, Amanda L. M.D.; Rivera, Glorimar M.D.; Lucas, Elena M.D.; John, George Ph.D.; Cuevas, Ileana Ph.D.; Castrillon, Diego H. M.D., Ph.D.

International Journal of Gynecological Pathology: November 2019 - Volume 38 - Issue 6 - p 503–513
doi: 10.1097/PGP.0000000000000549
Pathology of the Corpus: Original Articles

The diagnosis of endometrioid intraepithelial neoplasia (EIN) is challenging owing to limited sampling, hormonal status, and other confounding histologic variables. Markers such as PTEN or PAX2 can delineate EIN in some cases, but are not wholly reliable. Clearly, new markers of EIN are needed. We explored several potential markers of EIN based rationally on molecular pathways most frequently misregulated in endometrial cancer: the 3-phosphoinositide kinase (PI3K)/AKT, β-catenin, and mismatch repair pathways. We studied PTEN, PAX2, β-catenin, and MLH1, in conjunction with 2 new markers—FOXO1 and phosphorylated AKT (pAKT)—not previously investigated in EIN. Benign (n=14) and EIN (n=35) endometria were analyzed by immunohistochemistry. Staining patterns were interpreted, tabulated, and scored by “clonal distinctiveness” in neoplastic lesions; that is, pattern alterations relative to normal glands. In normal endometria, FOXO1 was cytoplasmic in proliferative phase, but nuclear in secretory phase, showing that PI3K/FOXO1 participates in endometrial cycling and that FOXO1 is a readout of PI3K status. pAKT expression was low across normal endometria. FOXO1 or pAKT expression was altered in the majority of EINs (27/35, 77%), with FOXO1 and pAKT being co-altered only in some (20/35, 57%). β-catenin or MLH1 also exhibited clonal distinctiveness in EINs, showing that these are also useful markers in some cases. This is the first study to demonstrate the potential of pAKT and FOXO1 as biomarkers in the histopathologic evaluation of EIN. However, variability in expression poses challenges in interpretation.

Department of Pathology and Simmons Comprehensive Cancer Center, Division of Gynecologic Pathology, UT Southwestern Medical Center, Dallas, Texas (A.L.S., G.R., E.L., G.J., I.C., D.H.C.)

Supported by CPRIT grant RP160211 to D.H.C. Research reported in this publication was also supported by the National Cancer Institutes of the National Institutes of Health under award number 5P30CA142543.

The authors declare no conflict of interest.

Address correspondence and reprint requests to Diego H. Castrillon, MD, PhD, Department of Pathology, UT Southwestern Medical School, 6000 Harry Hines Boulevard, NB6.452, Dallas, TX 75390-9072. E-mail:

©2019International Society of Gynecological Pathologists