Luteinizing Hormone/Human Chorionic Gonadotropin Receptor, GATA-4 and β-Catenin Expression in Human Adrenal Cortical Neoplasia

Presentation Number: MON 390
Date of Presentation: April 3rd, 2017

Nina Kogekar1, Kenneth Haines1, Alexander Kirschenbaum2, Shen Yao3, William B Inabnet III4 and Alice C Levine*5
1Icahn School of Medicine at Mount Sinai, 2Mount Sinai School of Medicine, New York, 3Mount Sinai School of Medicine, 4Mount Sinai Beth Israel Medical Center, 5Icahn School of Medicine at Mount Sinai, New York, NY

Abstract

Background: Post-gonadectomy induced adrenal cortical neoplasia has been reported in neutered ferrets and mice. These neoplasms demonstrate elevated expression of luteinizing hormone/human chorionic gonadotropin receptor (LH/hCGR), as well as expression of GATA-4, a transcription factor involved in the differentiation of gonadal tissues. Interestingly, adrenal cortical carcinomas (ACCs) in neutered ferrets completely regress with medical castration therapy using GnRH agonists. In humans, some aldosterone producing adenomas express LH/hCGR and GATA-4 and harbor activating mutations in β-catenin. However, there are few studies that have systematically examined LH/hCGR, GATA-4 and β-catenin protein expression with immunohistochemistry in human adrenal cortical neoplasia.

Hypothesis: Human adrenal neoplasms express LH/hCGR and GATA-4, and tissues with elevated expression of these markers may also demonstrate overexpression of β-catenin.

Materials & Methods: Archival adrenal tissues were immunostained for LH/hCGR, GATA-4, and β-catenin expression. Samples: 5 primary ACC, 2 liver metastases of ACC, 5 adrenal adenomas, 2 bilateral macronodular adrenal hyperplasia (BMAH), 1 adrenal rest tissue in a patient with untreated congenital adrenal hyperplasia (CAH; 21 hydroxylase deficiency), and 1 normal testis tissue (positive control). Slides were reviewed in a blinded fashion by three independent observers, and cytoplasmic, membrane, and nuclear expression of the markers was graded as 0, 1+, 2+ or 3+.

Results:. All adrenal tissues studied stained positive for LH/hCGR and GATA-4. Staining for both proteins in adrenal tissues was predominantly localized to the cytoplasm with some exceptions: membrane staining of LH/hCGR in 3/5 adrenal adenomas, and nuclear staining of GATA-4 in 1/5 adrenal adenomas and 1/5 ACC. Adrenal adenomas demonstrated a pattern of scattered, focal patches of intense expression of LH/hCGR and GATA-4, whereas the primary ACC specimens had a more diffuse, moderate intensity staining. In the normal testis tissues, Leydig cells exhibited cytoplasmic LH/hCGR and GATA-4 staining whereas Sertoli cells and spermatids had nuclear GATA-4 expression. All adrenal tissues studied also demonstrated some staining for β-catenin, that was predominantly cytoplasmic in ACC.

Conclusions:

We herein demonstrate that neoplastic and hyperplastic human adrenal cortical tissues, including adrenal cortical adenomas, BMAH, ACC primary and metastatic lesions, express both LH/hCGR and GATA-4, two proteins characteristic of gonadal cells. This indicates that human adrenal tumors also tend to differentiate toward a gonadal molecular profile, and may be sensitive to treatment with drugs acting on the gonadal axis. Concomitant β-catenin expression implies that activating mutations may play a role in the gonadal de-differentiation of adrenal tumors.

 

Nothing to Disclose: NK, KH, AK, SY, WBI III, ACL