Coexistence of Myelolipoma and Primary Bilateral Macronodular Adrenal Hyperplasia With GIP-Dependent Cushing's Syndrome

Abstract

Introduction: Adrenal myelolipomas are usually isolated benign adrenal lesions, but can be adjacent to steroid-secreting adrenocortical tumors. We studied the aberrant regulation of cortisol secretion in a 61 year-old woman with combined bilateral myelolipomas and primary bilateral macronodular adrenal hyperplasia (BMAH) causing Cushing's syndrome. Materials and Methods: Cortisol response was measured during in vivo tests that transiently modulated the levels of ligands for potential aberrant receptors, including GIP. Response to medical therapies decreasing GIP was monitored. Expression of ACTH and of GIP receptors were examined in resected adrenal tissues by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Results: In vivo, cortisol increased in response to mixed meals (+353%), oral 75 g glucose (+71%), GIP infusion (+416%), and hLH IV (+243%). Suppression of GIP by pasireotide improved cortisol secretion but produced hyperglycemia. The left adrenal was predominantly composed of myelolipoma and strands of BMAH, while the right was mainly composed of BMAH with some foci of myelolipoma on pathology. No ACTH was detectable by immunohistochemistry in BMAH or myelolipomas tissue. Ectopic GIP receptor was confirmed by RT-PCR and immunohistochemistry in BMAH tissues but not in the myelolipomas. No germline mutations were identified in the ARMC5 gene of the patient's leucocyte DNA. Conclusion: This is the first report of interspersed myelolipoma and BMAH with GIP-dependent Cushing's syndrome. In contrast with the BMAH tissues, myelolipoma tissue did not express specific GIP receptors. The potential mechanisms responsible for the interspersed growth of those two lesions remain to be identified.

Adrenocortical adenoma with myelolipomatous metaplasia: a potential diagnostic pitfall: a case report and review of the literature

“…[ 29 ] 53 F ACA HTN/DM Concurrent schwannoma in adrenal 17 Larose et al . [ 30 ] 61 F Macronodular adrenal hyperplasia – Bilateral 18 Fırat et al . [ 31 ] 62 F ACA – – 19 Fırat et al .…”

Overview of the 2022 WHO Classification of Adrenal Cortical Tumors

“…Moreover, additional somatic and/or germline gene variants have also been identified in a subset of individuals with this condition [5,7,8,12,14,93]. Intricate molecular mechanisms, for example aberrant G-protein-coupled receptor expression or dysregulation of the ACTH receptor may explain subsets of cases [94][95][96][97][98].…”

From the First Case Reports to KDM1A Identification: 35 Years of Food (GIP)-Dependent Cushing’s Syndrome

“…A cortisol aberrant response mediated by GIPR and LHCGR concomitantly, had been previously reported in two unrelated PBMAH female patients [69], and one of our patients had a clear response to both mixed meal and GnRH, but none of the studied patients were known to have clinical signs of Cushing's syndrome during pregnancy or after menopause. Larose et al, in 2019, also reported a patient with aberrant regulation of cortisol secretion by both GIP and LH [55].…”

“…Considering the neutralization of GIP action by somatostatin, specific medical treatment of FDCS by somatostatin analogs has been reported [19,24,[52][53][54][55], but usually with a transient control of cortisol secretion because GIP inhibition escapes after a few weeks or months or the rapid occurrence of side effects, limiting its use in clinical practice. Future prospects on the potential use of specific GIPR antagonists in FDCS would be valuable [42].…”