Adrenal Corticomedullary Mixed Tumor Associated With the FGFR4-G388R Variant

Abstract

Adrenal corticomedullary mixed tumors (CMMTs) are extremely rare: with only 20 cases being reported to date the pathogenesis has remained elusive. A 31-year-old woman developed gestational hypertension with psychiatric disturbances persistent to postpartum, diagnosed with pheochromocytoma, for which adrenalectomy was performed. Histological findings showed mixed adrenocortical adenoma and pheochromocytoma. Double immunostaining of inhibin and INSM1 (insulinoma-associated protein 1) showed that the two tumor components had distinct functional properties. Exome analysis of peripheral leukocytes and tumor (singular as anatomically it is only one mass) revealed a homozygous germline FGFR4-G388R variant. As a readout of the variant, serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was detected only in the nucleus of adrenocortical adenoma component but not in the pheochromocytoma component. No tyrosine phosphorylation of STAT3 was detected. We report a case of CMMT with the germline FGFR4-G388R variant. Although additional studies are required, our immunohistochemical analysis suggests that the variant may play a role in the development of the adrenocortical component within the pheochromocytoma, leading to CMMT.

Bilateral adrenal uptake of 123I MIBG scintigraphy with mild catecholamine elevation, the diagnostic dilemma, and its characteristics

“…Although coexistent cases of pheochromocytoma and cortisol-secreting adrenocortical adenoma have been previously reported 22 – 24 , it is quite rare. Even rarer, an adrenal corticomedullary mixed tumor has been shown, including in our group 19 . In contrast, AMH has been reported to coexist with adrenocortical adenomas with a relatively high prevalence (26%) 21 , suggesting that there is some pathological interaction between cortisol and CA excess, and which may be more frequently associated with AMH than pheochromocytomas.…”

“…Since FGFR4 -G388R variant has been shown to be a possible initiator of adrenocortical adenoma within pheochromocytoma 19 , we investigated the association between this variant and these adrenocortical adenomas besides AMH rather than mutations in protein kinase A (PKA) pathway, well-known genetic abnormalities in cortisol-producing adenomas 20 . We detected a somatic homozygous FGFR4- G388R variant from the adrenocortical adenoma specimens of Case 3, a heterozygous variant from Case 1, and wild-type FGFR4 - G388R from Case 2.…”

“…Regarding with the association between CA excess and adrenocortical adenomas, we have previously reported that the FGFR4 -G388R variant is involved in the pathogenesis in complication of pheochromocytoma and cortisol-producing adenoma 19 . Therefore, to elucidate the possible mechanism of cortical adenoma formation in AMH, we performed genetic analyses of this gene variant of the tumors from these 3 cases of adrenalectomy.…”

Mixed Corticomedullary Tumor Accompanied by Unilateral Aldosterone-Producing Adrenocortical Micronodules: A Case Report

“…Additionally, the etiology of MCMTs has remained unknown. However, several hypotheses have been proposed for the pathogenesis of this unique adrenal neoplasm [ 2 , 5-9 , 11 , 14-18 ].…”

“…This hypothesis has been reported to clearly explain the simultaneous occurrence of tumors derived from different germ layers in other organs [ 19 ]. Recently, a variant of fibroblast growth factor receptor-4 was reported to account for a case in which cells derived from medullary and cortical cells were identified in the same tumor cells [ 5 ]. However, in this case, the tumor did not contain any hybrid tumor cells, and it is improbable that this case could have been derived from a single stem cell.…”