Ectopic ACTH Cushing’s Syndrome: V3 Vasopressin Receptor But Not CRH Receptor Gene Expression in a Pulmonary Carcinoid Tumor

Abstract

In the etiological diagnosis of ACTH-dependent Cushing’s syndrome, it may be difficult to distinguish pituitary disease from ectopic ACTH production, specially when this is due to a benign neuroendocrine tumor. We describe a patient with partial dexamethasone suppression consistent with Cushing’s disease, an absent response to CRH suggesting ectopic ACTH production and an atypical, apparent circadian rhythm. Bilateral cavernous sinus catheterization suggested a nonpituitary source of ACTH and, in the search of an ectopic tumor, somatostatin receptor scintigraphy, abdominal CT scan, and duodenopancreatic endoscopic echography were performed and failed to reveal any abnormality. Thoracic CT scan disclosed a tiny right lung nodule that showed a definite tracer uptake on MIBG scintigraphy. After resection, the nodule proved to be an 8-mm typical pulmonary carcinoid, with positive immunostaining for the classical neuroendocrine markers and for ACTH, and showing tissue expression of the POMC gene. However, the CRH receptor gene was not expressed, explaining the absent CRH response in vivo, whereas the V3 vasopressin receptor gene was expressed in the tumor tissue. The latter feature appears to be characteristic of benign carcinoids and may contribute to explaining the CRH-independent circadian rhythm observed in this case.

Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing’s syndrome

“…The injection of desmopressin stimulates the secretion of ACTH in case of CD, and theoretically not in EAS (28). However, a few studies described occasional expression of desmopressin receptors in ectopic adrenocorticotropin secretion (15,16,29,30). Our study found a clear difference between both conditions after stimulation by desmopressin, with a significantly increased gradient in case of CD and not in EAS.…”

“…Desmopressin, a vasopressin agonist, could indeed theoretically stimulate adrenocorticotropin secretion by a pituitary tumor that expresses V2 and V3 receptors. However, few researchers observed the expression of V2 and V3 receptors in some ectopic tumors producing ACTH (15,16).…”

RT-PCR analysis of corticotroph-associated genes expression in carcinoid tumours in the ectopic-ACTH syndrome

“…The low level of V3R expression detected in ACTH-negative carcinoids most likely corresponds to the low level of expression already reported for all three vasopressin receptor subtypes in most human tumours (28), and thus should not be considered as an indicator of corticotroph differentiation. Similarly, CRHR1 expression had already been shown not to be strictly associated with the corticotroph phenotype and our results further establish this on a large series of tumours (21,29). In addition, the pattern of CRHR1 expression in ACTH-negative carcinoids may suggest either that some tumours have a partial corticotroph differentiation or that CRHR1 expression is a common feature of neuroendocrine tumours or tumours in general.…”

A Combined Dexamethasone Desmopressin Test as an Early Marker of Postsurgical Recurrence in Cushing’s Disease

“…However, even if desmopressin theoretically stimulates only adenomatous corticotroph cells as they express V2-V3 receptors (27,31), the imperfect accuracy of the desmopressin stimulation test suggests that a few nonadenomatous corticotroph cells might be stimulated by desmopressin. We had indeed previously shown that the desmopressin stimulation test could be a predictive factor of recurrence but that this test had 80% sensitivity and specificity (22).…”