Molecular Imaging Targeting Corticotropin-releasing Hormone Receptor for Corticotropinoma: A Changing Paradigm

Abstract

Background Corticotrophin releasing hormone (CRH) is the major regulator of ACTH secretion from the anterior pituitary and acts via CRH-1 receptors (CRH-1R). Corticotropinoma though autonomous still retain their responsiveness to CRH and hence, we hypothesize that in vivo detection of CRH-1 receptors on pituitary adenoma using Gallium-68 ( 68Ga) tagged CRH can indicate the functionality of adenoma and combining it with Positron emission tomography-computed tomography (PET-CT) can provide requisite anatomical information. Methods Subjects with ACTH dependent Cushing's syndrome (CS) [n = 27, 24: Cushing's disease (CD), 3: ectopic Cushing's syndrome (ECS)] underwent 68Ga CRH PET-CT. Two nuclear medicine physicians read these images for adenoma delineation and superimposed them on MRI sella. The information so provided was used for intra-operative navigation and compared with operative and histopathological findings. Findings 68Ga CRH PET-CT correctly delineated corticotropinoma in all the 24 cases of CD, including the ten cases with size < 6mm (four cases negative on MRI). Corticotropinoma location on 68Ga CRH PET fusion images with MRI were concordant with operative findings and further confirmed on histopathology. There was no tracer uptake in pituitary in two patients with ECS while in another, the diffuse uptake in pituitary suggested ectopic CRH production. Conclusion 68Ga CRH PET-CT represents a novel non-invasive molecular imaging targeting CRH receptors that not only delineates corticotropinoma and provides surgeon with valuable information for intra-operative tumour navigation but also helps in differentiating pituitary from extra-pituitary source of ACTH dependent Cushing’s syndrome.

Consensus on diagnosis and management of Cushing's disease: a guideline update

“…Alternative strategies (e.g., targeting CRH-R1 expression on corticotroph tumors) have also recently been proposed, but require further study. 68…”

“…Currently, this combination of laboratory and imaging testing as a noninvasive approach to distinguish between pituitary and ectopic ACTH-secreting tumors is likely limited to specialized centers. 82 68 Ga-DOTATATE is a modified (Tyr3)-octreotide molecule covalently linked to 1,4,7,10tetra-azacyclododecane-1,4,7,10-tetra-acetic acid (DOTA) combined with the radioactive 68 Ga isotope. The radiopharmaceutical, with a half-life of approximately 1 hour, binds to somatostatin receptors with affinity similar to octreotide and can be used as a tracer in PET imaging of ectopic ACTH-secreting NETs.…”

Effectiveness of dietary diabetes insipidus bundle on the severity of postoperative fluid imbalance in pituitary region tumours: A randomized controlled trial

“…There are several types of pituitary tumours with varied presentations and differing degrees of postoperative nursing issues (Das et al, 2020; Dutta et al, 2021; Gupta et al, 2018; Walia, Dutta, et al, 2021; Walia, Gupta, et al, 2021). The incidence of DI has been highly variable across literature, varying from as low as 4% to as high as 80% (Dumont et al, 2005; Hannon et al, 2012; Schreckinger et al, 2013).…”

Using Molecular Imaging to Enhance Decision Making in the Management of Pituitary Adenomas

“…In a single study to date, 68 Ga-DOTA-CRH PET/CT was reported to be positive in all 24 cases of Cushing disease studied, with intraoperative and histologic confirmation of PET findings. However, as a cautionary note, only 10 patients had microadenomas , 6 mm in size and, of these, only 4 had no lesion visible on MRI (44). Further studies will therefore be required to confirm whether these initial findings represent a significant step-change in functional imaging of corticotroph adenomas.…”

“…Recently, a novel PET tracer ( 68 Ga-DOTA-CRH) that binds to CRH-R1 on pituitary corticotrophs has been proposed for imaging in Cushing disease (44). Although autonomous, most (.90%) corticotroph tumors retain CRH-R1 expression and exhibit responsiveness to exogenous CRH (as exemplified in both peripheral CRH testing and bilateral inferior petrosal sinus sampling with CRH stimulation).…”