Molecular Imaging of Pituitary Adenomas
Molecular Imaging of Pituitary Adenomas
Background: Pituitary adenomas affect 10% of the population. Surgery offers the most
 cost-effective treatment modality but cure rates are only 40-70%, in part due to the
 limitations of Magnetic Resonance Imaging (MRI) in visualising small tumours (up to 40% are
 undetected) and discriminating adenomatous tissue from healthy pituitary or post-surgical
 change. Positron emission tomography (PET) imaging may improve localisation but current
 tracers have short half-lives and are unsuitable for routine use. The dopaminergic system
 regulates pituitary growth and function, as evidenced by the use of dopamine D2 receptor
 agonists as medical therapy. Dopaminergic PET tracers, including 18F-FDOPA
 (6-[18F]-L-fluoro-L-3,4-dihydroxyphenylalanine) and 18F (fluorine 18)-Fallypride (which binds
 to D2/D3 receptors), might thus improve management by enhancing tumour discrimination and
 quantifying D2 receptor expression.

 Aim: To establish whether imaging changes in dopaminergic transmission and receptor function
 has the potential to improve localisation of pituitary adenomas.

 Methods: Subjects with pituitary adenomas will undergo 18F-FDOPA and 18F-Fallypride PET scans
 in addition to standard pituitary MRI. Quantification of binding potential combined with MRI
 co-registration to provide enhanced anatomical definition will be applied. In vivo D2
 receptor binding will be correlated with ex vivo D2 receptor mRNA (messenger ribonucleic
 acid) and protein expression from tumour samples removed at surgery.
Aim: In this proof-of-concept study, the investigators will seek to establish whether imaging
 changes in Dopaminergic transmission and receptor function has the potential to improve
 localisation and management of pituitary adenomas.

 Methods:

 Patients will be recruited from the general endocrine and pituitary multidisciplinary clinics
 at the University Hospital of Wales. Patients will comprise those with a confirmed pituitary
 adenoma for whom pituitary imaging is indicated as part of standard clinical management.
 Tumour functionality (Cushing's syndrome, Acromegaly, Prolactinoma, TSHoma) and
 hypopituitarism will be established in accordance with established clinical practice.
 Detailed surgical, pathological and post-operative data will be collected in each case, in
 order to facilitate correlation of PET/MRI findings with key clinical outcomes.

 Histopathological examination:

 Surgical specimens will be fixed in 10% neutral buffered formalin and embedded in paraffin as
 per standard clinical practice. Histopathological confirmation of the presence and type of
 pituitary adenoma will be established by typical microscopic appearances of an adenoma
 supported by immunohistochemical staining for the relevant hormone (Growth hormone, ACTH
 [Adrenocorticotrophic Hormone], Prolactin, TSH [Thyroid Stimulating Hormone], LH/FSH
 [Luteinising hormone/Follicle Stimulating Hormone]). Tumour will also be stored snap frozen
 for subsequent RNA and protein extraction, in order to quantify dopamine D2 short and long
 isoform receptor expression. This will allow comparison of ex vivo receptor expression levels
 with in vivo 18F-fallypride uptake.

 PET-CT imaging:

 Subjects will undergo 18F-FDOPA and 18F-Fallypride imaging according to established protocols
 in the PET imaging centre (PETIC) at the University Hospital of Wales. Both compounds will be
 synthesised in compliance with good manufacturing practice, and have been produced and
 validated for human use in PETIC since 2015. Subjects will refrain from taking alcohol and
 caffeine for 4 hours before the PET scanning session. PET scans will be acquired using a
 PET-CT (Positron Emission Tomography-Computed Tomography) scanner with Time of Flight and a
 64 slice CT in 3D list mode. Patients will be placed in the scanner in the supine position,
 with the brain centred in the axial field of view. A CT scout view will be acquired to aid in
 positioning of the patient following which the head will be fixed using a piece of surgical
 tape.

 18F-FDOPA protocol: For 18F-FDOPA, participants will be pre-treated with 150 mg (milligrams)
 carbidopa and 400 mg entacapone 1 hour prior to radioisotope administration in order to block
 peripheral metabolism of FDOPA and enhance specific signal detection. A low dose CT scan will
 be acquired for positioning and attenuation correction. A single position Dynamic PET scan
 will be acquired as 26 time-frames over 94.5 minutes (1 × 30 sec, 4 × 1 min, 3 × 2 min, 3 × 3
 min, and 15 × 5 min). Immediately after the scan commences 111 MBq (Megabecquerels) of
 18F-DOPA in normal saline will be administered via a long connecting tube as an intravenous
 bolus at the start of scanning (avoiding brain stimuli). Data will be reconstructed using
 OSEM (ordered-subsets expectation maximisation) following corrections for attenuation,
 normalisation, scatter and patient movement. The cerebellum will be used to represent the
 reference region for the data analysis and enable the generation of binding potential
 parametric images using Logan plots.

 18 F-Fallypride protocol: Dynamic acquisition of the PET scan will be started with a 30
 second bolus administration of 18F Fallypride (2.6 MBq/kg body weight). Patients will undergo
 3 hours of dynamic imaging (3 × 20 s, 3 × 1 min, 3 × 2 min, 3 × 3 min, 21 × 5 min, 2 × 8 min
 and 4 × 10 min; 180 min in total)(with rest periods during the scan to reduce discomfort and
 allow urinary voiding to reduce radiation dose to the bladder wall). Data will be
 reconstructed using OSEM following corrections for attenuation, normalisation, scatter and
 patient movement. The cerebellum will be used to represent the reference region for the data
 analysis and enable the generation of binding potential parametric images using Logan plots.

 Standard and 3D gradient echo MRI:

 MR imaging will be performed on a 1.5T (Tesla) MRI unit. High resolution coronal T2-weighted
 images and coronal and sagittal T1-weighted spin echo (SE) images of the pituitary gland will
 be obtained before contrast injection. After intravenous injection of gadopentetate
 dimeglumine contrast the investigators will repeat the acquisition of the coronal and
 sagittal T1-weighted SE images of the pituitary gland and will also record a high resolution
 T1-weighted spoiled gradient (SPGR) acquisition sequence of the whole head to optimise
 co-registration with the PET/CT data.

 Image processing and analysis:

 Image analysis techniques to include detailed profiling of tracer uptake across the sella
 will be applied. Image processing will be performed using commercially available software
 packages.
Inclusion Criteria:

 -  Confirmed pituitary adenoma for whom pituitary imaging is indicated as part of
 standard clinical management

 Exclusion Criteria:

 -  Pregnancy, breastfeeding and any contraindications to MRI or intravenous contrast
 administration