Modern imaging in Cushing’s disease

Management of Cushing’s disease is informed by dedicated imaging of the sella and parasellar regions. Although magnetic resonance imaging (MRI) remains the investigation of choice, a significant proportion (30–50%) of corticotroph tumours are so small as to render MRI indeterminate or negative when using standard clinical sequences. In this context, alternative MR protocols [e.g. 3D gradient (recalled) echo, with acquisition of volumetric data] may allow detection of tumors that have not been previously visualized. The use of hybrid molecular imaging (e.g. 11C-methionine positron emission tomography coregistered with volumetric MRI) has also been proposed as an additional modality for localizing microadenomas.


Introduction
The sense of achievement that accompanies successful navigation of the first phase of investigation in Cushing's syndrome (CS) is often tempered by the knowledge that localizing the source in ACTH-dependent disease may represent an even greater challenge due to the occult nature of many corticotroph and neuroendocrine tumors [1,2]. However, help is at hand, with several recent advances in MRI, CT (computed tomography) and PET, facilitating the successful detection of tumors that may be only a few millimeters in diameter. Here, we outline a stepwise approach to modern imaging in suspected pituitary-dependent CS.

Pituitary MRI
Most corticotroph tumors are microadenomas (even 'picoadenomas') and many (up to 50%) are not readily visualized using lower field strength [1.5 Tesla (1.5 T)] MRI, especially if acquired using 2-3 mm slice thickness with gaps between consecutive slices. A tiered approach to sellar and parasellar MRI is therefore recommended, with early onward referral to a pituitary tumor center of excellence (PTCoE), especially when initial MRI findings are inconclusive [1][2][3].

Step 1b: recommended supplementary sequences
If the core protocol does not identify a macroadenoma or obvious microadenoma, consider proceeding immediately (ideally in the same session) to: • T1w gadolinium enhanced 3D-spoiled gradient (recalled) echo (3D-SGE/3D-GRE) MRI: -this allows volumetric (1 mm slice thickness) data acquisition, to provide better soft tissue contrast and improved detection of smaller lesions -and has been reported to localize up to 80-90% of corticotroph tumors [5,6].
• T1w gadolinium-enhanced dynamic MRI (dMRI): -which involves repeated data acquisitions every 10-20 s over 1-2 min, commencing with contrast injection (microadenomas show delayed enhancement during early phase): -however, although Liu and colleagues recently reported a high positive predictive value when dMRI was combined with high dose dexamethasone suppression testing [7], several groups have suggested that dMRI is inferior to SGE/GRE MRI and frequently yields false positive findings [1, 2, 6].
Step 2: optional supplementary sequences/ magnetic field strength When doubt remains as to the location of a corticotroph microadenoma, additional MR sequences or a higher magnetic field strength may be considered [1,2]: • Fluid-attenuated inversion recovery (FLAIR) with gadolinium enhancement -to detect delayed contrast washout in a microadenoma [8]. • Constructive interference in steady state (CISS) -a high spatial resolution fast T2w gradient echo sequence, which allows fast acquisition times, high signal-to-noise ratio, and improved contrast-to-noise ratio [9]. • Isotropic 3D-fast (turbo) SE (e.g. SPACE, Cube, VISTA, isoFSE, 3D MVOX) -which produces high resolution 3D images (with features of T1w, T2w and proton density MRI) [10]. • Ultra-high field (7 T) MRI Whichever sequences are deployed, access to an expert neuroradiologist, supported by a specialist pituitary multidisciplinary team, is critical to maximizing the chance of localizing the causative lesion, whilst avoiding false attributions to artifacts or incidental lesions [2].

Pituitary PET
Even in centers with access to the full range of MR sequences, structural imaging may return indeterminate or negative results. The adoption of higher resolution techniques also increases the chance of detecting incidental lesions. In these contexts, molecular (functional) imaging can confirm or refute the site of a suspected microadenoma or reveal a previously unsuspected abnormality. Several radioligands have been used with varying degrees of success and are summarized here.

C-methionine PET (Met-PET)
The introduction of hybrid imaging techniques [Met-PET/ MR or Met-PET/CT coregistered with volumetric MRI (Met-PET/MR CR )] has allowed several groups to demonstrate the utility of combining anatomical and functional imaging with 11 C-methionine to localize small corticotroph adenomas [11][12][13]. This approach has been successfully used in both de novo and recurrent disease [13], and the development of enhanced image analysis tools, together with algorithms for 3D reconstruction and sellar profiling, offer the potential to further increase confidence in localizing very small tumors (Fig. 1).

F-FET PET
A key limitation of Met-PET is the short half-life (~ 20 min) of 11 C-methionine, which restricts its use to centers with an on-site cyclotron. In contrast, 18 F-fluoroethyltyrosine (FET) with its longer half-life (~ 110 min) can be synthesized and then transported to off-site centers. Both methionine and fluoroethyltyrosine are taken up at sites of peptide synthesis, possibly via the same l-type amino acid transporter (LAT1). To date, only a small number of patients with Cushing's disease have been imaged using 18 F-FET-PET/MR, but initial findings suggest a high predictive value for localizing corticotroph microadenomas [12].

F-FDG PET
Although 18 F-fluorodeoxyglucose ( 18 F-FDG) shares the benefits of a longer half-life and is more widely available, studies of 18 F-FDG PET in Cushing's disease have proved largely disappointing, with no clear benefits over conventional MRI in most published series. However, Boyle and colleagues have proposed that prior corticotropin releasing hormone (CRH) injection may increase the sensitivity of 18 F-FDG PET in Cushing's disease [14].

Ga(-DOTA)-CRH PET
Recognizing that most corticotroph adenomas express CRH receptors (CRH-1R), Walia and colleagues observed that conjugation of 68 Ga-DOTA to CRH ( 68 Ga-CRH) yields a PET ligand with apparent high sensitivity and specificity for the detection of ACTH-secreting pituitary adenomas [15]. However, importantly, only 10 of 24 subjects had adenomas < 6 mm in size and in only four subjects was a lesion not visualized on MRI [15].

Conclusions
As set out in the recent Pituitary Society guideline update [3], MRI remains the imaging modality of choice for the localization of ACTH-secreting pituitary adenomas and, when conducted in a specialist unit with access to the full complement of sequences, will identify the causative lesion in many cases. However, when uncertainty persists,

Conflict of interest The authors declare no competing interests.
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