Primary hyperaldosteronism, characterised by hypertension and hypokalaemia, is a syndrome caused by aldosterone excess most commonly from either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Subtype classification can be challenging with cross-sectional imaging and even with interventional radiological techniques such as adrenal venous sampling. Imaging with 11C-metomidate positron emission tomography-computed tomography (PET-CT) is an emerging tool that facilitates functional characterisation and potentially successful surgical intervention of aldosterone-producing adenomas. This technique has highlighted that, although unilateral adenomas and bilateral hyperplasia represent opposite ends of the disease spectrum, a relatively common intermediate phenotype exists of unilateral/bilateral multinodular disease

Brown, M

Cuthbertson, DJ

Gurnell, M

Hardy, R

Helliwell, T

Ouyang, J

English

Apollo (Cambridge)

 1  1 11C-metomidate PET-CT scanning can identify aldosterone-producing adenomas after 2 unsuccessful lateralisation with CT/MRI and adrenal venous sampling.  3 Jing Ouyang1, Rob Hardy2, Morris Brown3, Tim Helliwell4, Mark Gurnell5, Daniel J 4 Cuthbertson1 5 1Neuroendocrine Tumour Group, University Hospital Aintree, Liverpool, L9 7AL. 6 2Department of General Surgery, University Hospital Aintree, Liverpool, L9 7AL. 7 3William Harvey Research Institute, Queen Mary University London, London, EC1M 6BQ 8 4Liverpool Clinical Laboratories, Royal Liverpool University Hospital, Liverpool, L7 8XW. 9 5 Institute of Metabolic Science, University of Cambridge and National Institute for Health 10 Research Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK, 11 CB2 0QQ 12  13 Running title: 11C-metomidate PET-CT scanning in primary hyperaldosteronism 14 Corresponding author and address for reprints: 15 Dr Daniel Cuthbertson 16 Clinical Sciences Centre, 17 Aintree University Hospital, 18 Lower Lane, 19 Liverpool, L9 7AL 20 E-mail: daniel.cuthbertson@liverpool.ac.uk 21 Tel 0151 529 5917, 22  Fax 0151 529 5888  23 There are no conflicts of interest to disclose 24  2  25 Overview 26 Primary hyperaldosteronism, characterised by hypertension and hypokalaemia, is a 27 syndrome caused by aldosterone excess most commonly from either a unilateral 28 aldosterone-producing adenoma or bilateral adrenal hyperplasia. Sub-type 29 classification can be challenging with cross-sectional imaging and even with 30 interventional radiological techniques such as adrenal venous sampling. Imaging with 31 11C-metomidate PET-CT is an emerging tool that facilitates functional characterisation 32 and potentially successful surgical intervention of aldosterone-producing adenomas. 33 This technique has highlighted that although unilateral adenomas and bilateral 34 hyperplasia represent opposite ends of the disease spectrum, a relatively common 35 intermediate phenotype exists of  unilateral/bilateral multinodular disease.   36 A 44 year old female presented to a tertiary endocrine clinic with a blood pressure of 188/114 37 mmHg, managed with several anti-hypertensive drugs including spironolactone 50 mg o.d., 38 having been previously investigated for secondary hypertension. Biochemically her baseline 39 investigations were consistent with primary hyperaldosteronism with an aldosterone:renin 40 ratio of 2125 prior to drug treatment. A high-resolution adrenal CT scan had suggested a 41 bulky left adrenal gland, and possible right adrenal nodule; however, subsequent adrenal 42 magnetic resonance imaging reported normal adrenal glands bilaterally. Adrenal venous 43 sampling (AVS) was attempted on two occasions, but was technically unsuccessful. Thus, in 44 the absence of an exact sub-type of primary aldosteronism (PA), medical management with 45 mineralocorticoid receptor antagonists was preferred with spironolactone titrated up to 100 46 mg b.d. The patient was intolerant of medication and sought referral to a supraregional 47 neuroendocrine tumour multi-disciplinary team (NET MDT).  48  3 Application of serial cross-sectional imaging and AVS had failed to localise the source of 49 aldosterone excess so an 11C-metomidate PET-CT scan was performed at Addenbrooke’s 50 Hospital, Cambridge. Dexamethasone 0.5 mg q.d.s. was administered for 72 hours prior to 51 the scan with the final dose being administered on the morning of the scan with the aim of 52 suppressing 11C-metomidate uptake into background normal adrenal tissue, thereby 53 facilitating identification of the functionally active nodules.  54 The medial limb of the right adrenal gland was noted to be thickened proximally, with an 55 apparent 9.5 x 7.0 mm nodule at this site, which showed focal tracer uptake (SUVmax 27.2) 56 (Figure 1A-C). A smaller 5.0 x 7.1 mm nodule was suspected in the body/proximal medial 57 limb of the left adrenal gland, corresponding to a site of less intense tracer uptake (SUVmax 58 23.8) (Figure 1A-C). The difference in maximal tracer uptake between the two sides 59 (SUVmax ratio = 1.14) did not reach the value (1.25) reported previously to discriminate 60 between unilateral and bilateral causes of PA. However, taken together, the cross-sectional 61 and 11C-metomidate PET findings indicated that the right adrenal nodule was likely to be a 62 significant contributor to excess aldosterone secretion in our patient. These findings were 63 discussed with the patient, and she was offered a unilateral right adrenalectomy, but on the 64 clear premise that although an improvement in blood pressure would be anticipated, it was 65 possible that she would be left with residual disease, requiring ongoing medical therapy, 66 following surgery.   67 A retroperitoneoscopic right adrenalectomy was performed uneventfully with discharge 48 68 hours post-surgery.  Macroscopic examination of the adrenal gland revealed a 6mm well-69 demarcated and unencapsulated nodule, which microscopically was composed of lipid rich 70 cells showing eosinophilic cytoplasm with many cells containing concentrically laminated 71 eosinophilic 'spironolactone bodies' consistent with an adrenal cortical adenoma (Figure 1 72 D/E). Immediately post-operatively, and throughout clinic follow-up during the last 12 73  4 months, her blood pressure has been consistently normal (around 130/80 mmHg) without 74 anti-hypertensive medication, with normal renal profile and a normal aldosterone:renin ratio 75 (aldosterone 106 pmmol/l; plasma renin activity 1.2 ng/ml/h) excluding residual PA.  76 Primary aldosteronism (PA) is a syndrome characterised by hypertension, with hypokalaemia 77 in a proportion of patients, caused by excess aldosterone secretion, most commonly 78 attributable to a unilateral aldosterone producing adenoma (APA) or bilateral adrenal 79 hyperplasia (idiopathic hyperaldosteronism, IH)1. However, increasingly an intermediate 80 phenotype of  unilateral or bilateral multinodular disease is emerging2.   81 Subsequent to a biochemical diagnosis of PA, the next stage of management is sub-type 82 classification with lateralisation of the source of the excess aldosterone to distinguish 83 between an APA, treated with unilateral adrenalectomy and IHA, treated with lifelong 84 mineralocorticoid receptor antagonists (using spirinoloactone or eplerenone). The initial 85 recommended imaging modality is an adrenal CT, useful for detecting larger adrenal masses 86 particularly those with malignant potential. However, the poor sensitivity and specificity of 87 adrenal CT scanning for detection of microadenomas and distinguishing between a non-88 functioning and an aldosterone-producing adenoma is well recognised, leading to consensus 89 guidelines recommending AVS to lateralise when surgical intervention is practical and 90 desired by the patient3. Lateralisation is confirmed in the presence of a 3-4 fold difference, 91 between adrenal veins, in the aldosterone to cortisol ratios.  92 Despite these recommendations AVS is technically challenging and is not widely available, 93 hence there is a need for less invasive, functional imaging modalities to manage patients with 94 PA.  11C-metomidate, a potent inhibitor of the adrenocortical steroidogenic enzymes, 11ß-95 hydroxylase and aldosterone synthase, has been developed as a novel tracer for positron-96 emission tomography (PET) scanning. In a case series of 173 patients with adrenal tumours, 97 Hennings et. al demonstrated sensitivity of 0.89 and specificity of 0.96 in proving the 98  5 adrenocortical origin of adrenal lesions i.e. adrenocortical adenomas or hyperplasias and 99 adrenocortical cancers (ACCs), with phaeochromocytomas, adrenal metastases and non-100 adrenal masses all MTO negative4. PET measurements using standardised uptake values 101 (SUV) differentiated aldosterone-producing adenomas from normal and contralateral adrenal 102 glands4. Burton et. al. subsequently demonstrated the sensitivity and specificity of MTO-103 PET, compared with the current gold standard of AVS, and found it able to detect even the 104 smallest microadenomas without the need for withdrawal from spironolactone or other anti-105 hypertensive drugs5. A 25% excess SUVmax between sides was reported to be diagnostic in 106 this cohort. Although this patient’s adenoma represented a predominant component of 107 bilateral nodular disease, rather than pure unilateral disease, it has been suggested that even 108 “removal of one randomly selected nodular adrenal might improve blood pressure and serum 109 potassium concentrations in nearly 100% of patients”2.  110 As the cost of 11C-metomidate PET-CT is less than that of AVS in most centres, this 111 imaging modality represents a cost-effective alternative for lateralisation in PA. We recognise 112 however, that at present only a few sites are able to offer functional imaging, although it is 113 anticipated that wider rollout of this tracer, or of next generation compounds (including 18F-114 labelled), will allow for greater access comparable to AVS. 115 In summary, we highlight what we believe to be a relatively common clinical scenario in 116 patients with PA, whereby the limitations and challenges of adrenal cross-sectional imaging 117 (CT/MRI) and interventional radiological techniques (AVS) preclude optimal management 118 and outcomes. In our patient, successful surgical intervention for an aldosterone-producing 119 adenoma was based on the identification of a right-sided micronodule as the site of greatest 120 11C-metomidate uptake. Results of further studies may potentially guide clinicians to wider 121 use of 11C-metomidate PET-CT in preference to AVS.  122  123  6  124 References  125 1. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H et al. The 126 Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: 127 An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016: 128 jc20154061. 129  130 2. Brown MJ, Drake WM. Splitting atoms: the Endocrine Society guideline for the 131 management of primary aldosteronism. Lancet Diabetes Endocrinol 2016; 4(10): 805-132 7. 133  134 3. Rossi GP, Auchus RJ, Brown M, Lenders JW, Naruse M, Plouin PF et al. An expert 135 consensus statement on use of adrenal vein sampling for the subtyping of primary 136 aldosteronism. Hypertension 2014; 63(1): 151-60. 137  138 4. Hennings J, Lindhe O, Bergstrom M, Langstrom B, Sundin A, Hellman P. 139 [11C]metomidate positron emission tomography of adrenocortical tumors in 140 correlation with histopathological findings. J Clin Endocrinol Metab 2006; 91(4): 141 1410-4. 142  143 5. Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV et al. Evaluation of 144 the sensitivity and specificity of (11)C-metomidate positron emission tomography 145 (PET)-CT for lateralizing aldosterone secretion by Conn's adenomas. J Clin 146 Endocrinol Metab 2012; 97(1): 100-9. 147  148  149  150  151  152  7  153 Figure 1 154 11C- metomidate PET-CT scan.  155 (A) CT demonstrates subtle thickening/nodular change in the body/proximal medial limb of 156 both adrenal glands.  157 (B) Raw PET findings suggest maximal tracer uptake bilaterally in the same locations, but 158 with greater uptake on the right.  159 (C) Merged PET-CT image confirming co-localisation of cross-sectional and functional 160 imaging findings. 161 Histology of the specimen 162 D) Low power image of the well-demarcated, unencapsulated nodule. The arrows indicate the 163 junction between the nodule and normal medullary tissue (haematoxylin and eosin).  164 E) High power image of the nodule showing lipid rich adrenal cortical cells with pale, foamy 165 cytoplasm. Several cells contain rounded, laminated eosinophilic ‘spironolactone’ bodies 166 (arrows) (haematoyxlin and eosin). 167  168  169  170 Figure 1    Right SUVmax = 27.2 Left SUVmax = 23.8                     Ratio = 1.14  A) B C CT PET PET-CT   D                                                      E 

11C-metomidate PET-CT scanning can identify aldosterone-producing adenomas after unsuccessful lateralisation with CT/MRI and adrenal venous sampling.

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11C-metomidate PET-CT scanning can identify aldosterone-producing adenomas after unsuccessful lateralisation with CT/MRI and adrenal venous sampling.

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