Adrenal oncocytoma: a rare presentation of a benign 18 8F-fluorodeoxyglucose PET avid virilising adrenal tumour
Danielle Leea,b, Jonathan Greenª, James Craneª, David R. Taylor”, Saira Reynoldsª, Wen Ngª, Koshy Jacobª, Benjamin Whitelawª, Simon Aylwinª, Gabriele Galataª, Dylan Lewisª and Matthew Seagera
A woman in her 70s presented with features of hyperandrogenism including clitoral enlargement and deepening of her voice. Biochemical investigations revealed raised plasma androgens and urinary androgen metabolites and imaging findings showed a highly F-18 fluorodeoxyglucose (FDG)-PET avid left adrenal tumour initially suspected to be a malignant adrenocortical carcinoma (ACC). She subsequently underwent an uncomplicated laparoscopic adrenalectomy where complete resection of her tumour was achieved. Histopathological analysis demonstrated a benign adrenal oncocytoma with no evidence of malignancy. This case illustrates a rare presentation of a functioning virilising adrenal oncocytoma as a benign mimic of ACC. Nucl Med
Commun 46: 367-372 Copyright @ 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
Nuclear Medicine Communications 2025, 46:367-372
Keywords: adrenal gland neoplasms, adrenocortical oncocytoma, F-18 fluorodeoxyglucose-PET, hyperandrogenism
aKing’s College Hospital NHS Foundation Trust, bFaculty of Life Sciences and Medicine, King’s College London, “Department of Clinical Biochemistry (Synnovis), King’s College Hospital NHS Foundation Trust, London and “Eastbourne District General Hospital, Eastbourne, UK
Correspondence to Danielle Lee, MRCP, Faculty of Life Sciences and Medicine, King’s College London, Strand, London, WC2R 2LS, UK Tel: +44 203 299 9000; e-mail: danielle.1.lee@kcl.ac.uk
Received 17 July 2024 Accepted 7 November 2024.
Case presentation
A woman in her 70s presented to her general practi- tioner after noticing that her voice had dropped in vocal range from soprano to alto as a singer with her local community choir. She had also noted clitoral enlarge- ment over the preceding year. She was otherwise well with no past medical history other than gastro-oesoph- ageal reflux. On examination, she was noted to have clitoromegaly but no other features of virilisation. She was referred to her local endocrinology team for further assessment, and a computed tomography (CT) scan was arranged, which identified a 6 cm left adrenal mass (Fig. 1) for which she was referred to our tertiary endo- crinology centre for discussion in our adrenal multi-dis- ciplinary team meeting.
Investigations
Her blood tests showed raised testosterone 3.5 nmol/L (normal 0.4-1.4 nmol/L) and dehydroepiandrosterone SO4 (DHEAS) 14.8 pmol/L (normal 0.9-11.6 pmol/L). Her adrenal biochemistry was otherwise normal, including normal plasma metanephrines, urinary cortisol, overnight dexamethasone suppression test, renin and aldosterone.
Her urine steroid profile showed high levels of the major androstenedione/testosterone metabolites androsterone 1936 µg/24 h (normal adult female mean
770 µg/24 h, SD 420 µg/24 h) and aetiocholanolone 4672 µg/24 h (normal adult female mean 937 µg/24 h, SD 621 µg/24 h), with an associated increase in dehydroan- drosterone (DHA) 852 µg/24 h (normal adult female mean 327 µg/24 h, SD 244 µg/24 h) and its metabo- lites 16aOH-DHA 2229 µg/24 h (normal adult female mean 205 µg/24 h, SD 231 µg/24 h) and androstenetriol 2016 µg/24 h (normal adult female mean 294 µg/24 h, SD 234 µg/24 h). There were otherwise no increases in other abnormal steroid metabolites that would typically be associated with adrenocortical carcinoma (ACC) [1].
Her adrenal CT and F-18 fluorodeoxyglucose PET (FDG-PET) scans showed an enhancing and highly FDG-avid left adrenal mass and no evidence of meta- static disease (Fig. 1). Her adrenal MRI showed inter- mediate T2 signal intensity, no intravoxel fat and mild restricted diffusion (Fig. 2).
Differential diagnosis
Her clinical presentation of hyperandrogenism, bio- chemical findings of raised plasma androgens and uri- nary androgen metabolites, and radiological findings of a highly FDG-PET avid adrenal lesion were initially felt to be suspicious for ACC.
ACC is a rare adrenal cortex malignancy with an esti- mated incidence of 1-2 per million a year. It is usually associated with a poor prognosis with a 5-year survival of <15% in metastatic disease [2]. Up to two-thirds of ACC cases present with clinical and/or biochemical features of
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Preoperative computed tomography (CT) scans. Noncontrast CT (a) of left adrenal mass (white arrow) shows a mean attenuation of 43 HU with enhancement on the portal venous phase (b) with mean attenuation of 88 HU. Coronal (c) and axial (d) F-18 fluorodeoxyglucose (FDG) PET find- ings show significant tracer uptake in the left adrenal mass, with a maximum standardised uptake value (SUVmax) of 15, and adrenal tumour to liver SUVmax ratio of 5.
steroid hormone excess, with adrenal androgens being the second most commonly produced hormones after cortisol in hormone-secreting ACCs [3]. The gold stand- ard for diagnosis is via histopathological analysis, with surgical resection being recommended over biopsy as a means to obtaining a tissue diagnosis in order to mini- mise the risk of tumour dissemination [2].
Treatment
The decision was therefore made for her to undergo sur- gical resection of her tumour in view of the high suspicion for ACC. She underwent an uncomplicated laparoscopic adrenalectomy, during which complete resection of her adrenal tumour was achieved. Intraoperatively, she was noted to have no evidence of organ or vascular invasion, with no metastatic lymph nodes.
Histopathological diagnosis
Histopathological analysis of her adrenal tumour demon- strated this to be an oncocytic adrenocortical adenoma with a low proliferation index (Ki67: 1-2.2%) and staining positively for inhibin, calretinin and MelanA. Macroscopically, there was evidence of complete tumour excision with an intact capsule and no histological evi- dence of metastasis (Fig. 3). Multiple risk scoring sys- tems namely the reticulin algorithm, Lin-Weiss-Biscelgia
(LWB), and Helsinki system, were used to assess for malignancy, all of which were negative.
The Weiss system is the most widely used system for determining the malignant potential of adrenocortical tumours in adults and assesses for the presence of nine morphological criteria related to tumour structure, cyto- logical features and evidence of tumour invasion, with the presence of three or more features being consistent with a diagnosis of ACC [4]. However, its use in oncocytic neoplasms is more limited, due to the features of eosin- ophilic cytoplasm, diffuse architecture and high nuclear grade being present universally in these tumours regard- less of malignant potential, therefore resulting in a falsely high Weiss score and subsequently a false diagnosis of malignancy [5].
The updated 2022 WHO classification of adrenal corti- cal tumours, therefore, recommends the use of alterna- tive scoring systems in the assessment of the malignant potential of oncocytic adrenal neoplasms, namely the LWB system, the Helsinki score, and the reticulin algo- rithm [6]. The LWB system was first developed in 2004 specifically for assessment of oncocytic variant adrenal neoplasms and defines the diagnosis of ACC by the pres- ence of at least one ‘major criteria’ (mitosis >5, atypical mitosis or vascular invasion) [7]. However, some studies
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Preoperative axial MRI imaging. In phase T1 (a) and opposed phase T1 (b) images show no evidence of intravoxel fat within the mass. T2 (c) imaging showing intermediate signal intensity. DWI B100 image (d) showing mild increased signal in the mass with corresponding reduced signal on the ADC map (not shown), indicating mild restricted diffusion. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging
have shown that this system can have the potential to overestimate malignant potential of oncocytic adrenocor- tical tumours [8].
The reticulin algorithm incorporates the presence of an altered reticulin network on a Gordon Sweet silver histo- chemical stain alongside one of the following parameters of high mitotic rate, tumour necrosis and vascular inva- sion to determine a diagnosis of ACC [9]. This method has been shown to have good interobserver reproducibil- ity for the diagnosis of ACC [10], and to accurately iden- tify malignant oncocytic adrenocortical tumours which follow an aggressive course [11].
The Helsinki score is viewed as the most reliable in dif- ferentiating between malignant and benign adrenocorti- cal neoplasms, with a sensitivity of 100% and specificity of 99.6% [12]. Studies have also shown that it has the high- est specificity for the identification of malignant onco- cytic adrenocortical tumours compared with other scoring systems [8]. It is the only scoring system that integrates the Ki67 proliferation index into its overall score, along- side mitotic rate and evidence of tumour necrosis, with a score of >8.5 being diagnostic for ACC, and a score of >17 being associated with a poor prognosis [13]. However, it does have the potential to underestimate the malignant
potential of oncocytic tumours, due to the increased diffi- culty with assessing mitoses in these cells [5].
In this case, histopathological analysis of the tumour demonstrated an LWB score of 0, a reticulin algorithm score of 0 and a Helsinki score of 2.2, which was consist- ent with a benign adrenal oncocytoma across all scoring systems.
Treatment outcome
She has made a full recovery following her surgery and currently remains under regular endocrinology outpatient follow-up with biochemical surveillance of her testoster- one and DHEAS. Her postoperative short-synacthen test showed evidence of ongoing adrenal insufficiency for which she remains on hydrocortisone, with a basal corti- sol of 81 nmol/L, rising to only 120 nmol/L after 30 min. She has otherwise remained in biochemical remission 1-year following her surgery, with her latest biochemistry showing normalisation of the urine steroid profile (Fig. 4) and serum androgens [DHES < 0.4 pmol/L (normal: 0.9-11.6 pmol/L) and testosterone <0.4 nmol/L (normal: 0.4-1.4 nmol/L)]. She, however, has not yet noticed any significant improvements to her symptoms of deepening voice or clitoromegaly 1-year following her surgery.
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Left adrenal gland histopathological analysis showing a 58 mm adrenal mass with an intact capsule and complete excision macroscopically (a). Microscopic analysis (b, c) showed positive staining for inhibin, calretinin and MelanA with a low proliferation Ki67 index of 1-2.2%.
Discussion
Adrenal oncocytomas are rare tumours, which are pre- dominantly benign and hormonally nonfunctional. Around 287 cases of adrenal oncocytic neoplasm have been described in the literature, with around 30% being described as functional and 30% being found to be malig- nant [14]. Oncocytomas are tumours where the dominant cell type consists of cells containing granular cytoplasmic eosinophilia due to numerous mitochondria [15]. They originate from epithelial cells and occur mainly in endo- crine and exocrine organs such as the thyroid, parathy- roids, kidneys, salivary gland and pituitary gland [16].
Imaging findings in adrenal oncocytoma are variable, although are typically characterised as well-demar- cated solid encapsulated masses on CT imaging [17]. Postcontrast, these lesions tend to demonstrate heter- ogeneous enhancement, and in contrast to renal onco- cytoma they usually lack a central scar [18]. On MRI, typical findings of adrenal oncocytoma are a heterogene- ous appearance in T1 and T2 weighted sequences, with hyperintensity of T2 and variable isointense to hypoin- tense signal on T1. Diffusion weighted imaging find- ings are also variable, with these lesions usually showing
moderate to intense diffusion restriction. They tend to show moderate enhancement following administration of gadolinium [19].
Benign lesions do not typically demonstrate high PET- avidity. However, several reports of highly PET-avid benign adrenal oncocytoma have been reported in the literature [20-25]. The mechanism of high FDG uptake in adrenal oncocytoma is not completely understood but is thought to be due to the presence of large numbers of intracellular mitochondria and resulting increased glu- cose utilisation [21,26].
FDG-PET has overall been shown to have good sensitiv- ity and specificity for characterisation of adrenal masses, with a recent meta-analysis showing an overall pooled sensitivity of 87.3% and specificity of 84.7% for the use of FDG-PET in the differentiation between benign and malignant adrenal lesions [27]. Analysis can take the form of either qualitative assessment by visual evaluation, or quantitative assessment by using adrenal SUVs (stand- ardised uptake values) or the adrenal lesion-to-liver SUV ratio. Studies have reported optimal adrenal SUVmax cut-off values for malignancy ranging from 2.1 and 4.1,
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3
5
4
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6.73e8
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Total ion current chromatograms from gas chromatography-mass spec- trometry (GC-MS) analysis of urinary steroid metabolites excreted (a) by the patient at diagnosis, (b) after her adrenalectomy. The abnormal steroid metabolites labelled in the preoperative sample are (1) andros- terone, (2) aetiocholanolone (both derived from androstenedione and testosterone), (3) DHA, (4) 16aOH-DHA and (5) androstenetriol (all derived from DHA). Postoperatively these steroid metabolites were no longer increased. The black stars indicate the position of exogenous internal standards.
and adrenal lesion-to-liver SUV ratio cut-off values rang- ing from 1.08 to 2.5 [28]. These have been shown to have overall high sensitivity (86-100% for SUVmax, and 85-100% for SUVratio), but lower specificity (66-75% for SUVmax, and 70-100% for SUVratio) for the detection of malignancy [28].
However, studies have demonstrated that benign adrenal lesions can exhibit variable FDG-PET avidity, resulting in false-positive diagnoses for malignancy [26]. Our case illustrates a further example of this, with her FDG-PET scan demonstrating an adrenal lesion SUVmax of 15, and an adrenal lesion-to-liver SUVmax ratio of 5, both of which fall within what is conventionally regarded a malignant range. There is also evidence that some func- tional adrenal lesions, such as phaeochromocytoma, show increased FDG uptake compared with nonfunctional
lesions, although the uptake intensity is variable between those which are malignant and benign, therefore limit- ing the utility of FDG-PET in differentiating benign from malignant lesions in these cases [29]. Other benign lesions that have demonstrated increased 18F-FDG- PET uptake include adrenal adenoma and hyperplasia, as well as infectious/inflammatory processes [30].
Conclusion
Adrenal oncocytoma should be considered a rare benign differential diagnosis of an FDG-PET avid adrenal lesion. Histopathological analysis is essential in the diagnosis of adrenal oncocytoma, and surgical resection is, therefore, the mainstay of management, both for the purposes of confirming a histological diagnosis, and as a curative treatment.
Acknowledgements
Written consent was obtained from the patient to publish this article.
Conflicts of interest
There are no conflicts of interest.
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