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Expert Review of Endocrinology & Metabolism
ISSN: 1744-6651 (Print) 1744-8417 (Online) Journal homepage: http://www.tandfonline.com/loi/iere20
Advances in our understanding of the prognosis of adrenal incidentaloma
Iain Mackay & Sebastian Aspinall
To cite this article: Iain Mackay & Sebastian Aspinall (2016): Advances in our understanding of the prognosis of adrenal incidentaloma, Expert Review of Endocrinology & Metabolism, DOI: 10.1080/17446651.2016.1233055
To link to this article: http://dx.doi.org/10.1080/17446651.2016.1233055
Accepted author version posted online: 08 Sep 2016. Published online: 08 Sep 2016.
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Journal: Expert Review of Endocrinology & Metabolism DOI: 10.1080/17446651.2016.1233055
Advances in our understanding of the prognosis of adrenal incidentaloma
Iain Mackay(1), Sebastian Aspinall (2)
(1) Higher Surgical Trainee, Royal Victoria Infirmary, Newcastle upon Tyne
(2) Consultant Surgeon, Northumbria Healthcare NHS Foundation Trust
Abstract
Introduction: As cross-sectional abdominal imaging is used increasingly, adrenal incidentaloma (AI) are being found frequently and present a clinical dilemma. The vast majority are benign and non-functioning, but a minority represent incidentally found functional or malignant tumours. In this review we summarise the current clinical, biochemical and radiological investigation of AI and discuss recent advances that differentiate clinically inconsequential lesions from functional and/or malignant AI. Areas covered: Prevalence, natural history, biochemical and radiological assessment, indications for surgery and surgical provision. Expert Commentary: Well established work-up of AI usually enables benign, non-functioning lesions to be differentiated from functioning and/or malignant AI. In indeterminate lesions recent advances in work-up such as urine steroid profiles measured by gas chromatography / mass spectrometry and functional imaging with 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) in addition to standard investigations have improved characterisation of these lesions. The management of AI showing mild autonomous hypercortisolism without overt features of Cushing’s syndrome remains controversial and is discussed in this review.
Keywords
Adrenal gland, incidentaloma, Cushing’s syndrome, phaeochromocytoma, primary hyperaldosteronism, adrenal adenoma, adrenocortical carcinoma, computed tomography, magnetic resonance imaging, and adrenalectomy.
1.Introduction
Adrenal incidentaloma (AI) is a relatively common clinical scenario. About 1000 publications exist on the matter, with many review articles, position statements, decision making algorithms and guidance to assist with the management of AI. Assessment of functionality, risk of malignancy and follow up of non-operated cases are the principal areas of discussion. Whilst there are emerging trends within the available data, unfortunately, there is not sufficient, conclusive data to make legitimately strong conclusions in all areas, thus some of the guidance is based on a pragmatic approach.
AI comprises a variety of diverse pathological entities with very different prognoses. The majority of AI is benign and non-functioning which after appropriate investigation can be discharged. Differentiating these benign, non-functioning AI from the rare malignant or functioning tumours of the adrenal gland is the main purpose for investigation.
The key clinical and research questions regarding AI are as follows:
1. What is the most accurate diagnostic investigation for characterising AI?
2. What are the indications for surgery?
3. What is the optimal follow-up (biochemical and radiological) in non-operated patients?
4. What is the optimal management (surgical versus medical) in subclinical hypercortisolism (SH)?
In this chapter we discuss the current biochemical and radiological work-up and management of AI and address these questions with reference to recent advances.
2. Incidence or Prevalence
The definition of AI is generally taken as being a lesion within the adrenal gland found on imaging when adrenal pathology was not specifically sought. The minimum size of AI recommended to instigate biochemical investigation is 1cm. Increased application of cross- sectional radiological techniques has resulted in an increase in the discovery of AI.
Post mortem series suggest a prevalence of 2.33% (13 series 71206 patients) (1). An invited review by Barzon et al observed the CT detected incidence of AI to be 0.64% of 82483 patients (6 series 1982-1994) (1) . Subsequent series have found a higher detection, with reports of about 4% being typical (2). Recent studies from routine clinical practice, rather than prospective studies conducted by radiologists with an interest in adrenal imaging, have found lower prevalence of AI (0.8%-1.8%) (3, 4). When specialist centres set out with the intention of specifically identifying AI on CT, higher prevalence rates are generally reported e.g. 4.5% (5) and 11.3%(6).
AI increases with age, found in 0.2% of 20-29 year olds and 7% aged over 70 (7, 8). 15% of AI are bilateral with most of these being metastases; congenital adrenal hyperplasia and bilateral adenomas comprising the majority of the remainder.
3. Investigation
The principal issues, raised by finding AI, are exclusion of autonomous endocrine function and risk stratification for malignancy (9)(10). Past medical history, family history, and symptomatic burden of disease should be sought, and clinical examination undertaken to look for features of excess hormone secretion. A personal or family history of endocrine disease, history of malignant disease, and symptoms or signs of endocrine dysfunction may alter the strategy of management, as they may increase the probability of a clinically significant AI.
The distribution of underlying pathologies presenting as AI reported in 2 large reviews are presented in the following table. These reviews from 2003 (1) and 2009 (11) included 3868 and 1804 patients respectively. The more recent review by Cawood et al showed a lower incidence of all pathologies except non-functioning adenoma and is more reflective of the real incidence of underlying pathology of “true Al”, as earlier series often contained a positive pathology bias, due to the inclusion of surgical series, studies including patients with a history of malignancy (past/present/suspected) and others containing functional / non-incidental AI.
Table 1
4. Biochemical assessment of hormonal activity
Biochemical investigation for hormonal activity should include measurement of plasma renin and aldosterone to exclude primary hyperaldosteronism (PHA); urine and/or plasma metanephrines and normetanephrines for phaeochromocytoma, serum adrenal androgens and their precursors such as dehydroepiandrosterone sulphate (DHEAS) and 17OH- progesterone; and urine free cortisol and low-dose dexamethasone suppression test to exclude autonomous cortisol secretion. Further confirmatory biochemical and radiological tests will usually be required. But the diagnosis of a functional adrenal tumour will usually prompt a discussion about surgical resection. Adrenocortical carcinoma (ACC) characteristically exhibits a mixed picture of excess hormone secretion from the adrenal cortex.
PHA needs to be excluded in patients with a history of hypertension and AI, especially since Conn’s adenomas are typically small tumours, mean size 15-20 mm, and may present as Al. PHA is best initially investigated by measuring plasma aldosterone to renin activity ratio (ARR) at a time when serum potassium is normalised and medication such as spironolactone, angiotensin converting enzyme inhibitors (ACEIs), angiotenson-II receptor blockers (AT2RBs), which affect the renin-angiotensin- aldosterone axis have been discontinued. The majority of patients with PHA have either bilateral idiopathic hyperplasia (IHA) or unilateral aldosterone-producing adenoma (APA). In one series of 3000 unselected hypertensive patients 177 (5.9%) had PHA of which 63.3% had IHA and 29.9% APA (12).
Wide variations in the prevalence of PHA have been reported mostly due to lack of standardisation of ARR cut-offs and inconsistent use of confirmatory tests for diagnosis. Differences in assay and laboratory methodology have resulted in variability in the ARR cut- off value for PHA, though this is commonly in the 20-40 range, with 30 being the most usual threshold (13).
Once the diagnosis of PHA is confirmed by fludrocortisone or saline suppression test consideration should be given to adrenalectomy in those patients with a solitary unilateral nodule willing and suitable to pursue the surgical option. Because the incidence of non- functioning adrenal adenoma increases with age and may co-exist with IHA it is important to determine the site (laterality) of aldosterone over-production prior to adrenalectomy. A recent consensus statement recommended that all patients with PHA, with the exception of those < 40 years with clear unilateral APA and normal contralateral adrenal gland on CT or suspected ACC at any age, should undergo adrenal vein sampling (AVS) prior to adrenalectomy (14).
Figure 1
4.2 Phaeochromocytoma
Phaeochromocytoma can be assessed with either fractionated metanephrines in 24 hour (or overnight) urine collections or free plasma metanephrines, which have a 97% and 99% sensitivity respectively, the latter having lower specificity at 85-89% (and 77% in patients over 60 years old), hence the need for repetition (15-17). Blood for plasma metanephrines should be taken with patient supine (ideally for 30 minutes). Plasma free metanephrines > 4 times the upper normal reference limit confirms the biochemical diagnosis unequivocally (18). Clonidine suppression test may be useful in persistently borderline results after eliminating confounding factors such as medication and illness that can lead to false positive results. Medications such as sympathomimetics, ephedrine, levodopa, methyldopa, labetolol, sotalolol and tricyclic antidepressants may affect metanephrine levels so should be discontinued ideally prior to investigation (19).
Following biochemical diagnosis of phaeochromocytoma and before embarking on surgical resection it is generally recommended to undertake functional imaging with 123Iodine- Metaiodobenzlguanidine (123I-MIBG) scintigraphy to confirm the presence of a phaeochromocytoma and exclude multifocal or metastatic disease, in addition to anatomical imaging.
In a study of 79 patients with current or previous history of phaeochromocytoma Wiseman et al found that a total body planar scan 24 hours after the administration of 123I-MIBG had a sensitivity of 87% and specificity of 73% for the diagnosis of phaeochromocytoma and the addition of single positron emission computed tomography (SPECT) of the thorax abdomen and pelvis did not significantly alter the efficacy of this investigation (sensitivity 88% and specificity 70% in 53 patients who had 123I-MIBG / SPECT) (20). False positives can occur due to physiological uptake of 123I-MIBG in the normal adrenal gland. Tumour necrosis and drugs that interfere with the accumulation of 123I-MIBG in the adrenal gland can give rise to false negative results.
18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) has also been used in the staging and functional confirmation of phaeochromocytoma showing a similar performance to 123I-MIBG for primary tumours and superior sensitivity for metastatic disease (21). Currently 123I-MIBG scintigraphy is recommended for the functional characterisation of phaeochromocytoma prior to surgery and 18F-FDG PET scintigaphy is reserved for the assessment of patients with metastatic disease (18).
Figure 2
4.3 Hypercortisolism
Overt hypercortisolism (i.e. Cushing’s Syndrome) rarely presents as an Al, and as such is no longer discussed in this review. Subclinical hypercortisolism (SH) is defined as a status of altered hypothalamicuitary-adrenal axis secretion in the absence of clinical features of cortisol excess (22). SH lacks agreed criteria for diagnosis and its natural history is far from clear, though progression to overt Cushing’s syndrome is rare (1). Given this, it is not surprising that the exact prevalence of SH varies depending on the diagnostic criterion and population studied. Analysis of 22 case series, albeit using differing diagnostic criteria, found the prevalence of SH was 9% in 2622 patients with AI (23).
The most widely recommended investigation for SH is a 1mg midnight dexamethasone suppression test (DST). The American Association of Clinical Endocrinologists recommended a cut-off of 5µg/dl (138 nmol/L) for serum cortisol the following morning. This is higher than the cut-off for the diagnosis of overt cortisol excess (1.8 ug/dl or 50nmol/L) to reduce false- positive results in AI (10). A 2 day low dose dexamethasone suppression test (LDDST) may be more accurate than DST in diabetes mellitus, alcoholism and psychiatric disorders, but otherwise holds no advantages over an overnight DST.
Dexamethasone is metabolised in the liver by the cytochrome p450 system. The enzyme complex CYP3A4, which is responsible for dexamethasone metabolism, can be activated by certain drugs such as phenytoin, carbamazepine, rifampicin and phenobarbital and impaired by itraconazole, fluoxetine, diltiazem and cimetidine, giving rise to false positive or negative results. False positive DST occurs in 2-12%, with other causes include stress, alcohol, and reduced intestinal absorption of dexamethasone (24). LDDST, urinary free cortisol and serum adrenocorticotrophic hormone (ACTH) are therefore recommended for confirmation of diagnosis (25), though demonstration of altered circadian cortisol secretion by midnight serum or salivary cortisol has also been advocated (26).
Although SH is not associated with the clinical features of Cushing’s syndrome there is a growing body of evidence linking SH with features of the metabolic syndrome such as diabetes mellitus type 2, hypertension, obesity and dyslipidaemia as well as osteoporosis and fracture risk. The following table shows the prevalence of these co-morbidities in series of patients with AI and SH (27) (28) (29) (30). Lower bone mineral density (BMD), increased fracture prevalence and reduced bone quality have also been shown in patients with AI and SH (31) and the incidence of cardiovascular events are higher in AI patients with SH compared to non-functioning lesions (32).
Table 2
Figure 3 4.4 Adrenocortical Carcinoma
Whilst the risk of AI being an adrenal adenocarcinoma (ACC) is best assessed by radiological means, often the biochemical results provide strong clues to the presence of ACC. A mixed pattern of hormonal secretion raises the suspicion of ACC (33), 18% in our regional series of ACC (34). Typically serum adrenal androgens such as DHEAS and cortisol are elevated, as well as their precursor hormones (35). Of all ACC in our series, 9% were detected as AI (34).Hormonal activity was seen in 62% of 602 reviewed cases of ACC (36). ACC not uncommonly are accompanied by combinations of virilisation, hypercortisolism and hyperaldosteronism, sometimes developing rapidly. Serum DHEAS levels should be assessed in all patients with AI as it is increased in 17% of ACC (and in 28% of ACC in patients <50 years), though DHEAS has therefore a low sensitivity for ACC, its specificity is high (93%) (37).
Urinary steroid profile with gas chromatography / mass spectrometry may become part of the standard work-up of indeterminate AI as elevated levels of serum steroid metabolites such as tetrahydro-11-deoxycortisol (THS) have shown great promise in differentiating benign adenoma from ACC. In a recent study by Kerkhofs et al elevated urinary levels of 7 out of 15 steroid metabolites had a sensitivity of >90% for detecting ACC, with THS showing 100% sensitivity and 99% specificity. Promising results of retrospective studies like these
need to be validated prospectively before the role of these tests in routine clinical practice can be established (38).
Figure 7
5. Radiological assessment of malignant risk
Whilst solitary, functional lesions of the adrenal gland should default to discussion about operation, malignant potential of AI is not so clear to define and predict. Both Barzon et al (1) and National Institute for Health “State of Science Statement” found that ACC account for <5% of all AI. Size on computed tomography (CT) scan is one of the stronger predictors of malignancy with 2% of lesions <4cm, 6% of 4.1-6cm and 25% of >6cm lesions being ACC (39). Worrisome radiological features of AI are increasing size, density, heterogeneous texture, irregular margins and local invasion.
Patients with non-functioning AI demonstrating typical radiological characteristics of an adrenal adenoma or myelolipoma can usually be reassured. It is not possible to assign a precise probability of malignancy for AI with indeterminate radiological features in every patient though a radiological risk stratification score has been proposed based on lesion size and density that when applied retrospectively to 157 indeterminate AI potentially reduced the need for surgery in a significant proportion of patients (40).
Figure 5
5.1 Computed Tomography
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Regarding radiological detection of AI (and therefore surveillance) CT is the most commonly performed modality, this simply reflects modern medical practice but other modalities still detect AI. In 2014 the 16th COMARE (Committee on Medical Aspects of Radiation in the Environment) report used HES (Hospital Episode Statistics) data from England (58 million population) showing that the annual number of CT scans performed, increased from one million in 1996/7 to five million in the 2012/3 year. It is difficult to quantify how many of these covered the adrenal glands but at a conservative 1-2% incidence, clearly AI is a very common occurrence (Review of Radiation Dose Issues from the use of CT in the UK, Department of Health, 2014).
Unenhanced CT (as well as chemical shift MRI) use the presence of intracellular lipid in adenomas to differentiate them from malignancy. The density of the lesion measured in Hounsfield Units (HU) on unenhanced CT is currently used to assess this. A cut off at 10 HU has a 96-100% sensitivity for ACC (41-45) therefore, most guidance suggests describing AI with density of >10 HU on unenhanced CT as indeterminate (though 30% adenomas are lipid poor and more dense) and as such, these AI should be characterised further with delayed enhancement contrast CT (CECT) i.e. a specific adrenal protocol CT. CT histogram analysis, a technique that uses a histogram analysis tool to examine a region of interest in an adrenal
mass and characterise its intracellular fat content, has been shown to be more sensitive (91%) than attenuation sensitivity on unenhanced CT (77%) in a series from 2010 (46).
Delayed washout of contrast on CECT aids diagnostic accuracy in differentiating between adenoma and non-adenoma with >10HU on unenhanced CT, due to adenoma having a faster contrast washout than ACC or metastases (32). The timing of delayed CT washout is debated, but a 15 minute delayed CT protocol using an absolute percentage washout > 60% has a sensitivity of 86-88% and specificity of 92-96% (29,30). Washout characteristics, whilst being useful, are less important than size and consistency / geneity of the mass: heterogeneous lesions having a much higher malignancy risk (47).
Quadriphasic CT (unenhanced, arterial, portal venous phase and 5-minute delayed enhancement) used commonly for pancreatic and liver imaging has also been shown to have high accuracy (97/101 or 97.1%) in the characterisation of AI, which may have practical benefits in busy radiology departments (48).
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Dual-energy computed tomography (DECT) is a relatively new radiological technique that uses two data sets for an anatomical location acquired at different energy levels to enable greater tissue characterisation compared to single energy techniques. Gupta et al reported the use of DECT to characterise 31 adrenal nodules (25 adenomas and 6 metastases). Using DECT at 140 and 80 (peak kilovoltage) kVp demonstrating a sensitivity of 50%, specificity and positive predictive value of 100% and negative predictive value of 28% for the diagnosis of adrenal adenoma suggesting some clinical use for DECT, though not currently sufficient to replace current conventional imaging (49).
5.2 Magnetic Resonance Imaging (MRI)
Lipid-poor adenomas (that is >10 HU on unenhanced CT) can also be assessed by MRI (using chemical shift analysis) which has the advantage of avoiding repeated ionising radiation, use of iodine-containing contrast needed for delayed enhancement CT, and superior tissue resolution. When used with chemical shift imaging there is evidence of its equivalence and possible superiority to CECT in differentiating benign from malignant adrenal masses (50, 51). Whilst MRI can be used in the assessment of the adrenal gland, pragmatically it is done less so, as most AI are detected on CT. MRI can also be used as an alternative to CT particularly for surveillance without concern for ionising radiation exposure, though not cost.
5.3 Ultrasonography
Ultrasonography (US) is demonstrably less sensitive than CT or MRI in characterising and identifying adrenal masses (52, 53), being only 65% sensitive for masses <3cm (54). The differentiation between benign and malignant masses is the main weakness of US (55) and as such should not be used for the initial radiological assessment of AI, but US is useful for surveillance in selected cases to monitor for increase in size.
5.4 18F-Fluorodeoxyglucose Positron Emission Tomography
In addition to CT and MRI, 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) has a role in the assessment of malignant potential in AI. FDG PET uses the high metabolic rate in malignancies to differentiate these from benign lesions. ACCs have avid uptake of FDG giving this investigation a very high sensitivity for ACC. The specificity varies from 83-91% with false positives occurring in benign adrenal disorders such as adenoma, inflammatory and infective lesions, phaeochromocytoma and pigmented macronodular adrenal hyperplasia (PMAH). The high negative predictive value of FDG PET (when maximum standardised uptake value (SUV) ratios are <1.45-1.6 compared to normal liver tissue) make FDG PET very useful clinically in potentially avoiding surgery in indeterminate AI (56-60).
5.5 Radiologically-guided Biopsy
Radiologically-guided biopsy of the adrenal gland has a very limited role. Phaeochromocytoma must not be biopsied if an adrenergic crisis is to be avoided. Likewise there is no role for biopsy of suspected ACC, due to potential for tumour seeding and frequently inconclusive histopathology (61). The only indication for radiologically-guided adrenal biopsy is metastases, when there is a previous history of malignancy, and only after endocrine functionality has been excluded and radiological assessment remains inconclusive. Solitary adrenal metastases are now increasingly being surgically excised rather than biopsied - that is to say adrenal biopsy is not frequently performed at all (62).
Figure 6
6. Management
If clinical, biochemical and radiological work-up of an AI confirms a hormone-secreting tumour with overt clinical features of hormone excess, then management options (medical and surgical) are well established, and discussed briefly below. When biochemical investigation demonstrates mild autonomous and excessive hormone secretion without overt clinical features of hormone excess, as occurs in SH, or radiological work-up is indeterminate the decision when to offer surgery is less clearly defined and much debated in the literature. To complicate this further, features of the metabolic syndrome, which are associated with SH, such as diabetes mellitus type 2, dyslipidemia, hypertension and obesity are common, and so it is not known on an individual basis to what extent the mild cortisol excess from an AI contributes to these morbidities. Though the higher prevalence of these co-morbidities seen in patients with SH and AI suggests a causative association.
6.1 Natural History
6.1.1 Hormone Secretion
Follow-up studies of non-operated Al generally fall into two groups - those that show the development of mild hormone hypersecretion in a proportion of patients with AI with time,
Védelmétandthe oldest) colonial One ,
leading to the recommendation for long-term biochemical follow-up, and those that don’t, concluding that patients with benign, non-functioning AI at initial assessment can be safely discharged. However all studies are agreed that the risk of development of overt clinical disease in AI is very low.
Morelli et al reported a multicentre retrospective study of 206 patients with AI and found that 8.2% developed SH during a median follow-up of 6 years. The risk of developing SH was increased in AI > 2.4cm and SH was associated with more cardiovascular events (63). Vassilatou et al showed in a study of 77 patients with AI that 12 (15.5%) had persistent and 12 (15.5%) intermittent mild autonomous cortisol hypersecretion over a median follow-up of 5 years (64). Bernini et al followed up 115 patients with AI for a median of 4 years and found frequent 31/115 (26.9%) subclinical changes in endocrine function, few of which 3/115 (2.6%) persisted. They concluded that mild fluctuations in endocrine function were common but did not herald progression to overt clinical disease (65).
In contrast Muth et al in a prospective study from Sweden of 212 patients with AI followed for a mean of 19 months showed that none developed autonomous hormone excess and so could not justify long-term biochemical follow-up based on these outcomes(66). Yeomans (67) et al were in agreement with these findings in a retrospective study of 194 patients with AI also from Sweden. Barzon in a comprehensive review from 2003 amalgamating follow up data (lasting 2-5 years in most studies) from 18 published series found that overall 1.7% of patients with AI develop biochemical hyperfunction at follow-up and this risk is higher in AI > 3cm (1).
Due to the lack of consensus on the diagnosis of SH, fluctuations in cortisol secretion with time, and lack of evidence of progression to overt clinical disease, it is not surprising that there are no high-level evidence-based guidelines for hormonal surveillance of AI. A sensible approach is to repeat biochemical tests for hypercortisolism annually for 5 years in those AI patients with possible or confirmed SH. As this group are at increased risk of deterioration of bone mineral density, blood glucose, hypertension and dyslipidaemia, it would be prudent also to monitor for these complications and manage them medically (22).
The American Association of Clinical Endocrinologists (AACE) and American Association of Endocrine Surgeons (AAES) guidelines for AI, while acknowledging the uncertainties, recommend annual biochemistry to investigate hormone excess for 5 years (6). The National Institute for Health’s state-of-the-science statement recommends DST and urinary catecholamine assays annually for 4 years (22).
6.1.2 Mass Enlargement
Size of adrenal adenoma has been reported to increase in a minority of AI on follow-up. Comleki et al in a study of 376 patients with AI found 10% of adenomas increased in size during 2 years follow-up and this was more commonly seen in the middle-aged and elderly
(68). This observation is consistent with studies showing that the incidence of AI increases with age (8) (7) and patients with larger AI are more likely to develop SH (1). Libe et al documented higher risks of mass enlargement of 6, 14, and 29% at 1, 2 and 5 years respectively (69). The results of individual case series vary, but overall reviews by Cawood et al and Barzon et al show that 16 and 9% of AI exhibit growth during follow-up though only a tiny proportion 0.09% (mean) and 0% (median) showed malignant transformation (1, 11).
Concerns about missed diagnosis at presentation are justified. ACC is an aggressive tumour, growing at >2cm annually (70) with a poor prognosis (16% 5-year survival), though 38% 5- year survival for early stage disease can be achieved. In the presence of incomplete resection or metastatic disease the median survival is 12 months (71). So missing an ACC presenting as an AI may have serious consequences, and guidelines therefore err on the cautious side, in the absence of clear evidence.
The National Institute for Health in their state-of-the-science statement recommend repeat imaging at 6-12 months then discharge if no growth occurs (39). The AACE/AAES medical guidelines for the management of AI recommend repeat scanning at 3-6/12 then annually for 1-2 years and consider surgery if >1cm increase in size occurs (10). The Mayo clinic suggest scanning at 6, 12 & 24 months but less frequently for AI <2cm and more so if suspicious (70).
6.2 Indications for surgery
If biochemical and radiological work-up confirms autonomous excess hormone secretion from the AI with overt clinical features then the management options medical and/or surgical are well established and briefly set out below. The decision when to operate when radiological work-up is indeterminate or biochemistry shows mild excess, autonomous hormone secretion is still the subject of debate and is discussed in more detail below. In terms of operative technique a systematic review by Assalia et al has shown decreased complication rates and shortened hospital stay with laparoscopic adrenalectomy compared to open techniques. So minimally invasive adrenalectomy has become the standard operation for AI which with increasing experience can be performed on tumours >10cm, though 12-15cm seems to be getting to the upper limit of feasibility (51). The variant techniques of minimally invasive adrenalectomy, such as transabdominal laparoscopic and endoscopic retroperitoneal, have similar outcomes with each having circumstantial advantages. Endoscopic retroperitoneal adrenalectomy seems to be more suited to smaller and/or bilateral adrenal tumours than the transabdominal laparoscopic approach (52, 53).
6.2.1 Primary Hyperaldosteronism
Hypertension should be controlled medically in PHA usually with the mineralocorticoid antagonist spironolactone. However other antihypertensive agents may be required to maintain normotension. Hypokalaemia needs to be corrected prior to surgery. Total rather
than partial adrenalectomy is preferred (13). Adrenalectomy has been shown to improve end-organ (e.g. cardiac and renal) damage due to aldosterone excess (72) (73). Hypertension improves following adrenalectomy but only returns to normal (<140/90mmHg) in 50-80% (74). Factors which predict failure of hypertension to normalise include advanced age, long duration of hypertension, need for multiple antihypertensive medications pre-operatively, male gender and family history of hypertension (75) (76). Recurrence after surgery is uncommon but has been described in 3/79 patients showing biochemical cure at 1 month post adrenalectomy, so long-term follow-up is advised (75).
6.2.2 Phaeochromocytoma
Medical control of sympathetic excess, preferably via a-adrenergic receptor blockade with phenoxybenzamine, should be undertaken prior to adrenalectomy for phaeochromocytoma. This can take several weeks to titrate the dose up to the limit tolerated due to the development of side-effects such as postural hypotension, nasal congestion or blurred vision. Consideration should be given to genetic testing (particularly in patients <50 years) for inherited conditions associated with adrenal phaeochromocytoma such as neurofibromatosis type 1 (NF1), Von Hippel-Lindau syndrome (VHL), and multiple endocrine neoplasia (MEN) type 2A and 2B. High sodium diet and fluid intake is recommended pre- operatively to prevent severe hypotension after tumour excision (18).
Minimally invasive adrenalectomy is the preferred surgical approach in phaeochromocytoma having fewer haemodynamic disturbances than open surgery (56). Blood pressure, heart rate and blood glucose should be monitored closely in the immediate post-operative period, often in a critical care setting. Annual assessment of metanephrines (urinary or plasma) is suggested at long-term follow-up, as recurrence or development of further phaeochromocytoma / paraganglioma does occur (18) (19).
6.2.3 Subclinical Hypercortisolism
The indications for surgery in patients with mild autonomous cortisol secretion has been the subject of several recent publications, though has yet to reach general agreement.
Sereg et al found that the prevalence of components of the metabolic syndrome such as diabetes mellitus type 2, hypertension, dyslipidaemia and obesity were higher even in patients with biochemically non-functioning AI, but found no benefit for adrenalectomy in this group over a 9 year follow-up, perhaps unsurprisingly (77). Iacobone et al reported that adrenalectomy in patients with AI and SH improved hypertension, glycaemic control, body mass index (BMI) and quality of life (QOL), measured by SF-36, in 20 patients compared to 15 controls managed conservatively(78). Likewise Chiodini showed that adrenalectomy improved BMI, hypertension and fasting glucose in 25 patients with AI and SH compared to 16 controls managed conservatively (79). Other smaller case series have also demonstrated improvement in hypertension, diabetes mellitus and BMI in 9 patients (80) and improved
hypertension but not BMI, diabetes mellitus and dyslipidemia in 11 patients with Al and SH managed surgically (81).
The only randomised controlled trial (RCT) by Toniato et al also showed an improvement in hypertension, diabetes mellitus and dyslipidaemia in 23 patients with AI and SH in 23 patients who underwent surgery compared to 22 controls over a mean follow-up period of 7.7 years, however no benefit was seen in the operated group in osteoporosis (82). Since then a recent report has shown a reduction in the incidence of vertebral fractures and a trend towards improved bone mineral density, measured by dual energy absorptiometry (DEXA) scan, at 40 months follow-up in patients with surgically treated Al with SH(83),
There is a growing body of evidence showing improvements in components of the metabolic syndrome and bone health following surgery in patients with AI and SH albeit from mostly non-randomised studies with small numbers. The lack of an agreed definition of SH complicates interpretation of the results. Adrenalectomy is a major operation, with a recognised, though low mortality of 0.6% (7/1257) in 4th National Audit Report, British Association of Endocrine and Thyroid Surgeons, 2012 and it is not clear if the results from specialist centres, above, are applicable to general clinical practice. There is a clear need for a large, prospective, and possibly randomised clinical trial to address the question of whether adrenalectomy is indicated in patients with AI and SH.
Medical co-morbidities should be medically managed prior to surgery in these patients. Hypercortisolism predisposes to infection and venous thromboembolism, so precautions should be taken peri-operatively to prevent these complications. Patients undergoing adrenalectomy for cortisol hypersecreting tumours are at risk of post-operative hypoadrenalism and so should receive peri-operative glucocorticoid replacement until the hypothalamicuitary-adrenal axis recovers, which may take several months(84).
6.2.4 Indeterminate Radiology
Features of AI on unenhanced CT associated with malignancy include size, heterogeneity, irregular margin, and local invasion. Of these size is the most important and a 4cm threshold continues to be recommended for considering surgery (10) based on the risk of malignancy. Montero et al in a study of 1096 patients with AI from 1980 to 1995 found that a 4cm cut off was 93% sensitive and 42% specific for malignancy (37). More recently Comlekci et al showed that a 4cm threshold was 73% sensitive and 55% specific for malignancy in 376 patients with AI (68).
After size, density (measured by Hounsfield units) on unenhanced CT is the commonest radiological feature used to assess malignant risk. Based on a cut off of 10 HU unenhanced CT has a sensitivity of 71% and specificity of 98% for adrenal adenoma (85). Hence approximately 30% of adrenal adenomas are lipid poor and remain indeterminate of unenhanced CT. As previously discussed these can be investigated with CECT to examine
washout characteristics or MRI with chemical shift. With 46/76 or 63% of adrenalectomies being performed in one study for benign, non-functioning AI (86) there is a clear need to improve the pre-operative risk stratification of AI, so potentially avoiding surgery in benign AI, and there is a growing body of evidence supporting the use of FDG PET/CT to distinguish benign from malignant lesions.
FDG PET is commonly used in conjunction with CT to provide functional and anatomical information. Metser et al reported that the addition of CT improved the ability of FDG PET to distinguish between benign and malignant AI in a series of 175 adrenal masses (sensitivity 100% specificity 98%) using quantitative PET analysis with a cut off of 3.1 standardised uptake values (SUV) (87). A more recent meta-analysis concluded that the accuracy of FDG PET was not improved by the addition of CT and both FDG PET and FDG PET/CT were highly accurate (97% sensitive and 91% specific) at differentiating between benign and malignant masses >1cm (88). There is a debate whether qualitative or quantitative (based on SUV) PET analysis is better, with Boland preferring qualitative methods due to the number of variables that can affect quantitative analysis.
Two quantitative studies investigating the accuracy of FDG PET/CT in 67 and 77 pathologically confirmed and radiologically indeterminate AI showed similar results (sensitivity 97 and 100%, specificity 83 and 88%) using adrenal/liver SUV ratio thresholds of 1.29 and 1.45 respectively (56, 89). False negatives do occur with FDG PET in small (<1cm) AI, haemorrhage/necrosis, and neuroendocrine metastases. In patients with proven or suspected cancer and AI, FDG PET has the added advantage of providing a whole body scan and is particularly useful - Yun et al showed in a series of 50 cancer patients that FDG PET was 100% sensitive and 94% specific in differentiating between benign and malignant AI (90).
It is clear therefore that due to the very high sensitivity and accuracy of FDG PET/CT there is a compelling role for its use in characterising indeterminate AI and potentially preventing the need for surgery in FDG PET negative lesions (91).
Figure 7 6.2.5 Malignancy
Esta-
ACC is a rare aggressive tumour, growing at >2cm annually (12) with a poor prognosis (16% 5-year survival), though 38% 5-year survival for early stage disease can be achieved. Although there is some evidence showing improved prognosis in patients with ACC presenting as AI {O’Neill, 2010 #109}, in the presence of incomplete resection or metastatic disease the median survival is 12 months; hence the concern about missed diagnosis at the initial presentation and low threshold for operative intervention in equivocal cases (42).
Currently surgery is the only curative option in ACC, though this is only achieved in a minority. When ACC is suspected, open rather than laparoscopic surgery is recommended as
there is evidence to suggest a greater risk of incomplete resection margins and shorter time to recurrence with minimally invasive surgery (43, 44). Weiss criteria are used to histopathologically assess the degree of malignancy in the indeterminate cortical tumours / ACC. Adjuvant therapy with mitotane has been shown to lengthen recurrence free survival after surgery - 42 months in 47 patients who received mitotane versus 10 and 25 months in 55 and 75 patients treated with surgery alone (53) - and radiotherapy to tumour bed maybe used, with some studies showing a reduction in local recurrence (54) , though the benefit of radiotherapy on overall survival remains unclear (92).
7. Surgical Provision
Many guidelines and position statements suggest AI should be managed in specialist/tertiary centres, involving a multidisciplinary team. As to whether this is a desirable or achievable long term goal is not clear. In a North of England district general hospital, it was noted retrospectively, that only 17% of AI had biochemical work-up. It is not clear if this is a fairly typical of secondary care hospitals in the developed world (3).
What has also, recently, been shown in England is that, large numbers of surgeons are performing a relatively small number of adrenalectomies. In the financial year 2013/4, according to HES data, in England, 795 adrenalectomies were performed by 222 surgeons, with only 36 performing 6 or more a year. It was noted that the higher volume group resulted in patients having shorter hospital stay and reduced readmission rates (93).
In the UK at least, many cases are neither being referred nor operated in specialist centres. Clearer guidance regarding the need for tertiary referral for AI is required. Though given the high incidence of AI it would seem impractical to insist all of these lesions need this input.
An interesting paper on AI from North America, using a cost effectiveness analysis with a decision tree model, found that, assuming 2% of AI of >4cm are malignant, it was more cost effective to operate on AI than to continue surveillance or discharge (particularly for AI >4cm in patients <65 years of age). This naturally made assumptions about malignant risk, prognosis of ACC and costs of all of the various treatment modalities, which will not be similar worldwide (94).
The principal time of risk is at the initial assessment and diagnosis as malignant change during follow up and diagnosis of malignancy after discharge form surveillance seem extremely rare. Allied with the, still, poor prognosis of ACC, this heightens the need to make the right decision at presentation.
8. Summary & Conclusion
AI is a common clinical dilemma comprising diverse adrenal pathologies with very different prognoses. Thorough clinical, biochemical and radiological work-up is required at diagnosis
to establish the small number of functioning or malignant adrenal tumours from the majority of clinically insignificant benign, non-functioning adenomas. Current biochemical and radiological investigations outlined in this chapter are usually adequate at achieving this. The indeterminate AI still poses a problem as surgical resection of these lesions may represent overtreatment if these turn out to be benign, whereas failure to operate may risk missing an ACC. Optimal length and frequency of surveillance, both biochemical and radiological, has yet to be defined as the natural history of AI, although most likely to be indolent has yet to be confirmed. The importance of accurate risk stratification at diagnosis has therefore to be stressed and recent advances in radiology and biochemistry outlined above may in the future better differentiate benign from malignant AI allowing safer discharge and reducing unnecessary surgery for benign lesions.
In answer to the questions posed in the introduction:
1. What is the most accurate diagnostic investigation for characterising AI? Most AI are first seen on unenhanced CT. If there are no radiologically suspicious features, density is <10 HU and they are biochemically non-functioning, then no further radiological investigation is usually required. Indeterminate AI on unenhanced CT should undergo CECT or MRI with chemical shift. Urinary steroid profile may also help establish the risk of malignancy. If these lesions remain indeterminate then 13F-FDG PET can be useful to risk stratify further and potentially avoid surgery in 15F-FDG PET negative cases.
2. What are the indications for surgery? Surgery is usually indicated if clinical and biochemical work up shows excess, autonomous hormone secretion with overt clinical features. If biochemical and radiological work up is suspicious of ACC then adrenalectomy is recommended. Surgery should be discussed in patients with AI that remain indeterminate after careful investigation particularly if >4cm in size.
3. What is the optimal follow-up (biochemical and radiological) in non-operated patients?
The clinical benefit of follow-up has yet to be fully established given that progression to clinically overt syndromes of hormone hypersecretion or malignant transformation are rare. Current radiological guidelines recommend repeat imaging routinely after an interval, but err on the side of caution given the consequences of missing an ACC at presentation. As initial radiological assessment of AI improves the need for follow-up imaging seems only be justified in indeterminate lesions. Mild fluctuations in hormone hypersecretion, particularly cortisol occur in AI, though the lack of an agreed definition and management of SH, raise uncertainty about the clinical benefit of investigating for these at follow-up. Given the association of SH with the metabolic syndrome
it is certainly sensible to monitor weight, blood pressure, blood glucose, lipids, and bone mineral density in non-operated patients with AI.
4. What is the optimal management (surgical versus medical) in subclinical hypercortisolism (SH)?
In order for this question to be answered a consensus agreement on the definition and diagnostic criteria for SH needs to be reached and ideally a large, prospective trial of surgery versus medical management undertaken. There is a growing body of evidence showing an association between SH and increased cardiovascular events, poor glycaemic control, fractures and osteoporosis. More work needs to be done to establish the role of surgery in SH.
9. Expert commentary
Increasing use of cross-sectional abdominal imaging, particularly in an ageing population in the developed world, has led to more AI being discovered. This raises the question of how should we investigate and manage these lesions. The first challenge is to make sure that AI are investigated and not ignored. Although guidelines universally recommend imaging to stratify malignant risk and biochemistry to exclude autonomous hormone secretion, it is apparent that in general clinical practice this recommendation is not always followed. The vast majority of Al are benign and non-functioning and therefore clinically inconsequential - but are minority comprise a group of potentially dangerous tumours including phaeochromocytoma and adrenocortical carcinoma, which if ignored can result in fatal consequences.
Biochemical tests are usually able to accurately confirm or exclude autonomous hormone secretion and there is no controversy about the role of adrenalectomy in functional tumours accompanied by clinical features of hormone excess. The role of surgery in mild, autonomous cortisol-secreting Al without overt features of Cushing’s syndrome (called in this review subclinical hypercortisolism, but also referred to as subclinical Cushing’s syndrome) is less clear and needs to be addressed by a well- designed randomised clinical trial.
In addition to confirming functionality biochemistry can give clues to the malignant risk of AI as adrenocortical carcinoma (ACC) frequently secretes excess of multiple steroids and/or their precursors. In addition measurement of urine steroid profile by gas chromatography / mass spectrometry shows great promise in risk stratifying AI biochemically, but results from retrospective studies need to confirmed in prospectively.
Unlike many lesions elsewhere in the human body, biopsy has no role in the assessment of AI, apart from investigating suspicious metastases in patients with a history of malignancy in other organs once functional lesions have been excluded. Radiological assessment has therefore a pivotal role in risk stratifying AI. Computed tomography (CT) is the commonest
imaging modality used in AI. Size, density, washout characteristics as well as other features associated with malignancy (such as heterogeneity) are used to risk stratify these lesions. Magnetic resonance imaging (MRI) with chemical shift is an alternative to CT with comparable results.
18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) has a high sensitivity for malignant AI and although false positives do occur, the high negative predictive value of FDG PET makes it useful clinically to potentially avoid surgery in indeterminate AI that are FDG PET negative. Size is correlated with malignant risk in AI and surgery should be considered in most lesions >4cm, though it may be that as confidence in radiological risk assessment increases this size threshold will creep upwards in lesions that otherwise appear benign.
Improved accuracy of radiological assessment at initial presentation and lack of evidence to support malignant transformation of AI has questioned the need for follow-up imaging, with its attendant costs and exposure to ionising radiation, except in indeterminate AI managed conservatively. Likewise the clinical benefit of long-term biochemical follow-up of AI is not proven, though recommended in guidelines, as the development of clinical syndromes of autonomous hormone secretion is a rarity.
10. Five-year View
The number of AI diagnosed will increase over the next 5 years due to greater use of cross- sectional abdominal imaging. As the incidence of AI increases with age, and populations in the developed world also age due to increased life expectancy, this situation will be compounded.
Awareness of the potential underlying pathologies in AI should prompt clinicians to investigate these lesions for functionality and malignant risk. Standard biochemical work-up is well established though the increased use of urine steroid profiles in indeterminate radiological AI may help risk stratification for malignancy.
The indications for surgery in AI showing mild autonomous cortisol secretion without overt clinical features of Cushing’s syndrome needs clarification and this should be addressed by a well-designed randomised clinical trial.
The use of functional radiological assessment of AI should improve risk stratification at presentation in particular the use of 18F-FDG PET to avoid the need for adrenalectomy and / or routine radiological surveillance in indeterminate AI if 18F-FDG PET negative.
Guidelines still recommend biochemical follow-up, though given progression to overt clinical syndromes of hormone excess is rare, the clinical benefit of routine biochemical surveillance needs to be fully established.
11. Key issues
. Al is present in at least 2% of cross-sectional abdominal imaging in routine clinical practice. As the life-expectancy in developed countries increases and cross-sectional imaging is used increasingly, more AI will be diagnosed.
. Al comprises a diverse group of pathologies the majority of which are clinically insignificant, but a minority comprise a group of uncommon, potentially dangerous tumours that cannot be ignored.
. All Al should be investigated to assess for excess autonomous hormone secretion and malignant risk, though currently this doesn’t always happen in routine clinical practice.
. ACC characteristically secretes excess of multiple steroids and/or their precursors. The use of urine steroid profiles measured by gas chromatography / mass spectrometry in addition to standard biochemical tests for functionality will improve assessment of malignant risk in indeterminate AI.
· Functional radiological techniques such as 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) may complement established radiological assessment with CT and/or magnetic resonance imaging (MRI) with chemical shift to risk stratify indeterminate AI.
. Biopsy of Al has little role except to confirm metastases where there is a history of primary malignancy in other organs.
· The clinical benefit of follow-up, both biochemical and radiological, needs to be fully established as progression to clinical overt syndromes of hormone excess and malignant transformation is rare.
. The role of surgery for Al is established in functional tumours accompanied by clinical features of hormone excess. Though the value of surgery in AI showing mild autonomous cortisol secretion without the associated clinical complications needs to be established.
· Surgery should be considered in indeterminate Al and in lesions >4cm though with better risk stratification, the size threshold for surgery may increase in the absence of any other adverse radiological, biochemical or clinical features.
Funding
No funding to declare.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Figure 1: Left Conn’s adenoma found incidentally in 45 year old man admitted as emergency with cholecystitis. There was a 10 year history of hypertension and hypokalaemia was present on admission. Endoscopic retroperitoneal adrenalectomy was undertaken without need for adrenal venous sampling. Blood pressure normalised post-operatively.
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Figure 4: Adrenocortical carcinoma found following investigation of routine chest radiograph showing incidental lung metastases from this lesion. Open adrenalectomy performed.
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| Frequency of Pathology in AI from published reviews | Barzon et al 2003(1) (n=3868) | Cawood et al 2009 (2) (n=1804) T |
|---|---|---|
| Non-functioning benign lesion (adenoma, myelolipoma, haemorrhage) | 78% | 88% |
| Adrenocortical carcinoma | 5% | 2% |
| Metastases | 2% | 1% |
| ACCEPTED Hyper-functioning tumour | MANO 16% | METRE 9% |
1. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol. 2003;149(4):273-85.
2. Cawood TJ, Hunt PJ, O’Shea D, Cole D, Soule S. Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink? Eur J Endocrinol. 2009;161(4):513-27.
| Frequency of co- morbidities in patients with AI and SH | Rossi et al (1) 2000 (n=50) | Morelli et al (2) 2010 (n=231) | Masserini et al (3) 2015 (n=93) | Tauchmanova et al (4) 2002 (n=28) ACCEP E.g . a. R |
|---|---|---|---|---|
| Hypertension | 48% | 62% | 68% | 61% |
| Impaired glucose tolerance or diabetes mellitus type 2 | 36% | 42% | 64% | |
| Diabetes mellitus type 2 | 24% | 25% | 36% | |
| Obesity | 36% | |||
| Dyslipidaemia | 28% | 41% | ||
| Vertebral fractures | 35% |
1. Rossi R, Tauchmanova L, Luciano A, Di Martino M, Battista C, Del Viscovo L, et al. Subclinical Cushing’s syndrome in patients with adrenal incidentaloma: Clinical and biochemical features. J Clin Endocr Metab. 2000;85(4):1440-8.
2. Morelli V, Masserini B, Salcuni AS, Eller-Vainicher C, Savoca C, Viti R, et al. Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects. Clin Endocrinol. 2010;73(2):161-6.
3. Masserini B, Morelli V, Palmieri S, Eller-Vainicher C, Zhukouskaya V, Cairoli E, et al. Lipid abnormalities in patients with adrenal incidentalomas: role of subclinical hypercortisolism and impaired glucose metabolism. J Endocrinol Invest. 2015;38(6):623-8.
4. Tauchmanova L, Rossi R, Biondi B, Pulcrano M, Nuzzo V, Palmieri EA, et al. Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocr Metab. 2002;87(11):4872-8,