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EJR EUROPEAN JOURNAL OF RADIOLOGY

Adrenocortical tumors: clinical symptoms and biochemical diagnosis

H. Vierhapper *

Department of Internal Medicine III, Division of Endocrinology and Metabolism, University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria

Received 8 October 2001; received in revised form 9 October 2001; accepted 10 October 2001

Abstract

Patients who are suspected clinically to suffer from hypersecretory disorders of their adrenal(s) should undergo an appropriate endocrinological investigation to confirm or exclude the presence of such disorders prior to any radiological investigation. In those patients in whom an adrenal mass is found ‘incidentally’ on imaging clinical symptoms of hormonal activity should be carefully followed up. Asymptomatic patients should be screened biochemically for latent hormonal hypersecretion syndromes including pheochromocytoma (urine catecholamine excretion), hypercortisolism (overnight dexamethason suppression test) and aldostero- nism (blood pressure and serum potassium). These investigations are mandatory in all patients scheduled for surgery. The decision to refer patients with inactive adrenal tumors to surgery is, in the absence of valid biochemical markers of malignancy, mainly influenced by tumor size but remains arbitrary. Patients who are not at first treated by surgery should be operated if follow-up indicates a progression in tumor size. @ 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Adrenal; Adrenal carcinoma; Adrenal adenoma; Pheochromocytoma; Cushing’s syndrome; Aldosteronism

1. Introduction

The more widespread use and the enhanced quality of high-resolution radiological techniques has increased the number of incidentally discovered adrenal tumors. Thus, 4% of all abdominal computerized tomographies will describe the presence of adrenal tumors not previ- ously suspected either clinically or biochemically [1]. It is likely that the incidence of these ‘incidentalomas’ will further increase in parallel with the ever increasing technical quality of radiological procedures, probably until the prevalence known from autopsy studies (10% [2,3]) has been reached. Since the development of adrenal nodules is a consequence of aging, the chance of finding an unsuspected adrenal adenoma on CT rises from only 0.2% in the third decade of life up to 6.9% in individuals older than 70 years [4]. In the absence of extraadrenal malignancies the majority of these lesion will turn out to be non-hypersecretory and benign. It is essential to recognize, among the plethora of these

histologically benign, endocrinologically ‘silent’-and hence, by definition, irrelevant-adenomas: the (rela- tively frequent) secondary manifestations of malignant tumors, the (relatively rare) adrenal tumors with en- docrine activity and the (very rare) adrenocortical car- cinomas in order to achieve fast and effective therapy of the latter two groups. This necessitates a diagnostic strategy with sufficient sensitivity but at the same time costs which are not prohibitive (Table 1). Hypersecre- tory tumors require a specific-mostly surgical-ther- apy but it is important to remember that a pheochromocytoma or an aldosteronoma will be found in only 6-7 out of 100 patients without clinically apparent symptoms of hormone excess. Less than 1% of these patients will harbor a cortisol-producing adrenal adenoma or an adrenocortical carcinoma [3]. Patients who are suspected on clinical grounds to suffer from endocrine disorders such as pheochromocytoma or Cushing’s syndrome should always undergo bio- chemical testing to confirm or exclude their diagnosis before any attempt is made to localize, by radiological methods, the potential source of an as yet unconfirmed

* Tel .: + 43-1-40400-4348; fax: + 43-1-40400-6210.

endocrinological disease. Secondly, in any patient al- ready known to harbor an adrenal mass, clinical symp-

catecholamines, cortisol, mineralocorticoids, androgens or estrogens should be pursued and an adequate bio- chemical screening should be done in each case-even in the absence of such symptoms.

2. Phaeochromocytoma

Historically up to 80% of patients with an unsus- pected catecholamine-producing adrenal tumor (pheochromocytoma) who underwent surgery or anes- thesia have died [5-8]. Even percutaneous needle biopsy of an unsuspected pheochromocytoma may re- sult in a potentially life-threatening hypertensive crisis [9,10]. A biochemical screening of all patients with adrenal tumors to exclude the possibility of pheochro- mocytoma is therefore imperative. An operation-and/ or a fine needle aspiration biopsy-are contraindicated until a pheochromocytoma has been excluded biochemically.

The predominant clinical manifestations of pheochromcytoma are, either alone or in combination: (1) paroxysmal tachycardia (64%); (2) paroxysmal (48%) or persistent (39%) hypertension; and (3) hyper- metabolism. Any patient who has clinical symptoms suggesting a pheochromocytoma (e.g. a hypertensive

Table 1 Adrenal 'incidentaloma': diagnostic workup to exclude/confirm en- docrine activity

Screening test	Additional test(s)	Localization
Pheochromocytoma
Urinary free catecholamines	Plasma cetecholamines	Scan (MIBG)
(24 h urine)	(before/after
	clonidin)
		CT/MRI/adrenal venous sampling
Cushing's syndrome
Dexamethasone	Dexamethasone	Scan (131J cholesterol)
suppression test (1 mg)	suppression test (0.5 mg q.i.d.,
	1.5 mg q.i.d.)
	CRF stimulation test	CT/MRI/adrenal venous sampling
Primary aldosteronism
Blood pressure	Aldosterone/PRA	Scan (131] cholesterol)
	(plasma)
K+(serum)	Aldosterone (urine)	CT/MR/adrenal venous sampling
Androgens |estrogens |other steroids
Only when clinically indicated

crisis with sweating, palpitations, and blanching/flush- ing) should be screened for the disorder. Pheochromo- cytoma may also be associated with unexplained cardiomyopathy, throbbing headache, heat intolerance, pyrexia of unknown origin, hypercalcemia and raised hematocrit [11]. While most patients have at least one of these symptoms, almost 10% are asymptomomatic [12] and radiologically detectable tumors may precede symptoms in some patients by months or even years [13]. Approximately, 5% of patients with adrenal inci- dentalomas harbor pheochromocytomas [3]. Family history is important, since pheochromocytomas may be part of the genetically determined ‘multiple endocrine neoplasia’ or other hereditary syndromes such as von Hippel-Lindau disease [14] and neurofibromatosis type I [15]. Between 10 and 13% of pheochromocytomas [16-18] and possibly a larger share of the dopamine-se- cretion variety [19] are malignant. Small intra-adrenal lesions are predominantly adrenaline-secreting, whereas larger tumors secrete proportionately more norepinephrine.

As a primary biochemical diagnostic measure the determination of the excretion rates of catecholamines in the 24-h urine (to be collected preferably following clinical symptoms, i.e. after a hypertensive episode) is superior to the determination of plasma catecholamines [13,20]. Although the latter are favored by some investi- gators [21], orthostasis, excercise and a number of drugs elevate plasma catecholamine concentrations lim- iting their diagnostic value if the determination is not done under well controlled conditions. Furthermore, normal plasma concentrations of catecholamines do not rule out the disease in asymptomatic patients [20]. Urine samples should be collected with 30 ml 6 M HCl, stored at 4 ℃ and analyzed by HPLC. Their specificity is greater than 95% and sensitivity approaches 100% [11,13]. The determination of vanillymandelic acid has only the character of a screening test. If positive it needs to be supplemented by the determination of catecholamines. The determination of metanephrines in plasma, though not in urine, may be superior to the assessment of catecholamines, especially in oligosymp- tomatic patients, but this method is not as yet univer- sally available [22-24]. The demonstration of increased urinary catecholamines generally is sufficient to docu- ment the presence of a pheochromocytoma biochemi- cally. Stimulation of catecholamine secretion with agents such as histamine, glucagone or tyramine may provoke a severe and unacceptably dangerous pressure response [25] and are therefore obsolete. If urinary catecholamine concentrations do not suffice cate- cholamines should be determined in plasma before and after the administration of clonidine. Since this com- pound will generally suppress catecholamines in healthy persons and in patients with essential hypertension but not in pheochromocytoma [26,27] its administration

increases the sensitivity and specificity of plasma cate- cholamine determination. Finally, the biochemical diag- nosis of pheochromocytoma will subsequently be supplemented by metaiodobenzylguanidin-[MIBI]- scanning, CT, MRI or venous sampling to localize pheochromocytoma. When interpreting the results of CT or MRI it is important to bear in mind that the potential presence of an additional non-functional adrenal tumor may be an important bias.

3. Cushing’s syndrome

Cushing’s syndrome associated with an adrenal ade- noma has an incidence approximately equal to that of adrenal carcinoma (2 in 10 00 000) and three-fold less than that of (ACTH-dependent) Cushing’s disease (5-6 in 10 00 000 [28]). In patients with cortisol producing masses clinically apparent manifestations of cortisol excess may present relatively late and are preceded by more subtle derangements of the pituitary-adrenal axis. Hence there are reports about a marginal excess of cortisol in a larger number of patients. As might be suspected the prevalence of this abnormality varies depending on the applied diagnostic criteria. Although it may represent the most frequent hormonal abnormal- ity to be detected in patients with adrenal incidentalo- mas [3] the clinical relevance (i.e. the natural history) of this ‘subclinical’ or ‘preclinical’ Cushing’s syndrome [29,30] is as yet unclear [4]: many patients with this preclinical disease will have an adrenal mass, but few patients with adrenal masses will develop manifest Cushing’s syndrome [30] and it is uncertain at what point glucocorticoid secretory autonomy leads to clini- cal morbidity. The more pronounced the cortisol ex- cess, the more likely the patient will, following surgical removal of the tumor, suffer from acute cortisol defi- ciency [31]. Adrenal insufficiency has been observed after the removal of ‘silent’ adrenal adenomas [32]. It is therefore of vital importance to exclude Cushing’s syn- drome in each patient scheduled for adrenal surgery. Furthermore, the demonstration of an adrenal tumor by CT or MRT in patients with Cushing’s syndrome does not necessarily imply that the source of abundant hormone production has been found. Assymetrical bi- lateral adrenal hyperplasia as well as additional non- functional adrenal tumors are important caveats [33].

The clinical picture of Cushing’s syndrome (i.e. the sequelae of excessive glucocorticoid production) in- cludes an abnormal distribution of body fat, striae, hirsutism, hypertension, ecchymoses and atrophic skin. However, patients with Cushing’s syndrome do not always present a clearcut clinical picture. Additional information may be provided by the presence of hy- pokalemia, impaired glucose tolerance or diabetes and polyglobulia. Unfortunately, these warning signs are

frequently overlooked and/or neglected and thus the diagnosis is delayed until additional complications, such as severe osteoporosis and the sequelae of hyper- tension have occurred. In this context it is worth re- membering that the natural course of Cushing’s syndrome is comparable to that of a malignant disease [34].

The biochemical diagnosis of Cushing’s syndrome comprises three stages. The objective of the first is to confirm/exclude hypercortisolism in suspected cases by demonstrating sustained cortisol overproduction. The second step consists of differentiation into the various entities which may be responsible for hypercortisolism. Only subsequently and thirdly anatomical localization of the responsible lesion is required. Thus, whether Cushing’s syndrome is caused by an ACTH producing adenoma of the anterior pituitary, an adrenal tumor producing cortisol or an ectopic source of enhanced ACTH secretion the biochemical evaluation must first confirm the presence of hypercortisolism, no matter where the potential source. Due to an overlap with the normal range the determination of basal (morning) plasma concentrations of cortisol and/or ACTH is in- sufficient to achieve this goal. Cortisol production rates as determined by the stable-lable isotope dilution tech- nique separate patients with Cushing’s syndrome from controls [35], but this technology is not generally avail- able and remains a research tool. Similarly, the determi- nation of integrated 24-h plasma cortisol concentrations [36] is not applicable in clinical routine. The most popular screening methods [37] are either the measurement of urinary free cortisol excretion rates or, preferably, the demonstration of an insufficient sup- pression of plasma corticol (>5 µg/dl) at 08:00 h. following the peroral administration of 1.0 mg of dex- amethasone at 23:00 h. Negative test results have a high negative predictive value, i.e. they markedly decrease the likelihood of disease. The diagnosis is confirmed when cortisol in plasma and urine fails to decrease after the administration of a larger dose of dexamethasone (0.5 mg q.i.d. for 3 days). The next step is to separate, by biochemical methods, the various diseases leading to hypercortisolism. An adrenal source of excessive corti- sol production is likely if cortisol in plasma and/or urine remains high after the administration of an even larger dose of dexamethasone (1.5 mg q.i.d. for 3 days) and if the i.v. administration of 100 µg corticotropin releasing factor (CRF) fails to induce a rise in plasma cortisol and ACTH [37,38]. None of these procedures have a sensitivity and/or a specificity of 100%. Indeed, there is no single test which will reliably separate pa- tients with Cushing’s syndrome from those without, nor is it always possible to distinguish with complete confi- dence between patients with pituitary-dependent Cush- ing’s disease and those with ectopic secretion of ACTH [39]. Nevertheless, in each patient the complete bio-

chemical evaluation must precede localization by sono- grapy, CT, MRI, 131J-cholesterol scanning and/or adrenal venous sampling [38] which-in the case of non-ACTH dependent disease-may subsequently be used to demonstrate the specific adrenal responsible.

4. Primary aldosteronism

Primary aldosteronism is characterized by sodium retention, hypertension, hypokalemia, metabolic alkalo- sis, suppressed plasma renin activity (PRA) and in- creased production of aldosterone [40]. Since the appropriate therapy depends on the respective patho- genesis it is important that there are at least six sub- types of the syndrome: unilateral adrenalectomy cures the hypertension and hypokalemia in the majority of patients with aldosterone producing adrenal adenomas whereas pharmacological therapy is the treatment of choice in idiopathic aldosteronism caused by bilateral adrenal hyperplasia. These two subtypes-aldosterone producing adrenal tumors and idiopathic aldostero- nism-are the most common forms of primary aldos- teronism. In both instances the abundance of aldosterone causes sodium retention; the expanded ex- tracellular space in turn induces hypertension and causes a fall in the production of renin. In contrast to pheochromocytoma and Cushing’s syndrome the pre- operative diagnosis of primary aldosteronism in a pa- tient with apparent adrenal ‘indidentaloma’ is not of vital importance since the disease per se does not have a negative impact on the outcome of adrenalectomy or on postoperative recovery if hypokalemia is well controlled.

The diagnostic workup of patients with suspected primary aldosteronism first has to confirm/exclude the diagnosis by screening tests. Blood pressure and serum potassium concentrations should be measured in all patients with adrenal tumors. Although there have been reports of patients with normotensive primary aldos- teronism [41,42] a normal blood pressure makes this diagnosis unlikely. Spontaneous hypokalemia is uncom- mon in patients with uncomplicated hypertension and suggests associated mineralocorticoid excess. Thus, in the absence of Cushing’s syndrome the possibility of primary aldosteronism must be considered in each case of hypokalemic hypertension [43]. The majority of pa- tients with primary aldosteronism will present a serum potassium concentration of <3.5 mmol/l, especially after sodium repletion. If serum potassium is >4.0 mmol/l primary aldosteronism is unlikely. However, dietary sodium restriction leads to potassium retention and this may account for those cases with primary aldosteronism (reportedly 7-38% of patients [44-46]) without spontaneous hypokalemia.

Suppressed plasma renin activity is not only seen in almost all patients with primary aldosteronism but also in about 30% of patients with essential hypertension. It is therefore not specific for primary aldosteronism [47]. However, primary aldosteronism is likely if-in the presence of elevated (> 20 ng/dl) plasma aldosterone concentrations-the calculated ratio of plasma aldos- terone (ng/dl) and plasma renin activity (ng/ml × h) is more than 50 [48-50]. Sodium balance and antihyper- tensive drugs other the spironolactone do not interfere with the interpretation of this screening test. In order to secure the diagnosis of primary aldosteronism biochem- ically it is, however, necessary to maintain the patient on a sodium-balanced diet and to temporarily discon- tinue all interfering factors such as oral contraceptives and almost all antihypertensive drugs. The diagnosis is made if the excretion of aldosterone is above normal in the presence of sodium repletion (120 mmol/die for 3 day prior to the investigation) and suppressed plasma renin concentration/activity. The demonstration of a normal plasma aldosterone concentration excludes pri- mary aldosteronism; suppressed aldosterone and renin with hypokalemia suggests a non-aldosterone mediated form of mineralocorticoid hypertension.

Once the diagnosis of primary aldosteronism is confi- rmed the different therapeutic strategies make it is important to separate patients with aldosteronoma from those with bilateral adrenal hyperplasia. Biochem- ical procedures such as the posture stimulation test are of limited value in this respect and it is therefore necessary to employ radiological and/or scintigraphic localization techniques. Since, as with other forms of endocrine active adrenal tumors, hormonal hyperfunc- tion cannot be inferred merely from the presence of a nodule the final diagnosis may depend on the determi- nation of aldosterone in adrenal venous plasma which is not only the oldest but also the most precise available localization technique [33,51].

5. Androgens, estrogens

Androgen- or estrogen-producing adrenal tumors are rare and the patients’ symptoms usually suggest hor- mone excess. The possibility of a sex-hormone produc- ing adrenal tumor should therefore always be considered in the presence of clinical disorders such as hirsutism, alopecia, gynecomastia and impotence [52- 56], whereas the routine determination of estradiol and/ or testosterone in asymptomatic patients is not cost-effective [3,57]. The potential usefulness of deter- mining DHEAS lies in the fact that the secretion of this adrenal androgen will be suppressed in the presence of suppressed ACTH concentrations, i.e. in adrenal Cush- ing’s syndrome [58]. However, in patients with subclini- cal Cushing’s syndrome the specificity, sensitivity and

prognostic power of this parameter is poor [59]. The determination of 17-OH-progesterone may help to rec- ognize unsuspected cases of congenital adrenal hyper- plasia (CAH) due 21-hydroxylase deficiency since CAH-when untreated for prolonged periods of time-will induce the formation of adrenal tumors [60,61]. Using the dexamethasone suppression test it is possible to separate these congenital enzymatic defects from autonomous adrenal tumors [52] and to avoid unnecessary operations in patients with CAH.

6. Adrenal carcinoma

Once an adrenal mass has been found hormonally inactive the possibility of primary or secondary malig- nancy must be considered. The incidence of adrenal carcinomas is about one in 500 000 and year [57]. Almost half of these tumors are hormonally inactive and there are no biochemical markers which may be used to recognize these rare cases which generally are characterized by a poor prognosis [62]. The probability that an adrenal tumor will be malignant is proportional to its size. Tumor size is however by no means a fool-proof criterium, since adrenocortical carcinomas as small as 1.2 cm in maximum diameter have been de- scribed [62]. On the other hand the majority of even large tumors will be benign. Based on the the prevalance of adrenal adenomas greater than 6 cm in diameter (1 in 4000) [64] it has been calculated that even at a threshold diameter of 6.0 cm more than 60 adrenalectomies are needed to remove one adrenocorti- cal carcinoma [52,64]. More recently, this figure has been criticized [3,65] and it has been suggested that the actual share of carcinomas among all adrenocortical tumors may be as high as 1 in 3, 1 in 6 and 1 in 12 using a 6.0, 5.0 or 4.0 cm cut-off point, respectively [3]. However, even these newer data clearly show that a substantial share of adrenal tumors up to 14 cm in diameter (indeed, 76% of all lesions >4.0 cm in that particular study) are histologically benign [65]. In the absence of other criteria large (> 6.0 cm) adrenal tu- mors are nevertheless generally referred to surgery [66]. The decision to remove these and even smaller, en- docrinologically inactive tumors may in part be moti- vated by the unwillingness of patients and/or their attending physician to accept uncertainty, even in the case of an extremely unlikely diagnosis [4]. It is, of course, important to follow up these smaller lesions within the first half year after diagnosis, since small carcinomas do occur [3,63] and since benign adrenal tumors generally do not show a rapid increase in size [64]. Long-term follow up of initially non-secretive adrenal tumors is also warranted since some lesions, albeit the minority, may develop autononous endocrine activity at a later stage [67]. Fine needle aspiration

biopsy-a procedure of considerable risk and doubtful benefit in the recognition of primary adrenocortical carcinomas [32,68,69]-is helpful only to differentiate metastasis from adrenal tissues. In the majority of patients with adrenal metastases the simultaneous ma- lignant spread to other locations makes their recogni- tion easy. More rarely adrenal metastases appear to occur isolatedly and in these cases the therapeutic ap- proach to the primary carcinoma may be altered [32].

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