Current management of incidentally discovered adrenal masses, with a review of Japanese literature

Biomed & Pharmacother 2000 ; 54 Suppl 1 : 133-9 © 2000 l~ditions scientifiques et mfdicales Elsevier SAS. All rights reserved

Mini review

C u r r e n t m a n a g e m e n t of incidentally discovered adrenal masses, with a review of Japanese literature M. Murai*, E. Kikuchi, H. Yanaihara, J. Nakashima Department of Urology, Keio University, School of Medicine, 35 Sinanomachi, Shinjukuku. Tokyo, 160-8582, Japan Summary - It is becoming increasingly common to discover adrenal masses incidentally on radiologic imaging studies. We herein present

our experience with 61 cases of incidentally discovered and surgically removed adrenal incidentalomas, including 11 pheochromocytomas. Only four were adrenocortical carcinomas. A review of the literature, including Japanese journals, for the prevalence of incidentantally discovered adrenal mass, their differential diagnosis and management are discussed. © 2000 l~ditions scientifiques et mfdicales Elsevier SAS adrenocortical adenoma / adrenal incidentaloma

Since the early 1980s, incidentally discovered adrenal masses have become a common clinical problem as a result of the more widespread use of computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US). In patients without a known extra-adrenal primary malignancy, the vast majority of these lesions are benign and non-hypersecretory. The current clinical approach to incidentally discovered adrenal masses must balance diagnostic costs, discomfort, risks, consequences of false positive results, and low disease prevalence against the value of making an expeditious diagnosis that may result in curative therapy in the minority of patients in whom intervention would be indicated. This article reviews the prevalence of incidentally discovered adrenal masses, their differential diagnosis along with their prevalence with special reference to Japanese literature, and currently used strategies for the evaluation and treatment of adrenal masses. There are various definitions and terminology seen in the literature. Incidentally discovered adrenal masses were defined as adrenal tumors that were detected incidentally and primarily as lesions on occasions unrelated to tumor signs and symptoms. Under this definition, previously unsuspected adrenal masses found during a routine health examination, or during diagnostic or

* Correspondence and reprints.

therapeutic procedures for unrelated diseases were considered to be incidental adrenal tumors even if the patient retrospectively proved to have had symptoms or signs attributable to an adrenal tumor. The term 'hypersecretion' is applied to adrenal mass lesions which produce hormonal secretions so sufficient to be recognizably abnormal on standard, global biochemical screening procedures such as the 1 mg overnight dexamethasone suppression test for glucocorticoid autonomy, or catecholamine evaluation for the diagnosis of pheochromocytoma. Therefore the term 'function' or 'functioning' should not be applied to describe hormonal biochemical status. The term 'function' refers to the ability of a mass lesion to accumulate adrenocortical tracers to permit scintigraphic visualization. INCIDENCE A d r e n a l masses are found in a p p r o x i m a t e l y 0 . 2 9 1.30% of patients imaged with CT for reasons other than suspected adrenal pathology [ 1-4]. However, the incidence of adrenal adenoma at autopsies was reported to be from 1.45% to 15.50%, depending on the size of the tumor and age of the patient [1, 5]. Hedeland et al. found 64 adrenocortical adenomas of 0.2 cm and over in diameter among 739 consecutive autopsied patients over 20 years of age [6]. In Japan, Iguchi et al. reported 89 cases of incidentally found adrenal tumor among 183

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surgically removed adrenal tumors in a local survey in the Kyushu area [7]. The incidence of adrenal tumors and incidentally found tumors were 1.26 and 0.61 per 100,000 persons per year, respectively. It is clear that a further increase in the prevalence of incidentally discovered masses may occur if the spatial resolving capacity of abdominal imaging technology progresses is used more frequently. PATHOLOGY

The clinical importance of adrenal incidentalomas depends on their pathology. They may represent both malignant and hypersecretory tumors but also abnormalities that do not require resection. Simple adrenal cyst, myelolipoma and adrenal hematoma can usually be identified by CT alone [8]. In our department for the past 30 years, two hundred and eighty-seven adrenalectomies were performed due to various reasons of primary adrenal lesions. Most of them were hypersecretory adrenal tumors, including 111 aldosterone-producing adenoma, one hyperplasia causing primary aldosteronism, 62 cortical adenomas causing Cushing's syndrome, four hyperplasias causing Cushing's syndrome, four nodular hyperplasias causing Cushing's syndrome, two cortical carcinomas causing Cushing's syndrome, two virilizing tumors, one feminizing tumor and 40 pheochromocytomas. Sixty-one cases out of 287 with surgical adrenal disease were incidentally discovered adrenal masses (table I). Fifteen c a s e s o f 61 i n c i d e n t a l o m a s were h y p e r s e c r e t o r y tumors, including 11 cases of pheochromocytoma, one case of Cushing's syndrome, one primary aldosteroTable I. Surgical pathology of incidentally discovered adrenal masses in 61 patients.

Non-hypersecretory Cortical adenoma - Cortical carcinoma - Ganglioneuroma - Myelolipoma - Cyst - Hematoma -

26 2 5 5 6 1

Hypersecretory Cortical adenoma • Cushing's syndrome • aldosteronism • DOC-producing tumor - Cortical carcinoma • feminizing tumor • virilizing tumor - Pheochromocytoma -

Total

1 1 1 1 I 11 61

nism, one DOC-producing tumor and one feminizing tumor, respectively. Of 61 incidentalomas, four proved to be adrenocortical carcinomas. According to Gajraj and Young [9], who reviewed 171 adrenal incidentalomas in eight series, only eight (4.7%) were primary carcinoma. Of 171 incidental adrenal masses, seven (4.1%) were metastases with no obvious primary malignant condition. Metastatic adrenal carcinoma is extremely uncommon in the absence of an obvious primary lesion. Among patients known to have a malignancy, metastasis is the most common cause of an incidental adrenal mass. Belldegran et al. described 33 patients with a known malignancy in association with an adrenal mass of whom 24 were found to have an adrenal metastasis [2]. In contrast, of 988 autopsy reports describing the adrenal gland, 73 glands were found to have a pathological abnormality of which 50 (68%) were metastases, although most of the patient were already known to be suffering from malignant diseases. Of the remaining 23 adrenal glands with a pathological abnormality, 19 were cortical adenoma, two myelolipoma, one a hematoma and one a pheochromocytoma. However, excluding metastatic malignant disease, most adrenal masses at autopsy proved to be benign cortical adenomas. This is also true of adrenal incidentaloma. Of 171 incidentalomas described, 44 (2.5%) proved to be cortical adenomas, only one of which was a hypersecretory tumor causing Cushing's syndrome. One adrenal incidentaloma was found to be a pheochromoc y t o m a and was associated with firm biochemical evidence of catecholamine excess. Aso and H o m m a reported 210 cases of adrenal incidentaloma in a nationwide Japanese survey [ 10]. The most common diagnosis was 69 non-functioning cortical adenomas, followed by 49 pheochromocytomas, 18 cysts and 15 myelolipomas. A total o f 14 m a l i g n a n t t u m o r s (6.7%) and 16 hypersecretory benign cortical lesions was also found. DIFFERENTIAL

DIAGNOSIS

OF

ADRENAL

INCIDENTALOMA Finding an 'incidentaloma' should alert the referring physician to reexamine the patients, looking for symptoms and signs of adrenocortical or adrenomedullary disease, or a malignancy. Management of adrenal incidentaloma depends first on whether there is an excess o f adrenal hormone and second on distinguishing between benign and malignant adrenal masses. Following is our diagnostic approach to incidentally discovered adrenal mass table 11.

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Table II. Recommended biochemical screening tests and imaging studies for incidentally discovered adrenal masses in all patients unless otherwise specified (MIBG Metaiodobenzylguanidine). Hypersecretory state

Screening test

Mineralocorticoid excess

Blood pressure Serum potassium Upright plasma renin activity and plasma adlosterone concentration 1-mg Oral dexamethasone overnight suppression test Serum dehydroepiandrosterone sulfate Serum estradiol Serum catecholamines 24-h urinary catecholamines 24-h urinary metanephrines 24-h urinary steroid profiles

Cushing's or pre-Cushing's syndrome Vilirizing tumor Feminizing tumor Pheochromocytoma Adenocortical carcinoma

Diagnosis of hypersecretory masses Hypersecretory masses require specific therapy that is most often surgical extirpation. Evidence of excess secretion of cortisol, androgens, estrogens, mineralocorticoids, and catecholamins should be considered in a patient's history and physical examination. Clues obtained from this evaluation should obviously be pursued. However, the need for initial adequate biochemical screening of all adrenal masses, without an obvious radiologic diagnosis, regardless of a non-suggestive history and examination, cannot be overemphasized. Primary aldosteronism Blood pressure and serum potassium should be measured in all patients to exclude mineralocorticoid excess. Sodium restriction leads to potassium retention and minimizes hypokalemia. The amount of daily dietary sodium intake should be adequate when serum potassium is determined in these patients. In patients with hypertension, upright plasma renin activity (PRA) and aldosterone concentration (PAC) should be determined. The presence of an elevated PAC along with suppressed PRA suggests the diagnosis of primary aldosteronism regardless of the patient's medications.

Imaging study

[ 1231]-or [ 1311]-MIBGscintigrapy T2-weighted MRI

Patients taking [3-blockers and antisympathetic agents may have falsely reduced PRA values; however, these agents do not cause elevation of PAC. Meanwhile, calcium channel blockers may rarely increase PRA and reduce PAC to normal in patients with primary aldosteronism [11]. The presence of suppressed PRA and PAC with hypokalemia suggests the presence of nonaldoterone-mediated minaralocorticoid hypertension, such as DOC-producing tumors.

Cushing's and pre-Cushing's syndrome A large body of data indicates that a spectrum of cortisol excess exists and that clinically obvious manifestations may occur relatively late along this spectrum, while loss of diurnal variation and loss of cortisol suppressibility often occur before baseline steroid hormone excretion exceeds established normal limits [12]. We followed up for ten years a patient with bilateral adrenal adenoma which was initially non-hypersecretory. Excess of cortisol secretion gradually developed eight years after initial discovery of the masses. Central obesity, osteoporosis and diabetes mellitus became obvious when she underwent right adrenalectomy and left partial adrenalectomy (figures I and 2). This case may suggest the functional shift of the adrenal incidentaloma

Figure 1. Sixty-two-year-oldwoman who was initially found to have bilateral adrenal masses by CT was followed up for 10 years until she developed Cushing's syndrome. Initial CT revealedbilateral adrenal mass (left). The masses were enlarged 10 years later (right).

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-,,- cortisol 30

-A- 1 7 - O H C S 40

503O 40-

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year Figure 2. Serial level of serum cortisol, ACTH and urinary

17-OHCS of a patient with incidentally discuvered bilateral adrenal mass (same

patient as in figure 1).

from non-hypersecretomy tumor to hypersecretory tumor and the existence of preclinical or pre-Cushing's syndrome, which is referred to biochemical evidence of Cushing's syndrome without physical stigmata. Thus, we recommend that the cortisol secretory status of patients with incidentalomas be initially investigated with an overnight 1.0 mg dexamethason suppression test. The determination of a cortisol secretory rhythm is also considered to be useful. However, the studies to support surgical intervention in the absence of diurnal variation of cortisol level with a normal overnight dexamethasone suppression test and absence of physical stigmata of Cushing's syndrome are not available [13]. The diagnosis and management of so-called preCushing's syndrome has been controversial. In 1998, the Japanese Study Group of Adrenal Diseases proposed diagnostic criteria for preclinical Cushing's syndrome (table III). Patients with pre-Cushing's syndrome that are not being operated upon certainly require a more careful follow-up than those with small nonhypersecretory adrenal tumors.

Vilirizing or feminizing tumor Dehydroepiandrosterone sulfate (DHES) as a marker of adrenal androgen excess (and so as a marker of adrenal carcinoma) should be measured in all incidentalomas. As the incidence of benign adrenocortical adenomas secreting masculinizing or feminizing hormones is rare, the determination of testosterone or estradiol level is not

Table II1. Diagnostic criteria for pre-clinical Cushing's syndrome. 1. Adrenal tumor detected by imaging studies 2. Lack of clinical features of Cushing's syndrome 3. Laboratory findings* 1) normal level of serum cortisol 2) autonomous secretion of cortiso] 3) suppression of ACTH level 4) accumulation of adrenocortical tracers in scintigraphy 5) lack of diurnal variation of cortisol level 6) low level of serum DHEA-S 7) adrenocortical malfunction after removal of the tumor * at least one of the 7 findings is necessary.

considered as a routine screening test in asymptomatic patients. Congenital adrenal hyperplasia should always be considered in the differential diagnosis of androgen and mineralocorticoid excesses.

Pheochromocytoma Although a large percentage of pheochromocytomas are not diagnosed during a lifetime, a tumor only discovered at autopsy may in fact have been the cause of death [14]. The high mortality rate of patients with unsuspected pheochromocytoma who underwent surgery or anesthesia is well known. We therefore strongly advocate that a screening biochemical investigation should be done in all patients to exclude the possibility of pheochromocytoma. We reviewed 17 resected pheochromocytomas comprising seven from symptomatic patients, and ten unsuspected and inci-

Current management of incidentally discovered adrenal masses

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Figure 3. Fifty-seven-year-old man who presented with epigas-

Figure 4. T2-weighted MRI revealed high signal intensity of the

tralgia was incidentally found to have a bilateral adrenal mass on CT. CT revealed a right adrenal mass measuring 5 cm in diameter; inhomogenous mass enhancement of contrast (black arrow). Highdensity mass measuring 2 cm in diameter was also visualized adjacent anterior to upper pole of left kidney (white arrow).

right adrenal mass (white arrow) and relatively low intensity of the left adrenal mass (black arrow). Pathological study of his surgical specimen proved to be pheochromocytoma of the right adrenal gland and cortical adenoma of the left adrenal gland.

dentally discovered tumors [15]. Although the clinical signs and findings in patients with incidental tumors were weaker than those with symptomatic disease, they were correctly diagnosed by excess secretion of catecholamines. MRI and t23I-or 13~I-metaiodobenzylguanidine (MIBG) scintigraphy were also useful in diagnosing incidentally discovered pheochromocytoma (figures 3 and 4). The utility of scintigraphy in patients with normal biochemistry and discordant adrenocortical scintigraphy is uncharacterized.

The determination of DHES level is valuable to differentiate primary adrenocortical carcinomas. We analyzed 24-hour urinary steroids from patients with adrecortical adenoma and carcinoma by gas chromatography and mass spectrometry. Increased level of metabolites of 11-deoxycortisol or 3 beta-hydroxy-5ene steroid were observed in patients with adrenocortical carcdinomas [17]. Hormonally non-hypersecretory carcinomas tend to present in males and older patients with a larger size and at a more advanced clinical stage [18]. Attempts to separate benign from malignant lesions on the basis of anatomical imaging studies initially focused on size and subsequently on other characteristics. Belldegran and coworkers reviewing six series found that 105 of 114 adrenocortical carcinoma were more than 6 cm in size [2]. Accordingly, solid adrenal lesions of more than 6 cm should be considered malignant until proven otherwise by exploration and adrenalectomy. The size of four adrenocortical carcinomas in our series ranged from 4.5 to 6.7 cm in diameter. The masses less than 6 cm in diameter can be followed by serial CT scans at six- to 12-month intervals. Enlargement of the masses is an indication for resection. Irregular margin of the mass or heterogeneous enhancement of solid component with dynamic contrast enhancement may suggest the possibility of malignancy. The use o f MRI to distinguish benign from

Diagnosis of malignant tumor Once an adrenal mass has been deemed hormonally non-hypersecretory, the possibility of primary or metastatic malignancy must be excluded. The mass, especially bilateral mass in patients known to have a malignancy, should be considered as a metastasis. CTor US-guided fine-needle aspiration biopsy is occasionally indicated to make diagnosis of metastatic malignancy. Primary adrenocortical carcinoma is rare. Ochiai et al. reported the usefulness of the US-guided needle biopsy for incidentally discovered adrenal tumors. Eighteen specimens of 21 biopsies were pathologically adequate specimens and reported to be benign [161.

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Incidental History, physical Biochemicall~

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Thick wall MRIT2 S i g n a l S i g n a l I I S e r i a l CTs T u m o r / L i v e r < 2 Resect S e r i a l CTs Aspiration >2 I I I Cytology(-) Cytology(+)

I

S e r i a l CTs

I

Resect

Resect

SerialCTs

Figure 5. Flow chart for the management of incidentally discovered adrenal masses.

m a l i g n a n t adrenal m a s s e s utilizing a d r e n a l - t o - l i v e r signal intensity ratio on T 2 - w e i g h t e d spin-echo images has been advocated [19]. On ]3tI-6[~-iodomethyl-norcholesterol adrenocortical scintigraphy, non-functioning primary and secondary malignancies of the adrenal gland demonstrate an imaging pattern o f decreased or absent radiocholesterol uptake by the affected adrenal gland [20]. MANAGEMENT

DISCOVERED

OF INCIDENTALLY

ADRENAL

MASSES

Recently, laparoscopic or retroperitoneoscopic adrenalectomy has been performed as a minimally invasive procedure [21]. Until 1993, the incidentally discovered adrenal masses over 3 cm in diameter were resected in our series. However, surgical intervention for incidentally discovered adrenal masses should be limited to malignant or hypersecretory tumors. M a n a g e m e n t of the incidentaloma must be guided by high prevalence of benign and clinically unimportant adrenal adenoma compared with the rarity of occult nonfunctioning adrenocortical carcin o m a or hypersecretory adenoma (figure 5). We have operated on only two patients with incidentally discovered adrenal masses while 33 patients have been followed without surgery since 1994. Although hormonal assessments to differentiate hypersecretory tumors are important, particularly in small lesions, the potential benefit of early removal of the rare primary adrenal carcinoma must

be balanced against the morbidity and mortality associated with surgery for the more c o m m o n benign lesions. Serial C T and M R I can be applied in the follow-up of masses less than 6 cm in diameter.

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Current management of incidentally discovered adrenal masses

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