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Approaches to Adrenal Incidentaloma...


April 30, 1997


An adrenal incidentaloma is defined as a mass lesion found unexpectedly in an adrenal gland by an imaging procedure performed for reasons other than suspected adrenal pathology. It has become a common clinical problem as a result of the more widespread use of high-resolution anatomical imaging procedures [CT, MRI, ultrasound].

The vast majority of incidentalomas are non-secretory, benign lesions. However, once discovered, two main questions arise: firstly, is the incidentaloma associated with hypersecretory syndrome and second, is the lesion benign or malignant.

Following the appropriate investigations, tumor produces hormones in sufficient quantity to cause symptoms should be removed, whether it is a cortical adenoma, carcinoma, or pheochromocytoma. Tumor more than 6 cm in size, particularly if they exhibit other features of malignancy on image studies, should also be removed. Smaller tumors with questional features of malignancy are probably best followed by interval scanning at a period of 3-6 months.

Case Presentation

A 44-year-old female was admitted on account of general weakness, chest tightness, and polyuria over the preceding two weeks. She has a history of DM and HT for about 7 years and an episode of stroke attack, which recovered completely. She received regular medications for DM and HT control. On physical examination disclosed no buffalo hump, no abdominal purplish striae, and no central obesity.

Because of the high serum aldosterone level (1414 pg/ml) found at OPD, a CT scan was arranged and an adenoma over Lt adrenal gland, 2-cm in size, was found. Assessment of adrenal functions showed a normal urinary catecholamine and VMA excretions, an elevated PRA (14.3 ng/ml/h) but normal aldosterone concentration (165 pg/ml), an elevated urinary free cortisol excretion (170 mg/24 h), and nonsuppressible cortisol secretion (15.6 mg/dl post 1 mg dexamethasone). Subsequent endocrine function studies showed non-suppressible cortisol secretion to both low- and high-dose dexamethasone and absent responses of plasma ACTH and cortisol to CRH stimulation, confirming a cortisol-secreting tumor.

She received retroperitoneoscopic adrenalectomy and pathology confirmed an adenoma. After the operation, a hypoadrenalism period developed which recovered completely one year later under the replacement of cortisone acetate. In addition, much improvement of DM and HT was noted. Currently, DM can be well-controlled with diet alone and HT with low-dose renitec.


Incidental adrenal masses are found in 1% to 4% of abdominal CT examination. The incidence in autopsy series is much higher (10%-15%). Most of the masses, however, are 1-2 cm in size. The reasons for this discrepancy are unclear, but is may be will be that as scanning techniques improves the prevalence is liable to rise.

Hypersecretion ?

Determination of biochemical activity is a fundamental consideration in the assessment of adrenal masses. However, hormonal screening should be cost-effective, posses a high degree of sensitivity (i.e., few false-negatives). Initially, selection should be guided by the clinical findings. If there is a clinical suspicions for Cushing's syndrome, this diagnosis should be pursued first; the same is true for clinical suspicion of hyperaldosteronism (i.e., hypokalemia and hypertension). Virilization in women and children should prompt the measurement of testosterone and the measurement of catecholamines if the patient is hypertensive. There are situations, however, in which the clinical clues are subtle, prompting a "screening approach" to avoid missing a hormone excess syndrome. There are three clinical syndromes associated with adrenal masses and hormone hypersecretion that can be silent and unrecognized. These are pheochromocytoma, hypercortisolism, and late-onset 21-hydroxylase deficiency. In the case of pheochromocytoma, if biopsied or removed without prior identification, a life-threatening severe hypertensive crisis can result. In the case of Cushing's syndrome, continued bone loss can cause severe osteopenia. Removing an unrecognized cortisol producing lesion sets the stage for postoperative acute adrenal insufficiency. Finally, adrenal masses has been reported in 45% of patients with late-onset 21-hydroxylase deficiency. These patients should not have surgery. Instead, they should be treated with hydrocortisone, suppressing ACTH, and shrinking the incidentally discovered adrenal mass.


About 4% of incidentally adrenal masses are pheochromocytoma. Most (93.8%) of these patients have the symptom complex of headache, palpitation, and diaphoresis. Thus, if hypertension or symptoms are absent, the presence of a pheochromocytoma is highly unlikely. Pheochromocytoma is, however, a lethal condition, and biochemical evaluation is required in all patients with an incidentaloma. A 24-hour urine collection for VMA, metanephrines, and catecholamines should suffice for patients with an asymptomatic adrenal mass. A normal 24-hour VMA excretion has a negative predictive value of 98%, although 24-hour urinary catecholamine excretion is superior to this as a screening test. If indicated, clonidine suppression test, which has a 97% sensitivity using the criteria of a plasma norepinephrine greater than 500 pg/mL three hours after 0.3 mg oral clonidine and concentration less than a 50% baseline, can be performed.


It is well-recognized that many incidentaloma, previously considered to be non-functional, display subtle states of cortisol excess, dubbed "pre-Cushing's syndrome" or "subclinical Cushing's syndrome" (biochemical evidence of Cushing's syndrome without physical stigmata). Although the prevailing plasma cortisol in these patients is insufficient to cause the protean clinical manifestations associated with the hypercortisolemia of Cushing's syndrome, or fully suppress circulating plasma ACTH, adrenal insufficiency has been described following excision of these tumors. Such hypothalamico-pituitary-adrenal axis abnormalities are more common in those patients with hypertension, obesity, and diabetes. Given the high prevalence of Cushing's or pre-Cushing's syndrome among patients with incidentalomas, laboratory examinations should include an overnight 1.0 mg dexamethasone suppression test or a standard low-dose dexamethasone suppression test (0.5 mg every 6 hours for 2 days), a 24-hour urine collection for cortisol, and determinations of cortisol secretory rhythm (0800 h and 2200 h).


Blood pressure and serum potassium should be measured in all patients to exclude mineralocorticoid excess. In patients without hypertension, no further investigation is required if the serum potassium is greater than 3.5 mmol/L. However, if there is spontaneously or easily provoked (< 3.5 mmol/L), or extreme diuretics-induced hypokalemia (< 3.0 mmol/L), further evaluation following salt loading should be performed with paired 0800 h recumbent and 4-hour ambulatory plasma renin and aldosterone estimation. A suppressed PRA and a high plasma aldosterone when recumbent that falls following ambulation is supportive evidence of an adenoma.


Benign adrenocortical adenoma secreting masculinizing or feminizing hormones is rare, therefore, determination of plasma testosterone or estradiol level is necessary only if there is any sign of hirsutism or virilization in a woman or a child. However, dehydroepiandrosterone sulfate (DHEAS), as a marker of adrenal androgen excess and also as a marker of adrenal carcinoma, should be measured in all incidentaloma. Reduced DHEAS values may suggest suppression of ACTH due to autonomous cortisol hypersecretion from the mass.

Benign or malignant ?

Once an adrenal mass has been documented hormonally non-hypersecretory, the possibility of primary or metastatic malignancy must be excluded as the adrenal glands are highly vascular organs and therefore are common sites of metastases from extra-adrenal malignancy.


Adenomas 6 cm or larger in diameter are rare; however, adenomas of up to 10.5 cm has been reported in autopsy series. In contrast, most adrenocortical carcinomas are over 6 cm in diameter.


On CT scanning, a benign adenoma is characterized by a small, well-circumscribed lesion, with a low, homogenous attenuation signal; in contrast, malignancy is suggested by large non-homogenous lesions, with poorly defined margins.

CT scan based on Hounsfield Unit (HU), in which water density is given zero HU, while anatomic structures with density less than water, reflecting an increases in lipid content, is expressed in negative HU. An enhanced CT attenuation of 0 HU or less has been reported as 100% specific for a benign adenoma vs. a metastatic lesion, but has a very low sensitivity (33%-47%), while with thresholds of 16.5-18 HU, yielding sensitivities of 88%-100% and specificities of 95%-100%.


T1-weighted images depicted the anatomy with a resolution comparable to that of CT. T2-weighted images provided some histologic specificity separating nonfunctioning adenomas with low signal-intensity from metastases with intermediate signal-intensity and pheochromocytoma with high signal-intensity. In 20% of the cases, metastases with low signal-intensity could not be distinguished from non-functioning adenomas.

Chemical shift MR imaging, which relies on the difference in resonance frequency between protons in water and triglyceride molecules to distinguish benign adrenal lesions with relatively high lipid content (adenomas, myelolipomas) from adrenal lesions with characteristically low lipid content (metastases, hemorrhages, cysts, and pheochromocytomas) is a potentially promising imaging technique. Mitchell et al. reported that benign adrenal masses demonstrated the typical signal intensity loss on chemical shift imaging using opposed-phase images with 95% sensitivity. These changes were not seen in a cyst, hemorrhage, or metastases.


Over the past decade the use of NP-59 adrenal scintigraphy has been advocated to distinguish benign from malignant adrenal masses. Nonfunctioning primary and secondary malignancies, as well as other space-occupying or destructive lesions (e.g. cysts and hemorrhages), of the adrenal gland demonstrate an imaging pattern of decreased, distorted, or absent radiocholesterol uptake by the affected adrenal gland. This imaging pattern is described as "discordant". Hormonally hypersecretory (Cushing's syndrome, mineralocorticoid excess, hyperandrogen states) and nonhypersecretory adrenal adenomas demonstrate NP-59 accumulation and thus scintigraphic visualization on the side of the known adrenal mass. This imaging pattern is described as "concordant". However, lesions of less than 2 cm in diameter are not reliably discriminated by this technique.


Fine needle aspiration under CT guidance may provide a definitive histological diagnosis, but is most effective at distinguishing between adrenal and nonadrenal tissue, and thus in distinguishing primary adrenal malignancy from metastases. However, it is not possible, on this test alone, to differentiate between a primary adrenal adenoma and carcinoma, as the latter requires evidence of capsular or vascular invasion. There is a significant morbidity associated this procedure (for example, hemorrhage, pneumothorax, pancreatitis) and it should be reserved for cases of doubt, and is not indicated where a hormonally active tumor has been identified, particularly if this is suspected to be a pheochromocytoma.


The incidental adrenal mass poses a challenging problem for the endocrinologist. The major challenges are to identify functioning lesions, accurately and efficiently differentiate between metastatic and primary adrenal lesions in the remainder, and remove those adrenal lesions likely to be malignant in a manner that has a favorable risk/benefit analysis. The protocol outlined should help the clinicians achieve these goals.

Table 1. Serendipitous Identification of an Adrenal Mass During Computed Tomographic Examinations
Author¡@n Examinedn FoundPercentage

Table 2. Autopsy Identification of Adrenal Masses
Author¡@n Examinedn FoundPercentage

Table 3. Reasons for Performing Computed Tomography and Discovering an "Incidental" Adrenal Mass
ReasonSeries 1 (Virkkala)Series 2 (Saruta)
Abdominal pain60%17.4%
Urologic complaints20%2.7%
Suspicion of abscess10%--
Nonspecific symptoms5%29.5%
Increased blood pressure--40.9%
Back pain--2.7%

Table 4. Incidence of Adrenal Incidentalomas Later Identified With Hormone Syndromes of Excess Cortisol, Catecholamines, or Late-Onset 21-Hydroxylase Deficiency
Subclinical Syndromen Screened/FoundPercent
21-hydroxylase deficiency (Heterozygotes)20/945

Table 5. Signs and symptoms of Cushing's syndrome in patients with nonfunctional incidentalomas (n=58), patients with cortisol-producing incidentalomas (preclinical Cushing's syndrome; n=8), and patients with overt adrenal Cushing's syndrome (n=8)
Patients with incidentalomasOvert Cushing's syndrome
Central obesity0587.5
Buffalo hump012.562.5
Striae rubrae0062.5
Psychiatric symptoms0050
Arterial hypertension467562.5
Diffuse obesity365012.5

Table 6. Nomenclature of adrenal scintigraphy for the characterization of nonhypersecretory incidentally discovered adrenal masses
Image patternDescription of patternLesion responsible
Concordant patternIncreased radiotracer uptake by the adrenal mass disclosed by previous anatomical imaging studyBenign adrenal adenoma or nodular hyperplasia
Discordant patternAbsent, decreased, or distorted adrenal radiotracer uptake by the adrenal mass disclosed by previous anatomical imaging studyDestructive or space occupying lesion (e.g. primary or metastatic malignancy, adrenomedullary tumor, hemorrhage, cyst, granulomatous disease)

Table 7. Differential Diagnosis of Bilateral Adrenal Masses
Functional LesionsNonfunctional Lesions
ACTH-dependant Cushing's syndromeInfection (tuberculosis, fungi)
Congenital adrenal hyperplasiaInfiltration (leukemia, lymphoma)
PheochromocytomaReplacement (amyloidosis)
Conn's syndrome, hyperplastic varietyHemorrhage
Micronodular adrenal diseaseBilateral metastases


  1. Copeland PM 1983 The incidentally discovered adrenal mass. Ann Intern Med 98:940-945
  2. Reincke M, Nieke J, Krestin GP, Saeger W, Allolio B, Winkelmann W 1992 Preclinical Cushing's syndrome in adrenal "incidentalomas": comparison with adrenal Cushing's syndrome. J Clin Endocrinol Metab 75:826-832
  3. Cook DM, Loriaux DL 1994 The incidental adrenal mass. Adv Endocrinol Metab 5:137-170
  4. Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B 1995 Incidentally discovered adrenal masses. Endocr Rev 16:460-484
  5. Newell-Price J, Grossman A 1995 Adrenal incidentaloma: subclinical Cushing's syndrome. Postgrad Med J 72:207-210

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