Scholarly article on topic 'Adrenal incidentaloma: A puzzle for clinician'

Adrenal incidentaloma: A puzzle for clinician Academic research paper on "Clinical medicine"

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Academic research paper on topic "Adrenal incidentaloma: A puzzle for clinician"

Review Article

Adrenal incidentaloma: A puzzle for clinician

Sunil M. Jain

Department of Endocrinology and Diabetology, TOTALL Diabetes Hormone Institute, Indore, Madhya Pradesh, India


An adrenal incidentaloma (AI) is a puzzle for clinician. In the era of widespread use of CT and MRI, it is becoming an increasingly frequent diagnosis. A detailed list of investigations is ordered to diagnose pathology responsible for AI. Most likely etiology of AI is pathology of AI is benign non-functional adenoma. But looking to the need of specific preoperative preparation for functional adrenal adenoma and importance of early diagnosis in adrenal carcinoma, a complete workup is essential. CT scan of adrenals with contrast gives maximum information about nature of lesion. In general, a lesion more than 6cm or a functioning AI or tumor signal intensity of more than 10HU on unenhanced image, significant enhancement on contrast and deenhancement in signal intensity of less than 50% is suggestive of carcinoma and must be removed. Those AI which are left for observation, also needs regular testing and if found functional on subsequent follow-up or if their size enlarge, they must be removed.

Key words: Adrenal carcinoma, adrenal incidentaloma, incidentally found adrenal lesion


An adrenal incidentaloma (AI) is defined as an adrenal lesion that is discovered on a radiologic study done for some other purpose. Adrenal incidentaloma is an "umbrella" term that covers much of pathologies sharing the same way of incidental discovery. In the era of widespread use of CT and magnetic resonance imaging (MRI), AI is becoming an increasingly frequent diagnosis. Further, when a diagnosis of AI is made, there are lot many concerns in mind of patient and family, primarily due to possibility of malignancy. This warrants a detailed investigation plan to diagnosis pathology responsible for AI.

The prevalence of adrenal incidentalomas based on reports summarizing the result of 25 autopsy studies is about 6%.[1-3] The mean prevalence of adrenal incidentalomas

using high-resolution computed tomography (CT) scans is about 4%.[4,5] As the age advances, prevalence of adrenal incidentalomas increases. AI is reported in less than 1% in patients younger than 30 years and up to 7% in patients over age of 70 years.[2,3,6]

Causes of Adrenal Incidentaloma

Pathology of AI may vary from simple benign cyst or lipoma to adrenal carcinoma. The differential diagnosis of the adrenal mass comprises a long list like adenoma, myelolipoma, cyst, lipoma, pheochromocytoma, adrenal cancer, metastatic cancer, hyperplasia and tuberculosis.[7]

Below mentioned table shows etiology of AI

The prevalence of some of the common underlying etiologies in patients with adrenal incidentaloma [Table 1].[8]

In general, there are 80% chances that AI will be a simple nonfunctioning adenoma, 10% chances are for functional adenoma most likely Cushing or pheochromocytoma, 2-3% will have adrenocortical carcinoma/metastatic lesion while remaining 6-7% AI will belong ganglioneuromas, myelolipomas or benign cysts.

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Corresponding Author: Dr. Sunil M Jain, TOTALL Diabetes Hormone Institute, A unit of Diabetes Thyroid Hormone Research Institute Pvt Ltd., BCM Health Island, PU4, Scheme 54, Behind Prestige Management Institute, Near Bombay Hospital, Indore - 452 010, Madhya Pradesh, India. E-mail:

Table 1: The prevalence of some of the common underlying etiologies in patients with adrenal incidentaloma

Etiology Prevalence

Adrenal cortical tumours

Non-functional adenoma 85 (71-93)

Sub-clinical Cushing's syndrome 6.4 (4.4-8.3)

Conn's syndrome 0.6 (0-1.2)

Adrenocortical carcinoma 1.9 (0.8-3.0)

Adrenal medullary tumours

Pheochromocytoma 3.1 (1.8-4.3)

Metastasis 0.7 (0-1.4)

Others <5

Objective of Investigating AI

When AI diagnosis is made, clinicians need to find answer for two questions:

1. Is the lesion functional?

2. What is the nature of the lesion - benign or malignant?

Looking to these 2 objectives, all patients with an adrenal incidentaloma should be evaluated for possibility of hyperfunctioning lesion of adrenal cortex i.e., Cushing's syndrome/hyperaldosteronism and adrenal medulla i.e., pheochromocytoma. If the AI is nonfunctional then all attempts are to be done to find nature of the tumor.

Clinical Approach and Work up in Case of AI

Any patient having AI should be worked up for functional status of tumor and its nature. For this objective, clinician should obtain relevant history to exclude possibility of functional tumor. History of weight gain or development of centripetal obesity, easy bruisability, severe hypertension, diabetes, virilization, proximal muscle weakness, fatigue, osteoporosis etc., are suggestive of Cushing syndrome. If patient informs about sudden or severe headaches, weight loss, anxiety attacks, sweating, cardiac arrhythmias, or palpitations etc., then possibility of pheochromocytoma is likely. While presence of hypertension, fluid retention or a history of hypokalemia suggests hyperaldosteronism. History should include information about risk factors for malignancy as well as recent weight loss. Common lesions which can metastasize to adrenal are carcinomas of the lung, breast, kidney and gastrointestinal tract and melanoma or lymphoma (Lau et al, 2002).[9] Generally adrenal metastases are typically bilateral and larger than 3cm but rarely, they may be unilateral and small.

Physical examination should include blood pressure and pulse and to look for physical signs of cortisol excess like

central obesity, striae, muscle wasting, hirsutism or other signs of virilization.

Investigations in a Case of AI

Endocrine tests

• Dexamethasone suppression test

• ACTH (adrenocorticotropic hormone) levels

• Plasma free metanephrine and normetanephrine levels

• 24 h total urinary metanephrines

• Ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA)

If cortisol level is more than 5.0^g/dL on 1mg overnight dexamethasone suppression test, this is suggestive of Cushing syndrome. If no clinical features of Cushing syndrome are present but cortisol levels are more than 5 on 1 mg overnight dexamethasone suppression test then this entity are known as sub-clinical Cushing syndrome or SCS. Presence of low ACTH further supports clinical or sub-clinical Cushing syndrome. Two day low-dose dexamethasone suppression test may also be needed to establish the diagnosis of CS or SCS.

Elevated plasma free metanephrine and normetanephrine levels and 24h total urinary metanephrines suggest the presence of pheochromocytoma. In patients with pheochromocytoma, hypertension may or may not be present. Radiology findings are very important clue to diagnosis. As a general rule, normal plasma metanephrine rules out a diagnosis of pheochromocytoma. Patients with elevated plasma metanephrines within three to four times, the upper limit of normal should undergo measurement of 24 h urine metanephrines.[10,11]

Patients with hypertension who have a ratio of plasma aldosterone concentration (PAC) (ng/dL) to plasma renin activity (PRA) (ng/mL per hour) of >20 while not taking spironolactone and mineralocorticoid receptor blockers is suggestive of primary aldosteronism. In addition to ratio, serum aldosterone level below 0.25 nmol/liter (9ng/dl) makes a diagnosis of primary aldosteronism highly unlikely.[12,13] Measurement of plasma aldosterone to renin ratio (ARR) is the best initial test for the evaluation of primary aldosteronism.[14-16]

For measurement of ARR it is better if it is done after correcting hypokalemia, while the patient is on salt restriction and in the morning in a sitting position after resting for at least 15 min.

In most patients, a combination of 1-mg overnight dexamethasone suppression test (ONDST), plasma

metanephrines along with aldosterone and plasma renin activity (PRA) measurements is in morning hour during sitting position, is a good initial screening plan to decide functional status of AI.

Radiologic imaging

The primary goal of imaging is to distinguish among adrenal adenoma, adrenal carcinoma, pheochromocytoma and metastatic lesions. The diagnosis of an adenoma relies on the presence of intracellular lipid in the adrenal lesion, which can be identified by CT or MRI. Generally MRI does not offer any advantage over CT except in case of pheochromocytoma which has very characteristic MRI image.

CT scan

If a protocol is followed for CT scan then many conclusions can be drawn. Adrenal protocol for CT scan includes unenhanced images and then images obtained 1 min after IV injection of contrast media to see enhancement and then imaging after a 10 to 15 min delay to look for de-enhancement.

Clinician should look for signal intensity of the lesion, which is expressed in Hounsfield units. HU of noncontrast image, then percentage enhancement in signal intensity at 1 minute post contrast and percentage deenhancement of signal intensity at 10 to 15 min should be studied.

A benign lesion generally has signal intensity of less than 10HU on unenhanced image, while it has deenhancement in signal intensity of more than 40 to 60% in 10 or 15 min. Benign adrenal lesions will commonly enhance up to 80 to 90HU and wash out more than 50% on the delayed scan, whereas Adrenal carcinoma/metastatic tumors and pheochromocytomas will show washout of less than 50% (8 [EL 2]). Caoili et a/.,[17] characterized 127 adrenal masses and reported the criteria for benign lesions as less than 10 HU on unenhanced CT scan and absolute percentage enhancement washout of at least 60% was 98% sensitive and 92% specific.

On non-contrast CT, some benign adrenal lesions do not have attenuation values of less than 10 HU and may have values of 20 to 40HU. This result is found in lipid poor adenomas. In these cases, a washout of >50% will often allow the diagnosis of an adenoma to be made.

Pheochromocytomas behave differently on CT scan. Pheochromocytomas have signal intensity of more than 100HU on non-contrast CT, while on contrast pheochromocytoma enhance and don't deenhance by more than 40-60% like other benign lesions so on CT these lesions behave like adrenal CA.

The accuracy of MRI to the differentiation between benign and malignant tumors is comparable to that of CT scan. Usually, malignant masses are hypointense on T1-weighted images and hyperintense on T2-weighted images, with strong enhancement after contrast injection and delayed washout.

MRI may be helpful in the diagnosis of pheochromocytoma, where it can provide better information than CT scan. High signal intensity on T2-weighted MRI is characteristic of pheochromocytoma.

Fine-needle aspiration

This test has very few indications for work up of AI. Image-guided fine-needle aspiration (FNA) can be done in suspected cases of metastasis with no primary visible or in a suspected case of Adrenal CA where pheochromocytoma has been ruled out.

Other tests

Include metaiodobenzylguanidine (MIBG) and 131I-iodocholesterol (NP-59) scintigraphy, adrenal vein sampling and many other biochemical tests which can be ordered for suspicion of specific diagnosis.

Management of Adrenal Incidentaloma

AI will need surgery or observation. All functional lesions, all malignant lesions as well as all suspicious lesions must be removed. If the clinical findings and work-up suggest a functional lesion then lesion specific preoperative and postoperative management is required.

Following is AACE guidelines for decision making in a case of AI [Figure 1]:

Figure 1: AACE guidelines for decision making in a case of Adrenal Incidentaloma

AI Needing Surgery

The risk of malignancy increases significantly with tumor size greater than 4cm and therefore, many organizations recommend removal of all adrenal incidentalomas more than 4cm in size that lack characteristic benign radiological features. But if size is more than 4cm and lesion is clearly benign on radiologically like a 5cm homogenous AI with non-contrast signal intensity or attenuation value of less than 10HU is close to 0%.[18-27]

Lack of change in the size of an adrenal mass has also been proposed as an indicator of the benign nature of an adrenal tumor.[28,29] In a recent study by Pantalone et a/.,[30] reporting on 75 surgically resected adrenal masses with at least two imaging studies 3 to 12m apart, a change in tumor size of 0.8cm provided the highest combined sensitivity (60%) and specificity (84.6%) for the differentiation of a benign vs. a malignant adrenal mass.

AI Needing Observation

If AI is non-functional, size is less than 4cm and has benign characteristics on imaging then it can be kept under observation. Benign CT characteristic is meant by attenuation value or signal intensity of less than 10HU, homogenous appearance, enhancement on contrast and deenhancement by more than 60%. Even if size is more than 4cm but less than 6cm and has benign characteristics then also it can be kept in observation.

During observation period, functional assessment and radiology has to be repeated. In general, no repeat testing is needed in hyperaldosteronism. While for pheochromocytoma and Cushing syndrome, annual biochemical screening is suggested. Although the cost-effectiveness of this strategy is unknown, most authors recommend annual biochemical screening for catecholamine and cortisol excess for 4 year.[1]

Patients with AI in observation should have a repeat CT study in 3 to 6 m and then yearly for 2 years. If lesion grow at least 0.8 cm over 3- to 12-month follow-up[30] then surgical excision should be considered.


As the name suggests, AI is incidentally detected. Objective of detailed investigations for this incidentally detected finding is to decide which AI needs surgery. For this objective, clinician has to first decide whether AI is functional or non-functional. In general, all functioning AI has to be surgically removed. If

AI is non-functional, and if risk of probability of malignancy is high then it must be removed. Size of AI and its radiologic characteristics can guide about malignant potential. Non functional AI with size of more than 6 cm needs removal. AI less than 4 cm, looking benign on imaging can be left for observation while AI of 4 to 6 cm size management is a area of uncertainty. If such AI noticed clearly benign by imaging criterion, then can be left for observation. Those AI which are left for observation, must undergo periodic testing and if there is increase in size or if it becomes functional then AI should be removed. Thus with the help of endocrine tests and CT scan, a vigilant clinician can take appropriate decision for the management of AI.


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Cite this article as: Jain SM. Adrenal incidentaloma: A puzzle for clinician.

Indian J Endocr Metab 2013;17:S59-63.

Source of Support: Nil, Conflict of Interest: None declared.

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