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- Alexander L. Shifrin, MD
The adrenal incidentaloma is an adrenal mass unexpectedly detected through an imaging procedure performed for reasons unrelated to adrenal dysfunction or suspected dysfunction . The identification of an adrenal mass as an incidental finding is common. Prevalence at autopsy ranges from 1.4% to 2.9%. An otherwise unsuspected adrenal mass on radiologic imaging, has been increasing and now approaches the 8.7% incidence reported in autopsy series . Screening with ultrasound identifies incidentalomas in 0.1% of people in general good health, while the prevalence among patients evaluated for nonendocrinologic complaints ranges from 0.4% to 1.9%. Among patients with a prior cancer diagnosis, the prevalence can be as high as approximately 4.4%. Aging is associated with increasing frequency of adrenal masses; adrenal masses identified at autopsy increase in prevalence from
During the evaluation of an adrenal mass, 3 questions need to be addressed: (1) Is the tumor hormonally active? (2) Does it have radiologic characteristics suggestive of a malignant lesion? And (3) Does the patient have a history of a previous malignant lesion? 
Table 1. Differential diagnosis of an incidentally discovered adrenal mass [1, 3].
- Adrenal cortical tumors
- Nodular hyperplasia
- Adrenal medullary tumors
- Other adrenal tumors
- Miscellaneous e.g., hamartoma, teratoma, lipoma, hemangioma
- Infections, granulomas, infiltrations
- Fungal infection, e.g., histoplasmosis, coccidiomycosis, blastomycosis, tuberculosis
- Cysts and pseudocysts
- Degenerative adenomas
- Congenital adrenal hyperplasia
- Pseudoadrenal masses
- Splenic, pancreatic, renal lesions
- Vascular lesions (esp. aneurysms and tortuous splenic veins)
- Technical artifacts
A larger tumors are more likely to be malignant than smaller ones. Adrenal carcinomas comprised 25% and metastases 18% of lesions larger than 6 cm, while adenomas accounted for only 18%. For tumors smaller than 4 cm, adrenal carcinomas comprised 2% and adenomas 65%. Adrenocortical carcinomas accounted for 6% of tumors 4–6 cm. Bilateral adrenal masses are found in about 10%–15% of cases. When masses are bilateral, several diagnoses are more likely, including metastatic disease, congenital adrenal hyperplasia, lymphoma, infection (e.g., tuberculosis, fungal), hemorrhage, adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome, pheochromocytoma, amyloidosis, and infiltrative disease of the adrenal glands. A few rare genetic syndromes predispose to adrenocortical tumors and there are some data on the relevant molecular targets. These include Beckwith–Wiedemann (overexpression of the insulin-like growth factor II (IGF II) gene) Li–Fraumeni (germline mutations in the p53 tumor suppressor gene), multiple endocrine neoplasia (MEN) 1, Carney complex, and McCune–Albright syndromes. Similarly, some other disorders such as multiple endocrine neoplasia 2 (2A, 2B) where abnormalities in the RET-2 proto-oncogene have been associated with pheochromocytoma, Von Hippel–Lindau disease, and neurofibromatosis type 1 predispose to adrenomedullary tumors .
Patients with an adrenal incidentaloma should undergo evaluation clinically, biochemically, and radiographically for signs and symptoms of hypercortisolism, aldosteronism (if hypertensive), the presence of a pheochromocytoma, or a malignant tumor .
1. Rule out functional tumors
The patient should be tested for evidence of hypercortisolism, aldosteronism (if hypertensive), and the presence of a pheochromocytoma.
A recent AACE and AAES medical guidelines for the management of adrenal incidentalomas  summary of the literature revealed that approximately 80% of patients with incidentalomas had a nonfunctioning adenoma, 5% had subclinical Cushing syndrome (SCS), 5% had a pheochromocytoma, 1% had an aldosteronoma,
All patients found to have an incidental adrenal mass should be screened for cortisol excess. The simplest screening test for autonomous cortisol secretion from an incidentaloma is a 1-mg overnight dexamethasone suppression test. There are three additional tests that could be performed: 3 tests (salivary cortisol, dexamethasone suppression, and urine free cortisol [UFC]) can be used .
Patients thought to have a pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour total urinary metanephrines and fractionated catecholamines (or both plasma and urine studies). About one-quarter of patients with a pheochromocytoma will have associated familial syndromes caused by mutations in the RET gene (multiple endocrine neoplasia type 2), VHL gene (von Hippel-Lindau disease), or succinate dehydrogenase genes; genetic study and counseling should be performed, especially for young patients or patients with an extra-adrenal pheochromocytoma .
Screening for aldosteronism should be performed in patients with an aldosterone-to-renin ratio (ARR) of >20. Diagnosis is confirmed in the setting of an adrenal incidentaloma by demonstrating lack of aldosterone suppression (24-hour urine study) with salt loading and adrenal venous sampling (AVS) in the majority of patients older than 40 years .
Figure 1. NIH diagnostic algorithm 
2. The noninvasive differentiation of benign and malignant lesions depends upon imaging characteristics [1, 4]:
a) CT scan. Appearance of an adrenal adenoma: small, well-defined homogenous lesions with clearly evident margins. Large intracytoplasmic lipid content results in lower attenuation as measured by Hounsfield units (HU). Hemorrhage, calcifications, or necrosis may be seen as well. Findings suggestive of malignancy include large size (>4 cm), irregular shape, vague contour, heterogeneous enhancement or ttenuation, poor margination, and, invasion into surrounding structures. CT scan may demonstrate fat within an adrenal incidentaloma and assist in specific diagnosis of myelolipoma [1, 5]. The presence of a large amount of microscopic or intracellular fat can result in densities with low Hounsefield units and a threshold value
b) MRI (Magnetic resonance imaging). Adrenal cortical adenomas typically exhibit homogeneous signal intensity and enhancement with T2-weighted intensity malignant masses are typically hypointense on both T1- and T2-weighted images with strong enhancement after contrast injection and delayed washout. High signal intensity on T2-weighted MRI is suggestive of pheochromocytoma .
Figures 2 and 3 represent non-functional left adrenal incidentaloma (4.6 cm), who I have recently operated on, she underwent left retroperitoneoscopic adrenalectomy (A. Shifrin).
Figure 2. MRI (frontal view) of the one of my patients with the left, 4.6 cm, adrenal incidentaloma who have recently had a surgery - left retroperitoneoscopic adrenalectomy.
Figure 3. MRI (transverse view) of the one of my patients with the left, 4.6 cm, adrenal incidentaloma who have recently had a surgery - left retroperitoneoscopic adrenalectomy.
c) PET CT (Positron emission tomography) scanning may be useful, particularly in patients with known malignancies 
d) Isotope imaging techniques. They include 131iodine or 123iodine-labeled metaiodobenzylguanidine (MIBG) and 131I-6-betaiodomethyl-norcholesterol (NP-59). MIBG has been used to identify function in adrenomedullary and NP-59 - adrenocortical tumors . MIBG has 87% sensitivity and 95% specificity for identification of pheochromocytoma. Positive and negative MIBG results, therefore, change the prior probability of pheochromocytoma in an incidentaloma from 3.5% to around 40% and 0.5%, respectively .
Treatment and Management.
Before consideration of surgical resection, a high degree of certainty of the diagnosis is critical and can be achieved with a combination of biochemical and radiographic studies. Patients who present with an adrenal incidentaloma should be referred to an endocrinologist or endocrine surgeon for assessment . Surgical resection should be performed for all pheochromocytomas. Pheochromocytomas necessitate careful preoperative preparation to avoid intraoperative and postoperative morbidity and mortality. In patients with primary aldosteronism, a thorough evaluation should be performed to ensure that they do not have adrenocortical hyperplasia and a nonfunctioning adrenal adenoma. In patients with primary aldosteronism and a unilateral source of aldosterone excess, laparoscopic total adrenalectomy is the treatment of choice because it yields excellent outcomes with low associated morbidity relative to open approaches (Patients with adrenal Cushing syndrome develop adrenal insufficiency after resection and will require steroid coverage and careful withdrawal . Nonfunctioning adrenal mass (and any adrenal mass with concerning radiographic characteristics) ≥4 cm should be resected because of increased risk of adrenal cancer. A small myelolipomas, benign cysts, or nonfunctioning adenomas can be diagnosed with considerable certainty and usually do not necessitate surgical resection unless symptomatic. Depending on the clinical circumstances, resection may be indicated (Figure 4) .
Figure 4. Algorithm for the evaluation and management of an adrenal incidentaloma
Patients with adrenal incidentalomas who do not fulfill the criteria for surgical resection need to have radiographic reevaluation at 3 to 6 months and then annually for 1 to 2 years. For all adrenal tumors, hormonal evaluation should be performed at the time of diagnosis and then annually for 5 years . The reason for follow up is the risk of the mass enlarging during 1, 2, and 5 years that is 6%, 14%, and 29%, respectively, and the risk of the mass becoming hormonally active during those time periods is 17%, 29%, and 47%, respectively . Should the tumor grow more than 1 cm or become hormonally active during follow-up, surgical excision should be considered .
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- Lau J, Balk E, Rothberg M et al. Management of Clinically Inapparent Adrenal Mass. Rockville, MD: Agency for Healthcare Research and Quality/Evidence Report/Technology Assessment, 2002. Number 56.
- Aron DC. Endocrine Incidentalomas. Endocrinology and Metabolism Clinics of North America. 2002;29:1–238
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- The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Zeiger MA, Thompson GB, Duh QY, Hamrahian AH, Angelos P, Elaraj D, Fishman E, Kharlip J; American Association of Clinical Endocrinologists; American Association of Endocrine Surgeons. Endocr Pract. 2009 Jul-Aug;15 Suppl 1:1-20.