Etiology

Benign, hormonally active

Cushing syndrome

  • Cushing syndrome is a rare disorder (incidence 0.7 to 2.4 per 1 million per year) but has important metabolic consequences and is associated with significant morbidity and mortality when untreated.[6]​

  • Results from inappropriate exposure to excessive glucocorticosteroids and is characterized as adrenocorticotropic hormone (ACTH)-dependent (85% cases, which include: ACTH-secreting pituitary adenomas 75%, ectopic corticotropin syndrome 10%) and ACTH-independent (15% cases).[7]

  • Adrenal Cushing syndrome (ACTH-independent Cushing syndrome) is due in most instances to a unilateral tumor: adrenocortical adenoma (about two-thirds of adrenal cases) or adrenocortical carcinoma (about one-third of adrenal cases). Rare causes of adrenal Cushing include macronodular adrenal hyperplasia; primary pigmented nodular hyperplasia, as isolated disease or as part of Carney complex; and McCune-Albright syndrome.[8]

Mild autonomous cortisol secretion (MACS)

  • This term is applied to adenomas that secrete low-levels of cortisol, giving rise to biochemical cortisol excess, without clinical signs of Cushing syndrome.[9][10]​​ The term subclinical Cushing syndrome may be applied.[11]​​ MACS is evident in around 8% of patients with adrenal incidentaloma.[12]

  • European guidelines define MACS as postdexamethasone serum cortisol concentration above >1.8 micrograms/dL (50 nmol/L) in patients without signs and symptoms of overt Cushing syndrome.[9]​ These patients may require further evaluation for signs of Cushing that may have been missed initially, and to demonstrate suppressed or low-normal morning plasma ACTH (which confirms ACTH independency).[9]

  • One systematic review found that patients with adenomas causing MACS rarely develop overt Cushing syndrome. However, there is a higher prevalence of hypertension, obesity, dyslipidemia, type 2 diabetes mellitus, and osteoporosis in patients with MACS, compared with people with nonfunctioning adrenal tumors.[11]​ European guidelines recommend screening patients with adrenal incidentaloma and MACS for hypertension and type 2 diabetes mellitus.[9]

Pheochromocytoma

  • Around 7% of patients with adrenal incidentalomas have a pheochromocytoma.[4]​ Although rare, these tumors are potentially lethal, and biochemical evaluation for exclusion of pheochromocytoma is required.[3]​​

Primary hyperaldosteronism

  • Caused by an aldosterone-producing cortical adenoma in 80% of cases; bilateral adrenal hyperplasia is found in 20% of cases.

  • All patients with an incidental adrenal mass with hypertension should be evaluated for primary aldosteronism. Approximately 1% of incidental adrenal masses are aldosterone-producing adenomas.[5]

Benign, hormonally inactive

Nonsecretory adrenal adenoma

  • Present as asymptomatic adrenal lesions, incidentally discovered on diagnostic imaging studies.

Adrenal cysts

  • Typically asymptomatic, solitary adrenal lesions, more frequently diagnosed in the fifth and sixth decades of life with a 1.2 to 1.5 times female preponderance.[13]

  • These lesions are classified as: endothelial cysts (48%), which can be either angiomatous or lymphangiomatous; pseudocysts (42%), which result from adrenal hemorrhage and subsequent clot organization within a normal adrenal gland or adrenal tumor; and epithelial cysts (10%), which include cystic adenomas, glandular or retention cysts, and cystic transformation of embryonal remnants.[14]

  • Large lymphangiomatous endothelial cysts of the adrenal gland are also known as adrenal lymphangiomas.

Adrenal myelolipomas

  • Usually unilateral, asymptomatic adrenal masses composed of mature fat and bone marrow.

  • Adrenal collision tumors occur when 2 independently coexisting neoplasms are identified within the adrenal gland. Most cases stem from the association of a solid adrenal lesion (usually an adenoma) with a myelolipoma, with demonstration of macroscopic fat content within an adrenal mass. The increasing frequency of reports of the myelolipoma-adenoma association is likely related to the increasing incidental detection of adrenal masses.

Adrenal hemangiomas

  • Rare, benign tumors, incidentally detected on imaging studies. Hemangiomas usually involve the adrenal cortex, and are mostly cavernous, rarely capillary.

  • Typically asymptomatic, or symptoms related to mass effect (abdominal pressure) if the tumor is large.

Adrenal ganglioneuroma

  • A rare benign neoplasm originating from the sympathetic ganglia; belongs to the group of neurogenic tumors, which also include neuroblastoma and ganglioneuroblastoma.[13] Account for 0.2% to 1.6% of adrenal tumors.[13]​

  • Very rarely, hormonally active neurogenic tumors have been reported with secretion of catecholamines, vasoactive intestinal peptides, or androgens.

  • Often asymptomatic; may present with abdominal pain if large.

Adrenal hematoma

  • May be traumatic (after severe abdominal trauma), spontaneous (associated with anticoagulant therapy, or severe stress caused by surgery, sepsis, or hypotension), postprocedural (after adrenal venous sampling), or idiopathic (usually associated with an underlying medical condition such as cyst, hemangioma, myelolipoma, or metastasis).[13]

Granulomatous infiltrative adrenal lesions

  • Include adrenal tuberculosis and disseminated histoplasmosis, which usually occur in endemic areas and/or in the setting of altered host immunity (neoplasms, AIDS).[15]

  • The adrenal glands may be the only demonstrable site of disseminated disease.

  • May present with weakness, fatigue, anorexia, nausea, vomiting, weight loss, and signs of adrenal insufficiency.

Malignant

Adrenocortical carcinoma

  • Although rare in the general population (incidence 1 to 2 per 1 million), it has been found in 4.7% of patients diagnosed with adrenal incidentaloma.[5][16][17]

  • Heterogeneous clinical presentation and a generally poor prognosis: median overall survival of 3.21 years, and a 5-year survival rate of 15% to 44%.[18]

  • Patients present with clinical and biochemical evidence of steroid hormone excess in 60% of cases. The most common presentation is rapidly progressing Cushing syndrome with or without virilization.[19]

  • May also present with symptoms related to mass effect (e.g., abdominal pressure or pain).

Adrenal metastases

  • Common; 8% to 38% of patients with known malignancy have adrenal metastases at autopsy.[20]

  • In patients with a history of malignancy, 75% of clinically inapparent adrenal masses are metastatic lesions, most commonly from cancers of the breast, lung, kidney, stomach, pancreas, ovary, colon, and esophagus.[1]

  • The possibility of a metastatic lesion should be considered in a patient who has a history of cancer and presents with an adrenal mass that does not meet the criteria for an incidentaloma.[21]

  • Metastatic lesions are found in 2.5% of patients with adrenal incidentalomas.[21]

  • Metastases to the adrenal gland may be unilateral or bilateral.

  • A very small percentage (0.4%) of adrenal masses are due to metastases without a known primary cancer.

  • Symptoms may be related to mass effect (e.g., abdominal pressure or pain) or related to the primary malignancy.

  • Patients with bilateral adrenal metastases may present with clinical symptoms and signs of adrenal insufficiency such as weakness, fatigue, anorexia, nausea, vomiting, weight loss, hypotension, hyponatremia, hypoglycemia, or hyperpigmentation of the skin and mucous membranes.

Adrenal malignant melanoma

  • A very rare tumor, occurring as a large hemorrhagic and necrotic adrenal mass. The main diagnostic difficulty is distinguishing primary adrenal melanoma from an adrenal metastasis of cutaneous, squamous, mucosal, or ocular melanoma.[22]​ The existence of primary adrenal melanoma is explained by the neuroectodermal origin of the medulla, chromaffin cells, and melanocytes having common embryogenesis.

  • It is hormonally inactive.

  • It is typically asymptomatic; when large, the patient may complain of symptoms of mass effect (e.g., abdominal pressure and pain).[23]

  • Radiologic appearance is that of a large, unilateral adrenal mass; possible central necrosis and calcification. 18-fluoro-2-deoxyglucose (FDG) positron emission tomography/computed tomography scan may display a metabolically avid lesion with possible central photopenia. Definitive diagnosis on demonstration of melanin in the tumor on pathology.[24]

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