Summary
Urgent Considerations
Malignancy
Endocrine function
Etiology
Benign, hormonally active
- 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]
- 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.[10] Some guidelines recommend screening for hypertension and type 2 diabetes mellitus in individuals with autonomous cortisol secretion to ensure these are appropriately treated if present.[9]
- 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
- Present as asymptomatic adrenal lesions, incidentally discovered on diagnostic imaging studies.
- 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.[12]
- 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.[13]
- Large lymphangiomatous endothelial cysts of the adrenal gland are also known as adrenal lymphangiomas.
- 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.
- 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.
- 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.
- 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).[12]
- Include adrenal tuberculosis and disseminated histoplasmosis, which usually occur in endemic areas and/or in the setting of altered host immunity (neoplasms, AIDS).[14]
- 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
- 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%.[17]
- 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.[18]
- May also present with symptoms related to mass effect (e.g., abdominal pressure or pain).
- Common; 8% to 38% of patients with known malignancy have adrenal metastases at autopsy.[19]
- 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.[20]
- Metastatic lesions are found in 2.5% of patients with adrenal incidentalomas.[20]
- 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.
- 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.[21] 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).[22]
- 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.[23]
Differential Diagnosis
Diagnostic Approach
Clinical assessment
- Cushing syndrome: weight gain, central obesity, facial rounding, plethora, supraclavicular fat pads, dorsocervical fat pad, easy bruising, purple striae, proximal weakness, mood changes, infection, irregular menses, acne, hirsutism, hypertension (if virilizing or feminizing tumor: hirsutism, amenorrhea or change in libido, gynecomastia). Individuals with mild autonomous cortisol secretion (MACS), or subclinical Cushing syndrome, may be asymptomatic, or patients may have metabolic alterations such as impaired glucose tolerance, diabetes mellitus, hypertension, or metabolic bone disease without other clinical stigmata.[5] [10] [26]
- Pheochromocytoma: severe or episodic hypertension, palpitations, pallor, retinopathy, tremor, fever.
- Primary hyperaldosteronism: hypertension, muscle cramps/weakness, cardiac arrhythmias, hypokalemia-induced nephrogenic diabetes insipidus (polyuria, dehydration).
- Mass effect (e.g., abdominal pain)
- Adrenal hypersecretion of cortisol (Cushing syndrome), androgens (hirsutism, acne, amenorrhea, or oligomenorrhea), estrogens (gynecomastia), or, very rarely, aldosterone (hypokalemia-related symptoms).
Laboratory evaluation
- Electrolytes: hypokalemia may suggest hyperaldosteronism; hypokalemia may be present in Cushing syndrome.
- Fasting lipid profile: hyperlipidemia may be present in Cushing syndrome.
- Fasting blood glucose: hyperglycemia may be present in Cushing syndrome or pheochromocytoma.
- Complete blood count: leukocytosis with neutrophilia may occur in Cushing syndrome.
- Screening for pheochromocytoma with fractionated plasma metanephrines.
- For pheochromocytoma, 24-hour urine total metanephrines and fractionated catecholamines.
- For hyperaldosteronism, plasma aldosterone concentration on an unrestricted salt diet, 24-hour urinary aldosterone excretion, and saline infusion test (saline suppression test).
Imaging
- CT or MRI: to assess size and morphologic characteristics of adrenal lesions.Image
Functional imaging studies
- procedure-related complications (2.8%; including abdominal pain, adrenal hematoma, hematuria, pancreatitis, pneumothorax, formation of an adrenal abscess)
- risk of needle tract metastasis (0.3% of subjects with long-term follow-up), and
- high rate of false-negative results.
Follow-up
Library
Workup of an adrenal mass incidentally found on imaging [Abbreviations: CT: computed tomography; CECT: contrast-enhanced CT; MRI: magnetic resonance imaging; CS-MRI: compressed sensing MRI; F-DOPA: 3,4-dihydroxy-6-(18)F-fluoro-l-phenylalanine; FDG: 18-fluoro-2-deoxyglucose; Ga/Cu DOTATATE: ⁶⁸Ga- or ⁶⁴Cu-DOTA-(Tyr3)-octreotate; FNAB: fine-needle aspiration (FNA) biopsy; HU: Hounsfield unit; MIBG: meta-iodobenzylguanidine; NP-59: iodine-131-6-beta-iodomethylnorcholesterol (or radio-iodine-labeled norcholesterol); PET: positron emission tomography; SUVmax: maximum standardized uptake value; US: ultrasound]
Incidentally discovered, 1.8 cm diameter, right adrenal mass in a 37-year-old man. Abdominal CT (A) depicts the mass as lipid-poor with atypical contrast enhancement; NP-59 scintigraphy done without dexamethasone suppression; (B) demonstrates a concordant pattern of imaging with right > left adrenal accumulation of iodocholesterol on the fifth and sixth days postinjection, compatible with a benign etiology
Left adrenal aldosteronoma depicted with dexamethasone suppression NP-59 imaging: 57-year-old woman with biochemical evidence of hyperaldosteronism and a left adrenal mass. Abdominal CT (A) demonstrates a 2 cm left adrenal mass (black arrow), anterior and posterior abdominal NP-59 scans (B and C) on the third day postinjection; anterior and posterior abdominal NP-59 scans (D and E) on the fifth day postinjection; abnormal left adrenal uptake (black arrows) occurs early, before day 5 postinjection (B and C); normal uptake in liver (L), bowel (B), and gallbladder (GB)
Meta-iodobenzylguanidine (MIBG) scan demonstrating intensely focal tracer activity in the left adrenal gland consistent with pheochromocytoma in a 56-year-old woman with HTN, elevated plasma norepinephrine levels, and a 3 cm left adrenal mass seen on cross-sectional anatomic imaging
Malignant, metastatic pheochromocytoma demonstrated by 123-I-meta-iodobenzylguanidine (MIBG) and CT in a 31-year-old woman after bilateral adrenalectomy and persistent HTN complicated by renal insufficiency and recent development of superior vena cava (SVC) obstruction; (A) anterior chest and abdomen scan. L = normal liver uptake while arrows depict multiple, abnormal foci of 123-1-MIBG in metastatic pheochromocytoma deposits in the mediastinum and para-aortic regions; (B) chest CT identifies the superior mediastinal mass responsible for SVC obstruction (white arrow)
18-fluoro-2-deoxyglucose (FDG) PET-CT: adrenal adenoma. 46-year-old man with squamous cell carcinoma of the neck (TxN1 tumor) status post-external beam radiation therapy; restaging PET-CT demonstrates low-attenuation, non-FDG avid, 3.7 cm left adrenal nodule consistent with adrenal adenoma; FDG PET study excluded distant metastasis to the adrenal gland
18-fluoro-2-deoxyglucose (FDG) PET-CT: adrenocortical carcinoma. 51-year-old woman with Cushing syndrome and large, multilobulated and intensely 18-F-FDG avid left adrenal mass and metastatic aortocaval and left para-aortic lymph nodes
Left adrenal metastasis (arrow) depicted by 18-fluoro-2-deoxyglucose (FDG) PET-CT (A-C) in a patient with a non-small cell lung cancer (arrow); corresponding chest (D) and abdominal (E) CT scans identify the lung primary and the adrenal metastasis (arrow)
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