Adrenal metastases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Overview

Adrenal metastases are the most common malignant lesions involving the adrenal gland and the second most common tumor of the adrenal gland after benign adenomas. These metastases were primarily found on autopsy. The pathogenesis of adrenal metastases is characterized by metastases from renal cell carcinoma, melanoma, lung cancer, colorectal cancer, breast cancer and lymphoma. On gross pathology, a unilateral, small asymptomatic lesion is a characteristic finding of adrenal metastasis. Adrenal metastases must be differentiated from other diseases that cause tumors in adrenal gland such as nonfunctional adenoma, primary carcinoma in adrenal glands, adrenal cyst, and non-functional pheochromocytoma. Adrenal metastases are thought to be present in up to 27% of patients with known malignant epithelial tumors at autopsy. Symptoms of adrenal metastases may include dizziness, faintness, fatigue, weakness, and weight loss. CT is the imaging modality of choice for adrenal metastases. The mainstay of therapy for adrenal metastases is chemotherapy.

Pathophysiology

Adrenal metastases occur secondary to hematogenous seeding of neoplastic cells from renal cell carcinoma, melanoma, lung cancer, colorectal cancer, breast cancer and lymphoma.
On gross pathology, a unilateral, small asymptomatic lesion is a characteristic finding of an adrenal metastasis.

Differentiating Adrenal metastases from other Diseases

Adrenal metastasis must be differentiated from other adrenal tumors such as adrenocortical adenoma, adrenal metastasis, adrenal medullary tumors, and Cushing’s syndrome.


Differential Diagnosis	Clinical picture	Imagings	Laboratory tests
Adrenocortical carcinoma	Mass effect symptoms Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid Symptoms related to excess androgen or estrogen secretion	Irregular shape Non-homogeneous density because of central areas of low attenuation due to tumor necrosis Tumor calcification Diameter usually >4 cm Unilateral location High unenhanced CT attenuation values (>20 HU) Non-homogeneous enhancement on CT with intravenous contrast Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Hypointensity compared with liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI High standardized uptake value (SUV) on FDG–PET-CT study Evidence of local invasion or metastases	Adrenal androgens (DHEAS) Androstenedione Bioavailable testosterone should be measured in every patient. 17-hydroxyprogesterone Serum estradiol in men and postmenopausal women Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime
Adrenal adenoma	Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid	Round, homogeneous with sharp margination Unilateral with diameter less than 4 cm Low unenhanced CT attenuation values (<10 HU) Rapid contrast medium washout after administration of contrast An absolute contrast medium washout of more than 50 percent Chemical shift: evidence of lipid on MRI Isointensity with liver on both T1 and T2 weighted MRI sequences	Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime Renin (PRA) or plasma renin concentration (PRC): very low in patients with primary aldosteronism, usually less than 1 ng/mL per hour for PRA and usually undetectable for PRC^[1]
Cushing’s syndrome	Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a “moon face“ Excess sweating Headache	Imaging may show mass if presents	24-hour urine cortisol Midnight salivary cortisol Low-dose dexamethasone suppression test; high cortisol level after the dexamethasone test is suggestive of hypercortisolism.
Pheochromocytoma	Palpitations especially in epinephrine-producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered incidentally after screening for MEN patients.	Increased attenuation on non-enhanced CT (>20 HU) Increased mass vascularity Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) High signal intensity on T2 weighted MRI Cystic and hemorrhagic changes Variable size and may be bilateral	Plasma fractionated metanephrines 24-hour urinary fractionated metanephrines
Adrenal metastasis	Symptoms and signs of primary malignancy especially lung cancer General constitutional symptoms: Fever Fatigue Weight loss	Irregular shape and non-homogeneous nature Tendency to be bilateral High un-enhanced CT attenuation values (>20 HU) and enhancement with intravenous contrast on CT Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Isointensity or slightly less intense than the liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI (representing an increased water content) Elevated standardized uptake value on FDG–PET scan

Epidemiology and Demographics

Adrenal metastases are thought to be present in up to 27% of patients with known malignant epithelial tumors at autopsy.

Natural History, Complications and Prognosis

If left untreated, 20-35% of patients with cancer may progress to develop adrenal metastases.^[2]
Complications of adrenal metastases include central necrosis with adrenal hemorrhage and paraneoplastic leukemoid reaction.

DIfferentiating Adrenal metastases from other diseases


Disease	Gene	Chromosome	Differentiating Features	Components of MEN			Diagnosis
Disease	Gene	Chromosome	Differentiating Features	Parathyroid	Pitutary	Pancreas	Diagnosis
von Hippel-Lindau syndrome	Von Hippel–Lindau tumor suppressor	3p25.3	Angiomatosis, Hemangioblastomas, Pheochromocytoma, Renal cell carcinoma, Pancreatic cysts (pancreatic serous cystadenoma) Endolymphatic sac tumor, Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)	–	–	+	Clinical diagnosis In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.
Carney complex	PRKAR1A	17q23-q24	Myxomas of the heart Hyperpigmentation of the skin (lentiginosis) Endocrine (ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease)	–	–	–	Clinical diagnosis
Neurofibromatosis type 1	RAS	17	Scoliosis Learning disabilities Vision disorders Cutaneous lesions Epilepsy.	–	–	–	Prenatal Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus. Postnatal Cardinal Clinical Features” are required for positive diagnosis. Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary (Crowe sign) or inguinal regions Optic glioma Two or more Lisch nodules (pigmented iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
Li-Fraumeni syndrome	TP53	17	Early onset of diverse amount of cancers such as Sarcoma Cancers of Breast Brain Adrenal glands	–	–	–	Criteria Sarcoma at a young age (below 45) A first-degree relative diagnosed with any cancer at a young age (below 45) A first or second degree relative with any cancer diagnosed before age 60.
Gardner’s syndrome	APC	5q21	Multiple polyps in the colon Osteomas of the skull Thyroid cancer, Epidermoid cysts, Fibromas Desmoid tumors	–	–	–	Clinical diagnosis Colonoscopy
Multiple endocrine neoplasia type 2	RET	–	Medullary thyroid carcinoma (MTC) Pheochromocytoma Primary hyperparathyroidism	+	–	–	Hypercalcemia Hypophosphatemia, Elevated parathyroid hormone, Elevated norepinephrine Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia
Cowden syndrome	PTEN	–	Hamartomas	–	–	–	PTEN mutation probability risk calculator
Acromegaly/gigantism	–	–	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin Hypertrichosis Hyperpigmentation Hyperhidrosis Carpal tunnel syndrome.	–	+	–	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.
Pituitary adenoma	–	–	Visual field defects classically bitemporal hemianopsia Increased intracranial pressure Migraine Lateral rectus palsy	–	+	–	Elevated serum level of prolactin Elevated or decreased serum level of adrenocorticotropic hormone (ACTH) Elevated or decreased serum level of growth hormone (GH) Elevated or decreased serum level of thyroid-stimulating hormone (TSH) Elevated or decreased serum level of follicle-stimulating hormone (FSH) Elevated or decreased serum level of luteinizing hormone (LH)
Hyperparathyroidism	–	–	– Kidney stones Hypercalcemia, Constipation Peptic ulcers Depression	+	–	–	An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism. Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium. An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.
Pheochromocytoma/paraganglioma	VHL RET NF1 SDHB SDHD	–	Characterized by Episodic hypertension Palpitations Anxiety Diaphoresis Weight loss	–	–	–	Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.
Adrenocortical carcinoma	p53 Retinoblastoma h19 Insulin-like growth factor II (IGF-II) p57^kip2	17p, 13q	Cushing syndrome (cortisol hypersecretion) Conn syndrome (aldosterone hypersecretion) virilization (testosterone hypersecretion)	–	–	–	Increased serum glucose Increased urine cortisol Serum androstenedione and dehydroepiandrosterone Low serum potassium Low plasma renin activity High serum aldosterone. Excess serum estrogen.
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013^[3]

Treatment

Medical Therapy

The mainstay of therapy for adrenal metastases is chemotherapy.

Surgery

Adrenalectomy in conjunction with chemotherapy is the most common approach to the treatment of adrenal metastases if primary disease is well controlled and the only site of metastasis is the adrenal gland.

Prevention

There are no primary preventive measures available for adrenal metastases.

References

↑ Manolopoulou J, Fischer E, Dietz A, Diederich S, Holmes D, Junnila R; et al. (2015). “Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays”. J Hypertens. 33 (12): 2500–11. doi:10.1097/HJH.0000000000000727. PMID 26372319.
↑ Lam KY, Lo CY (2002). “Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital”. Clin Endocrinol (Oxf). 56 (1): 95–101. PMID 11849252.
↑ Toledo SP, Lourenço DM, Toledo RA (2013). “A differential diagnosis of inherited endocrine tumors and their tumor counterparts”. Clinics (Sao Paulo). 68 (7): 1039–56. doi:10.6061/clinics/2013(07)24. PMC 3715026. PMID 23917672.

[pmid26372319-1] Manolopoulou J, Fischer E, Dietz A, Diederich S, Holmes D, Junnila R; et al. (2015). “Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays”. J Hypertens. 33 (12): 2500–11. doi:10.1097/HJH.0000000000000727. PMID 26372319.

[pmid11849252-2] Lam KY, Lo CY (2002). “Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital”. Clin Endocrinol (Oxf). 56 (1): 95–101. PMID 11849252.

[pmid23917672-3] Toledo SP, Lourenço DM, Toledo RA (2013). “A differential diagnosis of inherited endocrine tumors and their tumor counterparts”. Clinics (Sao Paulo). 68 (7): 1039–56. doi:10.6061/clinics/2013(07)24. PMC 3715026. PMID 23917672.

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