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A. Normal Adrenal Gland

  1. Adrenal Cortex
    1. Mainly steroid producing cells
    2. Three zones: glomerulosa, fasciculata, reticularis
    3. Glomerulosa mainly responsible for aldosterone production
    4. Fasciculata produces glucocorticoids and other stress steroids
    5. Reticularis produdes mainly sex steroids (typically androgens)
    6. Angiotensin II stimulates aldosterone production
    7. Increases in sympathetic neuronal activity also stimulate aldosterone
    8. ACTH (adrenocorticotropic hormone, corticotropin) stimulates glucocorticoid production
    9. Hypoglycemia and other stresses also stimulate glucocorticoid production
    10. Inflammatory mediators (IL1, IL6) stimulate steroidogenesis as well
    11. Tumor necrosis factor alpha (TNFa) inhibits steroid synthesis in fasciculata
    12. Some intermingling of medullary cells in the adrenal cortex
  2. Adrenal Medulla
    1. Main regulation by by preganglionic sympathetic neurons (acetylcholine)
    2. Produces mainly epinephrine and other sympathetic hormones
    3. Adrenal cortical cell "islets" are found in the medulla
  3. Thus, the anatomic separation of cortex and medulla is incomplete
  4. Cell biology and physiology observations support the interaction of cortex and medulla

B. Unilateral Adrenal Mass

  1. Adrenal masses are extremely common [4]
    1. ~3% of persons >50 years have subclinical adrenal mass (autopsy studies)
    2. Most of these cause no problems
    3. About 1 per 4000 is malignant
    4. Subclinical hormone mediated diseases may occur in some patients with adrenal mass
    5. Issues are functional versus nonfunctional and benign versus malignant
    6. Most adrenal masses are discovered accidently and called an "Incidentaloma" [4]
    7. ~75% of adrenal masses detected during cancer staging represent metastases
    8. May be increased in pregnancy; more common cause of Cushing's in pregnancy [6]
  2. Incidentalomas [1,2,4]
    1. Adrenal mass discovered on ~6% of imaging procedure for non-neoplastic disease
    2. Increased use of high resolution imaging technology leads to increasing detection
    3. May be benign (most common) or malignant, functional or non-functional
    4. Benign adrenal masses (1-2 cm) found in 4-6% of adults >50 years at autopsy
    5. Increasing with age, with 7% of persons >70 years with benign adrenal mass at autopsy
    6. ~70% of incidentalomas are nonfunctioning tumors
    7. ~15% of masses increase in size by at least 1cm
    8. ~5% of incidentalomas are cortisol-producing and ~5% pheochromocytomas
    9. ~1% of incidentalomas are aldosterone-producing tumors
    10. Predict malignant potential of incidentaloma initially by size, appearance on imaging
    11. If bilateral incidentalomas present, then higher risk for metastatic lesions (see below)
    12. Management discussed below
  3. Functional
    1. Adrenal Adenoma - aldosterone, cortisol, or androgens (may cause Cushing Syndrome) [6]
    2. Adrenal Carcinoma
    3. Pheochromocytoma - epinephrine, metanephrines
    4. Hyperplasia (usually hyperplasia is bilateral)
  4. Non-Functional
    1. Non-functional ademona
    2. Non-functional adrenal carcinoma (<1% of adrenal masses)
    3. Metastatic Disease - breast, lung, colon carcinomas
    4. Myelolipoma
    5. Cyst
    6. Ganglioneuroma

C. Bilateral Adrenal Mass [7]

  1. Adrenal Hyperplasia
    1. Congenital Adrenal Hyperplasia (CAH) [3]
    2. ACTH-Dependent Cushing Syndrome
    3. Idiopathic hyperplasia with hyperaldosteronism
    4. Idiopathic bilateral adrenal hypertrophy
  2. Primary Tumor
    1. Lymphoma
    2. Pheochromocytoma
    3. Adrenocortical carcinoma
    4. Neuroblastoma (pediatric)
  3. Non-Functional Lesions
    1. Infection
    2. Infiltration - leukemia, lymphoma
    3. Hemorrhage
    4. Amyloidosis
    5. Bilateral metastatic disease
  4. Infectious Disease
    1. Tuberculosis
    2. Fungal - histoplasmosis, blastomycosis, coccidiomycosis, cryptococcosis
  5. Metastatic Disease
    1. Lung carcinoma
    2. Breast carcinoma
    3. Renal malignant tumor
    4. Melanoma
    5. Colon cancer (rare)
  6. Miscellaneous
    1. Incidental adrenal tumors
    2. Myelolipoma
    3. Hemorrhage
  7. Bilateral Adrenal Hemorrhage
    1. Coagulopathy (45%)
    2. Post-operative (17%)
    3. Anti-coagulation (16%)
    4. Cardiac Disease (12%)
    5. Infection (11%)
  8. Micronodular Disease [5]
    1. Primary pigmented nodular adrenocortical disease (PPNAD)
    2. Bilateral micronodular adrenal disorder
    3. May be associated multiple endocrine and non-endocrine cancers (Carney Complex)
    4. Carney complex is skin lentigines, cardiac myxomas, and various other tumors [8]

D. Adrenal Cortical Tumors [2]

  1. Benign
    1. Nonfunctional adenoma
    2. Aldosterone-producing adenoma
    3. Cortisol-producing adenoma
    4. Virilizing adrenal adenoma
  2. Virilizing Adrenal Adenoma
    1. May cause precocious puberty in young persons
    2. Excessive production of DHEA leads to elevated DHEA, testosterone, estradiol levels
    3. Hirsutism (may require increased shaving)
    4. Determine testosterone, DHEA or DHEA-S, androstenedione, and estrogen levels
    5. Specify estrogens or androgens if heterosexual precocity
    6. Exogenous testosterone use does not elevate DHEA levels
  3. Malignant
    1. Adrenocortical Carcinoma
    2. Combined hormone excess syndrome
    3. Cushing's Syndrome and hirsutism in ~55%
    4. Abdominal mass
    5. Weight Loss
    6. Mutations in p53 tumor suppressor found in ~40% of spontaneous tumors
    7. Surgical resection of Stage I or II disease is generally curative
    8. Radical excision with en bloc reseaction for any local invasion
    9. Mitotane has been used with minimal success in treatment of later stages
  4. Familial Adrenal Cancer Syndromes
    1. MEN I
    2. CAH
    3. Carney Complex - atrial myxomas, schwannomas, lentigines, blue nevi
    4. Li-Fraumeni Syndrome
    5. McCune-Albright Syndrome
    6. Wiedemann-Beckwith Syndrome
  5. Gross Pathology of Benign Versus Malignant Adrenal Cortical Mass [2]
    1. Benign tumors median size 2cm, weight 10gm
    2. Benign well circumscribed with smooth cut surface
    3. Benign without hemorrhage or necrosis
    4. Adrenal cortical carcinomas are large (median 14cm, weight 510gm)
    5. Carcinomas hav eill-defined borders, nodular coarse surfaces with necrosis, hemorrhage
  6. Microscopical Pathology
    1. Nine histologic characteristics assessed for benign versus carcinoma
    2. Carcinoma: high mitotic rate (>4 per 50 high -power fields)
    3. Carcinoma has high nuclear (Fuhrman) grade 3-4
    4. Carcinoma has <25% of cells with clear cytoplasm
    5. Carcinoma has diffuse growth pattern in >33% of tumor
    6. Carcinoma with necrosis and/or sinusoidal invasion and/or capsular invasion
    7. If at least 3 of these histologic features present, carcinoma is diagnosed
    8. Fine needle biopsy can be used on incidentalomas after ruling out pheochromocytoma

E. Evaluation

  1. Incidental finding on CT scan is most common cause for initiating adrenal mass evaluation
  2. Pheochromocytoma must be ruled out
    1. Hormonal effects are most dangerous to patient
    2. About one-third of these tumors are metastatic
    3. High risk of bleeding and/or hormonal release with fine needle biopsy
  3. History and physical to evaluate for hormonal excess or insufficiency
  4. Cortrosyn (ACTH) Test
    1. Evaluate for hormonal excess or insufficiency
    2. If insufficiency present, consider infectious cause or hemorrhage or autoimmune
    3. Normal cortrosyn test prompts search for hormonal excess
    4. Evaluate cortisol, aldosterone, catecholamines and renin levels
    5. Excess of hormones should prompt surgical therapy in most cases
  5. Functional Adrenal Cortical Tumors [2]
    1. Production of cortisol may be autonomous but insufficient to suppress ACTH
    2. Autonomous production can be assessed with iodocholesterol scintography
  6. Normal Hormone Levels
    1. Consider fine needle biopsy once pheochromocytoma has been rule out
    2. Adrenal mass - surgical removal if >5-6cm regardless of symptoms
    3. Metastatic disease - search for primary
  7. Benign Versus Malignant Adrenal Mass [2]
    1. Risk for cancer <2% for tumors <4cm
    2. Cancer risk >25% in tumors >6cm
    3. Therefore, all adrenal masses >6cm should be excised
    4. Benign neoplasms usually with smooth borders without hemorrhage or necrosis

F. Mangement of Incidentaloma [1,4]

  1. All patients
    1. Rule out hypercortisolism: 1mg dexmethasone suppression test
    2. Rule out pheochromocytoma: free plasma metanephrines
  2. For patients with hypertension (hyperaldosteronism), measure:
    1. Serum potassium
    2. Plasma aldosterone concentration - plasma renin activity ratio
  3. Surgical Resection
    1. Pheochromocytoma
    2. Adrenal Tumors >6cm
    3. Tumors >4cm with other criteria (including CT or MRI appearance)
    4. Completely resected adrenocortical carcinomas benefit from adjuvant mitotane (Lysodren®) on recurrence free survival (42 months) versus placebo (10-25 months) [9]
  4. Postoperative adrenocortical insufficiency often occurs
    1. Stress hormone (hydrocortisone) replacement therapy must be used
    2. For unilateral adrenalectomy, usually taper replacement therapy over time

References

  1. Grumbach MM, Biller BMK, Braunstein GD, et al. 2003. Ann Intern Med. 138(5):424 abstract
  2. Dluhy RG, Maher MM, Wu CL. 2005. NEJM. 352(10):1025 (Case Record) abstract
  3. Speiser PW and White PC. 2003. NEJM. 349(8):776 abstract
  4. Young WF Jr. 2007. NEJM. 356(6):601 abstract
  5. Stratakis CA, Sarlis N, Kirchner LS, et al. 1999. Ann Intern Med. 131(8):585 abstract
  6. Klibanski A, Stephen AE, Greene MF, et al. 2006. NEJM. 355(21):2237 (Case Record) abstract
  7. Udelsman R and Dong HY. 2000. NEJM. 343(20):1477 (Case Record)
  8. Edwards RJ, Moss T, Sandeman DR. 2003. Lancet. 362(9395):1541 (Case Report) abstract
  9. Terzolo M, Angeli A, Fassnacht M, et al. 2007. NEJM. 356(23):2372 abstract