Chapter 33: Adrenals

Operations on the adrenal glands are performed for primary hyperaldosteronism, pheochromocytoma, hypercortisolism (Cushing disease or Cushing syndrome), and adrenocortical carcinoma. These conditions are usually characterized by hypersecretion of one or more of the adrenal hormones. Less commonly, surgery may also be performed for nonfunctioning tumors or metastases.

The normal combined weight of the adrenals is 7-12 g. The right gland lies posterior and lateral to the vena cava and superior to the kidney (Figure 33–1). The left gland lies medial to the superior pole of the kidney, just lateral to the aorta and immediately posterior to the superior border of the pancreas. An important surgical feature is the remarkable constancy of the adrenal veins. The right adrenal vein, 2-5 mm long and several millimeters wide, connects the anteromedial aspect of the adrenal gland with the posterolateral aspect of the vena cava. The left adrenal vein is several centimeters long and travels inferiorly from the lower pole of the gland, joining the left renal vein after receiving the inferior phrenic vein. Variant venous drainage (multiple or anomalous veins) occurs in about 5% of glands and are more common for pheochromocytomas and larger tumors. The adrenal arteries are small, multiple, and inconstant. They usually come from the inferior phrenic artery, the aorta, and the upper pole branch of renal artery.

With the exception of rare nonsecreting cancers, indications for adrenal surgery result from hypersecretory states. Diagnosis and treatment begin with confirmation of a hypersecretory state (ie, measurement of excess cortisol, aldosterone, or catecholamines in blood or urine). In order to determine whether the problem originates in the adrenal, levels of the trophic hormone in question (ie, adrenocorticotropic hormone [ACTH] or renin) must be measured. If levels of the trophic hormone are suppressed but hormone secretion is excessive, autonomous secretion is proved. The next step, except in pheochromocytoma, is to determine the degree of autonomy, a process that usually distinguishes hyperplasias (which respond to most but not all controlling mechanisms) from adenomas and adenomas from cancers. In general, cancers are under little if any feedback control. If the primary problem is not in the adrenal, as in Cushing disease, treatment must be directed elsewhere when possible.

The major principles of adrenal surgery are as follows:

• Whenever possible, the surgeon must be certain of the diagnosis and the location of the lesion before undertaking the operation.

• The patient must be thoroughly prepared so he or she can withstand any metabolic problems caused by the disease or by the operation.

• The surgeon and consultants must be able to detect and treat any metabolic crisis that occurs during or after operation.

Currently, almost all adrenal tumors are identified preoperatively by localization studies such as CT and MRI, so very few operations require general exploration of the abdomen. This permits the use of minimally invasive surgery. Almost all adrenal tumors can be removed laparoscopically. Traditional open adrenalectomy is necessary only when the tumor is especially large (eg, > 8-10 cm, depending on the surgeon’s experience) or for locally invasive adrenocortical cancer where resection of lymph nodes or adjacent organs may be required.

Laparoscopic adrenalectomy can be performed using a transabdominal or retroperitoneal approach. Transabdominal laparoscopic adrenalectomy involves medial rotation of the spleen and pancreas (on the left) or the liver (on the right), using gravity to drop the viscera away from the adrenal. Retroperitoneal adrenalectomy involved the use of high insufflation pressure to maintain the space for dissection and to decrease bleeding during dissection. Although transabdominal approach is more suitable for larger tumors and the retroperitoneal approach better for bilateral adrenalectomy and for patients with abdominal adhesions, surgeon preference usually dictate the choice of surgical approach.

The traditional open surgical approach is used when laparoscopic expertise is not available or when required by the size and invasiveness of the tumor. The advantages of laparoscopic operation are so great that it is strongly preferred.

The open anterior approach (midline, subcostal, or “L” incision) allows wide exposure for large tumors but causes more pain and wound complications, and it requires longer hospitalization. The open posterior approach through the bed of the 11th or 12th rib has been superseded by the laparoscopic approach. Thoracoabdominal incision may be used for large or invasive tumors.

PRIMARY ALDOSTERONISM

General Considerations

Aldosterone, the most potent mineralocorticoid secreted by the adrenal cortex, regulates the body’s electrolyte composition, fluid volume, and blood pressure. Excess aldosterone increases total body sodium, decreases potassium levels, increases extracellular fluid volume (without edema), and increases blood pressure. Under normal conditions, ­aldosterone secretion is regulated by the renin-angiotensin system in a feedback fashion and is also stimulated transiently by ACTH.

In primary aldosteronism, aldosterone levels are elevated and renin levels are suppressed. In secondary hyperaldosteronism, increased aldosterone is due to increased renin secretion. Examples of secondary hyperaldosteronism include renovascular disease, renin-secreting tumors, and cirrhosis with low intravascular volume or diuretic use. Among the subtypes of primary aldosteronism, aldosterone-producing adenoma (APA, aldosteronoma) and idiopathic hyperaldosteronism (IHA) with adrenal hyperplasia are the most common types. Unilateral primary adrenal hyperplasia, aldosterone-producing adrenocortical carcinoma, and familial hyperaldosteronism (FH) (eg, FH type I-glucocorticoid-remediable hyperaldosteronism and FH type II) are rare. Surgery is beneficial only in patients with APAs and in patients with unilateral primary adrenal hyperplasia.

Primary aldosteronism in its classic form is characterized by hypertension, hypokalemia, increased aldosterone secretion, and suppressed plasma renin activity (PRA). However, hypokalemia is not required to make the diagnosis; recent studies have shown that many patients have a normal potassium level. Primary aldosteronism was once thought to be present in about 1% of patients with hypertension, but its prevalence has increased to 5%-13% based on various studies when plasma aldosterone concentration (PAC)-to-PRA was used to screen for hyperaldosteronism in patients with hypertension who were not hypokalemic. Although rare, normotensive primary aldosteronism has been described.

Aldosteronomas are usually solitary and small (0.5-2 cm). They have a characteristic golden-yellow color when sectioned. Tumor cells typically have heterogeneous cytomorphology, resembling those of all three zones of the adrenal cortex, including hybrid cells having cytologic features of the zona glomerulosa and zona fasciculata. Hyperplasia is also often seen in glands harboring adenomas.

Clinical Findings

Aldosterone facilitates the exchange of sodium for potassium and hydrogen ions in the distal nephron. Therefore, when aldosterone secretion is chronically increased, serum potassium and hydrogen ion concentrations fall (hypokalemia and alkalosis), total body sodium rises, and hypertension results.

A. Symptoms and Signs

Symptoms, if present, are usually those of hypokalemia and depend on the severity of potassium depletion. Patients complain of a sense of malaise, muscle weakness, polyuria, polydipsia, cramps, and paresthesias. Tetany and hypokalemic paralysis occur rarely. Headaches are common. Hypertension is usually moderate to severe and may be refractory to medical therapy, but advanced retinopathy is rare. Although extracellular fluid volume is increased, edema is not seen unless renal failure occurs.

B. Laboratory Findings

1. Screening test

Primary aldosteronism should be suspected in patients with hypertension and hypokalemia—either spontaneous or following the administration of diuretics—and in patients with refractory hypertension. The diagnostic evaluation should start with screening tests. A simple ambulatory test determines the ratio of PAC, in nanograms per deciliter, to PRA, in nanograms per milliliter per hour, performed in the morning in a seated ambulant patient. A ratio greater than 20 with a PAC greater than 15 ng/dL suggests primary aldosteronism and warrants confirmatory biochemical studies. Hypertensive individuals without primary aldosteronism usually have ratios of less than 20. If the patient is taking an aldosterone receptor antagonist spironolactone or eplerenone, the data are uninterpretable, and estrogens increase PACs by increasing angiotensinogen. These agents should be discontinued for 6 weeks before the workup.

Many medications affect PAC and PRA. For example, PAC is decreased by angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), central alpha-2 agonists such as clonidine, dihydropyridine (DHP) calcium channel antagonists such as amlodipine, and beta-blockers. PRA is increased by ACE inhibitors, ARBs, and DHP-calcium channel antagonists. These medications should be discontinued for 2 weeks if necessary. Peripheral α-adrenergic blockers such as doxazosin, terazosin, prazosin, hydralazine, and non-DHP calcium channel blocker such as verapamil are the preferred antihypertensive agents during evaluation. In many patients, it is unwise to withdraw antihypertensive medications, and one must be content with imperfect data.

2. Confirmatory test

If the screening test is positive, failure to suppress aldosterone secretion with sodium loading will confirm the diagnosis of primary aldosteronism in most patients. Normally aldosterone can be suppressed by oral salt loading or intravenous sodium chloride infusion. The patient should consume a high-sodium diet (5000 mg of sodium for 3 days) or be supplemented with NaCl tablets (2-3 g with each meal) if necessary. A 24-hour urine sample is collected for aldosterone and sodium on the third day. Serum potassium should be monitored because the high-salt diet increases kaliuresis, and potassium chloride should be supplemented to avoid hypokalemia, which interferes with the test results by decreasing aldosterone secretion and may cause cardiac arrhythmias. Urinary aldosterone excretion higher than 12-14 μg/24 h distinguishes most patients with primary aldosteronism from those with essential hypertension on a high-salt diet, as confirmed by urinary sodium excretion exceeding 200 mEq/24 h. Alternatively, a PAC higher than 10 ng/mL after an infusion of 2 L of normal saline over 4 hours is also consistent with primary aldosteronism.

Differential Diagnosis

Once the diagnosis is established, the surgically correctable forms—APA (aldosteronoma), constituting approximately 35% of primary aldosteronism, and the rare unilateral primary adrenal hyperplasia—should be distinguished from IHA, comprising approximately 65% of primary aldosteronism, due to bilateral adrenal hyperplasia, for which medical therapy is the best management. Aldosteronoma and IHA are the most common subtypes. Compared with those with IHA, patients with aldosteronoma have more severe hypertension, more severe hypokalemia, higher aldosterone secretion (> 20 ng/dL), higher 18-hydroxycorticosterone concentrations (> 100 ng/dL), and are younger. Interestingly more than one third of aldosteronomas have a somatic KCNJ5 gene mutation.

Glucocorticoid-remediable hyperaldosteronism (FH type I) is inherited in an autosomal dominant fashion. The genetic defect results in a chimeric gene. The mutated gene juxtaposes the promoter for expression of the 11-hydroxylase gene, which is ACTH-responsive, with the coding sequence of the aldosterone synthase gene. This leads to aldosterone production under ACTH stimulation in the zona fasciculata. Glucocorticoid therapy reverses this type of hyperaldosteronism. These patients have a family history of onset of hypertension at an early age. The diagnosis can be established by genetic testing. Measurement of 24-hour urine 18-hydroxycortisol and 18-oxocortisol levels is less reliable. The molecular basis for FH type II is not clear although it is also inherited in an autosomal dominant fashion.

Aldosterone-secreting adrenocortical carcinoma is rare and should be suspected if the tumor is larger than 4 cm, especially if it also secrets cortisol and intermediate metabolites.

Tumor Localization

An APA can frequently be demonstrated by high-resolution CT or MRI scanning. Small aldosteronomas can be missed, and in such cases, a patient with a small aldosteronoma not seen on CT may be misdiagnosed as having adrenal hyperplasia. Aldosteronomas that coexist with nonfunctional adenomas can be mislabeled as adrenal hyperplasia because of multinodularity or bilateral masses on CT. Small abnormalities on CT scans may represent hyperplasia rather than true aldosteronomas. Therefore, unless an unequivocal unilateral tumor, preferably larger than 1 cm, is present on the CT scan and the contralateral gland is normal, the diagnosis and localization of aldosteronoma is not certain. When in doubt, adrenal vein sampling should be done. Blood is sampled from the adrenal veins and the inferior vena cava for aldosterone and cortisol levels at baseline and after ACTH infusion. Proper catheter placement is confirmed by finding high cortisol levels in adrenal venous blood compared with the inferior vena cava. Corrected aldosterone levels are calculated from the ratio of aldosterone to cortisol in each venous sample. A lateralization ratio of the corrected aldosterone level higher than 4 indicates unilateral aldosterone secretion, thereby confirming a diagnosis of aldosteronoma in most patients. Adrenal vein sampling is invasive and requires considerable skill and experience. The success rate for cannulating both adrenal veins is about 90% (60%-95% depending on experience of radiologists). Complication of venous sampling, such as adrenal hemorrhage can occur in 1% of patients. Some recommend adrenal vein sampling to be done routinely regardless of CT findings. Whereas others advocate using it selectively when CT scan findings are uncertain (no tumor, bilateral tumors, or small tumor < 1 cm in diameter).

Complications

Uncontrolled hypertension can lead to renal failure, stroke, and myocardial infarction. Severe hypokalemia can cause weakness, paralysis, and arrhythmia, especially in patients taking digitalis.

Treatment

The goal of therapy is to prevent the complications of hypertension and hypokalemia. Unilateral adrenalectomy is recommended for patients with aldosteronoma and medical therapy for those with IHA or those with aldosteronoma who are poor candidates for surgery.

A. Surgical Treatment

1. Preoperative preparation

Blood pressure and hypokalemia should be controlled before surgery. Spironolactone, a competitive aldosterone antagonist, has been the drug of choice. It blocks the mineralocorticoid receptor, promotes potassium retention, restores normal potassium concentrations, and reduces the extracellular fluid volume, thereby controlling blood pressure. Furthermore, it reactivates the suppressed renin-angiotensin-aldosterone system in the contralateral adrenal gland, reducing the risk of postoperative hypoaldosteronism. The medication should be continued to the day of operation. For additional information and medical regiments for preoperative preparation, see Medical Treatment section.

2. Surgery

Because aldosteronomas are almost always small and benign, laparoscopic adrenalectomy is the procedure of choice. It can be performed safely and with equally good results by several approaches. The lateral transabdominal approach uses gravity to help medially rotate the viscera (liver on the right and spleen and pancreas on the left) and exposes the adrenal gland. It is the most versatile approach since the anatomy is familiar to most abdominal surgeons. The posterior retroperitoneal approach is best in patients with prior upper abdominal operations, but the working space is more limited. Although some surgeons perform a subtotal resection for aldosteronoma, most excise the whole adrenal gland with the tumor. The surrounding adrenal tissue frequently appears hyperplastic. Small aldosteronomas may not be visible intraoperatively. Bilateral adrenalectomy is not indicated, since hypocortisolism will require steroid-replacement treatment. Patients with IHA should be treated medically.

3. Postoperative care

Occasional patients may develop transient aldosterone deficiency because of suppression of the contralateral adrenal gland by the hyperfunctioning adenoma. This is rare in patients treated with spironolactone preoperatively. Symptoms include postural hypotension and hyperkalemia. Adequate sodium intake is usually sufficient for treatment; rarely, short-term fludrocortisone replacement (0.1 mg/d orally) is required.

B. Medical Treatment

The goal is to control hypertension and hypokalemia. Spironolactone, a competitive aldosterone antagonist, has been the drug of choice. Initial dosages of 200-400 mg/d may be required to control hypokalemia and hypertension. Once blood pressure is normalized and hypokalemia is corrected, the dose can be tapered and maintained at about 100-150 mg/d. Spironolactone may have antiandrogenic side effects, such as impotence, gynecomastia, menstrual irregularity, and gastrointestinal disturbances. These potential side effects may make this medication less desirable for some patients. Unlike spironolactone, which also blocks androgen and progesterone receptors, eplerenone is a selective mineralocorticoid receptor antagonist and has fewer endocrine side effects. It has been approved for treatment of hypertension and for heart failure after myocardial infarction. Eplerenone may become the treatment of choice for primary aldosteronism because of its decreased side effects if it is proven as efficacious as spironolactone, in spite of its increased cost. Amiloride, 20-40 ng/d, a potassium-sparing diuretic, may be used alternatively or as a supplement to spironolactone. Other medications, such as ACE inhibitors, calcium-channel blockers, and diuretics, may be required to control hypertension.

Prognosis

Primary aldosteronism usually follows a prolonged and subtly changing course. Untreated hypertension may cause stroke, myocardial infarction, or renal failure.

Removal of an aldosteronoma normalizes potassium levels in nearly 100% of the patients, but hypertension is cured in about 50% of the patients. Persistent hypertension after operation is more common in overweigh men who preoperatively required more than three antihypertensive medications for more than 6 years, but residual hypertension is usually easier to control than before the operation. Essential hypertension and atherosclerosis due to chronic ­hypertension are contributing factors. Although patients with IHA should be treated medically, adrenalectomy is indicated for those with aldosteronoma because side effects of the medications and compliance make long-term medical treatment undesirable. The low morbidity, short hospitalization, and high success rate of laparoscopic adrenalectomy have made surgery preferable to long-term medical therapy.

General Considerations

Pheochromocytomas are tumors of the adrenal medulla and related chromaffin tissues elsewhere in the body (paragangliomas) that secrete epinephrine or norepinephrine, resulting in sustained or episodic hypertension and other symptoms of catecholamine excess.

Pheochromocytoma is found in less than 0.1% of patients with hypertension and accounts for about 5% of adrenal tumors incidentally discovered by CT scanning. Most pheochromocytomas occur sporadically without other diseases, but about one third are associated with various familial syndromes such as MEN2, NF1, VHL, and familial paraganglioma syndromes. Patients with multiple endocrine neoplasia (MEN)2A may have medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Those with MEN2B have medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, marfanoid habitus, and ganglioneuromatosis. Patients with neurofibromatosis type I have café au lait spots, neurofibromatosis, and pheochromocytoma. Patients with von Hippel–Lindau disease may have retinal hemangioma, hemangioblastoma of the central nervous system, renal cysts and carcinoma, pheochromocytoma, pancreatic cysts or neuroendocrine tumors, and epididymal cystadenoma. Familial paraganglioma syndromes are caused by mutations of the succinate dehydrogenase genes SDHx (SDHB, SDHD, SDHC, SDHA, and SDHAF2). All are associated with extra-adrenal paragangliomas. SDHB is particularly associated with malignant pheochromocytomas. These syndromes should be considered especially in young patients and in patients with multifocal, extra-adrenal, malignant, or recurrent tumors. Other genetic mutations associated with pheochromocytomas are TMEM127 and MAX. Because of the higher than previously expected prevalence of hereditary pheochromocytoma, all patients with pheochromocytoma should be considered for genetic counseling and testing. The specific genes tests should depend on clinical and biochemical findings and family history. Family members of patients who have been diagnosed with these syndromes also need screening to determine whether they are gene carriers and are at risk for developing the various tumors, including pheochromocytoma.

On pathologic examination, pheochromocytoma appears reddish-gray and frequently has areas of necrosis, hemorrhage, and sometimes cysts. The usual size is about 100 g, or 5 cm in diameter, but they can be as small as 2-3 cm or as large as 12-16 cm. Cells are pleomorphic, showing prominent nucleoli and frequent mitoses. Cytologic findings cannot be used to determine whether a pheochromocytoma is malignant or benign. The veins and capsules may also be invaded even in clinically benign tumors. Malignancy can only be diagnosed in the presence of metastases in nonchromoffin cell bearing tissues or invasion into surrounding tissues.

Clinical Findings

A. Symptoms and Signs

The clinical findings of pheochromocytoma are variable, and almost half of them come to attention because of an incidental finding of an adrenal tumor (incidentaloma) on CT or MRI scans performed to evaluate other diseases. Classically, the patient has episodic hypertension associated with the triad of palpitation, headache, and sweating. The patient may also complain of anxiety, tremors, weight loss, dizziness, nausea and vomiting, abdominal discomfort, constipation, and visual blurring. Rarely pheochromocytomas can secrete VIP causing severe diarrhea or ACTH causing Cushing syndrome. The physical examination may be unremarkable except during an attack, when pallor and excess sweating may be observed. Tachycardia, postural hypotension, and hypertensive retinopathy are other signs.

Hypertension, the most common feature of pheochromocytoma, occurs in 90% of patients. More than half have sustained hypertension, which may be mild to moderate, with or without other signs and symptoms of catecholamine excess, and the diagnosis may be missed. In some cases, basal blood pressure may not be elevated, and severe hypertension occurs only while the patient is under stress, such as general anesthesia or trauma. Patients with diastolic hypertension and postural hypotension who are not receiving antihypertensive medications may have pheochromocytoma. Hyperglycemia may occur because epinephrine raises blood glucose and norepinephrine decreases insulin secretion.

In children, hypertension is less prominent, and about 50% have multiple or extra-adrenal tumors. Paragangliomas due to SDHB mutations are more likely to metastasize. Pheochromocytomas occur in 40%-50% of patients with MEN2; they tend to be bilateral and multiple but are rarely extra-adrenal or malignant. Biochemical screening for gene carriers of hereditary pheochromocytoma should be performed routinely. Measurement of plasma free metanephrines (metanephrine and normetanephrine) is the most sensitive test for pheochromocytoma in familial syndromes.

B. Laboratory Findings

The diagnosis of pheochromocytoma is best confirmed either by 24-hour urinary fractionated catecholamines and metanephrines measured in the same collection or by plasma free metanephrines. Both tests have high diagnostic sensitivity and specificity (Figure 33–2). Plasma free metanephrines is more sensitive than the urine test, but it has a higher false-positive rate, especially in elderly patients. Urinary output of metanephrines and/or free catecholamines is elevated in more than 95% of patients with pheochromocytoma. In 80% of patients, the level exceeds twice normal. Measurement of urinary vanillylmandelic acid (VMA) is less sensitive, and this test should no longer be used. Assays using high-performance liquid chromatography (HPLC) reduce interference by drugs and diets, but HPLC assays differ among various testing labs, and many drugs and diets can potentially interfere with certain HPLC assays or affect the secretion and metabolism of catecholamines. Examples include ­acetaminophen, labetalol, vasodilators (nitroglycerin and nitroprusside), nifedipine, theophylline, stimulants (amphetamine, caffeine, nicotine, methylphenidate), many antipsychotics, antidepressants (especially tricyclic antidepressants), buspirone, prochlorperazine, and methyldopa. Interpretation of the study may also be affected by coffee, ethanol, bananas, radiographic dyes, drugs that contain catecholamines, and withdrawal from clonidine. These agents should be discontinued for 2 weeks before measuring urinary catecholamines and metanephrines. The interfering substances vary depending on the specific assays used, so a list and protocol for preparing the patient should be obtained from the specific laboratory. Liquid chromatography-­tandem mass spectrometry is a newer assay that has been shown to minimize drug interferences in the measurement of plasma and urinary metanephrines and may improve its diagnostic accuracy.

Overnight urinary collection and short collection periods following a paroxysm, indexed to creatinine, have also been used. Measuring plasma free metanephrines is 96%-100% sensitive and 85%-89% specific. Depending on the particular assay, caffeic acid found in coffee, acetaminophen, phenoxybenzamine, and tricyclic antidepressants may cause false-positive results. Provocative tests—using glucagon, histamine, or tyramine—are not accurate and are potentially dangerous; they are no longer used. Clonidine suppression tests are rarely used.

C. Tumor Localization

Localization studies should be performed only after biochemical studies have confirmed the diagnosis of a catecholamine-secreting tumor. Ninety percent of pheochromocytomas are found in the adrenal glands and most are larger than 3 cm in diameter. Of the extra-adrenal pheochromocytomas (also called paragangliomas), 75% are in the abdomen, 10% in the bladder, 10% in the chest, 2% in the pelvis, and 3% in the head and neck. Both CT and MRI can localize most pheochromocytomas. CT scan is less expensive and gives better anatomic details for the surgeons, but MRI avoids radiation exposure. Pheochromocytoma usually has a characteristic bright appearance on T2-weighted MRI. ¹²³I-MIBG scanning should be considered when searching for extra-adrenal, multiple, malignant, or metastatic pheochromocytomas. MIBG is more specific but less sensitive compared with CT or MRI for localization. PET-CT scans using various PET tracers have been studied. Compared to CT, MRI, and MIBG, 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET-CT is more sensitive for localizing metastatic paragangliomas in patients with SDHB mutations. Arteriography and fine-needle aspiration biopsy can precipitate a hypertensive crisis. They do not contribute to the diagnosis and are not indicated. Venous sampling for catecholamines is not indicated and can be misleading.

Differential Diagnosis

The differential diagnosis includes all causes of hypertension. Hyperthyroidism and pheochromocytoma have many features in common (weight loss, tremor, and tachycardia). The diagnosis of pheochromocytoma is easier if episodic hypertension is present. Acute anxiety attacks mimic the symptoms and may precipitate hypertensive episodes, but anxiety alone rarely produces severe hypertension. Carcinoid syndrome causing episodes of flushing may also be mistaken for pheochromocytoma. Urinary 5-HIAA level is usually markedly elevated, and CT scan may show liver metastases in patients with carcinoid syndrome. Labile essential hypertension is not associated with elevated catecholamine levels.

Pheochromocytoma in pregnancy, if not recognized, will kill half of the fetuses and nearly half of the mothers. Hypertension in pregnancy is usually ascribed to ­preeclampsia-eclampsia. The diagnosis of pheochromocytoma requires the same biochemical studies; MRI is indicated to localize the tumor when a biochemical diagnosis has been established. CT or MIBG is not used to avoid radiation exposure. α-Adrenergic and β-adrenergic blockers are well tolerated. Timing of the operation is individualized. If recognized early, the tumor is best removed early in the second trimester. Otherwise, α-adrenergic blockade is continued. A planned cesarean section at term is followed by laparoscopic adrenalectomy a few weeks postpartum.

Pheochromocytoma crisis may develop in patients with pheochromocytoma, usually precipitated by trauma, certain medications, surgery, or other procedures. It can also be triggered by glucocorticoids. Crisis usually occurs when α-adrenergic blockade has not been instituted. These patients may develop multisystem failure, especially cardiovascular complications. If pheochromocytomas crisis is not recognized, death is the usual result. Once pheochromocytoma is diagnosed, the patient should be stabilized and α-adrenergic blockade started. After adequate blockade (10-14 days), the pheochromocytoma can be resected either during the same hospitalization or the patient may be stabilized, discharged, and electively readmitted. Emergent operation is rarely necessary.

Complications

Pheochromocytoma causes complications because of hypertension, cardiac arrhythmia, and hypovolemia. The sequelae of hypertension are stroke, renal failure, myocardial infarction, and congestive heart failure. Sudden death can result from ventricular tachycardia or fibrillation. α-Adrenergic stimulation by the catecholamines causes vasoconstriction and a low total blood volume. The patient is therefore unable to compensate for a sudden loss of blood volume (bleeding) or catecholamines (tumor removal) and is at risk of cardiovascular collapse. Preoperative α-adrenergic blockade and restoration of blood volume can prevent these complications.

Treatment

A. Medical Treatment

Treatment with α-adrenergic blocking agents should be started as soon as the biochemical diagnosis is established. The aims of preoperative therapy are (1) to restore the blood volume, which has been depleted by excessive catecholamines; (2) to prevent a severe crisis, with its potential complications; and (3) to allow the patient to recover from cardiomyopathy. Close control of hypertension is necessary in order to keep blood volume normal.

Phenoxybenzamine, a nonselective α-adrenergic antagonist, has a long duration of action and is the preferred drug. It should be started at a dosage of 10 mg/12 h, and the dose should be increased by 10-20 mg every 2-3 days—as postural hypotension allows. Usual doses are 100-160 mg/d; however, dosages as high as 300 mg/d may be necessary. Most patients require 10-14 days of treatment, as judged by stabilization of blood pressure and reduction of symptoms. Nasal stuffiness is usually present when alpha blockade is well established. Calcium-channel blockers and competitive selective α-adrenergic blocking agents such as doxazosin and prazosin may also be effective. Metyrosine inhibits tyrosine hydroxylase and reduces catecholamine synthesis, and can be added to phenoxybenzamine as preoperative therapy.

β-Adrenergic blocking agents are often used to treat arrhythmias and tachycardia but should only be given after alpha blockade has been achieved. Otherwise, a hypertensive crisis may be precipitated because of the unopposed α-adrenergic effect of the catecholamines. Opioids should be avoided because they may stimulate histamine release and precipitate a crisis.

B. Surgical Treatment

The definitive treatment of pheochromocytoma is excision after preoperative localization and alpha-adrenergic blockade.

Smaller (< 5-6 cm) adrenal pheochromocytomas can be safely resected by laparoscopic adrenalectomy. Larger (> 8-10 cm), locally invasive and extra-adrenal tumors are technically more difficult and may require open resection.

During surgery, an arterial line is necessary for continuous blood pressure monitoring. Monitoring of pulmonary artery pressure is usually not necessary in patients who are well blocked.

Nitroprusside should be immediately available to treat sudden hypertension and beta-blockers to treat the cardiac dysrhythmias that may occur when the tumor is manipulated. Manipulation of the gland is less with laparoscopic adrenalectomy, which minimizes fluctuations in plasma catecholamine levels.

Very large malignant tumors may require a thoracoabdominal incision. Malignant pheochromocytomas may invade the adrenal vein or vena cava. Extra-adrenal pheochromocytomas (paragangliomas) are usually found along the abdominal aorta and in the organ of Zuckerkandl near the aortic bifurcation around the inferior mesentery artery. However, tumors have been found in widely scattered sites such as the bladder, the vagina, the mediastinum, the neck, and even skull base and pericardium. In general, extra-adrenal tumors should be localized with MIBG, CT, MRI, or PET-CT preoperatively to avoid a blind exploration.

In patients with MEN2 or VHL and bilateral pheochromocytomas, cortical-sparing subtotal adrenalectomy on the side of the smaller tumor may avoid postoperative adrenal insufficiency, though it increases the risk for recurrence. In patients with a known hereditary pheochromocytoma syndrome and a unilateral pheochromocytoma, prophylactic resection of the contralateral normal-appearing adrenal gland is not indicated, since bilateral adrenalectomy leads to lifelong hypoadrenalism requiring cortisol replacement. These patients should be followed with biochemical evaluations, and the contralateral adrenal gland should be resected only if pheochromocytoma develops.

Patients undergoing resection of pheochromocytoma who are not adequately prepared preoperatively may have hypertensive crises, cardiac arrhythmia, myocardial infarction, or acute pulmonary edema. In addition, these patients may experience intractable hypotension and die in shock after tumor removal. If the patient has been properly prepared with alpha-blockers, the changes in blood pressure will not be severe. Otherwise, intravenous infusion of large amounts of saline and vasopressors may be necessary to maintain blood pressure after the tumor is removed. Hypoglycemia may develop after tumor removal so blood glucose level should be checked until the patient is eating.

Prognosis

Patients with untreated pheochromocytoma are at high risk for complications from hypertensive crisis and cardiovascular disease, whereas the operative mortality rate is 0%-3%. Mild to moderate essential hypertension may persist after surgery. Second tumors in the remaining adrenal or metastatic tumors can occur years after excision of the primary pheochromocytoma; long-term follow-up is mandatory. Patients with pheochromocytoma should be offered genetic counseling and when appropriate tested for hereditary causes of pheochromocytoma. Long-term prognosis may depend on the mutation present (eg, risk for malignant pheochromocytoma in SDHB mutation gene carriers). Metastatic or recurrent malignant pheochromocytoma should be resected if possible to reduce the catecholamine load. Treatment with high-dose ¹³¹I-MIBG may be helpful in these patients.

General Considerations

Cushing syndrome is due to chronic glucocorticoid excess. It may be caused by excess ACTH stimulation or by adrenocortical tumors that secrete glucocorticoids independently of ACTH stimulation. Excess ACTH may be produced by pituitary adenomas (Cushing disease) or extrapituitary ACTH-producing tumors (ectopic ACTH syndrome). Cushing syndrome not dependent on ACTH is usually caused by primary adrenal diseases such as adrenocortical adenoma and micronodular or macronodular hyperplasia or carcinoma.

The natural history of Cushing syndrome depends on the underlying disease and varies from a mild, indolent disease to rapid progression and death.

Clinical Findings

A. Symptoms and Signs

See Table 33–1. The classic description of Cushing syndrome includes truncal obesity, hirsutism, moon facies, acne, buffalo hump, purple striae, hypertension, and diabetes, but other signs and symptoms are common. Weakness and depression are striking features. Weakness and other features are also seen after prolonged and excessive administration of adrenocortical steroids.

In children, Cushing syndrome is most commonly caused by adrenal cancers, but adenomas and nodular hyperplasia have been described. Cushing syndrome in children also causes growth retardation or arrest.

B. Pathologic Examination

The pathologic features of the adrenal gland depend on the underlying disease. Normal adrenal glands weigh 7-12 g combined. The hyperplastic adrenal glands in patients with Cushing disease weigh less than 25 g combined. In ectopic ACTH syndrome, the combined adrenal weight is greater—from 25 to 100 g.

Adrenal adenomas in Cushing syndrome range in weight from a few grams to over 100 g, usually over 3 cm in diameter, and are larger than APAs. The typical cells usually resemble those of the zona fasciculata. Variable degrees of anaplasia are seen, and differentiation of benign from malignant tumors is often difficult on the basis of cytology alone. These adrenal adenomas occur more frequently in women. Adrenal cancers are frequently very large—almost always over 5 cm in diameter. They are undifferentiated, invade the surrounding tissues, and metastasize via the blood stream.

Rare forms of ACTH-independent Cushing syndrome include ACTH-independent macronodular adrenal hyperplasia, which in some cases is due to aberrant expression of receptors in the adrenals that respond to stimuli other than ACTH. In these cases, the adrenal glands can be massively enlarged. Primary pigmented nodular adrenal disease or micronodular hyperplasia is associated with the syndrome of Carney complex that also includes cardiac myxoma and lentigines.

Rarely, ectopic adrenal tissue can be the source of excessive cortisol secretion. It has been found in various locations, most commonly near the abdominal aorta.

Cushing disease is caused by pituitary adenomas.

Ectopic ACTH syndrome is usually caused by small-cell lung cancer and neuroendocrine tumors (carcinoid tumors) of the pancreas, thymus, thyroid, prostate, esophagus, colon, and ovaries. Pheochromocytoma and malignant melanoma may also secrete ACTH.

C. Laboratory Findings

Since no single test is specific, a combination of tests must be used.

Normal subjects have a circadian rhythm of ACTH secretion that is paralleled by cortisol secretion. Levels are highest in the early morning and decline during the day to their lowest levels in the late evening. In Cushing syndrome, the circadian rhythm is abolished, and total secretion of cortisol is increased. In mild cases, the plasma cortisol and ACTH levels may be within the normal range during much of the day but abnormally high in the evening.

When Cushing syndrome is suspected, the first objective is to establish the diagnosis; the second is to establish the cause. An algorithm for the diagnosis is presented in Figure 33–3. When hypercortisolism is suspected, three tests are available as the initial tests to establish the diagnosis: overnight dexamethasone suppression test, measurement of 24-hour urinary free cortisol, and late night salivary cortisol sampling. Dexamethasone, 1 mg orally will suppress ACTH secretion and stop cortisol production in most healthy individuals. This low-dose dexamethasone, however, will not suppress excessive cortisol production from autonomous adrenocortical tumors or adrenals that are being stimulated by excess ACTH. Since dexamethasone does not cross-react in the assay for plasma cortisol, suppression of endogenous circulating cortisol is easily demonstrated. The test is done as follows: At 11 PM, the patient is given 1 mg of dexamethasone by mouth. A fasting plasma cortisol is measured the following morning between 8 and 9 AM. Suppression of plasma cortisol to 1.8 μg/dL (50 nmol/L) or less excludes Cushing syndrome. Higher cutoff levels have been recommended, but some patients with mild ACTH-dependent Cushing syndrome may be suppressed easily; thus, the response is falsely negative and the diagnosis of Cushing syndrome is missed. On the other hand, this low cutoff level increases the likelihood of a false-positive result. False-positive results are more common in patients with depression, alcoholism, physiologic stress, marked obesity, obstructive sleep apnea, or renal failure and in those taking estrogens or drugs that accelerate dexamethasone metabolism, such as phenytoin, rifampin, and phenobarbital. Estrogens increase cortisol-binding globulin and elevate total plasma cortisol concentrations. In these situations, measurement of 24-hour urinary free cortisol or salivary cortisol is preferred. Twenty-four-hour urinary cortisol directly measures the physiologically active form of circulating cortisol, integrates the daily variations of cortisol production, and is very sensitive and specific for the diagnosis of Cushing syndrome.

Late night salivary cortisol sampling can also assist in establishing the diagnosis of Cushing syndrome. The ­procedure involves chewing a cotton tube for 2-3 minutes between 11 PM and 12 AM. Salivary cortisol levels correlate highly with plasma and serum-free cortisol levels. One positive initial screening test result should be confirmed by a second initial screening test to establish the diagnosis. Once the diagnosis of Cushing syndrome is established, the next step is to determine the cause. Plasma ACTH measurement by immunoradiometric assay is the most direct method. A normal to elevated ACTH level is diagnostic of hypercortisolism due to pituitary adenoma or ectopic ACTH secretion. Suppressed ACTH levels are diagnostic of hypercortisolism due to a primary adrenal cause such as adenoma, carcinoma, or nodular hyperplasia.

The differential diagnosis of ACTH-dependent Cushing syndrome can be challenging. No test is perfect, and a combination of tests may be necessary. Since 90% of patients have Cushing disease, pituitary MRI is the first test to identify the source of ACTH secretion. However, 10% of normal adults have incidental pituitary lesions 3-6 mm in diameter on MRI, and many patients with Cushing disease have no detectable lesions. Lesions smaller than 3-4 mm are more likely to represent normal variation, artifacts, volume averaging, incidental nonfunctional adenomas, or cysts. An unequivocal pituitary lesion (ie, > 4-5 mm in diameter with decreased signal intensity on gadolinium) strongly suggests Cushing disease.

If the pituitary MRI does not show a definite lesion, the next step is inferior petrosal sinus sampling with corticotropin-releasing hormone (CRH) stimulation. Compared with other biochemical tests, such as high-dose dexamethasone suppression or CRH stimulation, petrosal sinus sampling is the most accurate way to identify an ACTH-secreting pituitary adenoma; the diagnostic accuracy is close to 100%. The test requires simultaneous bilateral venous sampling from the inferior petrosal sinuses. The inferior petrosal sinus connects the cavernous sinus to the jugular bulb and drains the pituitary. A central-to-peripheral ACTH ratio of 2 or greater without CRH stimulation is diagnostic of Cushing disease. CRH, 100 μg given intravenously as a bolus injection, can increase the diagnostic sensitivity to 100%; a peak central-to-peripheral ACTH ratio of 3 or greater is diagnostic of Cushing disease. The lack of a central-to-peripheral ACTH gradient is diagnostic of an ectopic ACTH-secreting tumor.

In Cushing syndrome caused by primary adrenal diseases, the plasma ACTH level is suppressed. Adenomas are usually 3-5 cm in diameter and secrete only cortisol. Adrenal carcinomas are typically larger than 5 cm in diameter, are usually rapidly progressive, and may cosecrete other hormones, such as adrenal androgens, deoxycorticosterone, aldosterone, and estrogens.

D. Imaging Studies

For Cushing syndrome caused by primary adrenal diseases, thin-section CT or MRI is able to detect virtually all of the adrenal tumors and hyperplasia. MRI of the sella is the imaging study of choice for pituitary adenomas. If a definitive adenoma is not seen, inferior petrosal sinus sampling with CRH stimulation can differentiate Cushing disease from ectopic Cushing syndrome. For ectopic Cushing syndrome, CT or MRI of the chest and abdomen may detect ACTH-secreting tumors. Bronchial carcinoids may be very small and difficult to find; high-resolution thin-cut CT of the chest is indicated. Occasionally, the source of an ectopic ACTH-secreting tumor cannot be determined (occult ectopic ACTH syndrome).

Complications

Severe or lethal complications may result from sustained hypercortisolism, including hypertension, cardiovascular disease, stroke, thromboembolism, infection, severe debilitating muscle wasting, and weakness. Psychosis is common. Death may also be caused by the underlying tumors, such as adrenal carcinoma, small cell lung cancer, and others causing ectopic ACTH syndrome.

The truncal obesity and muscle weakness in patients with Cushing syndrome predispose them to postoperative pulmonary complications. Atrophic skin and easy bruisability also predict poor wound healing.

Nelson syndrome, the progression of an ACTH-secreting pituitary adenoma following bilateral adrenalectomy for Cushing disease, occurred in as many as 30% of patients in the era when bilateral adrenalectomy was used as primary therapy. However, since transsphenoidal resection has become the initial procedure of choice for Cushing disease, and because MRI now allows accurate diagnosis of pituitary adenomas larger than 5 mm, Nelson syndrome occurs in less than 5% of patients.

These tumors in patients with Nelson syndrome are among the most aggressive of pituitary tumors, causing ­sellar enlargement and extrasellar extension. Plasma ACTH levels are markedly elevated. Patients are frequently hyperpigmented and hypopituitary, with symptoms of mass effects including headaches, visual field deficits, and even blindness from optic nerve compression. Removal of feedback control from hypercortisolism at the pituitary level probably explains the aggressiveness of these tumors.

Treatment

Resection is the best treatment for cortisol-producing adrenal tumors or ACTH-producing tumors. Other treatment options may be necessary to temporarily control hypercortisolism—or for patients not cured by resection or when complete resection is impossible.

A. Excision of Pituitary Adenoma

Patients with Cushing disease are usually treated by transsphenoidal microsurgical excision of the pituitary adenomas. Relief of symptoms is rapid, and the prognosis for adequate residual pituitary-adrenal function is good. Total or subtotal hypophysectomy may be performed in older patients if a discrete tumor is not found. Pituitary procedures fail in about 15%-25% of patients because of failure to find the adenoma, pituitary hyperplasia, or recurrence of adenoma. When pituitary surgery fails, the disease may respond to pituitary irradiation. In some patients, medical therapy or total adrenalectomy will be necessary. Because of the effectiveness of pituitary microsurgery, radiotherapy is usually not recommended as primary treatment for Cushing disease.

B. Adrenalectomy

Compared with patients with other adrenal tumors, those with severe Cushing syndrome are at a higher risk for postoperative complications such as wound infection, hemorrhage, peptic ulceration, and pulmonary embolism. Adrenalectomy, however, is usually successful in reversing the devastating effects of hypercortisolism.

Laparoscopic adrenalectomy causes less morbidity than open adrenalectomy and is preferred for benign hyperplasia or adenomas. Laparoscopic adrenalectomy for adrenocortical carcinoma is technically challenging. If necessary, the operation should be converted to laparotomy to achieve complete tumor resection without breaching the capsule. Local recurrence may be more common after laparoscopic resection for large and invasive cancer, especially if the capsule is breached during dissection.

Unilateral adrenalectomy is indicated for adrenal adenomas or carcinomas that secrete cortisol. The contralateral adrenal gland and the hypothalamic-pituitary-adrenal axis will usually recover from the suppression 1-2 years after the operation. Subtotal resection is not indicated because adenoma and carcinoma may not be readily distinguishable.

Total bilateral adrenalectomy is indicated for selected patients with Cushing disease or ectopic ACTH syndrome in whom the ACTH-secreting tumor cannot be found or resected. It is also indicated for patients with bilateral primary adrenal disease, such as pigmented micronodular hyperplasia or massive macronodular hyperplasia.

Bilateral adrenalectomy can almost always be accomplished by the laparoscopic approach.

Subtotal resection is not recommended in patients with Cushing syndrome, because it usually leaves inadequate adrenocortical reserve initially, and the disease frequently recurs with continuing ACTH stimulation. Total bilateral adrenalectomy with adrenal gland autotransplantation is rarely successful and offers little advantage over pharmacologic replacement.

C. Medical Treatment

Drugs are mainly used as adjuvant therapy. Hypercortisolism may be controlled with ketoconazole, metyrapone, or aminoglutethimide, all of which inhibit steroid biosynthesis. Ketoconazole is usually the first choice. A combination of drugs may be necessary to control hypercortisolism and to decrease dose-related side effects.

Mifepristone (RU 486), a progesterone and glucocorticoid receptor antagonist, is also effective, but it raises cortisol and ACTH levels, making it difficult to monitor the patient. Experience with the medication is still limited.

Mitotane is a dichlorodiphenyltrichloroethane derivative that is toxic to the adrenal cortex. It has been used with modest success in the treatment of adrenal hypersecretory states, especially adrenocortical carcinoma. Unfortunately, serious side effects are common at effective doses.

Pasireotide, a somatostatin analog, and cabergoline, a dopamine receptor (type 2) agonist, may be effective in controlling hypercortisolism in small subsets of patients with Cushing disease. Frequently, a combination of drugs is needed.

D. Postoperative Maintenance Therapy

For patients who require total adrenalectomy, lifelong corticosteroid maintenance therapy becomes necessary after total adrenalectomy. The following schedule is commonly used: no cortisol is given until the adrenals are removed during surgery. On the first day, give 50 mg of hydrocortisone intravenously every 6-8 hours. On the second day, give 25 mg every 6-8 hours. Thereafter, the dose should be tapered as tolerated. The same tapering process is used after ­excision of a unilateral cortisol-secreting adenoma, because the remaining adrenal may not function normally for months.

As the hydrocortisone dose is reduced below 50 mg/d, it is often necessary to add fludrocortisone (a mineralocorticoid), 0.1 mg daily orally if patients had bilateral adrenalectomy. The usual maintenance doses are about 15-20 mg of hydrocortisone and 0.1 mg of fludrocortisone daily. More than half the hydrocortisone dose is given in the morning.

Patients who have had a total bilateral adrenalectomy and are on maintenance therapy can develop addisonian crisis when under stress, such as general anesthesia or infection. Adrenal insufficiency causes fever, hyperkalemia, abdominal pain, and hypotension, and should be promptly recognized and treated with saline infusion and cortisol.

Prognosis

The prognosis is good after resection of benign adrenal adenomas, pituitary adenomas, or benign ACTH-secreting tumors. Patients with Cushing disease in remission after pituitary surgery have reversal of excess mortality. Symptoms and signs of hypercortisolism resolve, usually over months. Short-term adrenal insufficiency after surgery requires cortisol replacement. Cushing disease can recur after excision of a pituitary adenoma. An occult ACTH-secreting tumor may become apparent later and require removal.

Residual adrenal tissue or embryonic rests are present in up to 10% of patients after total adrenalectomy. Cushing syndrome can then recur if stimulation with ACTH continues.

The prognosis is extremely poor in patients with adrenocortical carcinoma and in those with malignant tumors causing ectopic ACTH syndrome.

In adults, hormonally active benign adrenal adenomas usually secrete aldosterone or cortisol. Virilizing tumors in women are more likely to be caused by ovarian tumors. Virilizing adrenal tumors are rare, and virilization is usually due to hypersecretion of adrenal androgens, mainly dehydroepiandrosterone (DHEA), its sulfate derivative (DHEAS), and androstenedione, all of which are converted peripherally to testosterone and 5-dihydrotestosterone. Very rarely, virilizing adrenal tumors secrete only testosterone.

The differentiation of benign from malignant adrenocortical tumors may be difficult when based on histologic features; some patients with histologically benign tumors may develop metastases, and others with histologically malignant tumors may never have recurrent disease. Malignancy is only definitely diagnosed from local or distant spread. Seventy percent of virilizing adrenal tumors exhibit ­malignant behavior. Adrenocortical carcinomas are usually large tumors with local spread or distant metastases. They often secrete multiple steroids, most commonly cortisol and androgens, leading to Cushing syndrome and virilization.

In children, adrenocortical tumors are rare, but virilization with or without hypercortisolism is the most frequent feature. Virilizing adrenal tumors are less likely to be malignant in children than in adults. Histologic features of malignancy do not always predict malignant behavior. Large tumors (> 100 g) have a worse prognosis.

Signs and symptoms of virilization include hirsutism, male-pattern baldness, acne, deep voice, male musculature, irregular menses or amenorrhea, clitoromegaly, and increased libido. Rapid linear growth with advanced bone age is common in children.

CT and MRI are used to image virilizing adrenal tumors. Resection is the only successful treatment.

Virilization can also be caused by congenital adrenal hyperplasia, an autosomal recessive disorder. The mutated genes encode enzymes essential for cortisol and mineralocorticoid synthesis. 21-Hydroxylase deficiency accounts for 90% of cases. The inhibition of cortisol synthesis leads to stimulated ACTH secretion, accumulation of precursors, and overproduction of androgens. Administration of glucocorticoids is the mainstay of treatment in patients with classic congenital adrenal hyperplasia. Mineralocorticoid replacement is also required. Corrective surgery may be needed in female infants born with ambiguous genitalia. The combination of antiandrogens, aromatase inhibitors, and lower dose glucocorticoid replacement to minimize the effect of excess androgen is being investigated. Adrenalectomy with lifelong steroid replacement is another approach in the most severely affected patients.

Estrogens are not normally synthesized by the adrenal cortex. Feminizing adrenal tumors are extremely rare and are almost always carcinomas. They are usually seen in men with feminization or in girls with precocious puberty. Vaginal bleeding may be the presenting symptom in adult women. Feminizing adrenal carcinomas frequently hypersecrete other hormones. The diagnosis is based on a finding of increased plasma estrogens. Ovarian tumors and administration of exogenous estrogen should be ruled out.

Definitive treatment is excision of the tumor. The prognosis is guarded.

Adrenocortical carcinomas are rare. More than half of patients have symptoms related to hypersecretion of hormones, most commonly Cushing syndrome and virilization. Feminizing and purely aldosterone-secreting carcinomas are rare. In some cases, hormone hypersecretion is subclinical and only found by biochemical studies. The adrenal mass may be palpable. The mean diameter of adrenal carcinoma is 12 cm (range, 3-30 cm). Adrenocortical carcinoma invades the surrounding tissues, and about half of the patients have metastases (lung, liver, and elsewhere) at the time of diagnosis. In those without local spread or distant metastases, a diagnosis of carcinoma based on cytologic features may be wrong.

The median survival is 25 months, and 5-year actuarial survival is 25%. Tumor stage at the initial operation predicts the prognosis. Surgery is the only treatment that potentially provides a cure; however, beneficial outcomes are confined to patients with localized disease. When grossly complete resection is possible, the 5-year survival is 50%. Thus, recurrence is common despite apparent complete resection due to micrometastases at initial presentation. Laparoscopic adrenalectomy is technically more difficult for adrenocortical carcinomas than for other adrenal tumors because the tumor is fragile and adjacent organs may have to be removed. Where the adrenal tumor is small, malignancy is uncertain, and the surgeon is technically capable, starting the operation laparoscopically is acceptable. However, the surgeon should have a low threshold for converting to open or hand-assisted adrenalectomy if a better operation could be accomplished that way. For local recurrent disease, reoperation is indicated and may prolong life. Patients with distant metastases at initial presentation usually die within 1 year. Resecting the adrenal tumor in these patients does not improve survival.

Mitotane, an adrenolytic agent, has been used as an adjuvant to surgery in patients with advanced adrenocortical carcinoma. It controls endocrine symptoms in 50% of patients, and the tumor regresses in some. Some cases of prolonged remission have been reported.

In patients who underwent complete primary resection, older reports of routine adjuvant mitotane therapy postoperatively did not confer definitive benefits. However, a recent large retrospective study showed that mitotane improved recurrence-free survival. Dose-related side effects (eg, gastrointestinal symptoms, weakness, dizziness, and somnolence) may limit its use. A variety of other chemotherapeutic agents has been tried with limited success. A recently completed international multicenter prospective randomized study showed combination chemotherapy of etoposide, doxorubicin, and cisplatin plus mitotane improved the rates of response and progression-free survival over that of mitotane plus streptozocin.

The role of radiation is limited and usually is for palliation, especially for bony metastases.

Adrenal tumors have traditionally been diagnosed after presentation with clinical symptoms of excess hormone secretion. However, the increased use of ultrasonography, CT, and MRI for various diseases in the abdomen has led to the discovery of what are referred to as adrenal incidentalomas. Most are small nonfunctioning adrenal cortical adenomas; some are functioning adenomas or pheochromocytomas with subclinical secretion of hormones; and some are adrenocortical carcinomas or metastases.

Incidentalomas are found in 4% of CT scans and 6% of random autopsies. The incidence increases with age. Based on a review of 10 studies, subclinical Cushing syndrome and Cushing syndrome account for 6.4% of incidentalomas, pheochromocytoma 3.1%, adrenocortical carcinoma 1.8%, metastatic carcinoma 0.7%, and aldosteronoma for 0.6% (Table 33–2). Thus, 90% of the patients have presumed nonfunctioning cortical adenomas. Simple adrenal cysts, myelolipomas, and adrenal hemorrhages can be identified by the CT characteristics alone. Adrenal cysts can be large but are rarely malignant. Adrenal hemorrhage may occur in preexisting adrenal tumors.

The major issues in managing a patient with an incidentaloma is to determine whether the tumor is hormonally active and whether it is a cancer; either would be an indication for resection. All functioning tumors should be excised. Large nonfunctioning tumors also should be excised because of the increased risk of cancer. Small nonfunctioning tumors are almost always benign adenomas; they can be followed with serial CT scans checking for changes in size. Since most incidentalomas are nonfunctioning adenomas, the workup should be selective to avoid unnecessary expense and ­procedures.

The workup should include a complete history and physical examination with specific reference to a history of previous malignancy and signs and symptoms of Cushing syndrome or pheochromocytoma. Hyperaldosteronism, pheochromocytoma, and virilizing or feminizing adrenocortical carcinoma should be investigated. Further laboratory studies may be indicated depending on the clinical presentation.

All patients—even those who do not have hypertension—should have a 24-hour urine collection for fractionated catecholamines and metanephrines or plasma free metanephrines to search for pheochromocytoma; the risk of unrecognized pheochromocytoma is high, and the hypertension may be absent or episodic. Most pheochromocytomas are over 2 cm in diameter and characteristically bright on T2-weighted MRI. Almost half of pheochromocytomas are found incidentally because of CT or MRI scans obtained for other indications.

Subclinical Cushing syndrome refers to autonomous cortisol secretion in patients without typical signs and symptoms of Cushing syndrome. Autonomous cortisol secretion is best assessed by overnight 1 mg dexamethasone suppression test.

Patients with subclinical Cushing syndrome may experience an addisonian crisis if the tumor is resected and glucocorticoid replacement is not adequate.

Patients who are hypertensive should also have plasma aldosterone and PRA measured to screen for primary hyperaldosteronism.

If the above studies show that the tumor is nonfunctional, the size and imaging characteristics of the tumor and the patient’s overall medical condition should determine the appropriate treatment. Nonfunctioning adrenal tumors larger than 5 cm in diameter should usually be removed because of higher risk of cancer. Nonfunctioning adrenal tumors smaller than 3 cm that are homogeneous and have low density on CT or MRI are unlikely to be cancers and can be safely followed. The patient’s age and overall medical condition and the CT scan findings will usually determine whether a tumor 3-5 cm in size should be resected. High density, delayed wash out of contrast, irregular borders, and heterogeneity make pheochromocytoma, adrenocortical carcinoma, and metastases more likely.

In patients with a previously treated malignancy such as lung or breast cancer, the chance of an adrenal tumor being metastatic is greater than 50% and even greater if the adrenal mass is larger than 3 cm. CT-guided fine-needle aspiration biopsy is rarely necessary, but can be used to diagnose metastatic cancer if it will change management of the patient. Fine-needle aspiration of an adrenocortical cancer may not be diagnostic, and breaching the capsule risks local spread of cancer. Needle biopsy of an unexpected pheochromocytoma can precipitate pheochromocytoma crisis. Biochemical screening for pheochromocytoma should be performed prior to biopsy. Resection of a solitary adrenal metastasis from a primary lung cancer may improve long-term survival (to about 25% at 5 years) if there are no other clinically obvious metastases. Patients with a metachronous solitary adrenal metastasis are more likely to benefit from adrenalectomy than are those with a synchronous metastasis. Patients with adrenal metastases from melanoma or renal cell carcinoma also benefit from resection even when there are other foci of metastases. Adrenal metastasis can be resected laparoscopically with minimal risk of local recurrence.