Chapter 31. Disorders of the Adrenal Glands

Disorders of the adrenal glands result in classic endocrine syndromes such as Cushing's syndrome, hyperaldosteronism, and catechol excess from pheochromocytoma (Figure 31–1). The diagnosis of these disorders requires careful endocrine evaluation and imaging with computed tomography (CT) or magnetic resonance imaging (MRI).

In addition, many adrenal lesions are discovered on cross-sectional imaging performed for other reasons. These “incidentalomas” require metabolic evaluation and assessment to determine their need for treatment.

Cushing's Syndrome

Cushing's syndrome is the clinical disorder caused by overproduction of cortisol. Most cases (80%) are due to bilateral adrenocortical hyperplasia stimulated by overproduction of pituitary adrenocorticotropic hormone (ACTH, corticotropin), known as Cushing's disease. About 10% of cases are due to the ectopic production of ACTH from nonpituitary tumors. Ectopic ACTH production occurs most frequently in small-cell lung carcinoma; other tumors producing ACTH include carcinoids (lung, thymic, gastrointestinal tract), islet cell tumors of the pancreas, medullary thyroid carcinoma, pheochromocytoma, and small-cell carcinoma of the prostate. Adrenal adenoma is the cause in 5% of cases and carcinoma in 5%. In children, adrenocortical carcinoma is the most common cause of Cushing's syndrome.

Pathophysiology

Overproduction of cortisol by adrenocortical tissue leads to a catabolic state. This causes liberation from muscle tissue of amino acids, which are transformed into glucose and glycogen in the liver by gluconeogenesis. The resulting weakened protein structures (muscle and elastic tissue) cause a protuberant abdomen and poor wound healing, generalized muscle weakness, and marked osteoporosis, which is made worse by excessive loss of calcium in the urine.

In addition, glucose is transformed largely into fat and appears in characteristic sites such as the abdomen, supraclavicular fat pads, and cheeks. There is a tendency to diabetes, with an elevated fasting plasma glucose level in 20% of cases and abnormal glucose tolerance in 80% of patients.

The cortisol excess also suppresses the immune mechanisms, making patients susceptible to infection. Inhibition of fibroblast function by excess cortisol further interferes with wound healing.

Hypertension is present in 90% of cases. Although the aldosterone level is not usually elevated, cortisol itself exerts a hypertensive effect when present in excessive amounts, as does 11-deoxycorticosterone. The hypertension may be accompanied by manifestation of mineralocorticoid excess (hypokalemia and alkalosis), especially in patients with ectopic ACTH syndrome or adrenocortical carcinoma.

Pathology

The cells in adrenal hyperplasia resemble those of the zona fasciculata of the normal adrenal cortex. Frank adenocarcinoma reveals pleomorphism and invasion of the capsule, the vascular system, or both (Figure 31–2). Local invasion may occur, and metastases are common to the liver, lungs, bone, or brain. Histologic differentiation between adenoma and adenocarcinoma is frequently difficult.

In the presence of adenoma or malignant tumor, atrophy of the cortices of both adrenals occurs because the main secretory product of the tumor is cortisol, which inhibits the pituitary secretion of ACTH. Thus, although the tumor continues to grow, the contralateral adrenal cortex undergoes atrophy.

Clinical Findings

Symptoms and Signs (Figures 31–3 and 31–4)

The presence of at least three of the following strongly suggests Cushing's syndrome:

1. Obesity (with sparing of the extremities), moon face, and fat pads of the supraclavicular and dorsocervical areas (buffalo hump).

2. Striae (red and depressed) over the abdomen and thighs.

3. Hypertension (almost always present).

4. Proximal myopathy with marked weakness, especially in the quadriceps femoris, making unaided rising from a chair difficult.

5. Emotional lability, irritability, difficulty in sleeping, and sometimes psychotic personality.

6. Osteoporosis (common), with back pain from compression fractures of the lumbar vertebrae as well as rib fractures.

7. In 80% of cases, postprandial hyperglycemia is present, and in 20%, there is an elevated fasting plasma glucose level.

8. To a variable extent, there are features of adrenal androgen excess in women with Cushing's syndrome; these are absent in the case of adenoma, most severe with carcinoma, and present to an intermediate degree with Cushing's disease. They consist of recession of the hairline, hirsutism, small breasts, and generalized muscular overdevelopment, with deepening of the voice.

It is not possible to differentiate the cause from the clinical presentation alone.

Laboratory Findings

The leukocyte count may be elevated to the range of 12,000–20,000/μL, usually with fewer than 20% lymphocytes. Polycythemia is present in over half the cases, with the hemoglobin ranging from 14 to 16 g/dL. Anemia, however, may occur in patients with malignant tumors ectopically secreting ACTH.

Blood chemical analyses may show an increase in serum Na+ and CO2 levels and a decrease in serum K+ levels. Hyperglycemia may occur.

Specific Tests for Cushing's Syndrome

The following tests are performed to determine whether the patient has Cushing's syndrome.

1. 24-Hour urinary cortisol level—Urine cortisol is measured in a 24-hour urine collection (normal range, 10–50 μg/24 h). A urine cortisol value more than twofold elevated is typical of Cushing's syndrome. False-positive elevations can occur in acute illness, depression, and alcoholism. However, obesity does not raise the level of urinary-free cortisol above normal.

2. Suppression of ACTH and plasma cortisol by dexamethasone—Dexamethasone in low doses is used to assess the feedback suppression of ACTH and cortisol production by glucocorticoids. If dexamethasone is given at 11 pm, ACTH is suppressed in normal persons but not in those with Cushing's syndrome. Dexamethasone is useful because it has 30 times the potency of cortisol as an ACTH suppressant and it is not measured in current plasma or urine cortisol methods.

The procedure is to give 1 mg of dexamethasone by mouth at 11 pm and to draw blood at 8:00 to 9:00 am for measurement of plasma cortisol. If the level is <5 μg/dL (normal is 5–20 mg/dL), Cushing's syndrome can be ruled out. If the value is >10 μg/dL, Cushing's syndrome is present. A level in the range of 5–10 μg/dL is equivocal, and the test should be repeated or the urine cortisol may be measured.

Women taking birth-control pills have high plasma cortisol levels because, as in pregnancy, the estrogen stimulates production of cortisol-binding globulin. The pills must be withheld for at least 3 weeks before the dexamethasone suppression test. Other conditions causing false-positive responses are acute illness, depression, and alcoholism. Also, about 15% of obese patients do not suppress cortisol with this test.

Specific Tests for Differentiation of Causes of Cushing's Syndrome

The various causes of Cushing's syndrome can be determined with great accuracy (95% of cases).

1. Plasma ACTH level—If the diagnosis of Cushing's syndrome has been established, this test will differentiate ACTH-dependent causes (Cushing's disease and the ectopic ACTH syndrome) from adrenal tumors, which are ACTH independent. The normal range is 10–50 pg/mL. Patients with Cushing's disease have ACTH levels that range from 10 to 200 pg/mL; in the ectopic ACTH syndrome, levels are usually >200 pg/mL; and patients with adrenal tumors have suppressed ACTH levels (<5 pg/mL).

2. Plasma androgen levels—In patients with adrenal adenomas, androgen levels are normal or low, and in adrenocortical carcinoma, these levels are often markedly elevated.

X-Ray Findings and Special Examinations

Localization of Source of ACTH Excess

When tests suggest Cushing's disease or the ectopic ACTH syndrome and an elevated plasma level of ACTH is present, the source of ACTH must be identified. Because the great majority of these patients have Cushing's disease and because most of the patients with ectopic ACTH secretion have an obvious malignancy, the first step is to perform pituitary MRI. These are positive in 50–60% of patients with Cushing's disease; in the remainder, the diagnosis should be established by the sampling of ACTH levels in the venous drainage of the anterior pituitary, that is, the cavernous sinuses and inferior petrosal sinuses. If the MRI and venous sampling do not reveal a pituitary source of ACTH, CT scans of the chest and abdomen are used to localize an ectopic tumor.

Localization of Adrenal Lesions

Patients with Cushing's syndrome with suspected adrenal tumors and suppressed ACTH levels should undergo a CT scan of the abdomen with 3-mm sections through the adrenals. Adrenal tumors causing Cushing's syndrome are usually >3 cm in diameter (Figure 31–5) and are therefore easily visualized. Adenomas are usually 3–6 cm in diameter; carcinomas are usually >5 cm in diameter (Figure 31–6) and are frequently locally invasive or metastatic to the liver and lungs at the time of diagnosis. In patients with adrenal tumors, the contralateral adrenal is suppressed and therefore appears atrophic or normal on CT scan. The finding of bilateral adrenal enlargement is typical of Cushing's disease or the ectopic ACTH syndrome. Ultrasound or MRI may also be used for adrenal localization, although these techniques do not appear to offer significant advantage over CT.

Treatment

Cushing's Disease

A pituitary microadenoma, which is the most common cause of bilateral adrenocortical hyperplasia, must be located and removed surgically. Transsphenoidal resection performed by an experienced neurosurgeon is the method of choice. Success is reported in >80% of cases, and in most instances, the endocrine functions of the pituitary gland are preserved.

Ectopic ACTH Syndrome

The treatment of these patients is difficult because most have an advanced malignancy and severe hypercortisolism. Removal of the primary tumor is clearly the therapy of choice; however, curative resection is limited to the few patients with benign tumors such as bronchial carcinoids. Patients with residual or metastatic tumors should be managed first with adrenal inhibitors, and if that is not successful, bilateral adrenalectomy should be considered.

Total Bilateral Adrenalectomy

Total bilateral adrenalectomy is indicated in patients with Cushing's disease in whom the pituitary tumor is not resectable and in whom medical therapy fails to control the cortisol excess. A laparoscopic approach to adrenalectomy is preferred, since it significantly decreases morbidity and length of hospital stay compared with open adrenalectomy. Bilateral adrenalectomy is also indicated in patients with ectopic ACTH syndrome who have life-threatening hypercortisolism that cannot be controlled by inhibitors of adrenal secretion.

Preoperative Preparation

Because removal of the source of excessive cortisol will inevitably lead to temporary or permanent adrenal insufficiency, it is of the utmost importance to administer cortisol preoperatively and to continue substitution therapy after surgery to control Addison's disease. In the postoperative period, the dose is tapered downward until oral medication provides sufficient control.

Postoperative Status

The patient feels moderately well following removal of the source of excess ACTH or adrenalectomy or while receiving a high dose of hydrocortisone in excess of the usual daily output of approximately 20 mg. It is important to reduce the steroid substitution gradually over a period of several days. On the day of operation, 200 mg of cortisol is given; the dosage is then reduced gradually on successive days (150, 100, 80, 60, and 40 mg) until a maintenance dosage of 20–30 mg cortisol combined with 0.1 mg fludrocortisone is reached.

Adrenal Adenoma and Adenocarcinoma

Virtually all adrenal adenomas and smaller adrenal carcinomas are now removed laparoscopically, again allowing decreased hospital stay and more rapid recovery from surgery. Most patients now have a 1-day hospitalization after laparoscopic adrenalectomy if their metabolic management allows. There is some emerging evidence that select small adrenal tumors can be percutaneously ablated with radiofrequency ablation (RFA). The long-term efficacy of this approach is not known. Adrenal carcinomas that are large, locally invasive or involve the inferior vena cava are best approached by an open operation.

Preoperative Preparation

Preoperative preparation is the same as that for bilateral hyperplasia, since, in this case, the remaining adrenal gland will be atrophic and thus the patient will be hypoadrenal.

Postoperative Treatment and Follow-Up

Cortisol is administered perioperatively in the doses described earlier and then tapered to a replacement dose of 20–30 mg/day. Hydrocortisone is given orally in a dosage of 10 mg three times daily initially and reduced within 2–3 weeks to 10 mg daily given at 7 or 8 am. Substitution therapy may be necessary for 6 months to 2 years depending on the rate of recovery of the residual gland. Mineralocorticoid therapy is rarely necessary, since the atrophic adrenal usually produces sufficient aldosterone. Patients with adrenocortical carcinoma are usually not cured by surgery and require additional therapy.

Medical Therapy

There is no effective method of inhibiting ACTH secretion; however, adrenal hypersecretion can be controlled in many patients by inhibitors of adrenal cortisol secretion. Medical therapy is indicated in patients who either cannot undergo surgery (eg, because of debility, recent myocardial infarction) or in those who have had unsuccessful resection of their pituitary, ectopic, or adrenal tumor.

Ketoconazole is the current drug of choice; it blocks cortisol secretion by inhibiting P450c11 and P450scc. The total dose required is 800–1600 mg/day given in two divided doses. Side effects are adrenal insufficiency, abnormal liver function tests, and hepatotoxicity in a few patients.

Metyrapone may be used alone or may be added if ketoconazole alone is unsuccessful in normalizing cortisol levels. The usual dosage is 1–4 g daily given in four divided doses.

Aminoglutethimide and trilostane also inhibit adrenal secretion, but they are uncommonly used at present.

Mitotane (o,p9´-DDD, Lysodren) is both an inhibitor of adrenal secretion and a cytotoxic agent that damages adrenocortical cells. It is used almost exclusively in patients with residual adrenocortical carcinoma, in whom it helps to reduce cortisol hypersecretion. The usual dosage is 6–12 g daily in three to four divided doses. About 70% of patients achieve a reduction in steroid secretion and 35% achieve a reduction in tumor size; however, there is no convincing evidence that the drug prolongs survival. Side effects occur in 80% of patients and include nausea, vomiting, diarrhea, depression, and somnolence.

Prognosis

Treatment of hypercortisolism usually leads to disappearance of symptoms and many signs within days to weeks, but osteoporosis usually persists in adults, whereas hypertension and diabetes often improve. Cushing's disease treated by pituitary adenomectomy has an excellent early prognosis, and long-term follow-up shows a recurrence rate of about 10%. Patients with the ectopic ACTH syndrome and malignant tumors in general have a poor prognosis. Patients with benign lesions may be cured by resection of the tumor. Removal of an adrenal adenoma offers an excellent prognosis, and these patients are cured by unilateral adrenalectomy.

The outlook for patients with adrenocortical carcinoma is poor. The antineoplastic drug mitotane reduces the symptoms and signs of Cushing's syndrome but does little to prolong survival. Radiotherapy and chemotherapy are not successful in these patients.

Adrenal Androgenic Syndromes

Adrenal androgenic syndromes are more common in females. Congenital bilateral adrenal hyperplasia and tumors, both benign and malignant, may be observed. In contrast to Cushing's syndrome, which is protein catabolic, the androgenic syndromes are anabolic. In untreated cases, there is a marked recession of the hairline, increased beard growth, and excessive growth of pubic and sexual hair, in general, in both sexes. In males, there is enlargement of the penis, usually with atrophic testes; in females, enlargement of the clitoris occurs, with atrophy of the breasts and amenorrhea. Muscle mass increases and fat content decreases, leading to a powerful but trim figure. The voice becomes deeper, particularly in females; this condition is irreversible, because it is due to enlargement of the larynx. In both sexes, there may be increased physical sexual aggressiveness and libido.

Congenital Bilateral Adrenal Androgenic Hyperplasia

Pathophysiology

A congenital defect in certain adrenal enzymes results in the production of abnormal steroids, causing a disorder of sexual differentiation (DSD) in females and macrogenitosomia in males. The enzyme defect is associated with excess androgen production in utero. In females, the Müllerian duct structures (eg, ovaries, uterus, and vagina) develop normally, but the excess androgen exerts a masculinizing effect on the urogenital sinus and genital tubercle, so that the vagina is connected to the urethra, which, in turn, opens at the base of the enlarged clitoris. The labia are often hypertrophied. Externally, the appearance is that of severe hypospadias with cryptorchidism.

The adrenal cortex secretes mostly anabolic and androgenic steroids, leading to various degrees of cortisol deficiency depending on the nature of the enzyme block. This increases the secretion of ACTH, which causes hyperplasia of both adrenal cortices. The cortices continue to secrete large amounts of inappropriate anabolic, androgenic, or hypertensive steroids. Absence or reduction of the usual tissue concentration of various enzymes accounts for blocks in the adrenocortical synthetic pathways. 21-Hydroxylase deficiency, which is the most common cause of congenital adrenal hyperplasia, does not allow for the transformation of 17α-hydroxyprogesterone to cortisol. This common deficiency occurs in two forms: the salt-losing variety, with low-to-absent aldosterone, and the more frequent non–salt-losing type. Infants present with adrenal insufficiency and DSD; older children develop pseudoprecocious puberty and accelerated growth and skeletal maturation. Other enzymatic defects cause specific defects in sexual differentiation, adrenal insufficiency, hypertension, or salt wasting.

Clinical Findings

Symptoms and Signs

In newborn girls, the appearance of the external genitalia resembles severe hypospadias with cryptorchidism. Infant boys may appear normal at birth. The earlier in intrauterine life the fetus has been exposed to excess androgen, the more marked the anomalies.

In untreated cases, hirsutism, excess muscle mass, and, eventually, amenorrhea are the rule. Breast development is poor. In males, growth of the phallus is excessive. The testes are often atrophic because of inhibition of gonadotropin secretion by the elevated androgens. On rare occasions, hyperplastic adrenocortical rests in the testes make them large and firm. In most instances, there is azoospermia after puberty.

In both males and females with androgenic hyperplasia, the growth rate is initially increased so that they are taller than their classmates. At about age 9–10 years, premature fusion of the epiphyses caused by excess androgen causes termination of growth so that these patients are short as adults.

Laboratory Findings

Urinary 17-ketosteroid levels are higher than normal for sex and age, and plasma androstenedione, DHEA, DHEA-S, and testosterone are elevated. Plasma ACTH is also elevated, and in patients with the most common defect (ie, 21-hydroxylase deficiency), plasma 17α-hydroxyprogesterone is markedly elevated. Chromosome studies are normal.

X-Ray Findings

X-rays show acceleration of bone age.

CT Scans

Scans usually show the hypertrophied adrenals.

Treatment

It is imperative to make the diagnosis early. Treatment of the underlying cause is medical, with the goal of suppressing excessive ACTH secretion, thus minimizing excess androgenicity. This is accomplished by adrenal replacement with cortisol or prednisone in doses sufficient to suppress adrenal androgen production and therefore prevent virilization and rapid skeletal growth. In patients with mineralocorticoid deficiency, fludrocortisone (0.05–0.3 mg, depending on severity and age) together with good salt intake is necessary to stabilize blood pressure and body weight.

After puberty, the vagina can be surgically separated from the urethra and opened in the normal position on the perineum. Judicious administration of estrogens or birth-control pills feminizes patients.

Prognosis

If the condition is recognized early and ACTH suppression is begun even before surgical repair of the genital anomaly, the outlook for normal linear growth and development is excellent. Delay in treatment inevitably results in stunted growth. In some female patients, menses begins after treatment, and conception and childbirth can occur when the anatomic abnormalities are minimal or have been surgically repaired.

Adrenocortical Tumors

Adrenocortical tumors producing androgens are most frequently carcinomas; however, a few benign adenomas have been reported. Most of the carcinomas also hypersecrete other hormones (ie, cortisol or 11-deoxycorticosterone), and thus, the clinical presentation is variable. Female patients present with androgen excess, which may be severe enough to cause virilization; many of these patients also have Cushing's syndrome and mineralocorticoid excess (hypertension and hypokalemia). In adult males, excess androgens may cause no clinical manifestations, and diagnosis in these patients may be delayed until there is abdominal pain or an abdominal mass. These patients may also present with Cushing's syndrome and mineralocorticoid excess.

The Hypertensive, Hypokalemic Syndrome (Primary Aldosteronism)

Excessive production of aldosterone, due mostly to aldosteronoma or spontaneous bilateral hyperplasia of the zona glomerulosa of the adrenal cortex, leads to the combination of hypertension, hypokalemia, nocturia, and polyuria. A syndrome resembling nephrogenic diabetes insipidus may occur as a result of reversible damage to the renal collecting tubules. The alkalosis may produce tetany.

Pathophysiology

Excessive aldosterone, acting on most cell membranes in the body, produces typical changes in the distal renal tubule and the small bowel that lead to urinary potassium loss together with increased renal sodium reabsorption and hydrogen ion secretion. This results in potassium depletion, metabolic alkalosis, increased plasma sodium concentration, and hypervolemia. With low serum levels of potassium, the concentrating ability of the kidney is lowered and the tubules no longer respond to the administration of vasopressin by increased reabsorption of water. Finally, impairment of insulin release secondary to potassium depletion increases carbohydrate intolerance in about 50% of cases.

Plasma renin and, secondarily, plasma angiotensin are depressed by excess aldosterone as a result of blood volume expansion. Early in the course of excess aldosterone production, there may be hypertension with a normal serum potassium level. Later, the potassium level will be low as well, and this suggests the diagnosis.

Clinical Findings

Symptoms and Signs

Hypertension is usually the presenting manifestation, and the accompanying hypokalemia suggests mineralocorticoid excess. Headaches are common, nocturia is invariably present, and rare episodes of paralysis occur with very low serum potassium levels. Numbness and tingling of the extremities are related to alkalosis that may lead to tetany.

Laboratory Findings

Before the tests (outlined later in the chapter) are done, one must ascertain that the patient is not taking oral contraceptives or other estrogen preparations, since these may increase renin and angiotensin levels and therefore aldosterone levels, thus raising the blood pressure artificially. Withdrawal of these medications for 1 week is mandatory. Diuretics must also be discontinued, since they lower blood volume and induce secondary aldosteronism and hypokalemia. Also, if the patient is following a salt-restricted diet, aldosterone is normally elevated.

In true aldosterone excess, serum sodium is slightly elevated and CO2 increased, whereas serum potassium is very low, for example, ≤3 mEq/L. Urine and serum potassium determinations while the patient is receiving good sodium replacement provide a screening test. Potassium wasting is established if the urinary potassium level is <30 mEq/L/24 h, but the serum potassium level is low (≤3 mEq/L).

Definitive diagnosis rests on demonstration of an elevated urine or plasma aldosterone level. The initial step is to obtain simultaneous plasma aldosterone and plasma renin levels. If the aldosterone is elevated and the renin is suppressed with a ratio of <20:1, the diagnosis is established. Further confirmation can be obtained by demonstrating an elevated aldosterone level in a 24-hour urine sample.

Localization

A thin-section CT scan is the initial procedure and will localize an adenoma in approximately 90% of patients (Figure 31–7). If no adenoma is visualized, adrenal vein sampling of aldosterone and cortisol will correctly differentiate adenoma from hyperplasia in virtually all cases.

Differential Diagnosis

Secondary hyperaldosteronism may accompany renovascular hypertension. This too is associated with hypokalemic alkalosis; however, the renin level is elevated rather than suppressed. Essential hypertension does not cause changes in the electrolyte pattern. Definitive tests for hyperaldosteronism show negative results.

Treatment

Aldosteronoma

If the site of the tumor has been established, only the affected adrenal need be removed. Again, the procedure of choice is laparoscopic unilateral adrenalectomy, which is highly successful at resolving the metabolic defect.

Bilateral Nodular Hyperplasia

Most authorities do not recommend resection of both adrenals, since the fall in blood pressure is only temporary and electrolyte imbalance may continue. Medical treatment is recommended.

Medical Treatment

If surgery must be postponed, if the hypertension is mild in an older person, or if bilateral hyperplasia is the cause, one may treat medically with spironolactone (Aldactone), 25–50 mg orally four times daily. Amiloride, a potassium-sparing diuretic, may be given in doses of up to 20–40 mg/day. Other antihypertensive agents may also be necessary.

Prognosis

Following removal of an adrenal adenoma, the hypokalemia resolves. Seventy percent of patients become normotensive and 50% of patients show some lowering of hypertension. Bilateral nodular hyperplasia is not amenable to surgical treatment, and the results of medical treatment are variable.

Pheochromocytoma

Pheochromocytoma, derived from the neural crest, is one of the surgically curable hypertensive syndromes. There is no gender predilection. Pheochromocytoma accounts for fewer than 1% of cases of hypertension, but it is readily diagnosed and treated. It usually occurs spontaneously, but 10% of cases occur in patients with other disorders such as neurofibromatosis or familial syndromes such as multiple endocrine neoplasia type II or von Hippel–Lindau disease. The tumor is bilateral or extra-adrenal in 10% of cases in adults and in an even greater percentage in children and is then most often familial.

Clinical Findings

Symptoms and Signs

Hypertension may be either sustained and indistinguishable from ordinary blood pressure elevation, or paroxysmal, coming on for variable lengths of time and then subsiding to normal levels. Such attacks are usually precipitated by trigger mechanisms of various sorts, for example, emotional upsets or straining at stool.

Headache is a frequent complaint and is commensurate in severity with the degree of hypertension. Increased sweating is common. Tachycardia with palpitations may occur. Postural hypotension is a frequent finding, as a result of diminished plasma volume. Profound weakness may occur after an attack of hypertension. Weight loss is common.

Decreased gastrointestinal motility, anxiety, and psychic instability are also common and due to excess circulating catechols.

Biochemical Diagnosis

Free-fractionated plasma metanephrines and the 24-hour urinary-fractionated metanephrine tests are the mainstay for pheochromocytoma testing. The 2005 International Symposium on pheochromocytoma concluded that one of these two tests should be used for the initial diagnosis and screening for pheochromocytoma. The choice of biochemical test and whether to measure plasma or urine values remain controversial, but certain principles are clear: (1) Screening the hypertensive population is not recommended because of the low incidence of pheochromocytoma (about 0.1%). (2) Patients with pheochromocytoma who have sustained hypertension usually have clearly elevated catecholamines or metabolites in both urine and plasma. More than 80% of these patients have urine values two times greater than normal and total plasma catecholamine (Epi + Norepi) >2000 ng/L. Levels of this magnitude are unusual in patients without pheochromocytoma except in acute major illness. (3) Patients with only episodic hypertension may have normal random plasma catecholamine levels and normal 24-hour urine values. Evaluation of these patients must be directed to obtaining plasma catecholamine during an episode or having the patient collect timed urine values (eg, 2–4 hours) from the onset of an episode. (4) Suppression or stimulation tests are not recommended except in the rare instances when the diagnosis cannot be established by routine procedures.

Urinary Measurements

Urine measurements are the traditional diagnostic procedure. Normal values are shown in Table 31–1, and recent series in patients with pheochromocytoma are summarized in Table 31–2. These data suggest that measurements of metanephrines (MNs) or catecholamine are more useful than measurement of vanillylmandelic acid, since >80% of patients have values that were elevated more than two times. Spot urinary MNs and normetanephrines (NMNs) measured by radioimmunoassay are very simple and highly accurate. At a cutpoint of 500 ng/mL creatinine for either MN or NMN, Ito et al (1998) reported 100% sensitivity and specificity. Patients with only episodic symptoms or episodic hypertension should be studied with shorter urine collections if 24-hour studies are normal.

Plasma Catecholamines

These values, when measured by specific methods, are elevated in most patients with pheochromocytoma; however, the frequency of false-positive values limits diagnostic utility. Thus, in patients with pheochromocytoma and sustained hypertension, 85% have plasma catecholamine values >2000 ng/L. When patients with only paroxysmal hypertension are included, however, only 75% have values >2000 ng/L. Values between 600 and 2000 ng/mL are commonly obtained in stressed or anxious patients without pheochromocytoma. This is especially true if samples are obtained by venipuncture without prior placement of an intravenous line with the patient supine for 30 minutes. Plasma catecholamine measurements do have a role, though, because markedly elevated levels during an episode may be diagnostic; conversely, the finding of normal values during episodes of severe hypertension essentially excludes the diagnosis.

Tumor Localization

Pheochromocytomas are intra-abdominal in 98% of cases, and 90% are intra-adrenal (10% are bilateral, especially in familial syndromes). Extra-adrenal pheochromocytomas are usually within the abdomen and are located along the sympathetic chain, the periaortic areas, and at the bifurcation of the aorta. The tumors may also arise from the bladder. Extra-abdominal pheochromocytomas occur in posterior mediastinum, rarely in the heart or pericardium and rarely in the neck. Tumors <2 cm in diameter are rare, and most are >3 cm (Figure 31–8). Thus, the vast majority of pheochromocytomas are larger than the lower limits of resolution of current imaging techniques.

CT Scans

CT scan is currently the initial imaging procedure of choice; with current technology, it demonstrates virtually all intra-abdominal tumors and most of those that are extra-adrenal. Small tumors in the abdomen, pelvis, and chest may be obscured by surrounding structures. CT scan is not useful in determining whether an adrenal mass is in fact a pheochromocytoma (ie, if the adrenal mass is found coincidentally or the catechol determinations are equivocal, the adrenal mass could be a nonfunctioning adenoma). In this case, MRI or metaiodobenzylguanidine (MIBG) techniques may be useful.

MRI

The accuracy of detecting pheochromocytoma with MRI is as good as that obtained with CT, but the cost is greater at most institutions. MRI has the advantage of greater diagnostic specificity in that T2-weighted images or those obtained with gadolinium enhancement show greater signal intensity of the pheochromocytoma (compared with liver) than that obtained with adrenal adenomas. Limited data suggest that MRI may be superior to CT in localizing extra-adrenal tumors.

MIBG Scanning

Radionuclide scanning with MIBG has assumed a prominent role in the localization of pheochromocytomas. The compound is taken up by pheochromocytomas, ganglioneuromas, neuroblastomas, and other neural crest tumors, as well as some carcinoids. MIBG scans are positive in about 85–90% of patients with pheochromocytomas. MIBG scans have great utility in the localization of (1) small lesions, (2) extra-adrenal lesions, (3) bilateral lesions, and (4) metastatic deposits in patients with malignant tumors.

Diagnostic Strategy

Patients in whom there is a high index of clinical suspicion and those who have a greater than twofold elevation of urine catechols should undergo an adrenal CT. If the CT reveals a unilateral tumor and the contralateral adrenal is normal, the diagnosis is established. Patients with familial syndromes and those in whom cancer is suspected should undergo MIBG scanning to determine the extent of disease. If the adrenal CT is negative, MIBG scanning or MRI of the chest and abdomen is indicated to localize the tumor.

If the clinical suspicion is low and urine catechols are normal, imaging procedures are not indicated. However, it is not infrequent that patients at low risk on the basis of clinical manifestations have persisting mild elevations of catecholamines. In this situation, a single negative adrenal imaging procedure should suffice to terminate the evaluation, and the patient may be followed clinically and reevaluated if appropriate.

Therapy

Preoperative Management

Once the diagnosis of pheochromocytoma is established, the patient should be prepared for surgery to reduce the incidence of intraoperative complications and postoperative hypotension. The greatest experience is with the long-acting alpha-adrenergic blocker phenoxybenzamine, and its use has minimized surgical mortality and morbidity. The initial dosage is 10 mg twice daily, and patients may require hospitalization for bed rest and intravenous fluids to overcome the initially increased orthostatic hypotension that occurs in most patients. The dose may then be titrated upward every 2–3 days over several weeks until the blood pressure is <160/90 mm Hg and symptoms are abolished. Doses in the range of 100–200 mg/day are routinely used; however, no data are available that establish the superiority of these dosage levels. Higher doses of phenoxybenzamine are not associated with a higher risk of postoperative hypotension. Beta-blockers are generally unnecessary unless tachycardia and arrhythmias are present.

Metyrosine (alpha-methylparatyrosine), an inhibitor of catecholamine synthesis, is also useful for preoperative management, although current experience is limited. Initial dosage is 250 mg every 6 hours, and total daily dosages of 2–4 g are required. Preoperative treatment for 1–2 weeks appears to be sufficient to prevent operative complications. Metyrosine can be used in conjunction with alpha-blockers.

Successful preoperative management with prazosin, calcium channel blockers, and labetalol has been reported.

Surgery

Surgery is the mainstay of therapy for pheochromocytoma; it requires adequate preoperative control of symptoms and hypertension with alpha-blockers or metyrosine. Intraoperatively, hypertension is controlled with nitroprusside, and antiarrhythmics are used as needed. Adequate volume replacement is essential and in conjunction with preoperative medical therapy prevents postoperative hypotension.

If CT and MIBG show only a solitary adrenal lesion in patients with sporadic disease, a unilateral laparoscopic approach is preferred. For small tumors or patients at risk for bilateral disease, partial adrenalectomy can usually be performed and is associated with similar outcomes as total adrenalectomy. Bilateral or malignant disease may require a transabdominal approach, and even if total resection is not feasible, debulking of tumor mass facilitates subsequent medical management of catecholamine excess.

Malignant Pheochromocytoma

The incidence of cancer in pheochromocytoma has been traditionally estimated to be approximately 10%, although recent series describe a higher incidence. Thus, all patients should undergo serial follow-up to detect early recurrences. Patients with known metastatic disease should undergo surgical debulking of accessible disease. Catecholamine excess can be controlled in most patients with alpha-blockade, metyrosine, or both. Despite encouraging reports of chemotherapy or 131I-MIBG therapy, it appears that only a minority of patients have sustained remissions.

Prognosis

In general, the prognosis is good. With better understanding of the disease, surgical deaths are now rare. Blood pressure falls to normal levels in most patients with benign tumors. Patients with cancer have persisting hypertension and require the multiple therapies described earlier.

Incidentaloma

The most common presentation of adrenal masses is incidental detection on cross-sectional imaging performed for other reasons. The differential diagnosis is quite broad (see Table 31–3) and includes benign adenoma, functional adrenal tumors as previously discussed, metastasis and benign adrenal lesions such as myelolipoma, and neurofibroma. A systematic approach is required to differentiate functional adrenal masses that deserve removal and those lesions with a significant risk of carcinoma from the more common benign nonfunctional adenoma.

Metabolic Evaluation

A careful history and physical examination with focus on obesity pattern, virilization, glucose intolerance, and hypertension is warranted. The NIH consensus statement recommends metabolic testing for all adrenal incidentalomas. Laboratory examination with serum electrolytes including glucose and potassium should be done. If hypokalemia exists, then further tests for aldosteronoma are indicated. There are three first line tests to screen patients with incidentalomas for Cushing syndrome: an overnight low dose dexamethasone suppression test, a late-night salivary cortisol test and traditional 24-hour urinary-free cortisol test. The Endocrine society recommends either of the first two tests as the urinary-free cortisol test may not be sufficiently sensitive to detect subclinical Cushing syndrome. Patient should also have free-fractionated plasma metenephrines or the 24-hour urinary fractionated metanephrine test to rule out pheochromocytoma. Additional metabolic tests are performed when there are suspicious signs or symptoms or when screening tests are abnormal.

If the test identified the adrenal mass was an ultrasound or CT, an MRI may be helpful to differentiate the various causes of adrenal masses. Because adrenal adenomas have abundant intracytoplasmic lipid, they can often be confirmed on CT and MRI.

Imaging

Lesions that are primarily cystic on CT or MRI are typically benign and can be followed with serial imaging. Benign adrenal cysts are characterized by thin nonenhancing walls; fluid attenuation on CT and thin calcifications may be present peripherally in about 50%.

Characteristics suspicious for malignancy include solid masses that are large, hemorrhagic, or necrotic. MRI is usually heterogeneous on T1- and T2-weighted images due to internal bleeding.

Masses with gross fat on CT (Hounsfield unit [HU] <30) are myelolipomas (Figure 31–9), benign nonfunctional adrenal lesions with lipid and myeloid components. Myelolipomas are usually asymptomatic or present with pain if they bleed.

Noncontrast CT sensitivity for benign adenomas ranges from 50% to 80% depending on the HU attenuation value threshold chosen (Figure 31–5). If a threshold of <10 HU is chosen, the specificity is 84–100%. Chemical-shift imaging is an MR technique to identify intracellular lipid. In-phase and out-of-phase T1-weighted images can distinguish water and fat protons from water photons only. Sensitivities of 81–87% with specificities of 92–100% have been reported for chemical-shift MRI (Figure 31–10).

Diagnostic Algorithm

Percutaneous CT-guided biopsy may be appropriate for adrenal masses with imaging characteristics suspicious for metastasis or in patients with known malignancy. All functional adrenal masses and those >5 cm should be removed. Laparoscopic adrenalectomy is the preferred technique and is used in most cases except very large masses suspicious for malignancy or with evidence of local extension. Nonfunctional adrenal masses <5 cm should be assessed for radiographic features concerning for malignancy and removed if they are irregular or hemorrhagic or have demonstrated growth. An individualized approach for nonsuspicious nonfunctional masses <5 cm can be taken. It may be appropriate to remove lesions in the 3–5 cm range in well-informed younger patients in order to avoid the burden of radiographic follow-up. Those <3 cm can generally be followed. There is growing evidence that some incidentalomas that have initial negative screening tests may be causing “subclinical” Cushing's disease. Therefore, if a patient with an incidentaloma has symptoms or signs of Cushing's disease, additional or repeat screening tests may be appropriate.

Neuroblastoma

Neuroblastomas are of neural crest origin and may therefore develop from any portion of the sympathetic chain. Most arise in the retroperitoneum, and 45% involve the adrenal gland. The latter offer the poorest prognosis. In childhood, neuroblastoma is the third most common neoplastic disease after leukemia and brain tumors. Most are encountered in the first 2 ½ years of life, but a few are seen as late as the sixth decade, when they seem to be less aggressive. Abnormalities of muscle and heart and hemihypertrophy have been observed in association with neuroblastoma.

Metastases spread through both the bloodstream and lymphatics. Common sites in children include the skull and long bones, regional lymph nodes, liver, and lungs. Local invasion is common. In infants, who enjoy the best prognosis, metastases are usually limited to the liver and subcutaneous fat.

The following staging of neuroblastoma is generally accepted:

• Stage I: Tumors confined to the structure of origin.
• Stage II: Tumors extending in continuity beyond the organ but not crossing the midline. Ipsilateral lymph nodes may be involved.
• Stage III: Tumors extending in continuity beyond the midline. Regional lymph nodes may be involved.
• Stage IV: Remote disease involving skeletal organs, soft tissues, and distant lymph node groups.
• Stage IV-S: Stage I or II patients with remote spread of tumor confined to one or more of the following sites: liver, skin, or bone marrow.

Clinical Findings

Symptoms

An abdominal mass is usually noted by parents, the physician, or the patient. About 70% of patients have metastases when first seen. Symptoms relating to metastases include fever, malaise, bone pain, failure to thrive, and constipation or diarrhea.

Signs

A flank mass is usually palpable and may even be visible; it often extends across the midline. The tumor is usually nodular and fixed, since it tends to be locally invasive. Evidence of metastases may be noted: ocular proptosis from metastases to the skull, enlarged nodular liver, or a mass in bone. Hypertension is often found.

Laboratory Findings

Anemia is common. Urinalysis and renal function are normal. Because 70% of neuroblastomas elaborate increased levels of norepinephrine and epinephrine, urinary vanillylmandelic acid and homovanillic acid levels should be measured. Serial estimations of these substances during definitive treatment can be used as tumor markers. A return to normal levels is encouraging, while rising levels imply residual or progressive tumor. Bone marrow aspiration may reveal tumor cells.

X-Ray Findings

Plain radiographs may show a mass and displacement of the kidneys or other organs. CT scans are used to define tumor size, vascular invasion (eg, of the vena cava), local tumor spread, and distant metastases. Further evaluation includes CT scan of the chest to determine whether lung metastases are present and a bone scan to define skeletal metastases. Many of these tumors take up 131I–MIB; thus, this test can be used for staging.

Differential Diagnosis

Wilms tumor is also a disease of childhood. Imaging shows the caliceal distortion characteristic of an intrinsic renal tumor; no such distortion is shown in neuroblastoma, which merely displaces the kidney. Hydronephrosis, polycystic renal disease, and neonatal adrenal hemorrhage may be confused with neuroblastoma. CT scan is very useful in differentiating the various lesions.

Treatment

Surgical excision of a tumor is standard care of stage I and stage II patients. Although neuroblastoma is radiosensitive, radiation therapy is typically used as part of multimodality therapy of high-risk disease. In stage IV and high-risk stage III disease, chemotherapy is typically given followed by surgery and radiation therapy for residual disease. Useful drugs include cisplatin, cyclophosphamide, doxorubicin, and etoposide. There is evidence that after chemotherapy and surgery/radiation for residual disease, bone marrow transplant followed by 13-cis-retinoic acid prolongs disease-specific survival in high-risk patients and is now standard care.

Prognosis

Patients with stage I and II diseases have an 80% survival rate. Including all patients, however, long-term survival occurs in only 15% of patients. Infants have the best prognosis; their 2-year survival rate approaches 60%, and if the tumor is confined to the primary site with or without adjacent regional spread, the cure rate is about 80%. Factors that define high-risk neuroblastoma include age >1 year, metastasis, amplification of the MYCN oncogene, and particular histologic findings.

In a few infants, spontaneous maturation of neuroblastoma to ganglioneuroma has been observed.

Bibliography

General

Cushing's Syndrome and Adrenocortical Tumors

Adrenal Androgenic Syndromes

Primary Aldosteronism

Pheochromocytoma

Incidentaloma

Neuroblastoma