nonfunctioning adenoma is statistically higher, may benefit from routine sampling. Percutaneous

transfemoral cannulation of both adrenal veins is performed and intravenous ACTH (50 μ/hr) is

administered. Simultaneous adrenal vein blood samples for aldosterone and cortisol are taken before

and after ACTH injection, and their ratios are determined. The PAC is markedly higher (at least

fourfold) on the side of an adenoma, whereas there is little or no left–right gradient present in cases of

bilateral adrenal hyperplasia. A 10-fold gradient of cortisol in adrenal veins to a peripheral sample

ensures adequacy adrenal vein cannulation. This study is greater than 90% accurate and has been shown

to alter management in 30% to 50% of patients, even in those with an apparent unilateral adenoma.

This test is technically difficult and may be unsuccessful in 25% of patients. Emerging data suggest that

adrenal vein sampling may be superior to CT in differentiating the source of aldosterone production in

patients with hyperaldosteronism.

Treatment

5 Surgical removal of an aldosterone-secreting adenoma (Fig. 77-7) results in durable improvement of

hypertension and hypokalemia in 70% to 90% of patients. Laparoscopic adrenalectomy is the preferred

approach to remove these tumors. Morbidity and mortality following these procedures are almost

negligible. Preoperative spironolactone or eplerenone and potassium are given to replenish potassium

stores and correct alkalosis before anesthesia. Preoperatively, a significant fall in blood pressure with

aldosterone receptor antagonists predicts a successful outcome after adrenalectomy. Response to

adrenalectomy is also influenced by the duration and severity of hypertension and by the presence of

histologic changes in the kidney. Age greater than 50 years, male sex, and the presence of multiple

nodules within the adrenal is also associated with a poor response to surgery.

Management of idiopathic adrenal hyperplasia is medical because fewer than 20% to 30% of patients

with this disease are cured by adrenalectomy. Idiopathic adrenal hyperplasia is treated with

spironolactone or with newer aldosterone antagonist eplerenone. Other potassium sparing diuretics may

be used including triamterene and amiloride. Treatment of glucocorticoid-suppressible

hyperaldosteronism includes dexamethasone 0.5 to 1.0 mg daily. Glucocorticoids are used in small doses

to avoid Cushing syndrome.

Congenital Adrenal Hyperplasia

6 The congenital adrenal hyperplasias are autosomal recessive conditions resulting from inherited

defects of one or several of the enzymes necessary for cortisol biosynthesis (Fig. 77-8). Cortisol

deficiency leads to ACTH overproduction and secondary hyperplasia of the adrenal cortex with shunting

of cortisol precursors into adrenal androgen pathways. Peripheral tissues convert the excess adrenal

androgens to testosterone, which causes virilization of the patient.

Most cases (>90%) of congenital adrenal hyperplasia are secondary to deficiency of 21-hydroxylase

(CYP21A2) resulting from mutation of the gene on the short arm of chromosome 6. Two forms of this

deficiency are recognized; partial or complete. The complete form is characterized by androgen excess

at birth, with virilization, hypovolemia, hyponatremia, hyperkalemia, and hyperpigmentation. The

partial form is characterized by virilization only and may present in adolescence or adulthood.

Figure 77-7. Aldosteronoma within right adrenal gland shown in Figure 77-6.

2192

Figure 77-8. Schematic representation of the mechanism underlying congenital adrenal hyperplasias. Enzymatic defects in the

adrenal gland prevent normal production of cortisol with resulting loss of negative feedback to the hypothalamus and pituitary.

Chronic adrenocorticotropic hormone stimulation of the adrenal gland shunts steroid precursors through androgenic and

mineralocorticoid pathways, leading to the overproduction of androgens and mineralocorticoids. The most common deficiencies

are CYP21A2 (21-hydroxylase), CYP11B1 (11β-hydroxylase), and 3-β-HSD (3-β-hydroxysteroid dehydrogenase).

Of the remaining causes of congenital adrenal hyperplasia, 11-beta-hydroxylase deficiency (CYP11B1)

is the second-most common cause, followed by 3-beta-hydroxydehydrogenase and 17-hydroxylase

(CYP17) deficiency. Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal

hyperplasia and is often fatal (Table 77-4).

Signs and Symptoms

Prenatal adrenal virilization in females produces ambiguous external genitalia (female

pseudohermaphrodism). The ovaries, fallopian tubes, and uterus develop normally and patients are

fertile. Postnatal congenital adrenal hyperplasia causes virilization of females and precocious puberty of

males. Females develop hirsutism, polycystic ovaries, and irregular menses. Male patients exhibit

secondary sexual characteristics by age 2 or 3 years. Fertility is often impaired. Both sexes experience

rapid somatic growth and short stature. Virilization, salt wasting, and hyperpigmentation are variably

present with the non–21-hydroxylase forms of congenital adrenal hyperplasias.

Diagnosis

Elevated plasma 17-hydroxyprogesterone is the most characteristic abnormality found in 21-hydroxylase

deficiency. Both plasma cortisol and 24-hour free urinary cortisol excretion are variably reduced.

Diagnosis of other forms of the disease involves demonstration of elevated levels of enzyme substrate:

corticosterone and 11-deoxycortisol for 11-beta hydroxylase; dehydroepiandrosterone and 17-delta-5

hydroxypregnenolone for 3-beta hydroxydehydrogenase; and deoxycorticosterone and corticosterone for

17-beta-hydroxylase deficiency (Table 77-4).

Treatment

The treatment of 21-hydroxylase deficiency is glucocorticoid and mineralocorticoid replacement.

Clinical management is often complicated by inadequately treated hyperandrogenism or iatrogenic

hypercortisolism, or both. New treatment approaches under investigation include combination therapy

to block androgen action and inhibit estrogen production, and bilateral adrenalectomy in the most

severely affected patients. Female patients with ambiguous genitalia may require surgical correction as

infants. Treatment of congenital adrenal hyperplasias caused by other enzyme deficiencies includes

steroid and electrolyte replacement and surgical correction of the external genitalia in affected female

infants.

2193

Virilizing and Feminizing Adrenal Tumors

Excess production of adrenal androgens by an adrenal adenoma or carcinoma can produce virilizing

features either alone or more commonly in addition to Cushing syndrome. Development of an adrenal

virilizing tumor in women causes hirsutism and masculinization. Males with these tumors may present

late with signs and symptoms of tumor enlargement or distant metastases develop. Virilizing tumors

secrete androgen precursor, dehydroepiandrosterone, which can be measured either directly in plasma

or in urine as a 17-ketosteroid. Feminizing adrenal neoplasms are extremely rare. Abdominal CT is

subsequently used to localize the lesion. Resection of tumor and involved adrenal gland is the primary

treatment for patients with adrenal virilizing tumors. Tumor recurrence is heralded by return of

virilization or by detection of increased 17-ketosteroids in the urine. Tumor debulking or inhibition of

steroidogenesis with aminoglutethimide or mitotane may be useful in controlling signs and symptoms in

patients with metastatic disease.

7 Adrenocortical Carcinoma

Adrenocortical carcinoma is a rare malignancy with an estimated incidence of 0.5 to 2 cases per million

per year. Presentation peaks in the first and fifth decades of life. The prevalence is higher in females

than in males (1.4 to 2:1). The cause of adrenocortical carcinoma is unknown, although somatic

mutations in P53 and inheritance of this tumor in patients with germline mutations in P53 (Li Fraumeni

syndrome) implicate this tumor suppressor gene in its pathogenesis (1).

Signs and Symptoms

Adrenocortical carcinoma is a very aggressive malignancy, and most patients (up to 75%) present with

locoregionally advanced or distant disease. Syndromes of adrenal hormone overproduction are frequent

(up to 60%) and may include hypercortisolism, hyperaldosteronism, or virilization. Patients with

rapidly progressive Cushing syndrome or mixed presentations with signs of both Cushing syndrome and

virilization should be suspected of having adrenocortical carcinoma. Nonfunctioning adrenocortical

carcinomas present most commonly as abdominal pain or mass with vague symptoms of nausea, weight

loss, and fatigue.

Diagnosis

Patients with suspected adrenocortical carcinoma should have biochemical testing to identify hormone

overproduction followed by staging investigations including cross-sectional imaging and bone scans.

Contrast-enhanced CT of the abdomen and chest is important to preoperatively diagnose local tumor

invasion and metastatic lesions as well as to confirm a functioning contralateral kidney (Fig. 77-9). In

the absence of distant metastases or local invasion, preoperative distinction between large adenomas

and carcinomas can be difficult, although large (>6 cm) adrenal masses that extend to nearby structures

on CT scanning should be approached as carcinomas. Biopsy of adrenal lesions suspected of being

adrenocortical carcinoma is unnecessary and should be avoided. The risk of seeding and the inability of

histologic examination to distinguish between adenoma and carcinoma underlie this approach. Biopsy of

extraadrenal lesions may be performed to confirm metastatic disease.

Table 77-4 Congenital Adrenal Hyperplasias

2194

Figure 77-9. Computed tomography scan of right adrenocortical carcinoma showing invasion of liver and inferior vena cava. Note

that a contralateral kidney is present and functioning.

A definitive diagnosis of adrenocortical carcinoma requires pathologic demonstration of tumor

invasion to adjacent organs or spread to lymph nodes or distant sites. Practically, any adrenal neoplasm

larger than 6 cm or weighing more than 100 g should be considered malignant. Histologic features of

tumor necrosis, hemorrhage, and local invasion are gross pathologic evidence of carcinoma, while cells

with large, hyperchromatic nuclei and more than 20 mitoses per high-power field suggest malignancy.

Treatment

Surgical resection is the mainstay of treatment for all stages of adrenocortical carcinoma. Complete

resection of locally confined tumor is the only chance for cure from adrenocortical carcinoma. However,

distant or local spread is evident in 65% of cases at presentation and a minority of patients is resectable

with curative intent. Recurrence rates after surgery range from 38 to 85%, depending on stage at

presentation (Table 77-5).

Many patients with adrenocortical carcinoma present with metastatic disease, involving the lung,

lymph nodes, liver, or bone. Resection or surgical debulking of locally advanced or metastatic lesions

may provide symptomatic relief for select patients, especially those with low-grade, slow-growing,

hormonally productive cancers. Symptomatic recurrent or metastatic disease is best treated by resection

2195

when feasible.

Chemotherapy for adrenocortical carcinoma usually includes mitotane, although no controlled studies

have established its efficacy in this disease. Partial responses to mitotane occur in less than a third of

patients, and survival is unchanged. Adjuvant chemotherapy with mitotane after complete resection for

adrenocortical carcinoma is unproven and toxic so that many oncologists reserve its use for recurrent,

unresectable or metastatic disease. Cisplatin in combination with mitotane or doxorubicin and 5-

fluoruracil have been applied in metastatic disease with partial responses noted.

STAGING

Table 77-5 American Joint Committee on Cancer Staging of Adrenocortical

Carcinoma, with 5-Year Survival Rates

The prognosis of adrenocortical carcinoma is poor. Median survival following diagnosis for all

patients is approximately 18 months. Overall survival following resection for all stages of

adrenocortical cancer is 15% to 47% at 5 years. Stage-specific 5-year survival is 30% to 45% for stage I,

12% to 57% for stage II, 5% to 18% for stage III, and 0 for stage IV disease.

DISEASES OF THE ADRENAL MEDULLA

Pheochromocytoma

8 Pheochromocytomas are functional adrenal tumors that arise from neuroectodermal cells of the

adrenal medulla or in certain extraadrenal sites. These tumors are uncommon, occurring in 0.005% to

0.1% of persons, but occur with increased frequency in hypertensive populations (0.2% incidence) and

in heritable endocrine tumor syndromes. The peak incidence of pheochromocytoma occurs during the

fourth and fifth decades of life, and men and women are affected about equally. The rule of tens is a

useful way to characterize pheochromocytoma: tumors are bilateral in 10% of cases, extraadrenal in

10%, familial in 10%, multicentric in 10%, and malignant in 10% and occur in children in 10% of cases.

Approximately 10% of pheochromocytomas are extraadrenal, although most (98%) are still located

within the abdomen. Extraadrenal pheochromocytomas can occur at any site in the abdomen where

chromaffin tissue is located and have been found in the paravertebral ganglia, the organ of Zuckerkandl,

and the urinary bladder. Clues to the presence of extraadrenal pheochromocytoma are predominance of

norepinephrine because extraadrenal sites lack the enzyme necessary to convert norepinephrine to

epinephrine.

Familial pheochromocytoma is a component of two autosomal dominant syndromes: von Hippel–

Lindau syndrome and multiple endocrine neoplasia (MEN) 2. Patients with von Hippel–Lindau

2196

syndrome have pheochromocytoma (usually bilateral), retinal angiomas, cerebellar hemangioblastoma,

epididymal cystadenoma, renal and pancreatic cysts, and renal cell carcinoma. Patients with MEN 2A

develop pheochromocytoma (usually bilateral), medullary carcinoma of the thyroid (MTC), and primary

parathyroid hyperplasia. Patients with MEN 2B develop pheochromocytoma (usually bilateral), MTC,

mucosal neuromas, intestinal ganglioneuromatosis, and have a characteristic marfanoid body habitus.

Pheochromocytoma also occurs in neurofibromatosis type 1 and familial paraganglioma. The frequency

of pheochromocytoma in these disorders is 10% to 20% in von Hippel–Lindau syndrome, 50% in MEN

2, and 0.1 to 5.7% with neurofibromatosis type 1.

In some families, patients with pheochromocytomas have no other clinical abnormalities, suggesting

the existence of a separate disease limited to the formation of adrenal medullary tumors. In a study of

three generations of an affected kindred, a novel mutation was found in the von Hippel–Lindau gene

even though there were no other clinical manifestations of this disorder. Patients with bilateral

pheochromocytoma, young patients with pheochromocytoma, and patients with paraganglioma should

be screened for MEN 2 and von Hippel–Lindau syndrome.

The etiology and pathogenesis of pheochromocytoma is unknown. A genetic component seems certain

because pheochromocytoma occurs not only as a part of familial syndromes but also as an isolated

disorder because of mutation in the RET gene or the MEN 2 gene. Familial pheochromocytoma as well

as sporadic pheochromocytoma occurs also with mutations in the succinate dehydrogenase complex,

subunit B, iron–sulfur protein (SDHB). Either germline or somatic mutations in the SDHD gene is

another cause of pheochromocytoma (2).

Signs and Symptoms

Symptoms of pheochromocytoma are attributable to the effects of excessive circulating catecholamines

on target tissues (Table 77-3). The classic triad of symptoms in patients with a pheochromocytoma is

episodic headache, sweating, and tachycardia. Hypertension is common with pheochromocytoma and is

sustained in roughly half of patients, is paroxysmal in one-third, and is absent in one-fifth. Orthostatic

hypotension results from diminished plasma volume and blunted autonomic reflexes. Other symptoms

include palpitations, anxiety, and tremulousness. Cardiovascular sequelae include myocardial infarction,

cardiac dysrhythmias, and stroke. Gastrointestinal motility is also impaired. Asymptomatic patients with

functioning tumors are rare, and nonfunctioning tumors are distinctly uncommon. Sudden death has

been reported in patients with pheochromocytoma who have undergone surgical procedures or

childbirth.

Diagnosis

Elevation of catecholamines and their metabolites in either urine or blood is essential for the diagnosis

of pheochromocytoma. Either a 24-hour urine collection for catecholamines and their metabolites

(metanephrines) or plasma-fractionated metanephrines can be used to make the diagnosis. Urine

catecholamines/metanephrines are the most reliable tests with a sensitivity and specificity of 98%.

Plasma fractionated metanephrines is similarly sensitive (99%), but lacks specificity (85%). Accordingly

plasma fractionated metanephrines should be reserved for patients with a high pretest probability for

pheochromocytoma – adrenal incidentalomas, classic symptoms, family history or genetic syndromes

associated with pheochromocytoma (MEN etc.) while urine catecholamines/metanephrines are useful as

screening tests for patients who are less likely to have a pheochromocytoma. Measurement of plasma

catecholamines is not as useful in distinguishing patients with pheochromocytoma from those with

essential hypertension. Measurement of plasma chromogranin A is nonspecific and a poor diagnostic but

potentially helpful confirmatory test.

Many medications alter or interfere with measurement or either plasma or urine catecholamines. Such

medications should be discontinued to ensure accurate testing. These drugs include acetaminophen,

labetolol, clonidine withdrawal, tricyclic antidepressants, antipsychotics and ethanol. To control blood

pressure, other antihypertensives such as calcium channel blockers may be substituted.

In normotensive or mildly hypertensive patients with elevated plasma catecholamine levels (1,000 to

2,000 pg/mL), a clonidine suppression test may be used to distinguish from pheochromocytoma. An oral

0.3-mg dose of clonidine suppresses centrally mediated release of catecholamines to less than 500

pg/mL within 2 to 3 hours but does not affect release of catecholamines by a pheochromocytoma.

Biochemical confirmation of the diagnosis should be followed by radiologic evaluation to locate the

tumor. Pheochromocytomas are best imaged with CT or MRI. Contrast-enhanced CT readily detects

tumors 1 cm and larger and has sensitivity of 87% to 100% for pheochromocytoma (Fig. 77-10A). MRI

is similarly sensitive, and a T2-weighted image brightness three times greater than liver is highly

2197