Chapter 60. The Adrenal Cortex & Medulla

Structure & Function

The paired adrenal glands are situated in the retroperitoneum above the kidneys. They are variably shaped and irregularly folded, flattened structures whose cut surface reveals an outer yellow cortex and an inner gray medulla. The normal adrenals have an aggregate weight of about 6 g (upper limit, 8 g).

The adrenal cortex is derived from the mesoderm of the urogenital ridge. Its origin is independent of that of the adrenal medulla, which is derived from the neural crest.

The cortex is composed of the subcapsular zona glomerulosa (10–15%), the zona fasciculata (80%), and the zona reticularis (5–10%). The zona glomerulosa secretes aldosterone and is controlled by the renin–angiotensin mechanism, which is independent of the pituitary. The zona fasciculata and reticularis secrete cortisol and androgenic hormones, respectively, and are under the regulatory control of the pituitary via corticotropin adrenocorticotropic hormone (ACTH). ACTH secretion by the pituitary is under the control of (1) hypothalamic corticotropin-releasing factor (Chapter 57: The Pituitary Gland) and (2) the feedback inhibitory effect of serum cortisol.

Adrenocortical hormones are synthesized from cholesterol (Figure 60-1) by a series of enzyme-directed reactions.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (adrenogenital syndrome) is a group of uncommon diseases that result from inherited deficiency of one of the several enzymes in the cortisol synthetic pathway (Figure 60-1). They have an autosomal recessive pattern of inheritance, and the genetic abnormality is on the short arm of chromosome 6. Decreased secretion of the end product (cortisol) stimulates, via the feedback mechanism, pituitary ACTH secretion. This in turn stimulates the zona fasciculata and reticularis to undergo bilateral hyperplasia and to secrete excessive amounts of precursor hormones. The clinical effects depend on the enzyme that is deficient and upon the products that accumulate prior to the block induced by the deficiency.

1. Complete 21-hydroxylase deficiency (30%) is a severe disease manifested by failure of cortisol and aldosterone secretion (Figure 60-2). Death usually occurs in infancy.

2. Partial 21-hydroxylase deficiency (60%) is the commonest of the group. 21-Hydroxylase levels are adequate to maintain normal aldosterone secretion under the renin–angiotensin stimulus so there is no sodium loss. Cortisol levels are also normal, the tendency to hypocortisolism having been compensated by adrenal hyperplasia via increased pituitary ACTH levels.

   The main effects of partial 21-hydroxylase deficiency are (1) adrenal hyperplasia; (2) high serum ACTH levels; and (3) increased secretion of androgens by the overstimulated zona reticularis, producing virilism in the female and precocious puberty in the male. Serum levels of 17-hydroxyprogesterone and dehydroepiandrosterone are increased.

3. 11-Hydroxylase deficiency (5%) is rare. It causes the hypertensive form of congenital adrenal hyperplasia. The enzyme deficiency leads to accumulation of 11-deoxycortisol and deoxycorticosterone, both of which are strong mineralocorticoids that cause sodium retention in the kidneys and result in hypertension. Virilization due to androgen excess is also present as a result of increased ACTH stimulation of the zone reticularis.

4. Other enzyme deficiencies, including desmolase deficiency, 17-hydroxylase deficiency, and 3β-dehydrogenase deficiency, are all extremely rare.

Excess Secretion of Adrenocortical Hormones

Excess Cortisol Secretion (Cushing's Syndrome)

Cushing's syndrome is a relatively common clinical abnormality of the adrenal cortex, usually affecting middle-aged individuals, women more often than men. It can be caused by several different disease processes (Table 60-1).

Pathology

Adrenocortical Adenoma

Grossly, adrenocortical adenomas appear as well-circumscribed nodular masses that are usually small (< 5 cm in greatest diameter and 5–50 g in weight; Figure 60-3). They usually have a bright yellow color and may show areas of cystic degeneration, fibrosis, and hemorrhage. The contralateral adrenal usually is atrophic.

Microscopically, adenomas are composed of uniform large cells arranged in nests and trabeculae. The cells have abundant lipid-filled cytoplasm and small uniform nuclei. Nuclear enlargement and pleomorphism are not uncommon, but mitotic figures are rare.

Not all adrenocortical adenomas produce hormones. Nonfunctional adrenocortical adenomas are present in about 5% of all autopsies and are being increasingly detected as incidental findings when abdominal computed tomography (CT) scans are performed for other reasons. The diagnosis of a functional adrenocortical adenoma is best made by careful chemical assays for hormones in the serum before the adenoma is removed. Pathologic features of nonfunctional adenomas and those that secrete different hormones are similar and do not allow diagnosis of specific hormone-secreting adenomas.

Adrenocortical Carcinoma

Adrenocortical carcinomas usually appear as large (> 6 cm and > 50 g), poorly circumscribed masses that commonly show infiltration of perinephric fat and kidney. Gross involvement of the adrenal and renal vein by the neoplasm may also occur.

Microscopically, adrenal carcinomas are composed of large, pleomorphic cells arranged in diffuse sheets. Mitotic figures are frequent and abnormal. Areas of necrosis, capsular invasion, and vascular invasion are common. The microscopic features permit accurate differentiation of adenoma and carcinoma.

Adrenal carcinoma behaves as a highly malignant neoplasm, metastasizing both to lymph nodes and via the bloodstream. Not all produce excess hormones; like adenomas, the pathologic features of nonfunctional carcinomas are similar to those that secrete hormones.

Bilateral Adrenal Hyperplasia

Once thought to be a primary disorder of the adrenal, bilateral adrenal hyperplasia is now believed to be almost invariably secondary to increased ACTH production, whether from a pituitary adenoma or a malignant nonpituitary neoplasm (usually small-cell undifferentiated carcinoma of lung). Both adrenal glands are enlarged to greater than their aggregate normal upper weight limit of 8 g. Careful weighing of the adrenal removed at surgery or autopsy after all periadrenal connective tissue has been dissected away is the most reliable means of making a diagnosis of adrenal hyperplasia. The enlarged glands may be nodular or diffuse. Microscopically, the zona fasciculata and reticularis are greatly widened.

Iatrogenic Hypercortisolism

In cases where hypercortisolism is the result of exogenous glucocorticoid administration, both adrenal cortices show diffuse atrophy due to inhibition of pituitary ACTH secretion by the exogenous steroids.

Clinical Features

Cortisol excess causes an extensive array of metabolic abnormalities (Table 60-2):

1. Redistribution of body fat from the extremities to the trunk results in moon facies and truncal obesity with thin extremities. Hypercholesterolemia and accelerated atherosclerosis also occur.

2. The antagonistic effect of cortisol on the action of insulin produces diabetes mellitus.

3. Protein catabolism is increased. Gluconeogenesis is stimulated by cortisol, leading to muscle wasting. Growth retardation occurs in children. Other consequences of increased protein catabolism include thinning of the skin with development of striae, easy bruising, and delayed wound healing. Decrease in the amount of the protein matrix of bone leads to osteoporosis.

4. Cortisol has a significant mineralocorticoid action that results in retention of sodium in the distal renal tubule at the expense of potassium and hydrogen. Hypertension and hypokalemic alkalosis may occur as a result.

5. Cortisol has an inhibitory effect on lymphocyte, macrophage, and neutrophil function, resulting in increased susceptibility to infections.

6. Cortisol in excess has an effect on brain cells, and patients with Cushing's syndrome frequently have psychiatric symptoms such as euphoria, mania, and psychosis (steroid encephalopathy).

7. Some degree of androgen excess coexists with cortisol excess in many patients, leading to hirsutism, acne, infertility, and menstrual disturbances in females.

Diagnosis

(Table 60-3)

The first step in the diagnosis is to establish the presence of excess cortisol secretion. The best tests to screen for increased cortisol secretion are (1) the finding of a plasma cortisol level > 140 nmol/L (> 5 μg/dL) in an 8 am sample after 1 mg of dexamethasone at midnight, and (2) an elevated 24-hour urinary free cortisol > 275 nmol/d (> 100 μg/d). In a patient who is positive on these screening tests, the definitive diagnosis of increased cortisol secretion is made when there is failure to suppress plasma cortisol in the low-dose 2-day dexamethasone suppression test. When hypercortisolism has been established, the cause can be determined with the high-dose 2-day dexamethasone test and plasma ACTH assay (Table 60-3).

Treatment

Functional adrenal neoplasms and pituitary neoplasms producing ACTH are surgically removed. In the ectopic ACTH syndrome, therapy is aimed at the responsible tumor, eg, chemotherapy for small-cell carcinoma of the lung.

Excess Aldosterone Secretion

Incidence & Etiology

Primary Hyperaldosteronism (Conn's Syndrome)

This disorder is rare and is most commonly the result of an aldosterone-secreting adrenocortical adenoma (Figure 60-3). Less commonly, it may result from bilateral hyperplasia of the zona glomerulosa. Adrenal carcinomas only very rarely secrete aldosterone. In a few cases of hyperaldosteronism, no definite abnormality is detected in the gland.

Secondary Hyperaldosteronism

Secondary hyperaldosteronism is common. It is caused by a high renin output from the juxtaglomerular cells of the kidney in response to (1) renal ischemia, such as occurs in renal artery stenosis and malignant hypertension; (2) reduced effective plasma volume, as occurs in cardiac failure and hypoproteinemic states; or (3) juxtaglomerular cell hyperplasia (Bartter's syndrome) or neoplasia.

Pathology

Most cases of primary aldosteronism are associated with an adrenocortical adenoma indistinguishable from an adenoma that produces cortisol except that it tends to be smaller (usually < 2 cm in diameter) (Figure 60-3).

The adrenals appear grossly normal in patients with secondary hyperaldosteronism; microscopic demonstration of hyperplasia of the zona glomerulosa is difficult and subjective.

Clinical Features

Aldosterone causes sodium retention in the distal renal tubule in exchange for potassium and hydrogen ions, resulting in hypertension and hypokalemic alkalosis. Hypertension is the usual presenting feature. Less than 1% of patients with hypertension have primary hyperaldosteronism, but this cause is important to identify because it represents a surgically curable cause. Hypokalemic symptoms may occasionally dominate. They include muscle weakness, fatigue, paralyses, and paresthesias. Alkalosis may cause a decrease in serum ionized calcium, leading to tetany.

Secondary hyperaldosteronism occurs as a complication of a variety of diseases whose clinical manifestations usually dominate the clinical picture. In this situation, increased aldosterone secretion is a normal compensatory phenomenon and produces few symptoms except sodium retention, thereby contributing to the genesis of edema under these conditions. Hypokalemic alkalosis and its effects may also be present.

It is of interest that edema is rare in patients with primary hyperaldosteronism even though there is marked sodium and water retention. Lack of edema is due to the fact that increased atrial natriuretic factor secreted by cardiac tissue limits sodium retention.

Diagnosis

The diagnosis of primary hyperaldosteronism must be suspected in any hypertensive patient who has hypokalemia without an apparent cause or who develops profound hypokalemia when treated with diuretics.

The diagnosis of primary hyperaldosteronism may be made by the presence of elevated serum aldosterone levels associated with low serum renin levels. This is usually confirmed by demonstrating failure of suppression of aldosterone secretion following intravenous saline loading. Renin and aldosterone levels are both elevated in secondary hyperaldosteronism.

Differentiation of aldosterone-secreting adenoma from bilateral hyperplasia of the zona glomerulosa is made by (1) abdominal CT scan (normal in bilateral hyperplasia and microadenomas), (2) bilateral adrenal vein catheterization and aldosterone assay—aldosterone is elevated on one side in adenoma and both sides in hyperplasia; and (3) iodocholesterol scan. Iodocholesterol (tagged with radioiodine) is taken up by zona glomerulosa cells and delineates adenoma (unilateral) and hyperplasia (bilateral).

Treatment

Primary hyperaldosteronism is best treated by surgical removal of the adrenal gland that contains the adenoma. Aldosterone antagonist drugs (eg, spironolactone) are useful in the management of patients with bilateral hyperplasia and secondary hyperaldosteronism.

Excess Sex Hormone Secretion

Excessive secretion of androgenic hormones by the adrenals is very rare. It may be due to adrenocortical neoplasms (particularly carcinomas) or congenital adrenal hyperplasia (adrenogenital syndrome). It may also occur as an associated phenomenon in patients with Cushing's syndrome.

Excessive estrogen secretion occurs very rarely with adrenocortical carcinomas.

Decreased Secretion of Adrenocortical Hormones (Addison's Disease)

Incidence & Etiology

Decreased secretion of adrenocortical hormones is uncommon.

Acute insufficiency may follow destruction of the adrenal cortices in severe bacteremias, most commonly meningococcal bacteremia (Waterhouse-Friderichsen syndrome). Clinically, this is a fulminant illness characterized by high fever, bacteremia, hemorrhagic skin rash, and shock, which progresses rapidly to death in most cases. Disseminated intravascular coagulation is believed to be responsible for petechial hemorrhages throughout the body, including the adrenals.

Acute adrenocortical insufficiency (addisonian crisis) is most commonly seen today as an iatrogenic disease in patients being treated with synthetic glucocorticoids (eg, prednisone) in high doses. These drugs suppress pituitary ACTH and result in atrophy of the adrenal cortex, destroying the patient's ability to secrete cortisol normally. If such a patient has a sudden increased demand for cortisol (as during stress or an infection) or if the exogenous steroids are withdrawn rapidly, acute adrenocortical insufficiency may occur.

Chronic insufficiency of adrenocortical hormone synthesis occurs in a variety of conditions associated with chronic destruction of the adrenal glands (Table 60-4).

With the declining incidence of tuberculosis and histoplasmosis, 90% of the adult cases in the USA are caused by autoimmune destruction of the adrenals. Fifty percent of patients with autoimmune Addison's disease have antiadrenal antibodies in the serum. The cell destruction is most likely mediated by sensitized cytotoxic T lymphocytes. Autoimmune Addison's disease is associated with other autoimmune diseases such as Hashimoto's thyroiditis, Graves' disease, and pernicious anemia.

Pathology

When the adrenals are the site of a disease (tuberculosis, fungal infection, metastatic carcinoma, hemochromatosis, amyloidosis, etc), the gland shows the specific morphologic features associated with those disorders.

In autoimmune Addison's disease, the adrenals are markedly atrophic, with an aggregate weight less than 4 g. There is loss of normal architecture and lipid depletion of cells, resulting in a brown color. Microscopically, the cortex is greatly narrowed, with a diffuse lymphocytic infiltrate and fibrosis.

Clinical Features

The dominant clinical features of Addison's disease are caused by decreased mineralocorticoid activity. There is increased weakness, fatigability, and weight loss (asthenia). Sodium excretion in the renal tubules is increased, with retention of potassium and hydrogen ions. Loss of sodium results in hyponatremia and contraction of plasma volume, leading to hypotension. Serum chloride is decreased, and there is a hyperkalemic acidosis. Hyperkalemia may cause muscular weakness and electrocardiographic abnormalities.

Patients are unable to respond to stresses such as infections, surgery, and trauma, which precipitate life-threatening circulatory collapse (addisonian crisis).

A compensatory increase in pituitary ACTH secretion occurs in all cases of adrenal insufficiency (except when caused by hypopituitarism). Plasma ACTH levels are increased. This causes increased skin pigmentation because of the melanocyte-stimulating property of ACTH.

In the early stages, patients have a normal plasma cortisol but a decreased adrenal reserve. This is best detected by ACTH stimulation tests, which fail to increase cortisol output by the adrenal. In later stages, plasma levels of cortisol and aldosterone are decreased.

Treatment is by glucocorticoid (cortisol) replacement. Fludrocortisone is usually necessary to correct the mineralocorticoid deficiency.

Structure & Function

The adrenal medulla is derived from the neural crest and is therefore closely related to the sympathetic ganglia and paraganglia. Paraganglia are a group of small organs located in the paravertebral region from the base of the skull to the parasacral region. Paraganglia have also been described at the aortic bifurcation (organ of Zuckerkandl) and in the wall of the urinary bladder. The glomus jugulare, carotid body, and aortic body are specialized paraganglia.

The medulla comprises about 10% of the adrenal weight. It is present only in the head and body regions of the adrenal, being absent in the tail. Microscopically, it is composed of large cells arranged in nests and trabeculae, separated by a rich vascular stroma. The cells of the adrenal medulla are richly innervated and form part of the sympathetic nervous system. Adrenal medullary secretion is controlled by the activity of the sympathetic nerves.

The adrenal medulla secretes the catecholamines norepinephrine (noradrenaline) and epinephrine (adrenaline). The adrenal medulla differs from extraadrenal paraganglia in having the enzyme phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine; the adrenal medulla secretes chiefly epinephrine.

Diseases of the Adrenal Medulla

Neoplasms constitute the only common disease process to affect the adrenal medulla (Table 60-5). Very rarely, adrenal medullary hyperplasia occurs as part of the multiple endocrine neoplasia syndrome (MEN type II).

Pheochromocytoma

Pheochromocytomas are catecholamine-producing neoplasms of the adrenal medulla or extra-adrenal paraganglia. The term paraganglioma is commonly used for these tumors when they occur outside the adrenal gland itself.

Pheochromocytoma is an uncommon neoplasm. It usually occurs sporadically, but 5% of patients give a positive family history for the following diseases: (1) Familial occurrence of pheochromocytoma, with an autosomal dominant pattern of inheritance, which is very rare; (2) Generalized neurofibromatosis (von Recklinghausen's disease) is associated with an increased incidence of pheochromocytoma; (3) Multiple endocrine neoplasia types IIa and IIb (see below); (4) von Hippel-Lindau disease (Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases); and (5) Sturge-Weber disease (Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Pathology

Pheochromocytoma is sometimes called “the 10% tumor” for the following reasons: (1) Its commonest location is in the adrenal medulla, but 10% of pheochromocytomas occur in extra-adrenal paraganglia—most often intra-abdominal, occasionally in the mediastinum, neck, or wall of the urinary bladder. (2) Ten percent of patients with pheochromocytoma have multiple tumors, most commonly involving both adrenal glands but also the extra-adrenal paraganglia. (3) Most pheochromocytomas behave as benign neoplasms, but 10% are malignant with local invasion and metastasis. In children, the 10% rule does not apply, as 25% are bilateral and 25% extra-adrenal.

Pheochromocytomas vary in size from very small (1 cm) to massive tumors, are well circumscribed, and frequently show areas of hemorrhage and necrosis (Figure 60-4). Fixation in a chromium salt fixative (such as Zenker's solution) imparts a brown color to the tumor—hence the older term chromaffin paraganglioma.

Microscopically, the tumor consists of large cells arranged in sheets and nests separated by a rich vascular stroma. Pleomorphism is common, but mitoses are rare. Invasion of capsule and vessels is common even in those neoplasms that behave in a generally benign fashion.

Electron microscopy shows the presence of membrane-bound, dense-core neurosecretory granules in the cytoplasm. Immunologic studies show the presence of markers for neuroendocrine cells such as neuron-specific enolase and chromogranin. Catechol-amines can be demonstrated in the tumor if a sample is assayed.

The biological behavior of a pheochromocytoma cannot be predicted by microscopic examination.

Extra-adrenal paragangliomas are more frequently malignant than adrenal pheochromocytomas. The diagnosis of malignant pheochromocytoma is made only when metastasis is demonstrated. Distinction must also be made between true metastases and multiple primary paragangliomas, which occur rarely and are usually benign. A diagnosis of metastatic pheochromocytoma is made only when a pheochromocytoma occurs in a site where paraganglia are not found (eg, lung, bone, liver, brain).

Clinical Features

The clinical manifestations of pheochromocytoma are due to increased catecholamine secretion.

Hypertension is the most common presenting feature. Blood pressure elevation is the result of peripheral vasoconstriction and increased cardiac output caused by the alpha and beta effects of catecholamines. Hypertension is commonly persistent but may be paroxysmal, with return of the blood pressure to normal between paroxysms. Paroxysmal hypertension is caused by sudden release of hormone from the neoplasm and may be precipitated by bending, increased abdominal pressure (as during physical examination), meals, and—in those rare cases where the tumor is located in the urinary bladder wall—by micturition. During a hypertensive crisis, the systolic pressure can rise to 300 mm Hg.

Hypertension, particularly when episodic, is accompanied by other manifestations of catecholamine excess such as palpitations, tachycardia, feelings of anxiety, and excessive sweating. Impaired glucose tolerance is common as the result of the insulin-antagonistic action of catecholamines.

Untreated, patients with pheochromocytomas die of cardiac failure or cerebral hemorrhage during a hypertensive crisis.

Diagnosis

Patients with hypertension—particularly if they are under 40 years of age—must be evaluated for the possibility of pheochromocytoma. The best screening tests are 24-hour urinary metanephrine and vanillylmandelic acid (breakdown products of catechol-amines), one or both of which is elevated in almost all cases. The diagnosis may be confirmed by urinary free catecholamine assay. Plasma catecholamine assay is difficult to interpret and is usually not necessary. Failure to suppress plasma catecholamine with clonidine supports a diagnosis of pheochromocytoma in cases with borderline elevation of urinary free catecholamine.

The ratio between epinephrine and norepinephrine in serum provides a means of differentiating adrenal from extra-adrenal pheochromocytoma. Adrenal tumors show elevation of both; extra-adrenal tumors, which lack the enzyme that converts norepinephrine to epinephrine, show a selective norepinephrine elevation.

When the diagnosis of pheochromocytoma has been made, the neoplasm or neoplasms should be localized prior to surgical removal. Localization is by (1) CT scan, which is sensitive in detecting tumors >1 cm in size; (2) adrenal vein catheterization and demonstration of elevated catecholamines selectively on the side of the tumor; and (3) metaiodobenzylguanidine (MIBG) scan. MIBG (radiolabeled metaiodobenzylguanidine) is taken up by the paraganglionic cells. A “hot spot” on a radionuclide scan after MIBG localizes the pheochromocytoma.

Treatment

Surgical removal of the tumor is the treatment of choice, but it is a complex procedure that requires sympathetic blockade, expert anesthesiological support, and meticulous fluid balance. Removal of the neoplasm may cause a sudden drop in blood pressure; if some fall in blood pressure does not occur after tumor removal, the possibility of a second pheochromocytoma must be suspected.

Neuroblastoma

Neuroblastoma is a malignant neoplasm composed of primitive neural crest cells. It occurs chiefly in very young children; the median age is 2 years, and 80% of cases occur under the age of 5 years. Neuroblastoma is rare past puberty.

The adrenal medulla is by far the most common site, followed by neural crest derivatives in the retroperitoneum. Extra-abdominal neuroblastomas may occur in the posterior mediastinum, pelvis, head, neck, and cerebral hemispheres. A specific form of the neoplasm—olfactory neuroblastoma—occurs in the nasal cavity in older individuals.

Neuroblastoma is the third most common malignant neoplasm in childhood, following leukemia–lymphoma and nephroblastoma. Most cases are sporadic. Very rarely, neuroblastoma occurs in families.

Genetic Abnormalities

Three distinctive cytogenetic features have been described: (1) Most cases of neuroblastoma show a near-terminal deletion of part of the short arm of chromosome 1 (partial monosomy 1), a finding that is of diagnostic value. This deletion is believed to be associated with loss of a neuroblastoma suppressor gene; (2) Chromosome 2 (rarely, some other chromosome) frequently shows a dense homogeneously stained region (HSR); and (3) Multiple double-minute (DM) chromatin bodies may be observed apart from the chromosomes (Figure 60-5).

Both HSR and DM chromatin bodies are believed to represent amplification sites of the oncogene N-myc. N-myc amplification is most often present in advanced disease (stages III and IV), and demonstration of N-myc amplification is thus considered a poor prognostic factor.

Pathology

Grossly, neuroblastomas tend to be very large infiltrative tumors. They are soft and friable and often show extensive hemorrhage and necrosis.

Microscopically, the neoplastic cells are small and round with large round nuclei and scanty cytoplasm. They are arranged in diffuse sheets with very little intervening stroma. The cells often bear nerve fibrils that appear as delicate pink filamentous structures. The formation of Homer-Wright rosettes—groups of cells arranged in a ring around a central mass of pink neural filaments—is characteristic (Figure 60-6).

Electron microscopy shows neurosecretory granules in the cytoplasm. Immunohistochemical studies show positivity for neuron-specific enolase. These findings permit differentiation of neuroblastoma from malignant lymphomas and other primitive mesenchymal neoplasms such as embryonal rhabdomyosarcoma, which can present similar gross and microscopic appearances.

Maturation, signified by differentiation of primitive cells into Schwann cells and large multinucleated ganglion cells, is not uncommon in neuroblastoma. When ganglionic differentiation is present, the tumor is called a ganglioneuroblastoma or differentiating neuroblastoma, and the prognosis is better than for an undifferentiated neuroblastoma. In a few cases of neuroblastoma with metastases, complete ganglion cell differentiation has been described, producing ganglioneuromas that then behave in benign fashion.

Clinical Features

Most patients with neuroblastoma present with an enlarging mass in the abdomen. Ninety percent of patients have increased catecholamine secretion, which can be identified by increased urinary levels of metanephrine and vanillylmandelic acid. Clinical evidence of catecholamine excess is, however, rare.

Hematogenous dissemination occurs very early. Patients fall into three fairly distinct patterns based on the pattern of metastasis: (1) extensive skull metastases, particularly involving the orbit and producing exophthalmos (Hutchinson type); (2) extensive liver metastases (Pepper type); and (3) extensive bone marrow involvement. It is not uncommon for patients with neuroblastoma to present with a metastatic lesion.

Treatment & Prognosis

Treatment of neuroblastoma is with combined surgery, chemotherapy, and radiation. Surgery is necessary to provide tissue for diagnosis and reduce tumor bulk. The increased effectiveness of chemotherapy has greatly improved survival statistics.

The prognosis of a patient with neuroblastoma depends on the following:

1. Clinical stage: (Table 60-6.) Patients with stage I or II have a 5-year survival rate > 90%; those with stage III or IV have a 20–30% 5-year survival rate; nearly all patients with stage IV-S survive.

2. Age of patient: The younger the age, the better the prognosis. Most patients with stage IV-S disease are under 1 year of age.

3. High expression of ferritin and neuron-specific enolase in tumor cells by immunohistochemistry is an adverse sign.

4. Amplification of N-myc oncogene in the cells is an adverse sign; patients with stage IV-S disease have normal N-myc levels.

5. Histologic evidence of ganglionic differentiation, which is common in stage IV-S, is a good prognostic sign. Differentiation is believed to result from presence of a nerve growth factor that is encoded by the Trk oncogene. High levels of Trk expression correlate with good prognosis. Ganglionic differentiation is associated with S100 protein positivity in the cells on immunoperoxidase staining.

The multiple endocrine neoplasia (MEN) or multiple endocrine adenomatosis (MEA) syndromes are characterized by the familial occurrence of multiple endocrine neoplasms. They are rare and are inherited as an autosomal dominant trait with variable penetrance.

Three types of MEN syndromes are recognized:

1. MEN (MEA) type I. MEN type I consists of pituitary adenoma, parathyroid hyperplasia or adenoma, and pancreatic islet cell neoplasms, including gastrinoma. Peptic ulcers also occur in these patients, probably related to gastrin production (Zollinger-Ellison syndrome). Adrenocortical adenomas rarely occur.

2. MEN type IIa (Sipple syndrome). MEN type IIa consists of medullary carcinoma and parafollicular cell hyperplasia of the thyroid and adrenal medullary hyperplasia or pheochromocytoma (Figure 60-4). Parathyroid hyperplasia or adenoma may also be present. These patients do not have pancreatic islet cell neoplasms or pituitary neoplasms and have no increased incidence of peptic ulcer.

3. MEN type IIb. A subgroup of MEN type II has been identified in which patients have mucocutaneous (tongue, eyelids, bronchus, intestine) neuromas in addition to the thyroid and adrenal neoplasms. This is sometimes also called MEN type III.