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Diagnosis

Urinary levels of metanephrine and VMA are the most reliable diagnostic screening tests. These levels are increased in 90%–95% of the cases.

Fractionated plasma and urinary catecholamine levels can increase the accuracy of the diagnosis to virtually 100%.

The need for potentially hazardous provocative tests using histamine, tyramine, and glucagon has been greatly reduced. These tests are used only in the rare patient who has equivocal biochemical findings.

Localization of the tumor

CT and MRI have emerged as the most accurate, minimally invasive means of localizing pheochromocytomas. They are accurate in more than 95% of cases.

Arteriography should be used only after adequate α-adrenergic blockade because it can precipitate a hypertensive crisis.

Scintigraphy with radioiodine-labeled m-iodobenzylguanidine (MIBG), which structurally resembles norepinephrine, has been helpful for cases in which CT has not localized the tumor, especially with small extra-adrenal tumors.

Vena cava sampling. If the pheochromocytoma still has not been localized, samples of blood can be taken by catheter from different parts of the vena cava and other veins for catecholamine analysis.

Surgical treatment

Preparation for surgery should include adrenergic blockade with both α- and β-blockers.

Adrenergic blockade is helpful for three reasons.

It provides preoperative control of hypertension.

It reduces the risk of dramatic swings in blood pressure during surgery.

It provides vasodilation, allowing restoration of a normal blood volume (blood volume can be about 15% less than normal in patients who have pheochromocytomas).

Alpha -blockade is achieved first. Phenoxybenzamine therapy is begun 2 weeks before surgery, starting with 40 mg/day and adjusting the dose until hypertension and associated symptoms are controlled.

β-blockade is then obtained with propranolol, starting about 3 days before surgery, to control tachycardia. A starting dose of 40 mg/day may need adjustment if tachycardia persists.

Operation

The patient should be monitored with an arterial and a central venous pressure line because of the potential for wide blood pressure changes and the large fluid requirements. A Swan -Ganz catheter should be used in elderly patients and in those with cardiac disease.

The approach may be transabdominal because of the high incidence of multiple and extraadrenal tumors. However, with more accurate imaging techniques, the laparoscopic approach can be used for smaller tumors.

Total adrenalectomy is the procedure of choice for pheochromocytomas.

Special situations

Malignant pheochromocytomas are treated by surgical excision of the tumor. If this cannot be accomplished, then as much tumor as possible is resected, and pharmacologic control of the catecholamine excess is started. Chemotherapy can be used for extensive metastatic disease.

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When pheochromocytoma is a component of multiple endocrine neoplasia , a bilateral total adrenalectomy should be performed. If only one gland is removed, there is a high incidence of recurrence on the other side.

H Adrenal cysts and other adrenal tumors

Adrenal cysts occur infrequently, showing up in fewer than 0.1% of autopsies.

Types. Most adrenal cysts are either endothelial cysts (lymphangiomatous or angiomatous) or pseudocysts, resulting from hemorrhage into normal adrenal tissue or into an adrenal neoplasm. Rarely are they retention cysts or cystic adenomas.

Symptoms. A large cyst can present as a palpable mass and can cause dull aching or gastrointestinal symptoms due to pressure. With cystic neoplasms, symptoms are those of the underlying process.

Diagnosis. CT and MRI are the best methods available for diagnosing adrenal cysts.

Treatment. Because a neoplasm cannot be excluded, these cysts should be surgically excised.

Virilizing tumors of the adrenal cortex are either adenomas or carcinomas.

Symptoms

In females, hirsutism, amenorrhea, and an enlarged clitoris are characteristic. In female patients, it is important to exclude other causes of virilization, particularly congenital virilizing hyperplasia in the young and an arrhenoblastoma of the ovary in older patients.

In males , pseudoprecocious puberty occurs.

In all patients , some of the features of Cushing's syndrome may be evident. The urinary excretion of 17 -ketosteroids is increased.

Diagnosis. CT or MRI provides the best localization of the tumor.

Treatment consists of complete surgical excision. Mitotane is used for metastatic disease.

Feminizing tumors of the adrenal cortex are either adenomas or carcinomas.

Symptoms. In females, the tumor causes rapid premature sexual development. In males, there will be

gynecomastia, decreased libido, and testicular atrophy.

Diagnosis. Localization is by CT or MRI.

Treatment. Complete surgical excision offers the only hope for cure. Mitotane is used for metastatic disease.

Nonfunctioning adrenal masses have been discovered at autopsy in up to 9% of patients. With the growing use of CT and MRI scanning, an increased number of these “incidentalomas” are being discovered during life.

Although adenomas cannot be distinguished from carcinomas except by excision and inspection, carcinomas are rare when lesions are nonfunctional and smaller than 6 cm in diameter.

These patients should probably be followed up with a repeat CT or MRI in 6 months. However, if a nonfunctioning mass is larger than 6 cm or is enlarging, surgical excision is the safest course to take.

A CT-directed needle biopsy of nonfunctional tumors less than 6 cm in diameter may be considered to establish a diagnosis. However, risks include bleeding (which could make any subsequent laparoscopic approach more difficult) or dissemination of tumor cells (which could make subsequent extirpation of the disease more difficult).

III Parathyroid Glands

A Introduction

The parathyroid glands are important to surgeons for two reasons. First, because surgeons treat patients with symptomatic hyperparathyroidism, they must know the cause and management of various hyperparathyroid conditions, and second, during operations for the neck, it is imperative that the integrity of the parathyroids be preserved to avoid injury, the consequence of which can be permanent hypoparathyroidism. There is no satisfactory replacement for endogenously produced parathyroid hormone, and the patient with hypoparathyroidism is doomed to a lifelong process of episodic, symptomatic hypocalcemia despite calcium and vitamin D therapy.

Embryology. In most individuals, there are two superior and two inferior parathyroid glands that differ in their embryologic origin.

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Superior parathyroid glands

The superior parathyroid glands arise from the fourth branchial pouch in close proximity to the origin of the thyroid (the floor of the foregut) and descend into the neck.

Because of the embryologic origin, abnormal parathyroid locations may be either intrathyroidal or within the posterior mediastinum near the tracheoesophageal groove or the esophagus.

Inferior parathyroid glands

The inferior parathyroids arise from the third branchial pouch in relationship to the thymic anlage. They cross the superior glands in their descent into the neck.

Frequently, they are associated with the thymus gland in the anterosuperior mediastinum.

Anatomy (Fig. 16 -5)

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Histopathology

The normal parathyroid gland has a significant amount of fat interspersed with chief and oxyphil cells.

Hypercellular glands, found in hyperparathyroid states, have a paucity of fat. The hypercellularity is mostly oxyphil -cell hyperplasia, but occasionally chief -cell hyperplasia may also be noted.

Histologically, one cannot distinguish the hypercellularity of a hyperplastic gland from that of a gland harboring an adenoma.

B Parathyroid hormone (parathormone, PTH)

Calcium metabolism regulation. PTH is a major regulator of calcium metabolism.

It acts in conjunction with calcitonin and activated vitamin D 3 to regulate the plasma concentration of

the ionized form of calcium. There is normally a reciprocal relationship between the serum calcium concentration and PTH secretion.

As serum calcium levels decrease, the secretion of PTH increases.

As serum calcium levels increase, the secretion of PTH decreases.

PTH exerts its biologic effect on bone, intestine, and kidney.

It increases the mobilization of calcium and phosphorous from bone by stimulating osteoclastic and osteolytic activity.

It acts synergistically with 1, 25 -dihydroxyvitamin D 3 to increase the absorption of calcium and phosphorus from the gut.

Renal effects

PTH raises the renal threshold for calcium by promoting the active reabsorption of calcium in the distal nephron.

It also lowers the renal threshold for phosphate by inhibiting phosphate reabsorption in the proximal tubule.

PTH secretion and phosphate depletion stimulate the activation of 1,25 -dihydroxyvitamin D3 via the activation of 1 α-hydroxylase.

Increased, unopposed PTH secretion has the following clinical effects on bone, intestine, and kidney:

Hypercalcemia

Altered calcium excretion

Initially, hypocalciuria occurs due to increased calcium reabsorption.

This reverts to hypercalciuria in chronic hyperparathyroid states when the hypercalcemia exceeds the renal threshold for calcium.

Hypophosphatemia

Hyperphosphaturia

Laboratory tests. Serum PTH levels can be measured by radioimmunoassay. Normal values vary from laboratory to laboratory, depending in part on whether the intact molecule or the C or N terminal of the PTH molecule is used in the assay. The intact molecule assay is more reliable.

C Hyperparathyroidism

Primary hyperparathyroidism

Incidence. Primary hyperparathyroidism is a relatively common disorder and is the most common cause of hypercalcemia in patients outside the hospital. It most commonly occurs sporadically but may occur as:

Part of a MEN syndrome (see Chapter 17)

Familial hyperparathyroidism

Ectopic or pseudohyperparathyroidism due to the production of a PTH-like substance from an extraparathyroidal tumor

Etiology and pathology

Between 85% and 90% of primary hyperparathyroidism cases are due to a solitary adenoma of one of the four glands.

Approximately 10%–15% are due to four-gland hyperplasia. The hyperplasia may be asymmetrical with one or two glands grossly enlarged. Microscopically, however, all glands show hypercellularity.

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Parathyroid carcinoma accounts for less than 1% of primary hyperparathyroidism cases.

About 0.4% of cases are due to multiple adenomas involving more than one gland.

Microscopically, the glands have a paucity of fat and appear hypercellular (see III A 2 d).

Clinical presentation

Most patients with primary hyperparathyroidism are asymptomatic, and the altered state is discovered only because an increased serum calcium level is noted on routine multichannel biochemical screening.

When patients are symptomatic, the symptoms follow the mnemonic “stones, bones, moans, and abdominal groans.”

Stones. Renal lithiasis occurs in 50% of patients with symptomatic primary hyperparathyroidism (although primary hyperparathyroidism occurs in fewer than 10% of all patients who have renal lithiasis).

Bones. Osteitis fibrosa cystica (von Recklinghausen's disease of bone) is found mostly in patients who have secondary and tertiary hyperparathyroidism, which are due to chronic renal disease (see III C 2, 3).

Moans. Psychiatric manifestations—personality disorders or frank psychosis—may accompany primary hyperparathyroidism but are relatively uncommon.

Abdominal groans

The incidence of peptic ulcer disease is increased in primary hyperparathyroidism, usually associated with hypergastrinemia that results from the hypercalcemia.

Cholelithiasis or pancreatitis may also occur, accounting for abdominal symptoms.

Most patients have nonspecific symptoms, such as weakness, easy fatigability, lethargy, constipation, and arthralgia.

Diagnosis

Laboratory studies

An increased serum calcium level is the cornerstone of diagnosis.

This should be shown on at least three blood specimens, drawn on different occasions.

While primary hyperparathyroidism is a relatively common cause of hypercalcemia, other causes must be excluded, such as metastatic bone disease, myeloma, sarcoidosis, the use of thiazide diuretics, milk -alkali syndrome, hypervitaminosis, thyrotoxicosis, and Addison's disease.

A serum PTH level that is disproportionately high for the serum calcium level (measured concomitantly) is diagnostic for primary hyperparathyroidism (Fig. 16 -6).

In patients who have metastatic bone disease, hypercalcemia occurs without a disproportionate increase of PTH level.

In patients who have secondary hyperparathyroidism, the serum PTH level is increased and the serum calcium is low.

In patients who have hypoparathyroidism, the serum calcium and serum PTH levels are both low.

The serum PTH level can also be increased in patients who have pseudohyperparathyroidism , a disorder characterized by an extraparathyroidal source of PTH. For example, tumors arising from the APUD cell system (see Chapter 17, II A 2) may produce a PTH-like substance that is indistinguishable from PTH by normal laboratory means.

The serum phosphorus level is decreased, and the serum chloride:phosphorus ratio usually exceeds 33:1.

The tubular reabsorption of phosphorus is less than 80%, resulting in hyperphosphaturia.

Measurement of urinary cyclic adenosine monophosphate shows increased levels.

Urinary calcium excretion is increased when the patient is on a calcium-restricted diet.

Radiographic studies

Radiographs of the skull may show a “ground -glass” appearance in the outer two thirds of the skull. Skull radiographs are also obtained to search for enlargement of the sella turcica due to a pituitary tumor, which may connote multiple endocrine neoplasia.

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FIGURE 16-6 The relationship between serum calcium and serum parathormone levels in primary hyperparathyroidism surgically proven (•), secondary hyperparathyroidism (○), hypoparathyroidism (▼), and hypercalcemia due to metastatic bone disease (▪).

Radiographs of the proximal ends of the long bones may show bony reabsorption or brown tumors of the bone.

Radiographs of the fingers may show subperiosteal absorption on the radial side of the middle phalanges and in the tufts of the terminal phalanges. Abnormal calcification in the digital vessels may also be found.