The tumors can be benign or malignant and can occur metachronously or synchronously. MEN-1 is

characterized by the concurrence of parathyroid hyperplasia, pancreatic islet-cell tumors, and pituitary

adenomas. MEN-2A consists of medullary thyroid carcinoma (MTC), pheochromocytoma, and

parathyroid hyperplasia. MEN-2B includes MTC, pheochromocytoma, mucosal neuromas, and a

distinctive marfanoid habitus. Together these syndromes encompass much of the spectrum of endocrine

neoplasia.

Pathogenesis

The genetic abnormality in MEN-1 has been identified and described in detail.55,56 As a tumorsuppressor gene, the first mutation is inherited and becomes unmasked only when a second mutation, in

some cases a deletion, develops in susceptible tissues. The resulting complete loss of the tumor

suppressor allows neoplasia to develop. The occurrence of multiple second mutations explains the

characteristic multicentric involvement of these diseases. Direct genetic testing is now available for

some families with known mutations.

Mutations of the RET protooncogene are the cause of MEN-2A.57,58 Genetic testing is now available to

identify affected family members and provide the opportunity for early treatment of MTC in affected

persons.

Clinical Features and Management of Multiple Endocrine Neoplasia Type 1

Characteristically, MEN-1 presents in the third and fourth decades, without any gender predilection.59

The syndrome is expressed with nearly complete penetrance, and autopsy studies suggest that all three

organs are affected in more than 90% of patients. The phenotype varies, however; more than 90% of

patients have hyperparathyroidism, but evidence of islet cell neoplasms (30% to 80%) and pituitary

tumors (15% to 50%) is less common. The cause of death in carriers of the MEN-1 mutation is related to

MEN-1 in about 45% of patients and often caused by malignant islet cell or carcinoid tumors.60

Parathyroid Disease

Hypercalcemia secondary to hyperparathyroidism is usually the first biochemical abnormality detected

in MEN-1 and represents the best screening opportunity for members of affected kindreds until direct

genetic screening is available in a specific family. Many of these patients are asymptomatic and have

relatively mild hypercalcemia. When symptoms do develop, they typically involve the urinary tract

rather than the skeleton.

Typically, the patients have four-gland disease, which may be particularly difficult to manage. The

disease is characterized by metachronous development of multiple parathyroid adenomas. There is no

curative operation; the two accepted approaches (subtotal parathyroidectomy and total

parathyroidectomy with autograft) each have faults (see earlier). Over time, the subtotal

parathyroidectomy approach is becoming the preferred choice by most surgeons.

Figure 76-17. Scatter plot of largest primary tumor size versus metastatic status in 43 patients with pancreatic islet cell tumors

associated with multiple endocrine neoplasia type I. Each point represents a single patient. Tumor size is not correlated with the

presence of liver or lymph node metastases. (From Lowney JK, Frisella MM, Lairmore TC, et al. Islet cell tumor metastasis in

multiple endocrine neoplasia type I: correlation with primary tumor size. Surgery 1998;124:1043–1049.)

Pancreatic Tumors

In patients with pancreatic tumors, multicentric and diffuse hyperplasia of the pancreatic islets may

occur in areas distant from any grossly evident tumor. The management of these tumors is controversial

because although some patients have aggressive, malignant tumors, many patients have a fairly benign

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course. No reliable criteria are available to detect malignant tumors. Tumor size is often cited as a

useful marker of prognosis, but substantial overlap has been noted between the sizes of primary benign

and malignant tumors (Fig. 76-17).61 Because of the difficulty in identifying the more aggressive subset,

some authors have chosen a liberal policy of early operation to try to prevent metastasis and death.

Pancreatic tumors are typically multicentric and frequently malignant. Somatostatin receptor

scintigraphy can be a useful imaging technique to demonstrate the extent of tumor (Fig. 76-18).62

Figure 76-18. Somatostatin receptor scintigraphy in a patient with multiple endocrine neoplasia type I. This scintiscan detected an

otherwise unrecognized metastasis to the left lateral segment of the liver (white arrow), which was resected along with the small

primary tumor (black arrow).

Gastrinoma is the most common functional tumor in MEN-1; typically, a severe ulcer diathesis

(Zollinger–Ellison syndrome) develops that is associated with secretory diarrhea. Serum gastrin levels

are usually markedly elevated (>1,000 pg/mL); when levels are equivocal (250 to 1,000 pg/mL),

provocative testing with secretin (2 m/kg) may be useful. An absolute serum gastrin increase of 200

pg/mL is diagnostic. The primary tumors are often in the submucosa of the duodenal wall.

Biochemical cure of these gastrinomas is almost never possible, which is different than patients with

sporadic gastrinomas, although exploration can reduce the need for antisecretory medications and may

reduce the risk for liver metastasis. Histamine 2-receptor antagonists or proton pump inhibitors are

effective in controlling acid secretion, although very high doses may be necessary; the malignant

disease is often indolent. Total gastrectomy is no longer ever necessary to eliminate acid secretion.

Insulinoma is the next most common functional pancreatic neoplasm in MEN-1. Patients present with

a history of sweating, dizziness, confusion, and syncope, consistent with neuroglycopenia; these

symptoms are relieved by consuming carbohydrates. The diagnosis is verified by documenting fasting

hypoglycemia associated with inappropriately elevated plasma insulin levels. Preoperative tumor

localization is usually achieved by a combination of CT and arteriography. Calcium is injected into

various pancreatic arteries and plasma insulin levels in the hepatic vein plasma are measured to detect a

gradient after the injection of specific pancreatic arteries localizing the area of the pancreas containing

the functional tumor.

Because the available medical therapy for insulinoma is limited, patients are treated operatively.

Lesions in the tail of the gland can be enucleated if they are small; however, distal pancreatectomy

carries little morbidity. Tumors of the head can usually be enucleated, so that pancreaticoduodenectomy

can be avoided. In patients with malignant disease, metastases may respond to streptozocin, diazoxide,

verapamil, or octreotide may successfully reduce insulin secretion and control symptoms. A diet of

complex carbohydrates can also help stabilize serum glucose levels in the hyperinsulinemic patient.

Nonfunctional tumors are the most common pancreas lesions in MEN-1. Their management is specific

to their size and risk of malignancy.

Pituitary Adenomas

Prolactin-secreting tumors occur most commonly in this setting, although Cushing disease or

acromegaly develops in an occasional patient. Symptoms may result from compression of the optic

chiasm, which produces bitemporal hemianopsia, or from prolactin excess, which produces amenorrhea

and galactorrhea in female patients and hypogonadism in male patients.

Bromocriptine inhibits prolactin secretion and shrinks many prolactinomas. Refractory tumors and

those producing other hormones can be managed by pituitary ablation or radiation.

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Other Tumors

MEN-1 is associated much less frequently with adrenocortical tumors and benign thyroid adenomas.

Lipomas and carcinoid tumors may also occur.

Clinical Features and Management of Multiple Endocrine Neoplasia Type 2

Like MEN-1, the MEN-2 syndromes are inherited in an autosomal dominant fashion with complete

penetrance but variable phenotype. Bilateral MTC occurs in every affected patient. More frequently

than the other syndromes, MEN-2B can arise as a new mutation that can be transmitted to subsequent

generations.

Figure 76-19. Medullary thyroid carcinoma. Coronal section of a total thyroid resection shows bilateral involvement by a firm,

pale tumor.

Medullary Thyroid Carcinoma

Medullary thyroid carcinoma accounts for about 10% of all thyroid malignancies, and 20% of cases

occur in the familial setting of MEN-2A, MEN-2B, or familial non-MEN MTC. It is usually the first tumor

that develops in these patients and typically appears in the second or third decade. Tumors are virtually

always bilateral and develop in multiple areas of the middle and upper portions of the thyroid lobe (Fig.

76-19). Occasionally, in young people, a diffuse proliferation of parafollicular C cells, termed C-cell

hyperplasia, is present without frankly invasive carcinoma. This finding is highly suggestive of one of the

familial MTC syndromes. Patients typically present with a neck mass and may have hoarseness,

dysphagia, or palpable cervical adenopathy. MTC may produce a variety of hormones, including

calcitonin, adrenocorticotropic hormone, prostaglandin, and serotonin. The hypercalcitoninemia is often

asymptomatic, although severe diarrhea can develop.

By detecting minimal elevations of plasma calcitonin, it is possible to diagnose MTC at a clinically

occult stage. Basal plasma calcitonin levels in normal subjects are in the range of 30 to 100 pg/mL. An

increase to levels of 150 to 200 pg/mL occurs, however, after the administration of the potent

secretagogues calcium and pentagastrin. The plasma calcitonin levels of patients with MTC show

striking increases (>1,000 pg/mL) after provocative testing, so that they can be identified readily.

Patients with occult disease may have only minimally elevated basal calcitonin levels that increase in

response to secretagogues. The combined infusion of calcium and pentagastrin was the most effective

screening test for familial MTC before genetic testing became available. By means of provocative

testing in kindred members at risk for disease, MTC was diagnosed at a preclinical stage, and a greater

percentage of these patients were cured by surgical therapy. With genetic testing now available,

prophylactic thyroidectomy to prevent the development of MTC is possible for all affected people.

Postoperatively, the presence of residual MTC can be readily detected by provocative testing.

Meticulous reoperation in patients with recurrent or persistently elevated plasma calcitonin levels

postoperatively, including mediastinal dissection on occasion, can normalize elevated plasma calcitonin

levels and apparently cure many of them.63 For the patient with unresectable metastases, few

therapeutic options are available. Neither radiation nor chemotherapy is of significant benefit.

The clinical course of patients with the MEN-2 syndromes is determined primarily by the status of

their MTC. In the setting of MEN-2A, the tumors are often indolent and survival prolonged, even in the

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presence of metastatic disease. By contrast, the tumors in patients with MEN-2B occur at an earlier age

and are generally more aggressive neoplasms. Patients may succumb to the disease at a young age. As a

consequence of this aggressiveness, the size of kindreds with the disease is typically small, and usually

only a few generations are affected.

Pheochromocytoma

Pheochromocytomas are usually detected during the initial screening or follow-up of patients in whom

MTC has already been diagnosed. They typically appear in the second or third decade of life, and about

80% are bilateral. Usually, pheochromocytomas are benign but multicentric, and they almost always

arise in the adrenal medulla. In patients with MEN-2A or MEN-2B, hyperplasia of the adrenal medulla

may develop first, grossly characterized by thickening of the medullary tissue in both adrenal glands.

Pheochromocytomas can be asymptomatic, but most commonly, patients have pounding frontal

headaches, episodic diaphoresis, palpitations, or anxiety. Hypertension also occurs and is often episodic.

The diagnosis is made by measuring the plasma concentration of metanephrines. Patients with MEN2A or MEN-2B and MTC should be evaluated for pheochromocytoma before they undergo

thyroidectomy. If a patient is found to have both lesions, adrenalectomy should be performed first,

followed by neck exploration. The abdomen is explored through a bilateral subcostal incision or, more

typically, with a laparoscope.64 Bilateral pheochromocytomas are treated by bilateral adrenalectomy. In

patients with MEN-2A or MEN-2B and a unilateral pheochromocytoma, only the diseased adrenal gland

is removed. In about 30% of patients treated in this manner, a tumor eventually develops in the

opposite gland. In the remaining patients, this approach avoids the need for glucocorticoid and

mineralocorticoid replacement and the risk for addisonian crisis. After unilateral adrenalectomy,

patients are carefully screened at 6-month or 1-year intervals with plasma metanephrine measurements.

Parathyroid Disease

Hyperparathyroidism develops in about one-third of patients with MEN-2A, although it is usually

asymptomatic. Occasionally, nephrolithiasis develops. Bone disease is unusual. Frequently, enlarged

parathyroid glands are found at operation for MTC, although the patient is still normocalcemic.

Multiglandular chief cell hyperplasia is the predominant histologic finding in MEN-2A. Significant

parathyroid disease rarely develops in MEN-2B.

Total parathyroidectomy and heterotopic autotransplantation are performed in hypercalcemic patients

with MEN-2A. In normocalcemic patients with MEN-2A undergoing thyroidectomy for MTC, total

parathyroidectomy and heterotopic autotransplantation are performed in one session to ensure that the

complete thyroidectomy does not compromise the parathyroid blood supply and to avoid reoperation in

the neck for subsequent hyperparathyroidism. Evidence suggests that these patients are more easily

treated, with a lower incidence of recurrent hyperparathyroidism, than patients with MEN-1.

Nonendocrine Manifestations of Multiple

Endocrine Neoplasia Type 2B. In addition to MTC and pheochromocytoma, marked abnormalities of

the nervous and musculoskeletal systems develop in patients with MEN-2B. The classic phenotype is

characterized by thick lips and a thin, marfanoid habitus (Fig. 76-20A,B). The incidence of associated

skeletal abnormalities is high; these include kyphosis, pectus excavatum, pes planus or cavus, and

congenital dislocation of the hip. Diffuse autonomic nervous hypertrophy is another feature. Mucosal

neuromas appear on the tongue (Fig. 76-20C), eyelids, lips, and pharynx. Slit-lamp examination may

reveal hypertrophied corneal nerves. Ganglioneuromatosis develops in the submucosal and myenteric

plexuses of the gastrointestinal tract. Constipation is common, and radiographic findings may suggest

megacolon or Hirschsprung disease.

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Figure 76-20. A,B: Characteristic appearance of patients with multiple endocrine neoplasia type IIB, including thick lips. C:

Multiple mucosal neuromas on the tongue of a patient with MEN-2B. (From Norton JA, Froome LC, Farrell FE, et al. Multiple

endocrine neoplasia type 2b: the most aggressive form of medullary thyroid carcinoma. Surg Clin North Am 1979;59:109.)

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