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MEN 1 (Wermer's syndrome)

Most patients with MEN type 1 present with symptoms of peptic ulceration related to the pancreatic gastrinoma (see II C 1 a) or with symptoms related to the pituitary tumor (see I B 1 c).

The hyperparathyroidism is typically asymptomatic and is usually detected by an increased serum calcium level.

MEN 2A (Sipple's syndrome)

The diagnosis should be suspected in all kindred of any patient with medullary carcinoma of the thyroid.

The inherited trait can be diagnosed in the premalignant stage, when C-cell hyperplasia is present before the medullary carcinoma develops by testing for mutation of the ret proto - oncogene.

Finding an increased serum calcitonin level leads to the diagnosis. Infusion of calcium and pentagastrin helps to stimulate an abnormal thyrocalcitonemia in those with C-cell hyperplasia or occult medullary carcinoma before either is clinically detectable.

Hyperparathyroidism is usually detected by increases in the serum calcium and parathyroid hormone levels.

Pheochromocytomas or adrenal medullary hyperplasia may be asymptomatic but should be detectable by biochemical screening for increased serum and urine catecholamines.

MEN 2B (mucosal neuroma syndrome)

Since MEN 2B assumes such an aggressive course, early diagnosis is important so that effective treatment can begin promptly.

The diagnosis is similar to that for MEN 2A. The early appearance of mucosal neuromas and the marfanoid body habitus should help in making the diagnosis.

DTreatment

MEN 1

If only the pancreatic and parathyroid components of this syndrome are present, the hyperparathyroidism is treated first. This may reduce the production of gastrin and relieve the peptic ulceration.

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Subtotal or total parathyroidectomy with arm reimplantation is required because the parathyroid disorder is usually four-gland hyperplasia.

If the hypergastrinemia and peptic ulceration persist, treatment is directed toward the Zollinger-Ellison syndrome (see II C 5). This involves removal of the gastrin -producing tumor, if possible, or, rarely, removal of the end organ (i.e., total gastrectomy) if the tumor cannot be removed and if the use of histamine 2 (H2 )-receptor antagonists or proton pump inhibitors (e.g.,

omeprazole) do not control the ulceration.

Pituitary tumors are usually treated medically with bromocriptine. Trans-sphenoidal hypophysectomy, using an operating microscope to minimize the risk of injury to the posterior pituitary, may be needed in some cases.

MEN 2A

Medullary carcinoma should be treated in the premalignant stage, when only C-cell hyperplasia is present, at which time total thyroidectomy is curative.

Pheochromocytoma or adrenal medullary hyperplasia, if present, should be treated before thyroidectomy because these hormone -producing disorders can lead to hypertensive crises during thyroidectomy. Simultaneous approaches have also been used.

Hyperparathyroidism can be treated at the time of total thyroidectomy by the protocol described in Chapter 16, III C 1, 2.

MEN 2B is treated similarly to MEN 2A. Since MEN 2B assumes such an aggressive course, prompt and effective treatment is important.

II Tumors of the Endocrine Pancreas

A Pathophysiology

The pancreatic islet cells and the endocrine cells of the gut (known as the amine p recursor u ptake and

d ecarboxylation cell system or APUD cells) originate from embryonic cells that have certain cytochemical properties in common.

They have a high amine content.

They have the ability for amine precursor uptake.

They produce the enzyme amino acid decarboxylase.

Tumors that arise from these APUD cells are termed apudomas. The various kinds of apudomas arising in the pancreas include:

Insulinomas

Gastrinomas (Zollinger-Ellison syndrome)

Glucagonomas

Vipomas (for vasoactive i ntestinal p eptide, or VIP )

Somatostatinomas

B Insulinomas

Overview. An insulinoma is a tumor originating from the beta cells of the pancreatic islets that releases abnormally high amounts of insulin.

Approximately 80%–90% of insulinomas are solitary, benign adenomas.

About 10% are malignant with the potential to metastasize.

The remainder are islet cell hyperplasia (termed nesidioblastosis in children).

Clinical presentation. The abnormally increased insulin levels and the resultant hypoglycemia produce the following clinical picture.

Bizarre behavior; unconscious episodes

Palpitations, nervousness, and other symptoms of sympathetic discharge

Whipple's triad:

Episodes of illness precipitated by fasting

Hypoglycemia during the episodes, usually with blood glucose levels less than 60 mg/dL

Relief of hypoglycemic symptoms by oral or intravenous administration of glucose

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Diagnosis. Once suspected, the diagnosis must be confirmed by documenting the abnormal circulating insulin levels.

Measurement of fasting insulin and glucose levels. An effective screening test is to have the patient fast for 72 hours or until symptoms of hypoglycemia appear and then to test the insulin and glucose levels. An increased insulin level in the presence of a low glucose level (insulin:glucose ratio greater than 0.25) effectively confirms an insulinoma. The presence of an elevated insulin C peptide is used to rule out iatrogenic insulin overdose.

Essentially, all patients with insulinomas will become hypoglycemic within 72 hours.

As many as 40% will develop symptoms within 2 hours of beginning the fast.

Comparing insulin and proinsulin levels can be helpful.

Proinsulin is the single -chain intracellular precursor that is cleaved, before secretion, into insulin and C peptide.

Normally, less than 20% of the total circulating immunoreactive insulin is proinsulin.

In patients who have insulinoma, proinsulin levels frequently represent more than 20% of the total circulating insulin.

Provocative tests rarely may be necessary to prove the diagnosis.

Tolbutamide or glucagon may be infused intravenously: An increased insulin level is diagnostic of insulinoma.

Fish insulin may be infused: Endogenous insulin levels will be suppressed in the normal individual but not in the insulinoma patient. (Fish insulin is not immunoreactive with human insulin.)

Calcium may be infused. This will cause the release of insulin and proinsulin in insulinoma patients, resulting in symptoms of hypoglycemia.

Treatment

Surgical treatment

Surgical management is based on preoperative localization of the tumor.

More than 75% of all insulinomas are smaller than 1.5 cm, so arteriography, computed tomography (CT), and magnetic resonance imaging (MRI) are less sensitive for detecting insulinomas than for larger tumors. Selective arteriography may detect 50% of these tumors.

Percutaneous catheterization of the portal vein with serial insulin measurements can also help to localize the area of the tumor.

Endoscopic ultrasound is probably the best imaging test for insulinomas.

Exploration of the entire pancreas for a palpable mass is undertaken first.

If the tumor is palpable or is visible as a reddish -brown discoloration, it should be either enucleated or removed as part of a distal pancreatectomy.

Intraoperative ultrasound is helpful to localize small insulinomas (Fig. 17 -1).

If lymph nodes adjacent to the tumor are firm and enlarged, suggesting carcinoma, or if the tumor feels malignant (i.e., firm and infiltrative), then a standard form of resectional therapy should be performed, such as pancreaticoduodenectomy or total pancreatectomy with lymphadenectomy.

The combination of careful palpation plus the use of intraoperative ultrasound should demonstrate the tumor in approximately 90% of patients. If the tumor is not localized, then the management is debatable.

The classic procedure is to resect the tail of the pancreas and examine the specimen pathologically. If a tumor is still not found, all of the pancreas but the head and the uncinate process is removed, and the operation is terminated.

The surgeon may proceed to total pancreatectomy if the tumor is not found in the tail of the pancreas.

The surgeon may resect only 80%–90% of the pancreas and then observe the patient for hyperinsulinism postoperatively. If medical measures then do not control the patient's symptoms, a total pancreatectomy may be necessary.

When islet cell hyperplasia is present, an 80%–90% subtotal pancreatectomy will usually control the symptoms.

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FIGURE 17-1 Intraoperative ultrasound of an islet cell tumor producing hyperinsulinism in a 34-year-old woman.

Blood glucose levels should be monitored in the operating room to prevent hypoglycemia.

Medical treatment is limited to patients who are incurable operatively or who have malignant disease.

Prognosis

Approximately 65% of patients are cured by surgery.

The operative mortality rate is 10%.

Patients who have malignant insulinomas have a 60% 2-year survival rate.

C Gastrinomas (Zollinger-Ellison syndrome)

Pathogenesis

Symptoms in this disorder result from oversecretion of gastrin, the consequence of which is peptic ulceration because of high gastric acid secretion.

The cause is usually a nonbeta islet cell tumor of the pancreas (i.e., a D-cell or δ-cell tumor).

Zollinger -Ellison syndrome may be a component of MEN type I.

Clinical presentation

Abdominal pain secondary to the peptic ulceration is present in more than 90% of the patients.

Diarrhea is common, resulting from:

Gastric hypersecretion, which creates a low duodenal pH and inactivates pancreatic enzymes, resulting in steatorrhea

Gastrin-stimulated intestinal motility, which impairs fluid and electrolyte absorption

Gastrointestinal (GI) hemorrhage from the peptic ulceration occurs in up to 40% of patients.

Ulcer perforation and gastric outlet obstruction also occur.

Profound dehydration and malnutrition may be present.

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Diagnosis

The following conditions should alert the physician to the possibility of Zollinger -Ellison syndrome:

Recurrent ulcer symptoms

Recurrent ulcer after a standard surgical procedure for peptic ulcer disease

An ulcer that is refractory to intensive treatment with antacids, H 2 -receptor blockers, or omeprazole

Laboratory findings provide the diagnosis.

Gastric acid hypersecretion is present in 70%–80% of patients. It is manifested by:

A 12 -hour overnight basal acid output (BAO) of more than 100 mmol of hydrochloric acid

A 1-hour BAO of more than 15 mmol

Little or no increase in gastric acid secretion after stimulation of pentagastrin or betazole

This test shows that the parietal cells are under maximal stimulation.

Results are expressed as the ratio of basal:maximal acid output (BAO:MAO), which usually exceeds 0.6 in patients who have Zollinger -Ellison syndrome.

Increased levels of serum gastrin are the key to the diagnosis.

Gastrin levels are determined by radioimmunoassay, which measures both the heptadecapeptide itself and its precursor form, G -34 or “big gastrin.”

Most patients who have Zollinger -Ellison syndrome have a fasting serum gastrin level of 500 pg/mL or more (the normal level is 20–150 pg/mL).

Some patients have an intermediate serum gastrin level of 200–500 pg/mL. A gastrin stimulation test may then aid in the diagnosis.

In Zollinger -Ellison syndrome, an infusion of calcium will increase the gastrin level by more than 300 pg/mL, and an infusion of secretin will increase it by 100 pg/mL or more.

Peptic ulcer patients and normal persons will not show this response.

Extremely high gastrin levels (more than 5000 pg/mL) or the presence of α-chain human chorionic gonadotropin in the serum strongly suggests a malignant gastrinoma.

Serum gastrin levels also may be increased by pathologic processes other than nonbeta islet cell carcinoma of the pancreas, including:

Nonbeta islet cell adenomas

Antral G -cell hyperplasia

Gastric outlet obstruction

A retained gastric antrum after incomplete antrectomy for peptic ulcer disease

Conditions that cause gastric hypoacidity (which is a stimulus for gastrin production), including pernicious anemia, atrophic gastritis, and gastric carcinoma

Another innovative technique combines selective injection of secretin into mesenteric arteries with simultaneous measurement of gastrin.

Radiographs will usually show upper GI ulceration.

Frequently, multiple ulcers are found.

Ulcers are sometimes found in the distal duodenum and jejunum.

Localization of the tumor. Localization studies are the same as described for insulinomas. Arteriography is less accurate for gastrinomas because these tumors are less vascular than insulinomas.

Treatment of Zollinger -Ellison syndrome is centered around removal of the causative tumor plus control of the end -organ (gastric mucosal) response.

The tumor should be removed if possible because approximately 60% are malignant.

Unfortunately, the tumor is frequently multifocal or difficult to identify at laparotomy.

Only about 20% are resectable.

Lesions in the wall of the duodenum (present in greater than 25% of cases) and in the tail of the pancreas are the most common types of resectable tumors.

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Most gastrinomas are located in the “Gastrinoma triangle,” which is an anatomic triangle defined by the junction of the cystic and common bile ducts superiorly, the junction of the second and third portions of the duodenum inferiorly, and the junction of the neck and body of