Endocrine Syndromes Associated with Pancreatic Islet Cell Tumors

Endocrine Syndromes Associated with Pancreatic Islet Cell Tumors MARVIN E. LEVIN, M.D.*

When Langerhans 30 in 1869 identified those small islands of special pancreatic cells which now bear his name, he ascribed no function to them. Now, almost one hundred years later, it is being recognized with increasing frequency that these cells, with a total estimated weight of only 1 gm. in a 60 to 100 gm. organ, not only are the source of at least two major hormones, insulin and glucagon, but also, after undergoing hyperplastic or neoplastic changes, can produce a variety of endocrine syndromes (Fig. 1). Islet cells show great variability along the phylogenetic scale. 37 The earliest appearance of islet tissue is in the hagfish and lamprey, where it is found embedded in the intestinal wall but not connected to the gut lumen. The types of islet cells found also vary from species to species. Amphibians have only beta cells, while reptiles and birds have chiefly alpha cells. In most mammals beta cells predominate; in man, 60 to 70 per cent of the islet cell population is composed of beta cells, with most of the remaining cells being alpha cells. A third type, the D cell, has also been identified in man. 49 It is now well accepted that the beta cell is responsible for insulin production and the alpha cell is the source of glucagon. Although no definite biologic function has been confirmed for the D cell, there are inferential data that it may be the source of gastrin production." Because the D cells comprise the smallest number of islet cells, they probably represent a rudimentary cell type which under normal conditions has no significant physiologic function. However, with hyperplastic or neoplastic changes, these cells may secrete large amounts of gastrin, which results in the Zollinger-Ellison syndrome. Normal islet cells can usually be identified by histochemical techniques (Table 1). However, the identification of cell types in islet tumors by tinctorial methods is more difficult and often fails to provide unequivocal identification. Examination of the ultrastructure of the islet ':'Assistant Professor of Clinical Medicine, Washington University School of Medicine; Assistant Physician, Barnes Hospital, and Associate Attending Physician, Jewish Hospital, St. Louis, Missouri

Medical Clinics of North America- Vol. 52, No. 2, March, 1968

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Multiple or Mixed Syndromes

LEVIN

- Hypoglycemia

Zoll inger -Ell ison Syndrome

Figure 1.

E.

Cushing's Syndrome

Endocrine syndromes which have been produced by islet cell tumors,

cells by electron microscopy has aided greatly the identification of both normal and neoplastic islet cells. The first detailed description of the fine structure of the beta cell was reported by Lacy28 in 1957. The beta cells are recognizable by their characteristic granules (Fig. 2). In man, the beta granules appear as round, irregular or bar-shaped structures which do not completely fill the limiting membrane of the granular sac. The alpha cells contain round, homogenous, dense-appearing granules which completely fill the limiting membrane (Fig. 3). When alpha and beta cells produce adenomatous or malignant tumors, they tend to maintain their ultrastructural characteristics. In the case reported by McGavran et al.3 4 of an alpha cell tumor producing glucagon, the ultrastructural nature of the alpha cell granules in the tumor were identical to normal alpha cell granules (Fig. 3). Lacy27 also observed the beta granules in the neoplastic cells of five beta cell tumors to have the same ultrastructure as normal beta cells, although there was some variation in the fine structure. However, this may not be a consistent finding, as Greider18 has observed striking alterations in the Table 1.

Histochemical Characteristics of Islet Cells

STAIN

ALPHA

BETA

DELTA

Chromhematoxylin-phloxin

Red

Blue

Negative

Silver Tryptophan

Positive

Negative

Positive

Positive

Negative

Negative

Aldehyde-fuchsin

Negative

Positive (purple)

Negative

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Figure 2. Electron micrograph of beta cell granules from a normal human islet. x about 25,000. (Courtesy of Dr. Malcolm McGavran, Department of Pathology, Washington University School of Medicine.)

ultrastructural morphology of the granules in some malignant beta cell tumors. She felt that since the granules were the storage form of hormonal secretion, an alteration in morphology of beta cell granules may have represented a shorter storage time or a change in the physical or chemical properties of the stored substance.

Figure 3. Electron micrograph of alpha cells from a normal human islet. x about 25,000. (Courtesy of Dr. Malcolm McGavran,'Department of Pathology, Washington University School of Medicine.)

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The first pancreatic cell tumor was reported by Nicholls in 1902. 40 Twenty-four years later only 20 cases had been reported; all without the endocrine function of the islet cells having been recognized. After 1926, however, islet cell tumors began to be reported with increasing frequency, so that by 1950 Howard et aU4 were able to review 398 cases. More than half of these were associated with hypo glycemia. Although the beta cell adenoma with hyperinsulinism and hypoglycemia is the most common islet cell tumor, it is becoming increasingly apparent that the islet cells are capable of producing a variety of humoral substances and endocrine syndromes. These do not include only those associated with excess production of the normally occurring hormone of the beta cells, insulin, and of the alpha cells, glucagon; islet cells which have undergone neoplastic change are also capable of producing corticotropin, melanocyte-stimulating hormone, the carcinoid syndrome with increased urinary excretion of 5-hydroxy-indoleacetic acid, the Zollinger-Ellison syndrome with the hypersecretion of gastrin, and combinations of these.

ENDOCRINE SYNDROMES OF NORMAL ISLET CELL ORIGIN Alpha Cell Tumors Alpha cell hypersecretion is probably rare. The only proven case to date of a functioning alpha cell tumor producing excessive amounts of glucagon (confirmed by immunoassay) has been described by McGavran et al.'l4 The patient, a 42-year-old female, presented with diabetes and a therapeutically resistant bullous eczematoid dermatitis. Two years later she developed evidence of malignant disease with liver metastases. At surgery she was found to have a malignant islet cell tumor. Histochemical and ultrastructural studies confirmed the alpha cell nature of the tumor and immunoassay techniques established the presence of abnormal amounts of glucagon in the tumor and plasma. Despite the metastases, the patient was alive and reasonably comfortable 2112 years after the recognition of the metastatic lesions. She had received no cancer therapy. Yoshinaga et a1. 58 recently described a pancreatic alpha cell tumor associated with severe diabetes mellitus. The tumor cells contained granules with the same staining characteristics as normal alpha cell granules. The patient's serum contained high levels of glucagon-like activity, which was determined by incubating extracts of the patient's serum with rabbit liver slices and measuring glucose release. A third probable case of glucagonoma was found in a patient with a histochemically proven alpha cell tumor of the pancreas. This patient had a diabetic glucose tolerance curve and a pruritic, purulent dermatitis of the extremities and body, particularly around the groin. The dermatitis was resistent to all topically applied medications. Acidalcohol extracts of the tumor, when injected into a rabbit, resulted in a hyperglycemic response. Bioassay revealed 10 to 15 units of glucagon activity per gram of wet tumor weight. 14

PANCREATIC ISLET CELL TUMORS

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The literature contains only a few additional case reports of alpha cell tumors in which the laboratory or clinical evidence suggested the possible hypersecretion of glucagon. In the case of Hess,23 the patient's plasma caused glucose release from liver slices. In Grossner and Korting's case,19 acid-alcohol extracts of the tumor caused a increase of 110 mg. per 100 ml. in the blood sugar of the rabbit. In the case of Keen,z6 extracts from liver metastases caused hyperglycemia. None of these represent proven cases of glucagonoma; however, the pathologic finding of alpha cell tumor and the fact that plasma or tumor extracts resulted in glucose release suggest that these may have been cases of glucagon-producing or glucagon-containing tumors. Because there are so few cases reported of alpha cell tumors which may be secreting glucagon, it is difficult to delineate a well-defined clinical syndrome. Skin lesions were present in the proven case of glucagonoma34 and in two of the possible cases. 12.19 However, it must be kept in mind that dermatitis associated with malignant disease is not uncommon. Evidence of an abnormal carbohydrate metabolism may be a critical feature of this syndrome. However, any malignant condition (especially of the pancreas), chronic illness or extensive liver involvement may be accompanied by an abnormal glucose tolerance test. Suspicion of a glucagon-secreting islet cell tumor should be aroused by the presence of a slowly growing pancreatic tumor with or without metastases in association with elevated blood sugars. The intravenousinjection of glucagon normally results in a rapid rise in serum insulin and glucose. Theoretically, in the face of chronic hyperglucagonemia, this mechanism may be operating maximally and further exogenous glucagon may have no effect. In the proven case of glucagonoma additional intravenous glucagon did fail to produce a rise in plasma insulin, and caused only a minimal rise in glucose. It is suggested that a blunted glucose and insulin response to additional glucagon may be a valuable screening test in suspected cases of glucagonoma. Before the diagnosis of a glucagonoma can be accepted the tumor cells should have morphologic resemblance to alpha cells, and abnormally high levels of glucagon in the plasma and tumor should be present.

Alpha Cell Hyperplasia An interesting association of hyperglucagonemia, chronic pancreatitis and hyperparathyroidism has been reported in two patients by Paloyan et aJ.42 The pancreas of each of these patients demonstrated alpha cell hyperplasia and calcific pancreatitis. In attempting to explain these apparently unrelated phenomena Paloyan and his co-workers have carried out a number of experimental studies. 41 A similar elevation of plasma glucagon occurs in dogs with experimentally induced pancreatitis. It has also been observed that glucagon tends to increase urine calcium and decrease serum calcium in acute experiments and leads to parathyroid hyperplasia in rabbits after prolonged glucagon administration. These workers have postulated that chronic pancreatitis

300

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led to hyperglucagonemia in their two patients. The tendency to lowered serum calcium resulting from the circulating glucagon led to secondary parathyroid hyperplasia, which eventually became independent of serum calcium and led to hypercalcemia (tertiary hyperparathyroidism). Much more evidence will be required before this formulation can be accepted.

Beta Cell Tumors There had been 766 cases of tumor of the islets of the pancreas reported in the world literature up to January 1958, and somewhat less than 100 additional cases reported by 1960.:19 Of this number, the principal clinical manifestation has been hypoglycemic episodes. In a review of 398 cases of islet cell adenomas associated with hyperinsulinism, Howard et aP4 found 10 per cent to be malignant, 12 per cent to be questionably malignant and 78 per cent to be benign. Of the benign group there were multiple adenomas in 12 per cent. Although the Illajority of islets are in the tail of the pancreas, insulinomas are found almost equally distributed throughout all portions of the pancreas, and in some instances they may be ectopic ally located, most often in the duodenal wall. The clinical manifestations of hypo glycemia are quite varied. Although repeated episodes tend to be similar in a given person, they may vary in severity from time to time. The symptoms may be divided into two categories; those associated with sympathetic nervous system stimulation consist of hunger, pallor, sweating, tremor, palpitation and weakness. More prolonged hypo glycemia results in central nervous system symptoms of several phases. These include mental disturbances, slow cerebration, aggressiveness and disorders of speech and gait. The somnolent-agitated phase includes somnolence alternating witfi agItation (tumbling, writhing, yelling and rarely seizures), increased deep tendon reflexes, positive Babinski sign and incoordination of ocular muscles. The next stage is that of deep coma with flaccidity or decerebrate rigidity, shallow respiration, cold moist skin and hypothermia. 3:1 Detailed descriptions of the clinical picture of hypoglycemic episodes associated with these tumors have been previously reviewed.:;' ~4, 57 Before the surgeon is given the formidable task of finding and removing a small insulinoma, all other possible causes of hypo glycemia must be ruled out. These include liver disease, hypopituitarism, Addison's disease, alcoholic hypoglycemia, mesothelial tumors, McQuarrie's infantile hypo glycemia and functional hypo glycemia. The possibility of exogenous insulin administration must always be kept in mind. The age of onset of hypoglycemic episodes is important in determining the etiology. During the first week of life the most common cause is transient neonatal symptomatic hypo glycemia. This is quite rare, with an incidence of 2.9 per thousand live births.R During the first 6 months of life leucine-sensitive and familial hypo glycemia are the most common. After 15 months of age the most common cause is ketotic hypoglycemia; and after 4 years of age tumors of the pancreatic islet cells and functional hypo glycemia predominate. 7

PANCREATIC ISLET CELL TUMORS

301

It might be reasoned that the diagnosis of hypoglycemia due to a beta cell adenoma could easily be confirmed by the finding of high levels of plasma insulin. However, this is not always possible. Berson and Yalow:l found by immunoassay higher than normal fasting plasma insulin concentrations in only 50 per cent of patients with pancreatic insulinomas. The problem of evaluating insulin production by insulinom as is further evidenced by the fact that although striking rises in plasma insulin may occur in these patients following intravenous tolbutamide, the resulting prolonged hypoglycemia is not necessarily accompanied by persistent hyperinsulinism. 57 Insulin assays can be helpful in the diagnosis of insulinomas but require cautious interpretation. Samols 45 has shown that patients with insulinomas may show any or all of the following abnormalities in serum insulin: (1) an exaggerated insulin response to intravenous tolbutamide; (2) elevated fasting levels with large spontaneous fluctuations; and (3) exaggerated response to Lleucine. None of these changes is diagnostic, and Samols makes the point that any patient with an insulinoma need not show all of these abnormalities. Thus, the ability to diagnose a functioning beta cell adenoma by measurements of plasma insulin must be correlated with measurements of blood glucose under conditions which provoke hypoglycemia. To date, the best diagnostic criteria for beta cell adenomas are fasting hypo glycemia and prolonged hypoglycemia following intravenous tolbutamide. An important clinical finding in some cases of beta cell adenoma is the paradoxical occurrence of a diabetic glucose tolerance curve, rather than the expected flat or hypoglycemic response to a glucose load. This may be related to an abnormal function of the non-neoplastic islets. Beta cells of these tumor may have lost their ability to release insulin when subjected to the normal stimulus of a glucose load. Furthermore, the production of insulin by the tumors may have kept the blood sugar relatively low for long periods. This, in turn, fails to keep the remaining normal beta cells stimulated. These dormant cells then tend to lose their ability to respond promptly to a glucose load. In addition, the hypoglycemia results in the release of free fatty acids, which inhibits the effect of insulin in lowering blood sugar. Plasma glucagon and growth hormones may also be increased; both substances can cause an elevation in blood sugar. The net result of these factors, plus the inability of glucose to stimulate insulin release from an insulinoma and from normal but dormant beta cells, may be an explanation for the diabetic curve seen in some of these patients.

Zollinger-Ellison Syndrome The association of an islet cell tumor with the syndrome of hyperacidity, gastric hypersecretion and a fulminating ulcer diathesis, frequently accompanied by atypical ulceration such as jejunal ulcers, was first recognized as an entity in 1955 by Zollinger and Ellison. 62 Since that time, the syndrome has been recognized with increasing frequency. More than 400 cases of a pancreatic islet cell tumor occurring with

302

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this syndrome were reported in a tumor registry in 1966. 57 The association of diarrhea and hypokalemia with this syndrome was first described by Priest and Alexander;4:l it occurs in approximately one third of the cases and may be the major symptom. The diarrhea may be severe, intractable and manifested as overt steatorrhea. In 7 per cent of the cases diarrhea is the only symptom and may occur without hypokalemia. 12 In still other cases there is no ulceration and the patient may actually have achlorhydria, or low acid production! The disease occurs one and one-half times more frequently in men than in women. Onset is most frequent in the third through the fifth decades, although 8 per cent of the cases have been observed in patients under age 20. There is a familial incidence of approximately 5 per cent, usually among siblings. 12 Sixty per cent of these tumors are malignant, with 44 per cent of the patients already having metastatic lesions when first diagnosed. However, the tumors tend to be slow-growing. A most striking example of this is a patient who was still alive with known islet cell metastases of 13 years' duration. 25 Islet cell tumors associated with the Zollinger-Ellison syndrome may be gross or microscopic, and in approximately 50 per cent of patients, the tumors are multiple. Therefore, partial resection of the pancreas as a method of controlling the disease is unsatisfactory. The treatment of choice in these patients is total gastrectomy. The principal active secretion of these tumors appears to be gastrin, a gastric secretogogue. Gastrin-like activity was first demonstrated from an islet cell tumor taken from a patient with the Zollinger-Ellison syndrome by Gregory et alY Since then, a gastric secretogogue has been isolated in 17 of 26 such tumors assayed. 12 Final proof that the active agent of these tumors is identical with gastric gastrin will require chemical isolation and proof of structure. However, since extracts of islet tumor tissue from patients with this syndrome have the same wide spectrum of biological activities as pure gastrin, it is likely that the active agent is either gastrin or a closely related substance. 16 Gastrin may be a component of normal islet tissue. Zollinger et al 61 have extracted from atrophic pancreatic tissue, in which islet but not acinar cells survive, a stimulant of gastric acid secretion which is not histamine or insulin. This lends support to the concept that the Zollinger-Ellison tumor originates in some variety of normally occurring islet cell. The exact type of cell responsible for gastrin secretion in the Zollinger-Ellison syndrome has not been determined. Earlier studies have suggested an alpha cell type; however, recent histochemical studies by Cavallero and Solcia5 have suggested that at least in some cases the tumors are composed of D cells. An observation of Solcia and Sampietro49 appears to be in keeping with this hypothesis. They have identified both by light and electron microscopy large numbers of cells which resemble the islet D cells in the anteropyloric mucosa of the stomach. Since gastrin is chiefly secreted by this area of the stomach, and the ZollingerEllison tumors contain large amounts of gastrin-like material, this functional and morphologic similarity suggests the D cells as the gastrinsecreting cells of the islets.

PANCREATIC ISLET CELL TUMORS

303

With neoplastic change the Zollinger-Ellison tumors may consist of cells with incomplete differentiation and functional capacity. Thus, the gastrin-like secretions of these tumor cells may have aberrations in their chemical structure. The resulting incomplete or disarranged gastrin molecules might explain the vanous clinical patterns seen with this syndrome, such as ulceration with or without diarrhea and with or without hypokalemia. More information is needed about the secretion of these tumors in order to correlate cytology and endocrine products with the clinical patterns of this syndrome.

Syndrome of Multiple Endocrine Adenomatosis Islet cell adenomas are frequently a part of the syndrome of multiple endocrine adenomatosis, sometimes referred to as Wermer's syndrome. This association of endocrine tumors may be transmitted as an autosomal dominant gene with variable expressivity.52 The occurrence of pituitary, parathyroid and islet cell adenomas or any combination of two of these in the same patient is quite rare. Yet the presence of anyone endocrine tumor should always alert the clinician to the possible existence of other endocrine adenomas and to the possibility that other members of the family may be affected. In an extensive study of this syndrome, Ballard et al.l found pancreatic islet cell involvement in 69 of 85 cases. Both beta cell and other types were found. Approximately 36 per cent of the patients in this series had hypo glycemia, which was given as the cause of death in five patients. Islet cell carcinoma occurred in 21 cases, but the malignancy appeared rather limited as only one patient had died from the complications of the .malignancy at the time of Ballard's report. There is also a high prevalance of peptic ulcer associated with the syndrome of multiple endocrine adenomatosis. Confirmation of this association is stressed in Ellison and Wilson's review of 260 cases of the Zollinger-Ellison syndrome. 12 In 21 per cent of these, or 56 patients, there was associated endocrine disease. A pituitary tumor was found in 17 of the 56 patients, and a parathyroid adenoma was recorded in over 50 per cent of them, although a diagnosis of hyperparathyroidism was made in only 15. It is also important to recognize that hypo glycemia may occur in association with the ulcerogenic Zollinger-Ellison syndrome. Six cases of hypo glycemia with functioning beta cell adenomas were reported in a series of 85 cases of this syndrome. 6o In their more recent review, Ellison and Wilson reported a total of 10 instances of beta cell adenomas associated with the Zollinger-Ellison syndrome. For some time, various authors have suggested that hypoglycemia may be an etiologic factor in peptic ulcer. 59 However, consideration should be given to the possibility that such patients may actually represent cases of the ulcerogenic Zollinger-Ellison syndrome with associated hypoglycemia; and the tense, neurotic nature of these patients may be a symptom of their disease rather than a cause. Evidence is now appearing that a single islet tumor may be responsible for both insulin and gastrin secretion. Islet cell tumors associated with the Zollinger-Ellison syndrome have been found to contain beta cells in addition to the predominately non-beta cell componentsY They

304

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LEVIN

may therefore represent mixed endocrine tumors theoretically capable of producing two hormonal substances, in this instance insulin and gastrin. Further evidence for this is illustrated in the case report of ShieberY In this case, high levels of insulin and a gastrin-like activity were found by bioassay in an islet cell tumor removed from a patient with the Zollinger-Ellison syndrome. The tumor was malignant and contained beta cells which may have been the source of insulin.

ABERRANT HORMONE OVERPRODUCTION BY TUMORS OF ISLET CELL ORIGIN

Malignant islet cell tumors have an unusual ability to produce hormones unrelated to their function in normal islet cells. In this regard, they share with malignant tumors of the lung, the thymus and the acinar tissue of the pancreas the ability to produce Cushing's syndrome and the carcinoid syndromes. The unusual ability of these divergent tissues to produce similar endocrine syndromes may be related to their common site of embryologic origin, the endoderm of the primitive foregut. 54 It is therefore not too surprising that with malignant change to less differentiated cell forms they might also have similar physiologic functions. Cushing's Syndrome The clinical picture produced by corticotropin secreted by malignant islet cell tumors is the same as that from other ectopic sites of corticotropin production. These patients may not demonstrate the full-blown picture of Cushing's syndrome. Indeed, the clinical features may be quite subtle, and only a high degree of suspicion will prompt the clinician to obtain urinary and plasma steroids for confirmation. Plasma corticotropin levels should be obtained if the steroid values are elevated. In a series of 36 patients with Cushing's syndrome studied between 1961 and 1964, nine cases were found to be due to ectopic corticotropin production.:J2 Of these nine patients, only two had the classical appearance of Cushing's syndrome. These patients are less likely to exhibit obesity, striae and osteoporosis; however, they frequently have hypokalemia and are about equally likely to exhibit ecchymoses and impaired carbohydrate tolerance. In women, amenorrhea, hirsutism and acne also occur. The other striking feature in these cases in the frequent finding of marked pigmentation and high plasma levels of melanocytestimulating hormone (MS H). The explanation for the above difference in the clinical picture of classical Cushing's disease and Cushing's syndrome due to corticotropin produced at aberrant sites probably resides in the fact that the patients with the ectopic corticotropin production have highly malignant tumors. Their food intake is poor, the disease is frequently fulminating, and the survival period is shorter than that of patients with a primary adrenal tumor or bilateral hyperplasia due to excess pituitary corticotropin production. The short life span of most of the patients with a highly malignant islet cell tumor producing aberrant hormones is in sharp contrast to the relatively long survival of the patients with the usually less malignant beta and alpha cell tumors.

PANCHEATIC ISLET CELL TUMOHS

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Ectopic corticotropin production cannot be suppressed by high doses of adrenocortical hormones or their analogues such as dexamethasone. This differentiates this disorder from Cushing's disease due to bilateral adrenal hyperplasia with pituitary hyperfunction. The high plasma levels of corticotropin associated with these aberrant tumors also helps to differentiate them from primary adrenocortical tumors, in which plasma levels of corticotropin are very low or absent. By the time the disease is detected in these patients, the tumor either has metastasized or is already unresectable. However, the clinical course can be palliated by removing the deleterious effects of the high steroid levels by doing a bilateral adrenalectomy. Recent investigations of Smilo et al. 48 have suggested the use of amino glutethimide might be helpful in some of these cases. This agent is effective in suppressing the function of adrenocortical tumors whose secretion is independent of corticotropin. It is only partially effective in cases of hyperplasia, presumably because corticotropin compensates for the reduced cortisol secretion. However, these authors feel that aminoglutethimide may also be beneficial in adrenocortical overactivity due to extrapituitary corticotropin-like stimulation from other tumors, since their corticotropin-like output appears to be fixed. Nine cases of Cushing's syndrome associated with islet cell carcinoma have been described (Table 2).9,12,20,;)1, :It;, 44, 46 These islet cell tumors were remarkable in that five out of the nine exhibited clinical evidence of the production of more than one hormone. Cases 3 and 5 2 ,36 were associated with hypo glycemia. Insulin-like activity was found to be elevated in Case 3, but not measured in Case 5. Case 4"1 was associated with elevated urinary aldosterone levels. From the information available, it is not clear whether the elevated aldosterone was primary or secondary. Case 5 36 exhibited not only excess production of corticotropin and melanocyte-stimulating hormone but, because of the associated hypoglycemia and clinical features of the Zollinger-Ellison syndrome, there was clinical evidence for the hypersecretion of insulin and gastrin by the tumor. Case 6 46 exhibited Cushing's syndrome associated with the carcinoid syndrome (flushing, asthma, diarrhea). This was confirmed by the finding of high urinary 5-hydroxy-indoleacetic acid (5-HIAA).. Case 8 31 also was associated with the Zollinger-Ellison syndrome, tumor analysis by bioassay showing large amounts of gastrin. An additional case of Cushing's syndrome of questionable islet cell origin is included in this group; Case 9 20 is a patient who developed a cushingoid appearance, marked pigmentation and had high levels of tumor corticotropin and MSH. The urinary 17-ketosteroids and 17ketogenic steroids were elevated. Despite the questionably carcinoidlike appearance of the tumor in this patient, the urinary 5-HIAA was normal.

Carcinoid Syndrome This syndrome is classically characterized by attacks of flushing and diarrhea, and asthma occasionally occurs. Laboratory findings are high levels of blood serotonin and the excretion of increased amounts of 5hydroxy-indoleacetic acid in the urine. Most instances of the syndrome Text continued on page 309

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AGE

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CASE

Cushing's syndrome Diabetes

Urinary 17-0HCS, 134 mg./24 hours. Urinary 17-KS, 59 mg./24 hours. K, 1.5 mEq./L. Aldosterone, 16 /Lg./24 hours (Normal, 20 /Lg./24 hours).

Urinary 17-KS, 28.1 mg./24 hours. "Corticoids" i Blood sugar, 30 mg./lOO mL ILA 1440 /LU./m!. (Normal, 100-300/LU'/ml.).

Cushing's syndrome

curve.

Urinary 17-0HCS, 41-48 mg./24 hours. K, 1.8 mEq./L. Diabetic glucose tolerance

Diabetic glucose tolerance curve

Cushing's syndrome

Cushing's syndrome

LABORATORY DATA

CLINICAL SYMPTOMS

Islet cell carcinoma.

Islet cell carcinoma. Special stains for alpha and beta cells not successfu!. Tumors stained an indiscriminate pale gray without recognizable granularity in both primary and metastatic foci. Bilateral adrenal hyperplasia.

Islet cell carcinoma. Adrenal hyperplasia.

Islet cell carcinoma

PATHOLOGY

Table 2. Aberrant Endocrine Syndromes of Islet Cell Tumors

Preoperative diagnosis "adrenal tumor." Case probably represents multiple hormonal production, ILA and ACTH by the islet cell tumor.

Patient thought to have primary adrenal disease preoperatively. The presence of watery stools raised the question that the patient may also have had carcinoid syndrome or a forme fruste of the Zollinger-Ellison syndrome, related to the islet cell tumor.

First reported case of pancreatic islet cell carcinoma producing Cushing's syndrome.

COMMENTS

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Islet cell carcinoma.

PATHOLOGY

Urinary 17-0HCS, 126-136 mg./24 hours. Urinary 17-KS, 91-113 mg./24 hours. K, 2.9 mEq./L. Tumor assay for ACTH, 21.7 mU'/mg.

Patient died 6 months after onset of symptoms.

Aldosterone assay norma!' Urinary 17-0HCS not suppressed by 2 mg. dexamethasone q6h. Hypokalemia and clinical signs of Cushing's syndrome corrected by adrenalectomy.

COMMENTS

Analysis of the tumor by bioassay showed large amounts of gastrin.

Table continued on following page

I slet cell carcinoma. Small cells arranged in sheets, cords, and ribbons. Hyperplastic adrenal cortex.

Preoperatively, patient was Islet cell tumor, thought to have adrenocorweight 34 gm., cells had eosinophilic tical carcinoma. cytoplasm, granules not demonstrated.

Urinary 17-KS, 21.8 mg./24 hours. Islet cell pattern. Urinary 5-HIAA i. No carcinoid K, 2.8 mEq./L. tumor found. Adrenal showed cortical hyperplasia.

Plasma ACTH, 13 mU./I00 m!. (Normal, <0.5 mU./100 m!.). Tumor assay positive for ACTH. Urinary 17-0HCS, 21-41 mg./24 hours. K, 2.0-3.8 mEq./L.

LABORATORY DATA

Cushing's syndrome. Plasma ACTH, 1.2 mU'/m!. Dark brown 1-2 cm. (Normal, <0.4 mU./m!.). papules scattered Plasma 17-0HCS, 30-91 over body. /Lg./I00 m!. Zollinger-Ellison syn- Urinary 17-0HCS, 16-54 mg. drome, with gasTumor assay for ACTH, tric hypersecretion, 1.3 mU'/mg. diarrhea, hypokalemia, and multipIe duodenal ulcers.

Cushing's syndrome Hypokalemia

Cushing's syndrome Diarrhea Flushing Carcinoid syndrome Hypokalemia

Cushing's syndrome Hypoglycemia Zollinger-Ellison syndrome.

CLINICAL SYMPTOMS

Table 2. Aberrant Endocrine Syndromes of Islet Cell Tumors (Continued)

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Carcinoid syndrome with flushing and asthma, diarrhea, hypo glycemia.

Cushing's syndrome.

CLINICAL SYMPTOMS

? Carcinoid pattern compatible with islet cell tumor. Stains for alpha and beta cells negative. Islet cell carcinoma. Tumor contained ribbons of columnar cells resembling gigantic islets. Methenamine silver reaction and the Schmorl reaction negative.

Urinary 5-HIAA, 53 + 80 mg./24 hours (Normal, < 10 mg./24 hours). Fasting blood sugar 30 mg./l00 m!.

PATHOLOGY

Urinary 17-KS, 32 mg./24 hours. Urinary KGS, 50 mg./24 hours. Tumor assay, ACTH, 60 mU./lOO gm.; MSH, 200,000 u./l00 g. Urinary 5-HIAA, norma!'

LABORATORY DATA

COMMENTS

No 5-hydroxytryptophan, serotonin, insulin or ILA found in tumor tissue obtained at necropsy. Patient lived 4 years after diagnosis. Negative assays may have been due to delay in extraction of postmortem tissue.

Histologic pattern also compatible with carcinoid. No clinical symptoms of carcinoid syndrome.

Table 2. Aberrant Endocrine Syndromes of Islet Cell Tumors (Continued)

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are due to malignant carcinoid tumors arising in the ileocecal region. However, the syndrome can also be produced by noncarcinoid tumors. Two have been reported in acinar carcinomas of the pancreas,'0,35 three in oat-cell carcinomas of the lung 1S , 22, 53 and one in a thyroid carcinoma.'lH Islet cell tumors can also produce this syndrome. In Table 2 are two representative cases, Nos. 6 and 10,46.51 of malignant islet cell tumors associated with high urinary excretion of 5-HIAA and the clinical picture of flushing and diarrhea. In Case 6, the syndrome was accompanied by hypoglycemic attacks. Although no insulin, serotonin, or 5-hydroxytryptophane was extracted from the tumor at postmortem examination, the possibility that these substances were present in the tumor in vivo cannot be ruled out. Since hypoglycemia is not induced by serotonin or related substances, the presence of hypo glycemia in this case is additional evidence that malignant islet cell tumors can simultaneously produce hypo glycemia and the carcinoid syndrome. From an embryologic point of view most noncarcinoid tumors associated with the carcinoid syndrome are derived from the primitive foregut. The pathologic similarity of these carcinoids is illustrated by the demonstration that some bronchial carcinoids have been found to resemble pancreatic islet tissues. 54 It may be difficult to decide whether a tumor arises from bona fide islet cells or from argentaffin tissue located in the pancreas. Since most functioning carcinoids occur in the ileocecal area, the absence of a tumor in this location in the presence of the carcinoid syndrome should direct the clinician's attention to the possibility that the syndrome is being produced by a noncarcinoid tumor, most likely in the lung or pancreas. In addition, the finding of multiple endocrine syndromes (for example, Cushing's syndrome or hypo glycemia occurring with the carcinoid syndrome) suggests the existence of an aberrant site and atypical tumor. Before it can be accepted that a single tumor is producing significant quantities of multiple hormones to account for a mixed clinical picture, careful extraction and bioassay and immunoassay of the tumor for the various suspect hormones must be carried out. In addition, it must be remembered that in those cases characterized by more than one endocrine syndrome one may be dealing with the syndrome of multiple endocrine adrenomatosis, and the pancreas may be harboring adenomas of different cell types and function. In this regard it is suggested that one cell type is responsible for one hormonal substance. This probably holds true for well-differentiated tumors of glandular origin. However, highly malignant islet tumors containing primitive or stem cells may have multihormonal capabilities.

SUMMARY AND CONCLUSIONS From the evidence reviewed in this paper, it is quite evident that, in man, cells of the islets of Langerhans possess seemingly unlimited hormonal capabilities. Hyperplastic and neoplastic changes of the normally occurring beta cells produce the expected syndrome of organic hypoglycemia, and the existence of a functioning alpha cell tumor

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producing the hyperglycemic hormone, glucagon, has now been confirmed. Whether the gastrin-producing ulcerogenic islet tumor of the Zollinger-Ellison syndrome arises from a normal cellular constituent, the D cell, remains to be confirmed. However, inferential data suggest that this may well be the case. With further malignant change, the multihormonal potentialities of the islet cells have become evident. Cushing's syndrome, the Zollinger-Ellison syndrome and the carcinoid syndromes, or a combination of these, at times associated with hypoglycemia, have been produced by islet cell tumors. Thus the clinician, when faced with an endocrine syndrome associated with a malignant picture, should be alerted to the possibility of an aberrant tumor. To date, most of these have been found in the lung, but the possibility of the tumor arising in the pancreas or in islet tissue should not be overlooked, especially if there is evidence of more than one endocrine syndrome present. Because islet cell tumors are frequently associated with adenomas of other endocrine origins, the physician should always be well aware that hypersecretion of several hormones from different glands may occur. It is obvious from this review that detailed histochemical and ultrastructural studies of most of these tumors have not been made. In cases of islet cell tumor in which two or more hormones are being produced, it has not been established whether they are being produced by one cell or several cell types. The surgeon and clinician are therefore ·strongly urged to submit these tumors or their metastases removed at surgery to detailed histochemical techniques and that the tissue be properly fixed so that its ultrastructural nature can be determined by means of the electron microscope. Only in this way can identification of cell types be achieved. The surgical pathologist should be alerted well in advance whenever it is anticipated that such a tumor may be found. Because islet cell tumors can produce a variety of hormones, the patient's urine and plasma should be assayed for their presence. Tumors removed at operation should be quickly frozen, so that tumor extracts for the various suspect hormones may be made by investigators equipped to perform such assays. Absolute confirmation of hormonal production by the tumor can be made only in this way. It is hoped that by these intensive clinical and pathological investigations of islet cell tumors, a better understanding and more complete spectrum of the functional capacities and pathologic nature of this unique tissue might be obtained. ACKNOWLEDGMENTS

I am deeply indebted to Dr. Malcolm H. McGavran and Dr. William H. Daughaday for their advice and review of this paper; to Dr. J ames E. McGuigan for his review of the section on the Zollinger-Ellison syndrome; to Miss Marilyn Hams for her assistance with the illustration; and to Mrs. Susan Sippel for her secretarial assistance.

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