Update on the Diagnosis and Treatment of Rare Neuroendocrine Tumors

Endocrine Surgery

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Update on the Diagnosis and Treatment of Rare Neuroendocrine Tumors

Stanley R. Friesen, M.D., Ph.D.*

The development of radioimmunoassays (RIA) of circulating peptides in the blood has revolutionized the recognition and diagnosis of hormonesecreting neuroendocrine tumors. Prior to that technical breakthrough of the application of RIA to clinical endocrinopathies, the diagnoses of syndromes resulting from hypersecreting tumors were made by astute observations of the association of clinical pictures with the presence of tumors-and the resulting disappearance of symptoms after tumor excision. A second watershed in the development of the pathophysiology of neuroendocrine tumors was the ability to assign functional capacities to neuroendocrine cells and tumors by means of immunocytochemical techniques, thus adding functional capabilities to the tumor over and above the usual morphologic changes. This designation of tumor potential followed earlier descriptions of a diffuse neuroendocrine system in the gastroenteropancreatic organs that contain cells having common cytochemical characteristics of amine precursor uptake and decarboxylation (APUD). 9• 30 The subsequent revelation that similarly functioning cells are also present in the brain has expanded our understanding of the vast regulatory system of peptides in the body. Re-emphasis on radiologic means of localizing neuroendocrine tumors has improved preoperative diagnostic ability. These techniques include ultrasonic and computerized tomography, isotopic scans, and arteriography with and without selective venous sampling of peptide concentrations. Furthermore, stimulation and suppression tests have improved diagnostic acumen. As a result of these revolutionary developments, coupled with an increased clinical awareness, new and rare syndromes and tumors have been described. Many neuroendocrine tumors, particularly malignant ones, contain more than one peptide, cytochemically. Usually however, only one *Professor of Surgery, University of Kansas Medical Center, Kansas City, Kansas

Surgical Clinics of North America-Vol. 67, No. 2, April 1987

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humoral culprit produces the clinical picture. In this issue some of the more common endocrinopathies related to the thyroid, parathyroids, adrenals, and pancreatic islets are described in depth. The recent delineation of the more rare but proven neuroendocrine tumors and syndromes is the subject of this article. ENDOCRINOPATHIES THAT AFFECT CARBOHYDRATE METABOUSM Pathologic entities that affect energy expenditure through their influence on carbohydrate metabolism include the islet cell tumors, insulinomas, glucagonomas, and somatostatinomas, and the thyroid and pituitary abnormalities that produce hyperthyroidism. The first and the last of these are covered in other articles of this issue. GLUCAGONOMA

Alpha-cell tumors of the islets that predominantly secrete glucagon influence carbohydrate metabolism toward catabolism. The diagnosis of these tumors is easily missed, because the clinical picture is similar to that of other common conditions such as diabetes mellitus, skin rashes, and vitamin deficiencies. For these reasons only 201 cases have been collected in a recent literature search. 38 When diagnosed early the cure resulting from surgical excision of a single, nonmetastatic primary lesion is dramatic. 16 Clinical Picture This syndrome has been variously called the diabetes-dermatitis syndrome, the hyperglycemic syndrome, and the catabolic syndrome. All of these terms characterize the usual features seen in patients with a glucagonoma (Fig. 1). The multifaceted clinical picture of the glucagonoma syndrome was meticulously described by Mallinson25 in 1974, although McGavran and associates 27 described a patient in whom glucagon was implicated as the humoral factor as early as 1966. Of the clinical presentations, the rash, though not always present, is the most characteristic; it is described as a necrotizing, migrating erythema. 25 This cutaneous manifestation most commonly involves the trunk, perineum, and thighs, but it can also be present in the face and legs. As the rash spreads as an erythema, the central area appears necrotic but heals. The rash is somewhat similar to that seen in patients with zinc deficiency but is more causally related to the catabolic hypoproteinemia (amino acid deficiency) and can be corrected by appropriate protein administration28 and by the administration of an analogue of somatostatin. 36 The primary endocrine effect of glucagon is on the liver, causing a glycogenolysis and thus raises the blood sugar level. As a result of this action, most patients with glucagonomas have been previously diagnosed as having mild type II diabetes mellitus, because of their hyperglycemia and glycosuria, but the usual complications of diabetes mellitus are seldom

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GLUCAGON SECRETING TUMOR (ALPHA CELL) "DIABETOGENIC" SYNDROME

tGLUCOSE +INSULIN tsECRETION -PANCREATIC -GASTRIC tMOTILITY

+SPLANCHNIC +RENAL BLOOD FLOW

~

+TACHYCARDIA +CARDIAC OUTPUT

.CATECHOLAMINES

DIAGNOSIS GLUCAGON SECRETING TUMOR PRESUMPTIVE HYPERGLYCEMIA GLUCOSE TOLERANCE TEST GLUCAGON PROVOCATIVE TEST

CONFIRMATORY IMMUNO ASSAY BIOASSAY HISTO CHEMISTRY ELECTRON MICROSCOPY SKIN BIOPSY

a..JNICAL

~(NME)

CATABOLIC

DIABETES (MILO) - WT. LOSS ANEMIA -+PROTEINS GLOSSITIS -tA.ACIOS ILEUS PHLEBITIS CHEILITIS DEPRESSION -PLASMA GLUCAGON -TUMOR-+ GLUCOSE -GLUCAGON +NSE -ex SECRETORY GRANULES -NME RASH

Figure 1. The clinical features and physiologic actions of glucagon from hyperfunctioning glucagonomas of the pancreas are "diabetogenic" and catabolic. (From Friesen SR: Functional pancreatic vipomas and glucagonomas. In Najarian JS, Delaney JP (eds): Advances in Breast and Endocrine Surgery. Chicago, Year Book Medical Publishers, Inc., 1986, with permission.)

present. Although patients may have been given insulin, usually it is not required, because the paracrine effect of glucagon on the beta cells increases secretion of endogenous insulin. Another catabolic effect of glucagon, in addition to glycogenolysis, is its lipolytic action. Resulting clinical features include unexplained weight loss, anemia, edema, and glossitis or cheilitis that are similar to findings in patients with vitamin deficiencies. Phlebothrombosis, sometimes associated with pulmonary embolism, occurs in patients with glucagonoma, probably stemming from the catabolism and chronic illness. The clinical expressions related to the pharmacologic actions of excessive glucagon secretion include tachycardia (which is partially attributable to a release of catecholamines) and glucagon's cardiovascular effects of increased cardiac output with increased splanchnic and renal blood flow.

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Ileus and constipation, often observed, are due to the spasmolytic effect of glucagon. Mental depression, occasional blackout spells without hypoglycemia or electrolyte imbalance, 10 and even sudden death have been observed; these manifestations may be due to an elaboration of unknown associated peptides from malignant glucagonomas. Glucagon, being a molecular member of the secretin family of peptides, does produce gastric hypochlorhydria, but unlike secretin, it decreases bicarbonate excretion from the pancreas; no symptoms are referable to these actions. Rarely, hyperglucagonemia becomes apparent only after excision of an insulinoma. This has occurred in several patients; in one instance it was due to the elaboration of glucagon from hepatic metastases that somehow secreted glucagon, rather than the expected insulin. 11 Glucagon may cause a secondary increase in plasma thyrocalcitonin and has also been implicated as a possible cause of secondary hyperparathyroidism with hypercalcemia, particularly in patients with multiple endocrinopathies. Glucagonoma occasionally occurs as an endocrinopathy within the multiple endocrine adenomatosis (MEA) I syndrome; Boden found increased concentrations of plasma glucagon in four of nine asymptomatic relatives of a patient with a glucagonoma.4 Diagnosis When the typical clinical picture is associated with hyperglucagonemia (plasma RIA concentrations greater than 50 pglml) the diagnosis is secure, because other conditions rarely raise plasma glucagon. Occasionally, islet cell malignancies in which another clinical picture is predominant may also produce modest hyperglucagonemia, particularly in MEA I. Other routine laboratory values consistent with glucagonomas include hyperglycemia and an abnormal, diabetes-like, oral glucose tolerance curve. Though it is seldom measured the blood glucose response to intravenous exogenous glucagon is also blunted, because basal glucagon levels are already elevated. Anemia and hypoaminoacidemia are typically present. A skin biopsy of the rash is diagnostic of a glucagonoma in these patients. The tumor, after biopsy or excision, can be designated as a neuroendocrine tumor by appropriate histochemical stains for neurone-specific enolase and by electronmicroscopy for the characteristic granules. Positive confirmation of a glucagonoma is obtained by immunoperoxidase staining for glucagon-containing cells. Further quantification of its glucagon content can be obtained by extraction for glucagon concentration by RIA. Tumor localization is nonspecific for glucagonomas, but computerized tomography (CT) of the pancreas and the liver usually detects tumors greater than 2.5 em in diameter. Arteriography is indicated only when CT is not helpful in localizing a primary lesion and when the surgeon deems its risk to be less than that of diagnostic surgical exploration in any particular patient. Because endoscopic retrograde pancreatography is more invasive and its yield is low, it is rarely done. In special circumstances, when it is particularly important to localize a small tumor (less than 2.5 em) preoperatively, selective venous assays of blood obtained by transhepatic, transportal venous catheterization (after arteriography to detail the venous anatomy) can localize sources of glucagon from small tumors. 17 Such

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maneuvers are time-consuming and costly and require special skills, usually in an investigative setting. Treatment

The initial priority in the management of patients with tumor hyperglucagonemia is a vigorous attempt to correct the effect of catabolism. The intravenous supplementation of proteins as appropriate amino acids is essential, and the addition of glucose, as with total parenteral nutrition, is most beneficial. 28 The rash should improve. Insulin administration may be necessary, depending on the degree of glycosuria. If phlebitis is present or if there is a history of pulmonary embolism, subcutaneous heparin anticoagulation is advisable. Whether or not tumor has been localized preoperatively, surgical exploration requires wide exposure for thorough inspection and palpation of every portion of the pancreas (and liver). If one is fortunate enough to identify a single tumor, it usually can be enucleated surgically, with care taken not to injure the major pancreatic duct. If the duct is injured, the area should be either resected distally or anastomosed to a Roux-en-Y segment of jejunum. An obviously malignant primary lesion requires partial pancreatectomy and is indicated even in patients with hepatic metastases as a cytoreductive maneuver. Multiple tumors or the presence of islet cell hyperplasia (or nesidioblastosis) on biopsy requires distal subtotal (85 per cent) pancreatectomy. When hepatic metastases remain in the patient after excision of the primary lesion, two options for the administration of chemotherapy are open. The intraoperative placement of a catheter in the hepatic artery via the gastroduodenal artery allows for localized intra-arterial administration of streptozotocin in the dosage of 1,500 mg/m 2/week. This route of injection, as contrasted to the systemic intravenous method, reduces the incidence of nephrotoxicity inherent in that drug. A beneficial response can be expected in approximately 50 per cent of patients. If the arterial route for streptozotocin administration is not a possibility, the intravenous use of dacarbazine (dimethyltriazenoimidazole carboxamide, or OTIC) has provided favorable responses at little risk. 19· 35 A side effect of nausea has been observed at an intravenous dosage of 650 mg/m 2 every 28 days. Adriamycin has been given intravenously in doses of 40 mg/m 2 once a month, but it may cause both cardiac and gastrointestinal side effects. Palliation of the rash and a decrease in the hyperglucagonemia have been reported with the intravenous or subcutaneous use of analogues of somatostatin, because of their inhibitory effect on release of glucagon and insulin. 36 Prednisone (40 mg/day) has also been shown to ameliorate the rash, but the complication of Cushing's syndrome may preclude its long-term use.

SOMATOSTATINOMA

Delta-cell tumors of the islets hypersecrete the peptide somatostatin, which affects carbohydrate metabolism and growth by virtue of its ability to inhibit the secretion of insulin, glucagon, growth hormone, and other

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PANCREATIC SOMATOSTATINOMA (SST) D-CELL TUMOR ---HYPERGLYCEMIA (.INSULIN)

HYPOTHALAMUS

IHG~\\

(. GWCAGON) (±)HYPOCHLORHYDRIA (. GASTRIN) SST(GRIF)

v----.STEATORRHEA (? • VIP) CHOLELITHIASIS ('? • CCK) •....---.WEIGHT LOSS

Figure 2. The inhibitory actions of somatostatin produce minimal symptoms, but the presence of steatorrhea and gallstones in a "diabetic" patient may suggest the possibility of a somatostatinoma of the pancreas.

peptides. Somatostatin was first isolated by Guillemin and colleagues5 in 1973 as a hypothalamic peptide sometimes called somatotropin release-inhibiting factor (SRIF), 34 but has since been found also to be entopically present in the delta cell of the islets and the gastric antrum, where it inhibits the release of gastrin and other peptides by means of its paracrine and endocrine functions. The first descriptions of delta-cell tumors were by Larsson, 22 Ganda, 15 and Kovacs 20 and their colleagues. In current literature reviews, 31• 38 only 31 patients have been reported to have somatostatinomas; of these, 16 tumors were situated in the various parts of the pancreas; the extra-pancreatic tumors were found in the duodenum, jejunum, and the biliary system. Clinical Picture The syndrome produced by excessive elaboration of somatostatin from islet tumors' has been designated the inhibitory syndrome because of its physiologic and pharmacologic effects of inhibition of the release of insulin, glucagon, gastrin, and cholecystokinin (Fig. 2). Its inhibitory actions on secretin, vasoactive intestinal polypeptide, motilin, thyroid-stimulating hormone, and growth hormone are not clinically apparent in the syndrome. The clinical findings associated with the presence of a somatostatinoma include diabetes, cholecystolithiasis, steatorrhea, indigestion, hypochlorhydria, and, occasionally, anemia. 21 Because of these commonplace clinical manifestations, the tumor is seldom detected preoperatively; indeed, the majority of tumors are found coincidentally at the time of cholecystectomy for cholecystolithiasis. However silent the syndrome appears, the constel-

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lation of gallstones in a diabetic patient with steatorrhea should alert the surgeon to thoroughly explore the foregut organs for a tumor, which when present is usually single, although it may metastasize to the liver. Extrapancreatic tumors of the duodenum and biliary structures may cause symptoms of bleeding, jaundice, and abdominal pain. Diagnosis The clinical picture associated with the presence of a tumor can be confirmed by RIA for increased plasma concentration of SRlF and ultimately by immunoperoxidase staining of the tumor. When the tumor is suspected preoperatively, computerized tomography and arteriography may localize it if it is larger than 2 em in diameter. An additional diagnostic feature of somatostatinomas is a decreased plasma concentration of both immunoreactive insulin and glucagon; this is in contrast to the elevated levels of these peptides observed in diabetic patients with glucagonomas. Occasionally the tumor, especially if malignant, may also elaborate thyrocalcitonin 14 and adrenocorticotrophin; 20 the latter may alter the clinical picture by causing Cushing's syndrome. Treatment As with other neuroendocrine tumors, the primary objective of management is complete surgical excision by whatever means consistent with the location and extent of the somatostatinoma. As compiled in recent reviews, 31 • 38 surgical excision was done by pancreaticoduodenectomy (Whipple) in 12 patients, total pancreatectomy in two, subtotal pancreatectomy in one, and distal partial pancreatectomy in three. Six patients received chemotherapy consisting of streptozotocin and 5-fluorouracil. At least two patients who received chemotherapy have demonstrated radiologically a decrease in the size of the tumor concomitant with a decrease in the plasma concentration of somatostatin. 33

ENDOCRINOPATHIES THAT AFFECT WATER AND ELECTROLYTE METABOLISM Pathologic neuroendocrine entities that produce diarrhea through their influence on water and electrolyte secretion and/or small intestinal motility include vipomas (islet and neural tumors), carcinoid tumors, gastrinomas, cholecystokininomas, medullary carcinomas of the thyroid, adrenocortical tumors that secrete aldosterone and cortisol, and, most rarely, pancreatic polypeptide apudomas. Gastrinomas and the tumors of the thyroid and the adrenal glands are discussed in other articles of this issue. In this article, the primary culprit in the causation of the rare diarrheogenic syndromes, vipomas, is presented in detail, and the other endocrinopathies associated with diarrhea are included for diagnostic differentiation. Carcinoid tumors as a cause of diarrhea are not rare; in a literature search, 14,293 patients have been collected. 32• 38

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VIPOMA

Neuroendocrine tumors that elaborate vasoactive intestinal polypeptide (VIP) in excess are found in the pancreas (90 per cent) and in neural tissue (neuroblastomas, ganglioblastomas) of the autonomic nervous system (ten per cent) including the adrenal medulla. YIP-containing tumors of the lung, kidney, and gut have been reported sporadically. There are collected in a literature review a total of 201 patients with vipomas. 38 Single primary neoplasms constitute 80 per cent of the pancreatic tumors, but hepatic metastases do occur in about one half of them; islet cell hyperplasia is present in ten to 20 per cent of the patients. The vasoactive peptide was isolated and characterized by Said and Mutt in 1970 and 1972, and synthesized by Bodanski in 1973. There is good evidence that the cellular source of VIP may be the neural cells within the pancreas and/or the endocrine cells of the islets. 7 Thus there is a dual role for VIP, neural modulation and endocrine. 6 The neural cell of origin is probably the most logical source, because VIP is a peptidergic neurotransmitter present in a ubiquitous fashion throughout the body, being found normally and abnormally in the ganglion cells of the autonomic nervous system, gastrointestinal tract (preponderantly), adrenal medulla, brain, bladder, and even penis. The neural component of the neurotransmitter modulates function, whereas the endocrine manifestations probably are due to the islet source of its hypersecretion. The potent endocrine function of vipomas stimulates cyclic AMP in the exocrine cells of the gut to produce a massive secretion of water and electrolytes into the small intestine that overwhelms the normal absorptive capacity of the colon. Because VIP is a molecular member of the secretin-glucagon family, it has endocrine functions similar to secretin, such as increased pancreatic bicarbonate excretion and gastric acid inhibition, as well as a glucagon-like action of abnormal glucose tolerance. There is also a vasomotor action of VIP that causes vasodilatation. Vipomas also have been shown to contain peptide histadine methionine (PHM), 2 neurone-specific enolase (NSE), and other agents that have been linked with the diarrhea seen in the syndrome, including prostaglandin E 2 , pancreatic polypeptide, thyrocalcitonin, and serotonin. Clinical Picture The diarrheogenic syndrome (Fig. 3) has several synonyms: the watery diarrhea, hypokalemia, and achlorhydria (or hypochlorhydria) (WDHA/H) syndrome; the secretory diarrhea syndrome; pancreatic cholera syndrome; and the syndrome of Vermer and Morrison, who described the early patients in 1958. 39 The most prominent feature clinically is the profuse watery diarrhea in volumes often exceeding three liters per day; it may be explosive, episodic, and tea-colored and may occur even during fasting. The resulting dehydration and hypokalemia produce weakness that may progress to hypotension, compounded also by the accompanying vasodilatation. The latter peripheral action may also produce flushing in some patients; only two such patients have demonstrated elevations of serum serotonin or urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. Acid-peptic ulceration does not occur because there is either hypochlorhydria or

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RARE NEUROENDOCRINE TUMORS DIARRHEOGENIC SYNDROME (WDHAIH) PANCREATIC CHOLERA VIPOMAS

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-ACHLORHYDRIA (GP+SECRETI>I)

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~~~--~~=---t~H~~~ t HYPERGLYCEMIA

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tiNSULII

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Figure 3. The diagnostic features of the diarrheogenic syndrome are, for the most part, due to the exaggerated physiologic actions of vasoactive intestinal peptide (VIP). The predominant actions are secretory and vasoactive. (From Friesen SR: Functional pancreatic vipomas and glucagonomas. In Najarian JS, Delaney JP (eds): Advances in Breast and Endocrine Surgery. Chicago, Year Book Medical Publishers, Inc., 1986, with permission.)

achlorhydria, in spite of normal parietal cells being present in the stomach. Distended and enlarged gallbladders have been observed at the time of operation in these patients, 41 presumably owing to hypersecretion of pancreatic bicarbonate. The lethargy seen in these patients may be due in part to the hypercalcemia observed in approximately 50 per cent; tetany has also been observed to be associated with hypomagnesemia. Diagnosis The clinical picture associated with increased plasma concentrations of vasoactive intestinal polypeptide by RIA is diagnostic of a vipoma. Confirmatory laboratory findings include hypokalemia, acidosis, prerenal azotemia, and decreased gastric acid secretion. The hypercalcemia, when present, is associated with normal blood phosphate levels. Though not necessary for diagnosis, elevations of serum prostaglandin E have therapeutic implication; elevations of alpha-chorionic gonadotrophin suggest a malignancy and therefore have prognostic significance. Differential Diagnosis It is important that other causes of diarrhea be ruled out before attempts are made to localize the tumor. Appropriate studies should be done for inflammatory bowel disease, intestinal villous adenomas (which also produce hypokalemia), polyps, carcinomas, and rectal strictures, as well as causes of mucosal malabsorption. Other endocrine tumors that produce diarrhea (in reality steatorrhea) include gastrinomas and somatostatinomas. Gastrinomas produce steatorrhea because acidification of the duodenum renders pancreatic enzymes inactive; acid-peptic ulcer disease is also usually present, and in the Zollinger-Ellison syndrome, gastric intubation with suction usually decreases the diarrhea; these circumstances do not occur with vipomas. Pseudo-Zollinger-Ellison syndrome (antral G-

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cell hyperplasia without tumor), 12 in which steatorrhea may be present, can similarly be ruled out. The diarrhea associated with somatostatinomas usually demonstrates unabsorbed fat, not seen in patients with vipomas. The carcinoid syndrome may be confused with the vipoma syndrome, but the intensity of flushing (livid with foregut carcinoids) and its predominance in the clinical picture in patients with hepatic metastases differentiate it clinically as carcinoid in origin. Mechanical symptoms related to a primary intestinal carcinoid lesion of the midgut and intestinal hypermotility are more likely to be present with the carcinoid syndrome. Lacrimation due to histamine release is also observed in patients with foregut carcinoid tumors. Elevations of serum serotonin and urinary 5-HIAA are much more common in the carcinoid syndrome. When plasma thyrocalcitonin (TCT) is elevated in patients with diarrhea, a medullary carcinoma of the thyroid should be ruled out by physical examination, thyroid scan, and pentagastrin stimulation of TCT release; these studies are usually normal in patients with vipomas. Pancreatic polypeptide (hPP) apudomas are usually associated with constipation, but one thoroughly studied patient having diarrhea has demonstrated elevated plasma hPP and tumor hPP concentrations without an abnormal increase in VIP. 23 Elevations of basal plasma hPP concentrations are possible, of course, if the pancreatic vipoma tumor also contains an increased content of pancreatic polypeptide. An exaggerated response of plasma hPP to a standard protein meal in a patient with a vipoma would be highly suggestive of the genetic trait of MEN I, 13 but the occurrence of vipomas in the MEA I complex is very unusual. A pseudo-Vermer-Morrison syndrome has been described in which islet cell hyperplasia containing VIP is present, but in these patients normal plasma VIP levels are sometimes found. 3 Diarrhea may occur in patients with catecholamine-secreting neural tumors, which must be differentiated from neural vipomas. These aminereleasing tumors include the pheochromocytomas, the chemodectomas of the carotid body, and glomus jugulare. The hypertension resulting from these tumors is not usually observed in patients with vipomas. Diarrhea has been reported as the primary clinical presentation in patients with ectopic elaboration of cholecystokinin-like hormone (CCK). 37• 40 In one patient, the pathologic source was considered to be islet cell hyperplasia. The clinical picture in this patient also included marked gastric acid hypersecretion (without ulceration), presumably due to the affinity of CCK for the gastrin receptor on the parietal cell. Serum gastrin concentrations were normal; further serum studies in this patient documented elevated cholecystokinin-like activity. This syndrome differs from the Zollinger-Ellison syndrome in that the serum gastrin concentration is not elevated; it differs from the Vermer-Morrison syndrome, in that there is acid hypersecretion and normal intestinal secretion. Another exceedingly rare endocrine cause of diarrhea to be differentiated from vipomas is called the gipoma. One patient with pancreatic cholera was studied and shown -to- have an islet cell tumor that elaborated gastric-inhibitory polypeptide (GIP). 8 The patient also demonstrated hypokalemia and hypochlorhydria like those associated with vipoma. The peptide

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GIP differs from VIP by the absence of vasomotor effects and by its potent insulin-stimulating effect, which prompted the renaming of GIP as glucosedependent-insulinotropic peptide. Localization and Confirmation of the Diagnosis of Vipomas When the diagnosis of vipoma has been substantiated, it is then necessary to determine whether the tumor is situated in the pancreas or in a rarer location, such as the ganglioneuromas of the adrenal medulla or autonomic nervous system, or the lung, kidney, or gastrointestinal tract. Computerized tomography of the chest and abdomen and other specific radiologic examinations are indicated. If the pancreas remains as the suspect organ, selective arteriography may localize the tumor. Surgical exploration is often necessary for diagnostic purposes. Confirmation of the diagnosis of vipoma as a neuroendocrine tumor is made by the immunocytochemical detection of neuron-specific enolase and by electronmicrosopy for secretory granules; a specific diagnosis of its secretory potential is confirmed by immunocytochemical demonstration of VIP in the tumor. Treatment It is imperative that dehydration and electrolyte imbalance be corrected preoperatively. Surgical excision of the hypersecreting vipoma is the objective of treatment. A complete cure can be expected with subtotal (85 per cent) pancreatectomy for biopsy-proven islet cell hyperplasia. Immediate improvement, with cessation of the diarrhea and vasomotor instability and a decrease in circulating VIP levels, follows complete removal of hypersecreting tissue (pancreatic or neural). Excision of the primary malignancy, even in the presence of metastases to the liver, is indicated as a cytoreductive procedure, thereby reducing the bulk of tumor for adjunctive chemotherapy. An objective and chemical response rate of approximately 50 per cent has been reported with the use of streptozotocin (STZ), whether it is used intra-arterially or intravenously. The usual dosage of STZ is 1,350 to 1,500 mg/meter given over a week's time in daily divided doses and repeated at monthly intervals. Streptozotocin is quite nephrotoxic (50 to 80 per cent of patients) and hepatotoxic and should not be given to patients with compromised renal function; if nephrotoxicity is noted during close monitoring of renal function while STZ is given, the drug should be discontinued immediately for reversal of that complication. An advantage of intra-arterial (hepatic artery) administration is that the incidence of nephrotoxicity is reduced by one third. Recent reports show that leukocyte interferon has been successfully used in two patients after failure of other measures to control the diarrhea, the potassium loss, and the excessive elaboration of vasoactive intestinal polypeptide. 29 Many palliative agents for symptomatic relief have been used with some benefit. These include analogues of somatostatin, 26 steroids, lithium, metoclopramide, clonidine, and, if prostaglandin E 2 is elevated, indomethacin.18

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ECTOPIC ENDOCRINOPATHIES Tumors that hypersecrete peptides that are not normally present in the organ in which the tumor has occurred are considered to be functioning in an ectopic fashion. The resulting paraneoplastic syndromes, named for the hypersecreting peptide, are usually associated with malignancies of endocrine tissues or with epithelial tumors that also contain neuroendocrine cells with APUD cytochemical characteristics. The neoplasms often secrete several peptides, but one is usually predominant, and the increased concentration in the plasma of its large molecular form is usually measurable, depending on the particular assay. Several mechanisms for the phenomenon of ectopia have been postulated. 1· 24 Ectopia can be explained as a cellular reversion to a primitive state in malignancies. With derepression there is a reactivation of totipotential stem cells, so that any of the peptides may be hypersecreted, irrespective of the location of the neoplasm. There is, in addition, an enzymatic defect, so that the large molecular forms are not all cleaved to the normal low molecular peptide. The clinical manifestations of the ectopic syndromes may be subtle and may not be recognized even after metastases have occurred. The more common sites of ectopically functioning endocrinopathies are the lung and the pancreas. The most common of the pulmonary examples of ectopia is the ectopic ACTH syndrome, and the most common ectopic tumor of the pancreas is the gastrinoma. The ectopic ACTH syndrome (or ectopic Cushing's syndrome) causes findings related to the ectopically stimulated hypercortisolemia from secondary bilateral adrenocortical hyperplasia. The most common tumors causing ectopic ACTH syndrome are those of the lung, thymus, and pancreas. Malignant ACTH-secreting tumor of the lung or pancreas sometimes also liberates melanocyte-stimulating hormone (MSH), in which case the presence of skin hyperpigmentation should call attention to the possibility of an ectopically secreting tumor as a cause of Cushing's syndrome. Both the small and the large ACTH molecules are elevated and measurable by RIA. The ectopic hypercalcemia syndrome consists of symptoms similar to those due to hyperparathyroidism in the presence of a nonparathyroid tumor. This syndrome may be caused by an excessive release of a parathyrinlike peptide from endocrine malignancies of the lung and pancreas. Hypercalcemia may also be attributable to other malignancies that are usually considered to be epithelial, such as in the breast, biliary tract, kidney, or colon. In such cases it has been observed recently that the epithelial tumors actually contain some endocrine cells that may secrete a calcium-releasing substance. Metastases to bone also cause hypercalcemia and should be ruled out. Most parathyroid hormone radioimmunoassays measure only that peptide from the parathyroid glands; hence the RIA for PTH in patients with ectopic endocrine tumors usually demonstrates undetectable levels. This hypercalcemic suppression of PTH release from normal parathyroid glands can be confirmed by noting an increase in PTH when the calcium level is brought down by phosphate or fluid administration, demonstrating

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normal parathyroid gland responsiveness. The parathyroid glands should not be removed unless it can be shown that they are the cause of excess PTH elaboration. The usual localization studies are required in patients with any of the ectopic syndromes, especially to rule out metastases. Treatment consists of surgical excision of the primary malignancies or, when liver metastases are present, of the end-organs, such as the adrenal glands in the ectopic ACTH syndrome and the stomach in the ectopic Zollinger-Ellison syndrome. Careful judgment is required in individual patients for specific therapeutic recommendations in such rare and multifarious endocrinopathies.

SUMMARY A growing knowledge and awareness of bizarre clinical presentations, the physiology of new peptides, and the more frequent use of radioimmunoassay techniques has led to the identification of more patients with glucagonomas, somatostatinomas, vipomas, and ectopic tumors. Definite clinical syndromes, though sometimes seemingly "silent," occur as a result of hypersecretion of newly identified hormones and neurotransmitters that act in endocrine, neurocrine, or paracrine fashion to alter normal metabolism of carbohydrates and electrolytes. Metabolically and clinically, glucagonomas are catabolic, somatostatinomas are inhibitory, and vipomas are diarrheogenic. The clinical syndromes can be differentiated from other, more common, endocrinopathies; the measurement of the plasma concentrations of the specific peptides is not only diagnostic, but prognostic. Specific pathologic confirmation of the functional potential of these tumors by immunocytochemical techniques is now possible. The goal of diagnosis is detection and tumor localization before metastases occur so that surgical excision may be curative. Objective clinical and humoral responses to chemotherapy for nonresectable or metastatic lesions can be expected in about 50 per cent of patients; specifically, dacarbazine (DTIC) is the agent of choice for glucagonomas, streptozotocin for somatostatinomas, and leukocyte interferon for vipomas.

REFERENCES 1. Baylin SB, Mendelsohn G: Ectopic (inappropriate) hormone production by tumors: Mechanisms involved and the biological and clinical implications. Endocr Rev 1:45-77, 1980 2. Bloom SR, Delamarter J, Kawashima E et a!: Diarrhoea in vipoma patients associated with cosecretion of a second active peptide (peptide histidine isoleucine) explained by single coding gene. Lancet 2:1163-1165, 1983 3. Bloom SR, Polak JM: VIP measurement in distinguishing Verner-Morrison syndrome and pseudo Verner-Morrison syndrome. Clin Endocr 5 (Suppl.)223x-228x, 1976 4. Boden G, Owen OE: Familial hyperglucagonemia-an autosomal dominant disorder. N Eng! J Med 296:534-538, 1977 5. Brazeau P, Vale W, Burgus Ret a!: Hypothalamic polypeptides that inhibit the secretion of immunoreactive pituitary growth hormone. Science 179:77-79, 1973

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