Nonfunctioning Islet Cell Tumors

RALEIGH B. KENT III, M.D., JONATHAN A. VAN HEERDEN, M.B., F.R.C.S.(C), F.A.C.S., LOUIS H. WEILAND, M.D.

In nonfunctioning islet cell tumors of the pancreas, hormone From the Departments of Surgery and production is not clinically evident. This type of tumor con- Surgical Pathology, Mayo Clinic and Mayo Foundation, stituted 15% of all islet cell tumors seen at the Mayo Clinic Rochester, Minnesota from 1960 through 1978. Although identical to functioning islet cell tumors embryologically and histologically, the nonfunctioning tumors differ in presentation, location, size, and rate of malignancy. At admission to the hospital, patients Recognition of the association of islet cell tumors often have pain or jaundice due to a large, solid, solitary with clinical syndromes has advanced rather re- lesion that occurs most commonly in the head of the pancreas. markably in the last 25 years.8 A second syndrome Extended survival is not excluded by the high malignancy of intractable, recurrent peptic ulcer disease was rate (92%) of these slow-growing tumors. The survival described in 1955 by Zollinger and rates at three and five years were 60% and 44%, respectively, Ellison,9 and in even though most patients had metastatic disease at the 1964, Gregory and Tracy10 designated gastrin as the time of exploration. hormone secreted by this tumor of the alpha-I or delta cell. In 1958, Verner and Morrison'" intro- T HE PANCREATIC ISLETS of Langerhans, first de- duced a syndrome consisting of refractory and scribed over 100 years ago, have, for many severe watery diarrhea along with hypokalemia, years, aroused medical curiosity. Of special interest achlorhydria, and islet cell tumors. In 1973, Bloom to surgeons have been the discovery and elucidation and associates'2 reported that a newly discovered of different hormones by functioning islet cell tumors. hormone, vasoactive intestinal peptide (VIP), was In any reported series of islet cell tumors, a cer- elevated in patients with this syndrome and that tain number are always nonfunctioning-these are the the responsible tumor contained VIP-producing cells. subject of this review. The first case of a glucagon-secreting alpha cell By way of historical background, it was Paul carcinoma was reported in 1966 by McGavran and Langerhans' who, in 1869, first described the islets of colleagues,'3 and in 1977, Ganda and associates'4 cells in the pancreas which now bear his name. The described the case of a patient who had a so- physiologic function of the islets was not known at that matostatin-containing tumor of the pancreas. Be- time, and it was not until 1922, with the isolation of cause of their common origin with other endocrine insulin by Banting and Best,2 that the role of the cells and their pluripotentiality, islet cell tumors pancreas as an endocrine organ was proved. Nicholls3 can secrete combinations of the above-mentioned described a pancreatic islet adenoma in 1902 and hormones'5"16 or ectopic hormones such as ACTH, Fabozzi4 followed in 1903 with the first report of catecholamines, and serotonin.17"18 islet cell carcinoma. Five years after the discovery Finally there are the islet cell tumors, as reported ofinsulin, Wilder and associates5 recorded biochemical here, that clinically are not associated with obvious proof of insulin production by a metastatic islet signs and symptoms of hormone overproduction. cell tumor in a patient operated on by W. J. Mayo, and in 1929, Graham removed an insulinoma and Materials and Methods thereby cured his patient's attacks of hypoglycemia.6 Patients in whom islet cell tumors of the pancreas Whipple described his triad of symptoms in patients had been diagnosed and treated at the Mayo Clinic with insulinoma in 1935,7 and thus for years func- from 1960 through 1978 were reviewed; 168 such tioning islet cell tumors were equated with hyper- patients were identified. Only those who underwent insulinism and hypoglycemia. operations were included. A patient was considered to have a nonfunctioning tumor when there was no Reprint address: J. A. van Heerden, F.R.C.S.(C), Mayo Clinic, clinical evidence of hormone hypersection in asso- Rochester, Minnesota. ciation with a known apudoma syndrome. The Submitted for publication: May 22, 1980. microscopic pathologic changes of malignancy (based

0003-4932/81/0200/0185 $00.80 © J. B. Lippincott Company 185 186 KENT, VAN HEERDEN AND WEILAND Ann. Surg. * February 1981 10 -

NUMBER 8 - OF PATIENTS - 6-

FIG. 1. Age range of patients 4- who had nonfunctioning islet cell tumors.

2 - F-I m m m a 0 -l I a I i -4 1 - I 2 I I 20 40 60 80 AGE - YEARS on perineural or vascular invasion, extrapancreatic patients were somewhat younger (24, 30, 44, and 74 extension, and, when present, metastatic spread to years of age) than the group as a whole. extrapancreatic sites) were reviewed. Twenty-five nonfunctioning islet cell tumors were thus identified. Associated Disease Follow-up periods ranged from nine months to 13.5 years, with a mean of 5.8 years. One patient was None of the patients had the multiple endocrine lost to follow-up 1.5 years after treatment. neoplasia type 1 syndrome, in which islet cell tumors are associated. However, one patient, a 24-year-old Clinical Features woman with a 1 cm benign islet cell tumor, had Age and Sex bilateral pheochromocytoma. Interestingly, this patient's mother had a right adrenal pheochromocytoma There were 14 men (56%) and 11 women (44%) and died of a malignant islet cell tumor at 29 years in this series. Their ages ranged from 24 to 79 years, of age.19 Although pheochromocytomas are char- with a median age of 56.8 years (Fig. 1). acteristic of multiple endocrine neoplasia type 2, this patient did not have other tumors such as Presentation

The most frequent presenting complaints were pain (nine patients) and jaundice (seven). Four patients were asymptomatic, their tumors having been found incidentally during other operative procedures. The remainder of the complaints included a mass in PAIN two patients and ascites, confusion, and steatorrhea \ 9 in one patient each (Fig. 2). Other associated symptoms included weight loss, fatigue, malaise, and mild glucose intolerance. The presenting symptoms seemed to correlate with the location of the tumor in the pancreas; 12 of 14 patients with lesions in the head of the pancreas had either pain or jaundice, while patients with lesions in the body and tail had varied symptomatology. The time from onset of pain to >-MASS 2 diagn-%is cF tumor was rather long, ranging from _annrvcr_A ASCITES 1 three months to seven years, the average duration being 2.7 years. CONFUSION 1 Four patients had tumors found incidentally during FIG. 2. Presentation of patients who had nonfunctioning islet cell other operative procedures. These asymptomatic tumors. Vol. 193 . No. 2 NONFUNCTIONING ISLET CELL TUMORS 187 0 INSULINOMA 102 *

FIG. 3. Distribution of various types of islet cell tumors in 168 patients (1960- 1978).

CATECHOLAMINE, GLUCAGON, GROWTH HORMONE

medullary carcinoma of the thyroid associated with involved two, five, and numerous lesions. All the this syndrome. tumors were solid, their size varying from 1 cm in diameter to as large as 20 x 15 cm (Fig. 4). Eighteen Pathology tumors (72%) were greater than 5 cm in diameter. The tumors were Of the surgically documented islet cell tumors found in all parts of the pancreas: 14 tumors (56%) were located in the in the 168 cases, insulinoma was the most common head, three (60%), followed by gastrinoma (18%); 25 patients tumors (12%) were located in the tail, and two tumors each were located in the head (15%) had clinically nonfunctioning tumors. The re- body, and body, body and tail, and entire gland. mainder of the islet cell tumors (7%) secreted a As with most endocrine variety of hormones; included were three tumors neoplasms, the diagnosis associated with the Verner-Morrison syndrome, three of malignancy was based more on the presence of metastatic tumor and on evidence tumors secreting ACTH, two tumors that were thought of definite perineural or vascular invasion on to secrete calcitonin, and one each that secreted than the cytologic catecholamine, glucagon, and growth hormone (Fig. 3). appearance of cells. Using this criteria, we found Of the 25 nonfunctioning islet cell tumors, 22 that 23 tumors (92%) were malignant, 18 had biopsy- metastases, (88%) were solitary lesions. The three other tumors proved and five had perineural and perivascular invasion without metastases. The liver was the most common site of metastasis (I1 patients). Two patients had metastases to the duodenum and one patient each had metastases to the retroperito- neum, hepaticoduodenal ligament, transverse meso- colon, superior mesenteric artery, and regional nodes. Two patients (8%) had benign islet cell tumors, each having been found incidentally. Surgical Management The diagnosis of a nonfunctioning islet cell tumor was not made in any of the patients preoperatively. All 25 patients were treated surgically, the operative procedures consisting of biopsy only in ten patients, biopsy and palliative procedure in three pa- FIG. 4. Large necrotic nonfunctioning islet call carcinoma of tients, a Whipple procedure in five patients, total pan- pancreas. createctomy in two patients, partial pancreatectomy 188 KENT, VAN HEERDEN AND WEILAND Ann. Surg. * February 1981 SURGICAL Years PROCEDURE 0 5 10 15 I 1 I Em 1.5 Yr 2 1.5 Yr LOST TO FOLLOWUP 3 _~~~1 Y _~~~~~~~~" BIOPSY 4 6 Yr ONLY 5 6.5 Yr

6 2 Mo CAUSE OF DEATH: METASTATIC DISEASE 7 t6 Mo is I 8 lt 8Mo of .. 9 tb 3 Yr if .. 10 * OPERATIVE MORTALITY 1 113 Yr BIOPSY AND 2 Yr PALLIATION 6.5 3 3.5 Yr FIG. 5. Surgical procedures and survival of 25 patients who had nonfunctioning , islet cell tumors (1960- 1 L 26 Yr t 1978). CVA: cerebrovas- I - cular 2 Ij9 Mo accident. WHIPPLE 3 12 Yr 4 t 5 Yr METASTATIC DISEASE 5 t 5Yr

4 Yr PANCREATECTOMY: 1 TOTAL 2 lt 2 Yr VENTRICULAR FIBRILLATION

1 I 7 Yr PARTIAL 2 | 5 Yr METASTATIC DISEASE 3 It1 Mo OPERATIVE MORTALITY 4 tt 5 Yr CVA

EXCISION 5 2 Yr in four patients, and simple excision of the tumor in the pancreas are shown in Figure 5. Two patients one patient. Two patients (8%) died in the postopera- who underwent a Whipple procedure and one tive period, one owing to intraperitoneal sepsis and patient who underwent a partial pancreatectomy had one as a result of ventricular fibrillation, which metastases to the liver at the time of resection, yet occurred during an otherwise uneventful recovery. they survived 5 years. Also of interest is that eight Long-term Results patients without resection presently are alive, four patients having survived more than five years. The The long-term results of treatment in the 25 survival rates at three and five years were 60% and patients who had nonfunctioning islet cell tumors of 44%, respectively. Vol. 193 * No. 2 NONFUNCTIONING ISLET CELL TUMORS 189 Discussion diagnosis, the Zollinger-Ellison syndrome is now being diagnosed earlier and the original malignancy rate of Islet cell tumors are rare, the prevalence having 44-60% is thought to have dropped to 25%.25 been estimated to be less than 1/100,000 of the As with most other endocrine neoplasms, it is dif- population.20 Despite the infrequency with which ficult to evaluate the malignant potential of islet cell these tumors are encountered, islet cell tumors have tumors on the basis of individual cytologic char- been the subject of extensive investigation, resulting acteristics. Determining the secretory function of islet in an increase in our understanding of the physiology cell tumors is not possible with the use of routine of the different cell types found in the islets of histologic stains, because the cell types appear Langerhans, and in the delineation and treatment of virtually identical, but modern methods of his- clinical syndromes caused by hypersecretion of tochemistry are helpful in defining the peptides that various hormones. are being produced by the tumor. Much less has been written, however, about those In contrast to ductal carcinoma of the pancreas, clinically nonfunctioning islet cell tumors that, in our which is usually fatal within six months of diagnosis series, constituted 15% of all islet cell tumors. In regardless of the type of therapy,26 the nonfunction- 1950, Howard et al.21 reviewed 398 published cases of ing islet cell tumors are slow growing and metastases islet cell tumors, of which 41% were nonfunctioning. do not exclude extended survival. Patients with In the past, however, "functioning" was equated suitable tumors should undergo the appropriate type with insulinoma and hypoglycemia, and thus many of resection. tumors described as "nonfunctioning" could, in fact, Patients with evidence of bile duct obstruction have been one of the more recently described should undergo appropriate biliary bypass. Duodenal functioning tumors. A more recent study of islet cell obstruction did not develop in any of our patients; tumors reflects the smaller percentage of nonfunction- therefore, gastrojejunostomy should be individually ing tumors, and places the figure at 21%.22 Some of judged. One patient initially had jaundice and had a the tumors presently classified as nonfunctioning may tumor in the head of the pancreas, with multiple be secreting a known hormone in amounts too small liver metastases. A cholecystojejunostomy was per- to produce symptoms, may be producing a hormone formed and she did well for eight years, when pain with no obvious associated complex of clinical developed in the right upper quadrant; at re-explora- symptoms, may be secreting a prohormone that is not tion, she was found to have choledocholithiasis. measured by conventional methods and is function- The patient is alive 13 years after diagnosis. ally inert, may be producing a hormone but failing to A similar illustration of how well some of these release it,23 or may be secreting a hormone not patients fare with unresectable metastatic lesions is that yet described. In our series, for example, four pa- of a 79-year-old woman who had a 5 x 6 cm nonfunc- tients experienced mild glucose intolerance, which tioning islet cell tumor in the head of the pancreas could theoretically be due to tumor infiltration of which extended to surround the mesenteric vessels. the islets or to excessive secretion of an anti-insulin She underwent a choledochoduodenostomy and, hormone. three years later, a total hip arthroplasty; she is Patients with nonfunctioning islet cell tumors have alive and doing well at 86 years of age. different symptoms than their counterparts who have The adjunctive therapeutic agent of choice in pa- functioning tumors. Symptoms, most commonly. pain tients with metastatic islet cell tumors is streptozotocin. and jaundice, are due to the mass effect of the tumor This broad-spectrum antibiotic, which is isolated and invasion of surrounding structures, and unlike from Streptomyces achromogenes, inhibits DNA syn- functioning tumors, the location of the tumor has a thesis. Approximately 60% of patients with non- direct bearing on the patient's symptoms. Most of the functioning islet cell tumors will respond to strep- nonfunctioning tumors in our patients were large, solid, tozotocin.27 solitary lesions located in the head of the pancreas, Symptoms of the islet cell tumors of the pancreas as compared with the functioning tumors, which were are usually caused by overproduction of metabolically usually small and were equally distributed throughout active peptides. Less commonly, nonfunctioning tu- the pancreas. The smallest tumors in our series were mors occur in which excessive hormone production found incidentally during unrelated operative procedures. is not clinically evident. As detection of presently The nonfunctioning islet cell tumors have a higher known functioning tumor syndromes improves, and as malignancy rate (92%) than their functioning counter- discovery of newer syndromes occurs, nonfunctioning parts. The malignancy rate of insulinomas is 8.3%,24 islet cell tumors of the pancreas should continue whereas, with more awareness of and advances in to decrease in frequency. 190 KENT, VAN HEERDEN AND WEILAND Ann. Surg. * February 1981 References a somatostatin-containing tumor of the endocrine pancreas. N Engl J Med 1977; 296:963-967. 15. Shieber W. Insulin-producing Zollinger-Ellison tumor. Surgery 1. Langerhans P. Beitrage zur mikroskopischen Anatomie der 1963; 54:448-450. Bauchspeicheldruse. Berlin, Gustav Lange. 1869. 16. Yoshinaga T, Okuno G, Shinji Y, et al. 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