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 pa- tient'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 pa- tients 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 symp- toms included weight loss, fatigue, malaise, and mild glucose intolerance. The presenting symptoms seemed to correlate with the location of the tumor in the pan- creas; 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 vari- ous types of islet cell tu- mors 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 peri- neural 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 opera- tive procedures consisting of biopsy only in ten pa- tients, 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 .