by Harwood Academic Publishers GmbH Printed in Malaysia Glucagonoma Associated with Calculous

Glucagonomas are rare, constituting only about 6% of all islet cell tumorsl’ 2. The incidence of islet cell tumors associated with pancreatitis is apparently much lower than that of pancreatic exocrine tumors3-5, only 13 patients currently being identified in the literature6-16. Although aware of another patient with a glucagonoma associated with chronic pancre atitis17, we currently find no report of such an association in the literature. Because of its rarity and its possbile implications, the observations of a pancreatic glucagonoma association with acute and chronic pancreatitis with pancreatic lithiasis seem worthy of presentation.


INTRODUCTION
Glucagonomas are rare, constituting only about 6% of all islet cell tumors l' 2. The incidence of islet cell tumors associated with pancreatitis is apparently much lower than that of pancreatic exocrine tumors3-5, only 13 patients currently being identified in the literature6-16. Although aware of another patient with a glucagonoma associated with chronic pancre atitis17, we currently find no report of such an association in the literature. Because of its rarity and its possbile implications, the observations of a pancreatic glucagonoma association with acute and chronic pancreatitis with pancreatic lithiasis seem worthy of presentation.

SUMMARY
A Patient with a glucagonoma associated with calculous pancreatitis is reported. The authors know of only one other such patient. Because the calculous pancreatitis developed both upstream and downstream from the tumor, it cannot be attributed to obstruction of the pancreatic duct by the tumor. Continued critical appraisal is needed to determine whether the association of the glucagonoma and pancreatitis is etiologically related or merely coincidental. Address  A 49 year-old white female business executive was rehospitalized with a 20 month history of recurrent attacks of acute pancreatitis. During the last eight months her abdominal pain had been severe, refractory and typical of chronic pancreatitis. Detailed exploration of her personal and familial history, as well as multiple biochemical and hematological profiles, including normal serum total protein, albumin, calcium, lipids, and glucose, revealed no suggestion of any etiological factor. She had no gallstones and had neither diabetes nor steatorrhea. There was no history of renal calculi nor hyperpara-thyroidism. Physical examination revealed a slender, energetic, intelligent woman with tenderness across the upper abdomen.
Her skin and tongue were normal.
CT scan and plain roentgenograms, showed pancreatic calcification, but no tumor in the head of the pancreas (Fig. 1). ERCP revealed a pancreatic duct which was dilated throughout its entire course (Fig. 2), no obstruction of the duct being detected. Longitudinal pancreaticojejunostomy was elected for interruption of her pancreatic pain.
At laparotomy, February 4, 1992, the pancreatic duct (1.0-1.3 cm diameter) was incised longitudinally in the body and head of the gland. The gland was atrophic, firm, and typical of advanced chronic pan-78 CHUANYAN MAO et al.   removed. Meanwhile, it had become apparent that the incision had transected a 1.0-1.5 cm pancreatic tumor overlying, but neither invading nor obstructing, the duct in the neck of the pancreas. Frozen section was reported as demonstrating a malignant tumor, "probably acinar cell" in type. Second and third opinions by pathologists concurred. A radical resection of the head and body of the pancreas, including skeletonization of the adjacent vessels, was performed. Histologically, the pancreas revealed atrophy of the acini with extensive fibrosis. The tumor consisted of small cell clusters scattered within a dense connective tissue. Most tumor cells were reactive with anti-glucagon antibody ( Fig. 3) and only a few with anti-insulin, or antisomatostatin. No reactivity was seen with anti-pancreatic polypeptide. In some areas, tumor cells, unreactive with any of the above antibodies, formed tubular or glandular structures (Fig. 4). Despite their apparent diffuse growth, no vascular nor neural invasion could be identified.
The patient's convalescence was uneventful. Over the ensuing three and a half years, she has remained entirely well. Her blood glucose levels remain normal, as do her biochemical and hematological profiles. Her plasma glucagon level is normal and repeated CT scans of the abdomen and chest x-rays reveal no evidence of metastasis.

DISCUSSION
In 1942, Becker et al. 8 reported an association between a pancreatic tumor and a peculiar dermatitis in a patient with diabetes, weight loss and anemia, but the .glucagonoma was not well recognized until 1966 when McGravan et al. 19 documented the presence of elevated glucagon levels in the blood and tumor tissue of a patient with an alpha-cell pancreatic neoplasm. To date, approximately 200 glucagonomas have been re-ported2'21. Most patients have presented, in varying degrees, with the "glucagonoma syndrome" (i.e. hypoaminoacidemia, anemia, glucose intolerance, migratory necrolytic dermatitis, weight loss, stomatitis,  Tumor cells forming small cords have reacted with antiglucagon, but the cells constituting the glandular structures within the tumor were unreactive with antibodies against insulin, glucagon, somatostatin or PP. Note the dense connective tissue. ABC method. Bar 100 tm. 80 CHUANYAN MAO et al. thromboembolism). Since the development of the radioimmunoassay and immunohistochemical staining, an increasing number of glucagonomas have been diagnosed earlier, apparently preceding the development of a "glucagonoma syndrome''22. Such a syndrome was not recognized, even retrospectively, in our patient. There was no glossitis, skin rash, elevated blood glucose level nor other sign of endocrine abnormality so that serum hormone levels had not been determined preoperatively. Immunohistochemical stains of the tumor demonstrate glucagon containing granules, indicative of their alpha-cell origin. Glucagonomas, as other islet cell neoplasms, may secrete multiple hormones, either entopic or ectopic, e.g. insulin, pancreatic polypeptide, somatostatin, ACTH8, or calcitonin23. In the current tumor, insulin and somatostatin were detected as minor hormone products on immunohistochemical staining. It has been estimated 24 that 70% of glucagonomas are malignant and over 50% have metastasized at the time of diagnosis. So far, we recognize no stigmata of malignancy in our patient.
Glucagonoma associated with pancreatitis, especially pancreatolithiasis, must be extremely rare as we have not found such a report in the literature. Through personal communication, we are aware of another patient in whom a glucagonoma invaded and obstructed the pancreatic duct, apparently causing chronic pancreatitis upstream from the obstruction17.
Glucagon suppresses secretion of pancreatic juice, but any mechanism of its possible induction of pancreatitis or pancreatic lithiasis is not evident. Mechanical obstruction of the pancreatic duct is usually considered the etiology of tumor-related pancreatitis, although parathyroid tumors are well recognized causes of pancreatitis and pancreatic lithiasis. Our clinical experience and a review of the literature of pancreatitis associated with islet cell tumors partially supports the obstructive mechanism9'1'13. On the other hand, the duct is not always obstructed. For example, Mitchenere et al. reported a patient with an islet cell adenoma associated with acute pancreatitis, no ductal obstruction being found by pancreatography. Kaufman et al. 11 reported a tumor in the tail of the pancreas, but a pseudocyst developed in the head. In the current case, the pancreatic duct was not obstructed by the tumor; the duct was dilated and filled with calculi both upstream and downstream from the tumor.
Allison and associates described the finding of calcific pancreatitis in an alcoholic patient with a malignant islet cell tumor which secreted gastrin, ACTH and apparently human chorionic gonadotro-phin. Perhaps our patient had chronic idiopathic pancreatitis, by chance associated with a glucagonoma, but a cause and effect relationship remains an intriguing possibility.
The rarity of acinar cell carcinomas and their cellular appearance have previously caused them to be erroneously diagnosed as islet cell tumors-the reverse of the currrent events.