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Background: Radiologic diagnosis of pancreatic tumors exhibits limited precision. The aim of this study was to investigate the outcome and complications of pancreatic core biopsy in patients with suspected pancreatic neoplasms., Methods: One hundred patients underwent ultrasonography-guided core biopsy of 1.2 mm external diameter. Medical charts were examined for biochemical and clinical signs of complications. Final diagnosis was settled by operation, autopsy, and clinical signs of the disease including survival with at least 2.3 years of follow-up., Results: Histopathologic biopsy evaluation showed correct discrimination between exocrine and endocrine tumors and nonneoplastic conditions in 89 patients. No false-positive cancer diagnosis was found, and guidance on nature of primary tumors was obtained for eight of eight metastases. The sensitivity was 91% for exocrine and 87% for endocrine pancreatic tumors, and negative predictive values of these diagnoses were 83% and 97%, respectively. No clinically significant complications were noted., Conclusions: Core biopsy is an attractive alternative to diagnostic laparotomy in unresectable pancreatic cancer and efficiently provides diagnosis of endocrine tumors and pancreatic metastases in conjunction with rare complications. Benign biopsy findings cannot be used to exclude presence of primary or metastatic pancreatic neoplasms.

We report on a case of malignant insulinoma occurring in a patient with genuine insulin-dependent diabetes mellitus (IDDM). A review of cases concerning patients with diabetes mellitus and insulinomas is presented, and reveals only patients with non-insulin-dependent diabetes mellitus (NIDDM). Our case appears to be the first in showing the combination of IDDM and a functioning malignant insulinoma.

The efficiency of pancreatic tumour localization was prospectively evaluated in 12 consecutive patients with multiple endocrine neoplasia type 1 (MEN1), who were subjected to extirpation of 56 islet cell neoplasms of 0.2-4 cm in diameter (mean 0.8 cm) during pancreatic resection and enucleation. Computed tomography, angiography of the coeliac trunc and superior mesenteric artery, and percutaneous ultrasound correctly localized 7-12% of the tumours and 21-37% of the 19 lesions measuring at least one centimetre in diameter. Transhepatic portal vein sampling correctly located tumour sites in the proximal or distal portions of the pancreas in four out of six patients, but demonstrated unsatisfactory specificity. Intra-operative ultrasound and bidigital palpation of the pancreas had overall sensitivities of 86 and 45%, respectively, and eight lesions below 0.3 cm in diameter remained undetected with intraoperative ultrasound. It is concluded that diagnosis of endocrine pancreatic neoplasms is biochemical in MEN1 and that broad screening of tumour markers efficiently reveals pancreatic involvement decades before the development of a clinically overt disease. Intra-operative ultrasound is a requisite for pancreatic endocrine surgery in MEN1, and it obviates the need for conventional pancreatic imaging unless a pre-operative search for metastatic disease and anatomical aberrations is considered important.

Although IAPP was first discovered and isolated from amyloid deposits in an endocrine pancreatic tumour (EPT), surprisingly few reports have investigated the potential use of IAPP as a marker for neuroendocrine tumour growth. In this study we present results from plasma measurements of IAPP in 102 patients with neuroendocrine tumours. Four of 35 patients (11%) with midgut carcinoid tumours, but none of the patients (4 and 5, respectively) with lung carcinoids or with rectal carcinoids displayed elevated plasma levels of IAPP. Five of 31 patients (16%) with sporadic EPT and 3 of 27 patients (11%) with EPT and multiple endocrine neoplasia type 1 syndrome disclosed elevated IAPP levels. Within the different syndromes, 1/11 individuals with insulinoma, 2/16 with gastrinoma, 0/2 with glucagonoma, 0/3 with VIPoma and 5/26 with non-functioning tumours showed elevated plasma levels of IAPP. In two patients, the plasma IAPP levels were extremely elevated. These patients also exhibited altered glucose homeostasis. In response to a standardised mixed meal test, IAPP increased in parallel to the insulin, pancreatic polypeptide, gastrin and glucose responses. In MEN1 patients with hypercalcaemia due to increased secretion of parathyroid hormone, the plasma levels of IAPP were significantly higher before than after surgical removal of the parathyroid adenomas. However in normocalcaemic patients, no correlation between the blood calcium and plasma IAPP levels was found. Immunocytochemical staining of tumour tissue showed that 9/13 (69%) of insulin producing tumours, 4/14 (29%) of non-functioning tumours and 1/9 (11%) of gastrin producing tumours were IAPP immunoreactive. Amyloid deposits were always IAPP immunoreactive. In conclusion, increased circulating levels of IAPP occurred in 12% of 102 patients with neuroendocrine tumours. In 2 patients with extremely elevated plasma levels of IAPP, effects on glucose homeostasis were recorded. Thus, IAPP may be useful as an additional marker for neuroendocrine tumour growth in selected cases.

Islet amyloid polypeptide or amylin is a polypeptide secreted mainly from the pancreatic beta cells together with insulin upon stimulation. High levels of islet amyloid polypeptide have also been shown to increase the peripheral insulin resistance and consequently a role for islet amyloid polypeptide in the glucose homeostasis has been suggested. We have studied the glucose homeostasis in a patient with a malignant endocrine pancreatic tumour producing large amounts of an islet amyloid polypeptide-like molecule (about 400 times the upper reference level for islet amyloid polypeptide). This patient developed insulin-requiring diabetes mellitus shortly after the tumour diagnosis. Both intravenous and oral glucose tolerance tests revealed inhibited early responses in insulin and C-peptide release, but the insulin and C-peptide response to glucagon stimulation was less affected. Aneuglycaemic insulin clamp showed normal insulin-mediated glucose disposal. In vitro experiments, where isolated rat pancreatic islets were cultured with serum from the patient, showed a moderately decreased islet glucose oxidation rate and glucose-stimulated insulin release compared to islets cultured with serum from healthy subjects. However, culture of rat islets with normal human serum supplemented with synthetic rat islet amyloid polypeptide did not affect the glucose-stimulated insulin release. In conclusion, the observed effects show that the diabetic state in this patient was associated with an impaired glucose-stimulated insulin release but not with an increased peripheral insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Among 33 patients with endocrine pancreatic tumors due to multiple endocrine neoplasia type 1 (MEN-1), 19 (58%) patients had hypergastrinemia, 7 (21%) patients had hyperinsulinism, and 7 (21%) patients had clinically non-functioning lesions. At least one gross tumor was found in all patients undergoing pancreatic surgery, including those with negative localization studies prior to operation. The patients also had additional macroscopic tumors as well as numerous microadenomas, and the lesions frequently were positive for immunostaining with multiple hormones, mainly pancreatic polypeptide, insulin, glucagon, and somatostatin. Duodenal endocrine lesions were found in 4 of 5 investigated patients and stained with gastrin and somatostatin antibodies. Distal, mainly subtotal pancreatic resection, was performed in 18 patients, eventually combined with caput tumor enucleation or duodenotomy, while a few patients underwent only tumor enucleation or a Whipple procedure. The long-term outcome of operation was most favorable in patients with hyperinsulinism; only 1 patient had clinical recurrence. Patients with hypergastrinemia experienced only transitory lowering of serum gastrin values after pancreatic surgery and 47% of them had or developed metastases. Such tumor spread was seen in 57% of the patients with non-functioning lesions. Nine patients died from progressive tumor disease during follow-up. Consistent with previous studies, we found that surgery is indicated in MEN-1 patients with hyperinsulinism even if a lesion is not visualized by radiology. In addition, these indications should be extended to also include patients with only biochemical markers of disease, including elevations of gastrin, as these indicate the presence of gross tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Islet amyloid peptide (IAPP) or amylin is a recently discovered polypeptide without settled physiology in man. We present a patient with an endocrine pancreatic tumor secreting huge amounts of IAPP-like immunoreactivity (20,000 mol/l) and a concomitant development of diabetes mellitus. The release of insulin and pancreatic polypeptide (PP) was totally absent after an oral glucose load and a mixed meal, respectively. Tumor secretion of IAPP-like immunoreactivity seemed to be influenced by cholinergic mechanisms and by nutrients. The observed effects on insulin and PP secretion by high circulating levels of IAPP-like immunoreactivity may be of beneficial value for further studies of the physiology of IAPP in man.

The expression of a proliferating antigen by Ki-67 immunohistochemistry was evaluated in 32 gastrointestinal carcinoids and in 5 pancreatic islet cell tumors. In the tissue sections the number of labelled nuclei was calculated per tumor area. The tumors were classified as low proliferating (less than 0.3 labelled cells/mm2), medium proliferating (0.3-1 labelled cells/mm2), and high proliferating (greater than 1 labelled cell/mm2). In 26 tumors obtained from patients receiving antitumor therapy (alpha-interferon) the proliferative activity was decreased. In treated midgut carcinoids the proliferative activity in metastatic tissue was significantly reduced (p less than 0.05). Though not statistically significant, primary midgut carcinoids collected from untreated patients displayed a lower proliferative activity than liver metastases. A survival analysis revealed that patients with tumors displaying low proliferative activity had a better survival than those with high proliferative activity (p less than 0.05). Single cell cytofluorometric DNA analyses showed regular diploid stem cell lines in the majority of tumors from untreated patients (9/11 cases). No correlation was found between the calculated proliferative activity and the DNA profile. The obtained results indicate that the expression of a proliferation antigen by Ki-67 immunohistochemistry can be used to evaluate the biological behavior of neuroendocrine tumors of the digestive system and predict survival.

A prospective study has been performed on 84 patients with endocrine pancreatic tumours evaluated at the Medical Department in Uppsala. Available information concerning the patients' presenting symptoms, age at diagnosis, clinical syndrome, tumour location, location of metastases, diagnostic radiology, biochemical and histopathological findings has been analysed. Our results indicate that most patients initially show rather vague and non-specific symptoms, with dyspepsia and pain being the most frequent presenting features. The median delay between appearance of the first symptom and diagnosis was 2 years; the delay was 35 months in sporadic cases and 14.5 months in familial cases. In spite of improvements in diagnostic methods, the median age at diagnosis (53 years) has not been reduced, and most patients are encountered when the tumour has reached an advanced stage. There is a need for a method of screening patients with still uncharacteristic abdominal symptoms for a neuroendocrine tumour. The presence of elevated levels of plasma chromogranin in all patients with a proven tumour suggests that such possibilities exist, and the use of this biochemical marker in the future might reduce the age at diagnosis and thus improve the likelihood of cure and survival of patients with endocrine pancreatic tumours.

A prospective study was performed on 84 patients with neuroendocrine pancreatic tumors. Fifty-nine (70%) had malignant tumors and received causal medical treatment. Streptozotocin in combination with 5-fluorouracil or doxorubicin was used as first-line treatment and produced overall objective responses in 20 of 44 (45%) patients with a median duration of response of 27.5 months. Thirty-two patients who failed on chemotherapy subsequently received interferon treatment and 20 (63%) responded objectively with a median duration of 20.5 months. Octreotide, third-line treatment in 14 patients, produced objective responses in four patients (28%) (median duration of response, 16 months). The median survival from diagnosis in malignant cases was 6.7 years. Even if none of the current medical therapies are curative for patients with malignant endocrine pancreatic tumors, a prolonged survival would be observed during the last decade. Since the age at diagnosis has not been dramatically reduced despite improvements in diagnostic methods, the prolonged survival might be attributed to causal medical treatment.

Chromogranins A, B, and C, proteins that are co-stored and co-released with peptides and amines, have been identified in a variety of neuroendocrine tissues, both normal and neoplastic. We examined the secretion of chromogranin A and chromogranin A + B by hormone-producing tumours in patients with endocrine pancreatic tumours, carcinoid tumours, pheochromocytomas, and small cell lung cancer. The radioimmunoassay determining the plasma concentrations of chromogranin A + B showed a greater sensitivity than that determining chromogranin A alone. All patients with endocrine pancreatic tumours, carcinoids, and pheochromocytomas had increased levels of chromogranin A + B, whereas a small number of the patients (5/18 with endocrine pancreatic tumours and 1/3 with pheochromocytomas) had normal levels of chromogranin A. Also in immunocytochemical stainings, our polyclonal antiserum detecting both chromogranin A and B showed a greater sensitivity than other available antisera against chromogranin A, B and C. We have demonstrated that a polyclonal antiserum against a mixture of chromogranin A and B might be a more sensitive marker than chromogranin A alone for diagnosing neuroendocrine tumours. This is not surprising, since both chromogranins are widely distributed in neuroendocrine cells.

The nuclear DNA contents of tumor cells in 73 patients with endocrine gastrointestinal tumors, 19 patients with endocrine pancreatic tumors (EPT) and 54 patients with malignant carcinoid tumors were determined before and after treatment. The DNA profiles were divided into diploid and aneuploid. In untreated patients, 9 out of 10 (90%) primary EPT and all 9 primary malignant carcinoid tumors (100%) were diploid. Tumor cell imprints from liver metastases of patients with untreated EPT showed aneuploidy in 5 of 11 cases, but only in 7 out of 46 DNA records from patients with untreated carcinoid liver metastases. DNA alteration from diploid to aneuploid profiles occurred in 2 patients with endocrine pancreatic tumors who had received chemotherapy. A change from diploid to aneuploid records was also seen in 7/23 (30%) carcinoid tumors after treatment. The DNA patterns before and after treatment did not show any correlation with survival or treatment response.

The hormone content of 72 endocrine tumors was determined by immunofluorescence and their amyloid content was investigated. Seventeen of the 72 tumors contained amyloid. Amyloid was frequently found in tumors producing calcitonin, insulin, or growth hormone, but was rarely found in other tumors. Thus, there is a relationship between the occurrence of amyloid in an endocrine tumor and the type of hormone it produces. The reason for this is not known, but there is evidence that the amyloid fibrils contain proteins related to the hormone produced by the tumors.

Ultrasonography-guided cutting needle biopsy of the liver was performed in 186 instances on 95 different patients with carcinoid and endocrine pancreatic tumors. In 171 cases, biopsy specimens were taken from liver metastases found on ultrasonography, and in 93% of these the obtained material was adequate for a correct diagnosis. In the 7% for which an incorrect diagnosis was made, all but one biopsy specimen contained normal liver tissue, indicating that the needle-guiding technique, and not the sampling technique, is the most critical part of the biopsy procedure. Tumor specimens were examined with silver stains and immunocytochemistry after application of monoclonal serotonin antibodies. The argyrophil silver stain of Grimelius could be applied on all specimens and had positive results in all but one case, demonstrating the neurohormonal endocrine origin of the metastases. The argentaffin reaction and/or serotonin immunoreactivity could be applied in 152 cases and had positive results in 115 of 122 (94%) of the mid-gut carcinoid tumors and negative results in 27 of 28 (96.4%) of the non-mid-gut carcinoid tumors and endocrine pancreatic tumors. Major complications occurred in 1.5%; none was lethal or required surgery. The results show that the technique used for tumor biopsy is very accurate and provides material sufficient for multiple histopathologic and immunocytochemical analyses without exposing the patients to high complication risks. It is further concluded that the staining techniques and immunocytochemical analyses applied on the biopsy specimens are valid for the prediction of the location of the primary endocrine tumor.

22 patients with advanced malignant endocrine pancreatic tumours were treated with human leucocyte interferon 3-6 X 10(6) IU per day. Objective responses (more than 50% reduction in tumour markers or tumour size) were seen in 7/7 with watery diarrhoea/hypokalaemia/achlorhydria syndrome, 3/4 with the Zollinger-Ellison syndrome, 6/9 with "non-functioning" tumours, and 1 with a mixed tumour mainly producing somatostatin. The median duration of response was 8.5 months, and all responders improved clinically. Adverse effects seemed more tolerable than those of cytotoxic treatment.

The increased knowledge of the pathobiology of gastrointestinal and pancreatic neuroendocrine tumours and the improved therapeutic possibilities have brought a demand for more precise diagnosis. Although the neuroendocrine tumours can often be tentatively recognized in routinely processed microscopic slides, their more accurate identification requires additional diagnostic procedures. General neuroendocrine markers, such as the argyrophil reaction of Grimelius and immunohistochemistry with application of antibodies against chromogranin A and of neuron-specific enolase are discriminatory staining methods which are used to reveal the neuroendocrine origin of almost all highly differentiated neuroendocrine tumours of the gastrointestinal tract (carcinoids) and pancreas (insulomas). Midgut carcinoids, which predominate among these tumours almost unexceptionally contain serotonin. This biogenic amine can be demonstrated by the argentaffin reaction of Masson, serotonin immunoreactivity or by formalin-induced fluorescence. The characteristic staining pattern of midgut carcinoids is almost invariably preserved in the metastases and can thus be used to reveal a primary midgut carcinoid. The enterochromaffin-like (ECL) cell carcinoids of the body and fundic area of the stomach are argyrophil with Sevier-Munger silver stain. Other neuroendocrine tumours, viz, antral, duodenal and rectal carcinoids and insulomas, should be studied by a battery of relevant peptide hormone antisera for adequate diagnosis. About 50% of all insulin-producing insulomas are endowed with stromal amyloid deposits, which chemically are composed of a peptide designated islet amyloid polypeptide. This molecule has been observed by electron microscopical immunocytochemistry to occur exclusively in the beta-cells and is co-stored with insulin in the beta-cell granules.

A primary pancreatic tumour in a 6-year-old boy was removed by radical excision. From both light and electron microscopic observations the tumour was considered to be of exocrine origin, with some differentiation towards acinar cells. Although the tumour was highly differentiated, it was regarded as probably malignant because of tumour growth into the surrounding fibrous capsule. The case is discussed in relation to earlier rare reports of pancreatic tumours in infants and children.

With the aid of ultrasonography, representative percutaneous biopsy specimens were obtained from 20 of 21 patients (95 percent) with liver metastases of carcinoids and endocrine pancreatic tumors. The specimens were examined with silver stains and immunocytochemically after the application of monoclonal serotonin antibodies. The Grimelius argyrophil silver nitrate stain was positive in all tumor metastases, demonstrating that they were of neurohormonal endocrine type. The argentaffin reaction stained 14 of 15 metastases of small intestinal carcinoids, whereas tumors with other primary sites were unreactive. Immunocytochemical analysis with monoclonal serotonin antibodies stained all metastases of small intestinal carcinoids, and the other endocrine tumor metastases were unreactive. With immunocytochemical analysis, optimal results were obtained in Bouin-fixed tumor specimens, whereas for the argentaffin reaction, formalin was preferable. The results show that silver stains and immunocytochemical analysis with monoclonal serotonin antibodies on small percutaneous biopsy specimens of liver metastases of endocrine tumors and carcinoids are valid for the prediction of the location of the primary tumors.

Twelve patients with malignant endocrine pancreatic tumors refractory to cytotoxic treatment were treated with human leukocyte interferon im at daily doses of 3 X 10(6)-6 X 10(6) IU. Ten of 12 patients showed an objective response with a mean duration of 15.2 months, median, 11 months (range, 2-36+). All ten patients had a decrease in tumor markers and an objective reduction in tumor size was also noted in four. Improvement of clinical manifestations was seen in all cases with an objective response. Adverse effects, including influenza-like syndrome, reduction of blood cells, and chemical signs of liver dysfunction occurred, but were reversible or could be circumvented by dose reduction. One patient developed hypothyreosis on an autoimmune basis; another patient developed liver steatosis. Although the number of patients is small, the results are promising. Interferon therapy seems to be as potent as cytotoxic treatment but with far less side effects. This study indicates that further trials with interferon in patients with less advanced stages of malignant endocrine pancreatic tumor should be performed.

An endocrine pancreatic tumour that had not caused any endocrine symptoms was examined by histological, immunocytochemical and electron microscopic techniques. The majority of the tumour cells were argentaffin and contained secretory granules of the enterochromaffin cell type. Immunocytochemically a minority of tumour cells reacted to antisera against beta-endorphin, met- and leu-enkephalin, gastrin, somatostatin and ACTH. The tumour was thus multihormonal, and appeared to be more closely related to the classic Carcinoid tumours of the mid-gut than to most pancreatic endocrine tumours.

Amyloid deposits localized to the islets of Langerhans are typical of non-insulin-dependent human diabetes mellitus and of diabetes mellitus in adult cats. Amyloid deposits also commonly occur in insulin-producing pancreatic tumors. We have purified a major protein--insulinoma or islet amyloid polypeptide (IAPP)--from human and cat islet amyloid and from amyloid of a human insulinoma. IAPP from human insulinoma contained 37 amino acid residues and had a theoretical molecular mass of 3850 Da. The amino acid sequence is unique but has greater than 40% identity with the human calcitonin gene-related peptide. A partial amino acid sequence of cat islet IAPP corresponding to positions 1-27 of human insulinoma IAPP was identical to the human IAPP except for substitutions in three positions. An antiserum raised to a synthetic human insulinoma IAPP-(7-17) undecapeptide showed specific immunohistochemical reactivity with human and cat islet amyloid and with islet B cells. The significance of this pancreatic neuropeptide-like protein is unknown, but it is suggested that it may exert an important endocrine regulatory effect.

Ten patients with malignant endocrine pancreatic tumors were treated with SMS 201-995 at doses of 50 micrograms twice daily, administered subcutaneously. Four out of 10 patients (40%)-1 patient with the Zollinger-Ellison syndrome and 3 of 6 with the watery diarrhea syndrome--responded objectively with more than 50% reduction of peptide levels, with a median duration of 15.5 months. All four patients improved symptomatically, with decreasing dyspeptic symptoms and decreasing diarrhoea. Three additional patients had a clear relief of symptoms without an effect on tumor-secreted peptides. The disease progressed in three patients during treatment. No reduction of tumor mass was seen in any of the patients. The main side effect noted was a slight but maintained increase in fasting blood glucose in four patients. In conclusion, SMS 201-995 had a beneficial effect in more than half of the patients and seems to be a valuable adjunct to other causal therapy in this patient category, especially in acute situations and weak patients because of its very few side effects.