Malignant glucagonoma syndrome: response to chemotherapy

A 58-year-old white woman with known metastatic glucagonoma had widespread necrolytic migratory erythema characteristic of the glucagonoma syndrome. She did not respond to conventional chemotherapy with streptozocin. After one course of dacarbazine therapy, she had remission of the glucagonoma clinically with regression of tumor metastases as defined by liver scanning. After 10 months and additional courses of dacarbazine therapy, she remains in clinical remission. Plasma glucagon levels have decreased although they remain at two to four times the upper limit of normal. On several occasions there was resolution of this patient's rash after intravenous glucose in the absence of supplemental amino acids. We conclude that dacarbazine is an effective mode of chemotherapy for malignant glucagonoma.     

Necrolytic migratory erythema and glucagonoma rising from pancreatic head

Glucagonoma syndrome encompasses necrolytic migratory erythema (NME), hyperglucagonemia, diabetes mellitus, anemia, weight loss, glossitis, angular cheilitis, steatorrhea, diarrhea, venous thrombosis, and neuropsychiatric disturbance. Of all the symptoms, NME is a rare skin disorder which is pathognomonic for glucagonoma. We present a 61-year-old woman diagnosed initially as pancreatic head adenocarcinoma with liver metastasis prior to the skin eruption. From the dermatologic finding and other clues, glucagonoma was diagnosed finally.     

Un érythème nécrolytique migrateur révélant un glucagonome: encore une nouvelle observation

Glucagonoma is a rare endocrine tumor that originates from pancreatic alpha cells. It represents 1% of all tumors of the gastro-enterohepatic pancreatic axis. Its clinical manifestations often show some characterized skin manifestations: necrolytic migratory erythema associated with biological and radiological signs. We report the case of a 51-year-old patient suffering from the right hypochondria pain that was preceded 7 months ago by a necrolytic migratory erythema, which strongly suggests a glucagonoma. The biological assessment has identified a normochromic normocytic anemia and a profound hypoprotidemia. The caudal pancreatic tumor associated to a liver metastasis was diagonised by abdominal CT, and the echoguided biopsy of a liver nodule confirmed endocrine nature. Considering the nonresecability of the liver metastasis, the patient has been proposed for chemotherapy. Glucagonoma is a rare pancreatic endocrine tumor, which develops slowly and is often diagnosed late with the presence of metastases in 80% of cases at the time of its diagnosis. Its treatment is essentially surgical.     

Recurrent glucagonoma 20 years after surgical resection

Glucagonoma is a rare islet alpha-cell pancreatic tumor. Patients usually present with necrolytic migratory erythema, diabetes mellitus, thromboembolism, and weight loss. Diagnosis is based on the presence of a pancreatic tumor in association with hyperglucagonemia. Tumor characterization is made by computed tomography and/or pancreatic endoscopic ultrasonic and indium-labeled octreo-scan. Surgery is the main component of the treatment, in some cases in association with chemotherapy. We report the case of a 72-year-old patient who developed a recurrent glucagonoma, 20 years after surgical resection.     

The glucagonoma syndrome: a review of its features and discussion of new perspectives

Glucagonoma syndrome is a paraneoplastic phenomenon characterized by an islet alpha-cell pancreatic tumor, necrolytic migratory erythema, diabetes mellitus, weight loss, anemia, stomatitis, thromboembolism, and gastrointestinal and neuropsychiatric disturbances. These clinical findings in association with hyperglucagonemia and demonstrable pancreatic tumor establish the diagnosis. Glucagon itself is responsible for most of the observed signs and symptoms, and its induction of hypoaminoacidemia is thought to lead to necrolytic migratory erythema. Liver disease and fatty acid and zinc deficiency states may also contribute to the pathogenesis of the eruption in some cases. Most patients are diagnosed too late in the clinical course for cure, but successful palliation of symptomatology can usually be achieved with surgical and medical intervention. This paper reviews the glucagonoma syndrome, paying particular attention to its cutaneous features, and provides new perspectives in our current understanding of this phenomenon.     

Nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas: review of the literature

We report a rare case of nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas. The patient's clinical presentation, diagnosis, treatment, pancreas pathology, and follow-up are reviewed. A 60-year-old patient was incidentally found to harbor a pancreatic mass with markedly elevated glucagon levels but without glucagonoma syndrome. She was initially diagnosed with glucagonoma, and the tumor was resected. Pathological examination demonstrated that the tumor was a nonfunctioning islet cell tumor and revealed nesidioblastosis and hyperplasia of alpha cells and microglucagonoma in the apparently normal surgical margin. The patient still had high postoperative glucagons levels which were suppressed by somatostatin analog treatment. No pancreatic tumors recurred 36 months after surgery. This is the third case of alpha-cell nesidioblastosis reported in the English literature. Nesidioblastosis and hyperplasia of alpha cells should be considered in the differential diagnosis of hyperglucagonemia. Somatostatin analog may be used to suppress glucagon secretion in alpha-cell hyperplasia.     

A rare combination consisting of primary hyperaldosteronism and glucagonoma

A 59-yr-old man with multiple pancreatic tumors is presented. Previously, he had undergone left adrenalectomy for primary hyperaldosteronism and left nephrectomy for renal cell carcinoma at the ages of 39 and 55 yr, respectively. This time, 3 yr after removal of renal cancer, two solid lesions in the pancreas associated with hyperglucagonemia were detected. Under a diagnosis of pancreatic metastasis from renal cell carcinoma or islet cell tumor of the pancreas, distal pancreatectomy with splenectomy and enucleation of the tumor in the pancreas head were performed. Microscopically, a glucagonoma, measuring 2.3 mm in diameter, was detected among five pancreatic metastases from renal cell carcinoma. Four years after surgery, the patient remains well, without signs of recurrence despite multiple pancreatic metastases. This is the first report of such a rare combination consisting of aldosterone-secreting adrenal adenoma and glucagonoma.     

Malign cystic glucagonoma presented with diabetic ketoacidosis: case report with an update

A 44-year-old woman was diagnosed with type II diabetes in 1998 and 1 year later she developed necrolytic migratory erythema, which is a specific skin lesion of glucagonoma. During the clinical investigation, a nodular 6 cm mass in the distal pancreatic region and multiple cystic liver metastases were found. She was operated on, and glucagonoma was detected and the long-acting, repeatable, octreotide treatment was started. 3 years after resection of a pancreatic glucagonoma she presented to a hospital emergency department with diabetic ketoacidosis. Hepatic multiple cystic metastases were visualized by computed tomography. During hospitalization she developed severe pulmonary embolism and deep-venous thrombosis of the lower extremities. Indium-labeled octeotide scintigraphy showed multiple cystic lesions in the liver with additional lesions in the iliocecal region, which had not been visualized by computed tomography. Despite somatostatin therapy the tumor had expanded in the liver. Arterial chemoembolization was performed but 6 months later she died.     

Metastatic insulinoma with long survival and glucagonoma syndrome

In 1966, during cholecystectomy for cholecystolithiasis, a 56-year-old man was found to have islet-cell carcinoma metastatic to the liver; his fasting serum glucose level was normal. In 1971, he developed peptic ulcer disease and symptoms of fasting hypoglycemia; inappropriate secretion of insulin was shown. His primary pancreatic tumor was removed in 1973. During the next 9 years, his liver metastases continued to grow and his fasting serum glucose level was maintained at 35 to 116 mg/dL with diazoxide and hydrochlorothiazide therapy. In 1982, he developed clinical evidence of the glucagonoma syndrome, with glucagon levels between 4000 and 11 000 pg/mL. Since then, his fasting serum glucose level has been maintained at 58 to 119 mg/dL without medication. This patient has survived 17 years with a malignant insulinoma and without islet-cell chemotherapy. His course shows that malignant insulinomas may secrete other peptide hormones that can induce various clinical syndromes.     

Necrolytic migratory erythema revealing glucagonoma without diabetes

We report a case of glucagonoma syndrome, revealed by a necrolytic migratory erythema that had developed for four Years, associated with anorexia, severe weight loss, anemia, hypoprotidemia, and hypoaminoacidemia. The fasting blood glucose level tended paradoxically to be low (0.6 g/l). Elevated plasma glucagon levels confirmed our diagnosis. The absence of diabetes was explained by an independent insulin secretion derived from this composite pancreatic tumor, authenticated by the histological analysis and the proinsulin level. This level was similar to those typically observed in insulinomas. Six Months after a complete surgical exeresis, symptoms disappeared and biological results returned to normal values.     

Curative resection for malignant glucagonoma

Glucagonoma is a rare endocrine tumor of the pancreas. We report curative resection for malignant glucagonoma in 60-year-old Japanese man admitted to our department because of hyperglycemia and a pancreatic tumor (detected at another institution). On admission, his serum glucagon level was 580pg/ml. Computed tomography (CT) showed a tumor measuring approximately 2 cm in diameter, in the head of the pancreas. Angiography revealed a hypervascular lesion fed from the gastro-duodenal artery. Endoscopic retrograde cholangiopancreatography (ERCP), revealed a stenosis of the pancreatic duct in the head of the pancreas and dilation of the caudal side, with indications that the tumor had invaded the pancreatic duct. The tumor was diagnosed as a glucagonoma in the head of the pancreas. Pancreaticoduodenectomy was successfully performed. In the resected specimen, the tumor, which was well defined within the peripheral parenchyma of the pancreas, measured 3.3× 2.5×2.0 cm. The clinico-pathological stage of the tumor on pTNM classification was Stage III (pT1b, pN1, pM0). Although the prognosis for malignant glucagonoma is very poor because distant metastasis is frequently present when the tumor is diagnosed, and because of the hormonal effects of the tumor, the patient was well when discharged, without any complications, and no recurrence has been detected in the 6 years since the operation.     

Calcified liver metastases from a non-functioning pancreatic neuroendocrine tumor

Neuroendocrine tumors consist of a spectrum of malignancies that arise from neuroendocrine cells throughout the body. Pancreatic neuroendocrine tumors are rare tumors, with an incidence of 3.65 per 100,000 individuals per year, and they account for 1–2 % of all pancreatic neoplasms. A non-functioning pancreatic neuroendocrine tumor with multiple liver metastases with calcifications was diagnosed in a 43-year-old female with diabetes mellitus. Early phase-enhanced computed tomography (CT) showed a hypovascular mass in the pancreatic body and tail with calcifications and multiple liver metastatic masses with calcifications. Percutaneous liver biopsy showed homogenous nuclear chromatins and tumor cells with acidophilic cytoplasm against the hyaline interstitium, and a non-functioning pancreatic neuroendocrine tumor was diagnosed. An interesting clinical image of a metastasis from a pancreatic neuroendocrine tumor is presented in which multiple liver tumors were accompanied by dystrophic calcifications. CT and percutaneous liver biopsy play an important role in the diagnosis of a non-functioning pancreatic neuroendocrine tumor, and are valuable diagnostic methods in planning treatment.     

Scintigraphic long-term follow-up of a patient with metastatic glucagonoma

Two years after resection of a pancreatic glucagonoma, scintigraphy with 111indium-labeled octreotide revealed hepatic metastases in a 48-yr-old man. Hepatic metastases were also visualized by CT, whereas an additional lesion in the chest was seen only by scintigraphy. A total of 11 follow-up examinations over 46 months proved somatostatin receptor scintigraphy to monitor reliably somatostatin receptor expression, growth and dissemination of glucagonoma metastases, and to indicate therapeutic readjustment if necessary. The survival time of the patient is now >75 months, in comparison with a mean survival time of 59 months reported for metastatic glucagonoma.     

Glucagon-Secreting Pancreatic Islet Cell Carcinoma, Containing Insulin and Somatostatin, with Hypoglycemic Attack

A patient with glucagonoma syndrome and hypoglycemic attack is presented. Total pancreatectomy was performed with splenectomy and excision of the metastatic nodule in the liver. Diagnosis of glucagon-secreting A cell carcinoma of the pancreas was confirmed by hormone assays and morphological studies with light and electron microscopy. Glucagon, insulin, and somatostatin were demonstrated immunohistochemically in the tumor tissue. Multihormonal features of the endocrine pancreatic tumors are discussed.     

Octreotide (SMS 201-995) in the treatment of metastatic glucagonoma: report of one case and review of the literature

We report 1 patient with a necrolytic migratory erythema, a high plasma glucagon concentration and a metastatic pancreatic endocrine tumor who has now been treated effectively for 33 months with the somatostatin analogue octreotide (SMS 201-995) (400 micrograms/day). The results of SMS 201-995 in the treatment of glucagonoma syndrome are reviewed.     

A malignant tumor of the pancreas producing glucagonoma syndrome: immunocytochemistry and ultrastructure of liver metastases and comparison with the primary tumor

In this study, liver metastases from a patient with a pancreatic glucagonoma producing the syndrome have been investigated histologically, ultrastructurally, and immunocytochemically. A comparison has also been made between the metastases and the primary pancreatic tumor investigated in a parallel study. In the metastatic tissue, glucagon-, pancreatic polypeptide (PP)-, and somatostatin-containing cells were found together with a majority of cells without any immunoreactivity. Glucagon-positive cells were much more numerous than PP- and somatostatin-immunoreactive cells. As in the primary tumor, double immunogold staining of ultrathin sections demonstrated the co-existence of glucagon and PP immunoreactivities in most of the granulated cells, but PP immunolabeling was often faint, so that it probably could not be revealed by the PAP method in light microscopical sections. Such a finding, together with the histological and ultrastructural features, is consistent with an ontogenic and phylogenetic primitiveness of the metastatic cell population.     

Treatment of metastatic glucagonoma to the liver: case report and literature review

Glucagonoma, a rare neuroendocrine pancreatic tumour, is frequently malignant and often accompanied by hepatic metastases. Our aim was to consider the different treatments of metastatic glucagonoma to the liver and their results. A case of glucagonoma with metachronous, small, multiple and bilobar liver metastases is reported. Combined treatment with octreotide and hepatic arterial chemoembolization was applied with good results in terms of symptom relief, plasma glucagon levels and regression of hepatic metastases. Survival rates were also improved. Based on our experience, glucagonoma with metachronous, multiple, diffuse and bilobar hepatic metastases should be treated with octreotide plus hepatic arterial chemoembolization with improved outcome and prognosis.     

Angiotensin- Ⅱ administration is useful for the detection of liver metastasis from pancreatic cancer during pharmacoangiographic computed tomography

AIM: To improve the preoperative diagnosis of liver metastasis from pancreatic cancer, we estimated computed tomography during arterial angiography (CTA) with/without administration of angiotensin- Ⅱ (AT-Ⅱ).METHODS: Thirty-five patients with pancreatic cancer were examined in this study. After conventional CTA was performed, pharmacoangiographic CTA was performed with a 1-3 microgram/5 mL solution of angiotensin Ⅱ injected through a catheter into the celiac artery during spiral computed tomography. We prospectively analyzed the relative region of interest (ROI) ratio of tumor to liver with/without AT- Ⅱ.RESULTS: In all patients, the relative ratio of each computed tomography (CT) number in the ROI was larger at pharmacoangiographic CT than at conventional angiographic CT. Administration of angiotensin-Ⅱ enhanced the metastatic liver tumor as compared with normal tissue. Intratumoral blood flow increased in all patients with malignant tumors due to the pressure effect of AT- n. Furthermore, the metastatic lesions in the liver of three patients were represented by only pharmacoangiographic CT, not by conventional CT and conventional CT angiography. In even peripheral and central areas of metastatic liver tumor, the lesions were enhanced after administration of AT- Ⅱ.CONCLUSION: These results support that high detection rate of liver metastasis revealed by pharmacoangiographic CT suggests the improvement of diagnosis on preoperative staging. Moreover, chemotherapy under AT- Ⅱ induced hypertension may have a better effect on the treatment of metastatic liver tumors.     

Angiotensin-Ⅱ administration is useful for the detection of liver metastasis from pancreatic cancer during pharmacoangiographic computed tomography

AIM: To improve the preoperative diagnosis of liver metastasis from pancreatic cancer, we estimated computed tomography during arterial angiography (CTA) with/without administration of angiotensin-Ⅱ (AT-Ⅱ). METHODS: Thirty-fi ve patients with pancreatic cancer were examined in this study. After conventional CTA was performed, pharmacoangiographic CTA was performed with a 1-3 microgram/5 mL solution of angiotensin Ⅱ injected through a catheter into the celiac artery during spiral computed tomography. We prospectively analyzed the relative region of interest (ROI) ratio of tumor to liver with/without AT-Ⅱ. RESULTS: In all patients, the relative ratio of each computed tomography (CT) number in the ROI was larger at pharmacoangiographic CT than at conventional angiographic CT. Administration of angiotensin-Ⅱ enhanced the metastatic liver tumor as compared with normal tissue. Intratumoral blood flow increased in all patients with malignant tumors due to the pressure effect of AT-Ⅱ. Furthermore, the metastatic lesions in the liver of three patients were represented by only pharmacoangiographic CT, not by conventional CT and conventional CT angiography. In even peripheral and central areas of metastatic liver tumor, the lesions were enhanced after administration of AT-Ⅱ. CONCLUSION: These results support that high detection rate of liver metastasis revealed by pharmacoangiographic CT suggests the improvement of diagnosis on preoperative staging. Moreover, chemotherapy under AT-Ⅱ induced hypertension may have a better effect on the treatment of metastatic liver tumors.     

Case of pancreatic endocrine tumor associated with Cushing's syndrome]

A 78-year-old woman was admitted complaining of edema of the bilateral lower extremities and face. Computed tomography (CT) and ultrasonography (US) of her abdomen revealed a pancreatic tumor and multiple liver metastases. After admission, hypokalemia and muscle weakness and edema of the bilateral lower extremities rapidly worsened. The diagnosis of Cushing's syndrome was established based on clinical and biochemical data and endocrine studies. We thought that the primary tumor was a pancreatic endocrine tumor based on the liver tumor biopsy findings, and that the pancreatic tumor and liver metastatic tumors were ectopic ACTH-producing tumors. A case of pancreatic endocrine tumor associated with Cushing's syndrome is relatively rare. We summarize previous reports.