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.     

Spontanhypoglykämien

Spontaneous hypoglycemic episodes occur unexpectedly and the main cause is insulin-producing tumors of the endocrine pancreas. If an insulinoma is suspected a supervised prolonged fast over at least 48 h should be performed to biochemically prove a tendency towards hypoglycemia and inappropriately elevated (pro-)insulin secretory parameters. A high diagnostic accuracy can be achieved using the amended insulin/glucose ratio at the time of discontinuation of prolonged fasts. Benign insulinomas (90 %) can be cured by surgical removal. Malignant (metastasizing) insulinomas should also be treated surgically with the aim of removing or at least debulking the tumor. In addition, chemotherapy (e.g. using streptozotocin), (chemo)embolization of hepatic metastases and anti-secretory medications (somatostatin analogues, diazoxide) can be used. Differential diagnoses, in the case of proven hypoglycemia, include postprandial reactive hypoglycemia, especially after gastric surgery, factitious hypoglycemia (self-medication with insulin, sulfonylureas or meglitinides), and erroneously determined low glucose concentrations (device defect, wrong preanalytic handling). If the suspicion is based on symptoms only, cardiovascular and neurological/psychiatric reasons for a loss of consciousness need to be considered.     

EUS-guided alcohol ablation of an insulinoma

BACKGROUND: Surgical resection is currently considered to be the criterion standard for treatment of insulinomas. Alternative treatments, despite medication with diazoxide, are lacking. EUS-guided ethanol ablation of endocrine tumors has not been reported before. INTERVENTION: A 78-year-old woman was referred with typical symptoms of an insulinoma. Diagnosis was confirmed by laboratory findings, EUS, and EUS-guided FNA. Because of severe complications during several hypoglycemic episodes, a poor general condition, and strict refusal of surgical resection, the decision was made to ablate the insulinoma by EUS-guided alcohol injection. A total of 8 mL 95% ethanol was injected into the tumor. RESULTS: The patient was discharged and exhibited no further hypoglycemic episodes, and her general condition improved rapidly. Based on clinical, morphologic, and biochemical criteria, we achieved a durable complete remission of the tumor. CONCLUSIONS: EUS-guided ablation may become a minimally invasive alternative for patients with insulinomas in whom surgery is not feasible.     

Hepatic artery embolization for treatment of endocrine gastrointestinal tumors with liver metastases

We report about six patients with endocrine gastrointestinal tumors and liver metastases (four insulinomas, one carcinoidtumor, one paraganglioma), who were treated with a transluminal embolization of the hepatic artery when cytostatic therapy was ineffective. In two patients a second embolization was necessary after recurrence of clinical symptoms. All patients tolerated the procedure without severe side-effects and improved clinically. Serum insulin levels and HIAA-secretion rapidly decreased. Survival lasted from 3 to 32 months (median 15 months). Five additional patients with metastatic endocrine gastrointestinal tumors, observed during the same time period, were regarded as not suitable for hepatic artery embolization. In selected patients, hepatic artery embolization may become an effective therapy for treatment of metastasing endocrine gastrointestinal tumors when conventional medication with cytostatic drugs has become ineffective.     

Malignant insulinoma which expressed a unique creatine kinase isoenzyme: clinical value of arterial embolization as a palliative therapy

A 76-year-old man with hypoglycemic coma was diagnosed as malignant insulinoma with multiple hepatic metastases. Embolization was done for two-thirds of the hepatic mass and it rapidly lowered the serum immunoreactive insulin. He was discharged without medication and has been free from hypoglycemia. After the embolization, the serum creatine kinase (CK) level increased transiently although there was no evidence of myocardial infarction. On electrophoresis, the CK activity showed an abnormal peak, suggesting mitochondrial CK. CK release after embolization has been reported in only a few cases with endocrine tumors, which might indicate some relationship between active energy metabolism and mitochondrial CK.     

Embolization in combination with radioiodine therapy for bone metastases from differentiated thyroid carcinoma

BACKGROUND: The outcome for patients with bone metastases from differentiated thyroid carcinoma is worse compared to the overall prognosis of patients with differentiated thyroid carcinoma. The aim of this study is to evaluate the effect of embolization with concomitant radioiodine treatment on the serum thyroglobulin (Tg) level, pain and neurological symptoms in patients with large bone metastases from differentiated thyroid carcinoma. PATIENTS AND METHODS: Five symptomatic patients, who presented with a large unresectable bone metastasis of differentiated thyroid carcinoma were treated with radioiodine and embolization. The effect of this combined treatment was compared to the effect of radioiodine without embolization in a previously treated control group of 6 patients. Serum Tg levels, pain and neurological symptoms were scored. Both groups were treated similarly with total thyroidectomy followed by ablation with 5.55 GBq 131I and a second dose of 5.55 GBq 131I three months later, except for embolization in the embolization group, which took place between the 2 radioiodine treatments. RESULTS: In the embolization group, serum Tg at the second 131I therapy had decreased by 88.7% (median, range: 77.1-99.3%), which was significantly more compared to the decrease of serum Tg in the control group (18.6%, range: -4.7-95%, P < 0.05). CT-scanning showed a median volume reduction of the metastasis after radioiodine treatment combined with embolization of 52.5% (range: 39-80%). Both strategies resulted in a rapid relief of pain and neurological symptoms. Embolization was not accompanied with severe complications. CONCLUSIONS: This preliminary study suggests that embolization of bone metastases of differentiated thyroid carcinoma in combination with radioiodine treatment results in a significant initial reduction of serum Tg level compared to radioiodine treatment alone. This suggests a beneficial reduction in tumour burden. In this patient category, embolization appears to be a safe and well tolerated procedure.     

Biliary obstruction due to pancreatic insulinoma

Summary Pancreatic insulinomas are rare tumors and their association with polycystic disease of the liver is uncommon. We report here a patient with pancreatic insulinoma with hepatic metastasis and biliary obstruction presenting with neuroglycopenic symptoms and cholestasis on a background of polycystic liver disease.     

Expression and functional consequences of oestrogen and progesterone receptors in human insulinomas

The expression of steroid receptors by tumours offers a therapeutic advantage if functionally responsive to exogenous hormones. Insulinomas represent a highly symptomatic group of pancreatic tumours and the steroid receptor status of these tumours is poorly understood. The object of the study was to characterise the sex steroid receptor status of human insulinomas and to investigate whether sex steroids alter insulin expression therein. At our tertiary referral University Hospital, archival and prospective tissues from 25 insulinoma patients collected over 14 years were analysed for oestrogen receptor-alpha (ERalpha), oestrogen receptor beta (ERbeta) and progesterone receptor (PR) expression. Tissue explants of insulinoma and control pancreatic tissue from two new insulinoma patients were cultured and treated with oestrogen and progesterone and insulin expression measured by RT-PCR and ELISA. The main outcome measures were established before data collection and included sex steroid receptor status of tumours and insulin expression in fresh tissue in response to exogenous sex steroids. PR was expressed in 24 out of 25, ERalpha in 10 out of 25 and ERbeta in 21 out of 25 insulinomas. In fresh insulinoma cultures, insulin expression was increased by oestrogen or progesterone, whereas no significant effect was observed in adjacent pancreatic tissue. This study demonstrates widespread expression of sex steroid receptors on human insulinoma tissue and provides in vitro evidence of functionality with increased expression of insulin by insulinoma explants in response to exogenous oestrogen or progesterone. Confirmation of these results may provide a therapeutic mechanism for reducing symptomatic insulin secretion by receptor blockade.     

Unusual bony colorectal metastases in post-hepatometastasectomy patients

Colorectal cancer metastases occur predominantly in the liver, with extrahepatic sites being far less common and equally distributed in the lung, brain, skin, and bone. We report two cases of unusual bony metastases of colorectal cancer. A 55‐year‐old man underwent an abdominoperineal resection for a Dukes B carcinoma of the rectum, followed 17 months later by a right hemihepatectomy for metachronous liver metastases. He subsequently presented 11 months later with a solitary metastatic deposit in the mandible. Seven months after resection and reconstruction, he remained well and disease‐free. A 67‐year‐old man underwent a right hemicolectomy and right hemihepatectomy for carcinoma of the cecum and synchronous liver metastases. He presented 16 months later with a lesion suspicious of metastases in his clavicle. He subsequently died 18 months after his original operation. The prolongation of survival after hepatic metastasectomy results in the presentation of metastases at sites not commonly seen in colorectal malignancy. Postoperative surveillance after apparently curative hepatectomy should be directed to the evaluation of any unusual new symptoms.     

Severe hypoglycaemia after long-acting octreotide in a patient with an unrecognized malignant insulinoma

Insulinomas are the most common hormone-producing pancreatic neuroendocrine tumours (NETs), and patients usually present with symptoms secondary to hypoglycaemia. Octreotide has been widely used in the symptomatic treatment of patients with pancreatic NETs, including insulinomas. We describe a case of a patient with a metastatic NET, subsequently identified as a malignant insulinoma, who developed severe hypoglycaemia after treatment with long-acting octreotide.     

Insulinoma: diagnostic strategies and surgical treatment. A 22-year experience.

BACKGROUND/AIMS: The efficacy of preoperative localization methods and the results of the surgical treatment of insulinoma were studied. METHODOLOGY: Fifty-nine patients referred for surgical treatment were studied and the results of the diagnostic tools for tumor localization were compared with findings at surgical intervention. The influence of the type of surgical procedure in the immediate and late postoperative course was also studied. RESULTS: Ultrasonography had a sensitivity of 30%, computed tomography 25%, angiography 54%, portal vein sampling 94%, endoscopic ultrasonography 27% and magnetic resonance 17%. Intraoperative palpation localized 98.2% of the tumors and by the addition of intraoperative echography, all lesions were identified. In 55 patients with benign lesions, 22 enucleations, 25 distal pancreatectomies, 7 pancreatectomies plus enucleation and one duodenopancreatectomy were performed. Malignant tumors were treated by pancreatic resection, postoperative hepatic artery embolization and systemic chemotherapy. There was no postoperative mortality. Pancreatic fistula was the most common complication. Three patients who underwent distal pancreatectomy developed late diabetes (9.3%). CONCLUSIONS: Extensive preoperative investigation, mainly with invasive methods, is not indicated and by combining intraoperative palpation and echography most of the cases can be adequately dealt with. Preservation of pancreatic tissue with enucleation and preservation of the spleen are the best choice for treatment of benign insulinomas.     

Intrahepatic Lymphatics Opacified during Hepatic Arteriography in a Patient with Hepatocellular Carcinoma

Extrahepatic lymph node metastases are not uncommon in advanced cases of hepatocellular carcinoma (HCC). This is the account of a HCC case in which intrahepatic lymphatics running toward the hepatic hilus were clearly opacified during hepatic arteriography. The patient was treated by hepatic artery embolization followed by selective embolization of the portal branches, but lymph node metastases at the hepatic hilus were later found during follow-up. The clinical course of this case suggests that the communication between the tumor and the lymphatics was responsible for the lymph node metastasis.     

Hepatic arterial infusion combined with systemic chemotherapy induced complete response of metachronous liver metastases after resection of pancreatic insulinoma

Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs). We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases to hepatic arterial infusion combined with systemic chemotherapy. A 58-year-old woman was admitted to our hospital following loss of consciousness. Examination revealed a pancreatic tumor, and she underwent distal pancreatectomy following diagnosis of insulinoma. Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3 months after surgery. Therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. We observed complete ablation of all metastatic liver nodules after 11 cycles of the chemotherapy using MRI. We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7 years after surgery.     

Surgical resection of solitary metastasis of malignant melanoma to the right atrium

Malignant melanoma has a very high tendency to metastasize to the heart. Although most cardiac metastases of melanomas are clinically silent, the lesions may present with life-threatening cardiac morbidities, including dysrhythmia, right ventricular outflow tract obstruction, myocardial dysfunction, pericardial effusion, or heart failure. In selected patients who have a solitary intracardiac melanoma, surgical resection can provide relief from clinical symptoms and minimize potential cardiac sequelae of the tumor. Because tumor embolization of cardiac melanoma has been reported, the presence of atrial metastatic melanoma can be another indication for surgery.Herein, we present the case of a 31-year-old man who had a right atrial metastatic melanoma of unknown primary origin. He underwent surgical resection of the tumor before beginning a course of chemotherapy. After 1 year, he was well and had no symptoms. We describe the clinical features of this rare presentation of melanoma.     

Familial insulinoma: description of two cases

We describe cases of isolated functioning insulinoma occurring in two members of the same family (father and daughter). The father had a first encapsulated insulinoma diagnosed at 14 years of age and at the age of 33 years he was operated on for a second insulinoma infiltrating the exocrine pancreas with lymph node metastases. The daughter was operated on for an encapsulated insulinoma in the tail of the pancreas when she was 6 years old. No clinical and laboratory signs of other endocrine disturbances have so far been detected in either care or in any other members of the family. Our report suggests the possibility of multiple familial insulinoma, although this is an extremely rare condition. Our data also indicate that insulinomas, even if well controlled by medical treatment, should always be removed by surgery because malignancy cannot be excluded with certainty. Moreover, patients should be closely followed up, as recurrence may develop up to 15 years after surgery.     

大肠癌肝转移介入治疗与静脉化疗的对比研究

目的　探讨结直肠癌肝转移的有效治疗方法。方法　肝动脉化疗灌注及栓塞治疗（ ＨＡＩＣＥ）２５ 例,第一次ＨＡＩＣＥ 后４ 周重复一次,以后每间隔３ － ６ 月行一次ＨＡＩＣＥ。静脉化疗（ＶＣ） 采用静脉给药,４ 周为１ 周期,２ 周期后间隔３－ ６ 月化疗一次。结果　ＨＡＩＣＥ 一疗程后上腹疼痛减轻或消失者占８８ ％ ,肝内肿块缩小占６８ ％ ,ＣＥＡ 降低病例占９２ ％ ;ＶＣ 一疗程后肝区疼痛减轻或消失者占１８ ％ ,肝内肿块缩小占８－３ ％ ;两组病例１ 、２ 、３ 年生存率分别为７２ ％ 、５２ ％ 、２４ ％ 和４１－７ ％ 、１６－７ ％ 、０ ％ （ Ｐ＜ ０－０１） 。结论　对于不能手术的结直肠癌肝转移,ＨＡＩＣＥ 在改善临床症状及延长生存期上较ＶＣ更有效,是一个较好的姑息性治疗方法     

EUS-Guided Ethanol Ablation of Insulinomas: Case Series and Literature Review

Surgical resection is a standard treatment for insulinomas; however, it is associated with a high risk of complications and limited to specific suitable candidates. In recent years, endoscopic ultrasound (EUS)-guided ethanol ablation of insulinomas has emerged as a new therapeutic option, especially for elderly patients and candidates unfit for surgery. We aimed to evaluate the feasibility and safety of this technique for insulinomas.Four patients diagnosed with insulinomas based on EUS–fine-needle aspiration and immunohistochemistry results underwent EUS-guided 95% ethanol ablation. A comprehensive literature review was performed to understand the current status of the feasibility, safety, and effects of EUS-guided ethanol ablation of insulinomas.EUS-guided ethanol ablation of insulinomas was successfully completed in all the 4 patients. There were no perioperative or postoperative complications. The patients were discharged at 3 days after the procedure. No recurrence of hypoglycemia or tumors was noted during follow-up (range, 3–6 months). Literature review showed 8 patients with insulinomas who underwent EUS-guided ethanol ablation. All the procedures were successful, with no need for further surgical treatment. Among these reviewed cases, 6 patients had no post-procedural complications, while other 2 patients showed a mild increase in the serum levels of lipase and/or pancreatic enzymes within 48 h post-procedure; furthermore, 1 of these 2 patients presented at a later date with medically controllable hematoma and ulceration. During follow-up, 6 patients remained asymptomatic and normoglycemic, while the 2 patients who presented post-procedural complications developed occasional mild confusion.EUS-guided ethanol ablation of insulinomas is an effective and safe modality, with an acceptable level of post-procedural complications. However, the long-term effects of this new therapeutic option need to be validated in a large randomized controlled trial with longer follow-up.     

Occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis C virus

Hepatoblastoma is a rare malignancy in adults. It is often diagnosed after the appearance of symptoms, therefore, the tumor size tends to be larger. In patients with no indication for a hepatic resection, the prognosis of adult hepatoblastoma is quite poor. A 54-year-old man with hepatitis C virus-associated liver cirrhosis was initially treated with a hepatic resection for a hepatic tumor, 3 cm in diameter. The tumor consisted of osteoid-like and cartilaginous foci, myxomatous stroma, and poorly differentiated hepatocellular carcinomatous cells and was diagnosed as a mixed epithelial and mesenchymal hepatoblastoma. Two years after the first operation, multicentric hepatocellular carcinomas developed in the remnant liver and were successfully treated with a secondary hepatic resection combined with radio-frequency ablation. The patient is now alive with no recurrence at 5 years after the initial hepatectomy. To the best of our knowledge, the primary hepatoblastoma was the smallest such tumor reported and this is the first report of a metachronous hepatoblastoma and hepatocellular carcinoma in an adult hepatitis patient.     

Liver transplantation for metastatic neuroendocrine tumor： A case report and review of the literature

Neuroendocrine tumors are divided into gastrointestinal carcinoids and pancreatic neuroendocrine tumors. The WHO has updated the classification of these lesions and has abandoned the term "carcinoid". Both types of tumors are divided into functional and non-functional tumors. They are characterized by slow growth and frequent metastasis to the liver and may be limited to the liver for long periods. The therapeutic approach to hepatic metastases should consider the number and distribution of the liver metastases as well as the severity of symptoms related to hormone production and tumor bulk. Surgery is generally considered as the first line therapy. In patients with unresectable liver metastases, alternative treatments are dependent on the type and the growth rate. Initial treatments consist of long acting somatostatin analogs and/or interferon. Streptozocin-based chemotherapy is usually reserved for symptomatic patients with rapidly advancing disease, but generally the therapy is poorly tolerated and its effects are short-lived. Locoregional therapy directed such as hepatic-artery embolization and chemoembolization, radiofrequency thermal ablation and cryosurgery, is often used instead of systemic therapy, if the disease is limited to the liver. However, liver transplantation should be considered in patients with neuroendocrine metastases to the liver that are not accessible to curative or cytoreductive surgery and if medical or locoregional treatment has failed and if there are life threatening hormonal symptoms. We report a case of liver transplantation for metastatic neuroendocrine tumor of unknown primary source and provide a detailed review of the world literature on this controversial topic.     

Hepatic encephalopathy secondary to transtumoral portal-hepatic venous shunting

Intrahepatic portal-systemic shunts causing hepatic encephalopathy are very rare. This is a case report of a patient with hepatic metastases of a pancreatic islet cell tumor that manifested with transtumoral shunts leading to hepatic encephalopathy. The diagnosis was confirmed with Doppler ultrasound and initially treated with selective transhepatic portal vein embolization followed by hepatic artery embolization, and eventually radiofrequency ablation of the largest metastases. Despite excellent short-term palliation, symptom recurrence necessitated liver resection, the results of which proved durable. A multidisciplinary treatment plan for the identification and management of potentially salvageable encephalopathy in similar patients is described.