Expression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1

Burgess JR, Greenaway TM, Shepherd JJ (Royal Hobart Hospital, and University of Tasmania, Hobart, Tasmania, Australia). Expression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 465–70.
In 1983 a large family with MEN-1 (designated Tasman 1) was identified in Tasmania. Kindred screening and case follow-up over the subsequent 15 years has yielded data on over 160 MEN-1-affected patients. Hyperparathyroidism is present in over 60% of gene carriers by age 20 years and 95% by age 30 years. Hyperplasia is the characteristic pathological finding. Kaplan–Meier analysis indicates hyperparathyroidism recurs in the majority of patients despite near-total parathyroidectomy. Gastrinoma, 'nonfunctioning' pancreatic adenoma and insulinoma occur in up to 60, 50 and 10% of patients, respectively. Metastatic gastroenteropancreatic (GEP) tumours develop in up to 35% of family members, being frequent in some branches of Tasman 1, whilst rare in others. Pituitary disease developed in 19% of patients. Prolactinoma and 'nonfunctioning' adenoma account for 76 and 24%, respectively, of pituitary abnormalities. Prolactinomas exhibit clustering within branches of the Tasman 1 kindred. Adrenal adenomas occur in 36% of patients. The majority of adrenal lesions are benign and nonsecretory and develop in association with pancreatic neoplasia. Carcinoid tumours are uncommon but important malignancies. Malignant thymic carcinoid occurs in male patients, whereas bronchial carcinoid occurs predominantly in women. Prior to recognition of MEN-1 in Tasman 1, complications of hyperparathyroidism and malignancy accounted for the majority of patient mortality. Since commencement of prospective screening, malignant GEP tumours and cardiovascular disease have become the most prevalent causes of death amongst MEN-1-affected patients.     

Co-existence of glucagonoma with recurrent insulinoma in a patient with multiple endocrine neoplasia-type 1 (MEN-1)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, the anterior pituitary, and the endocrine pancreas. Our patient was a 58-year-old man who manifested typical features of MEN-1 including primary hyperparathyroidism, lung carcinoid, and lipomas and insulinoma. He was admitted to our hospital because of recurrent hypoglycemia and a growth of pancreatic tumors. The first operation for insulinoma was performed when he was 20 years old. We found a germline mutation of the MEN1 gene (E45G, exon 2) in this patient. According to these examinations and his clinical course, the patient was diagnosed as having a recurrence of insulinoma. He subsequently underwent surgery for the pancreatic tumors. The majority of these tumor cells were immunohistochemically positive for insulin and negative for glucagon. A few nodules showed immunohistochemical staining positivity for glucagon but they were negative for insulin. Although it is uncommon for patients with MEN1 to exhibit insulinoma and glucagonoma, this case suggests the need for careful analysis of pancreatic tumors in patients with MEN1.     

Neuroendrocine pancreatic tumours: clinical presentation,biochemical and histopathological findings in 84 patients

Abstract. 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 3 5 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 abdominalsymptoms 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.     

Multiple endocrine neoplasia type 1: duodenopancreatic tumours

The pancreaticoduodenal disease in Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of death due to the syndrome, and the most controversial with regard to its management. This article discusses the current data and recommendations with respect to disease screening, functional tumour diagnosis, natural history, preoperative imaging, operative strategy and follow-up.     

Pathology of MEN-1: morphology, clinicopathologic correlations and tumour development

Komminoth P, Heitz PU, Klöppel G (University of Zürich, Switzerland; and University of Kiel, Germany). Pathology of MEN-1: morphology, clinicopathologic correlations and tumour development (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 455–64.
Multiple endocrine neoplasia type 1 (MEN-1) is an inherited syndrome which is characterized by the occurrence of neoplastic lesions in the parathyroids, the pancreas, duodenum, anterior pituitary and, less commonly, also in the stomach, thymus and lung. Its genetic defect has recently been identified and appears to involve a new type of tumour suppressor gene called mu on chromosome 11q13. In this overview, we will summarize the morphological features of the MEN-1 phenotype, discuss its clinicopathologic profile and prognosis and outline the recent findings on the molecular pathology of this syndrome.     

A meal stimulation test in the diagnosis of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

Background: The diagnostic value of the determination of the serum pancreatic polypeptide (PP) and gastrin concentrations after a standard meal for early diagnosis of patients with multiple endocrine neoplasia type 1 (MEN 1) is controversial. The aim of this study was to clarify this issue. Thirteen patients with MEN 1, seven healthy family members, and eight healthy controls were studied. Plasma PP and serum gastrin were measured before and after the ingestion of a standardized meal. The meal caused a statistically significant (p<0.05) increase of both PP and gastrin in all three groups studied. Concerning PP, no statistically significant difference was observed between patients and controls. In family members, the values were significantly (p<0.05) lower than in the other two groups. On the whole, no significant differences in gastrin levels were noted between patients and controls; in family members, the values were significantly (p<0.05) lower than in patients. All patients who had abnormally high postprandial values of PP and gastrin also had abnormally high basal values of these two peptides. The determination of serum PP and gastrin levels after a meal stimulation test in patients with MEN 1 adds no information about the presence of pancreatic endocrine tumors over that provided by basal values of the two peptides.     

Diagnostic and therapeutic criteria in patients with Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1

: Mignon M, Cadiot G (Bichat and Claude Bernard Hospital, Paris, France). Diagnostic and therapeutic criteria in patients with Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 489–94. About 25% of patients with ZES have MEN-1. Except for diarrhoea, less frequent in patients with ZES MEN-1 than in sporadic ZES, and specific MEN-1-related signs, clinical characteristics are similar in both ZES types. Acid output and gastrin level are also similar whether in the basal state or after secretin. Primary hyperparathyroidism (pHPT) exists in the majority of ZES MEN-1 patients, 30% have pituitary adenoma (prolactinomas for half), 30% adrenal involvement, 25–30% have ECLomas: bronchial and thymic carcinoids have probably been underevaluated. Gastrinomas are multiple predominantly located in the duodenal wall, but also in the pancreas in association with clinically silent endocrine tumours. The spread of the disease metastases to the liver (LM), mediastinum, bones, is evaluated best by Octreoscan. Associated endoscopic ultrasonography evaluates the number, size and anatomical characteristics of gastrinomas. Patients without LM have an excellent prognosis. Surgery never cures ZES, but is necessary in cases of associated life-threatening conditions such as insulinoma. Although the size of the tumour, when located in the pancreas >3 cm, favours metachronous LM occurrence, surgery in our experience has not been able to prevent LM development.     

Operative tumour yield obviates preoperative pancreatic tumour localization in multiple endocrine neoplasia type 1

Abstract. 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.     

Monitoring response to treatment in liver tumours

New imaging techniques offer better ways of measuring response to treatment and remain central to the formal assessment of response in clinical trials and routine clinical practice. Increasing tumour size is consistently associated with progressive disease. However, there is evidence that the designation 'partial response', as determined by conventional imaging techniques, may not always accurately reflect the degree of treatment-induced tumour necrosis. Thus, responses classified as partial on imaging grounds have, in some cases, been shown to be complete pathological responses after surgical resection, implying that residual tumour and necrotic/fibrotic tumour remnants cannot always be accurately distinguished by imaging. In this situation, serological tumour markers such as alphafetoprotein may be useful in measuring the true degree of response. While radiological imaging is likely to remain the main method of assessing response in phase II trials of drugs for the treatment of liver cancer, it may in some instances be useful to apply additional parameters such as alphafetoprotein level.     

Long-term endoscopic and clinical follow-up of untreated type 1 gastric neuroendocrine tumours

BACKGROUND AND AIMS: Type 1 gastric neuroendocrine tumour surveillance and treatment are a matter of debate. Endoscopic, or surgical, resection and chronic somatostatin analog therapy have been proposed. Based on the favourable behaviour of this neoplasm, we performed an endoscopic and clinical follow-up in 11 patients affected by type 1 gastric neuroendocrine tumours, avoiding any specific treatment. METHODS: Between 1994 and 2006, we prospectively recorded the data of 11 untreated patients with type 1 gastric neuroendocrine tumours who underwent an endoscopic and clinical follow-up. All the patients were also evaluated by means of an abdominal computed tomography scan, somatostatin receptor scintigraphy and blood tests. RESULTS: During the follow-up (median 54 months, range 9-136), the endoscopic picture of 4 (36%) out of 11 patients changed in terms of increased number of lesions. In none of the cases were detected any lesions that exceeded 10mm in diameter, and none of the patients demonstrated any evidence of local or distant metastases. CONCLUSIONS: Our data confirm the literature data of the indolent behaviour of type 1 gastric neuroendocrine tumours and suggest that a careful endoscopic follow-up, without any treatment, might represent a reasonable and safe option in selected patients.     

Co-expression of ghrelin and its receptor in pancreatic endocrine tumours

OBJECTIVE: Expression of ghrelin has been reported in pancreatic endocrine tumours, but data on ghrelin receptor protein expression are lacking. The aim of this study was to examine the ghrelin receptor, as well as ghrelin, in a selected series of these tumours, including multiple endocrine neoplasia 1 (MEN1) associated tumours, and to correlate data with clinical features including body mass index. DESIGN: Immunohistochemical detection of ghrelin and its receptor was performed on frozen tissue from 31 tumours: 9 MEN1 and 22 sporadic. Twenty tumours were analysed by quantitative PCR. Plasma ghrelin was assessed in 26 patients. RESULTS: Twenty-one (68%) of 31 tumours showed immunoreactivity for ghrelin (8/9 MEN1) and 19/20 expressed ghrelin mRNA. Ghrelin receptor protein was detected in 21/30 (70%) tumours (4/8 MEN1), and mRNA was detected in all analysed tumours. Insulinomas had significantly higher levels of receptor mRNA than other tumours. Five patients had elevated plasma ghrelin (> 2 SD above the control group mean). No significant difference in mean plasma ghrelin levels was found between patients (908 +/- 569 ng/l) and controls (952 +/- 164 ng/l). Mean BMI was 24.3 kg/m(2). There was no association between ghrelin or receptor expression and survival. CONCLUSIONS: We report the first immunohistochemical data on expression of the ghrelin receptor in pancreatic endocrine tumours: 70% of tumours in our material. Concomitant ghrelin and receptor expression was seen in 50% of tumours, indicating an autocrine loop. Ghrelin was expressed in 68% of tumours (8/9 MEN1). Despite frequent ghrelin expression, elevated circulating ghrelin is rare in these patients.     

Patient characteristics and clinical outcomes following initial surgical intervention for MEN1 associated pancreatic neuroendocrine tumours: A systematic review and exploratory meta-analysis of the literature

Background

This systematic review aimed to define the outcomes of different pancreatic resection procedures for multiple endocrine neoplasia type 1 (MEN1) associated pancreatic neuroendocrine neoplasms (pNENs).

Current concepts in the surgical management of multiple endocrine neoplasia type 1 pancreatic-duodenal disease. Results in the treatment of 40 patients with Zollinger–Ellison syndrome, hypoglycaemia or both

Thompson NW (University of Michigan, Ann Arbor, MI, USA). Current concepts in the surgical management of multiple endocrine neoplasia type 1 pancreatic-duodenal disease. Results in the treatment of 40 patients with Zollinger– Ellison syndrome, hypoglycaemia or both (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 495–500.
The management of multiple endocrine neoplasia type 1 (MEN-1) pancreatic-duodenal disease, particularly when the Zollinger–Ellison syndrome (ZES) is the presenting manifestation, has remained controversial. The management of hypoglycaemia and other syndromes as well as large tumours detected by imaging is less controversial, although standardized surgical techniques have not been generally adapted. The rationale for an aggressive operative management plan for ZES and other syndromes is based on the facts that neuroendocrine tumours of both the pancreas and the duodenum have malignant potential and that the functional manifestations can be controlled with appropriate surgical procedures based on current concepts of the MEN-1 disease. Of the ten concepts presented, the one critical to the surgical treatment of ZES is that a duodenotomy is essential in detecting the source of hypergastrinaemia in most MEN-1 patients. The complete operation is multifaceted and includes peripancreatic lymph node dissection (ZES), enucleation of any head or uncinate tumours and a distal pancreatectomy. Our results in 40 MEN-1 patients with functional syndromes treated with these procedures are encouraging. Ten patients with hypoglycaemia (four with concomitant ZES) have been 'cured' with follow-up as long as 18 years. Sixty-eight per cent of 34 patients with ZES have remained eugastrinaemic during follow-up as long as 19 years. One patient developed a solitary liver metastasis that was excised a year ago without other evidence of recurrence. There has been no operative mortality and three subsequent deaths were due to unrelated disease.     

Parathyroid hormone-related peptide in pancreatic neuroendocrine tumours associated with hypercalcaemia

BackgroundHypercalcaemia is a common paraneoplastic syndrome. In the context of pancreatic neuroendocrine tumours, it is occasionally caused by secretion of parathyroid hormone-related peptide (PTH-rP).Case outlinesTwo patients are reported in whom persistent hypercalcaemia was traced to a large neuroendocrine pancreatic tumour hypersecreting PTH-rP. Resection of the tumour reduced serum levels of calcium and PTH-rP transiently in each case until the patient developed bulky metastatic disease. A 33-year-old woman remained hypercalcaemic after the removal of all four hyperplastic parathyroid glands had rendered circulating parathormone levels undetectable. Radical distal pancreatectomy was followed over the next 4 years by operative debulking of liver metastases, multiple hepatic artery embolisations.octreotide injections and repeated admissions for intravenous fluid and biphosphonate therapy. A 41-year-old man presented with hypercalcaemia as well as features of somatostatinoma syndrome. Symptomatic improvement after radical distal pancreatectomy was short-lived, and hepatic artery embolisation failed to control his rapidly progressive disease.DiscussionMalignant hypercalcaemia associated with a neuroendocrine pancreatic tumour hypersecreting PTH-rP is difficult to treat and can be life-threatening. Aggressive surgical treatment is recommended initially, while somatostatin analogues and hepatic artery embolisation are alternative therapeutic options for metastatic disease.     

超声内镜诊断胰腺内分泌肿瘤的价值

目的探讨超声内镜诊断胰腺内分泌肿瘤的价值．方法胰腺内分泌肿瘤患者１０例,进行了超声内镜、血管造影、ＭＲＩ,ＣＴ及超声波检查．结果超声内镜对胰腺内分泌肿瘤的诊断率为９２３％,其中肿瘤直径在２ｃｍ以下的诊断率为８７５％,肿瘤轮廓清晰,边缘整,内部回声呈强回声、低回声、等回声和混合性回声;超声波的诊断率为４６２％;ＣＴ平扫和增强扫描的诊断率分别为３０７％和４６２％;ＭＲＩＴ１呈低信号、Ｔ２呈高信号,诊断率为７２７％;血管造影的诊断率为８４６％．结论超声内镜对胰腺内分泌肿瘤的定位诊断和定性诊断优于其他影像学检查,特别是对胰腺小肿瘤的诊断,更显示出它的价值．     

Ultrasound in the diagnosis of malignant pancreatic tumours

Ultrasonic scanning of the upper abdomen is a valuable method in diagnosing malignant pancreatic tumours. A series of 12 patients is presented. The method also provides information about the size of the gallbladder and the condition of the liver parenchyma.