Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients

AIM: To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. METHODS: Sixteen patients with genetically confirmed multiple endocrine neoplasia type 1 (MEN 1) and Zollinger-Ellison syndrome (ZES) underwent resection of both gastrinomas and duodenopancreatic neuroendocrine tumors (NETs) between 1991 and 2009. For localization of gastrinoma, selective arterial secretagogue injection test (SASI test) with secretin or calc...     

A case of Zollinger-Ellison syndrome produced by gastrinoma in the duodenum accompanied with multiple endocrine neoplasia type 1

A case of Zollinger-Ellison syndrome produced by gastrinoma in the duodenum accompanied by multiple endocrine neoplasia type-1 (MEN-1) is reported. A 46 year-old female underwent distal gastrectomy due to gastric ulcer 5 years ago. As ulceration of the residual stomach recurred, further examination was performed. Hyperprolactinemia, hypergastrinemia, primary hyperparathyroidism, pancreatic tumor, and duodenal carcinoid were evident, and the diagnoses of Zollinger-Ellison syndrome and MEN-1 were established. The origin of the gastrin secretion was suspected to be from the pancreatic tumor, so sampling of the portal blood was performed. As lesion on the gastrinoma in the pancreas could not be identified, total parathyroidectomy was performed for primary hyperparathyroidism. The level of the gastrin secretion, however, remained high. Partial resection of the duodenum for the duodenal carcinoid and a distal pancreatectomy were carried out concurrently. Immunohistochemical study of the anti-gastrin antibody revealed duodenal tumor cells. Initially, the gastrinoma was thought to be in the pancreas, however, the lesion accompanied with MEN-1 and the Zollinger-Ellison syndrome had occurred in the duodenum.     

Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma

No variant of multiple endocrine neoplasia type 1 (MEN1) has been reproducible among families. We examined two large kindreds with MEN1 variants, and we compared these to past reports. The two kindreds were followed up for 20-30 yr with MEN1 tumors in 30 members.Results in cases from two kindreds were that 93% showed parathyroid adenoma, 40% pituitary tumor (always prolactinoma), and 27% enteropancreatic endocrine tumor. The latter included 10% insulinoma, 7% nonfunctioning islet tumor, but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs. 42%, P < 0.01) and higher prevalence of prolactinoma (40% vs. 22%, P < 0.01) define this variant. Many possible biases of retrospective analyses were excluded as possible explanations. Previously sequenced DNA showed no characteristic MEN1 mutation in these two kindreds and in a third, reported previously; the lack of any shared MEN1 mutation also excluded common ancestry for MEN1 among the three kindreds. The causes for differences between this variant and typical MEN1 are unknown.In conclusion, this variant shows more frequent prolactinoma and less frequent gastrinoma than typical MEN1; the variant is reproducible among kindreds. MEN1 carriers in such families should have periodic monitoring adjusted for the expected penetrance of tumors.     

Experience with multiple endocrine neoplasia type 1 screening

Abstract. Screening for multiple endocrine neoplasia type 1 (MEN1) may be conducted for a variety of reasons. The principal aims may be more or less scientific, such as early identification of the trait. Other reasons for screening comprise attempts to avoid endocrine morbidity and possibly forthcoming problems from malignant transformation, as well as attempts to identify and treat gene carriers with a clinically overt disease. Several reports have substantiated the diagnostic yield from screening efforts among MEN1 kindreds. Such increases in detection of the disease ideally should be accompanied by enhanced rates of survival in order to fully justify an unlimited search for the trait. However, studies are lacking a clearly verifying reduction of mortality from the detection of presymptomatic MEN1 individuals. While waiting for the results of survival studies in progress, the generally prevailing opinion favours widespread screening because of the evidently decreased morbidity resulting from early diagnosis of the MEN1 trait, which apparently persists even during decades of follow-up. This paper presents the clinical features of the disease and experience derived from a prospective screening programme for MEN1 detection.     

Benefit of resection of metastatic gastrinoma in multiple endocrine neoplasia type I.

Although gastrinoma resection is generally advocated for patients with the sporadic form of nonmetastatic Zollinger-Ellison syndrome, there is controversy regarding the surgical management of the gastrinoma among patients with multiple endocrine neoplasia type I (MEN-I). Using strict criteria, to date no biochemical cures of the Zollinger-Ellison syndrome lasting greater than 5 months have been achieved by gastrinoma resection among patients with MEN-I. Whereas resections of hepatic metastases have been performed in patients with sporadic gastrinoma, none have been reported among patients with MEN-I. The current report describes a patient with MEN-I, closely followed up for 30 years, in whom enlargement of pancreatic gastrinoma and development of hepatic gastrinoma was observed to occur over 3 years. After preoperative localization, an 80% pancreatectomy and a left lateral segmentectomy of the liver were performed. Sixteen months after the operation, secretin and calcium provocative testing showed that the patient's fasting gastrin and stimulated plasma gastrin concentrations were normal; also, results of computerized tomographic angiography, selective abdominal angiography, and hepatic venous sampling for gastrin after intra-arterial secretin injection were negative for gastrinoma. By achieving a 16-month cure of gastrinoma, this case shows that an aggressive surgical approach can benefit certain patients with gastrinoma who have MEN-I even in the presence of hepatic metastases.     

Gonadotroph tumor associated with multiple endocrine neoplasia type 1

Although anterior pituitary tumors constitute a main clinical feature of multiple endocrine neoplasia type 1 (MEN1), and most types of pituitary tumors have been associated with MEN1, gonadotroph tumors have not previously been recognized clinically as part of this syndrome. We report here a woman who presented with ovarian hyperstimulation due to a gonadotroph tumor that was confirmed biochemically and immunohistochemically. She then developed hyperparathyroidism, and she was found to have three hypercellular parathyroid glands. Subsequently, she developed a temporal lobe metastasis of the gonadotroph tumor, demonstrating that it was a gonadotroph carcinoma. The diagnosis of MEN1 was confirmed by finding a deletion mutation (c.307delC) on the second exon of the MEN1 gene that predicts truncation of the resulting menin protein 15 codons downstream from the deletion (p.Leu103fsX15). This case illustrates that gonadotroph tumors, like other pituitary tumors, can be part of MEN1. The clinical implications of this case are that the clinical and biochemical features of gonadotroph tumors should be considered when evaluating patients for MEN1, and MEN1 should be considered in patients who have gonadotroph tumors.     

Cushing's syndrome in multiple endocrine neoplasia type 1

Objective In patients with multiple endocrine neoplasia type 1 (MEN1), Cushing’s syndrome (CS) from endogenous hypercortisolism can result from pituitary, adrenal or other endocrine tumours. The purpose of this study was to characterize the range of presentations of CS in a large series of MEN1 patients. Design Retrospective review of NIH Clinical Center inpatient records over an approximately 40‐year period. Patients Nineteen patients (eight males, 11 females) with CS and MEN1. Measurements Biochemical, imaging, surgical and pathological findings. Results An aetiology was determined for 14 of the 19 patients with CS and MEN1: 11 (79%) had Cushing’s disease (CD) and three (21%) had ACTH‐independent CS owing to adrenal tumours, frequencies indistinguishable from sporadic CS. Three of 11 MEN1 patients with CD (27%) had additional non‐ACTH‐secreting pituitary microadenomas identified at surgery, an incidence 10‐fold higher than in sporadic CD. Ninety‐one per cent of MEN1 patients with CD were cured after surgery. Two of three MEN1 patients with ACTH‐independent CS (67%) had adrenocortical carcinoma. One patient with adrenal cancer and another with adrenal adenoma were cured by unilateral adrenalectomy. No case of ectopic ACTH secretion was identified in our patient cohort. The aetiology of CS could not be defined in five patients; in three of these, hypercortisolism appeared to resolve spontaneously. Conclusions The tumour multiplicity of MEN1 can be reflected in the anterior pituitary, MEN1‐associated ACTH‐independent CS may be associated with aggressive adrenocortical disease and an aetiology for CS in MEN1 may be elusive in a substantial minority of patients.     

Candidate genes for multiple endocrine neoplasia type 1

Abstract. The aim of this study was to isolate and characterize candidates for the multiple endocrine neoplasia type 1 (MEN1) gene. The development of tumours related to MEN1 is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour-suppressor gene in this region. We have isolated five cDNA candidates located within the 900 kb remaining for the MEN1 gene, determined their sequence, and characterized their expression in normal tissues and several endocrine tumours. One of the candidates, encoding for phospholipase C-β3, showed properties consistent with the idea of a tumour-suppressor gene.     

Long-term follow-up of patients with multiple endocrine neoplasia type 1

Whether early surgical treatment of non-functioning pancreas islet cell tumor (NFPT) provides a favorable quality of life and life expectancy in patients with multiple endocrine neoplasia type 1 (MEN1) remains controversial. We analyzed the long-term clinical courses and surgical outcomes of 14 Japanese patients with MEN1-associated NFPTs. NFPTs smaller than 20 mm in diameter did not show any apparent growth over a long monitoring period. Furthermore, these small NFPTs did not metastasize to regional lymph nodes or the liver. On the other hand, the development of additional NFPTs or metastasis was found in five of six patients with large (35 mm or larger) NFPTs. Among the seven patients who underwent a partial pancreatectomy, six patients developed impaired glucose tolerance or diabetes. The accumulation of more prospective data is needed to clarify the optimal surgical indications for patients with NFPTs, especially among the Japanese population, which has a relatively low insulin secretion potency compared with non-Hispanic white and African-American populations.     

Thymic carcinoids in multiple endocrine neoplasia type 1

Teh BT (Karolinska Hospital, Stockholm, Sweden). Thymic carcinoids in multiple endocrine neoplasia type 1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 501–4.
Thymic carcinoid is a rare malignancy with about 150 cases reported to date. It is associated with multiple endocrine neoplasia type 1 (MEN-1), but compared with other MEN-1-related neoplasia little is known about it. We have recently described and studied 20 MEN-1-related cases and found that up to 25% of all reported thymic carcinoids are MEN-1 related. It is an insidious tumour not associated with Cushing's syndrome or carcinoid syndrome. Local invasion, recurrence and distant metastasis are common with no known effective treatment. Its male predominance, the absence of loss of heterozygosity (LOH) in the MEN1 region, clustering in some MEN-1 families and the findings of different MEN1 mutations in these clustered families suggest the involvement of additional aetiological factors. We propose that computed tomography (CT) or magnetic resonance imaging (MRI) of the chest should be included as part of the clinical workup for all MEN-1 patients. Prophylactic thymectomy should be considered during subtotal or total parathyroidectomy on MEN-1 patients to reduce the risk of this malignancy.     

New therapies for patients with multiple endocrine neoplasia type 1

In 1953, for the first time, Paul Wermer described a family presenting endocrine gland neoplasms over several generations. The transmission was autosomal dominant and the penetrance was high. Forty years later in 1997, the multiple endocrine neoplasia type 1 (MEN1) gene was sequenced, thus enabling diagnosis and early optimal treatment. Patients carrying the MEN1 gene present endocrine but also non-endocrine tumors. Parathyroid, pancreatic and pituitary impairment are the three main types of endocrine involvement. The present article details therapeutic management of hyperparathyroidism, neuroendocrine pancreatic tumors and pituitary adenomas in patients carrying the MEN1 gene. Significant therapeutic progress has in fact been made in the last few years. As concerns the parathyroid glands, screening of family members and regular monitoring of affected subjects now raise the question of early management of parathyroid lesions and optimal timing of parathyroid surgery. As concerns the duodenum-pancreas, proton-pump inhibitors are able to control gastrin-secreting syndrome, reducing mortality in MEN1 patients. Mortality in MEN1 patients is no longer mainly secondary to uncontrolled hormonal secretion but to metastatic (mainly pancreatic) disease progression. Tumor risk requires regular monitoring of morphological assessment, leading to iterative pancreatic surgery in a large number of patients. Finally, pituitary adenomas in MEN1 patients are traditionally described as aggressive, invasive and resistant to medical treatment. However, regular pituitary screening showed them to be in fact infra-centimetric and non-secreting in the majority of patients. Consequently, it is necessary to regularly monitor MEN1 patients, with regular clinical, biological and morphological work-up. Several studies showed that this regular monitoring impairs quality of life. Building a relationship of trust between patients and care provider is therefore essential. It enables the patient to be referred for psychological or psychiatric care in difficult times, providing long-term support and preventing any breakdown in continuity of care.     

Case of primary hepatic gastrinoma: Diagnostic usefulness of the selective arterial calcium injection test

Gastrinomas mainly occur in the duodenum and pancreas. Primary hepatic gastrinoma is rare and difficult to diagnose because the liver is a frequent site of metastatic gastrinomas. Clinical factors were assessed in a 28‐year‐old man with diarrhea and heartburn who was hospitalized for recurrent duodenal ulcers. Abdominal ultrasound, endoscopic ultrasound and computed tomography (CT) could not detect a tumor in the duodenum or pancreas. His gastrin level was 846 pg/mL and magnetic resonance imaging showed a mass 12 mm in diameter in the right robe of the liver. A selective intra‐arterial calcium injection (SACI) test and 68‐gallium edotreotide positron emission tomography CT (Ga‐DOTATOC PET‐CT) were therefore performed. Calcium gluconate injection into the proper hepatic artery resulted in a marked increase in serum gastrin concentration in the right hepatic vein, with Ga‐DOTATOC PET‐CT showing uptake only by the liver mass. Following a diagnosis of primary hepatic gastrinoma, the tumor was resected. A histopathological examination indicated gastrinoma. Six months postoperatively, he has no symptoms, is not taking proton‐pump inhibitors and his gastrin level remains within the normal range. The SACI test and the clinical course of this patient strongly suggest that the tumor was a primary hepatic gastrinoma. The SACI test is helpful in the diagnosis of primary hepatic gastrinoma.     

Prolactinoma presenting in identical twins with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type one (MEN 1) is characterized by tumours of the parathyroid glands, pancreatic islet cells and the anterior pituitary and follows an autosomal dominant pattern of inheritance. We report identical twins born to a family known to have the MEN 1 syndrome. The twins were identical until puberty. The first twin underwent puberty normally; the second, however, suffered an early pubertal arrest and was subsequently found to have a prolactinoma. Both were also subsequently shown to have primary hyperparathyroldism. Genetic studies have since confirmed the twins identical for the affected haplotype and show that this is inherited from the father who also has MEN 1. The gene for MEN 1 has now been localized to the long arm of chromosome 11. The current hypothesis is that expression of the syndrome involves two separate genetic mutations. The first mutation is inherited and thus present in all cells but the tumour manifests itself in the endocrine tissue only after a second mutation that represents ellmination of the normal allele. In the case described the twins are proven genetically identical. The marked phenotypic difference between the two must, by inference, represent a second somatic mutation and is further supportive evidence of the two-mutation model of tumour expression.     

Pituitary adenomas in adolescent patients with multiple endocrine neoplasia type 1

Two juvenile patients with multiple endocrine neoplasia type 1 (MEN1) who developed pituitary adenomas are reported. The first case, a 14-year-old girl, developed prolactinoma and manifested delayed puberty and growth arrest. The second case, a 16-year-old boy, was asymptomatic and a pituitary adenoma accompanied by mild elevation of PRL and GH was identified through family screening. His growth and pubertal development was not impaired. Medication with bromocriptine was started for both cases with good therapeutic responses. These cases emphasize relevance of early screening of endocrine disorders for members of families with MEN1.     

Mediastinal seminoma in a patient with multiple endocrine neoplasia type 1

A patient with multiple endocrine neoplasia type 1 (MEN1) developed a mediastinal seminoma. The patient was a 46-year-old man who presented with respiratory symptoms. A diagnosis of mediastinal seminoma was pathologically confirmed and a complete remission was achieved by chemotherapy. During his hospital stay, hyperparathyroidism and multiple pancreatic tumors associated with hypergastrinemia were found. A diagnosis of MEN1 was made genetically. Although patients with MEN1 manifest a variety of neoplastic disorders, no cases of concurrent seminoma and MEN1 have previously been reported. In addition, no etiological relationship between seminoma and MEN1 has yet been reported.     

Characteristics of the Danish families with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is caused by autosomal dominantly inherited mutations in the MEN1 gene. Here, we report 25 MEN1 mutations - of which 12 are novel - found in 36 Danish families with MEN1 or variant MEN1 disease. Furthermore, one FIHP family was found to have an earlier reported mutation. The mutations were predominantly found in exons 9 and 10 encoding the C-terminal part of menin. Seven of the mutations were missense mutations, changing conserved residues. Furthermore screening of 93 out of 153 consecutive patients with primary hyperparathyroidism (pHPT) identified five mutation carriers. Two of these belonged to known MEN1 families, whereas the only MEN1-related disease in the other three was pHPT. Screening of 96 consecutive patients with fore-/midgut endocrine tumours revealed five mutation carries out of 28 patients with sporadic gastrinomas, whereas no mutations were found in 68 patients with other fore-/midgut endocrine tumours. Moreover, screening of 60 consecutive patients with primary prolactinoma did not identify any mutation carriers. Our data indicate that MEN1 mutation screening is efficient in patients with familial MEN1. Screening should also be offered to patients with pHPT or gastrinomas after thorough investigation into the family history. In contrast, sporadic carcinoid tumours or primary prolactinomas are rarely associated with germ-line MEN1 mutations.