Duodenal and ampullary carcinoid tumors

Summary Twelve duodenal carcinoid tumours are presented, 4 of them located in the ampulla. Symptoms included the Zollinger-Ellison syndrome (4 patients), the carcinoid syndrome (1 patient), mechanical obstruction (3 patients), bleeding (1 patient) and abdominal pain (1 patient). Two further tumours were detected by chance.Three patients with the Zollinger-Ellison syndrome had additional endocrine tumours characteristic of the MEN I syndrome. In 2 of them the duodenal carcinoids were of very small size and were multiple. They were observed in close proximity to focal areas of endocrine cell hyperplasia.Immunohistochemical investigations showed gastrin and somatostatin to be the predominant polypeptide hormones produced by these tumours. No somatostatinoma syndrome was encountered. In half of our cases additional production of insulin, VIP or even calcitonin in smaller amounts was found.Two of our patients had cutaneous manifestations of von Recklinghausen's disease and in both of them the carcinoid was located in the ampulla. One of these patients also had a pheochromocytoma.     

An unusual variant of multiple endocrine neoplasia syndrome: a case report

A case of multiple endocrine neoplasia syndrome (MEN) in a 57-year-old woman with multiple endocrine tumours involving the pancreas, parathyroid and thyroid glands is reported. An unusual feature was the presence of collision tumours in the pituitary and adrenal. In the pituitary there were adenomas and a meningioma whereas in the adrenal there was a carcinoma along with a myelolipoma. Such collision tumours in the pituitary and adrenal as components of MEN syndrome have not been previously described.     

Multiple endokrine Neoplasien Typ 1

Multiple endocrine neoplasia type I (MEN1) is a rare hereditary cancer syndrome, which is manifested as a variety of endocrine and non-endocrine tumours and lesions caused by specific germline mutations of the MEN1 gene, a tumour suppressor gene. The detection of these germline mutations allows the early identification of affected, possibly still asymptomatic patients. The combined use of genetic and clinical tools for the diagnosis of MEN1-associated tumours substantially improves both the course of the disease and the quality of life of affected patients. This review summarizes the relevant morphological and clinical features of MEN1-associated endocrine and non-endocrine neoplasms and lesions.     

Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1)

Phenocopies may confound the clinical diagnoses of hereditary disorders. We report phenocopies in Multiple Endocrine Neoplasia type 1 (MEN1), an autosomal dominant disorder, characterised by the combined occurrence of parathyroid, pituitary and pancreatic tumours. We studied 261 affected individuals from 74 families referred with a clinical diagnosis of MEN1 and sought inconsistencies between the mutational and clinical data. We identified four patients from unrelated families with phenocopies. Patients 1 and 2 from families with MEN1, developed prolactinomas as the sole endocrinopathy but they did not harbour the germlineMEN1 mutation present in their affected relatives. Patient 3, had acromegaly and recurrent hypercalcaemia following parathyroidectomy, whilst patient 4 had parathyroid tumours and a microprolactinoma. Patients 3 and 4 and their relatives did not haveMEN1mutations, but instead had familial hypocalciuric hypercalcaemia (FHH) due to a calcium‐sensing receptor mutation (p.Arg680Cys), and the hyperparathyroidism‐jaw tumour (HPT‐JT) syndrome due to a hyperparathyroidism type 2 deletional‐frameshift mutation (c.1239delA), respectively. Phenocopies may mimic MEN1 either by occurrence of a single sporadic endocrine tumour in a patient with familial MEN1, or occurrence of two endocrine abnormalities associated with different aetiologies. Phenocopies arose in >5% of MEN1 families, and awareness of them is important in the clinical management of MEN1 and other hereditary disorders. ©2009 Wiley‐Liss, Inc.     

Analysis of the MEN1 gene in sporadic pituitary adenomas

The MEN1 gene on chromosome 11q13 is mutated in patients afflicted with multiple endocrine neoplasia syndrome type 1 (MEN1). These patients develop endocrine tumours of the pancreas, the parathyroid, and the anterior pituitary. In order to determine the role of MEN1 in sporadic pituitary adenomas, 61 pituitary adenomas were analysed from patients without evidence of a familial tumour syndrome. Single strand conformation polymorphism (SSCP) analysis was performed for the entire coding sequence of MEN1. Fragments with aberrant migration patterns were sequenced bidirectionally. Only a single somatic mutation was detected in this series. In addition, several previously reported and three novel polymorphisms were observed. Loss of heterozygosity analysis with 12 polymorphic markers, however, identified 13 pituitary adenomas with allelic deletions on chromosome 11. Allelic losses occurred significantly more often in pituitary adenomas with hormone secretion than in non-functioning adenomas. These data suggest that MEN1 mutations are rare events in sporadic pituitary adenomas. However, the discrepancy of only 1/61 adenomas with MEN1 mutation but 13/61 (22 per cent) with allelic loss on chromosome 11 may suggest the presence of a yet unknown tumour suppressor gene, relevant to the pathogenesis of sporadic pituitary adenomas. Copyright © 1999 John Wiley & Sons, Ltd.     

Solid tumors associated with multiple endocrine neoplasias

We present an update on molecular and clinical genetics of solid tumors associated with the various multiple endocrine neoplasias (MEN) syndromes. MEN type 1 (MEN1) describes the association of pituitary, parathyroid, and pancreatic islet cell tumors with a variety of many other lesions. MEN type 2 (MEN2) conditions represent at least four different syndromes that associate pheochromocytoma with medullary thyroid carcinoma, hyperparathyroidism, and a number of other manifestations. Other pheochromocytoma-associated syndromes include von Hippel-Lindau disease; neurofibromatosis 1; the recently defined paraganglioma syndromes type 1, 3, and 4; Carney-Stratakis syndrome; and the Carney triad. Carney-Stratakis syndrome is characterized by the association of paragangliomas and familial gastrointestinal stromal tumors. In the Carney triad, patients can manifest gastrointestinal stromal tumors, lung chondroma, paraganglioma, adrenal adenoma and pheochromocytoma, esophageal leiomyoma, and other conditions. The Carney complex is yet another form of MEN that is characterized by skin tumors and pigmented lesions, myxomas, schwannomas, and various endocrine neoplasias.     

Familial disorders of parathyroid glands

The molecular mechanisms underlying familial parathyroid diseases continue to be elucidated. The mechanisms of familial parathyroid diseases are better understood than many sporadic parathyroid diseases. Familial parathyroid disease is associated with multiple endocrine neoplasia type 1 which is associated with MEN1 mutation, multiple endocrine neoplasia type 2A caused by RET mutation, and multiple endocrine neoplasia type 4 is caused with CDKN1B mutation. Sporadic parathyroid tumours are identified with mutations of MEN1 but generally not of RET. CDKN1B mutations are also identified in sporadic forms of primary hyperparathyroidism, although very rarely. Calcium sensing receptor gene mutations are involved in familial hyperparathyroidism and hypoparathyroidism, but are generally not identified in sporadic parathyroid tumours. However, the HPRT2 (CDC73) gene, which is mutated in hyperparathyroidism jaw-tumour syndrome and a subset of cases of familial isolated hyperparathyroidism, is frequently mutated in sporadic parathyroid carcinomas. Germline activating GCM2 mutations were recently found associated with a subset of familial isolated hyperparathyroidism. Parafibromin, a protein encoded by HPRT2, has been used in the diagnostic setting. The understanding and pathogenesis of parathyroid disease continues to evolve.     

Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) occurs sporadically or as part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. In MEN 2A, germline missense mutations are found in one of five cysteine codons within exons 10 and 11 in the extracellular domain of the RET protooncogene. In MEN 2B, germline mutations occur in codon 918 (exon 16) within the catalytic core of the tyrosine kinase domain. To determine if RET mutations similar to those in MEN 2A and 2B play a role in the pathogenesis of sporadic MTC, we analysed 71 sporadic tumours comprising 68 primary tumours and three cell lines, for mutations in RET exons 10, 11, and 16. We found that 23% of sporadic MTC had RET codon 918 mutations, while only 3% had exon 10 mutations, and none had mutations in exon 11. We found no exon 16 mutations in MTC from 14 MEN 2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN 2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumourigenesis of a significant minority of sporadic MTC but not MEN 2A tumours. In addition to their biological interest, these findings may have some clinical application in determining whether a patient presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome.     

Parathyroid hyperplasia in multiple endocrine neoplasia type 1: a pathological and immunohistochemical reappraisal

Twenty-nine parathyroid glands from nine patients with multiple endocrine neoplasia type 1 (MEN 1) syndrome were examined histopathologically and immunocytochemically to characterize better the nature of the accompanying parathyroid hyperplasia. The parathyroids showed varying degrees of nodular and diffuse (partial and total) hyperplastic involvement as well as apparently normal tissue. The nodules were usually multiple within any one gland and showed a varied cytoarchitectural pattern. All glands studied showed both cellular argyrophilia and parathyroid hormone immunoreactivity. The staining pattern for parathyroid hormone ranged from negative or weak to strong and from patchy to diffuse in hyperplastic tissue from different glands and within the same gland. Apparently normal areas usually showed the strongest positive reaction. Amyloid material was observed within glandular lumens from hyperplastic areas in over half of the studied cases and stained positively for parathyroid hormone. This suggests that the hormone could be the precursor molecule of parathyroid amyloid as occurs with hormone-derived amyloid from other endocrine tumours. The overall findings indicate that the most striking feature of the parathyroid glands in MEN 1 is their variability, both morphological and functional, as indicated by their parathyroid hormone immunoreactivity.     

Lack of allelic loss at the multiple endocrine neoplasia type 1(MEN-1) gene locus in a pancreatic ductal (non-endocrine) adenocarcinoma of a patient with the MEN-1 syndrome

The gene responsible for multiple endocrine neoplasia type I (MEN-1) syndrome has been mapped to chromosome 11q13. It appears to function as a tumour-suppressor gene analogous to that for retinoblastoma and allelic losses involving the wild-type of the MEN-1 allele have been found in parathyroid and pancreatic endocrine tumours of MEN-1 patients. No genetic information has been provided so far on non-endocrine malignancies that may occur in MEN-1 patients. A case of exocrine pancreatic adenocarcinoma presenting as the terminal event in a woman with a long standing history of MEN-1 syndrome and multiple endocrine tumours of the pancreas was investigated for possible allelic losses at the MEN-1 gene locus using restriction fragment length polymorphisms (RFLPs) closely linked to the MEN-1 gene and polymerase chain reaction (PCR) for D11S533 locus. No allelic losses were found in tumour tissue with two informative RFLPs (D11S97, D11S146) or with PCR analysis. These findings suggest that the MEN-1 gene does not confer a predisposition to develop tumours other than those that typify the syndrome.     

MENX and MEN4

Multiple endocrine neoplasias are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two MEN syndromes have long been known and are well characterized: the MEN type 1 (MEN1) and type 2 (MEN2). These syndromes are caused by germline mutations in the MEN1 and RET genes, respectively, and have a different tumor spectrum. Recently, a variant of the MEN syndromes arose spontaneously in a rat colony and was named MENX. Affected animals consistently develop multiple endocrine tumors, with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, heterozygous germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized, which is caused by mutations in p27. Altogether, these studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here we review the characteristics of the MENX and MEN4 syndromes and we briefly address the main function of p27 and how they are affected by MENX/4-associated mutations.     

Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma

Familial paraganglioma is a dominantly inherited disorder characterised by the development of highly vascular tumours in the head and neck. Recently, a relationship between hereditary tumours derived from the autonomic nervous system and germline mutations in the gene encoding succinate dehydrogenase complex subunit D (SDHD) is increasingly a subject of study. Familial paraganglioma syndrome is embryologically related to phaeochromocytoma, another neuroendocrine tumour that shows great aetiological and genetic heterogeneity. Some hereditary phaeochromocytomas may be associated with germline mutations in VHL, RET and NF1 genes in genetic disorders such as von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2) and neurofibromatosis type 1 (NF 1), respectively. However, there are many cases that cannot be explained by mutations in these genes. In this report, we describe two previously unreported mutations in two patients from 25 unrelated kindreds with phaeochromocytoma and/or paraganglioma disorders and with or without familial antecedents: a mutation featuring the change of tryptophan to a termination codon in exon 2, and a 4-bp deletion in exon 4 that results in a truncated protein. We also describe one missense substitution of uncertain significance. The patients had previously tested negative for germline mutations in VHL and RET genes and had not been previously selected. The involvement of SDHD mutations in familial phaeochromocytoma and/or paraganglioma predisposition is of considerable interest since other studies have shown these alterations to be associated with highly expressed angiogenic factors.     

Diffuse ganglioneuromatosis of the gallbladder

Diffuse ganglioneuromatosis of the gallbladder is a rare entity consisting of a proliferation of mature neural tissue. This may occur sporadically but it is also associated with multiple endocrine neoplasia, type IIB (MEN2B), neurofibromatosis type I (NF1) and Cowden syndrome. Presented is a case of a 69-year-old woman who under routine cholecystectomy for cholelithiasis and chronic cholecystitis. Routine histology showed a proliferation of bland, wavy spindle cells and ganglion cells within the wall of the cystic duct; the lesional cells stained positively for S100 and neurofilament and were negative for glial fibrillary acid protein (GFAP). To date this patient has not shown any other clinical features suggesting a tumour syndrome. Also presented is a discussion on ganglioneuromatosis of the gastrointestinal (GI) tract and the importance of recognizing these lesions.     

The MEN1 gene and associated diseases: An update

Heterozygous germline mutations of the tumor suppressor gene MEN1 are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited familial cancer syndrome characterized by the combined occurrence of pituitary, parathyroid, and enteropancreatic tumors. Various types of mutations likely causing loss of the gene function have been identified throughout the entire gene region in patients with MEN1 and related disorders including a small fraction of familial isolated hyperparathyroidism (FIHP). Neither mutation hot spot nor phenotype-genotype correlation has been established in classical MEN1, although some missense mutations may be specifically associated with a phenotype of FIHP. Familial isolated pituitary tumor and atypical familial MEN1 consisting of only pituitary tumor and hyperparathyroidism usually lack germline MEN1 mutations, suggesting that these familial endocrine tumor syndromes are genetic entities distinct from MEN1. DNA test for MEN1 germline mutations is a robust tool for diagnosis of predisposition to MEN1, and will be useful for the counseling and management of patients and their families. In this review, we will summarize the most recent findings on the MEN1 gene, focusing primarily on germline mutations and associated diseases.     

Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and localization of multiple endocrine neoplasia type 1 related tumors are crucial for determining the best surgical strategies in each individual case with pancreatic endocrine tumors.     

Morphology and staining patterns of endocrine cell tumours in the gut, pancreas and bronchus and their possible significance

We have studied 109 endocrine cell tumours of the gastrointestinal tract, pancreas and bronchus in terms of histological pattern and histochemical staining with immunocytochemical studies on seven tumours. As a result we believe that previous histological classifications need modification. 5-Hydroxytryptamine secreting tumours have a carcinoid (A1) pattern with, in some cases, an additional tubuloacinar element (A1A2) and definable histochemical reactions; well differentiated gastrinomas, insulinomas and glucagonomas are associated commonly, but not exclusively, with particular histological patterns and argyrophilia, but no such association exists for less differentiated tumours. This may be related to the synthesis of precursor hormones by less differentiated tumours. Mixed patterns are common, particularly in tumours of foregut derivation. Prospective studies planned to correlate histology, histochemistry, immunocytochemistry and ultrastructure are needed on all endocrine cell tumours.     

Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes,related sporadic tumours,and Hirschsprung disease

The RET proto-oncogene codes for a receptor tyrosine kinase thought to play a role in the development of neural crest and its derivatives. Mutations in the RET proto-oncogene have been found in patients with the multiple endocrine neoplasia type 2 syndromes (MEN 2), the related sporadic tumours medullary thyroid carcinoma and pheochromocytoma, and familial and sporadic Hirschsprung disease, a syndrome of congenital absence of enteric innervation. Germline mutations in one of eight codons within RET cause the three subtypes of MEN 2, namely, MEN 2A, MEN 2B, and familial medullary thyroid carcinoma. Somatic mutation in an overlapping group of nine codons have been found in a proportion of sporadic medullary thyroid carcinoma and pheochromocytoma. In contrast to MEN 2, approximately 25% of patients with Hirschsprung disease have germline mutations scattered throughout the length of RET. Hum Mutat 9:97–109, 1997. © 1997 Wiley-Liss, Inc.     

Familial pheochromocytomas and paragangliomas: Stories from the sign-out room

In this overview we present five patients with apparently sporadic pheochromocytomas or paragangliomas which turned out to be associated with an inheritable familial disease. For each patient a family history together with clinical, morphological, as well as molecular data are reported. The identified syndromes include multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), and familial pheochromocytoma/paraganglioma syndrome (SDHx). A brief summary of phenotypes, the genes involved, and typical mutations in these syndromes is provided.     

A MEN1 syndrome with a paraganglioma

Germline mutations of the MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder characterized by tumors of the parathyroids, the pancreas, and the anterior pituitary. Paraganglioma (PGL) is a rare endocrine tumor, which can be sporadic or genetically determined. To date, PGL has never been reported as a feature of MEN1.We report here a patient presenting three features of MEN1 syndrome (hyperparathyroidism, pancreatic neuroendocrine tumor, and adrenocortical adenoma) associated with PGL. Genetic analysis of MEN1 gene revealed a new missense mutation in exon 5 (AGG→AAG), causing the substitution of arginine by lysine at codon 275. Screening for other genetic disorders (SDHx, TMEM127, MAX, CDKN1B) causing PGL was negative. Immunohistochemical analyses showed normal levels of succinate dehydrogenase (SDH)A and SDHB in the PGL. The proband''s sister, bearing the mutation, had primary hyperparathyroidism. It was the first typical MEN1 syndrome reported with an extra-adrenal PGL.