Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1: correlation with primary tumor size

BACKGROUND: Islet cell tumor (ICT) metastasis is one of the potentially lethal outcomes of multiple endocrine neoplasia type 1 (MEN 1). Management of ICT in patients with MEN 1 is controversial; some advocate resection based on biochemical evidence of progression, whereas others use tumor size to predict the risk of metastasis and the need for resection. This study correlates the size of primary ICT with the presence of metastases. METHODS: Forty-eight patients with MEN 1 with ICT, from 34 kindreds followed up in our multiple endocrine neoplasia program, were evaluated; 43 of the 48 have been explored for ICT. Metastases to the lymph nodes and liver were documented. RESULTS: Thirty-three percent of patients with pancreatic tumors less than 1 cm in greatest diameter had metastatic disease at surgery and in follow-up, whereas 34.8% of patients with tumors greater than 2 cm in diameter had metastases to lymph nodes or liver. The 2 patients with liver metastases each had primary tumors greater than 2 cm. Follow-up revealed subsequent metastasis in 1 patient. CONCLUSIONS: The size of primary tumors in MEN 1 does not correlate with metastatic potential. This is not a good criterion for exploration. Continued follow-up of these patients will be necessary to define the effect of operation on the course of ICT in MEN 1.     

Multiple endocrine neoplasia associated with multiple lipomas

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN-1) is characterized by tumors of the parathyroids, the neuroendocrine pancreas-duodenum and the anterior pituitary, but shows also a wide clinical variety of other symptoms. CASE REPORT: We present a case of a 68-year-old woman with a 18 year history of MEN-1 consisting of gastrinoma and primary hyperparathyroidism. Beside these typical symptoms, the patient suffered from thyroid adenoma, malignant kidney tumor and multiple subcutaneous lipomas. RESULT: While the number of autopsies declined from 113 in 1977 to 66 in 1984, the number of diagnostic techniques used increased continuously (94, 107, 118 and 140, amounting to 0.83, 1.34, 1.76 and 2.12 per patient). The premortal detection of abdominal abnormalities increased globally from 16.8 to 32.5%. This increase was largely due to better diagnosis of liver and gallbladder abnormalities which were in most cases of little relevance. CONCLUSION: Whether these non-endocrine tumors are associated to MEN-1 is unclear and has to be tested by examining the chromosomal regions 11q13 and 11q24/25 of the tumors sample, in which the possible MEN-1 involved tumor suppressor genes are located.     

Characteristic pathological associations in multiple endocrine neoplasia type 1

OBJECTIVES: Multiple endocrine neoplasia type 1 (MEN 1) is an inherited disorder characterised by slow progressing tumors of the parathyroids, of the endocrine pancreas and of the anterior pituitary. A genetic locus predisposing to this disease has been localised on chromosome 11. Predictive diagnosis of carriers of the defective gene is possible in families using genetic markers at this locus. However, this analysis presupposes a precise identification of affected subjects. Moreover, expression of the disease may vary from one family to the other. The aim of the present study was to define the typical clinical features of the syndrom. METHODS: We assessed retrospectively 26 cases of MEN 1 identified during 20 years in the same medico-surgical center. Among 11 men and 15 women, all those who had a genealogical investigation had a positive family history of MEN 1. RESULTS: Bifocal and trifocal tumors were the main patterns of associations, and were diagnosed at a mean age of 48.6 years. Parathyroid involvement was most frequent and earliest (96% of cases). The second most frequent was pancreatic involvement (69.2% of cases) predominantly manifesting with gastrinomas (N = 13). Multifocal tumors were usually diagnosed before or within 5 years following diagnosis of the first tumor. Among pituitary tumors one case of meningioma was observed, a feature not reported previously. An asymptomatic adrenal involvement was observed in about 1/3 of cases. Other silent tumors (euthyroid nodules, lipomas) were also noted. CONCLUSION: These data suggest that the clinical presentation and course of MEN 1 is homogeneous and are in agreement with the hypothesis of a recessive tumor-suppressor gene expressed in specific endocrine cell lines, suggesting that careful family studies should be conducted when a case of MEN 1 is diagnosed to facilitate early carrier detection among relatives.     

Molecular tools for presymptomatic testing in multiple endocrine neoplasia type 1

This study sought to determine the prevalence of upper-extremity musculoskeletal disorders (UEMSDs) among keyboard operators in Sao Paulo, Brazil, and to compare this prevalence with that among other office workers. One hundred and thirty keyboard operators (mean age 33 years, 60 male/70 female) and 138 office workers (mean age 35 years, 82 male/56 female) from two computing centers were interviewed by a research assistant using a standardized questionnaire. Symptomatic subjects, defined as those who reported upper extremity pain or lost work time due to pain in the preceding 12 months, were examined by a rheumatologist. Mean (SD) lengths of employment were 9 (6) years for keyboard operators and 8 (6) years for office workers. Upper-extremity pain during the preceding seven days was reported by 66 keyboard operators (51%) and by 18 office workers (13%) (p < 0.0001); during the preceding 12 months, by 90 keyboard operators (69%) and by 26 office workers (19%) (p < 0.0001). UEMSDs were diagnosed following physical examination in 50 keyboard operators and in 12 office workers (9%) (p < 0.0001). Tenosynovitis was the most common disorder diagnosed among the keyboard operators (n = 23). Among the keyboard operators the prevalence of UEMSDs was significantly lower for males (p = 0.017, OR = 0.38, 95%CI = 0.17-0.86). The presence of a diagnosed UEMSD was significantly associated with duration of employment (p = 0.005) and lack of or insufficient rest breaks (p = 0.012). Keyboard operators had significantly more UEMSDs than did office workers. Strategies aimed at the reduction of repetitive strain injuries among keyboard operators, such as the provision of adequate work breaks, should be evaluated.     

Gs alpha mutation may be uncommon in patients with multiple endocrine neoplasia type 1

Activating mutations of the Gs alpha gene, termed gsp, have been identified in various endocrine tumors. Recently, a high frequency of gsp mutation in patients with multiple endocrinopathies was reported, and a family with both McCune-Albright syndrome and multiple endocrine neoplasia type 1 was described. Each suggests that the oncogenic mutations of Gs alpha may play an important role in tumorigenesis in patients with multiple neoplastic endocrinopathies, and a search for the gsp mutation in multiple endocrine neoplasia type 1 (MEN1) should be undertaken. We, therefore, reevaluated the frequency of gsp mutations in endocrine tumors of patients with MEN1. Of 18 tumors from 13 patients with MEN1, we found no gsp mutations regardless of heredity. We conclude that the gsp mutation may be uncommon in endocrine tumors of MEN1 patients, and thus, this mutation plays little, if any, role in their tumorigenesis.     

Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders

Centrosomes and microtubules play crucial roles during cell division and differentiation. Spermatogenesis is a useful system for studying centrosomal function since it involves both mitosis and meiosis, and also transformation of the centriole into the sperm basal body. Centrosomin is a protein localized to the mitotic centrosomes in Drosophila melanogaster. We have found a novel isoform of centrosomin expressed during spermatogenesis. Additionally, an anticentrosomin antibody labels both the mitotic and meiotic centrosomes as well as the basal body. Mutational analysis shows that centrosomin is required for spindle organization during meiosis and for organization of the sperm axoneme. These results suggest that centrosomin is a necessary component of the meiotic centrosomes and the spermatid basal body.     

New etiopathogenic, clinical and therapeutic findings in multiple endocrine neoplasia type 1

Multiple Endocrine Neoplasia type 1 (MEN 1) syndrome comprises tumors or hyperplasia of different glands, including parathyroid, pituitary, adrenal cortex and the gastroenteropancreatic system. The vast majority of MEN 1 are found in familial clusters, although a few cases are sporadic. Hypercalcemia and/or nephrocalcinosis are the first and most common clinical manifestation in familial MEN 1 syndrome, followed by islet cell tumors (especially those secreting gastrin or insulin) and pituitary dysfunction due to either functioning or non-functioning microadenomas. Genetic studies indicate that familial MEN 1 syndrome is inherited through a dominant gene with incomplete penetrance and variable expression. The diagnosis of MEN 1 syndrome is mainly based on the careful assessment of the clinical history, symptoms physical evaluation along with the assay of serum electrolytes (i.e., calcium, phosphorus, etc.) and hormonal substances (i.e., gastrin, insulin, pancreatic polypeptide, prolactin, adrenocorticotropic hormone, etc.). In addition, several provocative tests have been used to identify endocrine tumors (particularly those of the gastroenteropancreatic system) and imaging techniques play a crucial role for the diagnostic approach in MEN 1 syndrome. Even though in the long term, the prognosis of MEN 1 syndrome is unfavourable. Recently, however, many therapeutic strategies, including both surgical and pharmacological options, have been developed to reduce the size of the neoplasm and control symptoms associated with hormone oversecretion.     

Surgical strategy for insulinomas in multiple endocrine neoplasia type I

An unusual presentation of a giant intracranial aneurysm is demonstrated. The patient was a 58-year-old woman who developed sudden onset of headache followed by generalized seizures. CT scan showed a high-density lesion in the middle cranial fossa with extensive vasogenic edema. Possible mechanisms for the edema are discussed.     

A novel germline mutation in exon 5 of the multiple endocrine neoplasia type 1 gene

The autosomal dominant multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by neoplasia of parathyroids, anterior pituitary, and gastrointestinal and pancreatic neuroendocrine tissues. Recently the gene responsible for the MEN1 syndrome has been identified on chromosome region 11q13. Most of the described mutations are nucleotide substitutions and small deletions affecting exons 2 and 3, causing protein truncation. Only one mutation in exon 5 has been found, and this corresponds to a MEN1 sporadic case. Small insertions are also rare. We studied a MENI family composed of five members, two of whom were clinically affected. We found a new germline 1 basepair insertional mutation affecting the exon 5 of the MEN1 gene in the two members affected in this MEN1 family.     

Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese

Germ-line mutations of the MEN1 gene were analyzed in five cases of familial and four cases of sporadic multiple endocrine neoplasia type 1 (MEN-1), six cases in three independent pedigrees of familial pituitary adenoma without MEN-1, and three cases of familial isolated primary hyperparathyroidism (FIHP) in Japanese. Eight different types of germ-line mutations in all nine cases of MEN-1 were distributed in exons 2, 3, 7, and 10 and intron 7 of the MEN1 gene. Loss of heterozygosity (LOH) on 11q13 was detected in all nine tumors of these cases with microsatellite analysis. No germ-line mutation of the MEN1 gene was detected in three pedigrees of familial pituitary adenoma and three cases of FIHP. LOH on 11q13 was detected in two cases in one pedigree of familial pituitary adenoma, and one of them showed a heterozygous somatic mutation of the MEN1 gene. No LOH on 11q13 was detected in three cases of FIHP. Based on these, we conclude that the loss of function of menin is etiological for familial or sporadic MEN-1, but not for FIHP or most familial pituitary adenoma without MEN-1.     

A case of multiple endocrine neoplasia type I with primary hyperparathyroidism, prolactin secreting pituitary microadenoma and gastrin secreting duodenal carcinoid

Actinomadura sp. strain 2966 can effectively convert compactin to pravastatin. The degree of conversion observed was 65% to 78% of compactin added and 65% to 88% of compactin taken up, depending on the concentration of compactin and duration of the experiment. Increasing the compactin concentration resulted in a higher final pravastatin concentration especially when compactin was added intermittently. Higher glucose concentrations had no effect on the bioconversion although uptake of compactin was inhibited. The conversion was linear over 16 hours. The system requires no induction and thus appears to be different from previously studied hydroxylases from actinomycetes.     

Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type I

In recent classifications of gastric endocrine tumors, tumors arising in patients with multiple endocrine neoplasia type 1 (MEN-1) are regarded to be regulated by the concomitant hypergastrinemia resulting from to pancreatic or, most commonly, duodenal gastrinomas and to have a benign behavior. In this article, we report on two cases of MEN-1 gastric neuroendocrine tumors having a fatal course. Case 1 was a young male with hyperparathyroidism and Zollinger-Ellison syndrome and with florid development of multiple gastric carcinoids and multiple duodenal gastrinomas. Metastases occurred in the liver, of exclusive gastric origin, in periduodenal lymph nodes, of exclusive duodenal origin, and in perigastric lymph nodes, of mixed origin. The patient died 48 months after diagnosis. Case 2 was an adult female patient with hyperparathyroidism, adrenocortical disorders, and gastric tumors but no hypergastrinemia. The patient died 3 months after tumor diagnosis. At autopsy, the stomach showed multiple benign carcinoids and two independent neuroendocrine carcinomas not reported before in MEN-1 and massively metastatizing to lymph nodes, liver, and peritoneum. Multiple islet cell tumors mostly producing pancreatic polypeptide were found, whereas gastrinomas were seen in neither the pancreas nor the duodenum. Allelic losses at the MEN-1 gene locus in chromosome 11q13, the mechanism responsible for tumor development in MEN-1 syndrome, were demonstrated in the carcinoid tumors of case 1 and in the neuroendocrine carcinoma of case 2. We conclude that gastric neuroendocrine tumors in patients with MEN-1 may have a poor outcome, they have the same genetic mechanism as MEN-1 tumors in other organs, and they may be independent of the trophic effect of hypergastrinemia.     

Identification of the gene associated with type 1 multiple endocrine neoplasia (NEM 1) susceptibility: a new pathway in the pathogenesis of neuro-endocrine tumors

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder characterized by tumors of the parathyroids, endocrine pancreas, anterior pituitary, thymic, bronchic and digestive neuro-endocrine tissues and adrenal glands. The MEN1 gene has been recently cloned by two independent groups. The function of the protein encoded by the MEN1 gene is unknown until now. Germline mutations associated to the diseases in MEN1 families are distributed throughout all the open reading frame, suggesting the absence of founder effect. No consistent genotype-phenotype correlations have been yet recognized. Further studies on the functional domains of the MEN1 encoded protein could be useful to relate clinical expression of the disease with each type of mutation.     

Multiple endocrine neoplasia type 1 is not rare in Japan

The ability to inhibit the in-vitro growth of mycobacteria within human monocytes is a useful screening assay for novel chemotherapeutic agents. In this study the MICs of a panel of new quinolones were determined by the broth microdilution method for two strains of Mycobacterium avium. Sixteen such compounds with MIC90s ranging from 2 to >32 mg/L were subsequently selected for the 7 day monocyte assay using ciprofloxacin for comparison. The degree of inhibition of intracellular growth correlated with the MICs. PD 139586, PD 143289, PD 135144, PD 119421 and PD 131575 were the most active new agents with activities superior to those of ciprofloxacin and sparfloxacin.     

Importance of endocrine imaging methods in multiple endocrine neoplasia type 2A proved by mutation analysis

Multiple endocrine neoplasias are rare, inherited disorders. The authors describe a case history of a patient with multiple endocrine neoplasia type 2A, who presented with unusual clinical manifestations. The diagnosis of phaeochromocytoma, which was the first manifestation of the disorder, was greatly facilitated with radiologic imaging methods. The authors review, on the basis of recent data from the literature, the importance of radiologic methods, which improved due to methodological advance. Finally, the authors emphasize the importance of follow-up for early diagnosis.