Mutations and allelic deletions of the MEN1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms.
Endocrine pancreatic tumors (EPT) and neuroendocrine tumors (NET) occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). We analyzed the frequency of allelic deletions and mutations of the recently identified MEN1 gene in 53 sporadic tumors including 30 EPT and 23 NET (carcinoids) of different locations and types. Allelic deletion of the MEN1 locus was identified in 18/49 (36.7%) tumors (13/30, 43.3% in EPT and 5/19, 26.3% in NET) and mutations of the MEN1 gene were present in 8/52 (15.3%) tumors (4/30 (13.3%) EPT and 4/22 (18.1%) NET). The somatic mutations were clustered in the 5' region of the coding sequence and most frequently encompassed missense mutations. All tumors with mutations exhibited a loss of the other allele and a wild-type sequence of the MEN1 gene in nontumorous DNA. In one additional patient with a NET of the lung and no clinical signs or history of MEN1, a 5178-9G-->A splice donor site mutation in intron 4 was identified in both the tumor and blood DNA, indicating the presence of a thus far unknown MEN1 syndrome. In most tumor groups the frequency of allelic deletions at 11q13 was 2 to 3 times higher than the frequency of identified MEN1 gene mutations. Some tumor types, including rare forms of EPT and NET of the duodenum and small intestine, exhibited mutations more frequently than other types. Furthermore, somatic mutations were not restricted to foregut tumors but were also detectable in a midgut tumor (15.2% versus 16.6%). Our data indicate that somatic MEN1 gene mutations contribute to a subset of sporadic EPT and NET, including midgut tumors. Because the frequency of mutations varies significantly among the investigated tumor subgroups and allelic deletions are 2 to 3 times more frequently observed, factors other than MEN1 gene inactivation, including other tumor-suppressor genes on 11q13, may also be involved in the tumorigenesis of these neoplasms. (+info
Gastroenteropancreatic neuroendocrine tumor metastases to the thyroid gland: differential diagnosis with medullary thyroid carcinoma.
Neuroendocrine tumors (NET) of the thyroid gland are rare. Apart from medullary thyroid carcinoma (MTC), metastases of gastroenteropancreatic (GEP) NET may also occur. Features of six patients (five men, one female: age range, 39-67 years) with thyroid metastases from a GEP-NET are described. Thyroid metastases were bilateral in all patients and were associated with enlarged neck lymph nodes in five. In four cases, the thyroid tumor was either the first sign of the disease (n = 2) or was an isolated site of recurrence (n = 2). The tumors were well (n = 3) or poorly differentiated (n = 3). Five tumors for which the primary site could be determined corresponded to foregut-derived tumors (3 lungs, 1 thymus and 1 pancreatic NET). One tumor demonstrated calcitonin (CT) production as shown by immunohistochemistry and elevated plasma CT levels. However, the disease history and the clinical features strongly favored a metastasizing GEP-NET. No tumoral RET proto-oncogene mutation was found in this patient. The differential diagnosis between metastatic GEP-NET and MTC is crucial because prognosis, work-up, and treatment differ greatly. (+info
Catecholamine production in patients with gastroenteropancreatic neuroendocrine tumors.
OBJECTIVE: Amine precursor uptake and decarboxylation is a classical feature of gastroenteropancreatic (GEP) neuroendocrine tumors (NET). Production of catecholamines was studied in GEP NET and non-NET patients. DESIGN: A cross-sectional study was undertaken. METHODS: We studied catecholamine and metabolite secretion in 115 consecutive GEP NET patients and in 20 patients with non-NET. After specific extraction, vanilmandelic acid, homovanilic acid, catecholamines (norepinephrine, epinephrine, dopamine) and methoxylated derivates (metanephrine, normetanephrine, methoxytyramine) in urinary extracts were analyzed by high performance liquid chromatography. Results were indexed to the 24-h urinary creatinine levels. RESULTS: Among the 115 patients with NET, 9 (8%) had an increase of at least one urinary catecholamine or metabolite; in 7 out of the 9 the increase was slight being less than twice the upper value of the normal range. Elevated urinary dopamine (3 patients), methoxytyramine (6 patients), norepinephrine (2 patients) and normetanephrine (2 patients) were found. No increased urinary excretion of epinephrine nor metanephrine was observed. An adrenal mass existed in one of these nine patients but metaiodobenzylguanidine scintigraphy was negative as was immunohistochemistry for epithelial markers. None of the 20 patients with non-NET demonstrated an increased excretion of catecholamine or metabolites. No relationships were found between catecholamine and metabolite excretions and patients' tumor and treatment characteristics. CONCLUSION: Production of catecholamines and metabolites is a rare event in GEP NET patients. Histological results, including positive immunohistochemistry for epithelial markers may help to diagnose GEP NET. (+info
Comparison of 111In-DOTA-Tyr3-octreotide and 111In-DTPA-octreotide in the same patients: biodistribution, kinetics, organ and tumor uptake.
Scintigraphy with [111In-diethylenetriamine pentaacetic acid0-D-Phe1]-octreotide (DTPAOC) is used to demonstrate neuroendocrine and other somatostatin-receptor-positive tumors. Despite encouraging results, this 111In-labeled compound is not well suited for peptide-receptor-mediated radiotherapy of somatostatin-receptor-positive tumors. Another somatostatin analog, [1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid0, D-Phe1, Tyr3]-octreotide (DOTATOC), can be labeled with the beta-emitter 90Y in a stable manner. METHODS: We compared the distribution, kinetics and dosimetry of 111In-DTPAOC and 111In-DOTATOC in eight patients to predict the outcomes of these parameters in patients who will be treated with 90Y-DOTATOC. RESULTS: Serum radioactivity levels for the radiopharmaceuticals did not differ significantly 2-24 h after injection (P>0.05). Up to 2 h postinjection they were slightly, but significantly, lower after administration of 111In-DOTATOC (P < 0.01 at most time points). The percentage of peptide-bound radioactivity in serum did not differ after administration of either compound. Urinary excretion was significantly lower after administration of 111In-DOTATOC (P < 0.01). The visualization of known somatostatin-receptor-positive organs and tumors was clearer after administration of 111In-DOTATOC than after administration of 111In-DTPAOC. This was confirmed by significantly higher calculated uptakes in the pituitary gland and spleen. The uptake in the tumor sites did not differ significantly (P > 0.05), although in three of the four patients in whom tumor uptake could be calculated, it was higher after administration of 111In-DOTATOC. CONCLUSION: The distribution and excretion pattern of 111In-DOTATOC resembles that of 111In-DTPAOC, and the uptake in somatostatin-receptor-positive organs and most tumors is higher for 111In-DOTATOC. If 90Y-DOTATOC shows an uptake pattern similar to 111In-DOTATOC, it is a promising radiopharmaceutical for peptide-receptor-mediated radiotherapy in patients with somatostatin-receptor-positive tumors. (+info
A case of synchronous double primary lung cancer with neuroendocrine features.
We report a case of unique double primary lung cancers with neuroendocrine features in a 63-year-old male smoker. The mass in the left lower lobe (LLL) was a small cell/large cell carcinoma with spindle cell sarcomatous areas and organoid structure. The mass in the left upper lobe (LUL) was a tubular adenocarcinoma with neuroendocrine features including organoid nests showing occasional rosette formation, nuclear palisading in the periphery of the nests and positive immunoreaction for CD56, chromogranin A and synaptophysin. The difference in histological structures between the two masses led us to diagnose double primary lung cancer. The combination of small cell lung carcinoma and spindle cell carcinoma is very uncommon. The relationship between LLL and LUL tumors remains unclear. Multiple lung cancers with neuroendocrine features have only rarely been reported in the literature. The patient in our case died of widespread cancer 2 years and 4 months after the surgery without adjuvant chemotherapy, a longer postoperative survival time than in cases of ordinary extensive small cell lung cancer. Multiple lung cancers with neuroendocrine features are extremely rare and similar cases have not been reported in the literature. Neuroendocrine differentiation has attracted widespread attention and, therefore, examining neuroendocrine features in lung cancers is important. (+info
Suppression of the neoplastic phenotype by transfection of phospholipase C beta 3 to neuroendocrine tumor cells.
The expression of phospholipase C beta 3 (PLCB3) is low or absent in several neuroendocrine neoplasias. To investigate the role of PLCB3 in the neuroendocrine tumorigenesis, we transfected a PLCB3 construct to three neuroendocrine tumor cell lines with a low PLCB3 expression. The growth rate and tumorigenicity were assessed in vitro by [3H]thymidine incorporation and cell counting, in vivo, by xenografting to nude mice. In vitro, PLCB3 expressing clones showed a significant growth inhibition. The tumor weight was reduced for one of the two xenografted PLCB3-transfected cell lines and in both, a reduced number of proliferating (Ki-67 positive) cells was observed. This study implies an essential role for PLCB3 in the neuroendocrine tumorigenesis. (+info
A new human chromogranin A (CgA) immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145-245).
Chromogranin A (CgA), a major protein of chromaffin granules, has been described as a potential marker for neuroendocrine tumours. Because of an extensive proteolysis which leads to a large heterogeneity of circulating fragments, its presence in blood has been assessed in most cases either by competitive immunoassays or with polyclonal antibodies. In the present study, 24 monoclonal antibodies were raised against native or recombinant human CgA. Their mapping with proteolytic peptides showed that they defined eight distinct epitopic groups which spanned two-thirds of the C-terminal part of human CgA. All monoclonal antibodies were tested by pair and compared with a reference radioimmunoassay (RIA) involving CGS06, one of the monoclonal antibodies against the 198-245 sequence. It appears that CgA C-terminal end seems to be highly affected by proteolysis and the association of C-terminal and median-part monoclonal antibodies is inadequate for total CgA assessment. Our new immunoradiometric assay involves two monoclonal antibodies, whose contiguous epitopes lie within the median 145-245 sequence. This assay allows a sensitive detection of total human CgA and correlates well with RIA because dibasic cleavage sites present in the central domain do not seem to be affected by degradation. It has been proved to be efficient in measuring CgA levels in patients with neuroendocrine tumours. (+info
Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms.
We initiated a transgenic model for primary pulmonary neuroendocrine cell (PNEC) hyperplasia/neoplasia using v-Ha-ras driven by the neural/neuroendocrine (NE)-specific calcitonin promoter (rascal). Previously, we showed that nitrosamine treated rodents develop PNEC hyperplasia but non-NE lung tumors, with variable outcomes presumably reflecting ras activation in multiple cell lineages. Interestingly, all rascal transgenic mouse lineages develop hyperplasias of NE and non-NE cells but mostly non-NE lung carcinomas, with rascal mRNA in differentiated PNECs and tumor cells. Analyses of embryonic lung demonstrate rascal mRNA in undifferentiated epithelium, consistent with expression in a common pluripotent precursor cell. These unexpected observations indicate that v-Ha-ras can lead to both NE and non-NE hyperplasia/neoplasia in vivo, opening new avenues for studies of lung carcinogenesis. (+info