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Objective: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the context of autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN2) syndromes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC), which are caused by activating germline mutations in the RET proto-oncogene. The aim of this study was to characterize the RET mutational spectrum in MEN2 families and apparently sporadic MTC (AS-MTC) cases originating from the central region of Portugal., Subjects and Methods: We studied a total of 82 individuals (64 affected and 18 family members), comprising five MEN2 families (four MEN2A and one MEN2B), as well as 53 AS-MTC cases. RET germline mutations were screened using PCR-DNA sequencing, SSCP and RFLP. The haplotypes associated with recurrent mutations were determined by fragment analysis of microsatellite markers, and by RFLP, in the case of intragenic polymorphisms., Results: Frequency of the Cys611Tyr (TGC-TAC) mutation was significantly increased in this region of Portugal, due to the fact that three apparently unrelated MEN2A/FMTC families, out of the five in which mutations were identified, harboured this specific mutation. Haplotype analysis revealed that a common haplotype was shared between two of these three families. We have also characterized a novel RET mutation, Arg886Trp, located in the tyrosine kinase domain, which was found in an AS-MTC case., Conclusions: There are regional specificities in the relative frequency of RET mutations, which are consistent with a cluster-like distribution of specific disease-causing mutations, as a result of the inheritance of a shared haplotype. These data, along with the finding of a novel RET mutation (Arg886Trp), have important implications towards facilitating and improving the molecular diagnosis of hereditary MTC on a regional basis.

The genetic basis of the sporadic form of medullary thyroid carcinoma, derived from "C" cells, is still poorly understood. Somatic mutations of RET proto-oncogene have been reported at a variable frequency ranging from 23% to 69%. The hypothesis that low penetrance factors, such as polymorphisms, might contribute to the phenotype of this neoplasm has been addressed in a few studies conducting to conflicting results. Herein, we studied 100 individuals (50 patients and 50 controls) aiming to compare the frequencies of G691S, L769L, S836S, and S904S RET polymorphisms observed in patients with respect to controls. Furthermore, meta-analysis of published studies including the present results was conducted. To test the contributory role of the above polymorphisms for the development of "C"-cell hyperplasia, we studied a group of 10 individuals selected for having a positive pentagastrin test despite the absence of a RET germline mutation. An over-representation of the G691S polymorphism, particularly in females, was observed in patients with respect to controls, although not reaching the level of significance. Allelic frequencies of the other three polymorphisms were not different in patients and controls. Results obtained in the admittedly small group of individuals with a positive pentagastrin test are unlikely to support a major influence of any polymorphism in the development of "C"-cell hyperplasia. The meta-analysis provided evidence for a significant association of the S691 allele with MTC (odds ratio 1.54, 95% confidence interval 1.12-2.12, p=0.008) and found no significant associations for the other polymorphisms.

Background and Objectives: Preoperative diagnosis of sporadic medullary thyroid carcinoma (MTC) has mainly relied on fine needle aspiration cytology (FNAC). The present study aimed to compare the sensitivity of this technique with serum calcitonin (CT) measurement and to assess the therapeutic implications of an inadequate preoperative diagnosis., Methods: We reviewed the clinical records of 91 MTC patients treated and/or followed at our institution between January 1990 and December 2003., Results: After revision of clinical records, 77 individuals were considered eligible for the study. FNAC was performed in 67 patients (87%) with a sensitivity of 63%; serum CT was measured in 56 patients (73%) with a sensitivity of 98%. Both FNAC and serum CT were assessed in 51 patients (66%). FNAC detected only 74.5% of MTCs suspected by elevated serum CT. Among patients with a cytological diagnosis of MTC, total thyroidectomy (TT) was performed in 95% of patients. Among patients without a cytological diagnosis of MTC, TT was performed in 83% of patients in whom serum CT was evaluated prior to surgery whereas it was performed in only 46% of patients in whom CT evaluation was lacking., Conclusions: Despite the higher sensitivity of serum CT measurement, as compared with FNAC to diagnose MTC (98% vs. 63%), only 9% of patients might have escaped to surgery based on FNAC results. However, indication for surgery based on suspicious FNAC may not alert the surgeon for the need of a TT and exploration of nodes at least in the central compartment.

Small tumors producing adrenocorticophic hormone (ACTH) ectopically may be very difficult to locate. We describe a 57-year-old woman who presented with ectopic Cushing's syndrome as diagnosed by bilateral inferior petrosal sinus catheterization with corticotrophin-releasing hormone (CRH) test. Thoracic pentetreotide (a somatostatin analogue) revealed a small "hot spot" in the base of the left lung. This "hot spot" was constant throughout the procedure. A second thoracic CT scan with 3-mm cuts showed a small image in the area under suspicion, similar to vascular images found elsewhere in both lungs. At surgery, an 8-mm tumor was found and excised. Pathological examination revealed a carcinoid tumor immunoreactive for ACTH, beta-endorphin, bombesin, serotonin, and the α-subunit. One month after surgery, the patient was clinically well and had normal adrenal function. An 111 ln-pentetreotide scintiscan clearly identified a small ACTH-producing neuroendocrine tumor of the lung undetectable by plain chest radiography or CT scan.