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Point mutations in exons 10 and 11 of the RET proto-oncogen are present
in more than 95% of patients with MEN IIA phenotype. Recently, variable
mutations of the RET proto-oncogen have been identified in patients with
familial Hirschsprungs' disease.
Caron et al., Paris, France, published a family with familial MTC and Hirschsprungs's disease. The authors found a point mutation (Cys 618-Arg) in the affected family members and hypothesized that this mutation could cause both disorders in this kindred. Assi et al., Arsizio and Legano, Italy, evaluated prognostic factors in MTC in 53 patients. They found that the stage of diseases (1988 UICC classification) was the most powerful prognostic factor, while survival was not affected by the majority of available immunohistochemical markers like argyrophylia, amyloid, calcitonin, carcino embryonic antigen, TG, calcitonin gen related peptide, chromogranin, neuron-specific enolase, and synaptophysin. Another major prognostic factor was the presence or absence of necrosis. A similar study was done by Brierley et al., who found retrospectively that, using multivariate analysis of patients treated for MTC between 1954 and 1992, the only prognostic factors were the presence of extraglandular invasion and of gross residual tumor. Postoperative external beem radiation appeared to be beneficial in 40 highrisk patients with regard to locoregional remission rate that was 86% at 10 years in irradiated patients as opposed to 52% in non-irradiated patients. (Comment: The authors conclude that postoperative irradiation in high-risk patients is advisable. This aspect whether to irradiate or not after operation is still controversial. This study does not seem to settle the question because this was a retrospective study. It would be advisable to generate a multicenter prospective trial to solve this important point. Who will take up this challenge!?) In another study Scopsi et al, Milano, Italy, prognostic factors of MTC in 117 consecutive patients were studied retrospectively. Also in this study it was concluded that extraglandular invasion appeared to be the worst prognostic factor. Two studies were reported regarding RET proto-oncogen mutations in sporadic MTC i.e. by Wohllk, Houston, TX, USA, and by Robinson et al., Sidney, Australia, and in both studies a mutation was found in codon 918 in tumor tissue, that occurred in the two studies in 20% and 66% respectively. Some other mutations in lower frequency were also identified. Learoyd et al., Sidney, Australia, evaluated 99mTc-sestamibiscanning in 8 patients with recurrent MTC and found positive images in at least one area in 6 patients all with serum calcitonin values between 2000-62000 ng/L. Uptake was found in nodules less than 1 cm and also in the mediastinum when CT scanning was negative. It is concluded that this technique is important in the management of patients with recurrent MTC. Lupoli et al., Naples, Italy, evaluated the therapeutical value of combined octreotide (150ug 3 times daily for 6 months) and a-IFN (5 million U.I. 3 times a week, presumably for the same period) treatment in 7 patients with advanced sporadic MTC. In 2 patients therapy had to be stopped but in all other patients CEA levels decreased to 50% of initial levels after 6 months. Calcitonin levels decreased variably. However, no significant changes in metastases occurred. Despite this, quality of life was improved by suppression of diarrhea and flushing in several patients. Heshmati et al., Mayo Clinic, Rochester, MN, USA, studied the relationship of specific mutations in exon 10 and 11 of the RET proto-oncogen in 82 patients with MEN IIa. In 82 patients (34 males) from 19 kindreds known to have positive RET mutations, DNA sequence analysis was performed on exon lO and 11 of the RET proto-oncogen. RET mutations involved codons 618 in 4 kindreds and 634 in the other 15 kindreds. Patients with codon 634 mutations had a higher frequency of pheochromocytoma than those with codon 618 mutations (51 % versus 17%). The frequency of hyperparathyroidism was not different (30 % versus 21 % respectively). Scopsi et al., Milano, Italy, performed a retrospective study in 117 patients with medullary carcinoma covering a follow-up period of 30 year. Riskfactors of poor survival were: male sex, age over 60 years, mixed cell subtype, tumorsize > 4 cm, spread of primary tumor beyond thyroid capsule, lack of ameloid, N1-,M1 stage and heterogenous calcitonin and catacalcin immunostaining pattern. In multivariate analysis, only capsule status, M stage and age at diagnosis significantly influenced overall survival. It was further concluded that re-operation for neck residual disease was useless in stage T4 patients, especially if over 60 and of the male gender. For T0-T3/M0 patients, especially if young, agressive surgical approach is warranted. Thomas et al., Cambridge, UK, studied the localization of RET peptide in 10 medullary carcinomas, 12 follicular carcinomas, 9 follicular adenomas, 33 papillary carcinomas and 6 oxyphil tumors. Positive immunoreactivity with antibody to the RET peptide was shown in 70% of medullary carcinomas, 58% of papillary carcinomas, 18% of follicular carcinomas and 34% of follicular adenomas. Only 2 of 6 oxyphil tumors were positive for RET peptide. No distinction could be made between normal or mutated RET oncogen. (Comment: As mutations in the RET gene cause medullary carcinoma, one would expect that no mutations would be present in the papillary carcinomas. Further studies in this direction should increase our knowledge about the importance of the RET oncogen in thyroid tumor formation.) |
