Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series.

BACKGROUND: Approximately 60% of sporadic medullary thyroid carcinomas (sMTC) remain orphan of a recognized genetic cause. Recently, a high percentage of RAS point mutations have been described in RET-negative sMTC. The aim of this study was to assess the prevalence of RAS point mutations in a large series of MTC collected in four Italian centers. METHODS: For this purpose, we studied codons 12, 13, and 61 of H-, K-, and N-RAS genes in 188 MTC samples, either hereditary or sporadic, by direct sequencing. Correlations between the RAS mutational status and the clinical-pathological features of MTC patients as well as a meta-analysis of all published data were performed. RESULTS: The prevalence of RAS mutations in the present series of MTC was 10.1%, and 17.6% when considering only RET-negative cases. RAS mutations were found in MTC tumoral tissue, but not in peripheral blood indicating their somatic origin. A novel mutation in codon 72 (M72I) was found, but with a low or null transforming potential. No association was found between the presence of RAS mutations and the clinical-pathological features of the patients. Although not statistically significant, a positive association between the presence of RAS mutations and a better outcome was observed. The meta-analysis of all published studies confirmed a prevalence of 8.8% for RAS mutations in MTC. CONCLUSIONS: The prevalence of RAS mutations in our MTC series was relatively low and consistent with the meta-analysis data. Only somatic RAS mutations were found and only in RET-negative sMTC. Likewise, MTCs that harbor a RAS mutation identify a subgroup of tumors with less aggressive behavior. To our knowledge, this is the largest series of MTCs studied for the presence of mutations in RAS genes and the first meta-analysis on this specific topic.

Locally advanced differentiated thyroid carcinoma: a 35-year mono-institutional experience in 280 patients.

AIM: Debate exists in the literature about the optimal treatment to be adopted in patients with locally advanced differentiated thyroid carcinoma. We aimed to better define the most appropriate diagnostic and therapeutic protocol for this type of tumour. METHODS: The clinical and histopathological records of 280 consecutive patients with locally advanced differentiated thyroid carcinoma, studied and operated on by the same surgical team in the period between 1967 and 2002, were reviewed. RESULTS: With regard to overall survival, at univariate statistical analysis, the patient's age at diagnosis (threshold, 45 years), primary tumour size, local cancer extension at diagnosis (subtypes of T4), extent of thyroidectomy, performance of lymph node dissection and performance of post-surgical external radiotherapy were found to be significant prognostic variables. With regard to the appearance of recurrent disease during follow-up, at univariate statistical analysis, the patient's age at initial diagnosis (threshold, 45 years), primary tumour size, local cancer extension at diagnosis (subtypes of T4), extent of thyroidectomy, performance of lymph node dissection, presence of metastatic lymph nodes, performance of post-surgical 131I therapy and performance of post-surgical external radiotherapy were found to be significant prognostic variables. At multivariate statistical analysis, the patient's age at initial diagnosis, extent of tumour, extent of thyroidectomy and performance of lymph node dissection were the only independent prognostic variables. CONCLUSIONS: In our experience, an aggressive surgical approach at first diagnosis appears to offer a better prognosis in terms of both overall survival and disease-free time interval in patients with locally advanced differentiated thyroid carcinoma, especially those over 45 years of age.

Nonpalpable thyroid carcinoma: clinical controversies on preoperative selection.

This article emphasizes some controversies concerning the preoperative selection of nonpalpable thyroid tumors. The prevalence of occult thyroid carcinoma in surgical series (1.8-10%) is not higher than in autopsy thyroid series (2.7-24%). The prevalence of occult thyroid carcinoma in thyroid glands examined in the same institution by ultrasound, for a clinical thyroid abnormality or for investigation of other neck structures without clinically evident or suspected thyroid disease, varies from 3% to 8% and is very similar independent of the fact that a thyroid abnormality is or is not the indication for ultrasonography. These data suggest that the presence of a thyroid disease is not a risk factor for harboring an occult thyroid carcinoma (except for C-cell hyperplasia in the rare case of MEN 2 syndromes). As it is not cost effective to examine all the nonpalpable lesions with fine-needle aspiration (FNA) guided by ultrasounds, it is necessary to define to which extent ultrasound is useful in selecting those lesions to be examined cytologically by FNA. The use of ultrasound to select these lesions is very controversial. Ultrasound-guided cytologic diagnosis of nonpalpable nodules is not as accurate as in the case of palpable nodules. Sampling of material adequate for cytologic analysis depends on the lesion size; it is 64% for a 0.7-cm lesion and it increases to 86.7% for a mean size of 1.1 cm. For the diagnosis of occult thyroid carcinomas (< or =1 cm), sensitivity is 35.8% and false-negative results are 49.3%. Nonpalpable nodules with a size of 1.5 cm represent an absolute indication to perform an ultrasound-guided FNA because this is the size limit for dividing thyroid nodules in probably innocuous or potentially dangerous categories and because the cytologic diagnosis of nodules of this size is sufficiently reliable. For the smaller incidentally discovered thyroid nodules following ultrasound, physicians should discuss with the patient whether and when to perform an ultrasound-guided FNA considering the patient's data (risk factors, age, health state, etc.), the natural history of a small thyroid carcinoma, as well as the accuracy of ultrasound and ultrasound-guided FNA in the specific institution.