We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.

The survival rate of patients with medullary thyroid carcinoma (MTC) is significantly better in patients diagnosed and treated when the tumor is limited to the thyroid. In a pioneer study carried out in 1991, we demonstrated that routine measurement of serum calcitonin (CT) in nodular thyroid disease allowed the preoperative diagnosis of unsuspected sporadic MTC with better accuracy than routine fine needle aspiration cytology (FNAC). This finding has been confirmed in subsequent studies. In the present study we report the results of CT screening in 10,864 patients with thyroid nodular disease seen in the years 1991-1998 (group 1). We analyzed the prevalence of MTC and compared their outcomes with those of a historical group of patients (group 2) diagnosed before the introduction of CT screening (1970-1990). The prevalence of MTC found by CT screening in group 1 was 0.40% (44 patients). A positive CT test had a higher diagnostic sensitivity and specificity compared with FNAC. CT screening allowed the diagnosis of MTC at an earlier stage compared with group 2 (P = 0.004). Normalization of serum CT levels (undetectable) after surgery was more frequently observed in group 1. At the end of follow-up, complete remission was observed in 59% of group 1 and in 2.7% of group 2 (P = 0.0001). Our study confirms that MTC is not an infrequent finding among patients with thyroid nodules (nearly 1 in 250 patients). In addition, screening thyroid nodules with serum CT measurement allows the diagnosis and treatment of MTC at an earlier stage, resulting in a better outcome compared with MTC not detected by serum CT measurement. One of the reasons for this finding is that increasing the preoperative diagnostic accuracy of MTC prompts the surgeon to perform a more radical and possibly curative treatment. On this basis, routine measurement of basal serum CT levels should be considered an integral part of the diagnostic evaluation of thyroid nodules.

Recently, a somatic point mutation of the B-RAF gene (V600E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC), with a prevalence variable among different series. Since discordant data on the clinico-pathologic features of B-RAF mutated PTC are present in the literature, the aim of the present co-operative study was to establish the prevalence of this genetic alteration and to perform a genotype-phenotype correlation in a large cohort of patients with PTC. To this purpose, a series of 260 sporadic PTCs with different histological variants were included in the study. The mutational analysis of the B-RAF gene was performed either by RT-PCR followed by single-stranded conformational polymorphism or by PCR and direct sequencing. Statistical analyses were obtained by means of 2 /Fisher's exact test and t-test. Overall, a heterozygous T > A transversion at nucleotide 1799 (V600E) was found in 99 out of 260 PTCs (38%). According to the histological type of the tumor, the B-RAF V600E mutation was present in 48.3% of cases of classic PTCs (85 out of 176), in 17.6% (nine out of 51) of follicular variants of PTCs, in 21.7% (five out of 23) in other PTC variants and in none of the ten poorly differentiated tumors. B-RAF V600E was significantly associated with the classic variant of PTC (P ¼ 0:0001) and with an older age at diagnosis (P ¼ 0:01). No statistically significant correlation was found among the presence of B-RAF V600E and gender, tumor node metastasis (TNM), multicentricity of the tumor, stage at diagnosis and outcome. In conclusion, the present study reports the prevalence of B-RAF V600E (38%) in the largest series of sporadic PTCs, including 260 cases from three different Italian referring centers. This prevalence is similar to that calculated by pooling together all data previously reported, 39.6% (759 out of 1914 cases), thus indicating that the prevalence of this genetic event lies around 38-40%. Furthermore, B-RAF V600E was confirmed to be associated with the papillary growth pattern, but not with poorer differentiated PTC variants. A significant association of B-RAF mutation was also found with an older age at diagnosis, the mutation being very rare in childhood and adolescent PTCs. Finally, no correlation was found with a poorer prognosis and a worse outcome after a median follow-up of 72 months.

DTC patients diagnosed after 1990 have smaller tumors with less advanced stage and a better prognosis. The question of whether this is related to the finding of tumors with a low clinical penetrance or to the anticipation of diagnosis remains to be clarified. Despite these significant differences, both advanced stage and older age still represent the most important poor prognostic factors for survival.