João Magalhães

BRAF mutations are associated with some histological types of papillary thyroid carcinoma

Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). The hot‐spot mutation BRAFV599E is frequently detected in PTC (36–69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC‐related entities—hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAFV599E mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAFV599E was present in 75% of Warthin‐like PTCs and 53% of conventional PTCs, whereas no BRAFV599E mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAFV599E was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular–papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAFV599E in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular–papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC. Copyright

Follicular thyroid carcinoma

Follicular thyroid carcinoma is being diagnosed less and less frequently despite the increasing incidence of well-differentiated thyroid carcinomas everywhere. This review will discuss the reasons underlying such an observation focusing on the evolution of the morphological and immunohistochemical diagnostic criteria of follicular thyroid tumors. It will address the differential diagnosis between follicular carcinoma and three tumor types—follicular adenoma, follicular variant of papillary carcinoma and poorly differentiated carcinoma—as well as the problems raised by the newly described categories of follicular tumors: follicular tumor of uncertain malignant potential, well-differentiated tumor of uncertain malignant potential and well-differentiated carcinoma, not otherwise specified. Finally, the prognostic and therapeutic significance of some promising molecular biomarkers will be discussed within the frame of the aforementioned histopathological classification.

Follicular, papillary, and “Hybrid” carcinomas of the thyroid

The existence of well-differentiated thyroid tumors sharing the clinicopathologic features of follicular and papillary carcinoma is discussed using the so-called diffuse (multinodular) form of the follicular variant of papillary carcinoma as a paradigm. Although the concept of a “hybrid carcinoma” of the thyroid is intellectuall very appealing, we conclude that there is not (yet) enough reliable genotypic or phenotypic evidence to support utilization of such a term.

Thyroid hormone receptor mutations in the 'hot-spot region' are rare events in thyroid carcinomas

Thyroid cancer constitutes the most frequent endocrine neoplasia. Targeted expression of rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) and V600E V-raf murine sarcoma viral oncogene homolog B1 (BRAF) to the thyroid glands of transgenic mice results in tumours similar to those of human PTC, providing evidence for the involvement of these oncogenes in PTC. Kato et al. developed a mouse model that mimics the full spectrum of the human follicular form of thyroid cancer (FTC). FTC rapidly develops in these mice through introduction of the thyroid hormone receptor beta (THRB)(PV) mutant on the background of the inactivated THRB wt locus. Our aim was to verify if, in the context of human follicular thyroid carcinogenesis, THRB acted as a tumour suppressor gene. We screened for mutations of the THRB gene in the hot-spot region, spanning exons 7-10, in 51 thyroid tumours and six thyroid cancer cell lines by PCR and direct sequencing. We did not find mutations in any of the tumours or cell lines analysed. Our findings suggest that, in contrast to the findings on the THRB-mutant transgenic mice, THRB gene mutations are not a relevant mechanism for human thyroid carcinogenesis.

Hyalinizing trabecular tumor of the thyroid displaying neuroendocrine differentiation

Dear Sir, Shikama and colleagues [3] reported recently an interesting case of a hyalinizing trabecular tumor of the thyroid (HTT) displaying neuroendocrine differentiation. We agree with the authors’ assumption that their finding suggests HTT can differentiate into both follicular cells and neuroendocrine cells [3]. The prevalence of such dual differentiation in HTT is not known, but it is likely to be more frequent than suspected by Shikama and colleagues, who claimed that “In the world literature to date, only two cases of HTT with endocrine cells, including the current case, have been reported” [3]. Shikama and colleagues did not take into account the two cases reported by our group [1, 2]. In one of these cases, we had the opportunity of performing electron microscopy but, at variance with Shikama and colleagues, we did not detect typical neurosecretory granules. The putative relationship between HTT and papillary thyroid carcinoma (PTC) is thoroughly reviewed by Shikama and colleagues, who pointed out similarities regarding CK19 and galectin immunoexpression and RET/PTC rearrangement in both tumor types [3]. Recently, we have shown that regarding the occurrence of BRAFV599E mutation, HTT differs from conventional PTC and resembles the follicular variant of PTC [4, 5]. It remains to be seen whether the aforementioned dual differentiation may occur in any type of HTT regardless of its association to PTC. One of the cases of HTT without dual difference we studied gave rise to nodal metastases, thus showing that these tumors may be malignant [2]. As Shikama and colleagues stress in their study, it remains to be clarified whether the dual differentiation in HTT may have some clinical significance [3].