Molecular profile of hyalinizing trabecular tumours of the thyroid: High prevalence of RET/PTC rearrangements and absence of B-raf and N-ras point mutations☆
Introduction
In 1987, Carney and co-workers described a previously unrecognised thyroid tumour with unusual but benign features and named it “hyalinizing trabecular adenoma”. The tumour was characterised by circumscription or encapsulation, trabecular growth pattern, polygonal and elongated cells, nuclear cytoplasmic inclusions and grooves, hyaline material, dilated sinusoids, laminated calcospherites, and cytoplasmic yellow bodies [1], [2]. The peculiar nuclear features of the tumour have raised intriguing questions regarding its morphological and biological classification. Although occasional aggressive hyalinizing trabecular neoplasms with vascular invasion have been described [3], the tumour as described by Carney colleagues [1] is generally accepted as being benign. The non-committal title “hyalinizing trabecular tumour” (HTT) is currently favoured for the lesion. Phenotypic heterogeneity on morphological and immunochemical grounds is very common in HTT [4], [5]. The neoplasm shares histological and cytological features with papillary thyroid carcinoma (PTC). These similarities include enlarged and clear nuclei with inclusions and grooves and calcifications resembling psammoma bodies [6]. A relationship between the neoplasms is further supported by the frequent concurrence of PTC and HTT [6]. In addition, tumours show positivity for epithelial-type cytokeratins (especially CK19) [7]. However, HTT is largely negative or only weakly positive for galectin-3, while most PTC show strong staining, suggesting a possible difference between the two tumours [8].
Molecular genetics advances over the past two decades offer unique opportunities today for studying the relationships between morphology, biology and genetics of thyroid tumours. Previous investigations have shown that gene rearrangements of RET and point mutations in B-raf oncogenes are hallmarks of PTC. RET encodes the tyrosine kinase (TK) membrane receptor for glial cell line-derived neurotrophic factors [9]. In PTC (2.5–40% of the cases), chromosomal inversions or translocations at 10q11.2 lead to the fusion of the RET TK-domain to heterologous genes (RET/PTC oncogenes) and consequently to the activation of its signalling and transforming properties [10]. RET/PTC1 (H4-RET) and RET/PTC3 (RFG-RET) are the most prevalent variants [11]. RET/PTC rearrangements have also been found in clinically occult papillary microcarcinomas [12], and Hurthle cell tumours [13]. Activating point mutations in B-raf were identified as another common feature of PTC (approximately 45% of the cases) [14]. All the B-raf mutations identified thus far affected nucleotide 1796 in exon 15, resulting in a thymine-to-adenine transversion, which translates into valine to glutamate substitution at residue 599 (V599E) [14]. B-raf belongs to the RAF family of serine/threonine kinases and it is located downstream of RAS small GTPases and upstream of MEK in the classic MAPK cascade [15]. This pathway is activated by all growth factor receptors with tyrosine kinase activity, and thus, presumably, by RET/PTC as well [16]. More rarely, PTCs, especially those belonging to the follicular variant, feature activating point mutations in RAS family members, with the N-ras mutation at codon 61 being the predominant one [17], [18].
Papotti colleagues [19] and Cheung and colleagues [20] reported that HTT frequently (4 out of 14 and 6 out of 8 cases, respectively) featured RET/PTC rearrangements. More recently, Trovisco and co-authors reported that none out of 5 HTT cases showed B-raf mutations [21]. Analysis of Ras mutations in HTT samples have never been reported. Here, we sought to perform a comprehensive molecular analysis of a large HTT series.
Section snippets
Tumours
Archival paraffin-embedded thyroid samples from 58 patients were retrieved from the files of Pathology Departments of the Mayo Clinic (Rochester, MN) and Hopital de L’Antiquaille (Lyon, France) following informed consent. The sample series included 28 HTT. As controls, we analysed eight non-toxic multinodular goitres (MNG), 12 follicular adenomas (FA) and 10 papillary carcinomas (PTC), including eight classic, one tall-cell and one follicular variant tumours. Clinico-pathological data including
Clinico-pathological findings
The clinical features of the patients are summarised in Table 1. The average age of the HTT patients was 44 ± 10 years and the female/male ratio was 4:1 (Table 1). The histopathological features of HTT are presented in Fig. 1.
B-raf mutations
B-raf exons 11 and 15 were PCR-amplified and subjected to direct sequencing from both genomic DNA and total RNA from all of the samples listed in Table 1. Three thyroid cell lines, BHT101 and FB1 (carrying a heterozygous V599E mutation) and 8505C (carrying a homo/hemizygous
Discussion
In this study, we provide a detailed characterisation of the genetic background of HTT with respect to RET/PTC rearrangements, and B-raf and N-ras mutations. Our results demonstrate the absence of B-raf and N-ras point mutations in 28 cases of HTT. By adding to our series a previously published analysis on a small HTT sample set (five cases), we can conclude that out of 32 HTT samples no sample was B-raf- positive. By contrast, 13 of 28 HTT showed RET/PTC rearrangements. In HTT, we found a
Conflict of interest statement
None declared.
Acknowledgement
We thank M. Papotti for helpful discussions.
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This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Progetto Strategico Oncologia of the CNR/MIUR, the Italian Ministero per l’Istruzione, Università e Ricerca Scientifica (MIUR), the BioGeM s.c.ar.l. (Biotecnologia e Genetica Molecolare nel Mezzogiorno d’Italia), and the Italian Ministero della Salute.