Ana Luísa Catarino

Aggressive metastatic follicular thyroid carcinoma with anaplastic transformation arising from a long-standing goiter in a patient with Pendred’s syndrome

In this article we describe detailed pathological and molecular genetics studies in a consanguineous kindred with Pendreds syndrome. The index patient was a 53-year-old female patient with congenital deafness and goiter. Her parents were first-degree cousins. She had a large goiter (150 g) that had been present since childhood. One of her sisters and a niece are also deaf and have goiter as well. The presence of Pendreds syndrome was confirmed by a positive perchlorate test and the demonstration of a Mondini malformation. Thyroid function tests (under levothyroxine [LT4] therapy) were in the euthyroid range with a thyrotropin [TSH] level of 2.8 microU/mL (0.2-3.2), a serum total thyroxine (T4) of 90 nmol/L (54-142), and a serum total triiodothyronine (T3) of 2.7 nmol/L (0.8-2.4). Total thyroidectomy was performed, and the mass in the right lobe was found to have invaded adjacent tissues. The histopathological findings were consistent with a follicular carcinoma with areas of anaplastic transformation and lung metastasis. The patient was treated twice with 100 mCi 131iodine (3,700 MBq) and received suppressive doses of LT4. Postoperatively, the serum thyroglobulin (Tg) levels remained markedly elevated (2,352 to 41,336 ng/mL). The patient died of a sudden severe episode of hemoptysis. Sequence analysis of the PDS gene performed with DNA from the two relatives with Pendreds syndrome revealed the presence of a deletion of thymidine 279 in exon 3, a point mutation that results in a frameshift and a premature stop codon at codon 96 in the pendrin molecule. We concluded that prolonged TSH stimulation because of iodine deficiency or dyshormonogenesis in combination with mutations of oncogenes and/or tumor suppressor genes, may result in the development of follicular thyroid carcinomas that undergo transformation into anaplastic cancers. It is likely that these pathogenetic mechanisms have been involved in the development of aggressive metastatic thyroid cancer in this unusual patient with Pendreds syndrome.

Loss of heterozygosity in follicular and papillary thyroid carcinomas

In this study we aimed at investigating the incidence and the role of 3p deletions, particularly at the 3p25 approximately pter region, in follicle cell-derived thyroid neoplasms, by using loss of heterozygosity (LOH) analysis. We analyzed 12 follicular adenomas (FA), 13 follicular thyroid carcinomas (FTC), and 15 papillary thyroid carcinomas (PTC) with 11 microsatellite markers for chromosome 3. One additional marker on 3q25.2 was also investigated for assessment of deletion extent on 3q. Microsatellite instability was detected at one locus in 1 of 15 PTC (7%) and at four loci in 1 of 13 FTC (8%). Loss of heterozygosity was found in 8 of 12 cases of FTC (67%), in 6 of 15 cases of PTC (40%), and in 2 of 12 FA (17%). We identified three minimal common deleted regions (CDR) involving significant sites of LOH: two in FTC (a new terminal region, of approximately 8 cM distal to D3S1620 at 3p25.3 approximately pter and the D3S1573-D3S1595 region at 3p21.2 approximately p12) and one in PTC (D3S1304-D3S1263 region at 3p25.3 approximately p24.2). The newly identified 3p25.3 approximately pter CDR seems to be specific for FTC. Our results suggest the existence of at least three distinct regions on 3p that might harbor tumor suppressor genes involved in the carcinogenesis processes of FTC and PTC.

A multinodular goiter as the initial presentation of a renal cell carcinoma harbouring a novel VHL mutation

BackgroundSecondary involvement of the thyroid gland is rare. Often the origin of the tumor is difficult to identify from the material obtained by fine-needle aspiration cytology. Renal cell carcinoma of the clear-cell type is one of the more common carcinomas to metastasize to the thyroid gland. Somatic mutations of the von Hippel-Lindau tumor suppressor gene are associated with the sporadic form of this tumor. We aimed to illustrate the potential utility of DNA based technologies to search for specific molecular markers in order to establish the anatomic site of origin.Case PresentationA 54-yr-old Caucasian male complaining of a rapidly increasing neck tumor was diagnosed as having a clear-cell tumor by fine-needle aspiration cytology. A positive staining for cytokeratin as well as for vimentin and CD10 in the absence of staining for thyroglobulin, calcitonin and TTF1 suggested a renal origin confirmed by computed tomography.Using frozen RNA, obtained from cells left inside the needle used for fine needle aspiration cytology, it was possible to identify a somatic mutation (680 delA) in the VHL gene.ConclusionIn the presence of a clear-cell tumor of the thyroid gland, screening for somatic mutations in the VHL gene in material derived from thyroid aspirates might provide additional information to immunocytochemical studies and therefore plays a contributory role to establish the final diagnosis. Moreover, in a near future, this piece of information might be useful to define a targeted therapy.

Medullary carcinomas of the thyroid: a monoclonal origin.

We studied the clonality of medullary thyroid carcinomas (MTC) from 16 female patients by determining X chromosome inactivation by polymerase chain reaction (PCR) amplification of a CAG repeat in exon 1 of the human androgen-receptor gene. One patient with sporadic medullary thyroid carcinoma (MTC) was homozygous for this microsatellite and was not considered for the assessment of clonality. Sixteen tumor samples from the informative 15 patients were studied: 11 were from sporadic cases and 5 were from familial cases (3 cases of multiple endocrine neoplasia type 2A [MEN 2A]; 1 case of familial medullary thyroid carcinoma [FMTC]). Fourteen tumor samples (10/11 sporadic, 3/4 MEN 2A and 1/1 FMTC) were clearly monoclonal with allelic cleavage ratios between 2.5 and 49.1. Sixty-four percent of these cases (9/14) had the preferential amplification of the shorter allele while 36 percent (5/14) had the preferential amplification of the longer allele. Two frozen tumor samples (1 sporadic and 1 MEN 2A) were polyclonal. However, the corresponding tumor embedded in paraffin from the sporadic case was monoclonal. The other polyclonal tumor was found in the right thyroid lobe of a patient with MEN 2A who had a monoclonal tumor in the left lobe. Our results clearly demonstrate that MTC have a monoclonal origin in the majority of the cases.