Elsa Fonseca

Sporadic ret‐rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms?

Despite the large amount of information accumulated on the role played by ret activation in the oncogenesis of papillary thyroid carcinoma (PTC), the biological and clinical significance of such activation ‘in vivo’ remains controversial. The aim of this study was to address some of the existing controversies by comparing two groups of unselected PTCs, one with and the other without ret rearrangement, with regard to several clinicopathological and biological features. Thirty‐three PTCs were selected at random. ret rearrangement was found in eight cases (24·2 per cent) using Southern blot analysis. The mean age of the patients with tumours displaying ret rearrangement (28±3·1 years) was significantly lower than that of the patients harbouring cases that did not present rearrangement (45±2·9 years). The large majority of the tumours with ret rearrangement displayed a papillary or mixed follicular–papillary pattern and very low proliferative activity. ret rearrangement correlated significantly with decreased cytoplasmic expression of E‐cadherin. No significant differences were found regarding the gender of the patients, tumour size, multicentricity, extrathyroidal growth, vascular invasion, lymphocytic infiltration, lymph node involvement or the expression of E‐cadherin (membrane), c‐erb‐B2, c‐met, Bcl‐2, and vimentin. It is proposed that sporadic PTCs harbouring a ret rearrangement occur frequently as slow growing, papillary, or predominantly papillary tumours that do not usually progress towards less differentiated neoplasms representing what might be described as a Bonsai phenotype.

BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas

Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated with different histotypes of papillary thyroid carcinoma (PTC). The V599E mutation is highly prevalent in PTC with a papillary or mixed papillary follicular growth pattern, and the K600E mutation is apparently restricted to the follicular variant of PTC. It is usually accepted that thyroid malignancies may follow a progression path from well-differentiated to poorly differentiated (PDC) and undifferentiated (UC) carcinomas. One would expect that at least some of the less differentiated carcinomas would harbour the genetic alterations of pre-existing well-differentiated tumours. In order to find the prevalence of BRAF mutations in PDC and UC, we screened a series of 19 PDCs and 17 UCs, as well as 3 UC-derived cell lines, for both mutation types. The group of PDCs was restricted to the so-called insular and insular-like PDCs, thus excluding PTCs with solid, insular or trabecular foci of growth and PDCs displaying typical PTC nuclei. No BRAF mutations were detected in any of the 19 cases of PDC, whereas 6 of the UCs (35%) and one UC-derived cell line presented the BRAFV599E mutation. The BRAFK600E mutation was not detected in any case. We conclude that UC may progress from BRAFV599E-mutated PTC. The absence of BRAF mutations in our series of PDC supports the assumption that pure insular and insular-like PDCs are more closely related to follicular carcinoma than to PTC.

E-cadherin loss rather than beta-catenin alterations is a common feature of poorly differentiated thyroid carcinomas.

Aims: To investigate the immunohistochemical and molecular genetic features of the cadherins/catenins complex in thyroid carcinoma based on the hypothesis that poorly differentiated carcinoma of the thyroid represents an intermediate step between well‐differentiated and undifferentiated carcinomas.

Cytogenetic investigations of 340 thyroid hyperplasias and adenomas revealing correlations between cytogenetic findings and histology

Cytogenetic analyses were performed on 340 follicular thyroid adenomas and goiters after short-term culture. Clonal chromosomal changes were found in 67 cases. Trisomy 7 as the sole abnormality or along with other trisomies was the most frequent type of aberration (19 cases). Other recurrent numerical changes were loss of chromosome 22 (4 cases) and the second X or the Y chromosome (5 cases). Translocations involving 19q13 (12 cases) were frequent structural chromosomal changes. Dicentric chromosomes or telomeric associations were frequent in goiters (12 cases). After a histopathologic classification of all cases, we have correlated the cytogenetic findings with the histology of the tumors. Only 8.4% of the goiters showed clonal abnormalities, whereas 44.9% of the adenomas revealed clonal abnormalities. Furthermore, simple clonal changes were predominantly found in goiters and complex changes in adenomas. The most impressive correlation was found in the group of lesions with trisomy 7. Although all but one lesion with one or two additional trisomies were goiters, those having three or more additional trisomies were all adenomas or adenomatous goiters.

Poorly Differentiated Carcinomas of the Thyroid Gland A Review of the Clinicopathologic Features of a Series of 28 Cases of a Heterogeneous, Clinically Aggressive Group of Thyroid Tumors

We evaluated the clinicopathologic, immunohistochemical, lectin histochemical, ultrastructural and morphometric characteristics of a series of 28 poorly differentiated carcinomas of the thyroid (PDCT). The 28 tumors were classified according to their predominant growth pattern as insular (n=12), trabecular (n=10) and solid subtypes (n=6). The overall mortality rate was 46%. No significant differences were found among the 3 subtypes. Data obtained by lectin histochemistry, electron microscopy, and morphometry point to a closer relationship of PDCT to follicular than to papillary carcinoma. Our results do not support the subdivision of PDCT into subtypes.

Pattern of expression of intermediate cytokeratin filaments in the thyroid gland: an immunohistochemical study of simple and stratified epithelial-type cytokeratins

The expression of simple and stratified epithelial-type cytokeratin (CK) intermediate filaments was evaluated by immunohistochemistry in a series of 41 papillary carcinomas, 10 follicular carcinomas, 2 poorly differentiated carcinomas and 34 specimens of normal thyroid parenchyma and lymphocytic thyroiditis. The aim of the study was to establish the CK profile of normal thyroid and thyroid carcinomas in order to clarify the putative application of CK immunostaining in diagnostic surgical pathology, and to evaluate whether the process of neoplastic transformation and tumour progression in the thyroid may be associated with any particular change in CK expression. Normal thyroid strongly expressed simple epithelial-type CKs 7 and 18 and, to a lesser degree, CKs 8 and 19, but did not express stratified epithelial-type CKs. The same pattern was found in lymphocytic thyroiditis, though the CK 19 immunoreactivity was stronger in these lesions than in the normal thyroid. Papillary and follicular thyroid carcinomas shared the expression of simple epithelial-type CKs 7, 8, 18 and 19. Immunoreactivity for CK 19 was frequently stronger and more widely distributed within each particular tumour in papillary than in follicular carcinomas, but it could also be detected, at least focally, in every follicular carcinoma. Strong expression of CK 19 highlighted small foci of papillary carcinoma not easily identifiable by conventional histological examination. Stratified epithelial-type CKs 5/6 and 13 were detected in a high percentage of papillary carcinomas, in contrast to their absence in follicular carcinomas and normal thyroid. The CK pattern was similar in primary and metastatic papillary carcinomas. We conclude that papillary carcinoma of the thyroid presents a distinct CK profile that may be used for diagnostic purposes.

Molecular pathology of well-differentiated thyroid carcinomas

The newly discovered molecular features of well-differentiated thyroid carcinomas derived from follicular cells are reviewed, within the frame of the 2004 WHO classification of thyroid tumours, under the following headings: “Follicular carcinoma”, “Papillary carcinoma”, “Follicular variant of papillary carcinoma” and “Hürthle cell tumours”. A particular emphasis is put on the meaning of PAX8–PPARγ rearrangements, RAS and BRAF mutations, and deletions and mutations of mitochondrial genes and of nuclear genes encoding for mitochondrial enzymes, for thyroid tumorigenesis.

Expression of stratified epithelial-type cytokeratins in hyalinizing trabecular adenomas supports their relationship with papillary carcinomas of the thyroid.

To evaluate the cytokeratin pattern of expression of hyalinizing trabecular adenomas and to verify whether or not these tumours, that share morphological features with papillary carcinomas, present the stratified epithelial‐type cytokeratins commonly found in ordinary papillary carcinomas.

Hürthle (Oncocytic) Cell Tumors of Thyroid: Etiopathogenesis, Diagnosis and Clinical Significance

The etiopathogenesis and the classification of oncocytic (Hurthle cell) tumors of the thyroid is reviewed with an emphasis on the role played by mitochondrial and nuclear genetic abnormalities that interfere with mitochondrial function. Oxyphilia is classified into primary or secondary and the so-called Hurthle cell carcinoma is divided into oncocytic (Hurthle cell) variants of papillary and follicular carcinoma.

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.