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Molecular Aspects of Thyroid Neoplasia and Diagnostic Implications


Juan Rosai
Istituto Nazionale Tumori
Milan, Italy


Among all types of epithelial tumors, carcinomas of the thyroid gland are, together with renal neoplasms, those in which the best genotype/phenotype correlations have been found. [4, 13] This is particularly true for thyroid medullary carcinoma and papillary carcinoma.

The gene involved in the development of medullary carcinoma is RET, a protooncogene located on chromosome 10q11.2 that encodes a transmembrane receptor with tyrosine kinase activity. [4, 6] This gene is affected in the form of various activating germline mutations. [15] In families with familial medullary carcinoma and MEN IIA, these mutations are in one of the six codons for CYS in exons 10 and 11. Codon mutation in exon 11 is by far the most common genetic abnormality in MEN IIA families, accounting for 85% of the kindred. Families with MEN IIB usually have mutations at codon 918 in exon 16. Mutations in codons 768 and 804 are more common in cases of familiar medullary carcinoma not associated with MEN, whereas mutations of codon 634 are associated statistically with pheochromocytoma. It should be mentioned here that RET mutations have also been detected in sporadic medullary carcinomas, particularly at codon 918; in contrast to the familial and MEN-related cases, these mutations are somatic, i.e., found only in the tumor cells. [4]

The cardinal molecular event in papillary carcinoma is also believed to be an alteration of RET, in this instance in the form of one or another of several somatic rearrangements, the most common of which are designated as RET/PTC1, RET/PTC3, and RET/PTC2 (listed in order of decreasing frequency). [13] It has been claimed that this aberration is specific for the papillary carcinoma type; that it correlates with the presence of the typical nuclear changes of this tumor and that it is directly responsible for them; that it correlates with the tumor subtype (RET/PTC1 with the classic and diffuse sclerosing types, and RET/PTC3 with the follicular/solid and tall cell variants); that tumors with RET rearrangements tend to be more indolent and not to progress toward lesser differentiated forms; and that introduction of this oncogene to transgenic mice induces the formation of papillary thyroid carcinomas in them. These are high claims indeed, which when taken together constitute powerful evidence of the pivotal role that molecular discoveries play in unravelling thyroid carcinogenesis. There are, however, some discordant notes in this enthralling story. To wit:

  1. The incidence of RET/PTC rearrangements in the reported series of papillary carcinoma has ranged from less than 3% to over 80%, and it is as yet unclear whether these wide discrepancies are due to racial, environmental, or technical factors.

  2. There have been two independent reports (challenged by other investigators) describing RET/PTC rearrangements in over 90% of thyroid glands with Hashimoto's thyroiditis without morphologic evidence of papillary carcinoma).

  3. RET/PTC rearrangements have been found in a high proportion of cases of Hürthle cell tumor without papillary carcinoma features (see below). [2]

  4. There is considerable skepticism about the reliability of immunohistochemical techniques in detecting expression of the RET product in the cells of papillary carcinoma, at least with the use of the currently available antibodies.

This body of evidence is disturbing, to say the least, and a clear indicator that additional research is needed before making too many diagnostic, prognostic, and therapeutic assumptions on the basis of these molecular findings.

Other genetic alterations found in papillary carcinoma involve the gene NTRK1 (formerly trek) located on chromosome 1, the gene BRAF (affected in 36 to 69% of the cases), [12, 14] point mutations in ras (said to be more common in the follicular variant), [16] and lack of expression of the Rb gene. Expression of the sodium iodide symporter is also reduced.

As far as follicular carcinoma is concerned, the incidence of ras point mutation has been found to be much higher than for papillary carcinoma (53% versus 17%); it has been suggested that this difference may be related to the known differences in epidemiology, pathology, and clinical behavior between the two tumors. A genetic abnormality that has been detected in a subset of follicular carcinomas is the t(2;3)(q13;q25) translocation, resulting in the PAX-PPAR gamma 1 fusion. [7, 11] It has been claimed that the follicular carcinomas with PPARgamma rearrangement tend to have vascular invasion and solid/nested histology.

No consistent abnormalities in oncogenes have been so far detected in follicular adenomas, although some of them harbor the PAX8-PPAR gamma 1 fusion. [9] The presence of this gene fusion was originally thought to be restricted to benign and malignant tumors of follicular type, but the group of Sobrinho-Simoes has recently shown that it is also present in a subset of cases of the follicular variant of papillary carcinoma. [1]

Oncocytic (Hürthle cell) neoplasms are accompanied by mDNA somatic alterations, in the form of point mutations and large deletions. A particularly frequent change is the so-called "mDNA common deletion", which is, however, not specific for these tumors. Abnormalities of chromosomal DNA are also frequent. [10]

A somewhat disturbing observation that was recently made and which was mentioned above concerns the fact that neoplastic (but not hyperplastic) Hürthle cell nodules frequently seem to exhibit the same type of RET/PTC oncogene activation that characterizes papillary carcinoma and which has long been regarded as being restricted to the latter tumor type. [2]

Alterations of p53 are largely restricted to the poorly differentiated and undifferentiated thyroid carcinomas. [3, 5] In the cases of these tumor types having a residual papillary component, these mutations are not present in the latter, suggesting that they had occurred after the development of the papillary carcinoma and that they played a role in the progression of this tumor. [8]

The combined analysis of these complex and sometimes conflicting results suggests that much still needs to be done before fully understanding the biologic role of these molecular alterations in the genesis and behavior of thyroid neoplasms, particularly in the case of follicular cell-derived lesions.

References

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  3. Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH, Koeffler HP. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993; 27: 226-233.

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  14. Trovisco V, Vieria de Castro I, Soares P, Maximo V, Silva P, Magalhaes J, Abrosimov A, Guiu XM, Sobrinho-Simoes M. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol 2004; 22: 247-251.

  15. Tsukada T, Yamaguchi K, Kameya T. The MEN1 gene and associated diseases: an update. Endocr Pathol 2001; 12: 259-273

  16. Zhu Z, Gandhi M, Nikiforova MN, Fisher AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol 2003; 120: 71-77.