Molecular Aspects of Thyroid Neoplasia and Diagnostic Implications
Istituto Nazionale Tumori
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.
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
This gene is affected in the form of various activating germline mutations.
 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.
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).  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:
- 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.
- 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).
- RET/PTC rearrangements have been found in a high proportion of cases of Hürthle cell tumor without papillary carcinoma features (see below). 
- 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),
point mutations in
ras (said to be more common in the follicular variant),  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.
It has been claimed that the
follicular carcinomas with PPARgamma rearrangement tend to have vascular invasion and solid/nested
No consistent abnormalities in oncogenes have been so far detected in follicular adenomas,
although some of them harbor the PAX8-PPAR gamma 1 fusion.  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. 
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. 
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. 
Alterations of p53 are largely restricted to the poorly
differentiated and undifferentiated thyroid
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.
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
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