Issue 4 - August 2010 - Pacini Editore

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RAS to cytoplasmic Ser/Thr kinases like BRAF, MEK, ERK
- the MAPK pathway - whose activity is pivotal in controlling
cell proliferation 6 . While these oncogenic events in thyroid
tumors that are not oncocytic have been well studied, their
prevalence in oncocytic thyroid lesions is unclear. Unclear is
also their relationship with mtDNA mutations.
Methods. H-, K-and N-Ras mutations as well as BRAF exon
15 mutation and RET/PTC rearrangements were analyzed in
45 thyroid oncocytic tumors (15 hyperplastic adenomatous
nodules, HANonc; 8 follicular adenomas, FAonc; 14 follicular
carcinomas, FConc; 8 papillary carcinomas with oncocytic
features, PConc) that had been previously characterized for
their mtDNA abnormalities 4 . Nucleic acids were extracted
from paraffin-embedded neoplastic tissue after examination
of the corresponding Hematoxylin and Eosins stained sections
using a commercial kit (RecoverAll Total Nucleic Acid
Isolation, Applied Biosystems/Ambion – Austin, TX). Direct
sequencing was used to analyze H-, K- and N-Ras and BRAF
exon 15, qRT-PCR to identify RET/PTC1 and RET/PTC3 rearrangement.
The entire mtDNA was sequenced and mtDNA
mutations were classified as disruptive, possibly/probably
damaging and absent.
Results. We found three cases with RAS mutations, two
cases with a BRAF V600E activating mutation, one case with a
RET/PTC1 rearrangement. All the above nuclear DNA alterations
did not overlap in any given tumor. Of the RAS mutated
cases, one had a NRAS Q61R mutation and was diagnosed as a
minimally invasive FConc; the second case had a KRAS Q61R ,
and was diagnosed as FAonc; a third case had HRAS Q61R mutation,
was diagnosed as a follicular variant PConc; mtDNA
mutations were identified in the last two cases, and in both
the mtDNA mutations were classified as possibly/probably
damaging. Both cases with the BRAF V600E activating mutation
were diagnosed as PConc, tall cell variant and did not have
mtDNA mutations. The single RET/PTC1 mutated case was
a Warthin-like PConc, with no mtDNA alterations. mtDNA
mutations classified as disruptive were identified in 5/14
(35.7%) FConc, 2/8 (25.0%) FAonc, 4/15 (26.7%) HANonc,
1/8 (12.5%) PConc. mtDNA mutations classified as possibly/
probably damaging were identified in 3/14 (21.4%) FConc,
4/8 (50.0%) FAonc, 3/15 (20.0%) HANonc, 3/8 (37.5%)
PConc.
Conclusion. RAS, BRAF V600E mutations and RET/PTC rearrangement
have been identified in malignant oncocytic tumors
and in one follicular adenoma. RAS mutations are uncommon
in oncocytic follicular neoplasms (both carcinomas and
adenoma), suggesting that other tumorigenic events may play
a role in their development. BRAF V600E mutations are associated
with tall cell variant papillary carcinomas with oncocytic
features. Pathogenic mtDNA alterations may overlap with the
oncogenic mutations commonly found in non-oncocytic thyroid
tumors. Disruptive mtDNA mutations are more common
in oncocytic follicular carcinomas than in papillary oncocytic
carcinomas. They are also more common in oncocytic follicular
neoplasms – both carcinomas and adenomas – and
hyperplastic adenomatous nodules with oncocytic features,
when compared with papillary oncocytic carcinomas.
references
1 Tallini G. Oncocytic tumors. Virchows Archives A (Anat Pathol)
1998;433:5-12.
2 World Health Organization Classification of Tumors-Pathology and
Genetics, Tumors of Endocrine Organs. Lyon (France): IARC Press,
2004.
3 Gasparre G, Bonora E, Tallini G, et al. Molecular features of thyroid
oncocytic tumors. Mol Cell Endocrinol. 2010;321:67-76.
5 th triennial congress of the italian society of anatomic Pathology and diagnostic cytoPathology
4 Gasparre G, Porcelli AM, Bonora E, et al. Disruptive mitochondrial
DNA mutations in complex I subunits are markers of oncocytic phenotype
in thyroid tumors. Proceedings of the National Academy of
Sciences USA 2007;104:9001-6.
5 Bonora E, Porcelli AM, Gasparre G, et al. Defective Oxidative Phosphorylation
in Thyroid Oncocytic Carcinoma Is Associated with
Pathogenic Mitochondrial DNA Mutations Affecting Complexes I and
III. Cancer Research 2006;66:6087-96.
6 Knauf JA, Fagin JA. Role of MAPK pathway oncoproteins pathogenesis
and as drug targets. Current Opinion in Cell Biology 2009;21:296-
303.
Trabecular neoplasms of the thyroid
M. Volante, I. Rapa, M. Papotti.
Department of Clinical and Biological Sciences at San Luigi Hospital,
University of Turin, Orbassano, Turin, Italy
Follicular and papillary growth patterns represent the most
common architectural features within thyroid nodules, in both
benign and malignant settings. Alternative to these, nodules
having a non follicular-non papillary structure may be encountered,
being solid/trabecular arrangement the most common
feature. In general, irrespective of the biological nature of
the lesion under analysis, trabecular growth is represented by
sheets of cells regularly arranged in one or few rows or more
irregularly anastomosing, separated by usually scarce connective
tissue and a thin vascular network. The solid growth is an
extreme of the trabecular architecture, being represented by a
more nodular arrangement with a wider thickness of cellular
islands and a more irregular and dispersed vascular network.
However, the border between compact trabecular growth and
solid pattern is poorly defined and since this latter is usually
mixed with and represents an architectural arrangement parallel
to the trabecular one, they will be considered together.
When dealing with a trabecular lesion in the thyroid, a wide
range of differential diagnoses exists, representing one of the
major diagnostic problems in the routine thyroid practice 1 ,
and include the following, among others:
a) Lesions derived from the follicular epithelium with
papillary carcinoma-type nuclear features. When follicular
cell derivation is morphologically or immunophenotypically
evident, the nuclear features – as conventionally considered
for follicular/papillary lesions – should be carefully examined
to check the presence of the diagnostic features of papillary
carcinoma. If clear-cut papillary-type nuclei are recognized,
the following two entities have to be considered. The
solid variant of papillary carcinoma is a rare and still poorly
characterized variant of papillary thyroid carcinoma, most
commonly found in children and young adults especially in
radiation-exposed individuals; the presence of irregular clear
nuclei with grooving and pseudo-inclusions is the cytological
hallmark whereas the solid growth pattern is accompanied
by vascular invasion and extra-thyroidal extension in about
one-third of cases. The clinical behaviour of the solid variant
of papillary carcinoma is characterized by a slightly higher
frequency of distant metastases and less favourable prognosis
than classical papillary carcinoma 2 . Hyalinizing trabecular
tumor (HTT) is a trabecular neoplasm of follicular derivation
with peculiar nuclear, architectural and histochemical
features, with a benign behaviour in the vast majority of
cases reported so far 3 . HTT is a well circumscribed lesion,
lacking morphological signs of capsular or vascular invasion.
Two principal features are diagnostic of HTT: a uniform
and diffuse solid and trabecular architecture, with markedly
hyalinized deposits containing basal membrane-type material,
typically located within the trabeculae rather than in the inter-