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Molecular Detection of the ETV6-NTRK3 Gene Fusion Differentiates
Congenital Fibrosarcoma From Other Childhood Spindle Cell Tumors
Jacqueline M. Bourgeois, M.D.; Stevan R. Knezevich, Ph.D.; Joan
A. Mathers, A.R.T.; Poul H. B. Sorensen, M.D., Ph.D.
From the Department of Pathology and Molecular Medicine (J.M.B.),
McMaster University Medical Centre, Hamilton, Ontario; and the Department
of Pathology and Laboratory Medicine (S.R.K., J.A.M., P.H.B.S.), Children's
and Women's Health Centre of British Columbia, Vancouver, British Columbia,
Canada.
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Am J Surg Pathol 2000;24:937-946 Abstract quote
Congenital fibrosarcoma (CFS) is a pediatric spindle cell tumor of
the soft tissues that usually presents before the age of 2 years. Although
these tumors display histologic features of malignancy and frequently
recur, they have a relatively good prognosis and only rarely metastasize.
CFS must therefore be differentiated from more aggressive spindle cell
sarcomas that occur during childhood, particularly adult-type fibrosarcoma
(ATFS), which can have an identical morphology. CFS must also be distinguished
from benign but cellular fibroblastic lesions of the same age group,
including infantile fibromatosis (IFB) and myofibromatosis (MFB). Unfortunately,
standard pathologic examination often does not differentiate CFS from
these other conditions.
The authors recently identified a novel chromosomal translocation in
CFS, t(12;15)(p13;q25), which gives rise to an ETV6-NTRK3 gene fusion.
They subsequently developed reverse transcription–polymerase chain reaction
(RT-PCR) assays that can detect ETV6-NTRK3 fusion transcripts in CFS
frozen or paraffin-embedded tumor specimens. To confirm the use of this
assay in the differential diagnosis of CFS, they have screened a larger
series of childhood pediatric spindle cell lesions for ETV6-NTRK3 gene
fusions, including 11 cases of CFS, 13 malignant spindle cell tumors
(including ATFS), and 38 benign spindle cell tumors (including IFB and
MFB). Of the 11 cases diagnosed as CFS, 10 showed the ETV6-NTRK3 gene
fusion, whereas none of the 51 other malignant or benign spindle cell
tumors demonstrated this fusion gene. They also compared their RT-PCR
findings with those of conventional cytogenetics and with immunohistochemical
detection of the ETV6-NTRK3 protein using antisera to NTRK3.
They conclude that RT-PCR analysis is superior to these techniques
for the detection of the ETV6-NTRK3 gene fusion in pediatric spindle
cell tumors, and it is a reliable and specific modality for the diagnosis
of CFS.
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| Congenital-Infantile Fibrosarcoma A Clinicopathologic
Study of 10 Cases and Molecular Detection of the ETV6-NTRK3 Fusion Transcripts
Using Paraffin-Embedded Tissues |
Am J Clin Pathol 2001;115:348-355
CIFSs have been found to have a novel recurrent reciprocal translocation
t(12;15)(p13;q25) resulting in the gene fusion ETV6-NTRK3 (ETS variant
gene 6; neurotrophic tyrosine kinase receptor type 3).
We studied immunohistochemical expression of NTRK3, and conducted a
reverse transcription-polymerase chain reaction (RT-PCR) assay to detect
the ETV6-NTRK3 fusion transcripts using archival formalin-fixed paraffin-embedded
tissues from 10 CIFSs.
Thirty-eight other spindle cell tumors were included as controls. The
ETV6-NTRK3 fusion transcripts were identified in 7 (70%) of 10 CIFSs.
Nucleotide sequence analysis showed that the fusion occurred between
ETV6 exon 5 and NTRK3 exon 13. The 38 control tumors were negative for
the fusion transcript. Immunohisto-chemically, CIFSs consistently expressed
NTRK3. But the expression of NTRK3 also was observed in 22 of 38 control
tumors.
Conclusions:
These results show the diagnostic usefulness of RT-PCR methods to detect
ETV6-NTRK3 fusion transcripts in archival formalin-fixed paraffin-embedded
tissue and the important role of NTRK3 in the development of CIFS, despite
its being a protein of little importance in differential diagnosis.
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ETV6 Rearrangements in Patients with Infantile Fibrosarcomas
and Congenital Mesoblastic Nephromas by Fluorescence In Situ Hybridization
Camilo Adem, M.D., David Gisselsson, Ph.D., Paola
Dal Cin, Ph.D. and Antonio G. Nascimento, M.D.
Department of Laboratory Medicine and Pathology (CA,
AGN), Mayo Clinic, Rochester, Minnesota; and Department of Pathology
(DG, PDC), Brigham and Women’s Hospital and Harvard Medical School,
Boston, Massachusetts
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Mod Pathol 2001;14:1246-1251 Abstract quote
Congenital mesoblastic nephroma (CMN) and infantile fibrosarcoma (IFS)
are two pediatric tumors arising in the kidneys and soft tissues of
infants, respectively. Recently, a t(12;15)(p13;q25) resulting in ETV6-NTRK3
gene fusion was detected in patients with IFS and in patients with the
cellular type of CMN, suggesting a common pathogenetic pathway.
We investigated the presence or absence of ETV6 rearrangements and
numerical abnormalities of chromosome 11 by using fluorescence in situ
hybridization on paraffin-embedded material from five cases of IFS,
two of CMN, and one of mixed type (CMN and IFS) found in our files.
In three cases of IFS, we found ETV6 gene rearrangement but a normal
copy number of chromosome 11. One case each of IFS, the cellular type
of CMN, and the mixed type (CMN and IFS) had both abnormalities. In
a case of classic CMN, neither trisomy 11 nor gene rearrangement was
found. It is possible that trisomy 11 is a later, nonessential event
in the pathogenetic process or that this secondary aberration is associated
with still-unrecognized clinical or biological characteristics.
We confirmed that IFS and the cellular type of CMN are cytogenetically
related and can occur synchronously in the same organ.
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