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In the era before immunohistochemistry and the electron microscope, most sarcomas were diagnosed as fibrosarcomas. With increasing sophistication, pathologists have refined the categorization of these tumors and today, fibrosarcomas are only rarely diagnosed. This refinement in the diagnosis has led to improved treatment modalities. In addition, molecular diagnostic techniques have identified unique chromosomal abnormalities in some of the congenital forms of this sarcoma.

Fibrosarcomas may occur in congenital and infantile cases. These tumors appear to be a distinct entity from the adult fibrosarcomas occurring almost exclusively in children younger than 2 yrs. It occurs on the extremities and axial regions. Under the microscope, they share histological similarity with adult cases with high cellularity, increased mitotic figures, necrosis, and nuclear atypia. Immunohistochemical studies reveal positivity for smooth muscle actin, desmin, S-100 protein, and CD34. It recurs locally in 40-50% of cases but metastasizes in only 10% of cases and has survival rates of >90%.

Because of the good prognosis but alarming histology of these tumors, the pathologist must be careful to exclude other spindle cell tumors of childhood including infantile fibromatosis and myofibromatosis. Immunoperoxidase studies are helpful. Recently, a unique fusion transcript has been detected in 10/11 cases. This fusion results from the translocation t(12;15)(p13;q25) giving rise to ETV6-NTRK3 gene fusion. It is absent in other spindle cell tumors of childhood as well as adult fibrosarcoma. It is detected by reverse transcription-polymerase chain reaction (RT-PCR).


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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.

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.

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.

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.

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

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.



Sclerosing Epithelioid Fibrosarcoma A Study of 16 Cases and Confirmation of a Clinicopathologically Distinct Tumor

Cristina R. Antonescu, etal.

Am J Surg Pathol 2001;25:699-709 Abstract quote

Sclerosing epithelioid fibrosarcoma (SEF) is an uncommon tumor of deep soft tissues, originally described in 1995 by Meis–Kindblom et al.

In the current study, the authors identified 16 cases of SEF in the pathology files of their institutions and studied their pathologic features and disease course. The group consisted of six male and 10 female patients (age range, 14–55 years; mean age, 40 years), and the tumors were located in a limb or limb girdle (n = 7), base of the penis (n = 1), back or chest wall (n = 3), and head and neck (n = 5). Tumor size ranged from 3.7 to 22 cm (mean, 8.9 cm).

Histologically, the SEFs were composed predominantly of small to moderate-size round to ovoid, relatively uniform cells, often with clear cytoplasm, embedded in a hyalinized fibrous stroma. The only consistent immunohistochemical finding was a strong, diffuse reactivity of tumor cells for vimentin. Ultrastructural analysis performed in eight cases confirmed their fibroblastic nature. Bone invasion and tumor necrosis, features not reported before, were found in six cases each. Treatment consisted of intralesional excision (n = 2), attempted wide local excision (n = 11), and amputation (n = 3), with either adjuvant radiation therapy (n = 9) or chemotherapy (n = 3). Follow-up of at least 1 year in 14 cases revealed persistent disease or local recurrence in seven patients (50%), and distant metastasis in 12 patients (86%). Eight patients (57%) died of disease 16 to 86 months after diagnosis. Five patients were alive with disease as of last follow-up.

SEF shares some pathologic features with two other fibrosing fibrosarcomas, low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes, but in the authors' experience behaves clinically as a fully malignant sarcoma.

Sclerosing epithelioid fibrosarcoma: a variant of fibrosarcoma simulating carcinoma.

Meis–Kindblom JM, Kindblom LG, Enzinger FM.

Am J Surg Pathol 1995;19:979–93.

Am J Surg Pathol 2000;24:937-946.

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Last Updated 4/21/2003

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