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Pathology International 2015; 65: 48–50

doi:10.1111/pin.12223

Letter to the Editor A case of pure sclerosing epithelioid fibrosarcoma with a cytogenetic and fluorescence in situ hybridization study To the Editor: Sclerosing epithelioid fibrosarcoma (SEF) is a variant of fibrosarcoma characterized by epithelioid fibroblasts arranged in cords and nests in a sclerotic stroma.1,2 It is known that a subset of SEF appears to be related to lowgrade fibromyxoid sarcoma (LGFMS).1,3SEF rarely contains the morphology of LGFMS and LGFMS also rarely contains the morphology of SEF.1,3 Doyle et al. applied the term ‘hybrid SEF-LGFMS’ for the tumor with hybrid features.4 MUC4 which was firstly found as a sensitive and specific marker for LGFMS was also shown as a useful marker for SEF later.1,3 Thus, the potential relationship between SEF and LGFMS is very interesting. On the other hand, the cytogenetic findings of SEF were not the same as the findings of LGFMS. The translocation, t(7;16)(q33;p11), resulting in the FUS-CREB3L2 fusion gene has been found in approximately two thirds of LGFMS cases.3 But, the SEF cases which were karyotyped did not show the cytogenetic changes observed in LGFMS although the cytogenetic information of SEF has been limited.1,3,5–7 Wang et al. showed that FUS rearrangements are rare (2 out of 22 cases) in pure SEF by fluorescence in situ hybridization (FISH).8 Arbajian et al. recently reported recurrent EWSR1CREB3L1 gene fusions in SEF.9 EWSR1 gene locates on chromosome 22q12.9 However, chromosomal abnomalities involving 22q12 have not been observed by the G-banded karyotypic analysis in SEF.5–7 We report a case of pure SEF with the karyotypic findings and FISH results. The patient was an 16-year-old Japanese female. She noticed an abdominal mass. Magnetic resonance imaging demonstrated a tumor in the right abdominal external oblique muscle. Biopsy and resection was performed. The patient was alive and free of disease for 18 months after surgery. Macroscopically, the tumor measuring approximately 3.5 × 3.2 × 3.0 cm was observed in the right abdominal external oblique muscle. The tumor was well circumscribed. The cut surface was yellowish-white (Fig. 1a). Necrosis was not observed. On microscopic examination, the tumor cells were embedded in dense fibrous stroma The cellularity was variable. Small to medium sized epithelioid cells were arranged in cords and nests embedded in fibrous stroma (Fig. 1b). The epithelioid cells had relatively bland round and ovoid nuclei. Bone formation and cartilage formation were focally observed (Fig. 1c). Giant cells or highly pleomorphic cells were not seen. The morphology of LGFMS was not found in the tumor.

Immunohistochemically, the tumor cells were diffusely positive for MUC4 (clone 8G7; Santa Cruz Biotechnology, Santa Cruz, CA, USA) (Fig. 1d) and vimentin (clone SP20; Nichirei, Tokyo, Japan). The tumor cells were focally positive for EMA (clone E29; DAKO Cyotomation, Glostrup, Denmark) in cytoplasm and negative for desmin (clone D33: Nichirei), beta catenin (clone 14: BD Transduction Laboratories, San Jose, CA, USA), S100 (polyclonal, DAKO Cytomation), cytokeratin (AE1/AE3, Nichirei), bcl-2 and alpha smooth muscle actin (clone 1A4, DAKO Cytomation). Karyotype analysis was performed with G-banding in Sapporo clinical laboratory (Sapporo, Japan) using fresh tissue sample from the surgical specimen. Twenty four metaphases were analyzed. All 24 metaphases revealed numerical and structural abnoromalities as follows: 45, XX, add(1)(p13)x2, + add(1)(p36), der(8)t(8;12)(q22; q13), add(11)(p11), del(11)(q?), −12, −15, −17, add(19) (p11), add(20)(q11), add(22)(q13)x2, + mar (Fig. 2a). FISH analysis was performed on paraffin sections following manufacturer’s protocol, using FUS and EWSR1 dual-color break-apart probes (Vysis, Abbot, IL, USA). Approximately 40% of 200 tumor cells showed one fused (red/green) signal and one or two red split signals per nucleus for EWSR1 break-apart probes (Fig 2b). The cutoff level for scoring aberration was 30% abnormal nuclei.9 The red split signals corresponded to the 5′ side of EWSR1. The green split signal corresponding to the 3′ side of EWSR1 was absent. The FISH results suggested presence of nonreciprocal translocation involving the EWSR1 gene. On the other hand, tumor cells showed 2 fused (red/green) signals per nucleus for FUS break-apart probes (Fig 2c). Pathologic diagnosis of the present case was pure SEF. FISH analysis suggested the presence of nonreciprocal translocation involving the EWSR1 gene. EWSR1 gene locates on chromosome 22q12.9 It is also uncertain whether the lack of green signal by FISH represents non-reciprocal translocation of EWSR1 gene or potential deletion involving the telomeric part of 22q12. However, recent literature suggested the presence of nonreciprocal translocation of EWSR1 gene in our ESF case.9,10 Recurrent EWSR1CREB3L1 gene fusion were recently shown in SEF by Arbajian et al.9 They showed that the split signals (2 cases) or the loss of the part flanking the 3′-part (3 cases) of the gene, indicative of involvement in a gene fusion, were seen in 5/10 informative SEF cases for the EWSR1 gene by FISH.9 It was also shown that RT-PCR for EWSR1-CREB3L1 fusion transcripts detected in-frame fusion in one SEF case with a loss of the part flanking the 3′-part of EWS gene by FISH.9 The loss of the part flanking the 3′-part of the EWS gene suggests

© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

Letter to the Editor

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Figure 1 Gross and histological features. (a) Macroscopic view of the tumor. The tumor was nodular and the cut surface was yellowish-white. (b,c) Photomicrography of the tumor. The tumor cells were embedded in fibrous stroma and small to medium sized epithelioid cells were arranged in cords and nests. Single file pattern was observed (b; hematoxylineosin stain, original magnification 24×). Bone formation and cartilage formation were observed focally (c; hematoxylineosin stain, original magnification 6×). (d) Immunohistochemically, the tumor cells were diffusely positive for MUC4 in the cytoplasm (d; original magnification 12×).

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b Figure 2 (a) G-banded karyotype. Arrows indicate structural aberration. (b,c) FISH analysis results. (b) FISH analysis using EWSR1 dual-color breakapart probe showed one red/green fused signal and one or two red split signals per nucleus in many tumor cells. (c) FISH analysis using FUS dual-color break-apart probe showed two red/green fused signals per nucleus in most tumor cells.

© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

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Letter to the Editor

the presence of nonreciprocal translocation of EWSR1 gene in SEF. To our knowledge, so far four SEF cases have been reported with the G-banded karyotypic analysis including our case.5–7 Ogose et al. described that rearrangement of 10p11 was found in two reported cases.1,5,7 Our case showed cytogenetic changes including add(22)(q13). Donner et al. also reported cytogenetic changes including add(22)(q13).6 Thus, the add(22)(q13) might be the common cytogenetic change in a subset of SEF cases. EWSR1 gene locates on chromosome 22q12.9 Although the recurrent EWSR1-CREB3L1 gene fusion was recently shown in SEF,9 chromosomal abnormalities involving 22q12 has not been observed with the G-banded karyotypic analysis in SEF including our case.5–7 It is interesting why chromosomal abnormalities involving 22q12 has not been detected in SEF. It is also interesting that the two cases of SEF showed the additional chromosomal material at 22q13 near the EWSR1 locus as described above.6 In fact, our SEF case having the additional chromosomal material at 22q13, showed FISH results suggesting the presence of nonreciprocal translocation involving the EWSR1 gene. Taken together, add(22)(q13) may be related to EWSR1 gene translocation in SEF although the mechanism is unknown. Table S1 summarizes reported cases of SEF and the present case. Our case confirmed the observation of recurrent genetic alteration involving EWSR1 gene in SEF by Arbajian et al.9 and suggested the possible chromosomal abnormality, add(22)(q13) which had been poorly described in the literature.

REFERENCES 1 Kindblom LG, Mertens F, Coindre JM et al. Sclerosing epithelioid fibrosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumours of Soft Tissue and Bone, 4th edn. Lyon: IARC, 2013; 97–8. 2 Meis-kindblom JM, Kindblom LG, Enzinger FM. Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma. Am J Surg Pathol 1995; 19: 979–93. 3 Folpe AL, Hornick JL, Mertens F. Low-grade fibromyxoid sarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumours of Soft Tissue and Bone, 4th edn. Lyon: IARC, 2013; 95–6. 4 Doyle LA, Wang WL, Cin PD et al. MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma. Association with FUS gene rearrangement. Am J Surg Pathol 2012; 36: 1444–51. 5 Gisselsson D, Andreasson P, Meis-Kindblom JM et al. Amplification of 12q13 and 12q15 sequences in a sclerosing epithelioid fibrosarcoma. Cancer Genet Cytogenet 1998; 107: 102–6. 6 Donner LR, Clauson K, Dobin SM. Sclerosing epithelioid fibrosarcoma: A cytogenetic, immunohistochemical, and ultrastructural study of an unusual histological variant. Cancer Genet Cytogenet 1999; 119: 127–31. 7 Ogose A, Kawashima H, Umezu H et al. Sclerosing epithelioid fibrosarcoma with der(10)t(10;17)(p11;q11). Cancer Genet Cytogenet 2004; 152: 136–40. 8 Wang WL, Evans HL, Meis JM et al. FUS rearrangements are rare in ‘pure’ sclerosing eithelioid fibrosarcoma. Mod Pathol 2012; 25: 846–53. 9 Arbajian E, Puls F, Magnusson L et al. Recurrent EWSR1CREB3L1 gene fusions in sclerosing epithelioid fibrosarcoma. Am J Surg Pathol 2014; 38: 801–8. 10 Lau PPL, Lui PCW, Lau GTC et al. EWSR1-CREB3L1 gene fusion. A novel alternative molecular aberration of low-grade fibromyxoid sarcoma. Am J Surg Pathol 2013; 37: 734–8.

SUPPORTING INFORMATION ACKNOWLEDGMENT This study was supported in part by the Health and Labour Science Research Expenses for Commission, Applied Research for Innovative Treatment of Cancer from the Ministry of Health, Labour and Welfare (H26-084).

Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Summary of reported cases of sclerosing epithelioid fibrosarcoma with cytogenetic analysis.

DISCLOSURE All authors declare that there is no conflict of interest. Hiroaki Suzuki,1 Hiroko Takeda,1 Katsushige Yamashiro,1 Tamotsu Soma,2 Toshihisa Osanai,2 Hiroaki Hiraga,2 Kazuo Isu,2 Mitsuharu Tamakawa3 and Takayuki Nojima4

Divisions of 1Diagnostic Pathology and 2Orthopedics, National Hospital Organization Hokkaido Cancer Center, 3 Department of Diagnostic Radiology, Sapporo Medical University, Sapporo and 4Department of Pathology, Kanazawa Medical University, Uchinada, Japan

© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

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A case of pure sclerosing epithelioid fibrosarcoma with a cytogenetic and fluorescence in situ hybridization study.

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