Epithelioid and spindle cell rhabdomyosarcoma with FUS-TFCP2 or EWSR1-TFCP2 fusion: report of two cases


The WHO Classification of Tumors of Soft Tissue and Bone divides rhabdomyosarcoma (RMS) into alveolar, embryonal, pleomorphic, and spindle cell/sclerosing types. Advances in molecular diagnostics have allowed for further refinement of RMS classification including the identification of new subtypes. Very rare RMS with epithelioid and spindle cell morphology, female predominance, marked osseous predilection, ALK expression, EWSR1/FUS-TFCP2 gene fusions, and highly aggressive clinical behavior have recently been recognized with only 23 cases reported in the English language literature. Herein, we report two additional cases with detailed clinicopathologic description and molecular confirmation. In brief, two young women presented each with a primary bone tumor—one with a frontal bone tumor and another with an osseous pelvic tumor. Both tumors showed epithelioid to spindle cell morphology, ALK expression, and EWSR1/FUS-TFCP2 gene fusions. Both patients died of disease less than 17 months from diagnosis despite administration of multiple lines of aggressive treatment. In addition, we review the literature and discuss differential diagnostic and potential treatment considerations.

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  1. 1.

    Fletcher CDM BJ, Hogendoorn PCW, Mertens F (2013) WHO classification of tumours of soft tissue and bone. 4 edn. International Agency for Research on Cancer, Lyon, France

  2. 2.

    Dickson BC, Childs TJ, Colgan TJ, Sung YS, Swanson D, Zhang L, Antonescu CR (2019) Uterine tumor resembling ovarian sex cord tumor: a distinct entity characterized by recurrent NCOA2/3 gene fusions. Am J Surg Pathol 43(2):178–186. https://doi.org/10.1097/pas.0000000000001153

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Liu S, Tsai WH, Ding Y, Chen R, Fang Z, Huo Z, Kim S, Ma T, Chang TY, Priedigkeit NM, Lee AV, Luo J, Wang HW, Chung IF, Tseng GC (2016) Comprehensive evaluation of fusion transcript detection algorithms and a meta-caller to combine top performing methods in paired-end RNA-seq data. Nucleic Acids Res 44(5):e47. https://doi.org/10.1093/nar/gkv1234

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Kallberg M, Cox AJ, Kruglyak S, Saunders CT (2016) Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32(8):1220–1222. https://doi.org/10.1093/bioinformatics/btv710

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Watson S, Perrin V, Guillemot D, Reynaud S, Coindre JM, Karanian M, Guinebretiere JM, Freneaux P, Le Loarer F, Bouvet M, Galmiche-Rolland L, Larousserie F, Longchampt E, Ranchere-Vince D, Pierron G, Delattre O, Tirode F (2018) Transcriptomic definition of molecular subgroups of small round cell sarcomas. J Pathol 245(1):29–40. https://doi.org/10.1002/path.5053

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Dashti NK, Wehrs RN, Thomas BC, Nair A, Davila J, Buckner JC, Martinez AP, Sukov WR, Halling KC, Howe BM, Folpe AL (2018) Spindle cell rhabdomyosarcoma of bone with FUS-TFCP2 fusion: confirmation of a very recently described rhabdomyosarcoma subtype. Histopathology 73(3):514–520. https://doi.org/10.1111/his.13649

    Article  PubMed  Google Scholar 

  7. 7.

    Wong DD, van Vliet C, Gaman A, Giardina T, Amanuel B (2019) Rhabdomyosarcoma with FUS re-arrangement: additional case in support of a novel subtype. Pathology 51(1):116–120. https://doi.org/10.1016/j.pathol.2018.09.056

    Article  PubMed  Google Scholar 

  8. 8.

    Agaram NP, Zhang L, Sung YS, Cavalcanti MS, Torrence D, Wexler L, Francis G, Sommerville S, Swanson D, Dickson BC, Suurmeijer AJH, Williamson R, Antonescu CR (2019) Expanding the spectrum of intraosseous rhabdomyosarcoma: correlation between 2 distinct gene fusions and phenotype. Am J Surg Pathol 43:695–702. https://doi.org/10.1097/pas.0000000000001227

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Tagami Y, Sugita S, Kubo T, Iesato N, Emori M, Takada K, Tsujiwaki M, Segawa K, Sugawara T, Kikuchi T, Hasegawa T (2019) Spindle cell rhabdomyosarcoma in a lumbar vertebra with FUS-TFCP2 fusion. Pathol Res Pract 215(8):152399. https://doi.org/10.1016/j.prp.2019.03.027

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Zhu G, Benayed R, Ho C, Mullaney K, Sukhadia P, Rios K, Berry R, Rubin BP, Nafa K, Wang L, Klimstra DS, Ladanyi M, Hameed MR (2019) Diagnosis of known sarcoma fusions and novel fusion partners by targeted RNA sequencing with identification of a recurrent ACTB-FOSB fusion in pseudomyogenic hemangioendothelioma. Mod Pathol 32(5):609–620. https://doi.org/10.1038/s41379-018-0175-7

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Le Loarer F, Cleven AHG, Bouvier C, Castex MP, Romagosa C, Moreau A, Salas S, Bonhomme B, Gomez-Brouchet A, Laurent C, Le Guellec S, Audard V, Giraud A, Ramos-Oliver I, Cleton-Jansen AM, Savci-Heijink DC, Kroon HM, Baud J, Pissaloux D, Pierron G, Sherwood A, Coindre JM, Bovee J, Larousserie F, Tirode F (2019) A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation. Mod Pathol 33:404–419. https://doi.org/10.1038/s41379-019-0323-8

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Lewin J, Desai J, Smith K, Luen S, Wong D (2019) Lack of clinical activity with crizotinib in a patient with FUS rearranged rhabdomyosarcoma with ALK protein overexpression. Pathology 51(6):655–657. https://doi.org/10.1016/j.pathol.2019.07.004

    Article  PubMed  Google Scholar 

  13. 13.

    Veljkovic J, Hansen U (2004) Lineage-specific and ubiquitous biological roles of the mammalian transcription factor LSF. Gene 343(1):23–40. https://doi.org/10.1016/j.gene.2004.08.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Hansen U, Owens L, Saxena UH (2009) Transcription factors LSF and E2Fs: tandem cyclists driving G0 to S? Cell Cycle 8(14):2146–2151. https://doi.org/10.4161/cc.8.14.9089

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Kotarba G, Krzywinska E, Grabowska AI, Taracha A, Wilanowski T (2018) TFCP2/TFCP2L1/UBP1 transcription factors in cancer. Cancer Lett 420:72–79. https://doi.org/10.1016/j.canlet.2018.01.078

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Swendeman SL, Spielholz C, Jenkins NA, Gilbert DJ, Copeland NG, Sheffery M (1994) Characterization of the genomic structure, chromosomal location, promoter, and development expression of the alpha-globin transcription factor CP2. J Biol Chem 269(15):11663–11671

    CAS  PubMed  Google Scholar 

  17. 17.

    Santhekadur PK, Rajasekaran D, Siddiq A, Gredler R, Chen D, Schaus SE, Hansen U, Fisher PB, Sarkar D (2012) The transcription factor LSF: a novel oncogene for hepatocellular carcinoma. Am J Cancer Res 2(3):269–285

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Agaram NP, Chen CL, Zhang L, LaQuaglia MP, Wexler L, Antonescu CR (2014) Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 53(9):779–787. https://doi.org/10.1002/gcc.22187

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Jiang H, Du J, Jin J, Qi X, Pu Y, Fei B (2014) LSF expression and its prognostic implication in colorectal cancer. Int J Clin Exp Pathol 7(9):6024–6031

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Yuedi D, Yuankun C, Jiaying Z, Han L, Yueqi W, Houbao L, Dexiang Z (2017) TFCP2 activates beta-catenin/TCF signaling in the progression of pancreatic cancer. Oncotarget 8(41):70538–70549. https://doi.org/10.18632/oncotarget.19741

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Broniarczyk JK, Warowicka A, Kwasniewska A, Wohun-Cholewa M, Kwasniewski W, Gozdzicka-Jozefiak A (2014) Expression of TSG101 protein and LSF transcription factor in HPV-positive cervical cancer cells. Oncol Lett 7(5):1409–1413. https://doi.org/10.3892/ol.2014.1967

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Goto Y, Yajima I, Kumasaka M, Ohgami N, Tanaka A, Tsuzuki T, Inoue Y, Fukushima S, Ihn H, Kyoya M, Ohashi H, Kawakami T, Bennett DC, Kato M (2016) Transcription factor LSF (TFCP2) inhibits melanoma growth. Oncotarget 7(3):2379–2390. https://doi.org/10.18632/oncotarget.6230

    Article  PubMed  Google Scholar 

  23. 23.

    Cheah AL, Zou Y, Lanigan C, Billings SD, Rubin BP, Hornick JL, Goldblum JR (2019) ALK expression in angiomatoid fibrous histiocytoma: a potential diagnostic pitfall. Am J Surg Pathol 43(1):93–101. https://doi.org/10.1097/pas.0000000000001103

    Article  PubMed  Google Scholar 

  24. 24.

    Folpe AL, Graham RP, Martinez A, Schembri-Wismayer D, Boland J, Fritchie KJ (2018) Mesenchymal chondrosarcomas showing immunohistochemical evidence of rhabdomyoblastic differentiation: a potential diagnostic pitfall. Hum Pathol 77:28–34. https://doi.org/10.1016/j.humpath.2018.03.012

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Reith JD, Bauer TW, Fischler DF, Joyce MJ, Marks KE (1996) Dedifferentiated chondrosarcoma with rhabdomyosarcomatous differentiation. Am J Surg Pathol 20(3):293–298. https://doi.org/10.1097/00000478-199603000-00005

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Billings SD, Folpe AL, Weiss SW (2003) Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol 27(1):48–57. https://doi.org/10.1097/00000478-200301000-00006

    Article  PubMed  Google Scholar 

  27. 27.

    Hornick JL, Fletcher CD (2011) Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol 35(2):190–201. https://doi.org/10.1097/PAS.0b013e3181ff0901

    Article  PubMed  Google Scholar 

  28. 28.

    Mosquera JM, Sboner A, Zhang L, Kitabayashi N, Chen CL, Sung YS, Wexler LH, LaQuaglia MP, Edelman M, Sreekantaiah C, Rubin MA, Antonescu CR (2013) Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer 52(6):538–550. https://doi.org/10.1002/gcc.22050

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Alaggio R, Zhang L, Sung YS, Huang SC, Chen CL, Bisogno G, Zin A, Agaram NP, LaQuaglia MP, Wexler LH, Antonescu CR (2016) A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol 40(2):224–235. https://doi.org/10.1097/pas.0000000000000538

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Rekhi B, Upadhyay P, Ramteke MP, Dutt A (2016) MYOD1 (L122R) mutations are associated with spindle cell and sclerosing rhabdomyosarcomas with aggressive clinical outcomes. Mod Pathol 29(12):1532–1540. https://doi.org/10.1038/modpathol.2016.144

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Tsai JW, ChangChien YC, Lee JC, Kao YC, Li WS, Liang CW, Liao IC, Chang YM, Wang JC, Tsao CF, Yu SC, Huang HY (2019) The expanding morphological and genetic spectrum of MYOD1-mutant spindle cell/sclerosing rhabdomyosarcomas: a clinicopathological and molecular comparison of mutated and non-mutated cases. Histopathology 74(6):933–943. https://doi.org/10.1111/his.13819

    Article  PubMed  Google Scholar 

  32. 32.

    Corao DA, Biegel JA, Coffin CM, Barr FG, Wainwright LM, Ernst LM, Choi JK, Zhang PJ, Pawel BR (2009) ALK expression in rhabdomyosarcomas: correlation with histologic subtype and fusion status. Pediatr Dev Pathol 12(4):275–283. https://doi.org/10.2350/08-03-0434.1

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Gasparini P, Casanova M, Villa R, Collini P, Alaggio R, Zin A, Bonvini P, Antonescu CR, Boldrini R, Caserini R, Moro M, Centonze G, Meazza C, Massimino M, Bergamaschi L, Luksch R, Chiaravalli S, Bisogno G, Zaffaroni N, Daidone MG, Sozzi G, Ferrari A (2016) Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma. Oncotarget 7(37):58903–58914. https://doi.org/10.18632/oncotarget.10368

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    van Gaal JC, Flucke UE, Roeffen MH, de Bont ES, Sleijfer S, Mavinkurve-Groothuis AM, Suurmeijer AJ, van der Graaf WT, Versleijen-Jonkers YM (2012) Anaplastic lymphoma kinase aberrations in rhabdomyosarcoma: clinical and prognostic implications. J Clin Oncol 30(3):308–315. https://doi.org/10.1200/jco.2011.37.8588

    Article  PubMed  Google Scholar 

  35. 35.

    Jo VY, Marino-Enriquez A, Fletcher CD (2011) Epithelioid rhabdomyosarcoma: clinicopathologic analysis of 16 cases of a morphologically distinct variant of rhabdomyosarcoma. Am J Surg Pathol 35(10):1523–1530. https://doi.org/10.1097/PAS.0b013e31822e0907

    Article  PubMed  Google Scholar 

  36. 36.

    Hornick JL, Nielsen GP (2019) Beyond “triton”: malignant peripheral nerve sheath tumors with complete heterologous rhabdomyoblastic differentiation mimicking spindle cell rhabdomyosarcoma. Am J Surg Pathol 43(10):1323–1330. https://doi.org/10.1097/pas.0000000000001290

    Article  PubMed  Google Scholar 

  37. 37.

    Chougule A, Taylor MS, Nardi V, Chebib I, Cote GM, Choy E, Nielsen GP, Deshpande V (2019) Spindle and round cell sarcoma with EWSR1-PATZ1 gene fusion: a sarcoma with polyphenotypic differentiation. Am J Surg Pathol 43(2):220–228. https://doi.org/10.1097/pas.0000000000001183

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bridge JA, Sumegi J, Druta M, Bui MM, Henderson-Jackson E, Linos K, Baker M, Walko CM, Millis S, Brohl AS (2019) Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma. Mod Pathol 32(11):1593–1604. https://doi.org/10.1038/s41379-019-0301-1

    Article  PubMed  Google Scholar 

  39. 39.

    Grant TJ, Bishop JA, Christadore LM, Barot G, Chin HG, Woodson S, Kavouris J, Siddiq A, Gredler R, Shen XN, Sherman J, Meehan T, Fitzgerald K, Pradhan S, Briggs LA, Andrews WH, Sarkar D, Schaus SE, Hansen U (2012) Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma. Proc Natl Acad Sci U S A 109(12):4503–4508. https://doi.org/10.1073/pnas.1121601109

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Rajasekaran D, Siddiq A, Willoughby JL, Biagi JM, Christadore LM, Yunes SA, Gredler R, Jariwala N, Robertson CL, Akiel MA, Shen XN, Subler MA, Windle JJ, Schaus SE, Fisher PB, Hansen U, Sarkar D (2015) Small molecule inhibitors of late SV40 factor (LSF) abrogate hepatocellular carcinoma (HCC): evaluation using an endogenous HCC model. Oncotarget 6(28):26266–26277. https://doi.org/10.18632/oncotarget.4656

    Article  PubMed  PubMed Central  Google Scholar 

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Author information




John Chrisinger: Project planning, slide review, data gathering, data analysis, literature review, and manuscript writing

Bret Wehrli: Data gathering, data analysis, and manuscript writing

Brendan Dickson: Data analysis, next generation sequencing, and manuscript writing

Samir Fasih: Data gathering, data analysis, and manuscript writing

Angela Hirbe: Data gathering, data analysis, and manuscript writing

David Shultz: Data gathering, data analysis, and manuscript writing

Gelareh Zadeh: Data gathering, data analysis, and manuscript writing

Abha Gupta: Data gathering, data analysis, and manuscript writing

Elizabeth Demicco: Project planning, slide review, data gathering, data analysis, literature review, and manuscript writing

Corresponding author

Correspondence to John S.A. Chrisinger.

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Chrisinger, J.S., Wehrli, B., Dickson, B.C. et al. Epithelioid and spindle cell rhabdomyosarcoma with FUS-TFCP2 or EWSR1-TFCP2 fusion: report of two cases. Virchows Arch (2020). https://doi.org/10.1007/s00428-020-02870-0

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  • Rhabdomyosarcoma
  • Epithelioid and spindle cell rhabdomyosarcoma
  • TFCP2
  • Bone