What is new in epithelioid soft tissue tumors?

  • Abbas AgaimyEmail author
Review Article


Epithelioid cell features mimicking carcinomas characterize a variety of histogenetically, phenotypically, and molecularly distinct subsets of mesenchymal neoplasms. In a pathogenetic sense, epithelioid soft tissue tumors basically fall into three main genetic categories: (1) switch/sucrose non-fermenting (SWI/SNF) complex-deficient tumors (with epithelioid sarcoma as their prototype); (2) epithelioid neoplasms driven by specific rare gene fusions (such as sclerosing epithelioid fibrosarcoma with EWSR1 fusions and GLI1-related malignant epithelioid soft tissue neoplasms); and (3) a heterogeneous group encompassing epithelioid variants of diverse other entities. Notably, lesions in the first and third groups may display variable, occasionally prominent, rhabdoid cell morphology, thus further complicating their differential diagnosis. This review summarizes the main clinicopathological, phenotypic, and genotypic features of these diseases and discusses their pertinent differential diagnostic considerations.


Epithelioid sarcoma Rhabdoid SMARCB1 SWI/SNF complex Sclerosing epithelioid fibrosarcoma GLI1 amplification GLI1 translocation KMT2A-YAP1 fusions NUT malignancies 


Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.


  1. 1.
    Folpe AL (2014) Selected topics in the pathology of epithelioid soft tissue tumors. Mod Pathol 27(Suppl 1):S64–S79PubMedCrossRefGoogle Scholar
  2. 2.
    Agaimy A (2019) SWI/SNF complex-deficient soft tissue neoplasms: a pattern-based approach to diagnosis and differential diagnosis. Surg Pathol Clin 12:149–163PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Miettinen M, Fetsch JF (2000) Distribution of keratins in normal endothelial cells and a spectrum of vascular tumors: implications in tumor diagnosis. Hum Pathol 31:1062–1067PubMedCrossRefGoogle Scholar
  4. 4.
    Miettinen M, Wang Z, Sarlomo-Rikala M, Abdullaev Z, Pack SD, Fetsch JF (2013) ERG expression in epithelioid sarcoma: a diagnostic pitfall. Am J Surg Pathol 37:1580–1585PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Schaefer IM, Hornick JL (2018) Diagnostic immunohistochemistry for soft tissue and bone tumors: an update. Adv Anat Pathol 25:400–412PubMedPubMedCentralGoogle Scholar
  6. 6.
    Wang X, Haswell JR, Roberts CW (2014) Molecular pathways: SWI/SNF (BAF) complexes are frequently mutated in cancer--mechanisms and potential therapeutic insights. Clin Cancer Res 20:21–27PubMedCrossRefGoogle Scholar
  7. 7.
    Albanese P, Belin MF, Delattre O (2006) The tumour suppressor hSNF5/INI1 controls the differentiation potential of malignant rhabdoid cells. Eur J Cancer 42:2326–2334PubMedCrossRefGoogle Scholar
  8. 8.
    Judkins AR (2007) Immunohistochemistry of INI1 expression: a new tool for old challenges in CNS and soft tissue pathology. Adv Anat Pathol 14:335–339PubMedCrossRefGoogle Scholar
  9. 9.
    Wu Q, Lian JB, Stein JL, Stein GS, Nickerson JA, Imbalzano AN (2017) The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics. 9:919–931PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Enzinger FM (1970) Epitheloid sarcoma. A sarcoma simulating a granuloma or a carcinoma. Cancer 26:1029–1041PubMedCrossRefGoogle Scholar
  11. 11.
    Fisher C (2006) Epithelioid sarcoma of Enzinger. Adv Anat Pathol 13:114–121PubMedCrossRefGoogle Scholar
  12. 12.
    Guillou L, Wadden C, Coindre JM, Krausz T, Fletcher CD (1997) “Proximal-type” epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series. Am J Surg Pathol 21:130–146PubMedCrossRefGoogle Scholar
  13. 13.
    Kosemehmetoglu K, Kaygusuz G, Bahrami A, Raimondi SC, Kilicarslan K, Yildiz Y, Folpe AL (2011) Intra-articular epithelioid sarcoma showing mixed classic and proximal-type features: report of 2 cases, with immunohistochemical and molecular cytogenetic INI-1 study. Am J Surg Pathol 35:891–897PubMedCrossRefGoogle Scholar
  14. 14.
    Chbani L, Guillou L, Terrier P, Decouvelaere AV, Grégoire F, Terrier-Lacombe MJ, Ranchère D, Robin YM, Collin F, Fréneaux P, Coindre JM (2009) Epithelioid sarcoma: a clinicopathologic and immunohistochemical analysis of 106 cases from the French sarcoma group. Am J Clin Pathol 131:222–227PubMedCrossRefGoogle Scholar
  15. 15.
    Stockman DL, Hornick JL, Deavers MT, Lev DC, Lazar AJ, Wang WL (2014) ERG and FLI1 protein expression in epithelioid sarcoma. Mod Pathol 27:496–501PubMedCrossRefGoogle Scholar
  16. 16.
    Machado I, Mayordomo-Aranda E, Scotlandi K et al (2014) Immunoreactivity using anti-ERG monoclonal antibodies in sarcomas is influenced by clone selection. Pathol Res Pract 210:508–513PubMedCrossRefGoogle Scholar
  17. 17.
    Sullivan LM, Folpe AL, Pawel BR, Judkins AR, Biegel JA (2013) Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod Pathol 26:385–392PubMedCrossRefGoogle Scholar
  18. 18.
    Sápi Z, Papp G, Szendrői M, Pápai Z, Plótár V, Krausz T, Fletcher CD (2016) Epigenetic regulation of SMARCB1 By miR-206, -381 and -671-5p is evident in a variety of SMARCB1 immunonegative soft tissue sarcomas, while miR-765 appears specific for epithelioid sarcoma. A miRNA study of 223 soft tissue sarcomas. Genes Chromosom Cancer 55:786–802PubMedCrossRefGoogle Scholar
  19. 19.
    Hornick JL, Dal Cin P, Fletcher CD (2009) Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol 33:542–550PubMedCrossRefGoogle Scholar
  20. 20.
    Kohashi K, Yamamoto H, Yamada Y, Kinoshita I, Taguchi T, Iwamoto Y, Oda Y (2018) SWI/SNF chromatin-remodeling complex status in SMARCB1/INI1-preserved epithelioid sarcoma. Am J Surg Pathol 42:312–318PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Li L, Fan XS, Xia QY, Rao Q, Liu B, Yu B, Shi QL, Lu ZF, Zhou XJ (2014) Concurrent loss of INI1, PBRM1, and BRM expression in epithelioid sarcoma: implications for the cocontributions of multiple SWI/SNF complex members to pathogenesis. Hum Pathol 45:2247–2254PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Folpe AL, Schoolmeester JK, McCluggage WG, Sullivan LM, Castagna K, Ahrens WA, Oliva E, Biegel JA, Nielsen GP (2015) SMARCB1-Deficient vulvar neoplasms: a clinicopathologic, immunohistochemical, and molecular genetic study of 14 cases. Am J Surg Pathol 39:836–849PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Arnold MA, Arnold CA, Li G, Chae U, el-Etriby R, Lee CC, Tsokos M (2013) A unique pattern of INI1 immunohistochemistry distinguishes synovial sarcoma from its histologic mimics. Hum Pathol 44:881–887PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Parham DM, Weeks DA, Beckwith JB (1994) The clinicopathologic spectrum of putative extrarenal rhabdoid tumors. An analysis of 42 cases studied with immunohistochemistry or electron microscopy. Am J Surg Pathol 18:1010–1029PubMedCrossRefGoogle Scholar
  25. 25.
    Fanburg-Smith JC, Hengge M, Hengge UR, Smith JS Jr, Miettinen M (1998) Extrarenal rhabdoid tumors of soft tissue: a clinicopathologic and immunohistochemical study of 18 cases. Ann Diagn Pathol 2:351–362PubMedCrossRefGoogle Scholar
  26. 26.
    Hasselblatt M, Gesk S, Oyen F, Rossi S, Viscardi E, Giangaspero F, Giannini C, Judkins AR, Frühwald MC, Obser T, Schneppenheim R, Siebert R, Paulus W (2011) Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 35:933–935PubMedCrossRefGoogle Scholar
  27. 27.
    Witkowski L, Carrot-Zhang J, Albrecht S, Fahiminiya S, Hamel N, Tomiak E, Grynspan D, Saloustros E, Nadaf J, Rivera B, Gilpin C, Castellsagué E, Silva-Smith R, Plourde F, Wu M, Saskin A, Arseneault M, Karabakhtsian RG, Reilly EA, Ueland FR, Margiolaki A, Pavlakis K, Castellino SM, Lamovec J, Mackay HJ, Roth LM, Ulbright TM, Bender TA, Georgoulias V, Longy M, Berchuck A, Tischkowitz M, Nagel I, Siebert R, Stewart CJ, Arseneau J, McCluggage W, Clarke BA, Riazalhosseini Y, Hasselblatt M, Majewski J, Foulkes WD (2014) Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet 46:438–443PubMedCrossRefGoogle Scholar
  28. 28.
    Young RH, Oliva E, Scully RE (1994) Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am J Surg Pathol 18:1102–1116PubMedCrossRefGoogle Scholar
  29. 29.
    Agaimy A, Daum O, Märkl B, Lichtmannegger I, Michal M, Hartmann A (2016) SWI/SNF complex-deficient undifferentiated/rhabdoid carcinomas of the gastrointestinal tract: a series of 13 cases highlighting mutually exclusive loss of SMARCA4 and SMARCA2 and frequent co-inactivation of SMARCB1 and SMARCA2. Am J Surg Pathol 40:544–553PubMedCrossRefGoogle Scholar
  30. 30.
    Agaimy A, Cheng L, Egevad L, Feyerabend B, Hes O, Keck B, Pizzolitto S, Sioletic S, Wullich B, Hartmann A (2017) Rhabdoid and undifferentiated phenotype in renal cell carcinoma: analysis of 32 cases indicating a distinctive common pathway of dedifferentiation frequently associated with SWI/SNF complex deficiency. Am J Surg Pathol 41:253–262PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Agaimy A, Fuchs F, Moskalev EA, Sirbu H, Hartmann A, Haller F (2017) SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1neg/CK7pos/HepPar-1pos immunophenotype. Virchows Arch 471:599–609PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Le Loarer F, Watson S, Pierron G et al (2015) SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat Genet 47:1200–1205PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Yoshida A, Kobayashi E, Kubo T, Kodaira M, Motoi T, Motoi N, Yonemori K, Ohe Y, Watanabe SI, Kawai A, Kohno T, Kishimoto H, Ichikawa H, Hiraoka N (2017) Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Mod Pathol 30:797–809PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Schaefer IM, Agaimy A, Fletcher CD, Hornick JL (2017) Claudin-4 expression distinguishes SWI/SNF complex-deficient undifferentiated carcinomas from sarcomas. Mod Pathol 30:539–548PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Foulkes WD, Clarke BA, Hasselblatt M, Majewski J, Albrecht S, McCluggage WG (2014) No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J Pathol 233:209–214PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Carter JM, O'Hara C, Dundas G, Gilchrist D, Collins MS, Eaton K, Judkins AR, Biegel JA, Folpe AL (2012) Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with “neuroblastoma-like” schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol 36:154–160PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Schaefer IM, Dong F, Garcia EP, Fletcher CDM, Jo VY (2019) Recurrent SMARCB1 inactivation in epithelioid malignant peripheral nerve sheath tumors. Am J Surg Pathol 43:835–843PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Jo VY, Fletcher CDM (2017) SMARCB1/INI1 loss in epithelioid schwannoma: a clinicopathologic and immunohistochemical study of 65 cases. Am J Surg Pathol 41:1013–1022PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Hornick JL, Fletcher CD (2003) Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol 27:1183–1196PubMedCrossRefGoogle Scholar
  40. 40.
    Thway K, Bown N, Miah A, Turner R, Fisher C (2015) Rhabdoid variant of myoepithelial carcinoma, with EWSR1 rearrangement: expanding the spectrum of EWSR1-rearranged myoepithelial tumors. Head Neck Pathol 9:273–279PubMedCrossRefGoogle Scholar
  41. 41.
    Hollmann TJ, Hornick JL (2011) INI1-Deficient tumors: diagnostic features and molecular genetics. Am J Surg Pathol 35:e47–e63PubMedCrossRefGoogle Scholar
  42. 42.
    Huang SC, Zhang L, Sung YS, Chen CL, Kao YC, Agaram NP, Antonescu CR (2016) Secondary EWSR1 gene abnormalities in SMARCB1-deficient tumors with 22q11-12 regional deletions: potential pitfalls in interpreting EWSR1 FISH results. Genes Chromosom Cancer 55:767–776PubMedCrossRefGoogle Scholar
  43. 43.
    Meis-Kindblom JM, Kindblom LG, Enzinger FM (1995) Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma. Am J Surg Pathol 19:979–993PubMedCrossRefGoogle Scholar
  44. 44.
    Wojcik JB, Bellizzi AM, Dal Cin P, Bredella MA, Fletcher CD, Hornicek FJ, Deshpande V, Hornick JL, Nielsen GP (2014) Primary sclerosing epithelioid fibrosarcoma of bone: analysis of a series. Am J Surg Pathol 38:1538–1544PubMedCrossRefGoogle Scholar
  45. 45.
    Doyle LA, Möller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL (2011) MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 35:733–741PubMedCrossRefGoogle Scholar
  46. 46.
    Doyle LA, Wang WL, Dal Cin P, Lopez-Terrada D, Mertens F, Lazar AJ, Fletcher CD, Hornick JL (2012) MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement. Am J Surg Pathol 36:1444–1451PubMedCrossRefGoogle Scholar
  47. 47.
    Prieto-Granada C, Zhang L, Chen HW, Sung YS, Agaram NP, Jungbluth AA, Antonescu CR (2015) A genetic dichotomy between pure sclerosing epithelioid fibrosarcoma (SEF) and hybrid SEF/low-grade fibromyxoid sarcoma: a pathologic and molecular study of 18 cases. Genes Chromosom Cancer 54:28–38PubMedCrossRefGoogle Scholar
  48. 48.
    Yoshida A, Arai Y, Tanzawa Y, Wakai S, Hama N, Kawai A, Shibata T (2019 May 28) KMT2A (MLL) fusions in aggressive sarcomas in young adults. Histopathology. [Epub ahead of print]PubMedCrossRefGoogle Scholar
  49. 49.
    Wang XT, Xia QY, Zhou XJ, Rao Q (2017) Xp11 Translocation renal cell carcinoma and the mesenchymal counterparts: an evolving concept with novel insights on clinicopathologic features, prognosis, treatment, and classification. Crit Rev Oncog 22:481–497PubMedCrossRefGoogle Scholar
  50. 50.
    Thway K, Fisher C (2015) PEComa: morphology and genetics of a complex tumor family. Ann Diagn Pathol 19:359–368PubMedCrossRefGoogle Scholar
  51. 51.
    Mariño-Enríquez A, Wang WL, Roy A, Lopez-Terrada D, Lazar AJ, Fletcher CD, Coffin CM, Hornick JL (2011) Epithelioid inflammatory myofibroblastic sarcoma: an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol 35:135–144PubMedCrossRefGoogle Scholar
  52. 52.
    Lee JC, Li CF, Huang HY, Zhu MJ, Mariño-Enríquez A, Lee CT, Ou WB, Hornick JL, Fletcher JA (2017) ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. J Pathol 241:316–323PubMedCrossRefGoogle Scholar
  53. 53.
    Antonescu CR, Agaram NP, Sung YS, Zhang L, Swanson D, Dickson BC (2018) A distinct malignant epithelioid neoplasm with GLI1 gene rearrangements, frequent S100 protein expression, and metastatic potential: expanding the spectrum of pathologic entities with ACTB/MALAT1/PTCH1-GLI1 fusions. Am J Surg Pathol 42:553–560PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Agaram NP, Zhang L, Sung YS, Singer S, Stevens T, Prieto-Granada CN, Bishop JA, Wood BA, Swanson D, Dickson BC, Antonescu CR (2019) GLI1-Amplifications expand the spectrum of soft tissue neoplasms defined by GLI1 gene fusions. Mod Pathol 12Google Scholar
  55. 55.
    Dickson BC, Sung YS, Rosenblum MK, Reuter VE, Harb M, Wunder JS, Swanson D, Antonescu CR (2018) NUTM1 gene fusions characterize a subset of undifferentiated soft tissue and visceral tumors. Am J Surg Pathol 42:636–645PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Stevens TM, Morlote D, Xiu J, Swensen J, Brandwein-Weber M, Miettinen MM, Gatalica Z, Bridge JA (2019) NUTM1-Rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum. Mod Pathol 32:764–773PubMedCrossRefGoogle Scholar
  57. 57.
    Schaefer IM, Dal Cin P, Landry LM, Fletcher CDM, Hanna GJ, French CA (2018) CIC-NUTM1 fusion: a case which expands the spectrum of NUT-rearranged epithelioid malignancies. Genes Chromosom Cancer 57:446–451PubMedCrossRefGoogle Scholar
  58. 58.
    French CA (2018) NUT carcinoma: clinicopathologic features, pathogenesis, and treatment. Pathol Int 68:583–595PubMedCrossRefGoogle Scholar
  59. 59.
    Nascimento AF, Bertoni F, Fletcher CD (2007) Epithelioid variant of myxofibrosarcoma: expanding the clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases. Am J Surg Pathol 31:99–105PubMedCrossRefGoogle Scholar
  60. 60.
    Jo VY, Mariño-Enríquez A, Fletcher CD (2011) Epithelioid rhabdomyosarcoma: clinicopathologic analysis of 16 cases of a morphologically distinct variant of rhabdomyosarcoma. Am J Surg Pathol 35:1523–1530PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Miettinen M, Enzinger FM (1999) Epithelioid variant of pleomorphic liposarcoma: a study of 12 cases of a distinctive variant of high-grade liposarcoma. Mod Pathol 12:722–728PubMedPubMedCentralGoogle Scholar
  62. 62.
    Makise N, Yoshida A, Komiyama M, Nakatani F, Yonemori K, Kawai A, Fukayama M, Hiraoka N (2017) Dedifferentiated liposarcoma with epithelioid/epithelial features. Am J Surg Pathol 41:1523–1531PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Agaimy A, Michal M, Hadravsky L, Michal M (2018) Dedifferentiated liposarcoma composed predominantly of rhabdoid/epithelioid cells: a frequently misdiagnosed highly aggressive variant. Hum Pathol 77:20–27PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Agaimy A, Specht K, Stoehr R, Lorey T, Märkl B, Niedobitek G, Straub M, Hager T, Reis AC, Schilling B, Schneider-Stock R, Hartmann A, Mentzel T. Metastatic malignant melanoma with complete loss of differentiation markers (undifferentiated/dedifferentiated melanoma): analysis of 14 patients emphasizing phenotypic plasticity and the value of molecular testing as surrogate diagnostic marker. Am J Surg Pathol 2016;40:181-91.Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of PathologyFriedrich-Alexander-University Erlangen-Nürnberg, University HospitalErlangenGermany

Personalised recommendations