High-grade endometrial stromal sarcoma likely encompasses underrecognized tumors harboring genetic abnormalities besides YWHAE–NUTM2 fusion. Triggered by three initial endometrial stromal sarcomas with ZC3H7B–BCOR fusion characterized by high-grade morphology and aggressive clinical behavior, we herein investigate the clinicopathologic features of this genetic subset by expanding the analysis to 17 such tumors. All of them occurred in adult women with a median age of 54 (range, 28–71) years. They were predominantly based in the endomyometrium and demonstrated tongue-like and/or pushing myometrial invasion. Most were uniformly cellular and displayed haphazard fascicles of spindle cells with mild to moderate nuclear atypia. Myxoid matrix was seen in 14 of 17 (82%) tumors, and collagen plaques were seen in 8 (47%). The mitotic index was ≥10 mitotic figures/10 high-power fields (HPFs) in 14 of 17 (82%) tumors with a median of 14.5 mitotic figures/10 HPFs. No foci of conventional or variant low-grade endometrial stromal sarcoma were seen. All tumors expressed CD10 with only limited or absent desmin, SMA and/or h-caldesmon staining. ER and PR expression in >5% of cells was seen in 4 of 12 (33%) tumors. Diffuse cyclin D1 and BCOR immunoreactivity was present in 7 of 8 (88%) and 7 of 14 (50%) tumors, respectively. Fluorescence in situ hybridization or targeted RNA sequencing confirmed ZC3H7B–BCOR fusion in all tumors, including four and two previously diagnosed as myxoid leiomyosarcoma and undifferentiated uterine sarcoma, respectively. Limited clinical data suggest that patients present at higher stage and have worse prognosis compared with published outcomes in low-grade endometrial stromal sarcoma. Tumors with ZC3H7B–BCOR fusion constitute a distinct group of endometrial stromal sarcomas with high-grade morphology that should be distinguished from other uterine mesenchymal neoplasms that may demonstrate myxoid morphology.

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  1. 1.

    , , et alMesenchymal tumors. In: , , , eds. WHO Classification of Tumours of Female Reproductive Organs 4th edn. International Agency for Research on Cancer: Lyon, France, 2014, pp 135–147.

  2. 2.

    , , et al. 14-3-3 Fusion oncogenes in high-grade endometrial stromal sarcoma. Proc Natl Acad Sci USA 2012;109:929–934.

  3. 3.

    , . Endometrial stromal tumors: the new WHO classification. Adv Anat Pathol 2014;21:383–393.

  4. 4.

    , , et al. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: a histologically high-grade and clinically aggressive tumor. Am J Surg Pathol 2012;36:641–653.

  5. 5.

    , , et al. YWHAE rearrangement identified by FISH and RT-PCR in endometrial stromal sarcomas: genetic and pathological correlations. Mod Pathol 2013;26:1390–1400.

  6. 6.

    , , et al. YWHAE rearrangement in a purely conventional low-grade endometrial stromal sarcoma that transformed over time to high-grade sarcoma: importance of molecular testing. Int J Gynecol Pathol (in press); e-pub ahead of print.

  7. 7.

    , , et al. High-grade endometrial stromal sarcomas: a clinicopathologic study of a group of tumors with heterogenous morphologic and genetic features. Am J Surg Pathol 2014;38:1161–1172.

  8. 8.

    , , et al. Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement. Am J Surg Pathol 2012;36:1562–1570.

  9. 9.

    , , et al. BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol 2017;30:1251–1261.

  10. 10.

    , , et al. Aggressive behavior and poor prognosis of endometrial stromal sarcomas with YWHAE-FAM22 rearrangement indicate the clinical importance to recognize this subset. Int J Gynecol Pathol 2014;24:1616–1622.

  11. 11.

    , , et al. A prognosis based classification of undifferentiated uterine sarcomas: identification of mitotic index, hormone receptors and YWHAE-FAM22 translocation status as predictors of survival. Int J Cancer 2015;136:1608–1618.

  12. 12.

    , , et al. Novel high-grade endometrial stromal sarcoma: a morphologic mimicker of myxoid leiomyosarcoma. Am J Surg Pathol 2017;41:12–24.

  13. 13.

    , , et al. Novel ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions in ossifying fibromyxoid tumors-molecular characterization shows genetic overlap with endometrial stromal sarcoma. Genes Chromosomes Cancer 2014;53:183–193.

  14. 14.

    , , et al. Fusion of the ZC3H7B and BCOR genes in endometrial stromal sarcomas carrying an X;22-translocation. Genes Chromosomes Cancer 2013;52:610–618.

  15. 15.

    , , et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn 2015;17:251–264.

  16. 16.

    , , et al. Recurrent BCOR internal tandem duplication and YWHAE-NUTM2B fusions in soft tissue undifferentiated round cell sarcoma of infancy: overlapping genetic features with clear cell sarcoma of kidney. Am J Surg Pathol 2016;40:1009–1020.

  17. 17.

    , , et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med 2014;20:1479–1484.

  18. 18.

    , . Recent developments in uterine mesenchymal neoplasms. Histopathology 2013;62:124–137.

  19. 19.

    , , et al. Myxoid smooth muscle tumors of the uterus: clinicopathologic study of 40 cases. Mod Pathol 2016;29:285A.

  20. 20.

    , , et al. Myxoid leiomyosarcoma of the uterus: a clinicopathologic analysis of 30 cases and review of the literature with reappraisal of its distinction from other uterine myxoid mesenchymal neoplasms. Am J Surg Pathol 2016;40:285–301.

  21. 21.

    , , . Myxoid leiomyosarcoma of the uterus. A report of six cases. Am J Surg Pathol 1982;6:589–598.

  22. 22.

    , , et al. The management of patients with uterine sarcoma: a debated clinical challenge. Crit Rev Oncol Hematol 2008;65:129–142.

  23. 23.

    , , et al. Endometrial stromal sarcomas and related high-grade sarcomas: immunohistochemical and molecular genetic study of 31 cases. Am J Surg Pathol 2008;32:1228–1238.

  24. 24.

    , , et al. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci USA 2001;98:6348–6353.

  25. 25.

    , . Uterine adenosarcoma. Arch Pathol Lab Med 2016;140:286–290.

  26. 26.

    , , et al. Uterine adenosarcomas are mesenchymal neoplasms. J Pathol 2016;238:381–388.

  27. 27.

    , , et al. Inflammatory myofibroblastic tumor of the uterus: clinical and pathologic review of 10 cases including a subset with aggressive clinical course. Am J Surg Pathol 2015;39:157–168.

  28. 28.

    , , et al. ALK-1 protein expression and ALK gene rearrangements aid in the diagnosis of inflammatory myofibroblastic tumors of the female genital tract. Arch Pathol Lab Med 2012;136:623–626.

  29. 29.

    , , et al. Inflammatory myofibroblastic tumor of the uterus: a clinicopathological, immunohistochemical, and molecular analysis of 13 cases highlighting their broad morphologic spectrum. Mod Pathol 2017;30:1489–1503.

  30. 30.

    , , et al. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev 2000;14:1810–1823.

  31. 31.

    , , et al. BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat Cell Biol 2009;11:1002–1009.

  32. 32.

    , , et al. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet 2004;36:411–416.

  33. 33.

    , , et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood 2011;118:6153–6163.

  34. 34.

    , , et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015;125:1367–1376.

  35. 35.

    , , et al. BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders. Blood 2013;122:3169–3177.

  36. 36.

    , , et al. Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type. Genes Chromosomes Cancer 2016;55:460–471.

  37. 37.

    , , et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 2012;481:329–334.

  38. 38.

    , , et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 2012;488:106–110.

  39. 39.

    , , et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 2016;164:1060–1072.

  40. 40.

    , , et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 2014;4:216–231.

  41. 41.

    , , et al. Whole transcriptome sequencing identifies BCOR internal tandem duplication as a common feature of clear cell sarcoma of the kidney. Oncotarget 2015;6:40934–40939.

  42. 42.

    , , . BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney. Genes Chromosomes Cancer 2016;55:120–123.

  43. 43.

    , , et al. Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 2015;47:861–863.

  44. 44.

    , , et al. Primary renal sarcomas with BCOR-CCNB3 gene fusion: a report of 2 cases showing histologic overlap with clear cell sarcoma of kidney, suggesting further link between BCOR-related sarcomas of the kidney and soft tissues. Am J Surg Pathol 2017;41:1702–1712.

  45. 45.

    , , et al. Novel BCOR-MAML3 and ZC3H7B-BCOR gene fusions in undifferentiated small blue round cell sarcomas. Am J Surg Pathol 2016;40:433–442.

  46. 46.

    , , et al. BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children. Mod Pathol 2015;28:575–586.

  47. 47.

    , , et al. BCOR-CCNB3-positive soft tissue sarcoma with round-cell and spindle-cell histology: a series of four cases highlighting the pitfall of mimicking poorly differentiated synovial sarcoma. Histopathol 2016;69:792–801.

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  1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Natasha Lewis
    • , Robert A Soslow
    • , Deborah F Delair
    • , Kay J Park
    • , Rajmohan Murali
    • , Travis J Hollmann
    • , Javier A Arias-Stella III
    • , Meera Hameed
    • , Ryma Benayed
    • , Marc Ladanyi
    • , Denise Frosina
    • , Achim A Jungbluth
    • , Cristina R Antonescu
    •  & Sarah Chiang
  2. Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    • Ben Davidson
  3. Faculty of Medicine, University of Oslo, Oslo, Norway

    • Ben Davidson
  4. Section for Cancer Cytogenetics, Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    • Francesca Micci
    •  & Ioannis Panagopoulos
  5. Department of Pathology, Vancouver General Hospital, Vancouver, BC, Canada

    • Lien N Hoang
  6. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    • Esther Oliva
    •  & Robert H Young
  7. Department of Pathology, Harvard Medical School, Boston, MA, USA

    • Esther Oliva
    •  & Robert H Young
  8. Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Martee L Hensley
  9. Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Mario M Leitao Jr


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The authors declare no conflict of interest.

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Correspondence to Sarah Chiang.

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