Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Xanthogranulomatous epithelial tumors and keratin-positive giant cell-rich soft tissue tumors: two aspects of a single entity with frequent HMGA2-NCOR2 fusions


Xanthogranulomatous epithelial tumor (XGET) and keratin-positive giant cell-rich soft tissue tumor with HMGA2-NCOR2 fusion (KPGCT) are two recently described neoplasms with both distinct and overlapping clinical and histopathologic features. We hypothesized that XGET and KPGCT may be related and represent a histologic spectrum of a single entity. To test this, we sought to characterize the clinical, radiographic, immunohistochemical, ultrastructural and molecular features of additional tumors with features of XGET and/or KPGCT, which we refer to descriptively as keratin-positive xanthogranulomatous/giant cell-rich tumors (KPXG/GCT). The archives were searched for potential cases of KPXG/GCT. Clinical and imaging features were noted. Slides were assessed for histologic and immunohistochemical findings. Ultrastructural and next generation RNA sequencing-based analysis were also performed. Nine cases were identified arising in seven women and two men [median age of 33 years (range: 12–87)]. Median tumor size was 4 cm (range: 2.4–14.0 cm) and tumors presented in the thigh (2), buttock (1), forearm (2), groin (1), cranial fossa (1), ilium (1), and tibia (1). Morphologically, tumors were most frequently characterized by a fibrous capsule, with associated lymphoid reaction, enclosing a polymorphous proliferation of histiocytes, giant cells (Touton and osteoclast-types), mixed inflammatory infiltrate, hemorrhage and hemosiderin deposition, which imparted a variably xanthogranulomatous to giant cell tumor-like appearance. One case clearly showed mononuclear cells with eosinophilic cytoplasm characteristic of XGET. All cases expressed keratin and 7 of 9 were found to harbor HMGA2-NCOR2 fusions including cases with xanthogranulomatous appearance. One patient developed local recurrence and multifocal pulmonary lesions, which were radiographically suspicious for metastases. Shared clinical, histologic and immunohistochemical features, and the shared presence of HMGA2-NCOR2 fusions supports interpretation of KPXG/GCT as a single entity which includes XGET and KPGCT. Given limited clinical follow-up to date and rare cases with apparently aggressive findings, we provisionally regard these tumors as having uncertain biologic potential.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Gross and imaging features of soft tissue tumors.
Fig. 2: Imaging features of bone tumors.
Fig. 3: Spectrum of histomorphology.
Fig. 4: Additional histologic features.
Fig. 5: Case 1 with typical histologic features of xanthogranulomatous epithelial tumor.
Fig. 6: Histologic and immunohistochemical features of tumors without identified fusion.
Fig. 7: Immunohistochemical features.
Fig. 8: Ultrastructural features.

Data availability

Available upon request.


  1. Fritchie, K. J., Torres-Mora, J., Inwards, C., Thway, K., Vaiyapuri, S., Jackson, R. et al. Xanthogranulomatous epithelial tumor: report of 6 cases of a novel, potentially deceptive lesion with a predilection for young women. Mod Pathol 33, 1889-1895 (2020).

  2. Agaimy, A., Michal, M., Stoehr, R., Ferrazzi, F., Fabian, P., Michal, M. et al. Recurrent novel HMGA2-NCOR2 fusions characterize a subset of keratin-positive giant cell-rich soft tissue tumors. Mod Pathol 34, 1507-1520 (2021).

  3. Dickson, B. C. & Swanson, D. Targeted RNA sequencing: A routine ancillary technique in the diagnosis of bone and soft tissue neoplasms. Genes Chromosomes Cancer 58, 75-87 (2019).

  4. Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G. et al. Integrative genomics viewer. Nat Biotechnol 29, 24-26 (2011).

  5. Thorvaldsdóttir, H., Robinson, J. T. & Mesirov, J. P. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14, 178-192 (2013).

  6. Robinson, J. T., Thorvaldsdóttir, H., Wenger, A. M., Zehir, A. & Mesirov, J. P. Variant Review with the Integrative Genomics Viewer. Cancer Res 77, e31-e34 (2017).

  7. Treffel, M., Lardenois, E., Larousserie, F., Karanian, M., Gomez-Brouchet, A., Bouvier, C. et al. Denosumab-treated Giant Cell Tumors of Bone: A Clinicopathologic Analysis of 35 Cases From the French Group of Bone Pathology. Am J Surg Pathol 44, 1-10 (2020).

  8. Wojcik, J., Rosenberg, A. E., Bredella, M. A., Choy, E., Hornicek, F. J., Nielsen, G. P. et al. Denosumab-treated Giant Cell Tumor of Bone Exhibits Morphologic Overlap With Malignant Giant Cell Tumor of Bone. Am J Surg Pathol 40, 72-80 (2016).

  9. Oliveira, A. M., Dei Tos, A. P., Fletcher, C. D. & Nascimento, A. G. Primary giant cell tumor of soft tissues: a study of 22 cases. Am J Surg Pathol 24, 248-256 (2000).

  10. Ho, J., Peters, T., Dickson, B. C., Swanson, D., Fernandez, A., Frova-Seguin, A. et al. Detection of CSF1 rearrangements deleting the 3’ UTR in tenosynovial giant cell tumors. Genes Chromosomes Cancer 59, 96-105 (2020).

  11. West, R. B., Rubin, B. P., Miller, M. A., Subramanian, S., Kaygusuz, G., Montgomery, K. et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A 103, 690-695 (2006).

  12. Mehine, M., Kaasinen, E., Mäkinen, N., Katainen, R., Kämpjärvi, K., Pitkänen, E. et al. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med 369, 43-53 (2013).

  13. Quade, B. J., Weremowicz, S., Neskey, D. M., Vanni, R., Ladd, C., Dal Cin, P. et al. Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. Cancer Res 63, 1351-1358 (2003).

  14. Tallini, G., Vanni, R., Manfioletti, G., Kazmierczak, B., Faa, G., Pauwels, P. et al. HMGI-C and HMGI(Y) immunoreactivity correlates with cytogenetic abnormalities in lipomas, pulmonary chondroid hamartomas, endometrial polyps, and uterine leiomyomas and is compatible with rearrangement of the HMGI-C and HMGI(Y) genes. Lab Invest 80, 359-369 (2000).

  15. Rabban, J. T., Dal Cin, P. & Oliva, E. HMGA2 rearrangement in a case of vulvar aggressive angiomyxoma. Int J Gynecol Pathol 25, 403-407 (2006).

  16. Rawlinson, N. J., West, W. W., Nelson, M. & Bridge, J. A. Aggressive angiomyxoma with t(12;21) and HMGA2 rearrangement: report of a case and review of the literature. Cancer Genet Cytogenet 181, 119-124 (2008).

  17. Bartuma, H., Hallor, K. H., Panagopoulos, I., Collin, A., Rydholm, A., Gustafson, P. et al. Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype. Genes Chromosomes Cancer 46, 594-606 (2007).

  18. Panagopoulos, I., Gorunova, L., Bjerkehagen, B., Lobmaier, I. & Heim, S. The recurrent chromosomal translocation t(12;18)(q14~15;q12~21) causes the fusion gene HMGA2-SETBP1 and HMGA2 expression in lipoma and osteochondrolipoma. Int J Oncol 47, 884-890 (2015).

  19. Panagopoulos, I., Gorunova, L., Agostini, A., Lobmaier, I., Bjerkehagen, B. & Heim, S. Fusion of the HMGA2 and C9orf92 genes in myolipoma with t(9;12)(p22;q14). Diagn Pathol 11, 22 (2016).

  20. Dahlén, A., Mertens, F., Rydholm, A., Brosjö, O., Wejde, J., Mandahl, N. et al. Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Mod Pathol 16, 1132-1140 (2003).

  21. Geurts, J. M., Schoenmakers, E. F., Röijer, E., Aström, A. K., Stenman, G. & van de Ven, W. J. Identification of NFIB as recurrent translocation partner gene of HMGIC in pleomorphic adenomas. Oncogene 16, 865-872 (1998).

  22. Panagopoulos, I., Gorunova, L., Andersen, H. K., Pedersen, T. D., Lømo, J., Lund-Iversen, M. et al. Genetic Characterization of Myoid Hamartoma of the Breast. Cancer Genomics Proteomics 16, 563-568 (2019).

  23. Medeiros, F., Araujo, A. R., Erickson-Johnson, M. R., Kashyap, P. C., Dal Cin, P., Nucci, M. et al. HMGA1 and HMGA2 rearrangements in mass-forming endometriosis. Genes Chromosomes Cancer 49, 630-634 (2010).

  24. Medeiros, F., Wang, X., Araujo, A. R., Erickson-Johnson, M. R., Lima, J. F., Meuter, A. et al. HMGA gene rearrangement is a recurrent somatic alteration in polypoid endometriosis. Hum Pathol 43, 1243-1248 (2012).

  25. Muir, L. D., 2nd, Woelfle, J. D., Schowinsky, J. & Wilky, B. A. High grade sarcoma presenting as multifocal recurrent seromas after inguinal hernia repair: A case report. Rare Tumors 12, 2036361320975746 (2020).

  26. Liu, J., Mao, R., Lao, I. W., Yu, L., Bai, Q., Zhou, X. et al. GLI1-altered mesenchymal tumor: a clinicopathological and molecular analysis of ten additional cases of an emerging entity. Virchows Arch (2021).

  27. Panagopoulos, I., Andersen, K., Gorunova, L., Lund-Iversen, M., Lobmaier, I. & Heim, S. Recurrent Fusion of the Genes for High-mobility Group AT-hook 2 (HMGA2) and Nuclear Receptor Co-repressor 2 (NCOR2) in Osteoclastic Giant Cell-rich Tumors of Bone. Cancer Genomics Proteomics 19, 163-177 (2022).

  28. Brahmi, M., Alberti, L., Tirode, F., Karanian, M., Eberst, L., Pissaloux, D. et al. Complete response to CSF1R inhibitor in a translocation variant of teno-synovial giant cell tumor without genomic alteration of the CSF1 gene. Ann Oncol 29, 1488-1489 (2018).

  29. Cupp, J. S., Miller, M. A., Montgomery, K. D., Nielsen, T. O., O’Connell, J. X., Huntsman, D. et al. Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol 31, 970-976 (2007).

  30. Martinez, A. P., Fritchie, K. J., Weiss, S. W., Agaimy, A., Haller, F., Huang, H. Y. et al. Histiocyte-rich rhabdomyoblastic tumor: rhabdomyosarcoma, rhabdomyoma, or rhabdomyoblastic tumor of uncertain malignant potential? A histologically distinctive rhabdomyoblastic tumor in search of a place in the classification of skeletal muscle neoplasms. Mod Pathol 32, 446-457 (2019).

  31. Michal, M., Rubin, B. P., Kazakov, D. V., Michalová, K., Šteiner, P., Grossmann, P. et al. Inflammatory leiomyosarcoma shows frequent co-expression of smooth and skeletal muscle markers supporting a primitive myogenic phenotype: a report of 9 cases with a proposal for reclassification as low-grade inflammatory myogenic tumor. Virchows Arch 477, 219-230 (2020).

  32. Cloutier, J. M., Charville, G. W., Mertens, F., Sukov, W., Fritchie, K., Perry, K. D. et al. “Inflammatory Leiomyosarcoma” and “Histiocyte-rich Rhabdomyoblastic Tumor”: a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as “Inflammatory Rhabdomyoblastic Tumor”. Mod Pathol 34, 758-769 (2021).

  33. O’Connell, J. X., Wehrli, B. M., Nielsen, G. P. & Rosenberg, A. E. Giant cell tumors of soft tissue: a clinicopathologic study of 18 benign and malignant tumors. Am J Surg Pathol 24, 386-395 (2000).

  34. Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet 45, 1479-1482 (2013).

  35. Amary, F., Berisha, F., Ye, H., Gupta, M., Gutteridge, A., Baumhoer, D. et al. H3F3A (Histone 3.3) G34W Immunohistochemistry: A Reliable Marker Defining Benign and Malignant Giant Cell Tumor of Bone. Am J Surg Pathol 41, 1059-1068 (2017).

Download references


Washington University School of Medicine Department of Pathology and Immunology; Mount Sinai Hospital Department of Pathology and Laboratory Medicine.

Author information

Authors and Affiliations



C.A.D. and J.S.A.C.—project conception and design, data gathering, data analysis, paper drafting, paper review/revision; J.C.B.—data gathering, data analysis, paper drafting, paper review/revision; R.B.—data analysis, paper drafting, paper review/revision; B.C.D.—data gathering, paper review/revision; R.E.S.—data gathering, data analysis, paper drafting, paper review/revision; E.G.D.—data gathering, data analysis, paper drafting, paper review/revision.

Corresponding author

Correspondence to John S. A. Chrisinger.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Study was approved by the institutional review boards of both participating centers.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dehner, C.A., Baker, J.C., Bell, R. et al. Xanthogranulomatous epithelial tumors and keratin-positive giant cell-rich soft tissue tumors: two aspects of a single entity with frequent HMGA2-NCOR2 fusions. Mod Pathol (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links