Recurrent novel HMGA2-NCOR2 fusions characterize a subset of keratin-positive giant cell-rich soft tissue tumors

Abstract

Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14–60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14–168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted.

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

“…tumors, exon 3 of HMGA2 fused in-frame to exon 20 of NCOR2(88). Thus, both studies, the present and that published by Agaimy and coworkers(88), showed HMGA2-NCOR2 fusion genes coding for similar chimeric proteins and that a group of giant cell-rich tumors of bone or soft tissue are characterized by the HMGA2-NCOR2 fusion gene.…”

“…While we were working on the present project, a publication appeared reporting the finding of an HMGA2-NCOR2 fusion gene in six giant cell-rich soft tissue tumors which expressed low-to high-molecular-weight keratins (the tumor cells stained positively with the immunohistochemical marker cytokeratin AE1/AE3, which is a mixture of two different clones of monoclonal antibodies to cytokeratin AE1 and AE3) (88). In four of the tumors, exon 3 of HMGA2 fused to exon 16 of NCOR2, i.e., the fusion transcript was identical to that found by us in case 1.…”

‘I Can’t Keep Up!’: an update on advances in soft tissue pathology occurring after the publication of the 2020 World Health Organization classification of soft tissue and bone tumours

“…Interestingly, however, other characteristic features of soft tissue giant cell tumours, such as a shell of bone and SATB2 expression, were lacking (Figure 7C–E). The natural history of HMGA2::NCOR2 soft tissue giant cell tumours appears to be similar to that of conventional tumours, with some risk of local recurrence, but not metastases 64 …”

“…The natural history of HMGA2:: NCOR2 soft tissue giant cell tumours appears to be similar to that of conventional tumours, with some risk of local recurrence, but not metastases. 64 A second novel subtype of giant cell-rich neoplasia was very recently reported by Fritchie et al, as 'xanthogranulomatous epithelial tumour'. 65 Although these unusual tumours share keratin expression with those reported by Agaimy et al, they differ from HMGA2::NCOR2 giant cell tumours in significant ways.…”

“…A very interesting recent study by Agaimy et al . identified a distinctive subset of soft tissue giant cell tumours characterised by the presence of keratin‐positive mononuclear cells and HMGA2 :: NCOR2 fusions 64 . These tumours occur in the subcutis, show a striking female predilection, and are morphologically quite similar to conventional soft tissue giant cell tumours, with a multinodular proliferation of bland, round to ovoid mononuclear cells, innumerable osteoclast‐like giant cells, and foci of haemorrhage.…”