Giant Cell Tumors With HMGA2::NCOR2 Fusion

Abstract

Giant cell tumors (GCTs) with high mobility group AT-Hook 2 (HMGA2)::nuclear receptor corepressor 2 (NCOR2) fusion are rare mesenchymal tumors of controversial nosology, which have been anecdotally reported to respond to CSFR1 inhibitors. Here, we performed a comprehensive study of 6 GCTs with HMGA2::NCOR2 fusion and explored their relationship with other giant cell-rich neoplasms. Tumors occurred in 4 females and 2 males ranging in age from 17 to 32 years old (median 24). Three lesions originated in subcutaneous soft tissue and 3 in bone. Tumor size ranged from 20 to 33 mm (median 27 mm). The lesions had a nodular/multinodular architecture and were composed of sheets of mononuclear "histiocytoid" cells with uniform nuclei intermingled with multinucleated giant cells. Mitotic activity was low and nuclear atypia and metaplastic bone were absent. Variable findings included necrosis, cystic degeneration, lymphocytic infiltrate (sometimes forming nodules), and xanthogranulomatous inflammation. On immunohistochemistry, all cases focally expressed pan-keratin and were negative with SATB2 and H3.3G34W. Whole RNAsequencing was performed in all cases of GCT with HMGA2:: NCOR2 fusion and a subset of giant cell-rich tumors (tenosynovial-GCT, n = 19 and "wild-type" GCT of soft tissue, n = 9). Hierarchical clustering of RNA-sequencing data showed that GCT with HMGA2::NCOR2 fusion formed a single cluster, independent of the other 2 entities. Methylome profiling showed similar results, but the distinction from "wild-type" GCT of soft tissue was less flagrant. Gene expression analysis showed similar levels of expression of the CSF1/CSFR1 axis between GCT with HMGA2::NCOR2 fusion and tenosynovial-GCT, supporting their potential sensitivity to CSFR1 inhibitors. Clinical follow-up was available for 5 patients (range: 10 to 64 mo; median 32 mo). Three patients (60%) experienced local recurrences, whereas none had distant metastases or died of disease. Overall, our study confirms and expands previous knowledge on GCT with HMGA2::NCOR2 fusion and supports its inclusion as an independent entity.

Keratin‐positive giant cell‐rich tumors of soft tissue with HMGA2::NCOR2 fusions

“…The mononuclear population of a single case (Case 7) showed cytologic atypia (D, 210Â, H&E).All seven cases had an HMGA2::NCOR2 fusion involving the 3 0end of HMGA2 (NM_003483.4) exon three and the 5 0 -end of NCOR2 exon 16 (NM_006312.5) (Figure4).4 | DISCUSSIONHerein, we describe seven additional cases of keratin-positive giant cell-rich tumors of soft tissue with HMGA2::NCOR2 fusions. In keeping with previous reports,[8][9][10][11] KPGCT-ST presented as a nodule or mass arising in the superficial soft tissue with a predilection for the extremities. It showed a distinct predilection for women and a younger age demographic (median age 23 years) compared to conventional GCT-ST.…”

“…Although cases in our series shared some histopathologic features with GCT-ST (both are multinodular proliferations of mononuclear cells with admixed osteoclast-like giant cells), KPGCT-ST uniformly lack metaplastic bone, have the propensity to harbor a lymphoid cuff, and show keratin expression. All of these features support prior hypotheses[9][10][11] that KPGCT-ST represents a distinct subtype of giant cell-rich tumors.…”

“…8 Another paper reported local recurrence in three of six patients at 8, 7, and 3 months, respectively. 11 In the present study, no patients experienced recurrence or metastasis, although our follow-up is limited. A single case in our cohort showed cells that exhibited moderate cytologic atypia; necrosis was also present in this case.…”

“…A table summarizing the clinicopathologic features of all previously reported cases of giant cell-rich tumors with HMGA2::NCOR2 fusions can be found in a recent paper. 11 The Since few cases of fusion-confirmed KPGCT-ST have been reported, its exact clinical behavior has yet to be fully elucidated. One reported case developed local recurrence at 101 months.…”

“…7 A giant cell-rich mesenchymal neoplasm with features reminiscent of GCT-ST but with a distinct female predominance, keratin expression, and harboring HMGA2:: NCOR2 fusions was recently reported, 8 and multiple additional cases series soon followed. [9][10][11] Fewer than 30 cases of these keratinpositive giant cell-rich tumor of soft tissue (KPGCT-ST) have been thus far reported in the English literature [8][9][10][11][12] ; herein we report a series of seven additional cases.…”