Abstract
Background: Giant cell tumor of tendon sheath (GCTTS) is a benign soft-tissue tumor that occurs predominantly in the fingers, with the capacity for local recurrence. The cytogenetic hallmark of GCTTS is the presence of 1p13 rearrangement. Several chromosomal segments have been recognized as translocation partners to 1p13. Herein, we describe a novel cytogenetic finding of GCTTS arising in the right thumb of a 71-year-old man. Case Report: Physical examination revealed a 4-cm, elastic hard, immobile, nontender mass. Magnetic resonance imaging demonstrated a nodular mass with reduced signal intensity on both T1- and T2-weighted images. Contrast-enhanced fat-suppressed T1-weighted images showed intense heterogeneous enhancement of the mass. After a needle biopsy, complete excision was performed. Histologically, the tumor was composed of mononuclear cells admixed with multinucleated osteoclast-like giant cells, hemosiderin-laden macrophages, foamy cells, and inflammatory cells. Cytogenetic analysis revealed a reciprocal t(1;1)(p13;p34) translocation as the sole structural aberration. Conclusion: To the best of our knowledge, this is the first report of this tumor with t(1;1)(p13;p34).
Giant cell tumor of tendon sheath (GCTTS), also known as localized-type tenosynovial giant cell tumor (TSGCT), usually presents as a slow-growing, painless mass in the fingers. It has a peak incidence in the third to fifth decades of life, with a slight female predominance. Magnetic resonance imaging (MRI) typically demonstrates a well-defined mass with low to intermediate signal intensity on all pulse sequences. Intense enhancement following gadolinium administration is seen in the vast majority of cases. Simple excision is the treatment of choice. The local recurrence rate is 4 to 30% (1) and is usually controlled by surgical re-excision.
Cytogenetic and molecular cytogenetic studies have demonstrated that the short arm of chromosome 1, in particular 1p13, is frequently involved in TSGCTs including GCTTS (2-17). Several chromosomal segments have been recognized as translocation partners to 1p13, and the most preferred rearrangement is t(1;2)(p13;q37) resulting in a collagen type VI alpha 3 (COL6A3)-colony stimulating factor 1 (CSF1) fusion gene (18,19). Several novel fusion genes involving CSF1 have recently been identified (20). It is not clear whether different fusion partners are associated with distinct biological behavior of GCTTS. In this article, we present the first case of GCTTS with a t(1;1)(p13;p34) translocation.
Case Report
A 71-year-old man presented with a 5-year history of a slowly growing, painless mass in the right thumb. Physical examination revealed a 4-cm, elastic hard, immobile, nontender mass. Neurologic and vascular examinations were unremarkable. Laboratory values were within the normal ranges. Plain radiograph showed a soft-tissue mass without calcification or pressure osseous erosion. MRI revealed a nodular mass. The mass exhibited low to intermediate signal intensity on T1-weighted images (Figure 1A) and heterogeneous low and high signal intensity on T2-weighted images (Figure 1B). Contrast-enhanced fat-suppressed T1-weighted images demonstrated intense heterogeneous enhancement of the mass (Figure 1C).
The patient underwent a needle biopsy and the pathological diagnosis was GCTTS. Complete excision was performed under general anesthesia with tourniquet control. Histologically, the tumor was composed of mononuclear cells admixed with multinucleated osteoclast-like giant cells, hemosiderin-laden macrophages, foamy histiocytes, and inflammatory cells (Figure 2). Atypical mitoses and nuclear atypia were not present. These findings were consistent with a diagnosis of GCTTS. There was no clinical evidence of recurrence during a follow-up period of 10 months.
Magnetic resonance images of giant cell tumor of tendon sheath involving the right thumb. The mass had low to intermediate signal intensity on T1-weighted image (A) and heterogeneous low and high signal intensity on T2-weighted image (B). Contrast-enhanced fat-suppressed T1-weighted image (C) revealed intense heterogeneous enhancement throughout the mass.
Histological finding of giant cell tumor of tendon sheath. The tumor consisted of mononuclear cells admixed with multinucleated osteoclast-like giant cells and hemosiderin-laden macrophages (original magnification ×100).
Cytogenetic analysis of short-term cultured cells from GCTTS revealed a t(1;1) translocation as the sole structural aberration in nine metaphase cells (Figure 3). The karyotype was as follows: 46,XY,t(1;1)(p13;p34)[3]/45,idem,-Y[6]47, XY,+7[1]/46,XY[10].
A representative GTG-banded karyotype of giant cell tumor of tendon sheath displaying a t(1;1)(p13;p34) translocation. Arrows indicate the structural chromosomal aberration.
Discussion
GCTTS is characterized by a recurrent chromosomal translocation involving 1p11-13, with 2q35-37 being the most common translocation partner (21). West et al. indicated that CSF1 is the gene at the chromosome 1p13 breakpoint (18). The t(1;2) translocation fuses CSF1 to COL6A3 (2q37). More recently, other fusion partners of CSF1, such as S100 calcium binding protein A10 (S100A10), vascular cell adhesion molecule 1 (VCAM1), fibronectin 1 (FN1), and cadherin 1 (CDH1), have been detected (16, 20). Notably, these CSF1 fusion transcripts result in the deletion of CSF1 exon 9, which is an important negative regulator of CSF1 expression. Furthermore, a very recent study confirmed that CSF1 alterations result in the loss of the 3’ untranslated region sequences involved in post-transcriptional regulation (22).
In the current case, we identified a novel t(1;1)(p13;p34) translocation as the sole structural abnormality. This chromosomal translocation has not been reported in any other neoplasm thus far, and appears to be characteristic for GCTTS. Several interesting genes have been mapped to chromosome band 1p34, including thyroid hormone receptor associated protein 3 (THRAP3), MYST/ESA1-associated factor 6 (MEAF6), and splicing factor proline and glutamine rich (SFPQ). THRAP3 encodes a 150-kDa subunit of the THRAP complex and may function as a transcriptional coactivator (23). Intriguingly, a ubiquitin specific peptidase 6 (USP6)–THRAP3 fusion has been described in primary aneurysmal bone cyst (ABC) (24). Histologically, ABC shows the occasional presence of multinucleated osteoclast-like giant cells similarly to GCTTS. MEAF6 is ubiquitously expressed and encodes a nuclear protein involved in transcriptional activation. The encoded protein may form a component of several different histone acetyltransferase complexes. Previous molecular studies have identified a MEAF6–PHD finger protein 1 (PHF1) fusion in ossifying fibromyxoid tumor (25) and endometrial stromal sarcoma (26). SFPQ is a protein coding gene and acts as a transcriptional regulator. Rao et al. reported that SFPQ is a very common fusion partner in transcription factor binding to IGHM enhancer 3 (TFE3) rearrangement-associated tumors including perivascular epithelioid cell tumor and melanotic Xp11 translocation renal cell carcinoma (27).
Tsuda et al. recently identified the presence of Cbl proto-oncogene (CBL) mutations in 35% of the TSGCT cases examined (20). CBL encodes a RING finger E3 ubiquitin ligase and negativelyand negatively regulates signal transduction of tyrosine kinase and negatively regulates signal transduction of tyrosine kinaseregulates signal transduction of tyrosine kinase. This gene has been found to be mutated in a variety of myeloid neoplasms (28). In the context of TSGCT, CBL mutations have been associated with increased Janus kinase 2 (JAK2) expression and shorter local failure-free survival (20). JAK2 inhibitors currently have therapeutic applications for the treatment of myelofibrosis (29) or rheumatoid arthritis (30). These findings underline the molecular heterogeneity of TSGCT and may contribute to the development of new targeted therapies in CBL-mutated cases.
In summary, we have described the first case of GCTTS with a novel t(1;1)(p13;p34) translocation. Further studies are required to elucidate the significance of this chromosomal translocation in the tumorigenesis of GCTTS.
Acknowledgements
This study was supported in part by the Ogata Foundation.
Footnotes
Authors' Contributions
Shizuhide Nakayama researched the literature and drafted the article. Jun Nishio performed the operation, supervised the research, and assisted with writing of the article. Kimihiko Nakatani provided direct patient care. Kazuki Nabeshima performed the histological examination. Takuaki Yamamoto reviewed the article. All Authors read and approved the final article.
Conflicts of Interest
The Authors declare no conflicts of interest associated with this article.
- Received June 5, 2020.
- Revision received July 3, 2020.
- Accepted July 6, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
