Discussion:
XGET is an unusual soft tissue and bone neoplasm with controversial and nonspecific radiological and histopathological features. A comprehensive literature search was conducted to identify previously reported cases of XGET. A total of 8 cases were identified, in a wide range of ages and with slight female predominance. The most common sites of involvement were soft tissue of the extremities, followed by bone. Clinical presentation varied from painless mass to localized pain or swelling. The tumor was first described by Fritchie et al. in 2020 as an unusual mesenchymal neoplasm with indolent biological behavior.1 Six cases were identified arising in five females and one male with a median age of 21 years {range:16-62}. Four cases arose in soft tissue in the lower extremities and trunk. Two cases are presented in bone. In 2022, the seventh case was described by Dehner et al., a 37-year-old female who presented with a calf mass.2 In a recent case report published by Svantesson et al. in 2023, they described a new case in a 66-year-old female who presented with a mass in her left thigh4(Table 1 ).
The pathogenesis of XGET remains uncertain and few theories regarding the cellular origin have been proposed. In 2021, Agaimy et al. hypothesized that the presence of HMGA2-NCOR2 gene fusion is potentially specific to a rare low-grade entity known as “Keratin positive giant cell tumor of soft tissue (KPGCT)”. To test the hypothesis, the author analyzed 15 cases of giant cell rich tumor that arose in soft tissue. Only keratin-positive cases harbored the distinctive HMGA2-NCOR2 gene fusion. While keratin-negative giant cell tumors were negative for this gene fusion.3 Since then, Dehner et al. studied the morphological, immunohistochemical, and molecular similarities between XGET and KPGCT. Both tumors were believed to be morphological variants of a single entity. HMGA2-NCOR2 gene fusion was detected in both neoplasms. The shared clinical, molecular, and immunohistochemical features supported the author’s theory.2
Histological findings were consistent across all reported cases of XGET, revealing sheets of foamy histiocytes accompanied by osteoclast and Touton-type giant cells. Additionally, mononuclear cells with bright eosinophilic cytoplasm were observed. While necrosis was reported in one case, no marked nuclear atypia or atypical mitoses were detected.1,2,4
Immunohistochemistry studies were conducted in all cases, yielding similar results. Cells exhibited at least focal positivity for keratin, CK7, and some displayed positivity for high molecular weight keratin. Additional immunohistochemistry studies, such as BRAF V600E and Histone H3G34W, were performed in some cases, all yielding negative results. Interestingly, MDM2 nuclear positivity by immunohistochemistry was observed focally in the eighth case, but no MDM2 gene amplification was detected by FISH analysis.
Molecular studies were performed in four cases. Case 1 displayed a PLEKHM1 mutation, which correlated with the patient’s osteopetrosis diagnosis.1 In the seventh case, HMGA2-NCOR2 gene fusion was identified.2 However, no gene fusions were detected in the remaining cases.
Radiological imaging studies were available for six cases (Table 2). Among soft tissue cases, the majority exhibited subcutaneous solid heterogeneous masses (cases 1, 5, and 7)1,2 or well-defined soft tissue mass with a suspected focal invasion of cortical bone (case 8)4. In contrast, bone tumors demonstrated lytic lesions with sclerotic rims (Cases 3 and 6). No imaging studies were available for cases 2 and 4.1 No evidence of metastasis in the eight cases.1,2,4
To date, the management of XGET poses several challenges due to its rarity and lack of established treatment guidelines. The optimal management of XGET is yet to be established. While surgical resection remains the cornerstone of therapy, the potential morbidity associated with extensive surgery underscores the importance of exploring alternative modalities.
Various management approaches were undertaken in the previous reported cases. Six of the cases were treated by surgical excision (cases 1, 2, 4, 5, 7, and 8), one case was biopsied only (case 3) and one case was planned for excision (case 6). Cases that underwent complete surgical resection appear to be disease-free upon follow-up (follow-up range: 3-15 months).1,2,4
Here, we discuss the therapeutic approach involving Denosumab as an alternative to extensive surgery. Studies have explored the role of Denosumab, a monoclonal antibody targeting the RANK ligand, in the management of giant cell tumors of bone,5 which share histopathological similarities with XGET. Denosumab has demonstrated promising results in reducing tumor size and alleviating symptoms in giant cell tumors, raising interest in its potential utility in other neoplasms such as XGET. However, further studies are warranted to assess the long-term efficacy and safety of Denosumab in the management of XGET.
Acknowledgments: Special thanks to Dr Andrew L. Folpe for reviewing this case and adding his expertise to our case report. The publication of this article was funded by Qatar National Library.
Statement of Ethics: Written informed consent was obtained from the patient for the publication of his case.
Disclosure statement : The authors have no conflict of interest.
Funding sources : The publication of this article was funded by Qatar National Library
Authors’ contributions: Dr. Muna Abuhejleh wrote the manuscript and reviewed cases in literature. Dr. Adham Ammar, is the pathologist who reviewed the case and edited the manuscript. Dr Ahmed Mounir ElSayed, Dr Renan Elsadeg Ibrahem and Dr Asmaa Elhassan Mohamed, provided us with the clinical/radiological findings and follow up clinical findings.