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.