Giant cell–rich tumors of soft tissue comprise a heterogeneous group of neoplasms that share a prominent population of multinucleated giant cells. Because of substantial morphological overlap among these lesions, accurate diagnosis can be difficult, particularly when tissue is limited. This review synthesizes clinicopathologic and genomic findings to provide a concise update on selected entities and to clarify features that assist differential diagnosis.
The authors frame the diagnostic problem as one in which histomorphology alone may be insufficient and where integration of clinical information, immunophenotype, and molecular testing increasingly informs tumor classification. The review emphasizes that genomic characterization has identified signature alterations for several tumor types, while others are defined by more complex or non-recurrent genomic landscapes.
The review covers nine distinct giant cell–rich soft tissue neoplasms. Each is unified by multinucleated giant cells but differs in typical clinical presentation, histologic context, and molecular features. The nine entities summarized are:
For each entity the review outlines clinicopathologic hallmarks and highlights distinguishing molecular findings where available. When a defining molecular alteration has been identified, the review presents that alteration as a diagnostic aid; when recurrent alterations are lacking, the review notes that genomic complexity can be a feature.
A central theme of the review is that recent genomic studies have revealed diagnostically useful gene fusions and rearrangements for several giant cell–rich tumors. The authors highlight specific recurrent fusions and genetic drivers that help define particular entities. Notable molecular findings cited include rearrangements and fusion genes such as USP6, NTRK1, FN1, CSF1, COL1A1-PDGFB, NAB2-STAT6, and HMGA2-NCOR2.
When present, these signature molecular events can provide strong supportive evidence for a specific diagnosis and can be used to distinguish morphologically similar lesions. The review underscores that awareness of these characteristic fusions can streamline interpretation of limited samples and avoid misclassification based solely on histology.
Not all giant cell–rich neoplasms demonstrate a single defining fusion or recurrent alteration. The review specifically notes that some entities are characterized by non-recurrent genomic changes or by highly complex genomic profiles. In these tumors, molecular testing may reveal a variety of structural or numerical abnormalities without a single pathognomonic driver.
This distinction—between fusion-driven lesions and those with complex non-recurrent genomics—is important because it affects how molecular results are interpreted and how they contribute to diagnostic confidence. For tumors lacking recurrent fusions, clinicopathologic correlation and exclusion of other fusion-positive entities remain essential.
Synthesizing clinicopathologic and genomic data, the authors argue that advanced molecular testing plays a critical role in several domains:
The review promotes a diagnostic approach that integrates histology, immunophenotype, and targeted molecular assays to achieve the most accurate classification possible. It also notes that recognition of characteristic fusions may have downstream implications for patient management when targeted agents are available for particular molecular alterations.
This review, titled "An Update on Selected Giant Cell-Rich Tumors of Soft Tissue," is authored by Jun Nishio and Mikiko Aoki and was published in Cancer Genomics Proteomics (2026 Sep–Oct;23[5]:899–913). The PubMed identifier is PMID 42674819 and the DOI is 10.21873/cgp.20607. Keywords emphasized in the article include giant cell-rich tumors, differential diagnosis, gene fusions, molecular diagnostics, and soft tissue neoplasms.
Note: This summary reflects the content and conclusions reported in the source abstract. Detailed entity-specific morphologic descriptions, case series data, and individual study results appeared in the full review and are not reproduced in this abstract-based summary.