The challenge of undifferentiated sarcomas

Undifferentiated sarcomas are an umbrella term encompassing multiple undifferentiated morphological subtypes that lack a particular line of differentiation and are difficult to classify. Overall, undifferentiated sarcomas account for 10–20% of all sarcomas, which makes them one of the leading subtypes and one of the main challenges in the field due to the lack of knowledge on their biology and evolution, biomarkers and tailored therapeutic approaches.

Diagnosis of undifferentiated sarcoma is made by exclusion after ruling out other well-defined subtypes. Historically, all non-otherwise classified sarcomas were grouped together under the common definition of malignant fibrous histiocytoma. In 2013, the term was abandoned and the World Health Organization (WHO) classification introduced the definition of undifferentiated pleomorphic sarcoma, along with other undifferentiated subtypes (Histopathology. 2014;64:2–11). Subgrouping into pleomorphic, spindle-cell, or epithelioid variants is performed based on microscopic appearance; however, its clinical significance is limited since tailored therapeutic options are not available.

Undifferentiated sarcomas are challenging for their presentation of complex genomic rearrangements affecting a broad range of genes and chromosomal regions, with no clear targetable drivers. The genomic and transcriptomic diversity within tumours and between patients limits the ability to define molecular subgroups; however, multiple studies have suggested the existence of distinct molecular subtypes.

As presented at the ESMO Sarcoma and Rare Cancers Congress 2026 (Lugano, 12–14 March), results from the NETSARC+ registry confirm high variability in incidence, clinical presentation, and long-term outcomes across 7,545 patients with five histologically defined subtypes of undifferentiated sarcomas (Abstract 79MO). Importantly, high variability in overall survival was noted, with median durations ranging from 65 months in undifferentiated epithelioid sarcoma to over 150 months in undifferentiated spindle cell sarcoma. Preliminary transcriptomic data underscore the different gene expression profiles of undifferentiated subtypes, as well as the limitations of histology-based classification, which are not clearly recapitulated by molecular profiling.

A better understanding of molecular characteristics, tumour evolution, and clinical traits in patients with undifferentiated sarcomas is paramount in the immunotherapy era of oncology. Undifferentiated sarcomas appear to be among the most responsive sarcomas to immune checkpoint inhibitors in the metastatic setting. Moreover, recent clinical trials with neoadjuvant immunotherapy combined with radiation therapy have shown very promising results with improved disease-free survival (DFS) compared with radiation therapy alone in the SU2C-SARC032 trial (Lancet. 2024;404:2053–2064) and high rates of pathological responses in the EFTISARC-NEO trial (Ann Oncol. 2025;36(Suppl 2):S1338).

Despite advances in the field, it remains unclear which patients with undifferentiated sarcomas benefit most from these therapies, as we lack reliable, reproducible biomarkers. The study presented in Lugano represents a tangible step toward a better understanding of undifferentiated sarcomas, but many questions remain. Can we identify molecular subtypes within a basket of undifferentiated sarcomas? Can we identify therapeutic targets or prognostic biomarkers hidden in the genomic complexity of these tumours? How should we stratify patients in clinical trials? How should we optimise immunotherapy in this population? A broad sarcoma community effort is needed to resolve these questions and demystify the concept of undifferentiated sarcomas as a basket of unknown and undefined entities.