New Biomarkers Show Promise in Improving Diagnosis, Prognosis in Uterine Sarcoma

A pair of circulating proteins may significantly improve both early identification and risk stratification for patients with uterine sarcoma, according to a new study.1 If further validated in future studies, having a reliable, non-invasive blood-based test could help improve diagnostic accuracy, personalize care, and potentially impact outcomes for patients with this aggressive disease, note the researchers of the study.

The researchers of the study, published in Scientific Reports, say their findings offer new evidence into how growth differentiation factor-15 (GDF15) and osteopontin (OPN) can meaningfully enhance the preoperative differentiation of uterine sarcoma from leiomyoma, with GDF15 additionally serving as an independent predictor of progression-free survival for the rare and aggressive soft tissue sarcoma.

These results align with growing evidence that GDF15 plays a central role in tumor biology. | Image credit: Елена Бутусова - stock.adobe.com

The disease, which accounts for just 1% to 2% of uterine cancers, remains one of the most challenging gynecologic cancers to diagnose before surgery, often masquerading as benign leiomyomas and leading to delayed or inappropriate treatment.

The rapid progression and nonspecific clinical presentation of uterine sarcoma, explained the researchers, make early detection critical. Standard imaging tools such as MRI and PET scans can help raise suspicion but often fall short in distinguishing malignant tumors from atypical leiomyomas, especially before surgical removal. Blood-based markers like lactate dehydrogenase (LDH) or CA125 have been examined previously but remain unreliable on their own. Against this backdrop, the identification of accessible, accurate biomarkers has become a pressing clinical priority.

The researchers of this new study analyzed serum and tumor tissue from 38 patients with uterine sarcoma and 67 with leiomyoma treated between 2015 and 2019. Concentrations of GDF15, OPN, and progranulin (PGN) were measured, while tissue expression levels were assessed through immunohistochemistry. The goal was twofold: to evaluate whether these markers could reliably differentiate malignant from benign disease and to determine whether any could predict patient outcomes, including progression-free survival (PFS) and overall survival (OS).

Serum levels of both GDF15 and OPN were significantly higher in uterine sarcoma compared with leiomyoma (P < .001), with strong diagnostic performance demonstrated through receiver operating characteristic and precision-recall analyses. Using established cutoff values, GDF15 achieved an area under the curve (AUC) of 0.883 (95% CI, 0.812-0.953), while OPN reached 0.881 (95% CI, 0.810-0.951), outperforming conventional markers such as LDH, CA125, and PGN, none of which showed meaningful discrimination in the full cohort. These results held true even when carcinosarcoma cases, often considered separately in clinical classification, were excluded.

Tissue-level analysis strengthened these observations. Immunostaining revealed markedly higher expression of GDF15, PGN, and OPN in sarcoma samples compared with benign tissue. Importantly, serum and tissue levels correlated significantly for GDF15 and OPN, demonstrating biological consistency and reinforcing their potential as clinically robust markers.

Beyond diagnosis, multivariate analysis showed that elevated GDF15 was the only independent prognostic factor for PFS (P < .001), tripling the risk of disease progression even when accounting for FIGO stage and other variables.

“The prognostic significance of PFS is particularly noteworthy as it provides insight into the time frame for tumor recurrence and the development of treatment resistance,” noted the researchers. “A reliable biomarker for PFS can be more useful than one for OS in guiding treatment choices in daily clinical practice and developing novel therapeutic agents.”

While LDH and CA125 were associated with worse outcomes in univariate models, only LDH remained independently predictive of OS in the broader cohort. Notably, in patients with sarcomas excluding carcinosarcoma, GDF15 retained its prognostic significance, underscoring its relevance across histologic subtypes.

These results align with growing evidence that GDF15 plays a central role in tumor biology.2 Previously linked to cancer proliferation, chemoresistance, immune evasion, and metastasis, the protein is increasingly viewed not only as a biomarker but also as a potential therapeutic target. Similarly, OPN has been implicated in multiple malignancies, but this study marks the first report supporting its diagnostic utility in uterine sarcoma, positioning it as a promising addition to preoperative evaluation.1

The researchers acknowledged limitations of their study including a small sample size owing to the rarity of the disease. Although statistical resampling techniques were used to minimize bias, larger multicenter studies will be required to validate cutoff values and determine how these markers should be incorporated into clinical practice. Moreover, while neither GDF15 nor OPN correlated with stage or histology, this independence could be both a strength and a challenge: useful for early detection yet requiring careful interpretation alongside imaging and clinical judgment.

References

1. Tsuyoshi H, Mizutani T, Uno M, et al. Diagnostic and prognostic values of circulating growth differentiation factor-15 and osteopontin in uterine sarcoma. Sci Rep. Published online November 19, 2025. doi:10.1038/s41598-025-24481-y

2. Fang M, Wang Z, Zhou Y, Yang F, Wu Z, Xiao J. Functional characteristics of fresh antitumor immune interferer GDF-15 in multiple cancers. Sci Rep. Published online August 22, 2025. doi:10.1038/s41598-025-16737-4