FET-rearranged Myoepithelial Tumors: Why Epigenetics Demands a Shift from Carcinoma to Sarcoma Classification

The Diagnostic Dilemma of Myoepithelial Tumors

For decades, myoepithelial tumors (MET) have presented a significant challenge to pathologists and clinicians alike. These neoplasms, which can arise in the salivary glands, skin (adnexal), soft tissue, and bone, exhibit a bewildering array of morphological patterns. Traditionally, the presence of myoepithelial differentiation—characterized by the expression of markers such as S100, SOX10, and various keratins—led to a unified classification, regardless of the primary site. However, the emergence of molecular pathology has begun to peel back the layers of this heterogeneity.

A critical distinction has long been observed: while salivary gland and cutaneous MET often show ductal or epithelial differentiation, many soft tissue and bone-based MET do not. The latter frequently harbor rearrangements in the FET family of genes (EWSR1 or FUS). A recent groundbreaking study published in Clinical Cancer Research by Michal et al. (2025) provides definitive evidence that these FET-rearranged tumors are not merely site-specific variants of their salivary counterparts but are, in fact, epigenetically distinct entities that more closely resemble sarcomas.

Highlights of the Research

The study provides several key insights that reshape our understanding of these rare neoplasms:

1. FET-rearranged MET are epigenetically unrelated to PLAG1-rearranged adnexal and salivary gland myoepithelial tumors.
2. Malignant FET-rearranged MET share a common epigenetic lineage with FET::NFATC2 sarcomas, suggesting a mesenchymal rather than epithelial origin.
3. Clinical outcomes are highly dependent on the specific fusion partner, with SS18::POU5F1 and EWSR1::KLF15 variants showing particularly aggressive behavior.
4. Age under 25 years is a robust independent predictor of poor progression-free survival, highlighting a vulnerable patient population.

Study Design and Methodological Rigor

To address the hypothesis that FET-rearranged MET are distinct from the classic PLAG1-driven models, the researchers utilized a multi-institutional cohort. The study design was robust, incorporating DNA methylation profiling—the current gold standard for epigenetic characterization—on 52 fusion-positive cases involving skin, soft tissue, and bone.

These cases were compared against a diverse control set, including salivary MET and other mesenchymal tumors. The cohort encompassed a wide spectrum of genetic drivers, including EWSR1::KLF15, EWSR1/FUS::KLF17, EWSR1::PBX1, EWSR1::PBX3, EWSR1/FUS::POU5F1, SS18::POU5F1, and EWSR1::ZNF444. Furthermore, the researchers performed a pooled clinicopathological and outcome analysis on a total of 185 cases, including both new and previously published data, to ensure statistical power in assessing rare subtypes.

Clinical Heterogeneity: A Fusion-Specific Landscape

The results revealed that the clinical presentation of MET is intrinsically tied to the underlying genetic fusion. The study identified distinct clinical niches for various rearrangements:

The Pediatric Predominance of EWSR1::KLF15

One of the most striking findings was the enrichment of EWSR1::KLF15 rearrangements in very young children, typically under five years of age. These tumors frequently displayed malignant histological features, suggesting that this specific molecular driver is associated with an aggressive, early-onset phenotype.

Site Specificity of PBX1 and PBX3 Fusions

Rearrangements involving PBX1 and PBX3 were notably enriched in tumors arising in the skin and bone. This suggests that the local microenvironment or the cell of origin in these sites may be particularly susceptible to the oncogenic signaling pathways activated by FET::PBX fusions.

Malignancy and POU5F1

Tumors harboring EWSR1/FUS::POU5F1 or SS18::POU5F1 fusions were almost universally associated with malignant histology. These variants, along with the KLF15-rearranged group, represented the most clinically aggressive subset of the study, often requiring intensive therapeutic intervention.

The Epigenetic Divide: FET vs. PLAG1

The core of the study’s argument lies in the DNA methylation profiling. The data showed a clean separation between FET-rearranged tumors and PLAG1-rearranged tumors. While PLAG1-rearranged MET (commonly found in salivary glands and as benign cutaneous mixed tumors) clustered together, the FET-rearranged MET grouped with FET::NFATC2 sarcomas and SS18::POU5F1 MET.

This finding is transformative. It suggests that the lack of ductal differentiation in FET-rearranged MET is not a random morphological variation but a reflection of a fundamentally different biology. These tumors do not share the epigenetic “memory” of salivary or adnexal epithelial tissues. Instead, they appear to be part of a broader family of FET-rearranged mesenchymal neoplasms, which includes Ewing sarcoma and clear cell sarcoma.

Survival Outcomes and Prognostic Factors

The survival data provided by Michal et al. underscore the high stakes of accurate diagnosis. The median disease-specific survival varied significantly across molecular subtypes:

1. SS18::POU5F1 MET: 31 months
2. EWSR1::PBX3 MET: 38 months
3. EWSR1::KLF15 MET: 45 months

In contrast, PLAG1-rearranged tumors were predominantly benign and associated with excellent long-term outcomes. Multivariate analysis identified age as a critical factor; patients younger than 25 years experienced significantly worse progression-free survival. This suggests that in younger patients, these tumors may possess a more unstable genome or a more aggressive biological drive.

Furthermore, the study correlated histological features with genome-wide copy number variation (CNV). Tumors with high CNV complexity were more likely to exhibit malignant morphology and poorer clinical outcomes, providing a potential molecular tool for risk stratification.

Expert Commentary: Redefining Nosology

The implications of this study reach far beyond the pathology lab. For clinicians, the move from classifying these tumors as “Myoepithelial Carcinoma” to recognizing them as “FET-rearranged Sarcomas” is a necessary shift.

Historically, the term “carcinoma” implied an epithelial origin and often guided clinicians toward treatment protocols designed for epithelial malignancies. However, if these tumors are biologically sarcomas, they may respond better to mesenchymal-targeted therapies or specific sarcoma chemotherapy regimens (such as those used for Ewing-like or SS18-related tumors).

Moreover, the study highlights the limitations of histology alone. Because many of these tumors share a common spindle or epithelioid cell morphology, molecular or epigenetic testing is essential to distinguish a benign PLAG1-rearranged cutaneous tumor from a highly aggressive FET-rearranged soft tissue sarcoma. In the era of precision medicine, an accurate molecular diagnosis is no longer optional—it is the foundation of care.

Conclusion: Impact on Clinical Practice

The work by Michal et al. provides a definitive biological roadmap for the classification of myoepithelial-like tumors. By demonstrating that FET-rearranged MET are epigenetically unrelated to cutaneous and salivary gland MET, the researchers have clarified a long-standing source of diagnostic confusion.

Key takeaways for the medical community include:
1. FET-rearranged MET should be considered a distinct clinical and biological entity from PLAG1-driven tumors.
2. The term “sarcoma” is more biologically appropriate than “carcinoma” for the malignant variants of FET-rearranged MET.
3. Molecular testing for EWSR1, FUS, and SS18 rearrangements is vital, particularly in pediatric and young adult patients where aggressive subtypes are common.
4. Future clinical trials should group FET-rearranged MET with other mesenchymal neoplasms to better evaluate targeted therapies.

As we move forward, integrating DNA methylation profiling and targeted sequencing into routine diagnostic workflows will be essential for ensuring that patients with these rare and heterogeneous tumors receive the most appropriate and effective care.

References

Michal M, Malik F, Mansour B, Hattery T, Dehner CA, Martinek P, Hájková V, Vaněček T, Chrisinger JSA, Machado I, Klubíčková N, Sumathi VP, Ng T, Warmke L, Oon ML, Petersson F, Argani P, Gross JM, Michal M, Antonescu CR, Dermawan JK. FET-rearranged Myoepithelial Tumors are Clinically Heterogeneous and Epigenetically Distinct from PLAG1-rearranged Adnexal and Salivary Gland Myoepithelial Tumors. Clin Cancer Res. 2025 Dec 4. doi: 10.1158/1078-0432.CCR-25-2426. Epub ahead of print. PMID: 41342886.