The role of molecular diagnostics in sarcomas 

Between Science and Clinical Practice 

The use of molecular diagnostics in sarcoma care is receiving growing international attention. Recent studies¹ show that comprehensive genomic analysis leads to a revised diagnosis or new treatment options in a subset of cases. At the same time, the prevailing expert consensus² is that next-generation sequencing (NGS) and whole-genome sequencing (WGS) should be used as complementary, targeted tools, in situations where they are expected to add real clinical value. 

At the intersection of scientific insights and efficient clinical implementation, we spoke with two sarcoma specialists from Leiden University Medical Center (LUMC), a recognized expert center for soft tissue and bone sarcomas: Prof. Judith Bovée, pathologist, and Prof. Hans Gelderblom, medical oncologist and Head of the Department of Medical Oncology. 

Molecular Diagnostics in daily practice 
For Judith Bovée, the role of molecular diagnostics in sarcoma care is clear: it is a valuable addition to classical pathology, but microscopy still forms the basis. Sarcomas are rare and often genetically heterogeneous, which means that molecular diagnostics can be highly informative for a subset of tumors. 

“Molecular diagnostics are mainly used when a diagnosis cannot be established with certainty based on histology alone, or when a tumor is characterized by a specific fusion or mutation,” Bovée explains. “For some soft tissue and bone sarcomas, this really helps to achieve accurate classification—for example in round cell sarcomas, where a definitive diagnosis usually cannot be established without molecular testing.  

According to Bovée, the use of molecular diagnostics varies by tumor type. “For some tumors, such as GIST, we perform NGS routinely; for others, we do not. Additional molecular testing is often discussed in consultation with the oncologist, particularly when there may be therapeutic implications.” 

Expertise and Experience 
Bovée emphasizes the importance of experience in evaluating rare tumors. “In specialized centers, pathologists see a high volume of sarcomas and testing is more targeted. There is less tendency to order tests ‘just in case.’ Outside reference centers, molecular testing may be requested more readily to compensate for diagnostic uncertainty. That is precisely where proper triage and multidisciplinary consultation are crucial. You want to test when it is necessary—not simply because it is possible.” 

What defines an expert? “Not the absolute number of sarcoma cases a pathologist sees, but their structural involvement in sarcoma care. There are no strict numerical thresholds. Ideally, you work in a reference center, participate in multidisciplinary tumor boards, and assess sarcomas on a regular basis. Only then do you build the experience needed to diagnose these rare tumors accurately.” 

Diagnostic reclassification 
As shown in the recent studies comprehensive genomic profiling leads to diagnostic reclassification in approximately 8–12% of cases. In most situations, such reclassification does not directly affect treatment, but for a small subgroup it can be clinically meaningful. 

Hans Gelderblom recognizes this pattern: “For most patients, it does not change much—but for that small percentage for whom it does make a difference… well, you would not want to be the patient who misses out.” 

Therapeutic perspective 
Gelderblom stresses that molecular diagnostics become clinically meaningful only when there is an indication for systemic treatment. “Many sarcomas are not treated systemically at all. They are managed locally, with surgery or radiotherapy. In those situations, extensive testing to identify therapeutic targets has limited added value.” 

When systemic therapy is indicated, molecular information comes into play. “It is truly a case-by-case decision. You consider the patient’s fitness, whether treatment is realistic, and we always discuss this in a multidisciplinary tumor board. The key question is: do you expect to find something that is relevant for this specific patient? Does it fit the clinical picture?” 

In the Netherlands, a dedicated reimbursement framework exists for broader diagnostics, including extensive NGS panels and WGS, allowing clinicians to look beyond standard panel testing. Precisely because these decisions are so patient-specific, Gelderblom advocates for centralized care. “In advanced sarcoma cases, these discussions should take place in an expert MDO, together with the pathologist. That allows for a well-informed assessment of whether molecular diagnostics are meaningful and helps avoid unnecessary delays.” 

Molecular diagnostics can also facilitate access to clinical trials or reimbursement. “In certain angiosarcomas, particularly those with a high mutational burden, molecular results can support eligibility for a trial or help secure reimbursement for treatment,” Gelderblom adds. 

Tissue requirements 
A practical limitation for the broader use of WGS is the availability of suitable tissue. Not all hospitals can process fresh or frozen material, which is required for certain diagnostic approaches. Reference centers usually have this well organized, whereas this can be more challenging elsewhere. According to both experts, this underscores the importance of centralization and uniformity of care. 

The importance of turnaround time 
Both Bovée and Gelderblom emphasize the importance of turnaround time—not only for clinicians, but especially for patients. Immunohistochemistry results are often available within a day; targeted NGS panels (DNA and/or RNA) typically take several days to just over a week, while WGS requires approximately (max) two weeks. 

Gelderblom explains: “It is essential to avoid diagnostic procedures themselves delaying care. For many patients, every day of waiting feels like an eternity, and for clinicians, even a week can determine whether therapy can be initiated. That is why treatment is sometimes started based on histology and clinical presentation, with molecular results becoming available at a later stage.”  

In the Netherlands, turnaround times for NGS and WGS are gradually improving. In addition, new sequencing technologies are being explored that may further accelerate diagnostics in the future. While this is not yet fully embedded in routine practice, the development in this area is clearly progressing.  

Data: Valuable, but fragmented 
The potential to learn from data is substantial, but current practice remains fragmented. Bovée points to technical and legal barriers: “Molecular results are recorded in PALGA, but not yet standardized everywhere, although significant efforts are being made. Linking WGS data with pathology findings and clinical outcomes is challenging. In practice, data integration remains a major obstacle.” 

Gelderblom observes the same issue from the clinical perspective: “For over a decade, we have struggled with the lack of comprehensive national registries. Genomics, pathology, and clinical outcomes are still insufficiently connected, making systematic learning difficult.” 

Both conclude that nationwide, uniform integration of these data sources is still lacking, despite being essential for improving care. 

Looking Ahead: smarter, faster, and better integrated 
When asked to describe their ideal scenario five years from now, Bovée and Gelderblom envision a similar direction. They see the greatest potential in faster generation of results, ensuring that relevant information becomes available earlier in the care pathway. 

Gelderblom also highlights organizational improvements: “All high-grade sarcomas should be discussed immediately in an expert MDO, with appropriate consent for diagnostics and research obtained upfront. That would make the entire process much more efficient.” 

According to both experts, progress does not lie in testing more or broader by default, but in smarter, faster, and better integrated diagnostic strategies, with molecular diagnostics serving as a valuable complement to both diagnosis and treatment selection. 

¹ Introduction and Impact of Routine Whole Genome Sequencing in the Diagnosis and Management of Sarcoma. British Journal of Cancer, 2024. 
Comprehensive Genomic Profiling Alters Clinical Diagnoses in a Significant Fraction of Tumors Suspicious of Sarcoma. Clinical Cancer Research, 2024. 
Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients. Cancers, 2022. 

² Guidelines for Next-Generation Sequencing in Sarcoma Diagnosis and Treatment. JAMA Oncology, 2025.