Objective:

To explore how molecular testing can improve tumor origin detection and guide patient care in cancers of unknown primary (CUP) and diagnostically ambiguous tumors, ultimately enhancing patient outcomes.

Key Findings:

• CUPs present significant diagnostic challenges due to broad differential diagnoses, as evidenced by specific case studies.
• Molecular testing can uncover actionable biomarkers in approximately one-third of patients, supported by recent data.
• 21.4% of CUP patients became eligible for targeted therapy based on genomic findings, highlighting the importance of molecular testing.
• NGS helps distinguish between separate primary tumors and metastases, which is crucial for treatment planning, as shown in clinical examples.

Interpretation:

Molecular testing enhances diagnostic accuracy and treatment options for difficult-to-classify tumors, particularly in the context of CUP, by identifying actionable targets that can guide therapy.

Limitations:

• Conventional pathology tools may not provide definitive answers, and their limitations should be acknowledged.
• Molecular testing may not be necessary for localized tumors without actionable targets, but its potential drawbacks should also be considered.

Conclusion:

Molecular testing is increasingly vital in oncology for identifying actionable treatments, especially in ambiguous cases, and should be integrated into standard diagnostic practices.