Diagnostic and Therapeutic Strategies for Brain Metastases from Unknown Primary Tumors: A Comprehensive Review

Brain metastases represent a heterogenous group of tumors, with distinct characteristics and prognosis, depending on the primary malignancy and on the patient performance status. In up to 28% of cases, neurological symptoms from a brain metastasis are the initial clinical manifestation of the primary cancer. If the primary neoplasm remains unidentified, patients are diagnosed with Brain Metastases for Cancer of Unknown Primary (BM-CUP). While brain metastases are far more common than primary brain tumors, CUP represents a rare malignancy, accounting for 2-5% of all cancer cases. It is characterized by an aggressive clinical course, rapid metastatic spread, low response rate to chemotherapy, and poor prognosis. Understanding BM-CUP remains a challenge, and being such a rare disease, there is still a significant lack of consensus regarding the management of these patients. Nevertheless, recent progression in diagnostic techniques, immunohistochemistry, and genomic sequencing open a new horizon to personalized therapies in selected cases. However, limitations persist, including biological heterogeneity and limited access to genomic sequencing, often leading to the use of empirical treatment. This review synthesizes recent advancements in the diagnosis and management of BM-CUP, highlighting the importance of a structured therapeutic approach for optimizing survival outcomes and preserving quality of life in this challenging patient population.