Cancer of an unknown primary with PDZRN3-RAF1 fusion and ATR splice site mutation, with atypical chemosensitivity pattern

Abstract

A cancer of an unknown primary (CUP) is diagnosed when the primary tumor cannot be identified using standard diagnostic methods. Worldwide, CUP constitutes 1.8% of all cancers, with annual mortality reaching 80%. This study describes a 54-year-old man who presented with fever and epigastric pain. Computed tomography detected multiple liver, peritoneal, and mediastinal metastases. Histopathology confirmed the presence of G3 adenocarcinoma, but its origin remained unclear. The patient was diagnosed with CUP and was treated with cisplatin and paclitaxel therapy with moderate effect. The second-line regimen with gemcitabine and capecitabine resulted in remarkable disease stabilization lasting over 2 years. A next-generation sequencing test was performed, revealing the presence of two pathogenic variants (PDZRN3-RAF1 fusion and ATR splice site), but no targeted therapy could be selected based on the findings. The subsequent treatment regimen with irinotecan and cyclophosphamide brought stabilization that lasted 6 months. FOLFOX7 therapy did not provide a response. Sorafenib resulted in 5-month disease control. Simultaneously, expanded histopathology indicated that the cancer could be hepatocellular carcinoma with an atypical immunophenotype. After starting cabozantinib, the patient developed a severe nephrotic syndrome and died after 4 years of oncological treatment. 

The complex and unique nature of each CUP makes both diagnosis and optimal management a great challenge. There is an ongoing need to improve workups to identify the primary. As a heterogeneous and poorly investigated entity, CUP may require treatment beyond established guidelines. More research is needed to establish new therapeutic options for CUP patients.