关键词: 原发灶不明肿瘤, 肿瘤分子检测, 经验性化疗, 器官特异性治疗

Abstract:

Cancer of unknown primary (CUP) refers to a group of histopathologically confirmed malignancies that cannot be identified in terms of their primary origin despite thorough investigations. CUP accounts for approximately 3%-5% of all newly diagnosed cancers worldwide, with an overall survival (OS) ranging from 2.7 to 16.0 months. CUP has long been a significant scientific challenge due to the elusive nature and heterogeneity of the primary sites. In the era of immunohistochemistry (IHC), IHC has been applied to identify the primary site in approximately 70% of CUP cases. However, IHC also has limitations for undifferentiated cancers of unknown primary, and results can be influenced by experimental and human factors. In recent years, with the development of molecular tumor profiling (MTP), techniques such as cytology, histology, gene expression profiling (GEP), genomics and epigenomics have been able to accurately detect the primary site in 90% of cases. Currently, the 90-gene tumor tissue origin test has been proven to have an accuracy rate of 94.4% in diagnosing the primary site of CUP, laying the foundation for precision treatment. In the past, platinum and taxane-based empirical chemotherapy was commonly used for treating CUP. However, these treatments did not yield significant improvements in patient survival and prognosis. Since 2008, there has been a global emergence of clinical studies on MTP-guided first-line therapy for CUP. However, due to study design flaws and result controversies, there is no international consensus on the superiority of organ-specific treatment over empirical chemotherapy in terms of improving progression-free survival (PFS) and OS for CUP. Based on this, our center conducted the world's first phase Ⅲ clinical trial in 2017, and demonstrated improved PFS and favorable OS by GEP-guided site-specific therapy of CUP, which established the primacy of site-specific first-line therapy for CUP. In this review, we detailed the epidemiology, pathogenesis, clinical characteristics and the progression of CUP diagnosis from the era of IHC to MTP. Furthermore, we reviewed the advancements in CUP treatment from empirical chemotherapy to MTP-guided organ-specific treatment. Additionally, this review delved into the exploration of second-line treatment options and the establishment of a clinical stratified management model, which are two topics in future research of CUP. This review aimed to summarize the progress in the diagnosis and treatment of CUP, further explore future research directions for CUP, and improve the survival and prognosis of patients with CUP.

Key words: Cancer of unknown primary, Molecular tumor profiling, Empirical chemotherapy, Site-specific therapy