From Biology to Diagnosis and Treatment: The Ariadne's Thread in Cancer of Unknown Primary

Cancer of unknown primary (CUP) encloses a group of heterogeneous tumours, the primary sites for which cannot be identified at the time of diagnosis, despite extensive investigations. CUP has always posed major challenges both in its diagnosis and management, leading to the hypothesis that it is rather a distinct entity with specific genetic and phenotypic aberrations, considering the regression or dormancy of the primary tumour; the development of early, uncommon systemic metastases; and the resistance to therapy. Patients with CUP account for 1-3% of all human malignancies and can be categorised into two prognostic subsets according to their clinicopathologic characteristics at presentation. The diagnosis of CUP mainly depends on the standard evaluation comprising a thorough medical history; complete physical examination; histopathologic morphology and algorithmic immunohistochemistry assessment; and CT scan of the chest, abdomen, and pelvis. However, physicians and patients do not fare well with these criteria and often perform additional time-consuming evaluations to identify the primary tumour site to guide treatment decisions. The development of molecularly guided diagnostic strategies has emerged to complement traditional procedures but has been disappointing thus far. In this review, we present the latest data on CUP regarding the biology, molecular profiling, classification, diagnostic workup, and treatment.

Automated summary

Cancer of unknown primary (CUP) is a diverse group of tumors that cannot be identified at diagnosis, posing challenges in diagnosis and treatment. CUP is believed to have distinct genetic and phenotypic abnormalities, with regression or dormancy of the primary tumor, early systemic metastases, and therapy resistance. CUP accounts for 1-3% of malignancies and can be classified into prognostic subsets. The standard evaluation for CUP includes medical history, physical examination, histopathologic assessment, immunohistochemistry, and CT scan. Molecularly guided diagnostic strategies have not been successful so far. This review provides the latest information on CUP biology, molecular profiling, classification, diagnostic workup, and treatment.