Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

Abstract

Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their illness within a year of diagnosis. The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. This review will outline the biology of CUP by exploring the hallmarks of cancer in order to rationalise the complexities of this enigmatic syndrome. This approach will help the reader to understand where research efforts currently stand and the pitfalls of this quest.

Brain Metastasis from Unknown Primary Tumour: Moving from Old Retrospective Studies to Clinical Trials on Targeted Agents

“…Other studies report a similar detection rate and confirmed the superiority of FDG-PET in identifying additional metastatic lesions [ 53 , 54 ]. Common serum tumour markers currently have no diagnostic, prognostic, or predictive value for CUP due to their unspecific expression [ 55 ]. Table 1 summarizes the imaging techniques used in the diagnosis of BM.…”

“…The difficulty in identifying the primary tumour might imply that the latter is undetectable either at diagnostic testing or at autopsy, or that CUP constitutes a distinct entity, which challenges classical models of metastasis pathogenesis. Most of the biological steps that are believed to contribute to the pathogenesis of CUP are hallmarks of cancer in general and shared with other neoplastic diseases: chromosomal alterations, self-sufficiency in growth signals, resistance to growth inhibitory signals, reprogramming of energy metabolism, evasion of apoptosis, unlimited replicative potential, bright angiogenesis, tissue invasion, metastasis, and evasion of immune attack [ 55 ].…”

“…In recent years, gene expression profiling (GEP) has become an additional tool for diagnostic, prognostic and predictive purposes. Second-generation microRNA-based assays, GEP-based microarray tests, or quantitative-PCR (qRT-PCR) low-density arrays have reached a sensitivity of 77–94% in identifying CUP [ 48 , 55 ]. Results from a blinded series of high-grade metastatic cases demonstrated the superior accuracy of a 92-gene assay versus standard-of-care IHC, supporting the diagnostic utility of a molecular investigation in difficult-to-diagnose metastatic cancer [ 62 ].…”

“…Moreover, significant discrepancy has emerged between the suspected primary tumour based on molecular profiling and autoptic confirmation. Finally, tumour cells may undergo extensive immunoediting (see the pathogenesis section), which raises doubts over the accuracy of a diagnosis based on GEP positivity [ 55 , 58 ]. Applications of these techniques to BM-CUP have been limited.…”

Narrative review on serous primary peritoneal carcinoma of unknown primary site: four questions to be answered

“…Thereafter, tumor cells migrate to the peritoneum either via the sloughed tubal cancer cells which disseminate into the peritoneal cavity or hematogenous spread with a predilection for implantation in the omentum (34). This dissemination may occur before local tumor growth according to two scenarios (35). In the first scenario which is characterized by independent genetic alterations between the primary tumor and metastatic sites (36), tumor cells alter their microenvironment and metastasize before generating a detectable tumor (37,38).…”