Update on clinical and mechanistic aspects of paraneoplastic syndromes

Many patients with cancer are afflicted with an array of severe ailments caused by remote effects of the neoplasm on distant organs, which it has not invaded or colonized. The growing local tumor dominates attention, but invisible chemical and cellular components released by this parasitic neoplastic growth can operate below the threshold of detection to derange feedback loops coordinating essential physiological functions. Ultimately, these changes cause serious signs and symptoms, collectively described as paraneoplastic syndromes (PNSs), which significantly diminish the patient's quality of life. PNS can appear before, or after, detection of the cancer and are sometimes surprising or even bizarre. The patterns of clinical changes seen in these patients are caused by a range of mechanisms that reveal intricate networks of communications between different body systems, normally utilized for healthy function. For example, these disorders demonstrate that (1) hormones, peptides, and other long- and short-range signaling molecules produced by the tumor and (2) immune reactions to tumor-related antigens, can mediate diverse destabilizing effects. However, comparative analysis of numerous PNS reveals valuable information indicating that the primary pathogenetic events instigating these disturbances are much more fundamental. This article provides an overview of the diverse clinical manifestations of paraneoplastic disorders, with representative examples and presents evidence that inappropriate gene expression in the tumor, caused by loss of regulatory control, is a novel unifying explanation for such wide effects of the neoplasm on the host. It also discusses treatment options and issues relating to conducting randomized clinical trials on these disorders.