Cancer of unknown primary site.

Copyright © 2014 Massachusetts Medical Society Cancer of unknown primary site is a heterogeneous group of cancers for which the anatomical site of origin remains occult after detailed investigations.1,2 The emergence of sophisticated imaging, immunohistochemical testing, and molecular-profiling tools has influenced our approach to unknown primary cancer, although it has also increased the ambiguity of designations for this disorder. In the era of tailored therapeutic strategies, this situation presents both an opportunity and a challenge. The past four decades have seen a shift in our understanding of unknown primary cancer (Fig. 1). First, improved imaging techniques increased our confidence in the classification of some cancers as having an occult primary origin. Later, subsets of unknown primary cancers with an apparently favorable prognosis were identified, primarily on the basis of histopathological findings, the pattern of spread, and serum markers.2 Subsequently, with the advent of new immunohistochemical markers and advances in diagnostic pathological tests, tissue-of-origin profiles were described that assigned additional putative primary sites to unknown primary cancer on the basis of immunohistochemical patterns.3-6 Current research involves the application of proteomic and genomic tools to unknown primary cancer. Cancer of unknown primary site was once viewed almost as a separate type of cancer, with the assumption that, regardless of the site of origin, the tumors in unknown primary cancers shared biologic properties, perhaps including rapid progression and dissemination, which contributed to their presentation. This view drove the conduct of phase 2 empirical trials over the past three decades, with the goal of developing standard chemotherapy regimens that would be effective in all patients with unknown primary cancer. The underlying assumption was that variations in presentation would not have a substantial effect on therapeutic approaches or survival. Our view of unknown primary cancer has evolved as our understanding of cancer biology in general has matured to become much more personalized. Many people now believe that tumors in unknown primary cancer may retain the signature of the putative primary origin and that extending the management of known cancers to subtypes of unknown primary cancer can contribute to advancements in therapies for this disease. Cancer of unknown primary site could even be seen as the epitome of personalized medicine, with individualized treatment driven by the mutational status of each patient. The biologic events that allow the primary site to remain obscure after the development of metastases have not yet been defined. Studies that have shown chromosomal abnormalities, microvessel density, aneuploidy, and overexpression of several genes suggest that these abnormalities are not unique to unknown primary cancer.7-11 With the use of the Sequenom MassARRAY platform, a study involving consecutive patients with unknown primary cancer showed a low rate of mutations (in 18% of patients).12 No new, low-frequency mutations were found with the use of a panel of mutations involving the phosphatidylinositol 3-kinase