Proliferation markers for the differential diagnosis of tumor and inflammation

FDG, the most common radiopharmaceutical for PET imaging in oncology, is not tumor-specific. Significant tracer accumulation can also occur in viral, bacterial and fungal infections, in other forms of inflammatory tissue and in brown fat. FDG accumulation in inflammatory tissue may cause false positives during cancer screening and false classification as a nonresponder during drug treatment. Yet, discrimination between benign and malignant processes is often possible when the kinetics of FDG uptake is taken into account (e.g., by delayed, dual or dynamic PET imaging). Other PET tracers which are considered as proliferation markers may allow an improved differential diagnosis of tumor and inflammation. These include lipid precursors, amino acids, nucleosides and receptor ligands. Strictly speaking, only labelled nucleosides which are incorporated into DNA (e.g. 2-(11)C-thymidine, (76)Br-bromofluorodeoxyuridine, (11)C-FMAU) are true proliferation markers, but the tissue kinetics of radiopharmaceuticals tracing amino acid transport, membrane metabolism, enzyme activity or receptor expression can be a surrogate marker of cellular proliferation if the activity of such processes is increased in rapidly dividing cells. Well-known imaging targets for oncology are: (i) glucose transport ((18)F-FDG); (ii) choline kinase activity ((11)C-choline); (iii) amino acid transport ((11)C-methionine); and (iv) activity of thymidine kinase 1 ((18)F-FLT). Radiolabeled choline, amino acids and nucleosides have been reported to show greater tumor-specificity than (18)F-FDG, both in experimental animals and in humans. However, the specificity of such tracers is not absolute. (11)C-choline is strongly accumulated in bacterial infections and sterile inflammation. (11)C-Methionine can show high uptake in brain abscesses. (18)F-FLT is taken up in non-metastatic reactive lymph nodes because of reactive B-lymphocyte proliferation. Moreover, FLT-PET cannot distinguish between benign lesions showing blood-brain barrier disruption and malignant brain tumors. Although proliferation is a key factor of malignancy, cell division can also occur in benign processes, including some forms of infection and inflammation. Because of such limitations, the tumor specificity of PET will never reach 100%. Each radiolabeled proliferation marker (or surrogate marker of proliferation) has high physiological uptake in some areas of the body and the tumor uptake of these radiopharmaceuticals is often lower than that of FDG. Proliferation markers should therefore not be considered as replacements of FDG, but rather as useful additions to the imaging arsenal which can provide additional diagnostic specificity and biological information for treatment planning and response monitoring.