Novel Tumor Markers for Pheochromocytoma

Pheochromocytomas are neuroendocrine tumors that produce and secrete catecholamines. Biochemical diagnosis is based on the detection of elevated plasma and/or urinary metanephrines. As of now, these biochemical markers have the highest sensitivity and specificity (Lenders et al., JAMA 2002). Many other serum or urinary markers including VMA, chromogranin A, and neuron-specific enolase are less reliable in establishing a pheochromocytoma diagnosis. Unfortunately, no markers can currently clearly distinguish benign from malignant pheochromocytomas. The only criterion remains the clinical detection of chromaffin tissue/metastases at sites where such tissue usually is not found – lung, liver, and bone (Clarke et al., 1998). However, many attempts have been made in the search for such markers including NCAM (CD56), SNAP25, cathepsin B and D, cyclooxygenase, and tenascin (an extracellular matrix glycoprotein). Immunohistochemical studies showed increased p53 and Bcl-2 expression in malignant pheochromocytomas compared to benign tumors (De Krijger et al., 1999). Increased human telomerase reverse transcriptase expression and telomerase activity has been found in some malignant pheochromocytomas, but other investigators did not confirm these findings (Boltze et al., 2003; Koch et al., JCEM 2002). Survivin, an apoptosis inhibitor, has recently been implicated as a prognostic marker in the diagnosis of various malignancies including neuroblastoma, a tumor related to pheochromocytoma. However, no differences in survivin expression have been found between malignant and benign pheochromocytomas (Koch et al., 2002). The MIB-1 mitotic index was found to be a useful marker in predicting the malignant behavior of a pheochromocytoma (Kumaki et al. 2002). EM66, a novel secretogranin II-derived peptide, was recently found to be elevated in malignant pheochromocytomas (Yon et al. 2003). An important aspect in this setting is the follow-up period, since the statement of whether a pheochromocytoma is benign or malignant largely depends on the detection of metastases in the period after initial surgery. Therefore, future studies searching for potential markers that can discriminate between benign and malignant pheochromocytomas will have to take a long time.