Biomarkers of metastatic disease in pheochromocytoma and paraganglioma.

Germline SDHB status, loss of SDHB protein expression on immunohistochemistry and elevated plasma 3-methoxytyramine are the best validated markers of metastatic risk.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours, of which roughly 10% to 20% progress to metastatic disease, with no histological system universally validated to identify aggressive tumours at diagnosis. This review surveys biomarkers of metastatic risk, covering histopathological scoring systems, genetic and molecular markers, biochemical phenotyping, liquid biopsy and imaging-based approaches. Among established tools, the authors retain germline SDHB mutation status, loss of SDHB protein expression on immunohistochemistry, elevated plasma 3-methoxytyramine and the GAPP and COPPS histopathological scores as the best validated in practice. Emerging markers, including somatic ATRX and TERT alterations, genomic instability indices, tumour immune microenvironment characterisation, circulating tumour DNA and oncometabolite quantification, are considered promising but require prospective validation before routine use.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

For the geneticist, the useful conclusion is that germline genotype remains the most robust prognostic variable in this disease: an SDHB result changes surveillance intensity from the day it is returned, ahead of any tumour marker. The limitation is one of format, a narrative review with no registered search protocol and no quantified performance comparison, which therefore allows neither ranking of the tools nor threshold setting. The emerging markers highlighted are moreover somatic and remain outside the scope of the cancer genetics clinic until prospectively validated.

Analysis by Dr Thibaut Benquey