Metastatic Disease in Phaeochromocytomas and Paragangliomas in Various Genotypes-A Systematic Review and Meta-analysis.

[BACKGROUND] Paragangliomas and phaeochromocytomas (PPGLs) are rare neuroendocrine tumours with 10% to 20% of patients developing metastatic disease. The tumors exhibit a high degree of heritability, and pathogenic genetic variants have been associated with metastases.

[OBJECTIVE] We aimed to investigate the association between the genotype of PPGL patients and their risk of metastatic disease, adjusting for time.

[METHODS] A systematic search was conducted in PubMed and Embase. The primary outcome was the rate of metastatic disease per 100 followed patient-years analyzed through meta-analyses.

[RESULTS] A significantly increased rate of metastatic disease per 100 followed patient-years was observed in all pathogenic germline variants included in the analyses, compared to the group with no identified variant. The group with no variant had a rate of 1.55 per 100 patient-years. SDHA, SDHC, SDHD, VHL, RET, NF1, and MAX had rates of 13.73, 6.27, 2.03, 2.34, 1.91, 4.11, and 9.66, respectively. The rate of SDHB is not presented as statistical heterogeneity exceeded 75%. The pathogenic somatic variant EPAS1 showed a rate of 3.82. Cluster-divided meta-analyses resulted in rates of 4.41 and 3.0 for cluster 1 and cluster 2, respectively. Meta-regression analysis revealed a 2.3-fold higher rate for the SDHB variant compared to the other cluster 1 variants.

[CONCLUSION] We present associations between genotype and metastatic disease in PPGL patients. Our results indicate that patients harboring a pathogenic genetic variant have a higher rate of metastases compared to patients with no identified variant. High heterogeneity in several analyses suggests that further large cohort studies are needed.