Phenotype of pheochromocytoma and paraganglioma by germline mutation: a Korean multicenter study

Abstract

Recent advances in genetic testing have challenged the traditional genotype-phenotype correlation in pheochromocytomas and paragangliomas (PPGL). We aimed to characterize the genotype-phenotype correlations in PPGL in a large Korean cohort and compare our findings with those from other countries. We retrospectively analyzed 627 patients with PPGL from two centers who underwent genetic testing for germline pathogenic variants (PVs) from 2000 to 2023 to examine the prevalence of clusters and their correlation with specific phenotypes. Moreover, we systematically reviewed 44 studies that investigated the frequency of germline PVs based on geographical differences. Germline PVs were identified in 29.7% of patients (n = 186). The prevalence of cluster 1A, 1B and 2 PVs was 10.6% (n = 67), 8.0% (n = 50) and 11.1% (n = 69), respectively. Cluster 1 patients were presented with more aggressive features, including younger age at diagnosis (39 years), higher rates of extra-adrenal (44.4%), and metastatic (27.8%) tumors, than did the wild-type and cluster 2 groups (P < 0.001). Cluster 1A patients had significantly higher metastasis rates than cluster 1B patients (38.8 vs 12.5%; P < 0.001). The cluster 2 group showed a high recurrence risk but rarely developed metastases. The cluster 1-to-cluster 2 ratio among Koreans (1.7) was lower than that among Europeans (2.9) and North Americans (3.3). This study underscores the genetic and clinical heterogeneity of PPGL among Korean patients based on genetic clusters and highlights geographic variations in PVs. These findings have significant implications for risk stratification, surveillance and management strategies for patients with PPGL.

Keywords: genetic testing; germline variant; paraganglioma; pheochromocytoma.