<p>Approximately 10–20% of patients with pheochromocytoma or sympathetic paraganglioma (PPGL) develop metastatic disease, most often as metachronous lesions. Unfortunately, there is a lack of accurate biomarkers that can predict the biologic behavior of a PPGL at the initial diagnosis. We investigated tumor samples from patients with PPGL and a diagnosis of either localized or metastatic disease with synchronous or metachronous metastases and performed a comprehensive molecular analysis through application of single-cell whole-genome sequencing and bulk transcriptome analysis, including variant detection analysis of RNA sequences. We found that PPGL displayed complex karyotypes with recurrent aneuploidies and substantial cell-to-cell karyotype variability, indicating ongoing chromosomal instability (CIN) in both localized and metastatic tumors. Transcriptome analysis on the other hand revealed several differences between localized and metastatic PPGL including TNFα and TGFβ signaling in metastatic PPGL that were already detectable in primary tumor samples of initially non-metastatic-appearing PPGLs that developed metachronous metastases. Altogether our findings indicate that while localized and metastatic PPGL in general have comparable genomic landscapes, they do show transcriptional differences that are already detectable in primary tumor PPGL before development of metastases. This finding could provide an important tool for improvement of patient stratification at initial diagnosis.</p>