Pheochromocytoma is a rare neuroendocrine tumor that affects people in the 4th and 5th decades of life. It can be benign or malignant, and present as isolated tumors or along with other neuroendocrine syndromes. We present a case of an elderly man who underwent laparoscopic adrenalectomy for pheochromocytoma when he was 58 years only to have a recurrence of metastatic malignant pheochromocytoma in his seventies. We also conducted a literature review to understand the epidemiology and presentation of the tumor and to emphasize that there should be a low threshold of suspicion for timely diagnosis and management of recurrent pheochromocytoma.

Introduction: Circulating tumor DNA (ctDNA) is newly diagnosed tumor DNA that can easily represent a tumor’s genetic and epigenetic change. Pheochromocytomas (PCCs) and Paragangliomas (PGLs) are rare tumors of adrenal gland tissue that have the potential to be detected by ctDNA. We aimed to study the potential of the methylation status of RDBP, SDHB, and SDHC genes in ctDNA of PCCs/PGLs patients as a diagnostic biomarker. Materials and Methods: Clinical data, fresh frozen tissue, the blood of 12 PCCs/PGL patients, and the blood of 12 age/sex-matched normal patients were collected. The methylation status of RDBP, SDHB, and SDHC was compared between cases and controls by MS-HRM analysis. Results: Amongst six promoter regions of RDBP, SDHB, and SDHC, promoter methylation quantification of SDHCa and RDBPb was significantly different between PCCs/PGLs and controls. SDHCa was methylated in 49.93% of PCCs/PGLs cases vs. 8.33 % of control samples, p-value: 0.026, area under curve AUC=0.757, and RDBPb in 74.9% of PCCs/PGLs cases vs. 25.0% of control samples, p-value: 0.032, AUC=0.750. Conclusions: This study suggests the ctDNA potential for a less invasive source of tumor epigenetic modification in PCCs/PGLs malignancies. The SDHCa and RDBPb hypermethylation warrant further exploration as diagnostic tools for PCCs/PGLs.

Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare neuroendocrine tumors characterized by catecholamine production in the adrenal medulla and extra-adrenal paraganglia. PPGL with metastasis was termed malignant PPGL. However, the distinction between “benign” and “malignant” PPGLs has been debated. Currently, all PPGLs are believed to have some metastatic potential and are assigned malignant tumors (ICD-O/3) by the WHO Classification of Endocrine Organs (2017, 4th edition). Therefore, the previous categories benign and malignant PPGL have been eliminated in favor of a risk stratification approach. The Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) is a tool for risk stratification for predicting metastasis and the prognosis of patients. At least 30% of PPGLs are hereditary, with 20 genes identified and genotype-phenotype correlations clarified. Of these, VHL, RET, and NF1 have been well investigated and are the primary cause of bilateral PCC. In addition, succinate dehydrogenase gene subunits SDHB and SDHD are strongly correlated with extra-adrenal location, younger age, multiple tumors, metastasis, and poor prognosis. Disease stratification by catecholamine phenotype and molecular profiling correlates with histological grading by GAPP. PPGLs should be understood comprehensively based on clinical, biochemical, molecular, and pathological data for patient care. A flow chart for pathological diagnosis is included.