Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10–12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include “old genes” associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up.

Background: To perform genetic screening for ARMC5 gene germline pathogenic variants in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH).Subjects and Methods: In a group of 10 PBMAH patients, we performed complete sequencing of the coding region of the ARMC5 gene and MLPA analysis for large deletion detection. In subjects with the ARMC5 variant, we searched ARMC5 gene somatic variants on tumor samples.Results: Among 10 PBMAH patients, we identified four ARMC5 germline variants (40%). One variant, c:174dupC p.Glu59Argfs*44, was already known; one variant p.Gly323Asp, was already reported and classified as likely disease‐causing VUS (class 3–4); two variants p.Leu596Arg and p.Arg811Pro, were never reported before. For p.Gly323Asp and p.Arg811Pro, we identified second deleterious variants at the somatic level, enforcing the possible pathogenic effect of germline variants.Conclusions: Our results underscore the importance of performing genetic testing also in sporadic PBMAH patients and broaden the spectrum of molecular variants involved in PBMAH syndrome.

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Timely diagnosis is necessary due to the dangerous effects of excess catecholamines on the cardiovascular system and also for the potentially aggressive biological behavior of PPGL. Diagnosis may be challenging due to the great variability in clinical presentation, even if nowadays PPGLs are often diagnosed incidentally due to the incidental finding of adrenal or retroperitoneal masses or thanks to surveillance in carriers of mutation in PPGL susceptibility genes. A biochemical diagnosis cannot be omitted before proceeding to the imaging study and it relies on plasma or urinary free metanephrine and normetanephrine testing. Appropriate preoperative evaluation is essential as PPGL surgery has a high risk of intraoperative hemodynamic lability. The alpha-adrenergic blockers doxazosin or phenoxybenzamine are the treatment of choice, and fluid replacement is often necessary to restore preoperative volume depletion and to treat postoperative hypotension. Distinguishing a benign PPGL from tumor with metastatic potential is very challenging: the size of the primary tumor, invasion of surrounding tissues, lymph node metastasis are all clinical predictors of metastasis, but also the molecular and biological characteristics are considered to predict the risk of malignancy.

Pheochromocytoma (PHEO) and paraganglioma (PGL) are tumors with strong genetic determinism: germline mutations in susceptibility genes are detected in 40% of subjects, with mutation frequency of 10–12% also in patients with sporadic presentation. Many susceptibility gene have been discovered and genetic screening should be proposed to all subjects with PHEO and PGL (PPGL). Genetic analysis is currently performed through next generation sequencing technologies, which allows for the simultaneous study of many genes, overcoming the difficulties associated with the study of diseases with high genetic heterogeneity. PPGL susceptibility genes include “old genes” associated with neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and multiple endocrine neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which are responsible for more than half of hereditary PPGL, and the less frequently involved TMEM, MAX, and FH genes. Mutations in different genes express a peculiar phenotype: the identification of a pathologic variant in susceptibility genes makes it possible to propose to the patient a tailored surveillance program according to the risk of relapse, malignancy, and involvement of other organs, and also allows extension of genetic analysis to relatives and implementation of presymptomatic surveillance in mutation carriers.