123 Review Article Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options Karren Antonio1,2, Ma Margarita Noreen Valdez1,2, Leilani Mercado-Asis3, David Taïeb4, Karel Pacak1 1Section on Medical Neuroendocrinology, The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; 2Division of Endocrinology, University of Santo Tomas Hospital, Manila, Philippines; 3Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines; 4Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix- Marseille University, Marseille, France Contributions: (I) Conception and design: All authors; (II) Administrative support: K Pacak; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Karel Pacak, MD, PhD, DSc, FACE. Chief, Section on Medical Neuroendocrinology, Professor of Medicine, Eunice Kennedy Shriver NICHD, NIH, Building 10, CRC, 1E-3140, 10 Center Drive, MSC-1109, Bethesda, MD 20892-1109, USA. Email: [email protected]. Abstract: Pheochromocytomas and paragangliomas (PPGLs), rare chromaffin/neural crest cell tumors, are commonly benign in their clinical presentation. However, there are a number of cases presenting as metastatic and their diagnosis and management becomes a dilemma because of their rarity. PPGLs are constantly evolving entities in the field of endocrinology brought about by endless research and discoveries, especially in genetics. Throughout the years, our knowledge and perception of these tumors and their genetic background has greatly expanded and changed, and each new discovery leads to advancement in the diagnosis, treatment and follow-up of PPGLs. In this review, we discuss the recent updates in the genetics, biochemistry, immunohistochemistry, metabolomics, imaging and treatment options of PPGLs. Keywords: Diagnosis; genetics; paraganglioma; pheochromocytoma; treatment Submitted Sep 24, 2019. Accepted for publication Nov 12, 2019. doi: 10.21037/gs.2019.10.25 View this article at: http://dx.doi.org/10.21037/gs.2019.10.25 Introduction particularly elevated blood pressure, headache, palpitations, and diaphoresis. PPGLs have an approximate incidence of Pheochromocytomas and paragangliomas (PPGLs) are rare 2–8 individuals per million population per year accounting neuroendocrine tumors (NETs) producing catecholamines for approximately 0.1% of individuals with hypertension (4). and originating from adrenal medulla chromaffin cells or from neural crest cells outside the adrenal gland. In 80% Most PPGLs are benign but there are a number of cases of cases, these tumors arise in the adrenal medulla and in presenting initially as metastatic with an approximate the remaining 20%, tumors arise outside the adrenal glands incidence of one per million population per year. Patients in the prevertebral and paravertebral sympathetic ganglia with metastatic PPGL have a survival rate of 40–77% located mainly in the chest abdomen and pelvis (1,2). Using in five years and progression free survival ranges from the latest WHO definitions, the term pheochromocytoma 4–36 months (5). Metastatic PPGLs behave in a variable is used for tumors arising from the adrenal gland while manner with some initially presenting with metastases tumors which arise outside the adrenal gland are termed and some developing metastases years after the initial as paraganglioma (3). Increased levels of catecholamines diagnosis of PPGL. Factors correlated with an accelerated accounts for characteristic clinical manifestations disease progression include male sex, diagnosis at an older © Gland Surgery. All rights reserved. Gland Surg 2020;9(1):105-123 | http://dx.doi.org/10.21037/gs.2019.10.25 106 Antonio et al. Pheochromocytoma/paraganglioma updates age, synchronous metastases, bigger tumor size, increased identification of the disease and first evidence of metastases dopamine level and failure to remove the primary tumor (6). (25,27). Interestingly, when compared to SDHD variant carriers who have a standard mortality ratio (SMR) of 0.93 which is comparable to the general population, SDHB Genetics variant carriers have a greater SMR at 1.89 which increases PPGLs have a high degree of heritability with 40% of cases to 2.88 among SDHB variant carriers with a personal history carrying a germline mutation. Throughout the years, there of PPGL (28). Given its risk for metastases and association has been more than 20 susceptibility genes identified. The with poor outcomes, multiple studies have been done to underlying mutation influences PPGL clinical presentation determine the PPGL penetrance among individuals with such as cell differentiation, specific catecholamine an underlying SDHB mutation. A study showed that SDHB production, tumor location, malignant potential and genetic mutation has a PPGL penetrance of 49.80% at 85 years anticipation (7-9) (Table 1). The Cancer Genome Atlas of age (29). Surprisingly, a difference in the age-related divided PPGL into 3 clinically useful molecularly defined PPGL penetrance was noted between males and females groups: Kinase signaling subtype, Pseudohypoxia subtype, with males having a 50% PPGL penetrance at age 74 but and Wnt-altered subtype (20). this was not reached in females (29). In addition, metastasis was noted in 85 out of 143 patients with PPGL (59.44%) with a median time of 3 years between initial diagnosis of Kinase signaling subtype PPGL and documentation of metastases. In another study, This subtype consists of somatic and germline mutations SDHB mutation was found to have a penetrance of 21% at in NF1, RET, TMEM127 and HRAS genes (Table 1). 50 years of age but in contrast, there was no difference Patients with these mutations typically present with in the age-related PPGL penetrance between males pheochromocytoma having adrenergic biochemical and females (30). Benn et al. developed an approach to phenotype corresponding to its high expression of estimate lifetime disease penetrance of SDHx mutation by phenylethanolamine N-methyltransferase (PNMT) that comparing allelic frequencies among individuals with and converts norepinephrine to epinephrine (20). Most of these without PPGL (31). Using this approach, SDHB variants pheochromocytomas are benign but have high degree of have an estimated lifetime disease penetrance of 22% as recurrence and multiplicity. compared to SDHC and SDHA variants which have an estimated lifetime disease penetrance of 8.3% and 1.7% respectively. Pseudohypoxia subtype FH mutation predisposes an individual to a syndrome Patients in this subtype present with both pheochromocytoma of leiomyomatosis, renal cell carcinoma together with and paraganglioma and may produce either norepinephrine pheochromocytoma or paraganglioma (32-34). FH-related or dopamine or both. Thus, typically, epinephrine and PPGLs are often metastatic or multiple. On the other metanephrine levels are within normal limits. This subtype hand, an EPAS1 mutation, also known as HIF2A mutation, is further divided into two main subgroups: tricarboxylic results in a syndrome of multiple PPGLs, duodenal acid cycle (TCA)-related PPGLs that include mainly somatostatinomas and polycythemia also known as the succinate dehydrogenase subunits A-D (SDHx), fumarate Pacak-Zhuang syndrome with a high metastatic potential hydratase (FH), isocitrate dehydrogenase (IDH), and and multiplicity (35-38). VHL/EPAS-related mutations. SDHx mutations are associated with PPGLs as well as gastrointestinal stromal Wnt-altered subtype tumors, pituitary adenomas, chondromas, neuroblastomas and very rarely gastroenteropancreatic tumors (21-24). This consists of adrenal pheochromocytomas associated SDHB mutation in particular was found to increase the with CSDE1 somatic mutations and MAML3 fusion genes risk for clinically aggressive PPGLs that are more likely activating the Wnt and Hedgehog signaling pathways (20). to develop metastases or locally aggressive or recurrent There are no known germline mutations in this subtype tumors (7,25,26). In fact, SDHB mutation greatly affects making it specific for sporadic pheochromocytoma. In outcome among patients with metastatic PPGLs exhibiting patients with these mutations pheochromocytomas present less disease-free interval and a shorter time interval between as recurrent or metastatic. © Gland Surgery. All rights reserved. Gland Surg 2020;9(1):105-123 | http://dx.doi.org/10.21037/gs.2019.10.25 Gland Surgery, Vol 9, No 1 February 2020 107 Crona et al. looked into PPGLs in a PanCancer MDH2 gene perspective (39). The PanCancer Initiative aims to ascertain A heterozygous variant on exon 4 of MDH2 was similarities across various types of cancer and cell origin or first detected in a patient with multiple metastatic within groups found to be associated based on anatomical paragangliomas (12). This gene was found to be responsible or morphological characteristics (40). In the analysis for encoding malate dehydrogenase enzyme that converts of Crona et al., they found that PPGLs clustered with malate to oxaloacetate in the TCA cycle. The study pancreatic NETs and neuroblastomas which challenges the demonstrated a lower MDH2 activity in mutated tumors but current clinicopathological classification of PPGLs. PPGLs they were