27 8 Endocrine-Related P L M Dahia et al. Metastatic pheochromocytomas/ 27:8 T41–T52 Cancer paragangliomas THEMATIC REVIEW HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES Metastatic pheochromocytomas and paragangliomas: proceedings of the MEN2019 workshop Patricia L M Dahia1, Roderick Clifton-Bligh2, Anne-Paule Gimenez-Roqueplo3,4, Mercedes Robledo5,6 and Camilo Jimenez7 1Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 2Department of Endocrinology, Royal North Shore Hospital, Northern Clinical School, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia 3Université de Paris, INSERM, PARCC, Paris, France 4AP-HP, Hôpital Européen Georges Pompidou, Genetics Department, Paris, France 5Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, Spain 6Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain 7Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence should be addressed to P L M Dahia: [email protected] This paper is part of a thematic section on current knowledge and future research opportunities in hereditary endocrine tumours, as discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27–29 March 2019, Houston, TX, USA. This meeting was sponsored by Endocrine-Related Cancer Abstract Key Words Pheochromocytomas and paragangliomas (PPGLs) are adrenal or extra-adrenal f pheochromocytomas autonomous nervous system-derived tumors. Most PPGLs are benign, but approximately f paragangliomas 15% progress with metastases (mPPGLs). mPPGLs are more likely to occur in patients f metastatic with large pheochromocytomas, sympathetic paragangliomas, and norepinephrine- f mutation secreting tumors. Older subjects, those with larger tumors and synchronous metastases, f SDHB advance more rapidly. Germline mutations of SDHB, FH, and possibly SLC25A11, or somatic f therapy MAML3 disruptions relate to a higher risk for metastatic disease. However, it is unclear whether these mutations predict outcome. Once diagnosed, there are no well-established predictors of outcome in mPPGLs, and aggressive tumors have few therapeutic options and limited response. High-specific activity (HSA) metaiodine-benzyl-guanidine (MIBG) is the first FDA approved treatment and shows clinical effectiveness for MIBG-avid mPPGLs. Ongoing and future investigations should involve validation of emerging candidate outcome biomarkers, including somatic ATRX, TERT, and microRNA disruptions and identification of novel prognostic indicators. Long-term effect of HSA-MIBG and the role of other radiopharmaceuticals should be investigated. Novel trials targeting molecular events prevalent in SDHB/FH mutant tumors, such as activated hypoxia inducible factor 2 (HIF2), angiogenesis, or other mitochondrial defects that might confer unique https://erc.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/ERC-19-0435 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 11:29:04AM via free access -19-0435 Endocrine-Related P L M Dahia et al. Metastatic pheochromocytomas/ 27:8 T42 Cancer paragangliomas vulnerability to these tumors should be developed and initiated. As therapeutic options are anticipated to expand, multi-institutional collaborations and well-defined clinical and molecular endpoints will be critical to achieve higher success rates in improving care for patients with mPPGLs. Endocrine-Related Cancer (2020) 27, T41–T52 Introduction The 16th International Workshop on Multiple Endocrine (Ayala-Ramirez et al. 2011). Head and neck paragangliomas Neoplasia (MEN2019) focused on new concepts and are more rarely metastatic (McCrary et al. 2019). Even treatment of malignant manifestations of cancers that though family history may be negative, a hereditary comprise hereditary endocrine cancer syndromes. This basis is present in 40–50% of mPPGLs. Synchronous meeting took place 27–29 March 2019 in Houston, Texas. metastases are present in 35–50% cases; metachronous The meeting addressed the state of the field and metastases can develop within months or after more discussed important outstanding research questions and than a decade (Baudin et al. 2014, Roman-Gonzalez & challenges, in the form of symposium presentations and Jimenez 2017). Median survival of mPPGL is ~6 years, two-day workshops. Workshop attendees weighed in although the rate of progression is highly variable. on key priority areas for future research and consensus Death is usually from metastatic progression, although points were collated. The next sections summarize hypersecretion of catecholamines is often morbid and presentations and workshop discussions on metastatic sometimes fatal. pheochromocytomas and paragangliomas (mPPGLs) and Five large clinical series (Amar et al. 2007, Ayala- conclude with proposed plans for the coming years and Ramirez et al. 2011, Turkova et al. 2016, Fishbein et al. future research projects for bridging these gaps. 2017a, Hamidi et al. 2017, Hescot et al. 2019) of mPPGL are shown in Table 1. Despite the heterogeneous nature of mPPGL, group statistics for these series are strikingly similar. Diagnosis of ‘malignant’ pheochromocytoma Risk factors for mPPGL include clinical, pathological, and paraganglioma: state of the science and genetic factors. The strongest clinical risk factors Under the revised WHO classification (2018), are tumor size and thoraco-abdominal (sympathetic) pheochromocytomas and paragangliomas (PPGLs) PGL. Tumor size is incorporated in the newly published are now referred to as ‘metastatic’ or ‘non-metastatic’ AJCC Cancer Staging system for PPGL (Amin et al. 2017): rather than ‘malignant’ or ‘benign’; metastases are still T1 tumors are <5 cm in greatest dimension, T2 tumors defined by deposits at sites where normal chromaffin are ≥5 cm or sympathetic PGLs of any size, and T3 tissue is not present (Lam 2017). Approximately 10% tumors are of any size with invasion into surrounding of pheochromocytomas and ~40% of sympathetic tissues. Metastasis is rare for pheochromocytomas below paragangliomas will be associated with metastases 4 cm; conversely, metastatic paraganglioma can occur Table 1 Clinical series of metastatic pheochromocytomas and paragangliomas. Ayala-Ramirez Amar et al. (2007) et al. (2011) Turkova et al. (2016) Hamidi et al. (2017) Hescot et al. (2019) Fishbein et al. (2017a,b) n 54 131 132 272 169 71 Timeframe n/r 1960–2009 2000–2014 1960–2016 1998–2010 2000–2016 PC/sPGL/HNPGL (%) 54/46/0 52/48/0 29/71/0 40/47/11 53/37/10 28/45/21a Synchronous metastasis 24 (44%) 67 (51%) 26 (20%) 96 (35%) 79 (47%)b 18 (25%)c Age (Dx primary), years 37.9 n/r 39 n/r 41 Age (Dx metastases), years 42 n/r 44 48 6.2 (0–44.77)d SDHB mutations 23/54 (43%) 9/21e (43%) 73/132 (55%) 42/272 (15%)e 63/151e (42%) 37/60e (62%) Died of disease 26/54 (48%) 87/131 (66%) 39/132 (30%) 73/272 (27%) 72/169 (43%) 19/71 (27%) Age at death (range), years 45 n/r 54 (7–91) n/r n/r aAn additional 5.6% had more than one tumor location; bmetastases within 1 year; cmetastases within 3 months; dyears (range) after primary diagnosis; enot all cases had genetic testing. Dx metastases: at the time of metastases identification; Dx primary: at first diagnosis; n/r: not reported. https://erc.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/ERC-19-0435 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 11:29:04AM via free access Endocrine-Related P L M Dahia et al. Metastatic pheochromocytomas/ 27:8 T43 Cancer paragangliomas from smaller primaries (Ayala-Ramirez et al. 2011). likely due to the presence of SDHB mutations in the A retrospective study by Hamidi et al. (2017) examined former (Richter et al. 2014). factors associated with rapid progression (death within Genetic risk factors for mPPGL include germline 5 years of initial presentation) and found the strongest pathogenic variants in SDHB, SDHA, SDHD, FH, MAX, predictors to be older age at primary diagnosis (OR 1.054 and SLC25A11 (Castro-Vega et al. 2014, Buffet et al. 2018) (95% CI 1.01–1.08)/year), primary tumor size (OR 1.12 and somatic MAML3 fusions (Fishbein et al. 2017b). The (1.009–1.25)/cm), and the presence of synchronous strongest genetic risk factor for mPPGL is a pathogenic metastases (OR 10.24 (3.76–31.18)). Another clinical risk SDHB variant, present in 40–50% cases (Amar et al. 2007, factor for the rate of progression is the site of metastatic Ayala-Ramirez et al. 2011, Turkova et al. 2016, Hamidi et al. disease: skeletal only metastases tend to be more 2017, Hescot et al. 2019); nevertheless, accumulating indolent (median survival 12 years), compared with non- evidence suggests that SDHB mutations are not associated osseous metastases (median survival 7.5 years) (Ayala- per se with rapid progression of disease (Hamidi et al. 2017, Ramirez et al. 2013). Biochemically, mPPGL is less likely Crona et al. 2019, Hescot et al. 2019). Recently, aberrant in epinephrine-secreting tumors (Ayala-Ramirez et al. telomere maintenance mechanisms (TMMs) have 2013); conversely, elevated plasma methoxytyramine, been associated with mPPGL: somatic ATRX mutations a byproduct of dopamine, is associated with mPPGLs associated with alternate