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Background: Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival (OS) in MPP patients., Patients and Methods: Retrospective multicenter study of MPP characterized by a neck-thoraco-abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010., Results: One hundred sixty-nine patients from 18 European centers were included. Main characteristics of patients with MPP were: primary pheochromocytoma in 53% of patients; tumor- or hormone-related symptoms in 57% or 58% of cases; positive plasma or urine hormones in 81% of patients; identification of a mutation in SDHB in 42% of cases. Metastatic sites included bone (64%), lymph node (40%), lung (29%), and liver (26%); mean time between initial and malignancy diagnosis was 43 months (range, 0 to 614). Median follow-up was 68 months and median survival 6.7 years. Using univariate analysis, better survival was associated with head and neck paraganglioma, age <40 years, metanephrines less than fivefold the upper limits of the normal range, and low proliferative index. In multivariate analysis, hypersecretion [hazard ratio 3.02 (1.65 to 5.55); P = 0.0004] was identified as an independent significant prognostic factor of worst OS., Conclusions: Our results do not confirm SDHB mutations as a major prognostic parameter in MPP and suggest additional key molecular events involved in MPP tumor progression. Aside from SDHB mutation, the biology of aggressive MPP remains to be understood., (Copyright © 2019 Endocrine Society.)

Context: Pheochromocytomas and paragangliomas (PPGLs) are characterized by a strong genetic component, with up to 40% of patients carrying a germline mutation in a PPGL susceptibility gene. International guidelines recommend that genetic screening be proposed to all patients with PPGL., Objective: Our objective was to evaluate how a positive genetic test impacts the management and outcome of patients with SDHx or VHL-related PPGL., Design: We performed a multicentric retrospective study involving 221 propositi carrying an SDHB, SDHD, SDHC, or VHL germline mutation. Patients were divided into two groups: genetic patients, who were informed of their genetic status within the year following the first PPGL diagnosis, and historic patients, who only benefited from the genetic test several years after initial PPGL diagnosis., Results: Genetic patients had better follow-up than historic patients, with a greater number of examinations and a reduced number of patients lost to follow-up (9.6% vs 72%, respectively). During follow-up, smaller (18.7 vs 27.6 mm; P = 0.0128) new PPGLs and metastases as well as lower metastatic spread were observed in genetic patients. Of note, these differences were reversed in the historic cohort after genetic testing. Genetic patients who developed metachronous metastases had a better 5-year survival rate than historic patients (P = 0.0127)., Conclusion: Altogether, our data suggest that early knowledge of genetic status had a positive impact on the management and clinical outcome of patients with a germline SDHx or VHL mutation., (Copyright © 2019 Endocrine Society.)

Pheochromocytomas and paragangliomas (PCCs/PGLs) are neural crest-derived tumours with a very strong genetic component. Here we report the first integrated genomic examination of a large collection of PCC/PGL. SNP array analysis reveals distinct copy-number patterns associated with genetic background. Whole-exome sequencing shows a low mutation rate of 0.3 mutations per megabase, with few recurrent somatic mutations in genes not previously associated with PCC/PGL. DNA methylation arrays and miRNA sequencing identify DNA methylation changes and miRNA expression clusters strongly associated with messenger RNA expression profiling. Overexpression of the miRNA cluster 182/96/183 is specific in SDHB-mutated tumours and induces malignant traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster appears as a potential driver in a subgroup of sporadic tumours. Altogether, the complete genomic landscape of PCC/PGL is mainly driven by distinct germline and/or somatic mutations in susceptibility genes and reveals different molecular entities, characterized by a set of unique genomic alterations.

Context: The natural history of malignant pheochromocytoma or paragangliomas (MPP) remain unknown., Objective: The primary aim of this study was to define progression-free survival at 1 year in therapy-naive patients with MPP. Secondary objectives were to characterize MPP and to look for prognostic parameters for progression at 1 year., Design and Setting: The files of MPP followed up between January 2001 and January 2011 in two French Endocrine Networks were retrospectively reviewed. Therapy-naive patients were enrolled., Main Outcome Measures: The main outcome was progression-free survival at 1 year in therapy-naive MPP patients according to Response Evaluation Criteria In Solid Tumors 1.1 criteria., Results: Ninety files (46 men, 44 women, mean age of 47.5 ± 15 years) were reviewed on site by one investigator. MPP characteristics were as follows: presence of an adrenal primary, a mitotic count exceeding 5 per high power field, hypertension, inherited disease, and presence of bone metastases in 50%, 22%, 60%, 49%, and 56% patients, respectively. Fifty-seven of the 90 patients with MPP (63%) were classified as therapy-naive. The median follow-up of these 57 patients was 2.4 years (range, 0.4-5.7). At 1 year, progression-free survival was 46% (CI 95: 33-59). Twenty-six of 30 (87%) patients with progression at 1 year had exhibited progressive disease at the first imaging workup performed after a median of 5.7 months. No prognostic parameter was identified., Conclusions: Half of the therapy-naive patients with MPP achieved stable disease at 1 year. In symptom-free patients with MPP, a wait-and-see antitumor policy seems appropriate as first line. Modality for a prospective follow-up is proposed.

Context: Recommendations have not been established concerning imaging to screen SDHx mutation carriers for paraganglioma and pheochromocytoma., Objective: Our objective was to compare the performance of gadolinium-enhanced magnetic resonance angiography, contrast-enhanced computed tomography, and [(123)I]metaiodo-benzylguanidine and somatostatin receptor scintigraphies for detecting head and neck and thoracic-abdominal-pelvic paragangliomas in SDHx mutation carriers., Design and Setting: We conducted a prospective, multicenter study from June 2005 to December 2009 at 23 French medical centers., Patients: A total of 238 index cases or relatives carrying mutations in SDHD, SDHB, or SDHC genes were included., Intervention: Images obtained by each technique were analyzed blind, without knowledge of results from other tests, first in each local center and then centrally., Main Outcome Measures: We evaluated sensitivity, specificity, and likelihood ratios for individual and combinations of tests, the gold standard being the consensus of an expert committee., Results: Two hundred two tumors were diagnosed in 96 subjects. At local assessment, the sensitivity of anatomical imaging for detecting all tumors was higher (85.7%) than that of both scintigraphic techniques (42.7% for [(123)I]metaiodo-benzylguanidine and 69.5% for somatostatin receptor scintigraphy), except for thoracic localizations where somatostatin receptor scintigraphy was more sensitive (61.5 vs. 46.2% for anatomical imaging and 30.8% for [(123)I]metaiodo-benzylguanidine scintigraphy). The best diagnostic performance during local assessment was obtained by combining anatomical imaging tests and somatostatin receptor scintigraphy (sensitivity 91.7%). Central assessment significantly increased the sensitivity (98.6%) of tests in combination., Conclusions: In routine practice, the imaging work-up for screening SDHx mutation carriers should include thoraco-abdomino-pelvic computed tomography, head and neck magnetic angiography, and somatostatin receptor scintigraphy. Expert centralized image assessment is recommended.

Context: Pheochromocytoma and paraganglioma are rare neural-crest-derived tumors. They are metastatic in 15% of cases, and the identification of a germline mutation in the SDHB gene is a predictive risk factor for malignancy and poor prognosis. To date, the link between SDHB mutations and malignancy is still missing., Objective: Epithelial to mesenchymal transition (EMT) is a developmental event, reactivated in cancer cells to promote cell mobility and invasiveness. The aim of this study was to address the participation of EMT in the metastatic evolution of pheochromocytoma/paraganglioma., Design and Patients: Transcriptomic profiling of EMT was performed on 188 tumor samples, using a set of 94 genes implicated in this pathway. Activation of EMT was further confirmed at protein level by immunohistochemistry in a second set of 93 tumors., Results: Hierarchical unsupervised classification showed that most SDHB-metastatic samples clustered together, indicating that EMT is differently regulated in these tumors. Major actors of EMT, metalloproteases and components of cellular junctions, were either up-regulated (LOXL2, TWIST, TCF3, MMP2, and MMP1) or down-regulated (KRT19 and CDH2) in SDHB-metastatic tumors compared with nonmetastatic ones. Interestingly, within metastatic tumors, most of these genes (LOXL2, TWIST, TCF3, MMP2, and KRT19) also allowed us to discriminate SDHB-mutated from non-SDHB-related tumors. In the second set of tumors, we studied Snail1/2 expression by immunohistochemistry and observed its specific nuclear translocation in all SDHB-metastatic tumors., Conclusion: We have identified the first pathway that distinguishes SDHB-metastatic from all other types of pheochromocytomas/paragangliomas and suggest that activation of the EMT process might play a critical role in the particularly invasive phenotype of this group of tumors.

Pheochromocytomas and paragangliomas are highly vascularized tumors which are candidates for anti-angiogenic therapies. Several studies have reported the association of vascular endothelial growth factor (VEGF) overexpression with malignancy, but none took into account the genetic status of the patients or tumors, which may have a major influence on such observations. Transcriptome studies indeed revealed that pheochromocytomas and paragangliomas can be classified into two major clusters depending on their gene expression profile: Cluster 1 comprises samples associated with a hypoxic signature such as SDHx- and VHL-related tumors and cluster 2 includes RET, NF1, and TMEM127-mutated tumors, as well as most of sporadic tumors. The aim of this study was to provide a comprehensive rationale for the targeting of angiogenesis in patients with malignant forms of the disease. We used in situ hybridization, immunohistochemistry, and microarray gene expression profiling to evaluate angiogenesis and the expression of several angiogenic factors in a large cohort of pheochromocytomas and paragangliomas. We also studied the activation of mTOR by assessing the phosphorylation of its targets, P70 S6 kinase and 4E-BP1. These results were correlated with both malignancy and transcription signature. Our results reveal that cluster 1 tumors display a marked increase in both vascularization and in the expression of major angiogenic molecules, including VEGF, its receptors, HIF2α, Angiopoietin-2, and the endothelin receptors ETA and ETB. These overexpressions were observed in both benign and malignant samples of cluster 1 and thus appeared to be mainly dependent on the pseudo-hypoxic status of these tumors. The mTOR pathway was potentially activated in half of the tumors studied, with a slight increase in cluster 2 pheochromocytomas. Our results suggest that there is a strong rationale for anti-VEGF-based therapeutic strategies in malignant pheochromocytomas and paragangliomas, in particular in those associated with mutations in the SDHB gene.

Mitochondrial succinate-coenzyme Q reductase (complex II) consists of four subunits, SDHA, SDHB, SDHC and SDHD. Heterozygous germline mutations in SDHB, SDHC, SDHD and SDHAF2 [encoding for succinate dehydrogenase (SDH) complex assembly factor 2] cause hereditary paragangliomas and pheochromocytomas. Surprisingly, no genetic link between SDHA and paraganglioma/pheochromocytoma syndrome has ever been established. We identified a heterozygous germline SDHA mutation, p.Arg589Trp, in a woman suffering from catecholamine-secreting abdominal paraganglioma. The functionality of the SDHA mutant was assessed by studying SDHA, SDHB, HIF-1alpha and CD34 protein expression using immunohistochemistry and by examining the effect of the mutation in a yeast model. Microarray analyses were performed to study gene expression involved in energy metabolism and hypoxic pathways. We also investigated 202 paragangliomas or pheochromocytomas for loss of heterozygosity (LOH) at the SDHA, SDHB, SDHC and SDHD loci by BAC array comparative genomic hybridization. In vivo and in vitro functional studies demonstrated that the SDHA mutation causes a loss of SDH enzymatic activity in tumor tissue and in the yeast model. Immunohistochemistry and transcriptome analyses established that the SDHA mutation causes pseudo-hypoxia, which leads to a subsequent increase in angiogenesis, as other SDHx gene mutations. LOH was detected at the SDHA locus in the patient's tumor but was present in only 4.5% of a large series of paragangliomas and pheochromocytomas. The SDHA gene should be added to the list of genes encoding tricarboxylic acid cycle proteins that act as tumor suppressor genes and can now be considered as a new paraganglioma/pheochromocytoma susceptibility gene.