Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study

Abstract

Background Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival in MPP patients. Patients and Methods Retrospective multicentric study of MPP characterized by a neckthoraco-abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010. Results We included 169 patients from 18 European centers. Main characteristics of MPP patients 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 the bone (64%), lymph node (40%), lung (29%) and liver (26%); mean time between initial and malignancy diagnosis was 43 months (0-614). 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 <5-fold the upper limits of the normal range and low proliferative index. In multivariate analysis, hypersecretion (Hazard Ratio 3.02[1.65-5.55]; p:0.0004) was identified as independent significant prognostic factors of worst overall survival. 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.

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…In the past, several studies have shown an association between SDHB ‐related metastatic PGL/PCC and a shorter survival in patients compared to sporadic metastatic PGL/PCC . In a recent analysis of Hescot et al, not the SDHB mutation status but hypersecretion of metanephrines and chromogranin A was found to be a significant prognostic factor for worst overall survival …”

“…48,49 In a recent analysis of Hescot et al, not the SDHB mutation status but hypersecretion of metanephrines and chromogranin A was found to be a significant prognostic factor for worst overall survival. 50 Other SDHB-associated tumors include RCC, although the risk for this manifestation seems low, varying between 4.7% and 8%. 21,40 GISTs are reported to occur in approximately 2% of SDHB carriers.…”

Summary of clinical characteristics of common primary adrenal malignancies in adults

“…In our study, for patients with ACC and PPGL, the non-metastatic had better OS and CSS. Poor survival was associated with synchronous metastasis, which can be seen in patients with PPGL [19][20][21][22] . Whereas for patients with SA, the non-metastatic group had a better OS, but there was no signi cant difference in CSS between the two groups.…”

Exploring the link between tumour metabolism and succinate dehydrogenase deficiency: A 18F‐FDOPA PET/CT study in head and neck paragangliomas

“…On subgroup analysis, SDHC-related PGLs were found to have higher 18 F-FDOPA uptake parameters, more particulary TL uptake compared to sporadic and SDHD ones. 7 It has also been shown that SDHB-related PPGL which are mostly of sympathetic origin are characterized by a greater propensity towards metastasis compared to other SDHx subgroups, 21,22 suggesting that beyond SDH deficiency common to SDHA/B/C/D mutants, additional events may promote an aggressive behaviour. The inter-and intra-patient differences observed on 18 F-FDOPA PET/CT in SDHx mutation carriers is still unexplainable.…”

“…It has also been shown that SDHB-related PPGL which are mostly of sympathetic origin are characterized by a greater propensity towards metastasis compared to other SDHx subgroups, 21,22 suggesting that beyond SDH deficiency common to SDHA/B/C/D mutants, additional events may promote an aggressive behaviour. The analysis of our three cases of metastatic HNPGL suggests that loss of 18 F-FDOPA uptake (immature phenotype) is not a prerequisite for metastatic spread and may occur at distant sites in host tissues.…”