Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono study): an ENS@T retrospective study

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 neck-thoraco-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

The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight

Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways

Long-term outcome of primary bilateral macronodular adrenocortical hyperplasia after unilateral adrenalectomy

CONTEXT Unilateral adrenalectomy has been proposed in selected patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but its long-term outcome is unclear. OBJECTIVE The aim of this study was to analyze long-term clinical and biochemical outcome of unilateral adrenalectomy versus bilateral adrenalectomy in patients with PBMAH in comparison to outcome of cortisol-producing adenoma (CPA) treated by unilateral adrenalectomy. DESIGN Retrospective observational study in three German and one Italian academic tertiary care center. PATIENTS AND METHODS 25 PBMAH patients after unilateral adrenalectomy (unilat-ADX-PBMAH), 9 patients with PBMAH and bilateral adrenalectomy (bilat-ADX-PBMAH) and 39 patients with CPA and unilateral adrenalectomy (unilat-ADX-CPA) were included. RESULTS Baseline clinical and biochemical parameters were comparable in unilat-ADX-PBMAH, bilat-ADX-PBMAH and unilat-ADX-CPA. Directly after surgery, 84% of the unilat-ADX-PBMAH patients experienced initial remission of Cushing's syndrome. In contrast, at last follow-up (median 50 months) 32% of the unilat-ADX-PBMAH patients were biochemically controlled compared to nearly all patients in the other two groups (p=0.000). Adrenalectomy of the contralateral side had to be performed in 12% of the initially unilat-ADX-PBMAH patients. 3 of 20 unilat-ADX-PBMAH patients (15%) died during follow-up presumably of Cushing's syndrome related causes whereas no deaths occurred in the other two groups (p=0.008). Deaths occurred exclusively in patients who were not biochemically controlled after unilateral ADX. CONCLUSIONS Our data suggest that unilateral adrenalectomy of PBMAH patients leads to clinical remission and a lower incidence of adrenal crisis, but less sufficient biochemical control of hypercortisolism potentially provoking a higher mortality

Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study

Background: Metastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC. Methods: A retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included. Results: Seventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases (p < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival. Conclusions: Liver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome

Pheochromocytoma and paraganglioma: Clinical feature based disease probability in relation to catecholamine biochemistry and reason for disease suspicion

OBJECTIVE Hypertension and symptoms of catecholamine excess are features of pheochromocytomas and paragangliomas (PPGLs). This prospective observational cohort study assessed whether differences in presenting features in patients tested for PPGLs might assist establishing likelihood of disease. DESIGN AND METHODS Patients were tested for PPGLs because of signs and symptoms, an incidental mass on imaging or routine surveillance due to previous history or hereditary risk. Patients with (n=245) compared to without (n=1820) PPGLs were identified on follow-up. Differences in presenting features were then examined to assess probability of disease and relationships to catecholamine excess. RESULTS Hyperhidrosis, palpitations, pallor, tremor and nausea were 30-90% more prevalent (P<0.001) among patients with than without PPGLs, whereas headache, flushing and other symptoms showed little or no differences. Although heart rates were higher (P<0.0001) in patients with than without PPGLs, blood pressures were not higher and were positively correlated to body mass index (BMI), which was lower (P<0.0001) in patients with than without PPGLs. From these differences in clinical features, a score system was established that indicated a 5.8-fold higher probability of PPGLs in patients with high than low scores. Higher scores among patients with PPGLs were associated, independently of tumor size, with higher biochemical indices of catecholamine excess. CONCLUSIONS This study identifies a complex of five signs and symptoms combined with lower BMI and elevated heart rate as key features in patients with PPGLs. Prevalences of these features, which reflect variable tumoral catecholamine production, may be used to triage patients according to likelihood of disease

Impact of 123 I-MIBG scintigraphy on clinical decision making in pheochromocytoma and paraganglioma

CONTEXT Cross sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is regarded as a first-choice modality for tumor localization in patients with pheochromocytoma and paraganglioma (PPGL). 123I-labeled metaiodobenzylguanidine (123I-MIBG) is widely used for functional imaging but the added diagnostic value is controversial. OBJECTIVE To establish the virtual impact of adding 123I-MIBG scintigraphy to CT or MRI on diagnosis and treatment of PPGL. DESIGN International multicenter retrospective study. INTERVENTION None. PATIENTS 236 unilateral adrenal, 18 bilateral adrenal, 48 unifocal extra-adrenal, 12 multifocal and 26 metastatic PPGL. MAIN OUTCOME MEASURES Patients underwent both anatomical imaging (CT and/or MRI) and 123I-MIBG scintigraphy. Local imaging reports were analyzed centrally by two independent observers who were blinded to the diagnosis. Imaging-based diagnoses determined by CT/MRI only, 123I-MIBG only, and CT/MRI combined with 123I-MIBG scintigraphy were compared with the correct diagnoses. RESULTS The rates of correct imaging-based diagnoses determined by CT/MRI only versus CT/MRI plus 123I-MIBG scintigraphy were similar: 89.4 versus 88.8%, respectively, (P=0.50). Adding 123I-MIBG scintigraphy to CT/MRI resulted in a correct change in the imaging-based diagnosis and ensuing virtual treatment in four cases (1.2%: two metastatic instead of non-metastatic, one multifocal instead of single, one unilateral instead of bilateral adrenal) at the cost of an incorrect change in seven cases (2.1%: four metastatic instead of non-metastatic, two multifocal instead of unifocal and one bilateral instead of unilateral adrenal). CONCLUSIONS For the initial localization of PPGL, the addition of 123I-MIBG scintigraphy to CT/MRI rarely improves the diagnostic accuracy at the cost of incorrect interpretation in others, even when 123I-MIBG scintigraphy is restricted to patients who are at risk for metastatic disease. In this setting, the impact of 123I-MIBG scintigraphy on clinical decision-making appears very limited

Delineating endogenous Cushing's syndrome by GC-MS urinary steroid metabotyping

BACKGROUND Diagnosing Cushing's syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS. METHODS We quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing's disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female). FINDINGS Cluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11β-OH-An + 11β-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%. INTERPRETATION GC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes. FUNDING The study was funded by the Else Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung