Metastatic disease and major adverse cardiovascular events preceding diagnosis are the main determinants of disease-specific survival of pheochromocytoma/paraganglioma: long-term follow-up of 303 patients.

Purpose: The natural history in unselected cohorts of patients with pheochromocytoma/ paraganglioma (PPGL) followed for a period >10 years remains limited. We aimed to describe baseline characteristics and outcome of a large cohort and to identify predictors of shorter survival. Methods: This retrospective single-center study included 303 patients with newly diagnosed PPGL from 1968 to December 31, 2023, in 199 prospectively supplemented since July 2020. Mean follow-up was 11.4 (range 0.3-50) years, germline genetic analyses were available in 92.1%. The main outcome measures were overall (OAS), disease-specific (DSS), recurrence-free (RFS) survival and predictors of shorter survival evaluated in patients with metastases at first diagnosis (n=12), metastatic (n=24) and nonmetastatic (n=33) recurrences and without evidence of PPGL after first surgery (n=234). Results: Age at study begin was 49.4 ± 16.3 years. There were 72 (23.8%) deaths, 15 (5.0%), 29 (9.6%) and 28 (9.2%) due to PPGL, cardiovascular disease (CVD) and malignant or other diseases, respectively. Median OAS, DSS1 (tumor-related) and DSS2 (DSS1 and death caused by CVD) were 4.8, 5.9 and 5.2 years (patients with metastases at first diagnosis), 21.2, 21.2 and 19.9 years, and 38.0, undefined and 38.0 years (patients with metastatic and with nonmetastatic recurrences, respectively). Major adverse cardiovascular events (MACE) preceded the first diagnosis in 15% (n=44). Shorter DSS2 correlated with older age (P ≤ 0.001), male sex (P ≤ 0.02), MACE (P ≤ 0.01) and primary metastases (P<0.0001, also for DSS1). Conclusion: The clinical course of unselected patients with PPGL is rather benign. Survival rates remain high for decades, unless there are MACE before diagnosis or metastatic disease.

Adverse skeletal related events in patients with bone-metastatic pheochromocytoma/paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications. Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset. In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled. SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0-246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309-0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410-0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877-0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396-0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405-0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274-0.718]; P = .001) were associated with a reduced risk of death. SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome.

Analysis of clinical and pathological characteristics of retroperitoneal paraganglioma and associated prognostic factors.

BACKGROUND AND OBJECTIVES: The aim of this study is to explore the long-term prognostic risk factors associated with patients diagnosed with retroperitoneal paraganglioma (RPGL) and examine their clinical and pathological characteristics. METHODS: Expressions of biomarkers were identified using immunohistochemistry (IHC) and case databases were retrospectively searched. Survival analysis was performed using Kaplan-Meier and Cox risk regression to identify the factors that influence the postoperative progression-free survival of patients with RPGL. RESULTS: A total of 105 patients, most of whom had tumors situated in the paraaortic region, and whose average tumor size was 8.6 cm, were enrolled in this study. The average follow-up duration was 51 months, with a mortality rate of 19% and a recurrence and metastasis rate of 41.9%. Tumors were assessed using the modified Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP), and SDHB, S-100, and Ki-67 were stained using IHC in all cases. Out of the total cases examined, negative in SDHB expression were observed in 18.1% of cases, S-100 expression was negative in 36.2% of cases, and endovascular tumor enboluswas present in approximately 25.7% of cases. The results of the univariate analysis indicated that several factors significantly influenced the progression-free survival of patients with PGL as follow: maximum tumor diameter (>5.5 cm), tumor morphological features, tumor grading (modified GAPP score > 6), SDHB negative, S-100 negative, and expression of proliferation index Ki-67 (>3%) (X2 = 4.217-27.420, p < 0.05). The results of the multivariate analysis indicated that negative of S-100 (p = 0.021) and SDHB (p = 0.038), as well as intravascular tumor thrombus (p = 0.047) expression were independent risk factors for progression-free survival in patients. CONCLUSION: RPGL is characterized by diverse biological features and an elevated susceptibility to both recurrence and metastasis. Both SDHB and S-100 can be employed as traditional IHC indicators to predict the metastatic risk of PGL, whereas the tumor histomorphology-endovascular tumor enbolus assists in determining the metastasis risk of RPGL.

Outcomes of SDHB Pathogenic Variant Carriers.

CONTEXT: Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase type B (SDHB) are at increased risk of developing pheochromocytomas and paragangliomas (PPGLs). Understanding their outcomes can guide recommendations for risk assessment and early detection. OBJECTIVE: We performed a systematic review and meta-analysis of the following outcomes in SDHB PV carriers: age-specific risk of developing tumors, metastatic progression, second primary tumor development, and mortality. METHODS: PubMed, MEDLINE, and EMBASE were searched. Sixteen studies met the inclusion criteria and were sorted into 4 outcome categories: age-specific penetrance, metastatic disease, risk of second tumor, and mortality. We assessed heterogeneity and performed a meta-analysis across studies using a random-effects model with the DerSimonian and Laird method. RESULTS: Penetrance of PPGLs for nonproband/nonindex SDHB PV carriers by age 20 was 4% (95% CI, 3%-6%), 11% (95% CI, 8%-15%) by age 40, 24% (95% CI, 19%-31%) by age 60%, and 35% (95% CI, 25%-47%) by age 80. The overall risk of metastatic disease for nonproband/nonindex carriers with PPGLs was 9% (95%, CI 5%-16%) per lifetime. In all affected cases (combining both proband/index and nonproband/nonindex carriers with tumors), the risk of a second tumor was 24% (95% CI, 18%-31%) and all-cause 5-year mortality was 18% (95% CI, 6%-40%). CONCLUSION: Penetrance for PPGLs in SDHB PV carriers increases linearly with age. Affected carriers are at risk of developing and dying of metastatic disease, or of developing second tumors. Lifelong surveillance is appropriate.

Management and outcome of metastatic pheochromocytomas/paragangliomas: a monocentric experience.

BACKGROUND: Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors releasing catecholamines. Metastatic pheochromocytomas/paragangliomas (PPGLs) occur in about 5-26% of cases. To date, the management of patients affected by metastatic disease is a challenge in the absence of guidelines. AIM: The aim of this study was to evaluate the overall survival (OS) and the progression-free survival (PFS) in metastatic PPGLs. METHODS: Clinical data of 20 patients referred to the Careggi University Hospital (Florence, Italy) were retrospectively collected. Follow-up ranged from 1989 to 2019. Site and size of primary tumor, biochemical activity, genetic analysis and employed therapies were considered. Data were analyzed with SPSS version 27. RESULTS: Nine PHEOs (45%) and 11 PGLs (55%) were enrolled. Median age at diagnosis was 43.5 years [30-55]. Mean follow-up was 104.6 ± 89.3 months. Catecholamines were released in 70% of cases. An inherited disease was reported in 50% of patients. OS from the initial diagnosis (OSpt) and from the metastatic appearance (OSmtx) were lower in older patients (OSpt p = 0.028; OSmtx p < 0.001), abdominal PGLs (OSpt p = 0.007; OSmtx p = 0.041), larger tumors (OSpt p = 0.008; OSmtx p = 0.025) and sporadic disease (OSpt p = 0.013; OSmtx p = 0.008). CONCLUSION: Our data showed that older age at the initial diagnosis, sympathetic extra-adrenal localization, larger tumors and wild-type neoplasms are related to worse prognosis. Notably, the employed therapies do not seem to influence the survival of our patients. At present, effective treatments for metastatic PPGLs are missing and a multidisciplinary approach is indispensably required.

Prognostic Nomograms for Predicting Overall Survival and Cancer-Specific Survival of Patients With Malignant Pheochromocytoma and Paraganglioma.

Background: Malignant pheochromocytoma and paraganglioma (PPGL) are rare tumors with few prognostic tools. This study aimed to construct nomograms for predicting 3- and 5-year survival for patients with malignant PPGL. Methods: The patient data was retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. A total of 764 patients diagnosed with malignant PPGL from 1975 to 2016 were included in this study. The patients were randomly divided into two cohorts; the training cohort (n = 536) and the validation cohort (n = 228). Univariate analysis, Lasso regression, and multivariate Cox analysis were used to identify independent prognostic factors, which were then utilized to construct survival nomograms. The nomograms were used to predict 3- and 5-year overall survival (OS) and cancer-specific survival (CSS) for patients with malignant PPGL. The prediction accuracy of the nomogram was assessed using the concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves. Decision curve analysis (DCAs) was used to evaluate the performance of survival models. Results: Age, gender, tumor type, tumor stage, or surgery were independent prognostic factors for OS in patients with malignant PPGL, while age, tumor stage, or surgery were independent prognostic factors for CSS (P <.05). Based on these factors, we successfully constructed the OS and CSS nomograms. The C-indexes were 0.747 and 0.742 for the OS and CSS nomograms, respectively. In addition, both the calibration curves and ROC curves for the model exhibited reliable performance. Conclusion: We successfully constructed nomograms for predicting the OS and CSS of patients with malignant PPGL. The nomograms could inform personalized clinical management of the patients.

Identification of vital prognostic genes related to tumor microenvironment in pheochromocytoma and paraganglioma based on weighted gene co-expression network analysis.

Pheochromocytoma and paraganglioma (PCPG) is a rare neuroendocrine tumor. This study aims to identify vital prognostic genes which were associated with PCPG tumor microenvironment (TME). We downloaded transcriptome data of PCPG from TCGA database and calculated the immune scores and stromal scores by using the ESTIMATE algorithm. DEGs related to TMB were then identified. We conducted WGCNA to further extract the TME-related modules. GO, KEGG pathway analysis, and PPI network were performed. Survival analysis was conducted to identify the hub genes associated with the prognosis of PCPG. A total of 150 PCPG samples were included in this study. We obtained 1507 and 2067 DEGs based on immune scores and stromal scores, respectively. WGCNA analysis identified the red module and brown module were correlated with immune sores while the turquoise module and red module were significantly associated with stromal scores. Functional enrichments analysis revealed that 307 TME-related genes were correlated with the inflammation or immune response. Survival analysis showed that three TME-relate genes (ADGRE1, CCL18, and LILRA6) were associated with PCPG prognosis. These three hub genes including ADGRE1, CCL18, and LILRA6 might be involved in the progression of PCPG and could serve as potential biomarkers and novel therapeutic targets.

Pregnancy and phaeochromocytoma/paraganglioma: clinical clues affecting diagnosis and outcome - a systematic review.

BACKGROUND: Phaeochromocytoma and paraganglioma (PPGL) in pregnancy, if not diagnosed antepartum, pose a high risk for mother and child. OBJECTIVE: To examine the clinical clues of antepartum and postpartum/postmortem diagnosis of PPGL. SEARCH STRATEGY: Case reports on PPGL in pregnancy published between 1 January 1988 and 30 June 2019 in English, German, Dutch or French. SELECTION CRITERIA: Case reports containing a predefined minimum of clinical data on PPGL and pregnancy. DATA COLLECTION AND ANALYSIS: Two authors independently performed data extraction and assessed data quality. We calculated odds ratios (OR) (with 95% confidence intervals) and used uni- and multivariable logistic regression analysis. MAIN RESULTS: Maternal and fetal/neonatal mortalities were 9.0% (18/200) and 14.2% (29/204), respectively. Maternal mortality was 42-fold higher with PPGL diagnosed postpartum/postmortem (17/58; 29.3%) than antepartum (1/142; 0.7%) (adjusted OR 45.9, 95% CI 5.67-370, P = 0.0003). Offspring mortality was 2.6-fold higher with PPGL diagnosed postpartum/postmortem than antepartum (OR 3.1, 95% CI 1.38-6.91, P = 0.0044). Hypertension at admission (OR 2.29, 95% CI 1.12-4.68, P = 0.022), sweating (OR 3.14, 95% CI 1.29-7.63, P = 0.014) and a history of PPGL, a known PPGL-associated gene mutation or adrenal mass (OR 8.87, 95% CI 1.89-41.64, P = 0.0056) were independent factors of antepartum diagnosis. Acute onset of symptoms (OR 8.49, 95% CI 3.52-20.5, P < 0.0001), initial diagnosis of pre-eclampsia (OR 6.34, 95% CI 2.60-15.5, P < 0.0001), admission for obstetric care (OR 10.71, 95% CI 2.70-42.45, P = 0.0007) and maternal tachycardia (OR 2.72, 95% CI 1.26-5.85, P = 0.011) were independent factors of postpartum diagnosis. CONCLUSION: Several clinical clues can assist clinicians in considering an antenatal diagnosis of PPGL in pregnancy, thus potentially improving outcome. TWEETABLE ABSTRACT: Systematic review of 204 pregnant patients with phaeochromocytoma identified clinical clues for a timely antepartum diagnosis.

Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma: A Comparison of PASS and GAPP Scoring Systems.

PURPOSE: The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP) are scoring systems to predict metastatic potential in pheochromocytomas (PCC) and paragangliomas (PGLs). The goal of this study is to assess PASS and GAPP as metastatic predictors and to correlate with survival outcomes. METHODS: The cohort included PCC/PGL with ≥5 years of follow-up or known metastases. Surgical pathology slides were rereviewed. PASS and GAPP scores were assigned. Univariable and multivariable logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards were performed to assess recurrence-free survival (RFS) and disease-specific survival (DSS). RESULTS: From 143 subjects, 106 tumors were PCC and 37 were PGL. Metastases developed in 24%. The median PASS score was 6.5 (interquartile range [IQR]: 4.0-8.0) and median GAPP score was 3.0 (IQR: 2.0-4.0). Interrater reliability was low-moderate for PASS (intraclass correlation coefficient [ICC]: 0.6082) and good for GAPP (ICC 0.7921). Older age (OR: 0.969, P = .0170) was associated with longer RFS. SDHB germline pathogenic variant (OR: 8.205, P = .0049), extra-adrenal tumor (OR: 6.357, P < .0001), Ki-67 index 1% to 3% (OR: 4.810, P = .0477), and higher GAPP score (OR: 1.537, P = .0047) were associated with shorter RFS. PASS score was not associated with RFS (P = .1779). On Cox regression, a GAPP score in the moderately differentiated range was significantly associated with disease recurrence (HR: 3.367, P = .0184) compared with well-differentiated score. CONCLUSION: Higher GAPP scores were associated with aggressive PCC/PGL. PASS score was not associated with metastases and demonstrated significant interobserver variability. Scoring systems for predicting metastatic PCC/PGL may be improved by incorporation of histopathology, clinical data, and germline and somatic tumor markers.

Bladder Preservation for Patients With Bladder Paragangliomas: Case Series and Review of the Literature.

Bladder paragangliomas are rare tumors, with no prospective studies or guidelines on the management of this disease. We present a case series of 6 patients managed with bladder preservation over a median follow-up period of 124 months. We also present a review of the recent literature on bladder paragangliomas. We aim to provide a timely synthesis of the recent evidence on bladder paragangliomas as changing paradigms necessitate individualized treatment.

Pheochromocytoma and Paraganglioma Patients With Poor Survival Often Show Brown Adipose Tissue Activation.

CONTEXT: Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on ß-adrenoceptors (ß-ARs). In some malignancies, BAT activation is associated with higher cancer activity. OBJECTIVE: To study the relationship between BAT activation and PPGL clinical outcomes. DESIGN: A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT [7.80%; age 27.50 (15.00-45.50) years; 10 female/6 male; body mass index [BMI] 24.90 [19.60-25.35] kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 [25.4-45.5] years; 21 female/15 male; BMI 25.0 [22.0-26.0] kg/m2). PRIMARY OUTCOME MEASURE: Overall survival. RESULTS: The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05-32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group [4.65 vs 0.55 times above the upper limit of normal; P < 0.01]. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups. CONCLUSIONS: Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL.

Transcriptome Analysis of lncRNAs in Pheochromocytomas and Paragangliomas.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors explained by germline or somatic mutations in about 70% of cases. Patients with SDHB mutations are at high risk of developing metastatic disease, yet no reliable tumor biomarkers are available to predict tumor aggressiveness. OBJECTIVE: We aimed at identifying long noncoding RNAs (lncRNAs) specific for PPGL molecular groups and metastatic progression. DESIGN AND METHODS: To analyze the expression of lncRNAs, we used a mining approach of transcriptome data from a well-characterized series of 187 tumor tissues. Clustering consensus analysis was performed to determine a lncRNA-based classification, and informative transcripts were validated in an independent series of 51 PPGLs. The expression of metastasis-related lncRNAs was confirmed by RT-qPCR. Receiver operating characteristic (ROC) curve analysis was used to estimate the predictive accuracy of potential markers. MAIN OUTCOME MEASURE: Univariate/multivariate and metastasis-free survival (MFS) analyses were carried out for the assessment of risk factors and clinical outcomes. RESULTS: Four lncRNA-based subtypes strongly correlated with mRNA expression clusters (chi-square P-values from 1.38 × 10-32 to 1.07 × 10-67). We identified one putative lncRNA (GenBank: BC063866) that accurately discriminates metastatic from benign tumors in patients with SDHx mutations (area under the curve 0.95; P = 4.59 × 10-05). Moreover, this transcript appeared as an independent risk factor associated with poor clinical outcome of SDHx carriers (log-rank test P = 2.29 × 10-05). CONCLUSION: Our findings extend the spectrum of transcriptional dysregulations in PPGL to lncRNAs and provide a novel biomarker that could be useful to identify potentially metastatic tumors in patients carrying SDHx mutations.

Paragangliomas of the Head and Neck: Local Control and Functional Outcome Following Fractionated Stereotactic Radiotherapy.

OBJECTIVES: To investigate local control and functional outcome following state-of-the-art fractionated stereotactic radiotherapy (FSRT) for paragangliomas of the head and neck. METHODS: In total, 40 consecutive patients with paragangliomas of the head and neck received conventionally FSRT from 2003 to 2016 at the Department of Radiation Oncology of the University Hospital Erlangen. Local control, toxicities, and functional outcome were examined during follow-up. In total, 148 magnetic resonance imaging studies were subjected to longitudinal volumetric analysis using whole tumor segmentation in a subset of 22 patients. RESULTS: A total of 80.0% (32/40) of patients received radiotherapy as part of their primary treatment. In 20.0% (8/40) of patients, radiation was used as salvage treatment after tumor recurrence in patients initially treated with surgery alone. The median dose applied was 54.0 Gy (interdecile range, 50.4 to 56.0 Gy) in single doses of 1.8 or 2 Gy. Local control was 100% after a median imaging follow-up of 52.2 months (range, 0.8 to 152.9 mo). The volumetric analysis confirmed sustained tumor control in a subset of 22 patients and showed transient enlargement (range, 129.6% to 151.2%) in 13.6% of cases (3/22). After a median volumetric follow-up of 24.6 months mean tumor volume had diminished to 86.1% compared with initial volume. In total, 52.5% (21/40) of patients reported improved symptoms after radiotherapy, 40% (16/40) observed no subjective change with only 7.5% (3/40) reporting significant worsening. CONCLUSIONS: State-of-the-art FSRT provides excellent control and favorable functional outcome in patients with paragangliomas of the head and neck. The volumetric analysis provides improved evidence for sustained tumor control.

Retrospective application of the pathologic tumor-node-metastasis classification system for pheochromocytoma and abdominal paraganglioma in a well characterized cohort with long-term follow-up.

BACKGROUND: A pathologic tumor-node-metastasis staging algorithm for pheochromocytoma and sympathetic paraganglioma was introduced recently in the 8th Edition of the cancer staging manual of the American Joint Committee on Cancer. There is no information, however, as to how this staging correlates to well-established clinical cohorts of pheochromocytoma and sympathetic paraganglioma with extensive follow-up. METHODS: We applied the pathologic tumor-node-metastasis staging retrospectively to a cohort of 118 patients with pheochromocytoma and sympathetic paraganglioma, in which the majority has been characterized for susceptibility gene mutations and global mRNA expressional patterns as well as histologic risk criteria using the pheochromocytoma of the adrenal gland scaled score (PASS). RESULTS: The overall tumor stage correlated with the presence of metastases, disease-related death, and PASS scores as well as established mutational and expressional clusters. CONCLUSION: Stage III to IV pheochromocytomas and sympathetic paragangliomas are associated with increased mortality, increased PASS scores, and mutational and expressional aberrancies in the pseudo-hypoxia pathway cluster. These findings validate the stratification proposed by the American Joint Committee on Cancer staging manual by linking malignancy-associated pheno- and genotypes to more advanced stages. Moreover, because few pheochromocytomas and sympathetic paragangliomas are metastatic at the time of the original presentation, the staging relies heavily on identifying histologic signs of extra-adrenal invasion.

COPPS, a composite score integrating pathological features, PS100 and SDHB losses, predicts the risk of metastasis and progression-free survival in pheochromocytomas/paragangliomas.

Current histoprognostic parameters and prognostic scores used in paragangliomas and pheochromocytomas do not adequately predict the risk of metastastic progression and survival. Here, using a series of 147 cases of paraganglioma and pheochromocytoma, we designed and evaluated the potential of a new score, the COPPS (COmposite Pheochromocytoma/paraganglioma Prognostic Score), by taking into consideration three clinico-pathological features (including tumor size, necrosis, and vascular invasion), and the losses of PS100 and SDHB immunostain to predict the risk of metastasis. We compared also the performance of the COPPS with several presently used histoprognostic parameters in risk assessment of these tumors. A PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 6 was significantly associated with the occurrence of metastases (P < 0.0001) and shorter PFS (P = 0.013). In addition, both MCM6 and Ki-67 LI correlated with worse PFS (P = 0.004 and P < 0.0001, respectively), and MCM6, but not Ki-67, was significantly higher in metastatic group (P = 0.0004). Loss of PS100 staining correlated with the occurrence of metastasis (P < 0.0001) and shorter PFS (P < 0.0001). At a value of greater or equal to 3, the COPPS correlated with shorter PFS (P < 0.0001), and predicted reproducibly (weighted Kappa coefficient, 0.863) the occurrence of metastases with a sensitivity of 100.0% and specificity of 94.7%. It thus surpassed those found for either PASS, SDHB, MCM6, or Ki-67 alone. In conclusion, while validation is still necessary in independent confirmatory cohorts, COPPS could be of great potential for the risk assessment of metastasis and progression in paragangliomas and pheochromocytomas.

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

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.

Paraganglioma of the head and neck region, treated with radiation therapy, a Rare Cancer Network study.

BACKGROUND: Paraganglioma of the head and neck (HNPGL) are rare often benign tumors. Surgery and radiation therapy (RT) are the main treatment choices. We present an analysis of outcome and toxicity after RT from 13 institutions of the Rare Cancer Network. METHODS: Data were collected using a questionnaire concerning patients' characteristics, treatment, and outcome. A total of 81 patients with 82 HNPGL were analyzed. RESULTS: The median follow-up was 48 months (1-456). Sixty-two lesions were treated with conventional RT and 20 lesions with stereotactic RT. Local control (LC) was achieved in 69 out of 77 lesions. Late toxicity occurred in 17 patients. Patients treated with stereotactic RT experienced neither disease progression nor late toxicity. Four patients with a follow-up longer than 20 years experienced disease progression. CONCLUSION: RT for HNPGL offered good local control with acceptable toxicity. Stereotactic RT might offer better results. Long-term follow-up is required.

Positive Impact of Genetic Test on the Management and Outcome of Patients With Paraganglioma and/or Pheochromocytoma.

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.

The who, when, and why of primary adrenal malignancies: Insights into the epidemiology of a rare clinical entity.

BACKGROUND: Primary malignancies of the adrenal glands are rare. Epidemiologic assessment of primary adrenal malignancies is lacking and has been limited to case reports and series. Population-level data can provide a better understanding of the incidence, distribution, and prognostic factors associated with these rare malignancies. METHODS: The Surveillance, Epidemiology, and End Results database (1973-2013) was queried for all patients who were diagnosed with primary adrenal malignancies, categorized in 5 histologic groups: adrenocortical carcinoma (ACC), pheochromocytoma and paraganglioma (PH), neuroblastoma (NE), non-Hodgkin lymphoma (NHL), and sarcoma (SA). Age-adjusted incidence, distribution trends, and cancer-specific survival (CSS) for each group were analyzed. RESULTS: In total, 4695 patients with primary adrenal malignancies were identified, including 2057 with ACC, 512 with PH, 1863 with NE, 202 with NHL, and 61 with SA. The age-adjusted incidence of all 5 histologic subtypes was rising. Age at presentation differed substantially by histologic group: NE was the most prevalent during the first decade of life, whereas ACC predominated after age 30 years, and NHL outnumbered PH after age 70 years. Patient-specific factors were not associated with advanced disease at the time of presentation. The 5-year CSS rate for each histologic subtype was 38% for ACC, 69% for PH, 64% for NE, 38% for NHL, and 42% for SA. Survival outcomes for patients with ACC, NHL, PH and SA remained unchanged over the 40-year study period. Multimodal therapy was associated with higher CSS in patients with NE. CONCLUSIONS: This first population-level analysis of all primary adrenal malignancies provides important initial data regarding presentation and clinical outcomes. Notably, except for patients with NE, the survival of patients with these rare cancers has not improved over the past 40 years.

Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers.

The succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle. Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis. Succinate accumulation inhibits 2-oxoglutarate-dependent dioxygenases, including DNA and histone demethylase enzymes and hypoxic gene response regulators. Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours. Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours. Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5-year mortality of 50%. There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours. However, there is no consensus on when and how surveillance should be performed in children and young adults. Here, we address the question: "What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?".