Genotype-phenotype correlations in paediatric and adolescent phaeochromocytoma and paraganglioma: a cross-sectional study.

Phaeochromocytoma (PC) and paraganglioma (PGL) syndromes associated with germline pathogenic variants are associated with high morbidity and mortality. Establishing genotype-phenotype correlations within a young population is challenging due to their rare occurrence. OBJECTIVE: To describe genotype-phenotype correlations in paediatric and adolescent patients diagnosed with PC/PGL. To establish the incidence of PC/PGL in a young population and prevalence of germline pathogenic variants within this group. STUDY DESIGN: We conducted a cross-sectional study of patients diagnosed with a PC/PGL aged 0-21 years old who were reviewed within Familial Cancer Services within New South Wales and the Australian Capital Territory, Australia. RESULTS: A germline pathogenic variant was detected in 80% (24/30) of patients; SDHB: n=12, VHL: n=11, and MAX: n=1. Only patients harbouring a germline pathogenic variant reported a family history of syndromic tumours, those with apparently sporadic disease did not (62.5% versus 0%, p=0.02). All patients with VHL presented with an adrenal tumour compared with 25% of those with SDHB (100% versus 25%, p=0.01). Occurrence of multiple primary PC/PGL was seen in patients with VHL however was absent in patients with SDHB (36% versus 0%, p=0.03). Incidence rate of paediatric PC/PGL was 0.45 cases per million person years. CONCLUSIONS: PC/PGL diagnosed in children and adolescents were strongly associated with germline pathogenic variants in VHL or SDHB. These patients should be referred to specialist services for family counselling and genetic testing along followed by investigations for the detection of bilateral, multifocal or metastatic disease, and lifelong surveillance for recurrent disease.

High incidence of occult familial SDHD cases amongst Czech patients with head and neck paragangliomas.

Introduction: Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors, which are mostly benign in nature. Amongst all genes, Succinate Dehydrogenase Subunit D (SDHD) is the most commonly mutated in familial HNPGLs. In about 30% of HNPGLs, germline mutations in SDHD can also occur in the absence of positive family history, thus giving rise to "occult familial" cases. Our aim was to evaluate the pattern of SDHD germline mutations in Czech patients with HNPGLs. Materials and methods: We analyzed a total of 105 patients with HNPGLs from the Otorhinolaryngology departments of 2 tertiary centers between 2006 - 2021. All underwent complex diagnostic work-up and were also consented for genetic analysis. Results: Eighty patients aged 13-76 years were included; around 60% with multiple PGLs were males. Carotid body tumor was the most frequently diagnosed tumor. Germline SDHD mutation was found in only 12% of the Czech patients; approximately 78% of those harboring the mutation had negative family history. The mutation traits had higher affiliation for multiple tumors with nearly 70% patients of ≤ 40 years of age. Conclusion: An SDHD mutation variant was shared amongst unrelated patients but no founder-effect was established. Our findings confirmed that the pattern of SDHD mutation distribution amongst HNPGLs in Czech Republic differs from most studies worldwide.

[Rare forms of hereditary endocrine neoplasia: co-existence of pituitary adenoma and pheochromocytoma/paraganglioma].

Functioning pituitary adenomas and pheochromocytomas/paragangliomas are rare in the general population. Pituitary adenomas occur in the familial setting in approximately 5% of cases, whereas pheochromocytomas/paragangliomas can be hereditary in 30-40% of cases. Hereditary syndromes associated with pituitary adenomas include multiple endocrine neoplasia types 1 and 4, familial isolated pituitary adenomas, and Carney complex. Hereditary syndromes associated with pheochromocytomas/paragangliomas and genes, mutations in which predispose to their development, are more numerous. The first clinical descriptions of the co-occurrence of pituitary adenoma and pheochromocytoma/paraganglioma in one patient date back to the mid 20th century, however delineating such a co-occurrence into a particular syndrome («3PAs¼ (pituitary adenoma, pheochromocytoma, paraganglioma)) was suggested only in 2015. To date, approximately 100 cases of such a co-occurrence have been described in the literature. Mutations in genes encoding subunits of succinate dehydrogenase complex II (SDHx) are revealed in the majority of cases, much less common are mutations in MAX, MEN1 and some other genes. This review summarizes the current information on the «3PAs¼ syndrome.

Genotype-phenotype associations in paragangliomas of the temporal bone in a multi-ethnic cohort.

BACKGROUND: Temporal bone paragangliomas are rare tumours with variable presentation that can be hereditary. Identification of clinical and genetic factors of aggressive tumour behaviour is important. OBJECTIVE: To determine the underlying genetic mutations and genotype/phenotype correlations in a multi-ethnic population of South Florida with sporadic temporal bone paragangliomas. METHODS: In a cohort of glomus tympanicum (GT) and glomus jugulare (GJ) cases, we assessed the frequency of pathogenic single nucleotide variants, insertions, deletions, and duplications in coding exons of genes that have been associated with paragangliomas (SDHB, SDHC, SDHD, SDHA, SDHAF2, RET, NF1, VHL, TMEM127, and MAX). RESULTS: None of the 12 GT cases had mutations. Among 13 GJ cases, we identified four mutation carriers (31%); two in SDHC, one in SDHB, and one in SDHD. All patients with pathogenic mutations were of Hispanic ethnicity, presented at a younger age (mean 27.5 versus 52.11 years), and with more advanced disease when compared to mutation-negative GJ cases.Conclusions and Significance: Mutations in the SDH genes are found in 31% of sporadic GJ. SDH-associated GJ had advanced disease and a 50% risk of metastasis. Our data supports emerging recommendations for genetic screening in all populations with GJ tumours as the genetic status informs management.

SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma.

BACKGROUND: Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy. METHODS: We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis. RESULTS: Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant. CONCLUSION: SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.

Recurrent Disease in Patients With Sporadic Pheochromocytoma and Paraganglioma.

CONTEXT: Long-term follow-up has been recommended for patients with pheochromocytoma or paraganglioma (PPGL) due to potential for recurrent disease. However, the need to follow patients with sporadic PPGL has recently become controversial. OBJECTIVE: To investigate the prevalence of recurrence among patients with sporadic compared with hereditary PPGL and to identify predictors of recurrence for sporadic disease. METHODS: This multicenter study included retrospective data from 1127 patients with PPGL. In addition to sex and age at primary tumor diagnosis, clinical information included location, size, and catecholamine phenotype of primary tumors, genetic test results, and subsequent development of recurrent and/or metastatic disease. Patients with sporadic PPGL were defined as those with negative genetic test results. RESULTS: Prevalence of recurrence among patients with sporadic PPGL (14.7%) was lower (P < 0.001) than for patients with pathogenic variants that activate pseudohypoxia pathways (47.5%), but similar to those with variants that activate kinase pathways (14.9%). Among patients with sporadic recurrent PPGL, 29.1% and 17.7% were respectively diagnosed at least 10 and 15 years after first diagnosis. Multivariable regression analysis showed that a noradrenergic/dopaminergic phenotype (HR 2.73; 95% CI, 1.553-4.802; P < 0.001), larger size (HR 1.82; 95% CI, 1.113-2.962; P = 0.017) and extra-adrenal location (HR 1.79; 95% CI, 1.002-3.187; P = 0.049) of primary tumors were independent predictors of recurrence in sporadic PPGL. CONCLUSION: Patients with sporadic PPGL require long-term follow-up, as supported by the 14.7% prevalence of recurrent disease, including recurrences at more than 10 years after first diagnosis. The nature of follow-up could be individualized according to tumor size, location, and biochemical phenotype.

Rates of Pheochromocytoma/Paraganglioma Screening in At-Risk Populations.

CONTEXT: Pheochromocytomas and paragangliomas (PPGL) are rare causes of secondary hypertension, but when unrecognized, they can lead to serious complications. Data regarding PPGL screening are lacking. OBJECTIVE: This study aimed to assess the rates and patterns of PPGL screening among eligible patients. METHODS: We conducted a retrospective review of adults with hypertension seen in outpatient clinics of a large academic center between January 1, 2017, and June 30, 2020. We included patients with treatment-resistant hypertension, hypertension at age < 35 years, and/or adrenal mass(es). RESULTS: Of 203 535 patients with hypertension identified, 71 088 (35%) met ≥ 1 inclusion criteria, and 2013 (2.83%) were screened for PPGL. Patients screened were younger (56.2 ± 17.4 vs 64.0 ± 17.1 years), more often women (54.1% vs 44.2%), and never-smokers (54.6% vs 47.5%, P < 0.001 for all). The rate of screening was highest in patients with hypertension and adrenal mass(es) (51.7%, vs 3.9% in patients with early-onset hypertension, and 2.4% in those with treatment-resistant hypertension). Multivariable logistic regression showed higher odds ratio (OR) of PPGL screening in women (OR [95% CI]: 1.48 [1.34-1.63]); Black vs White patients (1.35 [1.19-1.53]); patients with adrenal mass(es) (55.1 [44.53-68.15]), stroke (1.34 [1.16-1.54]), dyslipidemia (1.41 [1.26-1.58]), chronic kidney disease (1.40 [1.26-1.56]), and obstructive sleep apnea (1.96 [1.76-2.19]). CONCLUSION: PPGL screening is pursued in roughly half of patients with adrenal nodules and hypertension, but rarely in patients with treatment-resistant or early-onset hypertension. Similar to screening for other forms of secondary hypertension, PPGL screening occurs more often after serious complications develop.

Somatic IDH1 Hotspot Variants in Chinese Patients With Pheochromocytomas and Paragangliomas.

CONTEXT: IDH1 is a pheochromocytoma/paraganglioma (PPGL) susceptibility gene; however, its role, especially in the Chinese population, has not been characterized. OBJECTIVE: To determine the prevalence of somatic IDH1 hotspot variants in a large cohort of Chinese patients with PPGLs and to summarize associated phenotypes. METHODS: This retrospective cross-sectional study was based on a main cohort of 1141 patients with PPGLs from 2 tertiary-care centers in China. We included 50 cases with urinary bladder paragangliomas (UBPGLs), of whom 29 were part of the main cohort and 21 were from other centers. Two additional cases with IDH1 hotspot variants not part of the main cohort were also included for summarizing IDH1-associated phenotypes. Next-generation sequencing of tumor DNA was used to analyze a customized panel of genes. RESULTS: The overall prevalence of IDH1 hotspot variants in the main cohort was 0.5% (6/1141). Among those PPGLs without mutations in 15 common driver genes, the prevalence of IDH1 variants was 0.9% (4/455). When restricted to paraganglioma (PGL) without mutations, the prevalence reached 4.7% (4/86). Among UBPGLs, IDH1 hotspot variants accounted for 8% (4/50). Together, all 10 patients (9 PGLs and 1 pheochromocytoma) with IDH1 hotspot variants, including 3 females with concurrent EPAS1 hotspot variants, had apparently sporadic tumors, without metastasis or recurrence. There were 3 patients with biochemical data, all showing a non-adrenergic phenotype. CONCLUSIONS: The somatic IDH1 hotspot variants cause PPGL development in some Chinese patients, especially among those apparently sporadic PGLs with a non-adrenergic phenotype and without mutations in major PPGL driver genes.

Paraganglioma of the Head and Neck: A Review.

OBJECTIVE: To review the epidemiology, presentation, diagnosis, and management of head and neck paragangliomas. METHODS: A literature review of english language papers with focus on most current literature. RESULTS: Paragangliomas (PGLs) are a group of neuroendocrine tumors that arise in the parasympathetic or sympathetic ganglia. Head and neck PGLs (HNPGLs) comprise 65% to 70% of all PGLs and account for 0.6% of all head and neck cancers. The majority of HNPGLs are benign, and 6% to 19% of all HNPGLs develop metastasis outside the tumor site and significantly compromise survival. PGLs can have a familial etiology with germline sequence variations in different susceptibility genes, with the gene encoding succinate dehydrogenase being the most common sequence variation, or they can arise from somatic sequence variations or fusion genes. Workup includes biochemical testing to rule out secretory components, although it is rare in HNPGLs. In addition, imaging modalities, such as computed tomography and magnetic resonance imaging, help in monitoring in surgical planning. Functional imaging with DOTATATE-positron emission tomography, 18F-fluorodeoxyglucose, or 18F-fluorohydroxyphenylalanine may be necessary to rule out sites of metastases. The management of HNPGLs is complex depending on pathology, location, and aggressiveness of the tumor. Treatment ranges from observation to resection to systemic treatment. Similarly, the prognosis ranges from a normal life expectancy to a 5-year survival of 11.8% in patients with distant metastasis. CONCLUSION: Our review is a comprehensive summary of the incidence, mortality, pathogenesis, presentation, workup and management of HNPGLs.

Glycemic disorders in patients with pheochromocytomas and sympathetic paragangliomas.

The objective of our study was to determine the prevalence of glycemic disorders (diabetes mellitus and prediabetes) in patients with pheochromocytomas and sympathetic paragangliomas (PPGLs) and identify risk factors for their development and the likelihood of their resolution after surgery. A multicentric retrospective study of patients with PPGLs submitted to surgery between 2000 and 2021 in 17 Spanish hospitals was performed. Diabetes-specific data were collected at diagnosis, in the immediate- and long-term postsurgical follow-up. A total of 229 patients with PPGLs were included (218 with pheochromocytomas and 11 with sympathetic paragangliomas). Before surgery, glycemic disorders were diagnosed in 35.4% of the patients (n = 81): 54 with diabetes and 27 with prediabetes. The variables independently associated with a higher risk of glycemic disorders were sporadic PPGL (odds ratio (OR) = 3.26 (1.14-9.36)) and hypertension (OR = 3.14 (1.09-9.01)). A significant decrease in fasting plasma glucose and HbA1c levels was observed after surgery, in the short-term and long-term follow-up (P < 0.001). After a median follow-up of 48.5 months (range 3.3-168.9), after surgery, 52% of diabetic and 68% of prediabetic patients experienced a complete resolution. Lower body mass index (BMI) (P = 0.001), lower glucose levels (P = 0.047) and shorter duration of diabetes prior to surgery (P = 0.021) were associated with a higher probability of diabetes resolution. In conclusion, glycemic disorders in patients with PPGLs are present in more than a third of them at diagnosis. Sporadic PPGLs and hypertension are risk factors for their development. More than 50% of cases experience a complete resolution of the glycemic disorder after resection of the PPGLs.

Risk Factors for Cardiac Complications in Patients With Pheochromocytoma and Paraganglioma: A Retrospective Single-Center Study.

Background: Catecholamine excess arising from pheochromocytomas and paragangliomas (PPGLs) can cause a wide spectrum of cardiac manifestations. Although there are reviews of reported cases, these reviews lack detailed data, which makes it impossible to perform an accurate analysis. In this study, we conducted a comprehensive analysis of cardiovascular complications (CCs), including PPGL-related myocardial injury, cardiogenic shock, and arrhythmias requiring antiarrhythmic therapy, in a large cohort of patients with PPGL. Methods: We retrospectively analyzed the clinical data of consecutive patients with PPGL admitted between January 2018 and June 2020. The prevalence and the characteristics of patients with CCs were investigated. Moreover, comparisons were made between patients with and without CCs. Results: Compared with the non-CC group, the percentage of men was significantly lower (14/41 vs.92/175, 34.1% vs. 52.6%, p = 0.034) and the proportion of patients with paroxysmal hypertension was significantly higher (13/41 vs.29/173, 31.7% vs.16.8%, p = 0.03) in the CC group. More patients showed excessive sweating (19/41 vs 64/175, 46.3% vs. 24.0%, p = 0.004) and PPGL crisis (7/41 vs. 10/175, 17.1% vs.5.7%, p=0.035) in the CC group. In terms of laboratory findings, higher white blood cell [7.36 (6.49, 20.23) vs. 5.95 (5.1, 6.97)×109/L, p<0.001] and platelet [339.28 ± 108.54 vs. 250.66 ± 70.83(×109/L), p = 0.021] counts were more common in the CC group. There was also a higher prevalence of combination-producing PPGL in the CC group (13/24 vs.20/149, 54.2% vs.13.4%, p<0.001). However, the tumor size, invasive behavior on histology, and hemorrhage or necrosis on histology did not differ between the two groups. Platelet count [odds ratio (OR): 1.009; 95% confidence interval (CI) 1.001-1.016; p=0.023] and combination-secreting PPGL (OR: 5.009; 95% CI 1.365-18.38; p=0.015) are independent risk factors for CCs in patients with PPGL. Conclusions: In patients with PPGL, even in the absence of signs and symptoms of CCs, a work up of cardiology should be strongly considered. Importantly, if patients with PPGLs have higher platelet counts and the combination-secreting pattern, they are more likely to have CCs. Thus, a careful cardiac evaluation should be performed.

Surveillance Improves Outcomes for Carriers of SDHB Pathogenic Variants: A Multicenter Study.

CONTEXT: Carriers of succinate dehydrogenase type B (SDHB) pathogenic variants (PVs) are at risk of pheochromocytoma and paraganglioma (PPGL) from a young age. It is widely recommended carriers enter a surveillance program to detect tumors, but there are limited studies addressing outcomes of surveillance protocols for SDHB PV carriers. OBJECTIVE: The purpose of this study was to describe surveillance-detected (s-d) tumors in SDHB PV carriers enrolled in a surveillance program and to compare their outcomes to probands. METHODS: This was a multicenter study of SDHB PV carriers with at least 1 surveillance episode (clinical, biochemical, imaging) in Australian genetics clinics. Data were collected by both retrospective and ongoing prospective follow-up. Median duration of follow-up was 6.0 years. RESULTS: 181 SDHB PV carriers (33 probands and 148 nonprobands) were assessed. Tumors were detected in 20% of nonprobands undergoing surveillance (age range 9-76 years). Estimated 10-year metastasis-free survival was 66% for probands and 84% for nonprobands with s-d tumors (P = .027). S-d tumors were smaller than those in probands (median 27 mm vs 45 mm respectively, P = .001). Tumor size ≥40 mm was associated with progression to metastatic disease (OR 16.9, 95% CI 2.3-187.9, P = .001). Patients with s-d tumors had lower mortality compared to probands: 10-year overall survival was 79% for probands and 100% for nonprobands (P = .029). CONCLUSION: SDHB carriers with s-d tumors had smaller tumors, reduced risk of metastatic disease, and lower mortality than probands. Our results suggest that SDHB PV carriers should undertake surveillance to improve clinical outcomes.

Special situations in pheochromocytomas and paragangliomas: pregnancy, metastatic disease, and cyanotic congenital heart diseases.

The aim of our study was to describe the epidemiology, diagnosis, and treatment of the most complex pheochromocytoma and paraganglioma (PGL) cases, including pheochromocytoma/PGL during pregnancy, in cyanotic congenital heart diseases (CCHDs), and metastatic pheochromocytoma. The English and Spanish literature was thoroughly evaluated searching for articles reporting clinical studies, case reports, or reviews of pheochromocytoma/PGL in pregnancy and in CCHD and metastatic pheochromocytoma/PGL. Particular settings in the diagnosis and management of pheochromocytoma and PGLs remain challenging. Those special situations include the diagnosis during pregnancy or in the context of CCHD since the typical clinical features of pheochromocytoma may be confounded with preeclampsia during pregnancy and with the complications commonly observed in CCHD. In addition, although some clinical and genetic features have been associated with higher risk of metastatic pheochromocytoma, the detection and prediction of the development of metastatic disease involve another complex situation that may require special hormonal determinations as plasmatic 3-methoxytyramine and nuclear medicine studies including 18FDG PET-CT or 18F-FDOPA PET-CT, among others. Furthermore, the selection of the most appropriate treatment in these situations, as well as the moment to carry it out, requires special care as limited evidence is available. This article reviews the epidemiology, diagnosis, and treatment of the pheochromocytoma/PGL during pregnancy, metastatic pheochromocytoma/PGL, and pheochromocytoma/PGL in CCHD. The diagnosis, and especially the treatment, of metastatic pheochromocytomas and pheochromocytoma/PGL during pregnancy and in CCHD is challenging. Thus, these cases should be management in reference centres by multidisciplinary teams specialized in the pheochromocytoma/PGL treatment.

Re-evaluating the prevalence and factors characteristic of catecholamine secreting head and neck paragangliomas.

INTRODUCTION: We sought to characterize the prevalence and factors characteristic of head and neck paragangliomas (HNPGLs) that secrete catecholamines to inform best practices for diagnosis and management. METHODS: This was a retrospective cohort study from 2000 to 2020 at a single-institution tertiary centre. One-hundred fifty-two patients (182 tumours) with HNPGLs with at least one measurement of urine or plasma catecholamines and/or catecholamine metabolite levels prior to treatment were included. We differentiated and characterized those patients with increased level(s) of any nature and those with 'clinically significant' versus 'clinically insignificant' catecholamine production. RESULTS: Thirty-one (20.4%) patients had increased catecholamine and/or catecholamine metabolite levels. In most patients, these levels were ≤5-fold above the upper limit of the reference range. Four of these 31 patients with increased levels were ultimately found to have an additional catecholamine secreting mediastinal paraganglioma or pheochromocytoma. Fourteen of 31 patients with HNPGL were deemed clinically significant secretors of catecholamines based on hyper-adrenergic symptoms and/or profound levels of normetanephrines. This cohort was enriched for patients with paragangliomas of the carotid body or cervical sympathetic chain and those with SDHB genetic mutations. Ultimately, the prevalence of clinically significant catecholamine secreting Hangs was determined to be 9.2% and 7.7% based on a per-patient and per-tumour basis, respectively. CONCLUSIONS: The rate of catecholamine excess in the current cohort of patients with HNPGLs was higher than previously reported. Neuroendocrine tumours of any anatomic subsite may secrete catecholamines, although not all increased laboratory level(s) are indicative of clinically significant catecholamine secretion causing symptoms or warranting adrenergic blockade.

Correlation Between Plasma Catecholamines, Weight, and Diabetes in Pheochromocytoma and Paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and physiologic changes. OBJECTIVE: The objective was to evaluate relationships between plasma catecholamines, body weight, and hemoglobin A1c (HbA1c). We hypothesized that individual catecholamines would correlate negatively with weight and glucose control. DESIGN: A retrospective cohort study was performed (1999-2020). Wilcoxon rank-sum tests compared nonparametric, continuous variables; mixed-effect linear modeling (MEM) evaluated relationships between catecholamines and weight or HbA1c. The median study duration was 54.2 months [interquartile range (IQR) 19.0-95.1]. SETTING: Tertiary academic hospital. PATIENTS: 360 patients were identified prospectively by referral to our center for management or surveillance of PCC/PGL. The median age was 59 years (IQR 45-67) and 56.4% (n = 203) were female. MAIN OUTCOME MEASURES: The primary and secondary outcomes were weight and HbA1c, respectively. RESULTS: On multivariable MEM, norepinephrine (P < 0.0005) negatively correlated with weight when all catecholamines and their derivatives were tried in the model, and normetanephrine (P < 0.0005) correlated when only metanephrines were included. In the surgical cohort (n = 272), normetanephrine decreased postoperatively and was inversely associated with weight (P < 0.0005). Elevated norepinephrine or normetanephrine at the study termination, indicative of metastatic and/or recurrent disease (MRD), correlated with weight loss. Norepinephrine and normetanephrine (P < 0.0005) directly correlated with HbA1c. CONCLUSION: Plasma norepinephrine and its metabolite directly correlate with HbA1c and inversely correlate with weight in PCC/PGL. After resection, declining normetanephrine levels correlate with improving HbA1c despite an increase in patient body weight. Persistently elevated catecholamines and decreasing weight are observed in MRD.

Acute cardiac complications and subclinical myocardial injuries associated with pheochromocytoma and paraganglioma.

BACKGROUND: Catecholamine excess arising from pheochromocytomas and paragangliomas (PPGLs) can cause a wide spectrum of cardiac manifestations, including acute cardiac complications (ACCs) and subclinical myocardial injuries (SMIs). In this study, we aimed to conduct a comprehensive analysis of ACCs and SMIs in a large cohort of patients with PPGLs. METHODS: We retrospectively analyzed the clinical data of consecutive patients with PPGLs admitted between January 2013 and July 2020 (n = 189). The prevalence of ACCs and SMIs and characteristics of patients identified with ACCs and SMIs were investigated. Moreover, comparisons were performed between patients with and without ACCs. RESULTS: Fourteen patients (7.4%) fulfilled the criteria for ACCs, including nine (4.8%) who presented with Takotsubo-like cardiomyopathy, four (2.1%) with heart failure with preserved ejection fraction, and finally one (0.5%) with catecholamine-induced cardiomyopathy. Compared to those without ACCs (n = 175), patients with ACCs had a higher prevalence of epinephrine-producing PPGLs (81.8% vs 33.9%, P = 0.006) and were more likely to show invasive behavior (61.5% vs 27.3%, P = 0.022) or hemorrhage/necrosis (53.9% vs 17.4%, P = 0.005) on histology. The apical sparing pattern (5/7, 71.4%) was the dominant impairment pattern of longitudinal strain (LS) for patients displaying Takotsubo-like cardiomyopathy. In patients without cardiac symptoms, a fairly high proportion (21/77, 27.3%) of patients who underwent screening for troponin and/or natriuretic peptide and/or echocardiography had SMIs. CONCLUSIONS: One in every fourteen PPGL patients presented with ACCs, and in the patients with Takotsubo-like cardiomyopathy, the apical sparing pattern was the primary impairment pattern of LS. Additionally, nearly one-third of patients without symptoms had SMIs. The diagnosis of PPGLs should be considered in patients with acute reversible cardiomyopathy, especially in those exhibiting an apical sparing pattern of LS.

Pseudohypoxic pheochromocytomas and paragangliomas dominate in children.

OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that are associated with cancer predisposition syndromes in up to 80% of affected children. PPGLs can be divided into molecularly defined groups with comparable pathogenesis and biology: (1) pseudohypoxic, (2) kinase signaling, and (3) Wnt-altered. METHODS: We report the data of children and adolescents diagnosed with PPGL who have been registered with the German GPOH-MET registry since 1997. RESULTS: By December 2019, a total of 88 patients with PPGL were reported. Pheochromocytoma occurred in 56%, paraganglioma in 35%, and synchronous PPGLs in 9.1%. A total of 16% of patients presented with lymph node (5.7%) and distant metastases (10%). Median follow-up was 4.2 years (range 0-17.1). Overall and disease-free survival (DFS) were 98.6% and 54.0%, respectively. Local relapses, metastases, and subsequent PPGLs occurred in 11%, 4.5%, and 15% of patients. Germline mutations were detected in 83% of patients (51% in VHL, 21% in SDHB, 7.8% in SDHD, and one patient each in RET and NF1). One patient was diagnosed with Pacak-Zhuang syndrome. A total of 96% of patients presented with PPGL of the pseudohypoxic subgroup (34% TCA cycle-related, 66% VHL/EPAS1-related). In multivariate analyses, extent of tumor resection was a significant prognostic factor for DFS. CONCLUSIONS: Most pediatric PPGLs belong to the pseudohypoxia subgroup, which is associated with a high risk of subsequent PPGL events and metastatic disease. Comprehensive molecular profiling of children and adolescents with newly diagnosed PPGLs will open new avenues for personalized diagnosis, treatment, and surveillance.