Management and follow-up strategies for patients with head and neck paraganglioma.

OBJECTIVE: Head-neck paragangliomas (HNPGLs) are rare tumors with approximately half arising due to germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx). Patients with HNPGL have heterogeneous propensity to recur and metastasize. Thus, we aim to assess prevalence and predictors of recurrent (RD) and/or metastatic disease in patients with and without SDHx-related HNPGLs. DESIGN AND METHODS: This cross-sectional study used retrospective data of 214 patients enrolled in six referral centers. Data included sex, age, primary tumor treatment, location, and size, biochemical phenotype, germline PVs, presence of RD (locoregional or new tumor), and/or metastasis. RESULTS: Patients with and without SDHx-related HNPGLs showed 74% and 40% prevalence of RD, respectively. Patients without SDHx-related HNPGLs presented with recurrent tumors only in head-neck regions. The only independent predictor for RD in the entire cohort was presence of SDHx PVs. Metastatic prevalence reached 9%-13%. For patients with SDHx-related HNPGLs, large tumor size (>2.3 cm, OR:50.0, CI:2.6-977.6), young age at initial diagnosis (<42years, OR:27.3, CI:1.8-407.2), and presence of SDHB PV (OR:15.6; CI:1.5-164.8) were independent predictors of metastasis. For patients without SDHx-related HNPGLs, only carotid-body location was an independent predictor of metastasis (OR:18.9, CI:2.0-182.5). CONCLUSIONS: Patients without SDHx-related HNPGLs require long-term follow-up due to high prevalence of RD with imaging largely restricted to head-neck regions. As carotid-body HNPGLs have the highest metastatic risk among sporadic tumors, radical treatment with frequent follow-up is suggested until population-based data are available. Importantly, patients with SDHx-related HNPGLs might benefit from early radical treatment when tumors are still small to reduce metastatic risk.

Hypertension and cardiac damage in pheochromocytoma and paraganglioma patients: a large-scale single-center cohort study.

BACKGROUND: Hypertension (HT) is one of the most common manifestations in patients with catecholamine-secreting neuroendocrine tumors. Although the cardiovascular manifestations of these tumors have been described, there have been no large-scale investigations of the profile of HT and changes in cardiac structure and function that occur in patients with pheochromocytomas and paragangliomas (PPGL). MATERIALS AND METHODS: In this study, we investigated the prevalence of HT and left ventricular remodeling (LVR) in a cohort of 598 patients who underwent surgery for PPGL at our center between January 2001 and April 2022. Information on demographics, reason for hospitalization, medical history, biochemical parameters, findings on echocardiography, and tumor characteristics were recorded. The LVR index was compared according to whether or not there was a history of HT. RESULTS: The average age was 47.07 ± 15.07 years, and 277 (46.32%) of the patients were male. A history of HT was found in 423 (70.74%) of the 598 patients. Paraganglioma was significantly more common in the group with HT (26.00% vs. 17.71%, P = 0.030) and significantly less likely to be found incidentally during a health check-up in this group (22.93% vs. 59.43%, P < 0.001). Among 365 patients with complete echocardiography data, left ventricular mass index (86.58 ± 26.70 vs. 75.80 ± 17.26, P < 0.001) and relative wall thickness (0.43 ± 0. 08 vs. 0.41 ± 0.06, P = 0.012) were significantly higher in patients with PPGL and a history of HT. The proportions with left ventricular hypertrophy (LVH) (19.40% vs. 8.25%, P = 0.011) and LVR (53.73% vs. 39.18%, P = 0.014) were also higher when there was a history of HT. After adjusting for age, gender, body mass index, alcohol consumption, smoking status, diabetes, stroke, creatinine level, tumor location, and tumor size, a history of HT was significantly correlated with LVH (odds ratio 2.71, 95% confidence interval 1.18-6.19; P = 0.018) and LVR (odds ratio 1.83, 95% confidence interval 1.11-3.03; P = 0.018). CONCLUSION: HT is common in patients with PPGL (70.74% in this cohort). PPGL without a history of HT is more likely to be found incidentally (59.43% in our cohort). HT is associated with LVR in PPGL patients with complete echocardiography data. These patients should be observed carefully for cardiac damage, especially those with a history of HT.

Genetic predisposition to pheochromocytoma and paraganglioma: 21 years of experience in the field.

CONTEXT: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors with high heritability, justifying systematic genetic screening for a germline variant in one of the twenty predisposing genes described to date. PURPOSE: To describe the experience of one endocrine oncogenetic laboratory over a period of 21 years (2001-2022), from the beginning of PPGL genotyping with Sanger sequencing in 2001 to the implementation of next-generation sequencing (NGS). METHOD: The activity database of an academic oncogenetic laboratory was searched to extract patients/relatives identified with a pathogenic variant/likely pathogenic variant (PV/LPV) over a period of 21 years. Clinical and genetic data were compared. RESULTS: In total, 606 index cases with PPGL and 444 relatives were genotyped. Genotyping of index cases was performed by Sanger sequencing and gene deletion analysis in 327 cases and by NGS in 279. Germline PV/LPV spanning 10 genes was identified in 165 index cases (27.2%). Several recurrent PV/LPVs in SDHx were observed in non-related index cases, the most frequent being SDHD, c.170-1G>T (n=28). This subgroup showed great phenotypic variability both between and within families in terms of both tumor location and number. Four patients (1.1%) with PV/LPV in SDHx had 3PA (Pituitary Adenoma and pheochromocytoma/paraganglioma) syndrome. 258 relatives (58.1%) had inherited a PV/LPV in one driver gene. The rate of PV/LPV carriers who were symptomatic at first imaging evaluation was 32%, but varied between<20% in SDHB and SDHC and >50% in SDHD, VHL and MAX. CONCLUSION: Our experience confirmed previously established genotype-phenotype correlations, but also highlights atypical clinical presentations, even for the same genetic variant. These data must be taken into account for optimal patient follow-up and management.

Patient-reported burden associated with pheochromocytoma/paraganglioma diagnosis.

Pheochromocytoma and paragangliomas (PPGLs) originate from the chromaffin cells of the adrenal medulla or neural crest progenitors outside the adrenal gland, respectively. The estimated annual incidence of PPGL is between 2.0 and 8.0/million adults. Minimal data exist on the impact of PPGL from the patient's perspective. Therefore, a survey was adapted from a previously published study on gastroenteropancreatic neuroendocrine tumors to explore the voice of patients with PPGL and learn ways to improve clinical care while understanding the current gaps to direct future research. A self-reported online survey was available to patients with PPGL and those with genetic predisposition even without PPGL from June to July 2022. Survey questions captured sociodemographic and clinical characteristics, the diagnostic workup, treatment and monitoring, quality and access to care, and financial impact. Here, we report the most relevant findings on patient experience of disease burden following diagnosis. A total of 270 people responded, the majority of whom were from the USA (79%), Caucasian (88%), and female (81%). The results of this survey highlight the burden of disease on a patient's daily life, resulting in moderate to severe financial distress, increased travel time to specialized facilities resulting in loss of work and wages, and significant delays in care. Respondents reported being unheard and unacknowledged. With a median time to diagnosis just over 2 years, the physical, mental, and emotional toll are substantial. Increasing access to PPGL specialists and centers could lead to faster diagnoses and better management, which may reduce the burden on both patients and healthcare centers.

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.

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.

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.

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.

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.

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.

[Metastatic risk factors in pheochromocytoma/paraganglioma].

Currently, all pheochromocytoma/paraganglioma (PPGLs) are considered malignant due to metastatic potential. Consequently, PPGLs are divided into «metastatic¼ and «non-metastatic¼. Metastatic PPGLs can be with synchronous metastasis (metastases appear simultaneously with the identified primary tumor) or metachronous (metastases develop after removal of the primary tumor). The term metastatic PPGLs is not used in the presence of tumor invasion into surrounding organs and tissues, without the presence of distant metastases of lymphogenic or hematogenic origin. It is generally believed that about 10% of pheochromocytomas and about 40% of sympathetic paragangliomas have metastatic potential. On average, the prevalence of PPGLs with the presence of metastases is 15-20%. Risk factors for metastatic PPGLs are widely discussed in the literature, the most significant of which are groups of clinical, morphological and genetic characteristics. The review presents a discussion of such risk factors for metastatic PPGLs as age, localization and type of hormonal secretion of the tumor, the size and growth pattern of the adrenal lesion, the presence of necrosis and invasion into the vessels, the tumor capsule surrounding adipose tissue, high cellular and mitotic activity, Ki-67 index, expression of chromogranin B and S100 protein, the presence of genetic mutations of three main clusters (pseudohypoxia, kinase signaling and Wnt signaling).Over the past two decades, a number of authors have proposed various predictor factors and scales for assessing a probability of metastatic PPGLs. The review contains detailed description and comparison of sensitivity and specificity of such predictor scales as PASS, GAPP, M-GAPP, ASES and COPPS.

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.