Pheochromocytomas And Paragangliomas Research Articles

Nuclear and mitochondrial DNA alterations in pheochromocytomas and paragangliomas, and their potential treatment.

Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is little information about its involvement in pheochromocytomas and paragangliomas (PCCs/PGLs) formation. PCCs and PGLs are rare endocrine tumors of the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia that can synthesize and secrete catecholamines. Over the last 3 decades, the genetic background of about 60% of PCCs/PGLs involving nuclear DNA alterations has been determined. Recently, a study showed that mitochondrial alterations can be found in around 17% of the remaining PCCs/PGLs. In this review, we summarize recent knowledge regarding both nuclear and mitochondrial alterations and their involvement in PCCs/PGLs. We also provide brief insights into the genetics and the molecular pathways associated with PCCs/PGLs and potential therapeutical targets.

S-13-6: RECENT ADVANCES IN THE MANAGEMENT OF PHEOCHROMOCYTOMA AND PARAGANGLIOMA

Pheochromocytomas and paragangliomas (PPGL) are rare tumors that cause refractory hypertension and hypertensive crisis. Although metastatic disease accounts for 30% of PPGL, diagnosis of malignant is difficult without the presence of metastatic lesions. We review here several advancements in diagnosis and treatment of PPGL. A nationwide epidemiological survey in Japan revealed that the annual number of patients with PPGL was 3,000, higher than what was reported in previously. While plasma and urine fractionated metanephrines are recommended to be used as specific biochemical testing for diagnosis, creatinine-corrected fractionated metanephrines in spot urine samples which had been widely used in Japan as a convenient screening test was shown to be as useful as 24-hour urine fractionated metanephrines. Regarding imaging studies, a more specific functional imaging for PPGL, 68Ga DOTATATE, was newly developed. 68Ga DOTATATE provides a clear image with high sensitivity and specificity. Currently, PASS or GAPP histological scores and SDHB immunostaining are clinically used to attempt to discriminate benign from malignant tumor. However, since this distinguishing process remains difficult, all cases were classified as malignant with the possibility of metastasis in the WHO classification of endocrine tumor updated in 2017. Approximately 60% of PPGL have germline mutations of PPGL-related genes. Currently the genes are classified into 2 clusters based on their mechanism for etiology of tumorigenesis. Based on the possible mechanisms of tumor development associated with gene mutation, several molecular target drugs are under evaluation to explore more promising treatments for malignant PPGL.

Feohromocitom kao potencijalni uzrok napada epilepsije

Epileptic seizures are defined as the transient appearance of signs or symptoms due to excessive or synchronous neuronal activity in the cerebral cortex. Pheochromocytomas and paragangliomas (PPGL) are tumors of chromaffin cells that arise from the medulla of the adrenal gland in 80-85% of patients and from the extra-adrenal sympathetic tissue of the abdomen, pelvis and chest in 10-20% of patients. The clinical picture of PPGL is variable and ranges from the absence of symptoms to severe clinical picture, depending on the biochemical profile. They are most often manifested by paroxysmal hypertension, followed by episodes of severe headache or diaphoresis, while epileptic attacks are rare. Neurological symptoms are present in many patients with PPGL. Also, paroxysmal neurological conditions such as vasodilating headache, intracranial tumors, diencephalic-autonomic epilepsy, hypertensive encephalopathy, focal arterial disease of the brain and anxiety state have been described, which may have similar clinical manifestations with pheochromocytomas. We present a 44-year-old woman, who has been diagnosed with pheochromocytoma as possible etiological basis of epileptic seizures. Pheochromocytoma, with its low incidence and "chameleon" clinical spectrum, should be considered as a potential etiological factor of convulsions.

Epigenetic drugs in somatostatin type 2 receptor radionuclide theranostics and radiation transcriptomics in mouse pheochromocytoma models.

Pheochromocytomas and paragangliomas (PCCs/PGLs) are catecholamine-producing tumors. In inoperable and metastatic cases, somatostatin type 2 receptor (SSTR2) expression allows for peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE. Insufficient receptor levels, however, limit treatment efficacy. This study evaluates whether the epigenetic drugs valproic acid (VPA) and 5-Aza-2'-deoxycytidine (DAC) modulate SSTR2 levels and sensitivity to [177Lu]Lu-DOTA-TATE in two mouse PCC models (MPC and MTT). Methods: Drug-effects on Sstr2/SSTR2 were investigated in terms of promoter methylation, mRNA and protein levels, and radiotracer binding. Radiotracer uptake was measured in subcutaneous allografts in mice using PET and SPECT imaging. Tumor growth and gene expression (RNAseq) were characterized after drug treatments. Results: DAC alone and in combination with VPA increased SSTR2 levels along with radiotracer uptake in vitro in MPC (high-SSTR2) and MTT cells (low-SSTR2). MTT but not MPC allografts responded to DAC and VPA combination with significantly elevated radiotracer uptake, although activity concentrations remained far below those in MPC tumors. In both models, combination of DAC, VPA and [177Lu]Lu-DOTA-TATE was associated with additive effects on tumor growth delay and specific transcriptional responses in gene sets involved in cancer and treatment resistance. Effects of epigenetic drugs were unrelated to CpG island methylation of the Sstr2 promoter. Conclusion: This study demonstrates that SSTR2 induction in mouse pheochromocytoma models has some therapeutic benefit that occurs via yet unknown mechanisms. Transcriptional changes in tumor allografts associated with epigenetic treatment and [177Lu]Lu-DOTA-TATE provide first insights into genetic responses of PCCs/PGLs, potentially useful for developing additional strategies to prevent tumor recurrence.

PS-P10-7: SEVENTY YEARS OF PHEOCHROMOCYTOMAS AND PARAGANGLIOMAS IN ARGENTINA

In Argentina, data regarding Pheochromocytomas and Paragangliomas (PPGLs) are scarse. Objective: to describe demographic, biochemical and genetic characteristics of children and adults with confirmed PPGls. Design and method: Observational multicenter study of recruited participants surveyed from a retrospective cross sectional database from january 1953 until January 2022. Results: We included 486 patients (58.4% women) from 93 recruiting centers, mean age at diagnosis 38.3, 393 (80.9%) hypertensives, baseline office systolic/diastolic blood pressure 157.8/96.5 mmHg. Of all tumors, 382 (79.6%) were Pheochromocytomas, 67 (13.8%) paragangliomas and 11 (2.3%) mixed. The most prevalent cathecolamin secretion type was noradrenergic (35%), followed by adrenergic (30.6%) and mixed (20.3%). Local recurrence and mestastasis occured in 10% of subjects. The most common symptoms were headache (57%), sweating (57.5%) and palpitations (53.4%). In 147 patients with a genetic syndrome, we found 44 MEN2A, 7 MEN2B, 1 MEN1, 42 Von Hippel Lindau, 11 neurofibromatosis type 1, 32 PGL4, 6 PGL1, 2 MAX, 1 TMEM127, and 1 mosaic EPAS1/HIF2A. We found the genetic variant types in 102 patients. Conclusions: Our results are consistent with other publications from foreign databases. PPGls are rarely diagnosed in Argentina, and the genetic profile is lacking in three fourths of patients.

Genotype-Phenotype Correlations and Clinical Outcomes in 155 Cases of Pheochromocytoma and Paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours, often associated with germline mutations that influence the disease biology and clinical course. We aimed to describe the genotypic and phenotypic characteristics of a consecutive series of PPGL patients and correlate mutation status with clinical outcomes. We performed a retrospective cohort study of all PPGL patients who presented to a tertiary referral centre between March 2005 and February 2022. Genotypic, phenotypic and follow-up data were analysed. A total of 140 patients were included. Of these, 94 (67%) patients underwent genetic testing and a mutation was detected in 36 (38%) patients. Mutation presence was associated with younger age, smaller tumour size and bilateral adrenal tumours. Disease recurrence occurred at a median time of 5.4 (IQR 2.8-11.0) years after treatment in 21 (15%) patients, of which 14 (67%) had a mutation in a susceptibility gene. Recurrence pattern was influenced by mutation type; higher local recurrence risk for SDHA, SDHB, and MEN2B disease, and higher metastatic risk for SDHB, VHL and MEN2A disease. Recurrence occurred in three (3%) patients with mutation absence. Multivariate analysis revealed that age ≤40years and mutation presence were associated with increased risk of disease recurrence. Genotypic characteristics strongly influence disease presentation and recurrence risk, which may occur more than 5years after initial treatment. Routine genetic testing of PPGL patients is warranted given the high prevalence of mutations, allowing for prognostication and tailored follow-up. In the presence of germline mutations, follow-up should be life-long.

Development and validation of a novel nomogram predicting pseudohypoxia type pheochromocytomas and paragangliomas.

Pseudohypoxia type (PHT) pheochromocytomas and paragangliomas (PPGLs) are more likely to metastasize and have a poor prognosis. However, application of genetic tests has many restrictions. The study aims to establish a novel nomogram for predicting the risk of PHT PPGLs. This retrospective cross-sectional study included 242 patients with pathology confirmed PPGLs in one tertiary care center in China in 2010-2021. Clinical and biochemical characteristics were collected. Next-generation sequencing was performed in all PPGLs patients for detection of mutation. Univariate and multivariable logistic regression analyses were used to select risk factors for constructing the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the discrimination of the nomogram and the calibration curve was performed. Four variables including age ≤ 35years, hypertension, 24h urinary output of urinary vanillylmandelic acid (VMA) ≥ 100 umol/24h and urinary 17-ketosteroide (17KS) ≤ 50 umol/24h levels were independently associated with PHT PPGLs in the logistic regression analysis and were included in the nomogram. The nomogram showed a good discrimination performance with AUC of 0.829 [95% confidence interval (CI), 0.767-0.891] in the training set and 0.797 (95%CI, 0.659-0.935) in the validation set, respectively. The calibration curve showed a bias-corrected AUC of 0.809 vs. 0.795, and a Hosmer-Lemeshow (H-L) test yielded a p value of 0.801 vs. 0.885, indicating the nomogram's good ability to distinguish PHT PPGLs from non-PHT PPGLs. Our study has proposed a novel nomogram for individualized prediction of the PHT PPGLs, which may make contributions to guide the patients' personalized management, follow-up, and treatment.

Initial characterization of immune microenvironment in pheochromocytoma and paraganglioma.

Due to fewer adverse events, faster onset of action, and longer durable responses compared to chemotherapy, immunotherapy has been widely used to treat advanced solid tumors. Moreover, immunotherapy can improve the autoimmune status, thus allowing patients to benefit from the treatment in the long term. The immune microenvironment status is closely associated with the response to chemotherapies. Here, we analyzed the characteristics of the immune microenvironment in pheochromocytoma and paraganglioma (PPGL). Immunohistochemistry showed that PD-L1 is sparely expressed in PPGL with low positive rates and low expression levels, an expression pattern, that is, not correlated with tumor malignancy. Moreover, the level of intratumoral CD4+ and CD8+ lymphocyte infiltration in PPGL is low, suggesting that the immune microenvironment in PPGL may be in "immune desertification" or "immune rejection" states in which CD4+ and CD8+ lymphocyte infiltration is prevented, rendering immunotherapy less effective. In sum, our results indicate that PPGL is a microsatellite-stable tumor with low tumor mutational burden (TMB) levels, weak neoantigen production, and poor tumor antigenicity, hinting at a poor response of PPGL to chemotherapies.

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

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. This study aimed to assess the rates and patterns of PPGL screening among eligible patients. 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). 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]). 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.

Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype.

Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia-inducible factor 2 (HIF2)-mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death-ligand 1 (PD-L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD-L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD-L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD-L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD-L1 and CD8 expression was lower in norepinephrine than epinephrine-secreting PPGL. This in silico analysis also revealed the low PD-L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α-coding gene, EPAS1, which, together with SDH-mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension.

Neuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system. It produces and releases metanephrines, which are used as biomarkers for diagnosis in plasma and urine. However, plasma catecholamine concentrations remain generally normal in children with NB. Thus, unlike pheochromocytoma and paraganglioma (PHEO/PGL), two other non-epithelial neuroendocrine tumors, hypertension is not part of the usual clinical picture of patients with NB. This suggests that the mode of production and secretion of catecholamines and metanephrines in NB is different from that in PHEO/PGL, but little is known about these discrepancies. Here we aim to provide a detailed comparison of the biosynthesis, metabolism and storage of catecholamines and metanephrines between patients with NB and PHEO. Catecholamines and metanephrines were quantified in NB and PHEO/PGL patients from plasma and tumor tissues by ultra-high pressure liquid chromatography tandem mass spectrometry. Electron microscopy was used to quantify neurosecretory vesicles within cells derived from PHEO tumor biopsies, NB-PDX and NB cell lines. Chromaffin markers were detected by qPCR, IHC and/or immunoblotting. Plasma levels of metanephrines were comparable between NB and PHEO patients, while catecholamines were 3.5-fold lower in NB vs PHEO affected individuals. However, we observed that intratumoral concentrations of metanephrines and catecholamines measured in NB were several orders of magnitude lower than in PHEO. Cellular and molecular analyses revealed that NB cell lines, primary cells dissociated from human tumor biopsies as well as cells from patient-derived xenograft tumors (NB-PDX) stored a very low amount of intracellular catecholamines, and contained only rare neurosecretory vesicles relative to PHEO cells. In addition, primary NB expressed reduced levels of numerous chromaffin markers, as compared to PHEO/PGL, except catechol O-methyltransferase and monoamine oxidase A. Furthermore, functional assays through induction of chromaffin differentiation of the IMR32 NB cell line with Bt2cAMP led to an increase of neurosecretory vesicles able to secrete catecholamines after KCl or nicotine stimulation. The low amount of neurosecretory vesicles in NB cytoplasm prevents catecholamine storage and lead to their rapid transformation by catechol O-methyltransferase into metanephrines that diffuse in blood. Hence, in contrast to PHEO/PGL, catecholamines are not secreted massively in the blood, which explains why systemic hypertension is not observed in most patients with NB.

PD-L1 expression and association with genetic background in pheochromocytoma and paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors associated with poor prognosis and limited therapeutic options. Recent advances in oncology-related immunotherapy, specifically in targeting of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathways, have identified a new treatment potential in a variety of tumors, including advanced and rare tumors. Only a fraction of patients being treated by immune checkpoint inhibitors have shown to benefit from it, displaying a need for strategies which identify patients who may most likely show a favorable response. Building on recent, promising outcomes in a clinical study of metastatic PPGL using pembrolizumab, a humanized IgG4κ monoclonal antibody targeting the PD-1/PD-L1 pathway, we examined PD-L1 and PD-L2 expression in relation to oncogenic drivers in our PPGL patient cohort to explore whether expression can predict metastatic potential and/or be considered a predictive marker for targeted therapy. We evaluated RNA expression in the NIH cohort of 48 patients with known genetic predisposition (sporadic; pseudohypoxia: SDHB, VHL, EPAS1, EGLN1; kinase signaling: RET, NF1) and 6 normal medulla samples (NAM). For comparison, 72 PPGL samples from The Cancer Genome Atlas (TCGA) were used for analysis of gene expression based on the variant status (pseudohypoxia: SDHB, VHL, EPAS1, EGLN1; kinase signaling: NF1, RET). Expression of PD-L1 was elevated in the PPGL cohort compared to normal adrenal medulla, aligning with the TCGA analysis, whereas PD-L2 was not elevated. However, expression of PD-L1 was lower in the pseudohypoxia cluster compared to the sporadic and the kinase signaling subtype cluster, suggesting that sporadic and kinase signaling cluster PPGLs could benefit from PD-1/PD-L1 therapy more than the pseudohypoxia cluster. Within the pseudohypoxia cluster, expression of PD-L1 was significantly lower in both SDHB- and non-SDHB-mutated tumors compared to sporadic tumors. PD-L1 and PD-L2 expression was not affected by the metastatic status. We conclude that PD-L1 and PD-L2 expression in our cohort of PPGL tumors was not linked to metastatic behavior, however, the presence of PPGL driver mutation could be a predictive marker for PD-L1-targeted therapy and an important feature for further clinical studies in patients with PPGL.

RF33 | PSUN03 Rates of Pheochromocytoma/Paraganglioma Screening in At-Risk Populations

Abstract Background Hypertension is estimated to affect 1: 2 adults in the USA, and secondary hypertension accounts for up to 40% cases. Pheochromocytomas and paragangliomas (PPGL) are thought to be rare causes of hypertension, although their true prevalence might be underestimated. Less than half of patients with PPGL have prototypical symptoms. PPGL can lead to serious complications, including death, particularly if unrecognized. Expert guidelines recommend screening for secondary causes of hypertension in patients with resistant hypertension, patients with early-onset hypertension, and in those with hypertension and an adrenal mass. The rates of PPGL screening are unknown. Objective To evaluate the rates and patterns of PPGL screening among candidate patients. Methods We conducted a retrospective review of adult patients (age ≥ 18 years) with hypertension seen in a university-based outpatient setting between 01/01/2017 - 06/30/2020, and we included patients with: 1) resistant hypertension (uncontrolled hypertension while taking at least 3 antihypertensive agents OR taking ≥4 antihypertensive agents); 2) hypertension at age &amp;lt;35 years; 3) adrenal nodule(s). We excluded patients with renovascular hypertension, advanced chronic kidney disease (CKD stage ≥4), stage III and IV heart failure, adrenal insufficiency, and congenital adrenal hyperplasia. Results Of 203,535 patients with hypertension, 71,088 (35%) met at least one of the above criteria, and only 2013 (2.83%) were screened for PPGL. Overall, patients screened were younger (56.2 ± 17.4 vs. 63.9±17.1 years, p &amp;lt;0.001), more often women (54.1% vs. 44.2%, p=0.001), and non-smokers (54.6% vs. 47.5%, p&amp;lt;0.001) than those not screened. While most patients included in the study were white (80%), the proportion of black patients was larger among those screened (19.9% vs.13.3% of those not screened, p&amp;lt;0.001). Of the three indications for PPGL screening, the rates were highest in patients with hypertension and adrenal nodule(s) (51.7%), while patients with early onset hypertension and those with resistant hypertension were rarely screened (3.9% and 2.4%, respectively). Multivariable logistic regression with LASSO selection showed that the odds of PPGL screening were higher in black vs. white patients (1.35 [1.19-1.53]); those who never smoked (1.68 [1.41-2.00]); patients with stroke (1.34 [1.16-1.54]); dyslipidemia (1.41 [1.26-1.57]), CKD (1.40 [1.26-1.56); obstructive sleep apnea (1.96 [1.76-2.19]); and adrenal nodules (55.1 [44.53-68.17]). Conclusions Screening for PPGL is conducted in roughly half of patients with adrenal nodules and hypertension, but rarely in patients with resistant or early onset hypertension. Screening occurs more often in patients with complications known to be associated with PPGL, including cardiovascular accidents. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.

ODP583 Screening for Pheochromocytoma in a Cohort of Patients with Takotsubo Cardiomyopathy: New insights on Prevalence and Screening Tests Reliability Surrounding the Acute Cardiac Event

Abstract Background According to Takotsubo cardiomyopathy (TCM) diagnostic criteria, pheochromocytoma and paraganglioma (PPGL) should be excluded as secondary causes. However, it is unclear whether PPGL screening in the setting of acute TCM is reliable. We aimed to assess the prevalence of PPGL and the reliability of PPGL screening in a cohort of patients with TCM. Method: We retrospectively reviewed data from patients admitted in a tertiary hospital between August 2012 and January 2021 with a diagnosis of TCM proven by typical echocardiography findings and no acute occlusion on coronarography, who were screened for PPGL by plasma metanephrines/normetanephrines (M/NM). If the first screening was positive, a second plasma M/NM sample was used for confirmation. Time between TCM diagnosis and PPGL screening was collected. Results Among 64 patients identified with TCM, 42 underwent plasma M/NM screening. 81. 0% were female, and the mean age was 67.4 ± 9.9 years old. Ten patients (23.8%) had a positive result. Of those, 8 patients had a weakly positive result (1-2×upper limit of normal [ULN]) and 2 had a strongly positive result (&amp;gt;2×ULN). Of those 10 patients, 6 underwent a second screening: 5 had a normal result and 1 had a weakly positive result (plasma NM 1. 06×ULN). This patient underwent a third screening that was negative. In addition, an abdominal CT showed normal adrenal glands, and their chromogranin A levels were normal. Four patients had a positive initial PPGL screening, but they did not undergo a second screening: 3 died of causes unrelated to TCM before a second plasma M/NM sample was taken and one patient was lost to follow-up (his plasma NM was weakly positive at 1.29×ULN). They all had an abdominal CT that showed normal adrenal glands. Average time between TCM diagnosis and PPGL screening in all patients and in patients with a positive initial screening was 4.57 ± 3.91 and 3.38 ± 2.12 days, respectively. A linear regression model suggested an inverse relationship between plasma M/NM and time between TCM diagnosis and screening, with R2 = 0.2275. Conclusion TCM occurring as the initial presentation of PPGL is rare. All patients with a positive screening ended up being false positives in our study. The ratio of false positive results when screening for PPGL in the setting of acute TCM seems to be higher than in the general population, which could be explained by a hyperadrenergic state. It is unclear whether a shorter delay between TCM diagnosis and PPGL screening may be associated with more false positives. More research is needed to determine what is the optimal timing for PPGL screening in acute TCM and if higher cut-offs should be used to minimize false positive results. Presentation: No date and time listed

Sex-related Differences in a Canadian Cohort of Patients With Pheochromocytomas and Paragangliomas

The distinctions between biological males and females have long been ignored in the field of research. Our objective was to evaluate sex-related differences in signs and symptoms in a cohort of patients with pheochromocytomas and paragangliomas (PPGLs).

PSUN28 Factors Associated with False-positive Fractionated Metanephrines in Plasma and Urine

Abstract Context Plasma and 24-hr urine metanephrine (M) and normetanephrine (NM) are the standard of care tests used in the biochemical diagnosis of pheochromocytoma and paraganglioma (PPGL). Considering the rarity of PPGL, false positive (FP) results represent a challenge because they lead to additional investigations, healthcare burden, and uncertainty for the patient. The impact of medications on the rate of FP results is not fully established. Objective We aimed to identify the medications associated with the FP rate of 24-hr urine and plasma M and NM measured by the HPLC-MS/MS method. Methods We conducted a single-center study of patients who had 24-hour urine or plasma M and NM testing between 09/27/2015 and 02/15/2021, and who had a follow-up of at least 6 months. Results were considered FP if M/NM were &amp;gt; upper limit of the normal ranges (ULN) and there was absence of PPGL. Results were considered true negative (TN) when M/NM were within the reference ranges in patients without PPGL. Age- and sex-adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models. Results Plasma M/NM testing was performed in 3152 patients and 24-hr urine M/NM was performed in 2008 patients. The FP rate for the M fraction (plasma: 0.8%, urine: 1.3%) was much lower than the FP rate for NM (plasma: 16%, urine: 4.4%); thus, the impact of medications on FP rate was examined only for NM. In those with FP NM, the median degrees of elevation were 24% (IQR 10-46) &amp;gt;ULN in plasma and 26% (IQR 11-45) &amp;gt;ULN in urine. When compared to patients with TN results, patients with FP plasma NM were more likely to be treated with opioids (OR=1.29, 95%CI, 1.04-1.60), tricyclic antidepressants (OR=1.61, 95%CI,1.14-2.27), serotonin–norepinephrine reuptake inhibitors (OR=1.85, 95%CI, 1.35-2.53), second generation antipsychotics (OR=2.32, 95%CI, 1.28-4.20), but not first generation antipsychotics (OR=1.23, 95% CI, 0.86-1.75) when compared to the TN group. When compared to patients with TN results, patients with FP urine NM were more likely to be treated with opioids (OR=1.96 95%CI, 1.26-3.06), tricyclic antidepressants (OR=2.61, 95%CI, 1.47-4.65), serotonin–norepinephrine reuptake inhibitors (OR=2.20, 95%CI, 1.20-4.02), and both first (OR=3.06, 95%CI, 1.74-5.38) and second generation antipsychotics (OR=2.51, 95%CI, 1.03-6.13). Conclusion The plasma NM FP rate was 16% and 3-fold higher than the same measurement in urine (4.4%). Several classes of medications had a significant impact on the rate of FP NM. Clinicians should consider use of 24-hr urine M and NM in low suspicion cases of PPGL where the diagnosis simply needs to be excluded. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP051 Presymptomatic Genetic Screening Leading to the Diagnosis of Paraganglioma Associated with Duodenal and Pancreatic Neuroendocrine Tumours in a Carrier of a Pathogenic MAX Variant

Abstract Introduction MAXpathogenic variants have been found to predispose to pheochromocytomas and paragangliomas (PPGLs) and more recently to pituitary tumors 1. Clinical Case A 30 yo man presented to the emergency department for diplopia and high blood pressure (200/100mmHg). His workup showed elevated plasmatic normetanephrines (9. 01nmol/L; N &amp;lt;0.92) and a 3.7cm right adrenal mass with a density of 30HU. The patient underwent right laparoscopic adrenalectomy and the pathologist reported a 4.5cm pheochromocytoma with a PASS score of 4 and a Ki-67 of 2-4%. The patient was screened with a panel of 14 susceptibility genes for PPGLs (INVITAE, CA, USA) that revealed a pathogenic germline nonsense heterozygous MAX mutation (c.223C&amp;gt;Tp. Arg75*). This mutation was previously described in a family where four members suffered from bilateral PHEOs at a young age (28-35 yo) 2 . Following the identification of the pathogenic variant of MAX gene, the patient's father (61 yo) underwent genetic counselling and was found to carry the same germline mutation. His past medical history included long-standing hypertension with hypertensive cardiomyopathy and diabetes. His blood work showed a mildly elevated plasmatic normetanephrine (1.41nmol/L; N &amp;lt;1.2) with normal metanephrine. An abdominal CT-scan showed a 1.5cm precaval nodularity. On a complementary 18 F-FDG PET/CT, the precaval mass had a 3.5 SUVMax and a second mass was identified in the duodenum (D3) with an uptake of 4.9 SUVMax. The 68 GaDOTATE PET/CT confirmed the precaval (SUVMax36.3) and duodenal (SUVMax51.6) lesion and in addition, revealed a pancreatic mass (SUVMax9.3). The patient underwent a distal pancreatic, duodenal and precaval node resection. The pathology report showed a 1.7cm G1 pancreatic neuroendocrine tumor (NET) (Ki-67 &amp;lt;3%) and a 2.3cmG1 duodenal NET (Ki-67 &amp;lt;3%). The precaval node was a paraganglioma (PGL) with a preserved SDHB staining, negative cytokeratine 8/18 and a Ki-67 of 1.65%. The son had normal imaging of his pancreas. To our knowledge we report the second case of association of MAXmutation with gastrointestinal TNE. Conclusion This case presents the rare association of a familial MAX mutation presenting with a pheochromocytoma in the index case and a presymptomatic discovery of a PGL and multiple NETs in the father. This supports the hypothesis that MAXmutations might be associated with multiendocrinetumors 3.

Prognostic value of [18F]FDG-PET prior to [131I]MIBG treatment for pheochromocytoma and paraganglioma (PPGL).

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors arising from the neural crest cells that form the sympathetic and parasympathetic nervous systems. Radiotherapy with [131I]metaiodobenzylguanidine (MIBG) is recommended for unresectable PPGLs. We investigated the usefulness of the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) derived from [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) for predicting the prognosis of patients with unresectable PPGL(s) before receiving [131I]MIBG therapy. We retrospectively analyzed the cases of 25 patients with unresectable PPGLs treated with [131I]MIBG at our hospital between 2001 and 2020. The MTV and TLG were measured in reference to liver accumulation. We divided the patients into two groups based on median values for the maximum standardized uptake value (SUVmax), MTV, and TLG, and evaluated between-group differences using log-rank tests. Cox proportional hazards models were used to determine whether there were significant differences in prognosis with respect to tumor type (pheochromocytoma vs. paraganglioma), site of metastasis, age, past treatment (chemotherapy, external radiation or [131I]MIBG treatment before the current [131I]MIBG treatment), urinary catecholamine, SUVmax, MTV, and TLG. The median follow-up time was 42months (range 2-136months). The median overall survival was 63months. The overall survival (OS) was significantly shorter in the high-MTV group (log-rank test, p = 0.049) and the high-TLG group (p = 0.049), with no significant difference between the high- and low-SUVmax groups (p = 0.19). Likewise, there was no significant difference in prognosis according to pheochromocytoma or paraganglioma, metastasis location, age, or prior chemotherapy. A history of external radiation before [131I]MIBG treatment was associated with a significantly worse prognosis (hazard ration [HR] = 7.95, p = 0.0018). Urinary adrenaline and noradrenaline were not significant prognostic factors (p = 0.70, p = 0.25, respectively), but urinary dopamine did predict a worse outcome (p = 0.022). There was no increased risk of death for higher SUVmax or TLG (p = 0.63 and 0.057, respectively), but higher MTV did predict a worse outcome (HR = 7.27, p = 0.029). High MTV and high TLG were significantly associated with a poor prognosis after [131I]MIBG therapy for PPGLs. Other treatment strategies for such patients may need to be explored.

18 F-MFBG PET/CT Is an Effective Alternative of 68 Ga-DOTATATE PET/CT in the Evaluation of Metastatic Pheochromocytoma and Paraganglioma.

The current guidelines state that the functional imaging choice in the evaluation of metastatic pheochromocytoma and paraganglioma (PPGL) is 68 Ga-DOTATATE PET/CT. 18 F-meta-fluorobenzylguanidine ( 18 F-MFBG) is a new PET tracer and an analog of meta-iodobenzylguanidine (MIBG). This study aimed to compare 18 F-MFBG and 68 Ga-DOTATATE PET/CT in patients with metastatic PPGL. Twenty-eight patients with known metastatic PPGL were prospectively recruited for this study. All patients underwent both 18 F-MFBG and 68 Ga-DOTATATE PET/CT studies within 1 week. Lesion numbers detected were compared between these 2 studies. 18 F-MFBG PET/CT was positive for detecting metastases in all patients, whereas positive results of 68 Ga-DOTATATE PET/CT were in 27 (96.4%) patients. A total of 686 foci of metastatic lesions were detected by both 18 F-MFBG and 68 Ga-DOTATATE imaging. In addition, 33 foci of abnormal activity were only detected by 18 F-MFBG, whereas 16 foci were only shown on 68 Ga-DOTATATE PET/CT. Our data suggest that 18 F-MFBG PET/CT is an effective imaging method in the evaluation of metastatic PPGL and could be alternative of 68 Ga-DOTATATE PET/CT in this clinical setting.

Metanephrine and normetanephrine associated with subclinical myocardial injuries in pheochromocytoma and paraganglioma.

ObjectiveTo analyze the correlation between metanephrine and normetanephrines (MNs) and subclinical myocardial injuries (SMI) diagnosed by low left ventricular global longitudinal strain (LV GLS) in patients with pheochromocytoma and paraganglioma (PPGL).MethodsSeventy-six patients who underwent surgery for pheochromocytoma or paraganglioma from September 2017 to April 2022 were examined. All the patients enrolled had normal left ventricular ejection fraction (LVEF) and myocardial injury biomarkers including cardiac troponin I and B-natriuretic peptide. Univariate analysis and multivariate analysis were performed to evaluate the association of MNs and subclinical myocardial injury (SMI)(defined as LV GLS<18).ResultsLV GLS of 13(17.11%) PPGL patients was less than 18. The percentage of patients with elevation of single hormone (metanephrine, normetanephrine, 3-methoxytyramine) or any one of MNs was not significantly correlated with SMI (P=0.987, 0.666, 0.128 and 0.918, respectively). All MNs elevation was associated with SMI (OR: 11.27; 95% CI, 0.94—135.24; P= 0.056). After adjusting for age, All MNs elevation was significantly correlated with SMI (OR: 16.54; 95% CI, 1.22—223.62; P= 0.035).ConclusionMNs might be an important factor influencing myocardial function. All MNs elevation might indicate SMI. If all MNs elevated, LV GLS measurement was recommended for PPGL patients to detect SMI in the absence of decrease LVEF or other heart disease in clinical practice.