Continued Tumor Reduction of Metastatic Pheochromocytoma/Paraganglioma Harboring Succinate Dehydrogenase Subunit B Mutations with Cyclical Chemotherapy.

Patients harboring germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene present with pheochromocytomas and paragangliomas (PPGL) that are more likely malignant and clinically aggressive. The combination chemotherapy cyclophosphamide, vincristine, and dacarbazine (CVD) was retrospectively evaluated in patients with SDHB-associated metastatic PPGL.Query Twelve metastatic PPGL patients harboring SDHB mutations/polymorphisms with undetectable SDHB immunostaining were treated with CVD. CVD therapy consisted of 750 mg/m2 cyclophosphamide with 1.4 mg/m2 vincristine on day 1 and 600 mg/m2 dacarbazine on days 1 and 2, every 21-28 days. Treatment outcome was determined by RECIST criteria as well as determination of response duration and progression-free and overall survivals. A median of 20.5 cycles (range 4-41) was administered. All patients had tumor reduction (12-100% by RECIST). Complete response was seen in two patients, while partial response was observed in 8. The median number of cycles to response was 5.5. Median duration of response was 478 days, with progression-free and overall survivals of 930 and 1190 days, respectively. Serial [18F]-fluorodeoxyglucose positron emission tomography and computed tomography imaging demonstrated continued incremental reduction in maximal standardized uptake values (SUVmax) values in 26/30 lesions. During treatment administration, the median SUV decreased from > 25 to < 6, indicating the efficacy of chemotherapy over a prolonged period of time. Prolonged therapy results in continued incremental tumor reduction, and is consistent with persistent drug sensitivity. CVD chemotherapy is recommended to be considered part of the initial management in patients with metastatic SDHB-related PPGL.

Biochemical diagnosis of phaeochromocytoma using plasma-free normetanephrine, metanephrine and methoxytyramine: importance of supine sampling under fasting conditions.

OBJECTIVE: To document the influences of blood sampling under supine fasting versus seated nonfasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine. DESIGN AND METHODS: Biochemical testing for PPGL was performed on 762 patients at six centres, two of which complied with requirements for supine sampling after an overnight fast and four of which did not. Phaeochromocytomas and paragangliomas were found in 129 patients (67 noncompliant, 62 compliant) and not in 633 patients (195 noncompliant, 438 compliant). RESULTS: Plasma concentrations of normetanephrine and methoxytyramine did not differ between compliant and noncompliant sampling conditions in patients with PPGL but were 49-51% higher in patients without PPGL sampled under noncompliant compared with compliant conditions. The 97·5 percentiles of distributions were also higher under noncompliant compared with compliant conditions for normetanephrine (1·29 vs 0·79 nmol/l), metanephrine (0·49 vs 0·41 nmol/l) and methoxytyramine (0·42 vs 0·18 nmol/l). Use of upper cut-offs established from seated nonfasting sampling conditions resulted in substantially decreased diagnostic sensitivity (98% vs 85%). In contrast, use of upper cut-offs established from supine fasting conditions resulted in decreased diagnostic specificity for testing under noncompliant compared with compliant conditions (71% vs 95%). CONCLUSIONS: High diagnostic sensitivity of plasma normetanephrine, metanephrine and methoxytyramine for the detection of PPGL can only be guaranteed using upper cut-offs of reference intervals established with blood sampling under supine fasting conditions. With such cut-offs, sampling under seated nonfasting conditions can lead to a 5·7-fold increase in false-positive results necessitating repeat sampling under supine fasting conditions.

Plasma-free vs deconjugated metanephrines for diagnosis of phaeochromocytoma.

BACKGROUND: The diagnosis of phaeochromocytoma is commonly performed by the measurements of plasma-free normetanephrine and metanephrine. Plasma-deconjugated normetanephrine and metanephrine have been proposed as alternative, equivalent, but easier to measure biomarkers. OBJECTIVE: The aim of this study was to compare the diagnostic performance of plasma-free vs deconjugated normetanephrine and metanephrine in patients tested for phaeochromocytoma. METHODS: The study population included a reference group of 262 normotensive and hypertensive volunteers, 198 patients with phaeochromocytoma and 528 patients initially suspected of having the tumour, but with negative investigations after at least 2 years of follow-up. Measurements were performed using liquid chromatography with electrochemical detection. RESULTS: Plasma concentrations of free normetanephrine were 17-fold higher in patients with phaeochromocytoma than in the reference population, a 72% larger (P < 0·001) difference than that for the 10-fold higher levels of plasma-deconjugated normetanephrine. In contrast, relative increases in plasma concentrations of free and deconjugated metanephrine were similar. Using upper cut-offs established in the reference population, measurements of plasma-free metabolites provided superior diagnostic performance than deconjugated metabolites according to measures of both sensitivity (97% vs 92%, P = 0·002) and specificity (93% vs 89%, P = 0·012). The area under the receiver operating characteristic curve for the free metabolites was larger than that for the deconjugated metabolites (0·986 vs 0·965, P < 0·001). CONCLUSION: Measurements of plasma-free normetanephrine and metanephrine are superior to the deconjugated metabolites for diagnosis of phaeochromocytoma.

Clinical decision making in small non-functioning VHL-related incidentalomas.

The optimal treatment strategy for patients with small non-functioning VHL-related incidentalomas is unclear. We searched the Freiburg VHL registry for patients with radiologic evidence of pheochromocytoma/paraganglioma (PHEO/PGL). In total, 176 patients with single, multiple, and recurrent tumours were identified (1.84 tumours/patient, range 1-8). Mean age at diagnosis was 32 ± 16 years. Seventy-four percent of tumours were localised to the adrenals. Mean tumour diameter was 2.42 ± 2.27 cm, 46% were <1.5 cm. 24% of tumours were biochemically inactive. Inactive tumours were significantly smaller than active PHEO/PGL at diagnosis (4.16 ± 2.80 cm vs 1.43 ± 0.45 cm; P < 0.025) and before surgery (4.89 ± 3.47 cm vs 1.36 ± 0.43 cm; P < 0.02). Disease was stable in 67% of 21 patients with evaluable tumours ≤1.5 cm according to RECIST and progressed in 7. Time till surgery in these patients was 29.5 ± 20.0 months. A total of 155 patients underwent surgery. PHEO/PGL was histologically excluded in 4 and proven in 151. Of these, one had additional metastatic disease, one harboured another tumour of a different type, and in 2 a second surgery for suspected disease recurrence did not confirm PHEO/PGL. Logistic regression analysis revealed 50% probability for a positive/negative biochemical test result at 1.8 cm tumour diameter. Values of a novel symptom score were positively correlated with tumour size (Rs = 0.46, P < 0.0001) and together with a positive biochemistry a linear size predictor (P < 0.01). Results support standardised clinical assessment and measurement of tumour size and metanephrines in VHL patients with non-functioning incidentalomas <1.5 cm at one year following diagnosis and at individualised intervals thereafter depending on evolving growth dynamics, secretory activity and symptomatology.

Overnight/first-morning urine free metanephrines and methoxytyramine for diagnosis of pheochromocytoma and paraganglioma: is this an option?

OBJECTIVE: Sympathoadrenal activity is decreased during overnight rest. This study assessed whether urinary-free normetanephrine, metanephrine and methoxytyramine in overnight/first-morning urine collections might offer an alternative to measurements in 24-h collections or plasma for diagnosis of pheochromocytoma and paraganglioma (PPGL). DESIGN AND METHODS: Prospective multicenter cross-sectional diagnostic study involving 706 patients tested for PPGL, in whom tumors were confirmed in 79 and excluded in 627 after follow-up. Another 335 age- and sex-matched volunteers were included for reference purposes. Catecholamines and their free O-methylated metabolites were measured in 24-h collections divided according to waking and sleeping hours and normalized to creatinine. Plasma metabolites from blood sampled after supine rest were measured for comparison. RESULTS: Urinary outputs of norepinephrine, normetanephrine, epinephrine and metanephrine in the reference population were respectively 50 (48-52)%, 35 (32-37)%, 76 (74-78)% and 15 (12-17)% lower following overnight than daytime collections. Patients in whom PPGLs were excluded showed 28 (26-30)% and 6 (3-9)% day-to-night falls in normetanephrine and metanephrine, while patients with PPGLs showed no significant day-to-night falls in metabolites. Urinary methoxytyramine was consistently unchanged from day to night. According to receiver-operating characteristic curves, diagnostic accuracy of metabolite measurements in overnight/first-morning urine samples did not differ from measurements in 24-h urine collections, but was lower for both than for plasma. Using optimized reference intervals, diagnostic specificity was higher for overnight than daytime collections at similar sensitivities. CONCLUSIONS: Measurements of urinary-free catecholamine metabolites in first-morning/overnight urine collections offer an alternative for diagnosis of PPGL to 24-h collections but remain less accurate than plasma measurements.

Next-generation panel sequencing identifies NF1 germline mutations in three patients with pheochromocytoma but no clinical diagnosis of neurofibromatosis type 1.

OBJECTIVE: Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1). DESIGN: We performed genetic analysis of known tumor predisposition genes, including NF1, using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced. METHODS: Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients' blood and tumor samples. Validation was carried out by Sanger sequencing. RESULTS: Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified. CONCLUSIONS: Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co-occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients.

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Accuracy of recommended sampling and assay methods for the determination of plasma-free and urinary fractionated metanephrines in the diagnosis of pheochromocytoma and paraganglioma: a systematic review.

PURPOSE: To determine the accuracy of biochemical tests for the diagnosis of pheochromocytoma and paraganglioma. METHODS: A search of the PubMed database was conducted for English-language articles published between October 1958 and December 2016 on the biochemical diagnosis of pheochromocytoma and paraganglioma using immunoassay methods or high-performance liquid chromatography with coulometric/electrochemical or tandem mass spectrometric detection for measurement of fractionated metanephrines in 24-h urine collections or plasma-free metanephrines obtained under seated or supine blood sampling conditions. RESULTS: Application of the Standards for Reporting of Diagnostic Studies Accuracy Group criteria yielded 23 suitable articles. Summary receiver operating characteristic analysis revealed sensitivities/specificities of 94/93% and 91/93% for measurement of plasma-free metanephrines and urinary fractionated metanephrines using high-performance liquid chromatography or immunoassay methods, respectively. Partial areas under the curve were 0.947 vs. 0.911. Irrespective of the analytical method, sensitivity was significantly higher for supine compared with seated sampling, 95 vs. 89% (p < 0.02), while specificity was significantly higher for supine sampling compared with 24-h urine, 95 vs. 90% (p < 0.03). Partial areas under the curve were 0.942, 0.913, and 0.932 for supine sampling, seated sampling, and urine. Test accuracy increased linearly from 90 to 93% for 24-h urine at prevalence rates of 0.0-1.0, decreased linearly from 94 to 89% for seated sampling and was constant at 95% for supine conditions. CONCLUSIONS: Current tests for the biochemical diagnosis of pheochromocytoma and paraganglioma show excellent diagnostic accuracy. Supine sampling conditions and measurement of plasma-free metanephrines using high-performance liquid chromatography with coulometric/electrochemical or tandem mass spectrometric detection provides the highest accuracy at all prevalence rates.

[Xanthinuria type 1 in a woman with arthralgias: a combined clinical and molecular genetic investigation]. / Xanthinurie Typ 1 bei einer Patientin mit Gelenkschmerzen: Eine kombinierte konventionelle und molekulargenetische Ursachensuche.

HISTORY AND CLINICAL PRESENTATION: A 53-year old woman with recurrent polyarthralgias, negative test results in a recent rheumatologic work-up and an unmeasurably low uric acid serum concentration presented for suspected IgM paraproteinemia. INVESTIGATIONS: Physical examination, abdominal ultrasound and routine laboratory test results were unremarkable. Repeat determination confirmed a markedly decreased uric acid (UA) serum concentration. Urinary xanthine and hypoxanthine concentrations were increased by 14-fold and 7.5-fold, respectively. Fractional urinary UA excretion was not increased and the allopurinol loading test was normal. Sequencing of the xanthine dehydrogenase (XDH) gene revealed the pathogenic deletion c.641delC in the homozygous state. Segregation analysis showed that the patient's mother and her two adult sons were carriers of the mutation but not a half-sister and a half-brother of her deceased father. There was no evidence of parental consanguinity. These results established xanthinuria type 1 as the cause of the patient's recurrent polyarthralgias due to a previously unreported homozygosity for the known mutation c.641delC of the XDH gene. TREATMENT AND COURSE: The patient was advised to adhere to a low-purine diet and to ensure an increased daily fluid-intake of at least 2.5 l. She has since remained symptom free. CONCLUSION: Markedly lowered serum uric acid concentrations are a hallmark of xanthinuria and of hereditary renal hypouricemia, and in the absence of severe hepatic failure or evidence of an untoward drug effect should raise suspicion of these diseases. A targeted diagnostic work-up should then be initiated and factitious hypouricemia due to IgM paraproteinemia considered only in the case of equivocal test results. Molecular-genetic characterization and segregation analysis will ultimately establish the underlying genotype.

Dipping in Ambulatory Blood Pressure Monitoring Correlates With Overnight Urinary Excretion of Catecholamines and Sodium.

Nondipping blood pressure (BP) is associated with increased morbidity and mortality. This study examines the relationship of "dipping" in 24-hour ambulatory BP monitoring (ABPM) with awake and sleeping urinary norepinephrine (NE) and epinephrine (EPI), and that of urinary NE and EPI with urinary sodium (UNa). Fifty nondippers and 65 dippers were included in the present study. Collected data included age, sex, body mass index, history of hypertension, current antihypertensive treatment, ABPM data, and NE, EPI, and UNa values. Hierarchical multiple regression analysis with the night-to-day ratio (NDR) of systolic BP as a dependent variable showed that the composite term of the NDRs of urinary NE and EPI was a significant predictor for dipping. Results also show a differential role of NE and EPI in circadian UNa excretion in dippers and nondippers. These results indicate that the sympathetic nervous system is involved in the regulation of circadian BP variations and UNa excretion.

Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome.

Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings into perspective these experiences with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11-46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8-38) and SOMs at 29 years (range 22-38). PGLs were multiple, recurrent and metastatic in 100, 100 and 29% of all cases, and SOMs in 40, 40 and 60%, respectively. All PGLs were primarily norepinephrine-producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA). Therefore, [18F]-FDOPA PET/CT, not [68Ga]-(DOTA)-[Tyr3]-octreotate ([68Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges.

Measurements of plasma metanephrines by immunoassay vs liquid chromatography with tandem mass spectrometry for diagnosis of pheochromocytoma.

BACKGROUND: Reports conflict concerning measurements of plasma metanephrines (MNs) for diagnosis of pheochromocytomas/paragangliomas (PPGLs) by immunoassays compared with other methods. We aimed to compare the performance of a commercially available enzyme-linked immunoassay (EIA) kit with liquid chromatography-tandem mass spectrometric (LC-MS/MS) measurements of MNs to diagnose PPGLs. METHODS: In a substudy of a prospective, multicenter trial to study the biochemical profiles of monoamine-producing tumors, we included 341 patients (174 males and 167 females) with suspected PPGLs (median age 54 years), of whom 54 had confirmed PPGLs. Plasma MNs were measured by EIA and LC-MS/MS, each in a specialized laboratory. RESULTS: Plasma normetanephrine (NMN) and MN were measured 60 and 39% lower by EIA than by LC-MS/MS. Using upper cut-offs stipulated for the EIA, diagnostic sensitivity was only 74.1% at a specificity of 99.3%. In contrast, use of similar cut-offs for MN and overall lower age-adjusted cut-offs for NMN measured by LC-MS/MS returned a diagnostic sensitivity and specificity of 98.1 and 99.7%. Areas under receiver-operating characteristic curves, nevertheless, indicated comparable diagnostic performance of the EIA (0.993) and LC-MS/MS (0.985). Diagnostic sensitivity for the EIA increased to 96.2% with a minimal loss in specificity (95.1%) following use of cut-offs for the EIA adapted to correct for the negative bias. CONCLUSIONS: The EIA underestimates plasma MNs and diagnostic sensitivity is poor using commonly stipulated cut-offs, resulting in a high risk for missing patients with PPGLs. Correction of this shortcoming can be achieved by appropriately determined cut-offs resulting in comparable diagnostic performance of EIA and LC-MS/MS assays.

Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma.

BACKGROUND: Measurements of plasma normetanephrine and metanephrine provide a useful diagnostic test for phaeochromocytoma, but this depends on appropriate reference intervals. Upper cut-offs set too high compromise diagnostic sensitivity, whereas set too low, false-positives are a problem. This study aimed to establish optimal reference intervals for plasma normetanephrine and metanephrine. METHODS: Blood samples were collected in the supine position from 1226 subjects, aged 5-84 y, including 116 children, 575 normotensive and hypertensive adults and 535 patients in whom phaeochromocytoma was ruled out. Reference intervals were examined according to age and gender. Various models were examined to optimize upper cut-offs according to estimates of diagnostic sensitivity and specificity in a separate validation group of 3888 patients tested for phaeochromocytoma, including 558 with confirmed disease. RESULTS: Plasma metanephrine, but not normetanephrine, was higher (P < 0.001) in men than in women, but reference intervals did not differ. Age showed a positive relationship (P < 0.0001) with plasma normetanephrine and a weaker relationship (P = 0.021) with metanephrine. Upper cut-offs of reference intervals for normetanephrine increased from 0.47 nmol/L in children to 1.05 nmol/L in subjects over 60 y. A curvilinear model for age-adjusted compared with fixed upper cut-offs for normetanephrine, together with a higher cut-off for metanephrine (0.45 versus 0.32 nmol/L), resulted in a substantial gain in diagnostic specificity from 88.3% to 96.0% with minimal loss in diagnostic sensitivity from 93.9% to 93.6%. CONCLUSIONS: These data establish age-adjusted cut-offs of reference intervals for plasma normetanephrine and optimized cut-offs for metanephrine useful for minimizing false-positive results.

Pheochromocytoma - update on disease management.

Pheochromocytomas are rare endocrine tumors that can present insidiously and remain undiagnosed until death or onset of clear manifestations of catecholamine excess. They are often referred to as one of the 'great mimics' in medicine. These tumors can no longer be regarded as a uniform disease entity, but rather as a highly heterogeneous group of chromaffin cell neoplasms with different ages of onset, secretory profiles, locations, and potential for malignancy according to underlying genetic mutations. These aspects all have to be considered when the tumor is encountered, thereby enabling optimal management for the patient. Referral to a center of specialized expertise for the disease should be considered wherever possible. This is not only important for surgical management of patients, but also for post-surgical follow up and screening of disease in patients with a hereditary predisposition to the tumor. While preoperative management has changed little over the last 20 years, surgical procedures have evolved so that laparoscopic resection is the standard of care and partial adrenalectomy should be considered in all patients with a hereditary condition. Follow-up testing is essential and should be recommended and ensured on a yearly basis. Managing such patients must now also take into account possible underlying mutations and the appropriate selection of genes for testing according to disease presentation. Patients and family members with identified mutations then require an individualized approach to management. This includes consideration of distinct patterns of biochemical test results during screening and the appropriate choice of imaging studies for tumor localization according to the mutation and associated differences in predisposition to adrenal, extra-adrenal and metastatic disease.

Is there still a place for adrenal venous sampling in the diagnostic localization of pheochromocytoma?

Our objective is to outline the utility of adrenal venous sampling (AVS) with measurements of metanephrine to normetanephrine ratios for diagnostic localization of phaeochromocytoma in a patient with normal plasma levels of catecholamines. A 53-year-old-woman was referred for evaluation of recurrent pheochromocytoma following a right adrenalectomy 14 years earlier. Diagnosis of recurrent disease was established from elevations in plasma metanephrines with normal levels of catecholamines. Magnetic resonance imaging indicated two 1-2 cm masses in the right surgical bed and another 1-1.5 cm mass in the left adrenal. These masses were negative on (123)I-metaiodobenzylguanidine scintigraphy. There was no evidence of a hereditary syndrome. We, therefore, carried out two investigational approaches to identify the tumor masses. Hybrid positron emission tomography/computed tomography with (68)Ga-DOTATOC ((68)Ga-DOTATOC-PET/CT) confirmed the presence of recurrent disease in the right surgical bed and also suggested additional left adrenal involvement. Normal plasma catecholamines precluded the use of adrenal venous sampling (AVS) with catecholamine measurements. Hence, we performed AVS with measurements of plasma metanephrines, which were 4- to 7-fold higher in the left adrenal vein than in central venous plasma. We observed a reversal of the normally high metanephrine to normetanephrine ratio (mean value ± SD 5.28 ± 1.86; range 3.36-8.84, n = 13) to 0.73, establishing the presence of a left adrenal pheochromocytoma. Surgical pathology confirmed bilateral disease. This case highlights a scenario where a combination of (68)Ga-DOTATOC-PET/CT and AVS with measurement of the metanephrine to normetanephrine ratio was crucial for the preoperative assessment of a patient with bilateral pheochromocytoma.