Superiority of 68Ga-DOTATATE over 18F-FDG and anatomic imaging in the detection of succinate dehydrogenase mutation (SDHx )-related pheochromocytoma and paraganglioma in the pediatric population.

PURPOSE: To evaluate and compare diagnostic performance of 68Ga-DOTA(0)-Tyr(3)-octreotate (68Ga-DOTATATE) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) and anatomic imaging using computed tomography and/or magnetic resonance (CT/MR) imaging in detection of SDHx-related pheochromocytomas and paragangliomas (PPGLs) in pediatric patients. METHODS: Nine pediatric patients (5:4, girls:boys; 14.6 ± 2.0 years) with an SDHx-related mutation (SDHB:SDHA:SDHD, n = 7:1:1) were included in this retrospective study. At the time of initial diagnosis, 7/9 patients had metastatic disease. They underwent CT/MR imaging along with PET/CT using 68Ga-DOTATATE (n = 9), 18F-FDG (n = 8), and positron emission tomography-magnetic resonance imaging (PET/MR) using 18F-FDG (n = 1). In this manuscript, 18F-FDG PET/CT refers to both 18F-FDG PET/CT and 18F-FDG PET/MR. The per-lesion, per-region, and per-patient detection rates were compared and calculated for each of the imaging modalities. A composite of all functional and anatomic imaging studies served as the imaging comparator. RESULTS: Eight out of nine patients were positive for PPGLs on the imaging studies that demonstrated 107 lesions in 22 anatomic regions on the imaging comparator. The per-lesion detection rates for 68Ga-DOTATATE PET/CT, 18F-FDG PET/CT, and CT/MR imaging were 93.5% (95%CI, 87.0% to 97.3%); 79.4% (95%CI, 70.5% to 86.6%); and 73.8% (95%CI, 64.5% to 81.9%), respectively. The per-lesion detection rate for 68Ga-DOTATATE PET/CT was significantly higher than that of 18F-FDG PET/CT (p = 0.001) or CT/MR imaging (p < 0.001). In all of the anatomic regions except abdomen, the per-lesion detection rates for 68Ga-DOTATATE PET/CT was found to be equal or superior to 18F-FDG PET/CT, and CT/MR imaging. The per-region detection rate was 100% (95%CI, 84.6% to 100%) for 68Ga-DOTATATE PET/CT and 90.9% (95%CI, 70.8% to 98.9%) for both 18F-FDG PET/CT and CT/MR imaging. The per-patient detection rates for 68Ga-DOTATATE PET/CT, 18FDG PET/CT, and CT/MR imaging were all 100% (95%CI, 63.1% to 100%). CONCLUSION: Our preliminary study demonstrates the superiority of 68Ga-DOTATATE PET/CT in localization of SDHx-related PPGLs in pediatric population compared to 18F-FDG PET/CT and CT/MR imaging with the exception of abdominal (excluding adrenal and liver) lesions, and suggests that it might be considered as a first-line imaging modality in pediatric patients with SDHx-related PPGLs.

PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma.

PURPOSE: Pheochromocytomas/paragangliomas (PPGLs) and their metastases are tumors that predominantly express somatostatin receptor 2 (SSR2). (68)Ga-DOTA(0)-Tyr(3)-octreotate ((68)Ga-DOTATATE) is a PET radiopharmaceutical with both high and selective affinity for SSRs. The purpose of this study was to evaluate the utility of (68)Ga-DOTATATE in comparison with other specific and nonspecific radiopharmaceuticals recommended in the current guidelines for the localization of metastatic sporadic PPGL by PET/CT. METHODS: This prospective study included 22 patients (15 men, 7 women; aged 50.0 ± 13.9 years) with confirmed metastatic PPGL, a negative family history for PPGL, and negative genetic testing, who underwent (68)Ga-DOTATATE, (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/CT, and CT/MRI. Only 12 patients underwent an additional (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) PET/CT scan and only 11 patients underwent an additional (18)F-fluorodopamine ((18)F-FDA) PET/CT scan. The rates of detection of metastatic lesions were compared among all the imaging studies. A composite of all functional and anatomical imaging studies served as the imaging comparator. RESULTS: (68)Ga-DOTATATE PET/CT showed a lesion-based detection rate of 97.6 % (95 % confidence interval, CI, 95.8 - 98.7 %). (18)F-FDG PET/CT, (18)F-FDOPA PET/CT, (18)F-FDA PET/CT, and CT/MRI showed detection rates of 49.2 % (CI 44.5 - 53.6 %; p < 0.01), 74.8 % (CI 69.0 - 79.9 %); p < 0.01), 77.7 % (CI 71.5 - 82.8 %; p < 0.01), and 81.6 % (CI 77.8 - 84.8 %; p < 0.01), respectively. CONCLUSION: The results of this study demonstrate the superiority of (68)Ga-DOTATATE PET/CT in the localization of sporadic metastatic PPGLs compared to all other functional and anatomical imaging modalities, and suggest modification of future guidelines towards this new imaging modality.

Brief communication: radiographic contrast infusion and catecholamine release in patients with pheochromocytoma.

BACKGROUND: Contrast-enhanced computed tomography (CT) is useful for localizing pheochromocytoma. However, in patients with suspected pheochromocytoma, CT is often canceled or not performed because of the strong belief that intravenous contrast may induce hypertensive crisis. OBJECTIVE: To examine whether intravenous low-osmolar contrast administration during CT induces catecholamine release that increases blood pressure or heart rate. DESIGN: Prospective study. SETTING: Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: 22 patients with pheochromocytoma (15 nonadrenal and 7 adrenal) and 8 unmatched control participants without pheochromocytoma. MEASUREMENTS: Plasma catecholamine levels, blood pressure, and heart rate. RESULTS: Plasma catecholamine levels within and between groups did not significantly differ before and after intravenous administration of low-osmolar CT contrast. Patients with pheochromocytoma experienced a clinically and statistically significant increase in diastolic blood pressure that was not accompanied by corresponding increases in plasma catecholamine levels. The difference became non-statistically significant after adjustment for use of alpha- and beta-blockers. LIMITATION: The study lacked a placebo group, and the sample was relatively small. CONCLUSION: Intravenous low-osmolar contrast-enhanced CT can safely be used in patients with pheochromocytoma who are not receiving alpha- or beta-blockers. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health.

Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior.

Extra-adrenal pheochromocytomas, otherwise known as paragangliomas (PGLs), account for about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical behavior. We hypothesized that most mediastinal PGLs are associated with germ line SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data in a series of ten patients with mediastinal PGLs. All ten primary mediastinal PGL patients had germ line SDHx mutations, six in SDHB, and four in SDHD genes. Chest or back pain were the most common presenting symptoms (five patients), and catecholamines and/or their metabolites were elevated in seven patients. Additional tumors included head and neck PGLs in four patients, pheochromocytoma in one patient, and bladder PGL in another. Metastatic disease was documented in six patients (60%), and a concurrent abdominal mass was found in one patient. We conclude that mediastinal PGLs are strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and aggressive behavior. The present data suggest that all patients with mediastinal PGLs should be screened for SDHx gene mutations, regardless of age.

Use of 6-[18F]-fluorodopamine positron emission tomography (PET) as first-line investigation for the diagnosis and localization of non-metastatic and metastatic phaeochromocytoma (PHEO).

OBJECTIVE: Imaging modalities available for the localization of phaeochromocytoma (PHEO) include computed tomography (CT), magnetic resonance imaging (MRI), [(123)I]- or [(131)I]-labelled metaiodobenzylguanidine ((123/131)I-MIBG) scintigraphy and 6-[(18)F]-fluorodopamine ((18)F-FDA) positron emission tomography (PET). Our aim was to investigate the yield of (18)F-FDA PET vs. biochemical testing and other imaging techniques to establish the diagnosis and location of PHEO. PATIENTS AND MEASUREMENTS: The study included 99 consecutive patients (35 Males, 64 Females, mean +/- SD age 46.4 +/- 13.4 years), who underwent (18)F-FDA PET, biochemical testing (plasma catecholamines and free metanephrines) and CT and/or MRI. The majority (78%) also underwent (123/131)I-MIBG. RESULTS: In total 26 patients had non-metastatic PHEO, 34 patients had metastatic PHEO, and PHEO was ruled out in 39 patients. Investigations to rule out or confirm PHEO yielded the following sensitivity/specificity: plasma metanephrines 97/95%, (18)F-FDA 92/90%, (123)I-MIBG 83/100%, (123/131)I-MIBG 70/100%, CT 100/41%, MRI 98/60%. Sensitivities for localizing non-metastatic PHEO on a per-lesion base were: CT 97%, MRI 92%, (18)F-FDA 78%, (123)I-MIBG 78% and (123/131)I-MIBG 76%. Sensitivities for detecting metastases on a per-patient base were: CT and MRI 100%, (18)F-FDA 97%, (123)I-MIBG 85% and (123/131)I-MIBG 65%. CONCLUSION: For tumour localization, (18)F-FDA PET and (123/131)I-MIBG scintigraphy perform equally well in patients with non-metastatic PHEO, but metastases are better detected by (18)F-FDA PET than by (123/131)I-MIBG.

Radiofrequency ablation of metastatic pheochromocytoma.

In the present report on the preliminary safety and effectiveness of radiofrequency (RF) ablation for pheochromocytoma metastases, seven metastases were treated in six patients (mean size, 3.4 cm; range, 2.2-6 cm). alpha- and beta-adrenergic and catecholamine synthesis inhibition and intraprocedural anesthesia monitoring were used. Safety was assessed by recording ablation-related complications. Complete ablation was defined as a lack of enhancement within the ablation zone on follow-up computed tomography. No serious adverse sequelae were observed. Complete ablation was achieved in six of seven metastases (mean follow-up, 12.3 months; range, 2.5-28 months). In conclusion, RF ablation may be safely performed for metastatic pheochromocytoma given careful attention to peri-procedural management.

Malignant paraganglioma associated with succinate dehydrogenase subunit B in an 8-year-old child: the age of first screening?

Several studies have shown that patients with succinate dehydrogenase subunit B (SDHB) mutations have a very high risk for developing malignant paragangliomas. However, there is no consensus of what age screening for paragangliomas should start. We report a case of an 8-year-old white girl with a 3-year history of catecholamine excess-related complaints who was diagnosed with a malignant SDHB-associated mediastinal paraganglioma. The patient presented with intermittent sweating, headache, nausea, vomiting, fatigue and weight loss that had been present since she was 5 years of age. A large posterior mediastinal mass measuring 6.4 cm x 3.1 cm x 4.6 cm was discovered on computed tomography (CT) and magnetic resonance imaging (MRI). Laboratory data included an elevated level of urine normetanephrine of 45,400 microg/g creatinine (upper reference limit 718 microg/g) and elevated level of plasma normetanephrine of 62.4 nmol/l (upper reference limit <0.90 nmol/l). She was diagnosed with a thoracic paraganglioma and subsequently underwent surgical removal of the tumor and two lymph nodes. Histopathologic examination confirmed metastatic paraganglioma. Postoperatively, her blood pressure normalized and plasma normetanephrine levels remained normal. Our patient first presented with paraganglioma-associated signs and symptoms at the young age of 5 years. This case clearly illustrates the need for increased vigilance and screening for paragangliomas in families with SDHB at a younger age than previously thought.

Gallbladder Paraganglioma Associated with SDHD Mutation: a Potential Pitfall on 18F-FDOPA PET Imaging.

A 36-year-old male patient initially presented with hypertension, tinnitus, bilateral carotid masses, a right jugular foramen, and a periaortic arch mass with an elevated plasma dopamine level but an otherwise normal biochemical profile. On surveillance MRI 4 years after initial presentation, he was found to have a 2.2-cm T2 hyperintense lesion with arterial enhancement adjacent to the gallbladder, which demonstrated avidity on 68Ga-DOTATATE PET/CT and retrospectively on 18F-FDOPA PET/CT but was non-avid on 18F-FDG PET/CT. Biochemical work-up including plasma catecholamines, metanephrines, and chromogranin A levels were found to be within normal limits. This lesion was surgically resected and was confirmed to be a paraganglioma (PGL) originating from the gallbladder wall on histopathology. Pheochromocytoma (PHEO) and PGL are rare tumors of the autonomic nervous system. Succinate dehydrogenase subunit D (SDHD) pathogenic variants of the succinate dehydrogenase complex are usually involved in parasympathetic, extra-adrenal, multifocal head, and neck PGLs. We report an unusual location of PGL in the gallbladder associated with SDHD mutation which could present as a potential pitfall on 18F-FDOPA PET/CT as its normal excretion occurs through biliary system and gallbladder. This case highlights the superiority of 68Ga-DOTATATE in comparison to 18F-FDOPA and 18F-FDG in the detection of SDHD-related parasympathetic PGL. ClinicalTrials.gov Identifier: NCT00004847.

Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma.

Background: Pheochromocytoma and paraganglioma (PHEO/PGL) are rare neuroendocrine tumors which may cause potentially life-threatening complications, with about a third of cases found to harbor specific gene mutations. Thus, early diagnosis, treatment, and meticulous monitoring are of utmost importance. Because of low incidence of succinate dehydrogenase complex subunit A (SDHA)-related metastatic PHEO/PGL, currently there exists insufficient clinical information, especially with regards to its diagnostic and treatment characteristics. Methods: Ten patients with SDHA-related metastatic PHEO/PGL were followed-up prospectively and/or retrospectively between January 2010-July 2018. They underwent biochemical tests (n = 10), 123I-MIBG (n = 9) scintigraphy, and multiple whole-body positron emission tomography/computed tomography (PET/CT) scans with 68Ga-DOTATATE (n = 10), 18F-FDG (n = 10), and 18F-FDOPA (n = 6). Results: Our findings suggest that these tumors can occur early and at extra-adrenal locations, behave aggressively, and have a tendency to develop metastatic disease within a short period of time. None of our patients had a family history of PHEO/PGL, making them appear sporadic. Nine out of 10 patients showed abnormal PHEO/PGL-specific biochemical markers with predominantly noradrenergic and/or dopaminergic phenotype, suggesting their utility in diagnosing and monitoring the disease. Per patient detection rates of 68Ga-DOTATATE (n = 10/10), 18F-FDG (n = 10/10), 18F-FDOPA (n = 5/6) PET/CT, and 123I-MIBG (n = 7/9) scintigraphy were 100, 100, 83.33, and 77.77%, respectively. Five out of 7 123I-MIBG positive patients had minimal 123I-MIBG avidity or detected very few lesions compared to widespread metastatic disease on 18F-FDG PET/CT, implying that diagnosis and treatment with 123/131I-MIBG is not a good option. 68Ga-DOTATATE PET/CT was found to be superior or equal to 18F-FDG PET/CT in 7 out of 10 patients and hence, is recommended for evaluation and follow-up of these patients. All 7 out of 7 patients who received conventional therapies (chemotherapy, somatostatin analog therapy, radiation therapy, 131I-MIBG, peptide receptor radionuclide therapy) in addition to surgery showed disease progression. Conclusion: In our cohort of patients, SDHA-related metastatic PHEO/PGL followed a disease-course similar to that of SDHB-related metastatic PHEO/PGL, showing highly aggressive behavior, similar imaging and biochemical phenotypes, and suboptimal response to conventional therapies. Therefore, we recommend careful surveillance of the affected patients and a search for effective therapies.

Role of positron emission tomography and bone scintigraphy in the evaluation of bone involvement in metastatic pheochromocytoma and paraganglioma: specific implications for succinate dehydrogenase enzyme subunit B gene mutations.

We performed a retrospective analysis of 71 subjects with metastatic pheochromocytoma and paraganglioma (30 subjects with mutation of succinate dehydrogenase enzyme subunit B (SDHB) gene and 41 subjects without SDHB mutation). Sixty-nine percent presented with bone metastases (SDHB +/-: 77% vs 63%), 39% with liver metastases (SDHB +/-: 27% vs 47%), and 32% with lung metastases (SDHB +/-: 37% vs 29%). The most common sites of bone involvement were thoracic spine (80%; SDHB+/-: 83% vs 77%), lumbar spine (78%; SDHB +/-: 78% vs 75%), and pelvic and sacral bones (78%; SDHB +/-: 91% vs 65%, P=0.04). Subjects with SDHB mutation also showed significantly higher involvement of long bones (SDHB +/-: 78% vs 30%, P=0.007) than those without the mutation. The best overall sensitivity in detecting bone metastases demonstrated positron emission tomography (PET) with 6-[(18)F]-fluorodopamine ([(18)F]-FDA; 90%), followed by bone scintigraphy (82%), computed tomography or magnetic resonance imaging (CT/MRI; 78%), 2-[(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]-FDG) PET (76%), and scintigraphy with [(123/131)I]-metaiodobenzylguanidine (71%). In subjects with SDHB mutation, imaging modalities with best sensitivities for detecting bone metastases were CT/MRI (96%), bone scintigraphy (95%), and [(18)F]-FDG PET (92%). In subjects without SDHB mutations, the modality with the best sensitivity for bone metastases was [(18)F]-FDA PET (100%). In conclusion, bone scintigraphy should be used in the staging of patients with malignant pheochromocytoma and paraganglioma, particularly in patients with SDHB mutations. As for PET imaging, [(18)F]-FDG PET is highly recommended in SDHB mutation patients, whereas [(18)F]-FDA PET is recommended in patients without the mutation.

Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene.

CONTEXT: Patients with adrenal and extra-adrenal abdominal paraganglioma (PGL) almost invariably have increased plasma and urine concentrations of metanephrines, the O-methylated metabolites of catecholamines. We report four cases of biochemically silent abdominal PGL, in which metanephrines were normal despite extensive disease. OBJECTIVE: Our objective was to identify the mechanism underlying the lack of catecholamine hypersecretion and metabolism to metanephrines in biochemically silent PGL. DESIGN: This is a descriptive study. SETTING: The study was performed at a referral center. PATIENTS: One index case and three additional patients with large abdominal PGL and metastases but with the lack of evidence of catecholamine production, six patients with metastatic catecholamine-producing PGL and a mutation of the succinate dehydrogenase subunit B (SDHB) gene, and 136 random patients with catecholamine-producing PGL were included in the study. MAIN OUTCOME MEASURES: Plasma, urine, and tumor tissue concentrations of catecholamines and metabolites were calculated with electron microscopy and tyrosine hydroxylase immunohistochemistry. RESULTS: All four patients with biochemically silent PGL had an underlying SDHB mutation. In the index case, the tumor tissue concentration of catecholamines (1.8 nmol/g) was less than 0.01% that of the median (20,410 nmol/g) for the 136 patients with catecholamine-producing tumors. Electron microscopy showed the presence of normal secretory granules in all four biochemically silent PGLs. Tyrosine hydroxylase immunoreactivity was negligible in the four biochemically silent PGLs but abundant in catecholamine-producing PGLs. CONCLUSIONS: Patients with SDHB mutations may present with biochemically silent abdominal PGLs due to defective catecholamine synthesis resulting from the absence of tyrosine hydroxylase. Screening for tumors in patients with SDHB mutations should not be limited to biochemical tests of catecholamine excess.

Comparison of 6-18F-fluorodopamine PET with 123I-metaiodobenzylguanidine and 111in-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma.

UNLABELLED: We compared functional imaging modalities including PET with 6-(18)F-fluorodopamine ((18)F-DA) with (123)I-metaiodobenzylguanidine ((123)I-MIBG) and somatostatin receptor scintigraphy (SRS) with (111)In-pentetreotide in nonmetastatic and metastatic pheochromocytoma (PHEO). METHODS: We studied 25 men and 28 women (mean age +/- SD, 44.2 +/- 14.2 y) with biochemically proven nonmetastatic (n = 17) or metastatic (n = 36) PHEO. Evaluation included anatomic imaging with CT or MRI and functional imaging that included at least 2 nuclear medicine modalities: (18)F-DA PET, (123)I-MIBG scintigraphy, or SRS. Sensitivity of functional imaging versus anatomic imaging was assessed on a per-patient and a per-region basis. RESULTS: For this available cohort, on a per-patient basis overall sensitivity (combined for nonmetastatic and metastatic PHEO) was 90.2% for (18)F-DA PET, 76.0% for (123)I-MIBG scintigraphy, and 22.0% for SRS. On a per-region basis, overall sensitivity was 75.4% for (18)F-DA PET, 63.4% for (123)I-MIBG scintigraphy, and 64.0% for SRS. CONCLUSION: If available, (18)F-DA PET should be used in the evaluation of PHEO, because it is more sensitive than (123)I-MIBG scintigraphy or SRS. If (18)F-DA PET is not available, (123)I-MIBG scintigraphy (for nonmetastatic or adrenal PHEO) and SRS (for metastatic PHEO) should be the first alternative imaging methods to be used.

18F-FDOPA PET/CT Imaging of MAX-Related Pheochromocytoma.

Context: MYC-associated factor X (MAX) has been recently described as a new susceptibility pheochromocytoma (PHEO) gene with a total of ~40 reported cases. At present, no study has specifically described the functional imaging phenotype of MAX-related PHEO. Objective, Patients, and Design: The objective of the present study was to present our experience with contrast-enhanced computed tomography (CT) and 18F-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET)/CT in six consecutive patients (four at the initial diagnosis and two at the follow-up evaluation) with rare, but clinically important, MAX-related PHEOs. In five patients, 18F-FDOPA was also compared with other radiopharmaceutical agents. Results: The patients had five different mutations in the MAX gene that caused disruption of Max/Myc interaction and/or abolished interaction with DNA based on in silico analyses. All but one patient developed bilateral PHEOs during their lifetime. In all cases, 18F-FDOPA PET/CT accurately visualized PHEOs that were often multiple within the same gland or bilaterally and detected more adrenal and extra-adrenal lesions than did CT (per-lesion sensitivity, 90.9% vs 52.4% for CT/magnetic resonance imaging). The two PHEOs missed on 18F-FDOPA PET/CT were <1 cm, corresponding to nodular adrenomedullary hyperplasia. 68Ga-DOTA,Tyr3-octreotate PET/CT detected fewer lesions than did 18F-FDOPA PET/CT in one of three patients, and 18F-fluorodeoxyglucose PET/CT was only faintly positive in two of four patients with underestimation of extra-adrenal lesions in one patient. Conclusions: MAX-related PHEOs exhibit a marked 18F-FDOPA uptake, a finding that illustrates the common well-differentiated chromaffin pattern of PHEOs associated with activation of kinase signaling pathways. 18F-FDOPA PET/CT should be considered as the first-line functional imaging modality for diagnostic or follow-up evaluations for these patients.

Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.

CONTEXT: Mutations of the gene encoding succinate dehydrogenase subunit B (SDHB) predispose to malignant paraganglioma (PGL). Recognition of the SDHB phenotype in apparently sporadic PGL directs appropriate treatment and family screening. OBJECTIVE: The objective of the study was to assess mutation-specific clinical and biochemical characteristics of SDHB-related PGL. DESIGN: The study design was retrospective descriptive. PATIENTS: PATIENTS included 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. INTERVENTION: There was no intervention. MAIN OUTCOME MEASURES: Clinical presentations, plasma and urine concentrations of catecholamines and O-methylated metabolites, and genotype-phenotype correlations were measured. RESULTS: Mean +/- sd age at diagnosis was 33.7 +/- 15.7 yr. Tumor-related pain was among the presenting symptoms in 54% of patients and was the sole symptom in 14%. Seventy-six percent had hypertension, and 90% lacked a family history of PGL. All primary tumors but one originated from extraadrenal locations. Mean +/- sd tumor size was 7.8 +/- 3.7 cm. In this referral-based study, 28% presented with metastatic disease and all but one eventually developed metastases after 2.7 +/- 4.1 yr. Ten percent had additional head and neck PGLs. The biochemical phenotype was consistent with hypersecretion of both norepinephrine and dopamine in 46%, norepinephrine only in 41%, and dopamine only in 3%. Ten percent had normal catecholamine (metabolite) levels, consistent with biochemically silent PGL. No obvious genotype-phenotype correlations were identified. CONCLUSIONS: SDHB-related PGL often presents as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consists of hypersecretion of norepinephrine and/or dopamine, whereas 10% of tumors are biochemically silent. The clinical expression of these tumors cannot be predicted by the genotype.

Usefulness of standardized uptake values for distinguishing adrenal glands with pheochromocytoma from normal adrenal glands by use of 6-18F-fluorodopamine PET.

UNLABELLED: 6-(18)F-Fluorodopamine ((18)F-FDA) PET is a highly sensitive tool for the localization of pheochromocytoma (PHEO). The aim of this study was to establish cutoff values for pathologic and physiologic adrenal gland tracer uptake. METHODS: (18)F-FDA PET with CT coregistration was performed in 14 patients (10 men and 4 women; age [mean +/- SD], 42.9 +/- 13.3 y) with unilateral adrenal gland PHEO and in 13 control subjects (5 men and 8 women; age, 51.7 +/- 12.5 y) without PHEO. Standardized uptake values (SUVs) were compared between adrenal glands with PHEO and normal left adrenal glands in control subjects. RESULTS: (18)F-FDA accumulation was observed in all adrenal glands with PHEO and in 6 of 13 control adrenal glands (P = 0.02). The SUV was higher in adrenal glands with PHEO (mean +/- SD, 16.1 +/- 6.1) than in (18)F-FDA-positive control adrenal glands (7.7 +/- 1.4) (P = 0.005). SUV cutoffs for distinguishing between adrenal glands with PHEO and normal adrenal glands were 7.3 (100% sensitivity) and 10.1 (100% specificity). CONCLUSION: The SUVs of adrenal foci on (18)F-FDA PET facilitate the distinction between adrenal glands with PHEO and normal adrenal glands.

The effects of carbidopa on uptake of 6-18F-Fluoro-L-DOPA in PET of pheochromocytoma and extraadrenal abdominal paraganglioma.

UNLABELLED: 6-(18)F-fluoro-l-3,4-dihydroxyphenylalanine ((18)F-DOPA) PET is a useful tool for the detection of certain neuroendocrine tumors, especially with the preadministration of carbidopa, an inhibitor of DOPA decarboxylase. Whether carbidopa also improves (18)F-DOPA PET of adrenal pheochromocytomas and extraadrenal paragangliomas is unknown. The aim of this study was to investigate the sensitivity of (18)F-DOPA PET in the detection of paraganglioma and its metastatic lesions and to evaluate whether tracer uptake by the tumors is enhanced by carbidopa. METHODS: Two patients with nonmetastatic adrenal pheochromocytoma, and 9 patients with extraadrenal abdominal paraganglioma (1 nonmetastatic, 8 metastatic), underwent whole-body CT, MRI, baseline (18)F-DOPA PET, and (18)F-DOPA PET with oral preadministration of 200 mg of carbidopa. The dynamics of tracer uptake by these lesions and the physiologic distribution of (18)F-DOPA in normal tissues were recorded. RESULTS: Seventy-eight lesions were detected by CT or MRI, 54 by baseline (18)F-DOPA PET (P = 0.0022 vs. CT/MRI), and 57 by (18)F-DOPA PET plus carbidopa (P = 0.0075 vs. CT/MRI, not statistically significant vs. baseline). In reference to findings on CT and MRI, the sensitivities of baseline (18)F-DOPA PET were 47.4% for lesions and 55.6% for positive body regions, versus 50.0% (lesions) and 66.7% (regions) for (18)F-DOPA PET plus carbidopa (neither is statistically significant vs. baseline). Compared with baseline, carbidopa detected additional lesions in 3 (27%) of 11 patients. Carbidopa increased the mean (+/-SD) peak standardized uptake value in index tumor lesions from 6.4 +/- 3.9 to 9.1 +/- 5.6 (P = 0.037). Pancreatic physiologic (18)F-DOPA uptake, which may mask adrenal pheochromocytoma, is blocked by carbidopa. CONCLUSION: Carbidopa enhances the sensitivity of (18)F-DOPA PET for adrenal pheochromocytomas and extraadrenal abdominal paragangliomas by increasing the tumor-to-background ratio of tracer uptake. The sensitivity of (18)F-DOPA PET for metastases of paraganglioma appears to be limited.

SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations.

PURPOSE: Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma (PHEO/PGL). Limited information is available concerning PHEO/PGL penetrance among SDHB mutation carriers with regards to primary tumor location, specific mutation type, and gender. We assessed PHEO/PGL penetrance in SDHB mutation carriers and described the clinical presentation and disease course. METHODS: Asymptomatic relatives (N = 611) of 103 index patients were tested for SDHB mutations. Mutation carriers (N = 328) were offered PHEO/PGL screening, of which 241 participated and were included in penetrance analysis. For additional disease outcome analysis, the 103 index patients and 40 screened individuals who developed PHEO/PGL were included. Clinical data were collected between October 2004 and June 2016. RESULTS: Forty (16.60%) of the 241 screened individuals developed PHEO/PGL during the study. The penetrance estimate in this population was 49.80% (95% CI 29-74.9) at 85 years. A significantly higher age-related penetrance of disease was observed in males compared to females, with 50% penetrance achieved at age 74 vs. not reached. Age-related penetrance analysis demonstrated 4 mutations (Ile127Ser, IVS1+1G>T, Exon 1 deletion, Arg90X) presenting with a slower rate of disease development (50% penetrance ages, respectively: not achieved, 70, 63, 61 years) compared to Arg46X and Val140Phe mutations (50% penetrance at 38 years). CONCLUSIONS: Here, we found a higher estimated penetrance compared to several other studies, and a striking difference in age-related penetrance between male and female SDHB mutation carriers with no association between mutation and gender or tumor location.

Functional Imaging Signature of Patients Presenting with Polycythemia/Paraganglioma Syndromes.

Pheochromocytoma/paraganglioma (PPGL) syndromes associated with polycythemia have previously been described in association with mutations in the von Hippel-Lindau gene. Recently, mutations in the prolyl hydroxylase gene (PHD) 1 and 2 and in the hypoxia-inducible factor 2 α (HIF2A) were also found to be associated with multiple and recurrent PPGL. Such patients also presented with PPGL and polycythemia, and later on, some presented with duodenal somatostatinoma. In additional patients presenting with PPGL and polycythemia, no further mutations have been discovered. Because the functional imaging signature of patients with PPGL-polycythemia syndromes is still unknown, and because these tumors (in most patients) are multiple, recurrent, and metastatic, the goal of our study was to assess the optimal imaging approach using 4 different PET radiopharmaceuticals and CT/MRI in these patients. Methods: Fourteen patients (10 women, 4 men) with confirmed PPGL and polycythemia prospectively underwent 68Ga-DOTATATE (13 patients), 18F-FDG (13 patients), 18F-fluorodihydroxyphenylalanine (18F-FDOPA) (14 patients), 18F-fluorodopamine (18F-FDA) (11 patients), and CT/MRI (14 patients). Detection rates of PPGL lesions were compared between all imaging studies and stratified between the underlying mutations. Results:18F-FDOPA and 18F-FDA PET/CT showed similar combined lesion-based detection rates of 98.7% (95% confidence interval [CI], 92.7%-99.8%) and 98.3% (95% CI, 90.9%-99.7%), respectively. The detection rates for 68Ga-DOTATATE (35.3%; 95% CI, 25.0%-47.2%), 18F-FDG (42.3; 95% CI, 29.9%-55.8%), and CT/MRI (60.3%; 95% CI, 48.8%-70.7%) were significantly lower (P < 0.01), irrespective of the mutation status. Conclusion:18F-FDOPA and 18F-FDA are superior to 18F-FDG, 68Ga-DOTATATE, and CT/MRI and should be the radiopharmaceuticals of choice in this rare group of patients.

High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.

CONTEXT: Adrenal and extraadrenal paragangliomas are tumors of chromaffin cells that are usually benign but that may also develop into malignant disease. Mutations of the gene for succinate dehydrogenase subunit B (SDHB) are associated with a high risk of malignancy, but establishing the precise contribution requires relatively large numbers of patients with well-defined malignancy. OBJECTIVE: We assessed the prevalence of SDHB mutations in a series of patients with malignant paraganglioma. DESIGN: SDHB mutation testing was carried out in 44 consecutive patients with malignant paraganglioma. Clinical characteristics of patients with malignant disease due to SDHB mutations were compared with those without mutations. RESULTS: Pathogenic SDHB mutations were found in 13 of the 44 patients (30%). Close to one third of patients had metastases originating from an adrenal primary tumor, compared with a little over two thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%. CONCLUSION: This study establishes that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from an extraadrenal paraganglioma, may justify a high priority for SDHB germline mutation testing in these patients.

68Ga-DOTATATE PET/CT in the Localization of Head and Neck Paragangliomas Compared with Other Functional Imaging Modalities and CT/MRI.

UNLABELLED: Pheochromocytomas/paragangliomas overexpress somatostatin receptors, and recent studies have already shown excellent results in the localization of sympathetic succinate dehydrogenase complex, subunit B, mutation-related metastatic pheochromocytomas/paragangliomas using (68)Ga-DOTATATE PET/CT. Therefore, the goal of our study was to assess the clinical utility of this functional imaging modality in parasympathetic head and neck paragangliomas (HNPGLs) compared with anatomic imaging with CT/MRI and other functional imaging modalities, including (18)F-fluorohydroyphenylalanine ((18)F-FDOPA) PET/CT, currently the gold standard in the functional imaging of HNPGLs. METHODS: (68)Ga-DOTATATE PET/CT was prospectively performed in 20 patients with HNPGLs. All patients also underwent (18)F-FDOPA PET/CT, (18)F-FDG PET/CT, and CT/MRI, with 18 patients also undergoing (18)F-fluorodopamine ((18)F-FDA) PET/CT. (18)F-FDOPA PET/CT and CT/MRI served as the imaging comparators. RESULTS: Thirty-eight lesions in 20 patients were detected, with (18)F-FDOPA PET/CT identifying 37 of 38 and CT/MRI identifying 23 of 38 lesions (P < 0.01). All 38 and an additional 7 lesions (P = 0.016) were detected on (68)Ga-DOTATATE PET/CT. Significantly fewer lesions were identified by (18)F-FDG PET/CT (24/38, P < 0.01) and (18)F-FDA PET/CT (10/34, P < 0.01). CONCLUSION: (68)Ga-DOTATATE PET/CT identified more lesions than other imaging modalities. With the results of the present study, and the increasing availability and use of DOTA analogs in the therapy of neuroendocrine tumors, we expect that (68)Ga-DOTATATE PET/CT will become the preferred functional imaging modality for HNPGLs in the near future.