Head And Neck Paragangliomas Patients Research Articles

68Ga]DOTATOC PET-derived radiomics to predict genetic background of head and neck paragangliomas: a pilot investigation.

To investigate the [68Ga]DOTATOC PET radiomic profile of head and neck paragangliomas (HNPGLs) and identify radiomic characteristics useful as predictors of succinate dehydrogenase genes (SDHx) pathogenic variants. Sporadic and SDHx HNPGL patients, who underwent [68Ga]DOTATOC PET/CT, were retrospectively included. HNPGLs were analyzed using LIFEx software, and extracted features were harmonized to correct for batch effects and confronted testing for multiple comparison. Stepwise discriminant analysis was conducted to remove redundancy and identify best discriminating features. ROC analysis was used to define optimal cut-offs. Multivariate decision-tree analysis was performed using CHAID method. 34 patients harboring 60 HNPGLs (51 SDHx in 25 patients) were included. Three sporadic and nine SDHx HNPGLs were metastatic. At stepwise discriminant analysis, both GLSZM-Zone Size Non-Uniformity (ZSNU, reflecting tumor heterogeneity) and IB-TLSRE (total lesion somatostatin receptor expression) were independent predictors of genetic status, with 96.4% of lesions and 91.6% of patients correctly classified after cross validation (p < 0.001). Among non-metastatic patients, GLSZM-ZSNU and IB-TLSRE were significantly higher in sporadic than SDHx HNPGLs (p < 0.001). No differences were revealed in metastatic patients. Decision-tree analysis highlights multifocality and IB-TLSRE as useful variables, correctly identifying 6/9 sporadic and 24/25 SDHx patients. Model failed to classify one SDHA and three sporadic patients (2 metastatic). Radiomics features GLSZM-ZSNU and IB-TLSRE appear to reflect HNPGLs SDHx status and tumor behavior (metastatic vs. non-metastatic). If validated, especially IB-TLSRE might represent a simple and time-efficient radiomic index for SDHx variants early screening and prediction of tumor behavior in HNPGL cases.

Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients

Head and neck paragangliomas (HNPGLs), rare chemoresistant tumors curable only with surgery, are strongly influenced by genetic predisposition, hence patients and relatives require lifetime follow-up with MRI and/or PET-CT because of de novo disease risk. This entails exposure to electromagnetic/ionizing radiation, costs, and organizational challenges, because patients and relatives are scattered far from reference centers. Simplified first-line screening strategies are needed. We employed flow injection analysis tandem mass spectrometry, as used in newborn metabolic screening, to compare the plasma metabolic profile of HNPGL patients (59 samples, 56 cases) and healthy controls (24 samples, 24 cases). Principal Component Analysis (PCA) and Partial Least Discriminant Analysis (PLS-DA) highlighted a distinctive HNPGL signature, likely reflecting the anaplerotic conversion of the TCA cycle to glutaminolysis and catabolism of branched amino acids, DNA damage and deoxyadenosine (dAdo) accumulation, impairment of fatty acid oxidation, switch towards the Warburg effect and proinflammatory lysophosphatidylcholines (LPCs) signaling. Statistical analysis of the metabolites that most impacted on PLS-DA was extended to 10 acoustic neuroma and 2 cholesteatoma patients, confirming significant differences relative to the HNPGL plasma metabolomic profile. The best confusion matrix from the ROC curve built on 2 metabolites, dAdo and C26:0-LPC, provided specificity of 94.29% and sensitivity of 89.29%, with positive and negative predictive values of 96.2% and 84.6%, respectively. Analysis of dAdo and C26:0-LPC levels in dried venous and capillary blood confirmed that dAdo, likely deriving from 2′-deoxy-ATP accumulated in HNPGL cells following endogenous genotoxic damage, efficiently discriminated HNPGL patients from healthy controls and acoustic neuroma/cholesteatoma patients on easily manageable dried blood spots.

FDG PET-CT imaging in head and neck paragangliomas: A centre experience.

Clinical data on genetic testing and follow-up were collected for patients who had FDG PET-CT scans from 2004 to 2016. Receiver operator characteristic (ROC) analysis was used to compare standardized uptake values (SUVs), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) between lesions in patients who had a clinically related event: event (+) and those who did not: event (-). Similarly, we compared PET parameters between SDHx+ patients and a control group with low probability of mutation. Of 153 HNPGL patients, 73 (29 SDHx+) with 93 FDG-positive lesions were identified: 53.8% of lesions were assessed in a pre-therapeutic setting. In comparison with a reference extracted from clinicoradiological database, FDG PET-CT showed good performance to detect HNPGLs (96.6% accuracy). In this study population, 16 disease progression, 1 recurrence and 1 death were recorded and event (+) patients had lesions with higher SUVmax (p=.03 and p=.02, respectively). Conversely, there were no differences in PET parameters between lesions in SDHx+ patients and controls with low probability of SDHx+ mutations. FDG PET-CT has clinical utility in HNPGLs, mostly before local treatment. There were no significant differences in PET parameters between SDHx patients and a sporadic HNPGL population. However, regardless of SDHx mutation status, a high SUVmax was associated with more clinical events and prompts to a closer follow-up.

Dopamine concentration in blood platelets is elevated in patients with head and neck paragangliomas.

Plasma 3-methoxytyramine (3-MT), a metabolite of dopamine, is elevated in up to 28% of patients with head and neck paragangliomas (HNPGLs). As free dopamine is incorporated in circulating platelets, we determined dopamine concentration in platelets in patients with a HNPGL. A single center cohort study was performed between 2012 and 2014. Thirty-six patients with a HNPGL were compared to healthy controls (68 for dopamine in platelets and 120 for plasma 3-MT). Dopamine concentration in platelets was elevated in HNPGL patients compared to healthy controls (median [interquartile ranges] 0.48 [0.32-0.82] pmol/109 platelets vs. 0.31 [0.24-0.47] pmol/109 platelets; p<0.05), whereas plasma 3-MT concentration did not differ between both groups (0.06 [0.06-0.08] nmol/L vs. 0.06 [0.06-0.06] nmol/L; p=0.119). Based on 68 healthy controls, the reference interval for dopamine concentration in platelets was 0.12-0.97 pmol/109 platelets. Six (16.7%) patients with a HNPGL demonstrated an increased dopamine concentration in platelets compared to three (8.3%) patients with an increased plasma 3-MT level (p=0.053). The sensitivity and specificity were 16.7% and 98.5% for platelet dopamine and 8.3% and 97.5% for plasma 3-MT concentration (p=0.37). Dopamine concentration in platelets is elevated in patients with a HNPGL compared to healthy subjects, and may be a novel biomarker for dopamine producing paraganglioma.

Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites

A substantial number of patients with head and neck paragangliomas (HNPGLs) have biochemically active tumors, evidenced by increased urinary excretion of catecholamines and metabolites, including 3-methoxytyramine (3MT). It is unclear whether plasma levels of these parameters are more sensitive to detect biochemical activity in HNPGL patients than urinary excretion rates. To compare plasma free levels vs urinary excretion rates of deconjugated 3MT and combined metanephrines (MNs) in patients with HNPGL. We included 124 consecutive patients with HNPGL for screening of catecholamine excess by measurement of 24-h urinary excretion rates of deconjugated (nor)metanephrine, (nor)epinephrine, dopamine, vanillylmandelic acid, 3MT, and plasma free levels of (nor)metanephrine and 3MT. Plasma free 3MT levels were increased in 35 of the 124 patients (28%), whereas 24-h urinary excretion of deconjugated 3MT was increased in 30 patients (24%) (P=0.13). Plasma free MN levels were increased in seven patients (6%) and urinary deconjugated MN levels in six patients (5%) (P=1.00). Plasma free normetanephrine (NMN) levels were increased in seven patients (6%), and five patients had increased urinary excretion of deconjugated NMN (4%) (P=0.69). Plasma free combined MN levels (NMN, MN, and 3MT) were increased in 41 patients (33%), whereas 24-h urinary excretion rates of deconjugated combined MNs were increased in 33 patients (27%, P<0.05). The combined levels of free MNs and free 3MT in plasma indicate a higher number of biochemically active HNPGLs than the 24-h urinary excretion rates of these markers.

Urinary 5-HIAA Excretion is not Increased in Patients with Head and Neck Paragangliomas

Case reports have documented carcinoid-like features in head and neck paragangliomas (HNPGLs), which, in addition to catecholamine storing granules, may also contain granules with serotonin. Serotonin is metabolized to 5-hydroxyindoleacetic acid (5-HIAA). To assess the urinary excretion rates of 5-HIAA and catecholamines in HNPGL patients. In 114 consecutive HNPGL patients, normetanephrine, metanephrine, norepinephrine, epinephrine, VMA, dopamine, 3-methoxytyramine and 5-HIAA excretion rates were measured in two 24-hour urinary samples. Increased excretion rates were defined as an increase of the average hormone excretion rate of 2 urine samples above the reference range. In all patients with catecholamine excess, intrathoracic and abdominal paragangliomas were excluded by 123I-MIBG scintigraphy, MRI and/or CT. Genetic screening for mutations in genes of the succinate dehydrogenase (SDH) family was performed. Mean urinary 5-HIAA excretion rate was 14±9 μmol/24 hours (reference range 10-44 μmol/24 hours). Urinary 5-HIAA excretion was slightly increased in only 1 patient (48 μmol/24 hours). None of the 50 patients (44%) with increased urinary excretion rates of catecholamines and/or their metabolites had elevated 5-HIAA excretion. Urinary 5-HIAA excretion is within the normal reference range in almost all HNPGL patients. Therefore, this parameter has no clinical relevance in the routine clinical assessment of HNPGL patients.

Head-and-neck paragangliomas are associated with sleep-related complaints, especially in the presence of carotid body tumors

ObjectivesThe carotid body functions as a chemoreceptor. We hypothesized that head-and-neck paragangliomas (HNP) may disturb the function of these peripheral chemoreceptors and play a role in sleep-disordered breathing.DesignThis is a case–control study.SettingThis study was conducted in a tertiary referral center.Participants and main outcome measuresWe assessed fatigue, sleep, and exercise capacity in 74 HNP patients using three questionnaires (Epworth Sleepiness Scale, St. George Respiratory Questionnaire, and a standard clinical sleep assessment questionnaire). Outcomes were compared to those of age- and sex-matched controls.Results and conclusionsActivity, disturbance of psychosocial function, and total score were worse compared to controls (15.4 ± 18.5 vs. 7.2 ± 9.9, P = 0.007; 5.3 ± 10.5 vs. 1.2 ± 2.6, P = 0.008; and 10.4 ± 12.9 vs. 5.0 ± 4.8, P = 0.006, respectively). Patients reported more daytime fatigue, concentration difficulties, and depression (51% vs. 24%, P = 0.006; 31% vs. 10%, P = 0.010; and 19% vs. 2%, P = 0.012). Waking up was reported to be less refreshing in HNP patients (53% vs. 73%, P = 0.038). Dysphonia was a predictor of symptoms, activity, disturbance of psychosocial function, and total scores. Remarkably, the presence of a carotid body tumor was an independent predictor of increased daytime sleepiness (β = 0.287, P = 0.029). In conclusion, patients with HNP have remarkable sleep-related complaints. Especially the presence of carotid body tumors appears to be associated with increased daytime somnolence.

Increased Urinary Excretion of 3-Methoxytyramine in Patients with Head and Neck Paragangliomas

Patients with head-and-neck paragangliomas (HNPGL) are regularly screened for catecholamine excess. The clinical relevance of increased urinary secretion of 3-methoxytyramine is unclear in HNPGL. The aim of the study was to assess the prevalence and the clinical, biochemical, and radiological presentation of patients with HNPGL with increased urinary excretion of 3-methoxytyramine. A total of 136 consecutive patients with HNPGL were included and screened for catecholamine excess by measurement of 24-h urinary excretion of (nor)metanephrine, (nor)epinephrine, vanillylic mandelic acid, dopamine, and 3-methoxytyramine. In patients with catecholamine excess, abdominal/intrathoracic paragangliomas were excluded by (123)I-metaiodobenzylguanidine scintigraphy, magnetic resonance imaging, and/or computed tomography. Urinary 3-methoxytyramine excretion was increased in 31 of the 136 patients (23%). In 18 of these 31 patients, this was the only sign of biochemical activity of HNPGL. Dopamine excretion was higher in subjects with increased 3-methoxytyramine excretion (1.62 +/- 0.1 micromol/24 h vs. 2.5 +/- 0.3 micromol/24 h; P < 0.01). Of the 136 HNPGL patients, 21 (15%) had excessive excretion of at least one catecholamine and/or their metabolites when 3-methoxytyramine excretion was not taken into account. With the inclusion of patients with excessive 3-methoxytyramine excretion, 39 (29%) had excessive catecholamine excretion. Patients with 3-methoxytyramine excess had significantly more complaints of palpitations (P < 0.01), diaphoresis (P = 0.03), collapse (P < 0.05), and a higher pulse rate (P < 0.01). Increased excretion of 3-methoxytyramine was not associated with particular types of HNPGL or genotypes. A substantial number of HNPGL patients have biochemically active tumors, reflected in increased excretion of 3-methoxytyramine, associated with increased dopamine excretion. Some patients only display increased excretion of 3-methoxytyramine, but not of other catecholamines or their metabolites.

Clinical Features of Paraganglioma Syndromes

Head and neck paragangliomas (HNPs) and pheochromocytomas are rare tumors. Sporadic and hereditary forms are recognized. Four different paraganglioma syndromes (PGLs 1-4) have been described: PGL 1 is associated with mutations of the succinate dehydrogenase (SDH) subunit D (SDHD) gene; PGL 3 is caused by SDHC gene mutations; PGL 4 is caused by SDHB gene mutations; the susceptibility gene for PGL 2 is unknown. The objective of this study is to review distinct clinical features of the different PGLs. An international registry for HNPs was founded in Freiburg, Germany, in 2000. The data presented in this article have been acquired from registered HNP patients who have been screened for mutations of the genes SDHB, SDHC, and SDHD. Approximately 30% of apparent sporadic HNPs are caused by a germline mutation in one of these genes. Patients with PGL 1 or 4 have a very high lifetime risk of developing HNPs as well as thoracic and abdominal pheochromocytomas. Compared with sporadic HNPs, tumors developing in SDHB, SDHC, and SDHD mutation carriers arise at a significantly younger age. The SDHB mutations are associated with a high percentage of malignant paraganglionic tumors. We recommend molecular genetic screening of all HNP patients for SDHB, SDHC, and SDHD gene mutations. Mutation carriers must be screened for paraganglial tumors in the head, neck, thorax, and abdomen. Appropriately timed surgical intervention will minimize disease-specific morbidity and mortality. Lifelong follow-up is mandatory.

Malignant head and neck paragangliomas in SDHB mutation carriers

Three of four paraganglioma syndromes (PGLs) have been characterized on a molecular genetic basis. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D (SDHD) gene, PGL 3 is caused by SDHC gene mutations, and PGL 4 is caused by SDHB gene mutations. The objective of this study was to investigate whether PGLs are associated with malignant head and neck paragangliomas (HNPs). Through November 2005, we screened 195 HNP patients for mutations of the genes SDHB, SDHC, and SDHD. We detected 5 SDHC, 13 SDHB, and 45 SDHD gene mutations. In seven SDHB mutation carriers, there were distant metastases. No signs of metastases were found in SDHC and SDHD patients. One patient with a sporadic HNP presented with locally metastatic disease. SDHB mutations are associated with a high rate of malignant HNPs. In SDHB patients, a three-body region imaging and scintigraphy or DOPA-PET must be performed to exclude metastases.

Predictors and Prevalence of Paraganglioma Syndrome Associated With Mutations of the &lt;EMPH TYPE="ITAL"&gt;SDHC&lt;/EMPH&gt; Gene

Paraganglioma syndrome includes inherited head and neck paragangliomas (HNPs) and adrenal or extra-adrenal pheochromocytomas and are classified according to the susceptibility genes SDHB, SDHC, and SDHD. In contrast with those with germline mutations of the SDHB and SDHD genes, clinical and genetic data on patients with mutations of SDHC are scarce. To determine the prevalence and clinical characteristics of SDHC mutation carriers compared with patients with SDHB and SDHD mutations and with sporadic cases. Genetic screening for SDHC mutations in an international HNP registry of 121 unrelated index cases and in 371 sporadic cases from a pheochromocytoma registry, conducted January 1, 2001, until December 31, 2004. Identified index cases and affected relatives were clinically evaluated. Prevalence of and clinical findings for SDHC mutation-associated HNPs vs those with SDHB and SDHD mutations. The prevalence of SDHC carriers was 4% in HNP but 0% in pheochromocytoma index cases. None of the SDHC mutation carriers had signs of pheochromocytoma. We compared HNPs in 22 SDHC mutation carriers with the HNPs of SDHB (n = 15) and SDHD (n = 42) mutation carriers and with 90 patients with sporadic HNPs. Location, number of tumors, malignancy, and age were different: more carotid body tumors were found in SDHC (13/22 [59%]) than in sporadic HNPs (29/90 [32%], P = .03), as well as fewer instances of multiple tumors in SDHC (2/22) than in SDHD (24/42; P<.001), 0 malignant tumors in SDHC vs 6/15 in SDHB (P = .002), and younger age at diagnosis in SDHC than in sporadic HNPs (45 vs 52 years; P = .03). Patients with HNP, but not those with pheochromocytoma, harbor SDHC mutations in addition to those in SDHB and SDHD. In total, more than one quarter of HNP patients carry a mutation in 1 of these 3 genes. Head and neck paragangliomas associated with SDHC mutations are virtually exclusively benign and seldom multifocal. Analysis for germline mutations of SDHC is recommended in apparently sporadic HNP to identify risk of inheritance.