Neck Paragangliomas Research Articles

Vagal Paraganglioma of Neck Mimicking Carotid Body Tumor: Clues to Differentiate on Imaging.

Paragangliomas of the head and neck can arise in many locations along the carotid sheath and middle ear. A hypervascular tumor in relation to the major cervical vessels can be either a carotid body tumor or vagal paraganglioma. Carotid bifurcation separation is a characteristic feature of carotid body tumours. We present a case of vagal paraganglioma of the neck, causing carotid bifurcation separation similar to that of a carotid body tumor. In this case report, we highlight the imaging features that can differentiate these two paragangliomas in such a confusing situation.

SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma

BackgroundTraditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent...

Potential Biomarkers of Metastasizing Paragangliomas and Pheochromocytomas.

Paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors originating from paraganglionic tissue in many sites of the body. Most PPGLs are characterized by nonaggressive behavior but all of them have the potential to metastasize. PPGLs represent a great diagnostic dilemma as it is difficult to recognize tumors that are likely to be metastasizing; criteria of malignancy can be found both in benign and metastatic forms. This review aims to analyze the current knowledge of the nature of metastasizing PPGLs paying particular attention to head and neck paragangliomas (HNPGLs). Potential predictors of the malignancy risk for PPGLs were summarized and discussed. These data may also help in the development of diagnostic and prognostic strategies, as well as in the identification of novel potential therapeutic targets for patients with PPGLs.

Genetics of Head and Neck Paragangliomas

Paragangliomas of the head and neck (HNPGL) are rare neurogenic tumors, in which genetic factors play a certain role. So far, 10 genes related to HNPGL (SDHA、SDHB、SDHC、SDHD、SDHAF2、VHL、HIF2A、RET、NF1 and TMEM127) have been found. The clinical phenotypes of different gene mutations are different. SDHD、SDHC and SDHAF2 gene mutations are almost 100% related to HNPGL. SDHD and SDHAF2 gene mutations tend to form multiple paragangliomas, and its genetic pattern has obviously maternal imprinting. SDHB mutations have sympathetic paraganglioma and malignant tendency. Understanding the molecular mechanism and genotype-phenotypic relationship of paraganglioma can provide significant help for genetic counseling, diagnosis and treatment and follow-up strategies in patients with HNPGL.

Updated reference intervals for urine normetanephrine have no effect on test sensitivity but fewer false positives

ObjectiveWe previously highlighted the problem of frequent false positives in 24 h urine normetanephrine(UNM) measurements owing to reference intervals that are inappropriately low for the population being screened for pheochromocytoma. Using a large population database, we devised new age-stratified reference intervals for the 24 h UNM test that were higher compared to previous. However, it was uncertain as to whether this would compromise test sensitivity for true pheochromocytoma cases. Design and MethodsRetrospective analysis of all pheochromocytoma cases from a recently constructed provincial registry. All confirmed cases had their diagnostic UNM results retrospectively re-analysed according to the newly proposed UNM reference intervals to determine the percentage and phenotype of cases that might have been theoretically missed with the new reference range. ResultsAfter excluding pediatric and non-secretory head and neck paragangliomas, there were 60 confirmed pheochromocytoma cases. Using prior reference intervals, 51/60 (85%) had an abnormally high UNM. Of the 9 with normal UNM, 4 had a high urine metanephrine(UMN), 5 had normal levels of both UNM and UMN such that 55/60 had abnormal test results, representing the historical combined test sensitivity of 92%. Using the proposed reference interval, 43/60 (72%) had high UNM results. Of the 17 with normal UNM, 12 had high UMN, 5 had normal levels of both UNM and UMN. Therefore, 55/60 patients had had elevations in either UNM or UMN, corresponding to an identical combined test sensitivity of 92%. ConclusionsReference intervals for UNM derived from actual clinical population screening data are higher than in traditional healthy volunteers. Use of these more appropriate reference intervals can significantly reduce the false positive rate without compromising test sensitivity for true pheochromocytoma.

Meta-Analysis of the Effects of Preoperative Embolization on the Outcomes of Carotid Body Tumor Surgery

ABSTRACT Background Carotid body tumors (CBTs) are situated at the bifurcation of the common carotid artery within the adventitia, and are reported to be the most common head and neck paragangliomas. Surgery is the gold standard for curative treatment of resectable CBTs and is recommended in otherwise healthy patients because of the risk of local complications related to tumor size and a small but definite risk of malignancy. Preoperative embolization has been shown to reduce potential intraoperative blood loss and provide the surgeon with greater ease and safety in excising the tumor, thus reducing the operation time and morbidity. However, other physicians have stated that although blood loss may be reduced after preoperative embolization, transfusion requirements are not affected, and that the embolization procedure adds a significant risk for stroke. Therefore, the purpose of the current study was to compare the surgical outcomes of patients undergoing CBT surgical resection with and without preoperative embolization. Aim To evaluate the need for preoperative embolization for the treatment of carotid body tumor. Methodology A meta-analysis study is done to compare the surgical outcomes of patients undergoing CBT surgical resection with and without preoperative embolization. Results Our meta-analysis for evaluation of the effects of preoperative embolization on the outcomes of carotid body tumor surgery, included (14) studies with a total number of patients (n = 477).The results of these studies showed no statistically significant difference between preoperative embolization group and non embolization group in carotid body surgery for (blood loss & operation time). Preoperative embolization did not reduce risk of postoperative complications. Conclusion Preoperative embolization shows no statistically significant reducing in blood loss and operation time, also embolization does not decrease incidence of postoperative complications. It seems that embolization should not be a routine part of carotid body tumor surgery especially with the known potential risks and complications of this procedure .

SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.

Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively. This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.

Familial SDHB gene mutation in disseminated non-hypoxia-related malignant paraganglioma treated with [90Y]Y/[177Lu]Lu- DOTATATE.

Familial paraganglioma may be related to mutations in succinate dehydrogenase (SDH) enzyme complex genes. Among patients with hereditary paraganglioma, SDH subunit B (SDHB) gene mutations are associated with the highest morbidity and mortality related to a higher malignancy rate. We report a family with the c.689G>A (p.Arg230His) mutation in the SDHB gene identified in two family members, a father and his daughter. While the 14-year-old daughter had no evidence of clinical disease, recurrent and later disseminated [131I]metaiodobenzylguanidine uptake-negative head and neck paraganglioma with multiple bone metastases developed in the father who underwent peptide receptor radionuclide therapy with [90Y]Y/[177Lu]Lu-dodecane tetraacetic acid octreotate (DOTATATE) at the time of the genetic diagnosis. This treatment was repeated 6 years later due to disease progression and the patient, who is currently 49 years old, remains alive and in good overall clinical condition at 8 years of follow-up after the original presentation at our unit. The growing armamentarium of imaging methods available for such patients may inform decision making regarding choice of the optimal treatment approach, potentially contributing to improved outcomes.

Challenges for the Endocrine Surgeon in the Decision-making in Managing Head and Neck Paragangliomas

Challenges for the Endocrine Surgeon in the Decision-making in Managing Head and Neck Paragangliomas

Diagnostic Role of Diffusion-Weighted and Dynamic Contrast-Enhanced Perfusion MR Imaging in Paragangliomas and Schwannomas in the Head and Neck.

Distinguishing schwannomas from paragangliomas in the head and neck and determining succinate dehydrogenase (SDH) mutation status in paragangliomas are clinically important. We aimed to assess the clinical usefulness of DWI and dynamic contrast-enhanced MR imaging in differentiating these 2 types of tumors, as well as the SDH mutation status of paragangliomas. This retrospective study from June 2016 to June 2020 included 42 patients with 15 schwannomas and 27 paragangliomas (10 SDH mutation-positive and 17 SDH mutation-negative). ADC values, dynamic contrast-enhanced MRI parameters, and tumor imaging characteristics were compared between the 2 tumors and between the mutation statuses of paragangliomas as appropriate. Multivariate stepwise logistic regression analysis was performed to identify significant differences in these parameters. Fractional plasma volume (P ≤ .001), rate transfer constant (P = .038), time-to-maximum enhancement (P < .001), maximum signal-enhancement ratio (P < .001) and maximum concentration of contrast agent (P < .001), velocity of enhancement (P = .002), and tumor characteristics including the presence of flow voids (P = .001) and enhancement patterns (P = .027) showed significant differences between schwannomas and paragangliomas, though there was no significant difference in ADC values. In the multivariate logistic regression analysis, fractional plasma volume was identified as the most significant value for differentiation of the 2 tumor types (P = .014). ADC values were significantly higher in nonhereditary than in hereditary paragangliomas, while there was no difference in dynamic contrast-enhanced MR imaging parameters. Dynamic contrast-enhanced MR imaging parameters show promise in differentiating head and neck schwannomas and paragangliomas, while DWI can be useful in detecting SDH mutation status in paragangliomas.

Safety and technical efficacy of pre-operative embolization of head and neck paragangliomas: A 10-year mono-centric experience and systematic review

ObjectivesTo retrospectively evaluate the safety and technical success of pre-operative embolization (POE) of head and neck paragangliomas (HNP) in a single-center cohort over a 10-year period, and to benchmark our results with those derived from a systematic analysis of the available literature. MethodsAll consecutive HNP embolized between November 2010 and April 2020 were included and reviewed. In total, there were 27 HNP in 27 patients [8 (30%) males; 19 (70%) females; mean age 53 ± 16 years; range 30–86].Embolization technique, total procedure time, dose area product (DAP), complications, rate of HNP devascularization, and technical success (i.e. ≥80% devascularization of the HNP) were recorded and analyzed.A systematic analysis on the safety and technical success of POE was then conducted according to the Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ResultsTwenty-one (21/27; 78%) HNP were treated with an endovascular approach and 6/27 (22%) with a percutaneous or combined (endovascular/percutaneous) technique. Mean total procedure time and DAP were 108 ± 48 min (range 45–235) and 92.5 ± 61.3 Gy·cm2 (range 19.9–276.0), respectively. Two (2/27; 7%) complications (one minor, one major) were observed.Mean HNP devascularization was 88 ± 15% (range 23–100) with technical success achieved in 24/27 (89%) HNP.Literature analysis revealed a pooled rate of complication and technical success of 3.8% (95% CI: 0.5–8.8%) and 79.0% (95% CI: 63.6–91.6%), respectively. ConclusionsPOE of HNP is safe and results in extensive devascularization in the majority of treated tumors.

The Long-Term Outcome of CyberKnife-Based Stereotactic Radiotherapy for Head and Neck Paragangliomas: A Single-Center Experience

To assess long-term outcomes of hypofractionated stereotactic radiotherapy (hSRT) for head and neck paragangliomas (HNPGs). Patients who underwent hSRT with CyberKnife for HNPGs from 2010 to 2019 were retrospectively reviewed. A total of 34 HNPGs in 29 patients were identified. Mean patient age was 50 ± 16 years, and 15 patients (52%) were female. Fifteen patients (55%) had undergone previous procedures. Four cases (14%) were functional in hormone production. According to the Fisch classification, 1 (3%) case was B, 12 (42%) cases were C, 14 (48%) cases were D, and 2 (7%) cases were unclassified.1 The median prescribed dose covering 95% of the planning target volume was 2500 cGy (interquartile range 2100-2600 cGy), and the median target volume was 10 cm3 (interquartile range 6.0-18.3 cm3). The local control rate was 97%. The median progression-free survival was 66 months (interquartile range 28-95 months), and 96% of patients were free of tumor progression at 8 years. During follow-up, 1 case (3%) resulted in permanent facial nerve palsy (House-Brackmann grade II), and another case (3%) resulted in asymptomatic cerebellar radiation necrosis. Univariate and multivariate analysis showed that no previous surgical history (odds ratio 8.58, 95% confidence interval 1.2-59.7, P= 0.03) was a positive predictor of symptomatic improvement. hSRT for HNPGs was an effective treatment with minimal side effects over the long term and may have a role as first-line therapy, especially for symptomatic nonfunctional HNPGs, for better symptom control.

Quantitative biomarkers allow the diagnosis of head and neck paraganglioma on multiparametric MRI

PurposeThe aim of this study is to identify quantitative MR biomarkers in head and neck paragangliomas. MethodsThe study was approved by an institutional review board. A retrospective review of patients with head and neck paragangliomas (HNPGL) evaluated by time-resolved MRA sequences between 2009 and 2019 was performed. A control group investigated during the same period was analyzed, including nerve sheath tumors and metastatic lymph nodes from squamous cell carcinomas or undifferentiated nasopharyngeal cancer (UCNT). A gold standard was obtained for all cases. Semi-quantitative parameters of enhancement were extracted from time-intensity curves on time-resolved MRA sequences and diffusion weighted imaging/DWI was assessed for each lesion. ResultsSixty head and neck paragangliomas (HNPGLs) were included from 50 patients. The control group consisted of 30 parapharyngeal space lesions (27 patients), which included nerve sheath tumors (n = 12) and metastatic lymph nodes (n = 18) from squamous cell carcinomas or UCNT. PGLs showed a shorter time-to-peak value compared to other groups, measured at 25.0 +/− 29 sec. The wash-in and wash-out ratios were also significantly higher for PGLs, respectively measured at 5.34 ± 2.99 (p < 0,001) and 1.24 ± 0.80 (p < 0.001). On DWI sequences, the mean ADC value for PGLs (1.17 ± 0.19 10^-3 mm2/s) was significantly different than the other tumor groups (p < 0.001). HNPGLs were clearly distinguishable from other tumors on classification with regression tree based on TTP and ADC values. These distinct group features were also consistent on principal component analysis. ConclusionOur study identifies a multiparametric signature for disease subtyping, providing a strong impetus for switching from qualitative to quantitative analysis of deep soft-tissue tumors of the neck.

Facial Paresis and Pulsatile Middle Ear Mass.

Head and neck paragangliomas are uncommon pathologies that present with common symptoms such as pulsatile tinnitus and aural pressure. This article highlights an unusual presentation of a patient with facial paresis who was found to have a jugular paraganglioma. Emphasis is placed on how the otologic examination showed a pulsatile middle ear mass that led to the diagnosis. This case illustrates the importance of maintaining a healthy degree of clinical suspicion when encountering common complaints.

Paragangliomas of Nasal Cavity: A Case Report

Paraganglioma is a rare neuroendocrine tumor. Nasal localization is very rare. Head and neck paragangliomas represent only 0.6% of head and neck tumors and 3% of all paragangliomas. The treatment is based on surgery. Radiotherapy is indicated if the surgery does not provide complete resection. We report the case of a 36-year-old patient who has had left nasal obstruction with epistaxis for 2 years. The CT scan shows a solid mass centered on the left nasal cavity, puffy, without signs of aggression, benign-looking. The patient underwent a complete endoscopic endonasal tumor removal after preoperative external carotid embolization. Pathological analysis with immunohistochemistry confirmed the diagnosis of paraganglioma. The follow-up to the treatment was favorable.

High throughput proteomic and metabolic profiling identified target correction of metabolic abnormalities as a novel therapeutic approach in head and neck paraganglioma

Head and neck paragangliomas (HNPGLs) are rare neoplasms that represent difficult treatment paradigms in neurotology. Germline mutations in genes encoding succinate dehydrogenase (SDH) are the cause of nearly all familial HNPGLs. However, the molecular mechanisms underlying tumorigenesis remain unclear. Mutational analysis identified 6 out of 14 HNPGLs harboring clinicopathologic SDH gene mutations. The SDHB gene was most frequently mutated in these patients, and western blot showed loss of SDHB protein in tumors with SDHB mutations. The paraganglioma cell line (PGL-626) was established from a sample that harbored a missense SDHB mutation (c.649C > T). Spectrometric analysis using tandem mass tags identified 151 proteins significantly differentially expressed in HNPGLs compared with normal nerves. Bioinformatics analyses confirmed the high level of enrichment of oxidative phosphorylation and metabolism pathways in HNPGLs. The mitochondrial complex subunits NDUFA2, NDUFA10, and NDUFA4, showed the most significantly increased expression and were localized predominantly in the cytoplasm of PGL-626 cells. The mitochondrial complex I inhibitor metformin exerted dose-dependent inhibitory effects on PGL-626 cells via cooperative down-regulation of NDUFA2, 4, and 10, with a significant decrease in the levels of reactive oxygen species and mitochondrial membrane potential. Further metabolomic analysis of PGL-626 cells showed that metabolites involved in central carbon metabolism in cancer and sphingolipid signaling pathways, pantothenate and CoA biosynthesis, and tryptophan and carbon metabolism were significantly altered after metformin treatment. Thus, this study provides insights into the molecular mechanisms underlying HNPGL tumorigenesis and identifies target correction of metabolic abnormalities as a novel therapeutic approach for this disease.

Re-evaluating the prevalence and factors characteristic of catecholamine secreting head and neck paragangliomas.

IntroductionWe sought to characterize the prevalence and factors characteristic of head and neck paragangliomas (HNPGLs) that secrete catecholamines to inform best practices for diagnosis and management.MethodsThis was a retrospective cohort study from 2000 to 2020 at a single‐institution tertiary centre. One‐hundred fifty‐two patients (182 tumours) with HNPGLs with at least one measurement of urine or plasma catecholamines and/or catecholamine metabolite levels prior to treatment were included. We differentiated and characterized those patients with increased level(s) of any nature and those with ‘clinically significant’ versus ‘clinically insignificant’ catecholamine production.ResultsThirty‐one (20.4%) patients had increased catecholamine and/or catecholamine metabolite levels. In most patients, these levels were ≤5‐fold above the upper limit of the reference range. Four of these 31 patients with increased levels were ultimately found to have an additional catecholamine secreting mediastinal paraganglioma or pheochromocytoma. Fourteen of 31 patients with HNPGL were deemed clinically significant secretors of catecholamines based on hyper‐adrenergic symptoms and/or profound levels of normetanephrines. This cohort was enriched for patients with paragangliomas of the carotid body or cervical sympathetic chain and those with SDHB genetic mutations. Ultimately, the prevalence of clinically significant catecholamine secreting Hangs was determined to be 9.2% and 7.7% based on a per‐patient and per‐tumour basis, respectively.ConclusionsThe rate of catecholamine excess in the current cohort of patients with HNPGLs was higher than previously reported. Neuroendocrine tumours of any anatomic subsite may secrete catecholamines, although not all increased laboratory level(s) are indicative of clinically significant catecholamine secretion causing symptoms or warranting adrenergic blockade.

Genetic Variants in Patients with Multiple Head and Neck Paragangliomas: Dilemma in Management

Multiple head and neck paragangliomas (HNPGLs) are neuroendocrine tumors of a mostly benign nature that can be associated with a syndrome, precipitated by the presence of a germline mutation. Familial forms of the disease are usually seen with mutations of SDHx genes, especially the SDHD gene. SDHB mutations are predisposed to malignant tumors. We found 6 patients with multiple tumors amongst 30 patients with HNPGLs during the period of 2016 to 2021. We discuss the phenotypic and genetic patterns in our patients with multiple HNPGLs and explore the management possibilities related to the disease. Fifty percent of our patients had incidental findings of HNPGLs. Twenty-one biochemically silent tumors were found. Four patients had germline mutations, and only one had a positive family history. Three out of five underwent surgery without permanent complications. Preventative measures (genetic counselling and tumor surveillance) represent the gold standard in effectively controlling the disease in index patients and their relatives. In terms of treatment, apart from surgical and radiotherapeutic interventions, new therapeutic measures such as gene targeted therapy have contributed very sparsely. With the lack of standardized protocols, management of patients with multiple HNPGLs still remains very challenging, especially in those with sporadic or malignant forms of the disease.

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.

Case report of a man with multiple paragangliomas and pathogenic germline variants in both NF1 and SDHD

We report a novel case of multiple paragangliomas in a patient who was identified with pathogenic variants in both NF1 and SDHD genes.The proband is a man with known familial NF1 disease, diagnosed clinically in childhood. Multiple head and neck paragangliomas (HNPGL) were found during investigations for acute left sided neurological symptoms, in the region of his known plexiform neurofibroma. He was referred for genetic counselling. He underwent surgery to remove a left carotid body tumor (CBT).A pheochromocytoma and paraganglioma gene panel was tested. Blood and HNPGL tumor DNA were analyzed by whole exome sequencing.In addition to the NF1 truncating variant c.5107delA, p.(Ser1703AlafsTer7), the SDHD truncating pathogenic variant c.3G > A, p.(Met1?) was found. Tumor sequencing showed no LOH of SDHD or NF1, but monoallelic loss of 11p15 and 11q12.2-q12.3 was observed.Co-occurrence of pathogenic variants in multiple cancer susceptibility genes is rare but possible, identified by the increased use of panel testing. This is the first description of a patient presenting with NF1 and SDHD dual pathology, with HNPGL development due to SDHD. This case illustrates the central role of genetic sequencing in PPGLs and the strong genotype-phenotype correlations of different genes.