Comprehensive Genetic Study of Malignant Cervical Paraganglioma.

Malignant middle ear paraganglioma (MEPGL) is an exceedingly rare tumor of the neuroendocrine system. In general, MEPGLs represent as slow growing and hypervascularized benign neoplasms. The genetic basis of MEPGL tumorigenesis has been poorly investigated. We report a case of malignant MEPGL accompanied by the comprehensive genetic analysis of the primary tumor and metastasis. Based on whole-exome sequencing data, the germline pathogenic mutation p.R230H in the SDHB gene, encoding for subunit B of mitochondrial complex II, was found in a patient. Analysis of somatic mutation spectra revealed five novel variants in different genes, including a potentially deleterious variant in UNC13C that was common for the tumor and metastasis. Identified somatic variants clustered into SBS1 and SBS5 mutational signatures. Of note, the primary tumor was characterized by Ki-67 4% and had an elevated mutational load (1.4/Mb); the metastasis' mutational load was about 4.5 times higher (6.4/Mb). In addition, we revealed somatic loss of the wild-type SDHB allele, as well as loss of heterozygosity (LOH) at the 11p locus. Thus, germline mutation in SDHB combined with somatic LOH seem to be drivers that lead to the tumor's initiation and progression. Other somatic changes identified can be additional disease-causing factors. Obtained results expand our understanding of molecular genetic mechanisms associated with the development of this rare tumor.

The SDHD:p.H102R Variant Is Frequent in Russian Patients with Head and Neck Paragangliomas and Associated with Loss of 11p15.5 Region and Hypermethylation of H19-DMR.

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms derived from the parasympathetic paraganglia of the head and neck. At least 30% of HNPGLs are linked to germline mutations, predominantly in SDHx genes. In this study, we analyzed an extended cohort of Russian patients with HNPGLs using whole-exome sequencing and found a highly frequent missense variant p.H102R in the SDHD gene. We determined this variant in 34% of the SDHD mutation carriers. This variant was associated with somatic loss of the gene wild-type allele. Data from the B allele frequency method and microsatellite and microdeletion analysis indicated evident LOH at the 11p15.5 region and potential loss of the whole of chromosome 11. We found hypermethylation of H19-DMR in all tumors, whereas differential methylation of KvDMR was mostly retained. These findings do not support the paternal transmission of SDHD:p.H102R but are in agreement with the Hensen model. Using targeted sequencing, we also studied the variant frequency in a control cohort; we found SDHD:p.H102R in 1.9% of cases, allowing us to classify this variant as pathogenic. The immunohistochemistry of SDHB showed that the SDHD:p.H102R mutation, even in combination with wild-type allele loss, does not always lead to SDH deficiency. The obtained results demonstrate the frequent variant associated with HNPGLs in a Russian population and support its pathogenicity. Our findings help with understanding the mechanism of tumorigenesis and are also important for the development of cost-effective genetic screening programs.

Facial palsy after embolization with Squid® 12.

Endovascular procedures with liquid embolic agents such as ethylene-vinyl alcohol (EVOH) copolymers are indicated before surgical treatment of cervical paraganglioma. Consequently, these agents are now available as low viscosity formulations, one of which is Squid 12, which are demonstrating superior vascular penetration. Cases of facial paralysis secondary to embolization of cervical vascular lesions with classic embolic agents have been reported in the English literature, however, this complication has not been described with new generation options such as Squid 12.We describe the case of a 43-year-old patient with a left neck carotid paraganglioma. Embolization was performed under general anaesthesia before surgical excision. In the immediate postoperative period, the patient developed total left facial palsy. Since the imaging tests (Computed Tomography (CT) and Magnetic Resonance Imaging (MRI)) and neurological examination showed no involvement of additional cranial nerves (CN), we hypothesise that the main cause of this complication is ischemia of the vasa nervorum of CN VII secondary to embolization. Almost six months later, the patient continues to present total facial paralysis (Grade VI House-Brackmann facial paralysis scale), and palsy of the left CN X and XII as a complication secondary to surgical resection of the paraganglioma.This case is relevant since it is the first clinical case of permanent facial paralysis secondary to embolization with Squid 12.

A novel succinate dehydrogenase subunit B germline variant associated with head and neck paraganglioma in a Dutch kindred: A family-based study.

OBJECTIVE: In the Netherlands, the majority of hereditary head and neck paragangliomas (HNPGL) are caused by germline variants in the succinate dehydrogenase genes (SDHD, SDHB, SDHAF2). Here, we evaluate a four-generation family linked to a novel SDHB gene variant with the manifestation of a HNPGL. DESIGN: A family-based study. SETTING: The VU University Medical Center (VUmc) Amsterdam, a tertiary clinic for Otolaryngology and Head and Neck Surgery. PARTICIPANTS AND MAIN OUTCOME MEASURES: The index patients presented with an embryonic rhabdomyosarcoma and a non-Hodgkin lymphoma. Array-based comparative genomic hybridisation (aCGH) analysis and multiplex ligation-dependent probe amplification (MLPA) revealed a novel deletion of exon 1-3 in the SDHB gene, suspected to predispose to paraganglioma (PGL)/pheochromocytoma (PHEO) syndrome type 4. Subsequently, genetic counselling and DNA testing were offered to all family members at risk. Individuals that tested positive for this novel SDHB gene variant were counselled and additional clinical evaluation was offered for the identification of HNPGL and/or PHEO. RESULTS: The DNA of 18 family members was tested, resulting in the identification of 10 carriers of the exon 1-3 deletion in the SDHB gene. One carrier was diagnosed with a carotid body PGL and serum catecholamine excess, which was surgically excised. Negative SDHB immunostaining of the carotid body tumour confirmed that it was caused by the SDHB variant. The remaining 9 carriers showed no evidence of PGL/PHEO. CONCLUSION: Deletion of exon 1-3 in the SDHB gene is a novel germline variant associated with the formation of hereditary HNPGL.

18F-FDG PET/CT as a predictor of hereditary head and neck paragangliomas.

BACKGROUND: Hereditary head and neck paragangliomas (HNPGLs) account for at least 35% of all HNPGLs, most commonly due to germline mutations in SDHx susceptibility genes. Several studies about sympathetic paragangliomas have shown that (18)F-FDG PET/CT was not only able to detect and localize tumours, but also to characterize tumours ((18)F-FDG uptake being linked to SDHx mutations). However, the data concerning (18)F-FDG uptake specifically in HNPGLs have not been addressed. The aim of this study was to evaluate the relationship between (18)F-FDG uptake and the SDHx mutation status in HNPGL patients. METHODS: (18)F-FDG PET/CT from sixty HNPGL patients were evaluated. For all lesions, we measured the maximum standardized uptake values (SUVmax), and the uptake ratio defined as HNPGL-SUVmax over pulmonary artery trunk SUVmean (SUVratio). Tumour sizes were assessed on radiological studies. RESULTS: Sixty patients (53.3% with SDHx mutations) were evaluated for a total of 106 HNPGLs. HNPGLs-SUVmax and SUVratio were highly dispersed (1.2-30.5 and 1.0-17.0, respectively). The HNPGL (18)F-FDG uptake was significantly higher in SDHx versus sporadic tumours on both univariate and multivariate analysis (P = 0.002). We developed two models for calculating the probability of a germline SDHx mutation. The first one, based on a per-lesion analysis, had an accuracy of 75.5%. The second model, based on a per-patient analysis, had an accuracy of 80.0%. CONCLUSIONS: (18)F-FDG uptake in HNPGL is strongly dependent on patient genotype. Thus, the degree of (18)F-FDG uptake in these tumours can be used clinically to help identify patients in whom SDHx mutations should be suspected.

Proteomic characterization of head and neck paraganglioma and its molecular classification.

Background: Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors that pose significant challenges in both diagnosis and treatment. The pathogenic mechanism remains unclear, and there is no proteomic analysis-based molecular classification. Therefore, gaining a deeper understanding of this disease from the protein level is crucial because proteins play a fundamental role in the occurrence and development of tumors. Methods: We collected 44 tumor samples from patients diagnosed with HNPGL. The adrenal paraganglioma tissue (N = 46) was used as the disease control group and the chorda tympani nerves (N = 18) were used as the control group. High-pH reversed-phase liquid chromatography and liquid chromatography with tandem mass spectrometry analyses were used to build an integrated protein database of tumor samples. We then obtained two sets of differentially expressed proteins between the tumor group and the control group to identify the unique proteomic signatures of HNPGLs. Ingenuity pathway analysis annotations were used to perform the functional analysis. Subsequently, we developed a clinically relevant molecular classification for HNPGLs that connected the clinical characteristics with meaningful proteins and pathways to explain the varied clinical manifestations. Results: We identified 6,640 proteins in the HNPGL group, and 314 differentially expressed proteins unique to HNPGL were discovered via inter-group comparison. We identified two HNPGL subgroups that significantly differed in clinical manifestation and proteomic characteristics. On the basis of the proteomic results, we proposed a pathogenic mechanism underlying HNPGL. Conclusion: We conducted a comprehensive analysis of the molecular mechanisms of HNPGL to build, for the first time, a clinically relevant molecular classification. By focusing on differential proteomic analyses between different types of paragangliomas, we were able to obtain a comprehensive description of the proteomic characteristics of HNPGL, which will be valuable for the search for significant biomarkers as a new treatment method for HNPGL.

Head and Neck Paragangliomas: 16-year Single-center Experience and Mini Review on Diagnosis, Treatment, and Follow-up.

Objective: To investigate head and neck paraganglioma cases treated at a tertiary center from 2007 to 2023. The research includes a thorough examination of published studies that have focused on long-term outcomes. The additional goal is to contribute to the existing knowledge on head and neck paraganglioma, with a particular emphasis on refining diagnostic algorithms, treatment selection, and follow-up procedures. Methods: A total of 44 patients were retrospectively analyzed, and 39 were included. Demographic information, symptoms, radiological examination results, types, stages, and postoperative complications were recorded. A review was conducted to select articles that reported single-center experiences with large cohorts, long follow-ups, and different treatment modalities since 2010. Results: The mean age of the patients was 54 years, and the female/male ratio was 3.55:1. Among the 39 cases examined, 18 and 19 were identified as cervical paraganglioma and 19 as temporal bone paraganglioma. All patients initially underwent surgical resection. The mean follow-up duration was 5.42 years. Four residual cases and two recurrences were identified postoperatively, and a Gamma Knife was used as additional treatment. Subsequently, 17 articles were selected and summarized, and then a flowchart was prepared showing the possible options for diagnosis, treatment, and follow-up. Conclusions: Preoperative staging is essential for surgical planning and predicting potential intraoperative complications. Based on our findings and review of the articles, we have prepared a flowchart that includes all possibilities depending on the tumor stage to help in the diagnosis, treatment, and follow-up of head and neck paragangliomas.

[Advance in HIF expression and immune microenvironment in pseudohypoxic HNPGL].

This article systematically reviewed the pathological features, molecular mechanisms, and tumor microenvironment of head and neck paraganglioma（HNPGL）, with a focus on pseudohypoxic HNPGL. It was demonstrated that pseudohypoxic HNPGL mainly involves multiple gene mutations, such as SDHx and VHL/EPAS1, which affect the stability and activity of HIF protein and exacerbate the development of the tumor. Meanwhile, the paper also analyzed the expression patterns of HIF-1α and HIF-2α in HNPGL, and found that differences in HIF activation may have an impact on the therapeutic response of specific subtypes. In addition, the paper explored the tumor microenvironment of HNPGL and found that immune cells such as macrophages, CD4⁺T cells, and CD8⁺T cells play an important role in the tumor, and the heterogeneity of the immune microenvironment also affects the choice of therapeutic approaches and responsiveness. Through comprehensive analysis, these findings not only contribute to a deeper understanding of the pathogenesis and developmental process of HNPGL, but also provide clues for future personalized treatments for specific subtypes.

Basaloid squamous cell carcinoma clinically and radiologically masquerading as a head and neck paraganglioma: a case report and review of the literature.

BACKGROUND: This paper reports the first case of basaloid squamous cell carcinoma clinically and radiologically masquerading as a head and neck paraganglioma. CASE PRESENTATION: A 66-year-old Sinhalese male with unilateral hearing impairment and 7th-12th (excluding 11th) cranial nerve palsies was diagnosed radiologically with a head and neck paraganglioma by magnetic resonance imaging of the brain, which revealed a hypointense and hyperintense punctate mass centered at the jugular fossa with intracranial extension. The ascending pharyngeal artery, recognized as the major feeder, was embolized by percutaneous embolization following digital subtraction angiography. Gross total resection of the tumor was followed by an uneventful postoperative recovery. Combined immunohistochemistry and histopathological morphology revealed a basaloid squamous cell carcinoma, following which the patient completed radiotherapy and is at 3-month follow-up currently. CONCLUSION: This case report discusses the diagnostic pitfalls and management challenges of this rare entity on the basis of prior evidence, as well as a literature review and clinical and surgical analysis.

Genetic changes in the FH gene cause vagal paraganglioma.

Vagal paraganglioma (VPGL) is a rare neuroendocrine tumor that originates from the paraganglion associated with the vagus nerve. VPGLs present challenges in terms of diagnostics and treatment. VPGL can occur as a hereditary tumor and, like other head and neck paragangliomas, is most frequently associated with mutations in the SDHx genes. However, data regarding the genetics of VPGL are limited. Herein, we report a rare case of a 41-year-old woman with VPGL carrying a germline variant in the FH gene. Using whole-exome sequencing, a variant, FH p.S249R, was identified; no variants were found in other PPGL susceptibility and candidate genes. Loss of heterozygosity analysis revealed the loss of the wild-type allele of the FH gene in the tumor. The pathogenic effect of the p.S249R variant on FH activity was confirmed by immunohistochemistry for S-(2-succino)cysteine (2SC). Potentially deleterious somatic variants were found in three genes, SLC7A7, ZNF225, and MED23. The latter two encode transcriptional regulators that can impact gene expression deregulation and are involved in tumor development and progression. Moreover, FH-mutated VPGL was characterized by a molecular phenotype different from SDHx-mutated PPGLs. In conclusion, the association of genetic changes in the FH gene with the development of VPGL was demonstrated. The germline variant FH: p.S249R and somatic deletion of the second allele can lead to biallelic gene damage that promotes tumor initiation. These results expand the clinical and mutation spectra of FH-related disorders and improve our understanding of the molecular genetic mechanisms underlying the pathogenesis of VPGL.

The Additional Value of Somatostatin Receptor Positron Emission Computed Tomography ([68Ga]Ga-DOTATOC PET/CT) Compared with Magnetic Resonance Imaging of the Head and Neck Region in Paraganglioma Patients: A Pilot Study.

The Dutch guideline for patients suspected of head and neck paragangliomas (HNPGLs) recommends magnetic resonance imaging (MRI) and/or computed tomography (CT) of the head and neck area. Additionally, it suggests considering additional nuclear imaging. The aim of this study was to evaluate the outcomes of [68Ga]Ga-DOTATOC PET/CT compared to MRI in patients with suspected HNPGLs and carriers of genetic variations. METHODS: In this single-center pilot study, retrospective data were obtained from consecutive patients between 2016 and 2023. Both MRI and [68Ga]Ga-DOTATOC PET/CT were performed within 12 months. The primary outcome was the location of HNPGLs. RESULTS: A total of 25 consecutive patients were included, and 7 patients (28.0%, p = 0.5) showed differences between the imaging modalities, of whom 5 patients had unexpected localizations with additional uptake by somatostatin receptors (SSTR) on the [68Ga]Ga-DOTATOC PET/CT. CONCLUSIONS: The authors recommend performing baseline imaging with [68Ga]Ga-DOTATOC PET/CT (if available) in variant carriers and using MRI/CT for follow-up according to the regional protocol, thereby shifting the gold standard for baseline imaging from MRI/CT to [68Ga]Ga-DOTATOC PET/CT.

Paragangliomas Arising From the Laryngeal Paraganglia: Thyroid and Laryngeal Paragangliomas With Radiology-Pathology Correlation.

Paragangliomas are neuroendocrine tumors that arise from the embryonic neural crest cells of the extra-adrenal chromaffin and non-chromaffin cellular system. Paragangliomas arising from the laryngeal paraganglia, which occur in the thyroid and larynx, are a rare subset of paragangliomas compared to the more common locations of the carotid body, vagale, jugular, and tympanic paragangliomas. The preoperative diagnosis of both thyroid and laryngeal paragangliomas may pose a challenge due to cytological, pathological, and imaging non-specificity that overlaps with many other neoplasms. These lesions may be associated with significant intraoperative bleeding and complicated excision with adherence to nearby structures, including the recurrent laryngeal nerve. This article discusses the imaging appearance, pathological features, clinical and operative considerations and manifestations, and management of head and neck paragangliomas, as seen in two patients at our institution.

Succinate dehydrogenase mutations in head and neck paragangliomas: A systematic review and meta-analysis of individual patients' data.

BACKGROUND: Head and neck paragangliomas (HNPs) have been associated with gene mutations in the succinate dehydrogenase (SDH) complex, but the clinical significance remains unclear. We sought to explore the demographics, clinical characteristics, treatment methods, and outcomes of SDH-mutated HNPs. METHODS: Databases were systematically searched. Pooled event ratio and relative 95% confidence intervals were calculated for dichotomous outcomes. Meta-regression was performed. Cochran's Q test and I2 test assessed heterogeneity. Funnel plot and Egger's regression test assessed publication bias. RESULTS: Forty-two studies with 8849 patients were included. Meta-regression revealed a significant correlation between multifocality and SDHD mutations (0.03 ± 0.006, p < 0.0001) and between distant metastases and SDHB mutations (0.06 ± 0.023, p = 0.008). There was no correlation between sex, age, tumor size, or familial occurrences and SDH-related mutations. CONCLUSION: Multifocality of HNPs correlates with the SDHD mutational subtype, and metastases correlate with the SDHB subtype. Knowledge of HNP phenotypes associated with SDH-related mutations has the potential to influence the management approach to such HNPs.

Head and neck paragangliomas: Recent advances in translational and clinical research and guidelines for patient care.

Head and neck paragangliomas (HNPGLs), rare neuroendocrine tumors that mainly arise from parasympathetic ganglia along the cranial nerves, are challenging due to anatomic origin, tendency to aggressive neurovascular and skull base infiltration, unpredictable metastatic potential, radio-chemoresistance, and risk of multiplicity. Symptoms range from mild to life threatening depending on location/size, but rarely relate to catecholamine excess. Risk factors include female sex and pathogenic germline variants in genes affecting hypoxia signaling (foremost succinate dehydrogenase genes). Diagnostic work-up relies on imaging, measurements of plasma free metanephrines/methoxytyramine, genetic testing, and pathology/immunohistochemistry. Management is tailored to patient/tumor characteristics and encompasses wait-scan, upfront surgery, debulking surgery, and radiotherapy. Presurgical embolization is recommended, except for small tympanic and tympanomasoid tumors. Presurgical stenting is required for internal carotid artery involvement, and two-stage surgery for intradural extension. Current treatments for metastatic/inoperable HNPGL are non-curative, and long-term follow-up should be recommended for all patients to monitor local recurrence and new tumors.

Head and Neck Paragangliomas: Overview of Institutional Experience.

Head and neck paragangliomas (HNPGLs) are rare and have high rates of genetic mutations. We conducted a retrospective review of 187 patients with 296 PGLs diagnosed between 1974 and 2023. The mean age of diagnosis was 48.8 years (range 10 to 82) with 69.0% female and 26.5% patients with multiple PGLs. Among 119 patients undergoing genetic testing, 70 (58.8%) patients had mutations, with SDHB (30) and SDHD (26) being the most common. The rates of metastasis and recurrence were higher among patients with SDHB mutations or SDHD mutations associated with multiple PGLs. Metabolic evaluation showed elevated plasma dopamine levels were the most common derangements in HNPGL. MRI and CT were the most common anatomic imaging modalities and DOTATATE was the most common functional scan used in this cohort. Most patients (81.5%) received surgery as the primary definitive treatment, while 22.5% patients received radiation treatment, mostly as an adjuvant therapy or for surgically challenging or inoperable cases. Systemic treatment was rarely used in our cohort. Our single-center experience highlights the need for referral for genetic testing and metabolic evaluation and for a team-based approach to improve the clinical outcomes of patients with HNPGLs.

A Rapidly Progressing Carotid Body Tumor: A Case Report.

Carotid body tumors (CBTs) are a rare form of paragangliomas that often arise near the carotid bifurcation. They are typically slow growing and often asymptomatic. We report a case of a CBT in a 70-year-old man, who presented with a firm, painless, pulsatile neck mass that rapidly increased in size over the course of two months. The diagnosis was suspected based on the patient's clinical history and physical examination. The diagnosis was confirmed with CT angiography (CTA). The tumor was nonfunctioning based on normal urinary-free catecholamines, vanillylmandelic acid (VMA), and metanephrines levels. The patient then underwent a CT scan of his thorax, abdomen, and pelvis which did not detect any metastatic spread. The patient was referred to a tertiary vascular surgery center for definitive treatment. Our aim in presenting this case is to increase awareness of this rare type of paraganglioma with the hope of increasing early intervention and improving outcomes.

Comparison of the Sensitivity of 68 Ga-DOTATATE PET/CT with Other Imaging Modalities in Detecting Head and Neck Paraganglioma: Experience from Western India.

Background This study aimed to compare the sensitivity of 68 Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) with other imaging modalities in the detection of head and neck paraganglioma (HNPGL). Methods The data of consecutive HNPGL patients ( n = 34) who had undergone at least 68 Ga-DOTATATE PET/CT and anatomical imaging (contrast-enhanced computed tomography/magnetic resonance imaging [CECT/MRI]) were retrospectively reviewed. The diagnosis of HNPGL (the primary tumor) was confirmed either by histopathology ( n = 10) or was based on clinical follow-up and correlation of anatomical with functional imaging in whom histopathology was not available ( n = 24). The sensitivities of 68 Ga DOTATATE PET/CT, 18F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT), 131 I-metaiodobenzylguanidine ( 131 I-MIBG) scintigraphy, and CECT/MRI for primary HNPGL, associated primary pheochromocytoma + sympathetic paraganglioma (PCC + sPGL), and metastatic lesions were analyzed. Results Thirty-four patients (males: 15) [isolated HNPGL: 26, HNPGL + PCC: 04, HNPGL+ sPGL: 03, HNPGL + PCC + sPGL: 01] harboring 50 primary lesions were included. For total lesions, 68 Ga-DOTATATE PET/CT (99.3%) had significantly higher lesion-wise sensitivity than 18 F-FDG PET/CT (81.6%, p = 0.0164), 131 I-MIBG (15.2%, p ≤0.0001), CECT (46.3%, p ≤ 0.0001) but similar sensitivity as MRI neck (97%, p = 0.79). On head-to-head comparison (21 primary HNPGL and 39 metastatic lesions), 68 Ga DOTATATE PET/CT had significantly higher lesion-wise sensitivities for the detection of metastatic (100 vs. 71.9%, p = 0.04) and total lesions (100 vs. 77.2%, p ≤ 0.0001). Conclusion 68 Ga-DOTATATE PET/CT was the most sensitive imaging modality for the detection of HNPGL and related lesions with significantly higher lesion-wise sensitivities than those of 18 F-FDG PET/CT, 131 I-MIBG, and CECT.

Hypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes.

Despite two decades of paraganglioma-pheochromocytoma research, the fundamental question of how the different succinate dehydrogenase (SDH)-related tumor phenotypes are initiated has remained unanswered. Here, we discuss two possible scenarios by which missense (hypomorphic alleles) or truncating (null alleles) SDH gene variants determine clinical phenotype. Dysfunctional SDH is a major source of reactive oxygen species (ROS) but ROS are inhibited by rising succinate levels. In scenario 1, we propose that SDH missense variants disrupt electron flow, causing elevated ROS levels that are toxic in sympathetic PPGL precursor cells but well controlled in oxygen-sensing parasympathetic paraganglion cells. We also suggest that SDHAF2 variants, solely associated with HNPGL, may cause the reversal of succinate dehydrogenase to fumarate reductase, producing very high ROS levels. In scenario 2, we propose a modified succinate threshold model of tumor initiation. Truncating SDH variants cause high succinate accumulation and likely initiate tumorigenesis via disruption of 2-oxoglutarate-dependent enzymes in both PPGL and HNPGL precursor tissues. We propose that missense variants (including SDHAF2) cause lower succinate accumulation and thus initiate tumorigenesis only in very metabolically active tissues such as parasympathetic paraganglia, which naturally show very high levels of succinate.

A Four-Generational Report on Hereditary Head and Neck Paraganglioma.

Background This article investigates the inheritance, penetrance, clinical presentation, and therapeutic outcomes of hereditary head and neck paragangliomas (HNPGLs) by offering a four-generational report of an 18-member family affected by this rare condition. Methodology Information was compiled by examination of patients and a review of medical records and correspondence (retrospective case series). Results Six members of the 18-member family were diagnosed with HNPGL between 2002 and 2018. A known pathogenic point mutation in subunit D of the succinyl dehydrogenase complex (SDHD, c.317G>T, p.Gly106Val) was responsible for the tumor phenotype. The mutation could be revealed in seven family members, three diseased adults, one healthy adult, and three healthy children, out of the nine who consented to gene testing. The median age at diagnosis was 33.5 years (range: 22-50 years). Five of the eight primary tumors were glomus caroticum, two were glomus jugulare, and one was a glomus vagale tumor. The therapeutic approaches were multimodal and included embolization therapy, surgery, radiation, and watchful waiting. Follow-up was reported for five of the six patients (mean follow-up of 34.8 months after primary therapy); three showed no disease progression or recurrence. Conclusions This study exemplifies the autosomal dominant, parent-of-origin-dependent inheritance and the high disease penetrance in hereditary paraganglioma-pheochromocytoma syndromes. Six out of a total of eight adult descendants (75%) of the original SDHD mutation carrier developed tumors, and the morbidity associated with the disease as well as its therapy was especially high in late-diagnosed, advanced cases. This substantiates the necessity for early radiologic surveillance and genetic testing.

Case Report: Giant Paraganglioma of the Skull Base With Two Somatic Mutations in SDHB and PTEN Genes.

Head and neck paragangliomas (HNPGLs) are neuroendocrine tumors. They arise from the parasympathetic ganglia and can be either sporadic or due to hereditary syndromes (up to 40%). Most HNPGLs do not produce significant amounts of catecholamines. We report a case of a giant paraganglioma of the skull base with an unusually severe presentation secondary to excessive release of norepinephrine, with a good outcome considering the severity of disease. A 39-year-old Caucasian woman with no prior medical history was found unconscious and emaciated in her home. In the intensive care unit (ICU) the patient was treated for multi-organ failure with multiple complications and difficulties in stabilizing her blood pressure with values up to 246/146 mmHg. She was hospitalized in the ICU for 72 days and on the 31st day clinical assessment revealed jugular foramen syndrome and paralysis of the right n. facialis. A brain MRI confirmed a right-sided tumor of the skull base of 93.553 cm3. Blood tests showed high amounts of normetanephrine (35.1-45.4 nmol/L, ref <1.09 nmol/L) and a tumor biopsy confirmed the diagnosis of a paraganglioma. Phenoxybenzamine and Labetalol were used in high doses ((Dibenyline®, 90 mg x 3 daily) and labetalol (Trandate®, 200 + 300 + 300 mg daily) to stabilize blood pressure. The patient underwent two tumor embolization procedures before total tumor resection on day 243. Normetanephrine and blood pressure normalized after surgery (0.77 nmol/L, ref: < 1.09 nmol/L). The damage to the cranial nerve was permanent. Our patient was comprehensively examined for germline predisposition to PPGLs, however we did not identify any causal aberrations. A somatic deletion and loss of heterozygosity (LOH) of the short arm (p) of chromosome 1 (including SDHB) and p of chromosome 11 was found. Analysis showed an SDHB (c.565T>G, p.C189G) and PTEN (c.834C>G, p.F278L) missense mutation in tumor DNA. The patient made a remarkable recovery except for neurological deficits after intensive multidisciplinary treatment and rehabilitation. This case demonstrates the necessity for an early tertiary center approach with a multidisciplinary expert team and highlights the efficacy of the correct treatment with alpha-blockade.