Paraganglioma of the Head and Neck: A Review.

OBJECTIVE: To review the epidemiology, presentation, diagnosis, and management of head and neck paragangliomas. METHODS: A literature review of english language papers with focus on most current literature. RESULTS: Paragangliomas (PGLs) are a group of neuroendocrine tumors that arise in the parasympathetic or sympathetic ganglia. Head and neck PGLs (HNPGLs) comprise 65% to 70% of all PGLs and account for 0.6% of all head and neck cancers. The majority of HNPGLs are benign, and 6% to 19% of all HNPGLs develop metastasis outside the tumor site and significantly compromise survival. PGLs can have a familial etiology with germline sequence variations in different susceptibility genes, with the gene encoding succinate dehydrogenase being the most common sequence variation, or they can arise from somatic sequence variations or fusion genes. Workup includes biochemical testing to rule out secretory components, although it is rare in HNPGLs. In addition, imaging modalities, such as computed tomography and magnetic resonance imaging, help in monitoring in surgical planning. Functional imaging with DOTATATE-positron emission tomography, 18F-fluorodeoxyglucose, or 18F-fluorohydroxyphenylalanine may be necessary to rule out sites of metastases. The management of HNPGLs is complex depending on pathology, location, and aggressiveness of the tumor. Treatment ranges from observation to resection to systemic treatment. Similarly, the prognosis ranges from a normal life expectancy to a 5-year survival of 11.8% in patients with distant metastasis. CONCLUSION: Our review is a comprehensive summary of the incidence, mortality, pathogenesis, presentation, workup and management of HNPGLs.

Superior mediastinal paraganglioma initially suspected of being a mediastinal thyroid goiter.

Paraganglioma is a rare tumor arising from paraganglia. Few reports have described paragangliomas in the superior mediastinum. We report a case of superior mediastinal paraganglioma treated in our department. A 28-year-old woman visited our department because of suspected mediastinal tumor during a medical checkup. Contrast-enhanced CT showed a 39 × 35 × 65-mm tumor with a well-defined border extending from the lower pole of the left thyroid gland to the superior mediastinum. Laboratory tests showed no evidence of catecholamine overproduction. Mediastinal thyroid goiter was the most suspected preoperative diagnosis. We decided to perform a transcervical excision for both diagnosis and treatment. The tumor was easily detached from the lower pole of the left thyroid gland and was not continuous. The tumor capsule was brittle and bled easily. The operating time was 3 h and 11 min, and the amount of bleeding was 571 mL. The pathological diagnosis was paraganglioma. Paragangliomas are characterized by abundant blood flow and are likely to result in a high intraoperative bleeding volume. In addition, if the tumor is functional, circulatory abnormalities can occur during the perioperative period. Accurate preoperative diagnoses are important, and the possibility that paragangliomas can develop in the superior mediastinum should be considered.

Paraganglionas del cuerpo carotídeo. Nuestra experiencia / Carotid body paraganglioma. Our experience

El paraganglioma carotídeo, es un tumor considerado benigno que se origina a partir de las células del corpúsculo carotideo. Suubicación es a nivel del cuello en la bifurcación carotídea entre las arterias carótida interna y externa. Se realiza en el trabajo, unanálisis descriptivo, retrospectivo de estos tumores tratados en un periodo de 40 años. Se analizan datos demográficos con respectoal sexo y edad de presentación y otros morfológicos de tamaño y extensión, adscribiéndoles en los diferentes tipos de acuerdo a laclasificación de Shamblin. Se valora el tipo de tratamiento quirúrgico practicado y los resultados obtenidos. (AU)

Paraganglioma is a benign tumor that originates from the cells of the carotid corpuscle. Its location is at the level of the neck at thecarotid bifurcation between the internal and external carotid arteries. A retrospective analysis of these tumors treated over a periodof 40 years is carried out at work. Demographic data with respect to sex and age of presentation and other morphological data ofsize and extension are analyzed, assigning them to the different types according to the Shamblin classification. The type of surgicaltreatment performed and the results obtained are assessed. (AU)

Recent advances in the management of pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors that cause refractory hypertension and hypertensive crisis. Although metastatic disease accounts for 30% of PPGLs, the diagnosis of malignancy is difficult without the presence of metastatic lesions. Here, we review several advancements in the diagnosis and treatment of PPGL. A nationwide epidemiological survey in Japan revealed that the annual number of patients with PPGL was 3000, which was higher than that reported previously. While plasma and urine fractionated metanephrines are recommended for use in specific biochemical testing for diagnosis, creatinine-corrected fractionated metanephrines in spot urine samples that had been widely used in Japan as a convenient screening test were shown to be as useful as 24-h urine fractionated metanephrines. Regarding imaging studies, a more specific functional imaging for PPGLs, 68Ga DOTATATE, was newly developed. 68Ga DOTATATE provides a clear image with high sensitivity and specificity. Currently, PASS or GAPP histological scores and SDHB immunostaining are clinically used to attempt to discriminate benign from malignant tumors. However, since this distinguishing process remains difficult, all cases were classified as malignant with the possibility of metastasis in the WHO classification of endocrine tumors updated in 2017. Approximately 60% of PPGLs have germline mutations in PPGL-related genes. Currently, the genes are classified into two clusters based on their mechanism for the etiology of tumorigenesis. Based on the possible mechanisms of tumor development associated with gene mutations, several molecular target drugs are under evaluation to explore more promising treatments for malignant PPGL.

Comprehensive review of evaluation and management of cardiac paragangliomas.

Cardiac paraganglioma (PGL) is a rare neuroendocrine tumour causing significant morbidity primarily due to norepinephrine secretion potentially causing severe hypertension, palpitations, lethal tachyarrhythmias, stroke and syncope. Cardiologists are faced with two clinical scenarios. The first is the elevated norepinephrine, whose actions must be properly counteracted by adrenoceptor blockade to avoid catastrophic consequences. The second is to evaluate the precise location of a cardiac PGL and its spread since compression of cardiovascular structures may result in ischaemia, angina, non-noradrenergic-induced arrhythmia, cardiac dysfunction or failure. Thus, appropriate assessment of elevated norepinephrine by its metabolite normetanephrine is a gold biochemical standard at present. Furthermore, dedicated cardiac CT, MRI and transthoracic echocardiogram are necessary for the precise anatomic information of cardiac PGL. Moreover, a cardiologist needs to be aware of advanced functional imaging using 68Ga-DOTA(0)-Tyr(3)-octreotide positron emission tomography/CT, which offers the best cardiac PGL-specific diagnostic accuracy and helps to stage and rule out metastasis, determining the next therapeutic strategies. Patients should also undergo genetic testing, especially for mutations in genes encoding succinate dehydrogenase enzyme subunits that are most commonly present as a genetic cause of these tumours. Curative surgical resection after appropriate α-adrenoceptor and ß-adrenoceptor blockade in norepinephrine-secreting tumours is the primary therapeutic strategy. Therefore, appropriate and up-to-date knowledge about early diagnosis and management of cardiac PGLs is paramount for optimal outcomes in patients where a cardiologist is an essential team member of a multidisciplinary team in its management.

Recurrence and Progression of Head and Neck Paragangliomas after Treatment.

OBJECTIVE: To characterize the recurrence of head and neck paragangliomas and the factors associated with disease progression after treatment. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care center. SUBJECTS AND METHODS: In total, 173 adults with 189 paragangliomas (41.3% carotid body, 29.1% glomus jugulare, 19.0% glomus tympanicum, and 10.6% glomus vagale) treated between 1990 and 2010 were evaluated to determine the incidence and risk of recurrence using Cox proportional hazards. RESULTS: The mean (SD) follow-up duration was 8.6 (9.1) years. The incidence was 2.92 recurrences per 100 person-years. The rate of recurrence was 8.2% (95% confidence interval [CI], 3.7-12.7) after 4 years and 17.1% (95% CI, 10.2-24.0) after 10 years. Glomus jugulare tumors were more likely to recur (hazard ratio [HR], 3.69; 95% CI, 1.70-8.01; P < .001) while carotid body tumors were less likely (HR, 0.44; 95% CI, 0.21-0.97; P = .041). Radiation had a lower risk of recurrence or progression compared to surgical excision (HR, 0.30; 95% CI, 0.10-.94; P = .040). Recurrence was associated with right-sided paragangliomas (HR, 3.60; 95% CI, 1.63-7.75; P = .001). The median time to recurrence was 18.4 years. Six (3.2%) patients developed metastasis, which was more common with local recurrence (9.5% vs 1.4%, P = .015). CONCLUSIONS: Recurrence is more common with glomus jugulare tumors and less common with carotid body tumors. Radiation may have a lower risk of recurrence or progression than surgery for some paraganglioma types. Metastasis is rare but more likely with recurrent disease. Surveillance neck imaging is recommended every several years for decades after treatment.

PHEOCHROMOCYTOMA: A GENETIC AND DIAGNOSTIC UPDATE.

OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathologic studies are performed to prove, localize, treat, and monitor disease progression. Improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (<1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment. METHODS: This review outlines the most updated approach to PPGL patients and presents a new diagnostic protocol for physicians to increase earlier tumor identification and accurately assess metastatic behavior. CONCLUSION: We present the most recent advances in genetics, epigenetics, metabolomics, biochemical, and imaging diagnoses of this rare tumor to properly assess disease, decide treatment options, and manage follow-up. We also elaborate on new therapeutic perspectives in these very rare neoplastic entities. ABBREVIATIONS: ATRX = ATRX chromatin remodeler; ccRCC = clear cell renal cell carcinoma; c-MYC = MYC proto oncognene; CT = computed tomography; DOTATATE = DOTA-octreotate; EGLN1/2 = egl-9 family hypoxia inducible factor 1/2; EGLN2/PHD1 = egl-9 family hypoxia inducible factor 2; EPAS1/HIF2A = endothelial PAS domain protein 2/hypoxia-inducible factor 2α; ERK = extracellular signal-regulated kinase; HIFs = hypoxia-inducible factors; HIF-α = hypoxia-inducible factor alpha; HNPGLs = head and neck paragangliomas; 177Lu-DOTATATE = lutetium octreotate; MAX = myc-associated factor X; MDH2 = malate dehydrogenase; MIBG = metaiodobenzylguanidine; MN = metanephrine; MRI = magnetic resonance imaging; mTOR = mammalian target of rapamycin; NETs = neuroendocrine tumors; NF1 = neurofibromin 1; NMN = normetanephrine; PHD = prolyl hydroxylase domain protein; PI3K = phosphoinositide 3-kinase; PPGLs = pheochromocytoma and paragangliomas; PRRT = peptide receptor radionuclide therapy; Pvhl = von Hippel-Lindau protein; RAS = rat sarcoma oncogene; RET = rearranged during transfection proto-oncogene; SDH = succinate dehydrogenase; SDHA, -B, -C, -D = succinate dehydrogenase subunits A, B, C, D; SDHAF2 = succinate dehydrogenase complex assembly factor 2; SDHB, C, D = succinate dehydrogenase subunits B, C, D; SDHx = succinate dehydrogenase subunits; SSTRs = somatostatin receptors; VHL = von Hippel-Lindau.

Active surveillance management of head and neck paragangliomas: case series and review of the literature.

BACKGROUND: Head and neck paragangliomas are rare. They are usually slow-growing, benign, non-catecholamine secreting tumours, traditionally treated with surgical excision. Complications of surgical excision include lower cranial nerve palsies, stroke and death. METHOD: A retrospective case note analysis was conducted of patients with head and neck paragangliomas treated with a watch-and-scan policy from March 2003 to September 2015, and the relevant literature was reviewed. RESULTS: Fifteen head and neck paragangliomas were identified. None of the patients developed a new lower cranial nerve palsy or progression of their presenting hearing loss during the follow-up period. Five patients displayed an increase in maximum linear dimension of 4 mm over an average of 57.4 months. A review of the literature showed that a watch-and-surveillance scan policy is evolving as a treatment option for head and neck paragangliomas without malignant risk factors. CONCLUSION: Readily available surveillance scanning in head and neck paragangliomas enables the monitoring of head and neck paragangliomas, which may allow for avoidance of major surgery.

The Management of Locally Invasive Primary Thyroid Paraganglioma: A Case Report and Review of the Literature.

Paragangliomas (PG) are very rare neuroendocrine tumours, arising from neural crest derived paraganglia of the autonomic nervous system. Primary thyroid paraganglioma (PTPG) is a rare site of PG and only 45 cases have been previously reported. The preoperative diagnosis of PTPGs presents a challenge as the clinical, cytological and histological features overlap with more common primary thyroid cancers. A 55 year old male was found to have significant enlargement of the left lobe of his thyroid. Following lobectomy, the thyroid lobe showed unencapsulated tumour which was positive for synaptophysin, CD56 and S100 (sustentacular cells). Post-operative imaging demonstrated incomplete resection. There was no post-operative radiotherapy and monitoring was by 6-12 monthly MRI. 48 months after his surgery he is alive and well with no evidence of disease progression. The diagnosis of PTPG was only made postoperatively, and although rare should be considered in the differential diagnosis of a hypervascular thyroid nodule.

Arterial embolization with Onyx of head and neck paragangliomas.

OBJECT: To report the morbidity and long term results in the treatment of paragangliomas by transarterial embolization with ethylene vinyl alcohol (Onyx), either as preoperative or palliative treatment. METHODS: Between September 2005 and 2012, 18 jugulotympanic, 7 vagal, and 4 carotid body paragangliomas (CBPs) underwent Onyx embolization, accordingly to our head and neck multidisciplinary team's decision. CBPs were embolized preoperatively. Jugulotympanic and vagal paragangliomas underwent surgery when feasible, otherwise palliative embolization was carried out alone, or in combination with radiotherapy or tympanic surgery in the case of skull base or tympanic extension. Treatment results, and clinical and MRI follow-up data were recorded. RESULTS: In all cases, devascularization of at least 60% of the initial tumor blush was obtained; 6 patients underwent two embolizations. Post-embolization, 8 patients presented with cranial nerve palsy, with partial or complete regression at follow-up (mean 31 months, range 3-86 months), except for 2 vagal and 1 hypoglossal palsy. 10 patients were embolized preoperatively; 70% were cured after surgery and 30% showed residual tumor. 19 patients received palliative embolization, of whom 5 underwent radiotherapy and 3 received tympanic surgery post-embolization. Long term follow-up of palliative embolization resulted in tumor volume stability (75%) or extension in intracranial or tympanic compartments. Onyx embolization of CBPs resulted in more difficult surgical dissection in 2 of 4 cases. CONCLUSIONS: Onyx embolization is a valuable alternative to surgery in the treatment of jugulotympanic and vagal paragangliomas; tympanic surgery or radiosurgery of the skull base should be considered in selected cases. Preoperative Onyx embolization of CBPs is not recommended.

Management of vagal paragangliomas: review of 17 patients.

Vagal paragangliomas are very rare benign vascular tumors of neuroendocrine nature, and are much less frequent than carotid and jugulo-tympanic tumors. The goal of this retrospective study is to review the clinical and genetic findings, surgical treatment, and complications of vagal paragangliomas, as well as to discuss the management options. During the period 1990-2013, 17 patients with vagal paragangliomas were referred to our institution. There were ten patients with isolated tumors, and seven with multicentric paragangliomas. There were nine women and eight men. Mean age of patients was 51.4 years. Five cases had a positive family history of paraganglioma (29.4 %). Germline mutations of SDH genes were found in six of our patients (35.3 %). Many options were considered in the management of vagal paragangliomas. Surgical treatment was performed in 11 young patients (64.7 %) using different approaches: in 4 patients the tumor was resected through a transcervical approach; in 3 through a transcervical-transmandibular approach; in 1 it was resected using a transcervical-transmastoid approach, and in 3 a type A infratemporal fossa approach was performed. In all operated cases, the removal of the tumor led to sacrificing of the vagus nerve. Postoperative hypoglossal nerve deficit was reported in 4 cases (36.3 %). In six elderly patients (35.3 %), we decided to "wait-and-scan" in order to avoid creating greater morbidity than that of the tumor itself. Many factors should be considered in the treatment of vagal paragangliomas: the age and general condition of the patient, the biological behavior of the tumor, tumor size, genetic results, bilaterality, multicentricity, lower cranial nerve function, and of course the potential morbidity of the surgical treatment itself. Rehabilitation and, possibly surgery, are necessary to treat postoperative lower cranial nerve deficits.

Paraganglioma of the thyroid gland: a case report.

INTRODUCTION: Thyroid paraganglioma is a very rare malignant neuroendocrine tumor. Immunohistochemical features of thyroid paraganglioma are helpful for the diagnosis. CASE REPORT: A 69-year-old female came to hospital with the presence of a growing thyroid nodule of the left lobe. Ultrasonic neck examination showed 5 cm hypoechoic nodule in the left thyroid lobe. Thyroid scintigraphy showed a big cold nodule in the left lobe. Computed tomography (CT) scan showed left lobe thyroid tumor with tracheal deviation on the right site. Extended total thyroidectomy was done. Intraoperative consultation with the pathologist confirmed thyroid cancer. The pathologist diagnosed thyroid paraganglioma on the base of immuohistochemical investigation. This thyroid paraganglioma was positive for neuron-specific enolase, chomogranin A, synaptophysin, and S-100 protein highlighted the sustentacular cells. Tumor cells were negative for thyroglobulin, epithelial membrane antigen, cytokeratin, calcitonin, and carcinoembryonic. After the surgery the patient was treated with chemotherapy, peptide receptor radionuclide therapy, and permanent TSH suppressive therapy. The patient was followed with measurements of thyroid hormone and serum neuron-specific enolase, chromogranin A level, every 6 months. Gastroscopy, colonoscopy, chest and abdomen CT scan as well as further tests (chest xray, ultrasound of the neck, and whole body octreotide scintigraphy) were done. No primary neuroendocrine tumor in digestive sistem or in the chest was found. After more than 3 years the patient has no evidence of the recurrent disease. CONCLUSION: Radical resection of thyroid paraganglioma, followed by chemotherapy and peptide receptor radionuclide therapy, should be considered the treatment of choice in patients with thyroid gland paraganglioma.

Preoperative tumor embolization.

In this article, the authors review general principles and technical details of preoperative embolization of various hypervascular head, neck, and spinal tumors encountered in contemporary neuroendovascular practice. Indications, treatment goals, techniques, outcomes, and complications are discussed, and illustrative case examples are presented.

Experiences in the treatment of patients with multiple head and neck paragangliomas.

PURPOSE: To analyze treatment results in the multidisciplinary management of patients with multiple head and neck paragangliomas (HNPs). METHODS: Retrospective analysis including all patients with multiple HNPs (VP, vagal paraganglioma; JTP, jugulotympanic paraganglioma; CBT, carotid body tumor) treated between 2000 and 2013 at a tertiary referral center. RESULTS: Ten patients (three men, seven women) had 25 HNPs (two VPs, eight JTPs, and 15 CBTs). The age range at diagnosis was 31-71 years (mean 40.9 years, median 37 years). Nine tumors (four CBTs, three JTPs, two VPs) were treated only with stereotactic radiotherapy (SRT; 50.4-56Gy, mean 55.3Gy) or in one case intensity-modulated radiotherapy (60 Gy). Nine tumors were treated with surgery alone (eight CBTs, one JTP) and three JTPs with subtotal surgery combined with adjuvant SRT. A "wait and scan" strategy was used in three cases (two CBTs, one JTP). The mean follow-up period was 4.3 years (range 0.1-13 years, median 4 years). The rate of tumor control with surgery and/or SRT was 100% (21/21). One patient with a wait-and-scan strategy for CBT had slow asymptomatic progression during a 13-year follow-up. CONCLUSIONS: The treatment results in this series of patients with multiple HNPs show that a very high rate of long-term tumor control with low morbidity can be achieved using tailored and individualized approaches. All of the different treatment strategies available should be discussed with the patient. In particular, the treatment should involve a multidisciplinary team of experts in the fields of nuclear medicine, genetics, pathology, radiology, radio-oncology, and surgery.

Preoperative embolization of carotid chemodectoma: a technical challenge that can be customized according to angioarchitecture. Illustrative cases.

Preoperative embolization of carotid paraganglioma is increasingly used to reduce the risk of surgical bleeding obtaining a more precise and extensive tumor resection. Currently the technique can be customized in consideration of the different tumor angioarchitecture, thanks to embolic materials with different vascular penetration: solid particles of polyvinyl-alcohol (PVA), histoacryl glue, and liquid polymer (Onyx(®)). Two cases of swelling dissection with volume progression over time came to our observation. Both patients (45 and 70-year-old women) were studied with neck ultrasound imaging and computed tomography (CT) and/or magnetic resonance (MR). In both cases the radiological investigations confirmed the clinical suspicion of carotid paraganglioma. Both patients were sent for angiography control and preoperative devascularization of the lesion. The treatment was performed under general anesthesia using, depending on the type of tumor vasculature, in case 1 solid particles of PVA and histoacryl glue, and in case 2 Onyx(®) (Covidien, Irvine). The patients successfully underwent excision of the lesion via cervicotomy within a week from the embolization procedure, without any complications. The histological findings confirmed the diagnosis of chemodectoma, and macrophage infiltrates were seen in the regions previously embolized. At one-year follow-up, there was no evidence of recurrent disease. The preoperative embolization of vascular lesions of the neck represents a safe technique that yields the best results when customized over the type of vascularization of the lesion, enabling the use of the most appropriate materials, depending on the case to be treated.

Bilateral chemodectoma: medicolegal considerations on a case report of aeromedical concern.

The authors describe a case of bilateral carotid chemodectoma occurring in a military pilot who was assessed and evaluated in terms of aeromedical and medico-legal aspects for his fitness to fly. In view of the lack of specific guidelines and/or regulations, both national and international, we choose to follow a multidisciplinary clinical approach that included aero-physiological tests in the hypobaric chamber, in order to identify a standard protocol that could be used as reference for similar future cases, where this kind of assessment is necessary.