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.

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.

Update on Pheochromocytoma and Paraganglioma from the SSO Endocrine/Head and Neck Disease-Site Work Group. Part 1 of 2: Advances in Pathogenesis and Diagnosis of Pheochromocytoma and Paraganglioma.

This first part of a two-part review of pheochromocytoma and paragangliomas (PPGLs) addresses clinical presentation, diagnosis, management, treatment, and outcomes. In this first part, the epidemiology, prevalence, genetic etiology, clinical presentation, and biochemical and radiologic workup are discussed. In particular, recent advances in the genetics underlying PPGLs and the recommendation for genetic testing of all patients with PPGL are emphasized. Finally, the newer imaging methods for evaluating of PPGLs are discussed and highlighted.

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.

Primary parapharyngeal tumours: a review of 21 cases.

BACKGROUND: The diagnostic and therapeutic procedures performed in a series of patients with primary parapharyngeal space (PPS) tumours treated at the ENT Departments of San Giovanni Bosco Hospital, Turin, and of the Pugliese-Ciaccio Hospital, Catanzaro, Italy, in the period 2001-2010 are evaluated. MATERIALS AND METHODS: The retrospective review included 20 patients, 11 male and 9 female, average age of 41 years operated on for 21 primary PPS tumours. The most common tumours found were neurogenic neoplasms, while those of salivary origin were the next most common. RESULTS: There were 14 paragangliomas (7 originating from carotid glomus, 5 from vagal and 2 from tympanicum), 1 sympathetic chain schwannoma and 6 pleomorphic adenomas. All the tumours were benign in nature and gave rise to few signs or symptoms. Patients underwent preoperative computed tomography (CT) scan or magnetic resonance imaging (MRI) or both. Most contrast-enhanced masses were submitted to some type of angiography. Most of the surgeries were planned through imaging alone, as preoperative fine needle aspiration (FNA) biopsy was performed only in six cases. Four different approaches were adopted for tumour removal: transcervical, transcervical/transparotid, cervical-transparotid-transmandibular and infratemporal fossa approach. There was no operative mortality, though neurologic morbidity was significant. Follow-up, extended to a maximum of 11 years, did not reveal any recurrences. In conclusion, neurogenic tumours may be the most common of PPS masses. Surgery is the mainstay treatment and external approaches offer the potential for satisfactory tumour resection. Of such external approaches, transcervical and cervical/transparotid are the most often used in benign forms. CONCLUSION: The number of perioperative complications encountered in this series confirms the difficulty of performing surgery in this complex area, even in benign cases. The chances of avoiding vascular damage and saving the trunks or most of the nerve fibres involved depend not only on the skill and experience of the surgeon but also on the anatomy of the lesion, the type of connection between the tumour and the nerve from which it originates and the distribution of neural fibres in or around the tumour mass.

Acute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma.

OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) can cause acute catecholamine cardiomyopathy (ACC). We assessed the prevalence of ACC and compared the presentation of cases with and without ACC in a large series of PPGL. DESIGN: Single centre retrospective study. SETTING: Hypertension Unit, University Hospital, Paris. PATIENTS: 140 consecutive patients with PPGL, referred from January 2003 to September 2012. MAIN OUTCOME MEASURES: Left ventricular ejection fraction (LVEF), perioperative mortality. RESULTS: Fifteen patients (11%) had suffered an ACC, occurring in 14 cases before the diagnosis of PPGL. Precipitating factors were identified in 11 cases. Twelve patients presented with acute pulmonary oedema, including 10 with cardiogenic shock, requiring life support in eight cases. Seven patients (five with pulmonary oedema) presented with acute chest pain and cardiac dysfunction. Electrocardiographic abnormalities were present in 14 cases: ST segment elevation or pathological Q waves, ST segment depression, and/or diffuse T wave inversion. Six patients displayed classical (apical ballooning) or inverted (basal/mid ventricular stunning) takotsubo-like cardiomyopathy. Coronary arteries were always normal on angiography. In patients with ACC, median LVEF rose from 30% (IQR 23-33%) during ACC to 71% (50-72%) before surgery (n=11, p<0.001). Median LVEF before PPGL surgery was 65% (51-72%) and 65% (60-70%) in patients with and without a history of ACC, respectively (not significant). CONCLUSIONS: PPGL may present as ACC in 11% of cases, excluding patients dying from undiagnosed tumours. Left ventricular dysfunction is usually reversible before surgery. PPGL should be suspected in patients with acute heart failure without evidence of valvular or coronary artery disease.

High incidence of extraadrenal paraganglioma in families with SDHx syndromes detected by functional imaging with [18F]fluorodihydroxyphenylalanine PET.

PURPOSE: Knowledge of the genetic backgrounds of hereditary syndromes, which are increasingly being characterized, enables genetic screening of family members of affected patients. Upon detection of a mutation, genetic counselling and clinical screening including imaging modalities and biochemical analyses are commonly performed. METHODS: Unaffected, mutation-positive relatives of index patients with hereditary paraganglioma syndromes were offered PET imaging with [(18)F]fluorodihydroxyphenylalanine and the incidence of pathological findings was retrospectively analysed in relation to mutations of the succinate dehydrogenase enzyme complex. PET only or PET/CT was performed in 21 individuals from eight families with SDHD, one family with SDHC and two families with SDHB mutations. Screening was offered every 2 to 5 years. RESULTS: Of the 21 individuals, 14 showed paraganglioma during screening. In particular, in only 2 of 15 patients with a SDHD mutation were the findings completely unremarkable on PET screening. However, false-negative lesions for abdominal manifestations in two SDHD-positive patients were detected. CONCLUSION: FDOPA PET is a sensitive imaging modality which should be offered to patients with a detected SDHx (SDHD) mutation, preferably using a hybrid technique.

Tumores del cuerpo carotídeo. Experiencia en 22 años y protocolo de seguimiento y despistaje familiar / Carotid body tumours. Experience over 22 years and a family screening and follow-up protocol

Introducción: Los tumores del cuerpo carotídeo son tumores raros, muy vascularizados, originados en los quimiorreceptores de la bifurcación carotídea. Se ha descrito su malignización y asociación con otros tumores endocrinos. Pueden ser familiares en el 10-50% de los casos. Objetivo: Analizar nuestros resultados en el manejo de estos tumores y presentar un protocolo de actuación y seguimiento. Material y métodos: Entre 1986 y 2008 se trataron 25 casos en 23 pacientes (2 bilaterales), con una edad media de 51 años (r 31-78), el 82,6% mujeres, un caso familiar. Como pruebas diagnósticas se realizaron ecodoppler y arteriografía en todos los pacientes, y tomografía computarizada o resonancia magnética en 12. El seguimiento postoperatorio se llevo a cabo con ecodoppler. Resultados: En todos los casos se realizó la resección completa del tumor, los 14 últimos con embolización preoperatoria. Fue necesaria la reconstrucción vascular en 6 casos. Seis pacientes tuvieron lesión neurológica, uno rotura arterial y uno neumonía postoperatoria. Según los criterios de clasificación de Shamblin, 13 casos fueron tipo I, 5 tipo II y 7 tipo III. Las complicaciones y reconstrucciones vasculares estuvieron relacionadas con tumores tipo II y III. Durante el seguimiento se detectaron 4 recidivas, 2 tumores contralaterales (bilaterales), un feocromocitoma, una trombosis del injerto y 6 éxitus (uno por malignización y metástasis). Conclusiones: La cirugía en fase precoz disminuye la morbimortalidad. El seguimiento con ecodoppler permite detectar recidivas, bilateralidad y complicaciones de la reconstrucción vascular. La posible presentación familiar, recidivas, asociación a otros tumores o metástasis ,hacen necesario el seguimiento sistematizado del paciente(AU)

Background: Carotid body tumours are rare, highly vascular, arising from the chemoreceptors of the carotid bifurcation. Their relationship with malignancy and other endocrine tumours have already been described. There can be between 10% and 50% of cases in a family. Objective: To analyse the results in the management of these tumours, and present a protocol for action and monitoring. Material and methods: Between 1986 and 2008 a total 25 cases were treated in 23 patients (2 bilateral) with a mean age of 51 years (range 31-78), with 82.6% women, 1 family case. Doppler ultrasound and angiography were performed as diagnostic tests in all patients, with computed tomography or magnetic resonance imaging in 12 cases. They were monitored annually using Doppler ultrasound. Results: According to the Shamblin classification criteria, 13 cases were type I, 5 were type II and 7 type III. A complete resection of the tumour was performed in all cases, the last 14with preoperative embolisation. Vascular reconstruction was necessary in 6 cases. Six patients had neurological injury, an arterial rupture and a postoperative pneumonia. Complications and vascular reconstruction were associated with type II and III tumours. During follow-up four recurrences were detected, two contralateral tumours, a phaeochromocytoma, a graft thrombosis and six deaths, (1 from malignancy and metastasis). Conclusions: Surgery in the early stage reduces the morbidity and mortality. Follow-up should be with Doppler ultrasound to detect recurrence, bilaterality and complications of vascular reconstruction. The possible familial presentation, recurrence, association with other tumours or metastases, requires systematic monitoring of the patient(AU)

Paraganglioma maligno extrasuprarrenal / Malignant extra-adrenal paraganglioma: case report

Los paragangliomas malignos extrasuprarrenales son neoplasis extremadamente raras (frecuencia diez veces menor que los feocromocitomas), con mayor incidencia entre las tercera y cuarta décadas de la vida, y que a menudo son multiéntricos y malignos. Se presenta un caso de Paraganglioma maligno extrasuprarrenal, destacando los hallazgos clínicos y anatomopatológicos, diagnósticos diferenciales y factores pronósticos (AU)

El manejo de los paragangliomas en el Instituto Nacional de Cancerología / Management of the parangangliomas in the Instituto Nacional de Cancerologia

Los paragangliomas son tumores cuyas células se derivan del sistema extraadrenal cromafín. Se le conoce por una variedad de nombres que incluyen glomus, quemodectomas y glomerulocitomas. Ocurren con mayor frecuencia en el cuerpo carotídeo, en la mujer y en personas que viven en ciudades ubicadas en altitud elevada. Se realizó un estudio retrospectivo para evaluar las formas de diagnóstico y manejo de esta tumoración en el Instituto Nacional de Cancerología de la Ciudad de México. Se reportan 31 casos que ocurrieron exclusivamente en mujeres. La localización más frecuente fue en el cuerpo carotídeo (90.3 por ciento). El estudio de imagen más utilizado fue la tomografía computada (61.3 por ciento) seguido de la angiografía (51.6 por ciento). El tratamiento de elección fue la resección quirúrgica (81.8 por ciento), seguido de la radioterapia (6.1 por ciento); cuatro casos rechazaron tratamiento (12.1 por ciento). Con estas modalidades de tratamiento no se registraron defunciones ni secuelas y todos los pacientes se encuentran vivos en la actualidad.

Paraganglioma of the prostate. A case report and review of the literature.

Only five cases of paraganglioma of the prostate have been reported hitherto. The tumours may be functional (phaeochromocytomas) or non-functional and benign or malignant. We present a sixth case--a non-functional, benign paraganglioma of the prostate--with a review of the literature.

Gastric leiomyoblastoma associated with extraadrenal paraganglioma and pulmonary chondroma: a new case of Carney's triad.

Carney's triad is extremely rare. The authors report on a 12-year-old patient who had gastric epithelioid leiomyosarcoma, multiple pulmonary chondroma, and mediastinal paraganglioma. Thirty-five other cases are reviewed and analyzed.

[Abdominal paragangliomas. The experience of the Hospital 12 de Octubre]. / Paragangliomas abdominales. Experiencia del Hospital 12 de Octubre.

This is a revision of our experience between 1975 and 1992 over a total of 35 patients who underwent surgery in 40 occasions for pheochromocytoma. If we dismiss one case of pheochromocytoma with early metastatic malignant presentation and which was not removed, a total of 6 patients with abdominal paraganglioma (17%) have undergone surgery in 10 occasions. Three of them (50%) were multiple and recurrent, an one (16%) become malignant after multiple recurrences. Average age was 34.6 years with balanced sex distribution. No patient had neurofibromatosis, Von Hippel Lindau disease, MEN syndromes or Carney's triad and only one case, which corresponded to the malignant pheochromocytoma, showed direct familial background. All patients were hypertensive. Four cases (66%) presented with catecholamine crisis, one case was an incidentaloma that at the 24-hour monitoring presented hypertensive crisis during the sleep, and the last one was diagnosed while investigating a case of sustained HTA in a young female. All patients had high urinary catecholamine excretion. To establish location of the tumour MIBG scanning (90% sensitivity) was used in first place followed by guided CT (80% sensitivity) since both techniques have a good correlation in order to design the surgical approach. Angiography was reserved for cases where the other two techniques were inconclusive or when it was necessary to obtain a better profile of the surgical anatomy. A total of 15 paraganglioma were removed, the most frequent location being renal parahilar (26%) followed by preaortic in Zuckerkandl's organ (20%) and vesical (20%). The most relevant intraoperative complications were HTA crisis related to anaesthetics manoeuvres and tumoral handling (90%), and hypotension following tumour exercises (10%). During the postoperative period, three patients required blood transfusion and one of them had to be re-intervened for bleeding caused by unnoticed damage to the right renal vein. Currently, three patients (50%) are disease free, one with residual mild HTA controlled with diuretics. Two patients (33%) are awaiting for re-intervention due to recurrence (one with multiple extra-abdominal recurrence) after one and two prior interventions respectively. The last one (16%) is the malignant pheochromocytoma, operated four times for recurrence which currently shows lung metastasis with adequate drug control of clinical manifestations, after polychemotherapy failure and 27-months follow-up since metastasis has been detected. Revision of existing literature and discussion of issues related to signs and symptoms, diagnosis, surgical preparation and approach, as well as prognostic implications related to paraganglioma as compared with adrenal-located pheochromocytoma.

Chemodectoma of the head and neck: results of treatment in 84 patients.

Eighty-four patients with chemodectoma of the head and neck presented to the Royal Marsden Hospital between 1949 and 1985. For tumors arising at the skull base (glomus jugulare and glomus tympanicum) 46 were treated with radiotherapy alone resulting in an actuarial local control rate of 73% at 25 years; 13 were treated with surgery plus radiotherapy with no recurrences during a median follow-up of 9 years; 4 had surgery alone but all recurred by 7 years. For tumors of the soft tissues of the neck (carotid body and glomus vagale) 13 were treated with surgery alone with an actuarial control rate of 54% at 15 years; 4 were treated with radiotherapy which resulted in local control at 1, 2, 8 and 11 years; and one patient who received both surgery and radiotherapy remained controlled at 1 year. Although comparison between radiotherapy and surgery in terms of tumor control is not simple, the case is argued for more frequent use of radiotherapy at all sites. This case is strengthened by minimal morbidity from radiotherapy in doses which appear effective: in the range of 45-50 Gy in 25 daily fractions over 5 weeks.

[Chemodectomas of the temporal bone]. / Quemodectomas del hueso temporal.

Report of the results of radiotherapy in 12 patients suffering from chemodectomas of the temporal bone. Complete or partial remissions under both clinical and radiological aspects are argued. Discussion on radiotherapy versus surgery of these growths.

Extraadrenal retroperitoneal paraganglioma: clinical, pathologic, and CT findings.

Paragangliomas of the retroperitoneum arise from specialized neural crest cells distributed along the aorta in association with the sympathetic chain. In order to ascertain characteristic CT features of extraadrenal retroperitoneal paragangliomas to differentiate them from other retroperitoneal tumors, 31 discrete tumors and two cases of paragangliomatosis in 28 patients were reviewed retrospectively, and the CT features were correlated with clinical and pathologic findings. There were 16 men and 12 women. Average age was 37 years (range, 11-70 years). Twenty-four patients (86%) had hypertension. Of these, catecholamine levels were elevated in all 18 patients who had biochemical studies. Four patients (14%) had malignant paragangliomas. The discrete tumors were classified by location as suprarenal (26%), renal hilar (32%), or infrarenal (42%). Suprarenal paragangliomas could not be distinguished from the ipsilateral adrenal gland on CT. The average size of functional tumors was smaller (7.0 cm) than that of nonfunctional tumors (12.0 cm), but the sizes of the two groups overlapped. Smaller tumors were more likely to be homogeneous and have well-defined margins than were larger tumors. Our findings indicate that extraadrenal retroperitoneal paragangliomas are functionally active more often than previously reported and that they are readily detected by CT as soft-tissue masses closely associated with the entire length of the abdominal aorta. However, no CT feature was found that was unique for paraganglioma.

Neoplasms of the temporal bone.

A series of 209 patients with chemodectomas and malignant neoplasms of the external auditory canal and middle ear seen during a 20-year period at the Mayo Clinic was reviewed. Ninety-nine patients had chemodectomas, and 110 had malignant lesions; 57 of the 110 patients with malignancies had squamous cell carcinoma. The study revealed that patients with chemodectomas had a normal expected length of survival, whereas patients with malignant lesions (especially those with squamous cell carcinomas and embryonal rhabdomyosarcomas) did poorly.

Head and neck tumours in Rhodesia.

A retrospective 5-year study of head and neck tumours treated at a general hospital in Rhodesia and an attempted follow-up of the patients were undertaken in connection with the setting up of a joint head and neck clinic. The relevant data are outlined in this report.

IV. Multiple glomus tumors in the head and neck.

Eight of 76 glomus tumors in the head and neck region are multiple. The most common association is with carotid body tumors; the most common pattern is an ipsilateral glomus tympanicum and carotid body tumor. The approach to clinical evaluation is based on a complete otolaryngologic, neurologic, and neuroradiologic evaluation of all patients with glomus tumors. The rationale for priorities in management is the resection of the most dangerous lesions first. This study confirms the previous observations that glomus tumors have a definite proclivity for multicentricity (10 percent) and a high incidence for other associated malignancies (8 percent).