65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma.

Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

Selective neck dissection in surgically treated head and neck squamous cell carcinoma patients with a clinically positive neck: Systematic review.

Adequate treatment of lymph node metastases is essential for patients with head and neck squamous cell carcinoma (HNSCC). However, there is still no consensus on the optimal surgical treatment of the neck for patients with a clinically positive (cN+) neck. In this review, we analyzed current literature about the feasibility of selective neck dissection (SND) in surgically treated HNSCC patients with cN + neck using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. From the reviewed literature, it seems that SND is a valid option in patients with cN1 and selected cN2 neck disease (non-fixed nodes, absence of palpable metastases at level IV or V, or large volume ->3 cm-multiple lymph nodes at multiple levels). Adjuvant (chemo) radiotherapy is fundamental to achieve good control rates in pN2 cases. The use of SND instead a comprehensive neck dissection (CND) could result in reduced morbidity and better functional results. We conclude that SND could replace a CND without compromising oncologic efficacy in cN1 and cN2 cases with the above-mentioned characteristics.

Surgical options in benign parotid tumors: a proposal for classification.

Different surgical options are currently available for treating benign tumors of the parotid gland, and the discussion on optimal treatment continues despite several meta-analyses. These options include more limited resections (extracapsular dissection, partial lateral parotidectomy) versus more extensive and traditional options (lateral parotid lobectomy, total parotidectomy). Different schools favor one option or another based on their experience, skills and tradition. This review provides a critical analysis of the literature regarding these options. The main limitation of all the studies is the bias of selection for different surgical approaches. For this reason, we propose a staging system that could facilitate clinical decision making and the comparison of results. We propose four categories based on the size of the tumor and its location within the parotid gland. Category I includes tumors up to 3 cm, which are mobile, close to the outer surface and close to the parotid borders. Category II includes deeper tumors up to 3 cm. Category III comprises tumors greater than 3 cm involving two levels of the parotid gland, and category IV tumors are greater than 3 cm and involve more than 2 levels. For each category and for the various pathologic types, a guideline of surgical extent is proposed. The objective of this classification is to facilitate prospective multicentric studies on surgical techniques in the treatment of benign parotid tumors and to enable the comparison of results of different clinical studies.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.

IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry.

BACKGROUND: Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking. METHODS: Systematic registration of ELSTs from international centers of otorhinolaryngology and from multidisciplinary VHL centers' registries was performed. Molecular genetic analyses of the VHL gene were offered to all patients. RESULTS: Our population-based registry comprised 93 patients with ELST and 1789 patients with VHL. The prevalence of VHL germline mutations in apparently sporadic ELSTs was 39%. The prevalence of ELSTs in patients with VHL was 3.6%. ELST was the initial manifestation in 32% of patients with VHL-ELST. CONCLUSION: Prevalence of ELST in VHL disease is much lower compared to the literature. VHL-associated ELSTs can be the first presentation of the syndrome and mimic sporadic tumors, thus emphasizing the need of molecular testing in all presentations of ELST. © 2015 Wiley Periodicals, Inc. Head Neck 38: 673-679, 2016.

Current approaches and recent developments in the management of head and neck paragangliomas.

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors belonging to the family of pheochromocytoma/paraganglioma neoplasms. Despite advances in understanding the pathogenesis of these tumors, the growth potential and clinical outcome of individual cases remains largely unpredictable. Over several decades, surgical resection has long been the treatment of choice for HNPGLs. However, increasing experience in various forms of radiosurgery has been reported to result in curative-like outcomes, even for tumors localized in the most inaccessible anatomical areas. The emergence of such new therapies challenges the traditional paradigm for the management of HNPGLs. This review will assist and guide physicians who encounter patients with such tumors, either from a diagnostic or therapeutic standpoint. This review will also particularly emphasize current and emerging knowledge in genetics, imaging, and therapeutic options as well as the health-related quality of life for patients with HNPGLs.

Genetic susceptibility to head and neck squamous cell carcinoma.

Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is growing. Although environmental carcinogens and carcinogenic viruses are the main etiologic factors, genetic predisposition obviously plays a risk-modulating role, given that not all individuals exposed to these carcinogens experience the disease. This review highlights some aspects of genetic susceptibility to HNSCC: among others, genetic polymorphisms in biotransformation enzymes, DNA repair pathway, apoptotic pathway, human papillomavirus-related pathways, mitochondrial polymorphisms, and polymorphism related to the bilirubin-metabolized pathway. Furthermore, epigenetic variations, familial forms of HNSCC, functional assays for HNSCC risk assessment, and the implications and perspectives of research on genetic susceptibility in HNSCC are discussed.

Transmucosal core needle biopsy: a novel diagnostic approach to oral and oropharyngeal lesions.

PURPOSE: Oral and oropharyngeal tumors have often been characterized by a deep submucosal growth pattern under an intact mucous membrane. This will be particularly true for lesions of the tongue and could be associated with relevant difficulties regarding diagnosis and treatment planning. We hypothesized that the transoral transmucosal application of a core needle biopsy (CNB) for lesions of the tongue, the base of the tongue, and the floor of the mouth could be of considerable clinical usefulness for many patients. It has only previously been described in single cases and has not yet been separately discussed. MATERIAL AND METHODS: We report on the novel transoral use of CNB during rigid endoscopy with the patient under general anesthesia, with an emphasis on lesions of the tongue. A series of cases and illustrative patients are presented. RESULTS: Transmucosal CNB was accurate and of considerable clinical usefulness in all cases. The relevant advantages of this technique compared with conventional biopsy using biopsy forceps and transmucosal fine needle aspiration are presented. CONCLUSIONS: The transoral transmucosal approach to the submucosal space of the oral cavity and the oropharynx has further extended the field of application of CNB. In selected patients, this CNB approach offers essential diagnostic benefits, in particular, for tumors of the tongue.

Is elective neck dissection indicated during salvage surgery for head and neck squamous cell carcinoma?

Among patients with head and neck squamous cell carcinoma with a negative neck who are initially treated with (chemo)radiotherapy, a number of cases will recur locally without obvious neck recurrence. There is little information available as to the most efficacious management of the neck in these cases. We have reviewed the literature to see what conclusions can be drawn from previous reports. We conducted a bibliography search on MEDLINE and EMBASE databases. Studies published in the English language and those on squamous cell carcinoma of the oral cavity, nasopharynx, oropharynx, larynx and hypopharynx were included. Data related to neck management were extracted from the articles. Twelve studies satisfied the inclusion criteria. Five studies reported only one treatment plan (either neck dissection or observation), while the others compared neck dissection to observation. The rate of occult metastases ranged from 3.4 to 12 %. The studies included a variable distribution of primary sites and stages of the recurrent primary tumors. The risk of occult neck node metastasis in a clinically rN0 patient correlated with tumor site and T stage. Observation of the neck can be suggested for patients with T1-2 glottic tumors, who recurred with less advanced tumors (rT1-2). For patients with more advanced laryngeal recurrences or recurrence at other high-risk sites, neck dissection could be considered for the rN0 patient, particularly if the neck was not included in the previous radiation fields.

Causes of death of patients with laryngeal cancer.

Despite remarkable advances in the care of patients with laryngeal cancer over the past several decades, including a growing awareness of therapeutic complications and attention to quality of life, little is known about the causes of mortality in this population. In addition to the laryngeal malignancy itself, acute and late or chronic treatment-associated causes, second primary cancers, intercurrent disease and psychosocial factors are all responsible for patient morbidity and mortality. We examine the current literature related to the causes of death in patients with laryngeal cancer, in the hope of guiding future interventions to improve the longevity and quality of life of individuals with this cancer.

Genetics of hereditary head and neck paragangliomas.

BACKGROUND: The purpose of this study was to give an overview on hereditary syndromes associated with head and neck paragangliomas (HNPGs). METHODS: Our methods were the review and discussion of the pertinent literature. RESULTS: About one third of all patients with HNPGs are carriers of germline mutations. Hereditary HNPGs have been described in association with mutations of 10 different genes. Mutations of the genes succinate dehydrogenase subunit D (SDHD), succinate dehydrogenase complex assembly factor 2 gene (SDHAF2), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit B (SDHB) are the cause of paraganglioma syndromes (PGLs) 1, 2, 3, and 4. Succinate dehydrogenase subunit A (SDHA), von Hippel-Lindau (VHL), and transmembrane protein 127 (TMEM127) gene mutations also harbor the risk for HNPG development. HNPGs in patients with rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and MYC-associated factor X (MAX) gene mutations have been described very infrequently. CONCLUSION: All patients with HNPGs should be offered a molecular genetic screening. This screening may usually be restricted to mutations of the genes SDHD, SDHB, and SDHC. Certain clinical parameters can help to set up the order in which those genes should be tested.

EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma.

PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

Head and neck paragangliomas: clinical and molecular genetic classification.

Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic glomus. Head and neck paragangliomas are slowly growing tumors, with some carotid body tumors being reported to exist for many years as a painless lateral mass on the neck. Symptoms depend on the specific locations. In contrast to paraganglial tumors of the adrenals, abdomen and thorax, head and neck paragangliomas seldom release catecholamines and are hence rarely vasoactive. Petrous bone, jugular, and tympanic head and neck paragangliomas may cause hearing loss. The internationally accepted clinical classifications for carotid body tumors are based on the Shamblin Class I-III stages, which correspond to postoperative permanent side effects. For petrous-bone paragangliomas in the head and neck, the Fisch classification is used. Regarding the molecular genetics, head and neck paragangliomas have been associated with nine susceptibility genes: NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127. Hereditary HNPs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients. Head and neck paragangliomas are rarely associated with mutations of VHL, RET, or NF1. The research on SDHA, SDHAF2 and TMEM127 is ongoing. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. The treatment of choice is surgical resection. Good postoperative results can be expected in carotid body tumors of Shamblin Class I and II, whereas operations on other carotid body tumors and other head and neck paragangliomas frequently result in deficits of the cranial nerves adjacent to the tumors. Slow growth and the tendency of hereditary head and neck paragangliomas to be multifocal may justify less aggressive treatment strategies.

Is there an optimal scan time for 6-[F-18]fluoro-L-DOPA PET in pheochromocytomas and paragangliomas?

PURPOSE: To define the appropriate scan time for fluorine-18-labeled dihydroxyphenylalanine (F-18 DOPA) PET in oncological imaging of pheochromocytomas and paragangliomas. MATERIALS AND METHODS: F-18 DOPA PET examinations were performed in 9 patients with 7 pheochromocytomas and 4 head and neck paragangliomas using a dedicated PET scanner. The acquisition started with a dynamic single-bed scan in the tumor region over the first 60 minutes after tracer injection followed by a late time whole-body scan at approximately 130 minutes. Standard uptake values (SUVs) were calculated in tumors, surrounding background, and adjacent normal tissues of relevance. Furthermore, kinetic analysis was performed using a 2-compartment model with rate constants for uptake (K1'), release (k2'), metabolism (k3'), and reverse reaction (k4') for region of interest and pixel-wise analysis. RESULTS: All tumors show a marked increased F-18 DOPA uptake, which was visually detectable and distinguishable from the surrounding tissue. The SUV is significantly lower in neck paraganglioma compared with abdominal pheochromocytomas. Mean time-activity curves of F-18 DOPA in tumors show a rapid uptake of the tracer. Already 2 minutes after the injection, the activity in the tumor is beyond that of the blood pool. The average maximum value (SUVmean = 8.2) has already been reached after 20 minutes. Afterward, a very slight decrease of the tumor SUV starts, which still amounts to 80% of the maximum value after 132 minutes. Due to the continuous decrease of activity in the background tissue, the tumor-to-background ratio of SUVs shows a constant increase within the entire period of examination. The mean values of apparent kinetic constants obtained by region of interest analysis averaged over all tumors are as follows: K1' = 2.89 ± 2.56 min(-1), k2' = 2.59 ± 2.81 min(-1), k3' = 0.301 ± 0.395 min(-1), and k4' = 0.044 ± 0.043 min(-1). CONCLUSIONS: Pheochromocytoma and paraganglioma take up F-18 DOPA very quickly. At best, the acquisition for static clinical PET imaging of paraganglioma with F-18 DOPA can start at 20 minutes postinjection for maximum uptake in tumors. Separation of tumor, background, and adjacent normal tissues is feasible due to their differences in SUV values and kinetics. The kinetic analysis demonstrates an F-18 DOPA accumulation within the tumor due to considerable differences between the rate constants of uptake and metabolism. Second, in contradiction to healthy brain, paraganglionic tumors show a reversible F-18 DOPA metabolism.

Head and neck paragangliomas: clinical and molecular genetic classification

Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic glomus. Head and neck paragangliomas are slowly growing tumors, with some carotid body tumors being reported to exist for many years as a painless lateral mass on the neck. Symptoms depend on the specific locations. In contrast to paraganglial tumors of the adrenals, abdomen and thorax, head and neck paragangliomas seldom release catecholamines and are hence rarely vasoactive. Petrous bone, jugular, and tympanic head and neck paragangliomas may cause hearing loss. The internationally accepted clinical classifications for carotid body tumors are based on the Shamblin Class I-III stages, which correspond to postoperative permanent side effects. For petrous-bone paragangliomas in the head and neck, the Fisch classification is used. Regarding the molecular genetics, head and neck paragangliomas have been associated with nine susceptibility genes: NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127. Hereditary HNPs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients. Head and neck paragangliomas are rarely associated with mutations of VHL, RET, or NF1. The research on SDHA, SDHAF2 and TMEM127 is ongoing. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. The treatment of choice is surgical resection. Good postoperative results can be expected in carotid body tumors of Shamblin Class I and II, whereas operations on other carotid body tumors and other head and neck paragangliomas frequently result in deficits of the cranial nerves adjacent to the tumors. Slow growth and the tendency of hereditary head and neck paragangliomas to be multifocal may justify less aggressive treatment strategies.

Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites.

BACKGROUND: Hereditary pheochromocytoma is associated with germline mutations of a set of susceptibility genes to which the TMEM127 gene has recently been added. Patients with TMEM127 mutations have been thus far exclusively identified with adrenal tumors. PATIENTS AND METHODS: A population-based series of 48 consecutive individuals from the European-American Pheochromocytoma Paraganglioma Registry with multiple paraganglial tumors and, of these, one extraadrenal paraganglial tumor were selected for this study. They all had normal results when screened for germline mutations of the genes RET, VHL, SDHB, SDHC, and SDHD. Germline mutation analysis of the TMEM127 gene included a search for intragenic mutations and large rearrangements. RESULTS: Of the 48 eligible patients with extraadrenal paraganglial tumors, two (4.2%) were found to have TMEM127 mutations. One patient had multiple head and neck paraganglioma and one retroperitoneal extraadrenal and adrenal tumor. CONCLUSION: TMEM127 germline mutations confer risks of extraadrenal paraganglial tumors in addition to the documented adrenal pheochromocytoma. Thus, surveillance for extraadrenal and adrenal paraganglial tumors is likely warranted in TMEM127 mutation carriers, although the true prevalence should be evaluated in patients with extraadrenal paraganglial tumors.

Descending necrotizing mediastinitis: contemporary trends in etiology, diagnosis, management, and outcome.

OBJECTIVE: To evaluate contemporary trends in etiology, diagnosis, management, and outcome of descending necrotizing mediastinitis (DNM) and to draw the clinician's attention on this probably underappreciated disease. SUMMARY OF BACKGROUND DATA: An uncommon but one of the most serious forms of mediastinitis is DNM which is caused by downward spread of deep neck infections and arises as a major complication of "banal" odontogenic, pharyngeal, or cervicofacial foci. As most studies are based on small patient populations, current data on risk factors, etiology, and outcome vary significantly. Also, the optimal form of treatment remains controversial. METHODS: This retrospective study, which is the largest single-center study since 1960, is based on the management of 45 patients with DNM treated over a period of 12 years. Additionally, a meta-analysis of 26 studies on DNM published between 1999 and 2008 was performed and compared with own data and 2 previous meta-analyses covering the interval from 1960 to 1998. RESULTS AND CONCLUSIONS: Today DNM most commonly arises from pharyngeal foci and mixed polymicrobial aerobic and anaerobic infections. Reduced tissue oxygenation and impaired immune function promotes its development. Most cases of DNM are limited to the upper mediastinum and can be adequately drained by a transcervical approach. Formal thoracotomy should be reserved for cases extending below the plane of the tracheal bifurcation. Although DNM remains an aggressive infection with high morbidity, a favorable outcome can now be obtained in 85% of patients, even with this selective approach. Early diagnosis and surgical intervention are crucial.

Parasympathetic paragangliomas are part of the Von Hippel-Lindau syndrome.

CONTEXT: Von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary tumor syndrome manifested by hemangioblastomas, clear cell renal cell carcinomas, and pheochromocytomas. In addition, a multitude of other rare tumors, including parasympathetic paragangliomas, can occur and even be the sole manifestation of VHL disease. The VHL gene is a bona fide tumor suppressor gene with biallelic inactivation contributing to tumor formation. However, in parasympathetic paragangliomas occurring in VHL disease, biallelic inactivation of the VHL gene has not been demonstrated to date. DESIGN: The head and neck paragangliomas of two VHL patients were analyzed for mutations by direct sequencing of the VHL gene. In addition loss of heterozygosity analysis was performed for three microsatellite loci near the VHL gene. To rule out other underlying genetic causes of the parasympathetic paragangliomas, mutation analysis of the SDHB, SDHC, and SDHD genes was also performed. RESULTS: Apart from germline VHL mutations, no additional mutations were found in the paraganglioma-related tumor suppressor genes SDHB, SDHC, and SDHD. Analysis of paraganglioma tissue revealed loss of the VHL wild-type allele in both tumors, indicating that in these tumors biallelic VHL gene inactivation occurred. CONCLUSIONS: These findings indicate that parasympathetic paragangliomas in VHL disease, although rare, are part of the syndrome and related to VHL gene inactivation. Clinicians should be aware of the potential occurrence of parasympathetic paragangliomas in VHL disease.

Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2.

BACKGROUND: Head and neck paragangliomas (HNPs) occur as sporadic or familial entities, the latter mostly in association with germline mutations of the SDHB, SDHC, or SDHD (SDHx) genes. Heritable non-SDHx HNP might occur in von Hippel-Lindau disease (VHL, VHL gene), multiple endocrine neoplasia type 2 (MEN2, RET gene), and neurofibromatosis type 1 (NF1, NF1 gene). Reports of non-SDHx HNP presentations are scarce and guidance for genetic testing nonexistent. PATIENTS AND METHODS: An international consortium registered patients with HNPs and performed mutation analyses of the SDHx, VHL, and RET genes. Those with SDHx germline mutations were excluded for purposes of this study. Personal and family histories were evaluated for paraganglial tumors, for the major tumor manifestations, and for family history of VHL, MEN2, or NF1. RESULTS: Twelve patients were found to have hereditary non-SDHx HNPs of a total of 809 HNP and 2084 VHL registrants, 11 in the setting of germline VHL mutations and one of a RET mutation. The prevalence of hereditary HNP is five in 1000 VHL patients and nine in 1000 non-SDHx HNP patients. Comprehensive literature review revealed previous reports of HNPs in five VHL, two MEN2, and one NF1 patient. Overall, 11 here presented HNP cases, and four previously reported VHL-HNPs had lesions characteristic for VHL and/or a positive family history for VHL. CONCLUSIONS: Our observations provide evidence that molecular genetic testing for VHL or RET germline mutations in patients with HNP should be done only if personal and/or family history shows evidence for one of these syndromes.