Carsten Christof Boedeker

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US

EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma

2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.

Paragangliomas of the head and neck: diagnosis and treatment.

PurposeRadionuclide 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.MethodsGuidelines 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.ConclusionAlthough several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

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

Paragangliomas of the head and neck (HNP) represent rare tumors of neural crest origin. They are highly vascular neoplasms that are benign in the majority of cases. The site of origin defines the name given those tumors. In the head and neck, they most commonly occur at the carotid bifurcation, where they are referred to as carotid body tumors (CBT). Other common sites of origin are the jugular bulb (jugular paraganglioma; JP), the tympanic plexus on the promontory (tympanic paraganglioma; TP) and the vagal nerve (vagal paraganglioma; VP). Patients with cervical paragangliomas frequently present with a painless, slowly enlarging mass in the lateral neck. In many patients with TP and JP, tinnitus and hearing loss are early symptoms. JP patients often suffer from lower cranial nerve deficits. Evaluation by an imaging modality is necessary to establish the diagnosis. Imaging procedures frequently used include B-mode sonography with color-coded Doppler sonography, computed tomography (CT), magnetic resonance imaging (MRI) and digital substraction angiography (DSA). Debate exists in the literature regarding the different treatment modalities for paragangliomas which include surgery, radiotherapy and stereotactic radiosurgery. The role of preoperative angiography and embolization has also been a matter of discussion.The diagnostic work up and the different treatment options for patients with head and neck paragangliomas will be presented and discussed.

Germline Mutations of the TMEM127 Gene in Patients with Paraganglioma of Head and Neck and Extraadrenal Abdominal Sites

Objective:To evaluate contemporary trends in etiology, diagnosis, management, and outcome of descending necrotizing mediastinitis (DNM) and to draw the clinicians 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.

Head and Neck Paragangliomas in Von Hippel-Lindau Disease and Multiple Endocrine Neoplasia Type 2

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.

Malignant head and neck paragangliomas in SDHB mutation carriers.

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.

Role of Cat-Scratch Disease in Lymphadenopathy in the Head and Neck

OBJECTIVE: Three of four paraganglioma syndromes (PGLs) have been characterized on a molecular genetic basis. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D (SDHD) gene, PGL 3 is caused by SDHC gene mutations, and PGL 4 is caused by SDHB gene mutations. The objective of this study was to investigate whether PGLs are associated with malignant head and neck paragangliomas (HNPs). STUDY DESIGN AND SETTING: Through November 2005, we screened 195 HNP patients for mutations of the genes SDHB, SDHC, and SDHD. RESULTS: We detected 5 SDHC, 13 SDHB, and 45 SDHD gene mutations. In seven SDHB mutation carriers, there were distant metastases. No signs of metastases were found in SDHC and SDHD patients. One patient with a sporadic HNP presented with locally metastatic disease. CONCLUSIONS: SDHB mutations are associated with a high rate of malignant HNPs. SIGNIFICANCE: In SDHB patients, a three-body region imaging and scintigraphy or DOPA-PET must be performed to exclude metastases.

Spectrum and Management of Deep Neck Space Infections: An 8-Year Experience of 234 Cases

Bartonella henselae is the causative agent of cat-scratch disease (CSD), which usually manifests as acute regional lymphadenopathy. The causes of cervical lymphadenopathy, with special regard to CSD, were investigated in a study of 454 patients who presented with unclear masses in the head and neck from January 1997 through January 2001. Sixty-one patients (13.4%) experienced CSD; 54 (11.9%) had primary lymphadenopathy due to other infectious agents, and 41 (9.0%) had lymphadenopathy that occurred in association with primary infections of other organs. For 171 patients (37.7%), the cause of the cervical lymph node enlargement could not be found. B. henselae DNA was detected in extirpated lymph nodes only during the first 6 weeks of lymphadenopathy, which indicates that the results of polymerase chain reaction strongly depend on the duration of illness. CSD should be included in the differential diagnosis of adenopathy in the otorhinolaryngologic patient population, to avoid unnecessary treatment.

Head and neck paragangliomas: clinical and molecular genetic classification

OBJECTIVE: To study the clinical course and outcome of deep neck infections (DNI), with special emphasis on microbiology and histopathology. STUDY DESIGN: Two hundred thirty-four patients with DNIs were included in this study. Patients with peritonsillar or dental infections, infections arising from salivary glands, as well as subjects with abscesses caused by neck trauma were excluded. METHODS: Clinical analysis of all patients with DNIs who were treated between January 1, 1997 and May 31, 2005 in a single center. RESULTS: In 13 patients, the DNI was the first manifestation of a malignant tumor. In 17 cases, the DNI was associated with cat-scratch disease (CSD). Six patients suffered from tuberculosis, and in another 7, an infected lateral cleft cyst was found. In 176 patients, the origin of DNI remained unclear. CONCLUSIONS: Our results demonstrate that CSD, tuberculosis, and malignant tumors must be considered as possible causes of DNIs. The current study represents one of the largest series of DNIs in the modern medical literature.