Contiguous bilateral head and neck paragangliomas in a carrier of the SDHB germline mutation.

Paragangliomas are extremely rare neoplasms with multicentric presentation usually linked to familial tumor syndromes. This patient presented with the uncommon combination of concurrent bilateral carotid body tumors and a unilateral glomus jugulare mass that demonstrated vascular continuity. During treatment, the patient was found to be heterozygous for the SDHB germline mutation, an autosomal dominant genotype of the familial paraganglioma syndromes associated with increased malignancy. The unique profile of the SDHB patient as regards primary evaluation, surgical considerations, and extended surveillance was explored and has led to a proposed treatment algorithm for these patients.

Malignant head and neck paragangliomas in SDHB mutation carriers.

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.

Active succinate dehydrogenase (SDH) and lack of SDHD mutations in sporadic paragangliomas.

BACKGROUND: Paragangliomas are benign, slow-growing tumours of the head and neck region. The candidate gene for familial and some sporadic paragangliomas, SDHD (succinate dehydrogenase, subunit D), has been mapped to the PGL1 locus in 11q23.3. MATERIALS AND METHODS: Normal and tumour DNA of 17 patients with sporadic paragangliomas were analysed by sequencing (SDHD, SDHB and SDHC genes), fluorescence in situ hybridisation (FISH). In addition, loss of heterozygosity (LOH) and succinate dehydrogenase (SDH) enzyme activity assays were performed. RESULTS AND CONCLUSION: Only two patients from our collective showed SDH gene mutations, one in SDHD and one in SDHB, respectively. Moreover, SDH activity detected in 5/8 patients confirmed the fact that SDH inactivation is not a major event in sporadic paragangliomas. LOH and FISH analysis demonstrated a frequent loss of regions within chromosome 11, indicating that additional genes in 11q may play a role in tumour genesis of sporadic paragangliomas.

[The jugulotympanic paragangliomas: 41 cases report]. / Les paragangliomes tympano-jugulaires. A propos de 41 cas.

OBJECTIVE: The jugulotympanic paragangliomas (JTP) represents the most frequent tumour of the middle ear but also of the temporal bone, after the acoustic neurinoma. The management of these vascular tumours remains uncleared. The purpose of this study was to report our experience about JTP in the CHU of Grenoble. MATERIALS AND METHODS: Retrospective study of 41 patients, between 1973 and 1996. Six stages A, 8 stages B and 27 stages C are reported in whom 20 cases (49%) presented an intracranial extension (classification of Fisch). There were 2 familial cases with multiple localisations, in particular carotid. All the patients were divided in 3 groups: surgery or radiation therapy in first intention, surgery followed by radiation therapy. RESULTS: A total tumor removal without recurrence was achieved by surgery in more than 95% of the cases with 6 years follow-up but was associated with significant morbidity (major cranial nerve injury). We noticed one death by laryngospasme (C2Di2 tumour operated by infratemporal A approach). A stabilization of the tumour was obtained with radiotherapy in first intention in 75% of the cases (5 years follow-up) but with a risk of radionecrosis. A revision surgery was necessary in 3 cases. CONCLUSION: The comparaison of our different therapeutic management, surgery (23), radiation therapy (16) or combined (2), encourage us to perform a radical surgery whenever possible. Because of the slow rate of growth, the radiotherapy is indicated for older patients, at risk for surgery or extensive tumors. The objectives of the radiation therapy are to obtain a tumoral stabilization with improvement of the symptoms and low morbidity. The management of this rare pathology must be multidisciplinary. The recent discoveries on genes encoding three succinate dehydrogenase subunits (SDHD, SDHB et SDHC) will allow a genetic detection of asymptomatic case and will define the procedures for their management, coordinated by a national network PGL.NET. A retrospective study could also study the real incidence of familial paragangliomas.

Paraganglioma yugular bilateral: reporte de un caso y revisión de la literatura / Bilateral jugular paraganglioma: case report and review of the literature

Resumen El paraganglioma (PG) es una neoplasia infrecuente originada de las células paraganglionares, embriológicamente derivadas de la cresta neural. Se localizan en la cabeza, base de cráneo, cuello, mediastino, abdomen y pelvis. La mayor parte de los PG muestran un curso clínico benigno, sin embargo, algunos casos pueden mostrar un comportamiento biológico agresivo con invasión local y metástasis a distancia. Un avance significativo en patología molecular ha sido el reconocimiento que el 30%-40% de estas neoplasias presentan alteraciones genéticas. Se han descrito más de 45 genes involucrados, incluyendo mutaciones de la línea germinal succinato deshidrogenasa. Actualmente se recomienda hacer test genético a todos los portadores de PG incluyendo los de presentación esporádica. El PG más frecuente se ubica en la glándula suprarrenal llamado feocromocitoma. El diagnóstico definitivo se realiza con histología, sin embargo, el estudio imagenológico puede entregar una aproximación diagnóstica certera. Debido a la aceptación actual que todos los PG tienen potencial metastásico, el concepto de PG benigno y maligno ha cambiado a uno de estimación de riesgo de metástasis, aunque no existe un esquema único aceptado para tal efecto. El tratamiento considera la cirugía, la radioterapia, la observación y terapias combinadas. Dado el lento crecimiento de este tipo de neoplasia y las potenciales complicaciones de la terapia quirúrgica, la observación es una opción especialmente para pacientes añosos dejando las otras opciones para pacientes más jóvenes. En este trabajo se presenta un caso de paraganglioma yugular bilateral gigante tratado con radioterapia de intensidad modulada incluyendo una revisión bibliográfica pertinente.

Abstract Paraganglioma (PG) is a rare neoplasm derived from paraganglionic cells of the neural crest. They are located in the head, skull base, neck, mediastinum, abdomen and pelvis. Most PGs show a benign clinical course, however, some cases may show aggressive biological behavior with local invasion and distant metastasis. A significant advance in molecular pathology has been the recognition that 30%-40% of these neoplasms present genetic alterations; more than 45 genes have been described, including mutations of the germline succinate dehydrogenase. Currently it is recommended to make genetic test to all patients with PG, including sporadic presentation. The most frequent PG is located in the adrenal gland called pheochromocytoma. The definitive diagnosis is made with histology; however, the imaging study can provide an accurate diagnostic approach. It is now accepted that all PG have a metastatic potential, therefore the concept of benign or malignant has been changed to a metastasis risk stratification approach however no single scheme is been widely used. The treatment considers surgery, radiotherapy, observation and combination therapies. Given the slow growth of this type of neoplasia and the potential complications of surgical therapy, observation is an option especially for elderly patients leaving the other options for younger patients. In this work we present a case of giant bilateral jugular paraganglioma treated with intensity modulated radiation therapy, including a pertinent literature review.

p53 and p16INK4A mutations during the progression of glomus tumor.

Glomus tumors are significantly rare tumors of carotid body. The great majority of these tumors are benign in character. Here we present two brothers with hereditary glomus jugulare tumor who had consanguineous parents. Radiotherapy was applied approximately 8 and 10 years ago for treatment in both cases. Eight years later, one of these cases came to our notice due to relapse. The mutation pattern of p53, p57KIP2, p16INK4A and p15NK4B genes which have roles in the cell cycle, was analyzed in tumor samples obtained from the two affected cases in the initial phase and from one of these cases at relapse. The DNA sample obtained from the case in initial diagnosis phase revealed no p53, p57KIP2, p16INK4A or p15INK4B mutation. He is still in remission phase. Despite the lack of p53, p57KIP2, p16INK4A and p15INK4B mutation at initial diagnosis the tumor DNA of the other case in relapse revealed p53 codon 243 (ATG-->ATC; met-->ile) and p16 codon 97 (GAC-->AAC; asp-->asn) missense point mutations. No loss of heterozygosity in p53 and p16INK4A was observed by microsatellite analysis of tumoral tissues in these cases. P53 and p16INK4A mutations observed in relapse phase were in conserved regions of both genes. No previous reports have been published with these mutations in glomus tumor during progression. The mutation observed in this case may due to radiotherapy. In spite of this possibility, the missense point mutations in conserved region of p53 and p16INK4A genes may indicate the role of p53 and p16INK4A in tumor progression of glomus tumors.

Genetic analysis in the diagnosis of familial paragangliomas.

OBJECTIVES: In the management of two related patients with multicentric glomus jugulare tumors, given the incidence of 1:30,000 with approximately 20% familial cases, our objective was to review the genetic characteristics and inheritance patterns of these tumors and to determine what molecular genetic screening possibilities exist for the phenotypically normal family members. In addition, our aim was to review the incidence of various multicentric paraganglioma (PGL) tumor location combinations. METHODS: Molecular genetic linkage analysis testing was performed on the 2 patients and 14 other unaffected family members. We report the results of this screening and review the literature on the incidence and genetics of paragangliomas. RESULTS: The inheritance pattern in the literature demonstrates autosomal dominant transmission with maternal imprinting (inactivation). The proclivity for multicentric origin increases to 26% in familial cases, as reflected in our patients. In addition to the two patients, four unaffected family members demonstrated the presence of the disease haplotype at chromosome band 11q23, which indicates a very high likelihood of developing a paraganglioma, given the highly penetrant nature of the disease. CONCLUSIONS: It is clear that the familial PGL gene locus is situated at chromosome 11q23. The gene itself and its exact degree of penetrance, however, still await identification. Since early detection of paragangliomas reduces the incidence of morbidity and mortality, genotypic analysis as a screening tool in families of affected patients should play a front-line diagnostic role, leading to more timely and cost-effective patient management.

Molecular pathogenesis in sporadic head and neck paraganglioma.

HYPOTHESIS: Similar to familial tumors, sporadic head and neck paragangliomas are associated with chromosomal deletions at either 11q13 or 11q22-23. BACKGROUND: Familial paragangliomas are inherited in an autosomal dominant pattern with genomic imprinting of the maternal allele. Genetic studies of familial paragangliomas have localized the causative genetic defect to two separate loci: 11q13.1 and 11q22-23. The molecular pathogenesis of sporadic head and neck paragangliomas has not been studied. METHODS: Blood and tumor samples from patients with sporadic head and neck paragangliomas were screened for deletions on chromosome 11 using DNA microsatellite markers and polymerase chain reaction. Polymerase chain reaction-amplified alleles from tumor specimens were compared with those from the blood of eight patients. A greater than 50% reduction in band intensity (as determined by densitometric analysis) between blood and tumor sample was indicative of a chromosomal deletion. RESULTS: Three of the eight patients were found to have deletions at chromosome 11q: two at chromosome 11q22-23 and one at 11q13. CONCLUSIONS: Sporadic head and neck paragangliomas are associated with deletions at chromosome 11q13 and 11q22-23. It is thus likely that sporadic and familial paragangliomas share a similar molecular pathogenesis.

Expression of angiogenic growth factors in paragangliomas.

OBJECTIVE/HYPOTHESIS: To determine if angiogenic growth factors including vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) are expressed in human paragangliomas. STUDY DESIGN: A histopathologic and molecular examination of paraganglioma specimens obtained from surgical cases or retrieved from the Pathology Department of the Massachusetts Eye and Ear Infirmary. METHODS: Fresh tumor or archival, paraffin-embedded paraganglioma specimens were analyzed by immunohistochemistry, Western blotting, and ELISA. RESULTS: Positive immunohistochemical staining for VEGF was observed in five of nine surgical specimens and in six of eight archival specimens (11/17, or 65%). PD-ECGF immunoreactivity was detected in four of five surgical specimens and six of eight archival specimens (10/13, or 77%). The presence of PD-ECGF was confirmed by Western blot assay and ELISA confirmed the presence of VEGF in tumor extract. CONCLUSIONS: Both VEGF and PD-ECGF are expressed in paragangliomas and may contribute to the extreme vascularity of these tumors. Key Words. Vascular endothelial growth factor, platelet-derived, endothelial cell growth factor, hypoxia, tumor vasculature.

Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family: a founder effect?

OBJECTIVES/HYPOTHESIS: Hereditary paraganglioma is a rare condition that is inherited in an autosomal-dominant fashion. Four distinct loci have been associated with hereditary paraganglioma, including the SDHD, SDHC, and SDHB genes and a locus at 11q13. The SDHD, SDHC, and SDHB genes code for subunits of succinate dehydrogenase, which forms part of the mitochondrial respiratory chain. SDHD mutations are widely distributed along the gene with no apparent hot spots, although a founder effect has been described in the Dutch population. METHODS: Following a prior report of the SDHD M1I mutation in an Australian Chinese family, a second Chinese family with the same mutation is reported. The proband developed bilateral head and neck paragangliomas at age 34 years and a functioning adrenal pheochromocytoma and two extra-adrenal abdominal paragangliomas 7 years later. His brother had unilateral head and neck paraganglioma at age 39 years. Given the multicentricity of the proband's tumor and the familial clustering of paragangliomas, a clinical diagnosis of hereditary paraganglioma was made, and the proband was tested for a mutation in the SDHD gene. RESULTS: The proband was found to be heterozygous for the SDHD MII mutation that removes the start codon, and his brother subsequently tested positive for the same mutation. The family is not related to the Australian Chinese family. CONCLUSION: The finding suggests the possibility of a founder effect in the Chinese population and warrants further investigation.

Technical modifications required to treat cervical chemodactomas with stereotactic radiosurgery.

This report describes the radiosurgical treatment of a high neck lesion in a patient with familial multifocal bilateral chemodactoma. The necessary modifications to standard radiosurgery are described. The advantages of this treatment modality for patients with familial chemodactoma are discussed.

The basic science of glomus jugulare tumors.

Glomus tumors are a fascinating group of lesions. It is a challenge for neurosurgeons and otolaryngologists to resect them completely with minimal morbidity. Laboratory researchers have discovered extremely interesting genetic and molecular biology factors involved in the development and growth of glomus tumors. In this article the author reviews the genetics, protein mutations, angiogenesis and apoptosis associated with tumor formation, and the secretion of vasoactive substances is discussed as well. It is hoped that with further research less invasive measures may be developed to treat these tumors.

Familial multiple glomus tumors and pheochromocytomas.

Isolated cases of cervical cranial glomus tumors have been reported in association with pheochromocytoma. Two family pedigrees are presented and four individual cases discussed indicating a hereditary syndrome of pheochromocytoma associated with multiple glomus tumors of the head and neck. The hereditary potential has not previously been described. In three of the patients, the pheochromocytomas were asymptomatic at the time of initial presentation. These pheochromocytomas were discovered by arteriography after one of the patients developed a hypertensive crisis with the induction of anesthesia. The silent presence of pheochromocytomas in patients with multiple glomus tumors should be considered in the evaluation of these patients.

Jugular foramen tumors: diagnosis and treatment.

OBJECT: Jugular foramen tumors are rare skull base lesions that present diagnostic and complex management problems. The purpose of this study was to evaluate a series of patients with jugular foramen tumors who were surgically treated in the past 16 years, and to analyze the surgical technique, complications, and outcomes. METHODS: The authors retrospectively studied 102 patients with jugular foramen tumors treated between January 1987 and May 2004. All patients underwent surgery with a multidisciplinary method combining neurosurgical and ear, nose, and throat techniques. Preoperative embolization was performed for paragangliomas and other highly vascularized lesions. To avoid postoperative cerebrospinal fluid (CSF) leakage and to improve cosmetic results, the surgical defect was reconstructed with specially developed vascularized flaps (temporalis fascia, cervical fascia, sternocleidomastoid muscle, and temporalis muscle). A saphenous graft bypass was used in two patients with tumor infiltrating the internal carotid artery (ICA). Facial nerve reconstruction was performed with grafts of the great auricular nerve or with 12th/seventh cranial nerve anastomosis. Residual malignant and invasive tumors were irradiated after partial removal. The most common tumor was paraganglioma (58 cases), followed by schwannomas (17 cases) and meningiomas (10 cases). Complete excision was possible in 45 patients (77.5%) with paragangliomas and in all patients with schwannomas. The most frequent and also the most dangerous surgical complication was lower cranial nerve deficit. This deficit occurred in 10 patients (10%), but it was transient in four cases. Postoperative facial and cochlear nerve paralysis occurred in eight patients (8%); spontaneous recovery occurred in three of them. In the remaining five patients the facial nerve was reconstructed using great auricular nerve grafts (three cases), sural nerve graft (one case), and hypoglossal/facial nerve anastomosis (one case). Four patients (4%) experienced postoperative CSF leakage, and four (4.2%) died after surgery. Two of them died of aspiration pneumonia complicated with septicemia. Of the remaining two, one died of pulmonary embolism and the other of cerebral hypoxia caused by a large cervical hematoma that led to tracheal deviation. CONCLUSIONS: Paragangliomas are the most common tumors of the jugular foramen region. Surgical management of jugular foramen tumors is complex and difficult. Radical removal of benign jugular foramen tumors is the treatment of choice, may be curative, and is achieved with low mortality and morbidity rates. Larger lesions can be radically excised in one surgical procedure by using a multidisciplinary approach. Reconstruction of the skull base with vascularized myofascial flaps reduces postoperative CSF leaks. Postoperative lower cranial nerves deficits are the most dangerous complication.

Familiar non-chromaffinic paragangliomas (glomus tumors). Clinical and genetic aspects (abridged).

The presence of glomus tumors in a large family was investigated by clinical and angioscintigraphic screening methods. Of 295 members of this family 162 persons participated in the study. A total of 47 tumors of the head and neck region were found in 26 patients. The study revealed a preponderance for the male sex, a fairly equal distribution of the different locations in the head and neck and a marked tendency towards multiplicity. The inheritance is autosomal dominant, with a clear increase of the penetrance with age.

Familial multicentric paragangliomas in a child.

A 12-year-old girl presented with bilateral carotid-body paragangliomas and a unilateral jugular paraganglioma. The tumours were surgically removed. This is a rare combination of tumours in any patient and previously unreported in a child of this age. Her father died of a cerebellar astrocytoma and her mother underwent surgical removal of a large mediastinal paraganglioma. The association of astrocytoma with familial paragangliomas has never been documented. The literature on the epidemiology and inheritance pattern of familial paragangliomas is reviewed. The need for thorough pre-operative evaluation of the patient and close follow-up of family members is stressed.

Phenotypic variability and risk of malignancy in SDHC-linked paragangliomas: lessons from three unrelated cases with an identical germline mutation (p.Arg133*).

CONTEXT: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndrome types 1-4 and are associated with multiple and recurrent pheochromocytomas and PGLs. SDHC mutations most frequently result in benign, nonfunctional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date. OBJECTIVES: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue. DESIGN: In three unrelated patients referred for routine genetic testing, SDHB, SDHC, and SDHD genes were sequenced, and gross deletions were excluded by multiplex ligation-dependent probe amplification (MLPA). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry. RESULTS: In a patient with a nonfunctioning thoracic PGL metastatic to the bone, the lungs, and mediastinal lymph nodes, we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics, but both showed benign HNPGLs. CONCLUSIONS: We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL, although malignancy is probably rare.