Paraganglioma Patients Research Articles

The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family

Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. By using the Kaplan-Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a 'wait and scan' policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients.

Management of Paragangliomas in Otolaryngology Practice

Paragangliomas of the head and neck are highly vascular lesions originating from paraganglionic tissue located at the carotid bifurcation (carotid body tumors), along the vagus nerve (vagal paragangliomas), and in the jugular fossa and tympanic cavity (jugulotympanic paragangliomas) and should be considered in the evaluation of all lateral neck masses. The aim of this study is to review an institutional experience in the management of these tumors. Twenty-six patients with 27 paragangliomas were treated in our institution during a period of 7 years (2000-2007). There were 15 women (57.6%) and 11 men (42.4%) with a mean age of 33.5 years. A painless lateral neck mass was the main finding in 16 patients (61.5%). There was no evidence of a functional tumor. Carotid angiography was performed on all of our patients (100%) to define the vascular anatomy of the lesion. Twenty-two paragangliomas (of the 25 operated paragangliomas; 88%) underwent selective embolization of the major feeding arteries. We performed surgery on 24 (92.3%) patients. Two patients were treated with radiotherapy. Most lesions were paragangliomas of the carotid bifurcation (n = 14 [51.8%]), whereas 6 patients were diagnosed with jugular (22.2%), 1 with a vagal (3.7%), 1 with a tympanic paraganglioma (3.7%), 2 with jugulotympanic paraganglioma (7.4%), and 1 with laryngeal paraganglioma (3.7%). In 1 patient (3.8%), bilateral paragangliomas in the carotid bifurcation were detected. There was an evidence of malignancy in all cases (3.8%). Preoperative embolization has proven successful in reducing tumor vascularity in approximately 22 (of 25 who accepted surgery; 88%) paraganglioma patients. The common preoperative complication was vascular injury, which occurred in 6 (23%) of 26 patients; the main postoperative complication was transient cranial nerve deficit in 4 (15.3%) of 26 patients; and a permanent Horner syndrome was documented in 2 patients (7.6%). Cerebrospinal fluid leak occurred in 1 patient (3.7%). Postoperatively, stroke was occurred in 1 patient (3.7%). Two patients with jugular paraganglioma were treated with irradiation because of skull base extension with significant symptomatic relief. The primary therapeutic option for paragangliomas is complete excision of tumor with preservation of vital neurovascular structures. Combined therapeutic approach with preoperative selective embolization followed by surgical resection is the safe and the effective method for complete excision of the tumors with a reduced morbidity rate.

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

A major cause of paraganglioma and pheochromocytoma is germline mutation of the tumor suppressor genes SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH). While many SDH missense/nonsense mutations have been identified, few large deletions have been described. We performed multiplex ligation-dependent probe amplification deletion analysis in 126 point mutation-negative patients, and here we describe four novel deletions of SDHD and SDHC. Long-range PCR was used for the fine mapping of deletions. One patient had a 10 kb AluSg-AluSx-mediated deletion including SDHD exons 1 and 2, the entire TIMM8B gene, and deletion of exons of C11orf57. A second patient had a deletion of SDHD exons 1 and 2 and exon 1 of the TIMM8B gene. A third patient showed a deletion of exon 2 of SDHD, together with a 235 bp MIRb-Tensin gene insertion. In a fourth patient, a deletion of exons 5 and 6 of the SDHC gene was found, only the second SDHC deletion currently known. The deletions of the TIMM8B and C11orf57 genes are the first to be described, but do not appear to result in an additional phenotype in these patients. Four of the eight breakpoints occurred in Alu sequences and all three SDHD deletions showed an intron 2 breakpoint. This study underlines the fact that clinically relevant deletions may encompass neighboring genes, with the potential to modify phenotype. Gene deletions of SDHD and SDHC represent a substantial proportion of all mutations, and must be considered in paraganglioma patients shown to be negative for mutations by sequencing.

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$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 and the Pheochromocytoma—Paraganglioma Syndrome, the SDHX-Factor

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors that occur sporadically and in the context of hereditary tumor syndromes. One of these tumor syndromes is the PCC-PGL syndrome, where patients have multiple PGLs and/or PCCs. Although it has been known that most PGLs show loss of 11q, the associated tumor suppressor gene SDHD was only recently discovered. Mutations in this tumor suppressor gene were found in up to 60% of PGL patients. Recent investigations have shown that SDHD mutations not only cause this syndrome, but also that SDHB and SDHC are involved in the pathogenesis of the PCC-PGL syndrome. These studies have also shown that clinical indications (family history of PCC or PGL, multifocal disease, younger age) have high specificity but low sensitivity for the detection of PCC-PGL syndrome. In an international collaboration, we have shown, with SDHB immunohistochemistry (IHC), that SDH-related PCCs and PGLs can be easily distinguished from PCCs and PGLs with other genetic backgrounds. This detection of the inherited PCC-PGL syndrome is of major importance for PCC and PGL patients, as well as for their family members, because they are at increased risk for development of multiple, various, and malignant neoplasms. In addition, after identification of an SDHB, C, or D germline mutation, surveillance can be offered to family members carrying the mutation.

When should genetic testing be obtained in a patient with phaeochromocytoma or paraganglioma?

About 30% of phaeochromocytoma and paraganglioma patients harbour a germline mutation in one of the known susceptibility genes and in more than one-third of these patients there is no family history for these tumours. The genetic classification, risk assessment and specific management of the patients and at risk family members play an important role in preventive medicine. Distinct diagnostic or therapeutic approaches related to the genetic testing results are and will be even more relevant in the future for the detection of mutation carriers. In addition to a positive family history, other clinical features such as young age at time of manifestation, multifocal tumours and specific tumour location are highly associated with the presence of a germline mutation - genetic testing in these cases should be mandatory. Since several genes are involved in the genetics of phaeochromocytoma and paraganglioma, prioritizing which gene(s) to be tested first by using simple clinical information can reduce the efforts and costs of this analysis. The clinicians offering and performing the genetic testing should provide or make available adequate counselling as well as access to preventive and surveillance options to patients. Collaboration with referral centres and research groups in this field can help to coordinate the management of these patients.

Clinical Presentation and Management of Jugular Foramen Paraganglioma

ObjectivesJugular foramen paraganglioma is a locally invasive, benign tumor, which grow slowly and causes various symptoms such as pulsatile tinnitus and low cranial nerve palsy. Complete surgical resection is regarded as the ideal management of these tumors. The goal of this study is to identify the clinical characteristics and most effective surgical approach for jugular foramen paraganglioma.MethodsRetrospective analysis of 9 jugular foramen paraganglioma patients who underwent surgical resection between 1986 and 2005 was performed. Clinical records were reviewed for analysis of initial clinical symptoms and signs, audiological examinations, neurological deficits, radiological features, surgical approaches, extent of resection, treatment outcomes and complications.ResultsMost common initial symptom was hoarseness, followed by pulsatile tinnitus. Seven out of 9 patients had at least one low cranial nerve palsy. Seven patients were classified as Fisch Type C tumor and remaining 2 as Fisch Type D tumor on radiologic examination. Total of 11 operations took place in 9 patients. Total resection was achieved in 6 cases, when partial resection was done in 3 cases. Two patients with partial resection received gamma knife radiosurgery (GKS), when remaining 1 case received both GKS and two times of revision operation. No mortality was encountered and there were few postoperative complications.ConclusionNeurologic examination of low cranial nerve palsy is crucial since most patients had at least one low cranial nerve palsy. All tumors were detected in advanced stage due to slow growing nature and lack of symptom. Angiography with embolization is crucial for successful tumor removal without massive bleeding. Infratemporal fossa approach can be considered as a safe, satisfactory approach for removal of jugular foramen paragangliomas. In tumors with intracranial extension, combined approach is recommended in that it provides better surgical view and can maintain the compliance of the patients.

Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior

Extra-adrenal pheochromocytomas, otherwise known as paragangliomas (PGLs), account for about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical behavior. We hypothesized that most mediastinal PGLs are associated with germ line SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data in a series of ten patients with mediastinal PGLs. All ten primary mediastinal PGL patients had germ line SDHx mutations, six in SDHB, and four in SDHD genes. Chest or back pain were the most common presenting symptoms (five patients), and catecholamines and/or their metabolites were elevated in seven patients. Additional tumors included head and neck PGLs in four patients, pheochromocytoma in one patient, and bladder PGL in another. Metastatic disease was documented in six patients (60%), and a concurrent abdominal mass was found in one patient. We conclude that mediastinal PGLs are strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and aggressive behavior. The present data suggest that all patients with mediastinal PGLs should be screened for SDHx gene mutations, regardless of age.

Global and Regional CpG Methylation in Pheochromocytomas and Abdominal Paragangliomas: Association to Malignant Behavior

This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes. A panel of 53 primary tumors (42 benign, 11 malignant) was analyzed by quantitative bisulfite pyrosequencing. Based on methylation levels in the tumor suppressor genes, p16(INK4A), CDH1, DCR2, RARB, RASSF1A, NORE1A, TP73, APC, DAPK1, p14(ARF), and PTEN, a CpG island methylator phenotype (CIMP) was defined as concerted hypermethylation in three or more genes. Mean Z scores for the hypermethylated promoters were calculated to characterize overall promoter methylation. Global DNA methylation was quantified for LINE-1 promoter sequences and by using luminescent methylation analysis. Five primary tumors (9.4%) exhibited a CIMP phenotype, four of which were malignant paragangliomas. CIMP was significantly associated with malignant behavior (P = 0.005) and younger age at presentation (P < 0.007) but did not result from BRAF V600E mutation. Global hypomethylation of LINE-1 elements was observed in tumors compared with normal adrenal samples (P < 0.02). We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior, as well as young age at presentation. The findings raise a prospective for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis.

Overexpression of ERBB-2 was more frequently detected in malignant than benign pheochromocytomas by multiplex ligation-dependent probe amplification and immunohistochemistry

To analyze the genetic alterations of pheochromocytomas and evaluate the difference among malignant, extra-adrenal, and benign pheochromocytomas. Forty-three tumor samples were tested for genetic changes using multiplex ligation-dependent probe amplification. Among them, 39 samples were available for protein expression analysis by immunohistochemistry (IHC). All 43 patients (24 women and 19 men; mean age 44.6±13.6 years; range 18–75 years; 9 with malignant, 7 extra-adrenal, and 27 benign) showed multiple copy number losses or gains. The average copy number change was 13.10 in malignant, 13.93 in benign, and 13.47 in paraganglioma patients. There is no significant difference among the three groups of pheochromocytomas. However, we discovered that in the malignant pheochromocytomas, 6 of the 9 patients (67%) showed erythroblastic leukemia viral oncogene homolog 2 (ERBB-2) oncogene gain, whereas only 12 of the 34 (35%) identified change in the benign and extra-adrenal pheochromocytomas. Further, IHC confirmed that ERBB-2-positive staining was more frequent and stronger in malignant pheochromocytomas than in benign and extra-adrenal pheochromocytomas. Our study illustrates the chromosomal changes of the whole genome of Chinese pheochromocytoma patients. The results suggest that there may be certain progression of genetic events that involves chromosomes 1p, 3p, 6p, 11q, 12q, 17q, and 19q in the development of pheochromocytomas, and the activation of ERBB-2 located on chromosome 17q is an important and early event in the malignancy development of these tumor types. The overexpression of ERBB-2 identified by IHC suggested that this oncogene could be associated with the malignancy of pheochromocytomas and paragangliomas.

Reduced quality of life in patients with head-and-neck paragangliomas

The objective of this study was to assess the quality of life (QoL) in patients with head-and-neck paragangliomas ('glomus tumors'). We conducted a case-control study. We assessed QoL in 82 patients with head-and-neck paragangliomas using four validated health-related questionnaires: Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index (MFI-20), Short Form-36 (SF-36), and Nottingham Health Profile (NHP). Patient outcomes were compared with controls provided by the patients and with a large age- and sex-adjusted control group. The QoL scores in the paraganglioma patients were significantly reduced in 12 out of the 21 subscales compared with own controls, and in 18 out of the 21 subscales compared with age- and sex-adjusted values derived from the previous studies. In the MFI-20 questionnaire, patients reported more general fatigue, physical fatigue, mental fatigue, and a reduction in activity and motivation. The scores in the NHP showed a difference in energy, emotional reaction, and social isolation. General health perception, pain, and physical functioning were reported to be worse in the paraganglioma patients on the SF-36 scale. Although anxiety and depression did not reveal any significant differences between patients and their own controls, an increased score on both anxiety and depression was seen when compared with the extended control group. Especially, dysphonia contributes to a reduced QoL. QoL is considerably reduced in patients with head-and-neck paragangliomas.

Molecular characterisation of a common SDHB deletion in paraganglioma patients

Background:Hereditary susceptibility to familial paraganglioma syndromes is mainly due to mutations in one of six genes, including three of the four genes encoding the subunits of the mitochondrial succinate dehydrogenase...

Clinicopathological review of 46 primary retroperitoneal tumors

To clarify the clinical factors including diagnostic imaging findings that may correlate with the histopathological malignancy in primary retroperitoneal tumors. The clinical backgrounds and imaging findings of 22 benign and 24 malignant primary retroperitoneal tumors were retrospectively investigated, and the prognosis of patients with malignant retroperitoneal tumors was assessed. There were significant correlations between the presence of symptoms and malignancy (P < 0.01), as well as between the irregularity of tumor margins and malignancy (P < 0.01). On dynamic magnetic resonance imaging (MRI), 90% of malignant tumors showed early enhancement either with quick or slow washout, while 75% of benign tumors showed delayed and no enhancement (P < 0.002). All malignant and benign paraganglioma showed the same early enhancement with quick washout. Malignant lymphoma showed various enhancement patterns. The 2-year and 5-year cause-specific survival rates of the patients with malignant retroperitoneal tumors were 68.0% and 43.2%, respectively. All malignant lymphoma patients were mainly treated with chemotherapy after being diagnosed histologically. Malignant paraganglioma patients who could not meet complete resection needed chemotherapy for promising survival. The symptoms, the irregularity of the margins, and the specific enhancement pattern on the dynamic MRI may be important predictive factors of the primary malignant retroperitoneal tumors. Histological diagnosis was needed for malignant definition of paraganglioma because both benign and malignant paraganglioma showed similar clinical and imaging findings. Preoperative biopsy should be considered for selection of the appropriate treatment particularly in patients that are likely to have malignant lymphoma that could not be diagnosed definitively by the clinical and imaging findings.

Bone metastases from head and neck paragangliomas: Uncommon MR findings in an uncommon condition—Report of three cases

Malignancy (defined as metastatic disease) has been reported in nearly 5% of head and neck paragangliomas. Metastases preferentially target the lymph nodes, lung, liver, or bone. We describe three patients with multiple silent bone metastases exhibiting a fatty halo at MRI that coexisted with expansive bone lesions. In all cases, (123)I-metaiodobenzylguanidine ((123)MIBG) scintigraphy showed no abnormal tracer uptake, whereas (111)In-pentetreotide scintigraphy visualized a few silent bone metastases. These findings indicate that MRI should be included in the staging of paraganglioma patients with risk factors for malignancy.

Large Germline Deletions of Mitochondrial Complex II Subunits SDHB and SDHD in Hereditary Paraganglioma

More than 30% of adrenal pheochromocytomas are hereditary. These neuroendocrine tumors are major components of three inherited cancer syndromes: multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and pheochromocytoma/paraganglioma syndrome (PC/PGL). Germline mutations in RET; VHL; and SDHB, SDHC, and SDHD are associated with multiple endocrine neoplasia type 2, VHL, and PC/PGL, respectively. The majority (>70%) of hereditary extraadrenal PCs [catecholamine-secreting paragangliomas (PGL)] are accounted for by germline intragenic mutations in SDHB, SDHC, or SDHD. Therefore, a subset of hereditary PGL is not accounted for. Here we report two unrelated hereditary PGL families, one with a germline whole-gene deletion of SDHD (family 4194), the other a partial deletion of SDHB (family BRZ01). Although they were initially designated mutation negative for all of the PC-associated genes after PCR-based analysis, we suspected that a large deletion or rearrangement might be present. Genotyping around the PC-associated genes demonstrated that both families were consistent with linkage with one of these genes. Using fine structure genotyping and semiquantitative duplex PCR analysis, we identified an approximately 96-kb deletion spanning SDHD in family 4194 and an approximately 1-kb deletion involving the 5' end of SDHB in family BRZ01. Thus, including SDHB and SDHD deletion analysis could increase gene-testing sensitivity for PGL patients, which would aid in genetic counseling and management of patients and families.

Chromosome 11 monosomy in conjunction with a mutated SDHD initiation codon in nonfamilial paraganglioma cases

Paragangliomas of the head and neck region are a group of rare, usually benign, slow-growing tumors developing from paraganglionic chemoreceptors in most patients. Mutations in a subunit of the mitochondrial enzyme II complex (succinate dehydrogenase [SDHD]) were shown to be responsible for the formation of paragangliomas. In addition, loss of heterozygosity (LOH) on chromosome 11, mainly in 11q23 (PGL1), was observed recently. We analyzed DNA derived from tumor sections of three unrelated paraganglioma patients (one case with multiple paragangliomas, two cases with single tumors; all of them sporadic cases) for mutations in the SDHD gene by direct sequencing. Microsatellite-based LOH was performed, and events of chromosomal loss were validated by fluorescence in situ hybridization (FISH) on paraffin-embedded tumor and normal tissue by using centromeric satellite DNA. Sequence analysis revealed mutations in SDHD exon 1 in all patients, affecting the initiation codon (M1V). Another alteration was detected in exon 2 but was lacking in tumor DNA and therefore classified as polymorphism (H50R). LOH and FISH analyses demonstrated partial/total monosomy for chromosome 11 in the tumor samples tested. A common genetic mechanism appears to be the pathophysiologic basis for sporadic tumor development because the proposed two-hit model comprising both LOH and point mutation is manifest in our patients. Loss of chromosome 11 regions, including the deletion of PGL1 and PGL2 loci, may result in a more severe phenotype, as exemplified by the development of multiple tumors in one of the patients.

Absence of somatic SDHD mutations in sporadic neuroendocrine tumors and detection of two germline variants in paraganglioma patients.

Allelic loss of the long arm of chromosome 11 is frequent in neuroendocrine tumors (NET) of different organs. However, the MEN1 gene on 11q13 is mutated only in a subset of NET and allelic losses on 11q frequently extend to the telomere. In this genetic region lies the tumor suppressor gene SDHD which is associated with hereditary paragangliomas (PGL1). We sought to determine whether SDHD plays a role in the development of sporadic NET. By mutation and deletion analysis of SDHD we were unable to detect any SDHD mutation in 45 NET of the lung, gastrointestinal tract, pancreas or parathyroid. However, we found allelic deletions in 20 to 50% of all tumors but parathyroid adenomas. Furthermore, we found heterozygous germline variants in 2/8 paragangliomas. A first case of variant c.149 A>G (H50R) was found in a patient with an extra-adrenal pheochromocytoma, the other variant c.34 G>A (G12S) in a patient with a paratracheal paraganglioma, C-cell hyperplasia of the thyroid and hyperplasia of ACTH-producing cells of the pituitary gland. Both variants were absent in 93 controls. Our results demonstrate that somatic SDHD mutations are rare in sporadic NET. However, LOH alone could lead to a complete loss of function since SDHD is an imprinted gene. Furthermore, we describe two germline variants possibly causing hereditary paragangliomas.

Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas

Background: Paragangliomas are rare and highly heritable tumours of neuroectodermal origin that often develop in the head and neck region. Germline mutations in the mitochondrial complex II genes, SDHB, SDHC,...

Genomic structure of the human PLZF gene.

The human PLZF (promyelocytic leukaemia zinc finger) gene encodes a Krüppel-like zinc finger protein, which was identified via the reciprocal translocation t(11;17)(q23;q21) fusing it to the retinoic acid receptor alpha (RARalpha) gene in promyelocytic leukaemia. To determine its complete genomic organisation, we constructed a cosmid-map fully containing the hPLZF gene. The gene has seven exons, including a novel 5' untranslated exon, varying in size from 87 to 1358bp and spans at least 120kb. Flanking intronic sequences were identified and all splice acceptor and donor sites conformed to the gt/ag rule. Five polymorphic markers could be fine located in its vicinity. These data will facilitate mutation analysis of hPLZF in t(11;17) leukaemia cases, as well as assist mapping and loss-of-heterozygosity analysis. Here we have tested hPLZF as a possible candidate for the PGL1 locus involved in hereditary head and neck paragangliomas. However, mutation analysis revealed no aberration in 12 paraganglioma patients from different families.

Metastatic Retroperitoneal Paraganglioma in a 16-year-old Girl. Case report, Molecularpathological and Cytogenetic Findings

Retroperitoneal paraganglioma is a rare tumor, especially occurring in childhood and adolescence, with a marked tendency to become biologically malignant. It has not been possible to predict the clinical outcome of paraganglioma patients by conventional histology, hence malignancy can only be demonstrated by the occurrence of metastatic lesions. Currently, only limited information on the genetics of this tumor is available. We report on a 16-year-old girl with a large retroperitoneal paraganglioma and an osseous metastasis to the first lumbar vertebra. In addition to morphological and immunohistochemical examinations, a molecular cytogenetic analysis was performed. Comparative genomic hybridization (CGH) revealed imbalanced chromosomal aberrations with a loss of chromosome 1p and a gain of 1q, indicating isochromosome 1q. A loss of chromosome 3 as well as low-level gains of chromosomes 4, 5, 6q, 11q and 13q were detected. A PCR-based microsatellite analysis of 1p confirmed the loss of heterozygosity, including NB1 and NB2 putative tumor-suppressor gene regions. Telomerase activity, which is found in the majority of malignant tumors, could not be detected. The case presented here is the first more comprehensive molecular genetic analysis of a sporadic malignant paraganglioma.