Pheochromocytoma Paraganglioma Research Articles

Efficacy of [177Lu]Lu-DOTATATE in metastatic neuroendocrine neoplasms of different locations: data from the SEPTRALU study

BackgroundPeptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282).ResultsThe sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7–not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8–28.1) in pancreatic, and 17.6 months (14.4–33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity.ConclusionThis study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

P051: Distribution of variants and tumor presentation in pediatric patients diagnosed with hereditary pheochromocytoma paraganglioma syndrome*

P051: Distribution of variants and tumor presentation in pediatric patients diagnosed with hereditary pheochromocytoma paraganglioma syndrome*

Role of Preoperative Blockade in Pheochromocytoma-Paraganglioma: A Clinician's Perspective.

Pheochromocytoma–paraganglioma (PPGL) produces excessive catecholamines, which lead to peripheral vasoconstriction and hypertension. Intraoperative tumour handling causes wide fluctuations in blood pressure, with intraoperative surges and post-surgery hypotension. Non-selective alpha-blocker (NSAB), namely phenoxybenzamine, was described in 1967 to reduce the blood pressure fluctuations and enable preoperative volume re-expansion, bringing in the concept of preoperative blocking.[1] Subsequently, selective alpha-blockers (SAB) such as doxazosin, prazosin, and calcium channel blockers (nicardipine) were used. The choice of one drug over another is backed by sparse data in the form of observational studies and there is only one randomised controlled trial (PRESCRIPT trial) comparing phenoxybenzamine and doxazosin. Though the percentage time outside the target blood pressure (primary endpoint) was similar in both arms, the intraoperative hemodynamic instability score (secondary endpoint) was lesser with phenoxybenzamine.[2] In the meta-analysis (included one RCT and seven observational studies) comparing NSAB and SAB published in the current issue, the authors deduced that NSAB offers an advantage in the form of lesser intraoperative vasodilator requirements. Another recent meta-analysis (included 1 RCT and 10 observational studies) also concluded NSAB arm had a lesser intraoperative vasodilator requirement and had lower maximum intraoperative systolic blood pressures. Notably, both meta-analyses observed comparable (NSAB vs. SAB) intraoperative and postoperative hypotension risk and overall morbidity.[3] What additional information do these meta-analyses provide beyond that described in the PRESCRIPT trial? Meta-analysis is considered superior to RCT in the evidence pyramid, as it analyses a larger sample size with the inclusion of different populations. However, the results of meta-analyses need to be interpreted with caution. The pre-requisites for interpreting a meta-analysis are to ensure homogenous data and good-quality studies.[4] The inclusion of observational studies may lead to bias related to confounding factors and may exaggerate the treatment effect.[5] Both the authors of the meta-analyses addressing the efficacy of NSAB and SAB acknowledge the latter limitation of their analyses. The meta-analyses echo the findings of the PRESCRIPT trial. From the clinician’s purview, even though the vasodilator requirements (secondary endpoints) were lesser for the phenoxybenzamine arm, the duration outside the target blood pressure was similar for both groups. It then translates that good intraoperative anaesthetic techniques can maintain hemodynamic stability, irrespective of the type of alpha-blocker used for preoperative blocking. A pilot RCT comparing amlodipine with prazosin showed that the time outside the target blood pressure (primary endpoint) was significantly greater in the prazosin arm than in the amlodipine arm.[6] Furthermore, extensive studies to confirm these pilot observations and pharmacological effects of L-type calcium channel blockers on PPGL need to be carried out. What is the way forward? There is a need for well-planned, prospective, and randomised trials. Only then, such a meta-analysis will provide impactful results that may be practice-changing.

Dutch founder SDHB exon 3 deletion in patients with pheochromocytoma-paraganglioma in South Africa.

ObjectiveScreening studies have established genetic risk profiles for diseases such as multiple endocrine neoplasia type 1 (MEN1) and pheochromocytoma–paraganglioma (PPGL). Founder effects play an important role in the regional/national epidemiology of endocrine cancers, particularly PPGL. Founder effects in the Netherlands have been described for various diseases, some of which established themselves in South Africa due to Dutch emigration. The role of Dutch founder effects in South Africa has not been explored in PPGL.DesignWe performed a single-center study in South Africa of the germline genetic causes of isolated/syndromic neuroendocrine tumors.MethodsNext-generation panel, Sanger sequencing and multiplex ligand-dependent probe amplification for endocrine neoplasia risk genes.ResultsFrom a group of 13 patients, we identified 6 with PPGL, 4 with sporadic or familial isolated pituitary adenomas, and 3 with clinical MEN1; genetic variants were identified in 9/13 cases. We identified the Dutch founder exon 3 deletion in SDHB in two apparently unrelated individuals with distinct ethnic backgrounds that had metastatic PPGL. Asymptomatic carriers with this Dutch founder SDHBexon 3 deletion were also identified. Other PPGL patients had variants in SDHB, and SDHD and three MEN1variants were identified among MEN1 and young-onset pituitary adenoma patients.ConclusionsThis is the first identification of a Dutch founder effect for PPGL in South Africa. Awareness of the presence of this exon 3 SDHB deletion could promote targeted screening at a local level. Insights into PPGL genetics in South Africa could be achieved by studying existing patient databases for Dutch founder mutations in SDHx genes.

Catecholamines Induce Trained Immunity in Monocytes In Vitro and In Vivo.

Exposure to high catecholamine levels is associated with inflammatory changes of myeloid cells and atherosclerosis, but the underlying mechanisms are only partly understood. To investigate whether the proinflammatory effects of noradrenaline and adrenaline can, in part, be explained by the induction of an immunologic memory in innate immune cells, termed trained immunity. In vitro, we exposed human primary monocytes to (nor)adrenaline for 24 hours, after which cells were rested and differentiated to macrophages over 5 days. After restimulation with lipopolysaccharide on day 6, (nor)adrenaline-exposed cells showed increased TNF-α (tumor necrosis factor-α) production. This coincided with an increase in glycolysis and oxidative phosphorylation measured with Seahorse technology on day 6 before restimulation. Inhibition of the β-adrenoreceptor-cAMP signaling pathway prevented the induction of training. In vivo, we studied the functional, transcriptional, and epigenetic impact of peak-wise exposure to high catecholamine levels on monocytes isolated from pheochromocytoma/paraganglioma (PHEO) patients. In PHEO patients (n=10), the peripheral blood cell composition showed a myeloid bias and an increase of the inflammatory CD14++CD16+ (cluster of differentiation) intermediate monocyte subset compared with controls with essential hypertension (n=14). Ex vivo production of proinflammatory cytokines was higher in PHEO patients. These inflammatory changes persisted for 4 weeks after surgical removal of PHEO. Transcriptome analysis of circulating monocytes at baseline showed various differentially expressed genes in inflammatory pathways in PHEO patients; epigenetic profiling of the promoters of these genes suggests enrichment of the transcriptionally permissive chromatin mark H3K4me3 (trimethylation of lysine 4 on histone H3), indicative of in vivo training. Catecholamines induce long-lasting proinflammatory changes in monocytes in vitro and in vivo, indicating trained immunity. Our data contribute to the understanding of pathways driving inflammatory changes in conditions characterized by high catecholamine levels and propose that trained immunity underlies the increased cardiovascular event rate in PHEO patients.

A primer on the genetics of medullary thyroid cancer.

Medullary thyroid cancer is a rare type of neuroendocrine tumour that arises from the parafollicular cells (C cells) of the thyroid gland. It accounts for 3%-5% of thyroid cancer cases. Close to 25% of cases are familial, and 75% are considered sporadic. Familial cases are associated with a germline RET mutation; 43%-65% of sporadic cases harbour a somatic event in the gene. Germline RET mutations are associated with the autosomal-dominant inherited multiple endocrine neoplasia (men) 2a and 2b syndromes and the isolated familial medullary thyroid cancer syndrome. More than 100 RET codon mutations have been reported to date, with genotype-phenotype correlations that include the extent and aggressiveness of the medullary thyroid cancer and the presence of other features of the men2 syndromes. The latter include pheochromocytoma-paraganglioma, hyperparathyroidism, cutaneous lichen amyloidosis, and Hirschsprung disease. In this narrative review, we focus on RET proto-oncogene physiology and pathogenesis induced by germline and somatic RET mutations, the genotype-phenotype correlation, and the management and follow-up of patients with germline-mutated medullary thyroid cancer.

Preimplantation genetic diagnosis for a single gene mutation for succinate dehydrogenase subunit B (the genetic basis for malignant paraganglioma) with successful pregnancy

Purpose: To report the first successful case of the birth of normal baby using preimplantation diagnosis for hereditary paraganglioma (PGL) followed by embryo transfer and to emphasize the importance of using mild follicle stimulating hormone (FSH) stimulation for IVF in women with diminished oocyte reserve. Materials and Methods: The female partner had a baseline serum FSH of 16.5 mIU/mL and the male partner had the malignant hereditary form of the PGL - pheochromocytoma (PGL/PCC) syndrome related to a mutation of the nuclear mitochondrial enzyme, succinate-dehydrogenase enzyme (specifically the B subunit) (SDHB). He was suffering from the malignant transformation of these neuroendocrine tumors. Before his death, he wanted to enjoy for a short time a baby with his own genes but feared passing the SDHB autosomal gene mutation to their child. Results: Eight blastomeres from eight embryos biopsied on day 3 were tested for SDHB gene by polymerase chain reaction. These eight metaphase II oocytes were obtained following mild FSH stimulation (150 units from day 3). Intracytoplasmic sperm injection (ICSI) was performed using the frozen/thawed sperm of this 35-year-old male suffering from a malignant pheochromocytoma. Five of the eight embryos were found to have mutations of the SDHB gene. Two embryos with normal SDHB were transferred and one resulted in a healthy baby. Genetic testing of the baby confirmed the absence of the SDHB mutation. Discussion: The successful pregnancy supports, but does not prove, the importance of using mild FSH stimulation in the presence of diminished oocyte reserve to inhibit the iatrogenic development of a much higher percentage of embryos with aneuploidy.

Chromogranin A in the Laboratory Diagnosis of Pheochromocytoma and Paraganglioma.

This work discusses the clinical performance of chromogranin A (CGA), a commonly measured marker in neuroendocrine neoplasms, for the diagnosis of pheochromocytoma/paraganglioma (PPGL). Plasma CGA (cut-off value 150 µg/L) was determined by an immunoradiometric assay. Free metanephrine (cut-off value 100 ng/L) and normetanephrine (cut-off value 170 ng/L) were determined by radioimmunoassay. Blood samples were collected from PPGL patients preoperatively, one week, six months, one year and two years after adrenal gland surgery. The control patients not diagnosed with PPGL suffered from adrenal problems or from MEN2 and thyroid carcinoma. The clinical sensitivity in the PPGL group of patients (n = 71) based on CGA is 90% and is below the clinical sensitivity determined by metanephrines (97%). The clinical specificity based on all plasma CGA values after surgery (n = 98) is 99% and is the same for metanephrines assays. The clinical specificity of CGA in the control group (n = 85) was 92% or 99% using metanephrines tests. We can conclude that plasma CGA can serve as an appropriate complement to metanephrines assays in laboratory diagnosis of PPGL patients. CGA is elevated in PPGLs, as well as in other neuroendocrine or non-neuroendocrine neoplasia and under clinical conditions increasing adrenergic activity.

Malignant pheochromocytoma-paraganglioma: pathogenesis, TNM staging, and current clinical trials.

Pheochromocytomas and paragangliomas (PPGs) are rare neuroendocrine tumors. Over the last 15 years, substantial progress has been made toward understanding the clinical aspects and molecular origins of this disease. Nevertheless, predicting and managing malignancy remains the biggest challenge in clinical practice. The natural history of patients with malignant PPGs has not yet been described, and their prognosis varies. Currently, the diagnosis of malignant PPGs relies on the presence of metastases, by which time the disease is usually advanced. Better understanding of the clinical and molecular characteristics of patients with malignant PPGs has spurred several prospective clinical trials. Several molecular targeted therapies, a novel radiopharmaceutical medication that targets the catecholamine transporter, and immunotherapy are under evaluation for the treatment of patients with malignant PPGs. Furthermore, the identification of clinical predictors of malignancy and survival has led to the first TNM staging classification for PPGs. Prospective clinical trials are providing patients with therapeutic options beyond systemic chemotherapy. The knowledge derived from these trials and from the evaluation of the TNM staging in clinical practice will help to clarify how to most effectively treat malignant PPGs.

Fluorine-18-fluorodihydroxyphenylalanine Positron-emission Tomography Scans of Neuroendocrine Tumors (Carcinoids and Pheochromocytomas).

Objectives:Conventional methods of imaging neuroendocrine tumors with computed tomography, magnetic resonance imaging, indium-111-octreotide, or radiolabeled metaiodobenzilguanidine scintigraphy have limitations. This pilot study tried to improve the localization of these tumors with fluorine-18-fluorodihydroxyphenylalanine (F-DOPA) positron-emission tomography (PET) scanning.Materials and Methods:We studied 22 patients, the majority of whom were referred with clinical diagnosis or suspicion of carcinoid (n = 11), neuroendocrine tumors (n = 7) or pheochromocytoma/paraganglioma (PGL) (n = 4). The comparison was made with the prior conventional imaging.Results:The F-DOPA findings were compared with the results of subsequent surgery (2), endoscopy (1), or a long-term follow-up (mean duration, 49 months) for 17 patients. Two patients were lost to follow-up. Foci of F-DOPA deposition were detected in eight patients (final diagnosis of carcinoid in six, of neuroendocrine tumors in one, and of PGL in another). Comparison with the final diagnoses revealed concordance in 16 of the 22 patients. F-DOPA results appeared superior to those obtained with conventional imaging. Despite the small number and diagnostic heterogeneity, in a substantial fraction of patients F-DOPA PET added information relevant to clinical management.Conclusion:F-DOPA scanning added prognostic value, particularly when multiple abnormal foci versus a negative examination were considered.

Heritable Cancer Syndromes Related to the Hypoxia Pathway.

Families of tumor-suppressor genes, such as those involved in homologous recombination or mismatch repair, contain individual genes implicated in hereditary cancer syndromes. Collectively, such groupings establish that inactivating germline changes in genes within pathways related to genomic repair can promote carcinogenesis. The hypoxia pathway, whose activation is associated with aggressive and resistant sporadic tumors, is another pathway in which tumor-suppressor genes have been identified. von Hippel–Lindau disease, some of the hereditary paraganglioma–pheochromocytoma (PGL/PCC) syndromes, and the syndrome of hereditary leiomyomatosis and renal cell carcinoma are heritable conditions associated with genes involved or associated with the hypoxia pathway. This review links these heritable cancer syndromes to the hypoxia pathway while also comparing the relative aggression and treatment resistance of syndrome-associated tumors to similar, sporadic tumors. The reader will become aware of shared phenotypes (e.g., PGL/PCC, renal cell carcinoma) among these three hypoxia-pathway-associated heritable cancer syndromes as well as the known associations of tumor aggressiveness and treatment resistance within these pathways.

Functional Imaging Experience in a Germline Fumarate Hydratase Mutation–Positive Patient With Pheochromocytoma and Paraganglioma

ABSTRACT Objective: To report the functional imaging experience with a 29-year-old woman carrying a mutation in the fumarate hydratase (FH)-encoding gene and a history of a pheochromocytoma (PHEO) and retroperitoneal paraganglioma (PGL). Methods: The patient was found to have a splice-site mutation in the FH gene at intron 2, c.268-2A>G. To confirm this, immunohistochemical staining was performed on tumor tissue slides from the patient's previous surgeries. The patient underwent biochemical testing for PHEO/PGL, which included chromogranin A and plasma methoxytyramine. The patient's tumors were also imaged using several imaging modalities, including computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography (PET)/CT studies using l18F]-fluorodeoxyglucose (l18F]-FDG), l18F]-fluorodopamine (l18F]-FDA), l18F]-fluorodihydroxyphenylalanine (l18F]-FDOPA), and l68Ga]-tetraazacyclododecanetetraacetic acid–lTyr3]-octreotate (l68Ga]-DOTATATE) as tracers. Results: The patient received a comprehensive evaluation based on her symptoms and medical history. She was found to have 3 noradrenergic-secreting tumors that showed uptake on l18F]-FDG-(2/3), l68Ga]-DOTATATE-(2/3), l18F]-FDOPA-(3/3), and l18F]-FDA-(3/3) PET/CT. The patient was recommended to have the tumor sites removed (renal hilum, aortocaval, and periaortic regions) with lympadenectomies to address possible metastases. Pathology confirmed paraganglioma. Immunohistochemical staining from previous surgical slides showed negative staining for FH, consistent with a mutation in the gene. Conclusion: We share, for the first time, functional images for an FH mutation–positive PHEO/PGL patient using various PET radiopharmaceuticals. l18F]-FDA- and l18F]-FDOPA PET/CT served as the best imaging modalities. This case provides the appropriate selection of imaging studies and further evidence for the importance of screening for FH mutations in patients with noradrenergic PHEOs/PGLs. Abbreviations: CT = computed tomography l18F]-FDA = l18F]-fluorodopamine l18F]-FDG = l18F]-fluorodeoxyglucose l18F]-FDOPA = l18F]-fluorodihydroxyphenylalanine FH = fumarate hydratase l68Ga]-DOTATATE = l68Ga]-tetraazacyclododecanetetraacetic acid–lTyr3]-octreotate MTY = methoxytyramine NIH = National Institutes of Health PET = positron emission tomography PGL = paraganglioma PHEO = pheochromocytoma SDHB = succinate dehydrogenase complex, subunit B URL = upper reference limit

An uncommon cause of hypertension: Paraganglioma revisited

A significant number of secondary hypertension could be due to endocrine etiology. The pheochromocytoma/paraganglioma (PGL) syndrome is one among them. We herein report a case of PGL in a young woman, who presented to us with hypertension and its reversal after surgical treatment. In this review, we also discussed in detail about this rare entity.

Succinate dehydrogenase gene mutations and DNA methylation analysis in hereditary pheochromocytoma paraganglioma syndrome

Objective To detect the genetic mutations of succinate dehydrogenase B (SDHB),SDHC,SDHD,SDHAF2 and RET,VHL in hereditary pheochromocytoma (PHEO) paraganglioma (PGL) syndrome in order to analyze the relationship between the pathogenesis and SDHx mutations and DNA methylation.Methods SDH genes,VHL and RET were analyzed for germline mutations in 97 PHEOs/PGLs patients.Correlations were analyzed between the results and the clinical characteristics including age,tumor localization,multifocality,24 h urine CA,IGF and NSE.Direct DNA sequence analysis was carried out for SDHB (1q36.1-1q35,exons1-8),SDHC (1q21,exons 1-5),SDHD (11q23,exons 1-4),SDHAF2 (11q12.2,exons 1-4),RET (10q11.2,exons10,11,13,14&15,and 16) and VHL (3p25.3,exons 1-3) genes,and promoter region methylation of SDHB was detected in PHEO/PGL peripheral blood samples.Results Germinal mutations were found in 17 patients (17.5％),with 8 cases in RET proto-oncogene (8.2％),7 cases in SDHB genes (7.2％) and 2 cases in VHL gene (2.1％).The comparison of some of the clinical features in two groups (with and without promoter region methylation of SDHB) showed significant differences (P＜0.01).Conclusions Genetic predisposition is frequent in chromaffin tissue tumors,indicating that DNA analysis is necessary.The mutation of SDHB is highly associated with abdominal PGL and the following distant metastasis (malignant PGL). Key words: Pheochromocytomas; Paragangliomas; Succinate dehydrogenase; DNA mutational analysis; DNA methylation

Hereditary Pheochromocytoma

Pheochromocytomas (PHEO) and paragangliomas (PGL) are rare neuroendocrine tumors with an estimated occurrence of 2 to 5 patients per million per year and an incidence of about 1 per 100 000 in the general population. These tumors may arise sporadically or be associated to various syndromes, namely multiple endocrine neoplasia type 2, neurofibromatosis type 1, Von Hippel-Lindau syndrome, and hereditary paraganglioma-pheochromocytoma syndromes. This article aims to review the current epidemiology, pathogenesis, clinical presentation, and genetic aspects of syndromes associated with hereditary PHEO/PGL. The literature research, conducted at PubMed database, included review articles, published from February 2009 to February 2014, written in English or Portuguese, using as query: "Hereditary AND Pheochromocytoma." These tumors can be part of a myriad hereditary conditions that are not yet fully understood. Nevertheless, important systemic symptoms and even fatal outcomes can occur. Knowledge of these hereditary conditions can ensure a more efficient detection, treatment, and even prevention of these neuroectodermal tumors, thus new tests and studies should be conducted.

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

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. 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. 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. 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.

Mutation analysis of the SDHB and SDHD genes in pheochromocytomas and paragangliomas: identification of a novel nonsense mutation (Q168X) in the SDHB gene

Pheochromocytoma (PCC) and paraganglioma (PGL) are tumors of the autonomic nervous system. The former is a tumor that occurs in only adrenal glands, and the latter can be found in the head and neck or in the thorax and abdomen. In PCC and PGL, genetic mutations account for approximately 30% of functional (secrete catecholamines) and nonfunctional cases. In addition to RET, VHL and NF-1, genes encoding succinate dehydrogenase complex subunit B (SDHB), subunit C (SDHC), and subunit D (SDHD) are recognized as susceptibility genes for PCC and PGL. Recently, PCC and PGL caused by genetic mutations of SDHB, SDHC and SDHD were established as hereditary pheochromocytoma paraganglioma syndrome (HPPS). Approximately 15% of all PCCs and PGLs are recognized as HPPS. Among these three susceptibility genes, SDHB and SDHD are known to be strongly related to HPPS. The aim of this study was to analyze SDHB and SDHD mutations in PCC and PGL patients. Among 18 patients, we identified a novel heterozygous nonsense mutation at codon 168 resulting in a CAG (glutamine) to TAG (stop) substitution (Q168X) in the SDHB gene in a patient diagnosed with solitary sporadic PGL. A number of studies have reported that SDHB mutation-associated disease demonstrates a higher rate of malignancy. However, all seven patients diagnosed with malignancy in this study did not have genetic mutation of SDHB and only one patient with no malignant sign had genetic mutation of SDHB. Further accumulation of cases is necessary to confirm the association between SDHB mutation and malignant potential.

Diagnosing patients with hereditary paraganglial tumours

Although well-defined clinical criteria are present for familial tumour syndromes such as neurofibromatosis type 1, von Hippel–Lindau syndrome, and multiple endocrine neoplasia type 2, genetic testing is the only means by which a definitive diagnosis can be made for familial pheochromocytoma—paraganglioma syndrome, caused by mutations in genes encoding different subunits of the succinate dehydrogenase (SDH) complex: SDHD (type 1), SDHC (type 3), and SDHB (type 4).1,2

Functional study in a yeast model of a novel succinate dehydrogenase subunit B gene germline missense mutation (C191Y) diagnosed in a patient affected by a glomus tumor

Mutations of succinate dehydrogenase (SDH) subunits B, C and D are associated to pheochromocytoma/paraganglioma (PGL) development. The mechanisms linking SDH mutations to tumorigenesis are currently unknown. We report a novel germline missense SDHB mutation (C191Y) in a patient affected by a glomus tumor. The missense mutation hits an amino acid residue conserved from mammals to the yeast Saccharomyces cerevisiae. The pathogenic significance of the human mutation was validated in a yeast model. SDH2(C184Y) mutant allele equivalent to human SDHB(C191Y) did not restore the OXPHOS phenotype of the Deltasdh2 null mutant. In the mutant, SDH activity was also abolished along with a reduction in respiration. Sensitivity to oxidative stress was increased in the mutant, as revealed by reduced growth in the presence of menadione. Remarkably, the frequency of petite colony formation was increased in the mutant yeast strain, indicating an increased mtDNA mutability. Histochemistry demonstrates that SDH activity was selectively absent in the patient tumor tissue. Overall, our results demonstrate that the C191Y SDHB mutation suppresses SDH enzyme activity leading to increased ROS formation and mtDNA mutability in our yeast model. These findings further our understanding of the mechanisms underlying PGL development and point to the yeast model as a valid tool to investigate on the possible pathogenic relevance of SDH novel mutations and/or rare polymorphism.

Posterior mediastinal mass

<h3>Common</h3> Neurogenic neoplasms Arising from peripheral nerves Neurofibroma Neurilemoma or schwannoma (benign or malignant) Arising from sympathetic ganglia Ganglioneuroma (benign) Neuroblastoma } malignant Sympathicoblastoma Arising from paraganglionic cells Pheochromocytoma Paraganglioma } benign or malignant or chemodectoma Parasitic cysts (hydatid) Meningocele (meningomyelocele) Neurenteric (archenteric) cyst Gastroenteric cyst Thoracic duct cyst Primary esophageal lesions Neoplasm Esophageal diverticula Megaesophagus Esophageal hiatus hernia Hernia through the foramen of Bochdalek Diseases of thoracic spine Neoplasms Infectious spondylitis Tuberculous Nontuberculous Extramedullary hematopoiesis Aortic aneurysm <h3>Diagnosis</h3> Tuberculous spondylitis. <h3>Comment</h3> A 45-year-old woman was referred to the Lady Reading Hospital, Peshawar, Pakistan, in October 1972 for evaluation of an abnormal chest roentgenogram (Fig 1). The film was taken because of vague chest pains. A Casoni test for hydatid disease was negative. Results of a physical examination showed no abnormalities except for some tenderness in the midthoracic spine. There was no deformity of the spine nor of the