[Show abstract][Hide abstract] ABSTRACT: The management of hereditary pheochromocytoma has drastically evolved in the last 20 years. Bilateral pheochromocytoma does not increase mortality in multiple endocrine neoplasia type 2 (MEN 2) or von Hippel-Lindau (VHL) mutation carriers who are followed regularly, but these mutations induce major morbidities if total bilateral adrenalectomy is performed. Cortical sparing adrenal surgery may be proposed to avoid definitive adrenal insufficiency. The surgical goal is to leave sufficient cortical tissue to avoid glucocorticoid replacement therapy. This approach was achieved by the progressive experience of minimally invasive surgery via the transperitoneal or retroperitoneal route. Cortical sparing adrenal surgery exhibits less than 5% significant recurrence after 10 years of follow-up and normal glucocorticoid function in more than 50% of cases. Therefore, cortical sparing adrenal surgery should be systematically considered in the management of all patients with MEN 2 or VHL hereditary pheochromocytoma. Hereditary pheochromocytoma is a rare disease, and a randomized trial comparing cortical sparing vs. classical adrenalectomy is probably not possible. This lack of data most likely explains why cortical sparing surgery has not been adopted in most expert centers that perform at least 20 procedures per year for the treatment of this disease. This review examined recent data to provide insight into the technique, its indications, and results and subsequent follow-up in the management of patients with hereditary pheochromocytoma with a special emphasis on MEN 2.
No preview · Article · Aug 2015 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse "mutation hotspots" in 50 human cancer genes. Mutations were identified for HRAS (c.37G>C; p.G13R and c.182A>G; p.Q61R) in 7.1% (6/85); for BRAF (c.1799T>A; p.V600E) in 1.2% (1/85) of tumours; and for TP53 (c.1010G>A; p.R337H) in 2.35% (2/85) of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and no HRAS, BRAF, or TP53 mutations occurred in this group. Combining our data with previous reports of HRAS mutations in PCC/PGL we find that the mean frequency of HRAS/BRAF mutations in sporadic PCC/PGL is 8.9% (24/269) and in PCC/PGL with an inherited gene mutation 0% (0/148) suggesting that HRAS/BRAF mutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence for BRAF mutations in the pathogenesis of PCC/PGL/HNPGL.
Full-text · Article · Apr 2015 · International Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: The precise diagnosis of thyroid neoplasias will guide surgical management. Primary thyroid paraganglioma has been rarely reported. Data on prevalence, immunohistochemistry and molecular genetics in a systematic series of such patients are pending. We performed a multinational population-based study on thyroid paraganglioma and analyzed prevalence, immunohistochemistry and molecular genetics. Patients with thyroid paraganglioma were recruited from the European-American-Head-and-Neck-Paraganglioma-Registry. Demographic and clinical data were registered. Histopathology and immunohistochemistry were reinvestigated. All patients with thyroid paraganglioma underwent molecular genetic analyses of the genes SDHA, SDHB, SDHC, SDHD, VHL, RET, TMEM127, and MAX. Analyses included Sanger sequencing and MLPA for detection of large rearrangements. Of 947 registrants, 8 candidates were initially identified. After immunohistochemical analyses of these 8, 5 (0.5%) were confirmed with thyroid paraganglioma. Immunohistochemistry was positive for chromogranin, synaptophysin and S-100 and negative for calcitonin in all 5 thyroid paragangliomas whereas the 3 excluded candidate tumors stained for pan-cytokeratin. Germline variants, likely representing mutations, were found in 4 of the 5 confirmed-thyroid paraganglioma cases, 2 each in SDHA and SDHB, whereas the excluded cases had no mutation in the tested genes. Thyroid paraganglioma is a finite entity which must be differentiated from medullary thyroid carcinoma, because medical, surgical and genetic management for each is different. Notably, ~80% of thyroid paragangliomas are associated with germline mutations, with implications for additional tumors and a potential risk for the family. As opposed to sporadic tumors, surgical management and extent of resection are different for heritable tumors, each guided by the precise gene involved.
No preview · Article · Jan 2015 · Endocrine Related Cancer
[Show abstract][Hide abstract] ABSTRACT: This case describes a 50-yr-old man who was admitted to the Urology Ward upon the suspicion of a left kidney tumor. As part of the pre-operative check-up, an ultrasound and computed tomography of the kidneys were conducted. The results confirmed the initial diagnosis. The postoperative diagnosis was extra-adrenal pararenal phaeochromocytoma (ePCC) with succinate dehydrogenase complex, subunit B (SDHB) gene mutation. During the follow-up, a second tumor was detected by 3,4-dihydroxy-6-F-18-fluoro-L-phenylalanine positron emission tomography/computed tomography F-DOPA-PET CT that resulted in another surgery with complete resection of the tumor. The patient and his family were counseled by a genetic laboratory and remain under surveillance.
[Show abstract][Hide abstract] ABSTRACT: Background:
The purpose of this study was to give an overview on hereditary syndromes associated with head and neck paragangliomas (HNPGs).
Our methods were the review and discussion of the pertinent literature.
About one third of all patients with HNPGs are carriers of germline mutations. Hereditary HNPGs have been described in association with mutations of 10 different genes. Mutations of the genes succinate dehydrogenase subunit D (SDHD), succinate dehydrogenase complex assembly factor 2 gene (SDHAF2), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit B (SDHB) are the cause of paraganglioma syndromes (PGLs) 1, 2, 3, and 4. Succinate dehydrogenase subunit A (SDHA), von Hippel-Lindau (VHL), and transmembrane protein 127 (TMEM127) gene mutations also harbor the risk for HNPG development. HNPGs in patients with rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and MYC-associated factor X (MAX) gene mutations have been described very infrequently.
All patients with HNPGs should be offered a molecular genetic screening. This screening may usually be restricted to mutations of the genes SDHD, SDHB, and SDHC. Certain clinical parameters can help to set up the order in which those genes should be tested.
[Show abstract][Hide abstract] ABSTRACT: Background:
The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2.
This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy.
1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent.
The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.
Full-text · Article · Apr 2014 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: Extract: The fascination of hereditary tumor diseases, especially von Hippel-Lindau disease (VHL) and pheochromocytoma, has dominated my academic life for three decades. My background was the warm and rich atmosphere which gave me my parents, Colonel Joachim Neumann and Mechtild Zuckschwerdt, PhD, MA, descendent of an industrial family from Magdeburg. Together with 3 sisters and a brother, I spent my youth in Brunswick, Hamburg and Bonn with a classical education including Latin and Greek. I served 2 years in the artillery of the German army. From 1969 until 1974, I studied medicine at the Universities of Bonn and Heidelberg ...
No preview · Article · Jan 2014 · Endocrine Related Cancer
[Show abstract][Hide abstract] ABSTRACT: Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs.
Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted.
LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p < 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.
No preview · Article · Dec 2013 · World Journal of Surgery
[Show abstract][Hide abstract] ABSTRACT: A third of patients with paraganglial tumors, pheochromocytoma and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127 and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy was performed in patients diagnosed <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1 and one patient each in RET, SDHA and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (p=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, p=0.001, SDHD vs others, p=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, 10 at initial diagnosis and another 6 during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, p<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.
Full-text · Article · Oct 2013 · Endocrine Related Cancer
[Show abstract][Hide abstract] ABSTRACT: To document the influences of blood sampling under supine fasting versus seated non-fasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine.
Biochemical testing for PPGL was performed on 762 patients at six centres, two of which complied with requirements for supine sampling after an overnight fast and four of which did not. PPGL were found in 129 patients (67 non-compliant, 62 compliant) and not in 633 patients (195 non-compliant, 438 compliant).
Plasma concentrations of normetanephrine and methoxytyramine did not differ between compliant and non-compliant sampling conditions in patients with PPGL, but were 49-51% higher in patients without PPGL sampled under non-compliant compared to compliant conditions. The 97.5-percentiles of distributions were also higher under non-compliant compared to compliant conditions for normetanephrine (1.29 vs 0.79 nmol/l), metanephrine (0.49 vs 0.41 nmol/l) and methoxytyramine (0.42 vs 0.18 nmol/l). Use of upper cut-offs established from seated non-fasting sampling conditions resulted in substantially decreased diagnostic sensitivity (98% vs 85%). In contrast, use of upper cut-offs established from supine fasting conditions resulted in decreased diagnostic specificity for testing under non-compliant compared to compliant conditions (71% vs 95%).
High diagnostic sensitivity of plasma normetanephrine, metanephrine and methoxytyramine for detection of PPGL can only be guaranteed using upper cut-offs of reference intervals established with blood sampling under supine fasting conditions. With such cut-offs, sampling under seated non-fasting conditions can lead to a 5.7-fold increase in false-positive results necessitating repeat sampling under supine fasting conditions. This article is protected by copyright. All rights reserved.
No preview · Article · Sep 2013 · Clinical Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genome-wide copy number variation (CNV) analysis with microRNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significantly targeted by tumor-associated alterations. The “NOTCH signaling pathway” was the most significantly enriched term in the list (P = 0.002 after Bonferroni or Benjamini correction). Expression of the relevant NOTCH pathway proteins in sustentacular (glial), chief (neuroendocrine) and endothelial cells was confirmed by immunohistochemistry in 47 head and neck paraganglioma cases. There were no relationships between level and pattern of NOTCH1/JAG2 protein expression and germline mutation status in the SDH genes, implicated in paraganglioma predisposition, or the presence/absence of immunostaining for SDHB, a surrogate marker of SDH mutations. Interestingly, NOTCH upregulation was observed also in cases with no evidence of CNVs at NOTCH signaling genes, suggesting altered epigenetic modulation of this pathway. To address this issue we performed microarray-based microRNA expression analyses. Notably 5 microRNAs (miR-200a,b,c and miR-34b,c), including those most downregulated in the tumors, correlated to NOTCH signaling and directly targeted NOTCH1 in in vitro experiments using SH-SY5Y neuroblastoma cells. Furthermore, lentiviral transduction of miR-200s and miR-34s in patient-derived primary tympano-jugular paraganglioma cell cultures was associated with NOTCH1 downregulation and increased levels of markers of cell toxicity and cell death. Taken together, our results provide an integrated view of common molecular alterations associated with head and neck paraganglioma and reveal an essential role of NOTCH pathway deregulation in this tumor type.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1165-y) contains supplementary material, which is available to authorized users.
Full-text · Article · Aug 2013 · Acta Neuropathologica
[Show abstract][Hide abstract] ABSTRACT: Sporadic and hereditary forms of renal cell carcinoma (RCC), von Hippel-Lindau (VHL) disease and the familial paraganglioma syndromes are closely related in terms of their clinical, molecular, and genetic aspects. Most RCCs occur sporadically and the heritable fraction of RCC is estimated to be just 2-4%. An understanding of the molecular genetic basis, the disease-specific and gene-specific biology and the clinical characteristics of these cancer syndromes is of utmost importance for effective genetic diagnosis and appropriate treatment. In addition, such insight will improve our understanding of sporadic RCCs. To date, 10 different heritable RCC syndromes have been described. VHL syndrome is the oldest known hereditary RCC syndrome. Similar to VHL disease, phaeochromocytoma is a major manifestation of the paraganglioma syndromes types 1, 3 and 4 in which RCCs have been reported. These syndromes are therefore regarded as VHL-related disorders and are included in this Review. Multifocal tumours, bilateral occurrence, a young age at diagnosis and/or family history are clinical red flags suggestive of hereditary disease and should trigger referral for genetic and molecular analysis. The identification of an underlying genetic alteration enables gene-specific risk assessment and opens up the possibility of a tailored follow-up strategy and specific surveillance protocols as the basis of effective preventive medicine. The important goals of preventive medicine are to increase the life expectancy of affected patients and to improve their quality of life. The study of seemingly rare hereditary syndromes and their susceptibility genes has consistently revealed clues regarding the aetiology and pathogenesis of these diseases, and can aid diagnosis and the development of therapeutics for patients affected by much more common sporadic counterparts.