Familial Paraganglioma Research Articles

Rare vertebral metastasis in a case of Hereditary Paraganglioma

Paragangliomas are rare tumours with a prevalence of 1/10000 to 1/30000. Tumors arising from the paraganglia are characteristically of low malignant potential. Vertebral metastases are exceedingly rare, and only isolated case reports have described them. The authors present the clinical course of a 47 years-old female patient with a familial paraganglioma [PGL] with vertebral metastastization, who underwent an intralesional tumor excision and corpectomy. Genetic screening demonstrated a new germinal frameshift mutation of the SDHB exon 6 [c.587-591DelC]. After surgery there was normalization of the analytical parameters and imagiologic screening. One year later she presented a new image in the the pedicle of T11 on the contralateral side of the surgical incision. She performed 2 treatments with MIBG and 1 cicle of radiotherapy that made the new lesion regress. Currently the patient does not present any clinical or analytical evidence of new metastasis.This case outlines the clinical course of a patient with a PGL syndrome for whom a rare vertebral metastasis was diagnosed. It highlights the importance of identifying patients with germline SDHB mutations, as these patients are at a high risk of developing malignant disease.

Succinate Dehydrogenase B Subunit Immunohistochemical Expression Predicts Aggressiveness in Well Differentiated Neuroendocrine Tumors of the Ileum

Immunohistochemical loss of the succinate dehydrogenase subunit B (SDHB) has recently been reported as a surrogate biomarker of malignancy in sporadic and familial pheocromocytomas and paragangliomas through the activation of hypoxia pathways. However, data on the prevalence and the clinical implications of SDHB immunoreactivity in ileal neuroendocrine tumors are still lacking. Thirty-one consecutive, advanced primary midgut neuroendocrine tumors and related lymph node or liver metastases from 24 males and seven females were immunohistochemically assessed for SDHB. All patients were G1 tumors (Ki-67 labeling index ≤2%). SDHB immunohistochemistry results were expressed as immunostaining intensity and scored as low or strong according to the internal control represented by normal intestinal cells. Strong positivity for SDHB, with granular cytoplasmatic reactivity, was found in 77% of primary tumors (T), whilst low SDHB expression was detected in 90% of metastases (M). The combined analysis (T+M) confirmed the loss of SDHB expression in 82% of metastases compared to 18% of primary tumors. SDHB expression was inversely correlated with Ki-67 labeling index, which accounted for 1.54% in metastastic sites and 0.7% in primary tumors. A correlation between SDHB expression loss, increased Ki-67 labeling index and biological aggressiveness was shown in advanced midgut neuroendocrine tumors, suggesting a role of tumor suppressor gene.

Succinate dehydrogenase (SDHx) mutations in pituitary tumors: could this be a new role for mitochondrial complex II and/or Krebs cycle defects?

Succinate dehydrogenase (SDH) or mitochondrial complex II is a multimeric enzyme that is bound to the inner membrane of mitochondria and has a dual role as it serves both as a critical step of the tricarboxylic acid or Krebs cycle and as a member of the respiratory chain that transfers electrons directly to the ubiquinone pool. Mutations in SDH subunits have been implicated in the formation of familial paragangliomas (PGLs) and/or pheochromocytomas (PHEOs) and in Carney-Stratakis syndrome. More recently, SDH defects were associated with predisposition to a Cowden disease phenotype, renal, and thyroid cancer. We recently described a kindred with the coexistence of familial PGLs and an aggressive GH-secreting pituitary adenoma, harboring an SDHD mutation. The pituitary tumor showed loss of heterozygosity at the SDHD locus, indicating the possibility that SDHD's loss was causatively linked to the development of the neoplasm. In total, 29 cases of pituitary adenomas presenting in association with PHEOs and/or extra-adrenal PGLs have been reported in the literature since 1952. Although a number of other genetic defects are possible in these cases, we speculate that the association of PHEOs and/or PGLs with pituitary tumors is a new syndromic association and a novel phenotype for SDH defects.

The Heart of the Matter

b l PRESENTATION In this case, a man with multiple cardiac symptoms suffers cardiac arrest during his medical evaluation, is revived, and is then treated for a very unusual tumor. The patient was a 46-year-old, previously healthy man who presented with complaints of shortness of breath and chest heaviness. Further inquiry revealed generalized fatigue and numerous episodes of profuse sweating over the preceding 2 months. A review of systems was otherwise negative.

P1.24 Loss of Succinate Dehydrogenase in Midgut Carcinoids as Prognostic Factor: A New Marker of Personalized Cancer Medicine in Neuroendocrine Tumours?

ABSTRACT Background Gene mutations of the succinate dehydrogenase (SDH) complex have recently been involved in the pathogenesis of cancer cells. These mutations often are associated with SDH subunity B loss of activity and overexpression of HIF-1a, which play a central role in angiogenesis and cell proliferation. The immunoistochemical (IHC) loss of SDHB expression has recently been reported to be a surrogate marker of malignancy in sporadic and familial pheocromocytomas and paragangliomas via activation of hypoxia signals. Aims To evaluate SDHB levels expression in advanced midgut carcinoids and investigate its potential role as prognostic marker. Materials and methods 31 advanced midgut carcinoids were treated in our Istitution, including 24 males and 7 females, aged 55.5 yrs on average (range 19-75). All patients were G1 tumors with stage IV for synchronous liver metastases. 25/31 patients underwent surgical primary resection. IHC evaluation of the SDHB and MIB1 expression were carried out in 19 primary tumors (T) and 19 liver metastases (M). In 11 patients SDHB and MIB1 were tested in both T and M. SDHB was assessed according to the staining intensity scored 1 (low) or 2 (high) on the basis of the internal control represented by normal intestinal cells. Results High (2+) positivity for SDHB, with clear cytoplasmatic mitochondrial reactivity, was found in 14/19 (77%) T, whilst loss of SDHB expression (1+) was detected in 17/19 (90%) M. The combined analysis (T + M) confirmed the loss of SDHB expression in 9/11 (82%) metastases compared to 2/11 (18%) primary tumors. These findings were inversely proportional to Mib-1 distribution that was 1,54% in metastastic sites and 0.7% in the primaries, respectively. Conclusions This preliminary analysis suggests a possible correlation between SDHB expression loss (score 1+), MIB1 increase and biological aggressiveness of advanced midgut carcinoids. A more extensive clinico-biological evaluation is warranted to clarify its relationship with survival and explore the role of SDHB as predictive marker to response of antiangiogenetic agents. Download : Download full-size image Fig. 1 . SDHB immunoreactivity. a. SDHB staining in primitive ileal NET; b. SDHB staining in liver metastasis of ileal NET; c. SDHB staining in lymph node metastasis of ileal NET.

Genetic and clinical characteristics of head and neck paragangliomas in a chinese population

Head and neck paragangliomas (PGLs) are rare and frequently associated with germline mutations of the succinate dehydrogenase (SDH) genes, especially for familial cases. The purpose of the study was to explore genetic and clinical characteristics of head and neck PGLs in a Chinese population. Retrospective review. One hundred thirty-two patients who had undergone resection for head and neck PGLs between 1975 and 2010 were identified. Clinical characteristics and outcomes were reviewed. Analysis of the SDH genes was performed in 29 patients and one kindred with familial PGL to identify germline mutations in the SDHB, SDHC, and SDHD genes by direct DNA sequencing. There were 69 male (52.3%) and 63 female (47.76%) patients, with a mean age of 43.6 years (range, 13-72 years). Most lesions (61.4%) were PGLs of the carotid bifurcation. Others included jugular (25.0%), vagal (9.1%), and tympanic PGLs. Twenty-one patients (15.9%) had multiple PGLs, 25 patients (18.9%) had a malignant PGL, and 15 patients (11.4%) in four families were familial PGLs. Analysis of the SDH genes in 29 patients showed that four familial cases (including two patients) carried a heterozygotic missense mutation in SDHD. The mutation was W43X, located in SDHD-exon 2. Four sporadic cases carried samesense germline mutations in SDHB-exon 1, and they were all malignant PGLs. Multifocal occurrence, potential malignancy, and genetic aspect should be considered in patients with head and neck PGLs. The high frequency of founder mutations in SDHB suggests a higher prevalence of malignancy, and the SDHD mutation is usually associated with familial cases.

A comparison of the performance of 68Ga-DOTATATE PET/CT and 123I-MIBG SPECT in the diagnosis and follow-up of phaeochromocytoma and paraganglioma

To compare the sensitivity of (123)I-metaiodobenzylguanidine (MIBG) SPECT and (68)Ga-DOTATATE PET/CT in detecting phaeochromocytomas (PCC) and paragangliomas (PGL) in the initial diagnosis and follow-up of patients with PCC and PGL disease. Retrospective analysis of 15 patients with PCC/PGL who had contemporaneous (123)I-MIBG and (68)Ga-DOTATATE imaging. Of the 15 patients in the series, 8 were concordant with both modalities picking up clinically significant lesions. There were no patients in whom both modalities failed to pick up clinically significant lesions. There was discordance in seven patients: 5 had positive (68)Ga-DOTATATE and negative (123)I-MIBG, and 2 (12 and 14) had negative (68)Ga-DOTATATE and positive (123)I-MIBG. Utilizing (123)I-MIBG as the gold standard, (68)Ga-DOTATATE had a sensitivity of 80 % and a positive predictive value of 62 %. The greatest discordance was in head and neck lesions, with the lesions in 4 patients being picked up by (68)Ga-DOTATATE and missed by (123)I-MIBG. On a per-lesion analysis, cross-sectional (CT and MRI) and (68)Ga-DOTATATE was superior to (123)I-MIBG in detecting lesions in all anatomical locations, and particularly bony lesions. First, (68)Ga-DOTATATE should be considered as a first-line investigation in patients at high risk of PGL and metastatic disease, such as in the screening of carriers for mutations associated with familial PGL syndromes. Second, if (123)I-MIBG does not detect lesions in patients with a high pretest probability of PCC or PGL, (68)Ga-DOTATATE should be considered as the next investigation. Third, (68)Ga-DOTATATE hould be considered in preference to (123)I-MIBG in patients in whom metastatic spread, particularly to the bone, is suspected.

Screening of Mutations in Genes that Predispose to Hereditary Paragangliomas and Pheochromocytomas

Thirty per cent of the paragangliomas and pheochromocytomas reported are hereditary. Mutations in SDHB, SDHC, SDHD, and more recently SDHAF2 and TMEM127 genes have been described in these hereditary tumors. We looked for mutations in these 5 genes in a series of 269 patients with paragangliomas and/or pheochromocytomas. The SDHB, SDHC, and SDHD genes were analyzed in a series of 269 unrelated index patients with paragangliomas and/or pheochromocytomas using dHPLC screening of point mutations followed by direct sequencing and Multiplex PCR Liquid Chromatography to detect large rearrangements confirmed by quantitative PCR. In a second phase, we adapted Multiplex PCR Liquid Chromatography to the SDHAF2 and TMEM127 genes. This method and direct sequencing were applied to 230 patients without the SDHB, C, D mutations. Of the 269 patients, 44 carried a mutation (16.3%). Thirty-seven different mutations were identified: 18 in SDHB (including 2 large deletions), 8 in SDHD, 6 in SDHC, 5 in TMEM127, and no mutations in SDHAF2. Thirteen mutations have not been published so far. An exhaustive study of the different genes is needed to make possible a familial genetic diagnosis in paraganglioma and pheochromocytoma hereditary syndromes. Although mutations in SDHC and TMEM127 are less frequent than mutations in SDHB and SDHD, they also have less evident clinical feature indicators. Analyzing SDHAF2 must be restricted to familial extra-adrenal paragangliomas. Multiplex PCR Liquid Chromatography is a sensitive, fast, and inexpensive method for screening large rearrangements, which are infrequent in these syndromes.

Sporadic or familial head neck paragangliomas enrolled in a single center: Clinical presentation and genotype/phenotype correlations

The purpose of this study was to investigate clinical features and prevalence of germline mutations of patients with head/neck paragangliomas. Genetic analysis on known susceptibility genes for paragangliomas (VHL, RET, SDHB, SDHC, SDHD, and SDHAF2) was performed in 17 consecutive patients with head/neck paraganglioma (age range, 14-82 years) and 17 relatives. Head/neck paragangliomas were usually symptomatic with "mass effect" (88.2%), without family history (82.3%), often multifocal (41.2%), never functioning, and malignant. Germline mutations were detected in 7 of 17 patients (41%; 6 SDHD and 1 SDHB). Patients with mutations were younger, with head/neck paragangliomas usually multifocal and with higher biologic aggressiveness than wild-type subjects. To date, 4 families have been studied and the prevalence of carriers was elevated (58.8%). These mutated relatives (age range, 17-71 years) were disease-free, except 4 patients in whom multiple head/neck paragangliomas were detected. Adequate morpho-functional screening and follow-up and, if possible, genetic testing is advisable in patients with head/neck paraganglioma.

Gastrointestinal Stromal tumor of the stomach and retroperitoneal paraganglioma in Saudi woman, “A case report”

Gastrointestinal stromal tumor (GIST) and paraganglioma are uncommon tumors; mostly occur in a sporadic and isolated form. They are occasionally components of 3 clinical syndromes, familial paraganglioma and gastric GIST, neurofibromatosis type 1 and Carney triad. The latter does not show genetic mutations and affects young women predominantly. This article reports the occurrence of GIST and retroperitoneal paraganglioma in young Saudi woman aged 22 years. The initial clinical presentation was acute severe gastric bleeding. Gastric mass with retroperitoneal mass was discovered during surgical exploration. Histological and immunohistochemical study of both masses showed features of GIST and paraganglioma. The combination of GIST and retroperitoneal paraganglioma in the reported case may be incomplete expression of Carney triad or be coincidental occurrence.

Gastrointestinal Stromal tumor of the stomach and retroperitoneal paraganglioma in Saudi woman, “A case report”

Gastrointestinal stromal tumor (GIST) and paraganglioma are uncommon tumors; mostly occur in a sporadic and isolated form. They are occasionally components of 3 clinical syndromes, familial paraganglioma and gastric GIST, neurofibromatosis type 1 and Carney triad. The latter does not show genetic mutations and affects young women predominantly. This article reports the occurrence of GIST and retroperitoneal paraganglioma in young Saudi woman aged 22 years. The initial clinical presentation was acute severe gastric bleeding. Gastric mass with retroperitoneal mass was discovered during surgical exploration. Histological and immunohistochemical study of both masses showed features of GIST and paraganglioma. The combination of GIST and retroperitoneal paraganglioma in the reported case may be incomplete expression of Carney triad or be coincidental occurrence.

Genetic-clinical profile of subjects with apparently sporadic extra-adrenal paragangliomas

Background: Mutations in the genes encoding B, C, and D subunits of the succinate dehydrogenase (SDH) are involved in the pathogenesis of familial paraganglioma (PGL) syndrome. Many subjects with apparently sporadic extra-adrenal paragangliomas are found to be carrier for SDH mutation. Objective: Here we describe four subjects with apparently sporadic extra-adrenal paragangliomas with newly identified mutations in the SDH subunit B and the related clinical phenotype. Methods: Gene sequencing was performed to search for mutations in the SDHB (all exons), SDHC (all exons), and SDHD (all exons) genes as well as VHL (all exons) and RET (10, 11, 13, 14, 15, 16 exons) genes in all four index cases. A complete clinical, biochemical, and instrumental work-up was performed. Results: Three subjects were found to be affected with a nonsense SDHB germline mutation (Q30X, Y61X, and W201X, respectively). These mutations are predicted to encode for a truncated SDHB protein. The fourth subject presented a S195del frameshift mutation, causing a deletion of the codon AGC, encoding for a serine. Clinical presentation and course of each patient is described. Conclusions: Extra-adrenal paragangliomas, localized in the sympathetic ganglia (in the posterior thorax or in the abdomen), are very often SDHB-inherited form rather than sporadic tumor. Our data confirm the importance of genetic screening in patients affected with paragangliomas and enlarge the list of mutations responsible for the presence of these tumors.

Surgical Management of the Succinate Dehydrogenase–Associated Familial Paraganglioma Syndromes

Paragangliomas are rare neuroendocrine tumors arising from the neural crest cells in the extra-adrenal location. Paragangliomas can be sporadic or associated with a range of endocrine and genetic syndromes in 25% to 30% of all cases. Specifically, succinate dehydrogenase gene mutations are involved in the development of paraganglioma syndromes type 1 through type 4. In this article, we will describe 2 cases of succinate dehydrogenase-associated familial paraganglioma syndrome and provide a review of the existing literature on the condition's etiologic factors, diagnosis, and management.

Comparison of clinical and imaging features in succinate dehydrogenase-positive versus sporadic paragangliomas

Limited data exist concerning the clinical and imaging features that distinguish sporadic from familial paragangliomas (PGLs). Clinical, genetic (succinate dehydrogenase [SDHB] vs no SDHx), and imaging (computed tomography [CT], magnetic resonance imaging, (18)F-fluoro-deoxy-glucose positron emission tomography [(18)F-FDG-PET]) features obtained during a decade in 124 PGL patients were studied. Data were analyzed by Fisher's exact test or Wilcoxon rank-sum test. Mean age at diagnosis was younger in the SDHB-positive (SDHB+) group compared with the sporadic (no SDHx) group (28 vs 39 years, respectively, P < .001). Rate of supradiaphragmatic neoplasms were greater in the SDHB+ group (16.7 vs 4.7%, P = .11). Metastasis rates were greater in the SDHB+ group (78.9 vs 48.3%, P < .001), as was the existence of metastases or multiple PGLs at presentation (38.5 vs 16.7%, P < .05). Tumor volumes >250 mL were exclusively observed in SDHB+ patients (P < .05). On CT, SDHB+ tumors were more enhanced (P < .05). On (18)F-FDG-PET, SDHB+ tumors' had greater mean standard uptake values (12.3 vs 8.0, P < .05). Clinically young age, large tumor volume, greater rate of metastatic and multifocal PGLs, greater SUV values on (18)F-FDG-PET, and increased CT enhancement are observed in SDHB+ PGLs. These findings may warrant genetic screening. Because SDHB+ patients demonstrate more supradiaphragmatic lesions, whole-body imaging may be of particular value in these patients.

Paragangliomas múltiples asociados a mutación del gen SDHB: Caso clínico

Paragangliomas are tumors arising from sympathetic and parasympathetic tissues. The classic associated syndromes are neurofibromatosis type 1, multiple endocrine neoplasia type 2 and von Hippel-Lindau. Germline mutations of succinate dehydrogenase subunits genes, are associated with familial paraganglioma syndromes 1,2,3 and 4. We report a 29-year-old woman with a family background of pheochromocytoma and history of paroxysmal headache, nausea, sweating, palpitations, associated with severe hypertension. The patient had elevated plasma noradrenalin and urinary normetanephrines. Imaging studies revealed three retroperitoneal extra-adrenal masses. The clinical and laboratory study of classic syndromes associated with paraganglioma was negative. The patient was operated and the pathological study of the surgical specimen was consistent with paragangliomas. The genetic study showed a mutation in the SDHB succinate dehydrogenase gen, Exon 2 of CCTCA c.300_304 (p.P56delYfsX5).

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.

Pheochromocytoma

Pheochromocytoma

Long-term outcomes, branch-specific expressivity, and disease-related mortality in von Hippel-Lindau type 2A

Although a large kindred with familial pheochromocytoma (Pheo) and paraganglioma (PGL) was discovered in 1962 and later found to represent von Hippel-Lindau (VHL) type 2A (mutation Y112H), the phenotype lacks current characterization. Branch-specific expressivity was suspected based on oral family history. Family pedigree analysis, prospective interviews, and extensive record review were used to extend the pedigree, determine phenotype, examine branch-specific expression, and analyze mortality rates over 5 decades. In its 3 known affected branches the kindred now comprises 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. The mean ages for VHL and Pheo/PGL diagnosis were younger in successive generations. Branch II-4 predominately expressed RA, while branch II-5 predominantly expressed Pheo/PGL. Disease-specific mortality occurred early and was less frequent in successive generations. This analysis of Y112H VHL confirms a high cumulative risk for pheochromocytoma/paraganglioma. Over time, both age at diagnosis and disease-specific mortality have decreased. The observed branch-specific expressivity prompts further study of genetic and environmental disease modifiers in this large family.

A novel SDHD mutation associated with neck paraganglioma

The aim of this study was to describe a previously unreported mutation in the SDHD gene, which has been linked to familial paraganglioma. Clinical data were collected from all members of the family, which had four siblings affected with paraganglioma. For the index patient, genomic DNA extraction from whole blood was performed using the High Pure PCR Template Preparation kit. The nucleotide sequence in the index patient revealed a deletion in the SDHD gene, c.165_169+14del. The loss of nucleotides in the DNA led to production of an anomalous protein. RNA analysis showed the absence of exon 2 in the sequence that corresponded to the mRNA from the index case. Genetic testing of this deletion was extended to the symptomatic and asymptomatic brothers and sisters of the index patient and other family members at risk. The deletion was detected in both symptomatic brothers, in accordance with their phenotype, but not in the asymptomatic sister. In the other asymptomatic brother (II.7) the deletion was detected and magnetic resonance angiography revealed the vascular characteristics of two tumors in both carotid bifurcations. Thus, we report a novel punctual mutation in the SDHD gene, which is related to familial paraganglioma: the deletion was c.165_169 + 14del.

Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism

To investigate the SDHAF2 gene and its effect on primary hyperparathyroidism. Parathyroid tumors causing primary hyperparathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in parathyroid tumors occurring in about 40% of sporadic tumors. Only 15-19% display somatic mutations in the MEN1 gene, which suggest that this chromosomal region may harbor additional genes of importance in parathyroid tumor development. The SDHAF2 (formerly SDH5) gene is a recently identified neuroendocrine tumor suppressor gene at this locus, and inherited mutations of the SDHAF2 gene has been linked to familial paraganglioma. We demonstrate that the SDHAF2 gene is expressed in parathyroid tissue using RT-PCR. Because detection of inactivating mutations is the major criterion for validating a candidate tumor suppressor, we used automated sequencing of the coding region and intron/exon boundaries in 80 sporadic parathyroid adenomas from patients with pHPT. A known polymorphisms (A to G substitution; rs879647) was identified in 9/80 parathyroid tumors but no tumor-specific somatic mutational aberrations, such as nonsense, frameshift, or other inactivating mutations were identified. The SDHAF2 gene is expressed in parathyroid tissue. However, somatic mutations of the SDHAF2 tumor suppressor gene are unlikely to frequently contribute to parathyroid tumor development in sporadic pHPT.