18F-FDG avidity of pheochromocytomas and paragangliomas: a new molecular imaging signature?

UNLABELLED: Our objective was to evaluate (18)F-FDG PET uptake in patients with nonmetastatic and metastatic chromaffin-derived tumors. METHODS: Twenty-eight consecutive unrelated patients with chromaffin tumors, including 9 patients with genetically determined disease, were studied. A combination of preoperative imaging work-up, surgical findings, and pathologic analyses was used to classify the patients into 2 groups: those with nonmetastatic disease (presumed benign, n = 18) and those with metastatic tumors (n = 10). (18)F-FDG PET was performed in all cases. Visual and quantitative analyses were individually graded for each tumor. Somatic mutations of the succinate dehydrogenase subunits B and D and Von-Hippel Lindau genes were also evaluated in 6 benign sporadic tumor samples. RESULTS: All but 2 patients showed significantly increased (18)F-FDG uptake on visual analysis. The maximum standardized uptake value (SUVmax) ranged from 1.9 to 42 (mean +/- SD, 8.2 +/- 9.7; median, 4.6) in nonmetastatic tumors and 2.3 to 29.3 (mean +/- SD, 9.7 +/- 8.4; median, 7.4) in metastatic tumors. No statistical difference was observed between the groups (P = 0.44), but succinate dehydrogenase-related tumors were notable in being the most (18)F-FDG-avid tumors (SUVmax, 42, 29.3, 21, 17, and 5.3). Succinate dehydrogenase and Von-Hippel Lindau-related tumors had a significantly higher SUVmax than did neurofibromatosis type 1 and multiple endocrine neoplasia type 2A syndrome-related tumors (P = 0.02). (18)F-FDG PET was superior to (131)I-metaiodobenzylguanidine in all metastatic patients but one. By contrast, (18)F-FDG PET underestimated the extent of the disease, compared with 6-(18)F-fluorodopa PET, in 5 patients with metastatic pheochromocytoma. However, succinate dehydrogenase mutations (germline and somatic) and functional dedifferentiation do not adequately explain (18)F-FDG uptake since most tumors were highly avid for (18)F-FDG. CONCLUSION: (18)F-FDG PET positivity is almost a constant feature of pheochromocytomas and paragangliomas. It may be considered a molecular signature of such tumors, although which aspect of the plethora of molecular changes associated with dedifferentiation, germline genetic defects, or the adaptive response to hypoxia is responsible for this characteristic requires further elucidation.

Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: a comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines).

BACKGROUND: Thymic neuroendocrine tumors (Th-NET) present a poor prognosis for patients with multiple endocrine neoplasia type 1 (MEN1). The purpose of this article was to study the clinical, biological, and pathological features of Th-NET in a large cohort of patients with MEN1. METHODS: The 761-patient MEN1 cohort from the GTE registry was used (Groupe des Tumeurs Endocrines). RESULTS: The actuarial probability of occurrence was 2.6% (range, 1.3-5.5%) at aged 40 years. All, except one, Th-NET patients were men. Four patients had no other associated lesions. The youngest patient was aged 16 years. Mean age at the time of diagnosis was 42.7 (range, 16.1-67.5) years. The 10-year probability of survival was 36.1% (range, 11.5-62%). Seven patients (33%) belonged to clustered MEN1 families. The spectrum of associated lesions in patients with Th-NET was not statistically different from the spectrum of the remainder of the cohort. Various endocrine markers were high, but none were sensitive or specific enough to be useful for Th-NET detection. CT-scan and MRI were always positive at the time of diagnosis. No particular mutation was found to be associated with Th-NET. Five cases underwent prophylactic thymectomy without success. CONCLUSIONS: Several end points may be helpful for future guidelines: (1) earlier detection of Th-NET in MEN1 patients is required; (2) screening of both sexes is necessary; (3) a prospective study comparing MRI vs. CT scan in yearly screening for Th-NET is needed; (4) a reinforced screening program must be established for patients who belong to clustered families; and (5) thymectomies must be performed in specialized centers.

Mutations associated with succinate dehydrogenase D-related malignant paragangliomas.

OBJECTIVE: Hereditary paraganglioma (PGL) syndromes result from germline mutations in genes encoding subunits B, C and D of the mitochondrial enzyme succinate dehydrogenase (SDHB, SDHC and SDHD). SDHB-related PGLs are known in particular for their high malignant potential. Recently, however, malignant PGLs were also reported among a small minority of Dutch carriers of the SDHD founder mutation D92Y. The aim of the study was to investigate which SDHD mutations are associated with malignant PGL. DESIGN: Case histories; collaborative study between referral centres in France, the USA, and the Netherlands. PATIENTS: Six unrelated patients with metastatic PGLs of either sympathetic or parasympathetic origin. MEASUREMENTS: Assessment of SDHD mutations underlying malignant PGL. RESULTS: Germline SDHD mutations underlying metastatic PGL were G148D, Y114X, L85X, W43X, D92Y, and IVS2+5G-->A. CONCLUSION: Our findings indicate that malignant SDHD-related PGL is associated with several mutations besides D92Y.

Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A.

Germ line missense mutations in the RET proto-oncogene are responsible for the inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). The clinical presentation of the disease and the age at onset varies even within families, where patients carry the same mutation. These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset. Here, we investigate whether this observed association could be confirmed in a larger set of 384 individuals from MEN2 families from four different European populations. In addition, we tested as modifiers four other single nucleotide polymorphisms (SNPs), which we have found in a previous association study of RET, its coreceptors, and ligands to be associated with the risk of developing sporadic medullary thyroid carcinoma. We could not replicate the association between G691S/S904S and modifier effects in MEN2A families in any of the four European families analyzed. Of the other SNPs tested, only RET A432A showed a positive weak effect on tumor spectrum within MEN2A, which requires replication in a larger series.

Early malignant progression of hereditary medullary thyroid cancer.

BACKGROUND: An age-related progression from C-cell hyperplasia to medullary thyroid carcinoma is associated with various germ-line mutations in the rearranged during transfection (RET) proto-oncogene that could be used to identify the optimal time for prophylactic surgery. METHODS: In this European multicenter study conducted from July 1993 to February 2001, we enrolled patients who had a RET point mutation in the germ line, were 20 years of age or younger, were asymptomatic, and had undergone total thyroidectomy after confirmation of the RET mutation. Exclusion criteria were medullary thyroid carcinomas of more than 10 mm in greatest dimension and distant metastasis. RESULTS: Altogether, 207 patients from 145 families were identified. There was a significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, nodal metastasis in patients whose RET mutations were grouped according to the extracellular- and intracellular-domain codons affected and in those with the codon 634 genotype. No lymph-node metastases were noted in patients younger than 14 years of age. The age-related penetrance was unaffected by the type of amino acid substitution encoded by the various codon 634 mutations. The codon-specific differences in the age at presentation of cancer and the familial rates of concomitant adrenal and parathyroid involvement suggest that the risk of progression was based on the transforming potential of the individual RET mutation. CONCLUSIONS: These data provide initial guidelines for the timing of prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations.

Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.

CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland. MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined. RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008). CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.

Genetic testing in pheochromocytoma or functional paraganglioma.

PURPOSE: To assess the yield and the clinical value of systematic screening of susceptibility genes for patients with pheochromocytoma (pheo) or functional paraganglioma (pgl). PATIENTS AND METHODS: We studied 314 patients with a pheo or a functional pgl, including 56 patients having a family history and/or a syndromic presentation and 258 patients having an apparently sporadic presentation. Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria. RESULTS: We have identified 86 patients (27.4%) with a hereditary tumor. Among the 56 patients with a family/syndromic presentation, 13 have had neurofibromatosis type 1, and germline mutations on the VHL, RET, SDHD, and SDHB genes were present in 16, 15, nine, and three patients, respectively. Among the 258 patients with an apparently sporadic presentation, 30 (11.6%) had a germline mutation (18 patients on SDHB, nine patients on VHL, two patients on SDHD, and one patient on RET). Mutation carriers were younger and more frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, more frequently extra-adrenal, and malignant. CONCLUSION: Genetic testing oriented by family/sporadic presentation should be proposed to all patients with pheo or functional pgl. We suggest an algorithm that would allow the confirmation of suspected inherited disease as well as the diagnosis of unexpected inherited disease.

Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature.

Cushing's syndrome (CS) in medullary thyroid carcinoma (MTC) is rare. Only 50 cases have been reported. We report 10 cases of MTC with ectopic adrenocorticotropic hormone (ACTH)-dependent syndrome (EAS), analyzed retrospectively. Among 1640 patients with MTC, 13 developed EAS (0.7%). In 10 patients CS could unequivoqually be related to MTC (0.6%). CS was always clinically obvious. It revealed MTC in 3 cases and followed diagnosis by an average of 34.5 months in the others. Metastases were often present at diagnosis. Immunohistochemistry with ACTH antibodies was positive in one case. Diagnosis of ectopic CS was established according to clinical and biologic features, and absence of corticotropic adenoma as well as parallel evolution between tumor and CS. Therapy was medical and surgical: anticortisolic drugs alone or in association with somatostatin analogue, somatostatin analogue alone, and bilateral adrenalectomy. Eight patients died within 2 to 30 months, 4 of hypercortisolism complications (3 peritonitis and 1 hypokalaemia), 4 of MTC progression. EAS is a rare complication of MTC. The prognosis is poor because of frequency of metastasis at diagnosis. Persistent hypercortisolism can, by itself, lead to death, and has to be treated specifically.

When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations?

BACKGROUND: Once familial medullary thyroid carcinoma gene carrier status is established, thyroidectomy must be performed in infancy for mutations in exon 10, but in familial medullary thyroid carcinoma with non-cysteine RET mutations, which is characterized by a late onset of C-cell disease, the appropriate timing of thyroidectomy is unclear. METHODS: We analyzed the cases of 76 patients who underwent thyroidectomy (mean age, 35.2 years); 66 patients underwent concomitant lymphadenectomy. RESULTS: Before the operation, 35 patients had abnormal basal calcitonin levels. Nine and 30 patients had negative or positive pentagastrin test results, respectively. We found normal thyroid in 4% of the patients, C-cell hyperplasia in 29% of the patients, medullary thyroid carcinoma in 67% of the patients (microscopic in 82.4%), and nodal metastases in 19.6% of the patients. The aggressiveness of the disease varied significantly between those patients with preoperative positive pentagastrin test results and those patients with high basal calcitonin levels, with a surgical cure rate of 60% and 34.3%, respectively. All patient who did not achieve cure had high basal preoperative calcitonin levels, which were related to macroscopic medullary thyroid carcinoma and nodal metastases in 5 of 9 patients. CONCLUSION: Thyroidectomy should not be delayed until basal calcitonin level becomes abnormal, at which time advanced disease may be present. As soon as the pentagastrin stimulation test becomes abnormal, operation should be undertaken on early staged disease to achieve cure for the patient. When performed while pentagastrin stimulation test is still negative, thyroidectomy may be truly prophylactic and should be recommended at 5 to 6 years.

Cervical paragangliomas: is SDH genetic analysis systematically required?

To evaluate the prevalence of succinate dehydrogenase (SDH) B, C, and D germline mutations in a surgical series of cervical paragangliomas and to precise the characteristics of patients presenting with familial form. Among 29 patients operated on cervical paragangliomas (carotid or vagal body) at our institution between 1994 and 2007, 23 could be asked for a genetic analysis and a familial study. Clinical characteristics of patients harboring a germline SDH mutation were studied and compared with those presenting without mutation. Mutations were found in 8/23 (35%) patients, mostly in SDHD gene (6 cases), and in SDHB and SDHC gene, respectively, in one case each. Mean age at onset was significantly lower for patients with mutation (34 vs. 51.5 years, P = 0.01). In patients presenting with a mutation, 50% had a family history of paraganglioma compared with 0% for others (P = 0.008) and 87.5% had a multifocal form of paragangliomas versus 0% for others (P = 0.001). No difference was found concerning malignant forms between the two groups (12.5 vs. 13.3%). In the 16 patients who had an apparently sporadic paraganglioma, 6% had mutations in the SDH gene. A positive family history of paraganglioma and/or the presence of bilateral or multiple paragangliomas and/or an early age of onset are the main parameters associated with SDH mutations. Genetic testing should be considered for all patients with a cervical paraganglioma, even for those presenting with an apparently sporadic tumor as familial form may be such identified in 6% of cases.

Endocrine pancreatic tumors in von Hippel-Lindau disease: clinical, histological, and genetic features.

OBJECTIVES: Endocrine pancreatic tumors (EPTs) in von Hippel-Lindau (VHL) disease pose difficult management problems. We aimed to assess (1) the accuracy of somatostatin receptor scintigraphy, (2) histological features with focus on malignancy and genotype-phenotype correlations, and (3) prognosis of VHL-EPT. METHODS: Thirty-five patients with EPT-VHL (20 women; median age, 37 years) from 29 families were studied. Histological diagnosis was available in 29 patients. Endocrine pancreatic tumor patients were treated surgically (n = 22), medically (n = 8), or followed (n = 5). Somatostatin receptor scintigraphy was performed in 27 patients. Germinal alterations of the VHL gene were determined. RESULTS: Tumors were malignant in 58% of patients. Somatostatin receptor scintigraphy was positive in 60% of cases, and weak expression of the somatostatin receptor type 2A was found in 47% of tumors. In operated patients, there was no mortality or tumor relapse (median follow-up, 5 [1-10] years). Mortality rate due to EPT was 6%. Germinal mutations were mainly located in exons 3 and 1, and a specific mutation (P86S) was identified. CONCLUSIONS: Most EPTs in VHL patients are somatostatin receptor scintigraphy-positive and malignant, without correlation with the VHL genotype. Surgical resection is often required, but prognosis of these EPTs seems to be fairly good.

Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas.

OBJECTIVE: To analyze the penetrance and clinical course of isolated nonfunctioning tumors of the pancreas (NFTP) in MEN 1 patients, and to propose a strategy for managing them. SUMMARY BACKGROUND DATA: Pancreaticoduodenal tumors develop in a majority of MEN 1 patients and are a major cause of death. The natural history of NFTP is poorly defined, and no clear-cut guidelines have been widely accepted regarding treatment. METHODS: Data on 108 patients with isolated NFTP among 579 MEN 1 patients from the French Endocrine Tumor Study Group (GTE) were analyzed. Survival rates were calculated using the Kaplan-Meier method. RESULTS: The penetrance of NFTP was 34% at age 50, making it the most frequent pancreaticoduodenal tumor in MEN 1 patients. Forty-three patients (40%) underwent surgery, 32 of them curatively. No patient died because of surgery. Average life expectancy for patients with NFTP was shorter than that for MEN 1 patients who did not have pancreaticoduodenal tumors. Thirteen patients died during follow-up, 10 due to NFTP. Tumor size was correlated with the risks of metastasis and death. These risks were low for patients with tumors

Is surgery beneficial for MEN1 patients with small (< or = 2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE.

BACKGROUND: The management of small, nonfunctioning pancreaticoduodenal endocrine tumors (NFPET) in multiple endocrine neoplasia type 1 (MEN1) patients is still controversial. We therefore investigated the effect of surgery on survival and tumor progression in MEN1 patients with NFPET < or = 2 cm by analyzing data from the Groupe des Tumeurs Endocrines (GTE) registry. MATERIALS AND METHODS: Among 579 MEN1 patients in the registry, 65 had NFPET < or = 2 cm. Fifteen (23%) underwent pancreatectomy, 9 at least segmental pancreatectomies and 6 biopsies or enucleations (the surgery group), and 50 (77%) were followed conservatively (the no surgery group). Age at MEN1 and NFPET diagnosis was similar in both groups, as was size of the primary tumor. Seven (10.8%) patients had metastases. Five metastases were synchronous, and 2 (one in each group) were metachronous. Tumor size was similar in patients with or without metastasis. RESULTS: There was no perioperative mortality. The average follow-up time after NFPET diagnosis was 6.7 years in the surgery group and 3.3 years in the no surgery group. Three (4.6%) patients died during follow-up, 2 due to NFPET and 1 due to thymus tumor. The 2 patients who died of NFPET had undergone pancreatic surgery at the time of NFPET diagnosis. The 2 groups did not differ significantly with respect to tumor progression [5/15 (33%) vs 6/38 (16%), P = 0.16]. Overall life expectancy of patients with NFPET < or = 2 cm was not different than that of the 229 MEN1 patients in the registry without any pancreaticoduodenal tumor (P = 0.33). CONCLUSIONS: This study suggests that surgery may not be beneficial for MEN1 patients with NFPET < or = 2 cm.

Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1.

BACKGROUND: The frequency of pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1 (MEN1) remains unknown. AIM: To evaluate prospectively with endoscopic ultrasonography (EUS) the frequency of nonfunctioning (asymptomatic) pancreaticoduodenal tumors. PATIENTS AND METHODS: MEN1 patients without functioning pancreatic involvement underwent systematic pancreaticoduodenal EUS in nine GTE (Groupe des Tumeurs Endocrines) centers. Demographic and clinical factors predictive of pancreatic involvement were sought, and standardized biochemical measurements obtained. RESULTS: Between November 1997 and July 2004, 51 patients (median age: 39 [range: 16-71] yr) were studied. MEN1 had been diagnosed 3 [0-20] yr earlier, notably by genetic screening for 26 (51%) with asymptomatic disease. Twenty-five patients had minor biochemical anomalies (<2 x normal (N)) and serum somatostatin was 10.8 N in 1; EUS detected pancreatic lesions in 28 patients (54.9%; 95% CI: 41.3-68.7%). A median of three [1-9] tumors with a median diameter of 6 [2-60] mm was found per patient; for 19 (37.3%) patients a tumor measured > or =10 mm and > or = 20 mm in 7 (13.7%) patients. Only one duodenal lesion was found and three patients had peripancreatic adenopathies. Pancreatic tumors were not associated with any of the studied parameters, notably age, family history, biochemical anomalies. Sixteen of twenty-six patients underwent EUS monitoring over 50 [12-70] months; six (37.5%) had more and/or larger pancreatic lesions. CONCLUSION: The frequency of nonfunctioning pancreatic endocrine tumors is higher (54.9%) than previously thought. The size and number of these tumors can increase over time. Pancreatic EUS should be performed once MEN1 is diagnosed to monitor disease progression.

Can sporadic medullary thyroid carcinoma be biochemically predicted? Prospective analysis of 66 operated patients with elevated serum calcitonin levels.

Measuring serum calcitonin (CT) in patients with thyroid diseases allows preoperative diagnoses of sporadic medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH). The aim of this prospective study was to distinguish biochemically between CCH and MTC. Basal CT (bCT) was determined in 7276 consecutive patients referred for thyroid disease. Patients with recurrent, persistent, or familial MTC were excluded. When bCT was > 10 pg/ml a pentagastrin-stimulated CT (sCT) assay was performed. Patients were routinely operated on when bCT > 30 pg/ml or sCT > 100 pg/ml or when other indications for surgery were present. An extensive search for CCH or microscopic MTC was conducted by immunochemistry. Pathologic findings were correlated with the bCT and sCT values. In this study 66 patients were included. No morphologic alterations of C-cells were observed in 5 patients; 16 patients presented with CCH and 45 with MTC. Statistical analysis revealed a correlation of sCT and overall bCT with tumor size and staging (p <0.001). Considering cutoff values for bCT of < or = 30 pg/ml and for sCT of < or = 200 pg/ml, the positive predictive value of the test to detect MTC was 100% and the negative predictive value 63%. No patients with MTC at stage 2 to 4 had bCT <30 pg/ml or sCT <200 pg/ml. A bCT value of < or = 30 pg/ml or sCT < or = 200 pg/ml (or both) is highly predictive of MTC, requiring total thyroidectomy with lymph node dissection. Values of bCT <30 pg/ml and sCT <200 pg/ml do not distinguish between CCH and MTC at stage 1. In this case total thyroidectomy at least is recommended, and the role of nodal dissection might be discussed.