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B Gatta-Cherifi, O Chabre, A Murat, P Niccoli, C Cardot-Bauters, V Rohmer, J Young, B Delemer, H Du Boullay, M F Verger, J M Kuhn, J L Sadoul, Ph Ruszniewski, A Beckers, M Monsaingeon, E Baudin, P Goudet and A Tabarin

Objective

Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management.

Methods

Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas.

Results

Adrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC.

Conclusions

Adrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone–renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour.

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V:1. MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

V:1:1. Introduction

The presence of tumors in various endocrine organs is known under the term multiple endocrine neoplasia (MEN) syndrome. The first type, MEN 1, is characterized by the combined occurence of tumours of the pituitary gland and pancreatic islets and by hyperparathyroidism. The frequent association of medullary thyroid carcinoma (MTC) with adrenal phaeochromocytoma was first described by Sipple in 1961(1) and later called MEN 2. This is an autosomal dominant inherited disorder with a high degree of penetrance but varying in expression (2,3). MEN 2 is subdivided by Sizemore (4) into two phenotypes: MEN 2A and 2B. Type 2A or Sipple's syndrome is characterized by the occurrence of multifocal C-cell hyperplasia or medullary thyroid carcinoma, bilateral intra- and extra-adrenal phaeochromocytomas and hyperplasia, adenoma or even carcinoma of one or more of the parathyroid glands (5,6). Type 2B, the mucosoneural phenotype, is characterized by the

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Anouk Scholten, Menno R Vriens, Geert Jan E Cromheecke, Inne H M Borel Rinkes and Gerlof D Valk

Objective

Hemodynamic (HD) instability still underlies difficulties during pheochromocytoma resection. Little is known about HD instability in patients with multiple endocrine neoplasia (MEN) type 2-related pheochromocytoma. Our aim was to assess differences in HD during pheochromocytoma resection between MEN2 and non-MEN patients. In addition, we sought to identify risk factors for intraoperative HD instability.

Design

Retrospective cohort study.

Methods

A total of 22 MEN2 and 34 non-MEN patients underwent 61 pheochromocytoma resections at the University Medical Center Utrecht between 2000 and 2010. All MEN2-related pheochromocytomas were diagnosed by annual screening. HD instability was assessed by measuring the frequency of hypotensive (mean arterial blood pressure (MABP) <60 mmHg) and/or hypertensive (systolic arterial blood pressure (SABP) >200 mmHg) episodes.

Results

Compared with non-MEN patients, MEN2 patients were younger at diagnosis, had less symptoms, lower hormone levels, and smaller tumors. Intraoperatively, MEN2 patients had a similar frequency of hypertensive episodes (1.3 vs 1.9, P=0.162, 95% confidence interval (CI): −6.7 to 35.4) and a similar maximum SABP (200 vs 220 mmHg, P=0.180, 95% CI: −9.7 to 50.5). However, MEN2 patients experienced less frequent (1.04 vs 2.6, P=0.003, 95% CI: 0.57 to 2.6) and less severe hypotensive episodes after tumor resection (lowest MABP: 52.5 vs 45.6 mmHg, P=0.015, 95% CI: −12.6 to 1.16). Tumor size was an independent risk factor for HD instability for the total group after multivariate analysis.

Conclusion

MEN2 patients with pheochromocytoma, despite their smaller tumors, do not distinguish themselves from non-MEN patients in terms of hypertensive episodes during pheochromocytoma resection. Therefore, pretreatment with α- and β-blockade remains the standard of care in MEN2-related as well as in non-MEN-related pheochromocytomas.

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Sylvia L. Asa, William Singer, Kalman Kovacs, Eva Horvath, David Murray, Nicholas Colapinto and Michael O. Thorner

Abstract. We report the first documentation of GHRH production by a tumour associated with proven multiple endocrine neoplasia (MEN). A 30-year-old woman had hypoglycaemia, hyperparathyroidism, and pituitary adenoma with hyperprolactinaemia. Serum growth hormone elevation was attributed to hypoglycaemia but plasma GHRH was elevated. Subtotal pancreatectomy revealed multiple endocrine tumours and nesidioblastosis. Immunohistochemistry demonstrated insulin, glucagon, and somatostatin in several tumours. GHRH was localized in the largest one and was released from that tumour in vitro. Post-operative plasma GH returned to normal. Excess secretion of humoural factors by one tumour may stimulate growth of other tumours in MEN syndromes. The prevalence of GHRH in MEN-I tumours remains to be established.

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Nicolasine D Niemeijer, Johannes A Rijken, Karin Eijkelenkamp, Anouk N A van der Horst-Schrivers, Michiel N Kerstens, Carli M J Tops, Anouk van Berkel, Henri J L M Timmers, Henricus P M Kunst, C René Leemans, Peter H Bisschop, Koen M A Dreijerink, Marieke F van Dooren, Jean-Pierre Bayley, Alberto M Pereira, Jeroen C Jansen, Frederik J Hes, Erik F Hensen and Eleonora P M Corssmit

Objective

Succinate dehydrogenase B subunit (SDHB) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations.

Design

Retrospective descriptive study.

Methods

Retrospective descriptive study in seven academic centers.

Results

We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives. Mean age was 44.8 ± 16.0 years. Median duration of follow-up was 2.6 years (range: 0–36). Sixty persons (30.9%) carried the exon 3 deletion and 46 (23.7%) the c.423 + 1G > A mutation. Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas, 4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas. Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors. At study close, there were 111 (57.2%) unaffected mutation carriers. Statistical analyses showed no significant differences in the number and location of head and neck paragangliomas, sympathetic paragangliomas or pheochromocytomas, nor in the occurrence of metastatic disease or other tumors between carriers of the two founder SDHB mutations (exon 3 deletion vs c.423+ 1G > A).

Conclusions

In this nationwide study of disease-affected and unaffected SDHB mutation carriers, we observed a lower rate of metastatic disease and a relatively high number of head and neck paragangliomas compared with previously reported referral-based cohorts.

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B. Eriksson, H. Arnberg, K. Öberg, U. Hellman, G. Lundqvist, C. Wernstedt and E. Wilander

Abstract

Chromogranins A, B, and C, proteins that are co-stored and co-released with peptides and amines, have been identified in a variety of neuroendocrine tissues, both normal and neoplastic. We examined the secretion of chromogranin A and chromogranin A + B by hormone-producing tumours in patients with endocrine pancreatic tumours, carcinoid tumours, pheochromocytomas, and small cell lung cancer. The radioimmunoassay determining the plasma concentrations of chromogranin A + B showed a greater sensitivity than that determining chromogranin A alone. All patients with endocrine pancreatic tumours, carcinoids, and pheochromocytomas had increased levels of chromograin A + B, whereas a small number of the patients (5/18 with endocrine pancreatic tumours and ⅓ with pheochromocytomas) had normal levels of chromogranin A. Also in immunocytochemical stainings, our polyclonal antiserum detecting both chromogranin A and B showed a greater sensitivity than other available antisera against chromogranin A, B and C. We have demonstrated that a polyclonal antiserum against a mixture of chromogranin A and B might be a more sensitive marker than chromogranin A alone for diagnosing neuroendocrine tumours. This is not surprising, since both chromogranins are widely distributed in neuroendocrine cells.

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Domenico Salvatore, Angela Celetti, Nicole Fabien, Christian Paulin, Maria Luisa Martelli, Caterina Battaglia, Daniela Califano, Carmen Monaco, Giuseppe Viglietto, Massimo Santoro and Alfredo Fusco

Salvatore D, Celetti A, Fabien N, Paulin C, Martelli ML, Battaglia C, Califano D, Monaco C, Viglietto G, Santoro M, Fusco A. Low frequency of p53 mutations in human thyroid tumors; p53 and Ras mutation in two out of fifty-six thyroid tumours. Eur J Endocrinol 1996;134:177–83. ISSN 0804–4643

Objective: p53 is a well-known nuclear phosphoprotein encoded by a suppressor gene known to be mutated in various kinds of human tumours. A relationship between p53 gene mutation and tumour progression seems to be a common feature of several neoplasias. Desing: In order to investigate the role of p53 mutations in human thyroid tumours, DNA samples derived from fifty-six neoplastic tissues, ranging from benign adenomas to undifferentiated carcinomas, were examined for the presence of p53 gene mutations. Methods: The analysis has been conducted using polymerase chain reaction (PCR) amplification of the exons 5–9 of the p53 gene followed by single strand conformation polymorphism (SSCP) and sequence analyses. Results: One anaplastic carcinoma and one papillary carcinoma showed p53 gene mutations in exons 5 and 8, respectively. A cell line established from the papillary carcinoma showed the same mutation present in the original tumour. Both p53 mutations were heterozygous. The p53 positive samples were analysed for other genetic alterations frequently detected in human thyroid carcinomas (mutations of the RET, TRK, and ras oncogenes): both p53-mutated samples proved to be mutated at level of codon 13 of the c-Ki-ras gene. Conclusions: Our data confirm that p53 gene alterations are rare in well-differentiated thyroid tumours, that they are an important requirement for the establishment in culture of human thyroid carcinoma cell lines, and that they can be associated with other genetic alterations, namely ras mutations, in the malignant progression of thyroid tumours.

Alfredo Fusco, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, via S. Pansini 5, 80131, Napoli, Italy

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J. Kracht and N. Hantschmann

ABSTRACT

The tumour syntropies of Cushing's syndrome are discussed on the basis of a case of metastatic mediastinal tumour – a small round cell undifferentiated carcinoma – followed by a Cushing syndrome.

These tumoral syntropies are generally limited to the thymus, the bronchial tree and the pancreas, but may also occasionally appear elsewhere. The accompanying hyperfunction of the adrenal cortex may appear in various grades of intensity, i. e.

  1. 1) As a simple increase in the output of adrenal steroids without clinical symptoms of hyperadrenocorticism.

  2. 2) As an increase of adrenal cortex output accompanied by a hypochloraemic and hypopotassaemic alkalosis, however with no manifestation of Cushing syndrome.

  3. 3) A full blown Cushing syndrome.

Either the tumour or the hyperadrenocorticism may be the primary disease. The underlying pathogenetic factor which causes the correlation between the two diseases has not yet been ascertained.

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Thomas G Papathomas, Jose Gaal, Eleonora P M Corssmit, Lindsey Oudijk, Esther Korpershoek, Ketil Heimdal, Jean-Pierre Bayley, Hans Morreau, Marieke van Dooren, Konstantinos Papaspyrou, Thomas Schreiner, Torsten Hansen, Per Arne Andresen, David F Restuccia, Ingrid van Kessel, Geert J L H van Leenders, Johan M Kros, Leendert H J Looijenga, Leo J Hofland, Wolf Mann, Francien H van Nederveen, Ozgur Mete, Sylvia L Asa, Ronald R de Krijger and Winand N M Dinjens

Objective

Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.

Design and methods

Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC.

Results

Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.

Conclusions

These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.

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G Soto-Ares, C Cortet-Rudelli, R Assaker, A Boulinguez, C Dubest, D Dewailly and JP Pruvo

OBJECTIVES AND DESIGN: We performed a prospective study using magnetic resonance imaging (MRI) at regular post-operative intervals in non-irradiated patients with non-functioning pituitary adenomas (NFAs) to assess the frequency of tumoral regrowth and recurrences, in order to define the indications of post-operative radiotherapy. PATIENTS AND METHODS: Fifty-one patients aged 25--80 years (mean, 55.6plus minus12.3 years) were included. Post-operative MRIs were performed 3--12 months (mean, 5.2plus minus1.7 months) after surgery, 6 months later and then, every 12--18 months for at least 2 years. The mean post-operative follow-up was 67.7plus minus31.8 months (range, 24--144 months). RESULTS: In 17 patients (33%, group I) no tumoral residue was observed on post-operative MRIs and no tumoral recurrence was diagnosed. Tumour regrowth was detected in 13 of the 34 patients (38.2%) with post-operative tumoral residue (group II), 7--66 months (mean, 27.3plus minus17.3 months) after surgery. In this group, Kaplan--Meier analysis showed 78.8% recurrence free survival at 2 years and 60.9% at 5 years. Patients with tumoral regrowth had higher mean residual tumoral volume than patients without any tumoral regrowth in the group II (258plus minus165 vs 163plus minus165 mm(3), P=0.05). CONCLUSIONS: We suggest a MRI protocol that includes, a 4- to 6-, 12- and 24-month post-operative MRI for every patient. When no tumoral residue is seen, pituitary radiotherapy is useless. MRI must be repeated 3, 5 and 10 years after surgery to eliminate late recurrence. The observed frequency of tumoral regrowth in patients with tumoral residue does not justify systematic post-operative radiotherapy. It should be performed only when tumoral regrowth is proved by a yearly MRI survey.