Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study.

OBJECTIVE: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. METHODS: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. RESULTS: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10-4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. CONCLUSIONS: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.

The future: surgical advances in MEN1 therapeutic approaches and management strategies.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary autosomal dominant disorder associated with numerous neuroendocrine tumors (NETs). Recent advances in the management of MEN1 have led to a decrease in mortality due to excess hormones; however, they have also led to an increase in mortality from malignancy, particularly NETs. The main challenges are to localize these tumors, to select those that need therapy because of the risk of aggressive behavior and to select the appropriate therapy associated with minimal morbidity. This must be applied to a hereditary disease with a high risk of recurrence. The overall aim of management in MEN1 is to ensure that the patient remains disease- and symptom-free for as long as possible and maintains a good quality of life. Herein, we review the changes that occurred in the last 20 years in the surgical management of MEN1-associated functional and non-functional pancreatico-duodenal NETs and thymic and bronchial NETs.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines.

CONTEXT: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports. OBJECTIVE: To improve the knowledge of MEN1 natural history before 21 years old. METHODS: Obtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the "Groupe d'étude des Tumeurs Endocrines" MEN1 cohort. RESULTS: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-NET in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n = 9, 16%), hyperparathyroidism (n = 38, 31%), gastrinoma (n = 1, 33%), NSPT (n = 5, 36%), and all cases of insulinoma, adrenal tumors, and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases. CONCLUSIONS: Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.

Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database.

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.

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'etude des Tumeurs Endocrines.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed. OBJECTIVE: The aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1. DESIGN: Data regarding a study of 734 cases of MEN1 from the multicenter 'Groupe d'étude des Tumeurs Endocrines' were analyzed. RESULTS: There were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%). CONCLUSION: The phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.

[Birt-Hogg-Dubé syndrome and multiple recurrent tumors]. / Syndrome de Birt-Hogg-Dubé et tumeurs multiples récidivantes.

Birt-Hogg-Dubé (SBHD) syndrome is a rare autosomal dominant genodermatosis, predisposing to the occurrence of tumors associated with skin manifestations. We report a male patient who presented with a history of recurrent pneumothorax and was treated by nephrectomy for a left kidney carcinoma at 20 years old. Skin examination disclosed numerous fibrofolliculomas of the scalp. During follow-up, surgical resection of parotid oncocytomas and of a parathyroid adenoma were performed. SBHD was confirmed by molecular biology. In the presence of fibrofolliculomas and kidney tumors and recurrent spontaneous pneumothorax, a diagnosis of SHBD syndrome should be discussed, and tests need to be performed on the whole family.

Sacral nerve stimulation in faecal incontinence: position statement based on a collective experience.

OBJECTIVE: Since the first paper published by Matzel et al., in 1995, on the efficacy of sacral nerve stimulation (SNS) in patients with faecal incontinence, the indications, the contraindications, the stimulation technique and follow up of implanted patients have changed. The aim of this article was to provide a consensus opinion on the management of patients with faecal incontinence treated with SNS. METHOD: Recommendations were based on a critical review of the literature when available and on expert opinions in areas with insufficient evidence. RESULTS: We have reviewed the indications and contraindications, proposed an algorithm for patient management showing the place of SNS. The temporary test technique, the implantation technique, the patient follow up and the approach in case of treatment failure were discussed. CONCLUSION: We hope not only to provide a guide on patient management to clinical practitioners interested in SNS but also to harmonize our practices.

[Endoscopic thyroidectomy via median approach with gas insufflation: analysis of the first 100 cases]. / Thyroïdectomie endoscopique par une approche médiane avec insufflation gazeuse: analyse des 100 premiers patients.

OBJECTIVE: To report the initial experience with videoscopic thyroidectomy using a cervical approach with median placement of the optical trocar and gas insufflation. PATIENTS AND METHODS: Retrospective study of the first 100 consecutive patients. RESULTS: Seven isthmectomies, 86 lobectomies, and 7 total thyroidectomies were performed. Parathyroidectomy for hyperparathyroidism was also performed in 3 patients. Mean operative time was 77 minutes. No post-operative subcutaneous emphysema was noted. Conversion to open surgery occurred in 10% of cases but the conversion rate decreased to 2.6% when the harmonic scalpel became available. Post-operative complications included one transient recurrent laryngeal nerve palsy. There were no hematomas and no hypocalcemia. The mean post-operative pain scale was 2.7 (on a visual scale of 1-10). Mean hospital stay was 1.5 days. The cosmetic result was considered excellent. CONCLUSIONS: Endoscopic total thyroidectomy aided by gas insufflation is technically feasible. The harmonic scalpel aids greatly in dissection and hemostasis. It is a valid option in the surgical management of thyroid disease but careful pre-operative selection of patients is mandatory.

[A Multiple endocrine neoplasia type-1 observatory in a French-speaking area. A tool from the Endocrine Tumor study Group (GTE)]. / Observatoire francophone des néoplasies endocriniennes multiples de type 1. Un outil du Groupe d'étude des Tumeurs Endocrines (GTE).

Wermer's syndrome or Multiple Endocrine Neoplasia Type-1 (MEN1) is an autosomal dominant inherited disease, related to mutations in MEN1, an approximately 10-kb gene encoding menin, localized on chromosome 11q13. The Endocrine Tumor Group (GTE) has set up a MEN1 observatory of 1001 regularly followed MEN1 cases. This observatory aims at registering and evaluating MEN1 cases in a large cohort. Any new study on a particular unexplored aspect of the disease may be proposed by a physician to the GTE. This article describes the way to diagnose a new MEN1 case and to register it. Procedures for participating in a new study are presented. Some original results are quoted.

[Thoracic kidney: congenital or traumatic origin?]. / Rein thoracique: origine congénitale ou traumatique?

The discovery of a thoracic kidney in adult patients can lead to three diagnoses, yielding different prognoses and treatment. It can either mean traumatic or congenital diaphragmatic hernia, or a congenital ectopic kidney. Intrathoracic herniation of the left kidney trough a left diaphragmatic rupture is an exceptional discovery. We report the case of a 44 year-old man who met with a car accident 20 years ago, and presented abdominal pain. CT-scan showed an intrathoracic herniation of the left kidney trough a left posterior diaphragmatic rupture. Laparoscopic approach in lateral position showed a traumatic hernia of the left costo-diaphragmatic hiatus only containing the left kidney and its pedicle. After reduction of herniated left kidney into the abdomen, the hiatus was closed by non-resorbable prosthetic mesh. Postoperative course was uneventful.

[Laparoscopic adrenalectomy for large tumors]. / Exérèse laparoscopique des volumineuses tumeurs de la surrénale.

AIM OF THE STUDY: To analyze indications and results of laparoscopic adrenalectomy for large tumors (> 6 cm). METHODS: It is a retrospective study including patients between January 1994 and December 2003 operated on for large adrenal lesions > or =6 cm. The size was given by the pathologist. All the patients had a flank transperitoneal approach. Analysed Parameters were: operative difficulties; operative time; conversion rate; postoperative morbidity, follow-up and histologic data. RESULTS: Fourteen patients (10 female and 4 male) were included. Mean age at the time of the diagnosis was 52 years (range: 17-79). Mean size of the lesions was 7 cm (range: 6-10 cm). Mean operative time was 132 mn (range: 120-240 mn). None of the patients experienced surgical complications. Two conversions were needed (for vena cava attachments in one case and because of a retrocava localization in the other case). Three patients had morbidity: one intraperitoneal hemorrhage occurring at the second postoperative day and needing laparotomy; one left pneumopathy; and one case of neuralgia due to a port insertion. Mean hospital stay was 4,5 days. Histologic data showed: five ganglioneuromas, three pheochromocytomas, three adenomas, two adrenocortical carcinomas, and one postpancreatitis cytosteatonecrosis. CONCLUSION: Laparoscopic adrenalectomy is feasible for large lesions > or =6 cm when no evidence of malignity is demonstrated neither by the preoperative imaging study nor by the surgical exploration.

[Gastrinomas in multiple endocrine neoplasia type-1. A 127-case cohort study from the endocrine tumor group (ETG)]. / Les gastrinomes dans les néoplasies endocriniennes multiples de type 1. Une étude de cohorte de 127 cas du groupe des tumeurs endocrines (GTE).

UNLABELLED: On July 2000, 127 gastrinomas (31.1%) were studied by the Endocrine Tumour Group (GTE) using a 408-patient cohort of Multiple Endocrine Neoplasia Type 1 patients. The aim of this study was to assess clinical, biological, surgical data as well as their trends over three periods (<1980-1980/1989->1990). A Zollinger-Ellison syndrome (SZE) was present in 96% of the cases. Mean age at the onset of the disease was 39.4 years. There were 55.9% of men. Synchronous liver metastasis was present in 7.1%. Taken independently, the positivity of the four main diagnosis tests decreased over the time. The diagnosis of oesophagitis increased (4.5-29.7%), as well as the size of the resected tumours (9.9-16.8 mm). There was an increase in the familial background diagnosis (73.1-80%), an increasing use of Octreoscan scintigraphy and transduodenal ultrasound with positive detection of metastasis and tumours in 81.3% and 92.3%, respectively after 1991. Patients were operated on less frequently (96-52.5%), less frequently from the pancreas (87.5-37.5%), and from the gastro-intestinal tract (70.8-30%). The relative percentage of major pancreatic resections increased (with at least removal of the duodenum and the pancreatic head) (10-26.7%). The operative mortality disappeared. Six out of the seven patients (85.7%) who benefited from major pancreatic resections normalized their gastrine level postoperatively versus 15% in less radical techniques. Overall 5 years survival was 90 +/- 4.4%. Survival increased after 1985 (85 +/- 4.8% versus 95 +/- 3.6, P = 0.1). CONCLUSION: SZE in NEM1 were diagnosed at an earlier stage and were less frequently operated on. Nevertheless, the incidence of synchronous metastasis did not change significantly. Patients were mainly operated on for gastric emergencies and pancreatic tumours in order to prevent metastasis without mortality after 1991.

[Right laparoscopic adrenalectomy]. / Surrénalectomie droite par coelioscopie.

The transperitoneal laparoscopic approach for right adrenalectomy is performed in patients placed in a lateral decubitus position. Four ports are usually needed (2 or 3, 10 mm ports, 1 or 2, 5 mm ports), inserted in the right subcostal area. After liver retraction, the retroperitonéal space is opened close to the liver, exposing the right adrenal gland and the inferior vena cava. The periphrenic fat and the internal side of the gland are dissected close to the right side of the vena cava in order to expose the main adrenal vein. This vein is double clipped. At the inferior pole of the gland, the inferior adrenal artery is ligated with clips. Before removing and extracting the gland, the right side and the upper pole of the gland are dissected last.

[Does thyroidectomy worsen Graves'ophtalmopathy?]. / La thyroïdectomie aggrave-t-elle l'ophtalmopathie basedowienne?

AIM OF THE STUDY: To determine if thyroïd surgery increase or not the eye symptoms in patients with Graves'ophtalmopathy. MATERIALS AND METHODS: This retrospective study included between 1981 and 2001 two groups of patients: - group 1 : 24 patients who underwent thyroid surgery, - group 2 : 13 patients who were treated only by antithyroid drugs. Eye signs were evaluated according to the "NOSPECS" classification. The effect of the thyroid surgery and the medical treatment were evaluated with the NOSPECS classification modified by Orgiazzi in order to allow quantitative comparative data. The reasons why the patients were refered to surgery were:- the important size of the goitre (n = 10), - a recurrent hyperthyroidy despite an appropriated medical treatment (n = 10), - a pregnancy desire (n = 2), - a worsening of the eye signs (n = 2). Eighteen subtotal thyroidectomies and 6 total thyroidectomies were performed. RESULTS: after thyroid surgery, ophtalmic status was noted to improve in 18 patients, to remain inchanged in 1 patient and to deteriorate in 5 patients. In the non-operated group, the results were quite similar, but the mean goitre size was statistically lower and the ophtalmic lesions were statistically appearing later, these two parameters traducting a less serious disease in this group. CONCLUSIONS: This study suggests that thyroidectomy doesn't worsen the eye symptoms in patients with Graves'ophtalmopathy.

[Multiple endocrine neoplasia type I or Werner syndrome. What is important to know about surgery of a rate disease]. / La néoplasie endocrinienne multiple de type 1 ou syndrome de Wermer. Ce qu'il faut savoir en chirurgie d'une maladie rare.

Multiple endocrine neoplasia type 1 (MEN1) is a rare but misleading disease. The diagnosis is evocated when two main lesions are present (parathyroid, endocrine pancreas, pituary gland) but also when a family tree shows recurrent lesions. Other lesions must be taken into account (adrenal glands, neuroendocrine thymic or bronchic lesions, cutaneous lesions, lipomas, nervous central system tumors). Any surgical cure without knowing the MEN1 background leads to failure. Specific treatment of each lesion is reviewed. Genetic diagnosis is possible but the mutation is not found in all cases. Nevertheless, when the mutation is known in a family, a negative genetic test allows to exclude the disease. Prognosis is related to hepatic metastases and to thymic neuroendocrine tumors which are rare (2.1%) but aggressive. As a general rule, any apparently isolated endocrine lesion such hyperparathyroidism must prompt the surgeon to look for another endocrine lesion and to look for an abnormal family tree with recurent monoglandular or pluriglandular lesions.

[The "pneumoneck" in videocervicoscopy: operative technique and anatomic limits]. / Le "pneumocou" dans la vidéocervicoscopie: technique opératoire et limites anatomiques.

The aim of this study was to describe a technic in order to create a gas space "pneumoneck" during videoendoscopic surgery of the neck and to determine the anatomical limits of this space. Data were based on a surgical experience and on the dissection of two corpses. This space was located between the two layers of the pre-tracheal lamina of the cervical fascia. This space was enclosed and favourable to detachment with insufflated gas without subcutaneous emphysema. This approach can be used for parathyroid and thyroid surgery.