Caroline L. Lopez

Partial pancreaticoduodenectomy can provide cure for duodenal gastrinoma associated with multiple endocrine neoplasia type 1.

Objective: To evaluate the outcome of pancreaticoduodenectomy (PD) versus non-PD resections for the treatment of gastrinoma in multiple endocrine neoplasia type 1. Background: Gastrinoma in MEN1 is considered a rarely curable disease and its management is highly controversial both for timing and extent of surgery. Methods: Clinical characteristics, complications and outcomes of 27 prospectively collected MEN1 patients with biochemically proven gastrinoma, who underwent surgery, were analyzed with special regard to the gastrinoma type and the initial operative procedure. Results: Twenty-two (81%) patients with gastrinoma in MEN1 had duodenal gastrinomas and 5 patients (19%) had pancreatic gastrinomas. At the time of diagnosis, 21 (77%) gastrinomas were malignant (18 duodenal, 3 pancreatic), but distant metastases were only present in 4 (15%) patients. Patients with pancreatic gastrinomas underwent either distal pancreatic resections or gastrinoma enucleation with lymphadenectomy, 2 patients also had synchronous resections of liver metastases. One of these patients was biochemically cured after a median of 136 (77–312) months. Thirteen patients with duodenal gastrinomas underwent PD resections (group 1, partial PD [n = 11], total PD [n = 2]), whereas 9 patients had no-PD resections (group 2) as initial operative procedure. Perioperative morbidity and mortality, including postoperative diabetes, differed not significantly between groups (P > 0.5). All patients of group 1 and 5 of 9 (55%) patients of group 2 had a negative secretin test at hospital discharge. However, after a median follow-up of 136 (3–276) months, 12 (92%) patients of group 1 were still normogastrinemic compared to only 3 of 9 (33%) patients of group 2 (P = 0.023). Three (33%) patients of group 2 had to undergo up to 3 reoperations for recurrent or metastatic disease compared to none of group 1. Conclusions: Duodenal gastrinoma in MEN1 should be considered a surgically curable disease. PD seems to be the adequate approach to this disease, providing a high cure rate and acceptable morbidity compared to non-PD resections.

Bronchopulmonary Neuroendocrine Neoplasms and Their Precursor Lesions in Multiple Endocrine Neoplasia Type 1.

Objective: The prevalence and clinical behavior of bronchopulmonary neuroendocrine tumors (bNET) associated with multiple endocrine neoplasia type 1 (MEN1) are not well defined. This study aimed to determine the prevalence, potential precursor lesions and prognosis of bNET in patients with MEN1. Methods: A database of 75 prospectively collected MEN1 cases was retrospectively analyzed for bNET. Patient characteristics, imaging and treatment were evaluated. Resection specimens of operated patients were reassessed by two specialized pathologists. Available CT scans of the whole cohort were reviewed to determine the prevalence of bronchopulmonary nodules. Results: Five of the 75 MEN1 patients (6.6%; 2 male, 3 female) developed histologically confirmed bNET after a median follow-up of 134 months. The median age at diagnosis of bNET was 47 years (range 31-67), and all patients were asymptomatic. Four patients underwent anatomic lung resections with lymphadenectomy; the remaining patient with multiple lesions had only a wedge resection of the largest bNET. Tumor sizes ranged from 7 to 32 mm in diameter, and all bNET were well differentiated. Two patients had lymph node metastases. Two of 4 reevaluated resection specimens revealed multifocal bNET, and 3 specimens showed tumorlets (up to 3) associated with multifocal areas of a neuroendocrine cell hyperplasia within the subsegmental bronchi. One bNET-related death (1.3%) occurred during long-term follow-up. Review of the available CT scans of the patients without proven bNET revealed small bronchopulmonary lesions (≥3 mm) in 16 of 53 cases (30.2%). Conclusions: bNET in MEN1 might be more common than previously recognized. Their natural course seems to be rather benign. Multifocal tumorlets and multifocal neuroendocrine cell hyperplasia might represent their precursor lesions.

An unusual phenotype of MEN1 syndrome with a SI-NEN associated with a deletion of the MEN1 gene.

Summary We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation. Learning points Our patient presents an extraordinary course of disease. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors. This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.

Shortness: an unknown phenotype of multiple endocrine neoplasia type 1

OBJECTIVE An observation of shortness among the female participants of a regular screening program in multiple endocrine neoplasia type 1 (MEN1) patients has raised the question as to whether shortness represents a phenotype characteristic of the disease. METHODS The body height (cm) of genetically confirmed MEN1 patients at the time of diagnosis was compared with the body height of their unaffected relatives (parents, siblings, and children), the midparental body height, and the body height of the age-matched German population. Univariate analysis of the clinical variables was performed using the t-test, Mann–Whitney U test, and ANOVA as appropriate, and multivariate analysis was performed as a logistic regression analysis. P values <0.05 were considered statistically significant. RESULTS The mean body height of 22 female MEN1 patients (mean age 33.5 years) was 161 +/- 5 cm and thus significantly lesser than the body heights of their unaffected female relatives (mean 165.5 +/- 7.3 cm, P=0.027) and the age-matched German female population (mean 167 cm, P=0.0001) and mid-parental height (177.5 cm, P<0.0001). The mean body height of 24 male MEN1 patients (mean age 34.8 years) was also lesser (177 +/- 6.5 cm) than the average body height of German males in this age group (180 cm, P=0.031) and tended to be lesser than that of their unaffected male relatives (178.5 +/- 5.8 cm, P=0.0915) and the mid-parental body height (177.5 cm, P=0.124). CONCLUSIONS Small body height is a yet unrecognized phenotype characteristic of MEN1 patients, especially in women. The mechanisms behind this phenotypical characteristic warrant further investigation.

Is Enucleation Safe When the Distance Between the Tumor and the Main Pancreatic Duct Is Less Than 3 mm? Results from a Multi-Institutional Retrospective Study

Background Enucleation of small tumors can prevent pancreatic function impairment although the incidence of postoperative pancreatic fistula is relatively high. It has been suggested that this procedure should be avoided when the distance between the tumor and the main pancreatic duct is less than 3 mm. Objective To evaluate the safety of pancreatic enucleation for tumors distant less than 3 mm from the main pancreatic duct. Methods We reviewed the databases of the Department of Surgery of Marburg University (MU) and “Sacro Cuore” (SCH) Hospital of Negrar (1990-2012). All patients underwent intra-operative ultrasound (US) to measure the distance between the main pancreatic duct and the tumor. Binary logistic regression analysis of predictors of pancreatic fistula was performed. Results Sixty patients underwent enucleation in the two institutions. There were 21 males (35%) and 39 females (65%) with a median age of 50 years. The main reason for surgery was insulinomas (60%) followed by nonfunctioning neuroendocrine tumors (22%), gastrinomas (8%) and other tumors (6%). The median operative time was 137 minutes (IQR: 120-160). The overall rate of pancreatic fistula was 48% whereas the mortality was nil. The rate of pancreatic fistula was similar among the two institutions (55% in the SCH versus 42% in the MU; P=0.305). Overall, 31 patients (52%) had a distance between the tumor and the main pancreatic duct less than 3 mm. Re-exploration was necessary in 5 patients (8%) who had a tumor distant less than 3 mm from main pancreatic duct whereas the rate of grade C pancreatic fistula was similar among the two groups (25% vs . 29%; P=0.257). The only variable associated with a higher risk of pancreatic fistula was the distance between the tumor and main pancreatic duct less than 3 mm (odds ratio: 5.51; P=0.003). Conclusions Although the distance between the main pancreatic duct and tumor less than 3 mm is associated with a higher risk of pancreatic fistula, enucleation remains acceptably safe also in this group of patients. An intra-operative US is always mandatory to improve the post-operative management other than preventing main pancreatic duct injuries.