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Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy. This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999–2012). It focuses on patients without distant metastases (limited disease, LD, stage I–IIIB). Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p

The management of papillary microcarcinoma (PMC) of the thyroid is controversial, especially after partial thyroid resection for benign thyroid disease. In order to detect prognostic factors for PMC, we analyzed 116 patients with PMC for encapsulation status and lymph node metastases. Between 10/1992 and 12/2010, 116 patients with PMC have been operated in our department (87 females, 29 males, median age 49 years). Eighty per cent of PMCs were diagnosed postoperatively. Seventy-six patients (66%) received a more extended resection with either thyroidectomy, near total thyroidectomy, or Dunhill operation either primarily or after completion operation, whereas 40 patients (34%) had only partial resection. Fifty patients (43%) received radioiodine (RIA) ablation. Lymph node metastases were found in 21 patients (18%). Univariate analysis showed four risk factors to be significantly associated with the risk of lymph node metastasis (p

Background Double adenomas (DAs) occur in 2–15 % of primary hyperparathyroidism (pHPT) patients. To date, the existence of this distinct entity remains controversial. The aim of this study was to evaluate the clinical characteristics and anatomic distribution of DAs to identify anatomic patterns and implications for surgical management.

Liver metastases of GEP-NETs are a known major prognostic factor with a strong effect on patients’ survival. To date, various treatment options are available, whereas surgery remains the only curative option. Because large liver resections often cannot be performed due to insufficient remnant liver volume, a special operative technique, “cherry picking” (multiple nonanatomic liver resections), can be used as a tissue-preserving procedure. Of 91 patients with various GEP-NETs, 16 patients were identified with synchronous or metachronous multifocal, bilobular liver metastases (>10). All were treated with “cherry picking.” Patient records were reviewed retrospectively and clinical data and pathology results were analyzed. Mean survival after primary tumour resection was 82.8 versus 41.2 months after liver surgery. All 16 patients are still alive. Mean recurrence-free survival after primary tumour operation was 49.8 versus 24.6 months after liver surgery. Complications of cherry picking included two postoperative biliary leakages and three small hepatic abscesses (conservative/interventional approach 25 % (n = 4), surgical approach 6.25 % (n = 1). There was no postoperative mortality. Initial hormonal symptoms (5/16 patients) completely disappeared postoperatively in 2 patients and were significantly decreased in 3 patients. The tissue-preserving surgical technique “cherry picking” has developed due to improved imaging techniques and increased knowledge in liver anatomy, which has helped to make this approach safer and easier. Highly selected patients with multiple bilobular liver metastases of GEP-NET can benefit from this special surgical approach, also applicable for recurrent metastases.

The incidence of neuroendocrine neoplasias (NENs), especially of the gastro-entero-pancreatic (GEP), system relatively increased over the past decades, as a result of advanced diagnostic tools, a better clinical awareness, and distinguished pathological diagnostic recognition. Previous reports hypothesized an increased risk for secondary malignancies in patients with NEN especially in GEP-NENs. The present study was designed to investigate the coincidence of NENs and secondary malignancies in a large patient collective. A retrospective analysis was performed on 161 patients (85 female and 76 male) with NEN of various origins. Clinical data of these patients, different classification systems (TNM/WHO), proliferations-based grading, and clinical follow-up were collected and analyzed. Out of 143 patients with a sporadic NEN, 15 (10.49 %) patients were identified with secondary malignant tumors. Median age at the time of the primary operation for NEN was 65 years, whereas the median age of initial diagnosis of associated tumors was 59 years. Mean follow-up time was 61 months. The risk of developing a secondary malignancy was most elevated for patients with an NEN of the lung, the stomach, and the ileum (60, 50 and 20 %, respectively). The spectrum of secondary malignancies included various types of cancer. Kaplan-Meier survival analysis shows a difference suggesting that patients with a secondary malignancy demonstrate a worse survival compared to patients without a secondary tumor; no significance was detected (p = 0.349). Our data suggest that secondary malignancies in patients with NEN's especially in GEP-NENs are found more frequently than in general population. Therefore, patients with NEN need a continuous and detailed follow-up. The reason for the increased incidence of secondary malignancies in patients with NENs remains to be elucidated.

To date, very little is known about the development of benign organic hyperinsulinism and its metastatic potential. Typical morphologic, biochemical, or genetic differentiations for benign or malign tumor course of insulinomas do not exist. As signaling pathways may affect pancreatic cancer development and the maintenance of the neoplastic phenotype, the purpose of this study was to examine the role of Notch1 expression in organic hyperinsulinism. We examined 32 well-differentiated pancreatic endocrine tumors (wd PET); 11 wd PET of unknown behavior (wd PET ub); and 15 wd pancreatic endocrine cancer (wd PEC) for Notch1 expression by immunohistochemistry. Demographic data, clinical data, and follow-up of all patients were analyzed. Islets of the Langerhans show the strongest Notch1 staining in nearly 90 %. Positive Notch1 staining was absent in the acinar of the pancreas. In patients with a wd PET more than every second tumor (56.3 %/n = 18/32) demonstrated a negative Notch1 staining. The other 14 patients were positive for Notch1. Tumors of unknown behavior (wd PET ub) and malignant insulinomas had no signs of Notch expression in contrast to benign insulinomas. Considering the clinical and histomorphological tumor behavior, no correlation between Notch1 expression and clinical data was found. The missing Notch expression in the malignant tumor course might be used as a potential predictive marker, but further studies are needed to investigate the underlying molecular mechanism.

Background Portal vein embolization (PVE) has become a standard procedure to increase the future liver remnant (FLR) and enable curative resection of initially unresectable liver tumours. This study investigated the safety and feasibility of a new two-stage liver resection technique that uses in situ liver transection (ISLT) and portal vein ligation before completion hepatectomy. Methods A consecutive series of patients undergoing ISLT and extended right hepatectomy between 2009 and 2011 were compared with consecutive patients undergoing extended right hepatectomy after PVE. All patients had initially unresectable primary or secondary liver tumours, owing to an insufficient FLR (liver segments II/III). Results Fifteen patients who had PVE and seven who underwent ISLT before extended right hepatectomy were evaluated. ISLT induced rapid growth of the FLR within 3 days, particularly after insufficient PVE, from a mean(s.d.) of 293(58) ml to 477(85) ml, corresponding to a volume increase of 63(29) per cent. All patients who had ISLT underwent completion extended right hepatectomy within 8 days (range 4–8 days). Conclusion ISLT is an effective and reliable technique to induce rapid growth of the FLR, even in patients with insufficient volume increase after PVE.

Hintergrund: Neuroendokrine Tumoren (NET) des Verdauungstrakts sind seltene und heterogene Tumoren. Die Erhebung valider Daten zu Epidemiologie, Diagnostik, Therapie, Prognose und Risikofaktoren ist das Ziel des deutschen NET-Registers. Patienten/Methode: Das deutsche NET-Register erfasst bundesweit die Daten histologisch gesicherter NET-Patienten. Der hier dargestellte Erfassungszeitraum umfasst die Zeit von 1999 bis 2010 und wird seit 2004 prospektiv fortgefuhrt. Ergebnisse: 2009 Patienten aus 35 Zentren wurden von 1999–2010 analysiert. Das mittlere Follow-up betrug 34,5 Monate. Das Durchschnittsalter bei Erstdiagnose lag bei 56,4 Jahren. Haufigste Primartumorlokalisationen waren Pankreas (34,2 %), Dunndarm (25,8 %), Magen (6,5 %), Kolon (6,9 %) und Duodenum (4,8 %). Ein neuroendokrines CUP lag bei 12,6 % der Patienten vor. Eine synchrone Metastasierung fand sich bei 46 % der Erkrankten. Zweittumoren fanden sich bei 12 % der Patienten. Von 860 Patienten wurden 402 (46,7 %) als funktionell aktiv eingestuft. Es handelt sich um folgende endokrinologische Syndrome: Karzinoidsyndrom (19,1 %; n = 164), persistierende hyperinsulinamische Hypoglykamie (17,7 %; n = 152), Zollinger-Ellison-Syndrom (7,1 %; n = 61), Glukagonom (0,7 %; n = 15), Verner-Morrison-Syndrom (0,4 %; n = 8) sowie Somatostatinomsyndrom (0,1 %; n = 2). Eine chirurgische Therapie erhielten 78 % der Patienten, 28 % eine Therapie mit Somatostatinrezeptoranaloga (SSA), 19 % eine Peptidrezeptor-Radionuklidtherapie (PRRT), 18 % eine Chemotherapie (CTX) und 6,5 % eine Interferontherapie (IFN-Tx). Ausschlieslich operativ behandelt wurden 47 % der Patienten, 53 % der Patienten erhielten mindestens eine 2. Therapieform. Wahrend des Beobachtungszeitraums verstarben 14,9 % der Patienten. Die 2-, 5- und 10-Jahres-Uberlebensraten (JULR) waren 94, 85 und 70 % fur das tumorspezifische Uberleben. Die 5-JULR korreliert hochsignifikant mit der Therapieform Operation (OP) versus (vs.) Nicht-OP (82 vs. 61 %, p

PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor.

In den letzten 5 Jahren wurden durch die European Neuroendocrine Tumor Society (ENETS) grundlegende Empfehlungen fur eine standardisierte Pathologiediagnostik und Klassifikation neuroendokriner Neoplasien (NEN) des gastroenteropankreatischen Systems erarbeitet. Diese haben Eingang gefunden in die neue Klassifikation der Tumoren des Verdauungstraktes durch die Weltgesundheitsorganisation (WHO 2010) und teilweise auch in die TNM-Klassifikation der Union for International Cancer Control (UICC 2009). In dieser Ubersicht wird die empfohlene Diagnostik hinsichtlich (1) Basisdiagnostik, (2) optionaler klinisch orientierter Diagnostik, (3) proliferationsbasiertem Grading, (4) Nomenklatur und (5) TNM-Klassifikation vorgestellt. Es wird auf die Notwendigkeit der standardisierten Pathologiediagnostik von NEN, erhoben am Biopsat oder Operationspraparat, in Zusammenschau mit den klinisch-bildgebenden Befunden fur die optimale Einschatzung der Prognose und die Auswahl tumorspezifischer Behandlungsschemata hingewiesen. Eine enge interdisziplinare Zusammenarbeit ist hierfur die Voraussetzung.

Neuroendokrine Tumoren des gastroenteropankreatischen Systems (GEP-NET) sind charakterisiert durch die Expression neuroendokriner Marker sowie die Synthese, Speicherung und Sekretion von Peptidhormonen und/ oder biogenen Aminen. Es handelt sich um mehr als 50 unterschiedliche Tumorentitäten mit klinisch sehr unterschiedlichem Verlauf. Sie können sporadisch oder familiär auftreten. Die hohe biologische und klinische Vielfalt äußert sich in unterschiedlichen genetischen Profilen auf DNA- und mRNA-Ebene, welche wie folgt zusammengefasst werden können: 1. NET unterscheiden sich genetisch von den häufigen nichtneuroendokrinen Karzinomen des Verdauungstraktes. 2. Die klinisch-pathologische Heterogenität der GEP-NET spiegelt sich auch auf genetischer Ebene wider. 3. Bei pankreatischen NET finden sich deutliche genetische Unterschiede zwischen Insulinomen und anderen Entitäten. 4. Die Tumorprogression geht bei pankreatischen NET mit einer Zunahme von genetischen Veränderungen einher. 5. Pankreatische NET unterscheiden sich genetisch von gastrointestinalen NET. 6. Sporadische GEP-NET unterscheiden sich genetisch von hereditären (familiären) GEP-NET.

Background The aldosterone-to-renin ratio (ARR) is an established diagnostic tool in the screening for primary aldosteronism (PA). However, hormonal determinations are time consuming and expensive. Therefore, we studied the effectiveness of the serum sodium to urinary sodium to (serum potassium)2 to urinary potassium (SUSPPUP) ratio in the diagnosis of PA. Design This study included 35 patients with PA, 71 patients with essential hypertension to whom this diagnosis could be excluded, 23 normal subjects without hypertension, and 22 patients with primary adrenal insufficiency. We compared the SUSPPUP ratios with the ARR in these patient groups. Results We show that the ARR distinguished PA from essential hypertension with a sensitivity of 94·2% and a specificity of 92·1% at a cutoff of 33 (ng L−1: ng L−1). It correlated well with the SUSPPUP ratio. The sensitivity and specificity of SUSPPUP was 88·6% and 85·9% at a cutoff of 5.3 (mmol L−1)−1, respectively, and thus not as good as the ARR. Conclusions The ARR is a good parameter in the screening for PA. The SUSPPUP ratio is a cheap and rapid tool to assess the extent of mineralocorticoid excess and, therefore, can be offered to more patients. In addition, the application of the SUSPPUP ratio can be extended to patients who suffer from other forms of mineralocorticoid hypertension (e.g. with low aldosterone levels).

The simultaneous occurrence of different types of thyroid carcinoma in a single patient is an unusual event. We report the case of a 52-year-old man with the history of two previous thyroid operations for benign goiters, who developed a recurrent goiter. The patient was referred to our department for thyroidectomy. In the pathohistological examination the specimen showed a 5 cm follicular carcinoma and a 0.3 cm papillary microcarcinoma in the right lobe as well as a 1.5 cm medullary carcinoma in the left lobe. All tumors were clearly separated from each other, representing the pure entity of each type. Postoperatively, RET germline mutation was ruled out by sequence analysis of peripheral blood leucocytes. Postoperative I-131-radioiodine scan showed multiple lung and liver metastases, while calcitonin was negative. There is no known common cause of these three different tumor types and they developed most independently from each other. The personal history of our patient was interesting in two aspects: (1) he suffered a period of severe staphylococcal sepsis with temporal immunosuppression and (2) he worked for long years as a coremaker in a foundry. This work represented possible long term exposure to inhalative carcinogenous toxins like hydrazine, which caused thyroid parafollicular cell adenomas in an animal model.

Surgical therapy of incidentally postoperative diagnosed small sporadic medullary thyroid cancer (MTC) is discussed controversially. In principle completion thyroidectomy with neck dissection and regulary tumor follow-up are under discussion. A total of 277 patients with MTC were treated between 1986 and 2004. In 22 cases diagnosis of a small (pT1 or pT2) sporadic MTC was incidental and only postoperatively confirmed. Normally total thyroidectomy with neck dissection is standard surgical therapy of a known MTC. Because of postoperative incidental diagnosis in all 22 cases surgical therapy was less then total thyroidectomy. Mutation analysis of RET Proto-Oncogen and familial history were negative in all cases. All patients were systematically followed-up in defined intervals by calcitonin, pentagastrin stimulation test, carcinoembryonic antigen and ultrasound. Median follow-up is 6.2 years (range: 2-13 years) and although a hemithyroidectomy or less was performed all 22 patients are cured by the MTC. We conclude that completion thyroidectomy and neck dissection are not mandatory in such patients, if the tumor is completely resected and genetic background is excluded. Indispensably a systematic long term follow-up of at least 10 years, better a life-long, is mandatory.

Papillary-cystic and solid neoplasm (PCSN) are rare tumors. Two personal observations and a review of the literature are presented with a total of 44 pediatric patients in addition to a total of 67 published cases in the review of Cohen (Pediatr. Surg. Int. 6 (1991) 128) and Snadjauf (Eur. J. Pediatr. Surg. 9 (1999) 416). Overall, PCSN shows a clear predominance in females and only occasionally occurs in males. Typically they grow to a large tumor mass with minimal symptoms. Their histologic and immunocytologic characteristics cause diagnostic difficulties, especially on frozen sections of small biopsies. The tumors are assumed to origin from pluripotent stem cells and present as tumors of low malignancy with a favorable prognosis. Nevertheless 10 children have been reported to develop metastases, 5 have demonstrated an invasive growth pattern and 4 local recurrence. But only two of the 111 pediatric cases have died from their tumor burden. Treatment of choice is a complete surgical resection, which is true for the primary tumor and for metastases as well as local recurrences. In our 2 patients one had spleen-conserving left pancreatic resection and one mesopancreatectomy with roux-en-y-reconstruction leading to long-term cure. Adjuvant therapy in curative resected patients is unnecessary and does not appear to improve prognosis.

Pancreas divisum is the most common congenital anomaly of the pancreas, characterized by missing fusion of the ventral and dorsal pancreatic duct. It may cause pancreatitis, but is rarely associated with malignancy.We report herein for the first time the rare association, in a symptomless patient, of multiple neuroendocrine tumors of the pancreas with pancreas divisum and a failure of the exocrine system. Diagnosis was made incidentally by routine abdominal ultrasound. Laboratory examinations and a fine-needle aspiration revealed the neuroendocrine nature of the tumor. Spleen-preserving left pancreas resection was performed, with evidence of multiple neuroendocrine tumors of the pancreas with the typical histological characteristics. Eighteen months later the patient is still free of tumor burden.

The object of this study was to assess the extent of surgery required for small sporadic medullary thyroid cancers (sMTCs). We retrospectively studied 261 patients with MTCs treated in our institution between 1986 and 2002 and identified 15 patients with small pT1 or pT2 sMTCs. The tumors were diagnosed incidentally, so surgical therapy was less than total thyroidectomy. Total thyroidectomy with or without neck dissection was applied to all other patients as standard surgical treatment of care. Patients were systematically followed up by postoperative ultrasonography, calcitonin, carcinoembryonic antigen levels, and pentagastrin stimulation tests. On long-term follow-up over a period of 4.6 years, the rate of biochemical cure in these patients who underwent less than total thyroidectomy for a sporadic incidentally diagnosed tumor was 100%. We concluded that completion thyroidectomy and neck dissection are not mandatory in patients in whom a solitary small sMTC is incidentally discovered by histologic diagnosis following operation so long as a genetic background is excluded. Nevertheless, such patients require systematic careful long-term follow-up.

Summary The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%–40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H 2 O 2 , lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH.

Recently, a novel WHO-classification has been introduced that divided gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) according to their proliferation index into G1- or G2-neuroendocrine tumors (NET) and poorly differentiated small-cell or large-cell G3-neuroendocrine carcinomas (NEC). Our knowledge on primary NECs of the GEP-system is limited due to the rarity of these tumors and chemotherapeutic concepts of highly aggressive NEC do not provide convincing results. The aim of this study was to establish a reliable cell line model for NEC that could be helpful in identifying novel druggable molecular targets. Cell lines were established from liver (NEC-DUE1) or lymph node metastases (NEC-DUE2) from large cell NECs of the gastroesophageal junction and the large intestine, respectively. Morphological characteristics and expression of neuroendocrine markers were extensively analyzed. Chromosomal aberrations were mapped by array comparative genomic hybridization and DNA profiling was analyzed by DNA fingerprinting. In vitro and in vivo tumorigenicity was evaluated and the sensitivity against chemotherapeutic agents assessed. Both cell lines exhibited typical morphological and molecular features of large cell NEC. In vitro and in vivo experiments demonstrated that both cell lines retained their malignant properties. Whereas NEC-DUE1 and -DUE2 were resistant to chemotherapeutic drugs such as cisplatin, etoposide and oxaliplatin, a high sensitivity to 5-fluorouracil was observed for the NEC-DUE1 cell line. Taken together, we established and characterized the first GEP large-cell NEC cell lines that might serve as a helpful tool not only to understand the biology of these tumors, but also to establish novel targeted therapies in a preclinical setup.

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.

Ghrelin is a novel gastrointestinal-brain hormone that was first described by Kojima et al. as a growth-hormone-releasing peptide. It can be isolated and purified from different tissues. Evidence of antiproliferative effects in neoplastic cells (binding to normal and neoplastic tissues) supports the hypothesis that ghrelin also plays an important role in endocrine regulation. Whether ghrelin may be involved in formation of neuroendocrine tumours (NET) of the gastrointestinal tract (GIT) in cases of MEN-1 is under discussion. Over the last sixteen years, 227 patients with GIT NET were treated at our institution. Mutations of the menin gene were identified in twelve patients. Eleven of these tumours (islet cell tumours) were localized in the pancreas and one in the stomach. Tissues from these tumours were resected, fixed in formalin and embedded in paraffin. Sections were examined by immunohistochemistry with a primary antibody for ghrelin. Three out of twelve NET in MEN-1 patients (25%) showed ghrelin expression by immunohistochemistry. Comparison between ghrelin-positive and ghrelin-negative tumours regarding biological activity, morphological aspects and clinicopathological parameters shows no substantial differences. The reported incidence of ghrelin expression in NET of the gastrointestinal tract by MEN-1 was not seen in our patients. Whether or not ghrelin has an influence on neuroendocrine tumour development related to deficient menin-genes is unknown.

The incidence of primary hyperparathyroidism (pHPT) combined with nonmedullary thyroid carcinoma (NMTC) has been reported between 2-13%. To date, it remains controversial whether these 2 pathologies occur coincidental or are caused by specific risk factors or genetic changes. The aim of this study was to evaluate the clinical and histological characteristics of NMTC associated with pHPT. We reviewed prospective database records of 1 464 unselected, consecutive patients who were treated for pHPT in our institution between 1986 and 2012 and identified 41 NMTC (2.8%). The collective consisted of 35 papillary (PTC) and 6 follicular (FTC) thyroid carcinomas. Our collective of 41 NMTC including 34 single adenomas and 7 multiglandular diseases consisted of 33 females and 8 males. Patients with FTC demonstrated significant lower preoperative PTH levels compared to PTC. Interestingly, NMTC were predominantly located on the right side. FTC had significant larger tumors as well as demonstrated increased extrathyroidal growth and lymph node metastases. In 71% pHPT and NMTC were diagnosed synchronously. The comorbidity of pHPT and NMTC occurs in about 3%. As pHPT is often operated by a focal minimally invasive approach, we advocate a mandatory preoperative thyroid ultrasound for all patients with pHPT to be able to identify synchronous thyroid disease.

Die chirurgische Resektion des pankreatischen Hyperinsulinismus ist die einzige Moglichkeit der Heilung unabhangig von der Tumordignitat. Sichere medikamentose Therapien zur Beherrschung unkontrollierter Hormonexzesse gibt es nicht. Vor dem Hintergrund der in den letzten Jahren neu entdeckten und definierten Krankheitsbilder des pankreatischen Hyperinsulinismus (NIPHS) ist die vom Chirurgen zu wahlende adaquate Operationsmethode und -taktik komplexer geworden. Daher muss die chirurgische Vorgehensweise von einer grosen Variabilitat gekennzeichnet sein. Der endokrin erfahrene Pankreaschirurg verfugt in seinem Repertoire uber eine Vielzahl an situationsadaptierten „Standardvorgehensweisen“ bis hin zu modifizierten funktions- und morphologieadaptierten Resektionsmoglichkeiten. Chirurgische Standardvorgehensweisen sind die Enukleation, die Pankreasschwanz- oder Pankreassegmentresektion bis hin zur Whipple-OP mit z. B. kombinierter Enukleation oder auch die Pankreatektomie.

Hemorrhage caused by inflammatory vessel erosion represents a life-threatening complication after upper abdominal surgery such as pancreatic head resection. The gold standard therapeutic choice is an endovascular minimally invasive technique such as embolization or stent placement. Hepatic arterial hemorrhage in presence of pancreatitis and peritonitis is a particular challenge is if a standard therapeutic option is not possible. The management of five patients with massive bleeding from the common hepatic artery is described. All patients underwent a splenic artery switch. The splenic artery was dissected close to the splenic hilum and transposed end-to-end to the common hepatic artery after resection of the eroded part. Patients’ medical records, radiology reports, and images were reviewed retrospectively. Technical success was defined as immediate cessation of hemorrhage and preserved liver vascularization. Clinical success was defined as hemodynamic stability and adequate long-term liver function. Total pancreatectomy and splenectomy were performed in four of the five cases. Hemodynamic stability and good liver perfusion was achieved in these patients. Splenic artery switch is an effective, safe procedure for revascularization of the liver in case of hepatic arterial hemorrhage following pancreatic surgery, pancreatitis, and/or peritonitis. The technique is a promising option if a standard procedure—e.g., stent implantation, embolization and surgical repair with alloplastic prosthesis or autologous venous interposition graft—is not possible.

Neuroendocrine tumours (NET) are rare and heterogeneous neoplasia. To obtain valid data on epidemiology, diagnostics, therapy, prognosis and risk factors is the aim of the German NET registry.Data from 2009 histologically proven NET were collected from 35 NET centres between 1999 and 2010. Data collection has been performed prospectively since 2004. Results: Median follow-up was 34.5 months and median age at diagnosis 56.4 years. Primary tumour localisations were pancreas (34.2%), midgut (5.8%), stomach (6.5%), bowel (6.9%), duodenum (4.8%) and neuroendocrine CUP (12.6%). Synchronous metastases were seen in 46% and second malignancies in 12%. From 860 patients, 402 (46.7%) had functional tumours with the following hormone excess syndromes: carcinoid syndrome (19.1%; n = 164), persistent hyperinsulinaemic hypoglycaemia (17.7%; n = 152), Zollinger- Ellison syndrome (7.1%; n = 61), glucagonoma (0.7%; n = 15), Verner-Morrison syndrome (0.4%; n = 8) and somatostatinoma syndrome(0.1%; n = 2). Surgical therapy was performed in 78%, therapy with somatostatin receptor analogues(SSA) in 28%, peptide radioreceptor therapy (PRRT) in 19%, chemotherapy in 18% and interferon therapy in 6.5%. Only surgery was done in 47%, whereas 53% received a second therapy. General mortality rate during follow-up was 14.9%. The tumour-specific survival rates for 2, 5 and 10 years were 94, 85 and 70%. The 5-year survival is dependent on the surgical or non-surgical therapy (82 versus 61%, p0.001) and also on the primary tumour site (90/30% for midgut, 85/65% for pancreas, p0.001). Grading (G1, G2, G3) based on proliferation index Ki-67 recommended by the ENETS guidelines and WHO classification is highly correlated to the 5-year survival rate (88, 82, 33%, p0.001).The German NET registry provides valid multicentric data on NET in Germany. Surgical therapy is the most frequent and important therapy with good clinical outcome. In non-resectable, metastatic tumours, systemic therapies are common. Continuation and evaluation of the new WHO and TNM classifications for NET and their therapies will be a future focus of the registry.

Exercise-induced hyperinsulinism (EIHI) is a hypoglycaemic disorder characterised by inappropriate insulin secretion following anaerobic exercise or pyruvate load. Activating promoter mutations in the MCT1 gene (also known as SCLA16A1), coding for monocarboxylate transporter 1 (MCT1), were shown to associate with EIHI. Recently, transgenic Mct1 expression in pancreatic beta cells was shown to introduce EIHI symptoms in mice. To date, MCT1 has not been demonstrated in insulin-producing cells from an EIHI patient.In vivo insulin secretion was studied during an exercise test before and after the resection of an insulinoma. The presence of MCT1 was analysed using immunohistochemistry followed by laser scanning microscopy, western blot analysis and real-time RT-PCR of MCT1. The presence of MCT1 protein was analysed in four additional insulinoma patients.Clinical testing revealed massive insulin secretion induced by anaerobic exercise preoperatively, but not postoperatively. MCT1 protein was not detected in the patient's normal islets. In contrast, immunoreactivity was clearly observed in the insulinoma tissue. Western blot analysis and real-time RT-PCR showed a four- to fivefold increase in MCT1 in the insulinoma tissue of the EIHI patient compared with human pancreatic islets. MCT1 protein was detected in three of four additional insulinomas.We show for the first time that an MCT1-expressing insulinoma was associated with EIHI and that MCT1 might be present in most insulinomas. Our data suggest that MCT1 expression in human insulin-producing cells can lead to EIHI and warrant further studies on the role of MCT1 in human insulinoma patients.

Mature cystic teratomas are often found in gonadal sites, but are very rarely located extragonadally, for example, in retroperitoneum, mediastinum, central nervous system, lung, or liver. In the literature, only 10 cases of cystic teratoma originating from the diaphragm have been reported. Here, we report for the first time a metachronous occurrence of a benign mature cystic teratoma in the left diaphragm together with a serotonin-producing neuroendocrine tumor of the ileum. The 51-year-old, female patient received a partial resection of the ileum due to a neuroendocrine tumor (pT3N1M0) 4 years ago. Furthermore, she was operated for a benign cystadenoma of the right ovary 3 years ago. In her past medical history, she had an appendectomy in her childhood and a subtotal thyroidectomy 10 years ago. To our knowledge, this is the first report describing the metachronous occurrence of benign mature cystic teratoma in the diaphragm and a highly differentiated neuroendocrine tumor of the ileum. The possible coincidence of both diseases is discussed.

Here we tested whether global histone modifications predict survival in organic hyperinsulinism and whether global histone modification pattern can be used to distinguish benign from malignant primary insulinoma. A tissue microarray (TMA) was built, using samples from 63 patients with organic hyperinsulinism. The TMA was classified according to the WHO classification of 2004 [WHO 1A: benign insulinoma (wdPET); WHO 1B: unknown behavior (wdPETub); WHO 2/3: malignant insulinoma (wdPEC/pdPEC)]. The TMA consisted of tissue cores from islands of Langerhans, primary insulinomas, lymph node metastases, and hepatic metastases. Immunohistochemistry was performed on consecutive TMA slides with antibodies against H3K9Ac, H3K18Ac, H4K12Ac, H3K4diMe, and H4R3diMe. The Remmele immunoreactive scoring system was used to classify the staining. The IHC staining results were correlated to the WHO-classification of 2004 as well as to clinical follow-up data (mean: 107 months; range: 1-312 months). A nuclear staining pattern was observed for all antibodies directed against histone H3 and H4 acetylation/methylation sites. We observed significant differences in the distribution of the medians across all investigated tissue types (H3K9Ac, p=0.004; H3K18Ac, p=0.001; H4K12Ac, p=0.006; H4R3diMe, p=0.002) except for H3K4diMe (p=0.183). Correlation of the histone modification with the WHO-classification and clinical follow-up data, showed in the dichotomized groups ["low" (score 0-3), "moderate" (4-7) vs. "high" (≥8)] that patients with lower H3K18Ac levels ("low + moderate") had a significantly decreased relapse-free survival vs. patients with high H3K18Ac levels (p=0.038). The WHO classification and age were also of significant prognostic impact upon univariate analysis. A backwards Cox proportional hazards model revealed the independent prognostic effekt of H3K18Ac levels. Our data revealed low K18 acetylation levels of histone H3 as independent prognostic factor in organic hyperinsulinism. This result warrants validation with independent data sets of organic hyperinsulinism, but is in line with several previous studies in different cancer entities. The broad applicability of this potential biomarker might lead to standardized diagnostic tests in near future and may help to manage insulinoma patients more effectively.

During the last 5 years the European Neuroendocrine Tumor Society (ENETS) has developed basic recommendations for a standardized pathological diagnosis and classification of neuroendocrine neoplasms (NEN) of the gastroenteropancreatic system. These were included in the novel classification of tumors of the digestive system by the World Health Organization (WHO 2010) and the TNM classification of the union for international cancer control (2009). This review presents the pathology diagnosis regarding (1) basic diagnosis, (2) clinically relevant optional diagnosis, (3) proliferation-based grading, (4) nomenclature and (5) TNM classification. It is emphasized that a standardized diagnosis of NEN, together with clinical and radiological findings, is crucial for prognostic stratification and optimal therapy of patients with NEN. Therefore a close interdisciplinary collaboration is essential.

Hepatic resection is established as a safe procedure for colorectal, neuroendocrine, and sarcoma liver metastases. The present study evaluates whether liver resection is an option for patients with non-colorectal, non-neuroendocrine, and non-sarcoma metastases of the liver. According to data from our prospective clinical tumor registry, we reviewed the medical records of 44 consecutive patients with non-colorectal, non-neuroendocrine, and non-sarcoma liver metastases, who underwent hepatic resection from January 2000 to December 2008. Univariate Kaplan–Meier analysis and a stepwise multivariable Cox regression model were applied. Following hepatic resection, mean overall survival was 21 months, and 5-year survival was 20%. Following hepatic resection, gender, histology, and chemotherapy were of prognostic value in our patient cohort in univariate analysis (p

Background The occurrence of skin metastases are rare events in the course of a follicular thyroid carcinoma (FTC) and usually indicate advanced tumor stages. The scalp is the most affected area of these metastases. Case presentation We present a case of a 76 year old Woman with multiple giant scalp metastases of a follicular carcinoma. These metastases had been resected and wounds had been closed with mesh graft. The 14-months follow up is presented. Conclusion We demonstrate another case with multicentric form. Because of its location and size a primary wound closure was not possible. A healing could be reached using vacuum therapy and mesh graft transplantation.

Sandifer syndrome, named after the neurologist Paul Sandifer, was first reported by M. Kinsbourne in 1962 who noticed a disorder of the upper gastrointestinal tract with neurological manifestations occurring in children and adolescents. Sandifer syndrome is a combination of gastro-oesophageal reflux disease with spastic torticollis and dystonic body movements with or without hiatal hernia. It is hypothesised that the positioning of the head provides relief from abdominal discomfort caused by acid reflux. The true pathophysiological mechanisms of the condition are still unclear. We report the diagnosis of Sandifer syndrome in a 9-year-old boy with a history of chronic torticollis and dystonic episodes for 5 years associated with abdominal symptoms. The cause of the dystonic body movements had not been found, although multiple neuropsychiatric diseases were suspected. The patient had been seen by many different specialities including Paediatrics, Paediatric Neurology, Psychology, Orthopaedic Surgery and ENT but the reason for the torticollis remained elusive. Unclear abdominal discomfort was the indication for an endoscopy that revealed severe gastro-oesophageal reflux disease with oesophagitis III degrees and a hiatal hernia which led to the correct diagnosis of Sandifer syndrome. After medical treatment and laparoscopic floppy Nissen fundoplication the symptoms nearly resolved 3 months after operation. Few reports of this syndrome exist, but Sandifer syndrome is probably underrecognised. Children with torticollis, dystonic episodes or atypical seizures should be evaluated for GERD and Sandifer syndrome. Early surgery, for example a laparoscopic floppy Nissen fundoplication or a Toupet procedure, can resolve the symptoms.

Background and Aims: Patients with non-alcoholic steatohepatitis (NASH) have increased intestinal permeability and small intestine bacterial overgrowth. We aimed to test the hypothesis that endotoxaemia is associated with fatty liver in the general population and to study dietary factors associated with endotoxaemia. Methods: Community adult subjects were randomly selected from the Hong Kong Government’s census database and underwent proton-magnetic resonance spectroscopy and transient elastography to assess hepatic steatosis and fibrosis, respectively. Intrahepatic triglyceride content (IHTG) of 5% was the cutoff to define fatty liver. Endotoxaemia was assessed using the Limulus Amebocyte Lysate, lipopolysaccharide-binding protein (LBP) and EndoCab immunoglobulin G (IgG) assays. Dietary pattern was recorded by a 7-day food-frequency questionnaire. Results: 920 subjects were included (42% male, age 48±11, 23% body mass index ≥25kg/m and 5% diabetes). 263 (29%) had fatty liver; 60 (7%) had raised serum cytokeratin-18 fragment level (CK-18) suggestive of NASH; 27 of 887 (3%) subjects with reliable liver stiffness measurement had advanced fibrosis or cirrhosis. Compared with those without fatty liver, subjects with fatty liver had higher LBP (13.4±3.2mg/ml vs 11.4±2.7mg/ml; P < 0.001) and EndoCab IgG (228±247 GMU/ml vs 188±137 GMU/ml; P = 0.013) levels. Endotoxin markers also correlated positively with aminotransferases, IHTG, CK-18, insulin resistance and dyslipidaemia. Endotoxaemia was not associated with increased liver stiffness. Fetuin-A, the ligand linking fatty acid and Toll-like receptor 4, correlated with IHTG, insulin resistance and dyslipidaemia but did not have consistent association with endotoxaemia markers. Although total energy consumption and individual macronutrients were not associated with endotoxaemia, current drinkers (median alcohol consumption 20g/week [interquartile range 10–70 g]) had lower endotoxin, EndoCab IgG and fetuin-A levels than non-drinkers. Conclusions: Endotoxaemia is associated with fatty liver and possibly NASH in the general population. People with modest alcohol consumption have lower serum endotoxin. This may partly explain the lower risk of fatty liver and NASH in modest drinkers in previous observational studies. This study was supported by a grant from the Health and Medical Research Fund sponsored by the Hong Kong SAR Government [Ref CUHK-11120621]. P0981 ADAPTATION OF HEPATIC MITOCHONDRIAL FUNCTION IN OBESE HUMANS WITH OR WITHOUT NON-ALCOHOLIC STEATOHEPATITIS C. Koliaki, J. Szendroedi, K. Kaul, T. Jelenik, P. Nowotny, F. Jankowiak, C. Herder, M. Carstensen, M. Krausch, W. Trudo Knoefel, M. Schlensak, M. Roden. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Dusseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Dusseldorf, Germany; Department of Endocrinology and Diabetology, Heinrich Heine University, Dusseldorf, Germany; Institute of Pathology, Heinrich Heine University, Dusseldorf, Germany; Department of General, Visceral and Pediatric Surgery, Heinrich Heine University, Dusseldorf, Germany; General Surgery Department, St. Martinus Hospital, Dusseldorf, Germany, Dusseldorf, Germany E-mail: ckoliaki@yahoo.com

Surgical therapy of incidentally postoperative diagnosed small sporadic medullary thyroid cancer (MTC) is discussed controversially. In principle completion thyroidectomy with neck dissection and regulary tumor follow-up are under discussion. A total of 277 patients with MTC were treated between 1986 and 2004. In 22 cases diagnosis of a small (pT1 or pT2) sporadic MTC was incidental and only postoperatively confirmed. Normally total thyroidectomy with neck dissection is standard surgical therapy of a known MTC. Because of postoperative incidental diagnosis in all 22 cases surgical therapy was less then total thyroidectomy. Mutation analysis of RET Proto-Oncogen and familial history were negative in all cases. All patients were systematically followed-up in defined intervals by calcitonin, pentagastrin stimulation test, carcinoembryonic antigen and ultrasound. Median follow-up is 6.2 years (range: 2-13 years) and although a hemithyroidectomy or less was performed all 22 patients are cured by the MTC. We conclude that completion thyroidectomy and neck dissection are not mandatory in such patients, if the tumor is completely resected and genetic background is excluded. Indispensably a systematic long term follow-up of at least 10 years, better a life-long, is mandatory.

Primary hyperparathyroidism (pHPT) is a rare endocrine disease in children and young adults. The widespread use of new developments in pHPT surgery (i.e., unilateral and minimally invasive approaches) is based on the assumption that the solitary adenoma is the predominant intraoperative finding, but it has not been evaluated in the subgroup of young patients. From April 1986 to December 2002, a total of 1219 patients with pHPT have been operated on in our institution. The records of 64 patients (5.3%) younger than 30 years were extracted and compared to those of the older patients. The study group (median age 25 years, range 11–30 years) had significantly less bone pain, fewer signs of bone demineralization, and fewer neuropsychiatric symptoms. Eleven patients had hereditary disease. We found a solitary adenoma in only 32 of the 64 juvenile patients (p < 0.001), multiple gland disease in 25 patients (p < 0.001), and two suspected carcinomas. No adenoma could be identified in five patients. Follow-up of 54 patients after a median of 6.1 years revealed 42 normocalcemic patients, 5 hypocalcemic patients, and 7 patients with hypercalcemia. Altogether, 16 juvenile patients underwent parathyroid reoperations (25%) compared to 105 older patients (9%) (p = 0.003). Problems and difficulties with parathyroid surgery are pronounced in younger patients. The high rate of multiple gland disease requires bilateral cervical exploration as the standard procedure in pHPT patients younger than 30 years of age.

Maligne Pankreastumoren (PT) sind im Kindesalter auserst selten. Kaum ein einzelner Kinderchirurg oder Kinderonkologe verfugt uber ausreichende klinische Erfahrungen. Die Diagnose PT ist somit haufig verbunden mit der Unsicherheit, welche therapeutischen Masnahmen sinnvoll sind und welche Radikalitat die Operation beinhalten soll. Im Kindesalter kommen nur Pankreatoblastome (PB), papillar-zystische PT (PZT) und maligne APUDome (NET = Neuroendokrine Karzinome) vor. Echte Karzinome sind absolute Raritaten. Diese PT besitzen eine unterschiedliche Malignitat und erfordern eine vom allgemeinen Standard des Pankreaskarzinoms abweichende Behandlungsstrategie.

Differentiated thyroid cancer is a malignant tumour that has a fairly good prognosis, with patients surviving for many years. Multimodal therapy with surgery, radioiodine therapy and TSH suppressive medication is of proven efficacy. However, loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer, paralleled by an increase in tumour grading and loss of thyroid-specific functions (thyrotropin receptor, iodine accumulation). Such tumours may no longer be amenable to standard treatment protocols, including TSH suppression and radioiodide therapy. Retinoic acids have been shown to exert re-differentiating effects on thyrocytes in various experimental studies and case reports, and it was on this basis that this pilot study was initiated. Patients with advanced thyroid cancer and without the therapeutic options of operation or radioiodide therapy were treated with 13- cis-retinoic acid at a dosage of 1.5 mg/kg body weight daily over 5 weeks. Parameters for assessment of the therapeutic effect were serum thyroglobulin (TG) levels, radioiodine uptake, and tumour size prior to and after retinoid treatment. Fifty patients were evaluated for response, classified as reduction in tumour size and TG levels, stable disease or disease progression. Thirteen patients showed a clear increase in radioiodine uptake, and eight a mild increase. TG levels were unchanged or decreased in 20 patients. Tumour size was assessable in 37 patients; tumour regression was observed in six, and there was no change in 22. In total, a response was seen in 19 patients (38%). Response to retinoid therapy did not always correlate with increased radioiodine uptake, so other direct antiproliferative effects have to be assumed. The encouraging results of the study and the low rate of side-effects with good tolerability of retinoids warrant further studies with altered inclusion criteria and employment of other redifferentiating drugs or combinations of agents.

Einleitung: Die Leber ist der haufigste Metastasierungsort gastrointestinaler Tumoren. Neben einem kurativen Anspruch erzwingt hierbei haufig die ausgepragte Klinik funktioneller Tumoren einen Therapieansatz. Sind chirurgische Masnahmen (kurative Leberchirurgie/ palliatives „debulking“) nicht erfolgversprechend, kommen zunehmend therapeutische Alternativen wie die Chemoembolisation in Betracht. Der Stellenwert dieser Methode ist zu untersuchen. Patienten und Methoden: An der Heinrich-Heine-Universitat Dusseldorf sind 5 Patienten mit hepatisch metastasiertem neuroendokrinem Tumor unter Octreotid-Medikation zur Verhinderung krisenhafter Entgleisungen chemoembolisiert worden. Dokumentiert wurden Tumorart, -ausdehnung und operatives Vorgehen vor Embolisation. Erfasst wurden Nebenwirkungen der Chemoembolisation und Einfluss der Chemoembolisation auf die Funktion des Tumors. Die Effektivitat der Intervention wurde mittels CT nach definierten Zeitabstanden ausgewertet. Alle Patienten wurden bezuglich des Langzeitverlaufes („Tumorkontrolle“) untersucht. Ergebnisse: Schlussfolgerung: Eine Chemoembolisation ist bei nicht operablen Lebermetastasen zur Kontrolle der typischen Klinik funktioneller Tumoren („Flushkontrolle“) und zur Verlangerung der uberlebenszeit durch Tumormassenreduktion („Tumorkontrolle“) eine sinnvolle Therapiealternative