[Neuroendocrine neoplasms of the distal jejunum and ileum]. / Neuroendokrine Neoplasien des distalen Jejunums und Ileums.

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.

[Neuroendocrine tumours of the GI tract--data from the German NET Registry]. / Neuroendokrine Tumoren des Verdauungstrakts - Daten des deutschen NET-Registers.

BACKGROUND: 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. PATIENTS AND METHODS: 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%, p < 0.001) and also on the primary tumour site (90/30% for midgut, 85/65% for pancreas, p < 0.001). 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%, p < 0.001). CONCLUSION: 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.

Encapsulation status of papillary thyroid microcarcinomas is associated with the risk of lymph node metastases and tumor multifocality.

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<0.05): male gender, younger age, age group<50 years and nonencapsulation of the tumor. Multivariate analysis demonstrated statistical significance for gender and tumor capsulation status. The tumor capsulation status also correlated with tumor multifocality. Our data show that the risk of lymph node metastases is significantly higher in partially or nonencapsulated PMC than in encapsulated specimens. We therefore suggest that the WHO classification should be extended to a compulsory notification of the encapsulation status in PMC.

Coincidence of primary hyperparathyroidism and nonmedullary thyroid carcinoma.

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.

Secondary malignancy in patients with sporadic neuroendocrine neoplasia.

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.

In situ liver transection with portal vein ligation for rapid growth of the future liver remnant in two-stage liver resection.

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.

Association of exercise-induced hyperinsulinaemic hypoglycaemia with MCT1-expressing insulinoma.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Splenic artery switch for revascularization of the liver: a salvage procedure for inflammatory arterial hemorrhage.

BACKGROUND: 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. METHODS: 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. RESULTS: Total pancreatectomy and splenectomy were performed in four of the five cases. Hemodynamic stability and good liver perfusion was achieved in these patients. CONCLUSIONS: 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.

Global histone modification pattern predicts poor prognosis in organic hyperinsulinism.

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.

Loss of PTEN expression in neuroendocrine pancreatic tumors.

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.

Coincidence of mature cystic teratoma and serotonin-producing neuroendocrine tumor of the ileum.

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.

[Pathology of neuroendocrine neoplasms]. / Pathologie neuroendokriner Neoplasien.

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.

Standard-radical vs. function-preserving surgery of benign nodular goiter: a sonographic and biochemical 10-year follow-up study.

BACKGROUND: The necessary extent of thyroid resection in benign nodular goiter is under debate. The aim of our study was to compare the long-term outcome of different thyroid resection modes with special interest in the incidence of recurrent nodules and the use of oral thyroid hormone medication. MATERIALS AND METHODS: We performed a follow-up examination of 109 patients (23 men and 86 women) having been operated for benign nodular goiter at our department 10 years ago. Unilateral resections and function-preserving resections of at least one thyroid lobe were classified as function-preserving (FP). Total thyroidectomy, Dunhill's operation and bilateral subtotal thyroidectomy were rated as standard-radical (STR). On follow-up, we recorded current oral thyroid hormone medication, thyroid function tests and ultrasound of the neck. RESULTS: Seventy-three patients had FP resection (67%), while 36 were STR-operated (33%). The subsequent medical treatment was performed by dedicated endocrinologists (n = 19), internists (n = 11) or primary-care physicians (n = 59). Twenty patients had no medical attendance. Recurrent nodules were found in 13 cases in the FP group (18.6%) vs. 3 cases in the STR group (2.5%; p < 0.001). In both groups, about 80% of patients used thyroid hormone medication 10 years after operation. CONCLUSION: There was no advantage in thyroid function tests nor lesser medication in the FP group. The risk for recurrent nodules was significantly higher in the FP than in the STR-operated patients.

The serum sodium to urinary sodium to (serum potassium)2 to urinary potassium (SUSPPUP) ratio in patients with primary aldosteronism.

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).

Sandifer syndrome--a multidisciplinary diagnostic and therapeutic challenge.

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.

Diffuse nesidioblastosis as a cause of hyperinsulinemic hypoglycemia in adults: a diagnostic and therapeutic challenge.

Hyperinsulinemic hypoglycemia is caused by uncontrolled insulin release either from neoplastic pancreatic beta-cells or from functionally defective beta-cells. The latter disorder, which is usually seen in newborns, has been called nesidioblastosis and is divided histopathologically into a focal and diffuse type. In adults, nesidioblastosis is rare, and therefore its histopathologic and clinical features are not well known. In our institution, 4 of 128 adult patients (>3%) suffering from hyperinsulinemic hypoglycemia were found to have diffuse nesidioblastosis. The remaining patients had an insulinoma resected successfully in all but one patient. The diagnosis of diffuse nesidioblastosis was established histopathologically after removing a segment of the distal pancreas. Resection of up to 90% of the pancreas relieved 2 of the 4 patients of their symptoms. We conclude that diffuse nesidioblastosis is rare in adults but may account for more than 3% of patients with hyperinsulinemic hypoglycemia. The histopathologic diagnosis relies predominantly on demonstration of beta-cell hypertrophy. The cause of the disease is not known but may be related to defects in the glucose recognition system of the beta-cell. Treatment consists of operative reduction of the beta-cell mass, but the extent of pancreatic resection required is hard to judge, and there is a thin line between successful treatment, persistence of the disease, and pancreatic endocrine insufficiency.

Hyperinsulinemic hypoglycemia due to adult nesidioblastosis in insulin-dependent diabetes.

In neonates, persistent hyperinsulinemic hypoglycemia (PHH) is associated with nesidioblastosis. In adults, PHH is usually caused by solitary benign insulinomas. We report on an adult patient who suffered from insulin-dependent diabetes mellitus, and subsequently developed PHH caused by diffuse nesidioblastosis. Mutations of the MEN1 and Mody (2/3) genes were ruled out. Preoperative diagnostic procedures, the histopathological criteria and the surgical treatment options of adult nesidioblastosis are discussed. So far only one similar case of adult nesidioblastosis subsequent to diabetes mellitus II has been reported in the literature. In case of conversion of diabetes into hyperinsulinemic hypoglycemia syndrome, nesidioblastosis in addition to insulinoma should be considered.

Ghrelin expression in neuroendocrine tumours of the gastrointestinal tract with multiple endocrine neoplasia type 1.

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.

[Decision making in postoperative incidentally found small C-cell-carcinoma]. / Vorgehen beim postoperativen Zufallsbefund eines kleinen C-Zell-Karzinoms.

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.

Synchronous occurrence of a follicular, papillary and medullary thyroid carcinoma in a recurrent goiter.

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.