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Cardiac paragangliomas are extremely rare neoplasms with an incidence of 1% of all cardiac tumors and can be completely asymptomatic, therefore, diagnosis is difficult. This article reports the case of an 18-year-old man with a heart murmur detected during a routine physical examination. Echocardiography revealed a heart tumor measuring 7 cm in size in the right atrium. Due to the tumor size and the threat of tricuspid valve insufficiency, tumor resection was performed. The histopathological examination revealed a cardiac paraganglioma with positive reactions of the tumor cells for chromogranin A, synaptophysin and CD56. Differentiating a primary cardiac paraganglioma from other more common cardiac tumors and particularly from metastases of neuroendocrine neoplasms from other locations is essential not only for the further clinical treatment but also for the prognosis of the patient.

Epithelial neuroendocrine tumors of the upper respiratory tract are rare and are classified as typical and atypical carcinoid versus small cell neuroendocrine carcinoma. Furthermore, a giant cell variant of neuroendocrine carcinoma is suggested corresponding to the bronchopulmonary system as well as a recently described subtype of oropharyngeal small cell neuroendocrine carcinoma associated with human papillomavirus. Many arguments relying on clinical as well as on molecular findings indicate that the distinction between carcinoid and poorly differentiated neuroendocrine carcinoma does not only reflect different degrees of differentiation of otherwise related tumors but indicates the existence of substantially different types of neoplasms.

Classification: In the recently published 4th edition of the World Health Organization (WHO) classification of tumors of the lungs, pleura, thymus and heart, all neuroendocrine tumors of the lungs (pNET) are presented for the first time in one single chapter following adenocarcinoma and squamous cell carcinoma and before large cell carcinoma. In this classification, high grade small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are differentiated from intermediate grade atypical carcinoids (AC) and low grade typical carcinoids as well as from preinvasive lesions (DIPNECH). In the 3rd WHO classification from 2004, which dealt with resection specimens, SCLC and carcinoids each had a separate chapter and LCNEC was previously listed in the chapter on large cell carcinoma of the lungs. The new WHO classification is for the first time also applicable to lung biopsies., Diagnostics: Normally, common features of all pNET are a neuroendocrine morphology (as far as detectable in small biopsies) and expression of the neuroendocrine (NE) markers (chromogranin A, synaptophysin and CD56/NCAM). An immunohistochemical positive staining of at least one NE marker was already recommended in the 3rd edition of the WHO classification (2004) only for LCNEC. Differentiating features are a small or large cell cytomorphology/histomorphology, nuclear criteria and the mitotic rate (for SCLC >10 with a median of 80, for LCNEC >10 median 70, for AC 2 - 10, for TC < 2 each per 2 mm(2)). Tumor cell necrosis usually occurs in SCLC and LCNEC, partially in AC and not in TC. The guideline Ki67 proliferation rates are given for the first time in the new WHO classification for SCLC as 50-100 %, for LCNEC 40-80 %, for AC up to 20 % and for TC up to 5 %., Molecular Pathology: Molecular alterations occur in SCLC and LCNEC in large numbers and are very variable in quality. In AC and TC they occur much less frequently and are relatively similar., Conclusion: The direct comparison of all pNET in one chapter facilitates the differential diagnostics of these tumors, provides a better transparency especially of LCNEC and allows a further comprehensive development of the clinical practical and scientific evaluation of pNET. Although a separate terminology of pNET is maintained for the lungs, a careful approach towards the gastroentero-pancreatic NET (gepNET) can be observed.

Neuroendocrine neoplasms (NEN) of the breast are specific tumor entities. According to the literature up to 5% of breast neoplasms are malignant epithelial neoplasms of the breast. They are defined by a neuroendocrine (NE) architecture and cytology combined with an expression of the neuroendocrine vesicle markers chromogranin A and/or synaptophysin. The diagnosis is supplemented by the receptor status and the proliferative activity. According to the World Health Organization (WHO) classification of 2012 the following groups of NEN are distinguished: (1) invasive breast carcinoma with NE differentiation, (2) well-differentiated neuroendocrine tumor (NET) and (3) poorly differentiated small cell carcinoma (NEC). This review article focuses on (1) the definition and basic principles of diagnostics, (2) the history, nomenclature and WHO classification from 2003 and 2012, (3) the frequency of breast NEN, (4) the hereditary background and functional activity, (5) the expression of receptors and (6) the possible clinical implications. In addition, the first results of a retrospective single center study (n = 465 patients with breast cancer over a time period of 4 years) on the frequency of NEN of the breast at the Breast Center of the University Hospital Düsseldorf are presented. In this study a frequency of 4.5% of NEN was found based on a diagnostic cut-off of > 50% Chromogranin A and/or synaptophysin positive tumor cells.

Background: Neuroendocrine tumours of the gastroenteropancreatic system (GEP-NETs) are rare, in particular those of the gallbladder. Due to the limited therapeutic options, surgical resection is favoured., Case Report and Methods: Described below is the case of a 69-year-old male with a lymphogenically metastasising, poorly differentiated neuroendocrine carcinoma of the gallbladder who presented with unspecific abdominal pain., Results and Clinical Course: Following complete surgical resection of the tumour and the lymph node metastases he developed a recurrence 6  weeks post-operatively. The recurrence was treated with chemotherapy. Re-staging after three courses, however, showed further tumour progression. Prior to the start of a second-line treatment the patient died 13  weeks after surgery., Conclusions: This case demonstrates the complexity of this rare disease with diagnosis in advanced tumour stage and poor prognosis., (© Georg Thieme Verlag KG Stuttgart ˙ New York.)

Tailgut cysts are unusual benign cystic retrorectal malformations arising from persistent remnants of the postanal gut. Malignant transformation within this dysontogenetic lesion is very uncommon. We report the rare occurrence of a neuroendocrine tumor arising in a tailgut cyst with primary liver and lymph node metastases in a 55-year-old woman. The neuroendocrine differentiation of the tumor determines the therapeutic approach and prognosis.

We report on a remarkable diagnostic work up of suspect rectal palpation results in a 54-year-old patient. According to a transrectal ultrasound-guided punch biopsy the patient was suspected of having a carcinoma of the seminal vesicles and an aggressive operational approach was considered. After a median laparotomy a generalized peritoneal carcinomatosis was found. A goblet cell carcinoid of the vermiform appendix was identified as the primary tumor. This case report deals with metastazation of a primary goblet cell carcinoma into the seminal vesicles on both sides as an extremely rare reason for suspicious rectal palpation results. The tumor valency, diagnostic work up, therapy and further differential diagnoses are described.

We report a rare case of a neuroendocrine carcinoma located in the esophagus of a 62-year-old male patient. The initial diagnosis of a "small-cell tumor" was based on biopsy. Our diagnosis was based on the histomorphological examination of the resected material. Diagnostic criteria were the characteristic solid or clustered growth patterns, monomorphic cell nuclei, lack of necrosis, immunohistochemical detection of neuroendocrine markers like chromogranin, synaptophysin and neuron-specific enolase (NSE) as well as detection of cytoplasmic neuroendocrine granules by electron microscopy. In addition, we found an increased prolific activity by staining with Ki67 antigen. 30% of the cell nuclei displayed a positive reaction. Focal invasion of blood vessels was also detected. With 17 different chromosomal imbalances, comparative genomic hybridization (CGH) revealed a malignant tumor stage that was not visible at the microscopic level. According to the new WHO classification of neuroendocrine tumors the described tumor was identified as an intermediate between a well-differentiated neuroendocrine carcinoma and a low-differentiated neuroendocrine carcinoma.

Aim: The objective of the study was to gather further information about the pathogenesis of choroidal neovascularisations (CNV), which is still not clearly understood, and to establish criteria for making decisions on a appropriate therapy. Immunohistochemical characteristation should allow a more comprehensive evaluation of cellular components of the membranes and their functional role., Patients and Methods: In 29 patients (16 women, 13 men) with age-related macular degeneration ranging in age from 46 to 91 years (mean age, 76.4 years), CNV were excised by pars-plana vitrectomy. Sections were stained with hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) and examined by light microscopy. For the immunohistochemical characterisation of the surgical specimens the following anti-genetic determinants were used: glial fibrillary acid protein (GFAP) for glial cells, synaptophysin for neuronal cells, neuron-specific enolase (NSE) for neuronal and neuroectodermal cells, CD 31 for endothelial cells and pancytokeratin (KL1) for cells of the retinal pigment epithelium (RPE). Cells undergoing apoptosis were labeled with the TUNEL technique., Results: 22 (76%) surgical specimens showed TUNEL positive cells in the connective tissue, vascular endothelium and retinal pigment epithelium. Positive immunostaining of neuronal antigenetic determinants was found for glial fibrillary acid protein in 22 patients (76%), for synaptophysin in 28 patients (97%) and for neuron-specific enolase in 21 patients (72%) CNV. The epithelial marker KL1 was positive in 28 patients (97%) and the endothelial marker CD 31 in 20 patients (69%)., Conclusion: The immunohistochemical analyses of CNV showed that in the majority of cases during the excision of choroidal neovascularizations in addition to scar tissue and connective tissue also parts of the native retinal pigment epithelium and of the neurosensory retina are removed which is only partly visible with standard staining techniques. These findings suggest that the mostly not satisfying postoperative results are partly due to the damage of neuronal cells and a partial loss of the retinal pigment epithelium. Apoptosis as a regulating mechanism in choroidal neovascularization. The variable appearence of apoptosis suggests that it is possibly related to the degree of activity of CNV.

A 41-year-old woman with a chronic atrophic gastritis after endoscopic investigation diagnosed a carcinoid at the corpus of the stomach. There were more lesions in the mucosa of the stomach in the form of dysplasias. The labor investigation indicated an hypergastrinaemia. We performed a resection of the basis of the carcinoid. It has shown to be histologically tumor-free as the rest of the stomach. A gastrectomy was not necessary. After resection the patient was under therapy with vitamin B-12. The level of gastrin in blood was normal under this treatment. Two years later the patient remained symptom-free. Regular endoscopic investigations show a stagnation of the growth of the dysplastic lesions of the mucosa of the stomach.

The adhesion molecule on glia (AMOG) has been reported to function as cell adhesion molecule and also to constitute the beta 2-subunit of the murine Na,K-ATPase. In order to elucidate these functions in vivo, Magyar et al. have generated mice carrying a targeted deletion of the AMOG gene. These mice exhibit behaviourally normal development till postnatal day P16. At this time, they develop muscular weakness, incoordination, and tremor. Death invariably occurs 24-36 hours after onset of the symptoms. Histological and ultrastructural examination of brain sections show enlarged ventricles, brain edema, and swelling of astrocyte end feet. However, no disturbances of the architecture or cell migration in the brain can be detected. In order to identify long-term consequences of AMOG deficiency which might not yet be detectable at the time of death, we have established a CNS grafting model. The embryonal brain anlage (E10.5-E13.5) was grafted into the caudoputamen of wild type mice. The graft recipients are sacrificed up to 7 months after the procedure. Both wild type and AMOG deficient grafts develop and form solid neural tissue with neurons, myelinated axons, glial cells, and ventricular structures, as shown by histological and immunocytochemical analysis. However, no differences in grafts derived from wild type, heterozygous, and AMOG-deficient donors can be detected. Proliferation has been examined by BrdU immunocytochemistry. The blood-brain barrier as examined by repeated magnetic resonance imaging after injection of Gadolinium-DTPA has been shown to be largely reconstituted five weeks after grafting.

Rectal biopsies of 5 children with Hirschsprung's disease and biopsies of 41 patients with chronic constipation of other causes, such as neuronal intestinal dysplasia, hypoganglionosis and chronic intestinal pseudo-obstruction (CIPSO), were investigated, using a monoclonal antibody against synaptophysin. Electron microscopy was performed in some cases. Synaptophysin, which stained adrenergic, cholinergic and neuroendocrine structures, as well, consequently, was not a suitable marker for one particular transmitter system. Normo-, hypo- and hyperganglionotic submucous plexuses were reliably stained. Hypertrophic submucosal nerve fibers, characteristic of Hirschsprung's disease, were of poor synaptophysin positivity, whereas acetylcholinesterase-positive mucosal nerve fibers exhibited stronger immunoreactivity. A comparable but regionally varying staining reaction in mucosal nerve fibers was found in CIPSO cases. Mucosal portions of histologically normal biopsies were synaptophysin-negative. Synaptophysin antibodies may support acetylcholinesterase investigation and thus are useful under diagnostic aspects. However, they are practicable neither for better distinction in differential diagnosis of Hirschsprung's disease nor for pathogenetic research.

Gastrointestinal autonomic nerve (GAN)-tumors are extremely rare. So far seven cases of intestinal and four of gastric GAN-tumors were reported. GAN-tumors, also termed plexosarcomas, arise from autonomic nervous system plexuses of the gastrointestinal tract such as those of Meissner or Auerbach. We report a case of a metastatic gastric GAN-tumor in a 40-year-old woman. A small, 1 cm in diameter, submucosal plexosarcoma located in the posterior gastric wall and a 1.5 kg, 23 x 15 x 11-cm metastasis located retroperitoneally behind the stomach between liver, spleen and pancreas without discernable invasion of any of these organs were found. En-bloc resection of the retroperitoneal mass, the spleen, the pancreatic tail, and a part of the posterior gastric wall adhering to the mass were performed. In addition, lymph node metastases in splenic hilum were noted, and resected. In CT scan liver metastases were detectable fourteen months after surgery. The diagnosis is based on light microscopical, ultrastructural, and immunhistochemical analyses. The prognosis of GAN-tumors is fatal. In spite of radical excision 8 of 11 reported patients died few month after surgery while local recurrences and/or metastases in regional lymph nodes and in the liver were found. The response to chemotherapy was poor.