[Neuroendocrine neoplasms of the breast]. / Neuroendokrine Neoplasien der Mamma.

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.

[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.

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 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.

Trimodal therapy in squamous cell carcinoma of the esophagus.

Patients with ESCC (squamous cell carcinoma of the esophagus) are most commonly diagnosed with locally advanced tumor stages. Early metastatic disease and late diagnosis are common reasons responsible for this tumor's poor clinical outcome. The prognosis of esophageal cancer is very poor because patients usually do not have symptoms in early disease stages. Squamous cell carcinoma of the esophagus frequently complicates patients with multiple co-morbidities and these patients often require interdisciplinary diagnosis and treatment procedures. At present time, neoadjuvant radiation therapy and chemotherapy followed by surgery are regarded as the international standard of care. Meta-analyses have confirmed that this approach provides the patient with better local tumor control and an increased overall survival rate. It is recommended that patients with positive tumor response to neoadjuvant therapy and who are poor surgical candidates should consider definitive radiochemotherapy without surgery as a treatment option. In future, EGFR antibodies may also be administered to patients during therapy to improve the current treatment effectiveness. Positron-emission tomography proves to be an early response-imaging tool used to evaluate the effect of the neoadjuvant therapy and could be used as a predictive factor for the survival rate in ESCC. The percentage proportions of residual tumor cells in the histopathological analyses represent a gold standard for evaluating the response rate to radiochemotherapy. In the future, early response evaluation and molecular biological tests could be important diagnostic tools in influencing the treatment decisions of ESCC patients.

[Multimodal therapy in locally advanced gastric cancer]. / Multimodale Therapie beim lokal fortgeschrittenen Magenkarzinom.

Locally advanced gastric cancers are characterized by poor prognosis. Clinical outcome can be improved if surgery becomes part of a multimodal treatment approach. The purpose of neoadjuvant treatment includes downsizing of the primary tumor, improvement of the T- and N- categories, and early therapy of micrometastasis. Several controlled clinical trials showed that neoadjuvant chemotherapy as well as neoadjuvant combined radio-chemotherapy, especially for tumors of the gastroesophageal junction, can improve the rate of primary R0 resections, relapse-free survival, and overall survival. While patients with locally advanced tumors clearly benefit from this strategy, the approach is still controversial in patients with early stage disease. Nonresponders do not benefit from neoadjuvant therapy. Therefore, response evaluation and response prediction are of great importance. After successful neoadjuvant chemotherapy, patients should undergo gastrectomy with D(2)-lymphadenectomy because of a high probability of lymph node metastasis. This article summarizes current developments in this field.

The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract.

Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemo?radiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection.

Fibromuscular dysplasia in living renal donors: still a challenge to computed tomographic angiography.

BACKGROUND: Computed tomographic angiography has become the standard evaluating method of potential living renal donors in most centers. Although incidence of fibromuscular dysplasia is low (3.5-6%), this pathology may be relevant for success of renal transplantation. The incidence of FMD in our population of LRD and reliability of CTA for detecting vascular pathology were the aims of this study. MATERIALS AND METHODS: 101 living renal donors, examined between 7/2004 and 9/2008 by CTA, were included in a retrospective evaluation. The examinations were carried out using a 64 Multi-detector CT (Siemens Medical Solutions, Erlangen). The presence or absence of the characteristic signs of fibromuscular dysplasia, as "string-of-beads" appearance, focal stenosis or aneurysms, were assessed and graded from mild (=1) to severe (=3). Furthermore, vascular anatomy and arterial stenosis were investigated in this study. Retrospective analysis of CTA and ultrasound were compared with operative and histological reports. RESULTS: Four cases of fibromuscular dysplasia (incidence 3.9%) in 101 renal donors were diagnosed by transplanting surgeons and histopathology, respectively. Three cases could be detected by CTA. In one donor even retrospective analysis of CTA was negative. Ten accessory arteries, 14 venous anomalies and 12 renal arteries stenosis due to atherosclerosis were diagnosed by CTA and could be confirmed by the operative report. CONCLUSION: CTA is sufficient for detection of hemodynamic relevant stenosis and vascular anatomy. Only one patient with a mild form of FMD was under estimated. Therefore, if the CTA shows slightest irregularities which are not typical for atherosclerotic lesions, further diagnostic work up by DSA might still be necessary.

HIF-1alpha protein expression is associated with the environmental inflammatory reaction in Barrett's metaplasia.

The oxygen-regulated transcription factor subunit hypoxia inducible factor-1alpha (HIF-1alpha) is involved in angiogenesis, energy metabolism, cell survival, and inflammation. We examined the protein expression of HIF-1alpha within the progression of Barrett's sequence as well as the type and degree of the environmental inflammatory reaction. Squamous epithelium (SE), metaplastic, low- and high-grade dysplastic lesions, and tumor tissue of 57 resection specimens from patients with Barrett's adenocarcinoma were immunohistochemically analyzed. Active and chronic inflammatory reactions were classified according to the Updated Sydney System. HIF-1alpha protein expression increased significantly from SE to Barrett's metaplasia (BM) (P < 0.0001). From metaplasia through low- and high-grade dysplasia to cancer, no further increase could be detected. Active and chronic inflammation were also significantly different between SE and BM (P < 0.0001) but not during further progression in the sequence. HIF-1alpha protein expression did not correlate with histopathologic parameters or survival. HIF-1alpha protein expression pattern resembles the active and chronic environmental inflammatory reaction. All were significantly increased in metaplasia compared to SE without further change in tumor development. HIF-1alpha protein expression appears to be associated with inflammatory processes in the development of BM.

GNAS1 T393C polymorphism is associated with histopathological response to neoadjuvant radiochemotherapy in esophageal cancer.

Recent studies have shown an association between the GNAS1 T393C polymorphism and clinical outcome for various solid tumors. In this study, we genotyped 51 patients from an observational trial on cisplatin/5-FU-based neoadjuvant radiochemotherapy of locally advanced esophageal cancer (cT2-4, Nx, M0) and genotyping was correlated with histomorphological tumor regression. The C-allele frequency in esophageal cancer patients was 0.49. Pearson's chi(2)-test showed a significant (P<0.05) association between tumor regression grades and T393C genotypes. Overall, 63% of the patients in the T-allele group (TT+CT) were minor responders with more than 10% residual vital tumor cells in resection specimens, whereas T(-) genotypes (CC) showed a major histopathological response with less than 10% residual vital tumor cells in 80%. The results support the role of the T393C polymorphism as a predictive molecular marker for tumor response to cisplatin/5-FU-based radiochemotherapy in esophageal cancer.

Analysis of microsatellite instability in colorectal carcinoma by microfluidic-based chip electrophoresis.

Microsatellite analysis is an important tool in clinical research and molecular diagnostics because microsatellite instability (MSI) occurs frequently in various types of cancer. Approximately 10-15% of colorectal, gastric and endometrial carcinomas are associated with MSI, and this has an impact on clinical prognosis. The microsatellite loci Bat25, Bat26, D2S123, D5S346 and D17S250, recommended by the Bethesda guidelines, were analysed by microfluidic-based on-chip electrophoresis in 40 cases of colon carcinoma with known MSI status. In all cases, microfluidic separation of the PCR amplicons resulted in highly resolved, distinct patterns of each of the five microsatellite loci. Detection of MSI could be demonstrated by microsatellite-loci-associated, well-defined deviations in the electropherogram profiles of tumour and non-tumour material, and confirmed the classification of MSI cases performed by conventional technology. In conclusion, microfluidic chip technology is a simple and reliable approach for MSI detection that allows label-free and very fast analysis of microsatellite amplicons.

Serosal penetration is an important prognostic factor for gastrointestinal stromal tumors.

Predicting the malignant potential of gastrointestinal stromal tumors (GISTs) remains difficult. We assessed the value of serosal penetration, an established prognostic factor in solid tumors, to determine the clinical outcome in patients with GISTs. From 1996-2002, 25 consecutive patients with GIST underwent surgical resection at our Department. The histopathological presence of serosal penetration was assessed to predict clinical outcome. In addition, the established histopathological classification system by Franquemont (modified by using the Ki-67 proliferation index), was applied to each study patient. A Ki-67 index > or =5% (p<0.001) and a mitotic rate > or =5/50 high-power fields (p<0.047) significantly correlated with a shorter survival, whereas a tumor size >5 cm (p=0.07) tended towards a worse prognosis. The survival of patient groups defined by Franquemont (p=0.03) were of prognostic relevance. The presence of serosal penetration significantly correlated (p<0.01) with a shorter survival. Our data suggest that the presence of serosal penetration is a negative prognostic factor for GISTs. Serosal penetration may become a useful additional parameter for the classification of the malignant potential of GISTs. Since our data are merely hypothesis-generating, serosal penetration should be evaluated in large prospective databases.

Clinicopathological significance of MMP-2 and its specific inhibitor TIMP-2 in gastric cancer.

Matrix metalloproteinases (MMPs) can degrade type IV collagen of extracellular matrices and basal membranes and thus play a key role in the migration of malignant cells. In vivo, MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs). Since in a previous study we showed that the expression of MMP-2 correlates with clinicopathological parameters in gastric cancer, we have now investigated a possible correlation of MMP-2 and TIMP-2 expression with survival in gastric cancer, as well as the possible association of TIMP-2 with clinicopathological parameters. Tissue samples were obtained from 116 gastric cancer patients who underwent gastrectomy with extended lymphadenectomy. MMP-2 and TIMP-2 expression was analysed using immunohistochemical staining and was graded semiquantitatively (score 0 - 3). High epithelial MMP-2 immunoreactivity was significantly associated with tumor stage and poor survival using the Kaplan-Meier log-rank statistical method (log-rank statistics). However, using Cox regression analysis, high epithelial MMP-2 immunoreactivity was not an independent prognostic factor. TIMP-2 showed no association with survival in gastric cancer, but the intensity of TIMP-2 staining in tumor cells correlated significantly with tumor differentiation based on the WHO and Lauren and Ming classifications, as well as with presence of distant metastasis. Our results show that high epithelial MMP-2 expression in gastric cancer is associated with poor survival, although it is not an independent prognostic factor, and that aggressive forms of gastric cancer are associated with low TIMP-2 expression.

Comparative analysis of four histopathological classification systems to discriminate benign and malignant behaviour in gastrointestinal stromal tumors.

UNLABELLED: The prognostic value of the four most common histopathological classification systems in gastrointestinal stromal tumors (GISTs) was evaluated retrospectively. PATIENTS AND METHODS: Twenty-five consecutive patients with resected GIST and a follow-up of five years or more for surviving patients were included in this analysis. All the tumors were c-KIT (CD117) positive and were additionally re-evaluated for the number of mitoses per 50 high-power fields (HPF) and Ki-67 proliferation index. The four most commonly applied histopathological classification systems of the WHO, Franquemont (modified by using the Ki-67 proliferation index), Fletcher and Miettinen were applied to each patient. RESULTS: The survival of patient groups classified by Franquemont (p = 0.03) and the WHO (p = 0.031) were of prognostic relevance, while the grouping of patients by classifications according to both, Fletcher and Miettinen did not show a significant prognostic value. CONCLUSION: The classification systems of Franquemont (modified) or WHO appear to be advantageous for the evaluation of malignant potential and clinical outcome in patients with GISTs. Our data are merely hypothesis generating and should be validated in larger clinical studies.

MUC1 (EMA) expressing plasma cells in bone marrow infiltrated by plasma cell myeloma.

MUC1 (also called: epithelial membrane antigen, EMA) represents a mucin molecule strongly expressed in various epithelia and epithelial neoplasms. Its expression correlates with clinical and pathological factors as well as prognosis in some tumor types. Additionally, MUC1 was detected in normal haematopoietic cell lines and neoplasms, especially subgroups of human lymphomas including plasma cell myeloma. Therefore, the expression of MUC1 in trephine biopsies exhibiting infiltrates of plasma cell myeloma were investigated immunohistochemically. An immunoreactivity of two monoclonal antibodies (EMA and HMFG-2) was observed in about 50% of the cases. In cases exhibiting a so-called packed marrow, EMA immunoreactivity was reduced. However, MUC1 positivity did not correlate with the cytologic grade of differentiation, the fibre content of the marrow, or survival probability of the patients. However, its strong expression in a certain percentage of cases of plasma cell myeloma may be of therapeutic impact, since new therapeutic strategies include the enrichment of MUC1-specific T cells or MUC1 vaccination.

Association of COX-2 expression with corresponding active and chronic inflammatory reactions in Barrett's metaplasia and progression to cancer.

AIMS: Risk reduction for Barrett's cancer in individuals taking non-steroidal anti-inflammatory drugs has been reported. Cyclooxygenase (COX)-2, one of the inhibited enzymes, is putatively involved in Barrett's cancer pathogenesis. The aim of this study was to examine a possible association between COX-2 protein expression and the development and progression of the Barrett's metaplasia-dysplasia-carcinoma sequence and the type and degree of associated inflammatory reaction. METHODS AND RESULTS: Squamous epithelium, metaplastic, low-grade, high-grade dysplastic lesions and tumour tissue of 49 resection specimens from patients with Barrett's adenocarcinoma were immunohistochemically analysed. Active and chronic inflammatory reactions were classified according to the Updated Sydney System. Within the Barrett's sequence, a significant progressive increase in COX-2 expression was identified (P < 0.0001). The most significant differences were detected between squamous epithelium and Barrett's metaplasia (P < 0.001) and from low- to high-grade dysplasia (P < 0.0001). Active and chronic inflammation were significantly different between squamous epithelium and Barrett's metaplasia (P < 0.0001), but not during further progression in the sequence. CONCLUSIONS: Increasing COX-2 expression in Barrett's metaplasia is significantly associated with a change in the local inflammatory reaction, but not during further progression through dysplasia to cancer. This supports the potential of a chemoprevention strategy using COX-2 inhibitors independent of the extent and type of the inflammatory reaction in Barrett's oesophagus.

Is the urokinase-type plasminogen activator system a reliable prognostic factor in gastric cancer?

AIM: The aim of this prospective study was to evaluate the clinical and prognostic impact of immunohistochemically assessed uPA and PAI-1 in patients with gastric cancer. METHODS: This prospective study analyzed specimens obtained from 105 gastric cancer patients who underwent gastrectomy with extended lymphadenectomy. The immunohistochemical expression of uPA and PAI-1 was studied semiquantitatively in the tumor epithelium and was correlated with the clinicopathological features of each patient. RESULTS: Univariate analysis revealed no statistically significant association of uPA levels with pT and pN category (p=0.655 and 0.053, respectively), grading (p=0.374), depth of tumor invasion (p=0.665), UICC classification (p=0.21) and the Laurén classification (p=0.578). PAI-1 expression showed no statistically significant correlation with pT, pN and M category (p=0.589, 0.414, and 0.167, respectively), grading (p=0.273), and the Laurén classification (p=0.368). Only the UICC classification was significantly correlated with PAI-1 (p=0.016). Kaplan-Meier analysis revealed no significant association of uPA and PAI-1 with overall survival (p=0.0929 and 0.0870, respectively). CONCLUSIONS: Our results could not verify any prognostic value of uPA and PAI-1 levels in patients with gastric carcinoma. Therefore, the uPA-system as a biologically defined prognostic marker to identify high-risk gastric cancers should be applied with caution. However, considering the number of patients involved and the borderline level of significance observed in this study, a larger number of events may have resulted in significant differences.

[Combined laparoscopic/endoscopic treatment of gastric stroma tumors]. / Kombiniert laparoskopisch-endoskopische Resektion von Stromatumoren des Magens.

INTRODUCTION: Surgical therapy of Gastrointestinal stroma tumor (GIST) is the treatment of choice. Local resection will be carried out if technically possible. We describe the technique of laparoscopic wedge resection combined with intraoperative gastroscopy in order to achieve complete tumor resection. METHOD: We report on 4 cases with gastrointestinal stroma tumors which were located in the gastric corpus (n = 2) and the cardia (n = 2). RESULTS: In all patients the tumor could be removed completely without any perioperative complications using laparoscopic wedge resection controlled by intraoperative endoscopy. The duration of hospitalisation after operation was 7 days (5-10). On the basis of the mean tumor size (mean 3.8 cm) and the low mitotic activity (mean 2.75/high power fields) the tumors belong to the group with low malignant potential. There is no evidence of recurrence after a mean follow up period of 23 (6-30) months. CONCLUSION: Combined laparoscopic/endoscopic wedge resection is a safe method for total resection of GIST of the stomach and should be preferred as alternative to open surgery.

Lewis(y) antigen (CD174) and apoptosis in gastric and colorectal carcinomas: correlations with clinical and prognostic parameters.

Lewis(y) (Le(y)), also designated CD174, represents a carbohydrate blood group antigen which is strongly expressed in neoplastic gastrointestinal tissues. Previous reports indicated an association between Le(y) expression and apoptosis. Therefore, we tried to elucidate its clinicopathological relevance in a series of 160 gastric and 215 colorectal carcinomas by immunohistochemical detection of Le(y) and visualization of apoptotic cells applying the in-situ-end labelling (ISEL) method, followed by semiquantitative scoring of the specimens. In both gastric as well as colorectal carcinomas, between 40 and 50% of the cases were Le(y) reactive. Signet-ring cell carcinomas of the stomach exhibited a significantly stronger Le(y) expression compared to other tumor types. In colorectal cancers, Le(y) was associated with increased tumor staging, showing the strongest positivity in stage IV. Further correlations with clinicopathological variables or prognosis were not observed. On the other hand, the amount of apoptotic cells was significantly reduced in mucinous adenocarcinomas of the colorectum compared to non-mucinous carcinomas. Scoring of apoptotic cells did not result in any other clinicopathologically relevant correlations. In addition, a significant association between Le(y) antigen expression and apoptosis score could not be established. Therefore, the hypothesis of a functional relationship between these two aspects of gastrointestinal tumor biology is not confirmed by our data.