Anja Schmitt

Universität Bern, Berna, Bern, Switzerland

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Publications (43)159.91 Total impact

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    ABSTRACT: Neuroendocrine tumors (NET) are routinely graded and staged to judge prognosis. Proliferation index using MIB1 staining has been introduced to assess grading. There are vivid discussions on cutoff definitions, automated counting, and interobserver variability. However, no data exist regarding interlaboratory reproducibility for low proliferation indices which are of importance to discriminate between G1 and G2 NET. We performed MIB1 staining in three different university hospital-based pathology laboratories on a tissue micro array (TMA) of a well-characterized patient cohort, containing pancreatic NET of 61 patients. To calculate the proliferation index, number of positive tumor nuclei was divided by the total number of tumor nuclei. Labeling index was compared to mitotic counts in whole tissue sections and to clinical outcome. Linear regression analysis, intraclass comparison, and log-rank analysis were performed. Intraclass correlation showed moderate-to-fair agreement. Especially low proliferating tumors were affected by interlaboratory differences. Log-rank analysis was performed for each lab and resulted in three different cutoffs (5.0, 3.0, and 0.5 %). Every calculated cutoff stratified the patient cohort to a significant extent for the underlying stain (p < 0.001, <0.001, and <0.001) but showed no or lesser significance when applied to the other stains. Significant and relevant interlab differences for MIB1 exist. Since the MIB1 proliferation index influences grading, local cutoffs or external standardization should urgently be introduced to achieve reliability and reproducibility.
    No preview · Article · Sep 2015 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin

  • No preview · Article · Sep 2015 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
  • Annika Blank · Anja Schmitt · Aurel Perren
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    ABSTRACT: The classification of neuroendocrine neoplasms (NENs) has been evolving steadily over the last decades. Important prognostic factors of NENs are their proliferative activity and presence/absence of necrosis. These factors are reported in NENs of all body sites; however, the terminology as well as the exact rules of classification differ according to the location of the primary tumor. Only in gastroenteropancreatic (GEP) NENs a formal grading is performed. This grading is based on proliferation assessed by the mitotic count and/or Ki-67 proliferation index. In the lung, NEN grading is an intrinsic part of the tumor designation with typical carcinoids corresponding to neuroendocrine tumor (NET) G1 and atypical carcinoids to NET G2; however, the presence or absence of necrotic foci is as important as proliferation for the differentiation between typical and atypical carcinoids. Immunohistochemical markers can be used to demonstrate neuroendocrine differentiation. Synaptophysin and chromogranin A are, to date, the most reliable and most commonly used for this purpose. Beyond this, other markers can be helpful, for example in the situation of a NET metastasis of unknown primary, where a hormonal profile or a panel of transcription factors can give hints to the primary site. Many immunohistochemical markers have been shown to correlate with prognosis but are not used in clinical practice, for example cytokeratin 19 and KIT expression in pancreatic NETs. There is no predictive biomarker in use, with the exception of somatostatin receptor (SSTR) 2 expression for predicting the amenability of a tumor to in vivo SSTR targeting for imaging or therapy. © 2015 S. Karger AG, Basel.
    No preview · Article · Aug 2015 · Frontiers of hormone research
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    ABSTRACT: The tall cell variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent and the role of a minor tall cell (TC) component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and TERT promoter mutations. Using a novel approach, we enriched a collective with PTC harboring an adverse outcome, overcoming the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of them with an adverse outcome. The proportion of TC that constitute a poor prognosis was assessed. All tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody detecting the BRAF V600E mutation. A 10% cut off for TC was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that tall cells above 10% were the only significant factor for overall, tumor-specific and relapse-free survival. 7% of cases had a TERT promoter mutation while 61% demonstrated a BRAF mutation. The presence of TC was significantly associated with TERT promoter and BRAF mutations. TERT predicted highly significant tumor relapse (p<0.001). PTC comprising of at least 10% TC are associated with an adverse clinical outcome and should be reported accordingly. BRAF did not influence patient outcome. Nevertheless, a positive status should encourage the search for tall cells. TERT promoter mutations are a strong predictor of tumor relapse but their role as a surrogate marker for TC is limited.
    No preview · Article · Apr 2015 · Endocrine Related Cancer
  • Article: Gastrinoma
    Anja M. Schmitt · Annika Blank · Aurel Perren
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    ABSTRACT: Gastrinomas are neuroendocrine tumors occurring most frequently in the duodenum, followed by the pancreas. They are characterized by the secretion of gastrin, resulting in symptoms that are termed Zollinger-Ellison syndrome. Among functioning pancreatic neuroendocrine tumors, gastrinomas represent one of the most common malignant subtypes. Gastrinomas differ concerning their site of origin and their genetic background. Whereas sporadic gastrinomas occur either in the duodenum or the pancreas, hereditary gastrinomas in the setting of MEN1 are mostly due to multiple and small gastrinomas in the duodenal wall. Sporadic duodenal gastrinomas tend to be smaller and to run a less aggressive clinical course than their pancreatic counterparts. Duodenal gastrinomas in the setting of MEN1 are associated with a less aggressive behavior than sporadic tumors. Histologically, gastrinomas do not exhibit any specific features but are mostly well-differentiated neuroendocrine tumors with a trabecular and pseudoglandular growth pattern, usually corresponding to NET G1 or G2 tumors. In most instances, immunohistochemically they stain positive for gastrin
    No preview · Article · Jan 2015
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    ABSTRACT: Background/aims: O(6)-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico-pathological data and determine the role of MGMT to predict response to TMZ chemotherapy. Methods: We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR. Results: In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ. Conclusion: Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine.
    No preview · Article · Jul 2014 · Neuroendocrinology

  • No preview · Article · May 2014 · Neuropathology

  • No preview · Conference Paper · Jan 2014
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    ABSTRACT: AimsFollicular thyroid carcinoma (FTC) has been a diagnostic challenge for decades. The PAX8-PPAR rearrangement has been detected in FTC and classic papillary thyroid carcinomas (PTCs). The aims of this study were to assess the presence of PAX8-PPAR by using tissue microarrays in a large cohort of different thyroid neoplasms, and to assess its diagnostic and prognostic implications. Methods and resultsFluorescence in-situ hybridization (FISH) analysis for PAX8-PPAR was performed on 226 thyroid tumours, comprising FTCs (n=59), PTCs (n=126), poorly differentiated thyroid carcinomas (PDs; n=34), follicular thyroid adenomas (FTAs; n=5), and follicular tumours of unknown malignant potential (FTUMPs; n=2). PAX8-PPAR was detected in 12% of FTCs, 1% of PTCs, 7% of PDs, and in both cases of FTUMP. There was no correlation between the extent of capsular or vascular invasion and PAX8-PPAR, or between lymph node or haematogenous metastasis and PAX8-PPAR. Overall survival (OS), tumour-specific survival (TSS) and relapse-free-survival (RFS) were not influenced by PAX8-PPAR. Conclusions In this study, we demonstrate for the first time the presence of PAX8-PPAR in PDs and FTUMPs, whereas in FTCs and PTCs the prevalence of PAX8-PPAR is lower than previously reported. PAX8-PPAR did not correlate with invasiveness or affect prognosis in any tumour type.
    Full-text · Article · Mar 2013 · Histopathology
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    ABSTRACT: The human insulin gene enhancer-binding protein islet-1 (ISL1) is a transcription factor involved in the differentiation of the neuroendocrine pancreatic cells. Recent studies identified ISL1 as a marker for pancreatic well-differentiated neuroendocrine neoplasms. However, little is known about ISL1 expression in pancreatic poorly differentiated and in extrapancreatic well and poorly differentiated neuroendocrine neoplasms. We studied the immunohistochemical expression of ISL1 in 124 neuroendocrine neoplasms. Among pancreatic neuroendocrine neoplasms, 12/13 with poor differentiation were negative, whereas 5/7 with good differentiation but a Ki67 >20% were positive. In extrapancreatic neuroendocrine neoplasms, strong positivity was found in Merkel cell carcinomas (25/25), pulmonary small cell neuroendocrine carcinomas (21/23), medullary thyroid carcinomas (9/9), paragangliomas/pheochromocytomas (6/6), adrenal neuroblastomas (8/8) and head and neck neuroendocrine carcinomas (4/5), whereas no or only weak staining was recorded in pulmonary carcinoids (3/15), olfactory neuroblastomas (1/4) and basaloid head and neck squamous cell carcinomas (0/15). ISL1 stained the neuroendocrine carcinoma component of 5/8 composite carcinomas and also normal neuroendocrine cells in the thyroid, adrenal medulla, stomach and colorectum. Poorly differentiated neuroendocrine neoplasms, regardless of their ISL1 expression, were usually TP53 positive. Our results show the almost ubiquitous expression of ISL1 in extrapancreatic poorly differentiated neuroendocrine neoplasms and neuroblastic malignancies and its common loss in pancreatic poorly differentiated neuroendocrine neoplasms. These findings modify the role of ISL1 as a marker for pancreatic neuroendocrine neoplasms and suggest that ISL1 has a broader involvement in differentiation and growth of neuroendocrine neoplasms than has so far been assumed.
    Full-text · Article · Mar 2013 · Modern Pathology
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    Full-text · Article · Sep 2012
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    ABSTRACT: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.
    Full-text · Article · Apr 2012 · Journal of the National Cancer Institute
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    ABSTRACT:   Poorly differentiated thyroid carcinomas (PDTC) are an ongoing diagnostic challenge. Although the Turin consensus criteria for PDTC excluded consideration of oncocytic tumours, the World Health Organization (WHO) classification does recognise an oncocytic variant of conventional PDTC. The aims of this study were to establish whether the Turin criteria can be applied to oncocytic PDTC, and to determine if there are prognostic differences between conventional and oncocytic PDTC.   We applied the Turin criteria to 129 thyroid carcinomas. We identified 18 oncocytic PDTC and 16 conventional PDTC. Kaplan-Meier analysis revealed a significantly worse outcome for oncocytic PDTC with regard to overall and tumour-specific survival but no difference for relapse-free survival, all of which were confirmed by multivariate analysis. There was no association of survival with gender, age or tumour stage.   The Turin criteria can be applied to oncocytic PDTC and patients with this variant have a decreased survival using conventional radioiodine treatment compared to conventional PDTC and might therefore be candidates for novel treatment modalities.
    Full-text · Article · Feb 2012 · Histopathology
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    ABSTRACT: Poorly differentiated (PD) carcinomas of the thyroid are conceptually situated between well-differentiated (papillary or follicular) carcinomas and anaplastic thyroid carcinomas. Although the morphologic criteria for PD tumors are well defined, it is not clear how much of a PD area besides a well-differentiated component in a given tumor is required to allow such a diagnosis. We identified 42 patients suffering from thyroid carcinoma with an adverse clinical outcome. Fifty patients with follicular carcinoma were added as controls. We analyzed poorly differentiated areas by applying the Turin criteria of PD carcinomas. These criteria consisted of the presence of a solid/trabecular/insular growth pattern, lack of nuclear features of papillary carcinoma, and presence of 1 of the following features: (1) convoluted nuclei, (2) tumor necrosis, (3) 3 or more mitoses per 10 high-power fields. Using a cutoff value of 10% of PD areas per examined tumor surface, we identified a total of 35 PD carcinomas. Despite using a threshold of 10% of the tumor area as poorly differentiated, the survival data in a Kaplan-Meier analysis were significantly worse than those in the control group (P<0.001) and did not differ from tumors with a PD area >50%. In a multivariate analysis that included age, sex, tumor stage, and PD area >10% against survival data, the only consistent significant factor was PD differentiation (P<0.001). As even slight amounts of PD areas (≥ 10%) in a thyroid carcinoma affect the prognosis significantly, the presence of such areas may be worth reporting in thyroid carcinomas.
    Full-text · Article · Dec 2011 · The American journal of surgical pathology
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    ABSTRACT: We recently identified the transcription factor (TF) islet 1 gene product (ISL1) as a marker for well-differentiated pancreatic neuroendocrine tumors (P-NETs). In order to better understand the expression of the four TFs, ISL1, pancreatico-duodenal homeobox 1 gene product (PDX1), neurogenin 3 gene product (NGN3), and CDX-2 homeobox gene product (CDX2), that mainly govern the development and differentiation of the pancreas and duodenum, we studied their expression in hormonally defined P-NETs and duodenal (D-) NETs. Thirty-six P-NETs and 14 D-NETs were immunostained with antibodies against the four pancreatic hormones, gastrin, serotonin, calcitonin, ISL1, PDX1, NGN3, and CDX2. The TF expression pattern of each case was correlated with the tumor's hormonal profile. Insulin-positive NETs expressed only ISL1 (10/10) and PDX1 (9/10). Glucagon-positive tumors expressed ISL1 (7/7) and were almost negative for the other TFs. Gastrin-positive NETs, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). CDX2 was mainly found in the gastrin-positive P-NETs (5/8) and rarely in the D-NETs (1/10). Somatostatin-positive NETs, whether duodenal or pancreatic in origin, expressed ISL1 (9/9), PDX1 (3/9), and NGN3 (3/9). The remaining tumors showed labeling for ISL1 in addition to NGN3. There was no association between a particular TF pattern and NET features such as grade, size, location, presence of metastases, and functional activity. We conclude from our data that there is a correlation between TF expression patterns and certain hormonally defined P-NET and D-NET types, suggesting that most of the tumor types originate from embryologically determined precursor cells. The observed TF signatures do not allow us to distinguish P-NETs from D-NETs.
    No preview · Article · Aug 2011 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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    ABSTRACT: Serotonin-producing tumors of the pancreas are rare endocrine neoplasms composed of enterochromaffin (EC) cells that have been mainly described in the literature as case reports. This study analyzes the clinicopathologic features of a series of pancreatic EC cell neoplasms and their similarities to and differences from intestinal EC cell tumors. The morphological, immunohistochemical, ultrastructural, and fluorescent in situ hybridization features of 15 pancreatic and 20 intestinal serotonin-producing neoplasms were compared. In addition, we reviewed the literature on pancreatic serotonin-producing tumors to better understand the clinicopathologic features of this rare tumor type. The lack of substance P and acidic fibroblast growth factor immunoreactivity; the low immunohistochemical expression of CDX2, vesicular monoamine transporter 1, connective tissue growth factor, and prostatic acid phosphatase; the lack of S100-positive sustentacular cells; the strong expression of vesicular monoamine transporter 2; and peculiar ultrastructural features characterize pancreatic EC cell tumors and differentiate them from intestinal ones, although both categories show similar chromosome 18 cytogenetic alterations. The review of the literature indicates that pancreatic functioning tumors associated with the carcinoid syndrome arise in younger patients and are larger, more frequently malignant, and more aggressive neoplasms than pancreatic nonfunctioning ones. Pancreatic EC cell tumors show several different morphological features compared with related intestinal tumors despite similar cytogenetic alterations on chromosome 18.
    No preview · Article · Jun 2011 · Pancreas
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    ABSTRACT: Neuroendocrine tumor (NET) entities are rare malignancies. Higher awareness and improved diagnostic methods have led to an increasing incidence of these diseases, and most oncologists deal with such patients in their daily practice. The symposium on NETs that was held in Merano (Italy) in October 2009 was organized by the German-speaking European School of Oncology (dESO) and gathered specialists from different disciplines of transalpine countries to bring together experiences and observations regarding these tumors. The goal of the meeting and of this review was to illustrate both well- and poorly differentiated NETs and to encourage interdisciplinary approaches.
    No preview · Article · Mar 2011 · Onkologie
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    ABSTRACT: Prediction of malignant behaviour of pheochromocytomas/sympathetic paragangliomas (PCCs/PGLs) is very difficult if not impossible on a histopathological basis. In a familial setting, it is well known that succinate dehydrogenase subunit B (SDHB)-associated PCC/PGL very often metastasise. Recently, absence of SDHB expression as measured through immunohistochemistry was shown to be an excellent indicator of the presence of an SDH germline mutation in PCC/PGL. SDHB loss is believed to lead to tumour formation by activation of hypoxia signals. To clarify the potential use of SDHB immunohistochemistry as a marker of malignancy in PCC/PGL and its association with classic hypoxia signalling we examined SDHB, hypoxia inducible factor-1α (Hif-1α) and its targets CA-9 and GLUT-1 expression on protein level using immunohistochemistry on a tissue micro array on a series of familial and sporadic tumours of 115 patients. Survival data was available for 66 patients. SDHB protein expression was lost in the tumour tissue of 12 of 99 patients. Of those 12 patients, 5 had an SDHB germline mutation, in 4 patients no germline mutation was detected and mutational status remained unknown in parts in 3 patients. Loss of SDHB expression was not associated with increased classic hypoxia signalling as detected by Hif-1α, CA-9 or GLUT-1 staining. Loss of SDHB expression was associated with an adverse outcome. The lack of correlation of SDHB loss with classic hypoxia signals argues against the current hypoxia hypothesis in malignant PCC/PGL. We suggest SDHB protein loss as a marker of adverse outcome both in sporadic and in familial PCC/PGL.
    No preview · Article · Dec 2010 · Endocrine Related Cancer
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    ABSTRACT: After decades of confusion in lymphoma classification clearness was achieved with the publication of the REAL classification 1994 and of the WHO classification 2001. The revised 4th edition 2008 features some additional new categories. The WHO classification comprises B- and T-lymphoblastic neoplasms, mature B-cell lymphomas, mature T-cell and NK-cell lymphomas and Hodgkin lymphomas. A modern diagnostic work-up of lymphomas is based on morphology, immunohistochemistry and increasingly on molecular studies. Last but not least the evaluation of all these findings by an expert haematopathologist, who collaborates closely with the treating clinicians, is essential. The aim is to give an overview of the most frequent mature B-cell lymphomas and the most important classical Hodgkin lymphomas with focus on morphology and immunohistochemistry.
    No preview · Article · Oct 2010 · Therapeutische Umschau
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    ABSTRACT: Most of the lymphomas arising in the oral cavity are of B-cell origin. Among these, diffuse large B-cell lymphomas are the most common. Diffuse large B-cell lymphomas may exhibit more than one chromosomal rearrangement and are then referred to as 'double-hit' or 'triple-hit' lymphomas. We present a case of an intraoral 'double-hit' lymphoma in a 76-year-old male who had been referred by an oral surgeon in private practice. Intraoral examination exhibited a firm, exophytic lesion in the region of the right hard palate and buccal mucosa with extension to the soft palate. Radiographic examination exhibited a massive thickening of the right sinus membrane, and arrosion of the lateral and basal cortical sinus walls in the right maxilla. After diagnosis of the lesion, the patient was treated with six cycles of chemotherapy. Lymphomas arising within the oral cavity account for less than 5% of all oral malignancies and typically affect the palatine tonsils and the palate. 'Double-hit' lymphomas are associated with older age, usually present with an advanced stage of disease, and show an aggressive clinical behaviour. They normally have a poor prognosis, even when treated with intensive chemotherapy regimens. Nevertheless, in the case presented, the patient was free of symptoms 1 year after initial diagnosis.
    Full-text · Article · Oct 2010 · Oral and Maxillofacial Surgery

Publication Stats

883 Citations
159.91 Total Impact Points


  • 2010-2015
    • Universität Bern
      • Institute of Pathology
      Berna, Bern, Switzerland
  • 2012
    • Catholic University of the Sacred Heart
      • Institute of Pathological Anatomy
      Milano, Lombardy, Italy
  • 2008
    • Christian-Albrechts-Universität zu Kiel
      Kiel, Schleswig-Holstein, Germany
  • 2007-2008
    • Triemli City Hospital
      Zürich, Zurich, Switzerland
    • University Hospital Zürich
      Zürich, Zurich, Switzerland
  • 2006-2008
    • University of Zurich
      Zürich, Zurich, Switzerland