Verhandlungen der Deutschen Gesellschaft fur Pathologie最新文献

While most colorectal polyps can be classified as either adenomas (AD) or hyperplastic polyps (HP), approximately 5 % have some of the features of these lesions but are distinguishable from both. These lesions include sessile serrated adenoma or polyp (SSP), mixed polyp (MP), and traditional serrated adenoma (SA). These relatively recently described entities account for only about 3%, 1% and 1% of colorectal polyps respectively. Nevertheless, they may serve as the precursor lesions of the subset of colorectal cancer (15-20%) with extensive DNA methylation, mutation of BRAF, and DNA microsatellite instability. This overview summarises the key morphological features of traditional and newer types of colorectal polyps. It also discusses the differing molecular signatures of polyps, focusing on mutation of BRAF and KRAS and alterations of TP53 and the DNA repair genes O-6-Methylguanine DNA Methyltransferase (MGMT) and MLH1. A more detailed description of the features of MPs and SA is then developed and it is shown that these polyps are highly heterogeneous lesions in terms of both morphology and molecular pathology. Finally, a simple working nomenclature for the diagnostic reporting of colorectal polyps is suggested. In this system, MPs and SAs are combined as 'serrated polyps with dysplasia'. It is likely that the recognition and diagnosis of serrated polyps of the colorectum will assume increasing importance in the coming years and that their complex morphology and molecular heterogeneity will present interesting challenges for pathologists, scientists and clinicians.

In the last decades, a great variety of novel therapeutic regimens have become available for cancer. These therapies often are very specific and thus effective only in subsets of cancer patients. This has led to an increased need for the clinician to specifically choose the therapeutic strategy the patient profits most from, but at the same time avoiding over-treatment. This situation has a profound impact on the methods in diagnostic tumor pathology, since it requires precise pre-therapeutic tumor characterization to support the clinical management of the individual case. A common and early event in cancer is aberrant DNA methylation within gene regulatory regions which affects a variety of genes with different functions. Altered DNA methylation has been shown to carry prognostic as well as predictive information. As a DNA-based marker that can be analyzed in routine formalin fixed tissue, DNA methylation offers a series of technical advantages which allow for introduction into a routine lab. Here we review well established DNA methylation markers and discuss their potential for clinical use.

Rationale: The participation of circulating precursor cells in the development of experimental pulmonary fibrosing lesions in mice has been recently demonstrated.

Objectives: This study analyzes whether circulating, bone marrow-derived fibroblastic precursor cells contribute to the development of fibrosing lesions in human lungs, especially bronchiolitis obliterans.

Methods: The occurrence of in situ-microchimerism in bronchiolitis obliterans lesions of human lung allografts (n = 12) as well as of autologous lung tissue from patients post bone marrow-transplantation (n = 2) was analyzed using laser-assisted microdissection after immunohistochemical labeling of leukocytes followed by STR-PCR-based genotyping. Combined immunofluorescence and fluorescence in situ hybridization for sex chromsomes was performed for independent confirmation in cases with appropriate sex mismatch (n = 2).

Measurements and main results: The bronchiolitis obliterans lesions of all twelve lung transplant patients contained considerable numbers of recipient-derived fibroblasts (mean: 32 %). The fibrosing pulmonary lesions of the two bone marrow-transplanted patients displayed also clear in situ-microchimerism. The in situ detection methodology confirmed these results, although to a lower degree (6-16%).

Conclusions: These data clearly demonstrate the involvement of circulating fibroblastic precursor cells in the development of human fibrosing lung lesions and provide evidence that these cells are most probably bone marrow-derived. These results may open new venues regarding the prevention of fibrosis in lung transplants and potentially other organs.

The deregulation of receptor tyrosine kinases is an essentiell factor in die initiation and progression of malignant tumours. With the introduction of Herceptin in the adjuvant therapy of invasive breast cancer, the determination of the c-erbB2 expression status became an essential part in the workup of breast cancer biopsies. The commonly used diagnostic algorithm is based on a detailed knowledge about molecular mechanisms and downstream signal cascades. In contrast to c-erbB2, the underlying molecular mechanisms and potential predictive parameters, associated with the expression of the Epidermal Growth Factor Receptor (EGFR) are likewise unclear. With the introduction of anti-EGFR directed therapies in the treatment of malignant tumours, an improved knowledge about the role in the progression of breast cancers is urgently needed. This article will focus on important improvements in the knowledge of EGFR-overexpression in breast cancer cells, especially in the context of egfr-amplifications.

Relevant criteria to assess specific diseases have been heavily discussed since Rudolf Virchow when morphologic changes represented the center of interest. However, nowadays presence and severity of disease cannot exclusively depend on the mere absence or presence of morphologic criteria anymore. The progress in basic and clinical science, moral values and economic constraints imply to reflect, concretize and ultimately operationalize the goals of medical therapy. Recent advances in molecular biology and genetics have lead to further understanding of pathophysiological mechanisms of disease and opened new ways for sophisticated and individualized therapeutical approaches. It is important to reconsider the definition of health and appropriately address functional and quality of life aspects. The categorical classification of therapeutical options, i.e. curative versus palliative therapy, does not provide satisfying answers to several clinical scenarios such as early stage prostate cancer in older adults or functional limitations in patients with peripheral arterial disease. Clinical research does acknowledge increasingly that relevant outcomes extend well beyond the quantitative prolongation of life. The scientific field of health services research is supposed to increase the evidence base of these decisions. Lastly, the goals of therapy should not be defined by physicians alone. It is important to inform the patient appropriately and discuss individual prognosis, therapeutical options and goals. Ultimately, therapy should be based on a shared decision making process.

In the clinical pathway of diagnosis and therapy of diseases two decisions are distinguished: diagnostic and therapeutic decision. The former is analysed by decision tables, the latter by decision trees. In both decisions pathology plays a dominant role, especially as a gold standard that is a test to which most people have developed trust. This definition is remarkably soft. An efficient diagnostic prediction depends on a high prevalence of the disease. This is frequently forgotten when tests have a high sensitivity and specificity. The mathematical concept behind this observation is the Bayesian theorem. This is highly important for predictive pathology because it allows to combine attributes with high likelihood ratio simply by multiplication and has been shown to be remarkably stable, e. g. in the differential diagnosis of acute abdominal pain. Pathology should take the leadership in prediction since it has a considerable power as the gold standard of many tests. However, a network is advisable with other basic disciplines.

Aims: Urothelial neoplasms in patients 19 years or younger are rare, with conflicting data regarding clinical outcome and no molecular data available.

Methods: Urothelial tumors of 14 patients 4 to 19 years old were identified, reclassified according to the 2004 WHO classification and data on presentation, risk factors and outcome were collected. 14 cases were microdissected and extensive molecular analyses were done, including FGFR3 and TP 53 mutation screening, Comparative Genomic Hybridisation (CGH), Urovysion FISH analysis, PCR for HPV, microsatellite analysis using an extended NIH consensus panel for detection of microsatellite instability (MSI) and 6 LOH markers on chromosome arms 17p, 9p and 9q and immunohistochemistry for TP 53, MIB1, CK20 and the mismatch repair proteins hMSH2, hMLH1 and hMSH6.

Results: Based on the 2004 WHO classification, 1 urothelial papilloma, 7 PUNLMPs, 5 low grade, and 1 high grade papillary urothelial cancers were included. There were no multifocal tumors and only 1 patient had recurrence. All patients were alive with no evidence of disease (4.5 years follow-up). We did not find mutations in FGFR3, deletions of chromosome arms 9p, 9q or 17p, MSI or MRP loss or HPV positivity. Chromosomal alterations in CGH, urothelial dedifferentiation with CK20 over-expression or aneuploidy were rare and only detected in 3 cases. One TP53 mutation was found in the only tumor with overexpression of TP53.

Conclusions: Urothelial neoplasms in individuals younger than 20 years have predominantly a low grade and favourable clinical outcome. The most frequent genetic alterations found in elderly patients are extremely rare. Urothelial neoplasms in young patients could represent a biologically distinct form of bladder disease with lack of genetic instability in most cases.

Rhabdomyosarcomas (RMSs) are the most frequent malignant soft tissue tumors of childhood. Since even aggressive multimodality treatments including autologous stem cell rescue have failed to improve the < 20 % overall survival rate of children with metastatic RMS, novel treatment approaches are urgently needed. Looking for potential targets for immunotherapies, we identified the gamma subunit of the fetal acetylcholine receptor (fAChR) as a specific and overexpressed membrane antigen in RMS. Additionally we established a duplex RT-PCR with simultaneous amplification of alpha and gamma subunit message of the fAChR and the quantification of both transcripts resulting in alpha/gammaAChR ratio > 1 was 100% sensitive in alveolar and embryonal rhabdomyosarcoma. Since the fAChR was the first extracellular tumor marker that can distinguish rhabdomyosarcomas from nonrhabdomyomatous tumors and from normal muscle and therefore implies, that the fAChR may be a target for immunotherapeutic strategies, we synthesized a scFv antibody fragment directed against the fAChR and enigineered both a Pseudomonas exotoxin A based immunotoxin as well as a chimeric T cell receptor composed of the antigen-binding domain of the scFv fragment joined to the signaling domain of the T cell receptor zeta chain. The interaction of fAChzeta-transduced T cells with several RMS cell lines but not with fAChR-negative controls induced strong T cell activation, characterized by secretion of high amounts of interferon-gamma. Moreover after co-incubations with RMS cell lines fAChRzeta-transduced T cells as well fAChR specific immunotoxin induced specific receptor-concentration dependent tumor cell lysis. Therefore, fAChRzeta-transduced T cells and the fAChR specific immunotoxin respectively are promising new tools for the immunotherapy of rhabdomyosarcomas and may provide an effective complementary approach to eradicate residual or metastatic RMS cells in patients, since 1. RMS-direceted chemotherapies increase the expression of fAChR on residual RMS cells in vivo and 2. the fully human fAChR autoantibody fragment with low immunizing potential allows prolonged/permanent application of fAChRzeta-transduced T cells/immunotoxin.

Aims: Cytotoxic luteinizing hormone releasing hormone (LHRH) analogues AN-152 and AN-207 consist of [D-Lys6] LHRH linked to doxorubicin or its hyperactive derivate AN-201 and bind with high affinity to LHRH receptors. We evaluated the use of AN-207 and AN-201 in a nude mice model. In order to provide a rationale for the possible use of cytotoxic LHRH analogues in different malignancies we investigated the expression of LHRH-R in human renal cell carcinoma (RCC), melanoma and non Hodgkin's Lymphoma (NHL).

Methods: The expression of LHRH-R was examined in surgically removed human specimens of primary tumours and metastases from 37 RCC, 19 melanomas and 17 NHLs. In addition, human tumour cell lines expressing LHRH receptors were transplanted into nude mice and anti-tumour efficacy and systemic toxicity of AN-207 and its cytotoxic radical AN-201 were compared in various experiments.

Results: Positive staining for LHRH receptors was found in all of the RCC (37/37) and the melanoma specimens (19/19) as well as in 100% (10/10) of the NHLs. In in vivo experiments AN-207 significantly inhibited tumour growth while the cytotoxic radical alone was ineffective. Furthermore, side effects were reduced with targeted therapy.

Conclusions: LHRH receptor expression was found to be very high in melanomas, RCCs and NHLs. Therefore targeted therapy with cytotoxic LHRH analogues may be a promising, novel therapy for advanced stages of these tumours. A first clinical trial with AN-152 was initiated recently in breast cancer patients.

Human tissue, in particular tumour tissue, represents a basic requirement for the research topic "predictive pathology". For many approaches unfixed fresh frozen tissue is required. For the recruitment, asservation and storage standard operating procedures (e. g. "informed consent") have to be followed. The role of the pathologist in the organization of tumour banks is manifold. 1. The collection of fresh frozen tumour tissue has to be performed without interference with the diagnostic procedure, optimally by a trained pathologist within the operating theatre. 2. Prior to the use of fresh frozen tissue for non morphological prodecures a histopathological documentation of tissue has to be performed. 3. In many cases complementary analysis of paraffine embedded tumour tissue for the same cases is necessary (e. g. immunohistochemistry, tissue microarray analyses, etc.). 4. For special questions (laser)microdissection of tissue has to be applied and also requires pathohistological knowledge. 5. Interpretation of results of non morphological analysis has to be correlated with pathohistological findings. Furthermore, in addition to the above mentioned research goals, tumour banks are an important source for future diagnostic procedures in particular for individualiziation of tumour therapy which will be developed in the future. As a conclusion, the pathologist plays a pivotal role in the organization of tumour- respectively tissue banks. Care must be taken that banks should be organized on an interdisciplinary basis since besides tumour tissue clinical data are required for most scientific studies.