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Im Vergleich zwischen Screening- und Non-Screeningpatientinnen ist eine Tendenz zu prognostisch günstigeren Tumorstadien zugunsten der Screeninggruppe zu beobachten. Erstmalig konnte ein signifikanter Zusammenhang des tumorbiologischen Markers Ki-67 zwischen den beiden Gruppen nachgewiesen werden.

Since its first description at the Institute of Pathology in Kiel more than 34 years ago, the immunohistochemical proliferation marker Ki67 has been shown to be of prognostic significance in a huge number of retrospective and even some prospective trials on malignant tumours of various tissue derivation. Lack of standardization in the evaluation provides potential sources of variance in assessment. Tumour area to be assessed, minimum number of cells to be analyzed, tedious counting cell by cell or semiquantitative eyeballing, choice of immunohistochemical techniques represent nonstandardized issues that potentially lead to considerable assay heterogeneity. In addition, interpretation is not homogeneous, in particular with regard to thresholds between high and low proliferative activity. Due to these numerous potential methodological limitations, for a long time Ki67 was not generally accepted as a prognostic marker, in particular outside Germany and by nonpathologists. However, in recent years a shift has taken place. Despite the challenge that biological heterogeneity may be hidden by differences in assay performance, Ki67 now plays an important auxiliary role in grading of malignant neoplasms such as breast cancer, neuroendocrine tumours and malignant lymphomas. In this context it is applied in clinical diagnostics as well as in clinical trials for the purpose of stratification. Because of its widespread use, it is of utmost importance to raise awareness of the potential methodological limitations in order to use Ki67 in a meaningful way.

Of the numerous aspects involved in the diagnosis, treatment, and follow-up of cervical uterine precursor lesions, epidemiology, virology, cytology, human papillomavirus (HPV) testing, and diagnostic algorithms for equivocal and HPV-positive findings are important for pathologists. Cytology will continue to be used as a preventive medical check-up in young women, while HPV-based screening is suggested for older women. HPV screening has yielded a significant reduction in cancer precursors and invasive cervical carcinoma in numerous studies. In contrast to the sensitivity, the specificity of the HPV test is inferior to that of cytology and the morphological biomarker p16/Ki-67, so that they are suitable as methods in the triage of HPV-positive findings. Cytological abnormalities and mildly dysplastic changes could be further clarified by an HPV test or the p16/Ki-67 test. The HPV test should also be used in the follow-up of patients after conization.

Squamous cell carcinoma of the penis (SCCP) is a rare cancer type in Western industrialized nations; nevertheless, it shows an aggressive course of disease in advanced tumor stages with accordantly high recurrence and progression rates. While molecular biomarkers are not established in clinical routine for the management of SCCP patients yet, the accordant unmet need is enormous, as adequate biomarkers would be meaningful for prognostic determination, planning of modality and extent of primary therapy, indication for inguinal lymph node resection, adjuvant treatment, and as potential targets for specific systemic treatment. SCCP regularly develops from a precursor lesion. In this regard, human papillomavirus (HPV)-dependent and -independent pathways are differentiated. The potential for specific target therapy options is mainly based on the decoding of genetic and epigenetic signatures of distinct molecular pathways. In order to develop targeted and personalized treatment strategies based on molecular pathways, an increase in translational research in large multi-institutional collaborations must be promoted. This review article aims to summarize the current status of research concerning molecular changes related to SCCP under separate consideration of prognostic molecular markers, on the one hand, and biomarkers considered potential therapeutic targets, on the other hand. In addition, previous research activities of our own working group on this topic are briefly described.

Neuroendocrine Neoplasms are classified according to the new WHO classification in (1.) well differentiated neuroendocrine tumors G1 (NET G1, Ki67 ≤ 2 or mitosis count2) and (2.) well differentiated neuroendocrine tumors G2 (NET G2, Ki67 3-20 or mitosis count 2-20) and (3.) poorly differentiated neuroendocrine carcinomas G3 (NEC G3, Ki67 20 or mitosis count20).In this study 310 NENs of the Ludwig-Maximilians-University in Munich were reevaluated according to the new WHO classification.7% of the analyzed NENs were presented as neoplasias of the stomach. In NENs of the stomach three distinct subtypes are recognized: (1) type 1 associated with autoimmune chronic atrophic gastritis (2) type 2, associated with multiple endocrine neoplasia (MEN1) and Zollinger-Ellison Syndrom; and (3) type 3, sporadic tumors.Precursor lesions (i. e. hyperplasia of the ECL cells) are found in patients with hypergastrinaemia (type 1 and 2). This article should provide insights into the diagnosis of NENs of the stomach with emphasis on the new international standard.

Breast cancer can be divided into four molecular subtypes with different prognoses using immunohistochemical markers in the routine clinicopathological work-up. The protein Ki-67 is of central importance in this context, in particular to distinguish between luminal A and luminal B carcinomas. Determination of the Ki-67 index of a carcinoma also allows a prediction of the likelihood of the response to chemotherapy. Additionally, the expression of certain cytokeratins in tumor cells is associated with a poor response to chemotherapy. The heterogeneity of molecular subtypes with regard to the histological appearance indicates an even greater diversity of breast cancer. We were able to show that a high proportion of luminal B carcinomas display neuroendocrine differentiation. Further studies with particular emphasis on histomorphological criteria should be performed to attain a more accurate classification of breast cancer and to pave the way towards targeted therapies for a better prognosis in the future.

The current WHO classification of neuroendocrine tumors (NET) differentiates between typical carcinoids (low grade NET), atypical carcinoids (intermediate grade NET) and small cell and large cell carcinomas (high grade NET) according to the prognosis. Neuroendocrine neoplasms (NEN) of the gastrointestinal tract and the pancreas are graded in an identical way. Together with the TNM system this enables a preoperative estimation of the prognosis in biopsies and fine needle aspirates. Well-differentiated tumors are graded into G1 tumors by the number of mitoses,2 per 10 high-power fields (HPF) and the Ki-67 (index3 %) and G2 tumors (2-20 mitoses/10 HPF, Ki-67 3-20 %). Discrepancies between the number of mitoses and the Ki-67 index are not uncommon and in these cases the higher value of the two should be applied. The more differentiated tumors of the G3 type have to be differentiated from undifferentiated carcinomas of the small cell type and large cell type with a much poorer prognosis. Prognosis relevant grading of thyroid cancers is achieved by special subtyping so that the G1-G3 system is not applicable. The rare cancers of the parathyroid gland and of the pituitary gland are not graded. Adrenal tumors also have no grading system. The prognosis is dependent on the Ki-67 index and with some reservations on the established scoring systems.

From a historical perspective, histological grading was the earliest cell-based method for assessing tumor biology and the prognosis of breast cancer. This review article provides detailed and practical instructions for grading of breast cancer in routine diagnostics. Furthermore, the increasing relevance of precise histological grading in the era of molecular pathology is discussed.

Pituitary adenomas have to be studied in detail for structural characteristics, especially regarding the degree of granulation and immunohistochemical hormone expression, such as growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and proliferation markers (e.g. Ki-67 and p53) for correlation to clinical data and assessment of the prognosis. If histological and immunostaining data do not correlate to the patient data, explanations for the discrepancies must be found. All active adenoma types can also be present as inactive, so-called silent adenomas showing the same features. An increased Ki-67 index (3%), significant nuclear expression of protein p53 and mitoses are characteristic of atypical adenomas. Up to now the biological relevance of these atypical adenomas, especially their role as preneoplasms for pituitary carcinomas has not been fully elucidated. The only proof of a pituitary carcinoma is the existence of metastases. Extensive local invasion and a greatly increased Ki-67 index are not sufficient for this diagnosis. Craniopharyngiomas have to be classified into adamantinomatous types (intrasellar and suprasellar) and papillary types (only suprasellar). Regressive changes are found in adamantinomatous types only. Strong regression may lead to difficulties in the differential diagnosis of Rathke's cleft cysts with squamous metaplasia. Demonstration of nuclear expression of beta-catenin in these cases enables the diagnosis of craniopharyngioma. Papillary craniopharyngiomas are characterized by BRAF mutations that may be helpful in the differential diagnosis. All pituicytomas of the neurohypophysis, all spindle cell oncocytomas of the anterior pituitary and all granular cell tumors of the posterior pituitary express thyroid transcription factor 1 (TTF-1) and are thought to be variants of a common uniform spindle cell tumor of the pituitary.

Gene expression profiling has demonstrated the prognostic relevance of genes associated with proliferation in breast cancer. The immunohistochemical marker Ki-67 enables routine assessment of proliferation activity in pathology. In a number of retrospective but only few prospective studies the prognostic relevance of Ki-67 in breast cancer could be shown. Although there is no standardized approach with regard to which area of a histological section and how many cells should be counted in a quantitative or semiquantitative fashion as well as to the threshold, Ki-67 is broadly applied in breast pathology. This can be explained by the good reproducibility of the degree of proliferation assessed by Ki-67, at least in the low and high ranges, the possibility to substantiate grading and better practicability in core biopsies in comparison to mitotic counting. In neoadjuvant therapy of hormone receptor positive breast cancer, Ki-67 can probably predict the efficacy of pure hormone receptor blockade without chemotherapy.

In dieser Arbeit wurde das Gesamtkollektiv des duktalen Adenokarzinoms des Pankreas der Pathologie Ulm zusammengestellt und anhand dieses die Wertigkeit der Zellzyklusproteine Ki-67, p16 und Cyclin E als prognostische Biomarker untersucht. Das Gesamtkollektiv umfasste 122 Pankreaskarzinompatienten, welche im Zeitraum von 1996-2009 erkrankt waren. Das durchschnittliche Alter lag bei 65,5 Jahren, die mediane Überlebenszeit betrug 18,2 Monate, die 5-Jahres-Überlebensrate war 11%. Ein schlechter Differenzierungsgrad, ein hohes UICC 2002 sowie das Auftreten von Fernmetastasen gingen mit einer signifikant ungünstigeren Prognose einher. Zu den immunhistologischen Biomarkern: In der Überlebensanalyse war die Überexpression von Cyclin E und Ki-67 mit einer signifikant schlechteren Prognose assoziiert. Im Gegensatz dazu zeigte der p16-Verlust keinen Zusammenhang mit der Überlebenswahrscheinlichkeit der Patienten, 75% der Fälle waren p16 negativ.

Molecular biomarker analysis is increasingly being used as a basis for individualized therapy selection. In breast cancer established standard biomarkers are hormone receptors, HER2 and if indicated Ki67. In particular for hormone receptor positive, HER2 negative tumors, gene expression analysis provides additional information on proliferation and hormone receptor signalling. The results of the gene expression tests can be used to identify patients with a very good prognosis under an exclusive endocrine therapy. This group of patients can then be treated without conventional chemotherapy. The EndoPredict assay was validated in two large cohorts from clinical studies of the Austrian breast cancer study group (ABCSG). Furthermore, using a round robin test, the test method was established in several German institutes of molecular pathology. The EndoPredict assay can be carried out in local institutes of pathology and offers additional information to existing standard prognostic parameters.

Optimal management of breast cancer patients is based on efficient multidisciplinary cooperation. The role of pathologists is to survey those parameters that are crucial for the individually adopted therapy. Thereby, distinct quality criteria have to be considered concerning the handling of the tissue samples, including preparation and examination, as well as the analytical methods used. The interdisciplinary S3 guideline "Diagnosis, therapy and follow-up of breast cancer" includes recommendations concerning these aspects based on current evidence. Its third edition was published in July 2012. In this article an overview of the topics relevant for pathologists that have been modified in the latest edition is provided.

In the gastrointestinal tract an accurate diagnosis of tumor-like lesions can be challenging. In patients with reflux disease regenerative hyperplasia of esophageal squamous epithelium may show marked pleomorphism and atypia thereby simulating malignancy. Bizarre stromal cells are another diagnostic pitfall. We present the case of a 46-year-old patient with symptoms of reflux disease who was diagnosed with a benign inflammatory polyp at the distal end of the esophagus. Histology revealed bizarre cells within the stroma of the polyp characterized by nuclear hyperchromatism and enlargement. Mitoses were not observed. The atypical cells were positive for vimentin. The Ki67/MIB-1 proliferation rate was low. The morphology and etiology of bizarre stromal cells, including helpful features for differential diagnosis are thoroughly discussed.

In breast cancer, tumor biological markers are gaining impact and have become equal to traditional markers of pathology. Molecular expression profiling has led to new categories, which by receiving translation into immunohistochemical terms have entered routine pathology use. Besides the triple negative (basal) type, there are hormone receptor positive luminal A and B types and the HER2 type. The distinction between luminal A and B type is not yet clear cut and the proliferation marker Ki-67 as well as diverse RNA expression profiles are used for distinction in order to decide which patients might benefit from pure endocrine and which from combined chemo-endocrine therapy. Prospective studies are necessary to answer these questions. Study data are further awaited to clarify the heterogeneity of triple negative cases which include most of the BRCA1 associated cancers and to elucidate whether within the HER2 category, polysome or pseudopolysome cancer will respond to therapy.

Currently, lymphoma diagnosis is based on a combination of morphology, immunophenotyping, and molecular testing. Using the example of an unusual case of malignant non-Hodgkin lymphoma, we show that improved visualization using digital pathology contributes to the convergence of these complementary diagnostic modalities. A 45-year-old woman presented with skin rash and cervical lymphadenopathy. Histological workup of an excised lymph node showed loss of normal architecture with diffuse infiltration and increased mitotic activity. Immunohistochemistry for CD3/CD5 showed atypical arrangement and infiltration of a T-cell population that dominated over regionally dense, MUM1-positive plasmacellular infiltrates. Expanded CD21/CD23-positive meshworks of follicular dendritic cells were present within and between regressed follicles and the T-cell infiltrate; staining for CD56 and cyclin-D1 was negative. Quantification of Ki-67 staining within the T-, B- and plasmacellular compartments was achieved by digital image conversion, overlay and subsequent quantification algorithms that revealed proliferation within more than 60% of T-cells, over 50% of plasma cells and only 20% of B-cells. Clonality analysis by PCR revealed monoclonal rearrangement for both T-cell receptor gamma chains and immunoglobulin heavy chains. Taken together, we present an unusual combination of an angioimmunoblastic T-cell lymphoma (AITL) and simultaneous plasmacellular lymphoma. This report demonstrates how application of modern tools of digital pathology can visually integrate unusual morphological and molecular findings.

Especially the cytological diagnoses of mild and moderate dysplasia are often followed by unnecessary stigmatization of patients and uncertainty in further clinical follow-up and therapy. Data from 222 patients including additional investigations by high-risk human papillomavirus (HPV) testing and combined immunocytochemistry for p16(INK4a) and Ki-67 were documented, including cytological and histological follow-up. Overall for cytology, high risk HPV testing and dual staining the following characteristics concerning the presence of cervical intraepithelial neoplasia (CIN) 2+ were calculated (in %): sensitivity 100, 95.8 and 92.4, specificity -, 23.3 and 72.8, positive predictive value 53.6, 59.1 and 79.7, negative predictive value -, 82.8 and 89.3, respectively.There was a statistically significant advantage for higher specificity and positive predictive value for dual staining, especially for cytological diagnosis of low grade dysplasia. An objective individual risk stratification of patients with cytology of mild or moderate dysplasia is not available but the uncertainty in the management of these patients will be clearly reduced.

The assessment of the proliferation fraction is becoming more and more important; however, there is no consensus concerning optimal validation. Depending on the institute the proliferation fraction is determined either from a core biopsy (SB) or resection specimen (OP).The interobserver variability and the results of SB and OP were investigated whereby two pathologists independently estimated the proliferation fraction of 90 cases of invasive breast cancer. The results (Ki-67) were quantified, categorized, and compared.Identical (accuracy of 5% steps) results between the 2 pathologists were achieved in 43% (n=39) for SB, 47% (n=42) for OP and 60% (n=54) for SB versus OP. When categorizing the proliferation fraction (low ≤ 15%, moderate 20-30% and high ≥ 35%) the following results were achieved: 76% (n=68) for SB, 82% (n=74) for OP and 81% (n=73) for SB versus OP.There was a clear interobserver variability (SB: kappa=0.32, OP: kappa=0.34) but this could be dramatically improved by forming proliferation categories (SB: kappa=0.62, OP: kappa=0.72, 60 versus 81%). In SB with a low proliferation fraction a repeated analysis in OPs can be advisable as a higher proliferation fraction is observed in up to 12% of OPs.

Diagnosing and grading of cervical intraepithelial neoplasias (CIN) are part of the routine practice of pathologists. However, discriminating between reactive changes and CIN1 and determining the different degrees of CIN may be challenging. Aim of this study was the evaluation of the proliferation markers Ki-67 and Mcm2 as well as p16 for their potential to aid in the assessment of CIN. 297 samples of normal epithelium, CIN1, CIN2, and CIN3 were assessed for expression of the above mentioned markers using tissue microarrays. There was an increase in the expression of Ki67 and Mcm2 from normal epithelium, CIN1, CIN2 to CIN3 (p0.001 for both markers). Ki-67 was the most useful marker in differentiating between normal epithelium and CIN1. The number of p16-positive cases was 7% in CIN1, 46% in CIN2 and 86% in CIN3. There were no p16-positive cases in the group with normal epithelium. In order to grade CIN1 vs. CIN2 a combination of Ki-67 and p16 was helpful. Cases with a proliferation rate of25% assessed with Ki-67 were most likely CIN1 (sensitivity 91.7%, specificity: 54.3%, positive predictive value: 73.3%, negative predictive value 82.6%). P16 was the most helpful marker in distinguishing between CIN2 and CIN 3 as p16 negative cases were more likely to belong into the CIN2 category. In summary, the histopathological assessment of cervical biopsies is based on HE-stained slides. However, Ki-67 and p16 can be helpful in diagnosing and grading cervical intraepithelial neoplasia.

A 53-year-old female patient presented with a palpable mass in the right medial orbit which had been present for 18 months. The left eye had been enucleated in childhood due to a perforating injury. An orbital biopsy performed ex domo showed unspecific inflammatory tissue but no definite diagnosis was made and systemic therapy with corticosteroids was unsuccessful. A second orbital biopsy was performed in our clinic and revealed a solitary fibrous tumor (SFT) of the orbit. Medial orbitotomy with tumor excision followed and the histological examination of the excised tumor established the diagnosis of SFT of the orbit with focal sarcomatous transformation. The patient presented 3 years later with a new orbital mass in a control MRI examination. Relapse was suspected and orbitotomy with excision of the mass was performed. The histological examination revealed a relapse of the SFT with sarcomatous transformation in the whole extent of the tumor. Radiotherapy with a dosis of 59.4 Gy was subsequently performed. The patient remained tumor-free in the most recent control examination 3 years later.

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.

A 53-year-old female patient presented with cough and hoarseness for 3 years. Based on a biopsy of a bronchial tumor, a small cell neuroendocrine tumor of the lung was diagnosed and chemotherapy with etoposide and cisplatin was initiated. As the tumor progressed under chemotherapy, the bronchial biopsy was reevaluated and further biopsies of liver and adrenal metastases were obtained. The diagnosis was corrected, and an atypical neuroendocrine bronchial carcinoma was diagnosed. Under octreotide therapy, the patient remained stable for 1 year, when a discrete progress of the primary tumor in the lung was observed. Treatment with the mTOR (mammalian target of rapamycin) inhibitor everolimus was then initiated. Based on this case, the diagnostic criteria, prognostic factors and therapeutic options of neuroendocrine bronchial carcinomas are discussed.

A 7-cm cystic lesion in the upper left abdomen and additional smaller solid tumor nodules were diagnosed incidentally in a 15-year-old boy without tumor symptoms. The main tumorous cystic lesion showed a flattened single-cell tumor cell component in gradual transition to stratified, papillary and truly "invasive" typical desmoplastic areas of a desmoplastic small round-cell tumor (DSRCT). The Ki-67-proliferation index gradually increased within three histologic tumor patterns up to about 70% in the typical desmoplastic (infiltrating) component. Using microdissection techniques, EWS-WT1-gene fusion transcripts were detected in the cystic (single-cell-layered), the papillary and the solid tumor proliferations (exon 7 of EWS on chromosome 22 with exon 8 of WT1 on chromosome 11). The presented case illustrates a predominant cystic growth pattern of DSRCT, in which a stepwise development in the pathogenesis of DSRCT from cystic (-"mesothelioblastic") towards a more papillary proliferation and finally typical "infiltrative" desmoplastic tumor pattern might be discussed. The cystic pattern could represent an initial stage in the development of the neoplasia. The presence of specific EWS-WT1-gene fusion transcripts in all tumor growth patterns in this respect would indicate an early event in t(11;22)(p13;q12) translocation in the pathogenesis of DSRCT.

Tumor biological parameters for the prediction and prognosis of invasive breast cancer are gaining in importance compared to traditional pathological categories. The immunohistochemically determined steroid hormone receptor status is not only the decisive factor influencing whether endocrine therapy (which is indicated in cases of even slight expression) is given or not, but also whether chemotherapy is considered. The Her2 status is of similar importance and needs to be analysed in every case of invasive carcinoma, whereby reproducibility, which requires greater efforts than with steroid hormone receptors, has to be assured. Probably only a small portion of breast cancers will benefit from chemotherapy. Since traditional pathological categories are not sufficient for the identification of this subgroup, there has been an intense search for alternative prognostic parameters, whereby gene expression profiling has emerged as the most promising tool. Despite minimal concordance with regard to single genes, the various profiles available converge in the identification of the proliferative signature as the prognostically most relevant. Whether histopathological grading and immunohistochemical determination of the growth fraction with Ki-67 or genetic profiling will be more reliable in the identification of the aggressive subtype has yet to be clarified in clinical studies which encompass central pathological review.

Breast cancers with a genetic BRCA1-/BRCA2 background differ from each other and sporadic cases. A specific pathological surrogate marker, however, does not exist. In this study the results of a German reference centre are reported. BRCA1 associated cancers are predominantly high grade (G3), triple negative, highly proliferative (median Ki-67 55%) and only exceptionally accompanied by lobular intraepithelial neoplasia. Cancers with a BRCA2 germ line mutation are less frequent and resemble sporadic cases with a comparably higher proliferative activity and a lack of Her2 overexpression.

The differential diagnosis of villous forms of gestational trophoblastic disease (GTD) includes hydropic abortion, complete and partial hytatidiform mole and placental mesenchymal dysplasia. In addition to histologic criteria, p57(KIP2) immunohistochemistry might be helpful. Choriocarcinoma represents the most immature form of GTD. This and downregulation of HSP-27 might contribute to the high chemosensitivity, compared to placental site (PSTT) and epitheloid trophoblastic tumor (ETT). Within the differential diagnosis of the non-villous forms of GTD an algorithmic approach of immunohistochemistry is very helpful. With an incidence of 1.6% of all abortions within the first trimester the exaggerated placental site reaction (EPS) is rare. There is no molecular indication that the EPS represents a precursor lesion of PSTT. The morphologic prediction of the behaviour of PSTT is not well established. Factors which might be associated with adverse outcome are age35 years, interval since last pregnancy2 years, growth outside the uterus, deep myometrial invasion, destructive growth, extensive coagulative necrosis, presence of cells with clear cytoplasm, high mitotic rate and a Ki-67 labeling index50%. Recent molecular data suggest a neoplastic transformation of (cyto-) trophoblastic stem cells, within the pathogenesis of (non-villous) GTD. The detection of target molecules for a targeted therapy is currently irrelevant.

We present the clinical and histopathological findings in the unusual case of a recurrent corneal tumour in a child. Light and ultrastructural observations as well as immunohistochemistry indicate a benign reactive process. However, the prognosis regarding visual function is poor due to the infiltrative nature of the lesion and its tendency to recur. A possible diagnosis of nodular fasciitis is discussed.

Der Beitrag der Proliferation intimaler Zellen zur Pathogenese der Arteriosklerose wird derzeit kontrovers diskutiert. Die vorliegende Arbeit untersucht immunhistochemisch mit Hilfe des zellzyklusassoziierten Antigens Ki-67 die Zellproliferation in 41 gefässchirugisch gewonnenen Desobliteraten von fortgeschrittenen arteriosklerotischen Läsionen aus der Arteria carotis und der Arteria femoralis. Die Prolifertion ist fast ausschliesslich auf die Intima beschränkt und in der Media nur in Einzelzellbefunden nachzuweisen. Eine Ki-67-Expression wird überwiegend in entzündungsassoziierten Makrophagen und T-Lymphozyten im Rahmen struktureller Umbauvorgänge gefunden. Die tierexperimentell als primärer Pathomechanismus der Atherogenese postulierte Prolifertion glatter Muskelzellen erscheint somit für die humane fortgeschrittene Arteriosklerose nicht repräsentativ. On the basis of contradictory results found in animal experiments and coronary atherectomy tissue, there is an ongoing debate about the significance of cellular proliferation in human atherosclerosis. In the present study, the cell cycle-related antigen Ki-67 was detected for determination of cell turnover in 41 carotid and femoral arteries endarterectomy specimens. The cellular proliferation is limited to the intima and is predominantly found in macrophage- and lymphocyte-rich areas characterized by inflammatory processes and structural repair. In contradiction to result found in aminal experiments our results suggest, that the proliferation of smooth muscle cells does not play an important pathogenetic role in human atherosclerosis.

MALT lymphomas of the orbit are rare orbital tumors; the differential diagnosis needs to exclude inflammatory pseudotumors of the orbit, but also benign lymphoproliferations, pseudolymphomas, and other orbital neoplasms. After histological confirmation of the diagnosis staging is necessary, and - as long as the disease is localized exclusively in the orbit - radiation therapy should be started. The clinical picture of MALT lymphoma and its differential diagnosis and treatment are discussed with reference to an actual case.

The grading of invasive breast cancers according to Bloom and Richardson (Nottingham modification) provides one of the most important prognostic factors in addition to size and the status of the lymph nodes. Diagnostic reproducibility has been problematic in daily practice as the required criteria for selection and extent of the grading area are frequently not present in the punch biopsies.A total of 346 cases were retrospectively used to compare routine grading from surgical preparations with an equivalently small sample from punch biopsies. In addition, a modified grading of these small samples was developed with Ki-67 immunochemistry and the measurement of core size. In the case of modified grading, 1-3 points were given for Ki-67 and average maximum core diameter. Tubule development was evaluated with 1 or 2 points. A comparison for recurrence free survival and total survival showed significant prognostic differences between 3-5 points (low risk) and 6-8 points (high risk) in uni- and multivariate analyses. The evaluation criteria for Nottingham-Bloom-Richardson grading in a small tissue sample, such as that from a punch biopsy, can hardly be fulfilled. In our series, prognostic value was only found for nodal negative cases. After modification using objective parameters such as nuclear size measurement and Ki-67 proliferation index, a small tissue sample can prove to be of significant prognostic value for nodal negative as well as nodal positive cases.

Neurogenic neoplasms of the parotid gland are extremely uncommon. We present the case of a solitary intraparotid neurofibroma of the N. facialis occurring in a 55-year-old female who noted a painless left-side enlargement in the region of the parotid gland over a period of 2 years. Facial function was normal. Magnetic resonance imaging revealed a well-demarcated round mass within the left parotid. At surgery, a tumor was found involving the main trunk of the facial nerve, histopathologically representing a neurofibroma. Since solitary intraparotid neurofibromas are characterized by a very slow growth lacking the propensity for malignant transformation, the tumor was left to preserve facial nerve function. The clinical course over months or even years and the non-specific symptomatology are characteristic of intraparotid facial neurofibromas. Surgical management depends on the clinical setting in the individual case. Conservative treatment based on facial nerve preservation and leaving the tumor in situ is recommended, rather than radical tumor removal with resection of the segment of the N. facialis involved.

Nodular fasciitis is a frequently occurring pseudosarcomatous fibrous proliferation which usually affects the subcutaneous tissue. In the present study, we investigated tissue specimens from 26 patients with intramuscular nodular fasciitis. The median age of patients was 31 years, with the tumors occurring mainly in the extremities (11 patients) and the trunk (11 patients). These had an average size of 2.6 cm. Males predominated (male:female 9:4). Histological examination revealed a proliferation of myofibroblasts (positive for smooth muscle-actin) embedded in a myxoid or fibrous stroma. In 25/26 cases, myogenic giant cells were observed (positive for desmin, negative for smooth-muscle actin and CD 68). Less frequently (11/26 patients), osteoclastic giant cells were found (positive for CD 68, negative for desmin and smooth-muscle actin). In intramuscular nodular fasciitis, myogenic giant cells are encountered more often than previously described. They are relevant for the differential diagnosis of sarcoma and fibromatoses, since they can be misinterpreted as neoplastic giant cells. However, the uniformity of the myofibroblastic proliferate and the myogenic phenotype of the giant cells without proliferative activity (no mitoses, negativity for Ki-67) lead to a correct diagnosis.

"Ancient schwannomas" of the mouth floor are rare, benign neoplasms derived from the nerve sheath of peripheral nerves. They show many degenerative changes such as necrosis and vascular thrombosis. Ancient schwannomas show histopathological features, such as degenerative changes and atypical nuclei, and may easily be confused with malignant neoplasms. B-scan sonography for the mouth floor and MRT imaging may be helpful in differential diagnosis. Here, we report on a patient with ancient schwannoma of the floor of the mouth.

The Ki-67 antigen is only expressed in proliferating cells. Previously, it was shown that Ki-67 derived antisense oligonucleotides (asONs) specifically inhibit the proliferation of tumor cells and tumour growth in vitro and in subcutaneous bladder and prostate tumor models. We intended to evaluate the effects of this therapeutic concept in two renal cell carcinoma (RCC) models.Human RCC cells (SK-RC 35) were initially transfected with FITC-labeled ONs and diffferent cationic lipids to analyze the transfection efficacy by flow cytometry (FACS). The potency of 14 different ONs sequences was compared by quantitative RT-PCR in vitro. For in vivo testing, ONs were administered to immunocompetent Balb/c mice bearing orthotopic RENCA tumors as well as to SCID mice bearing subcutaneous RCC SK-RC 35 xenografts. Tumor sizes and final tumor weights were documented. Additionally, several immunohistochemical staining procedures were performed.FACS analysis showed highly effective transfection conditions in vitro. Systemic administration of asONs significantly decreased the tumour growth in the RENCA model (p0.05) and in the SCID mouse model (p = 0.009). Immunohistochemical staining of tumor specimens revealed a marked down-regulation of target protein and a slight increase in apoptotic cells after antisense treatment while the microvessel count was not significantly altered.These results demonstrate that the Ki-67 antigen represents a suitable antiproliferative target and that asONs directed against this target are potent drugs that induce a significant inhibition of renal tumor growth in different mouse models.

Oncological therapy strategies are increasingly concentrating on the causal, molecular changes involved in carcinogenesis. So called "smart drugs" such as antisense oligoneucleotide (AsON) can be used as specific inhibitors of individual genes. AsONs have shown their effectiveness in many studies. Clinical studies have demonstrated, however, that for many tumours the inhibition of a single gene is, due to multigenetic alteration, largely ineffective. The combination of AsONs with conventional chemotherapeutic agents is currently being investigated in phase III studies. In these studies, chemotherapeutic agents have been evaluated in cell culture together with AsON against the proliferation associated Ki-67 gene, as well as against the apoptosis associated bcl-2 gene via RT-PCR, immunochemistry and MTT cell viability assay. For both AsONs, significant target inhibition was achieved in cell culture with a high target gene expression. The prior treatment of tumour cells with bcl-2 AsON significantly increased the effectiveness of chemotherapy, while the combination of conventional chemotherapeutic agents with Ki-67 AsON showed no synergistic effects.

Tissue microarrays (TMAs) are still seldom used in oncological research, especially that involving otorhinolaryngology, although the benefit of this method has often been reported.We prepared ten different tumor probes from patients with head and neck cancer for immunohistochemistry and performed ki67 and proliferating cell nuclear antigen (PCNA) staining on the usual paraffin sections as well as on TMAs consisting of the same tissue.We conclude that investigation by means of TMA makes oncological research, and especially the screening of tumor probes, much more efficient since a high correlation ( r0.7, P0.0001) between both methods was found.

A chronic inflammatory reaction and an increased expression of Ki-67 positive cells in arthrofibrotic tissue and the increased proliferation of fibroblasts from arthrofibrotic tissue could be due to an immunopathological reaction. Compared to systemic and organ fibrotic tissue arthrofibrotic tissue is characterized by an increased expression of collagen type VI.