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The nipple-areola complex is the origin of various morphologically distinct tumors and tumor-like lesions, which can be delineated from the special structures of the nipple, in particular the intramammary ducts, skin-appendages, and the intramammary stroma. Benign tumors are most frequent and this includes epithelial tumors such as mammary adenoma and syringomatous tumor of the nipple. Less commonly observed are benign mesenchymal tumors such as leiomyoma of the nipple, or tumor-like lesions like pseudo-lymphoma. With excess formations of the nipple, the different forms of polythelia and polymastia have to be considered.

The classical Paget's disease of the nipple is histologically characterized by tumor cell infiltration originating in intraductal or invasive breast carcinoma, immunohistologically by a frequent overexpression of HER2 and clinically by eczema-like changes of the nipple and areola. Variants with different histological, immunohistological, and clinical features are observed in nonclassical forms of Paget's disease, such as isolated Paget's disease of the nipple, anaplastic Paget's disease, Paget's disease with invasion, and pigmented Paget's disease of the nipple. In the differential diagnosis of Paget's disease, benign changes have to be considered, including Toker cell hyperplasia, nipple eczema, and rare dermatoses.

The human breast consists of lobes with a luminal glandular and a basal myoepithelial layer. Immunofluorescence studies have shown that the breast epithelium contains cytokeratin (CK)5/14-positive precursor cells which give rise to CK8/18-positive glandular or sm-actin-positive myoepithelial cells. Only some of the glandular cells contain estrogen receptors. The luminal epithelium of the lobules shows a much higher glandular differentiation than the ductal system. Diagnostically important cytokeratins of normal breast epithelium and its proliferative epithelial processes include luminal cytokeratins (CK7, CK8 and CK18) as markers of glandular differentiation and basal cytokeratins (CK5, CK14 and CK17) as markers of progenitor cells and early cells of the glandular and myoepithelial differentiation pathway. The most important myoepithelial markers are currently CD10, SMA, SMM-HC and Calponin.

Proliferative epithelial breast lesions include a wide variety of benign hyperplastic and noninvasive neoplastic lesions, as well as invasive carcinomas. Mammographically these lesions may show microcalcifications, architectural distortions or mass lesions. The task of the pathologist begins with a preoperative diagnosis by means of minimally invasive biopsy. His diagnosis forms the basis for not only the radiological-pathological correlation diagnosis, but also for the management of benign proliferative breast disease lesions, as well as therapeutic decisions in the case of malignant lesions.In daily practice, immunohistochemistry is the method of choice for clarifying difficult cases. The aim of this chapter is to describe the relevant markers in breast pathology and to provide an algorithmic approach to different proliferative breast disease lesions.

Prognosefaktoren geben Informationen uber den Krankheitsverlauf (Rezidivfreiheit und Gesamtuberleben), die unabhangig von der Therapie sind. Zu ihnen gehoren der axillare Lymphknotenstatus, Tumordurchmesser und histologischer Differenzierungsgrad, Lymph- und Blutgefasinvasion sowie das Staging – Faktoren, die alle durch den Pathologen bestimmt werden. Der „Nottingham Prognostic Index“ (NPI) vereint die starksten Prognosefaktoren und ist nach Studienergebnissen als Modell fur die Brustkrebsprognose geeignet. Pradiktive Faktoren sagen die Wahrscheinlichkeit des Ansprechens eines Tumors auf eine bestimmte Therapie voraus. Hierzu gehoren der Hormonrezeptorstatus, die Invasionsmarker uPA/PAI-1, der Nachweis von isolierten Tumorzellen, ein Residualtumor und der histologische Resektionsrand. Prognostische oder pradiktive Faktoren sind klinisch relevant, wenn durch ihre Kenntnis Therapieentscheidungen ermoglicht werden, die zu einer Verbesserung des Gesamtuberlebens, des rezidivfreien Uberlebens oder der Lebensqualitat fuhren. Die internationale Konsensempfehlung von St. Gallen 2007 fordert als Grundlage fur risikoadaptierte Therapieentscheidungen: Tumorgrose, Grad, Alter, Nodalstatus, Hormonrezeptorstatus sowie Her2-Uberexpressions- oder -Amplifikationsstatus.

BACKGROUND In mammography screening programmes carried out according to European guidelines, minimally invasive biopsies (MIB) are performed on up to 3% of participants. The aim of this study was to analyse the spectrum of histopathological findings including B categories in MIBs with microcalcifications compared to MIBs without microcalcifications. MATERIAL AND METHODS Prospectively collected histological findings of MIBs taken during the period July 2006 to June 2007 were analysed using the Breast Screening Pathology Database of the Reference Centre in Munster. RESULTS Of the 4,326 MIBs investigated, 2,161 were benign (B1-B3) whereas 2,165 were malignant (B4-B5) resulting in an overall malignancy rate of 50.04%. Of the MIBs 1,809 contained microcalcifications and 2,517 did not. Cases with microcalcifications showed a different distribution of B categories: B2 was found in 44.5% versus 24.2%, B3 in 18.2% versus 5.5% and the malignancy rate of cases with microcalcifications was 36.8% versus 59.5%. Of all cases of ductal carcinoma in situ (DCIS) detected in the screening programme, 83.35% were diagnosed in MIBs containing microcalcifications. CONCLUSIONS MIBs containing microcalcifications showed a different spectrum of diagnoses, especially higher rates of B3 lesions. Even though MIBs without microcalcifications showed a higher overall malignancy rate, most cases of DCIS were diagnosed in MIB containing microcalcifications.

According to the WHO, flat epithelial atypia (FEA) is defined as a neoplastic epithelial proliferation of ductal type in either a single or in multiple terminal duct lobular unit(s) limited to the periphery of the ductules in a clinging growth pattern. The atypical cells may form between one and several layers of epithelial cells that show low grade cytologic atypia. FEA most often presents as mammographic microcalcifications, which are typically round (secretory type and psammomatous calcification in an eosinophilic matrix, so-called ossifying calcifications). Clinical relevance is dependent on whether the lesion appears in isolation or whether it is an excision biopsy or a minimally invasive biopsy. Currently available data suggest that the risk of subsequent breast carcinoma in the ipsilateral breast is very low following the diagnosis of FEA. The differential diagnosis should include atypical ductal hyperplasia, low-grade clinging ductal carcinoma in situ, blunt duct adenosis and apocrine metaplasia.

The definition of atypical ductal hyperplasia (ADH) encompasses qualitative and quantitative criteria. Qualitative criteria include cytological and architectural features similar to those of low grade ductal carcinoma in situ (DCIS), the quantitative criteria are characterized by metric features (2 mm or 2 ductules) or by the confines of lobules. In this article we discuss the morphology of ADH, the status of ADH in the low grade pathway of breast carcinoma development and its clinical significance. Furthermore, we comment some special forms of atypical epithelial proliferations of the ductal type.

In einer vergleichenden Mikrosatellitenuntersuchung wurden die Marker D7S522, D8S258, NEFL, D10S153, D13S153, D16S400, D16S402, D16S422 und D17S855 bei flachen epithelialen Atypien (FEAs), duktalen Carcinomata in situ (DCISs) und invasivem Mammakarzinom auf gemeinsame genetische Alterationen hin untersucht. Das Gewebe fur die DNA-Isolation wurde mittels PALM-Mikrolasertechnik mikrodissektiert. Dabei zeigte sich fur FEAs, dass neben einer hohen Alterationsfrequenz des Markers D13S153 (RB1) v. a. die Marker auf 16q betroffen waren. Andere Marker zeigten eine vergleichbar niedrigere Alterationsfrequenz. Die nachgewiesenen 16q-Alterationen finden sich vergleichbar haufig ebenfalls bei DCISs und invasiven Karzinomen. Besonders bemerkenswert ist, dass diese 16q-Alterationen bei FEA auch in assoziierten DCISs und invasiven Karzinomen derselben Patientin vorkommen. Da der fruhe Verlust von 16q fur eine Subgruppe des Mammakarzinoms und deren Pathogeneseweg charakteristisch ist, veranlasste uns dies zu der Annahme, dass die FEA eine Vorlauferlasion des sog. „low grade pathway“ sein konnte.

Papillom bezeichnet eine benigne Lasion des Mammagewebes, welche ein verzweigtes Stromagerust mit einer durch eine Basalmembran abgetrennte glandular/myoepitheliale Uberkleidung aufweist. Papillome konnen in jedem Teil des Milchgangsystems entstehen und werden nach ihrer Lokalisation in solitare, zentrale Papillome der grosen subareolaren Milchgange und in multiple, periphere Papillome in den dilatierten terminalen duktulolobularen Einheiten des peripheren Drusengewebes unterteilt. Sowohl Veranderungen des Stromas als auch epitheliale Meta- und Hyperplasien konnen ein Papillom modifizieren und die Diagnose erschweren. In einer signifikanten Anzahl von Papillomen konnen Atypien identifiziert werden, die uberwiegend vom duktalen Typ sind. Diese Lasionen mussen vom papillaren Typ des duktalen Carcinoma in situ (DCIS) differenziert werden. 17% aller Papillome sind mit synchronen In-situ- oder invasiven Karzinomen assoziiert, aber sie stellen zusatzlich eine Indikatorlasion dar, die ohne bzw. mit Atypien ein 1,8- bzw. 3,5-fach erhohtes Risiko anzeigen, ein (metachrones) Karzinom zu entwickeln. Als Konsequenz werden Papillome in der minimalinvasiven Biopsie als B3 klassifiziert und sind in der Regel chirurgisch zu exzidieren.

Die molekularbiologischen Ablaufe in der fruhen Pathogenese des Mammakarzinoms sind nur in Ansatzen bekannt. Speziell die Einschatzungen zu postulierten Vorlauferlasionen des invasiven Mammakarzinoms, wie der duktalen Hyperplasie und dem duktalen In-situ-Karzinom, werden bezuglich ihrer Pathogenese und Biologie kontrovers diskutiert. Neuere Forschungsergebnisse zu biologischen Regulationsmechanismen und genetischen Veranderungen im morphologisch unauffalligen, normalen Brustdrusengewebe geben einen fundierten Anlass zu einer Neuinterpretation der gangigen Progressionsmodelle des invasiven Mammakarzinoms. Speziell die Entdeckung von genetischen Alterationen im normalen, tumorfreien Brustdrusengewebe stellt die bisher postulierten Verwandtschaftsverhaltnisse zwischen den invasiven und prainvasiven Mammakarzinomen auf der einen Seite und benignen, proliferativen duktalen Mammalasionen auf der anderen Seite in Frage. Gestutzt werden diese Zweifel zudem durch die Beschreibung von verschiedenen Zellkompartimenten, einschlieslich eines „Progenitorzellkompartiments“ mit unterschiedlichen Zytokeratinexpressionsmustern und Parallelen dieser Expressionsmuster mit bekannten oder postulierten Vorstufen des Mammakarzinoms wie auch des invasiven Mammakarzinoms. Ziel dieser Arbeit ist, eine Ubersicht uber die neuesten Entwicklungen in der Mammapathologie zu geben und Konsequenzen fur ein in Bewegung befindliches Verstandnis zur Pathogenese des Mammakarzinoms aufzuzeichnen.

Xanthomatose Lasionen des Korpusendometriums sind am Abradat selten zu beobachtende Befunde, die Beachtung verdienen, da sie Endometriumkarzinome maskieren konnen. Unter dem Begriff einer sog. “xanthomatosen Endometritis” werden Befunde subsummiert, denen in der Regel ostrogeninduzierte Schaumzellreaktionen zugrunde liegen. In der vorliegenden Arbeit wird der Fall eines bislang in der Literatur nicht dokumentierten uterin metastasierten “Balloon”-Zell-Melanoms vorgestellt. Anhand der konventionell-lichtmikroskopischen, immunhistologischen und ultrastrukturellen Befunde werden unsere bisherigen Vorstellungen zur Histogenese dieser ungewohnlichen Variante eines malignen Melanoms diskutiert. Die Befunde stutzen die Hypothese zellularer Regressionsphanomene in der Genese der “Balloon”-Zell-Transformation der Melanomzelle. Der Melan-A- (MART-1-)Positivitat scheint fur das “Balloon”-Zell-Melanom im Gegensatz zu dem klassischen Melanommarker HMB 45 ein besonderes Gewicht zuzukommen.

Bioprothetische porzine Herzklappen neigen zur fruhzeitigen Degeneration und Kalzifikation, wobei die Ursachen bisher noch nicht eindeutig geklart sind. In fruheren Studien konnte gezeigt werden, das eine Vorbehandlung durch Lipidextraktion zu einer geringeren Verkalkung von Schweineklappen fuhrt. Um einen moglichen Zusammenhang von Fettverteilung und Verkalkung zu untersuchen, wurden 7 in Glutaraldehyd fixierte, fabrikneue Schweineklappenbioprothesen (St. Jude Medical, Bioimplant®) in toto mittels Sudanrot III gefarbt. Alle Klappenprothesen wiesen Lipidablagerungen in unterschiedlichem Ausmas auf. Funf dieser Klappen wurden nach 4wochiger Belastung in einer dynamischen Verkalkungsapparatur radiographisch auf ihre Verkalkung untersucht und das Ergebnis mit der Fetteinlagerung verglichen. Die Ubereinstimmung zwischen Lipidverteilung und Verkalkung nach 4wochiger dynamischer Belastung betrug 57–66%. Zwei der nicht belasteten Schweineklappenbioprothesen wurden histologisch aufgearbeitet und mit Hamatoxylin und der Silbermethode nach von Kossa zum Kalknachweis gefarbt. Histologisch zeigten sich im Bereich der Lipidablagerungen in der von-Kossa-Farbung Mikrokalzifikationen sowie im polarisierten Licht doppelbrechende Substanzen. Dabei handelt es sich am ehesten um praexistente Veranderungen der Schweineklappen, die moglicherweise als Ausgangspunkt fur spatere Verkalkungen anzusehen sind. Die Bedeutung von Lipidablagerungen bei der Verkalkung von Bioklappen sollte an umfangreicheren Fallzahlen weiter untersucht werden.

Bei den Vorgangen der Invasion und Metastasierung spielen Zell-Zell-und Zell-extrazellulare Matrix-Interaktionen eine wichtige Rolle. Diese Interaktionen werden durch Adhasionsmolekule wie z. B. CD44, Integrine, E-cadherin und N-CAM vermittelt. Die Funktion der Adhasionsmolekule in der Metastasierungskaskade ebenso wie ihre Bedeutung fur die Tumordifferenzierung und Progression sind Gegenstand dieses Ubersichtsartikels.

This review emphasizes the pathology of premalignant ductal breast diseases and its practical relevance to the patients management. The histological criteria for recognizing Ductal Hyperplasia (DH) are now well established. These include an intraluminal heterogeneous proliferation of glandular cells positive for keratins 8/18/19 and epithelial cells with expression of keratins 5/6/14. As a hyperplastic process the epithelial cells disclose an haphazard irregular growth with slit like irregular lumina (fenestrated growth pattern). The florid DH indicates a slight subsequent increased risk for cancer development. Our knowledge of the nature of noninvasive ductal neoplasia continues to evolve. Recent molecular genetic and immunohistochemical efforts have disclosed that atypical ductal hyperplasia (ADH) constituted a clonal neoplastic proliferation of an epithelial cell. Histological hallmarks of ADH are their cytologic features of uniformity and monotony of proliferation of cells and its micropapillary, cibriform or solid growth pattern. So from histology ADH simulates the highly differentiated DCIS, but can be distinguished from the latter quantitatively by the aggregate cross sectional diameter or the number of ducts that are completely involved by the atypical proliferation. ADH indicates a few fold subsequent increased risk for developing carcinoma. So this lesion requires a close follow up with 3 to 4 examinations per year and annual mammograms. Ductal carcinoma in situ (DCIS) consists of cytologically malignant cells in the parenchyma that have not invaded into the stroma. Recent studies have shown that DCIS is a heterogeneous group of tumors. Attempts have been made to classify it into histologic patterns, nuclear grades, tumors with or without comedo-necroses etc. We can draw the conclusion from several studies that the most important histologic feature is the nuclear grade. Holland et al. have suggested a very useful classification scheme that includes nuclear grade and histological features. The modifiers of treatment are as follows: 1. nuclear grade or differentiation of the DCIS 2. extension of the lesion 3. excision with clear margins So efforts to classify DCIS underscore the central role of pathology in determining the grade of the DCIS, its size and the adequacy of the surgical excision in terms of free margins. All three parameters are included in a score system of the Van Nuys Prognostic Index.

We report two cases of patients (one 65 and one 43 years of age, respectively) who died of Streptococcus-viridans induced endocarditis of the aortic valve with perforation into the right atrium. Whereas perforation in Staphylococcus-induced endocarditis is a common complication, it occurs rarely in Streptococcus-induced endocarditis. Because of its uncharacteristic symptoms, the endocarditis was clinically unknwon in both cases and was recognized to be the cause of death only at autopsy. To reduce the large number of complications in patients suffering from endocarditis, it is necessary to confirm the diagnosis as soon as possible if endocarditis might be suspected.

Neuroblastoma is the most frequent extracranial solid tumor of early childhood. Histologically and genetically, neuroblastoma represents a heterogeneous group of tumors with significant differences in clinical behavior. In the past, several different characteristic chromosomal aberrations of neuroblastoma have been described, of which a deletion on chromosome 1p and N-myc amplification have been shown to be of major prognostic significance. However, the role of various other nonrandom DNA imbalances in tumor development and progression needs to be clarified. Taking advantage of the recently established comparative genomic hybridization (CGH), we show that this method is able to accurately detect chromosomal imbalances of known prognostic impact. As CGH gives a comprehensive picture of genetic imbalances in just one experiment, it additionally sheds light on other abnormalities of possible prognostic relevance. We therefore recommend further use of this method not only in the field of research but also for the purpose of genetic routine diagnostics in neuroblastoma.

We report a case of a 60 year old male who presented with a therapy resistant endophthalmitis which led to an evisceratio bulbi. Histologically, a granulomatous inflammation was present, in which acid-fast bacilli could not be detected. Molecular genetic examination by means of polymerase-chain-reaction technique (PCR) of the routinely processed tissue material revealed the diagnosis of an atypical mycobacterial infection, because DNA specific for atypical mycobacteria was detected. This example shows that PCR technique provides a useful tool in the diagnosis of mycobacterial infections as an adjunct to surgical pathology.

Mit der Technik des feuchten Autoklavierens wird eine einfache, verlasliche und zeitsparende Methode zur Antigen-Demaskierung an Formalin-fixiertem und Paraffin-eingebettetem Gewebe vorgestellt. Anhand einer Reihe von Antikorpern (Ostrogen- und Progesteronrezeptoren, Zytoskelettproteine, verschiedene p53-Antikorper, mdm-2, bcl-2, MIB-1 u. a.) verwendeter Antikorper werden die Vorteile dieser Methode beschrieben. Das feuchte Autoklavieren ermoglicht bei einigen sonst nur am Gefrierschnitt einsetzbaren Antikorpern auch deren Anwendung am Paraffinschnitt. Fur den Routinepathologen ist die leichte Handhabung sowie die hohe Reproduzierbarkeit von Vorteil.

In dieser Studie wird eine Methode zum Nachweis von sog. argyrophilen Nukleolus Organisator Regionen assoziierten Proteinen (AgNORs) vorgestellt, die es erstmalig erlaubt, diese als Teilstrukturen des Nukleolus an formalinfixiertem und paraffineingebetteten Gewebe zu erkennen. Mit einer Vorbehandlung durch feuchte Autoklavierung werden am archivierten Material Farbeergebnisse erzielt, wie sie an alkoholfixiertem Frischmaterial erreicht wurden. Samtliche Farbeartefakte entfallen mit dieser neuen Methode. Weitere Vorteile bieten die einfache Handhabung sowie die Tatsache, das auch bei unterschiedlicher Fixations- und Einbettungsdauer standardisierte und somit vergleichbare Ergebnisse erzielt werden. Das vorgestellte Verfahren bietet somit die Moglichkeit, die Wertigkeit der AgNOR-Quantifizierung auch an archiviertem Paraffinmaterial in retrospektiven Studien reproduzierbar zu evaluieren.

Variable number tandem repeats (VNTR) are highly polymorphic DNA sequences which can be used as genetic markers in different fields of medicine. In this report, we describe the methodology of VNTR in diagnostic molecular pathology, using a rapid, DNA-based approach involving polymerase chain reaction (PCR) amplification and electrophoresis of highly polymorphic DNA satellite sequences. As concrete examples of the application of this approach, we present two case reports: 1. A B-cell lymphoma of the porta hepatis developed in a 54-year-old man 4.5 months after orthotopic liver transplantation for liver failure due to chronic hepatitis C infection. Using DNA polymorphisms as genetic markers, we showed that the tumor was of donor origin. This finding may be important for the patient's subsequent management. 2. An immature teratoma of the left ovary was found during delivery by cesarean section in a 27-year-old woman. The female newborn survived for 9 weeks and then died from central dysregulation because of an intracranial immature teratoma. Because the synchronous tumors were of similar histology, clonal origin in maternal tissues and metastatic spread were initially suspected. Analysis of highly polymorphic DNA markers clearly indicated that the teratoma carried by the child was of independent genetic origin from the mother's tumor.

Ewing's sarcomas and malignant peripheral neuroectodermal tumors (MPNTs) show very little evidence of differentiation and lack characteristic morphological features at the light-microscopic level. These malignancies have always presented a significant differential diagnostic challenge to the pathologist. Electron microscopy, immunohistochemical staining for neural antigens such as neuron-specific enolase (NSE), Leu 7, synaptophysin and, more recently, the detection of Mic-2 gene expression have been included in the routine histopathological diagnostic procedure. However, the expression of these antigens is not restricted to this entity. Thus, further modalities are required to prove diagnostic reliability. One consistent feature of the Ewing's sarcoma family is the presence of the reciprocal chromosomal t(11;22)(q24;q12) translocation. Recent cloning of the t(11;22) break point has led to the identification of the genes involved in this translocation. This provides the possibility of molecular genetic detection of the t(11;22) translocation in Ewing's sarcomas and MPNTs. We have established a method using reverse transcription and the polymerase chain reaction (RT-PCR) for the detection of the specific gene fusion transcript caused by the 11;22 translocation. The validity of our approach was proved by analyzing Ewing's tumor cell lines and tissue material obtained from primary biopsies and tumor resections. Molecular genetic detection of the 11;22 translocation by RT-PCR analysis should perhaps be included in the diagnostic work-up of suspected Ewing's sarcoma and MPNT.

The human breast consists of lobes with a luminal glandular and a basal myoepithelial layer. Immunofluorescence studies have shown that the breast epithelium contains cytokeratin (CK)5/14-positive precursor cells which give rise to CK8/18-positive glandular or sm-actin-positive myoepithelial cells. Only some of the glandular cells contain estrogen receptors. The luminal epithelium of the lobules shows a much higher glandular differentiation than the ductal system. Diagnostically important cytokeratins of normal breast epithelium and its proliferative epithelial processes include luminal cytokeratins (CK7, CK8 and CK18) as markers of glandular differentiation and basal cytokeratins (CK5, CK14 and CK17) as markers of progenitor cells and early cells of the glandular and myoepithelial differentiation pathway. The most important myoepithelial markers are currently CD10, SMA, SMM-HC and Calponin.

Proliferative epithelial breast lesions include a wide variety of benign hyperplastic and noninvasive neoplastic lesions, as well as invasive carcinomas. Mammographically these lesions may show microcalcifications, architectural distortions or mass lesions. The task of the pathologist begins with a preoperative diagnosis by means of minimally invasive biopsy. His diagnosis forms the basis for not only the radiological-pathological correlation diagnosis, but also for the management of benign proliferative breast disease lesions, as well as therapeutic decisions in the case of malignant lesions.In daily practice, immunohistochemistry is the method of choice for clarifying difficult cases. The aim of this chapter is to describe the relevant markers in breast pathology and to provide an algorithmic approach to different proliferative breast disease lesions.

According to the WHO, flat epithelial atypia (FEA) is defined as a neoplastic epithelial proliferation of ductal type in either a single or in multiple terminal duct lobular unit(s) limited to the periphery of the ductules in a clinging growth pattern. The atypical cells may form between one and several layers of epithelial cells that show low grade cytologic atypia. FEA most often presents as mammographic microcalcifications, which are typically round (secretory type and psammomatous calcification in an eosinophilic matrix, so-called ossifying calcifications). Clinical relevance is dependent on whether the lesion appears in isolation or whether it is an excision biopsy or a minimally invasive biopsy. Currently available data suggest that the risk of subsequent breast carcinoma in the ipsilateral breast is very low following the diagnosis of FEA. The differential diagnosis should include atypical ductal hyperplasia, low-grade clinging ductal carcinoma in situ, blunt duct adenosis and apocrine metaplasia.

The definition of atypical ductal hyperplasia (ADH) encompasses qualitative and quantitative criteria. Qualitative criteria include cytological and architectural features similar to those of low grade ductal carcinoma in situ (DCIS), the quantitative criteria are characterized by metric features (2 mm or 2 ductules) or by the confines of lobules. In this article we discuss the morphology of ADH, the status of ADH in the low grade pathway of breast carcinoma development and its clinical significance. Furthermore, we comment some special forms of atypical epithelial proliferations of the ductal type.

With the improvement of breast carcinoma screening, pre-malignant cell lesions such as flat epithelial atypia (FEA) are detected more frequently. Several studies have demonstrated that FEA show features of a ductal neoplasia, but is it really a precursor lesion? We have started a comparative genetic analysis of a panel of nine microsatellite markers on six different chromosomal regions to investigate whether FEAs show the same characteristic genetic alterations as ductal carcinomas in situ (DCISs) and invasive carcinoma of the breast. FEAs, DCISs and invasive carcinomas of the same patients were microdissected using PALM micro laser technology. DNA was isolated using the QIAamp DNA Micro Kit (QIAGEN). We have investigated a set of the polymorphic microsatellite markers D7S522, D8S522, NEFL, D10S541 (PTEN), D13S153 (RB1), D16S400, D16S402, D16S422 and D17S855 (BRCA1) using multiplex PCR for the detection of allelic imbalances. Most of the investigated FEAs showed a lower frequency of loss of heterozygosity than associated DCISs or invasive carcinomas. However, we were able to detect the same alterations in FEAs as in DCISs or invasive carcinomas in a number of cases. Notably, the microsatellite marker on 16q showed more prevalent allelic imbalances in FEAs than the other investigated markers. One of the hallmarks in the pathogenesis of a large subgroup of invasive breast carcinomas is the early loss of chromosome arm 16q. In this study, we were able to detect frequent genetic alterations on chromosome 16q in FEAs, associated DCISs and invasive carcinomas. This suggests that FEA is a precursor lesion in the low-grade pathway.

Only little information on the primary molecularbiological events involved in early breast is available. In particular, the definition of postulated precursor lesions of invasive breast cancer, such as ductal hyperplasia or ductal carcinoma in situ, is under an intense, controversial discussion in terms of pathogenesis and tumor biology. The most recent research on biological regulation mechanisms and genetic alterations in morphologically normally appearing breast tissue give rise for a reinterpretation for the most common progression models of breast cancer. The detection of genetic alterations within normal breast tissue in particular challenges the commonly postulated relationship between invasive and in situ breast carcinomas on the one hand, and benign, proliferative breast lesions on the other. The concerns about these relationship are further supported by the description of different cellular compartments within the normal female breast, including a "progenitor cell compartment" with different cytokeratin expression patterns, which can be transferred towards well known or suspected precursor lesions of invasive and in situ breast cancer. The aim of this manuscript is to provide an overview of the most recent results and developments in breast pathology, and to describe the consequences of our changing understanding of breast carcinogenesis.

The term papilloma applies to benign proliferative epithelial breast lesions with a papillary architecture. The papillae in such lesions contain an arborizing fibrovascular core, glandular surface epithelium and a basal myoepithelial layer. A basement membrane encloses these structures. Papilloma may occur at any site in the ductal lobular system and according to its localization is subdivided into two types: solitary (central) papilloma which are located in the major nipple/subareolar ducts or large segmental ducts and multiple (peripheral) papillomas in cystically dilated terminal ductal lobular units (TDLU). Stromal changes, epithelial metaplasia and/or proliferations and neoplasia may alter the prototypical architecture. In a significant number of papillomas atypia can be identified which have to be classified as atypical proliferates of the ductal type. These lesions must be distinguished from the papillary type of ductal carcinoma in situ. Some 17% of all papilloma are associated with (synchronous) intraductal or invasive carcinoma, but these also act as an indicator for subsequent (metachronous) carcinoma. As a consequence, in minimally invasive biopsy papilloma has to be classified as B3 and usually has to be followed by surgical excision.

Xanthomatous changes are unusual lesions of the corpus endometrium that may mask endometrial carcinoma. The term "xanthomatous endometritis" refers to morphological changes frequently induced by estrogen stimulation. We report for the first time a case of uterine metastasis of balloon-cell melanoma mimicking xanthomatous endometritis. Light microscopic, immunohistological, and ultrastructural results are presented and discussed in connection with our ideas on the pathogenesis of this peculiar tumor. The findings favor the hypothesis of a regressive phenomenon in the balloon-cell transformation of melanoma cells. The melan-A immunohistology seems to be more important in the diagnosis of balloon cell melanoma than the classic melanoma antibody HMB 45.

Ductal carcinoma in situ of the female breast and lobular carcinoma in situ are regarded as precursor lesions of invasive breast cancer. We used comparative genomic hybridization to analyze the genetic relationship between these two types of lesion and invasive breast cancer. The series included 166 patients with ductal or lobular carcinoma in situ and invasive breast cancer. Our results reflect the broad heterogeneity of morphologically different subtypes of invasive and noninvasive breast cancer. The data also provide evidence of multiple genetic pathways of invasive breast cancer associated with different morphological subtypes. In conclusion, we propose a combined model of morphological-genetic progression with various parallel pathways in the pathogenesis of invasive breast cancer.

Calcification is one of the main causes of failure of porcine bioprosthetic heart valves, a problem which has not been satisfactorily solved to date. Previous studies have shown that calcification is decreased in porcine heart valves that have undergone treatment for lipid extraction. The relation between lipid distribution and calcification of seven new commercially available porcine bioprosthetic heart valves (St. Jude Medical, Bioimplant) is assessed by Sudan red III staining to show preexisting lipids. All porcine bioprosthetic valves contained lipids to different degrees. Five valves were subjected to the pulsatile accelerated calcification process for 4 weeks. Distribution and level of calcification were evaluated by radiography and compared to the Sudan red-stained fatty areas. Comparison of the calcifications detected by radiography and the macroscopically detected lipids showed a coincidence of 57-66%. Two porcine bioprosthetic valves were histologically prepared and stained with Hematoxylin and von Kossa's stain, respectively. By light microscopy, the von Kossa staining revealed microcalcifications and polarizing microscopic investigation showed birefractive substances in areas with lipid deposits. These preexisting substances in porcine valve tissue may play a determinative role in the calcification of the tissue. Substantial studies are necessary to further determine the role of preexisting lipids in calcification.

Cell-Cell-and cell-extracellular matrix interactions are important in the process of tumor cell invasion and metastasis. These interactions are mediated by adhesion molecules e.g. CD44, integrins, E-cadherin and N-CAM. The role of adhesion molecules along metastatic cascade as well as their importance in tumor differentiation and progression are discussed herein.

This review emphasizes the pathology of premalignant ductal breast diseases and its practical relevance to the patients management. The histological criteria for recognizing Ductal Hyperplasia (DH) are now well established. These include an intraluminal heterogeneous proliferation of glandular cells positive for keratins 8/18/19 and epithelial cells with expression of keratins 5/6/14. As a hyperplastic process the epithelial cells disclose an haphazard irregular growth with slit like irregular lumina (fenestrated growth pattern). The florid DH indicates a slight subsequent increased risk for cancer development. Our knowledge of the nature of noninvasive ductal neoplasia continues to evolve. Recent molecular genetic and immunohistochemical efforts have disclosed that atypical ductal hyperplasia (ADH) constituted a clonal neoplastic proliferation of an epithelial cell. Histological hallmarks of ADH are their cytologic features of uniformity and monotony of proliferation of cells and its micropapillary, cibriform or solid growth pattern. So from histology ADH simulates the highly differentiated DCIS, but can be distinguished from the latter quantitatively by the aggregate cross sectional diameter or the number of ducts that are completely involved by the atypical proliferation. ADH indicates a few fold subsequent increased risk for developing carcinoma. So this lesion requires a close follow up with 3 to 4 examinations per year and annual mammograms. Ductal carcinoma in situ (DCIS) consists of cytologically malignant cells in the parenchyma that have not invaded into the stroma. Recent studies have shown that DCIS is a heterogeneous group of tumors. Attempts have been made to classify it into histologic patterns, nuclear grades, tumors with or without comedo-necroses etc. We can draw the conclusion from several studies that the most important histologic feature is the nuclear grade. Holland et al. have suggested a very useful classification scheme that includes nuclear grade and histological features. The modifiers of treatment are as follows: 1. nuclear grade or differentiation of the DCIS 2. extension of the lesion 3. excision with clear margins So efforts to classify DCIS underscore the central role of pathology in determining the grade of the DCIS, its size and the adequacy of the surgical excision in terms of free margins. All three parameters are included in a score system of the Van Nuys Prognostic Index.

We report two cases of patients (one 65 and one 43 years of age, respectively) who died of Streptococcus-viridans induced endocarditis of the aortic valve with perforation into the right atrium. Whereas perforation in Staphylococcus-induced endocarditis is a common complication, it occurs rarely in Streptococcus-induced endocarditis. Because of its uncharacteristic symptoms, the endocarditis was clinically unknown in both cases and was recognized to be the cause of death only at autopsy. To reduce the large number of complications in patients suffering from endocarditis, it is necessary to confirm the diagnosis as soon as possible if endocarditis might be suspected.

Comparative genomic hybridisation (CGH) is a new cytogenetic method, which is based on a combination of fluorescence microscopy and digital image analysis. The molecular genetic basis is the hybridization of a mixture of fluorescein labeled test-DNA and reference-DNA on normal metaphase chromosomes. Comparative analysis allows the identification of all unbalanced chromosomal aberrations of the test-DNA in a single experimental step. The resulting DNA gains or DNA losses on the chromosomal or subchromosomal level mirror possible amplifications of oncogenes or losses of suppress orgenes. As CGH can be performed with genomic DNA of formalin-fixed and fresh-frozen tissue or cells, this new method is a very effective tool for pathologists and cytologists in the extended genomic screening of tumors and genetically altered tissues. Despite CGH analysis at present is restricted to research applications; its widespread dissemination as a routine method in diagnostic pathology can be expected in the near future.

We report a case of a 60 year old male who presented with a therapy resistant endophthalmitis which led to an evisceratio bulbi. Histologically, a granulomatous inflammation was present, in which acid-fast bacilli could not be detected. Molecular genetic examination by means of polymerase-chain-reaction technique (PCR) of the routinely processed tissue material revealed the diagnosis of an atypical mycobacterial infection, because DNA specific for atypical mycobacteria was detected. This example shows that PCR technique provides a useful tool in the diagnosis of mycobacterial infections as an adjunct to surgical pathology.

Visualization of proteins associated with nucleolar organizer regions proteins (AgNORs) on formalin-fixed and paraffin-embedded archival tissues is substantially improved after application of wet autoclave pretreatment. Silver staining results are comparable to those obtained on tissues processed in alcohol based fixatives, illustrating AgNORs as substructures of the nucleoli without any staining artefacts. A highly reproducible staining quality was achieved irrespective of tissue origin or duration of formalin fixation. As a result of this novel and simple method, the grounds have been prepared for standardized AgNOR quantification on archival material.