[Accreditation in pathology and neuropathology : Paths and pitfalls]. / Akkreditierung in der Pathologie und Neuropathologie : Wege und Pitfalls.

There are many good reasons for accreditation in pathology or neuropathology as per DIN EN ISO/IEC 17020, regardless of the size and range of services of the facility. Only accreditation - in contrast to certification - also confirms professional competence. This article describes how to establish a quality management system that conforms to standards as effectively as possible and how to maintain it, involve staff, and avoid common pitfalls. Adequate resources and active management support are essential. In this way, not only can accreditation succeed, but the facility itself and its employees can benefit from quality management in their daily work.

The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites.

The aim of this study was to validate the prognostic significance of the lymph node ratio (LNR) in patients suffering from oral squamous cell carcinoma in regard to different anatomical subsites. A cohort of 430 patients was investigated to determine the rates of primary metastasis and local and regional disease recurrence. Correlation analysis of the LNR with relevant clinical and pathological parameters was performed. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the prognostic impact for different subsites. Significantly differing rates of primary metastasis and loco-regional disease recurrence were found for cancer of different anatomical subsites of the head and neck. Furthermore, ROC curve analysis suggested that LNR has prognostic relevance in subsets of cancer (tongue, P< 0.001; alveolar process, P= 0.04; maxilla, P= 0.03; buccal mucosa, P= 0.02). The LNR of cancer located in the soft palate (P= 0.6) and floor of the mouth (P= 0.11) showed little or no association with the clinical outcome. There is the need for a more sensitive consideration of the LNR as a factor in the assessment of risk and the treatment decision, as the anatomical subsite plays a crucial role in its impact on the clinical outcome.

[Donor liver histology : Joint recommendations of the DGP, DTG and DSO]. / Histologische Diagnostik bei Spenderlebern : Gemeinsame Empfehlungen von DGP, DTG und DSO.

BACKGROUND: The indications, implementation and reporting of liver biopsies for deceased organ donation are not mandatory or regulated. Reliable data on outcome quality and prognostic relevance are therefore not available. Defined standards are thus required to enable meaningful studies and to ensure high data quality of a national transplantation registry. OBJECTIVE: Presentation of a synopsis of available studies and literature-based recommendations. RESULTS AND CONCLUSION: Against the background of an organ shortage and a growing number of older donors, pretransplantation liver histology is of significant relevance to guide clinical decision making. With the joint recommendations of the German Transplantation Society (DTG), the German Society of Pathology (DGP) and the German Organ Transplantation Foundation (DSO) standardized procedures are defined for the first time.

[Diagnostics of benign ductal epithelial cell proliferation of the breast in biopsy material]. / Diagnostik benigner duktaler Epithelproliferationen der Mamma in der Stanzbiopsie.

The pathological evaluation of radiological or sonographical abnormalities by needle core biopsy of the breast frequently involves the differential diagnosis of benign epithelial cell proliferations. The lesions to be considered include usual type and atypical ductal epithelial cell hyperplasia, columnar cell changes including flat epithelial cell atypia, the spectrum of hyperplastic and atypical apocrine epithelial cell proliferations and papillary lesions. This review provides an overview of the diagnostic criteria, the current terminology and the differential diagnosis of these lesions. The clinical management and the prognosis of the lesions are discussed.

An in vivo RNAi screen identifies SALL1 as a tumor suppressor in human breast cancer with a role in CDH1 regulation.

The gold standard for determining the tumorigenic potential of human cancer cells is a xenotransplantation into immunodeficient mice. Higher tumorigenicity of cells is associated with earlier tumor onset. Here, we used xenotransplantation to assess the tumorigenic potential of human breast cancer cells following RNA interference-mediated inhibition of over 5000 genes. We identify 16 candidate tumor suppressors, one of which is the zinc-finger transcription factor SALL1. Analyzing this particular molecule in more detail, we show that inhibition of SALL1 correlates with reduced levels of CDH1, an important contributor to epithelial-to-mesenchymal transition. Furthermore, SALL1 expression led to an increased migration and more than twice as many cells expressing a cancer stem cell signature. Also, SALL1 expression correlates with the survival of breast cancer patients. These findings cast new light on a gene that has previously been described to be relevant during embryogenesis, but not carcinogenesis.

Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV) is a causal factor in virtually all cervical and a subset of oropharyngeal squamous cell carcinoma (OP-SCC), whereas its role in laryngeal squamous cell carcinoma (L-SCC) is unclear. METHODS: Formalin-fixed paraffin-embedded (N=154) and deep-frozen tissues (N=55) of 102 L-SCC patients were analysed for the presence of 51 mucosal HPV types. HPV DNA-positive (HPV DNA+) cases were analysed for E6*I mRNA transcripts of all high risk (HR)/probably/possibly (p)HR-HPV identified, and for HPV type 16 (HPV16) viral load. Expression of p16(INK4a), pRb, cyclin D1 and p53 was analysed by immunohistochemistry. RESULTS: Ninety-two patients were valid in DNA analysis, of which 32 (35%) had at least one HPV DNA+ sample. Among the 29 single infections, 22 (76%) were HPV16, 2 (7%) HPV56 and 1 each (4%) HPV45, HPV53, HPV70, HPV11 and HPV42. Three cases harboured HPV16 with HPV33 (twice) or HPV45. Only 32% of HPV DNA+ findings were reproducible. Among HPV16 DNA+ L-SCC, 2 out of 23 (9%) had high viral loads, 5 out of 25 (21%) expressed E6*I mRNA and 3 out of 21 (14%) showed high p16(INK4a) and low pRb expression (all three HPV16 RNA-positive), immunohistochemical marker combination not identified in any other HPV DNA+ or HPV DNA-negative (HPV DNA-) L-SCC, respectively. CONCLUSION: HPV type 16 has a causative role in a small subgroup of L-SCC (<5% in this German hospital series).

[Frozen section diagnostics in visceral surgery. Liver, bile ducts and pancreas]. / Schnellschnittdiagnostik in der Viszeralchirurgie : Leber, Gallenwege und Pankreas.

Intraoperative examination of specimens from the liver, bile ducts, gallbladder and pancreas are widely used in routine fresh frozen section diagnostics. The main clinical requests focus on diagnosis of masses of unknown dignity as well as evaluation of surgical margins in oncological resections. In addition, assessment of organ quality for transplantation is also often required.

Pantoprazole induces severe acute hepatitis.

A female patient receiving pantoprazole during a corticosteroid therapy for encephalomyelitis disseminata developed severe acute hepatitis one month after initiation of pantoprazole treatment. Other causes of hepatic dysfunction including viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, haemochromatosis or Wilson's disease were excluded. Liver biopsy showed severe hepatic lesions with extensive necroses of the parenchyma. One week after discontinuation of pantoprazole the liver function began to improve and gradually the patient fully recovered. One year earlier the patient had been treated with pantoprazole before and had developed a milder form of hepatitis then. This case argues for an idiosyncratic hepatocellular damage caused by pantoprazole.

Sporadic cases of acute autochthonous hepatitis E virus infection in Southwest Germany.

Hepatitis E infection is usually a self-limiting disease and an important cause of acute hepatitis in tropical and subtropical regions where the virus is endemic. In industrialized countries, sporadic cases of acute hepatitis E virus (HEV) infections have been described and the number of documented autochthonous infections seems to be increasing. We report three sporadic cases of autochthonous hepatitis E infections in Southwestern Germany which presented at our university hospital within two years. All cases were men who presented with acute hepatitis, icterus and elevated liver. In case 1 and case 2, liver biopsy revealed acute hepatitis, both patients were positive for anti-HEV antibodies, case 1 was also positive for HEV RNA with a viral load of 3.0 x 10(3)copies/ml in serum. In case 3, anti-HEV antibodies were detectable and HEV RNA was detected in serum (4.3 x 10(3)copies/ml) and stool (1.4 x 10(6)copies/ml). None of the patients had a recent travel history outside Germany and close contact to animals has been denied. HEV sequence analysis of two patients revealed genotype 3 with homologies to other European isolates and isolates from swine. Thus the source of infection remains unclear. Hepatitis E should be considered in differential diagnosis in patients with unexplained hepatitis and patients with acute hepatitis, whatever their age or travel history might be, should be tested for HEV.

[Activation of sonic hedgehog signaling in keratocystic odontogenic tumors]. / Aktivierung des Sonic-hedgehog-Signalwegs in keratozystischen odontogenen Tumoren.

BACKGROUND: Keratocystic odontogenic tumors are benign neoplasms of the viscerocranium that occur sporadically as well as in association with Gorlin-Goltz syndrome. Multiple basal cell carcinomas of the skin are another typical feature of Gorlin-Goltz syndrome. Aberrant activation of sonic hedgehog signaling has been reported for sporadic and hereditary basal cell carcinoma caused by specific genetic mutations, but for keratocystic odontogenic tumors, the role of aberrant sonic hedgehog signaling has not yet been evaluated in detail. MATERIALS AND METHODS: In the present study, 131 keratocystic odontogenic tumors were analyzed by immunohistochemistry for the expression of sonic hedgehog signaling proteins SHH, PTCH1, SMO, GLI1, and NMYC on tissue microarray sections. RESULTS: High expression of the analyzed proteins-between 67.3% (PTCH1) and 92.9% (SHH)-was found in the epithelial compartment of the keratocystic odontogenic tumors analyzed. In the stromal compartment of the tumors, high expression of the target proteins was found significantly less frequently (all p-values <0.001). CONCLUSION: Aberrant sonic hedgehog signaling is critically involved in the molecular pathogenesis of keratocystic odontogenic tumors. This finding underlines the neoplastic character of this intraosseous lesion. Because of high recurrence rates after local excision, more radical surgical approaches are recommended for treating keratocystic odontogenic tumors.

Recurrent acute liver failure and mitochondriopathy in a case of Wolcott-Rallison syndrome.

A 10-year-old Arabic boy of consanguineous parents has suffered eight episodes of acute liver failure with haemolysis triggered by intercurrent febrile illnesses. The first crisis occurred at 9 months of age, after which diabetes mellitus developed. By the age of 6 years, short stature, mild myopathy and later skeletal epiphyseal dysplasia also became evident. His psychosocial development and educational achievements have remained within normal limits. While there were no clear biochemical indicators of a mitochondrial disorder, an almost complete deficiency of complex I of the respiratory chain was demonstrated in liver but not in fibroblast or muscle samples. Molecular analysis of the eukaryotic translation initiation factor 2alpha kinase gene (EIF2AK3) demonstrated a homozygous mutation, compatible with a diagnosis of Wolcott-Rallison syndrome (WRS). This patient's course adds a new perspective to the presentation of WRS caused by mutations in the EIF2AK3 gene linking it to mitochondrial disorders: recoverable and recurrent acute liver failure. The findings also illustrate the diagnostic difficulty of mitochondrial disease as it cannot be excluded by muscle or skin biopsy in patients presenting with liver disease. The case also further complicates the decision-making process for liver transplantation in cases of acute liver failure in the context of a possible mitochondrial disorder. Such patients may be more likely to recover spontaneously if a mitochondrial disorder underlies the liver failure, yet without neurological features liver transplantation remains an option.

[Quality and quantity in hepatopathology. Diagnostic and clinically relevant grading for non-tumourous liver diseases]. / Mass und Zahl in der Hepatopathologie: Diagnostisch und klinisch relevante Graduierungen bei nichttumorösen Lebererkrankungen.

This article describes the grading and staging systems used in the clinical context for non-neoplastic liver diseases (chronic and autoimmune hepatitis, fatty liver and steatohepatitis, medicinal toxic liver damage, iron storage disease and gall duct diseases). Fibrotic parenchymal alterations can also be assessed as well as livers planned for transplantation, with respect to possible rejection reactions. The basis for the histopathological diagnostic procedure is the liver biopsy. The consistent and correct use of the histological scores is obligatory in the diagnostic assessment of non-neoplastic liver diseases. Different scores are available for the various liver diseases. These are qualitative and quantitative scores based on empiricism and the practical relevance has been effectively proven. Grading describes the inflammatory activity and staging the extent of fibrosis or structural disorders up to liver cirrhosis. In many instances staging is the histopathological criteria for the prognosis assessment and is, therefore, decisive for therapy indications and therapy initiation.

Taurine protects from liver injury after warm ischemia in rats: the role of kupffer cells.

BACKGROUND/AIMS: Warm ischemia to liver with subsequent Kupffer cell-dependent pathology is associated with many clinical conditions. Taurine prevents Kupffer cell activation and improves graft survival after experimental cold ischemia and liver transplantation. Thus this study was designed to assess its effects after warm hepatic ischemia. METHODS: The left liver lobe of female Sprague-Dawley rats (170-210 g) underwent 60 min of warm ischemia. Animals were given either intravenous taurine or Ringer's solution 10 min prior to warm ischemia. Transaminases, histology, in vivo microscopy, intercellular adhesion molecules-1 (ICAM-1) expression, TNF-alpha and tissue hydroperoxide were compared between groups using analysis of variance (ANOVA) or ANOVA on ranks as appropriate. RESULTS: Taurine significantly decreased transaminases and improved histologic outcome. Phagocytosis of latex beads, serum TNF-alpha levels and tissue hydroperoxide concentrations were also significantly reduced. Stickers in sinusoids and post-sinusoidal venules significantly decreased. In parallel, both leukocyte infiltration and ICAM-1 expression decreased (p < 0.05), while flow velocity of red blood cells as well as sinusoidal perfusion rate were improved (p < 0.05). CONCLUSION: This study demonstrates that taurine blunts Kupffer cell-dependent hepatic pathology after warm ischemia in vivo via mechanisms including leukocyte-endothelial interaction, microcirculation disturbances and protection against lipid peroxidation.

[Renal oncocytoma with metastasis from breast carcinoma: a contribution to the differential diagnosis of tumourous lesions of the kidney]. / Onkozytom der Niere mit Metastase eines Mammakarzinoms : Differenzialdiagnose tumoröser Läsionen der Niere.

The case of a renal oncocytoma involvement by metastasis from breast carcinoma in a 83-year-old woman is reported. The literature of tumour-into-tumour metastasis is reviewed. In conclusion, metastasis of breast carcinoma to a benign renal tumour is very rare.

Right ventricular expression of extracellular matrix proteins, matrix-metalloproteinases, and their inhibitors over a period of 3 years after heart transplantation.

Fibrillar collagens I and III, nonfibrillar collagen IV, and the glycoproteins fibronectin and laminin, are elements of the myocardial extracellular matrix (ECM). Alterations in the normal concentrations and ratios of these elements may reflect remodeling in response to physiologic stress. In the case of patients' post-heart transplantation (HTx), specific patterns of alteration may herald myocardial dysfunction. Right ventricular biopsies were taken from the same 28 HTx patients before implantation and 1 week, 2 weeks, and 1, 2, and 3 years after HTx. The above-noted five ECM proteins, six matrix metalloproteinases (MMPs) and two of their tissue inhibitors (TIMPs) were detected by immunohistochemistry and scored as cells per square millimeter or semiquantitatively. The total connective tissue fibers were detected by connective tissue stain and morphometry. Variations in these ECM components were followed in the same patient cohort over 3 years. In summary, during the first 2 weeks after HTx, a predominant increase in connective tissue occurred. Increases in MMP-8 and MMP-9 were found. By 3 years after transplantation, there was a decrease of connective tissue fibers and a significant reduction of all ECM components and an increase in MMPs and TIMPs. These findings may reflect a pattern of remodeling specific to the transplanted heart.

Extracellular matrix proteins and matrix metalloproteinases differ between various right and left ventricular sites in end-stage cardiomyopathies.

This study was undertaken to investigate whether there might be differences in the distribution of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), depending on their specific sites within the heart. We investigated 33 explanted human hearts, 15 with dilated cardiomyopathy (DCM) and 18 with ischemic cardiomyopathy (ICM). Transmural samples from the right ventricle, the interventricular septum and the left ventricle, either from near the apex or from near the base were taken from every heart. Frozen sections were processed for connective tissue staining and immunohistochemistry for collagens type I, III, IV, laminin and fibronectin, as well as MMP-1, -2 and -9. Volume densities of laminin in ICM as well as of fibronectin and collagen types I and IV in DCM showed significant differences between right and left ventricular sites. The volume densities of matrix proteins usually did not reveal significant differences among the three left ventricular sites tested in both DCM and ICM. MMPs partly showed differences between the right and the left ventricular myocardium. These results suggest that the distributions of ECM proteins and MMPs differ between the two ventricles in both end-stage DCM and ICM. This gives rise to the hypothesis that a specific pattern of ECM degradation exists in the right and left ventricular myocardium.

Amplification of Cyclin L1 is associated with lymph node metastases in head and neck squamous cell carcinoma (HNSCC).

Overrepresentation of chromosomal bands 3q25-q29 has been associated with shortened disease-specific survival in head and neck squamous cell carcinoma (HNSCC). To assess the prevalence of copy number gains (>4 signals per cell) and high-level amplifications (>8 signals per cell) from putative oncogenes in this chromosomal region (CCNL1, SNO, PIK3CA, TP73L), tissue microarray analysis was applied on 280 HNSCCs by fluorescence in situ hybridization. Overall frequency of additional copy numbers was 34.3% for CCNL1, 31.8% for SNO, 39.0% for PIK3CA and 38.3% for TP73L, respectively. In general, gains were more frequently detected in stage IV compared to stage I-III tumours. Performing multivariate logistic regression analysis, a significant association of CCNL1 gains and the presence of lymph node metastases was found, which was independent of anatomical site and T-stage of the primary tumour (P=0.049). Site-specific subgroup analysis further showed that copy number gains of CCNL1 and SNO occurred more frequently in oral carcinomas in advanced clinical stages as compared to N0 oral lesions (CCNL1: P=0.03; SNO: P=0.03). Finally, Kaplan-Meier analysis revealed that high-level amplifications of CCNL1 correlated with shorter overall survival of the patients. Our results indicate that CCNL1 plays a critical role in the loco-regional progression of HNSCC and may serve as an indicator for occult advanced tumour stages.

[Intraoperative endosonographic guided resection of tongue carcinoma]. / Intraoperative endosonographisch gesteuerte Resektion von Zungenkarzinomen.

BACKGROUND: Exact estimation of a tumor's size and the definition of adequate resection margins in carcinomas of the tongue are often difficult because of the tumor's extension and deep infiltration. METHODS: We have developed a method that allows intraoperative visualisation and marking of tumor margins. Intra-operative endosonography was performed on nine patients with carcinomas of the tongue using a 8-12 MHz linear array transducer. The oral cavity was flooded with normal saline solution and the transducer was immersed therein. This allowed scanning in a non-contact mode. The tumor margins were marked with a surgical suture under endosonographic monitoring. RESULTS: In the nine patients studied, the histological margins corresponded to the sonographic margins. The sonographic marking proved to be useful during the resection of the tumor and histological safety margins were respected in each case. CONCLUSIONS: This non-invasive procedure provides a quick and reliable orientation during the resection of tongue carcinoma, and a more precise and individual definition of resection margins is possible. Intraoperative non-contact use of endosonography is a promising method.