[Histopathological diagnosis of non-alcoholic and alcoholic fatty liver disease. Grade 2 consensus-based guidelines]. / Histopathologische Diagnose der nichtalkoholischen und alkoholischen Fettlebererkrankung. Konsensusbasierte Leitlinie der Stufe 2.

Both alcoholic (AFL) and non-alcoholic fatty liver (NAFL) are characterized by lipid deposition in hepatocytes. The diagnosis of steatosis is made when lipid deposition exceeds 5% of hepatocytes, while involvement of more than 50% is called "fatty liver ". An additional inflammatory reaction leads to alcoholic (ASH) or non-alcoholic steatohepatitis (NASH). Steatohepatitis is present when both inflammatory infiltrates of mixed cells in the small liver lobules as well as liver cell injury in terms of ballooning can be detected.Liver biopsy represents the "gold standard" for confirming diagnosis and determining inflammatory activity and potential fibrosis of fatty liver disease.The differential diagnosis of ASH-NASH cannot be made on the basis of histological criteria alone. Steatosis, inflammatory changes and hepatocytic injury can be semiquantified as a "Brunt Score" or "NAS" (NAFLD activity score), providing the basis on which to decide whether or not steatohepatitis is present.People at increased risk of developing a fatty liver possess an increased risk of developing chemotherapy-associated steatohepatitis (CASH).Histologically, pediatric NASH differs from adult NASH and is often only clinically manifest through a mild if persistent elevation in transaminases.

[Histopathological diagnose of non-alcoholic and alcoholic fatty liver disease]. / Histopathologische Diagnose der nicht alkoholischen und alkoholischen Fettlebererkrankung.

Alcoholic fatty liver (AFL) as well as non-alcoholic fatty liver (NAFL) are characterised by deposition of lipids into hepatocytes. The diagnosis of steatosis is made if lipid deposition exceeds 5 % of hepatocytes, in case of more than 50 % it is called "fatty liver". An additional inflammatory reaction, with ballooning of hepatocytes, leads to alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH). Both ASH or NASH may lead to fibrosis or cirrhosis. To date in clinical practice it is not possible to differentiate between steatosis and steatohepatitis just on the basis of non-invasive tests. Steatohepatitis is present if, along with steatosis, both inflammatory infiltrates of mixed cells in the small liver lobules and liver cell injury in terms of ballooning can be detected. Liver biopsy represents the "gold standard" for confirming the diagnosis and to determine inflammatory activity and potential fibrosis of fatty liver disease. Indications for biopsy should take into account the possible information and its consequences as compared to expense and complication rate and therefore should be assessed in the clinical context.

SAHA induces caspase-independent, autophagic cell death of endometrial stromal sarcoma cells by influencing the mTOR pathway.

Endometrial stromal sarcomas are rare and molecular mechanisms involved in their pathogenesis are poorly understood. Covalent modifications of histone proteins, in particular de/acetylation of lysine residues, play an important role in the regulation of gene transcription in normal and neoplastic cells, but there are only limited data about these processes in solid mesenchymal tumours. We treated endometrial stromal sarcoma cells (ESS-1) and non-malignant human endometrial stromal cells (HESCs) with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. SAHA was able to mediate the cell cycle and expression of genes related to the malignant phenotype of endometrial stromal tumours, eg p21(WAF1) and HDAC7. SAHA led to dose-dependent differentiation and death of ESS-1 cells but not of HESCs. Exposure of HESCs to SAHA resulted only in slightly decreased cell proliferation. SAHA also increased the p21(WAF1) expression and caused significant changes in the cell cycle by inhibiting the G1/S transition in ESS-1 cells. Recovery experiments indicated that these changes became irreversible when the tumour cells were treated with SAHA for longer than 24 h. In our experimental system, not apoptotic but autophagic processes were responsible for the cell death. Monodansyl cadaverine accumulation in treated ESS-1 cells and decreased expression of the mTOR and phospho-S6 ribosomal protein (S6rp) additionally supported this observation. Taken together, our study indicates that HDACs might be considered as potential drug targets in the therapy of stromal sarcomas and that SAHA might be a promising therapeutic agent for endometrial stromal sarcoma.

Mallory-Denk-bodies: lessons from keratin-containing hepatic inclusion bodies.

Inclusion bodies are characteristic morphological features of various neuronal, muscular and other human disorders. They share common molecular constituents such as p62, chaperones and proteasome subunits. The proteins within aggregates are misfolded with increased beta-sheet structure, they are heavily phosphorylated, ubiquitinylated and partially degraded. Furthermore, involvement of proteasomal system represents a common feature of virtually all inclusions. Multiple aggregates contain intermediate filament proteins as their major constituents. Among them, Mallory-Denk bodies (MDBs) are the best studied. MDBs represent hepatic inclusions observed in diverse chronic liver diseases such as alcoholic and non-alcoholic steatohepatitis, chronic cholestasis, metabolic disorders and hepatocellular neoplasms. MDBs are induced in mice fed griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidine and resolve after discontinuation of toxin administration. The availability of a drug-induced model makes MDBs a unique tool for studying inclusion formation. Our review summarizes the recent advances gained from this model and shows how they relate to observations in other aggregates. The MDB formation-underlying mechanisms include protein misfolding, chaperone alterations, disproportional protein expression with keratin 8>keratin 18 levels and subsequent keratin 8 crosslinking via transglutaminase. p62 presence is crucial for MDB formation. Proteasome inhibitors precipitate MDB formation, whereas stimulation of autophagy with rapamycin attenuates their formation.

The Genome Austria Tissue Bank (GATiB).

In the context of the Austrian Genome Program, a tissue bank is being established (Genome Austria Tissue Bank, GATiB) which is based on a collection of diseased and corresponding normal tissues representing a great variety of diseases at their natural frequency of occurrence from a non-selected Central European population of more than 700,000 patients. Major emphasis is put on annotation of archival tissue with comprehensive clinical data, including follow-up data. A specific IT infrastructure supports sample annotation, tracking of sample usage as well as sample and data storage. Innovative data protection tools were developed which prevent sample donor re-identification, particularly if detailed medical and genetic data are combined. For quality control of old archival tissues, new techniques were established to check RNA quality and antigen stability. Since 2003, GATiB has changed from a population-based tissue bank to a disease-focused biobank comprising major cancers such as colon, breast, liver, as well as metabolic liver diseases and organs affected by the metabolic syndrome. Prospectively collected tissues are associated with blood samples and detailed data on the sample donor's disease, lifestyle and environmental exposure, following standard operating procedures. Major emphasis is also placed on ethical, legal and social issues (ELSI) related to biobanks. A specific research project and an international advisory board ensure the proper embedding of GATiB in society and facilitate international networking.

How a cell deals with abnormal proteins. Pathogenetic mechanisms in protein aggregation diseases.

Defective protein folding is responsible for many diseases. Although these diseases seem to be quite diverse at the first glance, there is evidence for common pathogenetic principles. The basis of the pathological changes is the cell's inability to prevent protein misfolding, to revert misfolded proteins to normal or to eliminate misfolded proteins by degradation. This could result in deposition of potentially cytotoxic protein aggregates (protein aggregation diseases). Chronic degenerative diseases of the central nervous system (e.g. Alzheimer's and Parkinson's disease), the amyloidoses, but also chronic liver diseases, for example alcoholic and nonalcoholic steatohepatitis, belong to this category of disorders. This review highlights general pathogenic principles of protein aggregation diseases based on immunohistochemical and biochemical studies as well as observations in a mouse model for protein aggregation in the context of alcoholic and nonalcoholic steatohepatitis. The cellular defense mechanisms involved in protein quality control as well as the pathogenesis of protein aggregation diseases will be discussed.

Are the Mallory bodies and intracellular hyaline bodies in neoplastic and non-neoplastic hepatocytes related?

Mallory bodies (MBs) and intracellular hyaline bodies (IHBs) are cytoplasmic hepatocellular inclusions that consist of aggregated proteins. MBs are characteristically associated with alcoholic and non-alcoholic steatohepatitis, but may also be found in chronic cholestatic and metabolic (eg copper intoxication) diseases and hepatocellular neoplasms, particularly hepatocellular carcinomas. IHBs have hitherto only been described in hepatocellular carcinoma cells. In the present study hepatocellular carcinomas (HCCs) and a case of idiopathic copper toxicosis were evaluated with respect to the presence and mutual relationship of MBs and IHBs. IHBs alone were present in 8.6%, MBs alone in 16.1% and both types of inclusion in 7.5% of HCCs. It is shown that IHBs may also occur in non-neoplastic hepatocytes in association with idiopathic copper toxicosis, together with MBs. In HCCs and idiopathic copper toxicosis, MBs and IHBs may be present within the same cell. Moreover, hybrid inclusions holding an intermediate position between MBs and IHBs regarding light microscopy, ultrastructure and composition exist. MBs and IHBs contain p62, a stress-inducible adapter protein, as the major constituent. In MBs p62 is associated with keratins, whereas classical IHBs lack keratins. Light microscopic, electron microscopic and immunohistochemical data suggest a close pathogenetic relationship between MBs and IHBs. Both types of inclusion are the result of over-expression and accumulation of the stress protein p62. If p62 is induced alone, or at least prevails, IHBs may arise by aggregation. However, if abnormal keratins are present in addition to p62, p62 associates and co-aggregates with keratins, finally leading to classical MBs.

Prognostic relevance of tumour-associated macrophages and von Willebrand factor-positive microvessels in colorectal cancer.

Tumour-associated macrophages (TAM) are involved in tumour angiogenesis and anti-tumour immune response. In colorectal cancer (CRC), an association of high microvascular density (MVD) and unfavourable prognosis has been reported by some investigators. However, heterogeneous patient groups were studied. We, therefore, analysed the correlation between TAM and MVD and the prognostic relevance of MVD, TAM and T lymphocyte infiltration for long-term survival in a homogeneous group of 70 patients with moderately differentiated cancers of the International Union Against Cancer (UICC) stages II and III, who did not receive chemotherapy. MVD was evaluated using immunohistochemistry with antibodies against CD34 and von Willebrand factor (vWF). TAM and T lymphocytes were visualised with antibodies against CD68 and CD3, respectively. Statistical analysis did not reveal a significant correlation between TAM and T lymphocyte numbers and MVD. Multivariate analysis of immunohistochemical data from all CRC patients and the subgroup of patients with UICC stage-II CRC identified TAM- and vWF-positive microvessel numbers as prognostically relevant markers. Low numbers of TAM- and high numbers of vWF-positive microvessels were associated with an unfavourable prognosis. In conclusion, TAM- and vWF-positive microvessel numbers may serve as independent prognostic markers for patients with UICC stage-II and -III CRC and may help to identify patients with an unfavourable prognosis.

[Drug-induced liver injury]. / Medikamentöse Schädigungen der Leber.

Drugs may cause acute or chronic liver damage depending on their mode of action. Hepatotoxic drugs include anaesthetics, psychotropic and anticonvulsant drugs, antiinflammatory agents, steroids, antimicrobial agents and cardiovascular drugs as well as antineoplastic agents. Hepatotoxic agents, including drugs, fall into two categories: (i) intrinsic and obligatory liver toxins with dose-dependent and predictable adverse effects, and (ii) facultative (idiosyncratic) hepatotoxins with non-predictable and non-dose-dependent liver toxicity affecting only few exposed individuals. Intrinsic hepatotoxins may either injure hepatocytes directly, e.g. by direct physicochemical effects, or indirectly by interfering with specific metabolic processes. In the idiosyncratic type of liver injury immunologic hypersensitivity reactions or toxic metabolites may be involved. Clinical and morphologic consequences of adverse drug reactions are acute or chronic liver diseases, including parenchymal damage (finally leading to necrosis or apoptosis), steatosis, cholestasis, various types of vascular alterations, granuloma formation and also neoplastic transformation. Thus, drugs are important causes of liver diseases and may account for up to 40% of cases of hepatitis and up to 25% of fulminant hepatic failure. Moreover, drug-induced injury also plays a leading role as cause of acute cholestasis.

[Long-term outcome of stomach carcinoma achieved in an Austrian standard hospital with an oncologic focus]. / Langzeitergebnisse beim Magencarcinom erzielt in einem österreichischen Standardkrankenhaus mit onkologischem Schwerpunkt.

INTRODUCTION: Although two large prospective and randomized planned European studies failed to show any benefit of radical D2 lymphadenectomy for gastric cancer, the value of radical lymphadenectomy is still a matter of controversy. METHODS: A radical surgical approach principally using D2, D3 lymphadenectomy, as defined by the Japanese Research Society for Gastric Cancer, has been prospectively performed since January 1984. Out of 729 patients with gastric cancer, 521 were surgically treated for potential cure between 1984 and 31 December, 1998. Clinical, histopathological and surgical factors were evaluated for their influence on long-term survival by means of univariate and multivariate analysis. RESULTS: Tumor-specific 5- and 10-year survival rates for all patients were 58.5% and 57.5% for patients who underwent tumor resection 59% and 58%. For operated patients upon with the aim of achieving cures, the tumor-specific 5- and 10-year survival rates were 63.3% and 62.2% and the median survival time was more than 144 months. Postoperative hospital mortality was 7.7%, 4.6% for R0 resected patients, 8.6% for R1,2 resected patients and 21.3% for those undergoing palliative procedures. Multivariate analysis using the Cox model identified an age older than 65, total gastrectomy as well as high pN- and pT category as detrimental factors with an independent influence on survival. CONCLUSION: After updating the long-term results of gastric cancer, as already published earlier, it is impressively obvious that also in a European setting of gastric cancer patients, with a presupposed appropriate surgical technique and experience, very constant cure rates are achievable with comparatively low mortality and morbidity.

Insulinoma of the pancreas with insular-ductular differentiation in its liver metastasis--indication of a common stem-cell origin of the exocrine and endocrine components.

We describe an insulinoma of the pancreas in a 56-year-old patient, which showed insular-ductular differentiation in its liver metastasis. Although the primary tumor was uniformly endocrine in nature with insulin production, the metastasis contained two distinct cell types in organoid arrangement. One cell type was insulin-positive and was arranged in islet-like structures; the other was insulin-negative but distinctly pan-cytokeratin and cytokeratin 7 positive and arranged in ducts. In the primary tumor and the metastasis, the tumor cells were surrounded by a desmoplastic stroma. As to the histogenesis of the tumor and its metastasis, we discuss the following possibilities: (1) the tumor cells might derive from a common stem cell that matures into two phenotypically different cell lines, resembling the situation in embryogenesis and (2) one tumor cell type originates from the other by transdifferentiation (metaplasia). We conclude that the parallel occurrence of endocrine and ductal differentiation supports the concept that, under certain conditions, islet cells and ductular cells may also originate from islets and that mixed endocrine/exocrine pancreatic tumors do not necessarily arise from totipotent duct cells but might also have a primary endocrine cell origin.

Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases.

Reduced hepatobiliary transporter expression could explain impaired hepatic uptake and excretion of bile salts and other biliary constituents resulting in cholestasis and jaundice. Because little is known about alterations of hepatobiliary transport systems in human cholestatic liver diseases, it was the aim of this study to investigate such potential changes. Hepatic mRNA levels in hepatobiliary transport systems for bile salts (NTCP, BSEP), organic anions (OATP2, MRP2, MRP3), organic cations (MDR1), phospholipids (MDR3), and aminophospholipids (FIC1) were determined in 37 human liver biopsies and control livers by competitive reverse-transcription polymerase chain reaction (RT-PCR). Transporter tissue distribution was investigated by immunofluorescence microscopy. In patients with inflammation-induced icteric cholestasis (mainly cholestatic alcoholic hepatitis), mRNA levels of NTCP, OATP2, and BSEP were reduced by 41% (P <.001), 49% (P <.005), and 34% (P <.05) compared with controls, respectively. In addition, NTCP and BSEP immunostaining was reduced. MRP2 mRNA levels remained unchanged, but canalicular immunolabeling for MRP2 was also decreased. mRNA expression of MRP3, MDR1, MDR3, and FIC1 remained unchanged. In contrast to the alterations of transporter expression in inflammation-induced icteric cholestasis, transporter expression did not change in anicteric cholestasis caused by primary biliary cirrhosis (PBC) stages I and II. In conclusion, reduced expression of hepatobiliary transport systems for bile salts and other organic anions may contribute to inflammation-induced cholestasis in humans. Reduction of transporter gene expression can occur at the mRNA level as observed for NTCP, OATP2, and BSEP. However, reduced MRP2 immunostaining in the presence of conserved MRP2 mRNA levels suggests an additional role for posttranscriptional/posttranslational mechanisms.

[Chronic cholangitis]. / Chronische Cholangitis.

The term chronic cholangitis comprises a heterogeneous group of intra- and/or extrahepatic diseases that may either be bacterially caused or immunologically mediated. In this review, we will focus on the latter and present the clinicopathological and pathogenetic aspects of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The histopathological criteria are defined and differential diagnosis is discussed. Particular emphasis is given to overlap syndromes of PBC and PSC with autoimmune hepatitis. Finally, a diagnostic algorithm is presented.

[Alcoholic and nonalcoholic steatohepatitis. Histopathologic and pathogenetic considerations]. / Alkoholische und nichtalkoholische Steatohepatitis. Histopathologie und pathogenetische Uberlegungen.

Alcoholic (ASH) and nonalcoholic (NASH) steatohepatitis show an almost identical morphology. Since the clinical picture is not characteristic, liver biopsy is still the diagnostic gold standard. ASH and NASH are morphologically characterized by a combination of steatosis, hepatocellular injury (ballooning degeneration, apoptosis, necrosis), perivenular and pericellular fibrosis, and inflammation (mostly neutrophils). A definitive differentiation of ASH and NASH is only possible by exclusion of alcohol abuse. Although NASH comprises a syndrome with a multifactorial etiology, adipositas seems to be the most constant associated causal factor. The pathogenesis of both diseases is still unclear. Clinical evidence and experimental studies suggest an important toxic role of reactive oxygen species (oxidative stress). According to our experience, ballooning of hepatocytes is a constant morphologic feature of ASH and NASH and already present in the early stages of disease. Ballooned cells often (but not always) contain Mallory bodies (alcoholic hyalin), which are irregular cytoplasmic inclusions consisting of keratins and nonkeratin components, including ubiquitin. Ballooning is associated with a disturbance and finally almost disappearance of the keratin-intermediate filament cytoskeleton. In our studies on the pathogenesis of ASH and NASH, we concentrated on these cytoskeletal alterations and Mallory body formation. It could be shown that in the early stages overexpression and hyperphosphorylation of keratins take place. Moreover, the 1:1 ratio of keratin type I (keratin 18) and type II (keratin 8) necessary for the assembly of intermediate filaments is disturbed and the equilibrium shifted toward keratin 8. Thus, the pool of soluble keratin 8 increases. The resulting keratin monomers are sensitive to misfolding and either degraded or aggregated as inclusion bodies. If the proteolytic capacity is impaired (e.g., by inhibition of the proteasomal system) in the chronically stressed cell aggregation prevails,finally leading to Mallory body formation. Convincing evidence exists on the basis of clinical and experimental studies that keratins exert a nonskeletal protective function in simple epithelia (e.g., liver cells). Disturbance of the keratin system may thus significantly contribute to cell damage.

[Pathology and clinical medicine in the 21st Century]. / Pathologie für die Klinik im 21. Jahrhundert.

The major task of pathology is to bridge the gap between basic science and clinical medicine. Consequently, pathology has to keep pace particularly with the progress in molecular biology and genetics and has to transfer the progress of basic research to studies of disease. Pathology has to test and continuously incorporate new methods into its scientific and diagnostic repertoire to improve diagnostic sensitivity and accuracy. The recognition of genetic alterations, particularly associated with tumors and chronic degenerative diseases, and its consequences in correlation with morphology allows the evaluation of changes in the genetic set-up and related cellular functions. This greatly improves the basis for understanding the biological background and clinical behavior of disease, thus adding a dynamic component to the snap-shot picture provided by the histologic slide. Application of genomics and proteomics will have significant impact on diagnostic pathology in the 21st century regarding definition and classification of pathologic processes, assessment of prognosis and guidance of treatment. The modern pathologist has to accept this challenge in order to maintain his position in the center of clinical medicine. However, despite all present and future advances, experience and skills in the morphologic evaluation of disease processes will still remain the "gold standard" in our field and the basis for proper application of these new technologies. When we accept the promising new techniques and tools already at the present early stage of development we may not only improve the clinical relevance of our work but gain invaluable information on the nature of diseases and the basic principles responsible for the complex morphologic pictures we enjoy in our daily work.

Long-term prognosis for colon cancer related to consistent radical surgery: multivariate analysis of clinical, surgical, and pathologic variables.

Despite the improvement in its prognosis in most Western countries, death from colon cancer is still a major problem. In a prospectively planned observation study, a large patient collective from a single institution in Austria was analyzed in terms of the surgical approach and factors influencing survival. A total of 696 patients with colonic carcinomas were admitted to our surgical department between January 1, 1984 and December 31, 1997. Radical surgery for localized tumors was consistently performed, including wide resection margins and complete removal of the regional lymph drainage zones. Clinical, histopathologic, and therapy-related factors were examined for their influence on long-term survival by means of univariate and multivariate analysis. The overall tumor resection rate was 99.3% (691/696); complete tumor removal (R0) was possible for 84.8% (590/696) of all patients. The overall postoperative hospital mortality rate was 3.2% (22/696), and it was 13% (7/556) for potentially curative resections. Five- and ten-year tumor-specific survival rates for stage I to III R0 resections were 83.8% and 78.8%, respectively. Adjuvant chemotherapy reduced tumor recurrence for stage III patients by 52.4%. The depth of tumor infiltration, lymph node status, and adjuvant chemotherapy were found to have an independent influence on survival as identified by the Cox models. In conclusion, a consistent radical surgical approach for potentially curative resected colonic cancer patients had survival rates that surpassed those of most published series without sacrificing low complication rates. In addition, adjuvant chemotherapy for stage III substantially improved survival.

Lack of Pseudomelanosis coli in colonic adenomas suggests different pathways of apoptotic bodies in normal and neoplastic colonic mucosa.

Pseudomelanosis coli is characterized by pigment deposition in the lamina propria and caused by increased epithelial apoptosis. Pseudomelanosis coli is absent in colonic neoplasia. The aim of our studies was to investigate this phenomenon in more detail. Apoptotic fragments of epithelial cells and their distribution, cell proliferation (Ki-67, MIB 1 immunostaining), macrophages (CD68 immunostaining), Bcl-2 expression and apoptosis [terminal-deoxynucleotidyl-transferase mediated dUTP fluorescein nick end labeling (TUNEL) assay] were studied in adenomas arising in normal and melanotic colonic mucosa, in normal colonic mucosa and colonic mucosa with pseudomelanosis alone. In adenomas, we found 7.0 apoptotic bodies per 100 epithelial cells in the epithelial layer and only 0.2 apoptotic bodies per high power field (HPF) in the lamina propria. In contrast, in melanotic mucosa 1.7 apoptotic bodies per 100 epithelial cells in the epithelial layer and 2.5 per HPF in the lamina propria were found. Our results show that apoptotic fragments remain in the neoplastic (adenomatous) epithelium and do not reach (at least in higher amounts) the lamina propria. They can, therefore, not contribute to the development of pseudomelanosis in these lesions. However, macrophages are diminished in adenomas. Proliferation (Ki-67) and also Bcl-2 expression are highly increased in adenomas. The pathway of mucosal macrophages is also discussed.

Combined restorative proctocolectomy and pancreaticoduodenectomy for familial adenomatous polyposis.

This is a case report on FAP in a 41-year-old woman in which preoperative examination showed a giant tubulovillous adenoma of the descending duodenum surrounding the papilla of Vater, in addition to pancolon adenomatous polyposis, and isolated adenomas in the gastric antrum and corpus. As it was impossible to remove the giant villous adenoma in the duodenum endoscopically, prophylactic surgical treatment was chosen consisting of restorative proctocolectomy and additional pancreaticoduodenectomy. Flat tubulovillous adenomas in the gastric corpus were successfully removed by total snare biopsies before operation. FAP coli patients treated by prophylactic surgery are now known to be at risk of developing adenomas anywhere in the intestine and many affected patients later die from upper gastrointestinal tumors. In this single case report, the simultaneous occurrence of FAP coli and giant villous adenoma of the duodenum indicates the frequent outcome of this genetic alteration requiring lifelong surveillance. This rare case report includes a short survey of the relevant literature.

Gastric neuroendocrine neoplasms: tumour clonality and malignancy-associated large X-chromosomal deletions.

Type I gastric carcinoid tumours associated with corporal (body of stomach) atrophic gastritis (CAG) are benign tumours developing as the final step of a hyperplastic precursor sequence. The neoplastic nature of these tumours has been assumed but never proved. Type III gastric carcinoid tumours and neuroendocrine carcinomas are malignant neoplasms without known precursor lesions. To assess the neoplastic nature of type I carcinoids, the clonal status of 35 tumours from 23 female patients was investigated using the human androgen receptor (HUMARA) gene test, which is based on the pattern of X-chromosome inactivation. For comparison, the same test was also performed on four type III carcinoids and two neuroendocrine carcinomas. DNA extracted from paraffin sections was digested with Hha I restriction enzyme and then amplified by polymerase chain reaction (PCR) using established HUMARA primers. The PCR products were analysed in an automated DNA sequencer. In a complementary analysis of the same tumours, loss of heterozygosity (LOH) on the X chromosome was studied using three polymorphic markers (DXS989, DXS1003, DXS1192) in a PCR-microsatellite-based technique. After exclusion of non-informative cases, 14 of 16 type I carcinoids were found to be monoclonal on the basis of the pattern of X-chromosome inactivation. Monoclonality was also documented in one of three type III carcinoids and in the single neuroendocrine carcinoma, on the basis of LOH at the HUMARA locus, which per se can be regarded as evidence for clonality. Extensive LOH of the X chromosome involving at least two markers, was found in all metastasizing tumours (two type III carcinoids and two neuroendocrine carcinomas), but in none of the 27 benign carcinoids of types I and III. These results indicate that most type I carcinoids are true monoclonal neoplasms and that malignant evolution in gastric neuroendocrine tumours is associated with extensive allelic deletion of one X chromosome.

[Stomach carcinoma. Optimizing therapy by extended lymph node dissection]. / Magenkarzinom. Optimierung durch Erweiterung der Lymphknotendissektion.

BACKGROUND: The prognosis for surgically treated gastric cancer patients remains poor in most Western countries compared with reports of Japanese investigators over the last three decades. The aim of the study was to prove whether D2, D3 lymphadenectomy is able to improve long-term survival in a Western gastric cancer patients collective as well. METHODS: A radical surgical procedure using D2, D3 lymphadenectomy on principle as defined by the Japanese Research Society for Gastric Cancer was done prospectively since January 1984. Out of 626 patients with gastric cancer, 433 were surgically treated for potential cure between January 1st, 1984 and December 31st, 1996. Postoperative complications and long-term survival were evaluated. RESULTS: For curatively operated patients five- and ten-year tumor specific survival rates were 57.7% and 44.3%, the median survival time was 96 months. Postoperative hospital mortality was 4.8% for R0 resected patients and 10.4% for palliative procedures. CONCLUSION: Radical D2, D3 lymphadenectomy yielded survival rates similar to those in Japanese investigations without negative effect on low postoperative mortality. These results reaffirm the value of radical lymph node dissection with wide resection margins.