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After introduction of the Bethesda microsatellite test panel demonstration of microsatellite instability (MSI) and/or loss of mismatch repair proteins (MMRD) was primarily used as a marker for cancer predisposition of Lynch syndrome (LS, previous: HNPCC). Nowadays MSI/MMRD has become an important biomarker to predict therapy response to checkpoint immunotherapies. MSI can be determined either by polymerase chain reaction (PCR)-based technologies with or without specification of fragment sizes or next generation sequencing (NGS) methods. Depending on the individual tumor entities, these test methods are used differently. Currently, MSI/MMRD is a tumor biomarker which covers a broad spectrum of indications in tumor pathology, especially in colorectal, endometrial and gastric cancer. In advanced carcinomas, MSI is an established predictor of therapy response to checkpoint-directed immunotherapies.

The pathologist can contribute to recognizing hereditary causes of colorectal cancer via morphology. By identifying so-called index patients, it is possible to take preventive measures in affected families. The precise definition of the clinical presentation and the histopathological phenotype help to narrow the spectrum of expected genetic alterations. Novelties within Lynch syndrome include the recognition of EPCAM as a fifth gene locus, as well as the newly defined Lynch-like syndrome with evidence of somatic mismatch repair (MMR) mutations. With regard to polyposis-associated syndromes, the spectrum of polyps, whether serrated, hamartomatous or classic adenoma, is of crucial importance. The resulting differential diagnosis includes (attenuated) familial adenomatous polyposis ([a]FAP), MUTYH-associated polyposis (MAP), polymerase proofreading-associated polyposis (PPAP), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Peutz-Jeghers syndrome and juvenile polyposis, each with a specific genetic background.

Valid HER2 testing is essential for the optimal care of patients with HER2-positive gastric cancer and the correct use of first-line treatment. Although all cases of breast cancer are routinely tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is usually only done upon request by the therapist. An interdisciplinary group of German experts has taken on the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions on the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this article reflect the consensus of all participants and correspond to their opinions and long-term experience.

Lynch syndrome is the most frequent hereditary cancer syndrome, accounting for approximately 3-5 % of all colorectal cancers. In addition, it is the most frequent predisposing hereditary cause of endometrial cancer and is also associated with gastric cancer, ovarian cancer, cancer of the urinary tract as well as several other cancers. In clinical practise Lynch syndrome is frequently not detected and many clinicians admit uncertainties regarding diagnostic procedures. Also, counselling of patients is considered difficult regarding therapeutic - especially prophylactic surgical and chemopreventive options and recommendations. Based on a review of available literature we discuss optimized strategies for improved detection of suspected Lynch syndrome patients. The aim of this review is to establish a clinical algorithm of how to proceed on a diagnostic level and to discuss surgical options at the time of a colorectal cancer. In order to identify patients with Lynch syndrome, family history should be ascertained and evaluated in regards to fulfilment of the Amsterdam-II- and/or the revised Bethesda criteria. Subsequently immunohistochemical staining for the mismatch-repair-genes, BRAF testing for MLH1 loss of expression, as well as testing for microsatellite instability in some, followed by genetic counselling and mutation analysis when indicated, is recommended. Pathological identification of suspected Lynch syndrome is readily feasible and straightforward. However, the need of performing these analyses in the tumor biopsy at the time of (gastroenterological) diagnosis of CRC neoplasia is essential, in order to offer patients the option of a prophylactically extended surgery and - as recommended in the German S3 guidelines - to discuss the option of a merely prophylactical hysterectomy and oophorectomy (if postmenopausal) in women. Close cooperation between gastroenterologists, pathologists and surgeons is warranted, so that patients may benefit from options of extended or prophylactically extended surgery at the time of diagnosis of a colorectal primary. Patients nowadays must be involved in informed decision-making regarding prophylactic or extended prophylactic surgery at the time of a colorectal primary. To date, however, limitations in daily clinical practise, the failure to assess family history and the lack of awareness of this important hereditary syndrome is the major asset leading to severe underdiagnosis and putting to risk the indexpatients themselves and their families to (metachronous) CRC and the associated extracolonic cancers. If at all tumors of patients fulfilling Bethesda criteria will be analysed for MSI in the surgical specimen and therefore Lynch syndrome patients are not given the opportunity to opt for extended surgery. In clinical experience the postoperative MSI-analysis is inconsistently performed - even if the Bethesda criteria are fulfilled - and in case of suspected Lynch syndrome genetically counselling is not consistently recommended. Therefore affected cancer patients are left unaware of their increased genetic risk and in average 3 high-risk gene carriers per family miss the opportunity to actively engage in the recommended screening program.

Neuroendocrine neoplasms of the digestive system are classified by current World Health Organization (WHO) guidelines as G1 and G2 neuroendocrine tumors (NET) as well as neuroendocrine carcinoma (NEC) based on proliferation and differentiation. The G1 NET tumors are highly differentiated, low proliferating and usually exhibit a favorable course of the disease without the development of metastases. In the case presented here, angioinvasion by a pT3 NET G1 was demonstrated after complete work-up of the mesenterial fat by acetone compression. The findings indicate an unfavorable course of disease requiring intensive surveillance.

The introduction of total genome sequencing led to the confirmation that tumors show substantial genetic heterogeneity. This phenomenon, which describes the presence of different genetic cell clones within a tumor also complicates the diagnostics of HER2. This article gives a review of new knowledge on polysomy 17 and genetic tumor heterogeneity in connection with HER2 determination of breast cancer.

Although early stage malignant melanoma (MM) has a favorable prognosis five year survival rate is poor (10%) in patients suffering from distant metastases. Due to molecular typing of MM recently high response rates were achieved in metastatic MM by using specific inhibitors directed against the mutated form of BRAF kinase, e.g. Vemurafinib and Dabrafinib. Therefore BRAF mutation analysis has become standard of care in advanced MM and pathologists are urged to provide a quality guaranteed molecular diagnostics. However, squamous neoplasias (e. g., keratoacanthomas) and recurrences of MM mostly within 6 months during targeted therapy point to the need of further translational research. Thus new drugs, such as MEK inhibitors, based on the MAP-kinase pathway downstream of BRAF have already effectively been used. Finally, the impact of molecular characteristics in different subtypes of MM (acral, mucosal, uveal) will be discussed with respect to their specific mutational spectrum (e.g. cKIT , NRAS , GNAQ).

Tumors of the anal canal are mostly epithelial in origin. The transition of gland-forming rectal mucosa via specialized urothelium-like cells at the dentate line to anal non-keratinized and finally perianal keratinized squamous epithelium implies a broad spectrum of tumor types, with most cancers exhibiting a mixture of different histological features. Moreover, secondary neoplasias extending into or metastasizing to the anal region need to be considered. Based on epithelial metaplasia at the transformation zone, poorly differentiated squamous anal carcinomas may show co-expression of both the squamous (CK5/6) and glandular type keratins (CK7). Since HPV infection of high-risk types (often 16 and 18) is etiologically associated with anal cancer, p16(INK4a) is highly sensitive and specific in the detection of high-grade anal squamous intraepithelial neoplasias (ASIN) and corresponding invasive squamous carcinomas. Diagnosis of secondary malignancies, including pagetoid extension into the anogenital region, requires the application of specific immunohistochemical marker panels.

Non-neoplastic and non-hamartomatous colorectal polyps or tumor-like lesions comprise a very heterogeneous group of changes in the colorectal mucosa or the colon wall. Mucosal prolapse-associated lesions and inflammatory polyps, which are predominantly associated with chronic inflammatory bowel disease, are the most prominent examples for polypoid lesions difficult to distinguish from neoplastic lesions such as adenomas, hyperplastic/serrated polyps/adenomas and invasive carcinomas. The considerably less frequent tumor-like lesions like heterotopias, endometriosis, amyloid tumors and pseudolipomatous changes are histologically often well defined and should be considered in the differential diagnosis of colorectal lesions. The etiology, endoscopic and histological appearance of these entities and their most important differential diagnoses are discussed.

One third of colorectal carcinomas (CRC) show familial clustering of which about 5% have a monogenetic trait. Distinction between disease with and without polyposis, tumor histology and tumor spectrum in a given patient are all of diagnostic relevance. Familial adenomatous polyposis (FAP) underlies approximately 1% of CRC characterized by rapidly forming (100) adenomas. In contrast to these about 2%-3% of CRC have a hereditary background without polyposis (HNPCC). This is the only hereditary tumour syndrome to date for which a tissue-based molecular screening test is available. Accordingly, expression analysis of mismatch repair genes (MSH2, MSH6 and MLH1, PMS2) is performed first. In the case of an equivocal result with no complete loss of expression testing of microsatellite instability (MSI) is added. In contrast to the other diseases MYH-associated polyposis (MAP) follows a recessive trait with polyp numbers usually between 15-30 adenomas and should be distinguished from attenuated forms of FAP with100 polyps in the differential diagnosis. In the case of suspected familial cancer syndrome genetic counseling is warranted in order to decide ultimately whether there is an indication for genetic testing (evidence of a germ-line mutation).

Based on data from a large multicenter phase III trial (ToGA study) trastuzumab has very recently been approved by the EMEA for metastatic gastric cancer and adenocarcinoma of the gastro-esophageal junction. Only patients with tumors which over express Her2 as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, determined by an accurate and validated assay are eligible for trastuzumab therapy. However, testing of Her2 status by immunohistochemistry (IHC) differs from breast cancer in core aspects: 1. IHC2+/3+ is scored even though membranous staining is incomplete if membrane staining is clearly detectable even at low magnification (2.5x/5x, 3+) or medium magnification (10x/20x, 2+). 2. Additionally, membrane staining at the appropriate intensity found in at least 10% of tumor cells is restricted to resection specimens. Evaluation of Her2 in situ hybridization (ISH) is similar to breast cancer with ratio values ofor =2.0 indicating Her2 gene amplification. Taking these modifications into account and defining the HER2 positive subgroup as IHC 3+ and IHC2+/FISH+, approximately 16% of gastric cancers are considered Her2 positive, affecting mainly tumor regions with intestinal (gland forming) type carcinoma. In contrast to breast cancer, up to one-third of gastric cancers show a heterogeneous Her2 status both at IHC and ISH levels which favors bright field ISH over FISH.

Determining ErbB2/Her-2/neu status has become an essential part of breast cancer diagnosis and a prerequisite before considering a patient's eligibility for treatment with trastuzumab. Currently the most common techniques to assess ErbB2 status in routine practice are the identification of receptor overexpression by means of immunohistochemistry (IHC) and the analysis of gene amplification by means of dual color fluorescence in situ hybridisation (FISH). According to recent recommendations ("ASCO/CAP Guidelines" and German S3 guidelines for breast cancer) the choice of primary test procedure--IHC or ISH - is left to the individual institution. Both techniques are of equal predictive value provided that strict quality precautions have been taken: internal test validation by comparing IHC and (F)ISH, carrying out controls, and annual participation in round-robin tests. Equivocal IHC (score 2+) has to be checked by ISH for amplification. Borderline ISH (ratio 1.8-2.2 or gene copy number 4.0-6.0) should be retested by counting additional cells or performing IHC. In approximately 5% of cases these criteria give conflicting results and the gene copy number alone generates over 90% of the equivocal ISH cases, mostly due to chromosome 17 polysomy. These cases need to be tested by IHC since over-expression is very exceptional and only these tumors have the potential to be trastuzumab responders.

Today, more than 80% of men diagnosed with prostate cancer (PCA) by PSA screening do not die from the sequelae of their disease. About 70% present with early, organ-confined cancer and almost half of them are small (5 cm(3)) without evidence of progression over years (insignificant PCA). It is assumed that screening brings the diagnosis of PCA forward by about 9 years and that in almost one third of these cases immediate radical prostatectomy or radiotherapy would result in overtreatment. Thus, the treatment strategy of "active surveillance" with selective but delayed intervention for patients with organ-confined PCA could be an attractive alternative to the known curative therapy options. However, a prerequisite of such a therapeutic approach would be a precise identification of patients at high risk for cancer progression. Careful work-up of prostate core needle biopsies including improved pre-embedding preparation and detailed interpretation are of the utmost importance. A Gleason scoreor =6 and tumor in only one or two cores are considered predictive of organ-confined cancer. Pathologists should concentrate on correct Gleason scoring in core needle biopsies and identification of lesions that exclude a patient from active surveillance.

In the age of personalized medicine, and in addition to typing and grading, breast cancer pathologists are now also involved in determining biomarkers such as steroid hormone receptors and Her-2, which are of the utmost importance in adjuvant therapy. In order to assure quality of these biomarker assays, external proficiency testing has been implemented in Germany. Since 2002 trials have been conducted annually, with up to 180 participating laboratories. More than 85% of all participants achieved good results in clearly negative and positive cases seen in daily practice. If at all, discordant results were observed in the rarer low steroid-hormone receptor expressing tumors and Her-2 borderline cases (2+). Regular participation in interlaboratory testing leads to significantly improved immunohistochemical results, particularly in these problematic cases. Tissue microarrays (TMA) with 20-24 different breast cancer samples including cell lines meant that a huge number of pathologists were challenged with identical samples, providing the prerequisite for comparability. Participation is recommended for pathology departments involved in the service for breast units. The organizational frame work of the trials is described here. The confidence of cooperating disciplines in breast cancer biomarkers assessed by pathologists will be fostered by external proficiency testing as presented here.

More than 40 years ago Morson (1962) coined the paradigm that adenomas are the main precursors of colorectal carcinoma (CRC) whereas hyperplastic polyps are "non-neoplastic" lesions without cancer risk. Later-on (1988) this was supported by Vogelstein's molecular adenoma-carcinoma progression model with APC mutations being a key-initiating molecular event (classic adenoma-carcinoma pathway). In 1992 a new molecular mechanism, the mutator pathway of CRC was discovered in HNPCC patients. Deficiencies in mismatch repair (MMR-) gene function (mainly of MSH2 and MLH1) cause microsatellite instability (MSI) in about 15% of CRC. It's the merit of Jass (1999) to demonstrate that carcinogenesis in sporadic MSI-positive CRC is associated with serrated polyps. These polyps form the hallmark of a third "serrated (neoplasia) pathway" exhibiting a hyperplastic polyp-like morphology characterized by serrated crypt epithelium. In contrast to adenomatous polyps with readily apparent cytological atypia (dysplasia) the feature of dysplasia in serrated polyps is architectural distortion. Today four categories of serrated lesions can be delineated: (i) the most frequent classic hyperplastic polyp (HP, 80-90%), followed by (ii) sessile serrated adenoma (SSA, 15-20%) and (iii) by the rare traditional serrated adenoma (TSA,1%). Whereas HPP are benign, SSA are probably slowly progressing lesions and TSA as well as SSA with APC-type adenomatous atypias (iv. mixed SSA) indicate increased cancer risk. Molecularly serrated polyps seem to share a defect in apoptosis caused by either K-ras or BRAF gene mutation leading to CpG island methylation (CIMP) affecting MLHI (--MSI type CRC) or non-MMR oncogenes (--MSI-L or MSS type serrated CRC, Mäkinen 2007).

Her-2 status determination is an essential prerequisite before considering patient eligibility for treatment with trastuzumab. Currently the most common techniques to assess Her-2 status in routine practice are immunohistochemistry (IHC) and dual color FISH for receptor expression and gene amplification analysis, respectively. Despite both methods are well-established in breast cancer there are a variety of yet unsolved questions: 1. Do we really need IHC since interlab variation is still quite high (up to 30%)? 2. Are FISH and CISH equivalent techniques? 3. Are there any precautions to be taken if Her-2 is tested in non-breast cancer samples? 4. What is the value of Her-2 status in blood serum (ELISA)? 5. Do we get better response prediction if new Her2 antibodies, other techniques such as quantitative (q) RT-PCR or multiparameter assays according to downstream signalling pathways are applied? 6. Is Her-2 status still predictive when other therapeutic antibodies than trastuzumab (e. g. pertuzumab) or kinase inhibitors (e. g. lapatinib) are used? These questions will be discussed under the review of the recent literature and under own experiences obtained either by centralized Her-2 assessment in a variety of breast and non-breast cancer therapy studies and within international ring studies between reference labs from Australia (M. Bilous), Canada (W. Hanna), France (F. Penault-Llorcoa), Great Britain (M. Dowsett), Japan (R. Y. Osamura), and Netherlands (M. v. d. Vijver) in which we participated.

Intracranial vascular malformations are rare but tend to appear more frequently than usual in patients with type I neurofibromatosis (NFI). Aneurysms of the basilar artery have been described four times so far. We report two cases of 51- and 62-year-old patients with type I neurofibromatosis who showed long fusiform dilation of the basilar artery. Clinically both patients presented with locked-in syndrome and died 15 and 11 days after admission. The diagnosis was confirmed by autopsy. These are the first published cases of locked-in syndrome following thrombosis of a megadolichobasilar artery in association with neurofibromatosis I. Our results show that cerebral vascular malformations are found more frequently than random chance would predict in patients with NF I.

Heterozygote Mutationen in den TSG p53 und p16, sowie chromosomale Aneuploidie treten fruh im Rahmen der PanIN Sequenz einer CP auf, wahrend die definitive Inaktivierung der TSG durch LOH erst im spateren Verlauf stattfindet. Da sich Veranderungen des Ploidiestatus bereits in fruhen Lasionen nachweisen lassen, deutet dies moglicherweise auf die Relevanz der chromosomalen Instabilitat fur die Karzinogenese des Pankreaskarzinoms hin. Die Aneuploidiemessung konnte fur die Fruherkennung und Risikobewertung von Patienten mit langjahriger CP von Bedeutung sein.

Although twin studies indicate that inherited genetic factors contribute to about 35% of colorectal cancers (CRC), the exact genetic background has currently been elucidated in only 5-10% of cases. These comprise several hereditary cancer predisposition syndromes that present with a high number of syn- or metachronous neoplasms within an affected person and/or family. Many of these tumors exhibit typical histopathological changes. In general, one should discriminate between cancer syndromes associated with adenomatous and non-adenomatous (i.e., hamartomatous) polyps, the latter being quite rare. The patient's age often serves as a substantial hint to hereditary cancer. The next step of diagnostic work-up includes analysis of microsatellite instability (MSI) together with immunohistochemical detection of a loss of expression in one of the most frequently affected mismatch repair genes (MSH2, MSH6; MLH1, PMS2). Finally, the molecular demonstration of a gene mutation in the blood or germline is the most expensive and tedious procedure. This requires a signed informed consent from the patient after appropriate genetic counseling.

Thirteen families were included in our HNPCC surveillance program, eight of which met strict and three incomplete Amsterdam criteria. Two index patients were younger than 35 years of age. Tumors of all index persons showed microsatellite instabilities in at least 50% of the ten markers studied. Immunohistochemical analysis of tumor sections was performed using antibodies against hMLH1 and hMSH2 proteins in order to identify the mutated gene, which is not expressed in the tumor. Coding regions of hMLH1 and hMSH2 genes were amplified by PCR from genomic DNA and sequenced. In nine families pathogenetic mutations all resulting in a truncated protein, could be identified. Furthermore, 21 intron and exon polymorphisms were found. Since July 1997 we have offered surgical and genetic counseling to families with hereditary cancer syndromes in a special outpatient clinic. In addition to 13 index patients three asymptomatic gene carriers were included and eight noncarriers were excluded from the HNPCC surveillance program, as recommended by the HNPCC study group of Germany. Molecular diagnosis has considerable clinical implication in hereditary nonpolyposis colorectal cancer (HNPCC) families with respect to family members who actually have the disease as well as gene carriers and noncarriers.

The simultaneous occurrence of different hepatic tumors is rare. We present for the first time a concomitant manifestation of an angiomyolipoma, a focal nodular hyperplasia, a bile duct adenoma, and a cavernous hemangioma in a 63-year-old female patient. The largest of the tumors, preoperatively suspected to be hepatocellular carcinoma, was an angiomyolipoma with monotypic epithelioid histology and positive immunoreactivity for HMB-45, actin, desmin, and pancytokeratin. The significance of immunohistochemistry for the differential diagnosis of hepatic neoplasms is emphasized. Finally, a review of the literature with special regard to etiology and pathogenesis of neoplastic liver disease is given, leading to the assumption that the association of four different benign intrahepatic tumors is rather more fortuitous than pathogenetically related, despite the putative similar pathogenesis of focal nodular hyperplasia and hemangioma.

Three cases of acute segmental hemorrhagic antibiotic-associated colitis are described occurring in three male adults between 30 and 33 years of age after treatment with oral ampicillin or amoxicillin because of upper respiratory tract infection, tonsillitis, or HLO eradication therapy, respectively. All presented with cramping abdominal pain and bloody diarrhoea of acute onset, however, microbial analysis of fecal samples was negative. Endoscopy showed right-sided segmental hemorrhagic colitis. Histopathological examination demonstrated edema, patchy superficial hemorrhage and a scattered predominantly mononuclear infiltrate of the lamina propria. The surface epithelium was partly desquamated and displayed foci of grouped intraepithelial red blood cells. All patients spontaneously recovered after discontinuation of antimicrobial therapy. The value and limitations of diagnostic features are discussed with respect of the literature.

We present a case of pigmented adrenal paraganglioma in a 39-year-old female patient with associated neurofibromatosis type 1 (NF1). Histology showed features typical for phaeochromocytomas except for varying amounts of brown pigment within the cytoplasm of tumour cells, which proved to be melanin by histochemical and ultrastructural analysis. The occurrence of melanin is believed to reflect the origin of this neoplasm from multipotent cells of the neural crest. Pigmented phaeochromocytoma has to be taken in consideration in the differential diagnosis of pigmented neoplasms, especially in the adrenal gland, where it has to be discriminated from pigmented cortical adenoma (so-called black adenoma) and primary malignant melanoma.

Leser-Trélat-syndrome is characterized as the eruptive appearance of multiple seborrheic keratoses in association with underlying malignant disease. A 73 year old female patient with a metastatic adenocarcinoma of the colon presented with this paraneoplastic change. The rapid appearance of solitary seborrheic keratoses with associated inflammation, seen clinically and histologically, may be an early sign of Leser-Trélat-syndrome. The recognition of this inflammatory component as an early sign may contribute to the prompt diagnosis of this paraneoplasia, even before the eruption of numerous seborrheic keratoses.

Various inherited and acquired alterations affecting the genes and gene products of the WNT pathway appear to be involved in the different molecular routes leading to colorectal cancer (CRC). This study was initiated to investigate the prevalence of somatic mutations in the beta-catenin gene (CTNNB1) and the associated pathology in CRC with defective DNA mismatch repair.Paraffin and/or frozen sections of 33 primary CRC (including any liver and lymph node metastases present) with high-grade microsatellite instability (MSI-H; i.e. withor = 5 unstable microsatellite markers of 10 tested) were polytopically fractionated by microdissection. Genomic and c-DNA samples were sequenced across exons 2-4 of CTNNB1 and the expression patterns of beta-catenin (beta-C) analyzed by immunohistology and Western blotting.Seven somatic mutations affecting phosphorylation sites of exon 3 (2 deletions also encompassing parts of either intron 2 or exon 4 [delta X2/3 bzw. delta X3/4] and 5 missense mutations [2 x T41A, 2 x S45F, S45P]) were identified. Two mutations (delta X3/4 and S45F) were concordantly present in CRC primaries and their respective metastases whereas the S45P mutation was restricted to a hepatic metastasis. In the delta X2/3 CRC primary only a shortened 66 kD CTNNB1 gene product was present while its associated liver metastasis showed a total loss of beta-C expression.Both exon 3 and the entire locus coding for beta-C are somatically altered in approximately 20% of CRC with MSI-H at different stages of tumor progression. Thus CTNNB1 appears to be a genomic target for complex oncogenic mutations and deletional processes in a substantial fraction of this molecular subset of CRC.

Since gastric cancer is an exceptional heterogeneous tumor conflicting results have been obtained about the relationship between genotype and phenotype. From the molecular point of view gastric carcinoma diffuse type forms a distinct entity which is microsatellite stable, has almost no p53 mutations and exhibits in at least half of the cases mutations in the E-cadherin gene. In contrast, all other gastric carcinomas comprise a heterogeneous group of which about one third exhibits microsatellite instability (MSI) but no p53 protein stabilization or gene mutations. These tumors are either of pure intestinal (glandular) type or show large solid (medullary) tumor cell clusters. Thereby, in sporadic gastric cancer MSI is caused by loss of hMLH1 expression due to hypermethylation of the promotor region rather than by mutation of the gene itself. Tumors that are microsatellite stable (MSS) and show p53 alterations are either intestinal (about 70%) or a mixed-type encompassing at least 5% glandular and poorly differentiated diffuse components (about 30%). Whereas pure diffuse type gastric cancer is unlikely to develop from intestinal type carcinoma, this may, however, be the case in some advanced mixed-type gastric cancers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit cancer preventive effects and have been shown to induce regression of adenomas in FAP patients. In order to elucidate the probable underlying mechanism, the effect of NSAIDs on mismatch repair related microsatellite instability was investigated. Six colorectal cancer cell lines all but one deficient for human mismatch repair (MMR) genes were examined for microsatellite instability (MSI) prior and after treatment with Aspirin or Sulindac. For rapid in vitro analysis of MSI a microcloning assay was developed by combining Laser microdissection and random (PEP-) PCR prior to specific MSI-PCR. Effects of NSAIDs on cell cycle and apoptosis were systematically investigated by using flow cytometry and cell-sorting. MSI frequency in cells deficient of MMR genes (hMSH2, hMLH1, hMSH6) was markedly reduced after long-term (10 weeks) NSAID treatment. This effect was reversible, time- and concentration dependent. However, in the hPMS2 deficient endometrial cancer cell line (HEC-1-A) the MSI phenotype kept unchanged. According to cell sorting, non-apoptotic cells were stable and apoptotic cells were unstable. These results suggest that aspirin/sulindac induces a genetic selection for microsatellite stability in a subset of MMR-deficient cells and may thus provide an effective prophylactic therapy for HNPCC related colorectal carcinomas.

Restrictive dermopathy is a rare, fatal, autosomal recessive, congenital skin disease. Rigidity of translucent thin skin, which is thus highly vulnerable and tears, spontaneously causes intra-uterine fetal akinesia or hypokinesia deformation sequence (FADS), characteristic dysmorphic facies with fixed open mouth in O position, and generalized joint contractures (arthrogryposis). Polyhydramnios and pulmonary hypoplasia are distinctive manifestations, leading to respiratory insufficiency and premature delivery at about 31 weeks of gestation. We report on a case of a prematurely born infant who presented with the typical morphological features and describe the light- and electron-microscopical findings as described in the literature.

During the last few years, the molecular basis of several cancer predisposition syndromes has been discovered which offers new tools for cancer prevention and early detection. This will be demonstrated in one of the most frequent hereditary cancer syndromes, namely the hereditary nonpolyposis colorectal cancer (HNPCC) which accounts for about 5% to 8% of CRC. Thereby, families with exclusively CRC (Lynch type I syndrome) and those with extracolonic cancers especially of endometrium, stomach, small bowel and upper urinary tract (Lynch type II syndrome) can be discriminated. At the molecular level, HNPCC is caused by germline mutations in one of the mismatch repair genes (hMSH2, hMLH1, hMSH6, hPMS2). Thus, nucleotide mispairings occurring particularly within simple repetitive genomic sequences (microsatellites) during replication are no longer be repaired properly and can be demonstrated by PCR as so-called microsatellite instability (MSI). Since more than 90% of HNPCC associated and only about 15% of sporadic CRC show MSI, this test is a useful tool for HNPCC screening. In case of a negative result HNPCC is highly unlikely. In positive cases (withor = 2 out of 5 unstable defined microsatellite markers) the definite molecular diagnosis can only be obtained by sequencing the mismatch repair genes from the patient's blood or normal DNA. As immunohistochemistry reveals loss of hMSH2 or hMLH1 expression in most MSI positive CRC, these data provide useful information for the sequencing strategy. Molecular tumor screening by MSI test and immunohistochemistry is recommended in patients i.) with a positive family history (acc. to the Amsterdam criteria), ii.) suffering from multiple HNPCC related carcinomas, iii.) with HNPCC related cancer before 45 ys of age, and iv.) with right-sided CRC exhibiting medullary, signet-ring or mucinous differentiation. Finally, these tests as well as genetic counseling and treatment of the patient need to be done by an interdisciplinary approach. Thereby, the pathologist can substantially contribute to identify HNPCC related carcinomas either by clinical or morphological criteria and to initiate the molecular screening test.

A 25-year-old woman who had delivered a normal child after a normal pregnancy four months ago, was suffering from a common cold. The latter was treated by tetracyclines. A few days later she developed an acute severe hemolysis. Moreover she had signs of hepatic failure which was characterized by a considerably reduced synthetic capacity of the liver but low serum aminotransferase levels and a proximal renal tubular disorder. With a negative Coombs test an autoimmune hemolytic anemia was unlikely. Therefore diagnostic procedures were directed at the cause of the liver injury. An increased urinary excretion of copper, strongly elevated levels of liver tissue copper and the detection of a Kayser-Fleischer ring by slit-lamp examination proved the diagnosis of Wilson's disease-presenting clinically only as severe hemolysis. Ceruloplasmin concentration in serum was in low normal range and not diagnostic.

Microsatellite instability (or replication error phenotyp) is a new molecular phenotyp of a substantial fraction of human cancers. The microsatellite instability in these cancers arises from alterations in normal regions of the genome consisting short sequences of repeated DNA. Ubiquitous changes in length of microsatellite sequences between constitutional and tumor DNA occur in about 90% of cases of HNPCC and in about 15% of cases of non-familial, sporadic colorectal cancer. Microsatellite instability is also found in a substantial percentage of sporadic endometrial, and gastric cancer, as well as in additional sporadic cancers, such as lung cancer which is usually not associated with HNPCC. Thus far, four different mismatch repair genes (hPMS1, hPMS2, hMLH1 hMSH2), all homologous to bacterial DNA repair genes have been identified as involved in HNPCC kindreds, and consequently they are associated with microsatellite instability. In conclusion, these basic genetic informations provide new insights into a new molecular pathway in oncogenesis, i.e. the occurrence of mutations in genomic stability genes leading to an increased cellular mutation rate (replication error phenotyp) and thus to cancer.

This report reviews proliferative diseases of intermediate trophoblast cells and summarises clinical findings and pathohistological and immunohistochemical features of a placental site nodule. This recently described entity is an endometrial or endocervical benign proliferation of intermediate trophoblast cells occurring after intrauterine gestation. Patients usually present with a history of abnormal vaginal bleeding and frequently cells that are present in their cervical smears are misinterpreted as squamous dysplasia. In such cases it is important to distinguish the placental site nodule from squamous lesions or decidual polyps; this is possible by means of immunohistochemistry.

After aortic valve replacement for endocarditis, follow-up treatment with antibiotics is imperative. However, the question of how reliable preoperative and intraoperative diagnosis of endocarditis is in cases involving aortic defects is unclear. Of the 187 patients who underwent aortic valve replacement with or without coronary bypass surgery between June 1992 and June 1994, 150 exhibited no indications of endocarditis during preoperative and intraoperative examinations. In 17 cases (Group A) histological findings indicated acute florid endocarditis in 7 patients and chronic lymphocytic endocarditis in 10. Contrarily, histological examinations of 133 patients (Group B) revealed myxoid and/or sclerotic valve degeneration. WBC and LDH activity, examined one day preoperatively and on the first and second days postoperatively, exhibited no significant differences between the two groups, with the exception of LDH activity on the first postoperative day (Group A: 490 +/- 114, Group B: 403 +/- 132, p = 0.04). Of the clinically asymptomatic patients requiring aortic valve replacement, 11.3% exhibited acute florid endocarditis upon histologic examinations. This subgroup cannot be identified based upon routine preoperative or postoperative laboratory tests or intraoperative observation. Histological examination of the aortic valve is useful for identifying the high percentage of otherwise nonidentifiable endocarditis. Further study will be required to determine therapeutic recommendations based upon such diagnosis.

Whipple's disease is a systemic disease which may virtually affect any organ system, but in many cases it involves the small intestine causing gastrointestinal symptoms. The differential diagnosis is difficult since symptoms may be nonspecific. We report the case of a 44-year old white male patient with a history of migrating arthralgia and chronic fatigue. The patient newly developed an uveitis and underwent a vitrectomy; the further clinical work-up including gastroscopy with intestinal biopsy revealed no sufficient diagnosis. Subsequently, the patient's condition deteriorated with marked weight loss, fever and progressive weakness. An anaerobic sepsis with a corynebacterium was confirmed and with i.v.-antibiotics the patients's condition improved markedly. The further examinations disclosed enlarged mesenteric lymph nodes and the involvement of other organs (endocard, liver). CT-guided biopsy only showed fatty degeneration, but operative adenectomy confirmed Whipple's disease. The patient remained without relapse on long-term antibiotic treatment with doxycycline until today. Obviously, in our case the intestinal biopsies failed to detect Whipple's disease after the successful initiation of antibiotic treatment. In the absence of gastrointestinal findings and with concomitant secondary diseases the definitive diagnosis can be difficult. In addition, the previous uveitis and the endocardial involvement are most interesting.

Nucleolus-organizing regions (Ag-NORs) are silver-stained loops of DNA transcribing to ribosomal RNA. Quantitative analysis helps to differentiate normal tissue from malignant tissue and can be used for diagnosis in several kinds of tumours. The analysis of AgNORs can also be used in dermatopathology for diagnostic and prognostic purposes. Apart from skin tumours such as basal, cell carcinomas and squamous cell carcinomas, this technique is of interest principally for melanocytic lesions. Benign naevi can be distinguished from malignant melanomas by simple counting of the AgNOR dots. For the differentiation of dysplastic naevi, Spitz naevi and malignant melanomas, this parameter alone is not sufficient. By combination of several AgNOR parameters (number, size, pattern of dispersal) only, significant differentiation could be achieved. The prognostic value of AgNORs remains to be examined.

A 77-year-old man developed a fever up to 38.4 degrees C, with diarrhoea, acute renal failure (creatinine up to 8.7 mg/dl; urea up to 308 mg/dl) and marked jaundice (total bilirubin up to 24.3 mg/dl). In addition there was thrombocytopenia, conjunctivitis and epistaxis, as well as cerebral symptoms with somnolence and general slowing up. At first he was thought to have cholangitis resulting from previously diagnosed gall-stones, and he was therefore treated with ampicillin, 2 g two times daily, and metronidazole, 0.5 g two times daily. The fewer regressed, but the renal failure required haemodialysis and haemofiltration under strict fluid control. Endoscopy excluded obstructive jaundice, but a suspicion of inflammatory liver disease or possibly cirrhosis was raised in the differential diagnosis. Serology revealed an increased titre for Leptospira interrogans var. sejroe (1:200, later 1:1600). Liver biopsy finding was compatible with the diagnosis of leptospirosis. Because of the high inflammatory activity in the liver, 2 mega units of penicillin G were administered three times daily for six days. Gradually the renal functions and jaundice improved and, on discharge on the 36th day, the patient was again in generally good health, although creatinine and bilirubin values were still slightly elevated (1.7 mg/dl each).

Expression of two nucleolar antigens, p120 and B23, was studied in a prostatic carcinoma cell line (LNCaP) and in frozen and paraffin embedded tissue sections of 40 benign and malignant prostatic lesions. The percentage of p120 negative G0/G1 phase cells rose significantly during transition from exponential to plateau growth phase in vitro (from 9% to 32%). In contrast, B23 was equally expressed throughout different cell cycle and growth phases. Thus, nucleoli of almost all stromal and epithelial cells were stained by B23 in tissue sections. P120, however, selectively stained nucleoli of proliferating prostatic epithelium. Whereas 88% (13/15) of benign hyperplasia were p120 negative this was the case in only 24% (6/25) of carcinomas. Using microwave procedure both MoAbs reacted in paraffin sections, but the percentage of p120 negative cases doubled. A routine application to formalin fixed and paraffin embedded tissue cannot be recommended thus far.

Morphology and biological behaviour of tumours are closely related to each other and are the main objects of diagnostic tumour pathology. Anaplasia, for example, a well-known cytomorphological criterion of malignancy, is however only an indirect sign of impaired cellular growth control mechanisms. Nowadays, it is a goal of cancer research to investigate these regulatory processes in order to elucidate new diagnostic criteria of malignancy. Silver staining of nucleolar organizer regions (AgNORs) basically meets this new concept. NORs (rDNA) encode for ribosomal RNA and are thus of central importance for the protein synthesis of a cell. Silver stains NOR associated proteins and indicates activated rDNA. Therefore, AgNOR staining covers the proliferative potential of a given cell or a tumour respectively. A prerequisite of reliable application of the AgNOR method to diagnostic tumour pathology is standardization of the technique, which should be based upon scientific results obtained by basic research. Accordingly, in interphasic cells AgNORs are primarily substructures of nucleoli corresponding to the fibrillar centers at the ultrastructural level. This has been shown to be an important criterion to determine the quality of the silver staining reaction. Most artifacts result from inadequate tissue preservation (fixation), unspecific argyrophilic structures and the staining procedure itself. They should either be excluded or--when ever possible--controlled by a proper staining technique, i.e. adjustment to the stainability of every individual specimen. In this respect, digital image analysis proved to be a useful tool. The mean size of AgNORs in small lymphocytes of the same tissue sample is an equivalent of the argyrophilia of a given histological and cytological specimen (internal staining standard). By use of such a standardized staining technique a high diagnostic accuracy is achieved. The proliferative potential of a cell or a tumour can be determined by number, size, staining intensity and distribution of the silver stained dots. In histological tissue sections the quotient of the mean number of AgNORs/cell and the mean area of one AgNOR dot/cell has been shown to be a very sensitive diagnostic parameter. In cytological specimens determination of the total silver stained area per cell is superior to counting of AgNORs simply by eye. Normal and malignant tissue can reliably be discriminated by these morphometric values. In addition, the malignancy potential of the different preneoplastic lesions, e.g. of the urinary bladder, can precisely be described. Flat urothelial lesions with moderate cytological atypia (D2) exhibit AgNOR values in the range of well differentiated papillary carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)

The diagnostic accuracy and the clinical impact of routine ultrasonography performed by 4 surgeons, were prospectively studied in 366 unselected patients admitted for suspected acute appendicitis. Clinical and sonographic findings on admission were correlated with laparotomy findings, pathological outcome and clinical as well as follow-up data. The overall sensitivity, specificity and accuracy of the clinical diagnosis of acute appendicitis were 55.3%, 94.6% and 84.2% respectively (positive predictive value (PPV) 75.8%, negative predictive value (NPV) 87.3%). Ultrasound enabled visualization of the disease in 67 of 85 (prevalence 23.3%) patients with a histologically confirmed acute appendicitis; false positive results were recorded in 7 cases (sensitivity 78.8%, specificity 97.5%, accuracy 93.1%, PPV 90.5%, NPV 93.8%). Ultrasound was particularly useful in patients presenting with equivocal or highly unsuspective signs of acute appendicitis: of 38 patients with an acute appendicitis in this group ultrasonography enabled to make the diagnosis in 26. The combined approach of clinical evaluation and routine ultrasonography markedly improved the diagnostic accuracy (sensitivity 85.9%, specificity 96.4%, accuracy 94%) and substantially reduced the negative laparotomy rate (7.9%) in patients with suspected acute appendicitis. It is concluded, that ultrasonographic evaluation of the patient with suspected acute appendicitis performed by surgeons is of great assistance in surgical practice.

We report on the case of a 24 year old patient under medical treatment, because of sterility. The diagnosis of a rare sex cord tumour with annular tubules of the ovary before pregnancy, was followed by observation during this time and finally controlled after delivery by a sphenoidal excision from both ovaries. The influence of this disease on fertility and pregnancy and the influence of pregnancy on the tumour with its therapeutical consequences, will be discussed with reference to the current literature. The tumor is no reason for sterility. During pregnancy, an operative intervention may be inevitable. The histological status seems to be unchanged during pregnancy.

Although extracorporeal shock wave lithotripsy has become the standard therapy for urolithiasis, there are still indications for endoscopic stone treatment. Laser lithotripsy in association with flexible or semirigid "miniscopes" has become increasingly important for this form of therapy. So far the Nd: YAG and the pulsed dye laser have been used for laser lithotripsy in clinical applications. Since each system has its specific drawbacks, the new solid state alexandrite laser was developed to combine the advantages of the two existing systems. In order to evaluate the lithotriptic potential of the alexandrite laser, a stone model and eight human calculi were exposed to the laser in an experimental setting. Results with the stone model were comparable to those obtained with a reference Nd: YAG system. Adequate destruction was possible in all the human calculi except for one monohydrate stone. In the second part of the study, bladder and ureteric wall were exposed to the laser in ten female pigs, with different numbers of shock waves at various energy levels. While there was a relatively high incidence of early changes, late histological specimens 4-5 weeks after the exposure did not reveal any significant pathology. There was no stricture-formation in the ureter. Finally 12 patients were treated with ureteroscopical laser lithotripsy, and 8 of these were evaluatable. All were stone free without any additional lithotripsy and did not develop any secondary changes in the ureter. The alexandrite laser can therefore be expected to become a safe, reliable and cost-effective alternative for endoscopic stone treatment.

In a series of 59 consecutive renal cell carcinomas (pT3) cross sections were performed and grading was reevaluated on a cytological basis as described by Thoenes. Follow-up was at least 4 years. Only 20.3% of all tumors revealed monoform grading (92 resp. 93), while 79.9% consisted of more than one grading (G1+G2, G2+G3: 45.8%; G1+G2+G3: 33.9%). Prognosis in this series depended highly significantly (p less than 0.002) on the percentage of G3-area of the vital tumor (NED greater than 4 ys.: 11.4%; DOD less than 2 ys.: 51.6%). It is concluded that measuring different G-areas in cross section of renal cell carcinomas raise considerably prognostic value of histopathology.

Ultrasonic-guided fine-needle-biopsies of primary pancreatic tumours or liver metastasis were performed in 13 patients with neuroendocrine tumours of the gastrointestinal tract (5 carcinoids, 3 gastrinoma, 1 PPoma, 1 calcitoninoma, 1 insulinoma, and 2 non-functional tumours). Specimens obtained were examined on the light- and electronmicroscopic level. In all cases ultrastructural examination sufficiently revealed the correct diagnosis, due to the presence of cytoplasmic neuroendocrine granules within the tumour cells. Additionally performed immunocytochemical investigations at the ultrastructural level enabled the discrimination of gastrinomas, insulinomas, and PPomas. In contrast, light-microscopic examination was less sensitive for tumour classification. It is concluded that ultrastructural investigation of fine needle biopsies represents a valuable method to sufficiently discriminate neuroendocrine neoplasms.

Tropical diseases are rare in childhood in European countries, but tourism and an increasing number of immigrants from countries with endemic malaria may lead to a higher incidence. Our report is about a 24 year old german pregnant who was infected with malaria tropica in Togo during the last trimester of pregnancy. Twenty days after delivery by Caesarean section one of the geminies showed symptoms of florid infection: irritability, fever, haemolytic anaemia, hepato-splenomegaly, and thrombocytopenia. Both placenta and peripheral blood smear revealed plasmodium falciparum in the erythrocytes.