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Purpose Acute cellular rejection (ACR) is a frequent complication within the first year after lung transplantation (LTx) and an important risk factor for chronic lung allograft dysfunction (CLAD) and mortality. The revised classification for the standardization of nomenclature in the diagnosis of allograft rejection of 2007 was based on histologic findings using transbronchial forceps biopsy (TBFB). However, its diagnostic accuracy (DA) is limited due to the small sample size and crush artifacts. Transbronchial lung cryobiopsy (TBLC) is a technique for diagnosis of interstitial lung diseases with improved DA compared to TBFB, but with insufficient evidence in diagnosis and screening of ACR. This study aims to provide data on safety, diagnostic utility and impact on treatment decisions after TBLC in lung transplant recipients (LTRs). Methods Between December 2019 and June 2020, both TBFB and LBLC were obtained serially in LTRs during the same bronchoscopy session to detect ACR. According to our protocol, after 5 TBFB samples, 2 samples by TBLC were taken from different lung segments. The biopsies were scored according to the recent ISHLT criteria by a dedicated transplant pathologist, assessing TBFB and TBLC samples independently. The severity of bleeding we assessed with the Nashville Bleeding Scale (grade 1 - 4), and pneumothoraces were excluded with routine chest radiography. Results Totally, 25 consecutive procedures in 17 LTRs (13 males, median age 58) were performed either as routine surveillance bronchchoscopy (n = 19) or as clinically indicated (n = 6) using flexible bronchoscopy. Retrospective analysis of 125 TBFB and 50 TBLC samples was performed. ACR (A1 - A3) was detected in 6 cases (24%) by TBLC resulting in a change of immunosuppressive strategy, compared to 0% by TBFB. Non-diagnostic biopsy samples were noted in 3 cases (12%) of TBLC compared to 21 (84%) of TBFB. The biopsy procedure was complicated by moderate (grade 2) bleeding in 6 (24%) cases as a complication of TBCB, since it occurs immediately after this procedure. No pneumothorax was detected. Conclusion TBLC provided improved DA for diagnosis of ACR with an acceptable safety profile, leading to reclassification and a change of treatment strategy in 24% of the cases. Further prospective studies are needed to confirm these findings and recommend TBLC as gold standard to detect ACR.

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.

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.

Hintergrund Antikorper gegen PD-1 oder PD-L1 konnen beim nichtkleinzelligen Bronchialkarzinom (NSCLC) starke und dauerhafte antitumorale Immunreaktionen hervorrufen. Die immunhistochemische Untersuchung von PD-L1 (PD-L1-Immunhistochemie [IHC]) wird als pradiktiver Biomarker getestet; in klinischen Studien wurden mehrere IHC-Assays und Auswertekriterien parallel eingesetzt.

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.

Ki67 is a broadly used proliferation marker in surgical pathology with an obvious need for standardization to improve reproducibility of assessment. Here, we present results of the so far only existing round robin tests on Ki67, organized annually in Germany, Austria, and Switzerland from 2010 to 2015 with up to 160 participating laboratories (QuIP). In each quality assessment trial, eight probes from each breast cancer, neuroendocrine tumor, and malignant lymphoma were compiled on a tissue microarray (TMA). TMAs were stained in the participants’ laboratories with antibodies and procedures also applied in their daily routine. Participating pathologists were expected to assign Ki67 values to one of four different categories for each tumor type. All local stainings and evaluations were reassessed by the organizing panel and compared to a preset standard. On average, 95% of participants reached the benchmark of over 80% concordance rates with the Ki67 category pre-established by the panel. Automatization and type of antibody did not affect the success rate. Concordance rates differed between tumor entities being highest in each tumor type with either very high or very low labeling indices. Lower rates were seen for intermediate Ki67 levels. Staining quality improved during the observation period as did inter-observer concordance with 85% of participants achieving excellent agreement (kappa > 0.8) in the first year and over 95% in 2015. In conclusion, regular external quality assurance trials have been established as a tool to improve the reproducibility and reliability of the prognostic and predictive proliferation marker Ki67.

Mit etwa 3–5 % aller kolorektalen Karzinome (KRK) ist das Lynch-Syndrom das haufigste hereditare Pradispositions-Syndrom, bei dem neben kolorektalen Karzinomen gehauft Endometrium-, Magen-, Ovarial- und Urothelkarzinome, aber auch verschiedene andere Karzinome auftreten. Im klinischen Alltag wird das Lynch-Syndrom oft nicht erkannt und bei Verdacht auf das Vorliegen eines Lynch-Syndroms gibt es viele Unsicherheiten hinsichtlich des korrekten diagnostischen und therapeutischen Vorgehens. Daruber hinaus wird die Beratung in Bezug auf die verschiedenen Therapieoptionen und -empfehlungen – vor allem hinsichtlich einer erweiterten Resektion und der Chemotherapie – als schwierig angesehen. Anhand der Literatur werden Strategien zur Identifikation von Lynch-Syndrom-Patienten vorgestellt und kritisch diskutiert. Ziel ist es, einen interdisziplinar konsentierten Algorithmus zum diagnostischen Vorgehen bei Verdacht auf Lynch-Syndrom aufzuzeigen. Die sich daraus ergebenden Konsequenzen fur das operative Vorgehen bei Vorliegen eines Lynch-Syndrom-assoziierten KRK werden diskutiert. Der Verdacht auf ein Lynch-Syndrom kann durch die Erhebung der Familienanamnese und die Anwendung der revidierten Bethesda- und Amsterdam-II-Kriterien gestellt werden. Daran schliesen sich immunohistochemische Untersuchungen der Mismatch-Reparatur-Gene, eine BRAF-Untersuchung im Falle eines immunohistochemischen Expressionsverlustes von MLH1, ggf. zusatzlich eine Bestimmung der Mikrosatelliteninstabilitat (MSI) und zuletzt der Mutationsnachweis durch Gensequenzierung an. Die Moglichkeiten, Patienten mit Lynch-Syndrom durch pathologische Untersuchungen zu identifizieren, sind exzellent. Diese Untersuchungen sollten allerdings bereits praoperativ zum Zeitpunkt der endoskopischen Diagnosestellung eingeleitet werden, um so die Moglichkeit einer prophylaktisch erweiterten chirurgischen Resektion mit dem Patienten und ggf. eine leitliniengerechte, rein prophylaktische Chirurgie des Uterus und evtl. der Ovarien mit den (postmenopausalen) Patientinnen zusatzlich individuell zu besprechen. In der klinischen Praxis scheitert die Identifikation der Betroffenen allerdings haufig an Basisproblemen wie der Erhebung der Familienanamnese und einer nicht vorhandenen „Awareness“ hinsichtlich des Krankheitsbildes. Wenn daran gedacht wird, erfolgen die empfohlenen MSI-Untersuchungen postoperativ in dem Tumorresektat und Patienten werden in die Uberlegungen einer erweiterten prophylaktischen Chirurgie nicht mit einbezogen. Die klinische Erfahrung zeigt, dass die postoperative Analyse von Tumorresektaten hinsichtlich Mikrosatelliteninstabilitat – auch bei Erfullung der Bethesda-Kriterien – haufig nicht erfolgt und bei verdachtigem Befund die empfohlene humangenetische Beratung entweder nicht empfohlen oder nicht umgesetzt wird. Hierdurch wird die Chance einer lebenslangen jahrlichen Vorsorge der betroffenen Indexperson verpasst und durchschnittlich 3 Mutationstrager pro Familie verpassen die Moglichkeit, aktiv gegen ihr deutlich erhohtes Karzinomrisiko vorzugehen.

Background: While HER2 testing in breast cancer (BC) has been routine for over a decade, testing quality remains a challenge. Currently, HER2-positivity rate is the only recommended quality indicator. However, the large, observational, prospective NIU HER2 study in Germany quantified the impact of patient- and tumor-related characteristics such as histologic grade, hormone receptor (HR) status, histologic subtype, age, and nodal status on HER2-positivity, indicating that these factors need to be considered when evaluating HER2-positivity as a measure of testing quality (Rüschoff et al. Mod Pathol 2017). We now report the final analyses from the multicenter EPI HER2 BC study (ML29763, NCT02666261) in Germany where we compared NIU and EPI study data, and aimed to validate the NIU study model. Methods: Data from eligible patients with invasive BC were collected (HER2 test result; patient- and tumor-related factors) and variables influencing HER2-positivity identified and compared between studies. The NIU study model was validated and its predictive power determined using newly collected data from the EPI study, with cutoff and variable coefficients from the previous NIU analysis. Additional promising variables were explored, and their relative influence investigated, using multiple stepwise logistic regression. Results: In total, 14,729 (EPI) and 15,281 (NIU) BC samples were analyzed. Distributions of the main variables were comparable; overall HER2-positivity rates were 13.47% (EPI) and 14.24% (NIU). Fitting the NIU study model to EPI study data demonstrated that all five covariates from the NIU study analyses significantly affected HER2-positivity (p < 0.01); the influence for each covariate differed only slightly between studies (in EPI, histologic grade had most influence followed by histologic subtype, HR status, nodal status, and age). Prediction profiles were used to visualize the relationship between the model-predicted probability of HER2-positivity and the five identified covariates, which showed good comparability between studies. The receiver operating characteristics area under the curve (ROC AUC) of the NIU model used to predict HER2-positivity in the EPI study data was close to that of the model fitted to the NIU data, thus successfully validating the NIU model. To further improve the model, the categorical HR status was replaced by estrogen receptor (ER) and progesterone receptor (PgR) expression. Inclusion of ER and PgR as continuous variables improved the predictive strength of the model (ROC AUC = 0.74; sensitivity = 0.76; specificity = 0.63). Based on this improved model, PgR status had the highest influence on HER2-positivity, followed by histologic grade, histologic subtype, nodal status, ER status, and age. Conclusions: Results from our analyses confirm the statistically and clinically significant influence of patient- and tumor-related factors on HER2-positivity, and highlight the necessity to integrate these factors into the quality control assessment of HER2 testing. Implementation of this model in routine practice may assist in addressing issues with interlaboratory variation, and help to identify centers with HER2 testing problems more accurately. Citation Format: Rüschoff J, Lebeau A, Kreipe H, Sinn P, Schildhaus H-U, Decker T, Ammann J, Künzel C, Koch W, Untch M. Statistical modeling of influential variables affecting HER2-positivity in breast cancer: Final analyses from two large, multicenter, noninterventional studies in Germany [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-02-08.

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.

Mit Einfuhrung der Gesamtgenomsequenzierung konnte nachgewiesen werden, dass sich innerhalb eines Tumors eine erhebliche genetische Heterogenitat zeigt. Dieses Phanomen, welches das Vorkommen unterschiedlicher genetischer Zellklone in einem Tumor beschreibt, erschwert auch die HER2-Diagnostik. In diesem Ubersichtsartikel werden neue Erkenntnisse uber die Polysomie 17 und die genetische Tumorheterogenitat im Zusammenhang mit der HER2-Bestimmung des Mammakarzinoms dargestellt.

Although early stage malignant melanoma (MM) has a favorable prognosis five year survival rate is poor (

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.

Etwa ein Drittel der kolorektalen Karzinome (KRK) treten familiar gehauft auf, wobei etwa 5% einen monogenetischen Erbgang aufweisen. Diagnostisch hilfreich ist die Unterscheidung zwischen Erkrankungen mit und ohne Polyposis sowie die Berucksichtigung von Tumorhistologie und Tumorspektrum des jeweiligen Patienten. Etwa 1% der KRK lassen sich auf die familiare adenomatose Polyposis coli (FAP) mit rasenartig vermehrten (>100) Adenomen zuruckfuhren. Weitere 2–3% betreffen das nicht mit Polyposis assoziierte HNPCC- bzw. Lynch-Syndrom, fur welches als einzigem Darmkrebssyndrom ein molekularer Gewebetest zur Verfugung steht. Immunhistochemisch erfolgt zunachst die Prufung auf einen Verlust der Expression eines Mismatch-Reparatur-Gens, woran sich bei unsicherem oder negativem Ergebnis der Test auf Mikrosatelliteninstabilitat (MSI) anschliest. Im Unterschied zu den vorgenannten Syndromen wird die MYH-assoziierte Polyposis (MAP) rezessiv vererbt und weist nur masig erhohte Polypenzahlen (im Mittel 15–30) auf. Sie ist differenzialdiagnostisch von attenuierten Formen der FAP mit

Background: HER2 testing in breast cancer (BC), routine for >10 years, allows selection of patients (pts) for HER2-targeted therapy; however, testing quality remains a concern. While guidelines recommend assessment of HER2-positivity rates as a quality indicator, the influence of patient- or tumor-related factors on variability was unknown until we identified the effect (in order of influence) of histologic grade, hormone receptor (HR) status, histologic subtype, age, and nodal status in a large, multicenter, observational study in Germany (NIU HER2 study; Rüschoff et al., Mod Pathol 2017). Based on these variables and the statistical model developed, potential issues with HER2 testing quality in local practice may be identified. We now report interim analyses from a multicenter study in Germany (EPI HER2 BC study; NCT02666261), where data from the NIU and EPI studies were compared and the validity of the NIU study model assessed. Methods: Routine HER2 test results and patient- and tumor-related data were collected from eligible pts with BC. Factors influencing HER2-positivity rates in the EPI study were compared with those identified in the NIU study. The predictive power of the NIU study model, fitted to EPI data, was determined and assessments performed using the variable coefficients and cutoff resulting from the NIU study analysis. Attempts were also made to improve the model. Results: Analyses included 15281 (NIU) and 6019 (EPI) invasive BC samples. The distribution of relevant variables, including HER2-positivity rate (NIU: 14.4%; EPI: 13.5%), was comparable. When the NIU study model was fitted to EPI study data, all five covariates identified in the NIU analyses had a significant effect on HER2-positivity (p0.1407, the resulting sensitivity, specificity, and receiver operating characteristic (ROC) area under the curve (AUC) were 0.7032, 0.6622, and 0.7259, respectively. Thus, initial validation of the NIU study model with EPI data was successful. Semiquantitative estrogen and progesterone receptor expression data were available from EPI only; their inclusion as independent continuous, rather than categorical, variables improved the model (ROC AUC = 0.7533). Conclusions: The statistical modeling approach used to analyze data from the NIU study showed that patient- or tumor-related characteristics should be considered when assessing HER2 testing quality. Our present analysis validates and improves upon this statistical model and further highlights the need to assess HER2 testing quality in BC. Comparison of calculated vs actual positivity rates may help identify centers with potential HER2 testing quality issues. Citation Format: Rüschoff J, Lebeau A, Kreipe H, Gerharz CD, Sinn P, Schildhaus H-U, Tennstedt-Schenk C, Ammann JU, Künzel C, Koch W, Untch M. Variables influencing HER2-positivity in breast cancer: Assessment and validation of a statistical model based on two multicenter noninterventional studies in Germany [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-01.

Cystic tumor lesions of the pancreas are relatively uncommon. Advances in imaging and pathohistology, including immunohistochemistry, have led to the detection and classification of novel tumor entities. A promoting aspect is the extended indication profile in pancreatic surgery, in particular, because of lower perioperative morbidity and mortality. One of these classified cystic neoplasms of the pancreas is serous oligocystic adenoma (SOIA), a rare and benign tumor lesion. We report on a 41-year-old man with a cystic lesion within the pancreatic head. Therefore, he underwent pylorus-preserving cephal duodenopancreatectomy. Pathohistologic investigation revealed a SOIA. He had a medical history significant for subtotal colectomy because of a synchronous double colonic carcinoma. Both tumor tissue specimens had been characterized for a high level of microsatellite instability (MSI) and loss of hMLH1, as well as for a corresponding germ line mutation in hMLH1 gene, leading to the diagnosis of hereditary non-polyposis associated colon cancer (HNPCC). The case is remarkable since the SOIA revealed MSI and loss of hMLH1 protein in the tumor cells that has never been reported for this tumor type. In addition, there is a rare and extraordinary association between SOIA and HNPCC, which has never been published before, since SOIA, in this case, could have been developed in the setting of HNPCC syndrome.

There is a need for predictive biomarkers that identify non-small-cell lung cancer (NSCLC) patients most likely to respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. There are numerous potential candidates, although none has been proven in prospective clinical trials. The EGFR gene copy number evaluated by fluorescence in situ hybridisation (FISH) has been highlighted as one of the most effective markers for sensitivity to EGFR TKIs in large phase III, randomised placebo-controlled trials and has been used in clinical settings to assist physicians in defining the therapeutic regimen. The EGFR FISH assay has technical challenges and it is critical that detailed guidelines are provided to help clinical laboratories in performing and interpreting the test. Excellent assay reproducibility and portability rates among laboratories are crucial to guarantee that accurate clinical decisions can be made for patients with NSCLC. This article discusses the consensus outcomes of a global workshop convened to discuss key technical issues and standardise reading strategies for the EGFR FISH assay of NSCLC tumour tissue.

Die diagnostische Tumorpathologie sieht sich zunehmend mit einer neuen Herausforderung konfrontiert, die zunachst beim Mammakarzinom manifest geworden ist. Durch den Nachweis potenzieller Zielmolekule fur eine medikamentose Therapie, den sogenannten pradiktiven Markern, erlangt sie uber „Typing“ und „Grading“ hinaus eine gewachsene Informations- und Lenkungsfunktion fur die moderne Onkologie. Um dieser gerecht zu werden, wurden in Deutschland Ringversuche zur Uberprufung und Reproduzierbarkeit der am Tumorgewebe erfolgenden Bestimmungen der Steroidhormonrezeptoren und von Her-2 ins Leben gerufen, die seit 2002 jahrlich stattfanden und an denen jeweils bis zu 180 Institute teilnahmen. Mehr als 85% aller Teilnehmer erreichten gute Ergebnisse bei den in der taglichen Praxis vorherrschenden eindeutig positiven und negativen Fallen. Diskordante Bestimmungen waren eher bei den seltener vorkommenden niedrig-Steroidhormonrezeptor-exprimierenden Tumoren und den Her-2-Grenzfallen (2+) zu beobachten. Eine regelmasige Ringversuchteilnahme fuhrte gerade bei diesen problematischen Fallen zu deutlich verbesserten immunhistochemischen Farberesultaten. Die durch das Fach initiierte und sich selbst auferlegte Qualitatssicherung mit der erstmaligen Einrichtung von Ringversuchen wurde insbesondere durch die kooperierenden klinischen Facher als positive vertrauensbildende Masnahme begrust.

In a prospective study 404 unselected patients suspected of having acute appendicitis were examined by ultrasound, the results being compared with the initial clinical findings. Acute appendicitis was established in 27.2%, confirmed by histology. The overall accuracy of ultrasonography in relation to the diagnosis of appendicitis was 95.5%, 95.1% when positive, 95.7% when negative. An acutely inflamed appendix could not be demonstrated by ultrasound in 13 patients (sensitivity 88.2%), while in five there was a false-positive ultrasound result (specificity 98.3%). Complicated appendicitis with perforation occurred in 22 patients (20%): ultrasound sensitivity in this situation was 91%. Especially when the clinical picture was unclear (34.5% of all cases of appendicitis) a definitive diagnosis of acute appendicitis was made both earlier and more certainly by ultrasonography. Further-more, in many instances ultrasound was able to demonstrate other serious disease in the differential diagnosis from acute appendicitis. Negative laparotomy rate was lowered from 21.9% to 11.4% by taking into account ultrasonographic findings. Thus ultrasonography proved to be an important method as an imaging technique and in the differential diagnosis of acute appendicitis.

Besides typing and grading of breast cancer, Pathologists are involved in the determination of biomarkers, such as steroid hormone receptors and HER2, which are of utmost importance in adjuvant therapy. There have been concerns with regard to security and reproducibility of the biomarker assays done on tissue sections applying either immunohistochemistry or in-situ hybridisation. In order to assure the quality of these biomarker assays, a number of measures are required, among them external proficiency testing. Therefore, external quality assurance trials have been implemented in Germany. In the period of 2002-2007, 5 consecutive trials were conducted with up to 180 participating laboratories. Tissue microarrays with 20–24 different breast cancer samples including cell lines enabled that a huge number of pathologists were challenged with identical samples which provides the prerequisite for comparability. Because there is no legal duress to undergo external proficiency testing in histopathology, all laboratories that took part volunteered to do so. These innovative quality assurance trials (Qualitätsinitiative Pathologie, QuIP) will be continued in the future on an annual or bi-annual basis. Participation is recommended for pathology departments involved in the service for breast units. The organisational frame work of the trials is described here.

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.

Background and aims: Colorectal epithelial cells are prone to malignant transformation. Therefore, identification of differences in gene expression in the process from normal colonic crypts to adenomas with low grade dysplasia is essential for further insights into early tumorigenesis. To achieve this goal, a novel gene expression analysis strategy, screening for expressed transcripts in small histologically defined tissue samples, was performed. Methods: First, laser mediated microdissection was used to isolate normal and adenomatous crypts from colonic cryosections. Then, nested RNA arbitrarily primed polymerase chain reaction (RAP-PCR) for differential display was performed to screen mRNA populations and to generate hybridisation probes for cDNA expression arrays. After evaluation of cDNA expression arrays, differential expression was confirmed at the protein level by immunohistochemistry. Results: Evaluation of gene expression profiles of normal versus adenomatous colonic crypts of six different patients revealed, in general, dysregulation of up to 11% of all analysed genes (total number n=588): specifically, p21-rac1 was upregulated in four of six patients, mitogen activated protein kinase (MAPK) p38α in three of six patients, and interferon γ receptor in three of six patients. Conversely, FAST kinase was found to be downregulated in three of six patients, p53 in three of six patients, and thrombospondin 2 in three of six patients. Conclusions: For the first time, distinct gene expression profiles of dysplastic areas within colonic adenomas, using the combination of laser mediated microdissection with RAP-PCR and cDNA expression array, were shown. In these samples, upregulation of proliferation associated genes (ras-oncogene related p21-rac1 and MAPK p38α) as well as downregulation of apoptosis related genes (FAST kinase and p53) most likely reflects specific alterations in adenomas with low grade dysplasia. Based on upregulation of p21-rac1 and MAPK p38α, activation of the MAPK pathway appears to be an early event in colonic carcinogenesis.

Die Diagnostik der Barrett-Schleimhaut und ihrer verschiedenen Grade der intraepithelialen Neoplasie (fruher: Dysplasie) gilt in mehreren Aspekten als schwierig. Auf einer Konsensus-Konferenz der Arbeitsgemeinschaft "Gastroenterologische Pathologie der Deutschen Gesellschaft fur Pathologie" wurde daher versucht eine Standardisierung der histopathologischen Diagnostik in folgenden Punkten zu erarbeiten: Diagnostik und Terminologie der Barrett-Mukosa, Abgrenzung der Barrett-Mukosa von der intestinalen Metaplasie der Kardia, diagnostische Kriterien der intraepithelialen Neoplasie, Anzahl der zu entnehmenden Biopsien sowie Wertigkeit zusatzlicher immunhistologischer und/oder molekularbiologischer Methoden. Abschliesend wurde eine Empfehlung zur Einholung einer "zweiten Meinung" bei intraepithelialer Neoplasie formuliert.

Colour figures can be viewed onhttp://www.esacp.org/acp/2002/24‐4_5/heinmoeller.htm

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.

Beschrieben werden 3 Falle einer akuten segmentalen hamorrhagischen antibiotikaassoziierten Kolitis bei drei jungen Mannern im Alter von 30–33 Jahren, die wegen eines Infekts der oberen Luftwege, einer Tonsillitis oder im Rahmen einer HP-Eradikationstherapie oral mit Ampicillin oder Amoxicillin behandelt worden waren. Alle drei zeigten akut einsetzende krampfartige Bauchschmerzen und blutige Durchfalle, endoskopisch fand sich eine rechtsseitige segmentale hamorrhagische Kolitis, kein pathologischer Keimnachweis im Stuhl. Die histopathologische Untersuchung erbrachte den Befund eines Schleimhautodems mit fleckformigen oberflachlich betonten Einblutungen und eines schutteren mononuklearen Infiltrats der Lamina propria. Das Deckepithel war partiell desquamiert und wies intraepitheliale Ansammlungen von Erythrozyten auf. Bei allen Patienten kam es zu spontaner Restitution nach Absetzen der Medikation. Die diagnostischen Kriterien und deren Grenzen werden unter Berucksichtigung der vorliegenden Literatur diskutiert.

Das Leser-Trelat-Syndrom (LTS) ist charakterisiert durch das eruptive Auftreten multipler seborrhoischer Keratosen bei zugrunde liegender maligner Erkrankung. Wir stellen eine 73-jahrige Patientin mit dieser kutanen Paraneoplasie bei metastasierendem Adenokarzinom des Kolons vor. Die rasche Eruption einzelner seborrhoischer Keratosen und die begleitende ausgepragte entzundliche Komponente, die klinisch und histopathologisch nachweisbar waren, lassen sich als mogliches Fruhsymptom des LTS einstufen. Die Beachtung dieser entzundlichen Komponente als ein Fruhsymptom dieser Paraneoplasie kann zur fruhzeitigeren Diagnosestellung beitragen, insbesondere noch vor der zahlenmasigen Eruption der seborrhoischen Keratosen.

In 1971 Keutelet al. described a new syndrome in two siblings presenting with peripheral pulmonary stenoses, brachytelephalangism, neural hearing loss and abnormal cartilage calcification. Recent investigations provided evidence that mutations in the gene encoding the human matrix GLA protein cause Keutel syndrome. With these new insights in the disease the symptomatology of Keutel syndrome was reassessed. The follow-up of the two siblings was studied by clinical andpost mortemexamination.As a new feature of Keutel syndrome tracheobronchial stenosis and concentric calcification of pulmonary, coronary, hepatic, renal, meningeal and cerebral arteries were described.Complementary to the results in molecular genetics the symptomatology of Keutel syndrome could be revised by clinical andpost mortemexamination.

It is postulated that in addition to nerve-root compression, an inflammatory stimulus of the herniated lumbar disc is responsible for sciatic pain and radiculopathy. The clinical relevance of the histologically described inflammatory infiltrates is, however, not clearly defined [8, 22]. It was the aim of this study to assess the clinical relevance of inflammatory cells in herniated lumbar disc specimens. The presence of inflammatory cells was examined immunohistochemically in routinely processed resection specimens of the lumbar disc. The histological results were compared to prospectively obtained clinical data. Disc specimens of 179 patients who underwent surgery for lumbar disc herniation were studied immunohistologically. Preoperatively each patient received a visual analogue scale for classification of the pain level and general clinical data were recorded prospectively. Varying amounts of inflammatory cells could be demonstrated in the resected disc tissue. In the statistical workup no statistically significant correlation between the histological evidence of macrophage infiltrates and the pain grading scale or the clinical data could be found. In our study there is no statistically significant correlation between macrophage infiltrates in herniated lumbar disc specimen and the obtained clinical data.

BACKGROUND AND STUDY AIMS Endoscopic diagnosis of dysplastic lesions and early cancers in chronic ulcerative colitis is a major problem. Identification of suspicious lesions is influenced by the macroscopic appearance of the colon, but also by the endoscopist's experience. In this study we evaluated the identification of dysplastic lesions by the naked eye in an animal model of colitis after 5-aminoaevulinic acid-induced photosensitization. METHODS 80 male Wistar rats were examined. Acute and chronic colitis were induced by oral application of 5% dextrane sulfate sodium (DSS) in 1-7 cycles (1 cycle = seven days DSS and 10 days water). For sensitisation 5-aminolaevulinic acid (5-ALA) at different doses (0, 10, 25, 50, 75, 100, and 200 mg/kg) was used. The colonic fluorescence was examined under a blue light (390-436 nm) for excitation. Histological findings of fluorescent and non-fluorescent biopsy specimens were recorded. RESULTS Using 100 mg/kg 5-ALA intravenously for photosensitization, all dysplastic lesions (5/5) showed fluorescence (sensitivity 100%). However, at this concentration of 5-ALA, 60 false positive lesions were found out of 76 specimens taken from lesions that were not dysplastic--only 16 specimens of non-dysplastic lesions did not fluoresce (specificity 21%). Using 75 and 50 mg/kg 5-ALA intravenously sensitivity decreased to 92% (36/39) and 42% (5/12), respectively, while specificity increased to 35% (29/82) and 62% (45/73). Using 50 mg/kg 5-ALA intravenously, fluorescence-positive biopsy specimens showed inflammation of the colon in 31% whereas only 12% contained normal mucosa (p < 0.01). The distribution of fluorescence-positive biopsy specimens with histologically confirmed inflammation was similar for different grades of inflammation after sensitisation with 75 and 100 mg/kg 5-ALA, whereas with 50 mg/kg 5-ALA fluorescence-positive biopsy specimens contained significantly (p < 0.05) more moderate, massive, or ulcerative inflammation (79%) than mild inflammation (21%). CONCLUSION 5-ALA induced photosensitization gave a high sensitivity, but low specificity in identifying dysplastic lesions in DSS-induced colitis in rats. In this animal model inflammation is a major factor in disturbing the fluorescence localisation of dysplasia after sensitisation with 5-ALA.

Ret/PTC oncogene has been described with a frequency of 2.5-30% in papillary thyroid carcinomas. We examined the expression of ret/PTC in 99 German papillary thyroid carcinomas, including two recently described new variants of ret/PTC3 and identified eight ret/PTC-positive tumours (8%) but none with the new variants. Images Figure 2 Figure 3

The estrogen receptor alpha (ERα) is the central transcriptional regulator of ductal mammary epithelial lineage specification and is an important prognostic marker in human breast cancer. Although antiestrogen therapies are initially highly effective at treating ERα-positive tumors, a large number of tumors progress to a refractory, more poorly differentiated phenotype accompanied by reduced survival. A better understanding of the molecular mechanisms involved in the progression from estrogen-dependent to hormone-resistant breast cancer may uncover new targets for treatment and the discovery of new predictive markers. Recent studies have uncovered an important role for transcriptional elongation and chromatin modifications in controlling ERα activity and estrogen responsiveness. The human Suppressor of Ty Homologue-6 (SUPT6H) is a histone chaperone that links transcriptional elongation to changes in chromatin structure. We show that SUPT6H is required for estrogen-regulated transcription and the maintenance of chromatin structure in breast cancer cells, possibly in part through interaction with RNF40 and regulation of histone H2B monoubiquitination (H2Bub1). Moreover, we demonstrate that SUPT6H protein levels decrease with malignancy in breast cancer. Consistently, SUPT6H, similar to H2Bub1, is required for cellular differentiation and suppression of the repressive histone mark H3K27me3 on lineage-specific genes. Together, these data identify SUPT6H as a new epigenetic regulator of ERα activity and cellular differentiation.

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.

Das Kapitel behandelt die nichtneoplastischen osophagealen Erkrankungen und den Barrett-Osophagus. Der Schwerpunkt liegt auf den entzundlichen Veranderungen. Diese werden einschlieslich der Varianten und Vorstufen erortert, wobei, wo immer relevant, die Immunhistochemie, der genetische Hintergrund und die Differentialdiagnose zur Sprache kommen. Weitere wesentliche Themen sind die Entwicklung mit Missbildungen und die funktionellen Storungen. Die beschriebenen Erkrankungen sind mittels zahlreicher histologischer Bilder ausfuhrlich dokumentiert und durch endoskopische Bilder sowie Schemazeichnungen erganzt.

In the present study we investigated the susceptibility of high passages of the rat glial transplantation tumour G-XIII to chemotherapy using nitrosourea compounds. We observed a significant increase in lifespan (ILS) of animals treated with BCNU (37%, p0.01) and CCNU (27%, p0.01). There were no difference in the efficiency between these two substances. Using a semi-quantitative score system no histopathological changes were observed which were associated with the response to therapy. The only predicative parameter in the present study was the quantitative DNA distribution pattern. There was a close correlation between treatment and the occurrence of unimodal DNA distribution patterns indicating clonal regrowth of recurrent tumours. Moreover, we also observed a correlation of the DNA distribution pattern of recurrent tumours with the result of experimental chemotherapy. Survival times of animals suffering from tumours containing unimodal DNA histogram was significantly longer than survival times of rats with multimodal DNA distribution, i.e. bimodal or broad DNA histograms. A unimodal, near-diploid stem line was only present in treated animals suggesting that these clones are more resistant against therapy using nitrosourea compounds. Our data indicate DNA cytophotometry as comprehensive tool for the monitoring of therapy response and the design of experimental chemotherapy using rat glial tumours.

According to WHO (2010) adenocarcinomas of the esophagogastric junction (GEJ) are defined as tumors that cross the most proximal extent of the gastric folds regardless of where the bulk of the tumor lies. In addition, these neoplasms are now classified as esophageal cancers by UICC (2010). Recent studies, however, revealed two types of carcinogenesis in the distal oesophagus and at the GEJ, one of intestinal type (about 80 %) and the other of gastric type (about 20 %). These are characterized by marked differences in morphology, tumor stage at diagnosis, and prognosis. Furthermore, both cancer types show different targetable biomarker expression profiles such as Her2 in the intestinal and EGFR in the non-intestinal pathway indicating new therapy options. Due to the fact that carcinomas of the intestinal pathway were typically associated with Barrett's mucosa which was not the case in the non-intestinal-type tumors, this challenges the paradigm "no goblets no Barrett's". Moreover, even the cancer risk of intestinal-type metaplasia has seriously been questioned by a Danish population-based study where Barrett's mucosa turned out to be only a weak indicator of esophageal and GEJ cancer (1 case in 860 patients years). Thus, two biologically different types of cancer arise at the GEJ-esophageal and gastric type that open distinctive targeted treatment options and also question our current concept about the diagnostics of potential precursor lesions as well as the associated screening and surveillance strategy.