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Drug-induced injury to the gastrointestinal tract has gained growing significance in recent years, and the list of causative medications keeps expanding. Herein, we present the case of a 45-year-old female with major depressive disorder treated with two serotonin and norepinephrine reuptake inhibitors (venlafaxine and duloxetine). She developed nausea and weight loss. Endoscopic evaluation of the upper and lower gastrointestinal tract rendered grossly normal mucosa in all segments. Histological examination, however, revealed lymphocytic esophagitis, collagenous gastritis, celiac disease-like intraepithelial lymphocytosis of the duodenum, and incomplete collagenous colitis. Gastrointestinal side effects of psychoactive drugs are largely underrecognized. This is the first report of a mixed lymphocytic and collagenous pattern of injury affecting esophagus, stomach, duodenum, and colon triggered by combined treatment with venlafaxine and duloxetine. In patients with unclear symptoms, obtaining biopsies from mucosa that is normal upon endoscopic inspection may render decisive clues for clinical management.

Im Gastrointestinaltrakt wird ektopes (heterotopes) – an ungewohnlicher Stelle vorkommendes – Gewebe relativ haufig nachgewiesen. Dies ist zuruckzufuhren auf die komplexe gastrointestinale Organogenese, vor allem aber auf den relativ einfachen Nachweis durch endoskopisch-bioptische Untersuchungen. Biopsien oder Resektionen erfolgen dabei unter dem Verdacht des Vorliegens von Tumoren oder Entzundungsprozessen. Ektopes beziehungsweise heterotopes Gewebe kann im Verlauf des gesamten Gastrointestinaltraktes vorkommen. Zu den haufigsten Ektopien gehoren Ektopien der Magenschleimhaut und Ektopien von Pankreasgewebe. Wesentlich seltener sind ektope Brunner-Drusen oder ektope Speicheldrusen. In Einzelfallen finden sich auch Ektopien von Geweben anderer Organsysteme, wie z. B. Talgdrusen sowie Prostata- und Schilddrusengewebe. Am haufigsten betroffen von Ektopien sind der Dunndarm und hier vor allem das Duodenum, der Osophagus und der Magen. Im Dickdarm sind Ektopien ausschlieslich im Rektum dokumentiert. Ektopien gehen nur selten mit Symptomen oder Komplikationen einher und verursachen in der Regel auch keine differenzialdiagnostischen Probleme. Je nach Lage, Grose und Art des ektopen Gewebes konnen jedoch auch Komplikationen auftreten. Dazu gehoren Entzundungen, Ulzerationen, Perforationen, Obstruktionen, Invaginationen oder schwere Blutungen. Sehr selten konnen sich auf dem Boden von Ektopien auch Tumoren entwickeln. Von ektoper Magenschleimhaut konnen Pylorusdrusenadenome des Dunn- und selten auch des Dickdarmes und Adenokarzinome des Osophagus ausgehen. Ektopes Pankreasgewebe kann Ausgangspunkt von duktalen Pankreaskarzinomen, Azinuszellkarzinomen, intraduktalen papillaren Neoplasien und auch endokrinen Tumoren sein. Die vorliegende Arbeit fasst klinisch-topografisch ausgerichtet unseren aktuellen Wissensstand uber Ektopien des Gastrointestinaltraktes zusammen.

Die Mehrzahl der Magen- und Pankreaskarzinome tritt sporadisch auf. Eine familiare Haufung wird bei etwa 10 % der Falle beobachtet. Hereditare Karzinome sind nur fur 1–3 % der Magenkrebsfalle verantwortlich. Zwei Syndrome wurden beschrieben: das hereditare diffuse Magenkarzinom (HDGC) und das Magenkarzinom bei proximaler Polypose (GAPPS). Ein erhohtes Risiko fur die Entwicklung von Magen- oder Pankreaskrebs besteht auch bei anderen erblichen Syndromen, so bei Patienten mit erblichem Brust- und Ovarialkarzinomsyndrom (HBOC), Li-Fraumeni-Syndrom, Lynch-Syndrom, familiarer adenomatoser Polypose (FAP) und auch bei hamartomatosen Polyposesyndromen, speziell bei juveniler Polypose und Peutz-Jeghers-Polypose. Auch Patienten mit hereditarer Pankreatitis weisen ein erhohtes Krebsrisiko auf (40–55 %).

Aims Verrucous carcinoma (VC) is a variant of well differentiated squamous cell carcinoma and is in the anal region regarded as synonymous with giant condyloma (Buschke-Lowenstein tumor) (BLT). Etiology, diagnostic criteria and clinical behavior of both lesions are controversial. Recent studies suggest that VC at other sites is not associated with human papillomaviruses (HPV). We hypothesized that anal VC is also not related to HPV, while BLT is a HPV-induced lesion. Methods and results Ten cases of VC and 4 cases of BLT were included. Several techniques were used for HPV detection: in situ hybridization for HPV6, 11, 16 and 18, six different PCR protocols for detection of at least 89 HPV types from Alpha-, Beta-, Gamma- and Mu-PV genera, and in situ hybridization for high risk HPV E6/E7 mRNA. p16 immunohistochemistry and morphometric analysis were also performed. Alpha-, Gamma- and Mu-PVs were not found in any case of VC, while HPV6 was detected in all cases of BLT. p16 overexpression was not present in any of the lesions. Among microscopic features, only the absence of koilocytosis and enlarged spinous cells seem to be useful to distinguish VC from BLT. Conclusions Our results suggest that anal VC, similarly to VC at other sites, is not associated with HPV infection and must be distinguished from BLT which is associated with low risk HPV. Only with well-set diagnostic criteria will it be possible to ascertain clinical behavior and optimal treatment for both lesions. This article is protected by copyright. All rights reserved.

Summary In April 2020 during the COVID‐19 pandemic, a 41‐year‐old female presented to the emergency department with recurrent vomiting and abdominal pain that had been ongoing on for two days and additional hematemesis for several hours. The past medical history was unremarkable, except for bariatric gastric bypass surgery performed in 2016. During detailed inquiry the patient reported, she had intentionally taken 10 ml of Ethanol‐containing hand disinfectant orally per diem for a period of over three weeks in fear of being infected with COVID‐19. The product had been obtained from a regular pharmacy and had been produced locally according to WHO standards for hand disinfectan. Upper gastrointestinal endoscopy was performed and showed superficial mucosal damage in the oesophagus (Figure 1A), slightly increased mucosal redness in the stomach and severely injured small bowel mucosa with extensive fibrinous exudates (Figure 2A).

Tumor grade is a traditional prognostic parameter in colorectal cancer. Remarkably, however, there is still no generally accepted consensus how to perform tumor grading. In this study, we systematically compared the prognostic value of traditional grading based upon histological features, that is, gland formation alone with grading based upon both histological and cytological features, such as nuclear pleomorphism and anaplasia (“alternative grade”). Three hundred eighty-one tumors of randomly selected patients were retrospectively reviewed. Traditional and alternative tumor grades were related to various clinicopathological features and to progression-free and cancer-specific survival applying both univariate and multivariate testing. Traditional and alternative tumor grades were significantly associated with T and N classification, tumor size, lymphovascular invasion, as well as both progression-free and cancer-specific survival. In Cox’s proportional hazards regression models, the alternative grade was superior to the traditional tumor grade and was significantly associated with progression-free survival (hazard ratio 1.57, 95 % confidence interval 1.04–2.35; p = 0.031), independent of patients’ age and gender, T and N classification, and lymphovascular invasion. Likewise, patients with tumors with high alternative grade were more likely to die of disease (hazard ratio 1.30, 95 % confidence interval 0.85–2.00), but this difference was not statistically significant (p = 0.22). Tumor grade based upon both histological and cytological features was superior to grade based upon histological features alone and proved to be an independent prognostic parameter. Thus, tumor grade based upon both histological and cytological features may help to improve prognostic stratification and may thereby affect clinical decision-making and patient management.

Aims Medullary carcinoma of the large bowel occurs mainly right-sided in elderly females. The tumour is almost invariably microsatellite instable and has been associated with favourable outcome. Our study aimed to present three cases of medullary carcinoma originating from the small bowel. Methods and results We describe three cases of small bowel medullary carcinoma. Two patients had coeliac disease, diagnosed at the ages of 79 and 71 years, respectively. The tumours showed the characteristic syncytial growth pattern with marked intratumoral lymphocytic inflammation. Loss of MutL homologue 1 (MLH1) [and postmeiotic segregation increased 2 (S. cerevisiae) PMS2] expression was observed in all cases, consistent with high-level microsatellite instability. All tumours were negative for Epstein–Barr virus. Follow-up information was available for one patient, who is recurrence-free 6 years after resection. Discussion Medullary carcinoma of the small bowel is exceedingly rare. Our data and a review of the literature suggest that this tumour type is characteristic for coeliac disease and may be the histological type underlying small bowel cancers with high-level microsatellite instability in patients with coeliac disease.

In colorectal cancer, the presence and extent of eosinophil granulocyte infiltration may render important prognostic information. However, it remains unclear whether an increasing number of eosinophils might simply be linked to the overall inflammatory cell reaction or represent a self-contained, antitumoral mechanism that needs to be documented and promoted therapeutically. Peri- and intratumoral eosinophil counts were retrospectively assessed in 381 primary colorectal cancers from randomly selected patients. Tumors were diagnosed in American Joint Committee on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) stage I in 21%, stage II in 32%, stage III in 33%, and stage IV in 14%. Presence and extent of eosinophils was related to various histopathological parameters as well as patients' outcome. Overall, peri- and intratumoral eosinophils were observed in 86 and 75% cancer specimens. The peritumoral eosinophil count correlated strongly with the intratumoral eosinophil count (R=0.69; P

Microscopic colitis is a chronic inflammatory bowel disease characterized by chronic nonbloody diarrhea and specific histopathology features. Active disease, defined as 3 or more stools or 1 or more watery stools per day, significantly reduces quality of life. Epidemiologic studies have found the incidence and prevalence of microscopic colitis to be comparable with those of Crohn's disease and ulcerative colitis. Nevertheless, microscopic colitis is still under-recognized in clinical practice-most health care workers know little about its etiology and pathophysiology. Furthermore, there are many challenges to the diagnosis and treatment of patients. We review the epidemiologic and clinical features of this disorder and discuss its pathogenesis. We also outline the criteria for histopathologic evaluation of microscopic colitis, recently published by the European Consensus on Inflammatory Bowel Disease, and discuss a treatment algorithm created by the European Microscopic Colitis Group. Treatment options for patients with budesonide-refractory disease are discussed.

Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations of genetic events and epigenetic alterations. Chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) have been identified as the three major molecular characteristics, which interact with other significant mutations, such as mutations in the KRAS and BRAF genes. High-level MSI (MSI-H) is of eminent clinical importance. It is the seminal molecular feature for the identification of individuals with Lynch syndrome, but it may also occur in sporadic cancers with CIMP phenotype, which arise from serrated precursor lesions. MSI-H status is a marker of favorable prognosis and may be used for outcome prediction, that is, molecular grading. Among others, mucinous and medullary histology, signet-ring cell differentiation, and a marked anti-tumoral immune response are histological features suggesting MSI. Universal tumor testing is recommended and may be performed using immunohistochemistry (mismatch repair protein expression) or molecular analysis, as has recently been recommended by an international task force. In this review, we consider in detail the molecular pathogenesis of colorectal cancer, focusing on the diagnosis of MSI in both hereditary and sporadic tumors.

Objective Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA. Design Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated. Results Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61. Conclusions Although ‘substantial’ to ‘almost perfect’ ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument.

The pathological examination of early colorectal cancer specimens, in particular ‘malignant polyps', provides important prognostic information. The depth of invasion into the submucosal layer assessed according to the Haggitt (for pedunculated lesions) or Kikuchi (for nonpolypoid lesions) classification systems or by direct measurement has been associated with the risk of lymph node metastasis. Angioinvasion, in particular lymphatic invasion, budding, tumor differentiation or grade, and resection margin status have been identified as further risk factors. The combination of these parameters allows the stratification of affected individuals into low- and high-risk categories, which is pivotal for clinical management. For low-risk cancers, defined as a completely excised Haggitt level 1-3/Kikuchi sm1 tumor with no evidence of poor differentiation or angioinvasion, local excision is generally regarded as adequate treatment. Oncological surgical resection is, however, indicated for high-risk cancers, which show at least one of the following features: Haggitt level 4/Kikuchi sm3 invasion, the presence of lymphatic (or vascular) invasion, poor differentiation, or positive resection margin. The inclusion of molecular markers such as tumor suppressor genes and their products, markers involved in tumor vascularization, and markers related to tumor cell adhesion and invasion may help to refine risk stratification, but data on molecular markers are still limited in this regard.

Although often viewed as a single disease, colorectal cancer more accurately represents a family of diseases with different precursor lesions. Conventional (tubular, tubulovillous and villous) adenomas are the most common neoplastic lesions occurring in the large intestine. They have adenomatous polyposis coli (APC) mutations and arise from dysplastic aberrant crypt foci, initially as polyclonal lesions. In sporadic tumours, neoplastic progression follows the traditional pathway (chromosomal instability pathway), resulting in CpG island methylator phenotype (CIMP)-negative, microsatellite-stable (MSS), BRAF and KRAS wild-type cancers. Germline mutations in the APC gene lead to familial adenomatous polyposis. Conventional adenomas are also the precursors of Lynch syndrome-associated microsatellite-instable (MSI-high) cancers. Sessile serrated adenoma/polyp (SSA/P) is the principal precursor lesion of the serrated pathway, in which BRAF mutation can lead to colorectal cancer with MSI-high CIMP-high or MSS CIMP-high phenotype. SSA/Ps have been associated with synchronous and metachronous invasive adenocarcinomas as well as so-called interval carcinomas. Serrated polyposis is rare but most likely underdiagnosed. Affected individuals bear an increased but unspecified risk for the development of colorectal cancer; close endoscopic surveillance is warranted. Traditional serrated adenomas (TSAs) are much less common than the other serrated lesions. Cancers originating from TSAs may show KRAS mutation with a CIMP-high MSS phenotype.

In patients with gastroesophageal reflux disease (GERD), histology is generally believed to be a tool of limited diagnostic value. Our study aimed to assess the prevalence of microscopic esophageal lesions as defined by the Esohisto consensus guidelines, which have proven high interobserver agreement in previous studies. In the prospective Central European multicenter histoGERD trial, we recruited 1071 individuals (576 females and 495 males; median age, 53 years; range, 15-93 years) undergoing gastroscopy for nonselected reasons. Biopsy material was systematically sampled from above and below the gastroesophageal junction. Overall, histologic diagnosis of mild and severe esophagitis was made in 423 (39.5%) and 296 (27.6%) individuals, respectively, whereas the squamous mucosa of 352 individuals (32.9%) was normal upon histology or showed only insignificant findings. Proliferative changes of the squamous epithelium, in particular basal cell layer hyperplasia, papillary elongation, and intercellular space dilation, were more common than inflammatory cell infiltration. The presence of microscopic esophagitis was associated with male sex (P = .009), patients' symptoms (P = .003), history of proton pump inhibitor intake (P.001), and the endoscopic diagnosis of esophagitis (P.001). Notably, among the 450 patients with no endoscopic signs of esophagitis (Los Angeles Category N), 41.8% and 17.1% were identified with mild and severe (microscopic) esophagitis, respectively, indicating higher sensitivity of histologic diagnosis. In conclusion, our data illustrate the value of histology in the workup of patients with reflux disease. We suggest that biopsies should routinely be obtained when patients undergo upper gastrointestinal endoscopy for evaluation of GERD and may particularly be beneficial in patients with nonerosive reflux disease.

Pancreatic acinar cells are a well-recognized finding at the gastroesophageal junction, but their histogenesis and biological significance are unclear. From the prospective Central European multicenter histoGERD trial, we recruited 1,071 individuals undergoing gastroscopy for various non-selected reasons. Biopsy material was systematically sampled from the gastroesophageal junction and from the stomach. The study aimed to assess the prevalence of pancreatic acinar cells and to relate their presence to various histologic and clinical features. Overall, pancreatic acinar cells were observed in 184 (17.2 %) participants. Individuals diagnosed with pancreatic acinar cells were slightly younger than those without (median 50 vs. 53 years; p = 0.009). There was no association with patients’ symptoms and/or complaints or with an endoscopic diagnosis of esophagitis or Barrett’s esophagus. Regarding histology, pancreatic acinar cells were not associated with features of the squamous epithelium indicating reflux disease, such as basal cell hyperplasia, papillary elongation, dilation of intercellular spaces, and inflammatory cell number, but were associated with the presence of cardiac mucosa (p

Objective The natural history of urothelial carcinoma arising at the uretero-enteric junction (UEJ) is poorly defined, and the data guiding clinical management of these patients is limited. Therefore, we evaluated oncologic outcomes of patients treated for urothelial carcinoma at the UEJ. Methods Utilizing a multi-institutional database of patients treated with radical nephroureterectomy (RNU), we assessed the clinicopathologic parameters and oncologic outcomes of UEJ tumors compared with other upper tract urothelial carcinomas (UTUC). Survival analyses were performed to determine independent predictors of disease recurrence and cancer-specific mortality after RNU. Results The study included 1,363 patients, 921 men and 442 women with 36 months median follow-up after RNU. Compared with UTUC in the kidney or ureter, UEJ tumors ( n = 22) were more likely to demonstrate features of advanced disease, which were proved to be independent predictors of disease recurrence and cancer-specific mortality after RNU. The 5 year disease-free survival (DFS) and cancer-specific survival (CSS) rates were 25% and 39% in those with UEJ tumors vs. 69% and 73% in those with UTUC in the kidney or ureter ( P = 0.001 and P = 0.008, respectively). Conclusions UEJ tumors harbor features of locally advanced disease associated with high risk of systemic recurrence and death from cancer after RNU. Our findings suggest the need for integration of systemic therapy into the management paradigm of these patients.

Kongenitale zystische Duplikaturen des Osophagus entstehen wahrend der Embryonalperiode. Wir berichten uber eine 33-jahrige Patientin mit langjahriger, zuletzt zunehmender Dysphagie, die wegen einer zystischen Duplikatur operiert wurde. Fur die Diagnose sind die folgenden drei Kriterien masgeblich: Die Lasion besitzt eine unmittelbare Verbindung zum Osophagus. Die Wand der Zyste muss glatte Muskulatur enthalten und die Lichtung von Plattenepithel und/oder respiratorischem Flimmerepithel ausgekleidet sein. Die Differenzialdiagnosen umfassen Divertikel, bronchogene Zysten, aber auch zystische Neoplasien. Die zystische Duplikatur des Osophagus ist eine seltene Differenzialdiagnose bei Patienten mit Dysphagie im Erwachsenenalter.

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M (2012) Histopathology Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy Aims: Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice. Methods and results: A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1-3 cytokeratin-immunostained, whole-slide digital scans from 50 pT1-pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants' experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding-positive cases with all methods compared to H&E-stained slides, but did not influence agreement levels. Conclusions: An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.

In colorectal cancer, the morphology of the invasive tumor margin may reflect aggressiveness of tumor growth, thus providing important prognostic information. The tumor growth pattern according to Jass and the extent of tumor budding were analyzed in patients with American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) stage II disease.Tumors of 120 randomly selected patients with AJCC/UICC stage II disease were retrospectively reviewed for tumor growth pattern (expanding vs. infiltrating) and the extent of tumor budding, with high-grade budding reflecting presence of 10 or more budding foci scattered at the invasive tumor margin. Progression-free and cancer-specific survivals were determined by the Kaplan-Meier method. For multivariable analysis, Cox's proportional hazards regression models were performed.The infiltrating growth pattern was significantly associated with histological subtype and lymphovascular invasion, while high-grade budding was significantly associated with tumor grade and lymphovascular invasion. High-grade budding, but not the infiltrating growth pattern, was significantly associated with outcome in univariable analysis. Cox's proportional hazards regression models proved tumor budding to be an independent predictor of disease progression (hazard ratio 3.91, 95 % confidence interval 1.3-11.77; P = 0.02) and cancer-related death (hazard ratio 5.90, 95 % confidence interval 1.62-21.51; P = 0.007). The combination of infiltrating growth pattern and high-grade budding did not have a stronger prognostic significance than tumor budding alone.Tumor budding independently predicted patient outcome in patients with AJCC/UICC stage II colorectal cancer and may therefore be used for accurate prognostication, patient counseling, and design of clinical trials by using integrated multimodal therapy.

Membranous expression of the sodium iodide symporter (NIS) is a prerequisite for iodide uptake in thyrocytes. Previous studies reported heterogeneous results on the relative frequency of staining in various pathological conditions of the thyroid. The present study aimed at determining membranous staining by using confocal laser microscopy in benign and malignant thyroid diseases, complemented in a subgroup of patients with recurrent or metastatic disease with functional findings of radioiodine uptake (RIU).There were 380 malignant thyroid tumors (145 papillary, 51 follicular, 87 Hurthle cell, and 97 undifferentiated thyroid carcinomas [UTC]), 115 benign adenomas, 62 diffuse goiters, 89 inflammatory conditions (Graves', Hashimoto, Thyroiditis deQuervain, and lymphocytic thyroiditis), and 179 normal tissues (NT, fetal, and adult). These were subjected to NIS (two different antibodies) and thyroglobulin (TG) staining and evaluated by confocal microscopy.In a subgroup of 50 samples from patients with recurrent or metastatic disease, NIS staining was correlated with the RIU. As compared with NT, Graves' patients had significantly higher positive NIS membrane staining (97% vs. 69%) whereas patients with Hashimoto, lymphocytic thyroiditis but also benign adenomas scored lower than NT (56.7% and 55.8% vs. 69%). Depending on their differentiation NIS staining was significantly lower in thyroid carcinomas in parallel with TG staining with only 1/97 UTCs being positive. RIU was more frequently detectable than NIS staining.Confocal staining strictly evaluating only membranous expression of NIS has not used on a large scale before this study. We confirm the loss of membranous NIS in benign but more prominently in malignant thyroid tumors. NIS staining of diagnostic tissues cannot be used to predict RIU.

Whole slide imaging (WSI) has been used in conjunction with virtual microscopy (VM) for training or proficiency testing purposes, multicentre research, remote frozen section diagnosis and to seek specialist second opinion in a number of organ systems. The feasibility of using WSI/VM for routine surgical pathology reporting has also been explored. In this review, we discuss the utility and limitations of WSI/VM technology in the histological assessment of specimens from the prostate. Features of WSI/VM that are particularly well suited to assessment of prostate pathology include the ability to examine images at different magnifications as well as to view histology and immunohistochemistry side-by-side on the screen. Use of WSI/VM would also solve the difficulty in obtaining multiple identical copies of small lesions in prostate biopsies for teaching and proficiency testing. It would also permit annotation of the virtual slides, and has been used in a study of inter-observer variation of Gleason grading to facilitate precise identification of the foci on which grading decisions had been based. However, the large number of sections examined from each set of prostate biopsies would greatly increase time required for scanning as well as the size of the digital file, and would also be an issue if digital archiving of prostate biopsies is contemplated. Z-scanning of glass slides, a process that increases scanning time and file size would be required to permit focusing a virtual slide up and down to assess subtle nuclear features such as nucleolar prominence. The common use of large blocks to process prostatectomy specimens would also be an issue, as few currently available scanners can scan such blocks. A major component of proficiency testing of prostate biopsy assessment involves screening of the cores to detect small atypical foci. However, screening virtual slides of wavy fragmented prostate cores using a computer mouse aided by an overview image is very different from screening glass slides using a microscope stage. Hence, it may be more appropriate in this setting to mark the lesional area and focus only on the interpretation component of competency testing. Other issues limiting the use of digital pathology in prostate pathology include the cost of high quality slide scanners for WSI and high resolution monitors for VM as well as the requirement for fast Internet connection as even a subtle delay in presentation of images on the screen may be very disturbing for a pathologist used to the rapid viewing of glass slides under a microscope. However, these problems are likely to be overcome by technological advances in the future.

Langner C, Harbaum L, Pollheimer M J, Kornprat P, Lindtner R A, Schlemmer A, Vieth M & Rehak P (2012) Histopathology 60, 1060–1072 Mucinous differentiation in colorectal cancer – indicator of poor prognosis? Aims: To analyse the prognostic impact of mucinous differentiation in colorectal mucinous adenocarcinomas and adenocarcinomas with a mucinous component. Methods and results: A total of 381 tumours were reviewed for mucinous differentiation by two independent pathologists. Mismatch repair status was assessed by immunohistochemistry. Prognostic significance was assessed by univariate and multivariate analyses. Eighty-one (21%) tumours were Union Internationale Contre le Cancer (UICC) Stage I, 120 (31%) Stage II, 126 (33%) Stage III and 54 (14%) Stage IV. Mucinous adenocarcinomas accounted for 12% and adenocarcinomas with a mucinous component for 19% of tumours. Mucinous differentiation was associated significantly with mismatch repair protein deficiency. The presence of extracellular mucin, regardless of extent, did not affect patients’ outcome, while tumour grade, vascular and perineural invasion, tumour border configuration and budding were associated significantly with outcome. Cox analysis proved venous invasion to be an independent predictor of outcome in mucinous adenocarcinomas and both venous invasion and tumour budding as independent predictors of outcome in adenocarcinomas with any amount of mucin. Conclusions: Mucinous adenocarcinomas and/or adenocarcinomas with mucinous component do not differ from conventional adenocarcinomas with respect to prognosis and histological predictors of outcome. Hence, recording of mucinous differentiation may be used as an indicator of mismatch repair deficiency, but not for prognostic stratification.

Granularzelltumoren sind periphere neuroektodermale Tumoren und mussen im Gastrointestinaltrakt von den gastrointestinalen Stromatumoren (GIST) unterschieden werden. Wir berichten uber einen Granularzelltumor des Magens bei einem 61-jahrigen Patienten, der eine transmurale Infiltration bis in das Fettgewebe der kleinen Kurvatur zeigte. Immunhistochemisch war der Tumor positiv fur S100-Protein, negativ fur KIT, CD34 und SMA. Der MIB1-Proliferationsindex lag unter 2%. Der Gastrointestinaltrakt stellt eine seltene Lokalisation fur Granularzelltumoren dar, wobei uberwiegend Osophagus und Kolon betroffen sind. Die diagnostischen Kriterien und die Differenzialdiagnose werden eingehend diskutiert.

Metastatic involvement of the gastrointestinal tract is rare and may cause considerable difficulties with respect to differential diagnosis. The gastrointestinal tract may either be affected by direct invasion, intraperitoneal dissemination or hematogenous cancer spread, the latter most often originating from malignant melanoma, breast and lung carcinomas. Metastatic deposits primarily develop within the submucosa. Secondary involvement of the mucosa typically leads to centrally depressed and/or ulcerated (volcano-like) nodular lesions. In histology, lack of a mucosal in situ component favors diagnosis of metastasis, whereas presence of an adenomatous precursor lesion is regarded to be characteristic of primary tumors. This concept, however, has recently been challenged by demonstrating metastatic cancer growth along intact basement membranes within the mucosal layer, i.e. mucosal colonization. The histopathological, immunohistochemical and clinical features of secondary gastrointestinal tumors are discussed in detail, focusing on criteria for differential diagnosis. The prognosis of affected patients is generally poor.

Der Barrett-Osophagus ist und bleibt eine verwirrende Herausforderung, da man sich noch immer nicht uber die genaue Bedeutung der zugrunde liegenden Faktoren im Klaren ist. Neben der bekannten Interob

The following on histology and immunohistology of Barrett's esophagus (BE) includes commentaries on the various difficulties remaining in reaching a consensus on the definition of BE; the difficulties in the characterization of intestinal and cardiac mucosa, and in the role of submucosal glands in the development of BE; the importance of a new monoclonal antibody to recognize esophageal intestinal mucosa; the importance of pseudo goblet cells; the best techniques for the endoscopic detection of Barrett's epithelium; and the biomarkers for identification of patients predisposed to the development of BE.

The following on esophageal disease and pathology contains commentaries on the varied definitions of Barrett's esophagus (BE); the optimal biopsy strategy in BE; reliable biomarkers for progression to neoplasia in BE; and the role of bone marrow stem cells in the morphogenesis of Barrett's esophagus.

Harbaum L, Pollheimer M J, Kornprat P, Lindtner R A, Schlemmer A, Rehak P & Langner C (2011) Histopathology59, 225–234 Keratin 7 expression in colorectal cancer – freak of nature or significant finding? Aims: To assess the prevalence of keratin 7 (K7) expression in colorectal cancer and to correlate findings with clinicopathological parameters and patients' outcome. Method and results: A total of 370 patients were evaluated for K7 expression by immunohistochemistry using a tissue microarray technique. K7 expression was scored semiquantitatively as either focal ( 50%). In all, 32 (9%) tumours were immunoreactive for K7, with five cases showing extensive, four moderate and 23 focal expression, respectively. K7 expression was associated with poor tumour differentiation (P = 0.005) and the extent of tumour budding (P = 0.02). In whole sections, K7 immunoreactivity prevailed in single cells and small clusters of cells at the invasion front. Analysis of serial sections showed that K7-positive cells colocalized with keratin 20, whereas they lacked immunoreactivity for E-cadherin, MUC2 and MIB-1. Disease progression occurred in 52% of patients with K7-positive tumours and 41% with K7-negative tumours (P = 0.19); 48% of patients with K7-positive tumours but only 33% with K7-negative tumours died of disease (P = 0.06). Conclusions: Aberrant expression of K7 in budding cancer cells represents a modification of the epithelial phenotype (‘epithelial–epithelial transition’: EET) which may be linked to gains in motility and invasive potential.

Beim hereditaren diffusen Magenkarzinom handelt es sich um ein autosomal-dominant vererbtes Tumorsyndrom mit 70–80%iger Penetranz. Das Lebenszeitrisiko, an einem klinisch manifesten Magenkarzinom zu erkranken, betragt bei Frauen 63–83%, bei Mannern 40–67%. Das Durchschnittsalter bei Diagnosestellung ist 40 Jahre. Betroffene Patienten besitzen in etwa 25–40% der Falle eine Keimbahnmutation im CDH1-Gen. Dieses Gen kodiert fur das Transmembranprotein E-Cadherin, das eine Schlusselfunktion in der Zelladhasion und in der Signaltransduktion einnimmt. Klassifiziert nach Lauren haben die Patienten ein multifokales diffuses Magenkarzinom mit Siegelringzellen und in spaten Stadien eine Linitis plastica. Als Vorlauferlasionen kann ein siegelringzelliges In-situ-Karzinom in der Drusenhalsregion, dem Sitz gastraler Stammzellen, gefunden werden. Charakteristisch sind Lasionen mit pagetoider Anordnung der Siegelringzellen unterhalb erhaltenem nichtneoplastischem Epithel. Die Anwendung einer PAS-Farbung erleichtert die Entdeckung kleinster Tumorherde. Der vorliegende Beitrag beleuchtet den Blickwinkel des Pathologen und den des Humangenetikers sowie das komplexe multidisziplinare Management der Patienten.

Background and Aims The GI tract is rarely affected by secondary tumors. Patients often present at an advanced stage of the disease, and prognosis is dismal. This study aimed to analyze the clinical, endoscopic, and pathologic features of secondary tumors that had been diagnosed endoscopically. Methods We conducted a retrospective database analysis of 217 patients with secondary tumors of the GI tract. Endoscopic findings and histologic diagnoses were systematically re-evaluated. Results Malignant melanoma (n = 33, 15%), breast cancer (n = 32, 15%), and pancreatic cancer (n = 27, 12%) were the most common corresponding primaries. About one-third of secondary tumors were detected in the stomach (n = 76, 35%), followed by small intestine (n = 54, 25%) and rectum (n = 53, 24%). The median time between the diagnoses of primary and secondary tumors was 19 months (mean, 31; range, 0-251), and this time was particularly long for renal cell carcinoma and breast cancer (median, 38 and 45 months, respectively). Direct invasion from extra-GI malignancies was more common (56%) than vascular cancer spread (44%) and depended on both sites of tumor involvement and corresponding primary. The lesions presented with various endoscopic patterns. In patients for whom a definitive diagnosis of cancer was known before the examination (n = 168), a secondary tumor was included in the differential diagnosis in only 48% of lesions. It is of note that the remaining cases were diagnosed endoscopically as primary tumors and rarely also as nonneoplastic change. Conclusions Secondary tumors may affect all parts of the GI tract. Malignant melanoma and breast and pancreatic cancer represent the most common primaries. Diagnosis based on examination of biopsy specimens is crucial to avoid misclassification.

The role of human prolactin and its receptor, the prolactin receptor, in colorectal cancer is largely unknown. Our study aimed to assess the prevalence of prolactin receptor expression, its association with clinicopathological variables, as well as its prognostic value, comparing results of primary tissues with those of corresponding metastases. In all, 373 primary colorectal cancer and 171 corresponding metastases were evaluated for prolactin receptor expression by immunohistochemistry using a tissue microarray technique. Immunoreactivity was semiquantitatively scored as either focal (10% of tumor cells positive), moderate (10-50%), or extensive (50%). Prolactin receptor expression was related to clinicopathological parameters as well as patient outcome. To substantiate our findings, prolactin receptor expression was additionally assessed in HT-29 and SW-480 colorectal cancer cell lines using western blot. Prolactin receptor expression was observed in 360 out of 373 (97%) primary tumors, with 21 (6%) cases showing focal, 55 (15%) moderate, and 284 (76%) extensive expression, respectively. Extensive prolactin receptor expression was significantly associated with tumor size (P=0.002) and grade (P0.001) as well as histological subtype (P0.001). Somer's D coefficients for concordance of primary tumors with corresponding lymph node and distant metastases were D=0.719 (P0.001) and D=0.535 (P=0.001), respectively. Extensive prolactin receptor expression was significantly associated with disease progression (P=0.03) and cancer-specific survival (P=0.04) in patients with high-grade cancers. In conclusion, prolactin receptor expression is common in colorectal cancer, with high concordance between primary tumors and corresponding metastases. In view of evolving targeted therapy concepts in colorectal cancer, widespread prolactin receptor expression may offer a therapeutic perspective in affected patients.

Pseudoneoplastic regeneration has become an important differential diagnosis to gastric carcinoma. Increasing use of acetylsalicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) appears to be related to this entity. In recent years knowledge of pseudoneoplastic regeneration has continuously improved and the proportion of this designation among cases sent to our institute for second opinion decreased from more than 50% in 2000 to approximately 10% today. In diagnostically difficult cases the gastritis status may help: the majority of patients with gastric carcinoma show either active or treated Helicobacter gastritis, whereas individuals with pseudocarcinomatous regeneration often show chemical reactive gastritis (reactive gastropathy). Gastric ulcers should always be followed-up during the healing phase. A second opinion may confirm the differential diagnosis.

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

OBJECTIVES To determine whether a minimum number of lymph nodes (LNs) exist to detect lymph node invasion (LNI) in patients undergoing radical nephroureterectomy (RNU) for upper tract urothelial carcinoma. METHODS The study included 551 consecutive patients, from 13 centers worldwide, who underwent RNU and lymphadenectomy (LND) between 1992 and 2006. LND was performed at the discretion of the surgeon. All pathological slides were re-reviewed by uropathologists according to strict criteria. Receiver-operating characteristic curve coordinates were used to determine the probability of diagnosing LNI according to the total number of nodes removed. Additionally, the relationship between the number of nodes removed and the rate of positive LNs was tested in univariate and multivariate logistic regression models. RESULTS Median patient age was 68 years (range: 27-97). Of 551 patients, 140 (25.4%) had positive lymph nodes. Median number of lymph nodes removed was 5 (mean 6.7, range 1-41). The Receiver-operating characteristic coordinates plot indicated that the removal of 13 nodes yielded a 90% probability to detect >= 1 positive LNs. The removal of 8 nodes resulted in a 75% probability of finding >= 1 positive nodes. Removal of > 8 LNs (P = .03; odds ratio 1.49) was independently associated with LN1 after adjusting for pathological stage and grade. CONCLUSIONS Our data indicate that 8 LNs need to be removed at radical nephroureterectomy to achieve a 75% probability of finding >= 1 positive nodes. Further improvement of the specificity of LND will require the removal of more lymph nodes. UROLOGY 74: 1070-1077, 2009. (C) 2009 Elsevier Inc.

Background: Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce. Objective: We compared recurrence and cause-specific mortality rates of ONU and LNU. Design, setting, and participants: Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC). Measurements: Univariable and multivariable survival models tested the effect of procedure type (ONU [n = 979] vs LNU [n = 270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, Ureteralcuff management, previous urothelial bladder cancer, and previous endoscopic treatment. Results and limitations: Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p < 0.001) and less lymphovascular invasion (14.8% vs 21.3%, p=0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p=0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p < 0.001] and 2.0 [p = 0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p = 0.1 for both). Conclusions: Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Longterm follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC. (C) 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.

OBJECTIVES To investigate the incidence, clinical presentation and therapy of gastric metastases, an uncommon finding, in a large group of patients with renal cell carcinoma (RCC). PATIENTS AND METHODS We systematically searched the computerized RCC database of our institute, covering 2082 patients (1180 men and 902 women) who had surgery between January 1984 and September 2005, to identify those with a synchronous and/or metachronous diagnosis of cancer in gastric biopsies or resection specimens. The histopathological slides of both renal and gastric cancer probes, and the clinical presentation, treatment and outcome of affected patients, were reassessed. RESULTS Twelve patients with primary gastric cancer, one with local RCC recurrence affecting the antrum and five with clear cell RCC (three men and two women; mean age 73 years, range 65–83) with haematogenous cancer spread to the stomach were detected. The mean (range) time to gastric metastasis was 6.9 (1.7–13.1) years. There were metastases to other organs, most often the lung, in all patients. Three patients presented with symptoms of gastrointestinal bleeding, which was successfully controlled by local endoscopic therapy. Four patients died from disease at 3–19 months after diagnosis. One patient is still alive with disease after ≈2 years. CONCLUSIONS Gastric metastasis in patients with RCC appears to be a late event in the course of the disease. Most patients show concomitant tumour spread to other organs, and the outcome is generally poor. The use of targeted drugs might offer a new perspective for affected patients.

Background/Aims: Multidrug resistance protein 2 (Abcb4) gene knockout mice (Mdr2−/−) lack phosphatidylcholine (PC) excretion into bile and spontaneously develop sclerosing cholangitis, biliary fibrosis and hepatocellular carcinomas. We therefore aimed to test whether formation and hepatic retention of abnormal PC metabolites contribute to the pathogenesis of liver injury in Mdr2−/− mice. Methods: Mdr2−/− mice were either fed a diet supplemented with soybean lecithin 2.5% w/w [phosphatidylcholine-enriched diet (PCD), to increase hepatic PC content] or a choline-deficient diet (CDD, to reduce hepatic PC content) for 4 weeks; controls received chow with energy and nutrient content equivalent to PCD and CDD. Serum liver tests, liver histology, markers of fibrosis, cholangiocyte activation, cell proliferation and thin-layer chromatography for phospholipid (PL) composition were carried out. Results: PCD decreased serum alkaline phosphatase and total bilirubin levels compared with controls, while liver histology as well as hepatic hydroxyproline content as markers of liver fibrosis did not differ among groups. Both PCD and CDD decreased hepatocellular proliferation compared with controls. Hepatic, serum and biliary PLs remained unchanged despite dietary manipulations and no potentially toxic PL metabolites were detected. Conclusions: Mdr2−/− mice maintain stable hepatic, serum and biliary PL metabolism in response to dietary PC manipulations. Our findings therefore suggest that liver injury in Mdr2−/− mice is not due to formation of toxic PL metabolites.