Peter Johan Heiberg Engel

Skip inflammation of the appendiceal orifice: A prospective endoscopic study

Objective. The purpose of the study was to evaluate the incidence of discontinuous inflammation of the appendiceal orifice in patients undergoing colonoscopy for diagnosis or surveillance of colonic disease. Material and methods. Consecutive and unselected patients subjected to colonoscopy over a 3-year period were included in a prospective study. Biopsies were taken within 2 cm of the orifice of the appendix, from the caecum and from predefined colonic segments. Discontinuous inflammation of the appendiceal orifice was defined as an area of macroscopic inflammatory changes distinct from a normal caecum of ascending colon. The biopsies were graded histologically for the presence and severity of inflammation by a pathologist without knowledge of the endoscopic findings. Results. A total of 271 patients were included. The final diagnoses were: ulcerative colitis (UC) (83 patients), Crohns disease (CD) (54), indeterminate colitis (12), irritable bowel syndrome (IBS) (54), microscopic colitis (15) and other disease (53). Endoscopic discontinuous inflammation of the appendiceal orifice was found in 27% (95% CI: 17–38%) of patients with UC, 24% (95% CI: 13–39%) with CD, 40% (95% CI: 12–74%) with indeterminate colitis, 8% (95% CI: 0–36%) with microscopic colitis, 10% (95% CI: 3–24%) of patients with IBS and in 9% (95% CI: 2–21%) of other diseases (p < 0.05). A correlation was found for endoscopic and histological discrimination between normal and inflamed mucosa (p < 0.001). However, in 24% of patients, endoscopic inflammation was without histological signs of inflammation, primarily in an otherwise normal colon. Conclusions. Discontinuous inflammation of the appendiceal orifice is common in patients with IBD irrespective of clinical activity. However, patients with otherwise normal colon may also show congestion of this area without or with minimal microscopic inflammation.

Observer variability in the histopathologic diagnosis of microscopic colitis and subgroups

The diagnosis of microscopic colitis (MC) is based on histologic findings and includes collagenous colitis (CC) and lymphocytic colitis (LC). Incomplete MC (MCi) denotes patients with chronic diarrhea and a normal endoscopy and morphological changes that do not completely meet the histologic criteria of LC or CC. The aim of this study was to investigate the intraobserver and interobserver agreement on the MC subtypes of CC, LC, and MCi and the ability to discriminate MCi from normal and inflammatory bowel disease/nonspecific reactive changes. A single hematoxylin and eosin-stained specimen from biopsies of the following 5 groups were randomly selected and blinded: CC, LC, MCi, inflammatory bowel disease, and normal. Three pathologists independently reviewed the specimens. The specimens were relabeled and reinterpreted 4 months later. Intraobserver and interobserver agreement was evaluated by κ statistics. κ values for intraobserver agreement were good for 5 diagnostic groups varying from 0.70 to 0.83 and very good when simplifying to only 3 diagnostic groups varying from 0.88 to 0.96, separating MC/MCi from non-MC. κ values for interobserver agreement varied from 0.60 to 0.75 for 5 diagnostic groups and 0.81 to 0.89 for 3 diagnostic groups. The study shows that the intraobserver and interobserver agreement is high for discriminating between MC/MCi and non-MC, whereas the ability to discriminate MCi from CC and LC is lower. A revision and consensus on the histologic criteria of the MC subtypes seem warranted.

Expression of bcl-2 in fetal thymus, thymomas and thymic carcinomas : Association with p53 expression and review of the literature

Bcl‐2 is a proto‐oncogene inhibiting apoptosis, and p53 is a tumor supressor gene which induces apoptosis. Both seem to take part in tumorigenesis. An inverse relationship between the two genes has been reported in some neoplasms, although the exact mechanism is not fully understood. We have analyzed the expression of bcl‐2 and p53 in 18 fetal thymuses and 18 clinically benign and malignant thymomas: bcl‐2 was expressed by most medullary lymphocytes and epithelial cells of the normal thymus; p53 was not expressed at all. Bcl‐2 and p53 were co‐expressed in the majority of the thymomas and the staining reaction was stronger in the clinically malignant ones. It is concluded that although co‐expression of bcl‐2 and p53 is of doubtful prognostic relevance, the staining pattern of bcl‐2 supports the histogenetic classification system of Müller‐Hermelink.

The Temporal Evolution of Histological Abnormalities in Microscopic Colitis.

BACKGROUND AND AIMS Microscopic colitis (MC) is a common cause of chronic watery diarrhoea but long-term follow-up data are sparse. METHODS We performed a retrospective review of health records and all pathology reports in a regional cohort of patients with MC to describe the change in pre- and post-diagnostic colon biopsies. RESULTS MC was diagnosed in 468 patients with collagenous colitis (CC), 361 with lymphocytic colitis (LC) and 226 with incomplete MC (MCi). The 2014 incidence of CC, LC and MCi was 14.5, 14.9 and 5 per 10(5). Biopsies from both right and left colon were obtained in 237 (51%) patients with CC, 200 (55%) with LC and 107 (47%) with MCi. The diagnostic sensitivities of both left- and right-sided biopsies for MC were high and did not differ. Pre-diagnostic biopsies were obtained in 150 patients and lamina propria inflammation was described in 59, 47 and 43% of patients with a diagnosis of CC, LC and MCi respectively within 1 year, while histology was normal in 16, 13 and 21%. Post-diagnostic biopsies were obtained in 283 patients. MC persisted for up to one year in 77% with CC, 64% with LC and 45% with MCi, of whom 6, 9 and 18% respectively changed to a different MC subgroup. CONCLUSIONS Colonic biopsies obtained prior to the MC diagnosis often revealed increased lamina propria inflammation. The pathological changes of CC and LC are more persistent than those of MCi. Biopsies from the descending or sigmoid colon are sufficient to elucidate whether a patient with chronic watery diarrhoea has MC.

Absence of latent Epstein‐Barr virus in thymic epithelial tumors as demonstrated by Epstein‐Barr‐encoded RNA (EBER) in situ hybridization

Background: Several studies have established that Epstein‐Barr virus (EBV) is associated with lymphoproliferative disorders such as Burkitts lymphoma and Hodgkins disease. EBV is also present in undifferentiated nasopharyngeal carcinomas and in tumors of similar morphology (lymphoepithelioma‐like carcinomas) arising in a variety of organs, predominantly in stomach, salivary gland and thymus. As reports of EBV‐positive thymic epithelial tumors (TET) have been divergent and as different methods have been used to detect EBV, the aim of this study was to investigate the possible role of EBV in TET of Danish patients. Material and methods: Archival material of 157 cases of TET (105 thymomas and 52 thymic carcinomas, including 4 lymphoepithelioma‐like thymic carcinomas (LELTC)) was analyzed for EBV by applying a sensitive and specific method for detecting latently EBV‐infected cells (in situ hybridization for EBV‐encoded RNA (EBER)). Results: All investigated cases were EBER negative. Conclusions: EBV does not seem to be implicated in the pathogenesis of TET. However, a review of the literature showed that 28% of LELTC were EBER ISH positive. As they occurred in young people (mean 18 years), at an age when the patients were susceptible to infection by EBV, it is suggested that EBV merely acts as an innocent bystander.

CD3 immunohistochemical staining in diagnosis of lymphocytic colitis

Microscopic colitis (MC) is a common cause of chronic watery diarrhea. Traditionally, MC encompasses the 2 subgroups lymphocytic colitis (LC) and collagenous colitis, but recently, an additional subgroup, MC incomplete, has been introduced. Distinguishing between the subgroups relies exclusively on histopathologic evaluation. In the present study, 4 pathologists evaluated 156 archived biopsies originally diagnosed as LC or LC incomplete (LCi). Each pathologist assigned a diagnosis of LC, LCi, or nonspecific inflammation to all cases at 2 independent assessments. At the first assessment, hematoxylin and eosin (HE) stainings were available. At the second assessment, a supplementary CD3 immunohistochemical staining was also available. The aim was to evaluate whether a supplementary CD3 would increase the diagnostic agreement among pathologists, and whether a CD3 stain would change the diagnosis based on HE staining only. After the complete assessment, the cases were divided into 3 groups, that is, full agreement, partial agreement, and disagreement. The CD3 staining increased the number of cases with full agreement from 60 to 78. One hundred thirty-one cases with agreement or partial diagnostic agreement based on HE + CD3 were compared with the HE diagnoses. In 44 (34%) of 131 cases, CD3 changed the diagnosis. Cases assigned to the LCi category based on HE were often changed by a supplementary CD3. Conclusively, it is recommended to use a CD3 before giving the histopathologic diagnosis of LCi.

Histo-blood group antigens in human fetal thymus and in thymomas

The glycosylation of epithelial cell surface antigens follows cellular differentiation, and changes in the pattern of expression are seen in various premalignant and malignant epithelial lesions. The distribution of type‐2 chain ABH‐carbohydrate structures (N‐acetyl‐lactosamine, H‐type 2 chain, Le‐y, Le‐x and sialyl‐Le‐x) of the ABO‐histo‐blood group system was investigated in 19 normal fetal thymuses (gestational age 16 to 39 weeks) and in 19 thymomas in order to study possible tumor‐associated changes in the glycosylation pattern. The material was investigated by immunochemical stainings of formalin‐fixed paraffin‐imbedded tissue using monoclonal antibodies with defined specificity. In fetal thymus the epithelial cells of the medulla and the Hassals bodies strongly expressed elongated carbohydrate structures (Le‐y, Le‐x and sialyl‐Le‐x). In a few cases the cortical epithelial cells weakly expressed Le‐x and sialyl‐Le‐x. Compared with fetal thymus 16 of the thymomas showed a total loss, or a very much reduced expression of elongated carbohydrate structures. Three thymomas, which histologically had been reclassified according to Kirchner & Müller‐Hermelink (14) as high grade thymic carcinomas, revealed strong expression of Le‐y, moderate expression of Le‐x and weak expression of sialyl‐Le‐x. This is of interest as in other tumors Le‐y is correlated with increased cell motility and with poor prognosis.

Metastasizing sarcoma of the aorta

Sarcomas of the great vessels are rare. We report a case of a metastasizing sarcoma of the aorta. The patient was an 82‐year‐old male who presented with a subcutaneous tumour, which was initially classified as a malignant fibrous histiocytoma. Autopsy revealed a polypoid sarcoma of the luminal aspect of the aortic arch with metastases to several organs. By means of immunohistochemical staining, the aortic neoplasm was classified as an undifferentiated intimal sarcoma. The morphology of intimal sarcomas is very heterogeneous, and, when metastatic deposits are present, there may be considerable problems in differential diagnosis.

Automated image analysis in the study of collagenous colitis.

Purpose The aim of this study was to develop an automated image analysis software to measure the thickness of the subepithelial collagenous band in colon biopsies with collagenous colitis (CC) and incomplete CC (CCi). The software measures the thickness of the collagenous band on microscopic slides stained with Van Gieson (VG). Patients and methods A training set consisting of ten biopsies diagnosed as CC, CCi, and normal colon mucosa was used to develop the automated image analysis (VG app) to match the assessment by a pathologist. The study set consisted of biopsies from 75 patients. Twenty-five cases were primarily diagnosed as CC, 25 as CCi, and 25 as normal or near-normal colonic mucosa. Four pathologists individually reassessed the biopsies and categorized all into one of the abovementioned three categories. The result of the VG app was correlated with the diagnosis provided by the four pathologists. Results The interobserver agreement for each pair of pathologists ranged from κ-values of 0.56–0.81, while the κ-value for the VG app vs each of the pathologists varied from 0.63 to 0.79. The overall agreement between the four pathologists was κ=0.69, while the overall agreement between the four pathologists and the VG app was κ=0.71. Conclusion In conclusion, the Visiopharm VG app is able to measure the thickness of a sub-epithelial collagenous band in colon biopsies with an accuracy comparable to the performance of a pathologist and thereby provides a promising supplementary tool for the diagnosis of CC and CCi and in particular for research.

Differential expression of hMLH1 in sporadic human colorectal cancer tumors and distant metastases.

Somatic defects in the mismatch repair system constitute an important pathway in colorectal carcinogenesis. We have examined the expression of mismatch repair proteins in sporadic stage IV colorectal tumors and their derived metastases. Sporadic tumors were further examined for differences in expression between the tumor transition zone and the invasive front. Expression of hMSH2, hMLH1, and hPMS2 was screened immunohistochemically in 92 stage IV tumors and derived liver metastases. In cases with loss of mismatch repair protein expression, lymph node metastases were also examined. Clinicopathological parameters and Ki‐67 staining indexes were evaluated and compared. Four tumors displayed a complete loss of hMLH1/hPMS2 expression at the transition zone; however, three of these expressed both proteins at the invasive front and in liver and lymph node metastases. A further four were predominantly hMLH1/hPMS2 negative at the transition zone, but with distinct subclones of hMLH1/hPMS2‐expressing cells at the transition zone. All of these tumors expressed hMLH1/hPMS2 at the invasive front and in liver metastases, with three also expressing hMLH/hPMS2 in lymph node metastases. No significant difference in the proliferative index was observed for the hMLH1/hPMS2‐compromised group. In stage IV tumors re‐expression of hMLH1/hPMS2 occurred, leading to different patterns of expression within the primary tumor and between tumor and metastases. This may have functional importance for the chemosensitivity of metastases compared to the primary tumor.