Uta Flucke

Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl-Lewisa and sialyl-Lewisx antigens in colorectal adenocarcinoma

Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl‐Lewisa and sialyl‐Lewisx antigens in colorectal adenocarcinoma

Increased galectin-3 expression in gastric cancer: correlations with histopathological subtypes, galactosylated antigens and tumor cell proliferation.

Galectin-3 represents an endogenous galactoside-binding lectin which may be involved in tumor cell adhesion and proliferation. In order to evaluate its biological significance in human gastric cancer, we investigated its expression in the stomach of a large series of patients (n = 193) by immunohistochemical staining with the monoclonal antibody Mac-2. Compared to normal tissues, primary gastric adenocarcinomas showed a slight increase in galectin-3 expression. However, there was no correlation of membrane-bound and cytoplasmic galectin-3 with histopathological differentiation parameters (according to the WHO and Laurén classifications) or tumor progression (as documented by pTNM staging). Nuclear galectin-3 reactivity was significantly stronger in diffuse-type cancer compared to the intestinal-type tumors. Galectin-3 binds to terminal GalNAcα(1–3) bound to polylactosamine chains and related glycotopes. Therefore, the strong coexpression of membrane/cytoplasmic galectin-3 with Griffonia simplicifolia agglutinin I (GSA I) binding sites (Galα1–3Gal-, GalNAcα–) on carcinoma cells seems to be interesting. On the other hand, nuclear galectin-3 immunoreactivity did not correlate with the incidence of Ki-67-positive tumor cells. A prognostic value of galectin-3 regarding patient survival could not be established.

Immunoreactivity of cytokeratins (CK7, CK20) and mucin peptide core antigens (MUC1, MUC2, MUC5AC) in adenocarcinomas, normal and metaplastic tissues of the distal oesophagus, oesophago–gastric junction and proximal stomach

Aims:  Adenocarcinomas of the distal oesophagus and especially the oesophago–gastric junction have shown an increasing incidence during the last decade. Definition of subgroups according to different sites of development, histogenesis or aetiology may prove to be valuable for clinical diagnosis and treatment. Previous studies have shown differences in cytokeratin patterns between Barretts metaplasia of the oesophagus and intestinal metaplasia in the stomach. The aim of our study was to investigate whether the expression of certain cytokeratins (CK7, CK20) and mucins (MUC1, MUC2, MUC5AC) exhibit clear‐cut patterns, thus allowing a subclassification of adenocarcinomas of the oesophago–gastric junction. The possibility of a relationship between antigen expression and the presence or absence of Barretts metaplastic epithelium was also studied.

Loss of IL-6 Receptor Expression in Cervical Carcinoma Cells Inhibits Autocrine IL-6 Stimulation: Abrogation of Constitutive Monocyte Chemoattractant Protein-1 Production

IL-6 is synthesized in human pampilloma virus (HPV)-transformed cervical carcinoma cell lines and is supposed to stimulate these cells in an autocrine manner. We studied IL-6 production and responsiveness in nonmalignant HPV-transformed keratinocytes and cervical carcinoma cells in detail. IL-6 was detected in cervical carcinomas in situ. Correspondingly, HPV-positive carcinoma cell lines expressed high IL-6 levels. However, these carcinoma cell lines showed low responsiveness to IL-6 as revealed by low constitutive STAT3 binding activity, which was not further enhanced by exogenous IL-6. In contrast, in vitro-transformed nonmalignant keratinocytes without endogenous IL-6 production strongly responded to exogenous IL-6 with activation of STAT3. STAT3 protein expression levels were comparable in both responsive and nonresponsive cell lines. Also, gp130, the upstream signal-transducing receptor subunit conveying IL-6 signals into the cell, was expressed in all tested cell lines. However, the IL-6 binding subunit gp80 was lost in the malignant cells. Addition of soluble gp80 was sufficient to restore IL-6 responsiveness in carcinoma cells as shown by enhanced activation of STAT3 binding activity. As a consequence of the restored IL-6 responsiveness, carcinoma cells strongly produced the chemokine monocyte chemoattractant protein-1 (MCP-1). Our data demonstrate that cervical carcinoma cells producing high amounts of IL-6 only weakly respond to IL-6 in an autocrine manner due to limited gp80 expression. While production of IL-6 might contribute to a local immunosuppressive effect, silencing an autocrine IL-6 response prevents constitutive production of the mononuclear cell-attracting chemokine MCP-1. Both mechanisms might help the tumor to escape the immune system.

Differences between Biopsy- or Specimen-related Laurén andWorld Health Organization Classification in Gastric Cancer

The extent of stomach resection in gastric cancer depends on tumor size, tumor location, depth of invasion, and the histological allocation to intestinal or diffuse type according to Laurén. As the latter is based on preoperative findings we performed a retrospective histomorphological study to quantify the differences between biopsy-related and surgical specimen-related Laurén classification. Additionally the World Health Organization (WHO) classification of preoperative endoscopic biopsies and surgical specimens were compared. Preoperative biopsies and resected tumor specimens from 100 patients with primary gastric carcinoma were retrospectively classified according toLaurén and WHO. The reclassification was independently performed by three pathologists who were not aware of the previous diagnoses. In 74% the Laurén classification of pre- and postoperative specimens was identical, whereas 26% of the cases showed a disagreement. Out of 48 tumors with preoperative diagnosis of an intestinal type, 10 tumors (20.8%) exhibited a diffuse growth pattern in the gastrectomy specimens; and 16% of the cases showed a disagreement of the pre- and postoperative histopathological type according to the WHO classification. Preoperative biopsy-related and surgical specimen-related Laurén classification differ in about one-quarter of the cases. Mostly, the preoperative diagnosis of an intestinal tumor type must be corrected into a diffuse or mixed type according to Laurén. Since this may have consequences for the surgical strategy, the extent of surgical resection, rebiopsies, and reconfirmation of an intestinal type should be performed at least in those cases with any doubts of this classification.

Immunoreactivity of Monoclonal Antibody BW835 Represents a Marker of Progression and Prognosis in Early Gastric Cancer

The Thomsen-Friedenreich (TF) antigen is a well-known human pan-carcinoma antigen. It represents a carbohydrate core disaccharide (Galβ1-3GalNAc) which is predominantly bound to mucin peptide cores. Its immunoreactivity depends on changes in glycosylation which lead to a reduction in the carbohydrate chain length and the exposure of core carbohydrates. In the present study, we investigated 208 gastric adenocarcinomas with respect to their immunohistochemical reactivity applying two monoclonal antibodies (MAbs). MAb specifically detecting TF antigen (A78-G/A7) and MAb BW835 were included. The latter reacts with a certain glycoform of the MUC1 peptide core, characterized by core-type glycans like TF. A78-G/A7 epitopes were detected in 68.8% and BW835 epitopes in 57.7% of the carcinomas. BW835 immunoreactivity correlated with the presence of lymph node metastases. Both A78-G/A7 and BW835 staining were significantly stronger in tubular/papillary cancer (WHO classification) and intestinal-type cancer according to Laurén. In univariate survival analyses of all patients studied, BW835 immunoreactivity was a marker of an unfavorable prognosis (p < 0.05). The presence of A78-G/A7 and BW835 epitopes exerted a negative effect on the subgroup of pTNM stage I carcinomas. These results indicate that TF and MUC1-TF immunoreactivity defines a ‘high-risk’ subgroup of stage I patients in gastric cancer.

Comparative Quantitative Analysis of Macrophage Populations Defined by CD68 and Carbohydrate Antigens in Normal and Pathologically Altered Human Liver Tissue

Liver macrophages, which are involved in the different types of hepatitis, may indirectly induce hepatic fibrogenesis, since they have the possibility to activate hepatic stellate cells and fibroblasts by secretion of TGF-β , TNF-α and IL-1. To evaluate variations of the number of liver macrophages and their subpopulations, a quantification was carried out in normal human liver tissue, fatty liver, fatty liver hepatitis and hepatitis B. Identification was performed by the mab PG-M1 (anti-CD68) and, comparatively, four lectins, Griffonia simplicifolia agglutinin I (GSA-I), Erythrina cristagalli agglutinin (ECA), peanut agglutinin (PNA) and soybean agglutinin (SBA). A slight decrease in the frequency of macrophages in pericentral fields was observable in fatty liver and fatty liver hepatitis as compared to normal liver tissue. On the other hand, the number of CD68 cells was significantly enhanced in hepatitis B with moderate and severe inflammatory activity. The highest incidence of macrophages was found in portal tracts of liver with fatty liver hepatitis and, particularly, hepatitis B. The fraction of cells stained by ECA, PNA or SBA did not increase significantly under pathological conditions. In contrast, the percentage of GSA-I binding macrophages was higher in liver parenchyma of hepatitis B and in portal tract macrophages in fatty liver hepatitis and also hepatitis B. In conclusion, our results indicate that GSA-I may aid in the detection of the subpopulation of activated macrophages which are assumed to play a pivotal role in liver pathology.

Endoskopischer Stenosegrad und histologische Regression nach neoadjuvanter Radio-/Chemotherapie beim Plattenepithelcarcinom des Ösophagus

In einer prospektiven Studie wurde bei 20 vorbehandelten Patienten mit Plattenepithelcarcinom des Osophagus die Wertigkeit der flexiblen Osophagoskopie beim Restaging untersucht. Vor und nach neoadjuvanter Radio-/Chemotherapie wurde der Stenosegrad bzw. der intraluminale Tumorbefall evaluiert. Eine eventuelle Abnahme des endoluminalen Tumorbefalls wurde mit der endgultigen histologischen Tumorregression (modifiziert nach Junker/Muller) verglichen. Der Stenosegrad konnte bei 11 von 20 Patienten nach Vorbehandlung verbessert werden, eine Korrelation zur histologischen Regression ergab sich nicht. War endoluminal kein Tumor mehr nachweisbar, wurde in 2 von 4 Fallen auch histologisch eine komplette Remission erzielt.

Zytokeratin- und Muzinantigene: Korrelationen zu Histogenese, histopathologischem Subtyp und Tumorstadium der Adenokarzinome des ösophagogastralen Überganges

Einleitung: Eine weitere immunhistochemische Unterteilung der Adenokarzinome des osophagogastralen uberganges, die Ruckschlusse auf die exakte Lokalisation des Primartumors, die Histogenese oder atiologie zulassen wurde, konnte interessante neue klinische Aspekte ergeben. Vorausgegangene Studien zeigten Unterschiede zwischen Barrett-Metaplasien und intestinalen Metaplasien der Magenschleimhaut. Von diesen Daten ausgehend, zielte die vorliegende Untersuchung auf eine Evaluierung bestimmter Zytokeratin- (CK7, CK20) und Muzinantigene (MUC1, MUC2, MUC5AC) in diesem Zusammenhang ab. Methode: Insgesamt wurden 43 Adenokarzinome aus dem osophagogastralen Ubergang nach Siewert (6 Typ I-, 29 Typ II- und 8 Typ III-Karzinome) immunhistochemisch mittels monoklonaler Antikorper gegen CK7, CK20, MUC1, MUC2 und MUC5AC charakterisiert. Zur statistischen Analyse fand der chi-Quadrat Test Verwendung. Ergebnisse: CK7, CK20 und MUC1 wurden jeweils in deutlich uber 80% der untersuchten Adenokarzinome zumeist stark exprimiert, wahrend MUC2 und MUC5AC nur in 28% bzw. 65% dieser Tumoren bei deutlich schwacherer Immunreaktivitat nachweisbar waren. Die CK20-Expression korrelierte signifikant mit einem geringen Differenzierungsgrad, G3 (p < 0,0001), MUC1 mit histopathologischen Subtypen (p < 0,005), wobei Siegelringzellkarzinome eine signifikant schwachere Reaktivitat aufwiesen. Andere statistisch signifikante Korrelationen zwischen Antigenexpression und histopathologischen Klassifikationen (einschlieslich Anwesenheit/Abwesenheit von Barrett-Metaplasien, pTNM-Stadium) oder der Lokalisation waren nicht zu verzeichnen. Insbesondere konnten keine Unterschiede zwischen Barrett-Karzinomen und den ubrigen Adenokarzinomen des osophagogastralen ubergangsbereichs festgestellt werden. Schlussfolgerungen: Nach unseren Ergebnissen lasst die immunhistochemische Bestimmung von Zytokeratin- und Muzinantigenen keine weiteren Ruckschlusse auf die Pathogenese der Adenokarzinome des osophagogastralen uberganges zu. Eine besondere klinisch-pathologische Relevanz kommt ihr aufgrund dieser Daten nicht zu.