Franz Borchard

p53 protein expression and prognosis in squamous cell carcinoma of the esophagus.

Background. The p53 gene product is known to regulate cell growth and proliferation. Whereas the wild‐type p53 protein suppresses cell growth, the mutated p53 protein acts as an oncogene. Mutations in the p53 gene usually result in p53 protein stabilization and accumulation; so that the gene product can be detected by immunohistochemistry. Recently, the immunohistochemical detection of the p53 protein was associated with prognosis in breast, colorectal, and other types of cancer. However, its prognostic role in esophageal cancer remains to be elucidated.

Overexpression or ectopic expression of MUC2 is the common property of mucinous carcinomas of the colon, pancreas, breast, and ovary

Mucinous carcinomas of the colorectum have been reported to overexpress the intestinal mucin MUC2. The purpose of this study was to determine whether this alteration is shared by mucinous tumours of the ovary, breast, and pancreas. A total of 40 breast carcinomas (22 of mucinous and 18 of ductal invasive type), 39 ovarian adenocarcinomas (16 mucinous, 23 serous), 47 colorectal carcinomas (25 mucinous and 22 non‐mucinous), and 41 pancreatic adenocarcinomas (14 mucinous, 27 non‐mucinous) were investigated by immunohistochemistry with the anti‐MUC2 monoclonal antibody 4F1 and the expression pattern was ranked. MUC2 mucin is expressed in the normal colonic epithelium; in the normal epithelium of the breast, ovary, and pancreas, it was not detectable by immunohistochemistry or by reverse transcriptase‐polymerase chain reaction (RT‐PCR). In agreement with previous reports, the colonic mucinous carcinomas differed significantly from the non‐mucinous carcinomas by strong MUC2 expression. In all mucinous carcinomas of the ovary, breast, and pancreas, de novo expression of the MUC2 gene was observed, which differentiated mucinous and nonmucinous carcinomas of these tissues (P<0·001). The overexpression or ectopic expression of the MUC2 gene exhibited by mucinous carcinomas of four organs indicates a common genetic lesion associated with the mucinous tumour phenotype.

Effects of antioxidants and free radical scavengers in three different models of acute pancreatitis.

The present studies were done to evaluate the therapeutic potential of several antioxidants and free radical scavengers in three different models of acute pancreatitis. (a) Edematous pancreatitis with acinar cells necrosis was induced by seven hourly intraperitoneal injections of 50 > of caerulein per kg in mice. (b) Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet in mice. (c) Hemorrhagic pancreatitis was induced by retrograde infusion of 0.6 ml of 5% sodium taurocholate into the pancreatic duct in rats. The following antioxidants and free radical scavengers were given at various doses intravenously, subcutaneously, or in-traperitoneally before the onset of pancreatitis: Ebselen [2-phenyl-1,2-benziso-selenazol-3(2H)-one], superoxide dismutase, catalase, deferoxamine (Des-feral), dimethyl sulfoxide, or allopurinol. The severity of pancreatitis was assessed at various times after its onset by determination of serum amylase and pancreatic weight (edema), by grading of histological alterations, and by determination of survival (survival determined in models of hemorrhagic pancreatitis). In general, free radical scavengers and antioxidants ameliorated edema and inflammation to a greater degree than necrosis and the increase in serum amylase. Superoxide dismutase (as did Ebselen in previous studies) exerted beneficial effects on survival in diet-induced pancreatitis in the absence of marked effects on pancreatic necrosis, suggesting that these beneficial effects are due to amelioration of extrapancreatic complications that often contribute to mortality in acute pancreatitis. None of the antioxidants had major beneficial effects in taurocholate-induced hemorrhagic pancreatitis. Thus, formation of free radicals may be important for progression and outcome in diet-induced and, to a lesser degree, in caerulein-induced pancreatitis but not at all in taurocholate-induced pancreatitis. Different models of pancreatitis may, therefore, involve different degrees and mechanisms of free radical formation. Despite the amelioration of edema and the beneficial effects on mortality seen for some antioxidants in some of the models, antioxidants and free radical scavengers appear to have only a limited potential for treatment of acute pancreatitis.

Schönlein-Henoch purpura associated with gastric Helicobacter pylori infection

Schönlein-Henoch purpura is characterized by palpable purpura, colicky abdominal pain, gastrointestinal hemorrhage, arthralgias, and renal involvement. Bacterial and viral infections, as well as drugs and diseases associated with immune complexes, are thought to be responsible. We describe the case of a 21-year-old woman with Schönlein-Henoch purpura and chronic active gastritis with erosions. Helicobacter pylori was found in gastric mucosa using the newly introduced, nontoxic, noninvasive 13C-urea breath test; infection was confirmed by gastric mucosal biopsy. After eradication of H. pylori with omeprazole and amoxicillin, the skin changes, gastric complaints, and proteinuria disappeared. Ten months later, Schönlein-Henoch purpura recurred. H. pylori was again detected. After therapy, H. pylori was eradicated and the clinical manifestations faded. To our knowledge, H. pylori has not previously been described as a cause of Schönlein-Henoch purpura.

Comparative analysis of histology, DNA content, p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis

Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia, which is accompanied by genetic alterations. This study determined the time of onset of p53 and Ki‐ras mutations as well as DNA aneuploidy during histological progression towards carcinoma. In all, 278 samples of 7 colectomy specimens were analyzed by flow cytometry, histology and single‐strand conformation polymorphism analysis. Of the samples, 22% (61/278) were dysplastic and 43% (122/278) aneuploid, while 25% (71/278) showed p53 and 4% (11/278) Ki‐ras mutations. The correlation between aneuploid status and p53 mutations varied among the patients. A strong correlation was noticed between histological progression from low‐grade dysplasia to carcinoma and p53 mutations as well as DNA aneuploidy. Ki‐ras mutations were found in 40% (2/5) of the carcinomatous samples. The correlation between p53 mutations and the histological status of the samples suggest the involvement of this genetic event in the development of colon cancer in patients with ulcerative colitis. In contrast to Ki‐ras mutations, the appearance of p53 mutations is an early event. Therefore p53 analysis might be helpful in the classification of indefinite dysplasia and in the identification of patients at risk for cancer development. Further studies are necessary to detect the additional genetic alterations preceding the development of DNA aneuploidy. Int. J. Cancer 76:1–6, 1998.© 1998 Wiley‐Liss, Inc.

Cancer of the Distal Esophagus and Cardia: Incidence, Tumorous Infiltration, and Metastatic Spread

The report concerns the findings of autopsies performed at the Institute of Pathology, The University of Düsseldorf, where 68 patients with cancer of the distal esophagus and 117 patients with cancer of the cardia were observed between 1950 and 1982. The total number of autopsies during this 33-year observation period was 46,593. The male:female ratio was 5.8:1 in cancer of the distal esophagus, and 4.3:1 in cancer of the cardia. During the observation period, cancer of the distal esophagus accounted, on average, for about 40% of all esophageal cancers, whereas the percentage of cancers of the cardia among all gastric cancers was 15.4% on average. While the incidence of gastric cancer has decreased overall, a relative increase in cancers of the cardia has been found, especially in the last 8 years. In histological terms, most of the malignomas of the distal esophagus were squamous cell carcinomas (84%), and most of the cancers of the cardia were adenocarcinomas (96%). Tumor spread and lymphogenous and hematogenous metastasizing are discussed, and the findings are compared with the literature.

Assessment of cell proliferation in colorectal carcinomas using the monoclonal antibody KI‐67. Correlation with pathohistologic criteria and influence of irradiation

Cell proliferation was measured by a three‐step immunoperoxidase technique on cryostat sections of 61 resected colorectal adenocarcinomas using the monoclonal antibody Ki‐67 that is directed against a proliferation‐associated nuclear antigen. The percentage of Ki‐67‐positive cells was quantified with the point‐counting method. The frequency distribution of the percentage of Ki‐67‐positive tumor cells in 52 unirradiated carcinomas was gaussian with a mean of 38.7% (range, 7.7% to 75.3%). Analysis of the unirradiated tumors showed no relation between Ki‐67 staining and various clinicopathologic features including age, sex, tumor volume, tumor differentiation, location, and tumor stage. Although some tumors demonstrated intratumor heterogeneity of immunoreactivity, there was no significant difference in proliferative activity among peripheral, intermediate, and central tumor areas. Whereas the Ki‐67 index increased to 47.1% in recurrent carcinomas, it decreased significantly to 24.7% in rectal carcinomas given radiotherapy before surgery. Therefore, Ki‐67 immunostaining might be used as a tool to select and monitor patients with colorectal cancers who might benefit from radiotherapy. The marked differences of Ki‐67 expression among different tumors may relate to heterogeneity in growth kinetics and may therefore carry prognostic implications. Cancer 64:2501–2505, 1989.

Gastric-type well-differentiated adenocarcinoma and pyloric gland adenoma of the stomach

Since 1985, when gastric-type well-differentiated adenocarcinomas were demonstrated in hyperplastic polyps of the stomach, we have studied phenotypic expression in gastrointestinal epithelial lesions. The recent discovery of MUC genes coding core proteins of mucin has improved research on the phenotypic expression of gastrointestinal neoplasms. The disease entity of gastric-type well-differentiated adenocarcinoma has recently been accepted, especially in Japan and Europe. This entity has often become a clinicopathological subject of discussion, because its biological behavior is possibly highly malignant, in spite of the difficulty in making endoscopic and histopathological diagnoses. Even under these circumstances, the term “gastric adenoma” usually means flat adenoma of the intestinal type. Gastric-type adenomas have been regarded as exceptional until recently. Although gastric-type adenomas could theoretically be classified into foveolar type and pyloric-gland type, foveolar-type adenoma is, in practice, difficult to distinguish from gastric-foveolar-type adenocarcinoma. In 2003, we first reported systematic clinicopathological analyses of pyloric gland adenoma, demonstrating its unstable and precancerous nature. In this article, we review and discuss the clinicopathological and molecular pathological aspects of gastric-type well-differentiated adenocarcinomas and pyloric gland adenomas, mainly based on our published and unpublished data.

Frequent In activation of CDKN2A and Rare Mutation of TP53 in PCNSL

Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent patients (nineteen B‐cell lymphomas and one T‐cell lymphoma) were investigated for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%) hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL without homozygous CDKN2A loss revealed methylation of the CpG island within exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either completely negative or showed expression restricted to single tumor cells. None of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1 revealed no amplification, rearrangement or overexpression. The retinoblastoma protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG: Arg to Trp). No evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl‐2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous deletion or DNA methylation represents an important molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated appear to be of minor significance in these tumors.

Differential p53 protein expression in stomach adenomas of gastric and intestinal phenotypes: possible sequences of p53 alteration in stomach carcinogenesis

In a comparative study, the expression of p53 protein was investigated in intestinal- and gastric-type adenomas of the stomach. The former is a conventional type, which is well known to be a premalignant lesion of the stomach, but the latter is a rare, more recently noted entity. Of 28 intestinal-type adenomas, 17 (60.7%) contained more than 5% of p53 immunoreactive cells. In these adenomas, the extent of positivity for p53 protein was significantly higher in high-grade dysplasia than in low-grade dysplasia (P<0.05), suggesting that p53 alteration plays a part in the dysplastic progression of intestinal-type adenomas. Among 18 gastric-type adenomas in which most of the tumour cells displayed gastric-type mucin, substantial expression of p53 protein was found only in the 3 tumours with high-grade dysplasia. Thus, the incidence of p53 expression was significantly higher in intestinal-type adenomas than in gastric-type adenomas (P<0.01). These results suggest that p53 gene alteration is an earlier event in the gastric carcinogenetic sequence with the intestinal phenotype than in that with the gastric phenotype.