A. von Herbay

Involvement of the CD95 (APO-1/Fas) Receptor and Ligand System in Helicobacter pylori -induced Gastric Epithelial Apoptosis

Helicobacter pylori infection is associated with chronic gastritis, peptic ulceration, and gastric carcinoma. The potential role of CD95-mediated apoptosis was investigated in a panel of gastric biopsies obtained from patients with H. pylori-associated chronic gastritis (n = 29) and with noninfected normal mucosa (n = 10). Immunohistochemistry revealed increased CD95 receptor expression in epithelial and lamina propria cells in chronic gastritis. By in situ hybridization, CD95 ligand mRNA was absent or low in normal mucosa but expressed at high levels in lamina propria lymphocytes and, unexpectedly, in epithelial cells in chronic gastritis. Apoptotic cells were rare in normal mucosa but were observed regularly in chronic gastritis in close proximity to CD95 ligand mRNA expression throughout the epithelial and lamina propria cells. In a functional analysis gastric epithelial cell lines were incubated with supernatants of H. pylori. Treatment with the cytotoxic isolate H. pylori 60190 but not with the noncytotoxic isolate Tx30a upregulated CD95 in up to 50% of gastric epithelial cells and induced apoptosis in these cells. H. pylori-induced apoptosis was partially prevented by blocking CD95, demonstrating the functional role of the CD95 system. These findings suggest that H. pylori-associated chronic gastritis involves apoptosis of gastric epithelial cells by activation of the CD95 receptor and ligand system.

Solid-cystic tumour of the pancreas. An endocrine neoplasm?

Immunohistochemical studies and DNA flow-cytometric investigations were performed in a case of solid-cystic tumour of the pancreas in a 35-year-old woman. All tumour cells were immunoreactive for the neuroendocrine cell markers chromogranin A and neuron-specificγ-enolase. Moreover, about 10% of tumour cells were immunoreactive for insulin, while hypoglycaemia was absent. Few tumour cells (less than 1%) were immunoreactive for somatostatin, and no cells were found to be immunoreactive for pancreatic polypeptide or glucagon. No immunoreactivity was present for duct cell marker carcino-embryonic antigen and only individual cells were reactive forα 1-antitrypsin. Nuclear DNA content of the tumour cells was diploid and the proliferative activity was low. In confirmation of some reports on neuroendocrine markers in solid-cystic tumour of the pancreas, our findings support the theory that the lesion is a hormonally inactive neuroendocrine pancreatic tumour.

Epidemiology of Whipple's disease in Germany : Analysis of 110 patients diagnosed in 1965-95

BACKGROUNDnThe epidemiology of Whipples disease (WD) is obscure. To obtain basic data, we performed an evaluation of WD patients in Germany.nnnMETHODSnInformation was collected from 110 WD patients diagnosed during 1965-95 at 5 institutions in different regions of Germany. Four items were evaluated: 1) year in which the diagnosis was made; 2) residence and 3) age at the time of diagnosis; and 4) sex.nnnRESULTSnWD patients originated from all parts of Germany. The incidence of new cases was relatively stable, with a mean of one to two cases per year per collecting centre. In 1995, a maximum of 13 new WD patients was diagnosed. There was a significant increase in the mean age of patients (1965-75, 48.7 years; confidence interval, +/- 3.98 years; 1976-85, 50.7 years, +/- 3.69 years; 1986-95, 57.0 years, +/- 2.80 years; P < 0.01) and an increasing proportion of women (1965-85, 4%; 1986-1995, 22%).nnnCONCLUSIONSnWhipples disease is not quite as rare as commonly assumed. There is no obvious geographic predominance. During the past three decades, the demography of WD patients has changed.

Histology of intestinal whipple's disease revisited

Whipples disease is an infectious disorder with intestinal and extra-intestinal manifestations. We reinvestigated the intestinal histology in a series of 48 patients (10 females, 38 males; mean age 56.5 years, standard deviation of the mean ± 11.2 years). A total of 126 biopsy samples, obtained prior to, during, and after therapy, were evaluated by light microscopy. In 43 patients (90%), histology was consistent with common descriptions, while it was uncommon in 3 patients (6%), and non-diagnostic in 2 patients (4%). During treatment, several alterations occurred. Apart from a continuous decrease in PAS-positive macrophages, the pattern of mucosal infiltration changed from diffuse to patchy. Moreover, the cytological aspects of PAS-positive macrophages changed substantially, and this change was used to propose four different subtypes. Initially, subtype 1 macrophages predominated (74%), but showed a gradual decrease within a few months of therapy. After 15 months, subtype 3 and subtype 4 macrophages predominated (<80%). In 7 of 9 patients followed over long periods some subtype 3 or subtype 4 macrophages persisted. It is concluded that at diagnosis and during treatment the intestinal histology of Whipples disease is heterogeneous. A few PAS-positive macrophages commonly persist at long-term follow-up. This and other features suggest the presence of a persistent immune defect.

Lack of Association of Helicobacter pylori Seroprevalence and Gastric Cancer in a Population with Low Gastric Cancer Incidence

BACKGROUNDnPrevious studies have suggested that infection with Helicobacter pylori is associated with an increased risk of gastric adenocarcinoma.nnnMETHODSnWe examined the sera of 111 Caucasian patients with histologically confirmed gastric cancer (36 with cancer of the cardia, 70 with cancer of the body or antrum, and 5 with stump carcinomas after Billroth-II procedures) and 111 age-matched controls with colorectal carcinomas for the presence of H. pylori IgG antibodies by enzyme-linked immunoassay.nnnRESULTSnThe overall prevalence of H. pylori infection was 58.6% (65 of 111) in gastric cancer patients as compared with 50.5% (56 of 111) in matched control subjects (odds ratio, 1.39; 95% confidence interval, 0.82 to 2.36). Carcinomas of the cardia were not linked to H. pylori infection (odds ratio, 1.25; 95% confidence interval, 0.65 to 2.46), nor diffuse or intestinal-type carcinomas (odds ratios, 1.79 and 1.0; 95% confidence intervals, 0.69 to 4.67 and 0.34 to 2.91, respectively). Age, sex, and height of the IgG immune response did not affect risk.nnnCONCLUSIONSnIn contrast to previous results, these data do not provide evidence that the contribution of H. pylori infection to the carcinogenesis of gastric cancer is of major significance in a population with low gastric cancer rates and with high socioeconomic status.

Simultaneous gastric adenocarcinoma and MALT-type lymphoma in Helicobacter pylori infection

A 79-year-old women with upper abdominal pain, vomiting and weight loss was found at endoscopy to have a large tumour mass in the gastric body. Histology of forceps biopsies revealed an adenocarcinoma of intestinal type. Gastrectomy was performed, but extensive lymph node metastasis precluded a curative surgical approach. Histopathological study of the specimen, however, revealed two distict malignancies, which arose in the setting of Helicobacter pylori-associated chronic gastritis with partial mucosal atrophy. One tumour was a gastric carcinoma, while the other was a primary B-cell lymphoma of the stomach (CD20-positive). The lymphoma comprised both a low-grade component (mucosa-associated lymphoid tissue- or MALT-type lymphoma), and a high-grade component (large cell lymphoma with CD30-positive giant cells). Infection with H. pylori was confirmed by the serological presence of IgG antibodies to H. pylori-antigens, including antibodies against the 128 kDa protein of the cytotoxin-associated gene (cagA gene) of H. pylori.

Whipple's disease: a report of 22 patients.

SummaryTwenty-two patients with Whipples disease are reviewed (21 male, 1 female; mean age 49.3 years). All but one were diagnosed by small intestinal biopsy. The most frequent clinical symptoms at diagnosis were weight loss (14/21 patients), diarrhea (13/21), arthralgias (13/21), cramping abdominal pain (11/21), and skin pigmentation (8/21), which anteceded the diagnosis by from 6 months to 10 years (median 3.5 years). All but three patients were treated successfully with tetracycline given for at least 2 years. Follow-up was done for a median of 7.7 years (range 1–15 years). Two of 17 patients who were followed for 2 years relapsed, as did 2/11 followed for at least 5 years. One patient relapsed twice. Each relapse could be treated with success. In no case did relapse occur in the central nervous system. Thus, tetracycline appears to be effective in the treatment of Whipples disease if given for at least 2 years. In two further patients with confirmed central nervous system involvement at diagnosis, who were treated with ampicillin plus chloramphenicol, characteristic SPC cells disappeared from the cerebrospinal fluid. In addition, the recently recognized problems in the differential diagnosis of Whipples disease and atypical mycobacterial infection in AIDS patients are discussed.

Intussusception of the Appendix Secondary to Mucinous Cystadenoma

Intussusception of the appendix vermiformis in adults is an unusual entity. We present a 52-year-old male patient with intussusception of the appendix due to a mucinous cystadenoma, and discuss the clinical features, preoperative diagnosis, classification and therapy of this condition together with a review of the literature.

Morbus Whipple Histologische Diagnostik nach der Entdeckung von Tropheryma whippelii

ZusammenfassungSeit der mikrobiologischen Entdeckung von Tropheryma whippelii erfährt der Morbus Whipple eine vermehrte Berücksichtigung in der klinischen Medizin. Die Diagnostik erfolgt mittels Dünndarmbiopsie. Daher hat das Wissen um die histopathologischen Kriterien bei dieser Erkrankung und deren Differenzialdiagnosen an Bedeutung zugenommen. PAS-positive Makrophagen im Dünndarm sind zwar der diagnostische Leitbefund, aber heute ist eine weiter differenzierende Betrachtung von Bedeutung. Beim Morbus Whipple zu unterscheiden sind Makrophagen mit intensiv PAS-positiven, grobgranulären Partikeln im Zytoplasma (Typ 1) von Zellen mit blass PAS-positivem, nicht granuliertem Zytoplasma (Typ 3). Letztere bleiben auch bei erfolgreicher Behandlung noch für lange Zeit zurück, ohne die Diagnose einer intestinalen Remission zu beeinträchtigen. Weil jenseits des Dünndarms meist auch eine systemische Infektion mit Tropheryma whippelii vorliegt, die durch Dünndarmbiopsien aber nicht repräsentativ erfasst wird, erfolgen heute auch bei neurologisch asymptomatischen Patienten zusätzliche Untersuchungen des Liquors mittels Zytologie und Polymerasekettenreaktion (PCR). Speziell im Liquor ist zum Nachweis der Eradikation von T. whippelii eine PCR-Analyse sicherer als eine zytologische Untersuchung.AbstractSince the microbiological discovery of Tropheryma whippelii, Whipples disease has attracted to new attention in clinical medicine. As small intestinal biopsy is the diagnostic procedure, the impact of knowledge about the histopathological features of Whipples disease and its differential diagnosis has increased. PAS-positive macrophages in the intestinal mucosa are the diagnostic hallmark, but further subtyping of cells is important. In Whipples disease macrophages with intensely PAS-positive granular particles in the cytoplasm (type 1) should be distinguished from cells with faintly PAS-positive cytoplasm without granular particles (type 3). The latter type of macrophages may persist even for many years but does not affect a diagnosis of intestinal remission. However, as systemic infection with T. whippelii is common, but intestinal biopsy specimens are not representative for other organs, additional investigations are performed. These include analysis of the cerebrospinal fluid by means of cytology and polymerase chain reaction, even in patients without neurological symptoms. For ascertaining eradication of T. whippelii in the cerebrospinal fluid, polymerase chain reaction is more reliable than cytology. Seit der mikrobiologischen Entdeckung von Tropheryma whippelii erfährt der Morbus Whipple eine vermehrte Berücksichtigung in der klinischen Medizin. Die Diagnostik erfolgt mittels Dünndarmbiopsie. Daher hat das Wissen um die histopathologischen Kriterien bei dieser Erkrankung und deren Differenzialdiagnosen an Bedeutung zugenommen. PAS-positive Makrophagen im Dünndarm sind zwar der diagnostische Leitbefund, aber heute ist eine weiter differenzierende Betrachtung von Bedeutung. Beim Morbus Whipple zu unterscheiden sind Makrophagen mit intensiv PAS-positiven, grobgranulären Partikeln im Zytoplasma (Typ 1) von Zellen mit blass PAS-positivem, nicht granuliertem Zytoplasma (Typ 3). Letztere bleiben auch bei erfolgreicher Behandlung noch für lange Zeit zurück, ohne die Diagnose einer intestinalen Remission zu beeinträchtigen. Weil jenseits des Dünndarms meist auch eine systemische Infektion mit Tropheryma whippelii vorliegt, die durch Dünndarmbiopsien aber nicht repräsentativ erfasst wird, erfolgen heute auch bei neurologisch asymptomatischen Patienten zusätzliche Untersuchungen des Liquors mittels Zytologie und Polymerasekettenreaktion (PCR). Speziell im Liquor ist zum Nachweis der Eradikation von T. whippelii eine PCR-Analyse sicherer als eine zytologische Untersuchung. Since the microbiological discovery of Tropheryma whippelii, Whipples disease has attracted to new attention in clinical medicine. As small intestinal biopsy is the diagnostic procedure, the impact of knowledge about the histopathological features of Whipples disease and its differential diagnosis has increased. PAS-positive macrophages in the intestinal mucosa are the diagnostic hallmark, but further subtyping of cells is important. In Whipples disease macrophages with intensely PAS-positive granular particles in the cytoplasm (type 1) should be distinguished from cells with faintly PAS-positive cytoplasm without granular particles (type 3). The latter type of macrophages may persist even for many years but does not affect a diagnosis of intestinal remission. However, as systemic infection with T. whippelii is common, but intestinal biopsy specimens are not representative for other organs, additional investigations are performed. These include analysis of the cerebrospinal fluid by means of cytology and polymerase chain reaction, even in patients without neurological symptoms. For ascertaining eradication of T. whippelii in the cerebrospinal fluid, polymerase chain reaction is more reliable than cytology.

Cardiac damage in autologous bone marrow transplant patients: An autopsy study - Cardiotoxic pretreatment as a major risk factor

SummaryThe myocardium was studied histologically at autopsy in seven patients who died 9–85 days (median 22 days) after autologous bone marrow or blood-derived stem-cell transplantation. Clinical investigations including echocardiography suggested normal cardiac function in all patients prior to transplantation. Myeloablation was performed by total body irradiation (1200–1560 cGy) and cyclophosphamide (200 mg/kg). Morphological findings were graded semiquantiatively and correlated with previous and current therapy. Histological alterations did not correspond to the dosages of myeloablative therapy. However, cardiac failure, the primary cause of death in four patients, was associated with coagulative fiber necroses and contraction band necroses, which may be related to acute cyclophosphamide toxicity. In three of these patients high-dose cardiotoxic pretreatment with anthracyclines and mitoxantrone has been performed beyond the critical cardiotoxic level. High-dose pretreatment was correlated with histological hallmarks of anthracycline heart disease: marked chromatin clumping of myocardial cell nuclei (3/3 patients), occurrence of plurivesicular “adria” cells (3/3 patients), and diffuse interstitial myocardial fibrosis (2/3 patients). Our morphological observations indicate for the first time that pretreatment with anthracyclines and mitoxantrone may enhance cardiotoxicity of myeloablative therapy in bone marrow transplantation.