[Clinical pathology in the Hanseatic City of Lübeck from the planning of an institute to the formation of the "Medizinische Hochschule"]. / Die klinische Pathologie in der Hansestadt Lübeck. Von der Planung des Instituts bis zur Gründung der Medizinischen Hochschule.

The formation of an university institute of pathology at the Hanseatic city of Lübeck preceded a long, changeful planning, accompanied by a chain of historical events. In the 19th century, Lübeck owned seven different places for clinical or forensic autopsies. Thus, in the first years of the 20th century it was generally called for the formation of a "Central Institute of Pathology" that was completed after all in the year 1927. Two years later, Eberhard von Praun became head of the institute and was immediately confronted with the "Lübeck-disaster". He was followed 1935 by Ernst Jeckeln, who identified the "Enteritis necroticans" which appeared in North Germany in the first years after the "Second World War". He called the disease "Darmbrand", a term that is since then internationally used. Jeckeln became the first "Ordinarius for Pathology" at the "Medical Academy Lübeck", which was associated to the "University of Kiel". His long-time colleague was Alfred Wegener, who identified the "Wegener's granulomatosis". In the year 1972 Alfred Gropp became head of the institute, an all-round scientist and pathologist, e.g. well-known in the field of developmental pathology. During his term, the "Medical Academy" got the university status and was named "Medizinische Hochschule Lübeck".

Epstein-Barr virus infection in colorectal neoplasms associated with inflammatory bowel disease: detection of the virus in lymphomas but not in adenocarcinomas.

Epstein-Barr virus (EBV) is associated with several lymphoid and epithelial human malignancies. The latter include gastric adenocarcinomas, while sporadic colorectal adenocarcinomas (CRCs) have been reported to be EBV-negative. Recently, increased numbers of EBV-infected B lymphocytes have been detected in intestinal mucosal samples affected by ulcerative colitis (UC) and, to a lesser extent, Crohn's disease (CD). Both CRC and colorectal non-Hodgkin's lymphoma (NHL) are recognized complications of inflammatory bowel disease (IBD), but it is unclear to what extent EBV contributes to the development of these neoplasms. Seventeen cases of IBD-associated CRC and nine cases of IBD-associated colorectal NHL were therefore studied for the presence of EBV by in situ hybridization. EBV-positive cases were further studied for the expression of the EBV-encoded nuclear antigen (EBNA) 2 and the latent membrane protein (LMP) 1 of EBV by immunohistochemistry. Four out of seven cases of colorectal NHL associated with UC were shown to be EBV-positive. In addition, two of two colorectal NHLs developing in patients with CD were EBV-positive. Of the EBV-positive lymphomas, three displayed a pattern of EBV latent gene expression consistent with type I latency (EBNA2(-)/LMP1(-)), two a type II pattern (EBNA2(-)/LMP1(+)), and one a type III pattern (EBNA2(+)/LMP1(+)). These findings suggest that EBV infection is involved in the pathogenesis of a proportion of colorectal NHLs developing in IBD. Iatrogenic immunosuppression may contribute to the development of these lymphomas. By contrast, all 17 IBD-associated CRCs were EBV-negative, including a case of CRC occurring synchronously with an EBV-positive NHL. In conjunction with previous reports on sporadic CRCs, this suggests that EBV is not involved in the pathogenesis of CRC.

[Expression of galectin-3 in thyroid gland and follicular cell tumors of the thyroid. A critical study of its possible role in preoperative differential diagnosis]. / Untersuchungen zur Expression von Galectin-3 im Schilddrüsengewebe und in Follikelzelltumoren der Schilddrüse. Kritische Bewertung einer möglichen präoperativen differenzialdiagnostischen Nutzung.

Galectin-3 belongs to a group of endogenous lectins with an affinity to glycoconjugates containing beta-galactoside residues. It has been detected in numerous tissues and studied in connection with tumor growth, dedifferentiation, and metastasis. Only few studies have dealt with galectin-3 detection in tumors of the thyroid gland and with its possible role for differential diagnosis. We studied 118 cases of thyroid gland tumors with a monoclonal antibody against galectin-3; we compared the preparations by a semiquantitative score to determine differences in expression. Normal thyroid gland tissue, goiter tissue, and tissue with functional enhancement were largely negative for galectin-3. Adenomas with a typical cytological pattern were predominantly negative, but a focal positive reaction in single cells and cell groups or follicles was possible. Almost all papillary carcinomas showed a distinct galectin-3 expression. While findings in follicular carcinomas and oxyphilic adenomas and carcinomas were very uneven, with both positive and negative tumors, the galectin-3 reaction can be helpful in recognizing follicular variants of the papillary carcinoma. Investigation of the biological significance of tumors should always be cautious and consider known histological criteria for malignancy.

Filiform polyposis of the colon in chronic inflammatory bowel disease (so-called giant inflammatory polyps).

On the basis of 3 of our own cases, we describe unusually intense forms of filiform polyposis and local giant polyposis as a consequence of chronic inflammatory bowel disease. The patients are: A 52-year-old woman who for 7 years has been known to have Crohn's disease (CD); a 55-year-old man who for 14 years has been known to have chronic inflammatory bowel disease, which was first thought to have been ulcerative colitis, but, as a result of the findings on the subtotal colectomy specimen, had to be classified as Crohn's disease or colitis indeterminate; and a 53-year-old woman known to have had ulcerative colitis for 37 years. From the literature on the subject, we drew up a chronological list of a total of 43 cases with similar or completely identical findings. The clinical significance of the findings in their particularly massive intensity results from their necessary differentiation--in the context of differential diagnosis--from a malignant tumor, in particular from a carcinoma in association with chronic inflammatory bowel disease, or from a villous adenoma. The indication of a need to operate results from the impossibility of being able definitely to rule out a malignant degeneration by means of clinical methods. Also, experience shows that with massive findings of the kind described a spontaneous disappearance cannot be expected. Finally, too, the clinical symptoms and the patients subjective complaints necessitate balanced surgical treatment, taking into consideration the site and the extent of the lesion.

Defective post-transcriptional processing of MUC2 mucin in ulcerative colitis and in Crohn's disease increases detectability of the MUC2 protein core.

Ulcerative colitis (UC) and, to a lesser extent, Crohn's disease (CD) are associated with a reduction of the protective mucus layer in the large intestine; the role of this alteration in the pathogenesis of either disease is, however, not clear. To learn more about the molecular mechanism of the alteration of the mucus layer, the expression of the main intestinal mucin, MUC2, was investigated in relation to inflammation and dysplasia. Formalin-fixed, paraffin-embedded biopsies from 70 patients with UC and 16 patients with CD, and 13 biopsies from normal colonic mucosa, were used for detection of MUC2 mRNA by in situ hybridization with the SMUC41 probe, and MUC2 protein by immunohistochemistry with the antibody CCP58. The steady-state concentration of MUC2 mRNA was not affected by UC or CD. By contrast, the amount of the detectable MUC2 protein, assessed as the immunoreactive score (IRS), was significantly (p<0. 0001) increased in UC (IRS=8.0+/-3.8) and CD (8.0+/-3.7), compared with the normal colonic mucosa (IRS=2.0+/-1.5). This alteration occurred in the inactive phase of inflammation and persisted in the active phase of the disease. It was also observed during bacterial or protozoal inflammation (n=7). The IRS values did not correlate with the grade of inflammation or dysplasia. Simultaneous histochemistry with high iron diamine and immunohistochemistry indicated that the increase of detectable MUC2 is concomitant with low mucin sulphation in the same cells. These data indicate that the strong MUC2 protein staining in colonic mucosa of patients with UC or CD is due to a long-term alteration of the post-transcriptional modification of the MUC2 molecule, leading to its better detectability by the anti-MUC2 antibody CCP58. This alteration, induced by the inflammatory process, may affect the gel thickness and may contribute to a protracted autoimmune response.

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 non-mucinous 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.

Fulminant primary manifestation of Crohn's colitis "Hot Crohn's disease".

Following the very short course of a disease with watery diarrhea, fever, nausea, meteorism and a severe feeling of general illness, a 22-year-old patient was diagnosed as having a toxic megacolon, and a subtotal colectomy was carried out. The postoperative progression was uncomplicated and the patient recovered quickly. The examination of the operation specimen revealed a serious ulcerous colitis with relative omission of the rectum and the distal sigmoid colon. After critical evaluation of the histological findings, it was judged to be a fulminant Crohn's colitis and, for the purposes of differential diagnosis, differentiated from ulcerative colitis and colitis indeterminate. The formal pathogenesis of the inflammatory-ulcerous processes is discussed, in particular with regard to the activation of the macrophages and the very short anamnesis in a clinically established primary manifestation of the disease.

[Mucinous adenocarcinomas of the large intestine in Crohn disease]. / Mucinöse Adenocarcinome des Dickdarms bei Morbus Crohn.

In two patients with Crohn's disease of long duration after more than 17 and 12 years respectively a mucinous adenocarcinoma of the ascending colon and a perianal mucinous carcinoma deriving from the anal ducts developed. The possible pathogenetic connections between chronic inflammatory bowel disease and tumour origin are considered. In particular, both the histologically identifiable dysplasia of the mucosa and the fistulae originating in the anal ducts are discussed.

Malignant gastrointestinal lymphomas in patients with AIDS.

HIV-associated malignant lymphomas are a common complication in late HIV infection, and there is a high percentage of gastrointestinal tract involvement. Non-Hodgkin's lymphoma was found in 108 of 2,750 HIV-positive patients (3.9%) in our institution, whereas gastrointestinal manifestation was diagnosed in 48 of 108 patients (44.4%). 44 of these cases were found during endoscopy of the upper and lower gastrointestinal tract (or by laparotomy or laparoscopy in 4 cases). Endoscopy is a reliable procedure for the diagnosis of lymphoma. Unusual manifestations such as oral, esophageal or perianal lesions and multifocal disease were common findings. Life-threatening complications such as gastrointestinal bleeding, perforation, and obstruction occurred in 37.5%. High-grade B-cell lymphomas were found in all cases including mainly lymphoblastic, immunoblastic, centroblastic and Burkitt subtypes. 52% of the patients had disseminated lymphoma with Ann Arbor stage III or IV. Standard chemotherapy with cyclophosphamide, adriamycin, vincristine and prednisone was started in 25 patients and resulted in a mean survival time of 4.8 months. The prognosis of AIDS patients presenting with malignant gastrointestinal lymphoma depends mainly on the presence or absence of previous AIDS-defining diseases, not CD4 cells, lymphoma-associated gastrointestinal complications or the histopathologic lymphoma type at the time of diagnosis.

[Experiences with the NoToX formalin substitute solution]. / Erfahrungen mit der Formalinersatzlösung NoToX.

"NoToX Histological Fixative" is a formaldehyde substitute for the fixation of tissues prior to histological investigation. Intraoperative samples and necropsy tissue were tested. NoToX was substituted for formaldehyde in the fixation step, otherwise the same manufacturer-specified protocols were used for all reagents. Conventional histological and accepted immunohistological investigations, especially for tumour diagnosis, were used. In all tests, results with NoToX-fixated tissue were similar to those with tissue fixed with formaldehyde regarding both staining and diagnosis. NoToX is a useful substitute for formaldehyde.

Severe toxoplasmic ventriculomeningoencephalomyelitis in two AIDS patients following treatment of cerebral toxoplasmic granuloma.

Two patients with acquired immunodeficiency syndrome (AIDS) who were successfully treated for cerebral toxoplasmosis presented a few weeks later with neurologic abnormalities. Brain CT scan showed ventricular dilatation, ependymitis, and meningoencephalitis. Both patients died despite extensive treatment. Neuropathological examination showed enlargement of the cerebral ventricles, severe ventriculoencephalitis with large ependymal and subependymal necrosis, and numerous pseudomembranes within the ventricle lumen. Microscopic examination revealed severe necrotizing ventriculoencephalitis, meningoencephalitis and myelitis. Immunohistochemical studies revealed the presence of miriads of tachyzoites within and around the necrotic areas. Such form of toxoplasmosis as a diffuse meningo-encephalo-ventriculo-myelitis appear unique to AIDS and, to our knowledge, have not been previously documented.

Role of the systemic cellular immune response in the pathogenesis of Helicobacter pylori-associated duodenal ulcer.

20 patients colonized by H. pylori (9 with duodenal ulcer, 11 with antral gastritis) were examined for the presence of a systemic cellular immune response to H. pylori using an in vitro lymphocyte transformation assay. Infiltration of the antral mucosa by myelomonocytic cells was assessed by immunohistology as a parameter of local cellular immune response. A systemic H. pylori-induced cellular reaction could be demonstrated in 11 patients all of whom showed an intense myelomonocytic infiltration of the antral mucosa. In this group 7 of 9 duodenal ulcers occurred. The findings support the hypothesis, that a specific cellular immune response might be involved in the pathogenesis of H. pylori-associated gastritis and duodenal ulcer. A protective role of systemic cellular immunity to H. pylori seems rather unlikely.

Anergic disseminated toxoplasmosis in a patient with the acquired immunodeficiency syndrome.

Cerebral toxoplasmosis is the most common cause of focal brain disease in patients with the acquired immunodeficiency syndrome. A 24-year-old human immunodeficiency virus-infected woman with two previous episodes of Pneumocystis carinii pneumonia presented with diarrhea and fever. Despite antibiotic treatment, septic shock developed, and she died 3 weeks after the symptoms began. Histologic and histochemical studies revealed an anergic toxoplasmosis with dissemination in all examined organs. There were multiple foci of toxoplasmic cysts and free tachyzoites, sometimes with minute areas of necrosis, but no inflammatory reaction at all. Since effective treatment of toxoplasmosis is available, the occurrence of this rare form of toxoplasmosis should be kept in mind.

Comparative lectinhistochemical studies on paraffin- and glycol methacrylate-embedded CNS tissue specimens from AIDS autopsies. Mistletoe lectin I (ML I) as cell-marker.

Brain tissue and spinal cord tissue from 12 patients who had died of AIDS was fixed in neutral formalin; then after the embedment of some of it in paraffin and some of it in glycol methacrylate, it was analyzed lectinhistochemically with mistletoe lectin I (ML I). Mistletoe lectin (ML I) is a reliable marker for microglia cells and macrophages and for special cell forms (polynuclear giant cells, so-called pericytes) belonging to this cell system. In both the embedding procedures used, the representation of the cells is very clear and subtly differentiated so that the preparations are very well suited to the study of AIDS-associated tissue damage in the CNS. Whereas the immunological macrophage markers (CD 68 markers) KPI, PG-M1 produce good results on paraffin-embedded material but are completely useless on material embedded in glycol methacrylate, the cells of the monocyte-macrophage system can be represented very well and reliably after being embedded in glycol methacrylate with mistletoe lectin I (ML I).

Hyaline globules reacting positively with zidovudine antibody in brain and spinal cord of AIDS patients.

Histology of the central nervous system in nine AIDS showed extracellular hyaline globules in the white matter of the brain and the spinal cord. In immunohistochemical studies with a battery of antibodies, the only positive reaction of these globules was with an antibody to zidovudine. High-performance liquid chromatography showed the presence of a zidovudine isomer in eluates of brain tissue from these patients.