[Histopathological diagnose of non-alcoholic and alcoholic fatty liver disease]. / Histopathologische Diagnose der nicht alkoholischen und alkoholischen Fettlebererkrankung.

Alcoholic fatty liver (AFL) as well as non-alcoholic fatty liver (NAFL) are characterised by deposition of lipids into hepatocytes. The diagnosis of steatosis is made if lipid deposition exceeds 5 % of hepatocytes, in case of more than 50 % it is called "fatty liver". An additional inflammatory reaction, with ballooning of hepatocytes, leads to alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH). Both ASH or NASH may lead to fibrosis or cirrhosis. To date in clinical practice it is not possible to differentiate between steatosis and steatohepatitis just on the basis of non-invasive tests. Steatohepatitis is present if, along with steatosis, both inflammatory infiltrates of mixed cells in the small liver lobules and liver cell injury in terms of ballooning can be detected. Liver biopsy represents the "gold standard" for confirming the diagnosis and to determine inflammatory activity and potential fibrosis of fatty liver disease. Indications for biopsy should take into account the possible information and its consequences as compared to expense and complication rate and therefore should be assessed in the clinical context.

[Histopathological diagnosis of non-alcoholic and alcoholic fatty liver disease. Grade 2 consensus-based guidelines]. / Histopathologische Diagnose der nichtalkoholischen und alkoholischen Fettlebererkrankung. Konsensusbasierte Leitlinie der Stufe 2.

Both alcoholic (AFL) and non-alcoholic fatty liver (NAFL) are characterized by lipid deposition in hepatocytes. The diagnosis of steatosis is made when lipid deposition exceeds 5% of hepatocytes, while involvement of more than 50% is called "fatty liver ". An additional inflammatory reaction leads to alcoholic (ASH) or non-alcoholic steatohepatitis (NASH). Steatohepatitis is present when both inflammatory infiltrates of mixed cells in the small liver lobules as well as liver cell injury in terms of ballooning can be detected.Liver biopsy represents the "gold standard" for confirming diagnosis and determining inflammatory activity and potential fibrosis of fatty liver disease.The differential diagnosis of ASH-NASH cannot be made on the basis of histological criteria alone. Steatosis, inflammatory changes and hepatocytic injury can be semiquantified as a "Brunt Score" or "NAS" (NAFLD activity score), providing the basis on which to decide whether or not steatohepatitis is present.People at increased risk of developing a fatty liver possess an increased risk of developing chemotherapy-associated steatohepatitis (CASH).Histologically, pediatric NASH differs from adult NASH and is often only clinically manifest through a mild if persistent elevation in transaminases.

Mallory-Denk-bodies: lessons from keratin-containing hepatic inclusion bodies.

Inclusion bodies are characteristic morphological features of various neuronal, muscular and other human disorders. They share common molecular constituents such as p62, chaperones and proteasome subunits. The proteins within aggregates are misfolded with increased beta-sheet structure, they are heavily phosphorylated, ubiquitinylated and partially degraded. Furthermore, involvement of proteasomal system represents a common feature of virtually all inclusions. Multiple aggregates contain intermediate filament proteins as their major constituents. Among them, Mallory-Denk bodies (MDBs) are the best studied. MDBs represent hepatic inclusions observed in diverse chronic liver diseases such as alcoholic and non-alcoholic steatohepatitis, chronic cholestasis, metabolic disorders and hepatocellular neoplasms. MDBs are induced in mice fed griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidine and resolve after discontinuation of toxin administration. The availability of a drug-induced model makes MDBs a unique tool for studying inclusion formation. Our review summarizes the recent advances gained from this model and shows how they relate to observations in other aggregates. The MDB formation-underlying mechanisms include protein misfolding, chaperone alterations, disproportional protein expression with keratin 8>keratin 18 levels and subsequent keratin 8 crosslinking via transglutaminase. p62 presence is crucial for MDB formation. Proteasome inhibitors precipitate MDB formation, whereas stimulation of autophagy with rapamycin attenuates their formation.

Occurrence and immunolocalization of plectin in tissues.

Various tissues from rat were examined for the occurrence and cellular localization of plectin, a 300,000-dalton polypeptide component present in intermediate filament-enriched cytoskeletons prepared from cultured cells by treatment with nonionic detergent and high salt solution. The extraction of liver, heart, skeletal muscle, tongue, and urinary bladder with 1% Triton/0.6 M KCl yielded insoluble cell residues that contained polypeptides of Mr 300,000 in variable amounts. These high Mr polypeptide species and a few bands of slightly lower Mr (most likely proteolytic breakdown products) were shown to react with antibodies to rat glioma C6 cell plectin using immunoautoradiography and/or immunoprecipitation. By indirect immunofluorescence microscopy using frozen sections (4 micron) of stomach, kidney, small intestine, liver, uterus, urinary bladder, and heart, antigens reacting with antibodies to plectin were found in fibroblast, endothelial, smooth, skeletal, and cardiac muscle, nerve, and epithelial cells of various types. Depending on the cell type, staining was observed either throughout the cytoplasm, or primarily at the periphery of cells, or in both locations. In hepatocytes, besides granular staining at the cell periphery, conspicuous staining of junctions sealing bile canaliculi was seen. In cardiac muscle strong staining was seen at intercalated disks and, as in skeletal muscle, at Z-lines. In cross sections through smooth muscle, most strikingly of urinary bladder, antibodies to plectin specifically decorated regularly spaced, spot-like structures at the cell periphery. By immunoelectron microscopy using the peroxidase technique, antiplectin-reactive material was found along cell junctions of hepatocytes and was particularly enriched at desmosomal plaques and structures associated with their cytoplasmic surfaces. A specific immunoreaction with desmosomes was also evident in sections through tongue. In cardiac muscle, besides Z-lines, intercalated disks were reactive along almost their entire surface, suggesting that plectin was associated with the fascia adherens, desmosomes, and probably gap junctions. In smooth muscle cells, regularly spaced lateral densities probably representing myofilament attachment sites were immunoreactive with plectin antibodies. The results show that plectin is of widespread occurrence with regard to tissues and cell types. Furthermore, immunolocalization by light and electron microscopy at junctional sites of various cell types and at attachment sites of cytoplasmic filaments in epithelial and muscle cells suggests that plectin possibly plays a universal role in the formation of cell junctions and the anchorage of cytoplasmic filaments.

Hepatic organelle interaction. IV. Mechanism of succinate enhancement of formaldehyde accumulation from endoplasmic reticulum N-dealkylations.

Further evidence for organelle interaction during drug metabolism by the liver is presented. The apparent stimulation by succinate of formaldehyde accumulation in the medium, which was reported to occur with liver slices and homogenates as well as with mitochondria plus microsomes, has been shown to be the result of succinate inhibition of mitochondrial aldehyde dehydrogenase. The mechanism of succinate inhibition is shown to be by reverse electron transport, and an increase in the NADH to NAD+ ratio in the mitochondria; the aldehyde dehydrogenase requires the oxidized form of the pyridine nucleotide as its cofactor. Studies on in vitro N-demethylation by liver microsomes and endoplasmic reticulum segments which cosediment with the mitochondria indicate that formaldehyde produced by the mixed function oxidase is handled differently from formaldehyde added to the medium. The latter is mainly retained in the medium containing 5 mM semicarbazide, while the generated formaldehyde is more than 50% consumed by the mitochondria. Electron microscopy has indicated that the microsomes and the endoplasmic reticulum fragments have a tendency to align themselves close to the mitochondria when present in the same medium. Consequently, it is possible that formaldehyde released to the medium adjacent to the mitochondria, as by N-demethylation, would be exposed to semicarbazide for shorter periods than that added directly to the medium. In agreement with this suggestion, complexing of formaldehyde with semicarbazide was observed spectroscopically not to be an extremely rapid reaction even at 37 degrees C. This is believed to be the reason for the greater extent of consumption of formaldehyde generated by the endoplasmic reticulum.

SAHA induces caspase-independent, autophagic cell death of endometrial stromal sarcoma cells by influencing the mTOR pathway.

Endometrial stromal sarcomas are rare and molecular mechanisms involved in their pathogenesis are poorly understood. Covalent modifications of histone proteins, in particular de/acetylation of lysine residues, play an important role in the regulation of gene transcription in normal and neoplastic cells, but there are only limited data about these processes in solid mesenchymal tumours. We treated endometrial stromal sarcoma cells (ESS-1) and non-malignant human endometrial stromal cells (HESCs) with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. SAHA was able to mediate the cell cycle and expression of genes related to the malignant phenotype of endometrial stromal tumours, eg p21(WAF1) and HDAC7. SAHA led to dose-dependent differentiation and death of ESS-1 cells but not of HESCs. Exposure of HESCs to SAHA resulted only in slightly decreased cell proliferation. SAHA also increased the p21(WAF1) expression and caused significant changes in the cell cycle by inhibiting the G1/S transition in ESS-1 cells. Recovery experiments indicated that these changes became irreversible when the tumour cells were treated with SAHA for longer than 24 h. In our experimental system, not apoptotic but autophagic processes were responsible for the cell death. Monodansyl cadaverine accumulation in treated ESS-1 cells and decreased expression of the mTOR and phospho-S6 ribosomal protein (S6rp) additionally supported this observation. Taken together, our study indicates that HDACs might be considered as potential drug targets in the therapy of stromal sarcomas and that SAHA might be a promising therapeutic agent for endometrial stromal sarcoma.

The Genome Austria Tissue Bank (GATiB).

In the context of the Austrian Genome Program, a tissue bank is being established (Genome Austria Tissue Bank, GATiB) which is based on a collection of diseased and corresponding normal tissues representing a great variety of diseases at their natural frequency of occurrence from a non-selected Central European population of more than 700,000 patients. Major emphasis is put on annotation of archival tissue with comprehensive clinical data, including follow-up data. A specific IT infrastructure supports sample annotation, tracking of sample usage as well as sample and data storage. Innovative data protection tools were developed which prevent sample donor re-identification, particularly if detailed medical and genetic data are combined. For quality control of old archival tissues, new techniques were established to check RNA quality and antigen stability. Since 2003, GATiB has changed from a population-based tissue bank to a disease-focused biobank comprising major cancers such as colon, breast, liver, as well as metabolic liver diseases and organs affected by the metabolic syndrome. Prospectively collected tissues are associated with blood samples and detailed data on the sample donor's disease, lifestyle and environmental exposure, following standard operating procedures. Major emphasis is also placed on ethical, legal and social issues (ELSI) related to biobanks. A specific research project and an international advisory board ensure the proper embedding of GATiB in society and facilitate international networking.

Epithelial blood group antigens in human carcinomas of the distal colon: further studies on their pathologic significance.

Blood group antigen content of human carcinomas located in the distal large bowel (descending colon, sigmoid colon, and rectum) was determined by the specific red cell adherence reaction and was compared to several morphologic features of prognostic significance, e.g., differentiation, extent of tumor spread, peritumoral lymphoplasmocytic infiltration, and growth patterns. About 50% of the carcinomas expressed blood group antigens in either diffuse or patchy distribution. Classification of tumors according to the extent of local spread revealed that 60% of Dukes stage A tumors were blood group antigen-negative, whereas 58% of those in Dukes stage B were positive. Dukes stage C lesions had an intermediate position, and this limits the prognostic usefulness of blood group antigen determinations. No significant correlations were found between blood group antigenicity and the degree of histologic differentiation, the degree of peritumoral lymphoplasmocytic infiltration, and the mode of tumor growth.

Epithelial blood group antigens in colon polyps. I. Morphologic distribution and relationship to differentiation.

The distribution patterns of epithelial blood group AB antigens (BG) in colon polyps of varying degrees of differentiation were studied by the mixed cell agglutination reaction. BG appeared in colon polyps if a certain degree of dedifferentiation was present. Two different distribution patterns were recognized: 1) association of BG with the secretory part of goblet cells with slight-to-moderate atypia and 2) association of BG with the whole cells in cases of pronounced dedifferentiation and loss of secretory activity. The second type resembled the distribution pattern of BG found previously in colon carcinomas. With respect to BG, the mucosa of colon polyps behaved similarly to embryonal colon mucosa. The detection of BG represents a useful method to assess objectively the degree of dedifferentiation in most colon polyps.

Microsomal mixed-function oxidase and activities of some related enzymes in hyperplastic nodules induced by long-term griseofulvin administration in mouse liver.

Hepatic hyperplastic nodules induced in mice by long-term griseofulvin administration were examined for selected microsomal activities and responses to enzyme inducers. Despite a decrease in microsomal cytochrome P-450 in hyperplastic nodules, aminopyrine N-demethylase was at control levels. Benzopyrene hydroxylase activity was slightly lower in microsomes derived from hyperplastic nodules than in those of control liver. Reduced nicotinamide adenine dinucleotide-cytochrome b5 reductase was at control level, but reduced nicotinamide adenine dinucleotide- and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductases and the NADPH-ferricyanide reductase were increased. NADPH-supported lipid peroxidation was lower in microsomes from hyperplastic nodules than in those from control liver, whereas microsomal stearoyl coenzyme A desaturase activity was almost doubled in the nodules. NADPH-cytochrome c reductases isolated and semipurified from hyperplastic nodule and from control liver microsomes showed almost identical affinity for NADPH. Microsomal enzymes of hyperplastic nodules responded readily to phenobarbital induction, but sodium dodecyl sulfate-polyacrylamide gel electrophoresis disclosed differences in the polypeptide patterns in the molecular weight range from 47,000 to 54,000 between microsomes derived from hyperplastic nodules and control livers.

Effect of Griseofulvin on 5-aminolevulinate synthase and on ferrochelatase in mouse liver neoplastic nodules.

Treatment of mice with griseofulvin for 8 months induced hepatocellular nodules in the liver which persist after discontinuation of griseofulvin feeding. We investigated the porphyrogenic effect of griseofulvin on these nodules and surrounding nonneoplastic liver after renewed short-term exposure of tumor-bearing mice to this agent. Griseofulvin treatment for 4 days led to marked elevation of the activity of 5-aminolevulinate synthase in peritumoral (3.8-fold) and control (6-fold) liver. The increase in enzyme activity was much less pronounced in the nodules (1.5-fold). Ferrochelatase activity was markedly decreased under the same experimental conditions in both peritumoral and control livers (to 18 and 13.5%, respectively, of the pretreatment values), but the effect was considerably smaller in nodules (to 40% of the pretreatment value). These results may explain the lack of porphyrin accumulation in tumor tissue.

4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, a second-generation antineoplastic agent of the alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazone series.

4-Methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ-1) was studied to determine its potential for clinical trail as a second-generation antineoplastic agent of the alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazone class. MAIQ-1 was shown to be among the most potent known inhibitors of the major target for the expression of antineoplastic activity by this class of agents, the enzyme ribonucleoside diphosphate reductase, requiring only 0.06 micronM for 50% inhibition. This potency at the enzymatic level was consistent with its antineoplastic activity against the murine neoplasms Sarcoma 180, Leukemia L1210, Leukemia P388, and the B16 melanoma. The acetylation of the 5-amino group of the model substrate 5-amino-1,4-dimethylisoquinoline was lower than that of 5-amino-1-methylisoquinoline when incubated with acetyl-coenzyme A and rat liver homogenate. This finding suggests that the presence of the 4-methyl function offers steric hinderance to enzymatic substitution of the adjacent 5-amino group. In vivo metabolism of MAIQ-1 in mice, studied with [3'-14C]MAIQ-1 showed that relatively slow excretion of this agent occurred, since the cumulative urinary excretion of radioactivity was only 35% in 48 HR. About 51% of excreted urinary radioactivity was present in chromatograms in an area corresponding to the iron chelate of MAIQ-1, and only a minor quantity of material migrating like acetylated MAIQ-1 was present in urine, a finding consistent with enzymatic data with liver homogenates. The results indicate that MAIQ-1 has the antineoplastic activity, enzyme inhibitory potency, and relative resistance to metabolic inactivation required of an agent of this class for clinical trials.

Rearrangement of the hepatocyte cytoskeleton after toxic damage: involution, dispersal and peripheral accumulation of Mallory body material after drug withdrawal.

Large cytoplasmic aggregates (Mallory bodies) containing randomly arranged 10 to 20 nm thick filaments are characteristic structures of hepatocytes in certain liver diseases, especially alcoholic hepatitis of man and griseofulvin intoxication of mouse. Biochemical and immunological studies have shown that such Mallory bodies contain structural proteins related to the cytokeratins present in epithelial cells of various kinds, normal hepatocytes included. We have studied the mode of reorganization of the hepatocyte cytoskeleton during involution of Mallory bodies experimentally induced in mice by prolonged griseofulvin feeding after withdrawal of the drug, using immunofluorescence microscopy and electron microscopy. Dispersal of Mallory bodies into small granules accumulating in the hepatocyte periphery is a characteristic feature of Mallory body involution. Dispersed heaps of Mallory body material are seen in hepatocyte cortices at lateral (hepatocyte-to-hepatocyte) as well as at sinusoidal cell surfaces. Mallory body material dispersed to the cell periphery exhibits a filamentous ultrastructure an often shows conspicuous associations with desmosomes. Three different types of desmosome complexes can be discriminated in livers of mice allowed to recover from the intoxication: (i) desmosomes with normally looking bundles of tonofilaments; (ii) desmosomes associated with Mallory body filaments but few, if any, tono-filaments; and (iii) desmosomes lacking tonofilaments as well as Mallory body filaments. The associations between Mallory body filaments and desmosomes during Mallory body involution further strengthen the relationship between Mallory body filaments and tonofilaments. The observations suggest that Mallory body material, at least in part, may be utilized for rearrangement of the hepatocyte cytoskeleton, especially tonofilament-desmosome complexes.

Mouse model for protoporphyria. I. The liver and hepatic protoporphyrin crystals.

Outbred albino mice were rendered protoporphyric by a diet containing 2.5% (weight) of griseofulvin. There was a 5-fold increase in liver weight, hepatocellular degeneration and necrosis, cholestasis, ductular proliferation and cirrhosis. Liver protoporphyrin values were elevated and brown pigment granules were present in hepatocytes, Kupffer cells, and bile ducts. The granules showed red fluorescence, birefringence, and, at the ultrastructural level, consisted of aggregates of needle-like crystals. Crystals isolated from such livers showed solubility and absorption characteristics of protoporphyrin; in vitro recrystallization of protoporphyrin, extracted from protoporphyric mouse livers, yielded crystals identical with those observed in vivo, and commercial protoporphyrin exhibited similar morphologic features. The liver pathology and protoporphyrin crystals observed in these animals are identical to the liver pathology and crystals observed in the human disease, erythropoietic protoporphyria. In this mouse model, protoporphyrin crystals are intimately associated with hepatocellular injury and it appears that their accumulation within hepatocytes leads to hepatocellular destruction. A similar pathogenesis is postulated for the hepatic damage that occurs in some cases of erythropoietic protoporphyria.

Pronase pretreatment of tissue sections enhances sensitivity of the unlabelled antibody-enzyme (PAP) technique.

Treatment of dewaxed sections of formalin-fixed paraffin embedded material with 0.1% pronase for 15 min at 37 degrees C prior to the performance of the unlabelled antibody-enzyme (PAP) procedure greatly enhanced its sensitivity. This was shown by detection of immunoglobulin within plasma cells in chronic gastritis specimens.

Effect of protease pretreatment on immunomorphologic demonstration of hepatitis-B-surface antigen in conventional paraffin-embedded liver biopsy material: quantitative evaluation.

The effect of protease pretreatment on the demonstration of hepatitis-B-surface antigen by immunofluorescence (IF) and the unlabeled peroxidase-antiperoxidase technique (PAP) in conventionally processed (formalin-fixed, paraffin-emmbedded) liver biopsy material was quantitatively assessed by microphotometry. Protease digestion significantly enhances the intensity of specific staining by both methods, and, in addition, suppresses non-specific background fluorescence. The sensitivity of the immunomorphologic test is significantly enhanced, and antigen in low amounts, for example hepatitis-B-surface antigen associated with liver cell membrane ('membrane' staining), is easily detected.

The distribution of intermediate filament proteins, actin and desmoplakins in human placental tissue as revealed by polyclonal and monoclonal antibodies.

The distribution of intermediate filament proteins (cytokeratin, vimentin, desmin), actin, and desmoplakins in various placental compartments was studied by immunofluorescence microscopy using polyclonal and monoclonal antibodies. Trophoblast cells (cytotrophoblast, syncytiotrophoblast, isolated trophoblast cells, trophoblastic giant cells) were strongly stained by all types of cytokeratin antibodies. Antibodies to desmoplakins revealed the presence of desmosomes at all membranes, except the basal membrane of cytotrophoblast cells, and at the basal as well as the lumen-oriented membrane of the syncytiotrophoblast. After disappearance of the cytotrophoblast cell layer the distribution of desmosomes in the syncytiotrophoblast was unaltered. Isolated trophoblast cells contained desmosomes around their entire circumference. Amnion epithelial cells were heterogeneous with respect to cytokeratin composition as revealed, for example, by polyclonal antibodies with a broad range of cytokeratin reactivity and by monoclonal antibodies to cytokeratin No. 18. With the latter, a heterogeneous staining of amnion epithelial cells was achieved. Desmosomes (spots reactive with desmoplakin antibodies) were present at the lateral membranes of the amnion epithelial cells. In addition, vimentin filaments were coexpressed in these cells. Large vessels of the chorionic plate and stem villi showed thick walls consisting of vimentin-, desmin- and actin-positive cells. They were surrounded by mantles rich in vimentin-, desmin- and actin-positive cells, resembling myofibroblasts. This indicates that these cells may play a role in villous contractility and modulation of the intervillous space with effect on both maternal and fetal placental circulation.

Triple therapy with sucralfate, amoxycillin and metronidazole for healing duodenal ulcer and eradicating Helicobacter pylori infection.

METHODS: Seventy-seven chronic duodenal ulcer patients (50 male) were entered into this study. Treatment was started with sucralfate suspension (2 g b.d.) for 8 weeks. After 2 weeks the patients also received 750 mg amoxycillin t.d.s. plus 500 mg metronidazole t.d.s. for 12 days. Endoscopy with six antral biopsies (urease test, Gram staining, culture and histology) was performed before commencement of sucralfate therapy, 4 weeks after the end of antibiotic therapy, and during the follow-up examinations at 6 and 12 months. RESULTS: Seven patients were excluded prematurely from the study. Helicobacter pylori in five patients had primary resistance to metronidazole and these patients were also excluded. The ulcer healing rate 4 weeks after the end of antibiotic therapy was 92% and the H. pylori eradication rate was 82% (all per protocol). In all patients who were still H. pylori-positive, the bacterium became resistant to metronidazole and histologically the inflammatory state of the mucosa was the same as before treatment. All H. pylori-eradicated patients (n = 53) were re-examined after 6 and 12 months; no ulcer recurrence was observed and each time only one reinfection was found. CONCLUSIONS: In an open study, sucralfate with amoxycillin and metronidazole appeared to act together to eradicate H. pylori infection and to speed duodenal ulcer healing.

Lack of Pseudomelanosis coli in colonic adenomas suggests different pathways of apoptotic bodies in normal and neoplastic colonic mucosa.

Pseudomelanosis coli is characterized by pigment deposition in the lamina propria and caused by increased epithelial apoptosis. Pseudomelanosis coli is absent in colonic neoplasia. The aim of our studies was to investigate this phenomenon in more detail. Apoptotic fragments of epithelial cells and their distribution, cell proliferation (Ki-67, MIB 1 immunostaining), macrophages (CD68 immunostaining), Bcl-2 expression and apoptosis [terminal-deoxynucleotidyl-transferase mediated dUTP fluorescein nick end labeling (TUNEL) assay] were studied in adenomas arising in normal and melanotic colonic mucosa, in normal colonic mucosa and colonic mucosa with pseudomelanosis alone. In adenomas, we found 7.0 apoptotic bodies per 100 epithelial cells in the epithelial layer and only 0.2 apoptotic bodies per high power field (HPF) in the lamina propria. In contrast, in melanotic mucosa 1.7 apoptotic bodies per 100 epithelial cells in the epithelial layer and 2.5 per HPF in the lamina propria were found. Our results show that apoptotic fragments remain in the neoplastic (adenomatous) epithelium and do not reach (at least in higher amounts) the lamina propria. They can, therefore, not contribute to the development of pseudomelanosis in these lesions. However, macrophages are diminished in adenomas. Proliferation (Ki-67) and also Bcl-2 expression are highly increased in adenomas. The pathway of mucosal macrophages is also discussed.