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Virchows Arch

p53 mutation and overexpression in hepatocellular carcinoma and dysplastic nodules in the liver.

Kang YK. Kim CJ. Kim WH. Kim HO. Kang GH. Kim YI.
Department of Pathology, Inje University Seoul Paik Hospital, Seoul, Korea.
In hepatocarcinogenesis, both de novo and multistep pathways have been suggested and in the latter a dysplastic nodule is the proposed precancerous lesion. In this study, we tried to ascertain whether or not the p53 gene is altered in low-grade/high-grade dysplastic nodules (LDN/HDN) and to determine the role of p53 alteration in multistep hepatocarcinogenesis. Eight hepatocellular carcinomas (HCCs), 9 HDNs, 17 LDNs and 25 cirrhotic nodules (LCs) were examined by polymerase chain reaction-single strand conformation polymorphism/direct sequencing and immunohistochemical staining for p53. Four of the 8 HCCs (50%) revealed p53 overexpression and 2 (25%) had missense mutations. Four of the 9 HDNs (44%) showed weak and/or focal p53 overexpression but none had mutation in the exons examined. Neither p53 overexpression nor mutation was found in 17 LDNs and 25 LCs. These results suggest that p53 mutation might be an unusual event in precancerous lesions of multistep hepatocarcinogenesis (DN-HCC sequence) and may play a less crucial part than in colorectal carcinogenesis.

Frequent occurrence of apoptosis is an early event in the oncogenesis of human gastric carcinoma.

Ikeda M. Shomori K. Endo K. Makino T. Matsuura T. Ito H.
First Department of Pathology, Faculty of Medicine, Tottori University, Japan.
We examined the relationship between apoptosis and the progression of human gastric carcinoma. Studies were conducted on a total of 88 surgically removed stomachs, comprising 26 minute (less than 5 mm in diameter), 29 early (limited to the mucosal and submucosal layer) and 33 advanced carcinomas. Apoptotic cells were visualized by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labelling (TUNEL). Serial sections were immunostained for p53 and Ki-67. The mean apoptotic indices (AI: percentage of TUNEL signal positive cells) of minute, early, and advanced carcinomas were 4.1 +/- 0.6, 3.8 +/- 1.2, and 4.0 +/- 1.2 in 46 well differentiated carcinomas, and 2.1 +/- 0.5, 2.7 +/- 0.9, and 2.2 +/- 1.1 in 42 poorly differentiated carcinomas, respectively. Similarly, the mean Ki-67 labelling indices (KI) were 39.2 +/- 7.8, 47.2 +/- 12.8, 52.6 +/- 13.1 in the former, and 35.0 +/- 9.3, 36.9 +/- 10.3, and 40.0 +/- 9.2 in the latter, respectively. Both mean AI and mean KI were significantly higher in well differentiated than in poorly differentiated carcinomas (P < 0.05). However, the value of mean AI did not differ among minute, early, and advanced carcinomas in either histological type, while KI increased gradually with tumour progression. The frequency of nuclear p53 expression did not differ among the three categories, implying that the gene mutation is an early event in gastric carcinogenesis. There was no statistical significance between nuclear p53 expression and mean AI. These results suggest that the progression of gastric cancer is defined by a gradual increase of proliferative activity and constant occurrence of apoptosis and that naturally occurring apoptosis is induced predominantly via a p53-gene-independent pathway.

High incidence of upper gastrointestinal tract involvement in Crohns disease.

Oberhuber G. Hirsch M. Stolte M.
Department of Clinical Pathology, University of Vienna, Medical School, Austria. Georg.Oberhuber@akh-wien.ac.at
A better definition of gastric mucosal histology in Crohn's disease permits a more accurate estimation of the frequency of upper gastrointestinal tract involvement in Crohn's disease. In a retrospective study of 792 patients with known Crohn's disease the incidence of lesions associated with the disease was determined in the duodenum, duodenal bulb, and gastric antrum and body mucosa. Crohn's disease was identified histologically in the antrum in 41.5%, in the body in 37.1%, in the duodenum in 12.1%, and in the duodenal bulb in 13%. In a further 15% and 17.4% of cases, Crohn's disease of the duodenum and duodenal bulb, respectively, was suspected. The positive predictive value of focal gastritis in patients undergoing upper endoscopy and not yet known to have Crohn's disease is as high as 94%. Thus, a high proportion of Crohn's disease patients show upper gastrointestinal tract involvement, with the major involvement in the antrum. Focal gastritis suggesting Crohn's disease turned out to have a high positive predictive value in patients not known to have Crohn's disease at the time of gastroscopy.

Alpha-fetoprotein-producing gastric carcinoma presenting focal hepatoid differentiation in metastatic lymph nodes.

Kang GH. Kim YI.
Department of Pathology, Seoul National University College of Medicine, Chongno-gu, Korea.
Hepatoid adenocarcinoma (HA) is a rare variant of adenocarcinoma of the stomach, which is clinically characterized by increased level of serum alpha-fetoprotein (AFP) and poor prognosis. Microscopic findings include both adenocarcinomatous and hepatoid elements. A case of gastric adenocarcinoma with focal hepatoid differentiation confined within the metastatic lymph nodes occurred in a 55-year-old woman, who developed an advanced gastric carcinoma composed entirely of a typical papillo-tubular adenocarcinoma. Metastatic tumors were present in 8 of 13 perigastric lymph nodes, and 3 of these showed medullary and trabecular tumour growth reminiscent of hepatocellular carcinoma with immunohistochemical positivity for AFP. Preoperative serum AFP was 630 ng/ml and dropped to 76 ng/ml 2 weeks after the operation. Microscopic and immunohistochemical studies on the entire primary tumour tissue failed to demonstrate a focus of hepatoid or an AFP-positive area. This suggests that elevation of serum AFP may be reflected by focal hepatoid differentiation only in the metastatic lymph nodes, requiring extensive evaluation of the metastatic tumour in regional lymph nodes in the case of AFP-producing gastric carcinoma.

Are giant ganglia a reliable marker of intestinal neuronal dysplasia type B (IND B)?

Year 1998
Lumb PD. Moore L.
Department of Histo/Cytopathology, Central Manchester Healthcare Trust, UK.
It has been suggested that giant ganglia are a marker for a developmental bowel disorder, intestinal neuronal dysplasia of the submucosal plexus (IND B), diagnosed in a proportion of patients with severe intractable constipation. Diagnosis of this condition, however, remains controversial with a wide variation in the frequency of diagnosis in different centres. Our aim was to assess the frequency with which giant ganglia could be found in the bowel of individuals who did not give a history of life-long constipation. We also aimed to assess the reproducibility of giant ganglia counts. For this two pathologists independently assessed pieces of normal bowel taken away from the site of the lesion in patients who had undergone surgery for colorectal carcinoma. Giant ganglia containing seven or more ganglion cells were found in 76 and 78% of subjects by each of the two pathologists. There was 1 giant ganglion per 10 ganglia counted in those patients in whom they were identified and 1 giant ganglion per 10.9 ganglia overall. Sections from eight patients in whom there was a history of constipation and/or melanosis coli did not show a greater number of giant ganglia. We conclude therefore that so-called "giant ganglia" are a common feature in the submucosa of normal bowel and that the presence of occasional giant ganglia cannot be considered diagnostic of IND B.

De novo expression of nonhepatocellular cytokeratins in Mallory body formation.

Year 1998
Schirmacher P. Dienes HP. Moll R.
Institute of Pathology, University of Mainz, Germany.
Mallory bodies (MBs) are eosinophilic cytoplasmic inclusions observed predominantly in alcoholic liver disease. Although linked to disease activity, their pathogenesis is still unclear. Since intermediate filaments (cytokeratins) are major components of MBs, their cytokeratin polypeptide composition was analysed with monospecific antibodies for cytokeratins 7, 8, 14, 18, 19, and 20 by immunohistology. MBs were identified by light microscopy and ubiquitin immunostaining. All MBs were positive for cytokeratins 8 and 18. A significant percentage of the MBs was strongly positive for cytokeratins 19 and/or 20, which are not detectable in hepatocytes of normal liver and, in the case of cytokeratin 20, in hepatocytes of diseases devoid of MBs. MBs were essentially negative for cytokeratins 7 and 14. De novo expression of cytokeratins 19 and 20 was independent of the aetiology, occurring in all MB-associated diseases analysed, and seemed to precede MB formation, since in some hepatocytes a cytoskeletal-type staining pattern for these cytokeratins was present. In hepatocellular carcinomas cytokeratins 19 and 20 were frequently detected, but their cellular distribution was less closely associated with MBs. The ectopic expression of cytokeratins 19 and 20 appears to be related to MB formation and may take part in the derangement of the intermediate filaments during MB formation.

Comparison of matrix metalloproteinase expression in normal and cirrhotic human liver.

Year 1998
Lichtinghagen R. Breitenstein K. Arndt B. Kuhbacher T. Boker KH.
Institute of Clinical Chemistry I, Medizinische Hochschule Hannover, Germany.
To study the extend of ongoing tissue remodelling in end-stage cirrhosis, the expression of different matrix metalloproteinases [interstitial collagenase (MMP-1), Mr 72000 gelatinase (MMP-2), stromelysin-1 (MMP-3) and stromelysin-3 (MMP-11)] and of TIMP-1 was studied in 13 cirrhotic livers explanted at transplantation. The results were compared with those obtained in normal liver. Western blot, northern blot, ELISA, RT-PCR and zymogram analysis were used. Proenzymes of stromelysin-1 and -3, interstitial collagenase and Mr 72000 gelatinase were positive in normal liver, while activated enzymes were not detectable in western blot analysis. In cirrhosis proenzyme levels of the studied MMPs were reduced to a mean of 60-70%, but mRNA expression and gelatin-degrading activity increased. TIMP-1 expression was detectable on mRNA level and by ELISA in normal liver and also increased in cirrhosis. Our results show that mRNA expression of certain matrix metalloproteinases is increased in end-stage liver cirrhosis, while the amount of proenzyme is decreased, indicating enhanced MMP proenzyme turnover. These data suggest that besides increased TIMP-1 activity, altered MMP expression may also play a part in fibroproliferation in liver disease.

A pancreatic mucinous cystadenoma in a man with mesenchymal stroma, expressing oestrogen and progesterone receptors.

Year 1998
Wouters K. Ectors N. Van Steenbergen W. Aerts R. Driessen A. Van Hoe L. Geboes K.
Department of Pathology, University Hospitals Leuven, Belgium.
A 43-year-old man presented with abdominal discomfort caused by relapsing pancreatitis. Radiological examination revealed a multilocular cystic mass in the tail of the pancreas, which was resected. Gross examination showed a multilocular cystic lesion measuring 2.5 cm in diameter and containing clear fluid. Microscopically, a mucinous cystadenoma with mesenchymal stroma was diagnosed. The lesion showed two different components: a cyst lined by a columnar, mucin-secreting epithelium and a moderate cellular stroma composed of spindle cells. The stromal element appeared similar to primitive mesenchyme. Immunohistochemical staining confirmed this origin through vimentin expression and showed moderate to strong nuclear staining with oestrogen and progesterone receptor antibodies. Cystadenomas are rare tumours of the pancreas, but mesenchymal stroma is uncommon in such tumours; it is more frequently described in the liver and the bile ducts, and primarily in women.

Myoepithelial hamartoma of the duodenal wall.

Year 1998
Ryan A. Lafnitzegger JR. Lin DH. Jakate S. Staren ED.
Rush-Presbyterian-St. Luke's Medical Center, Department of Pathology, Chicago, IL 60612, USA.
A rare case of myoepithelial hamartoma of the duodenal wall is presented, and previous case reports found in the literature are reviewed. Myoepithelial hamartomas are thought to arise from displaced pancreatic anlage present along the gastrointestinal tract during embryogenesis, which can differentiate into various pancreatic elements; the most highly differentiated form is heterotopic pancreas. An alternative theory is pancreatic metaplasia of endodermal tissues. We describe a 41-year-old man who presented with abdominal pain and vomiting. CT scanning revealed a mass at the head of the pancreas. A pancreaticoduodenectomy was performed for presumed cystadenoma. Histology of the mass revealed a disorderly arrangement of smooth muscle, dilated and nondilated ducts, pancreatic acinar tissue and mucus glands. The relationship of myoepithelial hamartomas involving the small bowel to similar lesions in the stomach, bile ducts and gallbladder is discussed.

Characterization of the inflammatory infiltrate in autoimmune cholangitis. A morphological and immunhistochemical study.

Year 1998
Kaserer K. Exner M. Mosberger I. Penner E. Wrba F.
Department of Clinical Pathology, University of Vienna, School of Medicine, Allgemeines Krankenhaus, Austria. klaus.kaserer@akh.wien.ac.at
Autoimmune cholangitis (AIC) is characterised by clinical and/or laboratory features of cholestasis, the presence of antinuclear antibodies and the lack of antimitochondrial antibodies. Histologically, changes largely identical to those found in primary biliary cirrhosis (PBC) are typically found. It is not possible to differentiate between AIC and PBC on conventional morphological grounds, and we therefore wished to find whether there is a difference between these entities in the composition of the inflammatory infiltrate leading to bile duct destruction. In liver biopsies from ten patients with confirmed AIC and ten patients with PBC the inflammatory infiltrate was characterised with antibodies against CD 3, OPD 4 CD 8, GB 7, L 26, CD 56 and CD 57. In AIC, T cells were predominant in the portal inflammatory infiltrate in nine cases. Granzyme B-positive activated cytolytic T lymphocytes were found in the bile duct epithelium in five cases. All these five cases showed inflammatory bile duct destruction. No significant differences between the immunohistochemical findings in AIC and in PBC were found. We suggest that AIC is a subgroup of PBC, antimitochondrial antibody-negative type.

Membranous fat necrosis in appendices epiploicae. A clinicopathological study.

Year 1998
Ramdial PK. Singh B.
Department of Anatomical Pathology, Faculty of Medicine, University of Natal, Congella, South Africa.
Membranous fat necrosis (MFN) is a degenerative process involving mature systemic adipose tissue. It is characterised by the presence of membranocystic foci surrounded by a lipophagic fibro-inflammatory reaction typical of fat necrosis. Membranocystic foci are cysts lined by an eosinophilic membrane with pseudopapillary infoldings having the histochemical staining profile of ceroid. Although MFN is described in an increasing number of adipose tissue sites, it has not been described as a distinct entity in appendices epiploicae (AE). Macroscopically, MFN in AE mimics nodal tuberculosis or metastatic tumour with necrosis and cystic change. Ischaemia, which can be secondary to physiological or pathologic processes, is crucial in the pathogenesis of MFN in AE. Heightened awareness of MFN as a distinct entity in AE is essential for accurate diagnosis and establishment of the pathogenesis of this enigmatic pathological process.

Gastric carcinoma risk index in patients infected with Helicobacter pylori.

Year 1998
Meining A. Bayerdorffer E. Muller P. Miehlke S. Lehn N. Holzel D. Hatz R. Stolte M.
Department of Medicine II, Technical University of Munich, Germany.
Epidemiological data show an association between Helicobacter pylori gastritis and gastric carcinoma. However, most people infected with H. pylori do not develop gastric cancer. We have therefore evaluated histological criteria indicating an increased risk for gastric cancer. H. pylori gastritis was investigated in 117 patients with small (O

Defects of the respiratory chain in hepatic oncocytes.

Year 1998
Muller-Hocker J.
Pathologisches Institut der Ludwig-Maximilians-Universitat Munchen, Germany.
Oxyphilic hepatocytes, also called hepatic oncocytes, have been found in 20 of 47 cirrhotic livers (42%) with defects of the respiratory chain. Immunohistochemical studies using antisera against cytochrome-c-oxidase (complex IV) revealed respiratory chain-deficient oxyphilic foci in 16 of the 20 cases (75%). Fourteen percent of the oxyphilic areas were deficient, whereas only 8.5% of the nonoxyphilic liver nodules showed respiratory chain defects (P < 0.004). In addition, oxyphilic foci made up about 18% of all defective areas but were present in only 11.5% of the regenerative nodules. These results illustrate that oxyphilic cell change is associated with a higher propensity for the development of respiratory chain defects, but is not obligatory for this.

Poorly differentiated desmin-negative and vimentin-positive leiomyosarcoma of the stomach examined by the immunohistochemical and quick-freezing and deep-etching methods.

Year 1998
Hemmi A. Komiyama A. Ohno S. Fujii Y. Katoh R. Yokoyama A. Kawaoi A.
Second Department of Pathology, Yamanashi Medical University, Japan.
A poorly differentiated leiomyosarcoma of the stomach in a 41-year-old woman is reported. The diagnosis was confirmed by the diffuse immunohistochemical reaction to HHF35, and the presence of focal density and caveolas in some of the tumour cells by conventional electron microscopy. Immunohistochemically, most tumour cells had an undifferentiated nature, in which negative immunostaining for desmin, alpha-smooth muscle actin, and type IV collagen, and positive immunostaining for vimentin were observed. By the quick-freezing and deep-etching (QF-DE) method, these tumour cells revealed the loss of bundled actin and myosin filaments, which constitute desmin associated structures (focal densities and dense patchy areas). Their cytoplasm had many mitochondria and other cell organelles. The intermediate filaments (IFs), which were determined to be vimentin by immunohistochemistry, were observed in the inter-organellar spaces, and connected with these cell organelles. Actin filaments formed a meshwork structure and were distributed mainly in subplasmalemmal regions. Although a basal lamina was not detected by conventional electron microscopy, basal lamina-like structures, an association between the extracellular matrices and the cell membrane, were observed. Using the QF-DE method, three dimensional ultrastructural alterations of the cytoskeleton and extracellular matrix of the leiomyosarcoma were observed.

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