Abstract Background The immunohistochemical demonstration of Enhancer of zeste homologue 2 (EZH2) proved to be a useful marker in several tumor types. It has been described to distinguish reliably hepatocellular carcinomas from liver adenomas and other benign hepatocellular lesions. However, no other types of malignant liver tumors were studied so far. Methods To evaluate the diagnostic value of this protein in hepatic tumors we have investigated the presence of EZH2 by immunohistochemistry in hepatocellular carcinomas and other common hepatic tumors. EZH2 expression was examined in 44 hepatocellular carcinomas, 23 cholangiocarcinomas, 31 hepatoblastomas, 16 other childhood tumor types (rhabdomyosarcoma, neuroblastoma, Wilms’ tumor and rhabdoid tumor), 17 metastatic liver tumors 24 hepatocellular adenomas, 15 high grade dysplastic nodules, 3 biliary cystadenomas, 3 biliary hamartomas and 3 Caroli’s diseases. Results Most of the malignant liver tumors were positive for EZH2, but neither of the adenomas, cirrhotic/dysplastic nodules, reactive and hamartomatous biliary ductules stained positively. Conclusions Our immunostainings confirm that EZH2 is a sensitive marker of hepatocellular carcinoma, but its specificity is very low, since almost all the investigated malignant liver tumors were positive regardless of their histogenesis. Based on these results EZH2 is a sensitive marker of malignancy in hepatic tumors. In routine surgical pathology EZH2 could be most helpful to diagnose cholangiocarcinomas, because as far as we know this is the first marker to distinguish transformed and reactive biliary structures. Although hepatoblastomas also express EZH2, the diagnostic significance of this observation seems to be quite limited whereas, the structurally similar, other blastic childhood tumors are also positive. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1173195902735693
A 74 years old male patient was admitted to our department suffering from dysphagia for five months. Gastric Barium studies showed a cardia tumour with polypoid lesions in the wall of the esophagus, and gastro-esophageal reflux disease was also diagnosed. Endoscopy verified a cardia tumour with esophageal metastasis, and biopsy was obtained from the two lesions. Histology showed that both tumours were adenocarcinomas. Endoscopic ultrasonography classified the cardia tumour as grade T2. As observed during endoscopy, the wall of the esophagus at the level of the polypoid lesion was hypo-echogenic and thick which was result of thickened mucosa. Total gastrectomy and oesophagectomy was performed. Pathology showed that the cardia tumour was pT2N2 and type Siewert-Stein II. The esophageal polypoid lesion was also proved an adenocarcinoma, which was localized only to the mucosa. No tumour cells were found in the blood- or in lymph vessels between the tumour and the esophageal adenocarcinoma. We think that the polypoid adenocarcinoma in the esophagus is an esophageal metastasis implantation from the cardia adenocarcinoma. It is based on the exclusion of other possible tumour dissemination routes. Probably the gastro-esophageal reflux is responsible for the implantation of tumour cells.
Abstract Background It remains unclear if the vascular and connective tissue structures of primary and metastatic tumors are intrinsically determined or whether these characteristics are defined by the host tissue. Therefore we examined the microanatomical steps of vasculature and connective tissue development of C38 colon carcinoma in different tissues. Methods Tumors produced in mice at five different locations (the cecal wall, skin, liver, lung, and brain) were analyzed using fluorescent immunohistochemistry, electron microscopy and quantitative real‐time polymerase chain reaction. Results We found that in the cecal wall, skin, liver, and lung, resident fibroblasts differentiate into collagenous matrix‐producing myofibroblasts at the tumor periphery. These activated fibroblasts together with the produced matrix were incorporated by the tumor. The connective tissue development culminated in the appearance of intratumoral tissue columns (centrally located single microvessels embedded in connective tissue and smooth muscle actin‐expressing myofibroblasts surrounded by basement membrane). Conversely, in the brain (which lacks fibroblasts), C38 metastases only induced the development of vascularized desmoplastic tissue columns when the growing tumor reached the fibroblast‐containing meninges. Conclusions Our data suggest that the desmoplastic host tissue response is induced by tumor‐derived fibrogenic molecules acting on host tissue fibroblasts. We concluded that not only the host tissue characteristics but also the tumor‐derived fibrogenic signals determine the vascular and connective tissue structure of tumors.
Abstract Background and Aim: Oval cells, liver stem cell‐derived cells, are generated from the liver periportal region and spread into the parenchyma by an autocrine signaling pathway. The mechanism behind how oval cells take their place among packed silent hepatocytes, however, is not well understood. We hypothesized that apoptosis involves a decrease in hepatocytes surrounding oval cells. Methods: Male Fisher rats were treated using the AAF/PH protocol to induce oval cells in the liver. Apoptosis was assessed by measuring the activity of caspase‐3, ‐8 and ‐9, and apoptosis‐related molecules such as caspase‐3, Fas, Fas‐L and Bax were also assessed by immunohistochemical analysis and reverse transcriptase‐polymerase chain reaction (RT–PCR). Apoptosis was confirmed by TUNEL staining. Regarding antiapoptotic factors, nuclear factor‐κB (NF‐κB) DNA binding activity and proliferating cell nuclear antigen (PCNA) expression were examined. Results: NF‐κB elevated at the early stage of oval cell proliferation. Conversely, caspase activity increased after NF‐κB elevation. The mRNA of caspase‐3, Fas, Fas‐L and Bax was induced during and after AAF/PH treatment. Immunohistochemically, oval cells lacked the expression of these proteins, whereas the hepatocytes, particularly those surrounding oval cells, expressed strongly. Conclusions: The present study suggests that the apoptosis in hepatocytes through both extrinsic and intrinsic pathways mediates oval cell proliferation.
Chromogranin-A is a member of the granine protein family. It is produced in neuroendocrine cells via secretory granules. Many cleavage proteins are formed from chromogranin-A, from which some have well known biological activity, while the function of others is not yet fully known. Serum chromogranin-A levels are used in neuroendocrine tumour diagnostics. Recent studies showed that one of its cleavage protein, WE-14 may also play a role in the development of type 1 diabetes. WE-14 may function as an autoantigen for T-cells involved in the destruction of β-cells. This mechanism was previously observed only in non-obese diabetic mice. Novel results show that WE-14 also serves as a target for autoreactive cells in newly diagnosed type 1 diabetic patients as well, which reaction can be increased with transglutaminase. In this paper the authors summarize the recent knowledge about chromogranin-A and its potential role in the pathomechanism of type 1 diabetes mellitus.A kromogranin-A a granincsaládba tartozó fehérje, amelyet neuroendokrin sejtek termelnek és ezek szekréciós granulumaiból származik. A kromogranin-A-ból számos, mind ez idáig kevésbé tisztázott funkciójú fehérje képződik. Jelenleg a kromogranin-A vérben mérhető szintjének meghatározását elsősorban neuroendokrin daganatok laboratóriumi diagnosztikájában használják. A legfrissebb kutatások alapján azonban úgy tűnik, a kromogranin-A-ból származó WE-14 nevű fehérjének szerepe lehet az 1-es típusú cukorbetegség kialakulásában is. A WE-14 fehérje autoantigénként viselkedik a β-sejtek elpusztításában részt vevő T-sejtek számára. Ezt a mechanizmust eddig specifikusan a nem obes diabetogén egerekben figyelték meg. Újabb eredmények alapján a WE-14 a diabeteses egerek mellett az újonnan diagnosztizált 1-es típusú cukorbetegeknél is az autoreaktív sejtek célpontjaként szolgál, amely reakció szöveti transzglutamináz enzimmel fokozható. A szerzők jelen összefoglalójukban áttekintik a kromogranin-A bioszintézisét, biokémiai jellegzetességeit, szervezetbeli funkcióit, valamint ismertetik a cukorbetegség patomechanizmusában betöltött szerepére vonatkozó jelen ismereteket. Orv. Hetil., 2015, 156(5), 163–170.
