Lymphocytic oesophagitis: clinicopathological aspects of an emerging condition.

OBJECTIVE: Lymphocytic oesophagitis (LyE) has been reported in small series, but no consistent clinical correlations have emerged. The authors sought to determine the prevalence of LyE in a large population and define demographic, endoscopic and clinical findings associated with this condition. DESIGN: In a pilot study, the authors established and disseminated criteria for the histopathological diagnosis of LyE to a group of gastrointestinal pathologists. Eighteen months later the authors reviewed cases with this diagnosis, collected demographic, clinical and endoscopic data, and compared them with patients with either eosinophilic oesophagitis (EoE) or normal oesophageal biopsies. The authors also determined the density of oesophageal lymphocytes in normal controls and in adults with established Crohn's disease. RESULTS: There were 129,252 unique PATIENTS: 40,665 had normal mucosa (median age 55 years; 32% men); 3745 had EoE (median age 43 years; 66% men). A diagnosis of LyE was made in 119 patients (median age 63 years, 40% men). Dysphagia was as common in these patients as in those with EoE (53% vs 63%; ns); gastro-oesophageal reflux disease -the most common complaint in patients with normal biopsies (37%)-was low in both the LyE and the EoE groups (18% vs 19%, ns). EoE was suspected in one-third of the patients. CONCLUSION: LyE was detected in ∼0.1% of patients with oesophageal biopsies. The clinical and endoscopic characteristics of LyE and EoE overlap considerably; however, LyE affects predominantly older women. Although the precise clinical significance of oesophageal lymphocytic infiltrates remain to be defined, their association with dysphagia and possibly motility disorders warrants further investigations.

Hepatobiliary pathology.

PURPOSE OF REVIEW: Recent studies pertaining to the histopathology of the liver and biliary tract are reviewed. RECENT FINDINGS: Several studies are reviewed which describe the histologic features and clinical behavior of 'plasma cell hepatitis' in the posttransplant setting. Cytokeratin 7, EMA, and CD68 were found to be useful immunohistochemical stains in fibrolamellar hepatocellular carcinoma and may aid in the distinction between this variant and classic hepatocellular carcinoma. Arginase-1, another immunohistochemical stain, was found to have improved sensitivity over HepPar-1 in the diagnosis of classic hepatocellular carcinoma. Metabolic syndrome is common in children with nonalcoholic fatty liver disease and may be an indicator of more severe disease activity and fibrosis. Histologic features were described that may aid in the distinction between the steroid-responsive IgG4-associated cholangitis and the steroid-nonresponsive primary sclerosing cholangitis. In addition, immunohistochemical stains for IgM and IgG may be helpful in distinguishing between autoimmune liver diseases, with primary biliary cirrhosis and its antimitochondrial-negative variant, autoimmune cholangitis, being the two autoimmune liver diseases with a predominance of IgM-positive plasma cells. SUMMARY: Several informative studies pertaining to hepatobiliary pathology were published this year, with topics including posttransplant plasma cell hepatitis, familial hemophagocytic lymphohistiocytosis, pediatric nonalcoholic fatty liver disease, and the use of immunohistochemical stains specific for various immunoglobulin subtypes.

Management of monophasic synovial sarcoma of the small intestine.

BACKGROUND: Reports of primary intraabdominal synovial sarcomas are extremely rare. METHODS: A literature review using PubMed was performed. A retrospective review of the one known case at our institution was completed. RESULTS: Even the most experienced pathologists report that synovial sarcomas can be very difficult to diagnose correctly. One cytogenic abnormality that is common (> 90%) and pathognomonic for synovial sarcoma is a characteristic chromosomal translocation resulting in the SYT/SSX fusion gene. Wide regional excision has been performed for intraabdominal sarcoma, with improved results. Our patient is more than 24 months with no evidence of recurrent or metastatic disease. CONCLUSIONS: The prognosis for patients with intraabdominal synovial sarcoma remains poor. However, wide regional excision may allow for prolonged disease-free survival.

Aggressive resection of hepatocellular carcinoma with right atrial involvement.

Hepatocellular carcinoma with extension into the right heart is a recognized, albeit rare occurrence. Patients who present with tumors extending into the heart have generally been considered inoperable and had limited survival, many sustaining tumor embolism and/or sudden death. Resection has been fraught with intraoperative and perioperative mortality as well as considerable postoperative morbidity. We report an exceptional case of a patient with such a tumor successfully treated with an aggressive surgical approach and review the limited published experience.

Metastatic pancreatic carcinoma presenting as colon carcinoma.

Determining the origin of poorly differentiated adenocarcinomas remains a challenge for the pathologist. This manuscript reports the use of a panel of specific immunohistochemical stains to determine the primary site of a tumor in the colon. A 45-year-old man had a right hemicolectomy for adenocarcinoma. Immunohistochemical staining documented that the lesion was a metastasis from a primary pancreatic adenocarcinoma--an unusual pattern of spread. The case emphasizes the important use of immunohistochemistry in identifying the primary source of lesions, allowing for appropriate treatment and staging.

Resection of a large, ruptured, undifferentiated (embryonal) sarcoma of the liver in a child: a case report and review of the literature.

BACKGROUND: Undifferentiated (embryonal) sarcoma (UES) of the liver is a malignant hepatic neoplasm accounting for 7% of pediatric hepatic tumors. Current use of multimodal therapy, including chemotherapy and surgery, has greatly improved survival. Tumor rupture is uncommon and, prior to the adjuvant use of sarcoma based chemotherapy regimens, was thought to be poor prognostic sign. CASE PRESENTATION AND DISCUSSION: A 10-year-old girl presented with acute worsening of abdominal pain while being worked up for liver mass. At surgery, she was found to have a ruptured, 20 x 15 x 5 centimeter (cm) UES, the largest reported ruptured UES to be resected primarily. The size and position of her tumor required very aggressive surgery for complete resection. She subsequently received adjuvant chemotherapy and radiation. Twenty-four months following surgery she is doing well with no evidence of disease. CONCLUSION: Despite tumor rupture, complete tumor resection gives the patient the best chance of long-term survival. Aggressive surgery is warranted if the tumor can be completely resected.

Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in hepatitis C virus replicon.

BACKGROUND: Alpha interferon in combination with ribavirin is the standard therapy for hepatitis C virus infection. Unfortunately, a significant number of patients fail to eradicate their infection with this regimen. The mechanisms of IFN-resistance are unclear. The aim of this study was to determine the contribution of host cell factors to the mechanisms of interferon resistance using replicon cell lines. RESULTS: HCV replicons with high and low activation of the IFN-promoter were cultured for a prolonged period of time in the presence of interferon-alpha (IFN-alpha2b). Stable replicon cell lines with resistant phenotype were isolated and characterized by their ability to continue viral replication in the presence of IFN-alpha. Interferon resistant cell colonies developed only in replicons having lower activation of the IFN promoter and no resistant colonies arose from replicons that exhibit higher activation of the IFN promoter. Individual cell clones were isolated and nine IFN resistant cell lines were established. HCV RNA and protein levels in these cells were not altered by IFN- alpha2b. Reduced signaling and IFN-resistant phenotype was found in all Huh-7 cell lines even after eliminating HCV, suggesting that cellular factors are involved. Resistant phenotype in the replicons is not due to lack of interferon receptor expression. All the cell lines show defect in the JAK-STAT signaling and phosphorylation of STAT 1 and STAT 2 proteins were strongly inhibited due to reduced expression of Tyk2 and Jak-1 protein. CONCLUSION: This in vitro study provides evidence that altered expression of the Jak-Stat signaling proteins can cause IFN resistance using HCV replicon cell clones.

HCV-hepatocellular carcinoma: new findings and hope for effective treatment.

We present here a comprehensive review of the current literature plus our own findings about in vivo and in vitro analysis of hepatitis C virus (HCV) infection, viral pathogenesis, mechanisms of interferon action, interferon resistance, and development of new therapeutics. Chronic HCV infection is a major risk factor for the development of human hepatocellular carcinoma. Standard therapy for chronic HCV infection is the combination of interferon alpha and ribavirin. A significant number of chronic HCV patients who cannot get rid of the virus infection by interferon therapy experience long-term inflammation of the liver and scarring of liver tissue. Patients who develop cirrhosis usually have increased risk of developing liver cancer. The molecular details of why some patients do not respond to standard interferon therapy are not known. Availability of HCV cell culture model has increased our understanding on the antiviral action of interferon alpha and mechanisms of interferon resistance. Interferons alpha, beta, and gamma each inhibit replication of HCV, and the antiviral action of interferon is targeted to the highly conserved 5'UTR used by the virus to translate protein by internal ribosome entry site mechanism. Studies from different laboratories including ours suggest that HCV replication in selected clones of cells can escape interferon action. Both viral and host factors appear to be involved in the mechanisms of interferon resistance against HCV. Since interferon therapy is not effective in all chronic hepatitis C patients, alternative therapeutic strategies are needed to treat chronic hepatitis C patients not responding to interferon therapy. We also reviewed the recent development of new alternative therapeutic strategies for chronic hepatitis C, which may be available in clinical use within the next decade. There is hope that these new agents along with interferon will prevent the occurrence of hepatocellular carcinoma due to chronic persistent hepatitis C virus infection. This review is not inclusive of all important scientific publications due to space limitation.

Creation of a drug-coated glaucoma drainage device using polymer technology: in vitro and in vivo studies.

OBJECTIVE: To create and test a slow-release antifibrotic drug-coated glaucoma drainage device using in vitro and in vivo experiments. METHODS: A slow-release device incorporating mitomycin C in poly(2-hydroxyethyl methacrylate) disks was developed using redox-polymerization techniques. A standardized preparation of this drug delivery device was attached to the Ahmed glaucoma valve (model FP7; New World Medical, Inc, Rancho Cucamonga, California). Semicircular disks (5 x 6 mm) of P(HEMA)-mitomycin C containing varying concentrations of mitomycin C per gram dry weight of the gel were attached to the lower half of an Ahmed glaucoma valve plate. Water was pumped through the modified Ahmed glaucoma valve at a rate comparable to that of aqueous humor outflow, and mitomycin C release was measured. Modified and unmodified Ahmed glaucoma valves were implanted in a rabbit model, and drug release and fibrosis were assessed after 3 months. RESULTS: The P(HEMA)-mitomycin C device released mitomycin C in vitro over 1 to 2 weeks. Studies in rabbits revealed that mitomycin C was released from the disks during the 3-month implantation. Histologic analysis demonstrated a significant reduction in inflammatory reaction and fibrosis in the resulting blebs. CONCLUSION: Our slow-release drug-coated glaucoma drainage device decreased fibrosis and inflammation in the resulting bleb in a rabbit model. CLINICAL RELEVANCE: This device could reduce the failure rate of glaucoma drainage devices.

Characterization of esophageal submucosal glands in pig tissue and cultures.

The submucosal glands (SMGs) of the pig esophagus, like the human, secrete mucin and bicarbonate, which help in luminal acid clearance and epithelial protection. The aim of this study was to characterize histochemically the esophageal SMGs and a primary culture obtained from these glands. Tissues and cultures were stained with hematoxylin and eosin, periodic acid Schiff, Alcian blue, lectins, or cytokeratins. In the perfused esophagus, addition of carbachol increased mucin secretion by approximately 2-fold. The results indicate that [1] a method for culturing SMG cells was developed; [2] conventional staining indicates the presence of sulfated, acidic, and neutral mucopolysaccharides in glands and cultures; [3] lectin binding indicates the presence of N-acetyl glucosamine, N-acetyl neuraminic acid, N-acetyl galactosamine, and alpha-L: -fucose in mucous cells and cultures; [4] cytokeratin and lectin staining indicated similarities with Barrett epithelium (columnar metaplasia of the esophagus); and [5] cholinergic agonists enhance mucin secretion and this could play a significant role in esophageal protection.

Activation of interferon-stimulated response element in huh-7 cells replicating hepatitis C virus subgenomic RNA.

Interferon-alpha (IFN(alpha)) binds to receptors on the cell surface, which initiate a cascade of signal transduction pathways that leads to transcription of selected genes. This transduction pathway involves binding of transcription factors to a common cis-acting DNA sequence called IFN-stimulated response element (ISRE). To test whether these signaling pathways are functional in hepatitis C virus (HCV)-replicating cells, we studied the regulation of ISRE-mediated transcription of firefly luciferase gene in stable replicon cell lines. A plasmid construct was prepared (pISRELuc) which contains four tandem repeats of 9-27 ISRE sequences positioned directly upstream of the herpes virus 1 thymidine kinase promoter TATA box that drives the expression of firefly luciferase. Regulation of ISRE-mediated expression of firefly luciferase by IFN(alpha) was studied by transfecting this clone into Huh-7 cells replicating HCV subgenomic HCV RNA. The significance of ISRE-mediated transcriptional activation was studied in a replicon cell line by pretreatment of cells with actinomycin D, which inhibits cellular DNA-dependent RNA transcription. IFN treatment activates ISRE-mediated expression of luciferase, indicating that this pathway is functional in Huh-7 cells. Activation of ISRE-mediated transcription of luciferase is relatively high in two Huh-7 stable cell lines replicating HCV subgenomic RNA. Inhibition of ISRE-mediated transcription of luciferase by actinomycin D also makes HCV replication totally resistant to IFN(alpha). These in vitro studies suggest that activation of IFN-inducible genes is important in mounting a successful antiviral response against HCV.

Interferons alpha, beta, gamma each inhibit hepatitis C virus replication at the level of internal ribosome entry site-mediated translation.

Interferon (IFN)-alpha is the standard therapy for the treatment of chronic hepatitis C, but the mechanisms underlying its antiviral action are not well understood. In this report, we demonstrated that IFN-alpha, -beta and -gamma inhibit replication of the hepatitis C virus (HCV) in a cell culture model at concentrations between 10 and 100 IU/ml. We demonstrated that the antiviral actions each of each these IFNs are targeted to the highly conserved 5' untranslated region of the HCV genome, and that they directly inhibit translation from a chimeric clone between full-length HCV genome and green fluorescent protein (GFP). This effect is not limited to HCV internal ribosome entry site (IRES), since these IFNs also inhibit translation of the encephalomyocardititis virus (EMCV) chimeric mRNA in which GFP is expressed by IRES-dependent mechanisms (pCITE-GFP). These IFNs had minimal effects on the expression of mRNAs from clones in which translation is not IRES dependent. We conclude that IFN-alpha, -beta and -gamma inhibit replication of sub-genomic HCV RNA in a cell culture model by directly inhibiting two internal translation initiation sites of HCV- and EMCV-IRES sequences present in the dicistronic HCV sub-genomic RNA. Results of this in vitro study suggest that selective inhibition of IRES-mediated translation of viral polyprotein is a general mechanism by which IFNs inhibits HCV replication.

Langerhans cell histiocytosis: report of a single organ involvement in a child.

Langerhans cell histiocytosis is a rare disorder characterized by abnormal proliferation of Langerhans cells that can affect various organ systems. The disease usually presents as a unifocal lytic bone lesion and can affect any age group. Less frequently it presents as a disseminated disease with multisystem involvement. Hepatic manifestation in Langerhans cell histiocytosis is relatively rare and usually presents as a part of a disseminated process. We report a case of Langerhans cell histiocytosis involving only the liver in a 9-years-old child.

Two unusual cases of adult intussusception.

Adult intussusception is very rare. We report 2 unusual cases, a 58-year-old man with a transverse colo-colonic intussusception caused by a malignant sessile polyp that also had an asymptomatic synchronous neoplasm of the kidney, and an 18-year-old female with an ileocecolic intussusception caused by acute appendicitis. This report stresses the point that intussusception in adults may represent an underlying malignancy. The age of the patient and the anatomic location of the intussusception provide significant input as to the etiology and hence the most appropriate surgical procedure.

Phenotypic differences between esophageal and gastric intestinal metaplasia.

Intestinal metaplasia is a cancer precursor in the esophagus and the stomach. Marked differences exist between the carcinogenic processes in the two locations in terms of natural history and clinical significance. We investigated biopsies from 52 patients with Barrett's esophagus and from 50 patients with gastric intestinal metaplasia in an attempt to throw light on their pathogenic processes. Morphologic characteristics, presence of Helicobacter pylori (H. pylori), and markers of differentiation, inflammation, and proliferation were evaluated by histochemical and immunohistochemical techniques. The area covered by incomplete type of intestinal metaplasia and the proportion of sulfomucins were significantly higher in the esophagus than in the stomach. Immunoreactivity with MUC1, MUC2, MUC5AC, Das-1, cytokeratins 7 and 20, inducible nitric oxide synthase and cyclooxygenase-2 antibodies was also significantly greater in Barrett's esophagus than in gastric intestinal metaplasia. In gastric intestinal metaplasia, the presence of MUC1, MUC5AC, Das-1 and cytokeratin 7 was restricted to areas with the incomplete type of metaplasia. Cell proliferation (Ki-67) was significantly higher in Barrett's esophagus than in gastric intestinal metaplasia. H. pylori was absent in all of the patients with Barrett's esophagus, while it was present in 70% of the patients with gastric intestinal metaplasia. Our observations made clear that Barrett's esophagus shares some phenotypic characteristics with gastric intestinal metaplasia, leading us to suggest that both could arise in response to injuries with eventual carcinogenic potential. However, the progression to more advanced lesions could be modulated by the nature of the carcinogenic insult.

Interferon alpha-2b inhibits negative-strand RNA and protein expression from full-length HCV1a infectious clone.

We have established a T7-based model system for hepatitis C virus (HCV) 1a strain, which involves the use of a replication-defective adenovirus that carries the gene for T7 RNA polymerase and a transcription plasmid containing full-length HCV cDNA clone. To facilitate high-level expression of HCV, sub-confluent Huh7 cells were first infected with adenovirus containing the gene for the T7 RNA polymerase and then transfected with the transcription plasmid. As a negative control, part of NS5B gene of this clone was deleted which abolishes the HCV RNA-dependent RNA polymerase and prevents replication of viral RNA. This model produces high levels of structural (core, E1, E2) and nonstructural proteins (NS5), which were detected by Western blot analysis and immunofluorescence assay. Negative-strand HCV RNA was detected only in the wild-type clone in the presence of actinomycin D, and no RNA was detected with the NS5B deleted mutant control. As a practical validation of this model, we showed that IFN alpha-2b selectively inhibits negative-strand RNA synthesis by blocking at the level of protein translation. The inhibitory effect of IFN alpha-2b is not due reduction of transcription by T7 polymerase or due to intracellular degradation of HCV RNA. This in vitro model provides an efficient and reliable means of assaying negative-strand RNA, protein processing, and testing the antiviral properties of interferon.