Absence of human papillomavirus in esophageal carcinomas from southwestern Kenya.

Esophageal squamous cell cancer is highly prevalent in south-western Kenya. The role of human papillomavirus (HPV) in esophageal cancers from this region was evaluated. Biopsies of 29 esophageal squamous cell cancers were assayed for HPV DNA sequences by reverse line blot polymerase chain reaction, using 27 HPV type-specific probes. Viral sequences were found in none of the specimens. These results suggest the HPV is unlikely to be an etiologic factor for esophageal squamous cell cancers in this region.

Patterns of inflammation in mucosal biopsies of ulcerative colitis: perceived differences in pediatric populations are limited to children younger than 10 years.

The histologic criteria used to diagnose ulcerative colitis in colonic mucosal biopsies have been established for many years and include crypt architectural distortion, plasmacellular infiltrates, and neutrophils in the crypt epithelium and lumen. In several recent studies, it has been noted that colonic mucosal biopsies from children presenting with ulcerative colitis show fewer histologic abnormalities at initial presentation, especially less architectural distortion, than do biopsies from adults. In this study, colonic mucosal biopsies taken at the time of presentation of ulcerative colitis in 15 adults and 25 children were examined blindly by two pathologists. All biopsies were taken prior to the initiation of therapy. Twelve children were between 1 and 10 years of age, and 13 children were between the ages of 11 and 17 years. All patients had at least 1 year of follow-up, with clinical and pathologic confirmation of the diagnosis of ulcerative colitis. Five separate histologic features that are characteristic of ulcerative colitis were scored on mucosal biopsies. Children < or = 10 years of age had significantly less crypt branching, plasma cells in the lamina propria, cryptitis, crypt abscesses, and epithelial injury than adults (P values ranging from < 0.0001 to 0.0032). Children between the ages of 11 and 17 years had less cryptitis, crypt abscesses, and epithelial injury than adults (P values ranging from 0.0001 to 0.007) but similar degrees of crypt architectural distortion and plasma cell infiltrates. For all histologic features examined except epithelial injury, the significant findings were due to differences in biopsies taken proximal to the rectum. No significant differences in histology scores were found in rectal biopsies between any age group, except for epithelial injury, which was significantly less in children < or = 10 years. The findings show for the first time that the perceived differences between adults and children with ulcerative colitis are largely due to a decrease in histologic features of colitis in children less than 10 years of age. As children approach adulthood, the degree of inflammation and architectural distortion seen is similar to that found in adults. However, rectal biopsies show similar degrees of colitis in all age groups.

Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality of allogeneic stem cell transplantation. Strategies to control GVHD while maintaining graft versus leukemia (GVL) include herpes simplex virus thymidine kinase (HSV-tk) gene transduction of donor T cells followed by treatment with ganciclovir (GCV). Alternatively, GVHD and GVL may be mediated by distinct processes. In this regard, whether cytokine polarization occurs and to what degrees various subsets of cytokine-producing T cells mediate GVHD or GVL has been an active area of research using cytokine or cytokine antibody infusion or genetically deficient mice. This study takes a different approach that allows simultaneous investigation into both the mechanisms underlying GVHD reactions and the efficacy of HSV-tk suicide gene-based T-cell deletion. A source of donor T cells, splenocytes from mice transgenic for HSV-tk controlled by elements of either the interleukin-2 (IL-2) or IL-4 promoters (IL-2-tk and IL-4-tk, respectively) was used, thus allowing investigation into the roles of T1 and T2 cells in ongoing GVHD reactions. To assess treatment rather than prevention of GVHD, GCV was started at peak disease. Remarkably, treatment at this late time point rescued mice from the clinical effects of GVHD caused by T cells expressing either transgene. Thus, both T1 and T2 cells play an important role in clinical GVHD in a minor histocompatibility antigen-mismatched setting. In addition, because clinical disease was reversible even at its maximum, these observations provide controlled evidence that this strategy of treating ongoing GVHD could be effective clinically.

Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation.

Morphologic assessment of dysplasia in Barrett esophagus, despite limitations, remains the basis of treatment. We rigorously tested modified 1988 criteria, assessing intraobserver and interobserver reproducibility. Participants submitted slides of Barrett mucosa negative (BE) and indefinite (IND) for dysplasia, with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and with carcinoma. Two hundred fifty slides were divided into 2 groups. The first 125 slides were reviewed, without knowledge of the prior diagnoses, on 2 occasions by 12 gastrointestinal pathologists without prior discussion of criteria. Results were analyzed by kappa statistics, which correct for agreement by chance. A consensus meeting was then held, establishing, by group review of the index 125 slides, the criteria outlined herein. The second 125-slide set was then reviewed twice by each of the same 12 pathologists, and follow-up kappa statistics were calculated. When statistical analysis was performed using 2 broad diagnostic categories (BE, IND, and LG v HG and carcinoma), intraobserver agreement was near perfect both before and after the consensus meeting (mean kappa = 0.82 and 0.80). Interobserver agreement was substantial (kappa = 0.66) and improved after the consensus meeting (kappa = 0.70; P =.02). When statistical analysis was performed using 4 clinically relevant separations (BE; IND and LGD; HGD; carcinoma), mean intraobserver kappa improved from 0.64 to 0.68 (both substantial) after the consensus meeting, and mean interobserver kappa improved from 0.43 to 0.46 (both moderate agreement). When statistical analysis was performed using 4 diagnostic categories that required distinction between LGD and IND (BE; IND; LGD; HGD and carcinoma), the pre-consensus meeting mean intraobserver kappa was 0.60 (substantial agreement), improving to 0.65 after the meeting (P <.05). Interobserver agreement was poorer, with premeeting and postmeeting mean values unchanged (kappa = 0.43 at both times). Interobserver agreement was substantial for HGD/carcinoma (kappa = 0.65), moderate to substantial for BE (kappa = 0.58), fair for LGD (kappa = 0.32), and slight for IND (kappa = 0.15). The intraobserver reproducibility for the diagnosis of dysplasia in BE was substantial. Interobserver reproducibility was substantial at the ends of the spectrum (BE and HG/carcinoma) but slight for IND. Both intraobserver and interobserver variation improved overall after the application of a modified grading system developed at a consensus conference but not in separation of BE, IND, and LGD. The criteria used by the group are presented. HUM PATHOL 32:368-978.

Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study.

The objective of endoscopic surveillance in Barrett esophagus (BE) is to assess the risk of subsequent development of invasive carcinoma. Criteria for morphologic evaluation of dysplasia, the presumed precursor lesion, have been established, although there are surprisingly few data in the literature correlating biopsy diagnosis of dysplasia with outcome. We collected follow-up information on 138 patients with BE whose initial endoscopic biopsy specimens had been selected for submission in an interobserver variability study performed by 12 pathologists with special interest in gastrointestinal pathology and reviewed blindly twice each by all the participants. Cases were scored as BE with no dysplasia, atypia indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal carcinoma, and frankly invasive carcinoma, thus generating 24 scores on each biopsy specimen. Clinical follow-up was obtained and correlated with both the submitting diagnoses and majority diagnoses. Kaplan-Meier statistics were used to compare both the submitting and majority diagnoses with outcome using detection or documentation of invasive carcinoma as the endpoint. Using the submitting diagnoses, no invasive carcinomas were detected in 44 cases diagnosed as BE (median follow-up, 38.5 months). Carcinomas were detected in 4 of 22 (18%) cases submitted as IND (median progression-free survival of 62 months), in 4 of 25 (15%) cases of LGD (median progression-free survival of 60 months), in 20 of 33 cases of HGD (median progression-free survival, 8 months), and all 13 (100%) cases submitted as adenocarcinoma. Grade on initial biopsy correlated significantly with progression to invasive carcinoma (log-rank P =.0001). Majority diagnosis was achieved in 99 of the cases. Using the majority diagnoses, no invasive carcinomas were found in 50 cases of BE (median follow-up, 48 months), and carcinomas were detected in 1 of 7 (14%) IND cases (80% progression-free survival at 2 months), 3 of 15 (20%) LGD (median progression-free survival, 60 months), 9 of 15 (60%) HGD (median progression-free survival, 7 months), and all 12 (100%) carcinoma. Initial grading again correlated significantly with progression to invasive carcinoma (log-rank P =.0001). However, there were 39 cases without a majority diagnosis. Among these, no carcinomas developed in 8 cases with an average score between BE and IND. Carcinomas were detected in 9 of 21 (43%) cases with an average score between IND and LGD, and 7 of 10 (70%) cases with an average score between LGD and HGD. There were ulcers in 8 of 39 cases (20%) of the "no-majority" group and in 13 of 99 (13%) of the majority cases. Of 21 total ulcerated cases, cancer was demonstrated in 15 (71%) of these on follow-up. These data support combining the IND and LGD categories for surveillance purposes. Cases without dysplasia may be followed up conservatively. The data obtained from submitted diagnoses as opposed to those from blind review suggest that knowledge of the clinical findings aids in diagnosis. The data also support the assertion that HGD is strongly associated with invasive carcinoma. Rebiopsy of ulcerated areas should be considered because they may harbor malignancy. Histologic grading of dysplasia using established criteria is a powerful prognosticator in BE. HUM PATHOL 32:379-388.

Granular cells as a marker of early amiodarone hepatotoxicity.

Hepatotoxicity due to chronic amiodarone (AD) use is well described. However, hepatitis occurring after acute administration of AD has only occasionally been reported and the pathologic findings in the liver in this condition have not been well characterized. We describe an idiosyncratic reaction, in a 40-year-old man after 6 weeks of oral AD therapy, consisting of acute hepatitis, which resolved after withdrawal of the drug. The liver biopsy showed clusters of cells with granular cytoplasm. These cells were characterized as macrophages, and phospholipid membranous inclusions were demonstrated ultrastructurally in the granular cells and in the hepatocytes. Pathologists and clinicians should be aware of this subtle histologic finding when looking for evidence to support AD hepatotoxicity.

Evidence for the neoplastic transformation of Von-Meyenburg complexes.

Von-Meyenburg complexes (VMC) are seen frequently in the liver and are largely considered to be innocuous, with only 11 cases reported in the literature of neoplastic transformation of VMCs. The authors report three cases of cholangiocarcinoma, each occurring in a background of fibrosis and nodularity that was reported initially as micronodular cirrhosis. Although the livers showed cirrhosis, the central veins were often preserved, and regenerative activity was patchy and focal. Histologic examination revealed many VMCs, and a gradual transition from VMCs to hyperplastic or adenomatous lesions and cholangiocarcinoma. The adenomatous lesions consisted of extensive replacement of the parenchyma by tumor-like nodules of ductular proliferations without obvious features of malignancy. All three patients were older than 60 years of age and had portal hypertension. Computed tomographic scans showed multiple, small renal cysts in one patient. Immunohistochemical staining showed positivity for epithelial membrane antigen, carcinoembryonic antigen, and keratins (AE1/AE3 and CAM5.2) in tumor cells, consistent with cholangiocarcinoma. The pattern of fibrosis and nodularity in these cases is not typical of either congenital hepatic fibrosis or usual cirrhosis. The authors propose that these patients represent another aspect in the spectrum of ductal plate malformations that may be modified by other factors such as alcohol, drugs, or infection. To their knowledge, neoplastic transformation of VMCs in the background of such changes has never been reported before.

The histologic spectrum and clinical outcome of refractory and unclassified sprue.

The vast majority of patients with celiac disease respond to a gluten-free diet; yet, a small number of refractory patients do not respond and have persistent malabsorption and residual mucosal abnormalities of the small intestine. The histologic features of refractory/unclassified sprue have been published as case reports, often without long-term follow up, and no clear histologic picture has emerged. We present the results of a long-term study of the clinical and histologic features of 10 patients with refractory/unclassified sprue. The histologic features of small bowel biopsies in this group of patients were compared with those of 10 patients with responsive celiac disease and with 10 patients without malabsorption who had normal duodenal biopsies. Five of the 10 refractory patients ultimately developed collagenous sprue as a distinct histologic marker of refractory disease. Additional distinctive findings found in small bowel biopsies in the refractory group were subcryptal chronic inflammation (10 of 10) and marked mucosal thinning in three patients. Other nonspecific findings included acute inflammation and gastric metaplasia. One patient with collagenous sprue developed a B-cell lymphoma of the ileum, and in general collagenous sprue was associated with a poor prognosis. Two of five patients died whereas two others require total parenteral nutrition for survival. Pathologists evaluating small bowel biopsies in the setting of malabsorption should be aware of the subtle histologic changes described here that may portend a refractory course.

Prevention of graft versus host disease by inactivation of host antigen-presenting cells.

Graft versus host disease, an alloimmune attack on host tissues mounted by donor T cells, is the most important toxicity of allogeneic bone marrow transplantation. The mechanism by which allogeneic T cells are initially stimulated is unknown. In a murine allogeneic bone marrow transplantation model it was found that, despite the presence of numerous donor antigen-presenting cells, only host-derived antigen-presenting cells initiated graft versus host disease. Thus, strategies for preventing graft versus host disease could be developed that are based on inactivating host antigen-presenting cells. Such strategies could expand the safety and application of allogeneic bone marrow transplantation in treatment of common genetic and neoplastic diseases.

Biliary tract obstruction secondary to mycosis fungoides: a case report.

Mycosis fungoides is a cutaneous T-cell lymphoma that can disseminate to multiple organs. We report a patient who presented with obstructive jaundice caused by isolated involvement of the extrahepatic biliary tree by mycosis fungoides. Initially, endoscopic examinations and biopsies of the biliary tree and liver failed to reveal a cause for the obstructive symptoms. Finally, surgical resection of the gallbladder and extrahepatic ducts was performed. Examination revealed a dense, mixed lymphocytic infiltrate with atypical cells within the mucosa. Gene rearrangement studies confirmed the presence of a monoclonal T-cell population. The pattern of the gene rearrangement in the biliary tree was identical to that found in a previous skin biopsy that showed mycosis fungoides. Although liver involvement by mycosis fungoides is not uncommon, disease isolated to the extrahepatic biliary tree has not previously been reported. This case should alert clinicians and pathologists to yet another cause of obstructive jaundice.

Perforin protects against autoimmunity in lupus-prone mice.

The roles of cytolytic regulatory mechanisms in the immune system of lupus-prone mice were examined in perforin-deficient animals bearing functional or defective (lpr) Fas Ag (CD95). Perforin-deficient Fas+ animals developed accelerated autoimmunity, characterized by increased hypergammaglobulinemia, autoantibody production, and immune deposit-related end-organ disease compared with perforin-intact counterparts. In comparison, perforin-deficient lpr animals had accelerated mortality compared with perforin-intact lpr mice, associated with the abnormal accumulation of CD3+CD4-CD8- alphabeta T cells in conjunction with unaltered hypergammaglobulinemia, autoantibody production, and immune complex renal disease. These results indicate that cytolytic lymphoid regulation plays critical roles in the immune homeostasis of lupus-prone animals, and identify perforin-mediated cytotoxicity as a specific mechanism in the regulation of systemic autoimmunity.

A tumor-suppressor function for Fas (CD95) revealed in T cell-deficient mice.

Fas (CD95) and its ligand are central regulatory molecules in hematopoietic cells. Previous studies have suggested a role for Fas in the regulation of tumor progression, but Fas has not yet been conclusively identified as a tumor suppressor. Fas-deficient individuals lack malignant tumors, perhaps because of regulation by T cells. To investigate such a possibility, mice deficient in both T cells and Fas were generated, and they were found to develop severe B cell dysregulation characterized by malignant, lethal B cell lymphoma. Lymphoma arose from a monoclonal B220+CD19-CD5-CD23- B cell secreting immunoglobulin M, kappa rheumatoid factor. In contrast, animals containing alpha beta T cells, gamma delta T cells, and/or functional Fas suppressed the development of lymphoma. These data indicate that Fas functions as a tumor suppressor, and identifies roles for both alpha beta T cells and gamma delta T cells in Fas-independent tumor regulation.

Diffuse colonic mantle cell lymphoma in a patient with presumed ulcerative colitis: detection of a precursor monoclonal lymphoid population using polymerase chain reaction and immunohistochemistry.

Primary lymphoma of the colon, a rare and typically late complication of ulcerative colitis, exhibits high-grade morphology and behavior when it occurs. Recently, several reports of colonic lymphoma masquerading as ulcerative colitis have been described. These previous reports described inflammatory mucosal changes typical of ulcerative colitis as being present in superficial biopsies, leading to the initial diagnosis of ulcerative colitis; however, further workup resulted in a diagnosis of primary colonic lymphoma within several months in these cases, and all symptoms and mucosal changes resolved after treatment of the lymphoma. Herein we report a case of mantle cell lymphoma arising in the colon and rectum in a 71-year-old woman with a 4-year history of ulcerative colitis. Immunoglobulin heavy-chain gene rearrangements were detected using the polymerase chain reaction procedure in fixed tissue in the lymphoma as well as in a prior resection specimen that histologically appeared to show only changes of severe ulcerative colitis. This finding suggests that an indolent lymphoid proliferation may have been the underlying disease in this patient and raises questions about the role of colonic lymphoma in causing mucosal injury.

Carcinoid tumor of the common bile duct producing gastrin and serotonin.

Carcinoid tumors of the biliary tract are rare. We report a 47 year-old man who was unexpectedly found to have a nonobstructing carcinoid tumor of the common bile duct during orthotopic liver transplantation for decompensated cirrhosis. No metastases were noted. Five months after resection of the common bile duct and liver transplantation, the patient had no evidence of residual tumor. The carcinoid was a sclerotic tumor of insular type and was immunoreactive for gastrin and serotonin, but nonfunctional. We review the literature on carcinoids of the extrahepatic bile duct.

Pancreatitis associated with adult choledochal cysts.

We reviewed the records of 32 adult patients with choledochal cysts (CDC) to determine the characteristics of the associated pancreatic disease. Eighteen patients (56%) had 30 documented episodes of pancreatitis with epigastric pain and elevated serum amylase levels. Three patients developed a prolonged course with a pancreatic phlegmon and one patient died secondary to a pancreatic abscess after endoscopic retrograde cholangiopancreatography (ERCP). Pancreatitis occurred in all types of CDC and was not related to the age, gender or race of the patient. There was an association with the size of the CDC: 90% of patients with CDC > or = 5 cm developed pancreatitis compared with only 9% of patients with CDC < 5 cm (p < 0.0004). In addition, ERCP was performed in 14 patients and demonstrated an abnormal pancreaticobiliary duct junction in eight (57%). All eight patients with an abnormal pancreaticobiliary junction developed pancreatitis compared with only 2 out of 6 patients with normal pancreatic duct anatomy (p < 0.006). Patients undergoing surgical bypass rather than resection also tended to have higher rates of pancreatitis (80 vs. 50%). One patient with a Type I CDC and chronic pancreatitis was treated with surgical resection of the CDC and pancreatic head; this combined procedure relieved the pain. Microscopic examination of the CDC and the abnormal "common channel" within the pancreas revealed identical fibrous thickening of the duct walls with focal chronic inflammation and loss of surface epithelium. In conclusion, these data stress the previously unrecognized high incidence of symptomatic pancreatic inflammatory disease that accompanies adult CDC.(ABSTRACT TRUNCATED AT 250 WORDS)

Intragraft expression of messenger RNA for interleukin-6 and tumor necrosis factor-alpha is a predictor of rat small intestine transplant rejection.

Detection of rejection after small intestine transplantation (SIT) is difficult, relying largely on histopathology. The purpose of this study was to determine if the intragraft expression of messenger RNA (mRNA) for interleukin-2 receptor (IL-2R), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF) correlated with rejection in a unidirectional, heterotopic rat SIT model. Graft samples were obtained on postoperative day (POD) 3, 5, 7, 8, 9, 10, 12, and 14. After staining, formalin-fixed samples were blindly evaluated for rejection. Reverse transcriptase polymerase chain reaction (rtPCR) using primers specific for beta-actin, IL-2R, IL-6, and TNF was performed on liquid nitrogen-frozen samples. Semiquantitation was accomplished using radionuclide incorporation and beta-scintillation counting. Intestinal histopathology in all isografts (ISO) and POD 3 allografts (ALLO) was normal. Rejection progressed in ALLO from mild on POD 5 to severe by POD 8. rtPCR analysis revealed constitutive expression of IL-2R mRNA in both ISO and ALLO. TNF and IL-6 demonstrated significant increases in mRNA expression in ALLO compared to ISO beginning on POD 5. In summary, intragraft expression of IL-2R mRNA demonstrated late up-regulation in ALLO which did not correlate with rejection. TNF and IL-6 mRNA expression predicted rat SIT rejection. rtPCR analysis of TNF and IL-6 may serve as a useful diagnostic adjunct for rat SIT rejection.

Liver disease in the immunocompromised patient.

This chapter reviews the most common diseases of the liver that are associated immunodeficiencies resulting from AIDS, chemotherapy and radiation, and bone marrow and solid organ transplantation. Conditions described include liver disease, infection, venoocclusive disease, graft versus host disease, and others.