Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis.

BACKGROUND: Use of the immune checkpoint inhibitor ipilimumab is sometimes complicated by ipilimumab-associated colitis (Ipi-AC), an immune-mediated colitis that mimics inflammatory bowel disease. OBJECTIVE: We sought to characterize the histopathologic and immunophenotypic features of Ipi-AC and to directly compare these features to ulcerative colitis (UC). METHODS: This is a retrospective cohort study of 22 patients with Ipi-AC, 12 patients with treatment-naïve UC and five controls with diarrhoea but normal endoscopic findings. Immunohistopathologic features were described, and quantitative immunohistochemistry (IHC) was performed for CD4, CD8, CD20, CD138 and FOXP3. RESULTS: Endoscopic findings in both the Ipi-AC and UC groups included ulcerated, oedematous and erythematous mucosa. Involvement of the GI tract was more diffuse in Ipi-AC. As compared to UC, a smaller proportion of Ipi-AC biopsies had basal plasmacytosis (14% for Ipi-AC vs. 92% for UC, P < 0.0001) and crypt distortion (23% for Ipi-AC vs. 75% for UC, P = 0.003), whereas Ipi-AC biopsies had more apoptotic bodies in the left colon (17.6 ± 15.3 for Ipi-AC vs. 8.2 ± 4.2 for UC, P = 0.011). Cryptitis, ulcerations and crypt abscesses were common in both groups. Biopsy specimens from Ipi-AC had a lower density of CD20-positive lymphocytes than UC (275.8 ± 253.3 cells mm-2 for Ipi-AC vs. 1173.3 ± 1158.2 cells mm-2 for UC, P = 0.022) but had a similar density of CD4, CD8, CD138 and FOXP3-positive cells. CONCLUSIONS: Ipi-AC is a distinct pathologic entity with notable clinical and histopathological differences compared to UC. These findings provide insights into the pathophysiology of immune-related adverse events (iAEs) from ipilimumab therapy.

Gastric extremely well-differentiated intestinal-type adenocarcinoma: a challenging lesion to achieve complete endoscopic resection.

Extremely well-differentiated tubular adenocarcinomas (EWDAs) of the stomach are characterized by surface maturation and their mimicking of intestinal metaplasia. Endoscopically, intramucosal EWDAs are frequently ill defined with indistinct borders due to the pallor of the neoplastic mucosa and the lack of contrast against the background atrophic and metaplastic mucosa. We evaluated the effectiveness of endoscopic resection for EWDAs after endoscopic submucosal dissection (ESD). Among 872 patients with early gastric cancer, 17 EWDAs were identified (1.9 %). Endoscopically, the flat or depressed type was significantly more common among EWDAs (88.2 %) than among early gastric cancers of other histologies (37.8 %; P < 0.01). The discrepancy between endoscopically estimated tumor size and tumor size as confirmed in pathology reports was significantly greater among EWDAs (18.4 ±â€Š22.0  mm) than among others (5.8 ±â€Š7.5  mm). Involvement of the lateral resection margin was more common (29.4 % vs. 2.5 %; P < 0.05), and complete resection was achieved less often in EWDAs (47.1 % vs. 80.4 %; P = 0.01) compared to the others. EWDAs are associated with higher rates of incomplete resection after ESD, especially along the lateral margins. Pathologists should alert endoscopists when this diagnosis is made, with its associated risks; and endoscopists should pay particular attention to the extent of these tumors during resection.

Miami classification for probe-based confocal laser endomicroscopy.

An essential element for any new advanced imaging technology is standardization of indications, terminology, categorization of images, and research priorities. In this review, we propose a state-of-the-art classification system for normal and pathological states in gastrointestinal disease using probe-based confocal laser endomicroscopy (pCLE). The Miami classification system is based on a consensus of pCLE users reached during a meeting held in Miami, Florida, in February 2009.

Co-registered spectrally encoded confocal microscopy and optical frequency domain imaging system.

Spectrally encoded confocal microscopy and optical frequency domain imaging are two non-contact optical imaging technologies that provide images of tissue cellular and architectural morphology, which are both used for histopathological diagnosis. Although spectrally encoded confocal microscopy has better transverse resolution than optical frequency domain imaging, optical frequency domain imaging can penetrate deeper into tissues, which potentially enables the visualization of different morphologic features. We have developed a co-registered spectrally encoded confocal microscopy and optical frequency domain imaging system and have obtained preliminary images from human oesophageal biopsy samples to compare the capabilities of these imaging techniques for diagnosing oesophageal pathology.

Histopathology of Barrett's esophagus after ablation and endoscopic mucosal resection therapy.

This review focuses on the histopathological evaluation of endoscopic mucosal resection (EMR) specimens in Barrett's esophagus, and on the histopathological, biological, and molecular properties of postablation Barrett's esophagus. EMR may be used for both diagnostic and therapeutic purposes. Diagnostic accuracy regarding the grade and stage of neoplasms is improved with the use of EMR, but the value of this technique for treatment is more controversial because of the high prevalence rate of positive margins and the rate of metachronous lesions found elsewhere in the esophagus during follow-up. Ablation techniques, such as argon plasma coagulation, photodynamic therapy, and radiofrequency ablation, are used increasingly for the treatment of Barrett's esophagus and related neoplasms, often in combination with EMR. A common problem after use of these techniques is the development of islands of neosquamous epithelium (NSE) which can overlie buried Barrett's (and/or dysplasia) epithelium. This is, therefore, concealed to the endoscopist's view and may be allowed to progress to cancer without detection. NSE is histologically similar to normal esophageal squamous epithelium and does not possess the molecular aberrations characteristic of Barrett's esophagus. In contrast, residual nonburied Barrett's esophagus shows persistent pathologic and molecular abnormalities and may progress to cancer upon long term follow-up. The biological potential and rate of progression of nonburied residual Barrett's esophagus following ablation is unclear, but some preliminary studies suggest that the risk may decrease. Buried nondysplastic Barrett's esophagus appears to show decreased biological potential and this may be related to protection from the contents of the lumen by the barrier function of the overlying NSE. On the other hand, anecdotal reports have suggested that buried dysplasia may progress to cancer in some instances.

Natural orifice transesophageal mediastinoscopy and thoracoscopy.

BACKGROUND: Thoracoscopy and mediastinoscopy are common procedures with painful incisions and prominent scars. A natural orifice transesophageal endoscopic surgical (NOTES) approach could reduce pain, eliminate intercostal neuralgia, provide access to the posterior mediastinal compartment, and improve cosmesis. In addition NOTES esophageal access routes also have the potential to replace conventional thoracoscopic approaches for medial or hilar lesions. METHODS: Five healthy Yorkshire swine underwent nonsurvival natural orifice transesophageal mediastinoscopy and thoracoscopy under general anesthesia. An 8- to 9.8-mm video endoscope was introduced into the esophagus, and a 10-cm submucosal tunnel was created with blunt dissection. The endoscope then was passed through the muscular layers of the esophagus into the mediastinal space. The mediastinal compartment, pleura, lung, mediastinal lymph nodes, thoracic duct, vagus nerves, and exterior surface of the esophagus were identified. Mediastinal lymph node resection was easily accomplished. For thoracoscopy, a small incision was created through the pleura, and the endoscope was introduced into the thoracic cavity. The lung, chest wall, pleura, pericardium, and diaphragmatic surface were identified. Pleural biopsies were obtained with endoscopic forceps. The endoscope was withdrawn and the procedure terminated. RESULTS: Mediastinal and thoracic structures could be identified without difficulty via a transesophageal approach. Lymph node resection was easily accomplished. Pleural biopsy under direct visualization was feasible. Selective mainstem bronchus intubation and collapse of the ipsilateral lung facilitated thoracoscopy. In one animal, an inadvertent 4-mm lung incision resulted in a pneumothorax. This was decompressed with a small venting intercostal incision, and the remainder of the procedure was completed without difficulty. CONCLUSIONS: Transesophageal endoscopic mediastinoscopy, lymph node resection, thoracoscopy, and pleural biopsy are feasible and provide excellent visualization of mediastinal and intrathoracic structures. Survival studies will be needed to confirm the safety of this approach.

Reliability of histologic assessment in patients with eosinophilic oesophagitis.

BACKGROUND: The validity of the eosinophilic oesophagitis (EoE) histologic scoring system (EoEHSS) has been demonstrated, but only preliminary reliability data exist. AIM: Formally assess the reliability of the EoEHSS and additional histologic features. METHODS: Four expert gastrointestinal pathologists independently reviewed slides from adult patients with EoE (N = 45) twice, in random order, using standardised training materials and scoring conventions for the EoEHSS and additional histologic features agreed upon during a modified Delphi process. Intra- and inter-rater reliability for scoring the EoEHSS, a visual analogue scale (VAS) of overall histopathologic disease severity, and additional histologic features were assessed using intra-class correlation coefficients (ICCs). RESULTS: Almost perfect intra-rater reliability was observed for the composite EoEHSS scores and the VAS. Inter-rater reliability was also almost perfect for the composite EoEHSS scores and substantial for the VAS. Of the EoEHSS items, eosinophilic inflammation was associated with the highest ICC estimates and consistent with almost perfect intra- and inter-rater reliability. With the exception of dyskeratotic epithelial cells and surface epithelial alteration, ICC estimates for the remaining EoEHSS items were above the benchmarks for substantial intra-rater, and moderate inter-rater reliability. Estimation of peak eosinophil count and number of lamina propria eosinophils were associated with the highest ICC estimates among the exploratory items. CONCLUSION: The composite EoEHSS and most component items are associated with substantial reliability when assessed by central pathologists. Future studies should assess responsiveness of the score to change after a therapeutic intervention to facilitate its use in clinical trials.

17Beta-estradiol modulates gastroduodenal preneoplastic alterations in rats exposed to the carcinogen N-methyl-N'-nitro-nitrosoguanidine.

Gastric cancers are a significant cause of morbidity worldwide. Epidemiological studies and animal models show that males have higher incidences of gastric cancers compared with females, suggesting that sex hormones may modulate gastric cancer risk. An animal model of the initiation phase of gastric cancer was used to determine the effects of systemic estrogen administration on morphological progression of preneoplastic lesions and to define cell populations at which estrogens may act. Preneoplastic progression in antral and duodenal mucosa was examined in male rats that received the chemical carcinogen, N-methyl-N'-nitro-nitrosoguanidine (MNNG), during treatment with implants containing 17beta-estradiol or oil vehicle. Histopathological changes in antral and duodenal gland morphology, numbers of proliferating cells and apoptotic bodies, and antral gastrin cell numbers and protein storage levels were determined 4 weeks later. With MNNG treatment, duodenal villous heights were significantly decreased, and epithelial cells displayed histological features of hyperplasia and dysplasia. Antral glands showed epithelial hyperplasia and dysplasia, increased mucosal height, and decreased mucin levels. Antral gastrin storage protein levels were decreased by MNNG. Systemic treatment with 17beta-estradiol significantly reversed MNNG-induced alterations in duodenal gland heights while increasing mucin and gastrin levels in antral glands. Cell proliferation and apoptosis rates were not significantly different between groups. The present results indicate that systemic 17beta-estradiol treatment influences antral and duodenal gland differentiation during the initiation phase of chemical gastroduodenal carcinogenesis in male rats. These results explain, in part, a potential pathway through which protective effects of estrogens on chemical carcinogenesis are mediated in the upper gastrointestinal tract.

Carcinosarcoma of the prostate.

Carcinosarcoma of the prostate is a biphasic tumor containing adenocarcinoma (ACA) and recognizable sarcomatous components. It is a rare neoplasm with only 12 previous reported cases. We describe three additional cases arising between 4 and 6 years after initial diagnosis of prostatic ACA. Two patients were initially treated by prostatectomy, pelvic external beam radiotherapy, and hormonal manipulation. The third patient was treated by pelvic lymphadenectomy and 125I implants. After the development of the sarcomatous component, the first two are still alive with distant metastases and residual pelvic disease at 9 and 17 months. The third patient died with disease 7 months after diagnosis. Histologically, prostatic ACA was recognized in all three cases, as well as a neoplastic mesenchymal component that appeared later. Foci of osteosarcomatous, chondrosarcomatous, and myosarcomatous differentiation were recognized in two of the three cases. Based on the chronologic and the histologic evolution of the neoplasm, we favor sarcomatoid transformation of the ACA as the most likely histogenesis. It appears that radiotherapy and hormonal therapy may be important in the development of at least some of these tumors.

Gastrointestinal autonomic nerve tumors. A clinicopathological, immunohistochemical, and ultrastructural study of 12 cases.

The gastrointestinal autonomic nerve tumor (GAN tumor) is an uncommon stromal tumor of the intestinal tract and retroperitoneum first described by Herrera and associates in 1984. Distinction of GAN tumors from other gastrointestinal stromal tumors is based on electron microscopic findings. Thus far there have been 12 reported cases. We present an additional 12 GAN tumors, identified by us during 4 years. There were seven male and five female patients and they ranged in age from 10 to 85 years (mean: 58 years). Sites of the tumors were stomach (three), jejunum (two), ileum (four), mesentery (one), and retroperitoneum (two). Eight of the tumors measured > 10 cm in greatest dimension. Usually well circumscribed, the neoplasms were tan to light pink, sometimes hemorrhagic, and soft. There was a variety of histologic patterns including fascicles, palisades, and whorls. Mitotic activity varied from 0 to 23 mitosis per 10 high-power fields (HPF). Using a panel of 10 immunohistochemical stains, only vimentin was consistently positive. There was neuron-specific enolase reactivity in six and S-100 protein reactivity in two cases. All muscle markers were negative. Ultrastructural studies showed neuron-like cells with long axonic cytoplasmic processes ending in bulbous synapse-like structures containing dense-core neurosecretory granules and clear vesicles. Basement membrane was absent. These features are reminiscent of ganglia of the intestinal autonomic nervous system. The patients were followed for 5-125 months (mean of 26 months). Tumor recurred or metastasized to the liver in seven patients (58%) and four patients died with tumor. There were correlations between tumor size (> 10 cm), mitotic count (at least five per 10 HPF), and aggressive behavior.

Unbalanced chromosomal translocation, der(17)t(13;17)(q14;p11) in a solid and cystic papillary epithelial neoplasm of the pancreas.

We report on a solid and cystic papillary epithelial neoplasm of the pancreas containing the unbalanced chromosome translocation der(17)t(13;17)(q14;p11), resulting in loss of 13q14-->qter and 17p11-->pter. Although the clinical and pathologic characteristics of this case are largely typical of this uncommon pancreatic neoplasm, the presence of cellular pleomorphism, tumor giant cells, and a DNA tetraploid tumor population suggest that this tumor may have an increased metastatic potential. The unbalanced translocation between chromosomes 13 and 17 and the genes flanking the breakpoints may prove to be markers for solid and cystic papillary epithelial neoplasm of the pancreas and provide insight into its histogenesis.

Hepatic undifferentiated (embryonal) sarcoma arising in a mesenchymal hamartoma.

We report the case of a hepatic undifferentiated (embryonal) sarcoma (UES) arising within a mesenchymal hamartoma (MH) in a 15-year-old girl. Mapping of the tumor demonstrated a typical MH transforming gradually into a UES composed of anaplastic stromal cells. When evaluated by flow cytometry, the MH was diploid and the UES showed a prominent aneuploid peak. Karyotypic analysis of the UES showed structural alterations of chromosome 19, which have been implicated as a potential genetic marker of MH. The histogenesis of MH and UES is still debated, and reports of a relationship between them, although suggested on the basis of histomorphologic similarities, have never been convincing. The histologic, flow cytometric, and cytogenetic evidence reported herein suggests a link between these two hepatic tumors of the pediatric population.

Evaluation of gastric biopsies for neoplasia: differences between Japanese and Western pathologists.

Cited variations in the evaluation of gastric endoscopic biopsies for neoplasms between pathologists in Japan and those in the United States and Europe (the West) may have stemmed from several causes. The five-tiered group classification of the Japanese Research Society for Gastric Cancer (JRSGC) for interpretation of biopsies is not used in the West. Some differences may also exist in the morphologic criteria to reach a diagnosis of dysplasia or carcinoma. The goals of this study were to test the Western and Japanese classifications of gastric dysplasia and adenocarcinoma and to assess the differences between four Japanese and seven Western pathologists. One hundred biopsies, 20 from each of the five categories of the JRSGC scheme as determined by one observer, were collected. The Japanese observers used the JRSGC system, expressed in Roman numerals, whereas Western pathologists used a five- or six-tiered scheme expressed in diagnostic terms. Pairwise agreement was evaluated using k statistics within both groups. Consensus diagnosis on each biopsy was accepted as the opinion of the majority. The sensitivity and specificity of each reviewer for a certain diagnosis were also assessed. The intragroup agreements were moderate for both the Japanese (mean k = 0.663) and the Westerners (mean k = 0.652). The pairwise agreements between Japanese and Western observers were low (mean k = 0.542). Overall, the sensitivity was low for all Japanese observers for the diagnosis of dysplasia (38.7% vs 92.5%), and the sensitivity for the diagnosis of adenocarcinoma was high in both groups but higher among the Japanese observers (93.9% and 85.2%, respectively). Overall, the Japanese-Western interobserver agreement was moderate. The JRSCG scheme did not translate into higher interobserver agreement among Japanese observers. The sensitivity for the diagnosis of gastric adenocarcinoma was high for both groups, but the specificity was low among the Japanese. The cause seemed to be centered around the diagnosis of dysplasia in the Western system, which was a lesion frequently interpreted as carcinoma in Japan because of the different definitions of carcinoma in each system. Such a discrepancy might be important because it may explain some of the differences in the prevalence and prognosis of early gastric cancer between Japan and the West. An international effort is needed to harmonize morphologic criteria and analyze whether therapeutic consequences may stem from such discrepancies.

The utility of noninvasive serologic markers in the management of early allograft rejection in liver transplantation recipients.

BACKGROUND: Early allograft rejection after orthotopic liver transplantation (OLT) currently requires a biopsy for diagnosis. Alpha-glutathione S-transferase (alpha-GST) and Pi-glutathione S-transferase (Pi-GST) are potential noninvasive markers of hepatocyte and biliary epithelial cell injury. Our aim was to determine the utility of noninvasive serologic markers in the management of early hepatic allograft rejection. METHODS: Forty-four of 52 consecutive adult patients undergoing primary OLT at the University of Florida were included in the study. All had protocol liver biopsies between days 6 and 8 after OLT. Serum alpha-GST and plasma Pi-GST were determined using a sandwich enzyme immunoassay (Biotrin International, Dublin, Ireland). All biopsy specimens were retrospectively reviewed and scored for rejection and cholestasis. RESULTS: The biopsy specimens were scored for rejection as moderate to severe in 14 patients (group 1) or none to mild in 30 patients (group 2). Group 1 had statistically higher mean levels than group 2 for alpha-GST on days 6, 7, and 9; alanine aminotransferase on days 6 and 9; aspartate aminotransferase (AST) on days 6 and 7; alkaline phosphate (AP) on days 3 through 7, 9, and 10; and gamma-glutamyl transferase on day 3. No differences between groups were seen with Pi-GST or total bilirubin. Between days 6 and 8, the following values were found more frequently in group 1 than group 2: alpha-GST level >15 ng/ml (11/14 vs. 14/30; P<0.01); AST >100 U/L (8/14 vs. 2/30; P=0.002); and AP >120 U/L (14/14 vs. 17/30). Combining AP with either alpha-GST or AST led to improved detection of rejection over any single marker alone. In the first week after the initiation of rejection treatment, alpha-GST was the only marker that accurately predicted response. CONCLUSION: Serum alpha-GST may be useful in the management of early hepatic allograft rejection. A combination of noninvasive markers may be beneficial to diagnose early hepatic allograft rejection.

Significance of preformed anti-donor antibodies in liver transplantation.

The significance of a positive cross-match in liver transplantation remains controversial, as documented by a number of recent conflicting reports. In this study, we evaluated 195 consecutive orthotopic liver transplant recipients in whom the cross-match was either negative or positive for T or B cells. Special emphasis was placed on the outcome of patients with high levels of preformed IgG antibodies directed against donor T cells. IgG anti-donor antibodies were confirmed by flow cytometry in all cases. Of 10 patients with strong T-cell antibodies, there was one early death due to nonimmunological causes. Transplantation was successful in 9/10 patients followed for 3 months to 3 years. Graft survival, incidence of acute rejection, and number of liver biopsies in patients with a positive cross-match (strong T, weak T, or B cell) were not significantly different from those of patients with a negative cross-match. In the strong T cell antibody group, one patient had early graft dysfunction, with extensive hepatic necrosis and histological signs of antibody-induced damage. Two other patients also showed some evidence of possible antibody-mediated events, such as neutrophil infiltration and hepatocyte swelling. These lesions were reversible, and the patients had uneventful recoveries. Thus, in our experience, preformed antibodies did not preclude good graft survival.

The digestive system manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy): review of 11 cases.

Rosai-Dorfman disease (RDD), originally described as sinus histiocytosis with massive lymphadenopathy, is a rare histiocytic proliferative disorder with a distinctive microscopic appearance. Formerly thought to be a process limited to lymph nodes, involvement by RDD has now been documented in many organ systems, notably bone, skin and soft tissue, central nervous system, eye and orbit, and upper respiratory tract. The digestive system, however, is affected only exceptionally, as reflected by the existence of only a handful of individual case reports. In this article, we report 11 patients in which the disease involved intestinal tract, liver, or pancreas, and describe the most salient clinicopathologic features. The specific site of involvement within the digestive system was gastrointestinal tract in 5, liver in 5, and pancreas in 1. Most patients also had evidence of disease in other extranodal sites, as well as in 1 or more lymph node groups.

Spindle cell squamous carcinoma of the esophagus: analysis of ploidy and tumor proliferative activity in a series of 13 cases.

Spindle cell squamous esophageal carcinomas are distinctive polypoid "biphasic" tumors in which the sarcoma-like phenotype usually predominates over the epithelial component. To biologically assess both phenotypes, we compared the tumoral proliferative activity and DNA ploidy between the two histological components of 13 polypoid spindle cell squamous carcinomas of the esophagus. We studied the tumoral proliferative index (TPI) using MIB 1 monoclonal antibody (Ki-67) and determined the DNA histogram by image cytometry on Feulgen-stained sections. The DNA histograms were classified into four types (I to IV) according to the degree of dispersion of the DNA. The TPI of the carcinomatous regions ranged from 0.20 to 0.63 (mean, 0.44) and from 0.55 to 0.85 for the sarcoma-like areas (mean, 0.68) P < .0001. In all cases, the sarcoma-like areas were aneuploid, and 37.5% of the carcinomatous regions were diploid. Also, in all instances the carcinomatous areas were of either histogram type I or II, and the sarcoma-like areas showed histograms of type II or III. We conclude that in esophageal spindle cell squamous carcinomas the sarcoma-like phenotype differs biologically in two ways from the carcinomatous: (1) it has a higher TPI and (2) it has higher aneuploidy with a greater dispersion of the DNA content. We postulate that these characteristics could give a "growth" advantage to the sarcoma-like component of these tumors and explain its predominance over the carcinomatous component.

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.

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.

Gastroparesis following bone marrow transplantation.

Patients often develop nausea, vomiting and bloating after bone marrow transplantation (BMT). These symptoms may interfere with nutrition and the ability to take oral medications. Gastroparesis is a recognized cause of these symptoms in non-transplant patients but less is known about patients who undergo BMT. Between January 1996 and March 1997, a total of 151 patients underwent BMT. Eighteen patients (12%) developed persistent symptoms suggestive of gastroparesis (persistent nausea, vomiting or bloating). Scintigraphic gastric emptying studies were performed to assess for gastroparesis. Prokinetic agents were administered at the time of study. The records on these patients were compared with those of all other patients undergoing BMT during the same time period without these symptoms. Nine patients who demonstrated delayed gastric emptying were further evaluated with esophagastroduodenoscopy and biopsy. Biopsy samples were reviewed for evidence of graft-versus-host disease (GVHD). Fourteen of 18 patients demonstrated delayed gastric emptying and most responded to prokinetic agents given at the time of study. Age, conditioning regimen, cytomegalovirus antigenemia and acute GVHD did not appear to be associated with the development of gastroparesis. Allogeneic BMT recipients were at higher risk than autologous BMT patients (26% vs 0%, P < 0.0001). of allogeneic bmt recipients, there was a nonsignificant trend of patients receiving tacrolimus to be less likely to experience gastroparesis than those receiving cyclosporine (27% vs 48%, P = 0.08). For the nine patients undergoing upper endoscopy, GVHD on gastric biopsy was an uncommon finding and was mild when present. Gastroparesis appears to be a common cause of nausea, vomiting and bloating following allogeneic BMT. This may occur less often with tacrolimus than cyclosporine because of the former agent's prokinetic properties. Patients usually respond to prokinetic drugs at the time of scintigraphy. GVHD and CMV infection do not appear to be major contributing factors.