The utility of EUS and EUS-guided fine needle aspiration in detecting celiac lymph node metastasis in patients with esophageal cancer: a single-center experience.

BACKGROUND: The aims of this study were to determine the utility of EUS and EUS-guided fine needle aspiration (EUS-FNA) in the detection and confirmation of celiac lymph node metastasis in patients with esophageal cancer and to define EUS features predictive of celiac lymph node metastasis in these patients. METHODS: The records of 211 patients with esophageal cancer who underwent EUS staging were reviewed. The operating characteristics of EUS were determined in patients where either surgery, EUS-FNA of a celiac lymph node, or both were performed (n = 102). The association between selected variables and the presence of celiac lymph node metastasis was evaluated by univariate and multivariable analyses. RESULTS: EUS in 48 patients provided a true-positive diagnosis of celiac lymph node involvement, a false-positive and false-negative result, respectively, in 6 and 14 patients, and a true-negative diagnosis in 34 patients. The sensitivity of EUS in detecting celiac lymph node was 77% (95% CI [67, 88]), specificity 85% (95% CI [74, 96]), negative predictive value 71% (95% CI [58, 84]), and the positive predictive value 89% (95% CI [81, 97]). EUS-FNA was performed in 94% (51/54) of patients with celiac lymph nodes. The accuracy of EUS-FNA in detecting malignant celiac lymph nodes was 98% (95% CI [90, 100]). Advanced T-stage, the need for dilation, detection of peritumoral lymph nodes, and black race were associated with celiac lymph node involvement. In multivariable analysis, advanced T-stage was the strongest predictor of celiac lymph node involvement. CONCLUSION: EUS and EUS-FNA are highly accurate in detecting and confirming celiac lymph nodes metastasis. Depth of tumor invasion as assessed by EUS is a strong predictor of celiac lymph node metastasis in patients with esophageal cancer.

Hepatopulmonary syndrome occurring after orthotopic liver transplantation.

Hepatopulmonary syndrome (HPS) is an infrequent complication of liver cirrhosis. Orthotopic liver transplantation (OLT) has gained increasing acceptance as a treatment modality for HPS, although there have been reports of HPS developing after OLT with documented recurrence of cirrhosis. We describe the case of a 9-year-old boy who underwent OLT at 7 months of age because of biliary atresia. He subsequently developed HPS in the setting of chronic rejection without cirrhosis or evidence of portal hypertension. Re-OLT resulted in resolution of HPS and a good clinical outcome.

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.

Endoscopic ultrasonography with fine-needle aspiration: an accurate and simple diagnostic modality for sarcoidosis.

BACKGROUND AND STUDY AIMS: Sarcoidosis is a chronic multisystem granulomatous disease that is often diagnosed after a finding of hilar and mediastinal lymphadenopathy on a chest radiograph. This often requires further evaluation by transbronchial biopsy or other clinical parameters. The present study is a descriptive, retrospective one using endoscopic ultrasound with fine-needle aspiration (EUS-FNA) of mediastinal lymph nodes in seven patients with sarcoidosis. PATIENTS AND METHODS: Among 108 consecutive patients who underwent EUS-FNA of mediastinal lymph nodes for various clinical indications between July 1994 and October 1997, seven patients were found to have sarcoidosis on EUS-FNA, and the EUS morphology was studied in these patients. RESULTS: Sarcoidosis was diagnosed in seven patients using endosonographic characteristics and clinical follow-up. EUS with FNA showed cytological evidence of sarcoidosis in six patients. Seven patients were found to have subcarinal lymph nodes, and six patients had abnormally enlarged aortopulmonary (AP) window lymph nodes. The nodes in all patients had three endosonographic criteria for malignancy. The long axis of the largest mediastinal lymph nodes measured 3.44+/-1.42 cm (range 1.8-6.0 cm). The short axis measured 2.50+/-0.69 (range 1.0-4.0 cm). The average number of nodes seen in each patient was 2.80+/-0.75 (range 2-4). The nodes in all seven patients were discrete and well demarcated. A central hyperechoic strand was evident in these nodes in four patients (57%). There were no complications. CONCLUSIONS: Mediastinal lymph nodes in patients with sarcoidosis appear to have specific echo characteristics, and EUS-FNA can be used for confirmatory tissue diagnosis.

Accuracy of four commercially available serologic tests, including two office-based tests and a commercially available 13C urea breath test, for diagnosis of Helicobacter pylori.

BACKGROUND: Diagnosis of H. pylori infection may be made by endoscopic (invasive) tests, or by nonendoscopic (noninvasive) tests. Our aim was to evaluate recently available nonendoscopic tests, including two office-based serologic tests and a commercially available 13C urea breath test. METHODS: Gastric biopsy specimens (for culture and stain) from 178 patients (mean age 46 +/- 13.3 years, 79 men and 99 women), none of whom had received anti-H. pylori therapy, were tested for H. pylori infection. These tests were compared against two commercial serum IgG antibody immunoassays (Biowhittaker's Pyloristat, and Quidel), 2 office-based serum qualitative IgG antibody tests (FlexSure HP, and QuickVue One-Step), the Meretek 13C urea breath test, and the CLOtest (a biopsy urease test). RESULTS: The breath test (n = 147) had the best accuracy (96%) of the noninvasive tests studied. The serologic tests had similar accuracy to one another (84%-90%). The major drawback of the serologic tests was suboptimal specificity (75%-87%). Diagnosis of H. pylori based on the two office-based tests were not significantly different compared to the quantitative IgG antibody tests. The CLOtest had an accuracy of 97%. CONCLUSIONS: The Meretek 13C urea breath test is an excellent test, but is considerably more expensive than serologic tests. The FlexSure HP and the QuickVue One-Step office-based qualitative IgG serologic antibody tests gave similar results to laboratory based quantitative antibody tests, and are acceptable for initial diagnosis of H. pylori infection. The advantages of the office-based tests are low cost, simplicity, and immediacy of results.

Immunohistochemical evaluation of K-ras, p53, and HER-2/neu expression in hyperplastic, dysplastic, and carcinomatous lesions of the pancreas: evidence for multistep carcinogenesis.

The pathobiology of precursor lesions leading to invasive pancreatic adenocarcinoma remains a controversial area, but knowledge of the mechanisms of tumorigenesis may lead to possibly earlier detection, prevention, and treatment in the future. We hypothesize that ductal hyperplasia and dysplasia of the pancreas represent precursor lesions and are part of a continuous developmental spectrum evolving into ductal adenocarcinoma of the pancreas. To further define this sequence, we studied the immunohistochemical markers HER-2/neu, K-ras, and p53 in 15 adenocarcinomas and 15 nonmalignant specimens of the pancreas. The 15 nonmalignant specimens of the pancreas included both normal pancreas and chronic pancreatitis. Overall, HER-2/neu was positive in normal ducts, ductal hyperplasia, dysplasia, and carcinoma cells in 0 of 30, 11 of 20 (55%), 10 of 15 (67%), and 12 of 15 (80%), respectively, with progressive increase in the intensity of staining; p53 was positive in 1 of 30 (3%), 0 of 20, 3 of 15 (20%), and 13 of 15 (80%), respectively, and K-ras was positive in 1 of 30 (3%), 6 of 20 (30%), 11 of 15 (73%), and 8 of 15% (53%), respectively. These data support the hypothesis that ductal hyperplasia and dysplasia of the pancreas represent precursor lesions, and, in a fashion similar to that in colorectal tumorigenesis, pancreatic cancer seems to accumulate progressive genetic alterations.

Prospective comparison of H&E, Giemsa, and Genta stains for the diagnosis of Helicobacter pylori.

BACKGROUND: H. pylori is more easily visualized with special stains than with H&E, but this adds time and expense to the diagnostic workup. We sought to determine if the diagnostic accuracy was improved with special stains. METHODS: One hundred-one patients had two "jumbo" biopsies taken from the gastric antrum and two from the body for examination with H&E, Genta, and Giemsa stains. Four separate biopsy specimens were also taken from the antrum and the body for culture and for three types of rapid urease test, and 13C-urea breath tests were also performed. Mixed, coded biopsies were assessed for H. pylori, and density was scored from 0 to 4. A case was considered positive for H. pylori if culture was positive, two rapid urease tests and a urea breath test were positive, or two different stains were positive. Biopsy specimens were excluded from analysis if the slides were missing or there was inadequate tissue for review, or if the specimen showed a lack of staining. RESULTS: Fifty-two (13%) of 404 specimens were excluded because of a poor Genta stain. Sensitivities were comparable for the three stains (H&E, 92%; Giemsa, 88%; Genta, 91%), while H&E specificity (89%) was significantly lower than that of the special stains (98%). Sensitivity for all three stains was significantly lower at low (grade 0 to 1) H. pylori density than at high (grade 2 to 4) density (H&E, 70% vs 98%; Giemsa, 64% vs 96%; Genta, 66% vs 97%), and 20 of 22 false positives were grade 1. CONCLUSIONS: The sensitivities of H&E and special stains are comparable at around 90%, but the specificity of H&E is significantly lower. The Giemsa stain appears to be the preferred stain for H. pylori diagnosis on the basis of its good sensitivity, excellent specificity, and lack of technical difficulty in preparation. However, H&E provides excellent accuracy when more than minimal (grade 1) H. pylori density is present.

The influence of warming on rapid urease test results: a prospective evaluation.

BACKGROUND: A rapid urease test is the initial test of choice for the diagnosis of Helicobacter pylori at endoscopy. Incubating the CLOtest at 30 degrees to 40 degrees C is recommended, but this decreases simplicity and requires the purchase of additional equipment. We compared results of testing at room temperature versus incubation at 37 degrees C. METHODS: Four biopsy specimens were taken from the same portion of the antrum in 200 patients undergoing upper endoscopy. One was placed in each of two CLOtests and two were sent for histologic examination. One CLOtest was incubated at 37 degrees C while the other remained at room temperature (22 degrees to 24 degrees C). Tests were checked every 15 minutes for the first 3 hours, every 1 hour from 3 to 6 hours, and at 24 hours. RESULTS: One hundred twenty one (61%) of 200 patients had H. pylori on histologic examination. Median time to a positive test was 3/4 hour at 37 degrees C and 1 hour at room temperature (p < 0.0001). Sensitivities were greater at 37 degrees C at 1 hour (70% vs 49%; p = 0.001) and 2 hours (86% vs 76%, p = 0.07), but were nearly identical thereafter. Specificities, identical at the two temperatures, were 99% to 100% at 1 to 6 hours and 95% at 24 hours. The CLOtest became positive more rapidly at 37 degrees C in 72% of patients: more than 1/2 hour faster in 42%; and more than 1 hour faster in 16% of patients. CONCLUSIONS: Incubation of the CLOtest at 37 degrees C hastens the time to a positive test in most patients, although the time saved is usually less than 1 hour. Sensitivity is improved when the test is read at 1 to 2 hours, but no improvement is seen beyond this time. Specificity is not influenced by warming. CLOtest incubation at 37 degrees C should be done if a final reading of the CLOtest is desired within 1 to 2 hours of biopsy.

Orthotopic liver transplantation for bone-marrow transplant-associated veno-occlusive disease and graft-versus-host disease of the liver.

Bone marrow transplantation (BMT) is a highly successful and curative therapy for many primary hematologic malignancies. However, hepatic dysfunction and failure are important causes of morbidity and mortality in this patient group after BMT. Hepatic failure can occur as a result of involvement by graft-versus-host disease (GVHD) or as a result of veno-occlusive disease (VOD). Therapies for these complications are often ineffective, especially for VOD, as approximately one fourth of patients develop irreversible liver disease and die of multiorgan failure. Accordingly, we have reviewed our center's experience with orthotopic liver transplantation (OLT) to manage the hepatic complications of BMT. We describe two patients who were treated with OLT after developing hepatic failure post-BMT. One patient had VOD with mild cutaneous and gastrointestinal GVHD; in the other patient, the pathophysiologic process affecting the liver was severe GVHD. Based on our center's experience and review of the literature, we believe OLT should be considered in patients with severe hepatic dysfunction post-BMT.

Pathologist-gastroenterologist interaction. The changing role of the pathologist.

The importance of interaction between clinicians and pathologists is examined in the setting of gastroenterology and gastrointestinal disease, and the importance of communication is emphasized. The endoscopist must provide the pathologist with information about the patient, including results of the gross examination, biopsy location, relevant clinical history, bowel preparation, and current medications. The pathologist must provide a reproducible and useful report that answers the clinical questions posed by the endoscopist. This consultation between the gastroenterologist and pathologist provides the framework for proper patient care.