Manoop S. Bhutani

A comparison of the accuracy of echo features during endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration for diagnosis of malignant lymph node invasion.

BACKGROUND The purpose of this study was to re-evaluate echo features of lymph nodes during endoscopic ultrasound and assess the utility of these echo features and endoscopic ultrasound-guided fine-needle aspiration in predicting malignant lymph node invasion. METHODS Thirty-five lymph nodes in 25 patients with lung, esophageal, and pancreatic cancer were evaluated by endoscopic ultrasound. Endoscopic ultrasound examinations were performed with a radial scanning echoendoscope. Confirmation of benign lymph nodes was obtained by surgical resection while malignant lymph nodes were confirmed by real-time endoscopic ultrasound-guided fine-needle aspiration with a linear array echoendoscope. RESULTS Nineteen benign lymph nodes and 16 malignant lymph nodes in the mediastinum, celiac axis, and the peripancreatic area were included in the study. The following echo features were compared between benign and malignant lymph nodes: size greater than 1 cm, hypoechoic, distinct margins, and round shape. No single feature independently predicted malignant invasion. When all four of the above features were present in the same lymph node, the accuracy for predicting malignant invasion was 80%. However, all four features of malignant involvement were present in only 25% (4 of 16) of malignant lymph nodes. Our study also suggests that the above echo features may be a less reliable predictor of malignant invasion in pulmonary malignancies when compared to gastrointestinal cancers. Endoscopic ultrasound-guided fine-needle aspiration of lymph nodes in 22 patients revealed malignant lymph node invasion in 16 and benign cells in 6 patients. CONCLUSION Endoscopic ultrasound-guided fine-needle aspiration is an important adjunct for accurate lymph node assessment for malignancy.

Endoscopic ultrasound with fine-needle aspiration in the Diagnosis and staging of lung cancer

BACKGROUND Esophageal endoscopic ultrasonographic (EUS) guidance for fine-needle aspiration (FNA) of mediastinal lymph nodes has been introduced only recently. The utility of EUS/FNA in diagnosing and staging bronchogenic carcinoma is unknown. METHODS After a thoracic computed tomographic scan, 27 patients with known or suspected lung cancer underwent EUS. Accessible abnormal mediastinal lymph nodes were aspirated under EUS guidance. Patients with positive cytologic studies did not undergo further testing, whereas the remaining patients underwent mediastinal exploration. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated for both chest computed tomography and EUS/FNA: RESULTS Twenty-two of 27 patients had mediastinal adenopathy by computed tomography scan. Sixteen patients had positive findings on EUS, 15 with positive FNA (10 non-small cell lung cancer; 5 small cell lung cancer) and 1 with T4 status. Fourteen patients with positive FNA had lymph nodes sampled at level 5, level 7, or both. Of 11 patients with negative EUS/FNA, 2 had positive findings at operation (sensitivity 89%). The diagnosis of lung cancer was established in 7 patients. CONCLUSIONS The results showed that EUS/FNA improves the accuracy of computed tomographic scan in the staging of lung cancer. By accessing lymph nodes at levels 5 and 7, EUS/FNA complements mediastinoscopy and is considered the staging modality of choice in these regions. Positive EUS/FNA can obviate the need for further invasive staging.

Role of endoscopic ultrasound (EUS) and EUS-guided fine needle aspiration in the diagnosis and treatment of cystic lesions of the pancreas.

Introduction and Aims Cystic neoplasms of the pancreas may be inadvertently treated as benign pseudocysts in clinical practice, often without the use of cytology, cyst tumor markers, or histopathology. We assessed the utility of EUS-guided fine-needle aspiration (EUS-FNA) to assist in the diagnosis and management of pancreatic cysts. Methodology All patients who had pancreatic cysts detected by EUS over a 24-month period were analyzed. Preoperative diagnosis was derived from an algorithm combining clinical history and endosonographic features. In selected cases, EUS-FNA was performed and cyst fluid aspirates were analyzed. Surgical specimens served as diagnostic standard. Results A total of 43 patients with pancreatic cysts underwent 45 EUS examinations. Surgical specimens were obtained from 9 patients (mucinous cystadenocarcinoma, 3; adenocarcinoma, 3; pancreatic endocrine tumor, 2; and benign cyst, 1); diagnostic EUS correctly predicted malignant cysts in 8/9 (88.9%). One case inaccurately interpreted by EUS as cystic neoplasm turned out to be a benign cyst on resection. Twenty-one patients underwent EUS-FNA. The cytologic interpretation was adenocarcinoma in 9.5% (2/21); suspicious for malignancy or atypical cells in 19.0% (4/21); benign in 66.6% (14/21); and insufficient cells in 4.8% (1/21). Conclusion The information gathered from clinical history and EUS, complemented by fluid analysis after EUS-guided FNA, predicts neoplastic pancreatic cysts and assists in decision-making for medical or surgical approach.

Role of EUS-FNA-Based Cytology in the Diagnosis of Mucinous Pancreatic Cystic Lesions: A Systematic Review and Meta-Analysis

BackgroundPreoperative diagnosis of malignancy in pancreatic cystic lesions (PCLs) remains challenging. Most non-mucinous cystic lesions (NMCLs) are benign, but mucinous cystic lesions (MCLs) are more likely to be premalignant or malignant.AimThe aim of this study was to assess the sensitivity, specificity, and positive and negative likelihood ratios (LRs) of EUS-FNA-based cytology in differentiating MCLs from non-mucinous PCLs.MethodsWe conducted a comprehensive search of MEDLINE, SCOPUS, Cochrane, and “CINAHL Plus” databases to identify studies, in which the results of EUS-FNA-based cytology of PCLs were compared with those of surgical biopsy or surgical excision histopathology. A DerSimonian-Laird random effect model was used to estimate the pooled sensitivity, specificity, and LRs, and a summary receiver-operating characteristic (SROC) curve was constructed.ResultsWe included 376 patients from 11 distinct studies who underwent EUS-FNA-based cytology and also had histopathological diagnosis. The pooled sensitivity and specificity in diagnosing MCLs were 0.63 (95% CI, 0.56–0.70) and 0.88 (95% CI, 0.83–0.93), respectively. The positive and negative LRs in diagnosing MCLs were 4.46 (95% CI, 1.21–16.43) and 0.46 (95% CI, 0.25–0.86), respectively. The area under the curve (AUC) was 0.89.ConclusionsEUS-FNA-based cytology has overall low sensitivity but good specificity in differentiating MCLs from NMCLs. Further research is required to improve the overall sensitivity of EUS-FNA-based cytology to diagnose MCLs while evaluating PCL.

Diagnostic accuracy of EUS in differentiating mucosal versus submucosal invasion of superficial esophageal cancers: a systematic review and meta-analysis

BACKGROUND The prognosis of esophageal cancer (EC) depends on the depth of tumor invasion and lymph node metastasis. EC limited to the mucosa (T1a) can be treated effectively with minimally invasive endoscopic therapy, whereas submucosal (T1b) EC carries relatively high risk of lymph node metastasis and requires surgical resection. OBJECTIVE To determine the diagnostic accuracy of EUS in differentiating T1a EC from T1b EC. DESIGN We performed a comprehensive search of MEDLINE, SCOPUS, Cochrane, and CINAHL Plus databases to identify studies in which results of EUS-based staging of EC were compared with the results of histopathology of EMR or surgically resected esophageal lesions. DerSimonian-Laird random-effects model was used to estimate the pooled sensitivity, specificity, and likelihood ratio, and a summary receiver operating characteristic (SROC) curve was created. SETTING Meta-analysis of 19 international studies. PATIENTS Total of 1019 patients with superficial EC (SEC). INTERVENTIONS EUS and EMR or surgical resection of SEC. MAIN OUTCOME MEASUREMENTS Sensitivity and specificity of EUS in accurately staging SEC. RESULTS The pooled sensitivity, specificity, and positive and negative likelihood ratio of EUS for T1a staging were 0.85 (95% CI, 0.82-0.88), 0.87 (95% CI, 0.84-0.90), 6.62 (95% CI, 3.61-12.12), and 0.20 (95% CI, 0.14-0.30), respectively. For T1b staging, these results were 0.86 (95% CI, 0.82-0.89), 0.86 (95% CI, 0.83-0.89), 5.13 (95% CI, 3.36-7.82), and 0.17 (95% CI, 0.09-0.30), respectively. The area under the curve was at least 0.93 for both mucosal and submucosal lesions. LIMITATIONS Heterogeneity was present among the studies. CONCLUSION Overall EUS has good accuracy (area under the curve ≥0.93) in staging SECs. Heterogeneity among the included studies suggests that multiple factors including the location and type of lesion, method and frequency of EUS probe, and the experience of the endosonographer can affect the diagnostic accuracy of EUS.

Prognostic Biomarkers for Esophageal Adenocarcinoma Identified by Analysis of Tumor Transcriptome

Background Despite many attempts to establish pre-treatment prognostic markers to understand the clinical biology of esophageal adenocarcinoma (EAC), validated clinical biomarkers or parameters remain elusive. We generated and analyzed tumor transcriptome to develop a practical biomarker prognostic signature in EAC. Methodology/Principal Findings Untreated esophageal endoscopic biopsy specimens were obtained from 64 patients undergoing surgery and chemoradiation. Using DNA microarray technology, genome-wide gene expression profiling was performed on 75 untreated cancer specimens from 64 EAC patients. By applying various statistical and informatical methods to gene expression data, we discovered distinct subgroups of EAC with differences in overall gene expression patterns and identified potential biomarkers significantly associated with prognosis. The candidate marker genes were further explored in formalin-fixed, paraffin-embedded tissues from an independent cohort (52 patients) using quantitative RT-PCR to measure gene expression. We identified two genes whose expression was associated with overall survival in 52 EAC patients and the combined 2-gene expression signature was independently associated with poor outcome (P<0.024) in the multivariate Cox hazard regression analysis. Conclusions/Significance Our findings suggest that the molecular gene expression signatures are associated with prognosis of EAC patients and can be assessed prior to any therapy. This signature could provide important improvement for the management of EAC patients.

Current diagnosis and management of unusual pancreatic tumors

BACKGROUND The finding of a solid or cystic mass in the pancreas is becoming more common secondary to the increasing use of cross-sectional imaging and the improved sensitivity of such studies for the detection of pancreatic abnormalities. Because of the aggressive natural history of pancreatic cancer, this has caused concern that all pancreatic abnormalities may be cancer as well as confusion over proper diagnostic and treatment algorithms. This review provides an overview of the natural history, diagnostic considerations, and treatment recommendations for the less common tumors of the pancreas which can be misinterpreted as pancreatic cancer including: solid pseudopapillary tumors (SPT), acinar cell carcinoma (ACC), lymphoplasmacytic sclerosing pancreatitis (LPSP), primary pancreatic lymphoma (PPL), and metastatic renal cell carcinoma to the pancreas. DATA SOURCES A Medline search was conducted to identify studies investigating the clinicopathologic features, molecular genetics, pathogenesis, diagnosis, and treatment of SPT, ACC, LPSP, PPL, and pancreatic metastases. CONCLUSIONS It is often possible to obtain an accurate pretreatment diagnosis for these unusual pancreatic tumors and to successfully differentiate them from the more common pancreatic malignancies.

Genome-Wide Catalogue of Chromosomal Aberrations in Barrett's Esophagus and Esophageal Adenocarcinoma: A High-Density Single Nucleotide Polymorphism Array Analysis

To better understand the molecular mechanisms behind esophageal adenocarcinoma (EAC) tumorigenesis, we used high-density single nucleotide polymorphism arrays to profile chromosomal aberrations at each of the four sequential progression stages, Barretts metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC, in 101 patients. We observed a significant trend toward increasing loss of chromosomes with higher progression stage. For BM, LGD, HGD, and EAC, respectively, the average numbers of chromosome arms with loss per sample were 0.30, 3.21, 7.70, and 11.90 (P for trend = 4.82 × 10−7), and the mean percentages of single nucleotide polymorphisms with allele loss were 0.1%, 1.8%, 6.6%, and 17.2% (P for trend = 2.64 × 10−6). In LGD, loss of 3p14.2 (68.4%) and 16q23.1 (47.4%) was limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, whereas loss of 9p21 (68.4%) occurred in larger regions. A significant increase in the loss of other chromosomal regions was seen in HGD and EAC. Loss of 17p (47.6%) was one of the most frequent events in EAC. Many recurrent small regions of chromosomal loss disrupted single genes, including FHIT, WWOX, RUNX1, KIF26B, MGC48628, PDE4D, C20orf133, GMDS, DMD, and PARK2, most of which are common fragile site regions in the human genome. However, RUNX1 at 21q22 seemed to be a potential tumor suppressor gene in EAC. Amplifications were less frequent than losses and mostly occurred in EAC. 8q24 (containing Myc) and 8p23.1 (containing CTSB) were the two most frequently amplified regions. In addition, a significant trend toward increasing amplification was associated with higher progression stage. Cancer Prev Res; 3(9); 1176–86. ©2010 AACR.To better understand the molecular mechanisms behind esophageal adenocarcinoma (EAC) tumorigenesis, we used high-density single nucleotide polymorphism (SNP) arrays to profile chromosomal aberrations at each of the four sequential progression stages - Barrett9s metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC, in 101 patients. We observed a significant trend toward increasing loss of chromosomes with higher progression stage. For BM, LGD, HGD, and EAC, respectively, the average numbers of chromosome arms with loss per sample were 0.30, 3.21, 7.70, and 11.90 (P for trend= 4.82 × 10-7), and the mean percentages of SNPs with allele loss were 0.1%, 1.8%, 6.6%, and 17.2% (P for trend = 2.64 × 10-6). In LGD, loss of 3p14.2 (68.4%) and 16q23.1 (47.4%) was limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, whereas loss of 9p21 (68.4%) occurred in larger regions. Loss of 17p (47.6%) was one of the most frequent events in EAC. Many recurrent small regions of chromosomal loss disrupted single genes, including FHIT, WWOX, RUNX1, KIF26B, MGC48628, PDE4D, C20orf133, GMDS, DMD, and PARK2, most of which are common fragile site (CFS) regions in the human genome. But RUNX1 at 21q22 appeared to be a potential tumor suppressor gene in EAC. Amplifications were less frequent than losses and mostly occurred in EAC. The 8q24 (containing Myc) and 8p23.1 (containing CTSB) were the two most frequently amplified regions. In addition, a significant trend toward increasing amplification was associated with higher progression stage.

Comparative analysis of direct pancreatic function testing versus morphological assessment by endoscopic ultrasonography for the evaluation of chronic unexplained abdominal pain of presumed pancreatic origin

Objectives: The diagnosis of “minimal change” chronic pancreatitis (MCCP) is often considered when conventional imaging studies are unrevealing in a patient population with abdominal pain of presumed pancreatic origin. Direct pancreatic function testing using secretin as a secretagogue (ST) has been considered the most sensitive method to diagnose MCCP but is not widely available to clinicians. Endoscopic ultrasound (EUS) allows detailed imaging of pancreatic architecture, but the sensitivity and specificity for MCCP remain to be determined. We sought to compare the accuracy of EUS and ST in patients with presumed MCCP. Methods: Seventy-four patients referred to our pancreas clinic with unexplained abdominal pain and previously negative imaging studies underwent an ST for evaluation of possible MCCP. Twenty-one of these also underwent EUS. EUS images were read by 1 of 2 experts blinded to ST results. Results: Using ST as the “gold standard,” EUS had a maximum sensitivity of 71% when the cut-off for diagnosis was set at at least 3 EUS features. Conversely, maximum specificity (92%) was seen when the cut-off value was set at at least 6 EUS criteria. Diagnostic certainty was only 50% (positive predictive value = 0.5) when at least 6 criteria were used as the cut-off. MCCP was excluded with greater than 70% certainty when less than 3 criteria were present. At the best cut-off value of at least 4 features, EUS had a sensitivity of 57% and a specificity of 64%. Conclusions: In this patient population with abdominal pain of presumed pancreatic origin, EUS and standard pancreatic function testing are often discordant. If ST is assumed to be the reference against which other tests are compared, EUS is less accurate than ST in diagnosing MCCP.

A prospective controlled evaluation of endoscopic detection of angiodysplasia and its association with aortic valve disease

BACKGROUND In view of controversy about the association of aortic stenosis and angiodysplasia of the gut, we performed a prospective, controlled study to evaluate the relationship between aortic valve disease and gastrointestinal angiodysplasia. METHODS Forty patients who had endoscopy for clinical indications such as gastrointestinal bleeding, anemia, polyps, colon cancer, and dyspepsia, and who were found to have angiodysplasia of the gastrointestinal tract, underwent two-dimensional and Doppler echocardiography. Thirty-seven controls matched for age, sex, indication, and nature of endoscopic examination, but without angiodysplasia, underwent similar echocardiographic examination. RESULTS None of the patients in either group had aortic stenosis. The prevalence of aortic sclerosis, aortic insufficiency, and low left ventricular ejection fraction was similar in patients with and without angiodysplasia. CONCLUSIONS This study does not support the role of aortic valve disease as the cause of angiodysplasia of the gastrointestinal tract. A subgroup of patients with angiodysplasia with aortic sclerosis, with or without other valvular disease (but none with aortic stenosis), had increased prevalence of gastrointestinal bleeding when compared with controls. When aortic valve disease or decreased left ventricular ejection fraction were analyzed as independent predictors, none of them in and of itself appeared to be a factor in bleeding from these gastrointestinal lesions.