Julia K. Leblanc

Comparison of Endoscopic Ultrasonography and Multidetector Computed Tomography for Detecting and Staging Pancreatic Cancer

Context Clinicians often use multidetector computed tomography or endoscopic ultrasonography to detect and stage pancreatic cancer. Contribution This prospective study found that, among 80 adults with proven pancreatic cancer, the sensitivity of multidetector computed tomography and endoscopic ultrasonography for detecting a pancreatic mass was 86% (CI, 77% to 93%) and 98% (CI, 91% to 100%), respectively. Among 53 patients undergoing surgery, endoscopic ultrasonography was more accurate for staging local tumor spread, but both tests showed similar accuracy for nodal staging and detecting resectability. Cautions Optimal strategies to detect and stage pancreatic cancer may vary across sites depending on the expertise of radiologists and endosonographers. The Editors In the United States for the year 2003, it was estimated that pancreatic cancer would be diagnosed in approximately 30700 patients and contribute to 30000 deaths (1). Complete surgical removal with negative histologic margins (R0 resection) is an independent predictor of postoperative survival (2-4) and remains the only potential curative treatment for pancreatic cancer. At surgical exploration, however, only 5% to 25% of the tumors are amenable to resection (5-8). Therefore, the principle goal of preoperative evaluation is to identify patients with potentially resectable disease while avoiding surgical exploration in those with unresectable disease. There is no evidence-based consensus on the optimal preoperative imaging assessment of patients with suspected pancreatic cancer. Because of widespread availability, helical computed tomography (CT) is usually the initial study for this indication (9, 10). Dual-phase helical CT, during which postinjection contrast image acquisition is obtained in both the pancreatic (arterial) and portal venous phases, has improved detection rate and assessment of resectability in patients with suspected pancreatic cancer (11, 12). Current state-of-the-art CT imaging uses a multiple-row detector with narrow detector collimation, wide x-ray beam, and rapid table translation; these features offer faster acquisition and thinner image slices compared with single-detector CT (13-15). Whether multidetector CT offers improved detection and staging of pancreatic cancer, however, is unknown. Endoscopic ultrasonography has been shown to be superior to conventional CT for the detection (16-20) and staging (19, 20) of pancreatic cancer. When compared with helical CT, however, endoscopic ultrasonography is reported to be either equivalent for detection (21, 22) or superior for detection or staging (23-25). To date, no comparative studies of multidetector CT with other imaging tests, including endoscopic ultrasonography, for suspected pancreatic cancer have been performed. Therefore, we conducted a prospective trial to compare endoscopic ultrasonography and multidetector CT for the detection, staging, and resectability of suspected locoregional pancreatic cancer. Methods Patients The institutional review board at Indiana University Medical Center approved this study, and all patients signed written informed consent. Eligible patients were referred to our hospital with clinically suspected or recently diagnosed solid or cystic pancreatic cancer within the previous 8 weeks. The referral base for our hospital consists of gastroenterologists and surgeons from Indiana and the surrounding contiguous states. Patients were eligible only if they agreed to undergo endoscopic ultrasonography, CT, and surgery (if necessary) at our institution. Patients were excluded if they had previously undergone endoscopic retrograde cholangiopancreatography or endoscopic ultrasonography at our institution for suspected pancreatic cancer; declined or remained undecided about potential surgical intervention; were referred to our institution by surgeons outside our hospital system. Patients were also excluded if they were pregnant, were incarcerated, could not independently provide informed consent, or were considered high surgical risk (American Society of Anesthesiology class III to V). In addition, we excluded patients with known or suspected periampullary masses, cholangiocarcinomas, or cancer with suspected locally advanced arterial (superior mesenteric, hepatic, or celiac) involvement or metastatic disease (ascites, suspicious liver or pulmonary lesions, distant enlarged lymph nodes) detected by previous imaging studies. Patients with suspected nonocclusive involvement of the superior mesenteric vein or portal vein were considered eligible for enrollment. Study Design This was a prospective, single-center, observational study. All enrolled patients had to respond to an initial health and medical questionnaire, which was followed by same-day endoscopic ultrasonography. Computed tomography was performed within 1 week. Within 3 weeks after CT, a surgeon examined the patient and reviewed the results of endoscopic ultrasonography and CT to determine eligibility for potential resection. After surgery or the decision to pursue nonoperative management, we telephoned patients to assess quality of life at 1 month, 3 months, and every 6 months until death or until 24 months if clinical disease remained stable. Endoscopic Ultrasonography Technique Conscious sedation was performed with various combinations of intravenously administered propofol, meperidine, fentanyl, or midazolam. Initially, we examined all patients with a radial echoendoscope (Olympus GF-UM130 [Olympus America Inc., Melville, New York]). We then examined patients with a linear echoendoscope (using either Pentax FG-36UX [Pentax Precision Instruments, Orangeburg, New York] or Olympus GF-UC140P [Olympus America Inc.]). Unless cancer had been definitively confirmed previously, endoscopic ultrasonographyguided fine-needle aspiration was performed with a 22-gauge needle (Wilson-Cook Medical Inc., Winston-Salem, North Carolina) in all patients, when applicable. A cytotechnologist or cytopathologist was on-site for preliminary interpretations of all aspirations. One of 3 experienced gastroenterologists, each of whom had performed at least 1000 pancreatic examinations, performed all procedures. The operator was not blinded to previous radiographic data. Recorded information included the presence or absence, size, echocharacteristics, location, or locoregional extension of any visualized pancreatic mass, lymph nodes, or distant metastases. Lymph nodes that were not accessible to endoscopic ultrasonographyguided fine-needle aspiration were considered malignant if 3 or more of the following criteria were present: diffuse hypoechoic echogenicity, short-axis diameter of 5 mm or greater, well-defined borders, round shape, or location within 5 mm of the tumor. Well-defined hypoechoic or hyperechoic lesions within the liver with a short-axis diameter of 10 mm or greater and not accessible to fine-needle aspiration were defined as metastases. We considered vascular involvement by the tumor to be present if any 1 of the following were noted: loss of the normal hyperechoic interface between tumor and vessel for at least 5 mm (adherence), irregular tumor and vessel interface, tumor within vessel lumen (invasion), vessel encasement, and perigastric or periduodenal collaterals with associated venous occlusion. Immediately after the examination, any visualized mass was designated by the endosonographer as surgically resectable or unresectable and assigned a tumor, node, metastasis (TNM) staging according to the 1997 American Joint Committee on Cancer (AJCC) classification (Appendix Table) for staging of pancreatic cancer (26). Multidetector CT Technique We performed multidetector CT with a quad-channel scanner (MX 8000 Quad, Philips Medical Systems, Cleveland, Ohio) by using 0.5-second gantry rotation time and acquisition of 4 sections per rotation. All patients drank 500 mL of tap water as nonopaque oral intraluminal contrast media. A total of 150 mL (300 mg of iodine/mL) of low-osmolar contrast media (Isovue-300, Bracco Diagnostics, Princeton, New Jersey) was injected with a power injector (CT Envision Injector, Medrad, Pittsburgh, Pennsylvania) at a rate of 4.0 mL/s into an antecubital vein by using either an 18- or 20-gauge cannula. Examination was performed in a dual-phase mode. Image acquisition was first done during the pancreatic phase (35 seconds after the start of contrast infusion) from the top to the bottom of the pancreas with 4.0-mm beam collimation (nominal section thickness, 1.0 mm; effective section thickness, 1.3 mm), 0.5-mm reconstruction interval, 120 kVp, 205 mAs, and a pitch of 1.0 during a single breath-hold of 15 to 20 seconds. The second phase was performed during the portal venous phase (65 seconds after the start of contrast infusion) from the top of the liver to the iliac crests with 10-mm beam collimation (nominal section thickness, 2.5 mm; effective section thickness, 3.2 mm), 1.3-mm reconstruction interval, 120 kVp, 250 mAs, and a pitch of 0.875 during a single breath-hold of 15 seconds. Multiplanar (2-dimensional) reformatting was not routinely performed; however, when it was used, the entire data set was transferred to a workstation (MX View, Philips Medical Systems) for evaluation. No 3-dimensional (volume rendering) postprocessing was used in this study. One of 3 experienced gastrointestinal radiologists who were blinded to the results of the previous endoscopic ultrasonography examination interpreted all scans. Patient information provided to the interpreting radiologist included presenting symptoms; the size, location, and vascular involvement (if known) of any visualized pancreatic mass from previous CT; and the results of any previous endoscopic retrograde cholangiopancreatography (for example, presence or absence of ductal strictures) or pathology (for example, endoscopic brush cytology). Locoregional and distant adenopathy were considered malignant if they were greater than 10 mm in

Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study

BACKGROUND The role of pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts remains unclear. OBJECTIVE Our purpose was to evaluate the utility of a detailed DNA analysis of pancreatic cyst fluid to diagnose mucinous and malignant cysts. DESIGN Prospective, multicenter study. PATIENTS Patients with pancreatic cysts presenting for EUS evaluation. INTERVENTION EUS-guided pancreatic cyst aspirates cytology evaluation, carcinoembryonic antigen (CEA) level determination, and a detailed DNA analysis; incorporating DNA quantification, k-ras mutation and multiple allelic loss analysis, mutational amplitude, and sequence determination. MAIN OUTCOME MEASUREMENTS Cyst fluid analysis compared with surgical pathologic or malignant cytologic examination. RESULTS The study cohort consisted of 113 patients with 40 malignant, 48 premalignant, and 25 benign cysts. Cyst fluid k-ras mutation was helpful in the diagnosis of mucinous cysts (odds ratio 20.9, specificity 96%), whereas receiver-operator characteristic curve analysis indicated optimal cutoff points for allelic loss amplitude (area under the curve [AUC] 0.79; optimal value > 65%) and CEA (AUC 0.74; optimal value >148 ng/mL). Components of DNA analysis detecting malignant cysts included allelic loss amplitude over 82% (AUC 0.9) and high DNA amount (optical density ratio >10, AUC 0.79). The criteria of a high amplitude k-ras mutation followed by allelic loss showed maximum specificity (96%) for malignancy. All malignant cysts with negative cytologic evaluation (10/40) could be diagnosed as malignant by using DNA analysis. LIMITATIONS Limited follow-up, selection bias. CONCLUSIONS Elevated amounts of pancreatic cyst fluid DNA, high-amplitude mutations, and specific mutation acquisition sequences are indicators of malignancy. The presence of a k-ras mutation is also indicative of a mucinous cyst. DNA analysis should be considered when cyst cytologic examination is negative for malignancy.

EUS-guided FNA of pancreatic metastases: a multicenter experience

BACKGROUND Metastatic lesions of the pancreas are a rare but important cause of focal pancreatic lesions. The purpose of this study is to describe the EUS features, cytologic diagnoses, and clinical impact of a cohort of patients with pancreatic metastases diagnosed by EUS-guided FNA (EUS-FNA). METHODS Over a 6-year period, in a retrospective, multicenter study, patients had the diagnosis of pancreatic metastases confirmed with EUS-FNA. All examinations were performed by one of 5 experienced endosonographers. The EUS and the clinical findings of pancreatic metastases were compared with those of a cohort with primary pancreatic malignancy. RESULTS Thirty-seven patients with possible metastases were identified, and 13 were excluded because of diagnostic uncertainty. The remaining 24 underwent EUS-FNA (mean passes 4.1) of a pancreatic mass without complications. Diagnoses included metastases from primary kidney (10), skin (6), lung (4), colon (2), liver (1), and stomach (1) cancer. In 4 (17%), 16 (67%), and 24 (100%) patients, EUS-FNA provided the initial diagnosis of malignancy, tumor recurrence, and pancreatic metastases, respectively. Four (17%) metastases initially were discovered by EUS after negative (n = 3) or inconclusive (n = 1) CT scans. Compared with primary cancer, pancreatic metastases were more likely to have well-defined margins (46% vs. 4%) compared with irregular (94% vs. 54%; p < 0.0001) margins. No statistically significant difference between the two populations was noted for tumor size, echogenicity, consistency, location, lesion number, or number of FNA passes performed. CONCLUSIONS Pancreatic metastases are an important cause of focal pancreatic lesions and may occasionally be discovered during EUS examination after previously negative or inconclusive CT. Use of immunocytochemistry, when available, may help to confirm a suspected diagnosis. These lesions are more likely to have well-defined EUS margins compared with primary pancreatic cancer.

Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience.

BACKGROUND Accurate preoperative diagnosis and staging of cholangiocarcinoma (CCA) remain difficult. OBJECTIVE To evaluate the utility of EUS in the diagnosis and preoperative evaluation of CCA. DESIGN Observational study of prospectively collected data. SETTING Single tertiary referral hospital in Indianapolis, Indiana. PATIENTS Consecutive patients with CCA from January 2003 through October 2009. INTERVENTIONS EUS and EUS-guided FNA (EUS-FNA). MAIN OUTCOME MEASUREMENTS Sensitivity of EUS for the detection of a tumor and prediction of unresectability compared with CT and magnetic resonance imaging (MRI); sensitivity of EUS-FNA to provide tissue diagnosis, by using surgical pathology as a reference standard. RESULTS A total of 228 patients with biliary strictures undergoing EUS were identified. Of these, 81 (mean age 70 years, 45 men) had CCA. Fifty-one patients (63%) had distal and 30 (37%) had proximal CCA. For those with available imaging, tumor detection was superior with EUS compared with triphasic CT (76 of 81 [94%] vs 23 of 75 [30%], respectively; P < .001). MRI identified the tumor in 11 of 26 patients (42%; P = .07 vs EUS). EUS identified CCA in all 51 (100%) distal and 25 (83%) of 30 proximal tumors (P < .01). EUS-FNA (median, 5 passes; range, 1-12 passes) was performed in 74 patients (91%). The overall sensitivity of EUS-FNA for the diagnosis of CCA was 73% (95% confidence interval, 62%-82%) and was significantly higher in distal compared with proximal CCA (81% vs 59%, respectively; P = .04). Fifteen tumors were definitely unresectable. EUS correctly identified unresectability in 8 of 15 and correctly identified the 38 of 39 patients with resectable tumors (53% sensitivity and 97% specificity for unresectability). CT and/or MRI failed to detect unresectability in 6 of these 8 patients. LIMITATION Single-center study. CONCLUSION EUS and EUS-FNA are sensitive for the diagnosis of CCA and very specific in predicting unresectability. The sensitivity of EUS-FNA is significantly higher in distal than in proximal CCA.

Endoscopic ultrasound–guided fine needle aspiration cytology of solid liver lesions: a large single-center experience

OBJECTIVES:The aim of this study was to report the sensitivity, cytological diagnoses, endoscopic ultrasound (EUS) features, complications, clinical impact, and long term follow-up of a large single-center experience with endoscopic ultrasound–guided fine needle aspiration (EUS-FNA) of benign and malignant solid liver lesions.METHODS:A database of cytologic specimens from EUS-FNA was reviewed to identify all hepatic lesions aspirated between January, 1997, and July, 2002. Procedural indications, prior radiographic data, patient demographics, EUS examination results, complications, and follow-up data were obtained and recorded.RESULTS:EUS-FNA of 77 liver lesions in 77 patients was performed without complications. Of these 77 lesions, 45 (58%) were diagnostic for malignancy, 25 (33%) were benign, and seven (9%) were nondiagnostic. A total of 22 lesions were confirmed as negative for malignancy by follow-up (mean 762 days, range 512–1556 days) or intraoperative examination; however, seven lesions could not be classified as benign or malignant. Depending on the status of the seven unclassified lesions, sensitivity of EUS-FNA for the diagnosis of malignancy ranged from 82 to 94%. When compared with benign lesions, EUS features predictive of malignant hepatic masses were the presence of regular outer margins (60% vs 27%; p = 0.02) and the detection of two or more lesions (38% vs 9%; p = 0.03). Of the 42 patients with malignancy identified by EUS-FNA and other available imaging records, EUS detected the malignancy in 41% of patients with previously negative examinations. For the 45 subjects with cytology positive for malignancy, EUS-FNA changed management in 86% of subjects.CONCLUSION:EUS-FNA of the liver is a safe and sensitive procedure that can have a significant impact on patient management. Prospective studies comparing the accuracy and complication rate of EUS-FNA and percutaneous fine needle aspiration (P-FNA) for the diagnosis of liver tumors are needed.

Efficacy of venous reconstruction in patients with adenocarcinoma of the pancreatic head

Pancreaticoduodenectomy is often avoided in patients with portal or superior mesenteric venous involvement due to the perception that venous resection is complex, morbid, and carries a poor longterm survival. Our recent experience using state-of-the-art imaging and strict resection criteria show that venous reconstruction increases operative time, transfusion requirements, intensive care unit stay, and total hospital length of stay, but has no significant impact on operative morbidity rates, mortality rates, or the incidence of positive histologic margins. Kalpan-Meier life table analysis shows similar survival curves when compared to a contemporary cohort of patients who do not undergo venous reconstruction.

EUS for pancreatic neuroendocrine tumors: a single-center, 11-year experience.

BACKGROUND Pancreatic neuroendocrine tumors (PNTs) are rare tumors with malignant potential. EUS and EUS-guided FNA (EUS-FNA) have been shown to be superior to other imaging methods in the preoperative localization and diagnosis of PNTs. OBJECTIVES To evaluate the clinical presentation, EUS morphology, and sensitivity of EUS-FNA cytology in a large consecutive cohort with histologically and/or cytologically confirmed PNTs. DESIGN Retrospective study of all consecutive patients from July 1995 to November 2006 who underwent EUS for a known or suspected PNT and had a subsequently histologically confirmed PNT. SETTING Tertiary referral center. PATIENTS Ninety-two patients with suspected PNT. INTERVENTIONS EUS evaluation with or without EUS-FNA of PNTs. MAIN OUTCOME MEASUREMENTS Clinical and EUS features of PNTs and sensitivity of EUS-FNA for the diagnosis of PNTs. RESULTS Ninety-two patients underwent EUS; 76 patients had confirmed histopathology, of whom 69 (91%) were symptomatic. Patients with functional PNTs presented with diarrhea, peptic ulcer disease, and hypoglycemia. Tumor locations and echogenic features were similar except that nonfunctional PNTs tended to be larger and have cystic features. Patients with malignant PNTs were older (P = .03), presented with abdominal pain, and had larger tumors (P = .0006) with irregular margins. Eighty-nine percent of patients underwent EUS-FNA. Sensitivity of EUS-FNA for the diagnosis of a PNT was 87%. Sensitivity of EUS-FNA was similar in functional and nonfunctional PNTs. The sensitivity of EUS-FNA was higher for malignant PNTs (P = .008). LIMITATIONS Retrospective single tertiary center. CONCLUSIONS EUS and EUS-FNA are sensitive tools, especially in cases of suspected symptomatic PNTs in which other imaging modalities have failed.

EUS-guided Trucut biopsy of suspected nonfocal chronic pancreatitis

BACKGROUND The diagnosis of early chronic pancreatitis (CP) is difficult, and the role of EUS-FNA cytology for this indication remains unclear. The aim of this study is to determine the utility and the safety profile of EUS-guided Trucut biopsy (EUS-TCB) for the histologic diagnosis of suspected nonfocal CP. METHODS After radial EUS, patients with suspected CP (> or =3 EUS criteria) underwent attempted transgastric EUS-TCB of the pancreas. Histopathologic specimens were examined by one pathologist and were classified as nondiagnostic, normal pancreas, and probable or definite CP. Within 1 week after EUS, ERCP was performed by an endoscopist blinded to the EUS results. The severity of CP by ERCP was stratified by the Cambridge classification. Agreement between tests for the diagnosis of CP was evaluated by a kappa statistic. RESULTS Of 45 patients screened, 15 declined and 30 (12 men and 18 women, mean age 44 years) underwent diagnostic EUS. Of these, 18 (60%) had suspected CP and 16 underwent attempted biopsy. Calcific pancreatitis in two patients precluded EUS-TCB. EUS-TCB results were as follows: probable CP (1), normal pancreas (8), nondiagnostic (6), device malfunction (1). Complications after EUS-TCB occurred in two patients with normal pancreatic biopsies were the following: acute pancreatitis (1) and abdominal pain without pancreatitis (1), both of whom were hospitalized and discharged within 23 hours. Six patients refused ERCP and two (per protocol) did not undergo ERCP. For the remaining 22, agreement between diagnostic EUS and ERCP was moderate (kappa, 0.40). Agreement between EUS and ERCP with EUS-TCB were poor (kappa, 0) and fair (kappa, 0.25), respectively. CONCLUSIONS Transgastric EUS-TCB of suspected nonfocal CP infrequently demonstrates histologic CP in clinically suspected disease. Because of potential complications and limited diagnostic yield, this technique is not currently recommended for evaluation of these patients.

Performance characteristics of molecular (DNA) analysis for the diagnosis of mucinous pancreatic cysts

BACKGROUND Diagnosis of mucinous pancreatic cysts (MPCs) is challenging due to the poor sensitivity of cytology provided by EUS-guided-FNA (EUS-FNA). OBJECTIVE To quantify the test characteristics of molecular (DNA) analysis in suspected low-risk MPCs. DESIGN A prospective cohort study performed in between 2008 and 2011. SETTING Academic referral center. PATIENTS Consecutive patients who underwent EUS-FNA of suspected MPCs. INTERVENTION EUS-FNA and molecular (DNA) analysis of cyst fluid. MAIN OUTCOME MEASUREMENTS The sensitivity and specificity of molecular analysis in the diagnosis of MPCs using the criterion standard of surgical pathology in resected cysts. RESULTS Patients with suspected MPCs underwent EUS-FNA and cyst fluid DNA analysis. Surgical resection was performed in 48 patients (17%), confirming a mucinous pathology in 38 (79%). In this group, molecular analysis had a sensitivity of 50% and a specificity of 80% in identifying MPCs (accuracy of 56.3%). The combination of molecular analysis with cyst fluid carcinoembryonic antigen (CEA) and cytology resulted in higher MPC diagnostic performance than either one of its individual components, with a sensitivity, specificity, and accuracy of 73.7%, 70%, and 72.9%, respectively. There was no significant difference in accuracy between molecular analysis and CEA/cytology in this group. LIMITATIONS Single-center experience. CONCLUSION Molecular analysis aids in the diagnosis of MPCs when cytology is nondiagnostic or cyst fluid is insufficient for CEA or its level is indeterminate. Our results do not support the routine use of molecular analysis, which should be used selectively after review of imaging findings and cyst fluid studies. Further studies are needed to assess DNAs performance in malignant cysts.

A prospective, randomized study of EUS-guided celiac plexus neurolysis for pancreatic cancer: one injection or two?

BACKGROUND The technique of alcohol injection during EUS-guided celiac plexus neurolysis (CPN) in patients with pancreatic cancer-related pain has not been standardized. OBJECTIVE To compare pain relief and safety of alcohol given as 1 versus 2 injections during EUS-guided CPN (EUS-CPN). Secondary outcomes examined were characteristics that predict response and survival. DESIGN Single-blinded, prospective, randomized, parallel-group study. SETTING Tertiary-care center. PATIENTS This study involved patients with pancreatic cancer-related pain. INTERVENTION EUS-CPN done by injecting 20 mL of 0.75% bupivacaine and 10 mL 98% alcohol into 1 or 2 sites at the celiac trunk. Participants were interviewed by telephone at 24 hours and weekly thereafter. MAIN OUTCOME MEASUREMENTS Time until onset of pain relief, duration of pain relief, complications. RESULTS Fifty patients (mean age 63 years; 24 men) were enrolled and randomized (29 in 1-injection, 21 in 2-injections groups). Pain relief was observed in 37 (74%) patients: 20 (69%) in the 1-injection group and 17 (81%) in the 2-injection group (chi-square P = .340). Median onset of pain relief was 1 day for both 1-injection (range 1-28 days) and 2-injection (range 1-21 days) groups (Mann-Whitney P = .943). Median duration of pain relief in the 1-injection and 2-injection groups was 11 weeks and 14 weeks, respectively (log-rank P = .612). Complete pain relief was observed in 4 (8%) patients total, 2 in each group. There were no long-term complications. LIMITATIONS Single-blinded study. CONCLUSION There were no differences in onset or duration of pain relief when either 1 or 2 injections were used. There was no difference in safety or survival between the 2 groups.