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BACKGROUND & AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.
Subject(s)
Cystadenoma, Serous , Pancreatic Cyst , Pancreatic Neoplasms , Humans , Retrospective Studies , Cystadenoma, Serous/diagnosis , Prospective Studies , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/surgery , Pancreatic Cyst/diagnosis , Pancreatic Cyst/genetics , Pancreatic Cyst/therapy , High-Throughput Nucleotide Sequencing , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Genomics , Mitogen-Activated Protein Kinases/geneticsABSTRACT
BACKGROUND: Spontaneous pancreatic portal vein fistula (PPVF) - a rare complication of pancreatic inflammation - varies widely in presentation and means of diagnosis but has been previously associated with bleeding complications and mortality. A systematic review of published literature was performed to assess the frequency of outcomes. METHODS: A search of electronic databases (PubMed, Ovid MEDLINE, Scopus, EMBASE, gray literature) resulted in 1667 relevant unique manuscripts; 52 met inclusion criteria. RESULTS: A total of 74 unique (male n = 47, 63.5 %) patients were included. Mean age was 53.5 (±11.9) years. History of alcohol use was reported in 55 (74.3 %). Underlying chronic pancreatitis (CP) was present in 49 (66.2 %). In cases where presenting symptoms were reported (n = 57, 77.4 %), the most frequent were abdominal pain (63.5 %), weight loss (14.9 %), rash (12.2 %), nausea/vomiting (12.2 %), and polyarthritis (9.5 %). Computed tomography was the most common imaging modality used to confirm the diagnosis (n = 20, 27.0 %), followed by magnetic resonance cholangiopancreatography (n = 14, 18.9 %). Portal vein thrombosis was reported in 57 (77.0 %), and bleeding events (luminal, variceal, or intra-pseudocyst) were reported in 13(17.6 %) patients. Younger age was associated with higher risk of bleeding events. Mortality was reported in 12 (16.2 %) patients at any time during follow up. Older age and polyarthritis at presentation were associated with mortality. CONCLUSIONS: PPVF is a rare and potentially fatal condition, though rates of bleeding complication and death were relatively low in this population. High-quality observational studies are needed to better understand the pathophysiology and natural history of this diagnosis.
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OBJECTIVE: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.
Subject(s)
Pancreatic Cyst , Pancreatic Neoplasms , Humans , RNA , Early Detection of Cancer , Pancreatic Cyst/diagnosis , Pancreatic Cyst/genetics , Pancreatic Cyst/pathology , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , DNA , High-Throughput Nucleotide Sequencing , Pancreatic NeoplasmsABSTRACT
OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
Subject(s)
Intellectual Disability , Neuroendocrine Tumors , Pancreatic Neoplasms , alpha-Thalassemia , Co-Repressor Proteins/genetics , Genes, Homeobox , Homeodomain Proteins , Humans , Intellectual Disability/genetics , Molecular Chaperones/genetics , Neoplasm Recurrence, Local/genetics , Neuroendocrine Tumors/genetics , Nuclear Proteins/genetics , Pancreatic Neoplasms/pathology , Telomere/genetics , Telomere/pathology , Transcription Factors/genetics , X-linked Nuclear Protein/genetics , alpha-Thalassemia/geneticsABSTRACT
OBJECTIVE: To evaluate the significance of UDD in IPMNs. BACKGROUND: The uncinate process of the pancreas has an independent ductal drainage system. International consensus guidelines of IPMNs still consider it as a branch-duct, even though it is the main drainage system for the uncinate process. METHODS: A retrospective review of all surgically treated IPMNs at our institution after 2008 was performed. Preoperative radiological studies were reviewed by an abdominal radiologist who was blinded to the pathological results. In addition to the Fukuoka criteria, presence of UDD was recorded. Using multivariate analysis, the pathological significance of UDD in predicting advanced neoplasia [high grade dysplasia or invasive carcinoma (HGD/ IC)] was determined. RESULTS: Two hundred sixty patients were identified (mean age at diagnosis was 68âyears and 49% were females): 122 (47%) had HGD/IC. UDD was noted in 59 (23%), of which 36 (61%) had HGD/IC (P < 0.003). On multivariate analysis, UDD was an independent predictor of HGD/IC (odds ratio = 2.99, P < 0.04). Subgroup analysis on patients with IPMNs confined to the dorsal portion of the gland (n = 161), also demonstrated UDD to be a significant predictor of HGD/IC in those remote lesions (odds ratio: 4.41, P = 0.039). CONCLUSIONS: This is the largest study to evaluate the significance of UDD in IPMNs and shows it to be a high-risk feature. This association persisted for remote IPMNs limited to the dorsal pancreas, suggesting UDD may be associated with an aggressive phenotype even in remote IPMN lesions.
Subject(s)
Adenocarcinoma, Mucinous , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Adenocarcinoma, Mucinous/diagnostic imaging , Adenocarcinoma, Mucinous/surgery , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/surgery , Dilatation , Dilatation, Pathologic , Female , Humans , Male , Pancreas/pathology , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/surgery , Retrospective StudiesABSTRACT
BACKGROUND & AIMS: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. METHODS: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. RESULTS: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007). CONCLUSIONS: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/surgery , Endosonography , Humans , Neoadjuvant Therapy/methods , Neoplasm Staging , Pancreatectomy , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/surgery , Prognosis , Retrospective StudiesABSTRACT
INTRODUCTION: Treatment of pancreaticobiliary pathology following Roux-en-Y gastric bypass (RYGB) poses significant technical challenges. Laparoscopic-assisted endoscopic retrograde cholangiopancreatography (LA-ERCP) can overcome those anatomical hurdles, allowing access to the papilla. Our aims were to analyze our 12-year institutional outcomes and determine the learning curve for LA-ERCP. METHODS: A retrospective review of cases between 2007 and 2019 at a high-volume pancreatobiliary unit was performed. Logistic regression was used to identify predictors of specific outcomes. To identify the learning curve, CUSUM analyses and innovative methods for standardizing the surgeon's timelines were performed. RESULTS: 131 patients underwent LA-ERCP (median age 60, 81% females) by 17 surgeons and 10 gastroenterologists. Cannulation of the papilla was achieved in all cases. Indications were choledocholithiasis (78%), Sphincter of Oddi dysfunction/Papillary stenosis (18%), management of bile leak (2%) and stenting/biopsy of malignant strictures (2%). Median total, surgical and ERCP times were 180, 128 and 48 min, respectively, and 47% underwent concomitant cholecystectomy. Surgical site infection developed in 9.2% and post-ERCP pancreatitis in 3.8%. Logistic regression revealed multiple abdominal operations and magnitude of BMI decrease (between RYGB and LA-ERCP) to be predictive of conversion to open approach. CUSUM analysis of operative time demonstrated a learning curve at case 27 for the surgical team and case 9 for the gastroenterology team. On binary cut analysis, 3-5 cases per surgeon were needed to optimize operative metrics. CONCLUSION: LA-ERCP is associated with high success rates and low adverse events. We identify outcome benchmarks and a learning curve for new adopters of this increasingly performed procedure.
Subject(s)
Choledocholithiasis , Gastric Bypass , Laparoscopy , Cholangiopancreatography, Endoscopic Retrograde/methods , Choledocholithiasis/surgery , Female , Gastric Bypass/adverse effects , Gastric Bypass/methods , Humans , Laparoscopy/methods , Learning Curve , Male , Middle Aged , Retrospective StudiesABSTRACT
AIMS: National studies have demonstrated disparities in the treatment and survival of pancreatic cancer patients based on socioeconomic status (SES). This study aimed to identify specific differences in perioperative management and outcomes based on patient SES and to study the role of a multidisciplinary clinic (MDC) in mitigating any variations. METHODS: The study analyzed patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma in a large hospital system. The patients were categorized into groups of high and low SES and whether they were managed by the authors' pancreatic cancer MDC or not. The study compared differences in disease characteristics, receipt of multimodality therapy, perioperative outcomes, and recurrence-free and overall survival. RESULTS: Of the 162 low-SES patients and 119 high-SES patients, 54% were managed in the MDC. Outside the MDC, low-SES patients were less likely to receive neoadjuvant chemotherapy and had less minimally invasive surgery, a longer OR time, less enhanced recovery participation, and more major complications (p < 0.05). No SES disparities were observed among the MDC patients. Despite similar tumor characteristics, the low-SES patients had inferior median overall survival (21 vs 32 months; p = 0.005), but the MDC appeared to eliminate this disparity. Low SES correlated with inferior survival for the non-MDC patients (17 vs 32 months; p < 0.001), but not for the MDC patients (24 vs 25 months; p = 0.33). These findings persisted in the multivariable analysis. CONCLUSION: A pancreatic cancer MDC standardizes treatment decisions, eliminates disparities in surgical outcomes, and improves survival for low-SES patients.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Carcinoma, Pancreatic Ductal/surgery , Healthcare Disparities , Humans , Neoplasm Recurrence, Local , Pancreatectomy , Pancreatic Neoplasms/surgery , Social ClassABSTRACT
OBJECTIVES: Pain burn-out during the course of chronic pancreatitis (CP), proposed in the 1980s, remains controversial, and has clinical implications. We aimed to describe the natural course of pain in a well-characterized cohort. METHODS: We constructed the clinical course of 279 C P patients enrolled from 2000 to 2014 in the North American Pancreatitis Studies from UPMC by retrospectively reviewing their medical records (median observation period, 12.4 years). We assessed abdominal pain at different time points, characterized pain pattern (Type A [short-lived pain episodes] or B [persistent pain and/or clusters of recurrent severe pain]) and recorded information on relevant covariates. RESULTS: Pain at any time, at the end of follow-up, Type A pain pattern or B pain pattern was reported by 89.6%, 46.6%, 34% and 66% patients, respectively. In multivariable analyses, disease duration (time from first diagnosis of pancreatitis to end of observation) did not associate with pain - at last clinical contact (OR, 1.0, 95% CI 0.96-1.03), at NAPS2 enrollment (OR 1.02, 95% CI 0.96-1.07) or Type B pain pattern (OR 1.01, 95% CI 0.97-1.04). Patients needing endoscopic or surgical therapy (97.8 vs. 75.2%, p < 0.001) and those with alcohol etiology (94.7 vs. 84.9%, p = 0.007) had a higher prevalence of pain. In multivariable analyses, invasive therapy associated with Type B pain and pain at last clinical contact. CONCLUSIONS: Only a subset of CP patients achieve durable pain relief. There is urgent need to develop new strategies to evaluate and manage pain, and to identify predictors of response to pain therapies for CP.
Subject(s)
Abdominal Pain/etiology , Pancreatitis, Chronic/physiopathology , Abdominal Pain/diagnosis , Abdominal Pain/epidemiology , Adult , Aged , Disease Progression , Female , Humans , Logistic Models , Longitudinal Studies , Male , Middle Aged , Pain Measurement , Pancreatitis, Chronic/therapy , Retrospective Studies , Severity of Illness Index , Time FactorsABSTRACT
BACKGROUND AND AIMS: Patients with primary sclerosing cholangitis (PSC) and dominant biliary strictures carry increased risk for the development of cholangiocarcinoma. Although ERCP-based techniques including brush cytology and intraductal biopsy sampling represent first-line tissue sampling methods for dominant strictures, sensitivity is low. Probe-based confocal laser endomicroscopy (pCLE) offers microscopic-level imaging of subepithelial biliary mucosa. Because data regarding the use of pCLE in PSC are limited, we aimed to investigate its diagnostic performance in dominant strictures. METHODS: This was a multicenter prospective study involving PSC patients with dominant strictures. ERCP with pCLE was performed with use of the Miami classification (2+ criteria for malignant diagnosis) and Paris classification. Final malignant diagnoses required histopathologic confirmation, and benign diagnoses required a minimum of 1 year of follow-up without development of cancer. RESULTS: Fifty-nine patients (mean age, 49 years; 59% men) with 63 strictures were included in the study. Stricture locations included the common bile duct (31.7%), bifurcation (22.2%), and common hepatic duct (19%). Seven patients (11.9%) were found to have cholangiocarcinoma. The sensitivity and specificity of pCLE was 85.7% (95% confidence interval [CI], 42.1-99.6) and 73.1% (95% CI, 58.9-84.4), respectively. Within specific stricture locations, the highest sensitivity was seen at the bifurcation (100%; 95% CI, 2.5-100) and the right hepatic duct (100%; 95% CI, 29.2-100). The lowest sensitivities were seen at the common bile duct (25%; 95% CI, 5.5-57.2) and the left hepatic duct (28.6%; 95% CI, 3.7-70.9). CONCLUSIONS: In this prospective multicenter study, pCLE had a high sensitivity in detecting cholangiocarcinoma, but technical aspects of the probe may limit evaluation in the common bile duct and left hepatic duct. Further evaluation is needed to elucidate the role of pCLE in the algorithm of excluding neoplasia in biliary strictures associated with PSC. (Clinical trial registration number: NCT02736708.).
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Cholangitis, Sclerosing , Bile Duct Neoplasms/complications , Bile Duct Neoplasms/diagnostic imaging , Bile Ducts, Intrahepatic , Cholangiocarcinoma/complications , Cholangiocarcinoma/diagnostic imaging , Cholangiopancreatography, Endoscopic Retrograde , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/diagnostic imaging , Constriction, Pathologic/diagnostic imaging , Constriction, Pathologic/etiology , Female , Humans , Lasers , Male , Microscopy, Confocal , Middle Aged , Prospective Studies , Sensitivity and SpecificityABSTRACT
BACKGROUND AND AIMS: Expert endoscopists previously reported ERCP outcomes for the first commercialized single-use duodenoscope. We aimed to document usability of this device by endoscopists with different levels of ERCP experience. METHODS: Fourteen "expert" (>2000 lifetime ERCPs) and 5 "less-expert" endoscopists performed consecutive ERCPs in patients without altered pancreaticobiliary anatomy. Outcomes included ERCP completion for the intended indication, rate of crossover to another endoscope, device performance ratings, and serious adverse events. RESULTS: Two hundred ERCPs including 81 (40.5%) with high complexity (American Society for Gastrointestinal Endoscopy grades 3-4) were performed. Crossover rate (11.3% vs 2.5%, P = .131), ERCP completion rate (regardless of crossovers) (96.3% vs 97.5%, P = .999), median ERCP completion time (25.0 vs 28.5 minutes, P = .130), mean cannulation attempts (2.8 vs 2.8, P = .954), and median overall satisfaction with the single-use duodenoscope (8.0 vs 8.0 [range, 1.0-10.0], P = .840) were similar for expert versus less-expert endoscopists, respectively. The same metrics were similar by procedural complexity except for shorter median completion time for grades 1 to 2 versus grades 3 to 4 (P < .001). Serious adverse events were reported in 13 patients (6.5%). CONCLUSIONS: In consecutive ERCPs including high complexity procedures, endoscopists with varying ERCP experience had good procedural success and reported high device performance ratings. (Clinical trial registration number: NCT04223830.).
Subject(s)
Cholangiopancreatography, Endoscopic Retrograde , Duodenoscopes , Catheterization , Endoscopy, Gastrointestinal , HumansABSTRACT
OBJECTIVE: Despite improvements in imaging, serum CA19-9 and pathological evaluation, differentiating between benign and malignant bile duct strictures remains a diagnostic conundrum. Recent developments in next-generation sequencing (NGS) have opened new opportunities for early detection and management of cancers but, to date, have not been rigorously applied to biliary specimens. DESIGN: We prospectively evaluated a 28-gene NGS panel (BiliSeq) using endoscopic retrograde cholangiopancreatography-obtained biliary specimens from patients with bile duct strictures. The diagnostic performance of serum CA19-9, pathological evaluation and BiliSeq was assessed on 252 patients (57 trainings and 195 validations) with 346 biliary specimens. RESULTS: The sensitivity and specificity of BiliSeq for malignant strictures was 73% and 100%, respectively. In comparison, an elevated serum CA19-9 and pathological evaluation had sensitivities of 76% and 48%, and specificities of 69% and 99%, respectively. The combination of BiliSeq and pathological evaluation increased the sensitivity to 83% and maintained a specificity of 99%. BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies. Among patients with primary sclerosing cholangitis (PSC), BiliSeq had an 83% sensitivity as compared with pathological evaluation with an 8% sensitivity. Therapeutically relevant genomic alterations were identified in 20 (8%) patients. Two patients with ERBB2-amplified cholangiocarcinoma received a trastuzumab-based regimen and had measurable clinicoradiographic response. CONCLUSIONS: The combination of BiliSeq and pathological evaluation of biliary specimens increased the detection of malignant strictures, particularly in patients with PSC. Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.
Subject(s)
Cholangiopancreatography, Endoscopic Retrograde/methods , High-Throughput Nucleotide Sequencing/methods , Adolescent , Adult , Aged , Aged, 80 and over , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Biliary Tract Diseases/diagnosis , Biliary Tract Diseases/genetics , Biliary Tract Diseases/pathology , Biomarkers, Tumor/blood , CA-19-9 Antigen/blood , Constriction, Pathologic/diagnosis , Constriction, Pathologic/genetics , Diagnosis, Differential , Female , Humans , Liver Cirrhosis, Biliary/diagnosis , Liver Cirrhosis, Biliary/genetics , Liver Cirrhosis, Biliary/pathology , Male , Middle Aged , Prospective Studies , Sensitivity and Specificity , Specimen Handling/methods , Young AdultABSTRACT
AIMS: Abnormal p53 protein expression detected by immunohistochemistry (IHC) in Barrett's oesophagus (BO) is reported to be a prognostic biomarker for progression to high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC). We evaluated our use of p53 IHC for patients with BO under surveillance from 2010 to 2016 in a single academic institution. METHODS AND RESULTS: We identified 78 patients under surveillance for BO who had biopsies evaluated for abnormal p53 expression in conjunction with routine histology and 892 patients who had histological evaluation alone. All available p53 IHC slides were rescored as wild-type or abnormal. We evaluated the risk of subsequent diagnosis with HGD and OAC. p53-tested patients were significantly more likely to be diagnosed with indefinite dysplasia (IND) or low-grade dysplasia (LGD), compared to patients who were not tested (79.5 versus 10.8%, P = 7.4 × 10-40 ). Almost half (46.9%) of patients with abnormal p53 expression were diagnosed with HGD or OAC within 5 years, compared to 5.9% with wild-type p53, and 7.6% of patients not tested (P = 2.6 × 10-18 ). However, this difference was heavily influenced by other risk factors, including dysplasia grade, in multivariate analyses. In the subgroup of patients diagnosed with IND (n = 109), abnormal p53 expression was associated with a fourfold increase (1.2-13.3, P = 0.023) in risk of HGD/OAC relative to untested patients diagnosed with IND, independent of other risk factors. CONCLUSION: In patients under surveillance for BO in a single academic institution, we found evidence that selective use of p53 IHC in conjunction with routine histology modestly improved risk stratification by identifying patients with IND at higher risk of a subsequent diagnosis of HGD or OAC.
Subject(s)
Barrett Esophagus/pathology , Biomarkers, Tumor/analysis , Precancerous Conditions/pathology , Tumor Suppressor Protein p53/biosynthesis , Adolescent , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Immunohistochemistry , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: The identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTR patients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1 patients with chronic pancreatitis. METHODS: Histologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated. RESULTS: Patients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases. CONCLUSIONS: Within this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1 patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.
Subject(s)
Mutation , Pancreatitis, Chronic , Trypsin Inhibitor, Kazal Pancreatic , Abdominal Pain , Adolescent , Adult , Child , Child, Preschool , Genetic Predisposition to Disease , Humans , Middle Aged , Pancreatitis, Chronic/genetics , Trypsin Inhibitor, Kazal Pancreatic/genetics , Young AdultABSTRACT
Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.
Subject(s)
Biomarkers, Tumor/genetics , Cyclin-Dependent Kinase Inhibitor p18/genetics , Neuroendocrine Tumors/genetics , Nuclear Proteins/genetics , Pancreatic Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Chromatin Assembly and Disassembly/genetics , Cyclin-Dependent Kinase Inhibitor p16 , DNA Copy Number Variations , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Mutation , Neuroendocrine Tumors/mortality , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/surgery , Pancreatectomy , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Prognosis , Exome SequencingABSTRACT
OBJECTIVE: DNA-based testing of pancreatic cyst fluid (PCF) is a useful adjunct to the evaluation of pancreatic cysts (PCs). Mutations in KRAS/GNAS are highly specific for intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), while TP53/PIK3CA/PTEN alterations are associated with advanced neoplasia. A prospective study was performed to evaluate preoperative PCF DNA testing. DESIGN: Over 43-months, 626 PCF specimens from 595 patients were obtained by endoscopic ultrasound (EUS)-fine needle aspiration and assessed by targeted next-generation sequencing (NGS). Molecular results were correlated with EUS findings, ancillary studies and follow-up. A separate cohort of 159 PCF specimens was also evaluated for KRAS/GNAS mutations by Sanger sequencing. RESULTS: KRAS/GNAS mutations were identified in 308 (49%) PCs, while alterations in TP53/PIK3CA/PTEN were present in 35 (6%) cases. Based on 102 (17%) patients with surgical follow-up, KRAS/GNAS mutations were detected in 56 (100%) IPMNs and 3 (30%) MCNs, and associated with 89% sensitivity and 100% specificity for a mucinous PC. In comparison, KRAS/GNAS mutations by Sanger sequencing had a 65% sensitivity and 100% specificity. By NGS, the combination of KRAS/GNAS mutations and alterations in TP53/PIK3CA/PTEN had an 89% sensitivity and 100% specificity for advanced neoplasia. Ductal dilatation, a mural nodule and malignant cytopathology had lower sensitivities (42%, 32% and 32%, respectively) and specificities (74%, 94% and 98%, respectively). CONCLUSIONS: In contrast to Sanger sequencing, preoperative NGS of PCF for KRAS/GNAS mutations is highly sensitive for IPMNs and specific for mucinous PCs. In addition, the combination of TP53/PIK3CA/PTEN alterations is a useful preoperative marker for advanced neoplasia.
Subject(s)
Biomarkers, Tumor/genetics , Cyst Fluid/chemistry , High-Throughput Nucleotide Sequencing/methods , Pancreatic Cyst/diagnosis , Pancreatic Neoplasms/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/surgery , Chromogranins/genetics , DNA, Neoplasm/genetics , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Female , Follow-Up Studies , GTP-Binding Protein alpha Subunits, Gs/genetics , Humans , Male , Middle Aged , Mutation , Neoplasm Proteins/genetics , Neoplasms, Cystic, Mucinous, and Serous/diagnosis , Neoplasms, Cystic, Mucinous, and Serous/genetics , Neoplasms, Cystic, Mucinous, and Serous/surgery , Pancreatic Cyst/genetics , Pancreatic Cyst/pathology , Pancreatic Cyst/surgery , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Preoperative Care , Prospective Studies , Proto-Oncogene Proteins p21(ras)/genetics , Sensitivity and Specificity , Young AdultABSTRACT
BACKGROUND AND AIMS: The diagnosis of low-grade dysplasia (LGD) in Barrett's esophagus (BE) is subject to substantial interobserver variation. Our central aim in this study is to compare independent pathology practices using objective measures of BE risk stratification proficiency, including frequency of diagnosis and rate of progression, with high-grade dysplasia (HGD) or adenocarcinoma (EAC) after the first diagnosis of LGD. METHODS: We retrospectively evaluated over 29,000 endoscopic biopsy cases to identify 4734 patients under endoscopic biopsy surveillance for BE in a healthcare system with multiple independent pathology practices: a subspecialized GI pathology group (SSGI; 162 BE cases per pathologist annually), 3 high BE volume general surgical pathology practices (GSPs; >50 BE cases per pathologist annually), and multiple low BE volume GSPs (10.6 BE cases per pathologist annually). We measured LGD diagnosis frequencies and rates of diagnostic progression to HGD or EAC in patients diagnosed with LGD. RESULTS: The proportion of all BE cases diagnosed as LGD (LGD/BE diagnosis ratio) ranged from 1.1% to 6.8% in the different hospital settings (P < .001). The cumulative proportion of patients with HGD or EAC within 2 years of the first diagnosis of LGD was 35.3% in the SSGI and ranged from 1.4% to 14.3% in the GSPs (P < .001). LGD diagnosed by the GSP with the lowest LGD/BE diagnosis ratio had an adjusted risk of progression similar to LGD diagnosed by subspecialists (hazard ratio, .42; 95% CI, .06-3.03). However, when LGD was diagnosed by other generalists, the adjusted risk of progression was 79% to 91% lower than subspecialists (P < .001). When LGD was diagnosed in a low-volume GSP practice, the risk of progression was not significantly increased relative to patients with nondysplastic BE (hazard ratio, 1.3; 95% CI, .4-3.9). CONCLUSIONS: General surgical pathologists and subspecialists show highly significant differences with respect to LGD/BE ratio, risk of progression relative to nondysplastic BE, crude annual progression rates, and the cumulative 2-year progression rate after LGD. These metrics can be used to assess proficiency in BE risk stratification in historical cases. Some general practitioners were able to achieve results similar to subspecialists. General surgical pathologists with little annual experience evaluating BE biopsy specimens did not successfully risk stratify patients with BE.
Subject(s)
Barrett Esophagus/pathology , Disease Progression , Esophageal Neoplasms/pathology , Pathology/standards , Precancerous Conditions/pathology , Aged , Barrett Esophagus/physiopathology , Barrett Esophagus/surgery , Biopsy, Needle , Esophageal Neoplasms/physiopathology , Esophageal Neoplasms/surgery , Esophagoscopy/methods , Female , Humans , Immunohistochemistry , Male , Middle Aged , Observer Variation , Pathology/trends , Proportional Hazards Models , Retrospective Studies , Risk Assessment , Statistics, NonparametricABSTRACT
Gastrointestinal stromal tumors (GISTs) represent 1% of alimentary tract neoplasms. Up to 90% of GISTs are driven by activating mutations in tyrosine kinase KIT or PDGFRα genes. Imatinib mesylate is a tyrosine kinase inhibitor that has recently been used in a neoadjuvant role for locally advanced GIST. Pathologic complete response (pCR) to imatinib, however, is rare and may be limited to patients with certain mutations. We report on a 71-year-old woman with a large advanced gastric GIST near the gastroesophageal junction initially involving the pancreas, spleen, adrenal, and aortic wall. The tumor harbored a KIT exon 11 deletion mutation in codon 558, which predicts a favorable response to imatinib. After 6 months of neoadjuvant imatinib therapy, the tumor was downstaged to allow partial gastric resection without the need for total gastrectomy reconstruction. The patient underwent partial gastrectomy, distal pancreatectomy, and splenectomy, and histologic examination showed a margin-negative resection with a near-pCR, with <5% viable tumor. Prolonged neoadjuvant therapy was undertaken based on the prognostic significance of a KIT exon 11 deletion mutation in codon 558, which facilitated an R0 resection while minimizing the surgical extent of the resection. A near-pCR of a large gastric GIST after neoadjuvant imatinib therapy remains a rare occurrence. Molecular testing should be undertaken before neoadjuvant therapy, because specific mutations can identify patients who will respond to imatinib and those likely to achieve significant downstaging and pCR.
Subject(s)
Biomarkers, Tumor/genetics , Gastrointestinal Stromal Tumors/therapy , Imatinib Mesylate/therapeutic use , Proto-Oncogene Proteins c-kit/genetics , Stomach Neoplasms/therapy , Aged , Biopsy , Female , Gastrectomy , Gastrointestinal Stromal Tumors/diagnostic imaging , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , Humans , Imatinib Mesylate/pharmacology , Mutation , Neoadjuvant Therapy/methods , Positron Emission Tomography Computed Tomography , Prognosis , Stomach/diagnostic imaging , Stomach/pathology , Stomach/surgery , Stomach Neoplasms/diagnostic imaging , Stomach Neoplasms/genetics , Treatment OutcomeABSTRACT
GOALS: To report the clinical profile and natural course in a large series of patients with hypertriglyceridemia (HTG) and acute pancreatitis (AP). BACKGROUND: The natural history of HTG-related pancreatitis is poorly defined. STUDY: Medical records of 121 patients with serum triglycerides (TG) levels of ≥500 mg/dL suffering 225 attacks of AP between January 2001 to August 2013 treated at the University of Pittsburgh Medical Center were retrospectively studied. Structured data were collected on initial presentation and long-term outcomes (mean follow-up 64.7±42.8 mo). AP severity was classified using Revised Atlanta Classification. RESULTS: Most patients were young-middle aged (mean 44±12.7 y), male (70%), white (78%), and had sentinel AP (63%). Peak serum TG recorded was ≥1000 mg/dL in 48%. At least 1 secondary risk factor (diabetes, high-risk drinking, obesity, offending medications) was present in the majority (78%). Sentinel AP attack varied in severity between mild (41%), moderate (26%), and severe (33%). Recurrent AP attacks occurred in 32%, often in patients with poorly controlled diabetes, alcoholism, and TG levels. A cumulative increase in prevalence of pancreatic and/or peripancreatic necrosis was observed, with 45% patients having it at some time during observation. Local complications were higher in patients with serum TG ≥1000 mg/dL. Chronic pancreatitis was noted in 16.5% patients (new-onset in 9%). CONCLUSIONS: Patients with HTG-related pancreatitis have a high prevalence of secondary risk factors. Frequent recurrences in them are usually due to poor control of secondary factors or TG. Serum TG ≥1000 mg/dL increases the risk of local complications. A subset can have or develop chronic pancreatitis.
Subject(s)
Hypertriglyceridemia/blood , Pancreatitis/blood , Triglycerides/blood , Adult , Alcohol Drinking/adverse effects , Alcohol Drinking/blood , Cohort Studies , Diabetes Complications/blood , Diabetes Complications/complications , Diabetes Complications/epidemiology , Diabetes Mellitus/blood , Diabetes Mellitus/epidemiology , Female , Humans , Hypertriglyceridemia/complications , Male , Middle Aged , Obesity/blood , Obesity/complications , Obesity/epidemiology , Pancreatitis/etiology , Prevalence , Recurrence , Retrospective Studies , Risk Factors , Severity of Illness IndexABSTRACT
BACKGROUND AND AIMS: The optimal method for endoscopic placement of bilateral self-expanding metal stents (SEMS) for the management of malignant hilar biliary obstruction has not been determined. The aim of this study was to compare the efficacies and complication rates between SEMS placed above and across the sphincter of Oddi (SO) in patients with malignant hilar biliary obstruction. MATERIALS AND METHODS: A retrospective review of patients with malignant hilar strictures who underwent bilateral SEMS placement at 3 centers was performed. Patients were divided into 2 groups: group A (above SO, n=52) or B (across SO, n=120). Patient demographics, technical success (successful SEMS placement across the stricture), functional success (decrease in pretreatment bilirubin level), complications, stent occlusion, and patient survival in the 2 groups were evaluated. RESULTS: We identified 172 patients with malignant hilar biliary obstruction (106 males, mean age 67 y). Significantly more early complications (1.9% vs. 11.7%, P=0.04) were seen in group B, mainly post-endoscopic retrograde cholangio-pancreatography pancreatitis. Mean SEMS patency periods were 33 weeks for group A and 29.6 weeks for group B (P=0.3). Occlusion rates were 50% and 45% for groups A and B (P=0.61); occlusion was due to tumor in-growth or overgrowth in all patients. SEMS occlusion was successfully treated endoscopically in 85% (22/26) patients in group A and 96% (52/54) in group B (P=0.24). The median survival time was 26 weeks in the group A and 29 weeks in group B (P=0.49). DISCUSSION: Bilateral side-by-side SEMS placement above or below the SO results in similar success rates, stent patency duration, and stent occlusion rates. Significantly fewer complications, with a trend toward lower rates of pancreatitis, were observed for SEMS placed above the SO.