Person:

Brugge, William

Autoimmune pancreatitis (AIP) shows a unique spectrum of histologic features and commonly presents with an abundant IgG4-positive (IgG4+) plasma cell infiltration. However, differentiating AIP from other mass lesions, particularly pancreatic cancer [invasive ductal carcinoma (IDC)] can be clinically challenging. In this study, we evaluated the validity of IgG4 and IgG immunohistochemistry of ampullary and periampullary tissue for the diagnosis of AIP. Our study group consisted of 14 resected AIP cases with appropriate ampullary sections. Superficial ampullary tissue and "shouldering" duodenal mucosa were evaluated for several histologic variables. Immunohistochemistry for IgG4 and IgG was performed. The number of IgG4 and IgG-positive plasma cells was counted and an IgG4+ to IgG+ plasma cells ratio (IgG4/IgG ratio) was evaluated. A control cohort was composed of IDC (n=30) and chronic pancreatitis (CP) (n=29). Although an overlap was present between the groups, the overall inflammation and number of plasma cells in and around the ampulla was significantly increased in AIP compared with CP and IDC. Furthermore, although there was some overlap in the crude number of IgG4+ plasma cells of the ampullary and duodenal tissue between AIP, IDC, and CP, an IgG4/IgG ratio, especially of the ampulla, seems diagnostically useful in differentiating AIP from other "mass forming" lesions. When a cut-off of 0.10 was applied, the diagnostic sensitivity and specificity of the ampullary IgG4/IgG ratio was 86% and 95%, respectively. In conclusion, evaluation of ampullary histology and IgG4/IgG ratio might be proven beneficial in discriminating AIP from other mass forming pancreatic lesions.

Endoscopic mucosal resection (EMR) is being advocated as a diagnostic, staging, and therapeutic technique for the management of Barrett esophagus (BE)-related neoplasia. With the emergence of new endoluminal therapy including EMR for the treatment of BE-related superficial adenocarcinomas, accurate staging has become crucial to select patients for different treatment arms. Intramucosal adenocarcinomas can be successfully treated by endoluminal techniques, whereas submucosal invasive tumors with a greater risk of lymph node metastasis are likely candidates for esophagectomy. Endoscopic ultrasound (EUS) is used to stage superficial BE-related neoplasms, yet endoscopic staging can be incongruent to that obtained after pathologic examination. In this study, we sought to determine morphologic factors, which may influence EUS staging in 35 cases with intramucosal adenocarcinoma diagnosed by subsequent EMR, focusing on tumor characteristics and structural changes associated with BE. Among the latter duplication of the muscularis mucosae, either fragmented or well-organized, was seen in 64% of 11 cases that were overstaged as having submucosal invasion by EUS, compared with 38% of those accurately staged. A greater vertical thickness of the tumor was also associated with overstaging by EUS (1.61+/-0.75 mm in the discordant vs. 1.16+/-0.67 mm in the concordant groups, P=0.028). The results illustrate how morphologic factors may affect EUS staging of superficial esophageal adenocarcinomas. EUS alone is not sufficient for staging these neoplasms precisely, and to accurately stratify patients into different treatment arms, EMR should play a role as a complementary staging modality.

BACKGROUND: Expectant management of serous cystadenoma (SCA) of the pancreas requires an accurate preoperative diagnosis. Previously published cytologic diagnostic sensitivities have ranged widely, from 10% to 100%. In the current study, the authors evaluated the diagnostic sensitivity of endoscopic ultrasound (EUS)-guided fine-needle aspiration biopsy (FNAB) and cross-sectional imaging for SCA. METHODS: Group I consisted of 21 histologically confirmed SCAs. Group II (n = 7 lesions) lacked histologic confirmation and was defined by EUS findings that were consistent with SCA and a cyst fluid carcinoembryonic antigen (CEA) level <5 ng/mL. Group III was comprised of 2 nonserous and potentially malignant cysts of the pancreas for which a preoperative diagnosis of SCA was considered. Cross-sectional imaging data were recorded. The smears were evaluated for the presence of serous lining epithelium, gastrointestinal-contaminating epithelium, and inflammatory cells including hemosiderin-laden macrophages. The authors also evaluated the presence of hemosiderin-laden macrophages in a series of 110 FNA specimens from histologically confirmed neoplastic mucinous cysts of the pancreas and 45 pseudocysts of the pancreas. RESULTS: Prospectively among Group I lesions, the appearance on computed tomography (CT) was considered definitive for SCA in 3 of 12 cases (25%). The histologically confirmed SCA cases had CEA levels of <5 ng/mL, except for 1 case for which the CEA level was 176.5 ng/mL. A cytologic diagnosis of SCA was made prospectively in only 1 CT-guided case. Retrospectively, 3 intraoperative FNAs and 1 additional CT-guided aspirate contained rare epithelial cells of a SCA. None of the EUS-guided aspirates demonstrated serous epithelium. Among Group II aspiration specimens, only 1 contained serous epithelial cells. Approximately 52% of the EUS-guided aspirates demonstrated gastrointestinal contamination. This glandular epithelium was categorized as atypical in 2 cases. Hemosiderin-laden macrophages were identified in 43% of the SCAs. Conversely, only 2% of neoplastic mucinous cysts and 9% of pseudocysts produced hemosiderin-laden macrophages in aspirate fluid. CONCLUSIONS: In the current study, serous epithelial cells were identified in <20% of cases. Gastrointestinal-contaminating epithelium, often observed in EUS-guided aspirates, further contributes to difficulties in interpretation. The presence of hemosiderin-laden macrophages as a surrogate marker for SCA requires further study. A preoperative diagnosis of SCA remains a challenge, and an EUS-guided FNAB is unlikely to provide the high level of diagnostic accuracy necessary to permit a nonoperative approach.

Background: With conventional EMR, specimens are fragmented, metaplasia may be left behind, and invasive lesions could be missed because of incomplete sampling. Concentric subtotal esophageal mucosectomy would address these limitations. Objective: To examine en bloc esophageal mucosectomy (EEM). Design: A prospective case series. Setting: An academic hospital. Subjects: Nine swine. Interventions: Conventional EMR was performed in the proximal esophagus. The submucosal space was entered, and the distal two thirds of the esophageal mucosa was freed with blunt dissection. A snare was threaded over the column of mucosa to the gastroesophageal junction. The column was resected, and the mucosa was retrieved. Main Outcome and Measurements: Clinical examination, follow-up endoscopy, necropsy, and gross and histopathologic examination. Results: EEM permitted subtotal esophageal mucosectomy in 9 of 9 swine (tissue specimens removed ranged 9-15 cm in length). The mean procedure duration was 110 minutes. In the survival series, 4 of 4 swine thrived after surgery, for 9 to 13 days. At 9 days, there was no evidence of a perforation, stricture, or leak. At 13 days, 2 swine had a mild proximal stricture, which was easily traversed with a 9.8-mm gastroscope. On necropsy, the mediastinal and thoracic cavities were unremarkable in 3 of 4 swine. One swine was found to have a contained abscess containing cellulose, presumably secondary to ingestion of wood-chip bedding material postoperatively. Reepithelialization was present on histologic examination. Limitations: An animal study. Conclusions: EEM is feasible and enabled concentric subtotal esophageal mucosal resection. The technique could completely and circumferentially excise intramucosal lesions. Longer follow-up and larger studies are needed to evaluate infection, stricture, and safety.

BACKGROUND: Gastric hyperplastic polyps are the second most common subtype of gastric polyps. There has been an ongoing debate about their precise diagnostic criteria and etiological associations. MATERIALS AND METHODS: A total of 208 gastric polyps that were originally diagnosed as hyperplastic polyps in our department during an 8-year period were reviewed using recently emphasized diagnostic criteria, and their clinicopathologic associations were explored. RESULTS: Only 41 cases were confirmed as hyperplastic polyps, whereas 103 cases (49%) were reclassified as polypoid foveolar hyperplasia, and 64 cases (31%) were diagnosed as gastric mucosal prolapse polyps. Gastric mucosal prolapse polyps were distinguished by basal glandular elements, hypertrophic muscle fibers ascending perpendicularly from the muscularis mucosae, and by thick-walled blood vessels. This hitherto undescribed polyp is more commonly sessile than hyperplastic polyps (P=0.0452) and is found more often in the antropyloric region (P: 0.0053). Only 20.6% of hyperplastic polyps were associated with Helicobacter pylori infection. CONCLUSIONS: Our findings highlight that gastric polypoid lesions that have morphologic similarities may be related to various mechanisms, including inflammatory and prolapse processes. The predominantly antral location of gastric mucosal prolapse polyps, a zone of pronounced peristalsis, suggests that mucosal prolapse plays a role in the development of these common polyps. Evaluation of the prevalence and clinical associations of these distinctive polyps awaits further studies.

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

Introduction: Transesophageal endoscopic mediastinoscopy (MX) and thoracoscopy (TX) could reduce pain, eliminate intercostal neuralgia, provide better access to the posterior mediastinal compartment and pulmonary hilum, and improve cosmesis. The purpose of this study was to demonstrate the feasibility of transesophageal natural orifice translumenal endoscopic surgery (NOTES) and to determine the complications that might be seen in surviving animals. Methods: Using cap endoscopic mucosal resection and blunt dissection, a 15–20 cm submucosal tunnel was created in the esophagus and an endoscope passed through the tunnel into the mediastinum. One swine underwent MX; three swine underwent both MX and TX. The mediastinal compartment, hilar lymph nodes, pleura, lung, and esophagus were identified. Esophageal closure was obtained via submucosal tunnel flap-valve alone (two swine) or reinforcement with mucosal clips (two swine). The esophagus, mediastinum, and thorax were examined at necropsy. The esophagus was excised and sent for pathological examination. Results: NOTES MX and TX provided excellent visualization of mediastinal and thoracic structures. Pleural biopsy was easily accomplished. All animals survived the procedure, ate well, and showed no ill effects. Swine were sacrificed at either 8 or 12 days postoperatively. At necropsy, mild atelectasis was noted in each animal. One animal (mucosal clip closure) developed a fluid collection in the submucosal tunnel. There was no evidence of mediastinitis or thoracic contamination in any animals. Conclusions: Transesophageal endoscopic mediastinoscopy and thoracoscopy provide excellent visualization of mediastinal and intrathoracic structures. Pleural biopsy can be easily obtained under direct visualization. Structures that are difficult to visualize via traditional cervical mediastinoscopy and thoracoscopy are seen well with this approach. The submucosal tunnel creates a flap-valve that, alone, may be sufficient for preventing esophageal leak. These procedures can be performed safely in swine with short-term survival. Further study with a larger sample size and longer survival is warranted.

Background and aims: Pancreatic cyst fluid (PCF) CEA has been shown to be the most accurate preoperative test for detection of cystic mucinous neoplasms (CMNs). This study aimed to assess the added value of PCF KRAS mutational analysis to CEA for diagnosis of CMNs. Patients and methods: This is a retrospective study of prospectively collected endoscopic ultrasonography (EUS) fine-needle aspiration (FNA) data. KRAS mutation was determined by direct sequencing or equivalent methods. Cysts were classified histologically (surgical cohort) or by clinical (EUS or FNA) findings (clinical cohort). Performance characteristics of KRAS, CEA and their combination for detection of a cystic mucinous neoplasm (CMN) and malignancy were calculated. Results: The study cohort consisted of 943 patients: 147 in the surgical cohort and 796 in the clinical cohort. Overall, KRAS and CEA each had high specificity (100 % and 93.2 %), but low sensitivity (48.3 % and 56.3 %) for the diagnosis of a CMN. The positivity of KRAS or CEA increased the diagnostic accuracy (80.8 %) and AUC (0.84) significantly compared to KRAS (65.3 % and 0.74) or CEA (65.8 % and 0.74) alone, but only in the clinical cohort (P < 0.0001 for both). KRAS mutation was significantly more frequent in malignant CMNs compared to histologically confirmed non-malignant CMNs (73 % vs. 37 %, P = 0.001). The negative predictive value of KRAS mutation was 77.6 % in differentiating non-malignant cysts. Conclusions: The detection of a KRAS mutation in PCF is a highly specific test for mucinous cysts. It outperforms CEA for sensitivity in mucinous cyst diagnosis, but the data does not support its routine use.

Background: BRCA2 mutation carriers are at increased risk for multiple cancers including pancreatic adenocarcinoma (PAC). Our goal was to compare the effectiveness of different PAC screening strategies in BRCA2 mutation carriers, from the standpoint of life expectancy. Methods: A previously published Markov model of PAC was updated and extended to incorporate key aspects of BRCA2 mutation carrier status, including competing risks of breast- and ovarian-cancer specific mortality. BRCA2 mutation carriers were modeled and analyzed as the primary cohort for the analysis. Additional higher risk BRCA2 cohorts that were stratified according to the number of first-degree relatives (FDRs) with PAC were also analyzed. For each cohort, one-time screening and annual screening were evaluated, with screening starting at age 50 in both strategies. The primary outcome was net gain in life expectancy (LE) compared to no screening. Sensitivity analysis was performed on key model parameters, including surgical mortality and MRI test performance. Findings: One-time screening at age 50 resulted in a LE gain of 3.9 days for the primary BRCA2 cohort, and a gain of 5.8 days for those with BRCA2 and one FDR. Annual screening resulted in LE loss of 12.9 days for the primary cohort and 1.3 days for BRCA2 carriers with 1 FDR, but resulted in 20.6 days gained for carriers with 2 FDRs and 260 days gained for those with 3 FDRs. For patients with ≥ 3 FDRs, annual screening starting at an earlier age (i.e. 35–40) was optimal. Interpretation Among BRCA2 mutation carriers, aggressive screening regimens may be ineffective unless additional indicators of elevated risk (e.g., 2 or more FDRs) are present. More clinical studies are needed to confirm these findings. Funding American Cancer Society – New England Division – Ellison Foundation Research Scholar Grant (RSG-15-129-01-CPHPS).

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.