Thomas C. Smyrk

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.

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Warthin's description of family G, which he began studying in 1895. Warthin's observations were not fully appreciated until 1966 when two families with an autosomal dominant inheritance pattern of nonpolyposis colorectal cancer (CRC) and endometrial cancer were described. This condition was first termed the "cancer family syndrome" and was later renamed HNPCC. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome I, with hereditary predisposition for CRC having early (approximately 44 years) age of onset, a proclivity (70%) for the proximal colon, and an excess of synchronous and metachronous colonic cancers and Lynch syndrome II, featuring a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium. Transitional cell carcinoma of the ureter and renal pelvis and carcinomas of the stomach, small bowel, ovary, and pancreas also afflict some families. Current estimates indicate that HNPCC may account for as much as 6% of the total CRC burden. There are no known premonitory phenotypic signs or biomarkers of cancer susceptibility in the Lynch syndromes. This report will summarize current knowledge, with emphasis on the manner in which this knowledge can be employed effectively for diagnosis and management of HNPCC.

The Japan Pancreas Society criteria for diagnosis of autoimmune pancreatitis (AIP) mandate presence of characteristic imaging (diffuse pancreatic enlargement with diffusely irregular, narrow pancreatic duct). AIP has unique histologic features associated with infiltration of tissues of affected organs with abundant IgG4-positive cells. We propose expanded diagnostic criteria for AIP with a cohort of histologically confirmed AIP.We reviewed the pancreatic imaging findings on computed tomography scans, serum IgG4 levels, other organ involvement, and response to steroids in 29 consecutive patients who met histologic criteria for AIP.Computed tomography scans (n = 22) showed diffuse pancreatic enlargement in 6 (27%) patients; the rest had focal enlargement, distinct mass, normal pancreas, or focal acute pancreatitis. Serum IgG4 level was elevated in 15 of 21 (71%) patients, and other organ involvement (eg, intrahepatic biliary strictures) was noted in 11 of 29 (38%) patients. All 17 patients treated with steroids exhibited resolution/marked improvement of pancreatic/extrapancreatic manifestation. On the basis of this experience we propose that diagnosis of AIP can be made in patients with > or =1 of these criteria: (1) diagnostic histology, (2) characteristic imaging on computed tomography and pancreatography with elevated serum IgG4 level, or (3) response to steroid therapy of pancreatic/extrapancreatic manifestations of AIP. Twenty additional patients met expanded diagnostic criteria for AIP, and their demographic and clinical profile was similar to that of the 29 patients meeting histologic criteria.AIP defined by histological criteria shows a wide spectrum of radiologic features, with characteristic imaging seen only in a minority. Incorporation of additional features into current diagnostic criteria can identify the full spectrum of clinical presentations of AIP.

Background & Aims: Immunoglobulin (Ig)G4-associated cholangitis (IAC) is the biliary manifestation of a steroid-responsive multisystem fibroinflammatory disorder in which affected organs have a characteristic lymphoplasmacytic infiltrate rich in IgG4-positive cells. We describe clinical features, treatment response, and predictors of relapse in IAC and compare relapse rates in IAC with intrapancreatic vs proximal bile duct strictures. Methods: We reviewed clinical, serologic, and imaging characteristics and treatment response in 53 IAC patients. Results: IAC patients generally were older (mean age, 62 y) men (85%), presenting with obstructive jaundice (77%) associated with autoimmune pancreatitis (92%), increased serum IgG4 levels (74%), and abundant IgG4-positive cells in bile duct biopsy specimens (88%). At presentation, biliary strictures were confined to the intrapancreatic bile duct in 51%; the proximal extrahepatic/intrahepatic ducts were involved in 49%. Initial presentation was treated with steroids (n = 30; median follow-up period, 29.5 months), surgical resection (n = 18; median follow-up period, 58 months), or was conservative (n = 5; median follow-up period, 35 months). Relapses occurred in 53% after steroid withdrawal; 44% relapsed after surgery and were treated with steroids. The presence of proximal extrahepatic/intrahepatic strictures was predictive of relapse. Steroid therapy normalized liver enzyme levels in 61%; biliary stents could be removed in 17 of 18 patients. Fifteen patients treated with steroids for relapse after steroid withdrawal responded; 7 patients on additional immunomodulatory drugs remain in steroid-free remission (median follow-up period, 6 months). Conclusions: IAC should be suspected in unexplained biliary strictures associated with increased serum IgG4 and unexplained pancreatic disease. Relapses are common after steroid withdrawal, especially with proximal strictures. The role of immunomodulatory drugs for relapses needs further study. Background & Aims: Immunoglobulin (Ig)G4-associated cholangitis (IAC) is the biliary manifestation of a steroid-responsive multisystem fibroinflammatory disorder in which affected organs have a characteristic lymphoplasmacytic infiltrate rich in IgG4-positive cells. We describe clinical features, treatment response, and predictors of relapse in IAC and compare relapse rates in IAC with intrapancreatic vs proximal bile duct strictures. Methods: We reviewed clinical, serologic, and imaging characteristics and treatment response in 53 IAC patients. Results: IAC patients generally were older (mean age, 62 y) men (85%), presenting with obstructive jaundice (77%) associated with autoimmune pancreatitis (92%), increased serum IgG4 levels (74%), and abundant IgG4-positive cells in bile duct biopsy specimens (88%). At presentation, biliary strictures were confined to the intrapancreatic bile duct in 51%; the proximal extrahepatic/intrahepatic ducts were involved in 49%. Initial presentation was treated with steroids (n = 30; median follow-up period, 29.5 months), surgical resection (n = 18; median follow-up period, 58 months), or was conservative (n = 5; median follow-up period, 35 months). Relapses occurred in 53% after steroid withdrawal; 44% relapsed after surgery and were treated with steroids. The presence of proximal extrahepatic/intrahepatic strictures was predictive of relapse. Steroid therapy normalized liver enzyme levels in 61%; biliary stents could be removed in 17 of 18 patients. Fifteen patients treated with steroids for relapse after steroid withdrawal responded; 7 patients on additional immunomodulatory drugs remain in steroid-free remission (median follow-up period, 6 months). Conclusions: IAC should be suspected in unexplained biliary strictures associated with increased serum IgG4 and unexplained pancreatic disease. Relapses are common after steroid withdrawal, especially with proximal strictures. The role of immunomodulatory drugs for relapses needs further study. See Topazian M et al on page 364 in CGH. See Topazian M et al on page 364 in CGH. Early descriptions of autoimmune pancreatitis (AIP) included its association with other autoimmune disorders such as Sjögren’s syndrome, retroperitoneal fibrosis, and primary sclerosing cholangitis.1Montefusco P.P. Geiss A.C. Bronzo R.L. et al.Sclerosing cholangitis, chronic pancreatitis, and Sjogren’s syndrome: a syndrome complex.Am J Surg. 1984; 147: 822-826Abstract Full Text PDF PubMed Scopus (164) Google Scholar, 2Kawaguchi K. Koike M. Tsuruta K. et al.Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas.Hum Pathol. 1991; 22: 387-395Abstract Full Text PDF PubMed Scopus (568) Google Scholar, 3Uchida K. Okazaki K. Asada M. et al.Case of chronic pancreatitis involving an autoimmune mechanism that extended to retroperitoneal fibrosis.Pancreas. 2003; 26: 92-94Crossref PubMed Scopus (70) Google Scholar In a landmark study Hamano et al4Hamano H. Kawa S. Horiuchi A. et al.High serum IgG4 concentrations in patients with sclerosing pancreatitis.N Engl J Med. 2001; 344: 732-738Crossref PubMed Scopus (2158) Google Scholar reported that increased serum levels of the immunoglobulin (Ig)G4 subclass of IgG were highly sensitive and highly specific for AIP. Shortly thereafter, Kamisawa5Kamisawa T. IgG4-positive plasma cells specifically infiltrate various organs in autoimmune pancreatitis.Pancreas. 2004; 29: 167-168Crossref PubMed Scopus (91) Google Scholar reported that tissue infiltration with abundant IgG4-positive cells was a characteristic feature not only of AIP but also the other organs involved in AIP. Based on this observation they proposed the term IgG4-related systemic disease (ISD) to describe this condition.6Kamisawa T. Funata N. Hayashi Y. et al.A new clinicopathological entity of IgG4-related autoimmune disease.J Gastroenterol. 2003; 38: 982-984Crossref PubMed Scopus (1092) Google Scholar Other groups have since confirmed these observations.7Deshpande V. Chicano S. Finkelberg D. et al.Autoimmune pancreatitis: a systemic immune complex mediated disease.Am J Surg Pathol. 2006; 30: 1537-1545Crossref PubMed Scopus (275) Google Scholar, 8Zhang L. Notohara K. Levy M.J. et al.IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis.Mod Pathol. 2007; 20: 23-28Crossref PubMed Scopus (265) Google Scholar ISD can be defined as a syndrome characterized by increased levels of serum IgG4 and multifocal IgG4-rich lymphoplasmacytic infiltrate associated with intense sclerosis. Although the fibrosis associated with ISD may damage and even destroy the affected organ, the inflammatory process typically responds to steroid therapy.9Chari S.T. Smyrk T.C. Levy M.J. et al.Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience.Clin Gastroenterol Hepatol. 2006; 4: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar Although in many series of ISD the pancreas is reported to be the most commonly affected organ, there also are reports of predominant salivary gland involvement.10Zamboni G. Luttges J. Capelli P. et al.Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens.Virchows Arch. 2004; 445: 552-563Crossref PubMed Scopus (553) Google Scholar It is becoming increasingly clear that the disease can involve multiple organs including the biliary tree, salivary glands, retroperitoneum, lymph nodes, and kidneys.5Kamisawa T. IgG4-positive plasma cells specifically infiltrate various organs in autoimmune pancreatitis.Pancreas. 2004; 29: 167-168Crossref PubMed Scopus (91) Google Scholar, 7Deshpande V. Chicano S. Finkelberg D. et al.Autoimmune pancreatitis: a systemic immune complex mediated disease.Am J Surg Pathol. 2006; 30: 1537-1545Crossref PubMed Scopus (275) Google Scholar, 8Zhang L. Notohara K. Levy M.J. et al.IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis.Mod Pathol. 2007; 20: 23-28Crossref PubMed Scopus (265) Google Scholar, 11Takahashi N. Kawashima A. Fletcher J.G. et al.Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings.Radiology. 2007; 242: 791-801Crossref PubMed Scopus (122) Google Scholar The concept of a systemic IgG4 disease is relatively new. Previous reports have given distinct names to what now are recognized as manifestations of ISD in individual organs. For example, AIP is the pancreatic manifestation of ISD. The biliary tree also commonly is involved in ISD, especially in those with AIP. In a recent review, we introduced the term IgG4-associated cholangitis (IAC) to refer to the biliary manifestations of ISD.12Björnsson E. Chari S.T. Smyrk T.C. et al.IgG4 associated cholangitis: description of an emerging clinical entity based on review of the literature.Hepatology. 2007; 45: 1547-1554Crossref PubMed Scopus (196) Google Scholar Several small case series have described the association of AIP and biliary strictures.13Zen Y. Harada K. Sasaki M. et al.IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?.Am J Surg Pathol. 2004; 28: 1193-1203Crossref PubMed Scopus (501) Google Scholar, 14Nakazawa T. Ohara H. Sano H. et al.Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis.Gastrointest Endosc. 2004; 60: 937-944Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 15Takikawa H. Takamori Y. Tanaka A. et al.Analysis of 388 cases of primary sclerosing cholangitis in Japan; presence of a subgroup without pancreatic involvement in older patients.Hepatol Res. 2004; 29: 153-159Crossref PubMed Scopus (106) Google Scholar, 16Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar, 17van Buuren H.R. Vleggaar F.P. Willemien Erkelens G. et al.Autoimmune pancreatocholangitis: a series of ten patients.Scand J Gastroenterol. 2006; 243: 70-78Crossref Scopus (32) Google Scholar, 18Kamisawa T. Nakajima H. Egawa N. et al.IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy.Pancreatology. 2006; 6: 132-137Abstract Full Text PDF PubMed Scopus (245) Google Scholar, 19Hirano K. Shiratori Y. Komatsu Y. et al.Involvement of the biliary system in autoimmune pancreatitis: a follow-up study.Clin Gastroenterol Hepatol. 2003; 1: 453-464Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 20Uehara T. Hamano H. Kawa S. et al.Distinct clinicopathological entity ‘autoimmune pancreatitis-associated sclerosing cholangitis’.Pathol Int. 2005; 55: 405-411Crossref PubMed Scopus (75) Google Scholar, 21Sekhon J.S. Chung R.T. Epstein M. et al.Steroid-responsive (autoimmune?) sclerosing cholangitis.Dig Dis Sci. 2005; 50: 1839-1843Crossref PubMed Scopus (7) Google Scholar, 22Nakazawa T. Ohara H. Yamada T. et al.Atypical primary sclerosing cholangitis cases associated with unusual pancreatitis.Hepatogastroenterology. 2001; 48: 625-630PubMed Google Scholar Unlike biliary strictures seen in primary sclerosing cholangitis (PSC), and similar to the manifestations of ISD in other organs, the biliary strictures in ISD typically respond to steroid therapy.16Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar, 23Kojima E. Kimura K. Noda Y. et al.Autoimmune pancreatitis and multiple bile duct strictures treated effectively with steroid.J Gastroenterol. 2003; 38: 603-607Crossref PubMed Scopus (331) Google Scholar However, the response to treatment of IAC and its natural history after treatment has not yet been studied in depth. The strictures in IAC can occur distally, in the intrapancreatic portion of the bile, or more proximally. It is unclear whether distal strictures are a result of external compression from pancreatic enlargement or in fact represent disease involvement of the intrapancreatic bile duct wall. Whether distal strictures present and respond differently to treatment compared with proximal strictures is unknown. Since 1999, we have maintained a prospective database of patients investigated for AIP. From this database, we identified 53 patients with IAC. Based on this large cohort of patients with IAC, the aims of this study were as follows: (1) to describe the clinical, imaging, and serologic characteristics of IAC; (2) to describe the response to therapy and the natural history after surgical and steroid therapy; and (3) to compare the characteristics and treatment response of IAC patients with isolated intrapancreatic biliary strictures compared with those with proximal biliary strictures. The diagnosis of ISD and its manifestations in individual organs can be difficult. We recently suggested criteria for the diagnosis of AIP.9Chari S.T. Smyrk T.C. Levy M.J. et al.Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience.Clin Gastroenterol Hepatol. 2006; 4: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar On the basis of our experience with IAC, we propose guidelines for suspecting and diagnosing IAC and discuss treatment response and natural history in these patients. The protocol was approved by the Mayo Clinic institutional review board. From a database of patients with AIP, prospectively maintained by one of the authors (S.T.C.), we identified 49 patients with biliary strictures and proven AIP; 14 of these patients had undergone a pancreaticoduodenectomy for suspected pancreatic cancer owing to presentation with obstructive jaundice and a pancreatic head mass. AIP was diagnosed by the recently published HISORt criteria (Histology, Imaging, Serology, Other organ involvement, Response to therapy).9Chari S.T. Smyrk T.C. Levy M.J. et al.Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience.Clin Gastroenterol Hepatol. 2006; 4: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar In addition to the 49 patients with confirmed AIP, we identified 4 more patients who had undergone bile duct resection for suspected cholangiocarcinoma whose bile duct histology was characteristic for IAC (see later); these 4 patients did not have evidence of pancreatic disease (AIP) clinically or on imaging. Demographic data as well as clinical, laboratory, imaging, and histologic characteristics were assessed for all patients. In those patients treated with steroids, treatment response and relapse rates were evaluated. All histologic specimens were reviewed by a single pathologist (T.C.S.). IAC was diagnosed histologically from a resection specimen or core biopsy if there was a lymphoplasmacytic infiltrate within and around bile ducts with associated obliterative phlebitis and storiform fibrosis leading to sclerosis of the bile duct.13Zen Y. Harada K. Sasaki M. et al.IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?.Am J Surg Pathol. 2004; 28: 1193-1203Crossref PubMed Scopus (501) Google Scholar, 16Nishino T. Toki F. Oyama H. et al.Biliary tract involvement in autoimmune pancreatitis.Pancreas. 2005; 30: 76-82PubMed Google Scholar, 20Uehara T. Hamano H. Kawa S. et al.Distinct clinicopathological entity ‘autoimmune pancreatitis-associated sclerosing cholangitis’.Pathol Int. 2005; 55: 405-411Crossref PubMed Scopus (75) Google Scholar Tissue immunostaining using monoclonal anti-human IgG4 antibody was performed as previously reported.9Chari S.T. Smyrk T.C. Levy M.J. et al.Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience.Clin Gastroenterol Hepatol. 2006; 4: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar The number of IgG4-positive plasma cells per high-power field (hpf) was counted in each specimen (Nikon E 600, field diameter 0.625 mm; Nikon, Tokyo, Japan). Moderate (11–30 cells/hpf) to severe (>30 cells/hpf) infiltration with IgG4-positive cells5Kamisawa T. IgG4-positive plasma cells specifically infiltrate various organs in autoimmune pancreatitis.Pancreas. 2004; 29: 167-168Crossref PubMed Scopus (91) Google Scholar in the presence of characteristic histology was considered diagnostic of AIP. Available cholangiograms and computerized tomography scans were reviewed by a single radiologist (N.T.). Strictures were characterized as distal (intrapancreatic), proximal extrahepatic, and intrahepatic. IgG4 levels in serum (mg/dL) were measured in 38 patients using automated nephelometry24Vlug A. Nieuwenhuys E.J. van Eijk R.V. et al.Nephelometric measurements of human IgG subclasses and their reference ranges.Ann Biol Clin (Paris). 1994; 52: 561-567PubMed Google Scholar (Behring Nephelometer II; Dade Behring, Inc, Newark, DE). CA 19-9 levels were measured in 40 patients. Liver enzyme levels at presentation and after therapy were noted. The presence of AIP was identified by use of HISORt criteria.9Chari S.T. Smyrk T.C. Levy M.J. et al.Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience.Clin Gastroenterol Hepatol. 2006; 4: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar The presence or history of retroperitoneal fibrosis, sialoadenitis, mediastinal adenopathy, and kidney involvement was noted. Based on initial therapy at presentation the patients were classified into 3 groups: surgical treatment (resections performed for suspicion of malignancy in this group), steroid therapy, and no treatment. In patients treated with steroids or other immunomodulatory drugs the indications, dosage, and duration of therapy were noted. The most common protocol followed for initial steroid treatment and for monitoring therapeutic response is described (Table 1). Response to treatment was defined as a decrease in liver enzyme levels to less than 2× the upper limit of normal and/or improvement in strictures leading to sustained (>3 months) stent removal. Relapses after the initial response to treatment were classified as follows: (1) biochemical relapse: increase in liver enzyme levels (>2 fold increase); (2) serologic relapse: increase in serum IgG4 level (at least 2-fold). We also analyzed recurrence of symptoms with patients who relapsed. However, because of the nonspecific nature of many disease-related symptoms, recurrence of symptoms alone was not considered indicative of relapse in the absence of biochemical or serologic relapse.Table 1Most Commonly Used IAC Treatment and Monitoring ProtocolIAC initial steroid treatment protocolaThis is the initial treatment protocol only. For details on treatment of relapses, see Figure 3. This protocol assumes that a rigorous evaluation for cancer (eg, cholangiocarcinoma) has been unrevealing and the diagnosis of IAC is highly likely based on clinical, laboratory, and imaging features. A steroid trial should not be used as a substitute for a thorough search for the etiology of biliary strictures.Initial steroid regimen Prednisone 40 mg/day orally for 4 weeks then taper by 5 mg/wk for a total of 11 weeks of treatmentImaging Follow-up evaluation If biliary stent placed on presentation: endoscopic retrograde cholangiopancreatography repeated 6–8 weeks after initiating treatment; if improvement in strictures noted (no tight strictures), stents removed If no biliary stent placed, then no follow-up imaging performedLaboratory evaluation Initial Serum bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, IgG4, CA 19-9 at baseline Follow-up evaluation Biliary stent in place: earlier-described laboratory tests repeated 4 weeks after stent removal (see earlier for stent removal protocol), then every 8–12 weeks thereafter No biliary stent: earlier-described laboratory tests repeated 6–8 weeks after initiating steroid treatment; if a response is documented, then laboratory tests repeated every 8–12 weeks thereaftera This is the initial treatment protocol only. For details on treatment of relapses, see Figure 3. This protocol assumes that a rigorous evaluation for cancer (eg, cholangiocarcinoma) has been unrevealing and the diagnosis of IAC is highly likely based on clinical, laboratory, and imaging features. A steroid trial should not be used as a substitute for a thorough search for the etiology of biliary strictures. Open table in a new tab With institutional review board approval, study patients were contacted to obtain follow-up information. After patient consent, all recent clinical notes and imaging studies from outside institutions were sent to us and reviewed. Recent clinical and imaging follow-up data (within 6 months of the study or within 6 months of death) were available for 92% of study patients. Data were analyzed using JMP version 6.0.0 (SAS Institute Inc, Cary, NC). Differences between groups were evaluated by using the chi-square test or the Fisher exact test for qualitative variables, and the Student t test for quantitative variables. Nonparametric quantitative variables (eg, median follow-up times) were compared using the Mann–Whitney test. Kaplan–Meier curves were used to assess differences in relapse-free survival rates between groups over time. Values are represented as the mean ± standard error of the mean and a P value of less than .05 was considered significant. The mean patient age was 62 ± 2 years (range, 14–85 y) and 83% were older than age 50. The majority of patients were men (85%). Clinical features on presentation included obstructive jaundice in 41 (77%), weight loss in 27 (51%), steatorrhea in 8 (15%), new-onset diabetes mellitus in 4 (8%), and abdominal pain in 14 of the 53 patients (26%). Abdominal pain did not require narcotics in any patient. Four patients had resection (surgical) specimens that revealed a lymphoplasmacytic infiltrate in and around the bile duct with surrounding storiform fibrosis and obliterative phlebitis, a pattern that is characteristic for IAC. IgG4 immunostaining revealed more than 10 IgG4-positive cells per high-power field in all 4 patients. These 4 patients had IAC with no obvious evidence of AIP clinically or radiographically. Of the remaining 49 patients who had AIP, pancreatic resection specimens were available in 14 patients and core biopsy specimens in 15 patients. These specimens showed lymphoplasmacytic sclerosing pancreatitis with abundant IgG4-positive cells on immunostaining, a pattern characteristic for AIP. Endoscopic biopsy specimens of biliary epithelium were available in 16 patients. Although all specimens had adequate epithelial tissue present, a histologic diagnosis of IAC could not be made on any of these biopsy specimens. However, IgG4 immunostaining revealed more than 10 IgG4-positive cells per high-power field in 14 of 16 (88%) patients. Cholangiograms were available in all patients: 44 endoscopic retrograde cholangiograms, 5 magnetic resonance cholangiograms, and 4 percutaneous transhepatic cholangiograms. Intrapancreatic biliary strictures, resembling those seen in pancreatic cancer, were present in 37 of 53 patients (70%), and were present as an isolated finding in 27 of 53 patients (51%). Proximal extrahepatic biliary strictures, mimicking cholangiocarcinoma, were present in 18 of 53 patients (34%), yet were an isolated finding in only 5 of 53 patients (9%). Intrahepatic strictures, similar to PSC, were found in 19 of 53 patients (36%), and were found alone in 4 of 53 patients (8%). Seventeen patients (32%) had multifocal strictures. In patients with AIP (n = 49), pancreas protocol computerized tomography scans were available in 48 patients to evaluate the pancreas. Twenty-four patients had focal pancreatic enlargement, 17 had diffuse pancreatic enlargement, 2 had changes of acute pancreatitis, 3 had an atrophic pancreas, 1 had a normal-size gland with diffusely decreased enhancement, and 1 had a normal gland. All 4 histologically proven IAC patients (postresection) had a normal pancreas on computerized tomography imaging. Pancreatograms were available in 31 of 49 AIP patients and showed a diffusely irregular duct in 14 patients, a focal stricture in 13 patients (12 in the pancreatic head, 1 in the body), and a normal pancreatogram in 4 patients. In the patients with focal strictures (n = 13), moderate distal ductal dilation occurred only in 1 patient, mild dilation occurred in 3 patients, and the distal duct was normal or small in the remaining patients. Laboratory results including liver enzyme, serum IgG4, and carbohydrate antigen 19-9 (CA 19-9) levels are listed in Table 2.Table 2Pretreatment Laboratory and Serologic Data in 53 IAC PatientsLaboratory testsMean ± SEM (range)Normal rangeDistributionSerum IgG4 level, mg/dL516 ± 98 (6–2490)8–140>140 mg/dL: 74%>280 mg/dL: 50%CA 19-9 level, IU/mL91 ± 30 (1–1005)0–37>37 IU/mL: 48%>100 IU/mL: 18%Bilirubin level, mg/dL7.5 ± 1 (0.3–19.1)0.1–1.0>5 mg/dL: 65%Alkaline phosphatase level, U/L512 ± 64 (77–1556)45–115>115 U/L: 84%>500 U/L: 34%Alanine aminotransferase level, U/L190 ± 64 (18–2445)9–29>100 U/L: 62%Aspartate aminotransferase level, U/L98 ± 17 (16–745)12–31>100 U/L: 32% Open table in a new tab The pancreas was the most common other organ involved in our group of IAC patients with 49 of 53 (92%) having AIP. Other organs included kidney involvement (n = 14), retroperitoneum (retroperitoneal fibrosis, n = 5), salivary gland (sialoadenitis, n = 3), lymph nodes (mediastinal and axillary, n = 2), and lung (pulmonary infiltrates, n = 2). Histology revealing lymphoplasmacytic infiltration with IgG4-positive cells in the involved organ was available on 1 patient with kidney involvement (tubulointerstitial nephritis), 1 with sialoadenitis, 2 with lymphadenopathy, and 1 patient with pulmonary disease. Inflammatory bowel disease was present in 3 patients (6%). Eighteen patients were treated initially with surgical resection (all for suspected malignancy), 30 patients were treated with steroids, and 5 patients had spontaneous resolution of strictures on initial presentation and did not receive treatment. In the group with spontaneous resolution (n = 5), 1 patient died from unrelated causes and limited follow-up time was available on 1 other patient, leading us to exclude this group from comparative analysis with the other 2 groups. Baseline characteristics did not differ between the surgical and steroid-treated groups with regard to age, sex, IgG4 levels, liver enzyme levels at presentation, or stricture location. The median follow-up evaluation from the initial clinical presentation was longer in the surgical group (58 vs 29.5 months; P < .01), which is explained by the fact that our earlier patients primarily were treated surgically because of suspected malignancy. In the surgical group, 4 patients presented with isolated biliary strictures without pancreatic disease and these patients underwent segmental hepatectomy, bile duct resection, and hepaticojejunostomy for presumed cholangiocarcinoma. The remaining 14 patients had pancreatic disease and underwent pancreaticoduodenectomy for presumed pancreatic cancer. Because of increasing recognition of AIP, only 2 of 29 AIP cases diagnosed at our institution since 2003 have undergone surgical resection. In the surgical group, all patients responded to surgery, with normalization of liver tests postoperatively. Thirty patients were treated initially with steroids, all with prednisone. Of 30 patients, 29 (97%) showed a response to steroids. One patient was a nonresponder and has required prolonged biliary stent placement. In the steroid group, resolution of strictures and/or normalization of liver enzyme levels was achieved in 18 of 30 patients (60%) (Figure 1), and improvement in strictures and/or improvement in liver enzyme levels was achieved in 11 of 30 patients (37%). Relapse rates after treatment did not differ in the surgical vs the steroid-treated groups (44% vs 54%; P = .1) (Figure 2). Biochemical relapse occurred in all relapse patients except 3, who had isolated serologic relapse. Recurrence of disease-related symptoms was associated with biochemical and/or serologic relapse in 8 of 18 patients (44%). In the steroid group, relapse occurred less than 6 months after discontinuation of prednisone in 12 of 17 patients (71%). Two patients relapsed during prednisone taper before discontinuation of the drug. Factors predicting relapse in the steroid group were increased IgG4 levels and the presence of proximal strictures (proximal extrahepatic or intrahepatic, or both). Patient age, sex, symptoms (obstructive jaundice), and proportion who normalized IgG4 after treatment did not differ between relapsers and nonrelapsers. The presence of proximal strictures was predictive of relapse regardless of treatment group when compared with distal strictures alone (relapse rates of 64% vs 32%; P = .02) (Figure 3). The 2 groups (distal strictures alone vs any proximal strictures) were similar with respect to age, sex, proportion with obstructive jaundice, serum IgG4 levels, and other organ involvement; however, all patients with distal strictures alone had AIP, and all 4 patients who did not have AIP were in the proximal stricture group. Immunomodulatory drugs eventually were used (after at least one relapse) in a total of 7 patients, 6 in the steroid group and 1 in the surgical group (4 azathioprine, 2 mycophenolate mofetil, and 1 cytoxan). Two of these patients initially were started on low doses (azathioprine 50 mg/day, mycophenolate 500 mg

<h2>Abstract</h2> Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The ‘Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm²) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

John H. Stone, Arezou Khosroshahi, Vikram Deshpande, John K. C. Chan, J. Godfrey Heathcote, Rob Aalberse, Atsushi Azumi, Donald B. Bloch, William R. Brugge, Mollie N. Carruthers, Wah Cheuk, Lynn Cornell, Carlos Fernandez-Del Castillo, Judith A. Ferry, David Forcione, Gunter Kloppel, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Yasufumi Masaki, Kenji Notohara, Kazuichi Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant Sahani, Yasuharu Sato, Thomas Smyrk, James R. Stone, Masayuki Takahira, Hisanori Umehara, George Webster, Motohisa Yamamoto, Eunhee Yi, Tadashi Yoshino, Giuseppe Zamboni, Yoh Zen, and Suresh Chari

To clarify clinicopathologic features of idiopathic chronic pancreatitis with lymphoplasmacytic infiltration, we carried out a study of 35 cases. There were two histologic groups, which we have designated lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric chronic pancreatitis. Lymphoplasmacytic sclerosing pancreatitis (22 cases) was a fibrosing process with diffuse lymphoplasmacytic infiltrates involving pancreatic lobules and ducts, adipose tissue, blood vessels, and common bile duct. Obliterative phlebitis was found in every case except for one. The histologic features were similar to other idiopathic fibrosclerosing disorders, and one patient also had retroperitoneal fibrosis. Affected patients tended to be elderly men. Idiopathic duct-centric chronic pancreatitis (13 cases) was characterized by inflammatory infiltrates (including neutrophils) that were denser in the lobules than in interlobular fibrotic areas. Neutrophils were also prominent in the ducts, and destruction of the duct epithelium was commonly seen. Patient ages were more broadly distributed than in lymphoplasmacytic sclerosing pancreatitis. Two patients had inflammatory bowel disease. We conclude that idiopathic chronic pancreatitis with lymphoplasmacytic infiltration, sometimes called autoimmune pancreatitis, consists of at least two different processes. One of these, lymphoplasmacytic sclerosing pancreatitis, is a histologically unique lesion and could be a pancreatic manifestation of idiopathic fibrosclerosing disorders.

Objectives To evaluate the efficacy of rituximab (RTX) in IgG4-related disease (IgG4-RD) in an open-label pilot trial. Methods We treated 30 IgG4-RD patients with two doses of RTX (1000 mg each). The participants were either treated with RTX alone (n = 26; 87%) or required to discontinue baseline glucocorticoids (GC) within 2 months (n = 4; 13%). Disease activity was measured by the IgG4-RD Responder Index (IgG4-RD RI) and physician's global assessment (PGA). Disease response was defined as the improvement of the IgG4-RD RI by two points. The primary outcome, measured at 6 months, was defined as: (1) decline of the IgG4-RD RI ≥2 points compared with baseline; (2) no disease flares before month 6; and (3) no GC use between months 2 and 6. Complete remission was defined as an IgG4-RD RI score of 0 with no GC use. Results Disease responses occurred in 97% of participants. The baseline IgG4-RD RI and PGA values, 11±7 and 63±22 mm, respectively, declined to 1±2 and 11±16 mm at 6 months (both p&lt;0.00001). The primary outcome was achieved by 23 participants (77%). Fourteen (47%) were in complete remission at 6 months, and 12 (40%) remained in complete remission at 12 months. Among the 19 with elevated baseline serum IgG4, IgG4 concentrations declined from a mean of 911 mg/dL (range 138–4780 mg/dL) to 422 mg/dL (range 56–2410 mg/dL) at month 6 (p&lt;0.05). However, only 8 (42%) of the 19 achieved normal values. Conclusions RTX appears to be an effective treatment for IgG4-RD, even without concomitant GC therapy. Trial registration number ClinicalTrials.gov identifier: NCT01584388 .

To determine the sensitivity and specificity of elevated serum IgG4 level for the diagnosis of autoimmune pancreatitis (AIP) and its ability to distinguish AIP from pancreatic cancer, its main differential diagnosis.We measured serum IgG4 levels (normal 8-140 mg/dL) in 510 patients including 45 with AIP, 135 with pancreatic cancer, 62 with no pancreatic disease, and 268 with other pancreatic diseases.Sensitivity, specificity, and positive predictive values for elevated serum IgG4 (>140 mg/dL) for diagnosis of AIP were 76%, 93%, and 36%, respectively, and 53%, 99%, and 75%, respectively, for IgG4 of >280 mg/dL. Among subjects with elevated IgG4, non-AIP subjects (N = 32) differed from AIP subjects (N = 34) in that they were more likely to be female (45%vs 9%, P < 0.001), less likely to have serum IgG4 >280 mg/dL (13%vs 71%, P < 0.001), or elevation of total IgG (16%vs 56%, P < 0.001). Serum IgG4 levels were elevated in 13/135 (10%) pancreatic cancer patients; however, only 1% had IgG4 levels >280 mg/dL compared with 53% of AIP. Compared with AIP, pancreatic cancer patients were more likely to have CA19-9 levels of >100 U/mL (71%vs 9%, P < 0.001).Elevated serum IgG4 levels are characteristic of AIP. However, mild (<2-fold) elevations in serum IgG4 are seen in up to 10% of subjects without AIP including pancreatic cancer and cannot be used alone to distinguish AIP from pancreatic cancer. Because AIP is uncommon, IgG4 elevations in patients with low pretest probability of having AIP are likely to represent false positives.

Background & Aims: The aim of this study was to determine recurrence and long-term survival after resection of pancreatic intraductal papillary mucinous neoplasm and to correlate recurrence and survival with histology, extent of resection, and duration of follow-up. Methods: A single pathologist, without knowledge of previous interpretations of histology or clinical data, retrospectively reviewed and classified 113 resected intraductal papillary mucinous neoplasms as invasive carcinoma (n = 40) or as noninvasive neoplasms (adenoma, borderline, or carcinoma in situ; n = 73). Data on recurrence (locoregional or metastatic), follow-up, and cause of death were obtained from patient records and/or by contacting patients and their physicians. Results: In invasive intraductal papillary mucinous neoplasm, recurrence was similar after partial pancreatectomy (18/27; 67%) and total pancreatectomy (8/13; 62%) and occurred within 3 years of resection in 91%. Among noninvasive neoplasms, 5 of 60 (8%) recurred after partial pancreatectomy (median follow-up, 37 months); none recurred after total pancreatectomy (n = 13; median follow-up, 32 months). Recurrence after resection in noninvasive neoplasms was diagnosed after a median of 40 months (range, 23–75 months); recurrence was noninvasive in 3 and invasive cancer in 2. Five-year survival was better for noninvasive compared with invasive intraductal papillary mucinous neoplasm (84.5% vs. 36%; P < 0.001). Conclusions: Invasive intraductal papillary mucinous neoplasm recurs frequently even after a complete “curative” resection and portends poor survival. In contrast, noninvasive intraductal papillary mucinous neoplasm recurs infrequently after resection, and survival is excellent regardless of the degree of epithelial dysplasia in the tumor.GASTROENTEROLOGY 2002;123:1500-1507

Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Aldred Warthin's description of Family G a century ago. The phenotype features an excess of early onset colorectal carcinoma (CRC) with a propensity to involve the proximal colon, and a variety of extracolonic cancers, particularly carcinoma of the endometrium, ovary, stomach, small bowel, ureter, and renal pelvis. The recent discovery that HNPCC patients carry germline mutations in DNA mismatch repair genes has engendered great interest in the syndrome.This is a description of HNPCC based on the authors' experience with more than 170 families and a review of the world literature.This review describes the genotypic and phenotypic features of HNPCC. The distinctive natural history of the syndrome is discussed in light of the recent discovery that ineffective DNA mismatch repair is the principal abnormality in affected individuals.Clinical and molecular genetic knowledge about HNPCC is now available to physicians, and should enable them to provide highly targeted surveillance and management for patients with a high cancer risk. Genetic counseling can prove lifesaving. The study of HNPCC will likely contribute to knowledge about the causes and control of common forms of cancer in the general population.

Background & AimsThe risk for colorectal cancer in Crohn’s disease and ulcerative colitis patients from the United States currently is unknown. We estimated the risk for small-bowel and colorectal cancer in a population-based cohort of 692 inflammatory bowel disease patients from Olmsted County, Minnesota, from 1940 to 2001.MethodsThe Rochester Epidemiology Project was used to identify cohort patients with colorectal and small-bowel cancer. The cumulative probability of cancer and standardized incidence ratios (SIR) were estimated using expected rates from Surveillance, Epidemiology, and End Results, white patients from Iowa, from 1973 to 2000, and Olmsted County, from 1980 to 1999.ResultsColorectal cancer was observed in 6 ulcerative colitis patients vs 5.38 expected (SIR, 1.1; 95% confidence interval [CI], 0.4–2.4), but 4 of these occurred among those with extensive colitis or pancolitis (SIR, 2.4; 95% CI, 0.6–6.0). Six Crohn’s disease patients (vs 3.2 expected) developed colorectal cancer (SIR, 1.9; 95% CI, 0.7–4.1). Three Crohn’s disease patients developed small-bowel cancer vs 0.07 expected (SIR, 40.6; 95% CI, 8.4–118).ConclusionsThe risk for colorectal cancer was not increased among ulcerative colitis patients overall, but appeared to be increased among those with extensive colitis. The colorectal cancer risk was increased slightly among Crohn’s disease patients, who also had a 40-fold excess risk for small-bowel cancer. The risk for colorectal cancer in Crohn’s disease and ulcerative colitis patients from the United States currently is unknown. We estimated the risk for small-bowel and colorectal cancer in a population-based cohort of 692 inflammatory bowel disease patients from Olmsted County, Minnesota, from 1940 to 2001. The Rochester Epidemiology Project was used to identify cohort patients with colorectal and small-bowel cancer. The cumulative probability of cancer and standardized incidence ratios (SIR) were estimated using expected rates from Surveillance, Epidemiology, and End Results, white patients from Iowa, from 1973 to 2000, and Olmsted County, from 1980 to 1999. Colorectal cancer was observed in 6 ulcerative colitis patients vs 5.38 expected (SIR, 1.1; 95% confidence interval [CI], 0.4–2.4), but 4 of these occurred among those with extensive colitis or pancolitis (SIR, 2.4; 95% CI, 0.6–6.0). Six Crohn’s disease patients (vs 3.2 expected) developed colorectal cancer (SIR, 1.9; 95% CI, 0.7–4.1). Three Crohn’s disease patients developed small-bowel cancer vs 0.07 expected (SIR, 40.6; 95% CI, 8.4–118). The risk for colorectal cancer was not increased among ulcerative colitis patients overall, but appeared to be increased among those with extensive colitis. The colorectal cancer risk was increased slightly among Crohn’s disease patients, who also had a 40-fold excess risk for small-bowel cancer.

Data on secular trends and outcomes of eosinophilic esophagitis (EE) are scarce. We performed a population-based study to assess the epidemiology and outcomes of EE in Olmsted County, Minnesota, over the last 3 decades.All cases of EE diagnosed between 1976 and 2005 were identified using the Rochester Epidemiology Project resources. Esophageal biopsies with any evidence of esophagitis and/or eosinophilic infiltration were reviewed by a single pathologist. Clinical course (treatment, response, and recurrence) was defined using information collected from medical records and prospectively via a telephone questionnaire. Incidence rates per 100,000 person years were directly adjusted for age and sex to the US 2000 population structure.A total of 78 patients with EE were identified. The incidence of EE increased significantly over the last 3 of the 5-year intervals (from 0.35 [95% confidence interval (CI)], 0-0.87] per 100,000 person-years during 1991-1995 to 9.45 [95% CI, 7.13-11.77] per 100,000 person-years during 2001-2005). The prevalence of EE was 55.0 (95% CI, 42.7-67.2) per 100,000 persons as of January 1, 2006, in Olmsted County, Minnesota. EE was diagnosed more frequently in late summer/fall. The clinical course of patients with EE was characterized by recurrent symptoms (observed in 41% of patients).The prevalence and incidence of EE is higher than previously reported. The incidence of clinically diagnosed EE increased significantly over the last 3 decades, in parallel with endoscopy volume. Seasonal incidence was greatest in late summer and fall. EE also appears to be a recurrent relapsing disease in a substantial proportion of patients.

BACKGROUND Cells with deficient DNA mismatch repair develop microsatellite instability. Extensive microsatellite instability (MSI-high) is characteristic of colorectal carcinomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) and in 10–% 15% of sporadic colorectal carcinomas. Microsatellite instability-high colorectal carcinomas differ from others in important clinical and pathologic features. However, MSI typing is expensive and not widely available. Microsatellite instability type may be predicted by tumor-infiltrating lymphocytes (TILs), which can be evaluated with ordinary light microscopy. METHODS The authors evaluated TILs as a pathology screen for MSI-high status in 138 colorectal carcinomas that had been evaluated for MSI in a variety of studies. This case series was systematically enriched with HNPCC and other MSI-high cases to allow accurate sensitivity and specificity estimation. Tumor-infiltrating lymphocytes were quantitated as TILs per 10 high-power microscopic fields by an observer blinded to MSI status. RESULTS Of the 138 carcinomas studied, 67 (48.6%) were MSI-high, 22 (15.9%) were MSI-low, and 49 (35.5%) were MSI-stable. All 25 HNPCC colorectal carcinomas were MSI-high. Tumor-infiltrating lymphocytes counts ranged from 0 to 300, with a markedly skewed distribution (median, 11; mean, 36). Sensitivity and specificity for selected cut points of TIL count were computed. Using a TIL count of 5 as a cut point yields a sensitivity of 93% and specificity of 62%. In a population in which 12% were MSI-high, consideration of TIL could reduce the number of colorectal carcinomas referred for MSI testing by greater than one-half, and still 93% of the MSI-high carcinomas would be identified. CONCLUSIONS The presence of MSI defines a subset of colorectal carcinomas with special molecular etiology and characteristic clinical, pathologic features, inclusive of increased survival. The authors conclude that quantification of TILs may provide a simple, single criterion for choosing which colorectal carcinomas are candidates for MSI testing. Cancer 2001;91:2417–22. © 2001 American Cancer Society.

Adjuvant imatinib mesylate prolongs recurrence-free survival (RFS) after resection of localised primary gastrointestinal stromal tumours (GIST). We aimed to develop a nomogram to predict RFS after surgery in the absence of adjuvant therapy to help guide patient selection for adjuvant imatinib therapy.A nomogram to predict RFS based on tumour size (cm), location (stomach, small intestine, colon/rectum, or other), and mitotic index (<5 or > or =5 mitoses per 50 high-power fields) was developed from 127 patients treated at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, USA. The nomogram was tested in patients from the Spanish Group for Research on Sarcomas (GEIS; n=212) and the Mayo Clinic, Rochester, MN, USA (Mayo; n=148). The nomogram was assessed by calculating concordance probabilities and testing calibration of predicted RFS with observed RFS. Concordance probabilities were also compared with those of three commonly used staging systems.The nomogram had a concordance probability of 0.78 (SE 0.02) in the MSKCC dataset, and 0.76 (0.03) and 0.80 (0.02) in the validation cohorts. Nomogram predictions were well calibrated. Inclusion of tyrosine kinase mutation status in the nomogram did not improve its discriminatory ability. Concordance probabilities of the nomogram were better than those of the two NIH staging systems (0.76 [0.03] vs 0.70 [0.04, p=0.04] and 0.66 [0.04, p=0.01] in the GEIS validation cohort; 0.80 [0.02] vs 0.74 [0.02, p=0.04] and 0.78 [0.02, p=0.05] in the Mayo cohort) and similar to those of the AFIP-Miettinen staging system (0.76 [0.03] vs 0.73 [0.004, p=0.28] in the GEIS cohort; 0.80 [0.02] vs 0.76 [0.003, p=0.09] in the Mayo cohort). Nomogram predictions of RFS seemed better calibrated than predictions made with the AFIP-Miettinen system.The nomogram accurately predicts RFS after resection of localised primary GIST and could be used to select patients for adjuvant imatinib therapy.

In Brief Objective: To determine long-term survival after pancreatoduodenectomy for pancreatic ductal adenocarcinoma and to identify clinical factors associated with long-term survival. Summary Background Data: The prognosis for long-term survival even after potentially curative resection for pancreatic adenocarcinoma is thought to be poor. Clinical factors determining short-term survival after pancreatic resection are well studied, but prognostic factors predicting long-term survival with a potential for cure are poorly understood. Methods: A case-control study was conducted of 357 patients who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma between 1981 and 2001. Histologic specimens were reanalyzed to confirm diagnosis. Follow-up was at least 5 years or until death. Results: There was an improved survival throughout the observation period (P = 0.004). We found 62 actual 5-year survivors of whom 21 patients survived greater than 10 years, for a 5- and 10-year survival rate of 18% and 13%, respectively. Cohort analysis comparing patients with short-term (<5 years, n = 295) and long-term (≥5 years, n = 62) survival showed that more advanced disease (greatest tumor diameter, lymph node metastasis) and decreased serum albumin concentration were unfavorable for long-term survival (all P < 0.05). In contrast, the extent of resection and more aggressive histologic features did not correlate with long-term survival (all P > 0.05). En-bloc resection (P = 0.005) but not resection margin status (P > 0.05) was associated with long-term survival. Adjuvant chemoradiation therapy did not significantly influence long-term survival. Multivariate analysis identified lymph node status (OR 0.36, 95% CI 0.14–0.89, P = 0.03) as a prognostic factor for long-term survival. Five-year survival was no guarantee of cure because 16% of this subset died of pancreatic cancer up to 7.8 years after operation. Conclusion: Pancreatoduodenectomy for adenocarcinoma in the head of pancreas can provide long-term survival in a subset of patients, particularly in the absence of lymph node metastasis. One of 8 patients can achieve 10-year survival with a potential for cure. Most surgeons maintain a nihilistic view when considering long-term survival after resection with curative intent for pancreatic adenocarcinoma. This study provides data showing that long-term survival is possible in a subset of patients, supporting the concept that cure seems possible.

Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer.To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer.A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses.Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity.Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older.Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival.clinicaltrials.gov Identifier: NCT00079274.

Background & AimsAutoimmune pancreatitis (AIP) has been divided into subtypes 1 (lymphoplasmacytic sclerosing pancreatitis) and 2 (idiopathic duct centric pancreatitis). We compared clinical profiles and long-term outcomes of types 1 and 2 AIP.MethodsWe compared clinical presentation, relapse, and vital status of 78 patients with type 1 AIP who met the original HISORt criteria and 19 patients with histologically confirmed type 2 AIP.ResultsAt presentation, patients with type 1 AIP were older than those with type 2 AIP (62 ± 14 vs 48 ± 19 years; P < .0001) and had a greater prevalence of increased serum levels of immunoglobulin G4 (47/59 [80%] vs 1/6 [17%]; P = .004). Patients with type 1 were more likely than those with type 2 to have proximal biliary, retroperitoneal, renal, or salivary disease (60% vs 0; P < .0001). Inflammatory bowel disease was associated with types 1 and 2 (6% vs 16%; P = .37). During median clinical follow-up periods of 42 and 29 months, respectively, 47% of patients with type 1 and none of those with type 2 experienced a relapse. In type 1 AIP, proximal biliary involvement (hazard ratio [HR], 2.12; P = .038) and diffuse pancreatic swelling (HR, 2.00; P = .049) were predictive of relapse, whereas pancreaticoduodenectomy reduced the relapse rate (vs the corticosteroid-treated group; HR, 0.15; P = .0001). After median follow-up periods of 58 and 89 months (types 1 and 2, respectively), the 5-year survival rates for both groups were similar to those of the age- and sex-matched US population.ConclusionsTypes 1 and 2 AIP have distinct clinical profiles. Patients with type 1 AIP have a high relapse rate, but patients with type 2 AIP do not experience relapse. AIP does not affect long-term survival. Autoimmune pancreatitis (AIP) has been divided into subtypes 1 (lymphoplasmacytic sclerosing pancreatitis) and 2 (idiopathic duct centric pancreatitis). We compared clinical profiles and long-term outcomes of types 1 and 2 AIP. We compared clinical presentation, relapse, and vital status of 78 patients with type 1 AIP who met the original HISORt criteria and 19 patients with histologically confirmed type 2 AIP. At presentation, patients with type 1 AIP were older than those with type 2 AIP (62 ± 14 vs 48 ± 19 years; P < .0001) and had a greater prevalence of increased serum levels of immunoglobulin G4 (47/59 [80%] vs 1/6 [17%]; P = .004). Patients with type 1 were more likely than those with type 2 to have proximal biliary, retroperitoneal, renal, or salivary disease (60% vs 0; P < .0001). Inflammatory bowel disease was associated with types 1 and 2 (6% vs 16%; P = .37). During median clinical follow-up periods of 42 and 29 months, respectively, 47% of patients with type 1 and none of those with type 2 experienced a relapse. In type 1 AIP, proximal biliary involvement (hazard ratio [HR], 2.12; P = .038) and diffuse pancreatic swelling (HR, 2.00; P = .049) were predictive of relapse, whereas pancreaticoduodenectomy reduced the relapse rate (vs the corticosteroid-treated group; HR, 0.15; P = .0001). After median follow-up periods of 58 and 89 months (types 1 and 2, respectively), the 5-year survival rates for both groups were similar to those of the age- and sex-matched US population. Types 1 and 2 AIP have distinct clinical profiles. Patients with type 1 AIP have a high relapse rate, but patients with type 2 AIP do not experience relapse. AIP does not affect long-term survival.

The value of endoscopic surveillance of Barrett's esophagus and the appropriate management of high-grade dysplasia remain unclear. Seventeen patients who were referred from endoscopic surveillance programs for management of high-grade dysplasia or adenocarcinoma developing in Barrett's esophagus were compared with 35 patients who had a newly recognized Barrett's adenocarcinoma, who had not been in a surveillance program. The referral diagnosis in the surveyed group was adenocarcinoma in six and high-grade dysplasia in 11. After repeat endoscopy with aggressive biopsy, two additional patients with adenocarcinoma were identified. Of the nine patients who underwent esophagectomy for high-grade dysplasia, five had invasive adenocarcinoma in the esophagectomy specimen, which had been missed before the operation, despite the fact that the median number of biopsy specimens obtained per 2 cm of Barrett's mucosa was 7.8 (range 1.5 to 15.0). Overall, 13 patients in the surveyed group had adenocarcinoma, 12 staged early and one staged intermediate by the WNM classification. Surveyed patients were operated on at an earlier stage than the nonsurveyed patients (10 early, 14 intermediate, and 11 late stage tumors; chi 2 = 15.6, p < 0.01). Despite the presence of adenocarcinoma in 13 of the 17 surveyed patients, their survival was significantly better than that of the nonsurveyed group (chi 2 = 5.8, p < 0.05). Patients referred from surveillance programs for Barrett's esophagus have a better outcome and earlier stage tumors than nonsurveyed patients. Inasmuch as multiple biopsy procedures do not exclude the presence of adenocarcinoma, continued surveillance of high-grade dysplasia is dangerous and potentially destructive to surveillance efforts.

Background & AimsPatients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD).MethodsWe performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed H&E staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups.ResultsSubjects on the GCD had more bowel movements per day (P = .04); the GCD had a greater effect on bowel movements per day of HLA-DQ2/8–positive than HLA-DQ2/8–negative patients (P = .019). The GCD was associated with higher SB permeability (based on 0−2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8–positive than HLA-DQ2/8–negative patients (P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8–positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-α in response to gluten than rice (unrelated to HLA genotype).ConclusionsGluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8–positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.gov NCT01094041. Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD). We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed H&E staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups. Subjects on the GCD had more bowel movements per day (P = .04); the GCD had a greater effect on bowel movements per day of HLA-DQ2/8–positive than HLA-DQ2/8–negative patients (P = .019). The GCD was associated with higher SB permeability (based on 0−2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8–positive than HLA-DQ2/8–negative patients (P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8–positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-α in response to gluten than rice (unrelated to HLA genotype). Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8–positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.gov NCT01094041.

Background & AimsCellular changes associated with diabetic and idiopathic gastroparesis are not well described. The aim of this study was to describe histologic abnormalities in gastroparesis and compare findings in idiopathic versus diabetic gastroparesis.MethodsFull-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls. Sections were stained for H&E and trichrome and immunolabeled with antibodies against protein gene product (PGP) 9.5, neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide, substance P, and tyrosine hydroxylase to quantify nerves, S100β for glia, Kit for interstitial cells of Cajal (ICC), CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. Tissue was also examined by transmission electron microscopy.ResultsHistologic abnormalities were found in 83% of patients. The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers. On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading. On electron microscopy, a markedly increased connective tissue stroma was present in both disorders.ConclusionsThis study suggests that on full-thickness biopsy specimens, cellular abnormalities are found in the majority of patients with gastroparesis. The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity. These findings suggest that examination of tissue can lead to valuable insights into the pathophysiology of these disorders and offer hope that new therapeutic targets can be found. Cellular changes associated with diabetic and idiopathic gastroparesis are not well described. The aim of this study was to describe histologic abnormalities in gastroparesis and compare findings in idiopathic versus diabetic gastroparesis. Full-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls. Sections were stained for H&E and trichrome and immunolabeled with antibodies against protein gene product (PGP) 9.5, neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide, substance P, and tyrosine hydroxylase to quantify nerves, S100β for glia, Kit for interstitial cells of Cajal (ICC), CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. Tissue was also examined by transmission electron microscopy. Histologic abnormalities were found in 83% of patients. The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers. On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading. On electron microscopy, a markedly increased connective tissue stroma was present in both disorders. This study suggests that on full-thickness biopsy specimens, cellular abnormalities are found in the majority of patients with gastroparesis. The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity. These findings suggest that examination of tissue can lead to valuable insights into the pathophysiology of these disorders and offer hope that new therapeutic targets can be found.

There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality.We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis.The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections.We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.

There is a paucity of data on long-term management of type 1 autoimmune pancreatitis (AIP), a relapsing steroid-responsive disorder.We describe our experience with treatment of relapses and maintenance of remission using steroid-sparing immunomodulators (IMs) and induction of remission using rituximab (RTX).We obtained details of disease relapse and treatment in 116 type 1 AIP patients from clinic visits, medical records and telephone interviews. We compared relapse free survival in those treated with IMs versus those treated with steroids alone, assessed patients' response to RTX, and identified treatment-related complications.During a median follow-up of 47 months, 52/116 AIP patients experienced 76 relapse episodes. The first relapse was treated with another course of steroids in 24 patients, and with steroids plus IM in another 27 patients; subsequent relapse-free survival until a second relapse was similar in the two groups (p=0.23). 38 patients received an IM for >2 months; failure or intolerance of IM therapy occurred in 17 (45%). 12 patients with steroid or IM intolerance/resistance were treated with RTX, an antiCD20 antibody; 10 (83%) experienced complete remission and had no relapses while on maintenance therapy. Treatment-limiting side effects related to RTX were uncommon.In type 1 AIP relapses are common. Relapse-free survival is similar in those treated with steroids plus IM compared to those treated with steroids alone. Nearly half the patients on IMs will relapse during treatment. RTX is effective in the treatment of both IM resistant and steroid intolerant patients.

Autoimmune pancreatitis (AIP) and pancreatic cancer (PaC) have similar presentations; a diagnostic strategy is needed to distinguish the 2 diseases.We compared computed tomography images (for pancreas and other organ involvement), serum IgG4 levels, histology data, and the response to steroids between patients with AIP (n = 48) and those with PaC (n = 100).Pancreatic imaging findings stratified patients into 3 groups. Group 1 was highly suggestive of AIP, with diffuse pancreatic enlargement without group 3 features (n = 25, 100% AIP). Group 2 was indeterminate, with normal-sized pancreas or focal pancreatic enlargement without group 3 features (n = 20, 75% AIP). Group 3 was highly suggestive of PaC, with presence of >1 low-density mass, pancreatic duct cutoff, or upstream pancreatic atrophy (n = 103, 92% PaC). Although all patients in group 1 had AIP, only 20 of the 25 patients had increased serum IgG4 levels and/or other organ involvement. Of the patients in groups 2 and 3 who did not have cancer, all those with serum IgG4 levels >2-fold the upper limit of normal or a combination of increased serum IgG4 levels and other organ involvement (n = 15) had AIP. In AIP subjects without supportive serologic evidence or other organ involvement (n = 14), diagnosis required pancreatic core biopsy (n = 7), steroid trial (n = 5), or resection (n = 2).PaC can be distinguished from AIP by pancreatic imaging, measurement of serum IgG4 levels, and determination of other organ involvement. However, a pancreatic core biopsy, steroid trial, or surgery is required for diagnosis in approximately 30% of patients with AIP.

IgG4-related systemic disease is an autoimmune disease that was first recognized in the pancreas but also affects other organs. This disease may manifest as tubulointerstitial nephritis (IgG4-TIN), but its clinicopathologic features in the kidney are not well described. Of the 35 patients with IgG4-TIN whose renal tissue specimens we examined, 27 (77%) had acute or progressive chronic renal failure, 29 (83%) had involvement of other organ systems, and 18 of 23 (78%) had radiographic abnormalities. Elevated total IgG or IgG4 serum levels were present in 79%. All pathologic specimens featured plasma cell–rich TIN, with most showing diffuse, expansile interstitial fibrosis. Immune complexes along the tubular basement membranes were present in 25 of 30 (83%). All specimens had a moderate to marked increase in IgG4+ plasma cells by immunohistochemistry. We used a control group of 175 pathologic specimens with plasma cell–rich interstitial infiltrates that can mimic IgG4-TIN to examine the diagnostic utility of IgG4 immunostaining. Excluding pauci-immune necrotizing and crescentic glomerulonephritis, IgG4 immunohistochemistry had a sensitivity of 100% (95% CI 90–100%) and a specificity of 92% (95% CI 86–95%) for IgG4-TIN. Of the 19 patients with renal failure for whom treatment and follow-up data were available, 17 (89%) responded to prednisone. In summary, because no single test definitively diagnoses IgG4-related systemic disease, we rely on a combination of histologic, immunophenotypic, clinical, radiographic, and laboratory features. When the disease manifests in the kidney, our data support diagnostic criteria that can distinguish IgG4-TIN from other types of TIN.

Distinguishing drug-induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well-characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra-acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra-acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra-acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P ≤ 0.05). The four AIH-favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH.Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis.

Autoimmune pancreatitis typically produces an enlarged pancreas with narrowing of the pancreatic duct, and can mimic carcinoma. Autoimmune pancreatitis usually responds to corticosteroid treatment, making it important to differentiate from pancreatic ductal adenocarcinoma. Affected patients often have an elevated serum IgG4. It has been proposed that increased numbers of IgG4-positive plasma cells in tissue might be a marker for the condition. We investigated the role of IgG4 staining in the diagnosis of autoimmune pancreatitis, first in resected pancreas specimens (29 autoimmune pancreatitis, nine chronic alcoholic pancreatitis and 25 pancreatic cancer), then in pancreatic needle biopsies. Immunohistochemical stains for IgG4 were scored as none, mild, moderate or marked, according to published criteria. Moderate to marked numbers of IgG4-positive plasma cells were seen in 21/29 autoimmune pancreatitis patients, and were distributed in and around ducts, in interlobular fibrous tissue and in peripancreatic fat. In contrast, eight of nine examples of chronic alcoholic pancreatitis and 22/25 ductal adenocarcinomas had scores of none or mild. When we subdivided autoimmune pancreatitis into the histologic subtypes lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-destructive pancreatitis, 16/17 lymphoplasmacytic sclerosing pancreatitis had moderate to marked staining, compared to five to 12 idiopathic duct-destructive pancreatitis. Needle biopsies from nine patients suspected of having autoimmune pancreatitis had increased numbers of IgG4 cells. We conclude that pancreatic tissue from patients with autoimmune pancreatitis often shows moderate or marked infiltration by IgG4-positive plasma cells (>10/HPF). This is particularly so in the subtype we have designated lymphoplasmacytic sclerosing pancreatitis. We rarely see IgG4 staining in patients with chronic alcoholic pancreatitis and pancreatic ductal adenocarcinoma. IgG4-positive plasma cells are a useful marker for the tissue diagnosis of autoimmune pancreatitis.

Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes.We used a polymerase chain reaction-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n = 783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models.Tumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive. Three subtypes were MMR proficient: those with mutations in BRAF (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAF or KRAS mutations (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAF mutation and/or or hypermethylation of MLH1 and the familial type (2.6%), which lacked BRAF(V600E) or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAF(V600E) were proximal (76%), high-grade (44%), N2 stage (59%), and detected in women (59%), compared with MMR-proficient tumors without BRAF(V600E) or KRAS mutations (33%, 19%, 41%, and 42%, respectively; all P < .0001). A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF (hazard ratio = 1.43; 95% confidence interval: 1.11-1.85; Padjusted = .0065) or mutant KRAS (hazard ratio = 1.48; 95% confidence interval: 1.27-1.74; Padjusted < .0001) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations. The observed differences in survival rates of patients with different tumor subtypes were validated in an independent cohort.We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAF(V600E) or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers.

OBJECTIVES Biliary strictures, similar to primary sclerosing cholangitis (PSC), have been reported in patients with autoimmune pancreatitis, which is characterized by elevated serum IgG4 levels and responsiveness to corticosteroids. We sought to determine the frequency of elevated IgG4 in patients with PSC and to clinically compare PSC patients with elevated and normal IgG4 levels. METHODS We measured serum IgG4 in 127 patients with PSC and 87 patients with primary biliary cirrhosis, as disease controls. Demographic, clinical, and laboratory characteristics were compared between the PSC groups with normal and elevated IgG4 (>140 mg/dL). RESULTS Elevated IgG4 was found in 12 PSC patients (9%) versus one PBC patient (1.1%) (p = 0.017). Patients with elevated IgG4 had higher total bilirubin (p = 0.009), alkaline phosphatase (p = 0.01), and PSC Mayo risk score (p = 0.038), and lower frequency of IBD (p < 0.0001). Importantly, the time to liver transplantation was shorter in patients with elevated IgG4 (1.7 vs 6.5 yr, p = 0.0009). The type of biliary involvement (intrahepatic, extrahepatic, or both) and pancreatic involvement were similar in both groups. CONCLUSIONS A small proportion of PSC patients had elevated serum IgG4. In these patients parameters of liver disease severity were more pronounced and time to liver transplantation was shorter, suggesting a more severe disease course. It is possible that this subset of patients behaves similarly to autoimmune pancreatitis patients with biliary strictures, and could potentially respond to corticosteroids. Testing PSC patients for IgG4 and treating those with elevated levels with corticosteroids in clinical trials should be considered.

SOX2 (Sex-determining region Y (SRY)-Box2) has important functions during embryonic development and is involved in cancer stem cell (CSC) maintenance, in which it impairs cell growth and tumorigenicity. However, the function of SOX2 in pancreatic cancer cells is unclear. The objective of this study was to analyze SOX2 expression in human pancreatic tumors and determine the role of SOX2 in pancreatic cancer cells regulating CSC properties. In this report, we show that SOX2 is not expressed in normal pancreatic acinar or ductal cells. However, ectopic expression of SOX2 is observed in 19.3% of human pancreatic tumors. SOX2 knockdown in pancreatic cancer cells results in cell growth inhibition via cell cycle arrest associated with p21(Cip1) and p27(Kip1) induction, whereas SOX2 overexpression promotes S-phase entry and cell proliferation associated with cyclin D3 induction. SOX2 expression is associated with increased levels of the pancreatic CSC markers ALDH1, ESA and CD44. Importantly, we show that SOX2 is enriched in the ESA(+)/CD44(+) CSC population from two different patient samples. Moreover, we show that SOX2 directly binds to the Snail, Slug and Twist promoters, leading to a loss of E-Cadherin and ZO-1 expression. Taken together, our findings show that SOX2 is aberrantly expressed in pancreatic cancer and contributes to cell proliferation and stemness/dedifferentiation through the regulation of a set of genes controlling G1/S transition and epithelial-to-mesenchymal transition (EMT) phenotype, suggesting that targeting SOX2-positive cancer cells could be a promising therapeutic strategy.

Eosinophilic esophagitis (EE) is an increasingly recognized cause of dysphagia. We prospectively assessed the prevalence of EE using midesophageal biopsies in patients presenting with no endoscopically evident cause of dysphagia. We also aimed to determine the clinical and endoscopic factors predictive of EE in outpatients undergoing endoscopy for dysphagia.Outpatients (18-60 yr of age) undergoing endoscopy for dysphagia at Mayo Clinic, Rochester between June 2005 and June 2006 were enrolled. Patients completed the validated Mayo Dysphagia Questionnaire (MDQ). Biopsies were obtained from the midesophagus if there was no endoscopically evident cause of dysphagia or there were endoscopic findings suggestive of EE. EE was defined as the presence of >20 eosinophils/high-power field. Logistic regression was performed to identify predictors of EE.Of 376 patients enrolled, 238 (63%) completed the MDQ and 222 (59%) had midesophageal biopsies; 33 (15%, 95% CI 6%-12%) had EE by biopsy. Ten of 102 (9.8%) patients who appeared endoscopically normal had EE by biopsy, while 8 of 21 (38%) patients with endoscopic changes suggestive of EE had EE on biopsy. Predictors of EE were younger age, endoscopic features suggestive of EE, absence of use of proton pump inhibitors, and a history of any food impaction for greater than 5 min.Midesophageal biopsies from normal-appearing mucosa should be obtained in all patients with unexplained solid food dysphagia; this may diagnose EE in about one in 10 cases.

Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27).In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

We evaluated the effect of aerosolized fluticasone therapy on symptomatic dysphagia and histologic eosinophilia in adults with eosinophilic esophagitis (EoE).We performed a double-blind, randomized, placebo-controlled trial of fluticasone in 42 adult patients with a new diagnosis of EoE (30 men; mean age, 37.5 y). Participants were assigned randomly to groups that swallowed 880 μg of aerosolized fluticasone twice daily (n = 21), or took a placebo inhaler twice daily (n = 15) for 6 weeks. End points of the study were symptomatic and histologic response.A complete histologic response (>90% decrease in mean eosinophil count) was observed in 11 of 15 subjects who received 6 weeks of fluticasone (62%), compared with none of the 15 subjects who received placebo (P < .001), based on intention-to-treat analysis; histologic responses were observed in 68% of subjects who received fluticasone (13 of 19) compared with none of those who received placebo (0 of 15) by per-protocol analysis (P < .001). Intracellular staining for eosinophil-derived neurotoxin was reduced in 81% of subjects who received fluticasone (13 of 16) compared with 8% who received placebo (1 of 13) (P < .001). Dysphagia was reduced in 57% of subjects who received fluticasone (12 of 21) compared with 33% who received placebo (7 of 21) (P = .22) by intention-to-treat analysis; dysphagia was reduced in 63% of patients who received fluticasone (12 of 19) and 47% of those who received placebo (7 of 15) (P = .49) based on per-protocol analysis. Esophageal candidiasis developed in 26% of subjects who received fluticasone (5 of 19), but in none of the subjects in the placebo group (P = .05).Aerosolized, swallowed fluticasone leads to a histologic but not a symptomatic response in adults with EoE.

It is not clear whether symptoms alone can be used to estimate the biologic activity of eosinophilic esophagitis (EoE). We aimed to evaluate whether symptoms can be used to identify patients with endoscopic and histologic features of remission.Between April 2011 and June 2014, we performed a prospective, observational study and recruited 269 consecutive adults with EoE (67% male; median age, 39 years old) in Switzerland and the United States. Patients first completed the validated symptom-based EoE activity index patient-reported outcome instrument and then underwent esophagogastroduodenoscopy with esophageal biopsy collection. Endoscopic and histologic findings were evaluated with a validated grading system and standardized instrument, respectively. Clinical remission was defined as symptom score <20 (range, 0-100); histologic remission was defined as a peak count of <20 eosinophils/mm(2) in a high-power field (corresponds to approximately <5 eosinophils/median high-power field); and endoscopic remission as absence of white exudates, moderate or severe rings, strictures, or combination of furrows and edema. We used receiver operating characteristic analysis to determine the best symptom score cutoff values for detection of remission.Of the study subjects, 111 were in clinical remission (41.3%), 79 were in endoscopic remission (29.7%), and 75 were in histologic remission (27.9%). When the symptom score was used as a continuous variable, patients in endoscopic, histologic, and combined (endoscopic and histologic remission) remission were detected with area under the curve values of 0.67, 0.60, and 0.67, respectively. A symptom score of 20 identified patients in endoscopic remission with 65.1% accuracy and histologic remission with 62.1% accuracy; a symptom score of 15 identified patients with both types of remission with 67.7% accuracy.In patients with EoE, endoscopic or histologic remission can be identified with only modest accuracy based on symptoms alone. At any given time, physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adults with EoE. ClinicalTrials.gov, Number: NCT00939263.

The association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown.Resected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAF(V600E) (exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.dMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAF(V600E) or KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (P(interaction) = .009) and lymph node category (N1 v N2; P(interaction) = .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAF(V600E) (HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (P(interaction) = .037).The prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.

<h3>Background and objectives</h3> New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumour-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesise that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC-exosomes as the mediator of this lipolysis. <h3>Design</h3> Exosomes from patient-derived cell lines and from plasma of patients with PC and non-PC controls were isolated and characterised. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink Assay was used to study AM and adrenomedullin receptor (ADMR) interaction in adipocytes treated with exosomes. <h3>Results</h3> In murine and human adipocytes, we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by ADMR blockade. AM interacted with its receptor on the adipocytes, activated p38 and extracellular signal-regulated (ERK1/2) mitogen-activated protein kinases and promoted lipolysis by phosphorylating hormone-sensitive lipase. PKH67-labelled PC-exosomes were readily internalised into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis. <h3>Conclusions</h3> PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.

Abstract Background: Adenomatous polyps are the most common precursor to colorectal cancer, the second leading cause of cancer-related death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. Methods: We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n = 233) and without (n = 547). Results: Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, proinflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Our findings were consistent with previously reported shifts in the gut microbiota of colorectal cancer patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. Conclusions: These data hint that increased sugar, protein, and lipid metabolism along with increased bile acid production could promote a colonic environment that supports the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio. In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, which could play a role in catalyzing adenoma development and eventually colorectal cancer. Impact: This study suggests a plausible biological mechanism to explain the links between shifts in the microbiota and colorectal cancer. This represents a first step toward resolving the complex interactions that shape the adenoma–carcinoma sequence of colorectal cancer and may facilitate personalized therapeutics focused on the microbiota. Cancer Epidemiol Biomarkers Prev; 26(1); 85–94. ©2016 AACR.

Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation‐specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele‐specific real‐time target and signal amplification assays on independent plasma‐extracted DNA from 21 HCC cases and 30 controls with cirrhosis. A phase II plasma study was then performed in 95 HCC cases, 51 controls with cirrhosis, and 98 healthy controls using target enrichment long‐probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross‐validated by randomly splitting the data 2:1 for training and testing. Random forest (rForest) regression models performed on the training set predicted disease status in the testing set; median areas under the receiver operating characteristics curve (AUCs; and 95% confidence interval [CI]) were reported after 500 iterations. In phase II, a six‐marker MDM panel (homeobox A1 [ HOXA1 ], empty spiracles homeobox 1 [ EMX1 ], AK055957 , endothelin‐converting enzyme 1 [ ECE1 ], phosphofructokinase [ PFKP ], and C‐type lectin domain containing 11A [ CLEC11A ]) normalized by beta‐1,3‐galactosyltransferase 6 ( B3GALT6 ) level yielded a best‐fit AUC of 0.96 (95% CI, 0.93‐0.99) with HCC sensitivity of 95% (88%‐98%) at specificity of 92% (86%‐96%). The panel detected 3 of 4 (75%) stage 0, 39 of 42 (93%) stage A, 13 of 14 (93%) stage B, 28 of 28 (100%) stage C, and 7 of 7 (100%) stage D HCCs. The AUC value for alpha‐fetoprotein (AFP) was 0.80 (0.74‐0.87) compared to 0.94 (0.9‐0.97) for the cross‐validated MDM panel ( P &lt; 0.0001). Conclusion : MDMs identified in this study proved to accurately detect HCC by plasma testing. Further optimization and clinical testing of this promising approach are indicated.

Background & AimsIt is unclear how long pancreatic ductal adenocarcinomas (PDACs) are present before diagnosis. Patients with PDAC usually develop hyperglycemia and diabetes before the tumor is identified. If early invasive PDACs are associated with hyperglycemia, the duration of hyperglycemia should associate with the time that they have had the tumor.MethodsWe collected data on patients with PDACs from medical databases in Olmsted County, Minnesota, from 2000 through 2015 and from the Mayo Clinic’s tumor registry from January 1, 1976, through January 1, 2017. We compared glycemic profiles of patients with PDAC (cases) compared with patients without cancer, matched for age and sex (controls). We analyzed temporal fasting blood glucose (FBG) profiles collected for 60 months before patients received a PDAC diagnosis (index date) (n = 219) (cohort A), FBG profiles of patients with resected PDAC (n = 526) stratified by tumor volume and grade (cohort B), and temporal FBG profiles of patients with resected PDACs from whom long-term FBG data were available (n = 103) (cohort C). The primary outcome was to estimate duration of presence of invasive PDAC before its diagnosis based on hyperglycemia, defined as significantly higher (P < .05) FBG levels in cases compared with controls.ResultsIn cohort A, the mean FBG did not differ significantly between cases and controls 36 months before the index date. Hyperglycemia was first noted 36 to 30 months before PDAC diagnosis in all cases, those with or without diabetes at baseline and those with or without resection at diagnosis. FBG level increased until diagnosis of PDAC. In cohort B, the mean FBG did not differ significantly in controls vs cases with PDACs below 1.0 mL. The smallest tumor volume associated with hyperglycemia was 1.1 to 2.0 mL; FBG level increased with tumor volume. FBG varied with tumor grade: well- or moderately differentiated tumors (5.8 mL) produced the same FBG levels as smaller, poorly differentiated tumors (1.5 mL) (P < .001). In cohort C, the duration of prediagnostic hyperglycemia for cases with large-, medium-, or small-volume PDACs was 36 to 24, 24 to 12, and 12 to 0 months, respectively. PDAC resection resolved hyperglycemia, regardless of tumor location.ConclusionsIn a case–control study of patients with PDAC from 2 databases, we associated FBG level with time to PDAC diagnosis and tumor volume and grade. Patients are hyperglycemic for a mean period of 36 to 30 months before PDAC diagnosis; this information might be incorporated into strategies for early detection. It is unclear how long pancreatic ductal adenocarcinomas (PDACs) are present before diagnosis. Patients with PDAC usually develop hyperglycemia and diabetes before the tumor is identified. If early invasive PDACs are associated with hyperglycemia, the duration of hyperglycemia should associate with the time that they have had the tumor. We collected data on patients with PDACs from medical databases in Olmsted County, Minnesota, from 2000 through 2015 and from the Mayo Clinic’s tumor registry from January 1, 1976, through January 1, 2017. We compared glycemic profiles of patients with PDAC (cases) compared with patients without cancer, matched for age and sex (controls). We analyzed temporal fasting blood glucose (FBG) profiles collected for 60 months before patients received a PDAC diagnosis (index date) (n = 219) (cohort A), FBG profiles of patients with resected PDAC (n = 526) stratified by tumor volume and grade (cohort B), and temporal FBG profiles of patients with resected PDACs from whom long-term FBG data were available (n = 103) (cohort C). The primary outcome was to estimate duration of presence of invasive PDAC before its diagnosis based on hyperglycemia, defined as significantly higher (P < .05) FBG levels in cases compared with controls. In cohort A, the mean FBG did not differ significantly between cases and controls 36 months before the index date. Hyperglycemia was first noted 36 to 30 months before PDAC diagnosis in all cases, those with or without diabetes at baseline and those with or without resection at diagnosis. FBG level increased until diagnosis of PDAC. In cohort B, the mean FBG did not differ significantly in controls vs cases with PDACs below 1.0 mL. The smallest tumor volume associated with hyperglycemia was 1.1 to 2.0 mL; FBG level increased with tumor volume. FBG varied with tumor grade: well- or moderately differentiated tumors (5.8 mL) produced the same FBG levels as smaller, poorly differentiated tumors (1.5 mL) (P < .001). In cohort C, the duration of prediagnostic hyperglycemia for cases with large-, medium-, or small-volume PDACs was 36 to 24, 24 to 12, and 12 to 0 months, respectively. PDAC resection resolved hyperglycemia, regardless of tumor location. In a case–control study of patients with PDAC from 2 databases, we associated FBG level with time to PDAC diagnosis and tumor volume and grade. Patients are hyperglycemic for a mean period of 36 to 30 months before PDAC diagnosis; this information might be incorporated into strategies for early detection.

End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments.We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE.Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists.The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life.This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis.

The inhibition of apoptosis is a critical event in the development of colorectal malignancies, although the mechanism(s) remain incompletely understood. The anti-apoptotic proto-oncogene, AKT, has been implicated in the molecular pathogenesis of a variety of human malignancies; however, no data exist on the role of AKT in colon carcinogenesis. We therefore evaluated the presence of AKT in human and experimental colon neoplasms by immunohistochemistry. Normal colonic mucosa and hyperplastic polyps exhibited no significant AKT expression, in marked contrast to the dramatic AKT immunoreactivity seen in colorectal cancers (57% positive) and in both human colorectal cancer cell lines examined. Importantly, AKT was also detected in 57% of the adenomas examined, implicating overexpression of this proto-oncogene as an early event during colon carcinogenesis. Moreover, in the rodent-carcinogen model, azoxymethane (AOM)-treatment induced AKT expression in premalignant rat colonocytes. Tumors that evolve via different genetic pathways displayed a lower incidence of AKT overexpression. Indeed, only 22% of mismatch repair defective tumors and 42% of AOM-induced rodent tumors upregulated AKT. Staining with an antibody specific for AKT 2 duplicated findings with the AKT 1&2 antibody, suggesting that AKT 2 was the predominant isoform involved in colon carcinogenesis. Furthermore, utilizing an antibody that specifically recognizes the serine-473 phosphorylated form of AKT, we observed that activated AKT was detectable in the neoplastic but not normal epithelium.

<h3>Objective:</h3> To investigate the prevalence of Barrett's esophagus in patients with adenocarcinomas located at the gastroesophageal junction. <h3>Design:</h3> A case series of patients who underwent esophagogastrectomy for adenocarcinoma was retrospectively reviewed. Tumors were grouped by location as esophageal, cardiac, and subcardiac, and the prevalence of specialized intestinal metaplasia in the histological specimens was determined. <h3>Setting:</h3> A university department of surgery that specializes in esophageal diseases. <h3>Patients:</h3> One hundred patients with adenocarcinoma of the esophagus, cardia, or proximal stomach. <h3>Main Outcome:</h3> Cardiac adenocarcinomas were associated with Barrett's esophagus in 42% of the patients. <h3>Results:</h3> Specialized intestinal metaplasia was identified in the histological sections from the resected specimen in 42% (13/31) of cardiac adenocarcinomas and in 79% (38/48) of esophageal adenocarcinomas but in only 5% (1/21) of subcardiac adenocarcinomas. The preoperative endoscopic biopsy results concurred with the final diagnosis of Barrett's esophagus in 33 of the 38 esophageal tumors, six of the 13 cardiac tumors, and the one subcardiac tumor but failed to detect specialized intestinal metaplasia in 54% (7/13) of cardiac tumors. Cardiac tumors were associated with shorter lengths of Barrett's mucosa than esophageal tumors (2.7±1.8 cm vs 7.4±3.4 cm,<i>P</i>&lt;.01). The Barrett's metaplasia was dysplastic in 36 of the 38 esophageal tumors, 10 of the 13 cardiac tumors, but not in the subcardiac tumor. <h3>Conclusions:</h3> Adenocarcinomas located at the gastroesophageal junction were associated with Barrett's metaplasia in nearly one half of the patients. The length of the Barrett segment tends to be short and may be missed during endoscopy. The presence of high-grade dysplasia within Barrett's mucosa supports a Barrett's origin for half of the adenocarcinomas arising at this location. (Arch Surg. 1994;129:609-614)

Background & Aims: Sclerosing mesenteritis is a rare non-neoplastic disease that affects the small bowel mesentery with chronic fibrosing inflammation. There are few data on the natural history and therapeutic options for this condition. Methods: We performed a retrospective and prospective study to describe the clinical characteristics, therapy, and outcome of all cases of sclerosing mesenteritis diagnosed at the Mayo Clinic, Rochester, from 1982–2005. Results: Ninety-two cases were identified; 70% were male, with a median age of 65 years (interquartile range, 55–72). Common presenting symptoms included abdominal pain in 70%, diarrhea in 25%, and weight loss in 23%. Treatment included medical therapy alone in 26%, surgery alone in 13%, surgery followed by medical therapy in 9%, and 52% received no treatment. Ten percent responded to surgery alone, 20% responded to additional medical treatment after surgery, and 38% responded to medical therapy alone. Tamoxifen in combination with prednisone was used in 20 patients, and 60% improved. Non-tamoxifen–based regimens were used in 12 patients, and 8% improved. Eighteen deaths were noted during the study period, and 17% were attributed to complications of sclerosing mesenteritis or its treatment. Conclusions: Although a relatively benign condition, sclerosing mesenteritis can have a prolonged debilitating course with a fatal outcome. Our results suggest that symptomatic patients might benefit from medical therapy, particularly tamoxifen and prednisone combination treatment. Long-term follow-up is needed to substantiate these results. Background & Aims: Sclerosing mesenteritis is a rare non-neoplastic disease that affects the small bowel mesentery with chronic fibrosing inflammation. There are few data on the natural history and therapeutic options for this condition. Methods: We performed a retrospective and prospective study to describe the clinical characteristics, therapy, and outcome of all cases of sclerosing mesenteritis diagnosed at the Mayo Clinic, Rochester, from 1982–2005. Results: Ninety-two cases were identified; 70% were male, with a median age of 65 years (interquartile range, 55–72). Common presenting symptoms included abdominal pain in 70%, diarrhea in 25%, and weight loss in 23%. Treatment included medical therapy alone in 26%, surgery alone in 13%, surgery followed by medical therapy in 9%, and 52% received no treatment. Ten percent responded to surgery alone, 20% responded to additional medical treatment after surgery, and 38% responded to medical therapy alone. Tamoxifen in combination with prednisone was used in 20 patients, and 60% improved. Non-tamoxifen–based regimens were used in 12 patients, and 8% improved. Eighteen deaths were noted during the study period, and 17% were attributed to complications of sclerosing mesenteritis or its treatment. Conclusions: Although a relatively benign condition, sclerosing mesenteritis can have a prolonged debilitating course with a fatal outcome. Our results suggest that symptomatic patients might benefit from medical therapy, particularly tamoxifen and prednisone combination treatment. Long-term follow-up is needed to substantiate these results. See CME exam on page 524. See CME exam on page 524. Sclerosing mesenteritis (SM) is a rare fibroinflammatory disorder of unknown etiology that primarily affects the small bowel mesentery.1Emory T.S. Monihan J.M. Carr N.J. et al.Sclerosing mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy: a single entity?.Am J Surg Pathol. 1997; 21: 392-398Crossref PubMed Scopus (286) Google Scholar The first known series, comprising 34 cases of “retractile mesenteritis and mesenteric sclerosis,” was published in 1924.2Jura V. Sulla mesenterite e sclerosante.Policlinico (sezprat). 1924; 31: 575-581Google Scholar Subsequently, on the basis of the predominant histology, numerous terms have been used to describe this entity, including mesenteric lipodystrophy (predominantly fatty degeneration and necrosis),3Kipfer R.E. Moertel C.G. Dahlin D.C. Mesenteric lipodystrophy.Ann Intern Med. 1974; 80: 582-588Crossref PubMed Scopus (178) Google Scholar mesenteric panniculitis (marked chronic inflammation),4Durst A.L. Freund H. Rosenmann E. et al.Mesenteric panniculitis: review of the literature and presentation of cases.Surgery. 1977; 81: 203-211PubMed Google Scholar, 5Ogden 2nd, W.W. Bradburn D.M. Rives J.D. Mesenteric panniculitis: review of 27 cases.Ann Surg. 1965; 161: 864-875Crossref PubMed Scopus (103) Google Scholar and retractile mesenteritis or mesenteric fibrosis (predominant fibrosis).6Kelly J.K. Hwang W.S. Idiopathic retractile (sclerosing) mesenteritis and its differential diagnosis.Am J Surg Pathol. 1989; 13: 513-521Crossref PubMed Scopus (102) Google Scholar In 1997 after a review of 84 cases, Emory et al1Emory T.S. Monihan J.M. Carr N.J. et al.Sclerosing mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy: a single entity?.Am J Surg Pathol. 1997; 21: 392-398Crossref PubMed Scopus (286) Google Scholar concluded that these histologic variants are part of the spectrum of one disease process, and SM would be an appropriate umbrella term. The rarity of this condition has limited the ability to study demographic and clinical features, natural history, and response to therapy. Thus, treatment decisions are guided by anecdotal experience and small case series. Different therapeutic modalities, including corticosteroids, colchicine, immunosuppressive drugs, and hormonal therapies have been used with varying success.7Bala A. Coderre S.P. Johnson D.R. et al.Treatment of sclerosing mesenteritis with corticosteroids and azathioprine.Can J Gastroenterol. 2001; 15: 533-535Crossref PubMed Scopus (66) Google Scholar, 8Genereau T. Bellin M.F. Wechsler B. et al.Demonstration of efficacy of combining corticosteroids and colchicine in two patients with idiopathic sclerosing mesenteritis.Dig Dis Sci. 1996; 41: 684-688Crossref PubMed Scopus (63) Google Scholar, 9Mazure R. Fernandez Marty P. Niveloni S. et al.Successful treatment of retractile mesenteritis with oral progesterone.Gastroenterology. 1998; 114: 1313-1317Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 10Venkataramani A. Behling C.A. Lyche K.D. Sclerosing mesenteritis: an unusual cause of abdominal pain in an HIV-positive patient.Am J Gastroenterol. 1997; 92: 1059-1060PubMed Google Scholar Recently, successful use of thalidomide has been reported in an open-label pilot study of 5 patients with symptomatic SM.11Ginsburg P.M. Ehrenpreis E.D. A pilot study of thalidomide for patients with symptomatic mesenteric panniculitis.Aliment Pharmacol Ther. 2002; 16: 2115-2122Crossref PubMed Scopus (43) Google Scholar In the present study, we sought to describe the clinical features, treatment, and outcomes of patients with SM seen at our institution during the past 23 years. After approval by the Mayo Clinic’s Institutional Review Board, 65 patients with a diagnosis of SM and its variants were retrospectively identified from January 1982–November 2002 through the Mayo Clinic diagnostic index and Department of Pathology database. An additional 28 cases were prospectively identified as referrals to our gastroenterology outpatient clinic between December 2002–November 2005. One patient denied research authorization and was excluded from the study. All pathology slides were reviewed by a single pathologist (T.C.S.) for confirmation of diagnosis and identification of histologic subtype. Demographic, clinical, and treatment data were abstracted from the medical records, and outcome data were supplemented by follow-up telephone interviews for prospectively enrolled subjects and previously diagnosed patients who were alive at initiation of the study. Response to treatment was assessed by clinical and radiographic parameters and categorized as responsive (improved/resolution), persistent (nonprogressive/stable), and progressive (deterioration/worsening). Descriptive statistics were used to summarize the results. Medians and interquartile ranges (IQRs) were calculated as summaries of continuous variables. For categorical variables, percentages of patients in each category were computed, and group comparison was done with Fisher exact test. A 2-tailed P value <.05 was considered statistically significant. Ninety-two cases of SM were identified during the study period. Patient characteristics at presentation are shown in Table 1. The most frequent presenting symptoms were abdominal pain in 70%, bloating and distention in 26%, diarrhea in 25%, and weight loss in 23% (Table 2). SM was an incidental finding in 10% of cases when an abdominal surgery (3%), computed tomography (CT) scan (5%), or autopsy (1%) was performed for another indication, and there were no symptoms attributable to mesenteric disease.Table 1Demographic and Clinical Characteristics of Study PatientsFeatureNo. (%)Male64 (70)Median age at diagnosis, y (IQR)64.5 (55–72)SM as an incidental finding9 (10)Previous abdominal surgery32 (35)Elevated erythrocyte sedimentation rate at diagnosis9 (10)SM-related complication61 (66) Small bowel obstruction22 (24) Chylous ascites13 (14) Superior mesenteric vein thrombosis3 (3) Colonic variceal bleed1 (1)Associated rheumatologic conditions9 (10) RPF4 (5) Sjögren’s syndrome2 (3) Ankylosing spondylitis1 (1) Rheumatoid arthritis1 (1) Sarcoidosis1 (1)Follow-up >1 mo67 (73)Total deaths during study period18 (20)Deaths due to SM or its treatment3 (3) Open table in a new tab Table 2Presenting Clinical FeaturesSymptomsNo. (%)Asymptomatic9 (10)Abdominal pain65 (70)Bloating/distention24 (26)Diarrhea23 (25)Weight loss21 (23)Nausea and vomiting18 (21)Loss of appetite13 (16)Constipation10 (15)Fever5 (6)Night sweats2 (3)Physical exam Normal abdominal exam47 (51) Abdominal tenderness22 (24) Abdominal mass14 (15) Chylous ascites13 (14) Open table in a new tab A prior history of abdominal surgery was present in 35% (Table 1), and 6% of these patients had more than 1 surgery (Table 3). Concurrent intra-abdominal pathology was noted in 18% (Table 4). The diagnosis was established at laparotomy with biopsy in 65%, laparoscopy with biopsy in 25%, and CT-guided biopsy in 10%.Table 3Previous Abdominal Surgical ProceduresProcedureNo. (%)Cholecystectomy17 (18)Appendectomy12 (13)Abdominal hysterectomy4 (4)Partial colectomy for colon cancer3 (3)Whipple’s procedure for SP1 (1)Sigmoid resection for diverticular disease1 (1)Total38 (41)aSix patients had more than 1 surgical procedure.a Six patients had more than 1 surgical procedure. Open table in a new tab Table 4Concurrent Intra-abdominal PathologyPathologyNo. (%)Ovarian tumors3 (3) Mucinous cystadenocarcinoma Mucinous cystadenoma Serous cystadenomaNHL3 (3)Prostate cancer2 (2)Endometrial sarcoma1 (1)Lymphangioma of small bowel mesentery1 (1)Small bowel carcinoid tumor1 (1)Abdominal aortic aneurysm3 (1)SP2 (2)Metanephric adenoma1 (1)Total17 (18) Open table in a new tab Laboratory parameters were unremarkable except for elevated erythrocyte sedimentation rate (range, 24–122) in 14% of patients. Immunohistochemical staining was performed in 25% of cases and showed a mixed population of CD3-positive T cells and CD19/CD20-positive B cells. Keratin, S-100, bcl-2, kit (CD117) immunostain and T-cell receptor gene rearrangement studies were negative in all these cases. Additional immunohistochemical studies in 12 cases revealed abundant tissue infiltration of IgG4-positive plasma cells in 33%. SM-related complications included small bowel obstruction in 24% and chylous ascites in 14%. Vascular complications related to SM at the time of presentation included chronic superior mesenteric venous thrombosis in 3% and lower gastrointestinal bleeding caused by colonic varices in 1% of the cases. One patient had a spontaneous small bowel perforation requiring emergent laparotomy, and another patient with aggressive disease complicated by frequent bowel obstruction and ascites died of extensive bowel ischemia caused by mesenteric venous thrombosis 7 months after the diagnosis of SM. In 61% of cases, an abdominal CT showed a single soft-tissue mass in the root of the mesentery, often containing calcification (Figure 1A and B). In 34% of cases, there was subtle increased density of the mesenteric fat, suggesting mild mesenteric fibrosis or inflammation, with or without discrete soft-tissue masses (Figure 2). Small retroperitoneal and/or mesenteric lymph nodes, encasement of mesenteric vessels, and collateral circulation were frequently noted. In the remaining 5% of cases, the abdominal CT was not available for review.Figure 2Axial image from CT scan of abdomen performed with intravenous contrast. Subtle increased density of central mesenteric fat without adenopathy (arrow). There is no mass effect on the mesenteric blood vessels.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Histologically, a variable combination of fibrosis, chronic inflammation, and fat necrosis was noted. The most frequent histologic finding, noted in 53%, was prominent fibrosis with scant inflammation and some fat necrosis (retractile mesenteritis or mesenteric fibrosis) (Figure 3A). In 25% of cases, there was a predominant chronic inflammatory infiltrate (mesenteric panniculitis) (Figure 3B). In 22% of cases, lipid-laden foamy macrophages were noted infiltrating the mesenteric fat with relatively little fibrosis (mesenteric lipodystrophy) (Figure 3C). Overall, 44 of 92 (48%) patients, including 23 of the 28 prospectively enrolled cases, received some form of treatment (Table 5). Total parenteral nutrition was administered in 8 of 44 (18%) patients. Pharmacologic therapy alone was administered in 24 of 44 (56%) patients. Surgical intervention was done in 20 of 44 (45%); 12 of 20 (60%) only had surgery, whereas the other 8 of 20 (40%) received additional medical therapy after surgery. Treatment decisions, especially in the prospectively enrolled patients, were guided by the severity and type of symptoms. In 15 of the 20 patients (75%) in the surgical cohort, surgery was performed because of intractable bowel obstruction. Medical treatment was offered to all persistently symptomatic cases, and patients who remained asymptomatic, irrespective of the CT findings, did not receive any treatment.Table 5Summary of Treatment in 44 Patients With SMMedical (N = 24)Combined medical/surgicalaSurgery followed by medical therapy. (N = 8)Surgical (N = 12)Total (N = 44)Male (%)16 (66)6 (75)12 (100)34 (77)Median age, y (IQR)67 (56–72)60 (53–63)72 (57–77)65 (55–72)Median follow-up, mo (IQR)22.5 (8–45.3)9 (7.3–29)34 (1–83)29.5 (11.8–68.3)Presenting symptoms, N (%) Small bowel obstruction4 (17)5 (63)11 (92)20 (45) Weight loss12 (50)3 (38)3 (25)18 (41) Ascites5 (21)2 (25)1 (8)8 (18) Abdominal pain15 (63)8 (100)10 (83)33 (75)Treatment response, N (%) Responsive9 (38)4 (50)2 (17)15 (34)b12/15 responders received a combination of tamoxifen and prednisone. Persistent9 (38)2 (25)4 (33)15 (34) Progressive4 (16)2 (25)4 (33)10 (23)Lost to follow-up or <1-mo follow-up2 (8)02 (17)4 (9)a Surgery followed by medical therapy.b 12/15 responders received a combination of tamoxifen and prednisone. Open table in a new tab Complete or partial resection of the mesenteric mass with adherent small bowel was possible in 6 of 20 (30%) patients who underwent surgery. In the remaining 14 of 20 (70%) surgical patients, the mesenteric mass was unresectable; 8 of 14 (57%) required segmental small bowel resection as a result of severe vascular compromise from the contracted mesentery, 3 of 14 (21%) underwent a palliative bypass, and 3 of 14 (21%) had adhesiolysis only. Among the 32 patients who received any medical therapy, the pharmacologic agents that were used included tamoxifen, prednisone, budesonide, colchicine, azathioprine, methotrexate, and thalidomide (Table 6, Table 7). The median durations of treatment were: tamoxifen 20 months (range, 2–30 months), prednisone 13 months (range, 4–24 months), colchicine 8 months (range, 3–12 months), azathioprine 14 months (range, 4–36 months), and thalidomide 5 months.Table 6Patient Characteristics and Response to Medical TherapyNo.Age at diagnosis (y)GenderDrug, mg/day (mo drug received)Treatment responseF/U (mo)Outcome at last follow-up167FT 20 (24), P 45 (18), A 100 (12)Responsive3Alive255FT 20 (28), P 60aTapering dose of prednisone. (12), A 100 (20)Responsive12Alive366FT 20 (12), P 60 (4), C 1.8bColchicine 0.6 orally 3 times daily, T 20 = tamoxifen 10 mg orally twice daily. (6)Responsive41Alive472MT 20 (30), P 20 (24)Responsive57Alive568MT 20 (10), P 20 (2)Responsive10Alive672MT 20 (25), P 40 (6)Responsive25Alive781MT 10 (11), P 40aTapering dose of prednisone. (8)Responsive46Alive869MT 20 (9), P 40aTapering dose of prednisone. (9)Responsive14Alive952MT 10 (7)Responsive8Alive1064MTh 200 (5), P 40aTapering dose of prednisone. (36), A 100 (36)Persistent60Died of line sepsis1182MP 10 (24)Persistent4Alive1260MP 80aTapering dose of prednisone. (9)Persistent21Alive1347MP 60aTapering dose of prednisone. (2)Persistent2Alive1471FP 40aTapering dose of prednisone. (9)Persistent43Alive1551MT 20cTamoxifen 20 mg orally once daily. (2), C1.8bColchicine 0.6 orally 3 times daily, T 20 = tamoxifen 10 mg orally twice daily. (3)Persistent8Alive1661MT 20 (7), P 40aTapering dose of prednisone. (7)Persistent7Alive1784MT 20 (33), P 40aTapering dose of prednisone. (6)Persistent16Alive1858FT 20 (4), P 40aTapering dose of prednisone. (4)Persistent11Alive1971MP 50aTapering dose of prednisone. (3), A 50 (6), C1.2dColchicine 0.6 orally twice daily. (6)Progressive9Alive2068FT 20 (6), P 10 (24)Progressive89Alive2151FP 40aTapering dose of prednisone. (9), budesonide 3 (3)Progressive46Alive2276MP 40aTapering dose of prednisone. (9)Progressive33Alive2361MP 40Lost to F/U0Unknown2454FP 40Lost to F/U0UnknownA, azathioprine; C, colchicine; P, prednisone; T, tamoxifen; Th, thalidomide; F/U, follow-up from date of diagnosis to last clinical contact.a Tapering dose of prednisone.b Colchicine 0.6 orally 3 times daily, T 20 = tamoxifen 10 mg orally twice daily.c Tamoxifen 20 mg orally once daily.d Colchicine 0.6 orally twice daily. Open table in a new tab Table 7Patient Characteristics and Response to Medical Therapy After SurgeryNoAge at diagnosis (y)GenderCombined surgical/medical drug, mg/day (mo received)ResponseLength of F/U (mo)Outcome at last F/U161MT 20 (24), P 40aTapering dose of prednisone. (24)Responsive31Alive260MT 20 (16), P 40aTapering dose of prednisone. (4)Responsive23Alive342MP 40aTapering dose of prednisone. (6), C 1.2 (2)bColchicine 0.6 orally twice daily, T 20 = tamoxifen 10 mg orally twice daily. followed by A 100 (4)Responsive6Alive460FT 20 (5)Responsive13Alive554MT 20 (6), P 30 (4)Persistent7Alive652FT 20 (12), P 30aTapering dose of prednisone. (15), M 10 mg SQ weekly (3), C 1.2bColchicine 0.6 orally twice daily, T 20 = tamoxifen 10 mg orally twice daily. (4)Persistent10Alive769MP 60 (12), C 1.2bColchicine 0.6 orally twice daily, T 20 = tamoxifen 10 mg orally twice daily. (12)Progressive38Died of gastric lymphoma864MP 40aTapering dose of prednisone. (2), T 20 (<1)Progressive2Died of TTPC, colchicine; M, methotrexate; P, prednisone; T, tamoxifen; F/U, follow-up; SQ, subcutaneous; TTP, thrombotic thrombocytopenic purpura.a Tapering dose of prednisone.b Colchicine 0.6 orally twice daily, T 20 = tamoxifen 10 mg orally twice daily. Open table in a new tab A, azathioprine; C, colchicine; P, prednisone; T, tamoxifen; Th, thalidomide; F/U, follow-up from date of diagnosis to last clinical contact. C, colchicine; M, methotrexate; P, prednisone; T, tamoxifen; F/U, follow-up; SQ, subcutaneous; TTP, thrombotic thrombocytopenic purpura. Response to treatment was assessed by symptoms and abdominal CT studies. More than 1-month follow-up was available in 38 of 44 patients (86%) who had therapy. Among 20 patients who underwent any surgical intervention, only 2 of 20 (10%) responded to surgery alone, and 4 of 20 (20%) responded after receiving additional medical treatment. Among 32 patients who received any medical treatment, 13 of 32 (41%) improved, 11 of 32 (34%) had persistent symptoms, 6 of 32 (19%) had disease progression, and 2 of 32 (6%) were lost to follow-up (Table 6, Table 7). Tamoxifen along with a prednisone taper was used in 20 of 32 (63%) patients; 12 of 20 (60) responded within 12–16 weeks, 6 of 20 (30%) had persistent symptoms, and 2 of 20 (10%) progressed. One patient improved after receiving a combination of prednisone, azathioprine, and colchicine. None of the other treatment regimens were successful. Minor side effects including hot flashes, vaginal itching, and dryness were reported by 4 of 7 (57%) women on tamoxifen, and easy bruisability, fluid retention, and mood changes were reported by 26 of 29 (90%) patients on prednisone. Major side effects included deep venous thrombosis without any other known risk factors in 3 of 19 (16%) patients on tamoxifen (2 of whom were complicated by pulmonary embolism), and postoperative pulmonary embolism in 1 patient on prednisone and azathioprine. One patient developed transient leukopenia (white blood cell count, 3 × 109/L) while on azathioprine. There were 2 deaths that could possibly be treatment-related. One patient died of line-sepsis while on thalidomide and azathioprine for 5 months. Another patient developed a sudden thrombotic thrombocytopenic purpura–like clinical picture and died within 1 month of initiation of tamoxifen therapy. Follow-up of more than 1 month after the diagnosis of SM was available in 73% of all patients. The median length of follow-up was 20.5 months (IQR, 8–46) and 21 months (IQR, 7–72) in the cohort with and without treatment, respectively. Follow-up of less than 1 month occurred in 8% of the medical group, 0% of the combined medical/surgical group, 17% of the surgical group, and 44% of the group that was not treated. Among the cohort that did not receive any treatment and had more than 1-month follow-up, 26% remained asymptomatic, and 74% continued to have mild abdominal symptoms. There were 18 deaths in the cohort, 12 in the group without treatment and 6 in the group who had treatment (Table 8). One patient with concurrent monoclonal gammopathy of unknown significance (MGUS) progressed to multiple myeloma, one patient developed acute myeloblastic leukemia (subtype M1), and another one developed follicular B-cell lymphoma 5 years after the diagnosis of SM.Table 8Causes of Death Among 18 Patients Who Died During Study PeriodAge at diagnosis (y)GenderFollow-up (mo)Treatment groupCause of death64M72MedicalLine sepsis on thalidomide and azathioprine76M86SurgicalUnknown77M216SurgicalCardiac52M5SurgicalUnknown69M38CombinedGastric diffuse large B-cell lymphoma63M17CombinedDIC/TTP on tamoxifen63M33NoneSystemic amyloidosis71M124NoneUnknown57M0NoneHead injury (SM was an incidental autopsy finding)79M63NoneMultiple myeloma and sepsis64F80NoneMetastatic carcinoid87M140NoneMetastatic prostate68M11NoneUnknown62F7NoneBowel infarction as result of MVT69M0NoneUnknown82M21NonePneumonia43F37NoneMetastatic endometrial sarcoma67M2NoneUnknownDIC, disseminated intravascular coagulation; TTP, thrombotic thrombocytopenic purpura; MVT, mesenteric venous thrombosis. Open table in a new tab DIC, disseminated intravascular coagulation; TTP, thrombotic thrombocytopenic purpura; MVT, mesenteric venous thrombosis. The current study represents the largest series of patients reported to date with the diagnosis of SM or its variants and, to the best of our knowledge, the most comprehensive information on treatment responses currently available. Other than 2 prior large series including 53 and 84 patients, respectively,1Emory T.S. Monihan J.M. Carr N.J. et al.Sclerosing mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy: a single entity?.Am J Surg Pathol. 1997; 21: 392-398Crossref PubMed Scopus (286) Google Scholar, 3Kipfer R.E. Moertel C.G. Dahlin D.C. Mesenteric lipodystrophy.Ann Intern Med. 1974; 80: 582-588Crossref PubMed Scopus (178) Google Scholar most published reports are single patients or small case series8Genereau T. Bellin M.F. Wechsler B. et al.Demonstration of efficacy of combining corticosteroids and colchicine in two patients with idiopathic sclerosing mesenteritis.Dig Dis Sci. 1996; 41: 684-688Crossref PubMed Scopus (63) Google Scholar, 12Bashir M.S. Abbott C.R. Mesenteric lipodystrophy.J Clin Pathol. 1993; 46: 872-874Crossref PubMed Scopus (15) Google Scholar, 13Castillo M. Romero E. Medina E. et al.[Mesenteric lipodystrophy].Rev Gastroenterol Mex. 1995; 60: 27-29PubMed Google Scholar, 14Hemaidan A. Vanegas F. Alvarez O.A. et al.Mesenteric lipodystrophy with fever of unknown origin and mesenteric calcifications.South Med J. 1999; 92: 513-516Crossref PubMed Scopus (16) Google Scholar or reviews of existing literature.4Durst A.L. Freund H. Rosenmann E. et al.Mesenteric panniculitis: review of the literature and presentation of cases.Surgery. 1977; 81: 203-211PubMed Google Scholar, 5Ogden 2nd, W.W. Bradburn D.M. Rives J.D. Mesenteric panniculitis: review of 27 cases.Ann Surg. 1965; 161: 864-875Crossref PubMed Scopus (103) Google Scholar, 6Kelly J.K. Hwang W.S. Idiopathic retractile (sclerosing) mesenteritis and its differential diagnosis.Am J Surg Pathol. 1989; 13: 513-521Crossref PubMed Scopus (102) Google Scholar, 15Ikoma A. Tanaka K. Komokata T. et al.Retractile mesenteritis of the large bowel: report of a case and review of the literature.Surg Today. 1996; 26: 435-438Crossref PubMed Scopus (22) Google Scholar Because of the paucity of published cases, the clinical and pathologic features of patients with SM (or its variants), including etiologic factors, natural history, and optimal treatment options, remain uncertain. Overall, the clinical, histologic, and radiographic features observed in our patients agree for the most part with those described previously. SM is a disease of middle-aged or older adults, diagnosed primarily during the 6th–7th decade of life. The disease appears to be twice as common in men as in women,1Emory T.S. Monihan J.M. Carr N.J. et al.Sclerosing mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy: a single entity?.Am J Surg Pathol. 1997; 21: 392-398Crossref PubMed Scopus (286) Google Scholar, 3Kipfer R.E. Moertel C.G. Dahlin D.C. Mesenteric lipodystrophy.Ann Intern Med. 1974; 80: 582-588Crossref PubMed Scopus (178) Google Scholar, 4Durst A.L. Freund H. Rosenmann E. et al.Mesenteric panniculitis: review of the literature and presentation of cases.Surgery. 1977; 81: 203-211PubMed Google Scholar which is in agreement with our results. Most symptoms associated with SM are caused by the direct mechanical effect of the mesenteric mass encasing the bowel, blood vessels, and lymphatics, resulting in abdominal pain, bowel obstruction, ischemia, and chylous ascites. Although the overall prognosis is good, in about 20% of patients, SM is associated with significant morbidity and a chronic debilitating course. Occasionally, SM or its treatment can prove fatal.16Katsanos K.H. Ioachim E. Michail M. et al.A fatal case of sclerosing mesenteritis.Dig Liver Dis. 2004; 36: 153-156Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The pathophysiology of SM remains unknown. Various mechanisms have been postulated, including traumatic (including surgery), hypoxic, allergic, infectious, and autoimmune.17Parra-Davila E. McKenney M.G. Sleeman D. et al.Mesenteric panniculitis: case report and literature review.Am Surg. 1998; 64: 768-771PubMed Google Scholar, 18Schaffler A. Scholmerich J. Buchler C. Mechanisms of disease: adipocytokines and visceral adipose tissue–emerging role in intestinal and mesenteric diseases.Nat Clin Pract Gastroenterol Hepatol. 2005; 2: 103-111Crossref PubMed Scopus (130) Google Scholar In the current study, a history of abdominal surgery was present in about 40% of the patients. Most of these patients had cholecystectomy or appendectomy between 1960–1990. Before mid-1980, the use of powdered surgical gloves was a common practice, which might have a role in the development of peritoneal adhesions and fibrosis in some cases.19Edlich R.F. Woodard C.R. Pine S.A. et al.Hazards of powder on surgical and examination gloves: a collective review.J Long Term Eff Med Implants. 2001; 11: 15-27PubMed Google Scholar, 20Ellis H. Pathological changes produced by surgical dusting powders.Ann R Coll Surg Engl. 1994; 76: 5-8PubMed Google Scholar Concurrent intra-abdominal pathology was noted in 23%, and 13% were neoplastic lesions. In an earlier reported series from Mayo Clinic,3Kipfer R.E. Moertel C.G. Dahlin D.C. Mesenteric lipodystrophy.Ann Intern Med. 1974; 80: 582-588Crossref PubMed Scopus (178) Google Scholar malignant intra-abdominal neoplasms were noted in 30%, and half of these were lymphomas. However, in a later series by Emory et al,1Emory T.S. Monihan J.M. Carr N.J. et al.Sclerosing mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy: a single entity?.Am J Surg Pathol. 1997; 21: 392-398Crossref PubMed Scopus (286) Google Scholar only 2 concurrent lymphoma cases were reported in 84 cases, including Hodgkin’s disease and a large cell non-Hodgkin’s lymphoma (NHL). In the current series, 3 patients had concurrent int

BACKGROUND AND AIMS Recent consensus guidelines suggest that presence of ≥1 of the following is an indication for resection (IR) of branch duct intraductal papillary mucinous neoplasm (IPMN-Br): cyst-related symptoms, main pancreatic duct diameter ≥10 mm, cyst size ≥30 mm, intramural nodules, or cyst fluid cytology suspicious/positive for malignancy. Among a cohort of patients with IPMN-Br we determined if the consensus IR (CIR), presence of multifocal IPMN-Br, or growth of cyst size on follow-up predict malignancy. METHODS We identified 147 patients with IPMN-Br of whom 66 underwent surgical resection at diagnosis and 81 were followed conservatively, of whom 11 were resected during follow-up. Clinical, imaging, histological, and cyst fluid characteristics from all 147 patients with IPMN-Br were obtained from clinical records and/or by contacting the patients. In all cases, presence of CIR at baseline and during follow-up (N = 66), presence of multifocal cysts (N = 57), and increase in cyst size (N = 38) were noted. RESULTS Among the 77 resected IPMN-Brs, at initial evaluation 61 had at least one CIR and 16 had none. Malignancy was present in 9/61 (15%) with CIR and 0/16 without IR (P= 0.1). When presence of any one of the CIR was taken as an indicator of malignancy, the CIR had a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 23%, 14%, and 100%, respectively. Prevalence of malignancy in those with single versus multifocal IPMN-Br was similar (13%vs 11%). No patient has developed malignancy after a median follow-up of 15 months. So far, none of the 38 patients with increase in cyst size on follow-up has developed malignancy related symptoms. CONCLUSIONS Suggested consensus indications for resection identify all patients with malignancy; however, their specificity is low. In the short term it would be safe to follow patients without these features.

Background. The usual manifestation of familial adenomatous polyposis (FAP) is hundreds or thousands of colonic adenomas. The authors previously described a colon cancer-prone syndrome characterized by fewer adenomas (1–100), most located in the proximal colon, and upper gastrointestinal lesions, particularly fundic gland polyps and duodenal adenomas. The colonic adenomas are often flat rather than polypoid, a feature emphasized in earlier reports with the term “hereditary flat adenoma syndrome.” The syndrome has an autosomal dominant pattern of inheritance and is linked to the adenomatous polyposis coli [APC] locus at 5q. Methods. This is a descriptive study based on one family that was followed for more than a decade. Total cell RNA was isolated from cultured lymphoblasts, and an in vitro protein synthesis assay was used to detect APC mutations. Sixteen individuals whose APC mutation status was known had sequential endoscopic evaluations. Five patients were given one or more courses of sulindac. Results. There was perfect concordance between clinical affected status and an APC mutation. All affected members generated a 16-kDa polypeptide from the mutant allele, consistent with a 2-base pair deletion at the extreme 5′end of the APC gene. Sixteen mutation-positive individuals underwent upper gastrointestinal endoscopy and colonoscopy; 13 had colonic adenomas, with the number visualized at any one examination ranging from 1 to greater than 50. Upper gastrointestinal examination revealed fundic gland polyps in 15, gastric or duodenal adenomas in 4, and periampullary carcinoma in 1. Conclusion. AFAP is a phenotypically distinctive syndrome, differing from classic FAP by having fewer colonic adenomas that tend to be proximally distributed and flat rather than polypoid. The position of the APC germline mutation appears to allow for the molecular differentiation between FAP and the attenuated variant in that the extreme 5′ APC mutations are associated with the latter.

ArticlePlus Click on the links below to access all the ArticlePlus for this article. Please note that ArticlePlus files may launch a viewer application outside of your web browser. https://links.lww.com/MPA/A1 INTRODUCTION Dr. William M. Steinberg The term “autoimmune pancreatitis” (AIP) has been used to define a relatively new syndrome of clinical and histologic findings. This entity has been described in several articles published in Europe and Japan, yet few cases have been seen or reported in the United States. Therefore, it was thought that this was a timely topic for discussion at our Controversies in Clinical Pancreatology session at the American Pancreatic Association meetings on November 14, 2002. Five discussants participated in this session. Dr. Randall Pearson of the Gastroenterology Section, Mayo Clinic presented a case, and Dr. Dan Longnecker of the Department of Pathology, Dartmouth-Hitchcock Medical Center discussed the pathology. Dr. Suresh Chari of the Gastroenterology Section, Mayo Clinic, Dr. Kazuichi Okazaki of the Gastroenterology Section, Kyoto University, and Dr. Luca Frulloni of the Gastroenterology Section, University of Verona then proceeded with reports of the Mayo Clinic, Japanese, and Italian experiences with this syndrome. Finally, the discussants kindly submitted the following manuscripts for this article. BACKGROUND INDETERMINANT PANCREATIC MASS Dr. Randall K. Pearson A 53-year-old white woman in generally good health (postcholecystectomy) felt vaguely unwell for nearly 4 months with dyspeptic symptoms, two episodes of nausea and diarrhea characterized as “flu,” and a 20-pound weight loss. Two weeks prior, she noted dark urine, pale stools, and scleral icterus. She had no known history of pancreatitis, drank minimal amounts of alcohol, and had no family history of chronic pancreatitis. Biochemical studies confirmed jaundice, and computed tomography (CT) of the abdomen showed dilatation of the biliary tree down to the level of the pancreas. The pancreas was generally enlarged, but the cause of the obstruction was not obvious. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a distal bile duct stricture that was stented, and she was referred to the Mayo Clinic. After endoscopic stenting, she felt progressively better and was essentially without complaints. Her physical examination was normal. Laboratory studies were consistent with resolving obstructive jaundice. A CA 19-9 level was mildly elevated at 91.4 U/mL (normal, <40 U/mL). Repeat triple-phase contrast CT with thin cuts through the pancreas failed to reveal a mass or cause for biliary obstruction. Endoscopic ultrasound findings were suspicious for malignancy; a 3-cm mixed echogenicity region in the head was prominently seen in the setting of diffuse alteration in the parenchyma consistent with pancreatitis. Fine-needle aspiration of the mass and peripancreatic lymph nodes was negative. ERCP (Fig. 1) confirmed the distal bile duct stricture; a limited pancreatogram showed a normal duct in the head with slight narrowing at the neck of the pancreas and irregularity in the tail (Fig. 2).FIGURE 1.: Retrograde cholangiogram demonstrating a distal common bile duct stricture with proximal dilatation.FIGURE 2.: Mildly irregular pancreatic duct observed with endoscopic pancreatography.The patient underwent laparotomy, and a pancreaticoduodenectomy (Whipple resection) was performed. PATHOLOGY OF AUTOIMMUNE PANCREATITIS Dr. Daniel Longnecker The pathologic changes found in cases of pancreatitis associated with other autoimmune diseases, such as Sjögren disease and extrahepatic sclerosing cholangitis, 1 can be divided into two groups. The first group includes constant features characteristic and suggestive of AIP, i.e., found in all cases, and the second group comprises variable features seen in a fraction of cases that, when present, provide additional support for the diagnosis. On gross examination, the involved pancreas is firm or hard (a constant feature) and may be enlarged or “mass forming.” These features may lead to resection because of the suspicion that the lesion is a carcinoma. The lesion may be limited to one portion of the pancreas, most often the head, or less commonly may involve the body, tail, or whole organ. Thus, location in the pancreas, mass formation, and pancreatic enlargement are variable features. At the histologic level, the characteristic changes include sclerosing pancreatitis (Fig. 3) with prominent infiltrating lymphocytes and plasma cells, and conspicuous involvement of ducts in the inflammatory process (Fig. 4). The main duct, branch ducts, and the common bile duct (CBD) are commonly involved. Localization of the infiltrate in the duct wall is variable–-sometimes subepithelial (Figs. 4 and 5), sometimes focused in the stroma of the duct wall, and sometimes diffusely involving all layers and adjacent connective tissue. Immunostaining has demonstrated that T cells predominate over B cells among the infiltrating lymphocytes. 1 The lumen of inflamed ducts is characteristically narrowed (Fig. 4B), and scarring or edema may thicken their walls.FIGURE 3.: This field shows sclerosing pancreatitis with perilobular fibrosis and some atrophy of acinar tissue in lobules. This pancreas contained typical areas of ductal inflammation as described for autoimmune pancreatitis. Hematoxylin and eosin (H & E).FIGURE 4.: Large pancreatic ducts with a prominent subepithelial lymphoplasmacytic infiltrate, with thickening of the duct wall (A and B) and compression of the lumen (B). This specimen was classified as chronic pancreatitis, etiology unknown, when it was originally seen but in retrospect is regarded as autoimmune pancreatitis; H & E.FIGURE 5.: Lymphocytes and plasma cells are conspicuous in this duct, where they infiltrate the subepithelial layer and extend into the lumen (left). A few granulocytes are also present in the infiltrate. Figures 3–5 are from the same pancreas; H & E.Variable features include the presence of eosinophils or neutrophils in the leukocytic infiltrate, degree of epithelial injury and inflammation in the ducts, presence of vasculitis (veins more than arteries), and degree of acinar cell atrophy, scarring, and inflammation in lobular tissue. The epithelium of involved ducts is well preserved in some patients, whereas the infiltrate extends into the epithelium and lumen in others. Fibrosis may be perilobular but commonly extends into the lobules as acinar cells atrophy. Conspicuous negatives typically include the absence of calculi in ducts, absence of pseudocyst, and absence of more than minimal fat necrosis. Are these changes specific for AIP? There is growing confidence that AIP is a legitimate pathologic diagnosis for some cases of sclerosing pancreatitis that have the constant features of AIP and lack stigmata of alcoholic chronic pancreatitis. 1 However, many pathologists are more comfortable with a descriptive diagnosis, such as lymphoplasmacytic sclerosing pancreatitis (LPSP). In the past, cases of AIP have often been included with idiopathic chronic pancreatitis. Why are the changes so variable? One obvious explanation is that the lesions change with duration or progression of the disease. This seems certain to be at least part of the basis for the spectrum of changes. Another possible factor is that the immune response is triggered by different epitopes with varying cellular targets in patients with differing histologic changes. Thus, one pending issue is whether there are recognizable subtypes of AIP with different etiologies, different pathologic features, and perhaps different clinical courses. The patient presented by Dr. Pearson had a Whipple resection that included a 4.7-cm portion of the head of the pancreas containing a firm 3 × 2 × 2 cm mass. There were no stones or cysts. Histologic sections showed sclerosing chronic pancreatitis with a somewhat irregular distribution of lobular inflammation, fibrosis, and atrophy. A large pancreatic duct contained a conspicuous subepithelial leukocytic infiltrate consisting of lymphocytes and plasma cells. Medium-sized ducts in the same section contained a lymphoplasmacytic infiltrate throughout the fibrous wall (Fig. 6). Perilobular fibrous tissue contained leukocytic aggregates of lymphocytes, fewer plasma cells, and prominent eosinophils. A few lymphoid follicles were present in these scarred areas. Neutrophils were inconspicuous, and there were no stigmata of acute pancreatitis, such as fat necrosis or pseudocyst. The ducts were free of calculi or proteinaceous “plugs.” The original histopathologic diagnosis was “Chronic pancreatitis involving an area 3 × 2 × 2 cm with slight stricture of the distal common bile duct.” The features of this case fall within the spectrum of those described previously as typical of AIP.FIGURE 6.: Interlobular duct infiltrated by lymphocytes and plasma cells throughout the wall in the resected pancreas from the patient presented by Dr. Pearson. From a slide provided by Dr. Thomas Smyrk, Mayo Clinic, Rochester; H & E.CLINICOPATHOLOGIC FEATURES OF IDIOPATHIC TUMEFACTIVE CHRONIC PANCREATITIS Drs. Suresh T. Chari and Thomas C. Smyrk Some benign conditions simulate malignancy. In a recent review of 40 patients undergoing subtotal pancreatoduodenectomy for “benign but clinically suspicious” disease, the most common postoperative diagnosis was LPSP. 2 This idiopathic inflammatory pancreatitis has also been termed autoimmune pancreatitis, nonalcoholic duct-destructive pancreatitis, and chronic inflammatory sclerosis of the pancreas. The majority of reports of AIP have come from Japan, with few reports from Western countries. It is not clear whether this reflects the rarity of the disease or a failure to recognize it in Western countries. To identify potential cases, we studied patients with tumefactive chronic pancreatitis (TCP), defined as chronic pancreatitis presenting with a pancreatic mass or obstructive jaundice. The results of these studies have been reported in detail elsewhere. 3,4 We report here a summary of our findings. We reviewed a consecutive series of 254 pancreatic resections performed for benign disease at the Mayo Clinic in Rochester between 1985 and 2001. Twenty-seven patients met the three inclusion criteria for our study: dense lymphoplasmacytic periductal inflammation, no known cause for pancreatitis, and “tumefactive” presentation (i.e., presenting with a mass or obstructive jaundice). The mean age of patients with idiopathic TCP was 58 ± 2 years, and the median duration of symptoms was 3 months. Although two thirds of patients presented with jaundice, 70% of them had minimal or no pain. No patient had a personal or family history of autoimmune disorder. One patient had Crohn disease, and one had ulcerative colitis. One third of the patients with idiopathic TCP (9 of 27; 33%) had diffuse enlargement of the pancreas (6 on imaging studies and 3 at surgery). The most frequent findings on ERCP were strictures in the bile duct, pancreatic duct, or both ducts. Pancreaticoduodenectomy was performed in 25 patients: 1 patient had distal pancreatectomy, and 1 had total pancreatectomy. None of the patients were treated with steroids preoperatively or postoperatively, and none has had a recurrence on follow-up evaluation. Pathology review suggested the presence of two histologic subtypes. The first, which we have termed lymphoplasmacytic sclerosing pancreatitis, seemed to be a more generalized fibroinflammatory process. Thus, although there was prominent periductal inflammation, inflammation and fibrosis also extended into pancreatic parenchyma and peripancreatic soft tissue (Fig. 7). Obliterative phlebitis was a striking and consistent feature. Interestingly, duct epithelium tended to remain intact despite the dense periductal inflammation. Fourteen of the 27 patients were classified histologically with LPSP.FIGURE 7.: (A–D) LPSP features dense periductal inflammation without duct destruction (A). Inflammation and fibrosis extend into parenchyma (B) and peripancreatic soft tissue (C). Obliterative phlebitis is always seen (D).The second subtype was characterized by patchy inflammatory infiltrate involving mainly lobules and pancreatic ducts (Fig. 8). The infiltrate was confined to the pancreas. It was predominantly neutrophilic with occasional microabscesses. The inflammatory infiltrate involved the entire wall of pancreatic ducts, and epithelial destruction was commonly seen with obstruction of lumen. Obliterative phlebitis was rarely seen. We applied the descriptive term idiopathic duct-destructive pancreatitis (IDCP) and assigned 13 cases to this category.FIGURE 8.: (A–D) IDCP has periductal inflammation but includes neutrophils, and there is damage to epithelium (A and B). Inflammation is less in fibrous areas (C and D).Although histology suggests the existence of subtypes, the only clinical difference between patients with LPSP and IDCP was the prevalence of jaundice, which developed in 13 of 14 (93%) patients with LPSP but in only 5 of 13 of those with IDCP (p = 0.005). DISCUSSION A number of case reports and small series have described patients presenting with a pancreatic mass who prove to have a unique form of chronic inflammatory pancreatitis. The presence of increased gamma globulins, a nonspecific increase in various antibody titers, and a response to steroids has prompted the use of the term AIP. 5–11 Other nomenclatures, based on histology, include LPSP, nonalcoholic duct-destructive pancreatitis, and chronic inflammatory sclerosis of the pancreas. 12–14 Though the terms AIP and sclerosing pancreatitis have been used interchangeably, 10 the absence of specific serologic markers makes it unclear if all authors are describing the same disease. Do the patients with idiopathic TCP described in our study have the same disease as that described by Japanese authors as sclerosing pancreatitis or AIP? This question is difficult to answer with certainty because reports of sclerosing pancreatitis or AIP have used serologic criteria and response to steroids to make the diagnosis, and histology is generally not available. 10,15,16 Conversely, all of our patients have well-described pathology, but due to lack of clinical suspicion of AIP and the absence of associated autoimmune disorders, none of our patients had serologic parameters measured. Still, the histology of idiopathic TCP described in our study resembles that described as AIP or sclerosing pancreatitis. It may be a disservice to add a new term (IDCP) to a literature already overcrowded with terminology, particularly because LPSP and IDCP were clinically indistinguishable. It may be that our categories LPSP and IDCP are simply part of the spectrum of the same disease or perhaps different stages of the same disease. Still, we think it worth highlighting these two histologic patterns as a possible prelude to discovering different etiologies for this poorly understood condition. Interestingly, the features seen in our patients with IDCP are similar to those described by Ectors et al. 12 as nonalcoholic duct-destructive pancreatitis. Obliterative phlebitis was described only in 1 of their 10 patients, and that patient had Sjögren syndrome. Thus, it may be that some variation in description and nomenclature in the literature may derive from the fact that there is more than one type of chronic inflammatory pancreatitis. Chronic inflammatory pancreatitis is a distinctive pattern of histologic injury observed in patients with idiopathic TCP. We have described two histologic subtypes and designated them LPSP and IDCP, but it is not clear whether LPSP and IDCP are the same disease or represent two or more different entities. The condition(s) remains idiopathic. Resection of the mass prevents recurrence of symptoms. AUTOIMMUNE PANCREATITIS: THE JAPANESE EXPERIENCE Dr. Kazuichi Okazaki Definition and concept of AIP Since Sarles et al. observed a particular case of pancreatitis with hypergammaglobulinemia, occasional coexistence of pancreatitis with other autoimmune diseases, such as Sjögren syndrome, has been reported. These findings led us to the concept of autoimmune-related pancreatitis, called autoimmune pancreatitis. 17 Although it has not yet been widely accepted as a new clinical entity, the present section reports recent experiences of AIP in Japan. Although the pathogenesis and pathophysiology of AIP are still unclear, the characteristic findings in most cases of AIP can be summarized as follows 18: (i) increased levels of serum gamma globulin, IgG, or IgG4; (ii) presence of autoantibodies; (iii) diffuse enlargement of the pancreas; (iv) diffusely irregular narrowing of the main pancreatic duct and occasionally stenosis of intrapancreatic bile duct on ERCP imaging; (v) fibrotic changes with lymphocyte infiltration; (vi) no symptoms or only mild symptoms, usually without acute attacks of pancreatitis; (vii) rare pancreatic calcification or cysts; (viii) occasional association with other autoimmune diseases, and (ix) effective steroid therapy. AIP is a rare disorder, although the exact prevalence is still unknown. More than 309 cases have been reported as AIP or pancreatitis with narrowing of the pancreatic duct (PNPD) in the Japanese literature. We encountered 21 cases of AIP in a review of 451 cases of chronic pancreatitis, and incidence predominated in older men versus women in Japan. Although the correct morbidity of primary or secondary AIP is unclear, more than half of the cases are primary. It is still unclear whether the pathogenetic mechanism of secondary (or syndromic) AIP with other autoimmune diseases differs from primary AIP. Recently, “Diagnostic Criteria for Autoimmune Pancreatitis, 2002” was proposed by the Japan Pancreas Society and contained three criteria: pancreatic imaging, laboratory data, and histopathologic findings (Table 1) and associated diseases (Table 2). 19 Patients with AIP often show narrowing of the CBD mainly in the intrapancreatic area, which may result in dilatation of the upper biliary tract. Sclerosing changes of the extrapancreatic bile duct similar to primary sclerosing cholangitis (PSC) are reported. Unlike with PSC, steroid administration usually shows therapeutic effects on biliary lesions in patients with AIP, suggesting that the developmental mechanism of biliary lesions in AIP may be different from typical PSC.TABLE 1: Diagnostic criteria for autoimmune pancreatitis, 2002, proposed by the Japan Pancreas SocietyTABLE 2: Autoimmune pancreatitis and associated diseasesDiabetes mellitus (DM) is often observed in patients with AIP (in approximately 43–68%), and the majority has type 2 DM, with some patients improving after steroid therapy. 20 Although the mechanism is obscure, cytokines from T cells and macrophages suppressing the function of islet β-cells may be downregulated by steroid treatment. Clinical symptoms Patients with AIP usually have no or only slight discomfort in the epigastrium or back, in addition to symptoms related to other associated diseases. Thus, clinical symptoms are different from acute or severe pancreatitis. Obstructive jaundice due to the stenosis of the intrapancreatic CBD is characteristic for AIP and is rare in other types of pancreatitis. Laboratory data Patients with AIP usually show increased levels of serum pancreatic enzymes, hypergammaglobulinemia, and presence of several autoantibodies, such as antinuclear, antilactoferrin (LF), and anticarbonic anhydrase (CA-II) antibody and rheumatoid factor. 21 However, the antimitochondrial (M2) antibody specific for PBS is rarely observed (Fig. 9). CA-II and LF are distributed in the ductal cells of several exocrine organs, including the pancreas, salivary glands, biliary duct, and distal renal tubules. Serum levels of IgG4, immune complexes, and the IgG4 subclass of immune complexes are often increased in patients with AIP. 22 Patients with CBD stenosis show increased serum IgG4 and abnormalities in the serum bilirubin and hepatobiliary enzymes. For these patients, other liver diseases such as viral hepatitis, autoimmune hepatitis, or primary biliary cirrhosis (PBC) should be ruled out. After steroid therapy, many abnormal laboratory findings are reversible.FIGURE 9.: Prevalence of autoantibodies in AIP. Antinuclear antibodies, antilactoferrin antibodies, and anti-CAII antibodies were identified in 75%, 75%, and 55% of 20 cases, respectively. Ninety percent of the cases showed either antilactoferrin or anti-CA-II antibody, and 35% showed both antibodies, suggesting that immune responses against these proteins are heterogeneously activated.Pancreatic and biliaryimaging Computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US) demonstrate the diffusely enlarged pancreas, with a “sausage-like” appearance (Fig. 10) and a capsule-like rim showing low density on CT, low intensity on T2-weighted MRI, and delayed enhancement on dynamic MRI. Pancreatic calcification or pseudocyst is seldom observed. ERCP images of the AIP patients show segmental or diffuse narrowing of the main pancreatic duct (Figs. 11–13). Although magnetic resonance cholangiopancreatography (MRCP) poorly shows pancreatic duct stenosis, it can well demonstrate stenosis of the bile ducts mainly in the intrapancreatic area, resulting in dilatation of the upper biliary tract. Sclerosing changes of the extrapancreatic bile ducts similar to PSC are sometimes observed. Steroid therapy is usually effective for changes of the biliary and pancreatic ducts (Fig. 14).FIGURE 10.: CT of AIP. Diffusely enlarged pancreas similar to sausage appearance is typical of autoimmune pancreatitis. Contrast-enhanced CT often demonstrates delayed enhancement. After steroid therapy, the size of the pancreas becomes normal, often atrophic.FIGURE 11.: ERCP of AIP. In the lower left panel, diffusely irregular narrowing of the main pancreatic duct is observed. In the upper left panel, many patients show narrowing of intrapancreatic common bile duct and pancreatic duct. Narrowing of the terminal bile duct is supposed to be induced mainly by compression of the swollen pancreas. After steroid therapy, most patients remarkably improve as shown in the right picture.FIGURE 12.: ERCP of local type AIP. ERCP images show the locally irregular narrowing of the main pancreatic duct in the pancreatic tail (the upper left panel) and local narrowing in the pancreatic head (the lower left panel). Irregular narrowing is observed in more than one third of the length but not in the entire pancreas. After steroid therapy, most of these abnormal findings improve.FIGURE 13.: Pancreatogram of 20 patients with AIP. Of 20 cases, 11 showed diffuse narrowing in the pancreatic duct, 3 from the head to body, 2 in the head, and 4 in the tail.FIGURE 14.: PSC-like cholangiogram associated with AIP. PSC-like cholangiogram showing narrowing of upper or middle biliary tract is observed in 6 of 20 patients with AIP. Different from typical PSC, these abnormal findings responded to steroid therapy very well.Histopathology Microscopic findings, if obtained, show fibrotic changes with infiltration of lymphocytes and plasmacytes mainly around the pancreatic duct (Fig. 15). HLA-DR antigens are often expressed on pancreatic duct or acinar cells. HLA-DR+ T cells predominantly infiltrate over B cells in the pancreas, while plasma cells and lymph follicles are observed. HLA-DR antigens are expressed on the pancreatic duct cells and on CD4+ T cells, suggesting that an autoimmune mechanism may be involved in inflammation. In some patients with AIP, CD4+ Th1 cells predominate over Th2-type cells. Therefore, similar to SjS, Th1 cytokines may be essential in the induction or maintenance of AIP, whereas Th2 cytokines may be involved in disease process progression, especially local B-cell activation.FIGURE 15.: Histopathology and microscopic findings of the pancreas in AIP. Massive infiltration of lymphocytes and plasmacytes (A) and fibrotic changes (B) were observed mainly around the pancreatic duct. In most cases, T lymphocytes (C) predominantly infiltrate over B lymphocytes (D), with occasional follicle formation.Treatment and prognosis For most AIP patients, intensive treatment for acute pancreatitis is not required. For patients with jaundice, percutaneous transhepatic or endoscopic biliary drainage is often required, especially in cases complicated by bacterial infection. Steroid therapy is usually effective for narrowing of the bile ducts and pancreatic ducts. Notable is that some patients may spontaneously improve without treatment. The long-term prognosis of AIP is unknown. Conclusions In conclusion, our experience in Japan supports the concept of autoimmune-related pancreatitis, which appears to be a unique clinical entity. AUTOIMMUNE PANCREATITIS: THE ITALIAN EXPERIENCE Drs. Luca Frulloni and Giorgio Cavallini Definition: “The tower ofBabele” Since 1959, autoimmunity has been proposed as a pathogenetic mechanism in patients suffering from pancreatitis. 23 In 1993, we introduced the term “primary chronic pancreatitis” to define a disease characterized by an autoimmune reaction against the pancreatic ducts, resulting in an obliterating inflammatory fibrosis of the pancreatic duct system. 24 We suggested that the key step in the pathogenesis of the disease was an immune reaction against a target antigen in the epithelium of the pancreatic ducts, with secondary periductal inflammatory infiltration (mainly activated T lymphocytes), followed by an obliterating periductal fibrosis. 24,25 Many terms have been used later for this particular form of pancreatitis, such as “nonalcoholic duct-destructive chronic pancreatitis”, 26 “lymphoplasmacytic sclerosing pancreatitis”, 27,28 “autoimmune pancreatitis”, 29,30 “granulomatous pancreatitis”, 31 and “sclerosing pancreatocholangitis”. 32 The terminology was mainly used to identify the pathologic characteristics of the inflammatory process (duct-destructive, sclerosing, lymphoplasmacytic, granulomatous), but some definitions describe the postulated immune-mediated pathogenesis (primary, autoimmune) rather than the histologic pictures. In our opinion, perhaps an easier term we can use for this disease is autoimmune, to stress pathogenesis and address the physician in the use of steroids for management of this particular form of chronic pancreatitis. Epidemiology: “The tip of theiceberg” We do not know the current real incidence of AIP in Italy or in the world at large. In a recent Italian multicenter study coordinated by the University of Verona on the epidemiology of chronic pancreatitis in Italy, called “PanCroInf-AISP,” that involved 21 centers and enrolled 383 patients suffering from chronic pancreatitis during 2 years (2001 and 2002), autoimmunity was recognized as an associated factor in 23 patients (6%). Probably this is only “the tip of the iceberg” because there are many problems associated with the disease. The first problem is awareness of the disease, particularly by surgeons who probably first observe patients suffering from this form of pancreatitis and who frequently misdiagnose it as pancreatic tumor. In all surgical series, we probably find inflammatory pancreatitis in more than 5% of patients who undergo Whipple procedure for pancreatic cancer. 33 Furthermore, we not only need skilled pathologists but also skilled gastroenterologists, surgeons, radiologists, and endoscopists to recognize AIP. Finally, there are not codified criteria yet for the diagnosis of AIP. Typology of the disease:“Heterogeneity” Autoimmune pancreatitis is a heterogeneous disease with different clinical aspects. In our experience (33 patients with a definitive diagnosis of AIP), it may occur as acute pancreatitis (25% of patients) involving all or a part of the pancreatic gland. In some patients (25%), the clinical history, instrumental findings, and functional pancreatic tests are very similar to those observed in chronic pancreatitis. More frequently (50% of patients), it may present as a so-called “mass-forming pancreatitis,” that is, a mass generally localized in the head of the pancreas mimicking a pancreatic cancer. Half of these patients are free of pain at the onset of the disease. Jaundice may be the main clinical sign when the common bile duct is compressed by a pancreatic mass (40% of patients). In some patients, especially in those with a long history of pancreatic-type pain, we may observe diabetes or steatorrhorrea. Calcifications are rare (fewer than 20% of all patients), but their presence does not exclude the diagnosis of AIP. Most patients neither drink alcohol (70%) nor smoke (50%), but some patients (10%) drink more than 80 grams of alcohol a day, and one third smoke more than 10 cigarettes a day. In the past, these patients were probably classified as having alcoholic chronic pancreatitis. As in other cases, alcohol is a confounding factor. The sex ratio (male to female) is approximately one to one. The average age at onset is 42 years, as in chronic pancreatitis. 34 However, we may observe patients at any age, and the distribution of patients is more similar to that observed with idiopathic pancreatitis 34,35 than with alcoholic chronic pancreatitis. 34–36 How to diagnose the disease: “Thechallenge” The diagnosis of AIP is difficult. All patients with suspected AIP should have their clinical, biochemical, and instrumental results carefully evaluated. Japanese authors recently proposed som

Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome caused, in 30-40% of cases, by germline mutations of the E-cadherin/CDH1 gene. The presence of clinically undetectable early gastric cancers has been previously reported in ten of ten prophylactic gastrectomies from germline E-cadherin mutation carriers. In the present study, detailed maps of the distribution of invasive cancers in nine of these ten stomachs were produced and precursor lesions of HDGC searched for. The nine gastrectomy specimens contained from 1 to 161 foci of early diffuse gastric cancer, occupying 0.005-2.96% of the gastric mucosa. Seven specimens contained focal in situ signet ring carcinoma. Pagetoid spread of signet ring cells was observed beneath the epithelial lining of gastric foveolae/glands. Helicobacter pylori organisms and associated pathology were absent from all cases. Two-dimensional maps of the gastrectomy specimens revealed lesions throughout the gastric mucosa without evidence of antral clustering. The distribution and size of the cancers in the gastrectomy specimens indicate that standard endoscopic screening with random or geographically targeted biopsies is unlikely to provide sufficiently sensitive clinical screening for at-risk individuals. An in situ precursor of signet ring carcinoma was identified and a model for neoplastic progression in the setting of HDGC is proposed.

Although the epidemiology of microscopic colitis has been described in Europe, no such data exist from North America. We studied the incidence, prevalence and temporal trends of microscopic colitis in a geographically defined US population.In this population based cohort study, residents of Olmsted County, Minnesota, with a new diagnosis of microscopic colitis, and all who had colon biopsies for evaluation of diarrhoea, between 1 January 1985 and 31 December 2001 were identified. Biopsies were reviewed for confirmation (cases) and to identify missed cases (diarrhoea biopsies).Incidence rates, age and sex adjusted to the 2000 US white population. Poisson regression assessed the association of calendar period, age and sex with incidence.We identified 130 incident cases for an overall rate of 8.6 cases per 100,000 person-years. There was a significant secular trend, with incidence increasing from 1.1 per 100,000 early in the study to 19.6 per 100,000 by the end (p<0.001). Rates increased with age (p<0.001). By subtype, the incidence was 3.1 per 100,000 for collagenous colitis and 5.5 per 100,000 for lymphocytic colitis. Collagenous colitis was associated with female sex (p<0.001) but lymphocytic colitis was not. Prevalence (per 100,000 persons) on 31 December 2001 was 103.0 (39.3 for collagenous colitis and 63.7 for lymphocytic colitis).The incidence of microscopic colitis has increased significantly over time, and by the end of the study, the incidence and prevalence were significantly higher than reported previously. Microscopic colitis is associated with older age, and collagenous colitis is associated with female sex.

Pancreatic mucin-producing cystic neoplasms are classified into 2 distinct entities: mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm (IPMN). In previous studies, MCN often has been defined loosely and has not always been distinguished clearly from IPMN. Our aims were to determine the demographics, clinical features, and prevalence of invasive cancer in MCN defined by the presence of characteristic ovarian stroma.By using the presence of ovarian stroma as a requisite criterion for diagnosis of MCN, a single pathologist, unaware of clinical information, identified 56 MCNs from 243 mucin-producing neoplasms resected at Mayo Clinic between 1986 and 2003. Medical records of the MCN patients were reviewed to obtain clinical and demographic data.Patients with MCN were almost exclusively (98%) women; we identified 1 man with a neoplasm containing ovarian stroma. The mean (+/-SD) age at resection was 48 +/- 15 years (84% < 60 y). Abdominal pain was the most common presenting symptom; 16% were asymptomatic. Most MCN (93%) were in the pancreatic body/tail region. Their median size was 5 cm (61% > or =5 cm). Histologically, 50 (89%) were adenomas, 2 (4%) had carcinoma-in-situ, and 4 (7%) had invasive cancer. None of the 22 MCNs <5 cm in size had invasive cancer. No patient with noninvasive disease had a recurrence after resection.MCN defined by ovarian stroma has a distinct demographic and clinical profile and a low prevalence of invasive cancer. These observations suggest that ovarian stroma should be used as the defining criterion for diagnosing MCN.

<h3>Hypothesis</h3> Intraductal papillary mucinous neoplasm (IPMN) is an increasingly recognized disease of the pancreas. We report our experience with pancreatic resection for IPMN. <h3>Design</h3> Retrospective review from 1992 through 2005 with additional independent histopathologic confirmation. <h3>Setting</h3> Mayo Clinic Rochester, a tertiary care center. <h3>Patients</h3> All patients who underwent primary resection for pancreatic IPMN. <h3>Main Outcome Measures</h3> Disease-specific operative outcomes, survival, and recurrence patterns. <h3>Results</h3> Of 208 patients (mean age, 66 years) with IPMN of the pancreas, 168 underwent partial pancreatectomy, and 40 underwent total pancreatectomy; 88 were classified as having adenoma, 38 as having borderline neoplasm, 19 as having carcinoma in situ, and 63 as having invasive carcinoma. The prevalence of a malignant neoplasm was 64% in patients with main duct IPMN compared with 18% in patients with branch duct IPMN. Re-resection of the initial pancreatic margin was necessary in 21% of patients. Final negative margins were achieved in 89% of patients. Five-year survival with noninvasive IPMN was 94%. Patients with invasive IPMN had a similar 5-year survival compared with a matched cohort with ductal adenocarcinoma (31% vs 24%;<i>P</i> = .26). In patients with invasive IPMN, 58% experienced disease recurrence. In patients with noninvasive IPMN, 10% experienced disease recurrence after partial pancreatectomy and 0% experienced disease recurrence after total pancreatectomy. <h3>Conclusions</h3> Patients with main duct IPMN or high-risk branch duct IPMN should be considered for targeted pancreatectomy. Invasive IPMN behaves as aggressively as ductal adenocarcinoma, but resection seems to provide the only potential for cure. Even with negative resection margins, the pancreatic remnant harbors a risk of recurrence and, thus, careful long-term surveillance is warranted.

HepatologyVolume 45, Issue 6 p. 1547-1554 ReviewFree Access Immunoglobulin G4 associated cholangitis: Description of an emerging clinical entity based on review of the literature† Einar Björnsson, Corresponding Author Einar Björnsson einar.bjornsson@medic.gu.se Department of Internal Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg Sweden fax: (31) 822152.Department of Internal Medicine, Section of Gastroenterology and Hepatology, Med pol II, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden===Search for more papers by this authorSuresh T. Chari, Suresh T. Chari Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MNSearch for more papers by this authorThomas C. Smyrk, Thomas C. Smyrk Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MNSearch for more papers by this authorKeith Lindor, Keith Lindor Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MNSearch for more papers by this author Einar Björnsson, Corresponding Author Einar Björnsson einar.bjornsson@medic.gu.se Department of Internal Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg Sweden fax: (31) 822152.Department of Internal Medicine, Section of Gastroenterology and Hepatology, Med pol II, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden===Search for more papers by this authorSuresh T. Chari, Suresh T. Chari Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MNSearch for more papers by this authorThomas C. Smyrk, Thomas C. Smyrk Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MNSearch for more papers by this authorKeith Lindor, Keith Lindor Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MNSearch for more papers by this author First published: 30 May 2007 https://doi.org/10.1002/hep.21685Citations: 192 † Potential conflict of interest: Nothing to report AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat During the last decade, patients with steroid responsive sclerosing cholangitis have been described in a number of case reports and a few cases series. These patients meet diagnostic criteria for primary sclerosing cholangitis (PSC) but seem to have a better prognosis and are often, but not always, associated with autoimmune pancreatitis (AIP). Unlike biliary strictures in PSC, most PSC-like biliary strictures seen in association with AIP respond well to steroids and some have been shown to resolve after immunosuppressive treatment during prolonged follow-up. In addition, steroid-responsive dominant bile duct lesions, sometimes mimicking infiltrating hilar cholangiocarcinoma, without pancreatic abnormalities have also been reported. Abbreviations AIP, autoimmune pancreatitis; IAC, immunoglobulin G4 (IgG4) associated cholangitis; IgG4, immunoglobulin G4; PSC, primary sclerosing cholangitis. Here we review the literature on this emerging clinical entity and suggest that this condition of steroid responsive biliary strictures be named Immunoglobulin G4 (IgG4) Associated Cholangitis (IAC). We performed an electronic database search of MEDLINE for case reports and case series of sclerosing cholangitis with pancreatitis and/or pancreatic mass (1960–July 2006). Articles were limited to English and these case reports and cases series were reviewed and all references on the combination of sclerosing cholangitis and pancreatitis as well as IgG4 positive cholangitis without pancreatic involvement not identified by our original search were obtained. Terminology and Definition In 1963, two cases of PSC with pancreatic involvement1 seen at the Mayo Clinic were reported in the New England Journal of Medicine; these might have been the first two cases of IASC reported. A total of 54 articles with cases of suspected IgG4 associated cholangitis were included in the final analysis.1-54 From 1963–July 2006 a total of 215 cases of IAC have been reported.1-54 For obvious reasons it is difficult to be certain that all these cases are really IAC as IgG4 has not been measured in all and corticosteroids have not always been tried. This entity has had many descriptive names in the literature including "inflammatory pseudotumor from sclerosing cholangitis",9 "primary sclerosing cholangitis mimicking chronic pancreatitis"13 "pancreatic pseudotumor with multifocal idiopathic fibrosclerosis"14 "lymphoplasmacytic sclerosing pancreatitis with cholangitis",19 "sclerosing pancreato-cholangitis",31, 33, 40, 49 "atypical primary sclerosing cholangitis associated with unusual pancreatitis",34 "lymphoplasmacytic sclerosing cholangitis without pancreatitis"44 "immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis" and "autoimmune pancreatitis-associated sclerosing cholangitis". AIP is often associated with sclerosing cholangitis and this entity has therefore been called sclerosing pancreato-cholangitis31, 33, 40, 49, 50 Strictures of the biliary tract, in the hilar region or intrahepatic strictures have been well documented.31, 33-36, 40, 45, 48-50, 54 Definition of IAC. Strict criteria for IAC are lacking at the present time but one of the aims of this review is to propose radiological, histological, and serological criteria which might be helpful for the diagnosis of IAC. Since steroid responsiveness is its most distinguishing clinical feature, IAC may be defined as a biliary stricture that responds to or improves with steroid therapy. However, it remains to be determined if all IAC-related strictures respond to steroid therapy. It is likely that "burnt out" IAC may not show steroid responsiveness. It is also possible that in some cases IAC may resolve spontaneously. IAC can be defined as a steroid responsive biliary disease, frequently involving the extrahepatic ducts, that is often associated with other fibrosing conditions, especially autoimmune pancreatitis. It is characterized by elevation of IgG4 in serum and infiltration of IgG4 positive plasma cells in bile ducts. As opposed to PSC, IAC is not usually associated with colitis. The Concept of Autoimmune Pancreatitis Since steroid-responsive biliary strictures are often associated with AIP, we discuss first the concept of AIP as a part of a systemic disease and its relationship to IAC. Autoimmune pancreatitis is a recently recognized entity.55-57 It is a form of chronic pancreatitis which is characterized by typical features on histology, imaging, and serology and associated frequently with extrapancreatic organ involvement. The manifestations, both pancreatic and extra-pancreatic, respond to steroid therapy. Pancreatic immunostaining is diagnostic of AIP when it shows abundant IgG4 positive cells55-57 and it can distinguish AIP from alcoholic pancreatitis and inflammatory infiltrate surrounding pancreatic cancer.57 The most frequently reported clinical presentation is that of diffuse enlargement of the pancreas or a pancreatic mass that is very similar to pancreatic ductal adenocarcinoma.55-57 Although dramatic response to corticosteroids has been widely reported,55-57 spontaneous resolution of AIP has also been reported.57 The diagnosis of AIP is based on the current criteria of the Japan Pancreas Society which requires the presence of characteristic imaging findings showing a diffusely enlarged sausage-shaped pancreas and a diffusely irregular, attenuated pancreatic duct.55 However, recently these criteria have been shown to lack sensitivity and new criteria for AIP based on histology and the response to steroids have been proposed.57 In a recent series of prospectively collected cases of AIP at the Mayo Clinic from 1999-2005, other organ involvement was observed in 49% of patients.57 The biliary tract (other than the distal bile duct) was involved in 17% of patients.57 If only the intrapancreatic portion of the common bile duct is involved, the condition should not be called IAC but rather be considered a part of AIP. We have tried to include in our literature review only cases with more proximal common bile duct involvement in order to classify them as IAC cases. Clinical Features of IAC Prevalence Very limited epidemiological data exist on the prevalence of IAC and there are no data on its prevalence in the general population. Some studies have looked at its prevalence among subjects presenting as PSC. A study from a single center in Toronto Canada revealed that 5/72 (7%) PSC patients diagnosed between 1972 and 2003 had associated pancreatic problems43 including pancreatic insufficiency, acute pancreatitis and 3 patients presented with a pancreatic mass. All three patients with a pancreatic mass were initially suspected on both clinical and radiological findings to have a pancreatic malignancy but were found to have a pancreatic pseudotumor associated with PSC, fulfilling some of the criteria for IAC. Interestingly, among a multicenter study of PSC patients in Japan, diagnosed between 1975 and 2004, altogether 28 of 388 (7%) patients were found to have PSC associated with AIP.47 Recently, IgG4 levels were measured in a large cohort of PSC (n = 128) from stored sera and elevated levels were found in 9% of PSC patients whereas this was only found in one of 87 (1.1%) PBC patients.58 It is conceivable that they might represent a subset of PSC patients with IAC who potentially might be steroid responsive. Demographics IAC and PSC are diagnosed more commonly in male patients with two to one predominance over female patients.43, 45, 50, 54 This is somewhat paradoxical as autoimmune disorders are usually more common in females. The two largest series from Europe with 4 and 10 patients only included male patients.31, 54 Some of the patients in these two series are from one cohort of patients.31, 54 In the series from Japan the proportion of males has ranged from 62 to 70%44, 47, 49 (Table 1). Age of presentation is highly variable but generally, IAC patients are older at diagnosis than patients with classic PSC.59 No cases of IAC have been reported in children and although PSC can be steroid responsive in children this is probably due to a common overlap with AIH in children.59 The age and gender distribution among patients in the largest published series is shown in Table 1. Table 1. The Age and Gender Distribution in the Largest Published Series Erkelens 1999 Nakazawa 2001 Hirano 2003 Zen 2004 Nakazawa 2004 Takikawa 2004 Nakazawa 2005 Kamisawa 2006 van Buuren 2006 Cases 4 8 8 17 26 28 20 23 10 Age (range) 48 (19-62) 63 (59-70) 66 (49-75) 71 (55-79) 62 (-) - 65 (-) 68 (-) 55 (19-80) Male/females 4/0 5/3 6/2 12/5 16/10 18/10 14/6 - 10/0 Clinical Presentation The clinical picture of IAC is very variable as is the case in classic PSC but obstructive jaundice is a common clinical presentation in IAC4, 5, 19, 20, 29, 31, 34, 40, 43, 45, 47-50, 54 which is rarely observed at diagnosis in PSC.59 In a direct comparison of the clinical differences between classic PSC and patients with IAC the clinical presentation among IAC patients occurred more abruptly with obstructive jaundice in 15 of 20 patients (75%) whereas obstructive jaundice was only present in 1 of 27 (4%) patients with classic PSC.49 The clinical diagnosis of patients presenting with hepatic hilar strictures without pancreatic involvement7, 44, 45, 49, 50 has for obvious reasons been cholangiocarcinoma.45 Among PSC patients presenting with a pancreatic mass, the clinical diagnosis has instead been pancreatic malignancy43, 45, 54 and in a number of cases pancreatoduodenectomy has been performed in these patients.9, 19, 23, 24, 27, 35, 45, 46, 48, 49 Laboratory Data Levels of alkaline phosphatase47 and serum bilirubin levels49 were significantly higher in patients with IAC in comparison with classic PSC. Immunoserology Patients with IAC generally have increased gammaglobulin levels19, 37, 40, 49 indicating the presence of autoimmunity. However, no significant difference was found between IASC and PSC patients in gammaglobulin levels in general whereas IgG4 levels were significantly higher among the IAC patients.49 Hamano et al. found normal levels of IgG4 in classic PSC patients whereas elevated IgG4 levels were found in patients with AIP.56 It has been shown that some patients with IAC did not have increased levels of IgG4 initially but developed subsequently high levels during follow-up.40 Thus, it seems that IAC patients do not necessarily present with definite biochemical and immunological abnormalities at the time of diagnosis.40 Recently, the IgG4-positive plasma cell/mononuclear cell ratio was found to be significantly higher in IAC in comparison with classic PSC patients and this ratio was suggested to be a useful index to help distinguish IAC from PSC.52 High serum IgG4 is only found in a very limited number of other conditions, such as pemphigus vulgaris and atopic dermatitis.45, 60 Among patients presenting with a hepatobiliary disease, high serum IgG4 levels have been reported to be highly specific for AIP.56 However, at the present time the sensitivity and specificity of IgG4 levels for the diagnosis of IAC are not known. Tumor Markers Because an important differential diagnosis of IAC is cholangiocarcinoma, serum tumor markers are often measured in this context in order to help distinguish PSC, AIP, or IAC from cholangiocarcinoma. Interestingly, high levels of the tumor marker Ca 19-9 are common in patients with IAC.19, 28, 29, 40, 51, 54 Elevated levels of Ca 19-9 were found in 5 of 8 (63%) patients in one study and one patient had a value of 11470! (normal value <37 U/L).40 However, CEA levels were normal or only slightly elevated in most patients.40 Thus, Ca 19-9 levels do not seem to help to distinguish between IAC and cholangiocarcinoma and Ca 19-9 has generally been found to be unreliable for the diagnosis of CCA in PSC.61 Cholangiography and Imaging Features Characteristic of the cholangiographic features in patients with IAC is stenosis of the lower common bile duct. Sclerosing changes in the intrahepatic and extrahepatic bile ducts were found in half of the IAC patients in one study.49 Among patients with AIP, marked bile duct strictures were detected in 14 of 16 (88%) and the stricture were in the lower portion of the bile ducts in 9 patients, the middle portion in 2, and the lower middle, and intrahepatic portion in 2 patients.48 In a follow-up study of 8 patients with AIP, extrapancreatic bile duct changes were observed such as stricture of the bile duct at the hepatic hilus or within the intrahepatic area in 6 patients.40 Thus, imaging findings of the biliary tract can show abnormalities in all parts of the biliary tract in IAC. Although pancreatic involvement such as diffuse pancreatic enlargement or pancreatic mass is very common in patients with IAC, many cases have also been described with isolated biliary tract involvement without pancreatic disease.44, 45, 50 These strictures may mimic those due to cholangiocarcinoma. Recently, Nakazawa et al. compared cholangiographic changes in 26 cases of IAC with a group of patients with classic PSC.44 Segmental strictures, long strictures with prestenotic dilatation and strictures of the distal common bile duct were significantly more common in IAC patients whereas band-like strictures, beaded or pruned-tree appearance were significantly more common in classic PSC.44 The spectrum of IAC is shown in Fig. 1 (from Zen et al. 200445). Cholangiographic abnormalities in a patient with IAC are shown in Fig. 2. Figure 1Open in figure viewerPowerPoint A spectrum of IgG4 associated sclerosing cholangitis. In the paper by Zen et al. (2004 copyright by American Journal of Surgical Pathology, volume 28, pages 1193-1203, Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, et al, IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Reprinted with permission from Lippincott Williams & Wilkins). called sclerosing cholangitis. IgG4 related sclerosing lesions occur along the biliary tract and pancreatic duct, presenting with mass-forming or duct-stenosis. Black nodules and thick black wiggly lines are the site of the IgG4-related lesions. SP, sclerosing pancreatitis, SC, sclerosing cholangitis. Figure 2Open in figure viewerPowerPoint Common hepatic duct and intra-hepatic biliary strictures of IgG4 associated sclerosing cholangitis: Patient had a diffusely irregular, narrow pancreatic duct characteristic of AIP. Serum IgG4 was elevated at 720 mg/dl (normal value 8-140 mg/dl). Histopathology As in the pancreas, biliary involvement by IgG4-related autoimmune disease can be diffuse or localized, producing either a generalized but irregular thickening or a tumefactive lesion.45 The histological appearance is similar in both situations: lymphoplasmacytic inflammation, fibrosis (often with a swirling or storiform arrangement) and obliterative phlebitis.40, 45, 49, 52, 54 Despite the dense periluminal inflammation, the biliary epithelium is usually intact (Fig. 3). This is in distinct contrast to PSC, which often produces mucosal erosion. In another contrast with PSC, the inflammatory process is often more dense at the periphery of the duct45, 49, 53 (Fig. 4). This phenomenon is partly due to dense inflammation in the walls of periductal vein branches (Fig. 5), but lymphoplasmacytic inflammation around nerve twigs and forming nodular infiltrates in periductal soft tissue are also characteristic features of IAC. While lymphocytes and plasma cells predominate, eosinophils can be numerous45, 52 and are occasionally numerically dominant. Neutrophils, commonly seen in PSC, are not a feature of IAC. Figure 3Open in figure viewerPowerPoint Dense periluminal infiltration by lymphocytes and plasma cells. The bile duct epithelium is intact. Figure 4Open in figure viewerPowerPoint Cross-section of common bile duct in IAC. The wall is thickened and fibrotic. The inflammation is particularly dense at the periphery of the duct, and extends into periductal soft tissue. Figure 5Open in figure viewerPowerPoint Periductal artery (upper right): the obliterated vein is in lower left, replaced by lymphoplasmacytic inflammation. Obliterative phlebitis is a nearly ubiquitous finding in both AIP and IAC. As the term implies, a dense infiltrate of lymphocytes and plasma cells surrounds and compresses the vein lumen, occasionally obliterating it entirely. The corresponding artery is not affected. Inflammation in vein walls is not specific to IgG4-related disease, but it is helpful in distinguishing IAC from PSC or cholangiocarcinoma, as it is not seen in those conditions. Immunohistochemical staining for IgG4 is a useful tool for confirming the diagnosis of IAC. (Fig. 6).53 Scoring criteria have not been established for the biliary tract, but reported experience indicates that extrahepatic ducts affected by IAC usually have more than 30 IgG4-positive plasma cells per high-power microscopic field, corresponding to a score of 3 in the 0-3 system in use for the pancreas.62 Figure 6Open in figure viewerPowerPoint IgG4 stain showing many positive cells around duct. Is it possible to diagnose IAC in an endoscopically obtained bile duct biopsy? The fact that the most helpful features tend to be deep in the bile duct wall works against this idea, but a combination of lymphoplasmacytic inflammation and increased staining for IgG4 in a bile duct biopsy has been used to diagnose IAC.52 The sensitivity and specifity of IgG4 immunostaining in bile duct biopsies have not been established. Hepatic pathology in IAC is variable. Tumefactive nodules have been described,45 and it is likely that at least some "inflammatory pseudotumors" of the liver are manifestations of intrahepatic IAC. In the absence of a mass, liver biopsies from patients with IAC may not show specific changes. Mild to moderate lymphocytic portal inflammation, often accompanied by portal fibrosis and ductular proliferation, has been reported,4, 19, 20, 33, 40, 49 but these changes could be secondary to extrahepatic biliary obstruction by IAC. Bile duct lesions (periductal fibrosis) and ductopenia have not been described in IAC, and their presence favors PSC. Portal infiltration by IgG4-positive plasma cells has been described in IAC,53 but our experience suggests that it is less common than in the pancreas or extrahepatic bile ducts. Lack of Association with IBD and Cholangiocarcinoma In contrast to classic PSC, which in vast majority of cases is associated with IBD,59 patients with IAC in almost all reported cases lack this association. Thus, based on the existing literature, the presence of IBD argues against the diagnosis of IAC. Cholangiocarcinoma is a complication of classic PSC that develops in up to 10%-30% of patients.59, 61, 63 However, development of CCA has not been reported to occur in patients with IAC. Although, follow-up has been rather short in many reported cases, a recent study of 388 cases with PSC in Japan found that none of the 28 IAC cases developed bile duct cancer.47 Thus, the lack of association of IAC with IBD and potentially CCA, which are the most common associated conditions in classic PSC, suggests that these disorders have different underlying pathophysiologies. Diagnosis Many patients who have turned out to have IAC have only been diagnosed after a major surgical resection with pancreatoduodenectomy.9, 19, 23, 24, 27, 28, 35, 45, 46, 49 The accumulating literature of case reports and case series will hopefully minimize the need for major abdominal surgery in order to diagnose this condition. Obstructive jaundice is an uncommon presentation in classic PSC and this presentation should raise suspicion of IAC. However, PSC patients may present with cholangiocarcinoma which is therefore a very important differential diagnosis in this context. IAC should be clinically suspected when biliary strictures are associated with pancreatic duct irregularity or other pancreatic disease or other organ involvement (e.g., retroperitoneal fibrosis or salivary gland enlargement) and serum IgG4 levels are elevated. Diagnosis is confirmed if biliary or other organ histology shows marked infiltration with IgG4 positive cells (>10 cells/hpf) or the stricture responds/resolves with steroid treatment. Treatment Accumulating evidence suggests that the bile duct lesions and the concomitant pancreatitis in patients with IAC improve with corticosteroid treatment which distinguishes IAC from PSC.5, 14, 20, 22, 30-38, 42, 48, 50-52, 54 Resolution of jaundice and improvement in liver tests associated with steroid treatment has been reported as well as resolution or improvement in biliary strictures seen on cholangiograms.5, 14, 22, 30-37, 42, 48, 50-52, 54 Most of the early literature of steroid responsiveness in patients with IAC consists of single case reports.5, 14, 20-22, 30 Erkelens et al. reported 4 cases with weight loss, jaundice, pancreatic enlargement, and multiple bile duct strictures, but without IBD, that were treated with cortiocosteroids.31 In all cases a complete clinical remission was observed with normalization of liver tests and resolution of intrahepatic and extrahepatic strictures.31 In some case series, the diagnosis of IAC has only become apparent after a surgical procedure and corticosteroids have not always been tried early on and evaluation of the efficacy of steroid therapy has not been available for all cases in some series. In 4 of 8 patients in whom corticosteroids were tried, steroids were effective in terms of clinical improvement and resolution of imaging abnormalities of the bile ducts and pancreas.34 In another study of 7 IAC patients, liver tests improved after steroid therapy and improvement in pancreatic swelling, bile duct strictures and retroperitoneal fibrosis was noted.40 In a retrospective study from Japan, obstructive jaundice resolved after steroids in all 5 patients with jaundice and the bile duct strictures improved to various degree in all 7 patients after steroid therapy.48 The bile ducts improved to normal diameter in 60% of patients whereas the recovery was only slight to moderate in 40%.48 However, pancreatic enlargement and irregular narrowing of the pancreatic duct had improved to almost normal size in all patients treated.48 Apart from cases series of IAC patients in whom therapy results have been published in English,31, 34, 40, 48, 49, 54 Kojima et al. reviewed cases reported in the Japanese literature with steroid response in 13 of 14 patients.42 Corticosteroids and other immunosuppressive agents have generally not been effective in classic PSC.64 However, some patients with PSC had clinical and/or biochemical improvement while on corticosteroid therapy.64 It is conceivable that in a subgroup of PSC patients, the disease process might be steroid responsive due to an important autoimmune etiology. The recent finding of elevated IgG4 levels in 9% of unselected PSC patients might identify such a subset of patients.58 However, only prospectively evaluated trials will provide information about whether IgG4 might represent a marker for steroid sensitivity in these patients. Based on the literature it is difficult to give recommendations on the dose and duration of corticosteroid therapy. However, most researchers have used steroids for 2-3 months with a starting dose of 40 mg of prednisolone for 4 weeks with tapering by 5 mg per week thereafter. Prognosis Although most case series do not report long-term follow-up of patients with IAC it seems that the prognosis of these patients is more favorable than that of patients with classic PSC. Resolution of biliary strictures associated with corticosteroid therapy as experienced in patients with IAC is rare in classic PSC. Comparison between patients with classic PSC and IAC in Japan revealed that no patient with IAC underwent liver transplantation during a prolonged follow-up whereas liver transplantation was performed in substantial number of patients with classic PSC.47 However, very limited data exists on the prognosis and the natural history of IAC and more long-term follow-up studies are needed to provide information on the prognosis. Only one case with liver failure necessitating liver transplantation has been reported in IAC.23 Furthermore, cholangiocarcinoma in patients with IAC was not observed in the largest case series reported47 whereas cholangiocarcinoma develops in up to 10%-30% of patients with classic PSC.59, 61, 63 Conclusions We have reviewed the newly emerging clinical entity we choose to name IgG4 associated cholangitis. There seems to be important clinical, biochemical and histological differences between IAC and classic PSC. Patients with IAC more often have a rather abrupt clinical presentation with obstructive jaundice in comparison with patients with classic PSC. In the majority of cases pancreatic involvement is present and the diagnosis is supported by high levels of IgG4 in serum and lymphoplasmacytic infiltration on histology of the affected bile ducts, pancreas and other affected organs. A corticosteroid trial should be considered in cases with clinical, biochemical and imaging features of IAC. However, a steroid trial should only be given to patients with negative work-up for known etiologies for other pancreatic or biliary disease such as pancreatic and biliary carcinoma. Steroids should only be used in patients in whom response can be assessed with biliary and pancreatic abnormalities on imaging and liver biochemistries. Measurement of IgG4 should be performed in all newly diagnosed patients with PSC and steroids should be tried in those with elevated levels and clinical, biochemical and cholangiographic assessments should be performed in clinical studies. More studies on this very interesting newly recognized clinical entity are clearly warranted. References 1 Bartholomew LG, Cain JC, Woolner LB, Utz DC, Ferris DO. Sclerosing cholangitis: its possible association with Riedel's struma and fibrous retroperitonitis. Report of two cases. N Engl J Med 1963; 269: 8– 12. 2 Wenger J, Gingrich GW. Mendeloff J. Sclerosing cholangitis—a manifestation of systemic disease. Increased serum gamma-globulin, follicular lymph node hyperplasia, and orbital pseudotumor. Arch Intern Med 1965; 116: 509– 514. 3 Comings DE, Skubi KB, Van Eyes J, Motulsky AG. Familial multifocal fibrosclerosis. Findings suggesting that retroperitoneal fibrosis, mediastinal fibrosis, sclerosing cholangitis, Riedel's thyroiditis, and pseudotumor of the orbit may be different manifestations of a single disease. Ann Intern Med 1967; 66: 884– 892. 4 Waldram R, Kopelman H, Tsantoulas D, Williams R. Chronic pancreatitis, sclerosing cholangitis, and sicca complex in two siblings. Lancet 1975; 1: 550– 552. 5 Sjogren I, Wengle B, Korsgren M. Primary sclerosing cholangitis associated with fibrosis of the submandibular glands and the pancreas. Acta Med Scand 1979; 205: 139– 141.

Background The diagnosis of autoimmune pancreatitis can be difficult and often requires a larger specimen than can be provided by FNA alone to determine if the tissue sample obtained with EUS trucut biopsy (TCB) is sufficient to allow adequate histologic review to establish the diagnosis of autoimmune pancreatitis. Methods EUS TCB was performed in patients presenting with obstructive jaundice who were suspected of having autoimmune pancreatitis based on their clinical, laboratory and imaging studies. The charts were retrospectively reviewed to determine the feasibility of TCB. Results Between August 2002 and June 2004, 3 patients with obstructive jaundice and suspected autoimmune pancreatitis (AIP) underwent EUS TCB. In each case, a diagnosis of pancreatic cancer also was considered, and surgical resection was the planned therapy before the patient underwent EUS TCB. Histologic review of the TCB specimens established the diagnosis of AIP in two patients and identified nonspecific changes of chronic pancreatitis in the third patient. EUS-guided FNA was performed in two of the 3 patients and failed to establish the diagnosis in either patient. Other than mild transient abdominal pain (n = 1), no complications were identified. Conclusions This preliminary study suggests that EUS TCB can safely establish the diagnosis of AIP. Doing so helps guide management and may help to avoid unnecessary surgery. Prospective studies are needed to verify these findings and to more clearly define the role of EUS TCB in these patients. The diagnosis of autoimmune pancreatitis can be difficult and often requires a larger specimen than can be provided by FNA alone to determine if the tissue sample obtained with EUS trucut biopsy (TCB) is sufficient to allow adequate histologic review to establish the diagnosis of autoimmune pancreatitis. EUS TCB was performed in patients presenting with obstructive jaundice who were suspected of having autoimmune pancreatitis based on their clinical, laboratory and imaging studies. The charts were retrospectively reviewed to determine the feasibility of TCB. Between August 2002 and June 2004, 3 patients with obstructive jaundice and suspected autoimmune pancreatitis (AIP) underwent EUS TCB. In each case, a diagnosis of pancreatic cancer also was considered, and surgical resection was the planned therapy before the patient underwent EUS TCB. Histologic review of the TCB specimens established the diagnosis of AIP in two patients and identified nonspecific changes of chronic pancreatitis in the third patient. EUS-guided FNA was performed in two of the 3 patients and failed to establish the diagnosis in either patient. Other than mild transient abdominal pain (n = 1), no complications were identified. This preliminary study suggests that EUS TCB can safely establish the diagnosis of AIP. Doing so helps guide management and may help to avoid unnecessary surgery. Prospective studies are needed to verify these findings and to more clearly define the role of EUS TCB in these patients.

Seventy-six patients with Barrett's esophagus were cared for during a 10-year period. Fifty-six patients (74%) presented with complications of the disease. There were 20 strictures, 7 giant ulcers, 11 cases of dysplasia, and 29 patients with carcinoma. In patients with benign disease, 93% had mechanically defective sphincters and 83% had peristaltic failure of the lower esophageal body. Esophageal pH monitoring showed excessive esophageal exposure to pH less than 4 in 93% and excessive exposure to pH more than 7 in 34% of the patients tested. Ninety-three per cent of patients with excessive alkaline exposure had complications, compared to only 44% with normal alkaline exposure (p less than 0.01). Gastric pH monitoring, serum gastrin levels, and gastric acid analysis supported a duodenal source for the alkaline exposure. Antireflux surgery was performed using Nissen fundoplication in 30, Belsey partial fundoplication in 3, and Collis-Belsey gastroplasty in 2. Six required resection with colon interposition. Good symptomatic control was achieved in 77% after antireflux surgery. Four patients had symptoms and signs of duodenogastric reflux; three required a bile diversion procedure. Fifteen patients had an en bloc curative resection with colon interposition. One patient with high-grade dysplasia on biopsy was found to have intramucosal carcinoma after simple esophagectomy. Five tumors were intramucosal, seven were intramural, and four were transmural. Lymph node involvement occurred only in the latter two. Actuarial survival 5 years after curative resection was 53%. Median survival time for patients after palliative resection or no resection was 12 months. Study of en bloc specimens indicated that extent of resection should be adapted to extent of disease: esophagectomy for intramucosal disease, en bloc esophagectomy with splenic preservation for intramural and transmural disease. Serum CEA was useful in detecting recurrent disease after surgery when the primary tumor stained positively for CEA.

To describe the clinical features of patients with eosinophilic esophagitis and the use of topical corticosteroids for treatment.We evaluated the charts of 21 patients with a diagnosis of eosinophilic esophagitis seen at the Mayo Clinic in Rochester, Minn, between September 1, 1999, and December 31, 2001. The diagnosis was based on the presence of a "ringed esophagus" or a tapered distal esophagus on upper endoscopy as well as the presence of a dense eosinophilic infiltrate on esophageal biopsy. All patients were treated with topical corticosteroids, and follow-up was performed by telephone interviews.The 15 men and 6 women ranged in age from 27 years to 66 years at diagnosis (mean, 36 [corrected] years). All had solid-food dysphagia for at least 6 years, and 15 patients had prior food impaction. Eighteen patients had either a ringed-appearing esophagus or smooth tapering in the distal esophagus. All patients had a dense eosinophilic infiltration (> 20 eosinophils per high-power field) in the mid or distal esophagus. Topical corticosteroid therapy for 6 weeks resulted in complete dysphagia relief in all patients and lasted a minimum of 4 months.Eosinophilic esophagitis is an entity associated with food dysphagia (predominantly in young adults) and a ringed or smooth tapered distal-appearing esophagus. Our study found no association with gastroesophageal reflux symptoms. Topical corticosteroid therapy was effective.

Herein, we show that the hematopoietic-specific GEF VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter. Interestingly, VAV1-positive tumors had a worse survival rate compared to VAV1-negative tumors. Surprisingly, even in the presence of oncogenic KRAS, VAV1 RNAi abrogates neoplastic cellular proliferation in vitro and in vivo, thus identifying Vav1 as a growth-stimulatory protein in this disease. Vav1 acts synergistically with the EGF receptor to stimulate pancreatic tumor cell proliferation. Mechanistically, the effects of Vav1 require its GEF activity and the activation of Rac1, PAK1, and NF-κB and involve cyclin D1 upregulation. Thus, the discovery of prooncogenic pathways regulated by Vav1 makes it an attractive target for therapeutic intervention.

Genetic epidemiology studies of colorectal cancer (CRC) can identify persons who are at inordinately high risk and who thereby might benefit from targeted early detection and primary prevention programs, inclusive of prophylactic surgery in selected cases. The discipline of molecular genetics has identified germline mutations that include APC in familial adenomatous polyposis (FAP) and mutator genes, namely MSH2, MLH1, PMS1, and PMS2 in hereditary nonpolyposis colorectal cancer (HNPCC). These discoveries have significantly enhanced our ability to identify individuals whose cancer destiny can literally be determined at birth. This review updates HNPCC's differential diagnosis, heterogeneity, tumor spectrum, newly found evidence of accelerated colonic adenoma to CRC, survival advantage, and currently available surveillance and management programs. Emphasis has been on how knowledge of the genetics and natural history of HNPCC can be used effectively to promote early diagnosis or prevention of cancer.

Primary genetic factors are etiologic in at least 5–10% of patients with colon cancer. The polyposis syndromes (FPC) are easily identified examples because of the spectacular number of polyps. The hereditary nonpolyposis syndromes (HNPCC), although five times more common than FPC, arc usually not recognized because they do not have such a distinctive clinical, premonitory genetic marker. Colorectal cancer expression was surveyed in 10 extended, thoroughly documented HNPCC kindreds. One hundred sixteen patients were found to have 183 colorectal cancers. Despite the striking family history, less than 5% were correctly treated by subtotal colectomy. This provided a unique opportunity to study the natural history. Five findings differed significantly (p < 0.05) from patients with sporadic colon cancer: (1) mean age of initial colon cancer diagnosed was 45.6 years; (2) 69.1% of first colon cancers were located proximal to the splenic flexure of the colon; (3) 18.1% had synchronous colon cancer; (4) 24.2% had metachronous colon cancer develop with life table analysis showing the risk for a metachronous lesion at 10 years to be 40%; and (5) only 23.3% of cancers were located in the sigmoid colon or rectum. Based on this data, it is recommended that the family history of all patients with a newly diagnosed colon cancer be evaluated for evidence of this syndrome. If an autosomal dominant inheritance pattern emerges, an in-depth genetic investigation is indicated. When HNPCC is confirmed, the following recommendations apply: a subtotal abdominal colectomy is indicated at the time of the initial colon cancer because of the risk of synchronous and metachronous lesions. The rectum should be spared in favor of careful lifetime surveillance because of the proclivity for proximal colon cancer involvement. As yet unaffected members of a newly diagnosed HNPCC kindred who are in the “direct genetic line” should be cautioned that they are at 50% risk and must begin an intensive surveillance program beginning in the third decade with careful attention to the right colon. Patients from newly diagnosed HNPCC families who have had a previous conventional colectomy for colon cancer should, at the very least, enter an intensive surveillance program; a prophylactic completion subtotal colectomy should be considered for patients who arc less than totally compliant.

Solid pseudopapillary neoplasms of the pancreas are rare malignant lesions of the pancreas that typically occur in young women. Large series from any one centre are notably absent in the literature. The aim of this study was to determine long-term outcomes of operative therapy.The records of all 14 patients diagnosed with pseudopapillary neoplasms of the pancreas over 17 years were reviewed.Thirteen of the 14 patients were female and the mean age at diagnosis was 30 years. Solid pseudopapillary neoplasm was suspected in only half of these patients before operation. On computed tomography, ultrasonography and/or magnetic resonance imaging, three lesions were solid, three were largely cystic, and five had solid and cystic components. All 14 patients underwent surgical exploration and curative resections were possible in 13, including distal pancreatectomy in nine, pancreaticoduodenectomy in three and resection of a local intraperitoneal recurrence in one patient. After follow-up ranging from 3 months to 20 years, 12 patients were alive, including one who had undergone re-exploration and resection of local and subcutaneous recurrences 9 years previously.Solid pseudopapillary neoplasm of the pancreas should be considered in the differential diagnosis of any solid or partly cystic pancreatic mass in women aged less than 35 years. An attempt at en bloc resection without formal lymphadenectomy should be undertaken, including resection of synchronous or metachronous distant metastases.

Hereditary non-polyposis colorectal cancer (HNPCC) predisposes to cancers of the colon, endometrium and several other extra-colonic sites in the absence of premonitory physical stigmata (Muir-Torre syndrome excepted). Discovery of the several DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2) holds the potential for determining the cancer destiny of patients, theoretically in utero. Pre-symptomatic DNA testing is now possible in patients from HNPCC families and will be clinically available once inexpensive and simple tests for these germ-line mutations have been effected. Genetic counseling will be mandatory, given the myriad socio-psychological, insurance, and potentially other personal issues which may impact this knowledge. New findings in the pathology of HNPCC, particularly an increased frequency of interval cancers and the likely accelerated rate of the adenoma to cancer sequence, indicate the need for more frequent colonoscopic surveillance with an option for prophylactic subtotal colectomy in germ-line-positive individuals.

Carney triad, as originally described in 1977, was the association of 3 tumors: gastric epithelioid leiomyosarcoma [later renamed gastrointestinal stromal tumor (GIST)], extra-adrenal paraganglioma, and pulmonary chondroma. The disorder affected mostly young women and was not familial. We studied the clinical and pathologic features of the gastric neoplasm in 104 patients with the syndrome. Most (88%) were young women (mean age, 22 y), and the usual presentation was gastric bleeding. The tumors, commonly antral-based (61%), were multifocal, and ranged from 0.2 to 18.0 cm in dimension. Most (86%) featured round and polygonal (epithelioid) cells. Metastasis occurred in 49 patients (47%): to gastric lymph nodes (29%), liver (25%), and peritoneum (13%). Immunopositivity was detected in the tumors tested as follows: KIT, 100%; CD34, 75%; PKCθ, 21%; PDGFRA, 90%; and smooth muscle actin, 6%. Fourteen patients (13%) died of metastatic GIST at a mean age of 45 years (range, 30 to 69 y). Estimated 10 and 40-year survivals were 100% and 73%, respectively. Median survival time was 26.5 years (range, 16 to 60 y). There was no correlation between the National Institutes of Health tumor risk classification and the tumor behavior. Compared with sporadic gastric GISTs, the gastric stromal tumor in Carney triad showed distinctive features: female predilection, young patient age, epithelioid cell predominance, multifocality, frequent lymph node metastasis, serial tumor occurrence, and unpredictable behavior. Thus, the Carney triad gastric stromal tumor is different clinically, pathologically, and behaviorally from sporadic gastric GIST.

Cellular changes associated with diabetic (DG) and idiopathic gastroparesis (IG) have recently been described from patients enrolled in the Gastroparesis Clinical Research Consortium. The association of these cellular changes with gastroparesis symptoms and gastric emptying is unknown. The aim of this study was to relate cellular changes to symptoms and gastric emptying in patients with gastroparesis.Earlier, using full thickness gastric body biopsies from 20 DG, 20 IG, and 20 matched controls, we found decreased interstitial cells of Cajal (ICC) and enteric nerves and an increase in immune cells in both DG and IG. Here, demographic, symptoms [gastroparesis cardinal symptom index score (GCSI)], and gastric emptying were related to cellular alterations using Pearson's correlation coefficients.Interstitial cells of Cajal counts inversely correlated with 4 h gastric retention in DG but not in IG (r = -0.6, P = 0.008, DG, r = 0.2, P = 0.4, IG). There was also a significant correlation between loss of ICC and enteric nerves in DG but not in IG (r = 0.5, P = 0.03 for DG, r = 0.3, P = 0.16, IG). Idiopathic gastroparesis with a myenteric immune infiltrate scored higher on the average GCSI (3.6 ± 0.7 vs 2.7 ± 0.9, P = 0.05) and nausea score (3.8 ± 0.9 vs 2.6 ± 1.0, P = 0.02) as compared to those without an infiltrate.In DG, loss of ICC is associated with delayed gastric emptying. Interstitial cells of Cajal or enteric nerve loss did not correlate with symptom severity. Overall clinical severity and nausea in IG is associated with a myenteric immune infiltrate. Thus, full thickness gastric biopsies can help define specific cellular abnormalities in gastroparesis, some of which are associated with physiological and clinical characteristics of gastroparesis.

Background & Aims: Little is known about subjects with idiopathic tumefactive chronic pancreatitis (TCP), that is, chronic pancreatitis whose clinical presentation, usually with a mass or obstructive jaundice, suggests cancer. Methods: We independently reviewed clinical data and histology of 45 TCP (27 idiopathic, 18 alcohol induced) resected at Mayo Clinic (January 1985-March 2001). Follow-up data were obtained from medical records and mailed questionnaires. Results: Compared with alcoholic subjects, idiopathic TCP patients were older (58 ± 2 vs. 48 ± 3 yr, P < 0.001), had shorter symptom duration (median 3 vs. 24 wk, P < 0.001), were more likely to have no or mild abdominal pain (70% vs. 17%, P = 0.001), and were more often jaundiced (67% vs. 33%, P = 0.02). Three distinct histologic patterns were identified in TCP. Typical CP (n = 19) showed lobular atrophy, fat necrosis, and ductal changes (dilatation, protein plugs, and stones). Lymphoplasmacytic sclerosing pancreatitis (LPSP) (n = 14) was characterized by periductal lymphoplasmacytic infiltration, obliterative phlebitis, and cholangitis with edema. Idiopathic duct-centric CP (IDCP) (n = 12) had neutrophil-predominant lobular inflammation, without phlebitis. On correlation of clinical and histologic diagnosis, 17 of 18 (94%) patients with alcohol-induced TCP had typical CP, and 25 of 27 (93%) with idiopathic TCP had LPSP or IDCP. LPSP and IDCP were indistinguishable clinically except for higher incidence of jaundice in LPSP (93% vs. 42%, P = 0.005). In idiopathic TCP no recurrence of symptoms was observed after resection (median follow-up 49 mo). Conclusions: Idiopathic TCP is clinically and histologically distinct from alcohol-induced TCP. It is unclear whether LPSP and IDCP, 2 unique patterns of histologic injury observed in idiopathic TCP, are part of the spectrum of the same disease or represent 2 or more different entities. Resection of mass prevents recurrence of symptoms in idiopathic TCP.

Despite scattered case reports, the prevalence of inflammatory bowel disease (IBD) in patients with autoimmune pancreatitis (AIP) is unknown. We sought to better characterize the putative association between the conditions.Medical records of 71 patients meeting accepted criteria for AIP were reviewed to identify those with endoscopic and histological evidence of IBD. Colon samples in patients with both AIP and IBD were immunostained to identify IgG4-positive cells.Four patients with AIP (5.6%) had a diagnosis of IBD: 3 had ulcerative colitis (UC) and 1 had Crohn's disease (CD). The diagnosis of IBD preceded or was simultaneous to that of AIP. Two AIP-UC patients treated for AIP with prednisone had a recurrence of AIP, and 1 required 6-mercaptopurine for long-term corticosteroid-sparing treatment. Two AIP-IBD patients underwent Whipple resections, and 1 had recurrent AIP. All 3 patients with UC presented with pancolitis, and 2 required colectomy. Colon samples from 1 patient with UC and 1 patient with CD were available for review. Increased numbers of IgG4-positive cells (10 per high-power field) were noted on the colon sample from the patient with UC.Almost 6% of patients with proven AIP had a diagnosis of IBD, compared to a prevalence of approximately 0.4%-0.5% in the general population, potentially implying a 12-15-fold increase in risk. Patients with both AIP and IBD may have increased extent and severity of IBD. The finding of IgG4-positive cells on colon biopsy suggests that IBD may represent an extrapancreatic manifestation of AIP.

Biliary strictures occur in a third of patients with autoimmune pancreatitis and have been termed immunoglobulin G subclass 4 (IgG4) associated cholangitis (IAC). IAC often responds to steroid therapy.A patient with autoimmune pancreatitis and (IAC) refractory to steroids and 6-mercaptopurine was treated with rituximab, a monoclonal antibody directed against the CD20 antigen on B lymphocytes.The patient's biliary strictures improved after rituximab therapy, permitting removal of his biliary stents. Systemic manifestations of IgG4-associated disease also improved.Rituximab may be a treatment option for patients with refractory or recurrent autoimmune pancreatitis or IAC.

Lymphocyte-rich gastric carcinomas may have a better prognosis than cancers without a pronounced host inflammatory response. Two subsets of gastric cancer-Epstein-Barr virus-positive and microsatellite instability high-have been associated with a lymphocyte-rich phenotype. We assessed relationships between tumor-infiltrating lymphocytes, Epstein-Barr virus status, microsatellite instability status, and cancer-specific survival in 110 resected gastric cancers. Seven patients had Epstein-Barr virus-positive cancer, including 4 (3.7%) of 107 consecutive patients. Tumors from 17 patients (16%) were designated microsatellite instability high on the basis of negative immunohistochemical staining for MLH1; all tumors had intact expression of MSH2 and MSH6. Epstein-Barr virus-positive cancers had increased tumor-infiltrating lymphocytes compared with Epstein-Barr virus-negative cancers (median 450/10 HPF versus 21/10 HPF, P <.001). Microsatellite instability-high cancers also had increased tumor-infiltrating lymphocytes compared with non-microsatellite instability-high cancers (median 150/10 HPF versus 20/HPF, P <.001). Microsatellite instability-high cancers affected older patients and were more likely to be intestinal in the Lauren classification and expanding in the Ming classification. By univariate analysis, decreased risk of death from gastric cancer was significantly associated with low tumor stage, expanding growth pattern, increasing tumor-infiltrating lymphocyte count, and microsatellite instability-high status. High tumor-infiltrating lymphocyte count and microsatellite instability-high status retained statistical significance as favorable prognostic factors after adjustment for tumor stage in multivariate analysis. Tumor-infiltrating lymphocyte count retained statistical significance as a favorable prognostic factor after adjustment for microsatellite instability-high status; but microsatellite instability-high status did not remain a significant independent prognosticator after adjustment for tumor-infiltrating lymphocyte count. The association between microsatellite instability-high cancers and high tumor-infiltrating lymphocyte counts may account for the association of microsatellite instability-high gastric cancers with improved survival.

Primary sclerosing cholangitis (PSC) carries an increased risk (10% to 20%) of hepatobiliary malignancy, especially cholangiocarcinoma (CC). Dysplasia, adenomas, and carcinomas of the gallbladder have been described in PSC but are less common than bile duct carcinomas. However, the prevalence and risk factors for gallbladder neoplasia among patients with PSC undergoing orthotopic liver transplantation (OLT) have not been well studied. We evaluated 72 gallbladders from 100 consecutive liver explants for PSC, including 66 cholecystectomies performed at the time of OLT and 6 performed before OLT. All specimens were totally embedded for histologic examination. We evaluated the following histologic features: presence of diffuse lymphoplasmacytic chronic cholecystitis, pyloric metaplasia, intestinal metaplasia, dysplasia (low-grade or high-grade), and adenocarcinoma. Gallbladder dysplasia and adenocarcinoma were correlated with several clinicopathologic parameters using Fisher exact test and t test, including: (1) sex, (2) age, (3) PSC duration, (4) inflammatory bowel disease (IBD) at time of OLT, and (5) concomitant bile duct dysplasia or carcinoma. Lymphoplasmacytic chronic cholecystitis was present in 35 (49%), pyloric metaplasia in 69 (96%), intestinal metaplasia in 36 (50%), dysplasia in 27 (37%; low-grade in 12 and high-grade in 15), and adenocarcinoma in 10 (14%; 2 with lamina propria invasion and 8 with invasion into muscularis or adventitia). Gallbladder carcinoma was associated with intrahepatic bile duct dysplasia (P=0.001), CC (P=0.023), and IBD (P=0.03). Gallbladder dysplasia was associated with hilar/intrahepatic bile duct dysplasia (P=0.0006), CC (P=0.028), IBD (P=0.0014), and older age at OLT (P=0.007). Neither gallbladder carcinoma nor dysplasia had a significant association with sex or PSC duration. These results indicate that complete histologic evaluation of gallbladders in patients undergoing transplantation for PSC yields high frequencies of inflammatory, metaplastic, and neoplastic changes. The strong correlation between gallbladder dysplasia/adenocarcinoma and bile duct dysplasia/CC supports the concept of a neoplastic “field effect” along the intrahepatic and extrahepatic biliary tract in PSC.

Autoimmune pancreatitis (AP) is one manifestation of a systemic, steroid-responsive disease with elevated serum IgG4 and characteristic histopathology, including increased IgG4-positive (+) plasma cells in the tissue. The histopathology of pulmonary IgG4 disease has not been well established. Six lung biopsies from patients with documented AP were studied, along with 12 additional cases showing similar pulmonary histopathology. For comparison, we examined Erdheim-Chester disease (n=3), pulmonary Sjögren syndrome (n=19), inflammatory myofibroblastic tumor (n=10), various inflammatory and interstitial lung disease (n=61), and nodal or extranodal Rosai-Dorfman disease (RD) in adults (n=8). All cases were stained for IgG4 and scored as 1, 2, and 3 as described in AP according to the following criteria: 0, <5 (per high power field); 1, 5 to 10; 2, 11 to 30; and 3, >30. Five lung biopsies from AP patients showed IgG4 score of 3, and 1 had a score of 2. Consistent findings in lung biopsies of AP patients included endothelialitis of pulmonary vessels, active fibrosis, lymphangitic inflammatory infiltrates rich in plasma cells and histiocytes with or without nodule formation, and fibrinous pleuritis. Prominent lymphatic dilatation with histiocytes showing emperipolesis of lymphocytes was also seen. All 12 additional cases showing these histologic features also had the IgG4 score of 2 or 3. Among other conditions, an IgG4 score of 2 or 3 was seen in 6 of 8 RD, 4 of 10 inflammatory myofibroblastic tumors, and 8 of 61 inflammatory and interstitial lung disease, but in none of the rest. In conclusion, distinctive pulmonary histopathology was associated with increased IgG4+ cells in both AP patients and those unknown for AP status. The significance of increased IgG4+ cells in high proportion of RD cases merits further study as does overlap of RD and IgG4 disease.

<h3>Objective</h3> To assess the effect of R0 resection margin status and R0 en bloc resection in pancreatoduodenectomy outcomes. <h3>Design</h3> Retrospective medical record review. <h3>Setting</h3> Mayo Clinic, Rochester, Minnesota. <h3>Patients</h3> Patients who underwent pancreatoduodenectomy for pancreatic adenocarcinoma at our institution between January 1, 1981, and December 31, 2007, were identified and their medical records were reviewed. <h3>Main Outcome Measure</h3> Median survival times. <h3>Results</h3> A total of 617 patients underwent pancreatoduodenectomy. Median survival times after R0 en bloc resection (n = 411), R0 non–en bloc resection (n = 57), R1 resection (n = 127), and R2 resection (n = 22) were 19, 18, 15, and 10 months, respectively (<i>P</i> &lt; .001). A positive resection margin was associated with death (<i>P</i> = .01). No difference in survival time was found between patients undergoing R0 en bloc and R0 resections after reexcision of an initial positive margin (hazard ratio, 1.19; 95% confidence interval, 0.87-1.64;<i>P</i> = .28). <h3>Conclusions</h3> R0 resection remains an important prognostic factor. Achieving R0 status by initial en bloc resection or reexcision results in similar long-term survival.

The objective of this study was to evaluate and validate cyst fluid carcinoembyronic antigen (CEA) and amylase in differentiating (1) nonmucinous from mucinous pancreatic cystic lesions (PCLs), (2) benign mucinous from malignant mucinous PCLs, and (3) pseudocysts from nonpseudocysts (amylase only).A retrospective analysis of patients with histologically confirmed PCLs from February 1996 to April 2007 was performed. Cyst fluid CEA (n=124) and/or amylase (n=91) were measured and correlated to cyst type.Carcinoembyronic antigen levels (P=0.0001), but not amylase, were higher in mucinous versus nonmucinous cysts. The sensitivity, specificity, and diagnostic accuracy of CEA 200 ng/mL or greater for the diagnosis of mucinous PCLs were 60%, 93%, and 72%, respectively. Carcinoembyronic antigen levels did not differentiate benign from malignant mucinous cysts. Whereas amylase levels were higher in pseudocysts than nonpseudocysts (P=0.009), 54% of noninflammatory PCLs had a level greater than 250 IU/L, including mucinous cystic neoplasms (median, 6800 IU/L; interquartile range, 70-25,295 IU/L). Malignant mucinous cysts had lower amylase levels than benign mucinous cysts (P=0.0008).Cyst fluid CEA and amylase levels are suggestive but not diagnostic in differentiating PCLs. Unlike CEA, amylase may help differentiate benign from malignant mucinous cysts. Novel biomarkers are needed.

Abstract Purpose: We have shown recently that glycogen synthase kinase-3 (GSK-3) β regulates nuclear factor-κB (NF-κB)–mediated pancreatic cancer cell survival and proliferation in vitro. Our objective was to determine the localization of GSK-3β in pancreatic cancer cells and assess the antitumor effect of GSK-3 inhibition in vivo to improve our understanding of the mechanism by which GSK-3β affects NF-κB activity in pancreatic cancer. Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the localization of GSK-3β in human pancreatic tumors. We studied the effect of GSK-3 inhibition on tumor growth, cancer cell proliferation, and survival in established CAPAN2 tumor xenografts using a tumor regrowth delay assay, Western blotting, bromodeoxyuridine incorporation, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling. Results: We found nuclear accumulation of GSK-3β in pancreatic cancer cell lines and in 62 of 122 (51%) human pancreatic adenocarcinomas. GSK-3β nuclear accumulation is significantly correlated with human pancreatic cancer dedifferentiation. We have found that active GSK-3β can accumulate in the nucleus of pancreatic cancer cells and that inhibition of GSK-3 kinase activity represses its nuclear accumulation via proteasomal degradation within the nucleus. Lastly, we have found that inhibition of GSK-3 arrests pancreatic tumor growth in vivo and decreases NF-κB-mediated pancreatic cancer cell survival and proliferation in established tumor xenografts. Conclusions: Our results show the antitumor effect of GSK-3 inhibition in vivo, identify GSK-3β nuclear accumulation as a hallmark of poorly differentiated pancreatic adenocarcinoma, and provide new insight into the mechanism by which GSK-3β regulates NF-κB activity in pancreatic cancer.

IgG4-related disease (IgG4-RD) is a systemic immune-mediated disease that typically manifests as fibro-inflammatory masses that can affect nearly any organ system. Renal involvement by IgG4-RD usually takes the form of IgG4-related tubulointerstitial nephritis, but cases of membranous glomerulonephritis (MGN) have also been described. Here we present a series of 9 patients (mean age at diagnosis 58 years) with MGN associated with IgG4-RD. All patients showed MGN on biopsy, presented with proteinuria (mean 8.3 g/day), and most had elevated serum creatinine (mean 2.2 mg/dl). Seven patients had known extrarenal involvement by IgG4-RD, with 5 patients having concurrent IgG4-related tubulointerstitial nephritis. Immunohistochemical analysis for the phospholipase A2 receptor, a marker of primary MGN, was negative in all 8 biopsies so examined. Six of 7 patients with available follow-up (mean 39 months) were treated with immunosuppressive agents; one untreated patient developed end-stage renal disease and underwent transplantation, without recurrence at 12 years after transplant. All 6 treated patients showed decreased proteinuria (mean 1.2 g/day), and most showed decreased serum creatinine (mean 1.4 mg/dl). Thus, MGN should be included in the spectrum of IgG4-RD and should be suspected in proteinuric IgG4-RD patients. Conversely, patients with MGN and an appropriate clinical history should be evaluated for IgG4-RD.

Abstract Purpose: Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer–derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion. Experimental Methods: We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown. Results: Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. Conclusions: Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin+/CA19-9+ exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response. Clin Cancer Res; 21(7); 1722–33. ©2014 AACR. See related commentary by Korc, p. 1508

HNPCC is an autosomal dominantly inherited disorder with proclivity to early onset colorectal cancer in the absence of multiple polyps of the colon. There is a predilection for proximal colonic location (70 per cent) and an excess of synchronous and metachronous colorectal cancers. HNPCC is subdivided into Lynch syndrome I, which is restricted to site-specific colon cancer susceptibility, and Lynch syndrome II, which shows all of the features of Lynch syndrome I, but in addition, patients are at inordinately increased risk for carcinoma of the endometrium, ovary, and other anatomic sites. The frequency of HNPCC is conservatively estimated to be 4 to 6 per cent of the total colorectal cancer burden. Because of the fact that the family history is underreported almost uniformly in medical practice, we believe that the true frequency of this disease may be much greater. Heterogeneity may be extant with respect to tumor association, in that in certain Lynch syndrome II kindreds, carcinoma of the pancreas, kidney, breast, and other anatomic sites may predominate. Knowledge of the natural history of HNPCC predicates surveillance and management strategies. Thus, because of the early onset of and proximal predilection for colorectal cancer, we recommend initiation of colonscopy at age 25 and annually thereafter. We also recommend guaiac testing of the stool at least twice a year. In the case of Lynch syndrome II, in addition to colonscopy, we recommend intensive surveillance for the endometrium, including aspiration biopsies. Other targeted organs, depending on the tumor spectrum in the family, should be given priority attention. Because of an excess of synchronous and metachronous colorectal cancer in HNPCC, subtotal colectomy with ileorectal anastomosis is the treatment of choice for initial colorectal cancer. In women presenting with initial colorectal cancer who have completed their families, consideration should be given to prophylactic hysterectomy and bilateral salpingo-oophorectomy at the time of surgery for colorectal cancer. Needed are biomarkers of acceptable sensitivity and specificity for the genotype, because HNPCC lacks premonitory physical signs. We believe that increased knowledge about colorectal cancer etiology and carcinogenesis can be attained through the study of families prone to the Lynch syndromes.

Objectives: To develop and validate histologic diagnostic criteria for autoimmune pancreatitis (AIP) and its types. Methods: Thirteen pathologists participated in this 2-phase study to develop diagnostic criteria for AIP types 1 and 2 (phase 1) and validate them (phase 2). A virtual library of 40 resected pancreata with AIP and other forms of chronic pancreatitis (CP) was constructed. Readers reviewed the slides online and filled out a questionnaire for histopathologic findings and diagnosis. Results: Diagnostic criteria for AIP and its types were proposed according to the results from the top 5 reviewers in phase 1. The interobserver agreement was significantly improved in phase 2 by applying the proposed diagnostic criteria. Features distinguishing AIP from alcoholic and obstructive forms of CP were periductal lymphoplasmacytic infiltrate, inflamed cellular stroma with storiform fibrosis, obliterative phlebitis, and granulocytic epithelial lesions. Although there was overlap, 2 types of AIP were recognized. Type 1 had dense lymphoplasmacytic infiltrate with storiform fibrosis and obliterative phlebitis, whereas type 2 was distinguished from type 1 by the presence of granulocytic epithelial lesions. Conclusions: Autoimmune pancreatitis can be distinguished from other forms of CP with substantial interobserver agreement. The 2 types of AIP can be distinguished by the proposed consensus histopathologic diagnostic criteria.

New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer.Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls).Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not.Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.

Inflammatory bowel disease is characterized by chronic inflammation which predisposes to colorectal cancer. The mechanisms by which inflammation promotes tumorigenesis are not fully known. We aimed to investigate the links between colonic inflammation and tumorigenesis via epigenetic gene silencing. Colon cancer specimens were assessed for the expression of DNA methyltransferase-1 (DNMT-1) using immunohistochemistry. Colorectal carcinoma cell lines were assessed for DNMT1 expression, methylcytosine content, promoter methylation, gene expression, and tumorigenesis in response to interleukin (IL)-6. DNMT1 was expressed at higher levels in both the peritumoral stroma and tumor in inflammatory bowel disease-associated cancers compared with sporadic colon cancers. IL-6 treatment of colon cancer cells resulted in an increase in DNMT1 expression, independent of de novo gene expression. IL-6 increased the methylation of promoter regions of genes associated with tumor suppression, adhesion, and apoptosis resistance. Expression of a subset of these genes was downregulated by IL-6, an effect that was prevented by preincubation with 5-azadeoxycytidine, a DNMT1 inhibitor. Anchorage-independent growth and migration of colon cancer cells was also increased by IL-6 in a 5-azadeoxycytidine-sensitive manner. Our results indicate that DNMT-mediated gene silencing may play a role in inflammation-associated colon tumorigenesis.

Purpose To evaluate the diagnostic performance and examination success rate of magnetic resonance (MR) elastography and vibration-controlled transient elastography (VCTE) in the detection of hepatic fibrosis in patients with severe to morbid obesity. Materials and Methods This prospective and HIPAA-compliant study was approved by the institutional review board. A total of 111 patients (71 women, 40 men) participated. Written informed consent was obtained from all patients. Patients underwent MR elastography with two readers and VCTE with three observers to acquire liver stiffness measurements for liver fibrosis assessment. The results were compared with those from liver biopsy. Each pathology specimen was evaluated by two hepatopathologists according to the METAVIR scoring system or Brunt classification when appropriate. All imaging observers were blinded to the biopsy results, and all hepatopathologists were blinded to the imaging results. Examination success rate, interobserver agreement, and diagnostic accuracy for fibrosis detection were assessed. Results In this obese patient population (mean body mass index = 40.3 kg/m2; 95% confidence interval [CI]: 38.7 kg/m2, 41.8 kg/m2]), the examination success rate was 95.8% (92 of 96 patients) for MR elastography and 81.3% (78 of 96 patients) or 88.5% (85 of 96 patients) for VCTE. Interobserver agreement was higher with MR elastography than with biopsy (intraclass correlation coefficient, 0.95 vs 0.89). In patients with successful MR elastography and VCTE examinations (excluding unreliable VCTE examinations), both MR elastography and VCTE had excellent diagnostic accuracy in the detection of clinically significant hepatic fibrosis (stage F2-F4) (mean area under the curve: 0.93 [95% CI: 0.85, 0.97] vs 0.91 [95% CI: 0.83, 0.96]; P = .551). Conclusion In this obese patient population, both MR elastography and VCTE had excellent diagnostic performance for assessing hepatic fibrosis; MR elastography was more technically reliable than VCTE and had a higher interobserver agreement than liver biopsy. © RSNA, 2016 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on January 25, 2017.

Changes in miRNA expression are a common feature in colon cancer. Those changes occurring in the transition from normal to adenoma and from adenoma to carcinoma, however, have not been well defined. Additionally, miRNA changes among tumor subgroups of colon cancer have also not been adequately evaluated. In this study, we examined the global miRNA expression in 315 samples that included 52 normal colonic mucosa, 41 tubulovillous adenomas, 158 adenocarcinomas with proficient DNA mismatch repair (pMMR) selected for stage and age of onset, and 64 adenocarcinomas with defective DNA mismatch repair (dMMR) selected for sporadic (n = 53) and inherited colon cancer (n = 11). Sporadic dMMR tumors all had MLH1 inactivation due to promoter hypermethylation. Unsupervised PCA and cluster analysis demonstrated that normal colon tissue, adenomas, pMMR carcinomas and dMMR carcinomas were all clearly discernable. The majority of miRNAs that were differentially expressed between normal and polyp were also differentially expressed with a similar magnitude in the comparison of normal to both the pMMR and dMMR tumor groups, suggesting a stepwise progression for transformation from normal colon to carcinoma. Among the miRNAs demonstrating the largest fold up- or down-regulated changes (≥4), four novel (miR-31, miR-1, miR-9 and miR-99a) and two previously reported (miR-137 and miR-135b) miRNAs were identified in the normal/adenoma comparison. All but one of these (miR-99a) demonstrated similar expression differences in the two normal/carcinoma comparisons, suggesting that these early tumor changes are important in both the pMMR- and dMMR-derived cancers. The comparison between pMMR and dMMR tumors identified four miRNAs (miR-31, miR-552, miR-592 and miR-224) with statistically significant expression differences (≥2-fold change).

Background & AimsManagement of eosinophilic esophagitis (EoE) requires repeated endoscopic collection of mucosal samples to assess disease activity and response to therapy. An easier and less expensive means of monitoring of EoE is required. We compared the accuracy, safety, and tolerability of sample collection via Cytosponge (an ingestible gelatin capsule comprising compressed mesh attached to a string) with those of endoscopy for assessment of EoE.MethodsEsophageal tissues were collected from 20 patients with EoE (all with dysphagia, 15 with stricture, 13 with active EoE) via Cytosponge and then by endoscopy. Number of eosinophils/high-power field and levels of eosinophil-derived neurotoxin were determined; hematoxylin-eosin staining was performed. We compared the adequacy, diagnostic accuracy, safety, and patient preference for sample collection via Cytosponge vs endoscopy procedures.ResultsAll 20 samples collected by Cytosponge were adequate for analysis. By using a cutoff value of 15 eosinophils/high power field, analysis of samples collected by Cytosponge identified 11 of the 13 individuals with active EoE (83%); additional features such as abscesses were also identified. Numbers of eosinophils in samples collected by Cytosponge correlated with those in samples collected by endoscopy (r = 0.50, P = .025). Analysis of tissues collected by Cytosponge identified 4 of the 7 patients without active EoE (57% specificity), as well as 3 cases of active EoE not identified by analysis of endoscopy samples. Including information on level of eosinophil-derived neurotoxin did not increase the accuracy of diagnosis. No complications occurred during the Cytosponge procedure, which was preferred by all patients, compared with endoscopy.ConclusionsIn a feasibility study, the Cytosponge is a safe and well-tolerated method for collecting near mucosal specimens. Analysis of numbers of eosinophils/high-power field identified patients with active EoE with 83% sensitivity. Larger studies are needed to establish the efficacy and safety of this method of esophageal tissue collection. ClinicalTrials.gov number: NCT01585103. Management of eosinophilic esophagitis (EoE) requires repeated endoscopic collection of mucosal samples to assess disease activity and response to therapy. An easier and less expensive means of monitoring of EoE is required. We compared the accuracy, safety, and tolerability of sample collection via Cytosponge (an ingestible gelatin capsule comprising compressed mesh attached to a string) with those of endoscopy for assessment of EoE. Esophageal tissues were collected from 20 patients with EoE (all with dysphagia, 15 with stricture, 13 with active EoE) via Cytosponge and then by endoscopy. Number of eosinophils/high-power field and levels of eosinophil-derived neurotoxin were determined; hematoxylin-eosin staining was performed. We compared the adequacy, diagnostic accuracy, safety, and patient preference for sample collection via Cytosponge vs endoscopy procedures. All 20 samples collected by Cytosponge were adequate for analysis. By using a cutoff value of 15 eosinophils/high power field, analysis of samples collected by Cytosponge identified 11 of the 13 individuals with active EoE (83%); additional features such as abscesses were also identified. Numbers of eosinophils in samples collected by Cytosponge correlated with those in samples collected by endoscopy (r = 0.50, P = .025). Analysis of tissues collected by Cytosponge identified 4 of the 7 patients without active EoE (57% specificity), as well as 3 cases of active EoE not identified by analysis of endoscopy samples. Including information on level of eosinophil-derived neurotoxin did not increase the accuracy of diagnosis. No complications occurred during the Cytosponge procedure, which was preferred by all patients, compared with endoscopy. In a feasibility study, the Cytosponge is a safe and well-tolerated method for collecting near mucosal specimens. Analysis of numbers of eosinophils/high-power field identified patients with active EoE with 83% sensitivity. Larger studies are needed to establish the efficacy and safety of this method of esophageal tissue collection. ClinicalTrials.gov number: NCT01585103.

Background & AimsPenetration of the esophageal epithelium by food antigens is an early event in the pathogenesis of eosinophilic esophagitis (EoE), but the precise relationship among eosinophilia, dilated intercellular spaces (DIS), and decreased barrier function is unclear. We investigated the correlation between site-specific mucosal impedance (MI) measurements of ion flux and esophageal histology, and whether MI measurements can be used to distinguish between patients with active and inactive EoE.MethodsMI was measured (in Ω) in 10 patients with active EoE (>15 eosinophils [eos]/high-power field [HPF]) and in 10 with inactive EoE (<15 eos/HPF, as a result of treatment), and mucosal biopsy specimens were collected from 4 esophageal sites (2, 5, 10, and 15 cm above the Z-line). MI also was measured in 10 individuals without esophageal symptoms (controls). MI measurements, eos/HPF, and DIS grade were compared among patients with EoE and controls.ResultsThe esophageal MI values were significantly lower in patients with active EoE (1909 Ω) compared with inactive EoE (4349 Ω) or controls (5530 Ω) (P < .001). Biopsy specimens from 4 patients with active EoE contained fewer than 15 eos/HPF and lower-grade DIS than in patients with active disease. There were significant inverse correlations between MI and eos/HPF (rs = -.584), as well as between MI and DIS (rs = -.531; P < .001). The MI cut-off value of 2300 Ω identified patients with active EoE with 90% sensitivity and 91% specificity, and high-grade DIS with 89% sensitivity and 82% specificity.ConclusionsIn patients with EoE, eosinophilia and DIS correlate with MI measurements of ion flux. Endoscopic MI measurement in the esophagus is safe and easy to perform, and can be used to assess activity of diseases such as EoE. Penetration of the esophageal epithelium by food antigens is an early event in the pathogenesis of eosinophilic esophagitis (EoE), but the precise relationship among eosinophilia, dilated intercellular spaces (DIS), and decreased barrier function is unclear. We investigated the correlation between site-specific mucosal impedance (MI) measurements of ion flux and esophageal histology, and whether MI measurements can be used to distinguish between patients with active and inactive EoE. MI was measured (in Ω) in 10 patients with active EoE (>15 eosinophils [eos]/high-power field [HPF]) and in 10 with inactive EoE (<15 eos/HPF, as a result of treatment), and mucosal biopsy specimens were collected from 4 esophageal sites (2, 5, 10, and 15 cm above the Z-line). MI also was measured in 10 individuals without esophageal symptoms (controls). MI measurements, eos/HPF, and DIS grade were compared among patients with EoE and controls. The esophageal MI values were significantly lower in patients with active EoE (1909 Ω) compared with inactive EoE (4349 Ω) or controls (5530 Ω) (P < .001). Biopsy specimens from 4 patients with active EoE contained fewer than 15 eos/HPF and lower-grade DIS than in patients with active disease. There were significant inverse correlations between MI and eos/HPF (rs = -.584), as well as between MI and DIS (rs = -.531; P < .001). The MI cut-off value of 2300 Ω identified patients with active EoE with 90% sensitivity and 91% specificity, and high-grade DIS with 89% sensitivity and 82% specificity. In patients with EoE, eosinophilia and DIS correlate with MI measurements of ion flux. Endoscopic MI measurement in the esophagus is safe and easy to perform, and can be used to assess activity of diseases such as EoE.

Sclerosing cholangitis can be primary (PSC) or secondary. One unusual cause of secondary sclerosing cholangitis is the newly recognized entity of IgG4-associated cholangitis. The prevalence and significance of IgG4+ plasma cells in patients, who are clinically and radiologically classified as PSC, however, are unknown. Clinical information and histology of liver explants of 98 consecutive liver transplants performed for PSC were reviewed. IgG4 immunohistochemical stain was performed on sections from hilar areas that contained large bile ducts and corresponding cholecystectomy specimens (available in 74 cases). Serum IgG4 levels were measured in stored serum from 81 cases. Tissue IgG4 positivity (≥10 IgG4+ plasma cells/high power field) was correlated with clinical features (age, sex, presence of inflammatory bowel disease and cholangiocarcinoma, pancreatogram, PSC duration, PSC recurrence after transplant, and number of acute rejection episodes) and histologic findings (periductal lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis) in the liver explants. Twenty-three (23%) liver explants showed periductal infiltration with IgG4+ plasma cells. Eighteen cases (22%) had elevated serum IgG4 levels, including 8 without tissue IgG4 positivity. All cases showed dense periductal fibrosis; none had storiform fibrosis or obliterative phlebitis. IgG4 positivity in the liver strongly correlated with moderate-to-marked periductal lymphoplasmacytic inflammation (P=0.002). Clinically, IgG4 positivity in tissue, but not in serum, was correlated with shorter PSC duration before transplant and higher risk of recurrence after transplant. Nearly one quarter of explanted livers that carry a clinical diagnosis of PSC contain increased IgG4+ periductal plasma cell infiltrates and positive serum IgG4 levels. However, none of the explants show histologic features diagnostic of IgG4-associated cholangitis. PSC with tissue IgG4 positivity has a more aggressive clinical course manifested by shorter time to transplant and a higher likelihood of recurrence than IgG4 negative PSC.

Eosinophilic gastroenteritis (EG) is a rare disorder characterized by eosinophilic infiltration of the gastrointestinal (GI) tract. Despite the increasing prevalence of eosinophilic GI disorders, the epidemiology of EG has not been well studied. We evaluated the clinical spectrum of EG.We reviewed data from patients diagnosed with EG, allergic gastroenteropathy, or eosinophilia and referred to gastroenterologists from 1987 to 2007 (n = 59; 52 with mucosal, 3 with muscularis, and 4 with subserosal disease). The study included subjects diagnosed with EG and those with a history that suggested EG, defined by GI symptoms; eosinophilic infiltration of the GI tract, eosinophilic ascites, or characteristic radiographic findings with eosinophilia; and no parasitic or extraintestinal disease. Findings were compared with those from patients with unexplained GI symptoms and peripheral eosinophilia (n = 11).Associations between clinical variables and EG subgroups did not differ between patients with EG and peripheral eosinophilia. Fifty percent of patients with EG who underwent food allergy testing had a positive test result; only 32% of those with EG who underwent radiographic imaging had positive test results. Patients with EG received steroid therapy; 75% with mucosal, 67% with muscle, and 100% with subserosal disease received prednisone. Eighty-eight percent of patients who received only steroids (mean follow-up period, 7 mo) and 94% of patients who received steroids in combination with another therapy (mean follow-up period, 4 mo) had improved or resolved disease.Unlike eosinophilic esophagitis, EG is rare. Results from this large study suggest that EG disease type has shifted toward that of the mucosal layer.

Objectives: IgG4-associated systemic disease (ISD) is a multiorgan fibroinflammatory disorder whose pancreatic manifestation is called autoimmune pancreatitis (AIP). We describe 3 patients who developed non-Hodgkin lymphoma during the follow-up of ISD. Methods: At our institution's pancreas clinic, we have prospectively and retrospectively examined patients with ISD with (n = 101) or without (n = 10) AIP (mean age, 59 years; 90 males and 21 females). We reviewed the medical records of all 111 patients to identify patients who developed non-Hodgkin lymphoma during the follow-up since their first presentation of ISD. Standardized incidence rate was calculated. Results: The 111 patients with ISD with or without AIP had 331 patient-years of observation during which 3 patients had a diagnosis of non-Hodgkin lymphoma 3 to 5 years after the diagnosis of ISD. In these patients who later developed lymphoma, ISD involved the pancreas (AIP) in 2 and salivary gland in 1. Non-Hodgkin lymphoma had extranodal involvement in all patients (liver [n = 2], adrenal glands [n=1], kidney [n= 1], and lung [n = 1]). Standardized incidence rate was 16.0 (95% confidence interval, 3.3-45.5). Conclusions: We report 3 cases of non-Hodgkin lymphoma that developed during the follow-up of ISD suggesting that patients with ISD may be at an increased risk of developing non-Hodgkin lymphoma.

Steroid responsive biliary strictures in patients fulfilling criteria for primary sclerosing cholangitis (PSC) have been reported. The clinical course and response to therapy in patients with PSC with elevated immunoglobulin G4 (IgG4) levels has not been investigated previously. Patients with PSC were screened for IgG4-related biliary disease during 2006 to 2008 and data were collected prospectively. A total of 33 out of 285 (12%) patients with PSC (18 males) had elevated IgG4 (>140mg/dL) with a median age of 46 years (interquartile range 29-60); 24 could be evaluated. All patients had both intrahepatic and extrahepatic biliary strictures. Pancreatic disorders were found in 4 (17%), and 11 of 24 (46%) presented with jaundice; 8 of 24 (33%) received biliary stenting for a median time of 4 months (0-6). Liver cirrhosis was diagnosed in 12 of the 24 (50%). Overall, 18 patients were treated with corticosteroids and 6 patients managed conservatively. Nine of 10 patients with elevated bilirubin had improvement. Alkaline phosphatase decreased significantly at 2 months and at last follow-up. IgG4 levels at baseline were 242 (216-357) mg/dL and decreased to 109 (80-236) at 2 months (P < 0.05) and 174 (115-269) at last follow-up (P < 0.05). A total of 39% had adverse effects of steroids, mostly hyperglycemia. Relapses occurred in 7 of the 14 (50%), but biliary stents could be removed in all. Elevated IgG4 levels were observed in 12% of typical patients with PSC. Prevalence of cirrhosis was high, suggesting a severe liver disease course. Most patients had a good biochemical response to steroids, but adverse effects were common. Future work should be directed at finding therapy that is more effective, better tolerated, and of more lasting benefit.

Probe-based confocal laser endomicroscopy (pCLE) and volumetric laser endomicroscopy (VLE) (also known as frequency domain optical coherence tomography) are advanced endoscopic imaging modalities that may be useful in the diagnosis of dysplasia associated with Barrett's esophagus (BE). We performed pCLE examination in ex-vivo EMR specimens and compared the diagnostic performance of using the current VLE scoring index (previously established as OCT-SI) and a novel VLE diagnostic algorithm (VLE-DA) for the detection of dysplasia.A total of 27 patients with BE enrolled in a surveillance program at a tertiary-care center underwent 50 clinically indicated EMRs that were imaged with VLE and pCLE and classified into neoplastic (N = 34; high-grade dysplasia, intramucosal adenocarcinoma) and nonneoplastic (N = 16; low-grade dysplasia, nondysplastic BE), based on histology. Image datasets (VLE, N = 50; pCLE, N = 50) were rated by 3 gastroenterologists trained in the established diagnostic criteria for each imaging modality as well as a new diagnostic algorithm for VLE derived from a training set that demonstrated association of specific VLE features with neoplasia. Sensitivity, specificity, and diagnostic accuracy were assessed for each imaging modality and diagnostic criteria.The sensitivity, specificity, and diagnostic accuracy of pCLE for detection of BE dysplasia was 76% (95% confidence interval [CI], 59-88), 79% (95% CI, 53-92), and 77% (95% CI, 72-82), respectively. The optimal diagnostic performance of OCT-SI showed a sensitivity of 70% (95% CI, 52-84), specificity of 60% (95% CI, 36-79), and diagnostic accuracy of 67%; (95% CI, 58-78). The use of the novel VLE-DA showed a sensitivity of 86% (95% CI, 69-96), specificity of 88% (95% CI, 60-99), and diagnostic accuracy of 87% (95% CI, 86-88). The diagnostic accuracy of using the new VLE-DA criteria was significantly superior to the current OCT-SI (P < .01).The use of a new VLE-DA showed enhanced diagnostic performance for detecting BE dysplasia ex vivo compared with the current OCT-SI. Further validation of this algorithm in vivo is warranted.

Abstract Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote KrasG12D-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer–promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1–STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. Significance: Our study points to the existence of an oncogenic NFATc1–STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1–STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies. Cancer Discov; 4(6); 688–701. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 621

Abstract Purpose: Discriminant markers for pancreatic cancer detection are needed. We sought to identify and validate methylated DNA markers for pancreatic cancer using next-generation sequencing unbiased by known targets. Experimental Design: At a referral center, we conducted four sequential case–control studies: discovery, technical validation, biologic validation, and clinical piloting. Candidate markers were identified using variance-inflated logistic regression on reduced-representation bisulfite DNA sequencing results from matched pancreatic cancers, benign pancreas, and normal colon tissues. Markers were validated technically on replicate discovery study DNA and biologically on independent, matched, blinded tissues by methylation-specific PCR. Clinical testing of six methylation candidates and mutant KRAS was performed on secretin-stimulated pancreatic juice samples from 61 patients with pancreatic cancer, 22 with chronic pancreatitis, and 19 with normal pancreas on endoscopic ultrasound. Areas under receiver-operating characteristics curves (AUC) for markers were calculated. Results: Sequencing identified &amp;gt;500 differentially hyper-methylated regions. On independent tissues, AUC on 19 selected markers ranged between 0.73 and 0.97. Pancreatic juice AUC values for CD1D, KCNK12, CLEC11A, NDRG4, IKZF1, PKRCB, and KRAS were 0.92*, 0.88, 0.85, 0.85, 0.84, 0.83, and 0.75, respectively, for pancreatic cancer compared with normal pancreas and 0.92*, 0.73, 0.76, 0.85*, 0.73, 0.77, and 0.62 for pancreatic cancer compared with chronic pancreatitis (*, P = 0.001 vs. KRAS). Conclusions: We identified and validated novel DNA methylation markers strongly associated with pancreatic cancer. On pilot testing in pancreatic juice, best markers (especially CD1D) highly discriminated pancreatic cases from controls. Clin Cancer Res; 21(19); 4473–81. ©2015 AACR.

To evaluate the utility of magnetic resonance elastography (MRE) in screening patients for hepatic fibrosis, cirrhosis, and hepatocellular carcinoma after the Fontan operation.Hepatic MRE was performed in conjunction with cardiac magnetic resonance imaging in patients who had undergone a Fontan operation between 2010 and 2014. Liver stiffness was calculated using previously reported techniques. Comparisons to available clinical, laboratory, imaging, and histopathologic data were made.Overall, 50 patients at a median age of 25 years (range, 21-33 years) who had undergone a Fontan operation were evaluated. The median interval between Fontan operation and MRE was 22 years (range, 16-26 years). The mean liver stiffness values were increased: 5.5 ± 1.4 kPa relative to normal participants. Liver stiffness directly correlated with liver biopsy-derived total fibrosis score, time since operation, mean Fontan pressure, γ-glutamyltransferase level, Model for End-Stage Liver Disease score, creatinine level, and pulmonary vascular resistance index. Liver stiffness was inversely correlated with cardiac index. All 3 participants with hepatic nodules exhibiting decreased contrast uptake on delayed postcontrast imaging and increased nodule stiffness had biopsy-proven hepatocellular carcinoma.The association between hepatic stiffness and fibrosis scores, Model for End-Stage Liver Disease scores, and γ-glutamyltransferase level suggests that MRE may be useful in detecting (and possibly quantifying) hepatic cirrhosis in patients after the Fontan operation. The correlation between stiffness and post-Fontan time interval, mean Fontan pressure, pulmonary vascular resistance index, and reduced cardiac index suggests a role for long-term hepatic congestion in creating these hepatic abnormalities. Magnetic resonance elastography was useful in detecting abnormal nodules ultimately diagnosed as hepatocellular carcinoma. The relationship between stiffness with advanced fibrosis and hepatocellular carcinoma provides a strong argument for additional study and broader application of MRE in these patients.

The ultrastructural changes in diabetic and idiopathic gastroparesis are not well studied and it is not known whether there are different defects in the two disorders. As part of the Gastroparesis Clinical Research Consortium, full thickness gastric body biopsies from 20 diabetic and 20 idiopathic gastroparetics were studied by light microscopy. Abnormalities were found in many (83%) but not all patients. Among the common defects were loss of interstitial cells of Cajal (ICC) and neural abnormalities. No distinguishing features were seen between diabetic and idiopathic gastroparesis. Our aim was to provide a detailed description of the ultrastructural abnormalities, compare findings between diabetic and idiopathic gastroparesis and determine if patients with apparently normal immunohistological features have ultrastructural abnormalities. Tissues from 40 gastroparetic patients and 24 age- and sex-matched controls were examined by transmission electron microscopy (TEM). Interstitial cells of Cajal showing changes suggestive of injury, large and empty nerve endings, presence of lipofuscin and lamellar bodies in the smooth muscle cells were found in all patients. However, the ultrastructural changes in ICC and nerves differed between diabetic and idiopathic gastroparesis and were more severe in idiopathic gastroparesis. A thickened basal lamina around smooth muscle cells and nerves was characteristic of diabetic gastroparesis whereas idiopathic gastroparetics had fibrosis, especially around the nerves. In conclusion, in all the patients TEM showed abnormalities in ICC, nerves and smooth muscle consistent with the delay in gastric emptying. The significant differences found between diabetic and idiopathic gastroparesis offers insight into pathophysiology as well as into potential targeted therapies.

The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial.To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX.The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009.Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study.Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status.Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P = .03).The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy.clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.

Background & AimsThe increasing incidence of microscopic colitis has been partly attributed to detection bias. We aimed to ascertain recent incidence trends and the overall prevalence of microscopic colitis in a population-based study.MethodsUsing data from the Rochester Epidemiology Project, we identified residents of Olmsted County, Minnesota, who were diagnosed with collagenous colitis or lymphocytic colitis from January 1, 2002, through December 31, 2010, based on biopsy results and the presence of diarrhea (N = 182; mean age at diagnosis, 65.8 years; 76.4% women). Poisson regression analyses were performed to evaluate associations between incidence and age, sex, and calendar period.ResultsThe age- and sex-adjusted incidence of microscopic colitis was 21.0 cases per 100,000 person-years (95% confidence interval [CI], 18.0–24.1 cases per 100,000 person-years). The incidence of lymphocytic colitis was 12.0 per 100,000 person-years (95% CI, 9.6–14.3 per 100,000 person-years) and collagenous colitis was 9.1 per 100,000 person-years (95% CI, 7.0–11.1 per 100,000 person-years). The incidence of microscopic colitis and its subtypes remained stable over the study period (P = .63). Increasing age (P < .001) and female sex (P < .001) were associated with increasing incidence. On December 31, 2010, the prevalence of microscopic colitis was 219 cases per 100,000 persons (90.4 per 100,000 persons for collagenous colitis and 128.6 per 100,000 persons for lymphocytic colitis).ConclusionThe incidence of microscopic colitis in Olmsted County residents has stabilized and remains associated with female sex and increasing age. The increasing incidence of microscopic colitis has been partly attributed to detection bias. We aimed to ascertain recent incidence trends and the overall prevalence of microscopic colitis in a population-based study. Using data from the Rochester Epidemiology Project, we identified residents of Olmsted County, Minnesota, who were diagnosed with collagenous colitis or lymphocytic colitis from January 1, 2002, through December 31, 2010, based on biopsy results and the presence of diarrhea (N = 182; mean age at diagnosis, 65.8 years; 76.4% women). Poisson regression analyses were performed to evaluate associations between incidence and age, sex, and calendar period. The age- and sex-adjusted incidence of microscopic colitis was 21.0 cases per 100,000 person-years (95% confidence interval [CI], 18.0–24.1 cases per 100,000 person-years). The incidence of lymphocytic colitis was 12.0 per 100,000 person-years (95% CI, 9.6–14.3 per 100,000 person-years) and collagenous colitis was 9.1 per 100,000 person-years (95% CI, 7.0–11.1 per 100,000 person-years). The incidence of microscopic colitis and its subtypes remained stable over the study period (P = .63). Increasing age (P < .001) and female sex (P < .001) were associated with increasing incidence. On December 31, 2010, the prevalence of microscopic colitis was 219 cases per 100,000 persons (90.4 per 100,000 persons for collagenous colitis and 128.6 per 100,000 persons for lymphocytic colitis). The incidence of microscopic colitis in Olmsted County residents has stabilized and remains associated with female sex and increasing age.

Abnormalities in exocrine pancreatic function have been reported in diabetes mellitus (DM). We reviewed published literature to determine the nature of structural and functional alterations in the exocrine pancreas in DM.We identified and abstracted data from original studies (n = 50) describing morphological, structural, and functional changes in the exocrine pancreas in types 1 and 2 DM.Pancreatic weight and volume are markedly lower in type 1 DM (P < 0.005) with insignificant decrease in type 2 DM compared with age-, sex-, and body mass index-matched controls. Pancreatic histopathological changes seen in most subjects with DM at autopsy (n = 7 studies, 1272 autopsies) include mild-to-marked interacinar fibrosis, scant inflammatory infiltrate, no pancreatic ductal changes, and hyalinization of arteries. In subjects with DM, pooled prevalence of decreased fecal elastase 1 (<200 μg/g) is higher, coefficient of fat absorption is near normal (mean, 91%-94%), and pancreatic exocrine dysfunction is nonprogressive over time. Diabetes mellitus is asymptomatic in regard to the exocrine pancreas.In types 1 and 2 DM, moderate-to-severe subclinical pancreatic fibrosis and modest exocrine dysfunction occurs in the absence of clinical or histopathological evidence of chronic pancreatitis. We call this novel entity "diabetic exocrine pancreatopathy."

Germline mutations in SPRTN cause Ruijs–Aalfs syndrome (RJALS), a disorder characterized by genome instability, progeria and early onset hepatocellular carcinoma. Spartan, the protein encoded by SPRTN, is a nuclear metalloprotease that is involved in the repair of DNA–protein crosslinks (DPCs). Although Sprtn hypomorphic mice recapitulate key progeroid phenotypes of RJALS, whether this model expressing low amounts of Spartan is prone to DPC repair defects and spontaneous tumors is unknown. Here, we showed that the livers of Sprtn hypomorphic mice accumulate DPCs containing Topoisomerase 1 covalently linked to DNA. Furthermore, these mice exhibited DNA damage, aneuploidy and spontaneous tumorigenesis in the liver. Collectively, these findings provide evidence that partial loss of Spartan impairs DPC repair and tumor suppression.

The potential negative impact of cytomegalovirus (CMV) in ulcerative colitis (UC) and Crohn's disease (CD) warrants efforts to improve the yield of diagnostic techniques.We retrospectively determined the optimal biopsy location and number from sixty-eight patients with inflammatory bowel disease (66% UC, 31% CD, and 3% inflammatory bowel disease-unclassified) with CMV disease between 2005 and 2011. Biopsies with endoscopic and histologic inflammation were analyzed by immunohistochemistry and/or in situ hybridization. The proportion of positive biopsies was determined, and using data from the 25th percentile, we assessed the number of biopsies required to achieve an 80% probability of a single positive biopsy.Of the patients with a diagnosis by immunohistochemistry and/or in situ hybridization, 27 of 61 (44%; 95% confidence interval, 32-57) were positive by hematoxylin and eosin, and 11 of 36 (31%; 95% confidence interval, 16-46) had systemic CMV by polymerase chain reaction. Of the patients with biopsies proximal and distal to the splenic flexure, 1 of 11 with UC and 4 of 8 with CD had a diagnosis limited to the right colon. Twenty percent of biopsies were positive by immunohistochemistry or in situ hybridization (20% in UC and 17% in CD). Eleven biopsies in UC and 16 in CD were required to achieve an 80% probability of a positive biopsy.Biopsy location and number are important considerations when assessing for CMV. We recommend a flexible sigmoidoscopy with 11 biopsies in UC and a colonoscopy with 16 biopsies in CD.

Tumor budding in colorectal carcinoma has been associated with poor outcome in multiple studies, but the absence of an established histologic cutoff for "high" tumor budding, heterogeneity in study populations, and varying methods for assessing tumor budding have hindered widespread incorporation of this parameter in clinical reports. We used an established scoring system in a population-based cohort to determine a histologic cutoff for "high" tumor budding and confirm its prognostic significance. We retrieved hematoxylin and eosin-stained sections from 553 incident colorectal carcinoma cases. Each case was previously characterized for select molecular alterations and survival data. Interobserver agreement was assessed between 2 gastrointestinal pathologists and a group of 4 general surgical pathologists. High budding (≥ 10 tumor buds in a ×20 objective field) was present in 32% of cases, low budding in 46%, and no budding in 22%. High tumor budding was associated with advanced pathologic stage (P < 0.001), microsatellite stability (P = 0.005), KRAS mutation (P = 0.010), and on multivariate analysis with a > 2 times risk of cancer-specific death (hazard ratio = 2.57 [1.27, 5.19]). After multivariate adjustment, by penalized smoothing splines, we found increasing tumor bud counts from 5 upward to be associated with an increasingly shortened cancer-specific survival. By this method, a tumor bud count of 10 corresponded to approximately 2.5 times risk of cancer-specific death. The interobserver agreement was good with weighted κ of 0.70 for 2 gastrointestinal pathologists over 121 random cases and 0.72 between all 6 pathologists for 20 random cases. Using an established method to assess budding on routine histologic stains, we have shown that a cutoff of 10 for high tumor budding is independently associated with a significantly worse prognosis. The reproducibility data provide support for the routine widespread implementation of tumor budding in clinical reports.