Suresh T. Chari

International Consensus Guidelines for Management of Intraductal Papillary Mucinous Neoplasms and Mucinous Cystic Neoplasms of the Pancreas.

Non-inflammatory cystic lesions of the pancreas are increasingly recognized. Two distinct entities have been defined, i.e., intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). Ovarian-type stroma has been proposed as a requisite to distinguish MCN from IPMN. Some other distinct features to characterize IPMN and MCN have been identified, but there remain ambiguities between the two diseases. In view of the increasing frequency with which these neoplasms are being diagnosed worldwide, it would be helpful for physicians managing patients with cystic neoplasms of the pancreas to have guidelines for the diagnosis and treatment of IPMN and MCN. The proposed guidelines represent a consensus of the working group of the International Association of Pancreatology.

Consensus statement on the pathology of IgG4-related disease.

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.

International Consensus Diagnostic Criteria for Autoimmune Pancreatitis: Guidelines of the International Association of Pancreatology

Objectives: To achieve the goal of developing international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP). Methods: An international panel of experts met during the 14th Congress of the International Association of Pancreatology held in Fukuoka, Japan, from July 11 through 13, 2010. The proposed criteria represent a consensus opinion of the working group. Results: Autoimmune pancreatitis was classified into types 1 and 2. The ICDC used 5 cardinal features of AIP, namely, imaging of pancreatic parenchyma and duct, serology, other organ involvement, pancreatic histology, and an optional criterion of response to steroid therapy. Each feature was categorized as level 1 and 2 findings depending on the diagnostic reliability. The diagnosis of type 1 and type 2 AIP can be definitive or probable, and in some cases, the distinction between the subtypes may not be possible (AIP-not otherwise specified). Conclusions: The ICDC for AIP were developed based on the agreement of an international panel of experts in the hope that they will promote worldwide recognition of AIP. The categorization of AIP into types 1 and 2 should be helpful for further clarification of the clinical features, pathogenesis, and natural history of these diseases.

Immunoglobulin G4–Associated Cholangitis: Clinical Profile and Response to Therapy

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.

Idiopathic Chronic Pancreatitis With Periductal Lymphoplasmacytic Infiltration: Clinicopathologic Features of 35 Cases

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.

Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer.

OBJECTIVES: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.METHODS: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.RESULTS: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).CONCLUSION: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.

Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations

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

Differences in Clinical Profile and Relapse Rate of Type 1 Versus Type 2 Autoimmune Pancreatitis

BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis

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.

Do consensus indications for resection in branch duct intraductal papillary mucinous neoplasm predict malignancy? A study of 147 patients

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.