Thomas C. Smyrk

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.

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.

Esophageal Eosinophilia with Dysphagia A Distinct Clinicopathologic Syndrome

Small numbers of intraepithelial esophageal eosinophils (IEE) may be seen in 50% of patients with gastroesophageal reflux disease and occasionally in normal volunteers. High concentrations of IEE are rarely seen in either setting. During a two-year period we idetified 12 adult patients with very dense eosinophil infiltrates in esophageal biopsies (defined as >20 IEE/high-power field). Dysphagia was the presenting complaint in each, but no evidence of anatomical obstruction could be found. Endoscopic esophagitis was absent, but biopsy showed marked squamous hyperplasia and many IEE. Eleven patients had normal esophageal acid exposure on 24-hr pH monitoring. Esophageal manometry showed a nonspecific motility disturbance in 10 patients. For comparison, 90 patients with excess esophageal acid exposure on 24-hr pH monitoring were studied. Thirteen (14%) had motility disturbance, and 21 (23%) had dysphagia. Esophageal biopsies were devoid of IEE in 47 patients; none of the 43 with IEE had infiltrates as dense as those seen in the 12 study patients. The presence of high concentrations of IEE in esophageal biopsies from patients with dysphagia, normal endoscopy, and normal 24-hr esophageal pH monitoring represents a distinctive clinicopathologic syndrome not previously described.

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.

Outcome of adenocarcinoma arising in Barrett's esophagus in endoscopically surveyed and nonsurveyed patients

The value of endoscopic surveillance of Barretts 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 Barretts esophagus were compared with 35 patients who had a newly recognized Barretts 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 Barretts 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 Barretts 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.

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

Epidemiology of Eosinophilic Esophagitis Over Three Decades in Olmsted County, Minnesota

BACKGROUND & AIMS 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Long-term survival after pancreatoduodenectomy for pancreatic adenocarcinoma: is cure possible?

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.

Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.

CONTEXT 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. OBJECTIVE 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. DESIGN, SETTING, AND PARTICIPANTS 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. MAIN OUTCOME MEASURES Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. RESULTS 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. CONCLUSION 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00079274.