Michael B. Farnell

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.

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.

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.

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.

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.

Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors

Pancreatic endocrine tumors (PETs) are uncommon tumors with an annual incidence <1 per 100 000 person-years in the general population. The PETs that produce hormones resulting in symptoms are designated as functional. The majority of PETs are non-functional. Of the functional tumors, insulinomas are the most common, followed by gastrinomas. The clinical course of patients with PETs is variable and depends on the extent of the disease and the treatment rendered. Patients with completely resected tumors generally have a good prognosis, and aggressive surgical therapy in patients with advanced disease may also prolong survival. The epidemiology, prognosis, and established and novel prognostic markers of PETs are reviewed.

Nonoperative Management of Blunt Splenic Trauma: A Multicenter Experience

The experience of six referral trauma centers with 832 blunt splenic injuries was reviewed to determine the indications, methods, and outcome of nonoperative management. During this 5-year period, 112 splenic injuries were intentionally managed by observation. There were 40 (36%) patients less than 16 years old and 72 adults. The diagnosis was established by computed tomography in 89 (79%) patients, nuclear scan in 23 (21%), ultrasound in four (4%), and arteriography in two (2%). There were 28 Class I, 51 Class II, 31 Class III, two Class IV, and no Class V splenic injuries. Nonoperative management was unsuccessful in one (2%) child and 12 (17%) adults (p less than 0.05). Failure was due to ongoing hemorrhage in 12 patients and delayed recognition of pancreatic injury in one patient. Of the 12 patients ultimately requiring laparotomy for control of hemorrhage, seven (58%) were successfully treated with splenic salvage techniques. Overall mortality was 3%; none of the four deaths was due to splenic or associated abdominal injury. This contemporary multicenter experience suggests that patients with Class I, II, or III splenic injuries after blunt trauma are candidates for nonoperative management if there is: 1) no hemodynamic instability after initial fluid resuscitation; 2) no serious associated abdominal organ injury; and 3) no extra-abdominal condition which precludes assessment of the abdomen. Strict adherence to these principles yielded initial nonoperative success in 98% of children and 83% of adults. Application of standard splenic salvage techniques to treat the patients with persistent hemorrhage resulted in ultimate splenic preservation in 100% of children and 93% of adults.

Hepatic Resection for Colorectal Metastases: Value for Risk Scoring Systems?

Introduction:Predictors of outcome in patients with metastatic colorectal cancer remain inconsistent. We aimed to identify predictors of outcome in these patients, to develop a prognostic scoring system, and to assess the general applicability of the current major risk scoring systems. Materials and Methods:Following IRB approval, medical records of 662 consecutive patients undergoing resection of colorectal metastases to the liver during 1960 to 1995 were reviewed. Clinicopathologic and outcome data were assessed from records and mailed questionnaire. Clinicopathologic variables were tested using univariate and multivariate analyses; best-fit models were then generated to study the effect of each independent risk factor on outcome. To validate existing scoring models, our independent data set was applied to those scores. The relative concordance probability estimates were calculated for these models and compared with that of the proposed Mayo model. Results:The overall and disease-specific 5-year survival rates were 37% and 42%, respectively. The probability of recurrence at any site was 65% at 5 years. Perioperative blood transfusion and positive hepatoduodenal nodes were the major determinants of survival and recurrence. To assess the general applicability of the proposed risk scoring systems, we imported the data from our patient population into 3 other scoring systems. Neither survival nor recurrence among our patients was stratified discretely by any of the scoring systems. Based on probability estimates, all models were only marginally better than chance alone in predicting outcome. Conclusion:Broad application of risk scoring systems for patients with metastatic colorectal cancer has limited clinical value and refinement and external validation should be undertaken before utilization.

Hepatic Resection of Hepatocellular Carcinoma in Patients With Cirrhosis: Model of End-Stage Liver Disease (MELD) Score Predicts Perioperative Mortality

Hepatic resection for hepatocellular carcinoma (HCC) in patients with cirrhosis is generally recommended for patients with Child-Turcotte-Pugh (CTP) Class A liver disease and early tumor stage. The Model for End-Stage Liver Disease (MELD) has been shown to accurately predict survival in patients with cirrhosis, but whether MELD is useful for selection of patients with cirrhosis for hepatic resection is unknown. We examined whether MELD was predictive of perioperative mortality and correlated MELD with other potential clinicopathologic factors to overall survival in patients with cirrhosis undergoing hepatic resection for HCC. A retrospective chart review was undertaken of patients with HCC and cirrhosis undergoing hepatic resection between 1993 and 2003. Eighty-two patients (62 men, 20 women; mean age, 62 years) were identified. Forty-five patients had MELD score ≥9 (range, 9–15) and CTP score ranged from 5 to 9 points. Fifty-nine patients underwent minor (<3 segments) hepatic resections (MELD ≤8, n = 29; MELD ≥9, n = 30) and 23 underwent major (≥3 segments) hepatic resections (MELD ≤8, n = 8; MELD ≥9, n = 15). Perioperative mortality rate was 16%. MELD score ≤8 was associated with no perioperative mortality versus 29% for patients with an MELD score ≥9 (P < 0.01). Multivariate analysis demonstrated that MELD score ≥9 (P < 0.01), clinical tumor symptoms (P < 0.01), and ASA score (P = 0.046) are independent predictors of perioperative mortality. Multivariate analysis showed MELD ≥9 (P < 0.01), tumor size >5 cm(P < 0.01), high tumor grade (P = 0.03), and absence of tumor capsule (P < 0.01) as independent predictors of decreased long-term survival. MELD score was a strong predictor of both perioperative mortality and long-term survival in patients with cirrhosis undergoing hepatic resection for HCC. In patients with cirrhosis, hepatic resection (minor or major) for HCC is recommended if the MELD score is ≤8. In patients with MELD score ≥9, other treatment modalities should be considered.

Experience With 208 Resections for Intraductal Papillary Mucinous Neoplasm of the Pancreas

HYPOTHESIS Intraductal papillary mucinous neoplasm (IPMN) is an increasingly recognized disease of the pancreas. We report our experience with pancreatic resection for IPMN. DESIGN Retrospective review from 1992 through 2005 with additional independent histopathologic confirmation. SETTING Mayo Clinic Rochester, a tertiary care center. PATIENTS All patients who underwent primary resection for pancreatic IPMN. MAIN OUTCOME MEASURES Disease-specific operative outcomes, survival, and recurrence patterns. RESULTS 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%; P = .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. CONCLUSIONS 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.