Jonathan E. Clain

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.

THE DIFFERENT COURSES OF EARLY- AND LATE-ONSET IDIOPATHIC AND ALCOHOLIC CHRONIC PANCREATITIS

BACKGROUND/AIMS Compared with alcoholic pancreatitis, little is known about the natural history of idiopathic pancreatitis. Two hundred forty-nine patients with alcoholic pancreatitis and 66 patients with idiopathic chronic pancreatitis seen at our institution between 1976 and 1982 were investigated. METHODS Records were analyzed retrospectively from the onset of symptomatic disease, and patients were followed up prospectively until 1985. Patients with early-onset (n = 25) and late-onset (n = 41) idiopathic chronic pancreatitis had a median age at onset of symptoms of 19 and 56 years, respectively. RESULTS The gender distribution was nearly equal in idiopathic chronic pancreatitis, but 72% of patients with alcoholic pancreatitis were men (P = 0.001 vs. idiopathic). In early-onset idiopathic pancreatitis, calcification and exocrine and endocrine insufficiency developed more slowly than in late-onset idiopathic and alcoholic pancreatitis (P = 0.03). However, in early idiopathic chronic pancreatitis, pain frequently occurred initially (P = 0.003 vs. late and alcoholic) and was more severe (P = 0.04 vs. late and alcoholic). In late-onset idiopathic pancreatitis, pain was absent in nearly 50% of patients. CONCLUSIONS There are two distinct forms of idiopathic chronic pancreatitis. Patients with early-onset pancreatitis have initially and thereafter a long course of severe pain but slowly develop morphological and functional pancreatic damage, whereas patients with late-onset pancreatitis have a mild and often a painless course. Both forms differ from alcoholic pancreatitis in their equal gender distribution and a much slower rate of calcification.

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.

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.

A Diagnostic Strategy to Distinguish Autoimmune Pancreatitis From Pancreatic Cancer

BACKGROUND & AIMS Autoimmune pancreatitis (AIP) and pancreatic cancer (PaC) have similar presentations; a diagnostic strategy is needed to distinguish the 2 diseases. METHODS 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). RESULTS 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). CONCLUSIONS 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.

Utility of EUS in the evaluation of cystic pancreatic lesions.

BACKGROUND Preoperative differentiation of benign and malignant/potentially malignant pancreatic cystic lesions is problematic. Data to support the role of EUS and EUS-guided fine-needle aspiration (EUS-FNA) are limited. This study assessed the sensitivity, specificity, and accuracy of EUS, cytopathology, and analysis of cyst fluid for pancreatic cystic lesions. METHODS Retrospectively, 111 consecutive patients were identified (54 men, 57 women; mean age 59 years, range 18-79 years) who underwent EUS from July 1997 to September 2000 because of known or suspected pancreatic cystic lesions based on CT or transabdominal US. Thirty-four patients (16 men, 18 women; mean age 55 years, 25-79 years) who underwent surgery formed the basis for this analysis. EUS diagnosis was compared with surgical pathology. Selected patients underwent EUS-FNA to obtain specimens for cytopathologic analysis and for determination of carcinoembryonic antigen levels. Based on surgical pathology, cysts were classified as benign (simple cyst, pseudocyst, serous cystadenoma) or malignant/potentially malignant (mucinous cystadenoma, intraductal papillary mucinous tumor, cystic islet cell tumor, cystic adenocarcinoma). RESULTS EUS-FNA with cytopathologic assessment of cyst fluid was performed for 18 of the 34 patients; carcinoembryonic antigen level was determined in 11 cases. For EUS, cytopathology, and carcinoembryonic antigen, sensitivity was, respectively, 91%, (p = 0.01 vs. cytology), 27%, and 28%; specificity was, respectively, 60%, 100%, and 25%; and, accuracy was, respectively, 82%, 55%, and 27%. The sensitivity of EUS in all 13 patients with cystic islet cell tumor, intraductal papillary mucinous tumor, or cystic adenocarcinoma was 100%. Combining EUS, cytopathology, and carcinoembryonic antigen results did not improve accuracy. There were no complications related to the EUS or EUS-FNA. CONCLUSIONS EUS alone is sensitive and accurate in identifying malignant/potentially malignant pancreatic cystic lesions. EUS-FNA to obtain specimens for cytopathologic analysis and determination of carcinoembryonic antigen levels, although safe, does not enhance diagnostic yield.

Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience

Background There is a paucity of data on long-term management of type 1 autoimmune pancreatitis (AIP), a relapsing steroid-responsive disorder. Objective We describe our experience with treatment of relapses and maintenance of remission using steroid-sparing immunomodulators (IMs) and induction of remission using rituximab (RTX). Methods 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. Results 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. Conclusions 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.

Pancreatic mucinous cystic neoplasm defined by ovarian stroma: Demographics, clinical features, and prevalence of cancer

BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Initial evaluation of the efficacy and safety of endoscopic ultrasound-guided direct ganglia neurolysis and block

BACKGROUND:Celiac plexus neurolysis and block are considered safe but provide limited pain relief. Standard techniques target the region of the celiac plexus but do not attempt injections directly into celiac ganglia. The recent recognition that celiac ganglia can be visualized by endoscopic ultrasound (EUS) now allows direct injection into celiac ganglia for neurolysis (CGN) and block (CGB).AIMS:To determine the safety and initial efficacy (at 2–4 wk) of direct ganglia injection in patients with moderate to severe pain secondary to unresectable pancreatic carcinoma or chronic pancreatitis.METHODS:An EUS database was reviewed to identify patients undergoing CGN and CGB. Data were retrieved from the medical records and phone follow-up.RESULTS:Thirty-three patients underwent 36 direct celiac ganglia injections for unresectable pancreatic cancer (CGN N = 17, CGB N = 1) or chronic pancreatitis (CGN N = 5, CGB N = 13) with bupivacaine (0.25%) and alcohol (99%) for CGN, or Depo-Medrol (80 mg/2 cc) for CGB. Cancer patients reported pain relief in 16/17 (94%) when alcohol was injected and 0/1 (00%) when steroid was injected. For chronic pancreatitis, 4/5 (80%) who received alcohol reported pain relief versus 5/13 (38%) receiving steroids. Thirteen (34%) patients experienced initial pain exacerbation, which correlated with improved therapeutic response (P < 0.05). Transient hypotension and diarrhea developed in 12 and 6 patients, respectively.CONCLUSIONS:Initial experience suggests that EUS-guided direct celiac ganglion block or neurolysis is safe. Alcohol injection into ganglia appears to be effective in both cancer and chronic pancreatitis. Prospective trials are needed to confirm the efficacy of this new approach.