Focal Autoimmune Pancreatitis Morphologically Mimicking Pancreatic Cancer: A Case Report and Literature Review.

BACKGROUND Autoimmune pancreatitis (AIP) is identified as an outlier in the clinical practice of chronic pancreatitis caused by autoimmune system dysfunction. AIP is classified into 3 subtypes: AIP type 1 and AIP type 2, which are both sensitive to corticosteroids, and the recently introduced AIP type 3. CASE REPORT We present a case of a patient who presented with painless obstructive jaundice. Computed tomography (CT) revealed hyperdense gallbladder material, further dilatation of intrahepatic bile ducts, and distention of the bile duct (15 mm). Based on the available clinical data, which were strongly compatible with pancreatic cancer, Whipple surgery was selected as the treatment for this case. The consequent histopathological report revealed areas of pancreatic parenchyma with fibrous connective tissue development and dense inflammatory cell infiltration with lymphocytes and plasmacytes, which showcased IgG4 positivity. The clinical results suggested a diagnosis of AIP type 1, and the patient was referred to his treating physician for further treatment of AIP. Preoperative histological examination of the pancreas, along with evaluation of the radiological and serological features, could have aided in determining the diagnosis of AIP type 1 pancreatitis despite the unique abnormality of this particular case. CONCLUSIONS Given the aforementioned conditions, AIP, even as a rare clinical entity, emerges as a canonical ailment and should be considered a viable possibility in clinical practice since it can exclude the patient from an unnecessary surgery.

Prevalence of autoimmune pancreatitis in pancreatic resection for suspected malignancy: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Autoimmune pancreatitis (AIP) is a diagnosis-challenging disease that often mimics pancreatic malignancy. Pancreatic resection is considered to be a curative treatment for pancreatic ductal adenocarcinoma (PDAC). This meta-analysis aims to study the incidence of AIP in patients who have undergone pancreatic resection for clinical manifestation of cancer. METHODS: A comprehensive search was conducted in three databases, PubMed, Embase and the Cochrane Library, using the terms 'autoimmune pancreatitis' and 'pancreatic resection' and supplemented by manual checks of reference lists in all retrieved articles. RESULTS: Ten articles were included in the final analysis. 8917 pancreatic resections were performed because of a clinical suspicion of pancreatic cancer. AIP accounted for 140 cases (1.6%). Type 1 AIP comprised the majority of cases, representing 94% (132 cases), while type 2 AIP made up the remaining 6% (eight cases) after further classification. AIP accounted for almost 26% of all cases of benign diseases involving unnecessary surgery and was overrepresented in males in 70% of cases compared to 30% in females. The mean age for AIP patients was 59 years. Serum CA 19 - 9 levels were elevated in 23 out of 47 (49%) AIP patients, where higher levels were detected more frequently in patients with type 1 AIP (51%, 22 out of 43) than in those with type 2 AIP (25%, 1 out of 4). The sensitivity of IgG4 levels in type 1 AIP was low (43%, 21/49 patients). CONCLUSION: Even with modern diagnostic methods, distinguishing between AIP and PDAC can still be challenging, thus potentially resulting in unnecessary surgical procedures in some cases. Serum CA 19 - 9 levels are not useful in distinguishing between AIP and PDAC. Work must thus be done to improve diagnostic methods and avoid unnecessary complicated surgery.

A prospective study on the histological evaluation of type 1 autoimmune pancreatitis using endoscopic ultrasound-guided fine needle biopsy with a 19-gauge Franseen needle.

BACKGROUND/PURPOSE: To assess the diagnostic efficacy and safety of endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a 19-gauge Franseen needle for autoimmune pancreatitis (AIP). METHODS: Twenty patients suspected of having type 1 AIP were prospectively enrolled and underwent EUS-FNB with a 19-gauge Franseen needle. Their data were compared with those of historical controls: a total of 29 type 1 AIP patients had EUS-FNB with a 22-gauge Franseen needle. RESULTS: Specimens suitable for histological evaluation were obtained from 19 of the 20 patients (95%), and the median total tissue area was 11.9 mm2. The histological diagnosis rate of AIP was 65% (95% CI: 43.2%-82%). Adverse events were observed in three patients (15%), and a switch to 22-gauge needles occurred during transduodenal puncture in two patients. Compared to those punctured with 22-gauge needles, patients punctured with 19-gauge needles had greater prevalence of each characteristic feature of lymphoplasmacytic sclerosing pancreatitis, but the difference was not statistically significant. CONCLUSIONS: EUS-FNB using a 19-gauge Franseen needle demonstrated favorable performance for the histological diagnosis of AIP and allowed for large tissue samples, potentially facilitating pathological diagnosis. However, during transduodenal puncture, maneuverability is reduced; therefore, the needle may need to be selected according to the puncture site.

Diagnostic performance of F-18 FDG PET/CT in differentiating autoimmune pancreatitis from pancreatic cancer: a systemic review and meta-analysis.

OBJECTIVES: This study aims to evaluate the utility of F-18 FDG PET/CT in the non-invasive diagnosis of autoimmune pancreatitis (AIP) and differentiating it from pancreatic cancer (CaP) based on the amount and pattern of FDG uptake, as well as involvement of extra-pancreatic sites. METHODS: A systematic search was conducted using PubMed, Scopus, Cochrane Library and Google Scholar. Only those studies that compared the findings of F-18 FDG PET/CT in terms of SUVmax, pattern of FDG uptake and presence of FDG-avid extra-pancreatic sites in both AIP and CaP were included. Studies were qualitatively assessed for risk of bias and publication bias. The diagnostic performance of parameters on PET/CT was examined through pooled sensitivity, specificity, diagnostic odd's ratio (DOR) and summary receiver operator characteristic (SROC) curve analysis. RESULTS: Six studies were included with a total of 580 patients. 178 patients had AIP (Age 18-90 years, male, M: female, F ratio-8.4:1) and 402 patients had CaP (Age 22-88 years, M:F ratio-1.5:1). Type of AIP was reported in only 3 studies, with the included cases predominantly being type 1 AIP. All studies were retrospective with heterogeneity and a risk on patient selection and index test. The FDG uptake, expressed as SUVmax, was lower in AIP with a weighted mean difference of -3.11 (95% confidence interval, CI: -5.28 to -0.94). To diagnose AIP, the pooled sensitivity, specificity and DOR of diffuse pattern of FDG uptake were 0.59 (95% CI: 0.51-0.66), 0.89 (95% CI: 0.86-0.92) and 21.07 (95% CI: 5.07-88.32), respectively, with an area under curve (AUC) of 0.717 on SROC analysis. The pooled sensitivity, specificity and DOR of FDG-avid extra pancreatic sites were 0.55 (95% CI: 0.45-0.65), 0.58 (95% CI: 0.52-0.64) and 2.33 (95% CI: 1.40-3.89), respectively, with an AUC of 0.632. CONCLUSION: On F-18 FDG PET/CT, a pancreatic lesion of AIP has a lower SUVmax value than CaP. A diffuse pattern of FDG uptake and presence of an extra-pancreatic FDG-avid site are nearly 21 times and twice more likely in AIP than CaP, respectively.

The Role of Gut Microbiota and Innate Immune Response in an Autoimmune Pancreatitis Model.

BACKGROUND: Although the involvement of intestinal microbiota in innate immunity has been reported recently, the pathogenicity of autoimmune pancreatitis (AIP) remains unclear. This study aimed to investigate whether probiotics ameliorate inflammation in AIP through interactions with innate immunity. MATERIALS AND METHODS: The AIP mouse model was generated by intraperitoneal administration of Escherichia coli to C56BL/6 female mice. Alterations in the intestinal microbiota in the AIP group were evaluated using high-throughput sequencing. Peritoneal macrophages (PMs) were collected and cocultured in vitro with Lactobacillus gasseri (LG) or ligands of Toll-like receptors (TLRs). LG was administered intraperitoneally to AIP model mice, and pancreatitis activity was evaluated to examine the ameliorative effects of LG. RESULTS: In the AIP model mice, inflammation was significantly induced in the pancreas, and the intestinal microbiota was altered with decreased LG. Antimicrobial treatment suppressed pancreatitis. In vitro, E. coli stimulation increased inflammatory cytokine expression, which was significantly decreased when the LG or TLR7 ligand was cocultured with PMs. Intraperitoneal administration of LG to AIP model mice significantly suppressed pancreatitis. CONCLUSION: The mouse model demonstrated the involvement of intestinal microbiota in pancreatitis, and LG administration suppressed pancreatitis, possibly through TLR7 signaling in PMs. LG may be a helpful probiotic for treating AIP.

The effect of steroid therapy on pancreatic exocrine function in autoimmune pancreatitis.

BACKGROUND/OBJECTIVES: Autoimmune pancreatitis (AIP) is a steroid-responsive inflammatory disease of the pancreas. Few studies investigated pancreatic exocrine function (PEF) in patients suffering from AIP and no definitive data are available on the effect of steroids in PEF recovery. Aim of the study is the evaluation of severe pancreatic insufficiency (sPEI) prevalence in AIP at clinical onset and after steroid treatment. METHODS: 312 Patients with diagnosis of AIP between January 1st, 2010 and December 31st, 2020 were identified in our prospectively maintained register. Patients with a pre-steroid treatment dosage of fecal elastase-1 (FE-1) were included. Changes in PEF were evaluated in patients with available pre- and post-treatment FE (between 3 and 12 months after steroid). RESULTS: One-hundred-twenty-four patients were included, with a median FE-1 of 122 (Q1-Q3: 15-379) µg/g at baseline. Fifty-nine (47.6 %) had sPEI (FE-1<100 µg/g). Univariable analysis identified type 1 AIP, radiological involvement of the head of the pancreas (diffuse involvement of the pancreas or focal involvement of the head), weight loss, age and diabetes as associated with a greater risk of sPEI. However, at multivariable analysis, only the involvement of the head of the pancreas was identified as independent risk factor for sPEI. After steroids, mean FE-1 changed from 64 (15-340) to 202 (40-387) µg/g (P = 0.058) and head involvement was the only predictor of improvement of sPEI. CONCLUSION: The inflammatory involvement of the head of the pancreas is associated with PEF severity, as well as PEF improvement after treatment with steroids in patients with AIP.

Recent advances in IgG4-related autoimmune pancreatitis.

The incidence of IgG4-related autoimmune pancreatitis (IgG4-AIP) is high in Asia and other countries, and unnecessary treatment is often undertaken due to both missed diagnosis and misdiagnosis in clinical practice. Although IgG4-AIP has attracted increasing attention, the details of IgG4-AIP pathogenesis and systemic immune response, including its relationship to tumor pathogenesis, are still unclear. In recent years, research on serum immunological detection, pathological features, clinical manifestations, diagnosis and treatment measures for IgG4-AIP has gradually increased. It is of great importance to summarize and discuss the latest progress regarding IgG4-AIP disease.

Understanding autoimmune pancreatitis: Clinical features, management challenges, and association with malignancies.

In this editorial we comment on the article by Jaber et al. Autoimmune pancreatitis (AIP) represents a distinct form of pancreatitis, categorized into AIP-1 and AIP-2, characterized by obstructive jaundice, lymphoplasmacytic infiltrate, and fibrosis. AIP-1, associated with elevated immunoglobulin G4 (IgG4) levels, exhibits higher relapse rates, affecting older males, while AIP-2 is less common and linked to inflammatory bowel disease. AIP is considered a manifestation of IgG4-related systemic disease, sharing characteristic histological findings. Steroids are the primary treatment, with emerging biomarkers like interferon alpha and interleukin-33. AIP poses an increased risk of various malignancies, and the association with pancreatic cancer is debated. Surgery is reserved for severe cases, necessitating careful evaluation due to diagnostic challenges. AIP patients may have concurrent PanINs but display favorable long-term outcomes compared to pancreatic cancer patients. Thorough diagnostic assessment, including biopsy and steroid response, is crucial for informed surgical decisions in AIP.

IgG4-related autoimmune pancreatitis and sclerosing cholangitis: A case report and literature review.

RATIONALE: Immunoglobulin G4-related disease (IgG4-RD) can involve various organs throughout the body, primarily manifesting as endocrine dysfunction, visual impairment, jaundice, and limited sexual function. IgG4-related autoimmune pancreatitis is triggered by autoimmune reactions and characterized by structural changes in the pancreas and pancreatic ducts. The disease mainly affects middle-aged and elderly males, typically presenting as progressive painless jaundice and misdiagnosed as cholangiocarcinoma or pancreatic cancer. PATIENT CONCERNS: This study reports a 54-year-old male who consulted with different institutions multiple times due to diabetes, pancreatitis, elevated liver enzymes, and jaundice. DIAGNOSES: Magnetic resonance imaging revealed swollen head of the pancreas and atrophic tail. Liver and pancreatic tissue pathology showed IgG4 plasma cell infiltration, while liver biopsy indicated interface hepatitis, liver fibrosis, and pseudolobule formation, with no evidence of bile duct damage. INTERVENTIONS: Following hormone therapy, the patient's serum IgG4 levels and liver enzyme levels returned to normal. OUTCOMES: The disease relapsed 2 years after maintaining hormone therapy, and the patient underwent additional hormone-induced remission therapy combined with azathioprine. LESSONS: The purpose of this research report is to enhance the awareness and understanding of IgG4-RD, emphasizing the necessity for personalized treatment strategies that take into account its recurrence, associations, and imaging features. This report provides valuable insights and guidance for clinicians in managing and diagnosing patients with IgG4-RD.

Unmet needs in biomarkers for autoimmune pancreatitis diagnosis.

Autoimmune pancreatitis (AIP) is a rare chronic autoimmune disorder. The diagnosis of AIP mainly depends on histopathology, imaging and response to treatment. Serum immunoglobulin 4 (IgG4) is used only as collateral evidence in diagnostic criteria for AIP because of its moderate sensitivity. Serum IgG4 levels are normal in 15%-37% of type 1 AIP and most of type 2 AIP patients. In these patients, the indeterminate imaging and histopathology may lead to the difficulty in definitive diagnosis of AIP. Therefore, discovery of new biomarkers is important for AIP diagnosis. Here, we provide some views on the progression and challenges in identifying novel serological biomarkers in AIP diagnosis.

Autoimmune pancreatitis: Cornerstones and future perspectives.

Autoimmune pancreatitis (AIP) is an autoimmune subtype of chronic pancreatitis resulting from the aberrant immune response against the pancreas, leading to inflammation and fibrosis. Although AIP is rare, its incidence is increasing and is often misdiagnosed as other pancreatic diseases. AIP is commonly classified into two types. Type 1 AIP (AIP-1) is typically associated with elevated serum immunoglobulin G4 (IgG4) levels and systemic manifestations, while type 2 AIP is typically a more localized form of the disease, and may coexist with other autoimmune disorders, especially inflammatory bowel diseases. Additionally, there is emerging recognition of a third type (type 3 AIP), which refers to immunotherapy-triggered AIP, although this classification is still gaining acceptance in medical literature. The clinical manifestations of AIP mainly include painless jaundice and weight loss. Elevated serum IgG4 levels are particularly characteristic of AIP-1. Diagnosis relies on a combination of clinical, laboratory, radiological, and histological findings, given the similarity of AIP symptoms to other pancreatic disorders. The mainstay of treatment for AIP is steroid therapy, which is effective in most cases. Severe cases might require additional imm-unosuppressive agents. This review aims to summarize the current knowledge of AIP, encompassing its epidemiology, etiology, clinical presentation, diagnosis, and treatment options. We also address the challenges and controversies in diagnosing and treating AIP, such as distinguishing it from pancreatic cancer and managing long-term treatment, highlighting the need for increased awareness and knowledge of this complex disease.

Association of autoimmune pancreatitis and intraductal papillary mucinous neoplasm. A retrospective analysis from a tertiary care referral center.

BACKGROUND: Autoimmune Pancreatitis (AIP) is a rare chronic inflammatory disease affecting the pancreas. Chronic pancreatic inflammation represents a risk factor for pre-neoplastic conditions such as Intraductal Papillary Mucinous Neoplasia (IPMN). Due to the rarity of AIP, the incidence, and clinical features of IPMN occurring in AIP patients remains unknown. AIMS: In the present study we aimed to explore the relationship between AIP and IPMN and to characterize the clinical features and outcomes of IPMN occurring in the context of AIP. METHODS: We retrospectively (2008-2020) analyzed the clinical and radiological records of a large single center cohort of patients with AIP and investigated the prevalence of IPMN. We then compared the clinical, laboratory and radiological characteristics of patients with IPMN and AIP with a cohort of patients with isolated IPMN. RESULTS: Five hundred and nineteen patients were included in this retrospective study. Sixteen patients had concomitant IPMN and AIP(3%); 61 patients had isolated AIP (12%); 442 patients had isolated IPMN (85%). The prevalence of IPMN in patients with AIP was higher than that observed in the general population (21%vs8-10%). Worrisome Features and High-Risk Stigmata were more frequently observed in IPMN occurring together with AIP compared to isolated IPMN(p < 0.05). Based on radiological features IPMN in the context of AIP was more frequently of main-duct type compared to isolated IPMN(p < 0.05). CONCLUSION: Our data suggest that AIP represents a chronic inflammatory condition that might favor IPMN development with high-risk features. Prolonged surveillance of these patients and longitudinal studies are required to further test the association with AIP and malignant and pre-malignant conditions.

Relapse and side effects of steroid therapy beyond 3 years in autoimmune pancreatitis: A multicenter retrospective study.

BACKGROUND: The impact of extended steroid administration on patients with autoimmune pancreatitis after a 3-year maintenance period remains poorly understood. This study analyzed the advantage and disadvantage of continuing steroid therapy beyond 3 years. METHODS: In this retrospective multicenter study across 17 institutions, patients who successfully completed 3 years of maintenance therapy without experiencing relapse were categorized into two groups: the maintenance therapy discontinuation group, who discontinued steroid therapy after the initial 3-year period, and maintenance therapy continuation group, who continued steroid therapy beyond 3 years. The cumulative relapse rate after 3 years of maintenance therapy was the primary outcome. Relapse predictors were compared using the Gray test for cumulative relapse incidence by specific factor. RESULTS: Of 211 patients, 105 experienced no relapse during the 3-year maintenance therapy and were divided into two groups: 69 in the maintenance therapy discontinuation group and 36 in the maintenance therapy continuation group. The relapse rate was lower in the maintenance therapy continuation group than in the maintenance therapy discontinuation group (P = 0.035). Predictors of relapse after 3 years included cessation of maintenance therapy (hazard ratio [HR] = 3.76; 95 % confidence interval [CI] = 1.07-13.3, P = 0.040) and renal involvement (HR = 2.88; 95 % CI = 1.04-7.99, P = 0.042). The maintenance therapy continuation group showed a significantly higher prevalence of macrovascular complications, compared with the maintenance therapy discontinuation group (P = 0.005). CONCLUSIONS: Cessation of steroid maintenance therapy and renal involvement were predictors of relapse after 3 years of maintenance therapy. However, the long-term use of steroids may increase the risk of macrovascular complications.

Maintenance steroid therapy is associated with decreased risk of malignancy and better prognosis of patients with autoimmune pancreatitis: A multicenter cohort study in Japan.

BACKGROUND/OBJECTIVES: The association between autoimmune pancreatitis (AIP) and pancreatic cancer (PC) remains controversial. This study aimed to clarify the long-term prognosis and risk of malignancies in AIP patients in Japan. METHODS: We conducted a multicenter retrospective cohort study on 1364 patients with type 1 AIP from 20 institutions in Japan. We calculated the standardized incidence ratio (SIR) for malignancies compared to that in the general population. We analyzed factors associated with overall survival, pancreatic exocrine insufficiency, diabetes mellitus, and osteoporosis. RESULTS: The SIR for all malignancies was increased (1.21 [95 % confidence interval: 1.05-1.41]) in patients with AIP. Among all malignancies, the SIR was highest for PC (3.22 [1.99-5.13]) and increased within 2 years and after 5 years of AIP diagnosis. Steroid use for ≥6 months and ≥50 months increased the risk of subsequent development of diabetes mellitus and osteoporosis, respectively. Age ≥65 years at AIP diagnosis (hazard ratio [HR] = 3.73) and the development of malignancies (HR = 2.63), including PC (HR = 7.81), were associated with a poor prognosis, whereas maintenance steroid therapy was associated with a better prognosis (HR = 0.35) in the multivariate analysis. Maintenance steroid therapy was associated with a better prognosis even after propensity score matching for age and sex. CONCLUSIONS: Patients with AIP are at increased risk of developing malignancy, especially PC. PC is a critical prognostic factor for patients with AIP. Although maintenance steroid therapy negatively impacts diabetes mellitus and osteoporosis, it is associated with decreased cancer risk and improved overall survival.

Can serum immunoglobulin G4 levels and age serve as reliable predictors of relapse in autoimmune pancreatitis?

We are writing in response to the paper published in the World Journal of Gastroenterology by Zhou et al. The authors identified higher serum immunoglobulin (Ig) G4 levels and age over 55 years as independent risk factors for disease relapse. Despite notable strengths, it is crucial to address potential biases. Firstly, the cohort study included 189 patients with autoimmune pancreatitis (AIP) type 1 (with higher IgG4 seropositivity and higher relapse) and 24 with type 2 (with lower IgG4 seropositivity and lower relapse). Consequently, most, if not all, AIP type 2 patients were assigned to the normal group, possibly inflating the association of higher serum IgG4 levels with relapse and potentially exaggerating the association of older age with relapse. Secondly, the authors did not provide sufficient details regarding AIP diagnosis, such as the ratio of definitive vs probable cases and the proportion of biopsies. In cases where histological evidence is unavailable or indeterminate, AIP type 2 may be misdiagnosed as definitive type 1, and type 1 may also be misdiagnosed as probable type 2, particularly in cases with normal or mildly elevated serum IgG4 levels. Lastly, in this retrospective study, approximately one-third of the consecutive patients initially collected were excluded for various reasons. Accordingly, the impact of non-random exclusion on relapse outcomes should be carefully considered. In conclusion, the paper by Zhou et al offers plausible, though not entirely compelling, evidence suggesting a predictive role of elevated serum IgG4 levels and advanced age in AIP relapse. The foundation for future investigations lies in ensuring a reliable diagnosis and accurate disease subtyping, heavily dependent on obtaining histological specimens. In this regard, endoscopic ultrasound-guided fine-needle biopsy emerges as a pivotal component of the diagnostic process, contributing to mitigating biases in future explorations of the disease.