Increase diagnostic accuracy in differentiating focal type autoimmune pancreatitis from pancreatic cancer with combined serum IgG4 and CA19-9 levels

Abstract

Background/objectives

To distinguish autoimmune pancreatitis (AIP), especially focal type, from pancreatic cancer, is a greatest challenge for clinician. The aim of the study is to compare the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of combined serum IgG4 and CA19-9 levels to differentiate AIP from pancreatic cancer by HISORt, Asian and international consensus diagnostic criteria.

Methods

We measured serum IgG4, CEA, and CA19-9 levels in 188 AIP patients, 86 non-AIP chronic pancreatitis patients, and 130 pancreatic cancer patients. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were compared with different diagnostic criteria. We also compared the diagnostic performance in patients with or without jaundice.

Results

The serum level of IgG4 was significantly higher in AIP than those in non-AIP chronic pancreatitis and pancreatic cancer. The optimal cutoffs of IgG4 and CA19-9 to differentiate AIP from pancreatic cancer were 175 mg/dL and 85.0 U/ml based on ROC analysis. Combining IgG4 level over 280 mg/dL and CA19-9 below 85.0 U/ml could yield a best diagnostic accuracy (85.6%) to distinguishing AIP from pancreatic cancer in all of the HISORt, Asian and international consensus diagnostic criteria. With the combination of serological test, focal type AIP could be diagnosed with comparable accuracy as diffuse type AIP.

Conclusions

Our study demonstrated that combined use of serum IgG4 (over 280 mg/dL) and CA19-9 9 (below 85.0 U/ml) together increases the diagnostic accuracy to distinguish AIP from pancreatic cancer non-invasively, especially in focal type autoimmune pancreatitis.

Introduction

Autoimmune pancreatitis (AIP) is a unique type of chronic pancreatitis characterized by elevated serum immunoglobulin G4 (IgG4), swelling of pancreas, irregular narrowing of main pancreatic duct, histological evidence of lymphoplasmacytic inflammation, and a good response to steroid therapy [1]. Although some advance has been made in the diagnosis and treatment of AIP over the past years [2], the diagnosis of AIP is still a great clinical challenge, especially in the differential diagnosis from pancreatic cancer [3], [4], [5].

Hamano et al. firstly reported that elevation in serum IgG4 was a characteristic feature of AIP [6]. The elevated serum IgG4 level with different cut-offs has been used to constitute one of the items of different diagnostic criteria of AIP. In 2002, the Japan Pancreas Society proposed the diagnostic criteria for AIP based on imaging, serology, and histology. At that time, the serological criteria included elevated γ-globulin, immunoglobulin G (IgG), and auto-antibodies [7]. In 2006, the revised Japanese criteria were modified and added IgG4 to the serological criteria [8]. In 2008, the Asian diagnostic criteria proposed to use IgG, and auto-antibodies or IgG4 as the serological criteria but γ-globulin was deleted [9]. In the United States, the HISORt criteria allow only serum IgG4 as the serological criterion [10], [11]. In 2011, the international consensus diagnostic criteria (ICDC) were proposed to use serum IgG4 alone as the serological criterion for type I AIP. In the ICDC criteria, the serum IgG4 level was further classified into two levels according to cutoffs set at 140 and 280 mg/dL to diagnose the type I AIP [12]. However, focal or tumor forming AIP, different from typical diffuse type AIP, is difficult to distinguish from pancreatic cancer [13]. The cutoff of serum IgG4 levels in differentiating pancreatic cancer from AIP with atypical pancreatic imaging (especially the focal type enlargement) remains to be elucidated. Sumimoto K. et al. recently compared the diagnostic ability of 5 criteria, including ICDC, Korean, Asian, JPS-2011, and HISORt criteria, in 61 patients with AIP and 56 patients with pancreatic cancer [14]. They found that by serology, the accuracy, sensitivity, and specificity of level 1 serology by ICDC criterion were 75.3%, 63.6%, and 96.7%, respectively, while those of level 2 were 91.8%, 90.9%, and 93.3%, respectively [14]. However, their results were based on a small population and needed to be verified in larger and different populations. CA19-9, considered as a biomarker in pancreatic cancer, could also elevate in other pancreatic diseases such as chronic pancreatitis or other pathological status [15]. Till now, it still lacks a simple serological test to diagnose and to differentiate AIP from pancreatic cancer.

The first aim of this study was to evaluate whether the combined measurement of serum IgG4 and CA19-9 could increase the diagnostic accuracy for AIP from pancreatic cancer in different diagnostic settings including HISORT, Asian, and ICDC criteria in serology aspect. The second aim of this study was to determine the optimal way to diagnose focal type AIP and differentiate it from pancreatic cancer by serology.