Desmond P Toomey1, Niall Swan2 William Torreggiani3, Kevin C Conlon1
1Professorial Surgical Unit, 2Department of Pathology, and 3Department of Radiology, The University of Dublin, Trinity College, Adelaide and Meath Hospitals Incorporating the National Children’s Hospital, Tallaght. Dublin, Republic of Ireland
Received January 24th, 2007 - Accepted April 3rd, 2007
Context Autoimmune pancreatitis is characterised by a lymphoplasmacytic infiltrate consisting in part of plasma cells that produce large amounts of IgG4. It can manifest as focal or diffuse enlargement of the pancreas with associated strictures of the pancreato-bilary tree giving rise to symptoms including abdominal pain, weight loss and obstructive jaundice; thus it can be extremely difficult in both presentation and investigation to distinguish from pancreatic carcinoma. Recent advances now facilitate preoperative diagnosis and effective medical management, including steroid treatment of autoimmune pancreatitis so preventing major surgical intervention. Case report Two cases of autoimmune pancreatitis are described, each of which presented with obstructive jaundice and a relatively painless pancreatic mass, one with vascular involvement. They each had elevated serum CA 19-9 and ultimately required surgical exploration to definitely exclude malignancy before embarking on non operative treatment. The first case settled spontaneously while the second rapidly improved with steroid treatment. Conclusion These two cases illustrate the difficulties in diagnosing this condition, the efficacy of steroid therapy and the role of surgical intervention in unresponsive cases or those where a diagnostic dilemma remains.
Autoimmune Diseases; Immunoglobulin G; Pancreatic Neoplasms; Pancreatitis; Steroids
AIP: autoimmune pancreatitis
Approximately 2% of patients operated on for an apparently malignant pancreatic mass are found instead to have a subtype of chronic pancreatitis characterised by a lymphoplasmacytic infiltrate [1, 2]. The classical risk factors of alcohol excess and familial pancreatitis are absent in these cases . Previously it has had many different classifications such as “non alcoholic duct destructive pancreatitis”, however this condition is currently referred to as “lymphoplasmacytic sclerosing pancreatitis” or in reference to its likely pathogenesis “autoimmune pancreatitis” (AIP) [2, 5, 6]. Due to remarkably similar clinical and radiological profiles, AIP can be extremely difficult to distinguish from malignancy, in many cases provoking major pancreatic resection . Recently, steroids have emerged as an effective treatment and, with a preoperative diagnosis, can prevent surgical intervention [7, 8, 9]. We present two Irish patients with AIP and review the literature, to clarify the salient issues surrounding its diagnosis and management, in particular to highlight the features that distinguish it from cancer and the need for surgical exploration in ambiguous cases.
A 47-year-old lady presented with a 3 day history of epigastric pain, new onset pale stools and dark urine and 14 kg weight loss in the previous 8 months. Her past history is unremarkable apart from a partial colectomy for a diverticular bleed. She was a non smoker and did not drink alcohol. On admission she was noted to be jaundiced, her liver function tests had an obstructive pattern (Table 1) and her CA 19.9 was elevated at 444.7 U/mL (reference range: 0-60 U/mL).
Abdominal ultrasound demonstrated a dilated common bile and intrahepatic ducts with a possible mass in the head of her pancreas. Endoscopic retrograde cholangiopancreatography (ERCP) delineated a tapered stricture of the distal common bile duct consistent with a pancreatic neoplasm. The patient was transferred to a tertiary centre where computed tomography (CT) confirmed intraand extra-hepatic duct dilatation although the pancreatic duct was obscured. There was also a 1.5 cm mass in the head of the pancreas which involved the superior mesenteric vein. This was highly suspicious for (“but not definitely”) pancreatic adenocarcinoma (Figure 1a).
As carcinoma could not be adequately excluded, the patient proceeded to staging laparoscopy, which showed no sign of metastatic disease. Open examination of the pancreas then revealed that the organ was grossly inflamed throughout and unresectable however it was questionable whether any mass or tumour was present. Pancreatic head biopsies were taken and a choledochojejunostomy was fashioned.
Histological examination of the biopsies showed no evidence of malignancy but demonstrated all four cardinal features of AIP (Figure 2). These histological findings alone fulfilled the Mayo Clinic diagnostic criteria  and when combined with the ERCP and CT images also satisfied the Japanese criteria . Following biliary bypass the patients jaundice receded and her CA 19-9 returned to normal levels (17.4 U/mL). As the patient’s symptoms had settled while awaiting histology results, steroids were not com- menced and she was discharged home with tramadol hydrochloride for any recurrent pain and oral pancreatic enzyme supplements for pancreatic exocrine insufficiency.
She re-presented 5 months post operatively complaining of right upper quadrant pain. CT showed marked resolution of the pancreatic abnormalities (Figure 1b). She was not jaundiced however her liver function tests were abnormal (Table 1) with a hepatitic pattern prompting a liver biopsy which showed a mild cholestatic and portal lobular inflammation suggestive of mild chronic hepatitis. This was reported as consistent with several possible diagnoses including common bile duct obstruction, primary sclerosing cholangitis and primary biliary cirrhosis. A slightly raised IgG at 16.7 g/L (reference range: 6-16 g/L) (IgG4 quantification was not available at that time), and positive autoantibodies (namely anti-nuclear antibody: 1:80, homogenous), anti-dsDNA antibody and anti-smooth muscle antibody raised the suspicion of autoimmune hepatitis and a diagnosis of overlap syndrome (metachronous or synchronous autoimmune pancreatitis and hepatitis) was made. Her symptoms settled spontaneously and her liver function tests now show only mild derangement (Table 1).
She was subsequently assessed for a complaint of dry mouth and dry eyes and, based on a salivary gland biopsy and positive anti-salivary gland antibodies, a diagnosis of Sjögren’s syndrome was made for which she was prescribed artificial tears and saliva. She is currently 2.5 years post laparotomy and continues to do well. Her pain returns episodically and is managed with simple analgesia, she has a good appetite and has gained weight.
A 59-year-old lady, with a background history of hypercholesterolaemia, was referred for a tertiary opinion with an eight week history of slight epigastric discomfort, unquantified weight loss and jaundice, which had not resolved despite halting statin therapy. Her biochemical investigations suggested a hepatitic picture (Figure 3) which was supported by ultrasound imaging showing a diffusely echogenic pattern with periportal distribution. However, both ultrasound and subsequent computed tomography of her abdomen delineated a solid mass in the body of her pancreas with no evidence of biliary tree or pancreatic duct dilatation (Figure 4a). Her CA 19-9 was elevated at 426 U/mL. Hepatitis A, B and C serology, as well as liver auto-antibodies, were negative and she denied any excessive alcohol consumption. Fine needle aspiration cytology from the pancreatic mass showed some atypical epithelial cells, moderately suggestive of malignancy, and occasional inflammatory cells. A differential diagnosis of hepatotoxicity secondary to rosuvastatin with concomitant pancreatic mass, possibly carcinoma, or autoimmune pancreatitis and biliary sclerosis was made. The patient underwent a diagnostic laparoscopy with laparoscopic ultrasound which demonstrated no evidence of malignancy, a segmental hyperaemia of the pancreas with a diffusely enlarged pancreatic neck and no ductal dilatation. Histology of an intra-operative liver biopsy suggested cholestatic hepatitis consistent with drug induced injury, primary biliary cirrhosis or primary sclerosing cholangitis while hepatic artery lymph node biopsies showed reactive changes and not malignancy. IgG4 level was within the normal range (0.535 g/L; reference range: 0.045-1.635 g/L).
Although not all diagnostic criteria for AIP, either American  or Japanese criteria were satisfied, malignancy had been adequately excluded and so oral prednisolone therapy (40 mg daily followed by reducing dose over 8 weeks to zero) was commenced based on a working diagnosis of AIP. There was resolution of the pancreatic mass on follow up CT, four weeks later (Figure 4b), with some residual fullness of the body, which coupled with a marked improvement of the patient’s jaundice and a reduction in CA 19-9 to 118 U/mL, supported this diagnosis. Repeat CT 4 months later (Figure 4c) showed resolution of this fullness and the patient continues to do well 6 months post operatively.
Two atypical cases of AIP are presented which demonstrate the role of surgical exploration when all diagnostic criteria cannot be fulfilled. AIP has a spectrum of morphology from a focal, tumorifactive process, most often in the head of the pancreas, but also in the body and tail, to a disease that is diffusely distributed throughout the organ [2, 12, 13]. It can be difficult, particularly in the former scenario, to confidently rule out carcinoma before initiating medical treatment .
In Case 1, histology was required to enable a diagnosis. All four cardinal histological features of AIP, namely lymphoplasmacytic infiltration of the pancreas with a periportal distribution of inflammation, interstitial fibrosis and periphlebitis (Figure 2), are necessary for a diagnosis . The lymphoplasmacytic infiltrate consists of lymphocytes and plasma cells (often producing high levels of IgG4)  with occasional macrophages, neutrophils and eosinophils. The resultant interstitial fibrosis
centres on the medium and large intralobular ducts [4, 6, 15, 16, 17] but may involve the smaller ducts in advanced cases and generally results in luminal narrowing without the distal dilatation seen with malignant lesions . The vasculitic element is usually limited to a phlebitis of the venules with arterial sparing [5, 15, 17, 19]. In advanced disease the acini can become inflamed and sclerotic with loss of the normal architecture [2, 4].
Similar infiltration and fibrosis of the biliary tree, which is strongly associated with focal disease of the pancreatic head, also occurs and culminates in obstructive jaundice, a common presenting symptom. As seen in Case 2, where the mass is distant from the common bile duct, obstructive jaundice is likely due to this duct wall infiltration and not ductal compression by the mass. Follicular hyperplasia, present in both patients, may also result in local lymphadenopathy [2, 4, 5, 15, 17, 19].
Case 1 later presented with metachronous hepatitis and Sjögren’s syndrome, both autoimmune diseases associated with AIP. Similarities between AIP and primary sclerosing cholangitis suggest an autoimmune aetiology and numerous series and case reports link AIP with different autoimmune diseases (Table 2) [2, 3, 4, 5, 11, 16, 19, 20, 21, 22, 23, 24]. In many cases a similar lymphoplasmacytic infiltrate has been found in other symptomatic organs . A significant proportion of patients produce auto-antibodies against carboanhydrase II, nuclear antigen, lactoferrin and smooth muscle and this, in combination with the disease regression invoked by steroids, is suggestive of an autoimmune origin [2, 16, 18, 19, 22].
AIP most commonly presents in men in the 6th and 7th decade however cases as young as 10-year-old have been reported [1, 6, 15, 18, 19, 25]. The incidence of this condition remains obscure but seems to account for 4 to 11% of chronic pancreatitis cases [14, 26]. Both patients had a classical presentation of mild abdominal pain, obstructive jaundice, anorexia and weight loss [4, 5, 6, 9, 15, 19], notably similar to the presenting complaint in patients with pancreatic cancer. By definition, AIP occurs in the absence of the normal risk factors for pancreatitis. Up to 40% of cases have a clinical history of other autoimmune diseases [3, 4, 6, 22]. Other fibrotic diseases, including members of the multifocal idiopathic fibrosclerosis family of diseases and inflammatory pseudotumour, may also occur synchronously or metachronously with AIP [5, 11, 23, 24].
Serum IgG4 levels can distinguish between masses due to AIP and pancreatic cancer with levels corresponding with disease activity. Although, according to Hamano et al. , a cut-off level of 135 mg/dL was 95% sensitive and 97% specific for distinguishing between AIP and pancreatic cancer, results that are supported by Hirano et al. ; serum IgG4 was either unavailable or unhelpful in both these patients, demonstrating the need for expansive diagnostic criteria. Quantification of serum autoimmune antibodies and rheumatoid factor may demonstrate elevated levels but their specificity is low and they may be indicative of an autoimmune comorbidity . Serum CA 19-9, a marker usually associated with cancer, may be elevated in AIP [12, 15] as seen in both these patients, however, this may be associated with jaundice rather than the specific disease process.
Depending on the morphology of the disease in a given patient, CT can delineate a diffuse enlargement of the pancreas or a mass/focal fullness [3, 6, 15]. The latter are most common in the head and may be multiple but both frequently resemble malignancy . Furthermore, there may be bilary tree dilatation with thickening of the bile duct walls. Distinguishing CT features of AIP include minimal/absent peripancreatic stranding, an organ with a sharp outline and homogenous attenuation, absence of vascular encasement and a halo of low attenuation secondary to fibro-inflammatory changes in peripancreatic adipose tissue [3, 15, 18, 21, 28]. In addition, we have found that, unlike invasive ductal carcinoma, there is no pancreatic ductal dilatation associated with lesions of the pancreatic neck, body and tail. Unusually, the mass in Case 1 involved the superior mesenteric vein and neither patient demonstrated the classical halo.
Although magnetic resonance cholangiopancreatography can show primary sclerosing cholangitis-like, intra-hepatic duct beading, or stricture of the pancreato-biliary tree it is inferior to endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography [18, 19, 28, 29].
Transabdominal ultrasound is relatively non specific in AIP; however, the ongoing development of contrast enhanced ultrasonography, which characterises lesions by dynamic imaging of vascularity and perfusion patterns, is a promising new imaging tool for differentiating these masses from cancer [30, 31]. Endoscopic ultrasound (EUS) may complement CT findings by imaging diffuse or focal organ enlargement and altered echotexture . Guided fine needle aspiration cytology, as utilized in Case 2, has a role limited to detection of malignant cells as histology is required for a pathological diagnosis of AIP. The false negative rate of core biopsy (possibly due to the focal nature of this disease) may be minimised by use of transabdominal ultrasound or EUS guided core biopsy [18, 32]. The technique of using IgG4 positive lymphoplasmacytic infiltrates from biopsies of other involved organs to support the diagnosis of AIP was not available in either case as they had no synchronous disease.
Recent advances in the treatment of AIP has produced alternatives to surgical resection. Improved preoperative diagnosis allows for a trial of medical treatment with close follow up to ensure adequate disease regression. There are isolated reports of spontaneous resolution of these pancreatic masses, similar to Case 1 ; however, recent evidence supports the use of steroids, as in Case 2. Steroids can induce sustained and often complete, clinical and radiological remission with normalization of laboratory results, improvement or disappearance of pancreato-biliary strictures and restoration of organ function [7, 8, 9, 12, 18, 22, 34, 35, 36]. However, a significant proportion of patients experience relapses of pancreatitis, duct strictures and extrapancreatic manifestations with corresponding fluctuations in IgG4 levels . Also steroids have been successfully used to treat recurrent strictures in cases where previous resection has provided a histopathological diagnosis .
Several groups have composed diagnostic criteria in an effort to avoid surgical exploration without risking misdiagnosing malignancy. Previous publications from Japan relied quite heavily on radiological criteria  but a recent audit from the Mayo Clinic has suggested an algorithm which has a strong emphasis on clinical, serological and histological factors with less weighting of radiological results (Table 3) . Their use of steroids as a diagnostic modality is controversial and care must be taken to ensure that malignancy is not inappropriately treated . We generally will employ a short trial of steroid treatment in cases where a clinical and radiological or histological suspicion of AIP is combined with a raised IgG4 level allowing improving symptoms, imaging and serology to verify the diagnosis. However, the described cases illustrate failings in the existing criteria and the need to maintain a low threshold for surgical exploration, either laparoscopic or open, where diagnostic doubts exist or disease is unresponsive or progressive.
Surgical resection, when required, is more treacherous than that for cancer . We have found that a very vigorous peripancreatic, fibrotic reaction distorts surgical planes and strongly adheres the organ to the peripancreatic vessels making dissection difficult in significantly more cases resulting in higher blood losses and longer operating times. Furthermore, these cases tend towards higher overall complication rates . In conclusion, AIP has a significant prevalence and can be difficult to distinguish from malignancy but it is being recognised more frequently than before. Although it often shows a good response to steroids, surgical exploration or resection are still required in cases where any doubt remains about a possible diagnosis of malignancy or when symptoms fail to respond to medical treatment.
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