Controversies in Clinical Pancreatology

Abstract

ArticlePlus Click on the links below to access all the ArticlePlus for this article. Please note that ArticlePlus files may launch a viewer application outside of your web browser. https://links.lww.com/MPA/A1 INTRODUCTION Dr. William M. Steinberg The term “autoimmune pancreatitis” (AIP) has been used to define a relatively new syndrome of clinical and histologic findings. This entity has been described in several articles published in Europe and Japan, yet few cases have been seen or reported in the United States. Therefore, it was thought that this was a timely topic for discussion at our Controversies in Clinical Pancreatology session at the American Pancreatic Association meetings on November 14, 2002. Five discussants participated in this session. Dr. Randall Pearson of the Gastroenterology Section, Mayo Clinic presented a case, and Dr. Dan Longnecker of the Department of Pathology, Dartmouth-Hitchcock Medical Center discussed the pathology. Dr. Suresh Chari of the Gastroenterology Section, Mayo Clinic, Dr. Kazuichi Okazaki of the Gastroenterology Section, Kyoto University, and Dr. Luca Frulloni of the Gastroenterology Section, University of Verona then proceeded with reports of the Mayo Clinic, Japanese, and Italian experiences with this syndrome. Finally, the discussants kindly submitted the following manuscripts for this article. BACKGROUND INDETERMINANT PANCREATIC MASS Dr. Randall K. Pearson A 53-year-old white woman in generally good health (postcholecystectomy) felt vaguely unwell for nearly 4 months with dyspeptic symptoms, two episodes of nausea and diarrhea characterized as “flu,” and a 20-pound weight loss. Two weeks prior, she noted dark urine, pale stools, and scleral icterus. She had no known history of pancreatitis, drank minimal amounts of alcohol, and had no family history of chronic pancreatitis. Biochemical studies confirmed jaundice, and computed tomography (CT) of the abdomen showed dilatation of the biliary tree down to the level of the pancreas. The pancreas was generally enlarged, but the cause of the obstruction was not obvious. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a distal bile duct stricture that was stented, and she was referred to the Mayo Clinic. After endoscopic stenting, she felt progressively better and was essentially without complaints. Her physical examination was normal. Laboratory studies were consistent with resolving obstructive jaundice. A CA 19-9 level was mildly elevated at 91.4 U/mL (normal, <40 U/mL). Repeat triple-phase contrast CT with thin cuts through the pancreas failed to reveal a mass or cause for biliary obstruction. Endoscopic ultrasound findings were suspicious for malignancy; a 3-cm mixed echogenicity region in the head was prominently seen in the setting of diffuse alteration in the parenchyma consistent with pancreatitis. Fine-needle aspiration of the mass and peripancreatic lymph nodes was negative. ERCP (Fig. 1) confirmed the distal bile duct stricture; a limited pancreatogram showed a normal duct in the head with slight narrowing at the neck of the pancreas and irregularity in the tail (Fig. 2).FIGURE 1.: Retrograde cholangiogram demonstrating a distal common bile duct stricture with proximal dilatation.FIGURE 2.: Mildly irregular pancreatic duct observed with endoscopic pancreatography.The patient underwent laparotomy, and a pancreaticoduodenectomy (Whipple resection) was performed. PATHOLOGY OF AUTOIMMUNE PANCREATITIS Dr. Daniel Longnecker The pathologic changes found in cases of pancreatitis associated with other autoimmune diseases, such as Sjögren disease and extrahepatic sclerosing cholangitis, 1 can be divided into two groups. The first group includes constant features characteristic and suggestive of AIP, i.e., found in all cases, and the second group comprises variable features seen in a fraction of cases that, when present, provide additional support for the diagnosis. On gross examination, the involved pancreas is firm or hard (a constant feature) and may be enlarged or “mass forming.” These features may lead to resection because of the suspicion that the lesion is a carcinoma. The lesion may be limited to one portion of the pancreas, most often the head, or less commonly may involve the body, tail, or whole organ. Thus, location in the pancreas, mass formation, and pancreatic enlargement are variable features. At the histologic level, the characteristic changes include sclerosing pancreatitis (Fig. 3) with prominent infiltrating lymphocytes and plasma cells, and conspicuous involvement of ducts in the inflammatory process (Fig. 4). The main duct, branch ducts, and the common bile duct (CBD) are commonly involved. Localization of the infiltrate in the duct wall is variable–-sometimes subepithelial (Figs. 4 and 5), sometimes focused in the stroma of the duct wall, and sometimes diffusely involving all layers and adjacent connective tissue. Immunostaining has demonstrated that T cells predominate over B cells among the infiltrating lymphocytes. 1 The lumen of inflamed ducts is characteristically narrowed (Fig. 4B), and scarring or edema may thicken their walls.FIGURE 3.: This field shows sclerosing pancreatitis with perilobular fibrosis and some atrophy of acinar tissue in lobules. This pancreas contained typical areas of ductal inflammation as described for autoimmune pancreatitis. Hematoxylin and eosin (H & E).FIGURE 4.: Large pancreatic ducts with a prominent subepithelial lymphoplasmacytic infiltrate, with thickening of the duct wall (A and B) and compression of the lumen (B). This specimen was classified as chronic pancreatitis, etiology unknown, when it was originally seen but in retrospect is regarded as autoimmune pancreatitis; H & E.FIGURE 5.: Lymphocytes and plasma cells are conspicuous in this duct, where they infiltrate the subepithelial layer and extend into the lumen (left). A few granulocytes are also present in the infiltrate. Figures 3–5 are from the same pancreas; H & E.Variable features include the presence of eosinophils or neutrophils in the leukocytic infiltrate, degree of epithelial injury and inflammation in the ducts, presence of vasculitis (veins more than arteries), and degree of acinar cell atrophy, scarring, and inflammation in lobular tissue. The epithelium of involved ducts is well preserved in some patients, whereas the infiltrate extends into the epithelium and lumen in others. Fibrosis may be perilobular but commonly extends into the lobules as acinar cells atrophy. Conspicuous negatives typically include the absence of calculi in ducts, absence of pseudocyst, and absence of more than minimal fat necrosis. Are these changes specific for AIP? There is growing confidence that AIP is a legitimate pathologic diagnosis for some cases of sclerosing pancreatitis that have the constant features of AIP and lack stigmata of alcoholic chronic pancreatitis. 1 However, many pathologists are more comfortable with a descriptive diagnosis, such as lymphoplasmacytic sclerosing pancreatitis (LPSP). In the past, cases of AIP have often been included with idiopathic chronic pancreatitis. Why are the changes so variable? One obvious explanation is that the lesions change with duration or progression of the disease. This seems certain to be at least part of the basis for the spectrum of changes. Another possible factor is that the immune response is triggered by different epitopes with varying cellular targets in patients with differing histologic changes. Thus, one pending issue is whether there are recognizable subtypes of AIP with different etiologies, different pathologic features, and perhaps different clinical courses. The patient presented by Dr. Pearson had a Whipple resection that included a 4.7-cm portion of the head of the pancreas containing a firm 3 × 2 × 2 cm mass. There were no stones or cysts. Histologic sections showed sclerosing chronic pancreatitis with a somewhat irregular distribution of lobular inflammation, fibrosis, and atrophy. A large pancreatic duct contained a conspicuous subepithelial leukocytic infiltrate consisting of lymphocytes and plasma cells. Medium-sized ducts in the same section contained a lymphoplasmacytic infiltrate throughout the fibrous wall (Fig. 6). Perilobular fibrous tissue contained leukocytic aggregates of lymphocytes, fewer plasma cells, and prominent eosinophils. A few lymphoid follicles were present in these scarred areas. Neutrophils were inconspicuous, and there were no stigmata of pancreatitis, such as fat or The ducts were of calculi or The diagnosis was pancreatitis involving 3 × 2 × 2 cm with slight stricture of the distal common bile The features of this the spectrum of described as typical of duct by lymphocytes and plasma cells throughout the wall in the pancreas from the patient presented by Dr. a by Dr. Mayo Clinic, H & OF PANCREATITIS Suresh Chari and In a of patients for but the most common diagnosis was 2 This idiopathic inflammatory pancreatitis has also been autoimmune pancreatitis, pancreatitis, and chronic inflammatory of the pancreas. The of reports of AIP have from Japan, with few reports from is not whether this the of the disease or a to it in cases, patients with chronic pancreatitis as chronic pancreatitis with a pancreatic mass or obstructive jaundice. The of these studies have been reported in a of our findings. a of pancreatic for disease at the Mayo Clinic in and patients the for our lymphoplasmacytic inflammation, no known cause for pancreatitis, and with a mass or obstructive The of patients with idiopathic was 2 and the duration of was 3 two of patients presented with jaundice, of had minimal or no patient had a or family history of autoimmune One patient had and one had One of the patients with idiopathic of had diffuse enlargement of the pancreas on studies and 3 at The most findings on ERCP were in the bile duct, pancreatic duct, or was in 1 patient had distal and 1 had of the patients were with or and has had a on the presence of two histologic The have lymphoplasmacytic sclerosing pancreatitis, to be a more Thus, there was prominent inflammation, inflammation and fibrosis also into pancreatic parenchyma and peripancreatic tissue (Fig. was a and consistent duct epithelium to the of the patients were classified with features inflammation without duct and fibrosis extend into parenchyma and peripancreatic tissue is seen second was characterized by inflammatory infiltrate involving lobules and pancreatic ducts (Fig. The infiltrate was to the pancreas. was with The inflammatory infiltrate involved the wall of pancreatic ducts, and epithelial was commonly seen with obstruction of was the descriptive term idiopathic pancreatitis and cases to this has inflammation but includes and there is to epithelium (A and is less in fibrous areas and the of the clinical patients with and was the of jaundice, in of patients with but in of of with A of reports and have described patients with a pancreatic mass to have a of chronic inflammatory pancreatitis. The presence of a in and a response to has the of the term on include pancreatitis, and chronic inflammatory of the pancreas. the AIP and sclerosing pancreatitis have been used the absence of specific it all are the same disease. the patients with idiopathic described in our have the same disease as that described by as sclerosing pancreatitis or AIP? This is to with because reports of sclerosing pancreatitis or AIP have used and response to to the diagnosis, and is generally not all of our patients have but to lack of clinical suspicion of AIP and the absence of associated autoimmune of our patients had the of idiopathic described in our that described as AIP or sclerosing pancreatitis. may be a to a new term to a with because and were may be that our and are part of the spectrum of the same disease or perhaps different of the same disease. it these two histologic as a possible to different for this the features seen in our patients with are to described by as pancreatitis. was described in 1 of their patients, and that patient had Sjögren syndrome. Thus, it may be that some in and in the may from the that there is more than one of chronic inflammatory pancreatitis. inflammatory pancreatitis is a of histologic injury observed in patients with idiopathic have described two histologic subtypes and and but it is not whether and are the same disease or two or more different The of the mass of AUTOIMMUNE Dr. Kazuichi Okazaki and of AIP observed a of pancreatitis with of pancreatitis with other autoimmune diseases, such as Sjögren has been These findings to the of pancreatitis, autoimmune pancreatitis. it has not yet been as a new clinical the present section reports experiences of AIP in the and of AIP are the characteristic findings in most cases of AIP can be as of or presence of diffuse enlargement of the pancreas; diffusely irregular narrowing of the main pancreatic duct and of bile duct on ERCP changes with no or symptoms, without of pancreatitis; pancreatic or with other autoimmune diseases, and AIP is a the is than cases have been reported as AIP or pancreatitis with narrowing of the pancreatic duct in the cases of AIP in a of cases of chronic pancreatitis, and in in the of or AIP is more than of the cases are is whether the of AIP with other autoimmune from for was by the and contained pancreatic and findings 1) and associated with AIP often narrowing of the in the may in dilatation of the biliary changes of the bile duct to sclerosing are with shows on biliary lesions in patients with AIP, that the of biliary lesions in AIP may be different from typical for autoimmune pancreatitis, by the pancreatitis and associated is often observed in patients with AIP and the has 2 with some patients the is from T cells and the of may be by Clinical with AIP have no or slight in the or in to to other associated Thus, clinical are different from or pancreatitis. to the of the is characteristic for AIP and is in other of pancreatitis. Laboratory with AIP of pancreatic and presence of several such as and and However, the specific for is observed (Fig. and are in the ductal cells of several the pancreas, biliary duct, and distal of immune and the of immune are often in patients with with and in the and these patients, other such as autoimmune or biliary be After many findings are of in and were in and of cases, of the cases showed or and showed that immune these are and tomography and the diffusely enlarged pancreas, with a (Fig. and a on on and on Pancreatic or is ERCP of the AIP patients or diffuse narrowing of the main pancreatic duct (Figs. cholangiopancreatography shows pancreatic duct it can well of the bile ducts in the in dilatation of the biliary changes of the bile ducts to are sometimes is for changes of the biliary and pancreatic ducts (Fig. CT of enlarged pancreas to is typical of autoimmune pancreatitis. CT often After the of the pancreas often ERCP of In the diffusely irregular narrowing of the main pancreatic duct is In the many patients narrowing of common bile duct and pancreatic of the bile duct is to be by compression of the pancreas. After most patients as in the ERCP of ERCP the irregular narrowing of the main pancreatic duct in the pancreatic tail and narrowing in the pancreatic head narrowing is observed in more than one of the but not in the pancreas. After most of these findings of patients with cases, showed diffuse narrowing in the pancreatic duct, 3 from the head to body, 2 in the head, and 4 in the cholangiogram associated with cholangiogram narrowing of or biliary is observed in of patients with from typical these findings to changes with of lymphocytes and the pancreatic duct (Fig. are often on pancreatic duct or acinar cells. T cells infiltrate over B cells in the pancreas, plasma cells and lymph follicles are are on the pancreatic duct cells and on T cells, that autoimmune may be involved in In some patients with AIP, cells predominate over cells. Therefore, to may be in the or of AIP, whereas may be involved in disease process and findings of the pancreas in of lymphocytes and and changes were observed the pancreatic In most cases, T lymphocytes infiltrate over B lymphocytes with and most AIP patients, for pancreatitis is not patients with jaundice, or endoscopic biliary is often in cases by is for narrowing of the bile ducts and pancreatic is that some patients may without The of AIP is In our in the of pancreatitis, to be a clinical AUTOIMMUNE Luca Frulloni and has been as a in patients from pancreatitis. In the term chronic pancreatitis” to define a disease characterized by autoimmune the pancreatic ducts, in inflammatory fibrosis of the pancreatic duct that the in the of the disease was immune a in the epithelium of the pancreatic ducts, with inflammatory T by have been used for this of pancreatitis, such as chronic sclerosing “autoimmune and The was used to the pathologic of the inflammatory process but some the than the histologic In our perhaps term can for this disease is to and the in the of for of this of chronic pancreatitis. of not the of AIP in or in the at In a Italian by the University of Verona on the of chronic pancreatitis in that involved and patients from chronic pancreatitis 2 and was as associated factor in patients this is of the because there are many associated with the disease. The first is of the by first patients from this of pancreatitis and it as pancreatic In all inflammatory pancreatitis in more than of patients Whipple for pancreatic not pathologists but also and to Finally, there are not yet for the diagnosis of of the pancreatitis is a disease with different clinical In our patients with a diagnosis of it may as pancreatitis of involving all or a part of the pancreatic In some patients the clinical and pancreatic are to observed in chronic pancreatitis. of it may present as a that a mass generally in the head of the pancreas a pancreatic of these patients are of at the of the disease. may be the main clinical when the common bile duct is by a pancreatic mass of In some patients, in with a history of may or are than of all but their presence not the diagnosis of patients but some patients more than of a and one more than a In the past, these patients were classified as alcoholic chronic pancreatitis. in other cases, is a The to is one to The at is as in chronic pancreatitis. However, may patients at and the distribution of patients is more to that observed with idiopathic pancreatitis than with alcoholic chronic pancreatitis. to the The diagnosis of AIP is patients with AIP have their and some and and histologic findings. not with this because in our have found most of these not specific for the disease. the of and have been reported to be in patients with AIP, may be elevated not in patients with AIP but also in patients with other of pancreatitis, such as pancreatitis associated with obstructive pancreatitis, and of the wall in our 4 was reported as a specific of AIP, is not so In the plasma of are in patients with AIP and in with pancreatic other of chronic pancreatitis, or pancreatitis. In our the main for the diagnosis of AIP are and the with other autoimmune diseases, of the such as sclerosing cholangitis, and Sjögren and response to the for the diagnosis of AIP, but The main findings are the presence of a T the ducts, and of the pancreatic At may the of the pancreatic duct with of granulocytes in a a fibrosis the lumen duct and a of the duct may in the by the for the first The of patients underwent for a mass on the head of the pancreas and in the diagnosis was chronic pancreatitis. may to AIP in these However, because other of chronic pancreatitis may a pancreatic not AIP not but also pancreatitis or of the wall these patients, a and to clinical and histologic findings typical for the different of pancreatitis. In clinical to the disease can be in inflammatory cells plasma cells, with epithelial cells not the and of this for AIP, for a diagnosis with pancreatic In our was in of patients with a diagnosis of AIP, but this is a a involving patients with a mass of the pancreas to the of aspiration to patients with AIP or pancreatic A second is the with autoimmune may autoimmune in more than of our The most common is of and less common are sclerosing cholangitis, and Sjögren syndrome. In cases, observed autoimmune autoimmune and autoimmune the diagnosis of autoimmune was the of pancreatitis in the patients, may to a diagnosis of However, in the of patients, the diagnosis was the of pancreatitis, because for In may or of the in these In other for patients with AIP, the presence of associated disease may the diagnosis, but not present at the of the for The main to AIP is the response to articles have been published that the clinical of in these some also demonstrated the of histologic findings of the pancreas with of the pancreatic that of patients with a mass in the head of the pancreas had pancreatic so are for to have clinical and that may with this In our observed some more typical for pancreatic and more typical for AIP but aspiration a may a patient with there is a clinical history suggestive for AIP and the diagnosis with aspiration at of to this all patients and in with of all patients with 1 a few patients with chronic AIP a with to of autoimmune pancreatitis from pancreatic it a patients with AIP for a and pancreatic patients were in good and a few observed one patient from the diagnosis of One of patients underwent resection of the head of the pancreas with a clinical and diagnosis of pancreatic The of and was the of patients underwent pancreatic were present in of disease is a new of pancreatitis that may be as pancreatitis, chronic pancreatitis, or pancreatic The most common clinical of AIP may be a at with no pancreatic a clinical history of autoimmune of the and presence of jaundice. may a slight of a normal main pancreatic duct, the absence of pancreatic and involvement on examination of this The diagnosis is and is the in the presence of a However, the diagnosis may be with and histologic to a diagnosis of pancreatic and for this a of and to when and to the Dr. William M. Steinberg The sections a syndrome with and histologic have the of the and in to at some of of are that patients with this present with obstructive with a mass in the head of the pancreas. all histologic features on the of The response to when it has been can also be the not this response as a for the The have seen patients with obstructive jaundice, pancreatitis, and chronic pancreatitis. The and Mayo Clinic experiences of obstructive jaundice. The and on the of associated autoimmune the Mayo Clinic findings The and and as and relatively specific for this The Italian not these findings are Mayo is limited in this to be The entity of AIP, may be clinical syndrome. This discussion be a to the diagnosis in the clinical with obstructive jaundice, they are or have of or associated autoimmune diseases, may a of resection to their disease Dr. chronic pancreatitis is clinical entity that may be for pancreatitis, other of chronic pancreatitis, or pancreatic to pancreatic resection of with The clinical have been well 5), but the is and the cellular is Clinical of autoimmune to autoimmune pancreatitis include sclerosing pancreatitis, inflammatory pancreatitis, lymphoplasmacytic pancreatitis, chronic pancreatitis with diffuse narrowing of the pancreatic duct, and sclerosing the Mayo group 3 has that this disease be included the of chronic pancreatitis and into lymphoplasmacytic sclerosing pancreatitis and idiopathic duct pancreatitis seems that the and is the of the The in is more involving the parenchyma and In the is to lobules and the This is a and more than also because autoimmune pancreatitis with and without other autoimmune diseases, bile duct and narrowing of the portion of the common bile sclerosing associated with autoimmune pancreatitis include Sjögren or biliary Okazaki and that it is whether the of and autoimmune pancreatitis and whether patients originally with autoimmune pancreatitis other autoimmune by the cellular immune of autoimmune pancreatitis are In patients and in a and were specific for sclerosing pancreatitis. this is this of autoimmune pancreatitis from other pancreatitis, or associated with other autoimmune that is not specific for autoimmune pancreatitis, but not provide This is a and also found that the of the was in autoimmune pancreatitis to in chronic pancreatitis. the may the of autoimmune pancreatitis, it is whether or the of the are in patients with autoimmune have clinical findings of pancreatitis, these of patients were not by or Thus, at this there is no specific for autoimmune and on In of the of autoimmune pancreatitis and of the Dr. Longnecker the of autoimmune pancreatitis lymphocytes and plasma cells and conspicuous involvement of the ducts in the inflammatory of T cells over B cells, scarring and edema of the is that this of the of autoimmune pancreatitis provide the to there is the the for diagnosis be tissue diagnosis. The and of pancreatic the of a tissue diagnosis, and the diagnosis be to be the diffuse of the disease. autoimmune pancreatitis be as with other autoimmune and with other autoimmune the of the autoimmune pancreatitis may to be to because other autoimmune are not at diagnosis of autoimmune pancreatitis or may Dr. Longnecker Dr. Mayo Clinic, and Dr. University of for the of histologic from AIP patients for the of this