Section 6 -

Pancreatitis and Other Lesions as Mimickers of Pancreatic Cancer Günter Klöppel, David S. Klimstra and N. Volkan Adsay Departments of Pathology University of Kiel, Kiel, Germany Memorial Sloan-Kettering Cancer Center, New York, New York, USA Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA

Introduction The nonneoplastic lesions of the pancreas that mimic pancreatic cancer may be divided into solid and cystic lesions. Both are detected by imaging methods as tumor-like lesions. These pseudoneoplastic changes of the pancreas are found in approx. 5% of the pancreatectomies performed with an initial clinical diagnosis of pancreatic cancer [2, 3, 21, 22]. The cystic changes that imitate cystic neoplasms of the pancreas have increased in recent years since improved imaging techniques are able to detect lesions as small as 1 cm [7, 12]. Nonneoplastic Lesions of the Pancreas that May Mimic Solid Pancreatic Cancer The most important nonneoplastic solid lesions that may form pseudotumors are autoimmune (lymphoplasmacytic sclerosing) pancreatitis, inflammatory myofibroblastic tumors associated with autoimmune pancreatitis, paraduodenal pancreatitis, infectious pseudotumors, ampullary adenomyoma, splenic heteropia, lipomatous pseudohypertrophy and hamartoma. Autoimmune (Lymphoplasmacytic Sclerosing) Pancreatitis Most cases of autoimmune pancreatitis (AIP) have been misdiagnosed clinically as ductal adenocarcinoma of the pancreatic head region [5, 9, 10, 14, 23, 24]. This is because AIP usually affects the pancreatic head and the distal bile duct, leading to narrowing of the bile duct and the pancreatic duct and swelling of the pancreatic head. As the main symptom of AIP, i.e. jaundice, often occurs within a few weeks and the patients are at the same age as patients with ductal adenocarcinomas, they fulfill many of the criteria for pancreatic cancer [3, 20, 23, 24]. The typical pathological features of AIP include periductal lymphoplasmacytic (and occasionally eosinophilic) infiltration with a distinctive type of sclerosis that expands into periductal, perilobular and intralobular areas. In addition, there may be intraepithelial neutrophils (i.e. granulocytic neutrophilic lesions), obliterative venulitis and arteritis and a dense infiltrate of IgG4-positive plasma cells [1, 14, 24]. Some of the patients develop intense myofibroblastic fibrosis that has been misdiagnosed as inflammatory myofibroblastic tumor [6, 10, 13]) . Interestingly, AIP is associated with retroperitoneal fibrosis, multifocal idiopathic fibrosclerosis, sclerosing mesenteritis and stenosing papillitis [3, 17]. From a number of reports, particularly from Japan, it is known that AIP may respond to steroid therapy, thus making a pancreatic resection unnecessary in some patients. Paraduodenal Pancreatitis Paraduodenal pancreatitis, also known as cystic dystrophy of heterotopic pancreas on duodenal wall, paraduodenal-duodenal wall cysts and groove pancreatitis [8, 18, 19], affects primarily the duodenal wall in the vicinity of the minor papilla. Usually, there is severe duodenal sclerosis with trabeculation of the duodenal musculature by a myofibroblastic stromal proliferation including lobules of pancreatic tissue, dilated ducts and pseudocysts. Pseudotumors associated with pancreas divisum also show similar characteristics [3]. Predominantly solid examples of paraduodenal pancreatitis are most apt to be misdiagnosed as pancreatic cancer. Paraduodenal pancreatitis is seen almost exclusively in males with a mean age of 50, a history of alcohol abuse, abdominal pain, weight loss and vomiting. Infectious Pseudotumors Infections of the pancreas forming pseudotumors are mainly of mycobacterial origin, i.e. tuberculosis. However, also fungal and parasitic infections as well as sarcoidosis may produce a tumorous swelling of the organ. Ampullary Adenomyoma This change is focused on the ampulla of Vater. Grossly, the ampulla of Vater is thickened and the distal bile duct may be narrowed. Histological examination reveals an accentuated and sometimes disorganized version of normal histological components of the ampulla of Vater, showing lobules of ducts lying within thickened muscle bundles. It is a very rare lesion, but when it occurs, it usually does so in patients in their early 60s. Splenic Heterotopia Accessory spleens mimic small solid tumors and are less than 2 cm in diameter. They are found in the tail of the pancreas and, because they are relatively homogeneous, round and well demarcated, are mostly mistaken for endocrine neoplasms. The lesion is usually detected in patients between 50 and 70 years of age. Lipomatous Pseudohypertrophy This rare change of the pancreas leads to a replacement of pancreatic tissue by mature benign fatty tissue. There is no fibrotic change. Lipomatous pseudohypertrophy has been observed in children as well as in adults [3]. Hamartoma Solid hamartomas have recently been described in the pancreas [15, 16]. They usually occur in adults and display sharply delimited solid and occasionally also cystic lesions. Histologically, they are composed of haphazardly distributed acinar, ductal and endocrine elements embedded in stromal tissue whose cells are positive for CD34 and occasionally also c-Kit (CD117). Cystic Nonneoplastic Lesions of the Pancreas Among the cystic lesions of nonneoplastic nature that may mimic cystic neoplasms of the pancreas are pseudocysts, lymphoepithelial cysts, cystic hamartomas, and mucinous noncystic lesions [4, 11, 12]. These lesions have to be distinguished from intraductal papillary-mucinous neoplasms, mucinous noncystic neoplasms, serous cystic neoplasms, solid pseudopapillary neoplasms, ductal adenocarcinoma with cystic structures, cystic endocrine neoplasms, acinar cell cystadenocarcinoma and acinar cell cystadenoma. Conclusion There are a number of solid and cystic mimickers of pancreatic cancer. The increasing knowledge of these lesions and changes and the improvements in imaging techniques will probably decrease their rate of misdiagnosis as pancreatic cancer. References Abraham SC, Leach S, Yeo CJ, Cameron JL, Murakata LA, Boitnott JK, Albores-Saavedra J, Hruban RH (2003) Eosinophilic pancreatitis and increased eosinophils in the pancreas. Am J Surg Pathol 27:334-342 Abraham SC, Wilentz RE, Yeo CJ, Sohn TA, Cameron JL, Boitnott JK, Hruban RH (2003) Pancreaticoduodenectomy (Whipple resections) in patients without malignancy. Are they all 'chronic pancreatitis'? Am J Surg Pathol 27:110-120 Adsay NV, Bandyopadhyay S, Basturk O, Othman M, Cheng JD, Klöppel G, Klimstra DS (2004) Chronic pancreatitis or pancreatic ductal adenocarcinoma? Semin Diagn Pathol 21:268-276 Adsay NV, Hasteh F, Cheng JD, Bejarano PA, Lauwers GY, Batts KP, Klöppel G, Klimstra DS (2002) Lymphoepithelial cysts of the pancreas: a report of 12 cases and a review of the literature. Mod Pathol 15:492-501 Ectors N, Maillet B, Aerts R, Geboes K, Donner A, Borchard F, Lankisch P, Stolte M, Lüttges J, Kremer B, Klöppel G (1997) Non-alcoholic duct destructive chronic pancreatitis. Gut 41:263-268 Esposito I, Bergmann F, Penzel R, di Mola FF, Shrikhande S, Büchler MW, Friess H, Otto HF (2004) Oligoclonal T-cell populations in an inflamatory pseudotumor of the pancreas possibly related to autoimmune pancreatitis: an immunohistochemical and molecular analysis. Virchows Arch 444:119-126 Fernandez-del Castillo C, Targarona J, Thayer SP, Rattner DW, Brugge WR, Warshaw AL (2003) Incidental pancreatic cysts: clinicopathologic characteristics and comparison with symptomatic patients. Arch Surg 138:427-433; discussion 433-434 Fléjou JF, Potet F, Molas G, Bernades P, Amouyal P, Fékété F (1993) Cystic dystrophy of the gastric and duodenal wall developing in heterotopic pancreas: an unrecognized entity. Gut 34:343-347 Hardacre JM, Iacobuzio-Donahue CA, Sohn TA, Abraham SC, Yeo CJ, Lillemoe KD, Choti MA, Campbell KA, Schulick RD, Hruban RH, Cameron JL, Leach SD (2003) Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis. Ann Surg 237:853-859 Klöppel G, Lüttges J, Löhr M, Zamboni G, Longnecker D (2003) Autoimmune pancreatitis: pathological, clinical, and immunological features. Pancreas 27:14-19 Kosmahl M, Pauser U, Anlauf M, Klöppel G (2005) Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform. Mod Pathol 18:1157-1164 Kosmahl M, Pauser U, Peters K, Sipos B, Lüttges J, Kremer B, Klöppel G (2004) Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal. Virchows Arch 445:168-178 Mizukami H, Yajima N, Wada R, Matsumoto K, Kojima M, Klöppel G, Yagihashi S (2006) Pancreatic malignant fibrous histiocytoma, inflammatory myofibroblastic tumor, and inflammatory pseudotumor related to autoimmune pancreatitis: characterization and differential diagnosis. Virchows Arch 448:552-560 Notohara K, Burgart LJ, Yadav D, Chari S, Smyrk TC (2003) Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases. Am J Surg Pathol 27:1119-1127 Pauser U, da Silva MTS, Placke J, Klimstra DS, Klöppel G (2005) Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117). Mod Pathol 18:1211-1216 Pauser U, Kosmahl M, Kruslin B, Klimstra DS, Klöppel G (2005) Pancreatic solid and cystic hamartoma in adults: characterization of a new tumorous lesion. Am J Surg Pathol 29:797-800 Sahin P, Pozsár J, Simon K, Íllyés G, László F, Topa L (2004) Autoimmune pancreatitis associated with immune-mediated inflammation of the papilla of Vater. Report on two cases. Pancreas 29:162-166 Solcia E, Capella C, Klöppel G (1997) Tumors of the pancreas. AFIP Atlas of Tumor Pathology, third series, fascicle 20. Armed Forces Institute of Pathology, Washington, D.C. Stolte M (1984) Chronische Pankreatitis: Morphologie, Pankreatographie, Differentialdiagnose. Perimed, Erlangen Suda K, Takase M, Fukumura Y, Ogura K, Ueda A, Matsuda T, Suzuki F (2005) Histopathologic characteristics of autoimmune pancreatitis based on comparison with chronic pancreatitis. Pancreas 30:355-358 van Gulik TM, Reeders JWAJ, Bosma A, Moojen TM, Smits NJ, Allema JH, Rauws EAJ, Offerhaus GJA, Obertop H, Gouma DJ (1997) Incidence and clinical findings of benign, inflammatory disease in patients resected for presumed pancreatic head cancer. Gastrointest Endosc 46:417-423 Wakabayashi T, Kawaura Y, Satomura Y, Watanabe H, Motoo Y, Okai T, Sawabu N (2003) Clinical and imaging features of autoimmune pancreatitis with focal pancreatic swelling or mass formation: comparison with so-called tumor-forming pancreatitis and pancreatic carcinoma. Am J Gastroenterol 98:2679-2687 Weber SM, Cubukcu-Dimopulo O, Palesty JA, Suriawinata A, Klimstra D, Brennan MF, Conlon K (2003) Lymphoplasmacytic sclerosing pancreatitis: inflammatory mimic of pancreatic carcinoma. J Gastrointest Surg 7:129-139 Zamboni G, Lüttges J, Capelli P, Frulloni L, Cavallini G, Pederzoli P, Leins A, Longnecker D, Klöppel G (2004) Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch 445:552-563