Calcifying Obstructive Pancreatitis: A Study of Intraductal Papillary Mucinous Neoplasm Associated With Pancreatic Calcification

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:57 63 Calcifying Obstructive Pancreatitis: A Study of Intraductal Papillary Mucinous Neoplasm Associated With Pancreatic Calcification MAURICIO ZAPIACH,* DHIRAJ YADAV,* THOMAS C. SMYRK, JOEL G. FLETCHER, RANDALL K. PEARSON,* JONATHAN E. CLAIN,* MICHAEL B. FARNELL, and SURESH T. CHARI* Divisions of *Gastroenterology and Hepatology, Anatomic Pathology, and Gastroenterologic and General Surgery; and Department of Radiology, Mayo Clinic Rochester, Rochester, Minnesota Background & Aims: We have observed intraductal papillary mucinous neoplasm (IPMN) associated with pancreatic calcification. The aim of this study is to describe the profile of IPMN associated with calcification and gain insights into the pathogenesis of calcification in IPMN. Methods: We identified 10 patients with IPMN with pancreatic calcification, of whom 7 underwent pancreatic resection. We reviewed demographic data, history of previous pancreatitis, and radiological and histological features of these patients. Results: In patients with IPMN with calcification (mean age, yr; 50% men), a diagnosis of chronic calcifying pancreatitis was entertained in 5 of 10 patients; 2 patients had undergone previous endoscopic therapy for stone removal. There was no previous history of pancreatitis in 9 of 10 patients. Radiologically, calcifications were seen diffusely throughout the gland in 8 of 10 patients and interpreted as chronic calcific pancreatitis. Although 1 of the 7 patients who underwent resection had diffuse IPMN throughout the gland, 6 patients had IPMN confined to the head or uncinate process (mean size, 2.75 cm; range, cm). Histologically, 6 of 7 IPMNs were adenomas, and 1 patient had invasive cancer. No patient had intratumoral calcification. All 7 patients had calcification within the main pancreatic duct and/or side branches, often within inspissated mucus. Conclusions: IPMN associated with pancreatic calcification can lead to misdiagnosis and inappropriate treatment for chronic calcifying pancreatitis. In the absence of intratumoral calcification or a previous history of long-standing chronic pancreatitis, calcification in IPMN likely represents a unique and hitherto unrecognized form of calcifying obstructive pancreatitis caused by prolonged partial obstruction of the pancreatic duct. Intraductal papillary mucinous neoplasm (IPMN) is being diagnosed with increasing frequency since it was first described in 1982 by Ohhashi. 1 However, IPMN is still often misdiagnosed as chronic pancreatitis because of symptoms of relapsing abdominal pain, pancreatitis, and steatorrhea and imaging findings of a dilated pancreatic duct. Pancreatic calcification generally is considered to be pathognomonic of chronic calcifying pancreatitis. Until 1998, only 6 cases of calcification associated with IPMN had been cited in the literature. 2 At the Mayo Clinic (Rochester, MN), we have seen more than 40 patients with IPMN in the past 3 years, 10 of whom have had calcification. The association of pancreatic calcification with IPMN further adds to the difficulty in distinguishing IPMN from chronic pancreatitis. There are several possible explanations for the occurrence of pancreatic calcification in IPMN. Calcification may be occurring in dysplastic tumoral tissue, IPMN may be a complication of long-standing chronic calcifying pancreatitis, or IPMN may predispose to a form of calcifying obstructive pancreatitis. Understanding the pathogenesis of calcification in IPMN has important implications for the management and treatment of these patients. For example, if calcification in IPMN were intratumoral, the presence of calcification throughout the gland would imply diffuse involvement of the gland by IPMN and require a total pancreatectomy for cure. However, if calcification were the result of chronic ductal obstruction, limited resection to remove the tumor and, consequently, the obstruction should suffice. The aim of this study is to describe clinical, radiological, and histological findings in patients with IPMN with calcification to gain insights into the pathogenesis of calcification in IPMN. Methods The study was approved by the Mayo Foundation Institutional Review Board. In the past 3 years, more than 40 Abbreviations used in this paper: CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; IPMN, intraductal papillary mucinous neoplasm by the American Gastroenterological Association /04/$30.00 PII: /S (04)

2 58 ZAPIACH ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 1 Table 1. Demographic Features, Alcohol Use, Smoking History, and Clinical Features at Presentation and Follow-up of the 10 Patients With IPMN With Calcification Patient no. Age (yr) Sex Alcohol consumption Smoking history History of pancreatitis Clinical features at presentation Weight loss Pancreatic insufficiency Jaundice 1 51 F None M 1 drink/wk M None F 2 drinks/d F None F None F None M 2 drinks/d a 9 62 M None M 2 drinks/wk 5 NOTE. Patients 1, 2, 6, 8, and 10 initially were diagnosed as having chronic calcifying pancreatitis. a Lost to follow-up., Ever used;, never used. Follow-up (mo) patients with IPMN have been diagnosed and treated at Mayo Clinic Rochester. Of these, 10 patients were noted to have pancreatic calcification on either computed tomography (CT) or endoscopic retrograde cholangiopancreatography (ERCP). We reviewed medical records of these 10 patients with attention to demographic data, including age, sex, race, presenting symptoms, and clinical history. All imaging studies (CT and ERCP) were reviewed by a single radiologist (J.G.F.), who was blinded to endoscopic and histological results. The location and distribution of the calcification were noted and classified as main pancreatic duct (i.e., intraluminal within the main pancreatic duct on axial images), peripheral (outside the main pancreatic duct), or combined main pancreatic duct and peripheral. When possible, patterns of calcification on CT and ERCP were correlated with pathological findings. A single pathologist (T.C.S.) reviewed all original sections of the 7 resected tumors. When necessary, additional sections were cut, stained, and reviewed. We noted tumor size in all patients and classified them according to World Health Organization criteria 3 (adenoma, n 6; invasive cancer, n 1). The location and distribution of the calcification seen histologically were classified as being in the main duct, side branches, or stroma. Figure 1. Non-contrast CT scan showing extensive pancreatic calcification in a patient (no. 2) with a small IPMN in the head of the pancreas. ERCP showed dilated pancreatic duct with mucin pouring out of the ampulla. Figure 2. ERCP showing a dilated pancreatic duct with multiple intraductal stones. Prior to referral to Mayo, patient (no. 1) was diagnosed with chronic pancreatitis and treated with stenting of pancreatic duct stricture and extracorporeal shockwave lithotripsy for dissolution of stones.

3 January 2004 CALCIFYING OBSTRUCTIVE PANCREATITIS 59 Table 2. Radiological Features of the 10 Patients With IPMN With Calcification Patient no. Number Focal/ diffuse Calcification MPD Location CT Peripheral Largest calculus (mm) Other radiological findings 1 5 Diffuse 10 Solid/cystic mass head of pancreas ERCP Pancreas divisum with pancreatic duct stricture, distally dilated duct with intraductal stones treated with extracorporeal shock-wave lithotripsy 2 10 Diffuse 10 Pancreatic atrophy Mucin extruding from ampulla, dilated and tortuous pancreatic duct 3 10 Diffuse 5 Pancreatic atrophy Normal-appearing ampulla, diffusely dilated pancreatic duct with ectatic side branches, mucin plug in pancreatic duct 4 10 Diffuse cm solid/cystic mass pancreatic head 5 5 Focal (tail) 6 10 Diffuse 5 Cystic lesion at the pancreatic head (before referral to Mayo Clinic) 7 5 Focal (head) Mucin extruding from ampulla, markedly dilated pancreatic duct, unable to fill duct beyond the neck of pancreas, likely due to obstructing stone 5 1-cm cyst in the head ERCP after pancreaticoduodenectomy: pancreatic duct not opacified ERCP after pancreaticoduodenectomy: irregular pancreatic duct with cystic side branches in the tail cm cystic lesion in the uncinate process 8 10 Diffuse 5 Dilated pancreatic duct, atrophy of distal gland 9 10 Diffuse 5 Diffuse ductal dilation with multiple cysts Diffuse 3 5 Cystic lesion at the head with nodal involvement CT, computed tomography; MPD, main pancreatic duct; ERCP, endoscopic retrograde cholangiopancreatography. Prominent ampulla, dilated biliary tree, dilated pancreatic duct with intraductal stones, pancreatic sphincterotomy done and stones extracted Mucin extruding from ampulla, dilated pancreatic duct with cystic dilations giving chain-of-lakes appearance Mucin extruding from ampulla, obstructing ampullary stone, cystic pancreatic duct dilation Mucin extruding from ampulla, 3-cm long pancreatic duct stricture, multiple filling defects Results Demographic and Clinical Features Mean age of patients with IPMN with calcification was years, and 50% were men (Table 1). Nine of 10 patients with IPMN with calcification had no history of pancreatitis before presentation with IPMN. Eight patients had evidence of pancreatic insufficiency before the diagnosis of IPMN (diabetes, n 4; steatorrhea, n 4). Radiological Features at CT and ERCP The radiological appearance of calcification on CT was indistinguishable from that seen in alcoholic chronic calcifying pancreatitis (Figures 1 and 2). Calcification was located only within the main pancreatic duct in 1 patient, peripherally in 3 patients, and both within the main pancreatic duct and peripherally in 6 patients. Eight patients had numerous calcifications spread diffusely throughout the gland, whereas the remaining 2 patients had focal calcification. ERCP showed intraductal stones or debris in 4 patients, all of whom also had calcifications within the main duct on CT. On duodenoscopy, mucin was seen pouring from the ampulla in 5 of 10 patients, whereas 1 patient had a mucin plug in the pancreatic duct (Table 2). In the 7 patients who underwent surgical resection, a cystic lesion was seen on CT in 6 patients (5 lesions, in the head; 1 lesion, in the uncinate process; Table 2). Histological Features Of 7 patients who underwent surgical resection, 5 patients had IPMN confined to the pancreatic head; 1 patient, in the uncinate process; and 1 patient, involving the entire gland (Table 3). Mean tumor size in patients with focal disease was 2.75 cm (n 6; range, 1.1 5cm). The pancreas was firm in consistency, with a beanbag feel because of its multiple intraductal stones. On histological examination of the resected specimen, 6 of 7

4 60 ZAPIACH ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 1 Table 3. Surgical Procedure, Pathological Features of IPMN, and Distribution of Calcification on Histological Examination in the 7 Patients Who Underwent Surgical Resection IPMN Calcification Patient no. Surgical procedure Indication for surgery 1 Pancreaticoduodenectomy Obstructive jaundice with cystic lesion in the head of the pancreas 2 Total pancreatectomy IPMN suspected because of mucin pouring out of ampulla on ERCP 3 Pancreaticoduodenectomy IPMN suspected because of diffusely dilated pancreatic duct with ectatic side branches and mucin plug in pancreatic duct 4 Total pancreatectomy IPMN suspected due to mucin pouring out of ampulla on ERCP 5 Pancreaticoduodenectomy IPMN suspected due to cystic lesion head of pancreas 6 Pancreaticoduodenectomy followed by completion total pancreatectomy Persistent pain following resection of IPMN in the head of pancreas 24 months prior at an outside institution 7 Pancreaticoduodenectomy Multiple cystic lesions head of pancreas with jaundice Location Dimensions (cm) Histology Main duct Side branches Intratumoral Head Invasive cancer Head Adenoma Head Adenoma Head Adenoma Uncinate Adenoma Diffuse Adenoma Head Adenoma ERCP, endoscopic retrograde cholangiopancreatography; IPMN, intraductal papillary-mucinous neoplasm. patients had adenoma, and 1 patient had invasive cancer. One patient (no. 10) had an unresectable cancer diagnosed by fine-needle aspiration of the pancreatic head lesion. All patients who underwent resection (n 7) had intraluminal calcification in the main duct (Figure 3A and B) and side branches, often within inspissated mucus (Figure 4A), indistinguishable from that seen in chronic calcifying pancreatitis. Calcification also was seen in the pancreatic duct wall (Figure 4B), and there was no intratumoral calcification. Diagnosis of IPMN and Indication for Surgery The initial diagnosis of IPMN was made by a variety of methods. Seven of 10 patients were diagnosed endoscopically, whereas in the remaining 3 patients (no. 1, 6, and 7), the diagnosis was preoperatively suspected, but only confirmed after resection. Five of the 7 patients diagnosed endoscopically had a prominent ampulla with mucin pouring out of it, 1 patient had a mucin plug, and 1 patient was noted to have mucinous intraductal debris. In addition, 5 of these patients also underwent imaging studies notable for cystic lesions in either the pancreatic head or uncinate process. In 2 patients (no. 1 and 7), surgery was performed to remove a cystic lesion in the pancreatic head that was causing obstructive jaundice. One patient (no. 6) underwent a completion pancreatectomy for persistent pain after a resection for IPMN of the pancreatic head 24 months previously at an outside institution. Discussion We report 10 patients with IPMN and pancreatic calcification. In most patients, the calcification was extensive, indistinguishable from chronic calcifying pancreatitis on imaging studies. This led to a delay in the diagnosis of IPMN and inappropriate endoscopic therapy. Chronic pancreatitis has been classified broadly into chronic calcifying pancreatitis and chronic obstructive pancreatitis. 4 The majority of patients with chronic calcifying pancreatitis, usually referred to in the literature simply as chronic pancreatitis, develop pancreatic calcification. Conversely, chronic obstructive pancreatitis in-

5 January 2004 CALCIFYING OBSTRUCTIVE PANCREATITIS 61 Figure 3. (A and B) Calcification in peripherally located small ducts. (B) There is also duct wall calcification. Note that there is no IPMN associated with the calcification. variably is caused by ductal obstruction and is not associated with pancreatic calcification. 4 We propose that IPMN causes a unique form of calcifying obstructive pancreatitis. IPMN is not uncommonly misdiagnosed as chronic pancreatitis because of its similar clinical presentation, with recurrent pancreatitis, steatorrhea, and jaundice, as well as its radiological findings of cystic lesions that are frequently confused with pseudocysts. In a patient with pancreatic calcification, the diagnosis of IPMN becomes considerably more challenging. Additionally, misdiagnosis of IPMN as chronic pancreatitis can lead to serious errors in management, illustrated by 2 of our patients. One of our patients was treated with sphincterotomy and stone removal, whereas another patient was being treated with pancreatic duct stenting and extracorporeal shockwave lithotripsy for months before being referred to our institution. Our study shows that IPMN should be considered in the differential diagnosis of chronic calcific pancreatitis. In patients with calcification, the presence of a markedly dilated pancreatic duct and 1 or more persistent cystic lesions should raise the suspicion of IPMN. The presence of mucin in the pancreatic duct, identified by mucin Figure 4. (A) Intraluminal and (B) duct wall calcification. (A) Squamous metaplasia is seen in adjacent duct. Pancreatic ducts shown were located remotely from the region of pancreas involved by IPMN.

6 62 ZAPIACH ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 1 pouring out of a gaping ampulla on duodenoscopy or by cyst puncture, confirms the diagnosis of IPMN. Ultimately, when other modalities have been nondiagnostic, as in 3 of our patients, only surgical resection can confirm the diagnosis. What is the pathogenesis of calcification in IPMN? Apart from the highly unlikely possibility of coincidentally occurring IPMN and chronic calcifying pancreatitis, there are 3 possible explanations for the calcification seen in IPMN. First, it may be the result of tumoral calcification, as seen in an array of other slow-growing pancreatic neoplasms, such as in serous or mucinous cystadenomas. 5 9 The central sunburst calcifications seen in serous cystadenomas are considered a pathognomonic finding for this entity, whereas rim calcifications indicate malignant transformation in mucinous cystic neoplasm. 5,6 Tumoral calcification also has been reported in solid-pseudopapillary neoplasms and rarely in ductal adenocarcinomas. 7,8 Although they are not neoplasms, pancreatic pseudocysts also have been known to calcify. 9 In our patients, careful histological examination did not show tumoral calcification in any patient. The calcification tended to be diffuse and remote from the tumor, which was often fairly small, and located in the head of the pancreas. A second explanation for calcification in IPMN could be that the tumor developed as a complication of longstanding chronic calcifying pancreatitis. Epidemiological studies have shown that irrespective of cause, chronic calcifying pancreatitis predisposes to ductal adenocarcinoma, and the risk increases with duration of pancreatitis. 10 Although the exact pathogenesis of ductal adenocarcinoma in chronic pancreatitis is not known, it is believed that increased cell turnover caused by chronic inflammation and smoking has a significant role. 3,10 Pancreatic intraepithelial neoplasms are preneoplastic lesions that also have been reported in chronic pancreatitis and resemble the histological stages of IPMN. 11,12 Consequently, it is possible that chronic pancreatitis could predispose some patients to develop IPMN, rather than ductal adenocarcinoma. In our series, only 1 patient gave a history suggestive of recurrent pancreatitis. In all other patients, IPMN was prospectively or retrospectively identified at the onset of symptoms. In our clinical practice, we have seen patients with established chronic calcific pancreatitis develop ductal adenocarcinoma, but we have yet to see 1 patient develop IPMN. It is highly unlikely that the 10 patients in our series developed IPMN as a complication of long-standing chronic calcifying pancreatitis. A third explanation for calcification is that in IPMN, chronic partial ductal obstruction predisposes to intraductal calcification. All patients with IPMN with ductal obstruction develop an obstructive form of chronic pancreatitis in the gland upstream from the obstruction. This is similar to findings in patients with ductal adenocarcinoma or other forms of ductal obstruction. However, calcification rarely, if ever, develops in obstructive pancreatitis secondary to neoplastic, traumatic, or postpancreatitis stricture. 13,14 The novelty of our observations is that we describe an obstructive form of pancreatitis in which extensive calcifications develop and delay or obscure the diagnosis of an underlying IPMN. Experimental studies in dogs have shown that pancreatolithiasis occurs with partial, rather than complete, obstruction of the duct Moreover, in these canine studies, the incidence of calcification increased with the duration of obstruction, such that 50% of these dogs developed calcifying lesions by 4 months. 17,18 In humans with obstructive pancreatitis who present with recurrent pancreatitis and pain, the obstruction is dealt with expeditiously, and the pain is relieved promptly. Therefore, the duration of obstruction is not long enough to precipitate calcifications in the majority of patients with obstructive pancreatitis. However, IPMN is a slow-growing neoplasm that may take several years to be diagnosed. 19,20 We believe that intermittent obstruction of the pancreatic duct by mucin and/or intraductal tumor in IPMN leads to intraductal calcification. Thus, IPMN represents a novel and unusual form of calcifying obstructive pancreatitis. References 1. Ohhashi K. Four cases of mucin producing cancer of the pancreas on specific findings of the papilla of vater. Prog Dig Endosc 1982;20: Origuchi N, Kimura W, Muto T, Esaki Y. Pancreatic mucin-producing adenocarcinoma associated with a pancreatic stone: report of a case. Surg Today 1998;28: Longnecker DS, Adler G, Hruban RH, Kloppel G. Intraductal papillary-mucinous neoplasms of the pancreas. In: Hamilton SR, Aaltonen LA, eds. World Health Organization classification of tumours. Pathology and genetics of tumours of the digestive system. Lyon: IARC Press, 2000: Singer MV, Gyr K, Sarles H. Revised classification of pancreatitis. Report of the Second International Symposium on the Classification of Pancreatitis in Marseille, France, March 28 30, Gastroenterology 1985;89: Warshaw AL, Compton CC, Lewandrowski K, et al. Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 1990;212: ; discussion, Furukawa H, Takayasu K, Mukai K, et al. Ductal adenocarcinoma of the pancreas associated with intratumoral calcification. Int J Pancreatol 1995;17: Kim T, Murakami T, Takahashi S, et al. Ductal adenocarcinoma of

7 January 2004 CALCIFYING OBSTRUCTIVE PANCREATITIS 63 the pancreas with intratumoral calcification. Abdom Imaging 1999;24: Machiki Y, Nimura Y, Kamiya J, et al. Clinicopathologic study on pancreatic cancer associated with pancreatic stones. Int J Pancreatol 1997;22: Demos TC, Posniak HV, Harmath C, et al. Cystic lesions of the pancreas. AJR Am J Roentgenol 2002;179: Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993;328: Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity. Ann Surg 2001;234: ; discussion, Biankin AV, Biankin SA, Kench JG, et al. Aberrant p16(ink4a) and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma. Gut 2002;50: Suda K, Mogaki M, Oyama T, et al. Histopathologic and immunohistochemical studies on alcoholic pancreatitis and chronic obstructive pancreatitis: special emphasis on ductal obstruction and genesis of pancreatitis. Am J Gastroenterol 1990;85: Sahel J, Cros RC, Durbec JP, et al. Multicenter pathological study of chronic pancreatitis. Morphological regional variations and differences between chronic calcifying pancreatitis and obstructive pancreatitis. Pancreas 1986;1: Layer P, Yamamoto H, Kalthoff L, et al. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994;107: Ammann RW, Akovbiantz A, Largiader F, et al. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984;86: Konishi K, Izumi R, Kato O, et al. Experimental pancreatolithiasis in the dog. Surgery 1981;89: Sakakibara A, Okumura N, Hayakawa T, et al. Ultrastructural changes in the exocrine pancreas of experimental pancreatolithiasis in dogs. Am J Gastroenterol 1982;77: Kloppel G. Clinicopathologic view of intraductal papillary-mucinous tumor of the pancreas. Hepatogastroenterology 1998;45: Loftus EV Jr, Olivares-Pakzad BA, Batts KP, et al. Intraductal papillary-mucinous tumors of the pancreas: clinicopathologic features, outcome, and nomenclature. Members of the Pancreas Clinic, and Pancreatic Surgeons of Mayo Clinic. Gastroenterology 1996;110: Address requests for reprints to: Suresh T. Chari, M.D., 200 First Street SW, Mayo Clinic, Rochester, Minnesota chari.suresh@mayo.edu; fax: (507)