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Case report
Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases Q2
Eva C. Vaquero a, Maria T. Salcedo b, Míriam Cuatrecasas c, Hannah De Leon d, Xavier Merino e, Salvador Navarro a, Àngels Ginès a, Monder Abu-Suboh f, Joaquim Balsells g, Laureano Fernández-Cruz h, Xavier Molero d, * a
Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBEREHD, IDIBAPS, Barcelona, Spain Department of Pathology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic, University of Barcelona and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Barcelona, Spain d Exocrine Pancreatic Diseases Research Group, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain e Department of Radiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain f Department of Endoscopy, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain g Department of Surgery, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain h Department of Surgery, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBEREHD, IDIBAPS, Barcelona, Spain b c
a b s t r a c t
Q1
Keywords: Autoimmune pancreatitis IPMN CFTR IgG4 Chronic pancreatitis
Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation. Copyright Ó 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
1. Introduction Intraduct papillary mucinous neoplasm (IPMN) of the pancreas is characterized by neoplastic intraductal papillary epithelial growth, mucin production and cystic dilatation of the ducts [1]. A number of IPMNs may progress towards invasive carcinoma, which are often difficult to distinguish from pancreatic ductal adenocarcinoma (PDAC) [2]. Both IPMN and PDAC may be associated with chronic pancreatitis in the surrounding pancreas (fibrosis, acinar cell atrophy and occasional inflammatory infiltrate) [3] thought to be the result of obstructive or inflammatory
* Corresponding author. Exocrine Pancreatic Diseases Research Group, Institut de Recerca Hospital Universitari Vall d’Hebron, Pg Vall d’Hebron 119-129, Barcelona 08035, Spain. E-mail address: [email protected] (X. Molero).
pancreatitis in the nearby tissue. However, some IPMNs and PDACs arise on long evolving chronic pancreatitis, raising the suspicion that IPMN and PDAC may develop on a chronic pancreatitis background. Certainly, chronic pancreatitis seems to be an independent risk factor for IPMN [4], as much as it is for PDAC [5]. On the other hand, patients at risk of genetically-determined pancreatic cancer may disclose IPMN and/or chronic pancreatitis features either at imaging or at histology [6]. Furthermore, a family history of PDAC is also a risk factor for IPMN [4]. Altogether, these findings suggest that pathogenetic mechanisms involved in IPMN, chronic pancreatitis and PDAC development may be related. Autoimmune pancreatitis (AIP) is a particular form of chronic pancreatitis [7]. Two major forms of AIP (type-1 and -2) have been described that differ in both clinical and histologic patterns [8]. The combination of periductal lymphoplasmacytic infiltration, increased IgG4þ cells, storiform fibrosis, and obliterative phlebitis
http://dx.doi.org/10.1016/j.pan.2014.04.032 1424-3903/Copyright Ó 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Please cite this article in press as: Vaquero EC, et al., Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases, Pancreatology (2014), http://dx.doi.org/10.1016/j.pan.2014.04.032
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is considered to be characteristic of type-1 AIP according to the Honolulu diagnostic criteria [9] and sufficient to establish the diagnosis according to the Guidelines of the International Association of Pancreatology [7]. Type-1 AIP appears to affect older individuals who may have raised serum levels of IgG4. In addition, type-1 AIP may be a part of IgG4-related disease, a condition for which diagnostic criteria have been redefined in the so-called “Boston criteria”: increased tissue IgG4þ cells >50/HPF and IgG4þ/IgGþ ratio >40% in conjunction with other histological features of PAI is highly specific for IgG4-related pancreatitis [10]. Type-2 AIP is defined by the presence of granulocytic epithelial lesions (GELs) and none or few IgG4þ cells [7,9]. The long-term natural history of AIP, and particularly its relationship to cancer, remains a focus of clinical concern. Recent reports show the occurrence of a number of neoplasias at various organs, including the pancreas, in patients with type-1 AIP [11]. Moreover, type-1 AIP has been reported in association with both PDAC and IPMN in a very limited number of patients [12,13]. In this report we describe the clinical, radiological and histological features of two patients presenting with IPMN associated with chronic pancreatitis displaying morphological features fulfilling the Honolulu and Boston diagnostic criteria for type-1 AIP. Characteristic AIP lesions were not limited to the pancreas surrounding IPMN, but diffusely involved the whole pancreas and extrapancreatic tissues. One of the patients carried a CFTR class I mutation. Interestingly, a) previous pancreatic resection of focal IPMN did not show features of AIP, and b) serum IgG4 levels gradually decreased to normal values after IPMN resection. 2. Case reports 2.1. Case 1 A 74 year-old woman was referred to our Unit for evaluation of a pancreatic tumor. She smoked 20 cigarettes a day but denied alcohol consumption. She had high blood pressure and diabetes mellitus from the age of 69. At 72 she had a ventriculoperitoneal shunt placement for normotensive hydrocephaly. She complained of intermittent diarrhea and irregular abdominal pain attributed to local irritation of the peritoneal shunt. Her blood tests were unremarkable except for raised IgG4 levels (256 mg/dL; normal A/-genotype. Magnetic resonance imaging (MRI) revealed severe atrophy of the pancreatic head with a filiform MPD. At the body-tail transition a 1.5 cm solid-microcystic tumor was identified that induced slight upstream dilatation of the MPD and severe atrophy of the pancreatic tail. A large lymph node 2.5 cm in diameter was detected adjacent to the tumor (Fig. 1). Endoscopic ultrasonography (EUS)-guided fine-needle aspiration
cytology revealed cells with normal nuclei and mucinous cytoplasm. A body-tail pancreatectomy was performed that revealed cystic dilation of the MPD entirely surrounded by a fibroinflammatory tumor-like mass with ill-defined borders measuring 2 1.8 cm. The epithelium of the cyst showed mucinous hyperplasia with focal papillary structures (Fig. 2A) of biliary-pancreatic phenotype (MUC1þ, MUC2, MUC4þ) and signs of moderate dysplasia (p53þ, CEA). The whole pancreas showed intense periductal lymphoplasmacytic inflammation with >50 IgG4þ plasma cells/HPF in at least 3 different fields (Fig. 2B). The IgG4þ/ IgGþ ratio was 71.6 7.4% (mean SEM). The epithelial lining of the ducts was preserved and GELs were not found. The pancreatic parenchyma was replaced by a dense fibrous stroma showing a focal storiform pattern. Obliterative phlebitis was easily detected. Islets were preserved. Lymph nodes had a hyperplastic follicular reaction without atypia and increased IgG4þ plasma cells with an IgG4þ/IgGþ ratio of 78.1 2.3%. On follow-up serum IgG4 gradually decreased from 256 to 227, and 218 mg/dL, and finally it became undetectable (50 IgG4þ plasma cells/HPF, obliterative phlebitis and dense fibrosis. The whole resected pancreas was diffusely involved except for intestinal-type IPMN detected in some peripheral ducts. Increased IgG4þ cells and lymphoplasmacytic infiltration were also present in the gallbladder and in peripancreatic lymph nodes. The IgG4þ/IgGþ ratio on the pancreas, gallbladder and lymph nodes was 41.4 6.3%, 79.2 4.7% and 44.7 2.5%. Serum IgG4 was not determined. The pancreatic tail resected 6 years before had no histological criteria of AIP and IgG4þ plasma cells were scarce or absent.
Fig. 1. MRI findings of case 1. Left panel: 1.5 cm tumor at the body of the pancreas (black arrow) with upstream dilatation of the main pancreatic duct (white arrow). Right panel: Severe atrophy of the pancreatic tail (white arrow). Juxtapancreatic 2.5 cm lymph node (black arrow).
Please cite this article in press as: Vaquero EC, et al., Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases, Pancreatology (2014), http://dx.doi.org/10.1016/j.pan.2014.04.032
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Fig. 2. Microphotograph samples of case 1. A: IPMN surrounded by a dense fibrous tissue and isolated groups of pancreatic acini (hematoxylin and eosin, OM 100). B: IgG4 immunohistoquemistry. Dense fibrous stroma, intense lymphoplasmacytic inflammation and abundant IgG4-positive plasma cells within the inflammatory infiltrate surrounding a ductal lumen (OM 100). OM: original magnification.
3. Discussion Several aspects of these two clinical reports deserve attention. The association of AIP and IPMN has only been described recently in a few case reports [12,13], all of them being IgG4-related (type-1 AIP). In most of these cases histological lesions suggesting AIP were confined to the vicinity of IPMN and in only 3 cases lesions of AIP were detected distant to IPMN. In the two case reports described here lesions characteristic of type-1 AIP embraced the whole resected specimen and there was also evidence for lymphoplasmacytic infiltration and increased IgG4þ cells in peripancreatic lymph nodes and the gallbladder. These findings support the diagnosis of type-1 AIP as a credited differentiated entity from coincident IPMN. Being two rare diseases, it is remarkable to find coexisting AIP and IPMN. The proportion of patients developing PDAC from chronic pancreatitis of any etiology is estimated to be 4% [5] and IPMN is just a particular form of pancreatic neoplasm that may evolve to invasive carcinoma. Type-1 AIP may also be associated to cancer development in several organs, including the pancreas [11]. From the above reasoning it could be tempting to consider type-1 AIP a predisposing condition for IPMN. However, this association may be purely coincidental since none of the two series that recently evaluated cancer incidence after a firm diagnosis of type-1 AIP have reported IPMN formation [11]. In this report we show histological proof of IPMN being present years before the onset of newly generated AIP that finally involved the whole pancreas and extrapancreatic tissues. We can only speculate on possible casual relationships between AIP and IPMN, although the observation that serum IgG4 levels gradually decreased after IPMN excision is intriguing and may invite to consider IPMN as a predisposing factor for AIP initiation. On the other hand, common risk factors may play together to facilitate AIP and IPMN inception (and perhaps cancer) independent of each other. Both patients in this report shared some common risk factors for cancer development such as advanced age, smoking and diabetes. In addition, a CFTR gene mutation was detected in case 1, which brings genetic profile into the discussion grounds. Mutations in the CFTR gene have been associated to increased gastrointestinal cancer risk, including PDAC [14]. Although CFTR mutations have not been previously associated to IPMN, one single clinical report has recently described a patient with AIP carrying the R75Q mutation [15]. It can be argued that mutations in the CFTR gene in patients with AIP or IPMN may be incidentally detected, but it should also be acknowledged that patients with AIP are not systematically investigated for CFTR mutations.
In summary, the present report describes two cases of IPMN associated with type-1 AIP that fulfilled the Honolulu and Boston histologic diagnostic criteria and involved extrapancreatic tissues. Common risk factors to IPMN and AIP may facilitate its coincidental generation. References [1] Augustin T, Vandermeer TJ. Intraductal papillary mucinous neoplasm: a clinicopathologic review. Surg Clin North Am 2010;90:377e98. [2] Yamaguchi K, Kanemitsu S, Hatori T, Maguchi H, Shimizu Y, Tada M, et al. Pancreatic ductal adenocarcinoma derived from IPMN and pancreatic ductal adenocarcinoma concomitant with IPMN. Pancreas 2011;40:571e80. [3] Katabi N, Klimstra DS. Intraductal papillary mucinous neoplasms of the pancreas: clinical and pathological features and diagnostic approach. J Clin Pathol 2008;61:1303e13. [4] Capurso G, Boccia S, Salvia R, Del Chiaro M, Frulloni L, Arcidiacono PG, et al. Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. Am J Gastroenterol 2013;108: 1003e9. [5] Bang UC, Benfield T, Hyldstrup L, Bendtsen F, Beck Jensen JE. Mortality, cancer, and comorbidities associated with chronic pancreatitis e a Danish nationwide matched-cohort study. Gastroenterology; 2013 Dec 31. http://dx.doi.org/ 10.1053/j.gastro.2013.12.033. pii:S0016-5085(13)01847-7. [Epub ahead of print]. [6] Schneider R, Slater EP, Sina M, Habbe N, Fendrich V, Matthäi E, et al. German national case collection for familial pancreatic cancer (FaPaCa): ten years experience. Fam Cancer 2011;10:323e30. [7] Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas 2011;40:352e8. [8] Sah RP, Chari ST, Pannala R, Sugumar A, Clain JE, Levy MJ, et al. Differences in clinical profile and relapse rate of type 1 versus type 2 autoimmune pancreatitis. Gastroenterology 2010;139:140e8. [9] Chari ST, Kloeppel G, Zhang L, Notohara K, Lerch MM, Shimosegawa T. Histopathologic and clinical subtypes of autoimmune pancreatitis: the honolulu consensus document. Pancreatology 2010;10:664e72. [10] Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25: 1181e92. [11] Hart PA, Kamisawa T, Brugge WR, Chung JB, Culver EL, Czakó L, et al. Longterm outcomes of autoimmune pancreatitis: a multicentre, international analysis. Gut 2013;62:1771e6. [12] Bateman AC, Culver EL, Sommerlad M, Chetty R. Intraduct papillary mucinous neoplasm of the pancreas: a tumour linked with IgG4-related disease? J Clin Pathol 2013;66:671e5. [13] Loos M, Esposito I, Hedderich DM, Ludwig L, Fingerle A, Friess H, et al. Autoimmune pancreatitis complicated by carcinoma of the pancreatobiliary system: a case report and review of the literature. Pancreas 2011;40:151e4. [14] Maisonneuve P, Marshall BC, Knapp EA, Lowenfels AB. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J Natl Cancer Inst 2013;105:122e9. [15] Patel H, Levine J, Weinstein T. Combination of CFTR gene mutation and autoimmune pancreatitis presenting as necrotizing pancreatitis. Pancreas 2012;41:970e1 [letter].
Please cite this article in press as: Vaquero EC, et al., Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases, Pancreatology (2014), http://dx.doi.org/10.1016/j.pan.2014.04.032
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Contents lists available at ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Case report
Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases Q2
Eva C. Vaquero a, Maria T. Salcedo b, Míriam Cuatrecasas c, Hannah De Leon d, Xavier Merino e, Salvador Navarro a, Àngels Ginès a, Monder Abu-Suboh f, Joaquim Balsells g, Laureano Fernández-Cruz h, Xavier Molero d, * a
Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBEREHD, IDIBAPS, Barcelona, Spain Department of Pathology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic, University of Barcelona and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Barcelona, Spain d Exocrine Pancreatic Diseases Research Group, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain e Department of Radiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain f Department of Endoscopy, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain g Department of Surgery, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain h Department of Surgery, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBEREHD, IDIBAPS, Barcelona, Spain b c
a b s t r a c t
Q1
Keywords: Autoimmune pancreatitis IPMN CFTR IgG4 Chronic pancreatitis
Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation. Copyright Ó 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
1. Introduction Intraduct papillary mucinous neoplasm (IPMN) of the pancreas is characterized by neoplastic intraductal papillary epithelial growth, mucin production and cystic dilatation of the ducts [1]. A number of IPMNs may progress towards invasive carcinoma, which are often difficult to distinguish from pancreatic ductal adenocarcinoma (PDAC) [2]. Both IPMN and PDAC may be associated with chronic pancreatitis in the surrounding pancreas (fibrosis, acinar cell atrophy and occasional inflammatory infiltrate) [3] thought to be the result of obstructive or inflammatory
* Corresponding author. Exocrine Pancreatic Diseases Research Group, Institut de Recerca Hospital Universitari Vall d’Hebron, Pg Vall d’Hebron 119-129, Barcelona 08035, Spain. E-mail address: [email protected] (X. Molero).
pancreatitis in the nearby tissue. However, some IPMNs and PDACs arise on long evolving chronic pancreatitis, raising the suspicion that IPMN and PDAC may develop on a chronic pancreatitis background. Certainly, chronic pancreatitis seems to be an independent risk factor for IPMN [4], as much as it is for PDAC [5]. On the other hand, patients at risk of genetically-determined pancreatic cancer may disclose IPMN and/or chronic pancreatitis features either at imaging or at histology [6]. Furthermore, a family history of PDAC is also a risk factor for IPMN [4]. Altogether, these findings suggest that pathogenetic mechanisms involved in IPMN, chronic pancreatitis and PDAC development may be related. Autoimmune pancreatitis (AIP) is a particular form of chronic pancreatitis [7]. Two major forms of AIP (type-1 and -2) have been described that differ in both clinical and histologic patterns [8]. The combination of periductal lymphoplasmacytic infiltration, increased IgG4þ cells, storiform fibrosis, and obliterative phlebitis
http://dx.doi.org/10.1016/j.pan.2014.04.032 1424-3903/Copyright Ó 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Please cite this article in press as: Vaquero EC, et al., Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases, Pancreatology (2014), http://dx.doi.org/10.1016/j.pan.2014.04.032
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is considered to be characteristic of type-1 AIP according to the Honolulu diagnostic criteria [9] and sufficient to establish the diagnosis according to the Guidelines of the International Association of Pancreatology [7]. Type-1 AIP appears to affect older individuals who may have raised serum levels of IgG4. In addition, type-1 AIP may be a part of IgG4-related disease, a condition for which diagnostic criteria have been redefined in the so-called “Boston criteria”: increased tissue IgG4þ cells >50/HPF and IgG4þ/IgGþ ratio >40% in conjunction with other histological features of PAI is highly specific for IgG4-related pancreatitis [10]. Type-2 AIP is defined by the presence of granulocytic epithelial lesions (GELs) and none or few IgG4þ cells [7,9]. The long-term natural history of AIP, and particularly its relationship to cancer, remains a focus of clinical concern. Recent reports show the occurrence of a number of neoplasias at various organs, including the pancreas, in patients with type-1 AIP [11]. Moreover, type-1 AIP has been reported in association with both PDAC and IPMN in a very limited number of patients [12,13]. In this report we describe the clinical, radiological and histological features of two patients presenting with IPMN associated with chronic pancreatitis displaying morphological features fulfilling the Honolulu and Boston diagnostic criteria for type-1 AIP. Characteristic AIP lesions were not limited to the pancreas surrounding IPMN, but diffusely involved the whole pancreas and extrapancreatic tissues. One of the patients carried a CFTR class I mutation. Interestingly, a) previous pancreatic resection of focal IPMN did not show features of AIP, and b) serum IgG4 levels gradually decreased to normal values after IPMN resection. 2. Case reports 2.1. Case 1 A 74 year-old woman was referred to our Unit for evaluation of a pancreatic tumor. She smoked 20 cigarettes a day but denied alcohol consumption. She had high blood pressure and diabetes mellitus from the age of 69. At 72 she had a ventriculoperitoneal shunt placement for normotensive hydrocephaly. She complained of intermittent diarrhea and irregular abdominal pain attributed to local irritation of the peritoneal shunt. Her blood tests were unremarkable except for raised IgG4 levels (256 mg/dL; normal A/-genotype. Magnetic resonance imaging (MRI) revealed severe atrophy of the pancreatic head with a filiform MPD. At the body-tail transition a 1.5 cm solid-microcystic tumor was identified that induced slight upstream dilatation of the MPD and severe atrophy of the pancreatic tail. A large lymph node 2.5 cm in diameter was detected adjacent to the tumor (Fig. 1). Endoscopic ultrasonography (EUS)-guided fine-needle aspiration
cytology revealed cells with normal nuclei and mucinous cytoplasm. A body-tail pancreatectomy was performed that revealed cystic dilation of the MPD entirely surrounded by a fibroinflammatory tumor-like mass with ill-defined borders measuring 2 1.8 cm. The epithelium of the cyst showed mucinous hyperplasia with focal papillary structures (Fig. 2A) of biliary-pancreatic phenotype (MUC1þ, MUC2, MUC4þ) and signs of moderate dysplasia (p53þ, CEA). The whole pancreas showed intense periductal lymphoplasmacytic inflammation with >50 IgG4þ plasma cells/HPF in at least 3 different fields (Fig. 2B). The IgG4þ/ IgGþ ratio was 71.6 7.4% (mean SEM). The epithelial lining of the ducts was preserved and GELs were not found. The pancreatic parenchyma was replaced by a dense fibrous stroma showing a focal storiform pattern. Obliterative phlebitis was easily detected. Islets were preserved. Lymph nodes had a hyperplastic follicular reaction without atypia and increased IgG4þ plasma cells with an IgG4þ/IgGþ ratio of 78.1 2.3%. On follow-up serum IgG4 gradually decreased from 256 to 227, and 218 mg/dL, and finally it became undetectable (50 IgG4þ plasma cells/HPF, obliterative phlebitis and dense fibrosis. The whole resected pancreas was diffusely involved except for intestinal-type IPMN detected in some peripheral ducts. Increased IgG4þ cells and lymphoplasmacytic infiltration were also present in the gallbladder and in peripancreatic lymph nodes. The IgG4þ/IgGþ ratio on the pancreas, gallbladder and lymph nodes was 41.4 6.3%, 79.2 4.7% and 44.7 2.5%. Serum IgG4 was not determined. The pancreatic tail resected 6 years before had no histological criteria of AIP and IgG4þ plasma cells were scarce or absent.
Fig. 1. MRI findings of case 1. Left panel: 1.5 cm tumor at the body of the pancreas (black arrow) with upstream dilatation of the main pancreatic duct (white arrow). Right panel: Severe atrophy of the pancreatic tail (white arrow). Juxtapancreatic 2.5 cm lymph node (black arrow).
Please cite this article in press as: Vaquero EC, et al., Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases, Pancreatology (2014), http://dx.doi.org/10.1016/j.pan.2014.04.032
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Fig. 2. Microphotograph samples of case 1. A: IPMN surrounded by a dense fibrous tissue and isolated groups of pancreatic acini (hematoxylin and eosin, OM 100). B: IgG4 immunohistoquemistry. Dense fibrous stroma, intense lymphoplasmacytic inflammation and abundant IgG4-positive plasma cells within the inflammatory infiltrate surrounding a ductal lumen (OM 100). OM: original magnification.
3. Discussion Several aspects of these two clinical reports deserve attention. The association of AIP and IPMN has only been described recently in a few case reports [12,13], all of them being IgG4-related (type-1 AIP). In most of these cases histological lesions suggesting AIP were confined to the vicinity of IPMN and in only 3 cases lesions of AIP were detected distant to IPMN. In the two case reports described here lesions characteristic of type-1 AIP embraced the whole resected specimen and there was also evidence for lymphoplasmacytic infiltration and increased IgG4þ cells in peripancreatic lymph nodes and the gallbladder. These findings support the diagnosis of type-1 AIP as a credited differentiated entity from coincident IPMN. Being two rare diseases, it is remarkable to find coexisting AIP and IPMN. The proportion of patients developing PDAC from chronic pancreatitis of any etiology is estimated to be 4% [5] and IPMN is just a particular form of pancreatic neoplasm that may evolve to invasive carcinoma. Type-1 AIP may also be associated to cancer development in several organs, including the pancreas [11]. From the above reasoning it could be tempting to consider type-1 AIP a predisposing condition for IPMN. However, this association may be purely coincidental since none of the two series that recently evaluated cancer incidence after a firm diagnosis of type-1 AIP have reported IPMN formation [11]. In this report we show histological proof of IPMN being present years before the onset of newly generated AIP that finally involved the whole pancreas and extrapancreatic tissues. We can only speculate on possible casual relationships between AIP and IPMN, although the observation that serum IgG4 levels gradually decreased after IPMN excision is intriguing and may invite to consider IPMN as a predisposing factor for AIP initiation. On the other hand, common risk factors may play together to facilitate AIP and IPMN inception (and perhaps cancer) independent of each other. Both patients in this report shared some common risk factors for cancer development such as advanced age, smoking and diabetes. In addition, a CFTR gene mutation was detected in case 1, which brings genetic profile into the discussion grounds. Mutations in the CFTR gene have been associated to increased gastrointestinal cancer risk, including PDAC [14]. Although CFTR mutations have not been previously associated to IPMN, one single clinical report has recently described a patient with AIP carrying the R75Q mutation [15]. It can be argued that mutations in the CFTR gene in patients with AIP or IPMN may be incidentally detected, but it should also be acknowledged that patients with AIP are not systematically investigated for CFTR mutations.
In summary, the present report describes two cases of IPMN associated with type-1 AIP that fulfilled the Honolulu and Boston histologic diagnostic criteria and involved extrapancreatic tissues. Common risk factors to IPMN and AIP may facilitate its coincidental generation. References [1] Augustin T, Vandermeer TJ. Intraductal papillary mucinous neoplasm: a clinicopathologic review. Surg Clin North Am 2010;90:377e98. [2] Yamaguchi K, Kanemitsu S, Hatori T, Maguchi H, Shimizu Y, Tada M, et al. Pancreatic ductal adenocarcinoma derived from IPMN and pancreatic ductal adenocarcinoma concomitant with IPMN. Pancreas 2011;40:571e80. [3] Katabi N, Klimstra DS. Intraductal papillary mucinous neoplasms of the pancreas: clinical and pathological features and diagnostic approach. J Clin Pathol 2008;61:1303e13. [4] Capurso G, Boccia S, Salvia R, Del Chiaro M, Frulloni L, Arcidiacono PG, et al. Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. Am J Gastroenterol 2013;108: 1003e9. [5] Bang UC, Benfield T, Hyldstrup L, Bendtsen F, Beck Jensen JE. Mortality, cancer, and comorbidities associated with chronic pancreatitis e a Danish nationwide matched-cohort study. Gastroenterology; 2013 Dec 31. http://dx.doi.org/ 10.1053/j.gastro.2013.12.033. pii:S0016-5085(13)01847-7. [Epub ahead of print]. [6] Schneider R, Slater EP, Sina M, Habbe N, Fendrich V, Matthäi E, et al. German national case collection for familial pancreatic cancer (FaPaCa): ten years experience. Fam Cancer 2011;10:323e30. [7] Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas 2011;40:352e8. [8] Sah RP, Chari ST, Pannala R, Sugumar A, Clain JE, Levy MJ, et al. Differences in clinical profile and relapse rate of type 1 versus type 2 autoimmune pancreatitis. Gastroenterology 2010;139:140e8. [9] Chari ST, Kloeppel G, Zhang L, Notohara K, Lerch MM, Shimosegawa T. Histopathologic and clinical subtypes of autoimmune pancreatitis: the honolulu consensus document. Pancreatology 2010;10:664e72. [10] Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25: 1181e92. [11] Hart PA, Kamisawa T, Brugge WR, Chung JB, Culver EL, Czakó L, et al. Longterm outcomes of autoimmune pancreatitis: a multicentre, international analysis. Gut 2013;62:1771e6. [12] Bateman AC, Culver EL, Sommerlad M, Chetty R. Intraduct papillary mucinous neoplasm of the pancreas: a tumour linked with IgG4-related disease? J Clin Pathol 2013;66:671e5. [13] Loos M, Esposito I, Hedderich DM, Ludwig L, Fingerle A, Friess H, et al. Autoimmune pancreatitis complicated by carcinoma of the pancreatobiliary system: a case report and review of the literature. Pancreas 2011;40:151e4. [14] Maisonneuve P, Marshall BC, Knapp EA, Lowenfels AB. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J Natl Cancer Inst 2013;105:122e9. [15] Patel H, Levine J, Weinstein T. Combination of CFTR gene mutation and autoimmune pancreatitis presenting as necrotizing pancreatitis. Pancreas 2012;41:970e1 [letter].
Please cite this article in press as: Vaquero EC, et al., Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases, Pancreatology (2014), http://dx.doi.org/10.1016/j.pan.2014.04.032
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