Journal of Cystic Fibrosis 14 (2015) 523 – 525 www.elsevier.com/locate/jcf
Case Studies
Intraductal papillary mucinous neoplasm of the pancreas in an adult patient with cystic fibrosis after double-lung transplantation W. Eigner a,⁎, I. Mesteri b , B. Tribl a , A. Ba-Ssalamah c , J. Friedl d , M. Trauner a , L. Kazemi-Shirazi a a
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria b Department of Pathology, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria c Department of Radiology, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria d Department of Surgery, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria Received 30 January 2015; revised 22 March 2015; accepted 23 March 2015 Available online 9 April 2015
Abstract We report on an adult patient with cystic fibrosis after double-lung transplantation under triple immunosuppression with non-specific abdominal symptoms and a pancreatic cystic tumor, resulting in the diagnosis of an intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Pancreatic cysts in adult patients with cystic fibrosis, especially after transplantation, merit close attention and thorough investigation. © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Pancreas; IPMN; Diagnosis; Cancer
1. Introduction Cystic fibrosis (CF) is a multisystem disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene with prominent involvement of the lungs and the gastrointestinal (GI) tract. With improved treatment strategies and the possibility of lung transplantation for end-stage lung disease, the survival of CF patients has substantially improved. As a result of increasing life expectancy an increase in cancer incidence in this patient population may be anticipated. Although the overall risk for malignancies is not elevated compared to that of the general population, several studies in large European and American patient cohorts have demonstrated a substantially increased risk for GI cancer in CF patients (OR 6.4; CI 95%) [1,2], especially after transplantation [3]. GI tumors seem to occur at a very young age in these patients (OR for patients 20–29 years of age: 20.2; CI 95%) with high mortality [1]. ⁎ Corresponding author at: Währignergürtel 18-20 in 1090 Vienna, Austria. E-mail address: [email protected] (W. Eigner).
In a cohort study of 412 CF patients, with an observation period of at least 28 years, pancreatic cancer occurred in two patients (23 and 58 years of age) [2]. Neglia et al. described significant associations for esophagus (OR 14.3), small and large bowel (OR 9.3), and pancreatic tumors (OR 31.5; all CI 95%) in CF [1]. In a review of the English literature between 1985 and 2005, Rittenhouse et al. described seven CF patients with pancreatic tumors (age at diagnosis 18–42 years, majority pancreatic insufficient (PI), six with pancreatic ductal adenocarcinoma, one with mucinous cystadenoma). This high risk for pancreatic cancer may be due to high levels of CFTR expression in the pancreas. Eighty-five percent of all CF patients are PI, with consecutive maldigestion that requires life-long pancreatic enzyme replacement therapy (PERT). Recurrent pancreatitis, a relatively uncommon complication, occurs almost exclusively in pancreatic-sufficient (PS) patients. Conversely, patients with pancreatic cancer often carry CFTR mutations [4,5]. Here we describe for the first time a case of IPMN in an adult patient with CF.
http://dx.doi.org/10.1016/j.jcf.2015.03.011 1569-1993© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
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W. Eigner et al. / Journal of Cystic Fibrosis 14 (2015) 523–525
2. Case history A 56-year-old female (154 cm; 44.5 kg; BMI 18.7 kg/m2) with CF and double-lung transplantation in 2001 under triple-immunosuppression (IS) with Prednisolone, Tacrolimus and Sirolimus presented to our clinic in June 2010 with upper abdominal pain radiating to the back and vomiting for 10 days. The patient (delta F508/G542X) was PI and suffered from CF-related diabetes (CFRD), as well as several IS-associated comorbidities including chronic kidney insufficiency (CKI), arterial hypertension and hypercholesterinemia. Abdominal ultrasound revealed a pancreatic cyst of five centimeters in diameter in the pancreatic head, as well as a two-centimeter retroperitoneal lymph node. Serum tumor markers were elevated (carbohydrate antigen (CA) 19-9:990 kU/l). In July 2010 an initial endoscopic ultrasound (EUS) with fine needle aspiration (FNA) was performed. The histological evaluation showed an acute inflammatory process with no signs of neoplastic infiltration. In addition, pancreatic MRI with secretin-enhanced MRCP and gadoxetic acid (Primovist®) was performed which revealed an enlarged pancreatic head (6.2 cm) with cystic degeneration of the whole pancreas. The entire pancreatic duct was moderately dilated. Furthermore there were diffusely distributed dilated side branches with direct communication to the main duct. The common bile duct was not dilated and enlarged lymph nodes were not detected. From the radiological point of view these features are compatible with the diagnosis of mixed type IPMN (Fig. 1).
Fig. 1. Axial T2-weighted HASTE sequences show enlargement of the pancreatic head and body, which is replaced by cystic structures, partially tubular and partially rounded, consistent with the histopathologically proven IPMN.
Due to recurring abdominal pain and inconclusive histology, a second EUS with FNA was performed in September 2010. The pancreatic duct was now diffusely dilated (12 mm). Again, cytology and histology revealed no signs for malignancy. In November 2010 ERCP with papillotomy of the pancreatic sphincter was performed. The pancreatic duct with its side branches in the head region were massively dilated with multiple cysts draining into the duct. The pancreatic duct appeared normal in the pancreatic body and showed no contrast in the tail. Brush cytology of the pancreatic duct and histological specimens were obtained and were negative for malignancy. The guide wire could not be advanced beyond the pancreatic head during ERCP. Subsequently EUS guided FNA was performed for the third time. Again the pancreatic head showed multiple cysts. In addition the EUS revealed cystic formations in the pancreatic tail with papillary protrusions, which could be a morphological sign for malignancy. In the fluid aspirated from the cyst, carcinoembryonic antigen (CEA) levels were N 10,000 but cytology did not show any malignant cells. In addition serum CA 19-9 levels increased to N 1000 kU/l. Due to pancreatic morphology and increased tumor markers an interdisciplinary tumor board recommended surgical resection. In March 2011 a spleen-preserving total duodenopancreatectomy, cholecystectomy with choledochojejunostomy and duodenojejunostomy were performed. The postoperative course was unremarkable. Sirolimus was paused perioperatively to avoid impairment of wound healing. The histological report confirmed the suspected mixed-type IPMN of the pancreatic head (low grade pancreatic intraepithelial neoplasia = PanIN-1) with characteristic dilation of the main pancreatic duct and side branches and pronounced pancreatic atrophy (Fig. 2). Lymph nodes were tumor-free and there were no signs of tumor invasion. Up to date, the patient is asymptomatic and is followed up every three months at our CF outpatient service. Between September 2012 and September 2014 the patient weight has increased from
Fig. 2. Dilated pancreatic ducts, lined by partially flat but mostly papillary mucinous epithelium, occasionally with branching. The epithelium shows atypical hyperplasia with low-grade to moderate dysplasia (hematoxylin-eosin, original magnification × 20).
W. Eigner et al. / Journal of Cystic Fibrosis 14 (2015) 523–525
525
38 to 40 kg and the BMI from 16 to 17 kg/m2. At the moment the patient receives 10 units of Insulin detemir daily with Insulin aspart according to bread units. The daily need for pancreatic enzyme supplementation is approximately 560,000 IE per day. In our patient gastric and colonic tumors were exclude by endoscopy.
disease, distal ileal obstruction syndrome, intussuception,…) which can present with similar symptoms, pancreatic malignancy should always be considered as a differential diagnosis. Thus, a thorough evaluation and high awareness of the possibility of pancreatic cystic neoplasms in CF patients is recommended.
3. Discussion
Conflict of interest
Pancreatic cysts are diagnosed with increasing frequency and can be either neoplastic or non-neoplastic. To the best of our knowledge this is the first case of a histologically confirmed IPMN described in an adult lung-transplanted patient with CF. Patients who carry a CFTR mutation seem to have an increased risk for gastrointestinal cancer such as pancreatic ductal adenocarcinoma (PDAC) [3]. So far no association has been found between mutations in the CFTR gene and the occurrence of IPMN. IPMNs are mucin-producing papillary neoplasms of the pancreatic ductal system with malignant potential and cause dilation of the pancreatic ducts. They may involve the main pancreatic duct (main duct IPMN), its side branches (side branch IPMN) or both (mixed-type IPMN — as described in our patient). Patients with IPMN involving the main duct are at increased risk of malignant transformation compared to those with side branch IPMN. The risk of carcinoma in situ or invasive carcinoma in main duct IPMN is approximately 70%. There are no radiographic or clinical characteristics that reliably predict malignancy in main duct IPMN [6]. Patients with IPMN appear to be at increased risk for extrapancreatic malignancies particularly gastric, colorectal and bile duct cancer [7,8]. The issue of colon cancer surveillance seems especially important in the context of CF patients following transplantation as these patients already have a very high risk for colon cancer due to CF and immunosuppression [9]. It has been suggested that lung transplant programs should consider early and (perhaps) sequential screening colonoscopy regardless of age for adult patients with CF following lung transplantation. In conclusion CF patients might be particularly at risk for late or missed diagnosis of cystic pancreatic neoplasms. As we can see in the presented case the diagnosis of such can be very challenging in CF patients as symptoms are not specific for pancreatic malignancy. Amongst other complications (such as pancreatitis, hepatobiliary disease, gastroesophageal reflux
There is no conflict of interest. Acknowledgments No acknowledgments. References [1] Neglia JP, FitzSimmons SC, Maisonneuve P, Schöni MH, Schöni-Affolter F, Corey M, et al. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. N Engl J Med 1995;332:494–9. [2] Sheldon CD, Hodson ME, Carpenter LM, Swerdlow AJ. A cohort study of cystic fibrosis and malignancy. Br J Cancer 1993;68:1025–8. [3] 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;105:122–9. [4] Rittenhouse DW, Talbott VA, Anklesaria Z, Brody JR, Witkiewicz AK, Yeo CJ. Subject review: pancreatic ductal adenocarcinoma in the setting of mutations in the cystic fibrosis transmembrane conductance regulator gene: case report and review of the literature. J Gastrointest Surg 2011;15: 2284–90. [5] McWilliams RR, Petersen GM, Rabe KG, Holtegaard LM, Lynch PJ, Bishop MD, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma. Cancer 2010;116:203–9. [6] Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–97. [7] Larghi A, Panic N, Capurso G, Leoncini E, Arzani D, Salvia R, et al. Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Oncol 2013;24:1907–11. [8] Sugiyama M, Atomi Y. Extrapancreatic neoplasms occur with unusual frequency in patients with intraductal papillary mucinous tumors of the pancreas. Am J Gastroenterol 1999;94:470–3. [9] Meyer KC, Francois ML, Thomas HK, Radford KL, Hawes DS, Mack TL, et al. Colon cancer in lung transplant recipients with CF: increased risk and results of screening. J Cyst Fibros 2011;10:366–9.
Case Studies
Intraductal papillary mucinous neoplasm of the pancreas in an adult patient with cystic fibrosis after double-lung transplantation W. Eigner a,⁎, I. Mesteri b , B. Tribl a , A. Ba-Ssalamah c , J. Friedl d , M. Trauner a , L. Kazemi-Shirazi a a
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria b Department of Pathology, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria c Department of Radiology, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria d Department of Surgery, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria Received 30 January 2015; revised 22 March 2015; accepted 23 March 2015 Available online 9 April 2015
Abstract We report on an adult patient with cystic fibrosis after double-lung transplantation under triple immunosuppression with non-specific abdominal symptoms and a pancreatic cystic tumor, resulting in the diagnosis of an intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Pancreatic cysts in adult patients with cystic fibrosis, especially after transplantation, merit close attention and thorough investigation. © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Pancreas; IPMN; Diagnosis; Cancer
1. Introduction Cystic fibrosis (CF) is a multisystem disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene with prominent involvement of the lungs and the gastrointestinal (GI) tract. With improved treatment strategies and the possibility of lung transplantation for end-stage lung disease, the survival of CF patients has substantially improved. As a result of increasing life expectancy an increase in cancer incidence in this patient population may be anticipated. Although the overall risk for malignancies is not elevated compared to that of the general population, several studies in large European and American patient cohorts have demonstrated a substantially increased risk for GI cancer in CF patients (OR 6.4; CI 95%) [1,2], especially after transplantation [3]. GI tumors seem to occur at a very young age in these patients (OR for patients 20–29 years of age: 20.2; CI 95%) with high mortality [1]. ⁎ Corresponding author at: Währignergürtel 18-20 in 1090 Vienna, Austria. E-mail address: [email protected] (W. Eigner).
In a cohort study of 412 CF patients, with an observation period of at least 28 years, pancreatic cancer occurred in two patients (23 and 58 years of age) [2]. Neglia et al. described significant associations for esophagus (OR 14.3), small and large bowel (OR 9.3), and pancreatic tumors (OR 31.5; all CI 95%) in CF [1]. In a review of the English literature between 1985 and 2005, Rittenhouse et al. described seven CF patients with pancreatic tumors (age at diagnosis 18–42 years, majority pancreatic insufficient (PI), six with pancreatic ductal adenocarcinoma, one with mucinous cystadenoma). This high risk for pancreatic cancer may be due to high levels of CFTR expression in the pancreas. Eighty-five percent of all CF patients are PI, with consecutive maldigestion that requires life-long pancreatic enzyme replacement therapy (PERT). Recurrent pancreatitis, a relatively uncommon complication, occurs almost exclusively in pancreatic-sufficient (PS) patients. Conversely, patients with pancreatic cancer often carry CFTR mutations [4,5]. Here we describe for the first time a case of IPMN in an adult patient with CF.
http://dx.doi.org/10.1016/j.jcf.2015.03.011 1569-1993© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
524
W. Eigner et al. / Journal of Cystic Fibrosis 14 (2015) 523–525
2. Case history A 56-year-old female (154 cm; 44.5 kg; BMI 18.7 kg/m2) with CF and double-lung transplantation in 2001 under triple-immunosuppression (IS) with Prednisolone, Tacrolimus and Sirolimus presented to our clinic in June 2010 with upper abdominal pain radiating to the back and vomiting for 10 days. The patient (delta F508/G542X) was PI and suffered from CF-related diabetes (CFRD), as well as several IS-associated comorbidities including chronic kidney insufficiency (CKI), arterial hypertension and hypercholesterinemia. Abdominal ultrasound revealed a pancreatic cyst of five centimeters in diameter in the pancreatic head, as well as a two-centimeter retroperitoneal lymph node. Serum tumor markers were elevated (carbohydrate antigen (CA) 19-9:990 kU/l). In July 2010 an initial endoscopic ultrasound (EUS) with fine needle aspiration (FNA) was performed. The histological evaluation showed an acute inflammatory process with no signs of neoplastic infiltration. In addition, pancreatic MRI with secretin-enhanced MRCP and gadoxetic acid (Primovist®) was performed which revealed an enlarged pancreatic head (6.2 cm) with cystic degeneration of the whole pancreas. The entire pancreatic duct was moderately dilated. Furthermore there were diffusely distributed dilated side branches with direct communication to the main duct. The common bile duct was not dilated and enlarged lymph nodes were not detected. From the radiological point of view these features are compatible with the diagnosis of mixed type IPMN (Fig. 1).
Fig. 1. Axial T2-weighted HASTE sequences show enlargement of the pancreatic head and body, which is replaced by cystic structures, partially tubular and partially rounded, consistent with the histopathologically proven IPMN.
Due to recurring abdominal pain and inconclusive histology, a second EUS with FNA was performed in September 2010. The pancreatic duct was now diffusely dilated (12 mm). Again, cytology and histology revealed no signs for malignancy. In November 2010 ERCP with papillotomy of the pancreatic sphincter was performed. The pancreatic duct with its side branches in the head region were massively dilated with multiple cysts draining into the duct. The pancreatic duct appeared normal in the pancreatic body and showed no contrast in the tail. Brush cytology of the pancreatic duct and histological specimens were obtained and were negative for malignancy. The guide wire could not be advanced beyond the pancreatic head during ERCP. Subsequently EUS guided FNA was performed for the third time. Again the pancreatic head showed multiple cysts. In addition the EUS revealed cystic formations in the pancreatic tail with papillary protrusions, which could be a morphological sign for malignancy. In the fluid aspirated from the cyst, carcinoembryonic antigen (CEA) levels were N 10,000 but cytology did not show any malignant cells. In addition serum CA 19-9 levels increased to N 1000 kU/l. Due to pancreatic morphology and increased tumor markers an interdisciplinary tumor board recommended surgical resection. In March 2011 a spleen-preserving total duodenopancreatectomy, cholecystectomy with choledochojejunostomy and duodenojejunostomy were performed. The postoperative course was unremarkable. Sirolimus was paused perioperatively to avoid impairment of wound healing. The histological report confirmed the suspected mixed-type IPMN of the pancreatic head (low grade pancreatic intraepithelial neoplasia = PanIN-1) with characteristic dilation of the main pancreatic duct and side branches and pronounced pancreatic atrophy (Fig. 2). Lymph nodes were tumor-free and there were no signs of tumor invasion. Up to date, the patient is asymptomatic and is followed up every three months at our CF outpatient service. Between September 2012 and September 2014 the patient weight has increased from
Fig. 2. Dilated pancreatic ducts, lined by partially flat but mostly papillary mucinous epithelium, occasionally with branching. The epithelium shows atypical hyperplasia with low-grade to moderate dysplasia (hematoxylin-eosin, original magnification × 20).
W. Eigner et al. / Journal of Cystic Fibrosis 14 (2015) 523–525
525
38 to 40 kg and the BMI from 16 to 17 kg/m2. At the moment the patient receives 10 units of Insulin detemir daily with Insulin aspart according to bread units. The daily need for pancreatic enzyme supplementation is approximately 560,000 IE per day. In our patient gastric and colonic tumors were exclude by endoscopy.
disease, distal ileal obstruction syndrome, intussuception,…) which can present with similar symptoms, pancreatic malignancy should always be considered as a differential diagnosis. Thus, a thorough evaluation and high awareness of the possibility of pancreatic cystic neoplasms in CF patients is recommended.
3. Discussion
Conflict of interest
Pancreatic cysts are diagnosed with increasing frequency and can be either neoplastic or non-neoplastic. To the best of our knowledge this is the first case of a histologically confirmed IPMN described in an adult lung-transplanted patient with CF. Patients who carry a CFTR mutation seem to have an increased risk for gastrointestinal cancer such as pancreatic ductal adenocarcinoma (PDAC) [3]. So far no association has been found between mutations in the CFTR gene and the occurrence of IPMN. IPMNs are mucin-producing papillary neoplasms of the pancreatic ductal system with malignant potential and cause dilation of the pancreatic ducts. They may involve the main pancreatic duct (main duct IPMN), its side branches (side branch IPMN) or both (mixed-type IPMN — as described in our patient). Patients with IPMN involving the main duct are at increased risk of malignant transformation compared to those with side branch IPMN. The risk of carcinoma in situ or invasive carcinoma in main duct IPMN is approximately 70%. There are no radiographic or clinical characteristics that reliably predict malignancy in main duct IPMN [6]. Patients with IPMN appear to be at increased risk for extrapancreatic malignancies particularly gastric, colorectal and bile duct cancer [7,8]. The issue of colon cancer surveillance seems especially important in the context of CF patients following transplantation as these patients already have a very high risk for colon cancer due to CF and immunosuppression [9]. It has been suggested that lung transplant programs should consider early and (perhaps) sequential screening colonoscopy regardless of age for adult patients with CF following lung transplantation. In conclusion CF patients might be particularly at risk for late or missed diagnosis of cystic pancreatic neoplasms. As we can see in the presented case the diagnosis of such can be very challenging in CF patients as symptoms are not specific for pancreatic malignancy. Amongst other complications (such as pancreatitis, hepatobiliary disease, gastroesophageal reflux
There is no conflict of interest. Acknowledgments No acknowledgments. References [1] Neglia JP, FitzSimmons SC, Maisonneuve P, Schöni MH, Schöni-Affolter F, Corey M, et al. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. N Engl J Med 1995;332:494–9. [2] Sheldon CD, Hodson ME, Carpenter LM, Swerdlow AJ. A cohort study of cystic fibrosis and malignancy. Br J Cancer 1993;68:1025–8. [3] 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;105:122–9. [4] Rittenhouse DW, Talbott VA, Anklesaria Z, Brody JR, Witkiewicz AK, Yeo CJ. Subject review: pancreatic ductal adenocarcinoma in the setting of mutations in the cystic fibrosis transmembrane conductance regulator gene: case report and review of the literature. J Gastrointest Surg 2011;15: 2284–90. [5] McWilliams RR, Petersen GM, Rabe KG, Holtegaard LM, Lynch PJ, Bishop MD, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma. Cancer 2010;116:203–9. [6] Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–97. [7] Larghi A, Panic N, Capurso G, Leoncini E, Arzani D, Salvia R, et al. Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Oncol 2013;24:1907–11. [8] Sugiyama M, Atomi Y. Extrapancreatic neoplasms occur with unusual frequency in patients with intraductal papillary mucinous tumors of the pancreas. Am J Gastroenterol 1999;94:470–3. [9] Meyer KC, Francois ML, Thomas HK, Radford KL, Hawes DS, Mack TL, et al. Colon cancer in lung transplant recipients with CF: increased risk and results of screening. J Cyst Fibros 2011;10:366–9.
![[Intraductal papillary mucinous neoplasm of the pancreas].](/assets/img/hold.png)
