Pancreas
Letters to the Editor
after previous therapy with sunitinib and everolimus. The authors declare no conflict of interest. Una Graham, MD, MRCP Regional Centre for Endocrinology and Diabetes Royal Victoria Hospital Belfast, United Kingdom [email protected]
Martin Eatock, MD, FRCP Northern Ireland Cancer Centre Belfast City Hospital Belfast, United Kingdom
Brew Atkinson, MD, FRCP Regional Centre for Endocrinology and Diabetes Royal Victoria Hospital Belfast, United Kingdom
REFERENCES 1. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501Y513. 2. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514Y523. 3. Karhoff D, Sauer S, Schrader J, et al. Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target. Neuroendocrinology. 2007;85:45Y53. 4. Jeong HK, Roh SY, Hong SH, et al. Pancreatic endocrine tumors: a report on a patient treated with sorafenib. J Korean Med Sci. 2011;26:954Y958. 5. Hobday TJ, Rubin J, Holen K, et al. MC044h, a phase II trial of sorafenib in patients with metastatic neuroendocrine tumors (NET): a phase II consortium study. J Clin Oncol. 2007;25:18S.
Review of 43 Patients With Autoimmune Pancreatitis Based on the International Consensus Diagnostic Criteria in China To the Editor:
A
utoimmune pancreatitis (AIP) is a unique type of chronic pancreatitis whose pathogenesis involves an autoimmune component.1,2 Within the past decade in China, many patients with AIP were misdiagnosed with pancreaticobiliary cancer and underwent operations because clinicians were unfamiliar with the concept of AIP or did not recognize its features. Therefore, the aims of this study were to systematically analyze and identify clinical features of the largest cohort of patients with AIP from a single institution in China.
810
www.pancreasjournal.com
MATERIALS AND METHODS A database of patients suspected to have or diagnosed as having AIP (used Japanese Pancreas Society criteria or Mayo Clinic’s histology, imaging, serology, other organ involvement and response to steroid therapy criteria for AIP) was prospectively maintained from January 2007 to December 2012 in our hospital. The medical records of 48 patients were reviewed to obtain information on demographics, clinical presentation, laboratory data, imaging and histologic features, response to treatment, and relapse on follow-up. Fortythree patients fulfilled the International Consensus Diagnostic Criteria3 for AIP.
RESULTS A total of 43 patients had a diagnosis of AIP based on the International Consensus Diagnostic Criteria for AIP (definitive type 1, 34/43 patients; probable type 1, 2/43 patients; type 2, 0/43 patients; and AIP [not otherwise specified], 7/43 patients). The mean age at presentation was 55.8 years (range, 31Y75 years). Three fourths (3/4) of the patients were 50 years and older and male. The most common presenting symptoms included new-onset obstructive jaundice in 77% of the patients, weight loss in 44% of the patients, abdominal pain in 42% of the patients, and hyperamylasemia in 12% of the patients. Serum IgG4 levels were increased to above 135 mg/dL and above 270 mg/dL in 15 and 13 of the 17 patients, respectively. Diffuse and focal pancreatic enlargements were found in 79% and 21% of the patients, respectively. Peripancreatic vessels involvement, masses around the superior mesenteric artery (SMA), pancreatic pseudocysts, and massive ascites were observed in our cases (Table 1, Fig. 1). These lesions were dramatically improved by steroid treatment. Extrapancreatic involvement was observed in 23 patients during the clinical course, and the spectrum is reported in Table 1. Eleven patients had only 1 associated disease, 8 patients had 2 associated diseases, and 4 patients had 3 associated diseases. Renal involvement was observed in 15 patients and was the most frequent extrapancreatic lesion (Fig. 1). Pulmonary inflammatory pseudotumors and interstitial pneumonia were observed in 5 patients. These lesions were partially resolved after steroid therapy. Histologic examination and IgG4 staining in 2 pancreatic resection specimens confirmed the diagnosis of type 1 AIP. The histologic findings of superficial lymph node specimens supported the diagnosis of AIP-related lymphadenopathy with positive IgG4 staining in 5 patients. Two patients with focal AIP in the head underwent a pancreaticoduodenectomy
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Volume 43, Number 5, July 2014
for suspected pancreatic adenocarcinoma. Thirty patients received steroids as the initial treatment. The usual regimen was 40 mg/d of oral prednisone for 4 weeks followed by a taper of 5 mg/wk. Among the 27 patients with a complete response to steroid, 4 had a recurrence. All 3 patients with an incomplete response eventually responded to the combination of prednisone and mycophenolate mofetil (750 mg twice daily) followed by steroids alone. Among the remaining 11 patients not receiving steroid treatment, 8 patients with obstructive jaundice underwent biliary drainage by surgical or endoscopic procedure. One patient had massive postoperative ascites, and 1 year later, the patient died. Ten patients had spontaneous remission of AIP-related lesions. Two patients had recurrent pancreatic swelling. Two patients were lost to follow-up.
DISCUSSION In this study, the prevalence of peripancreatic vascular involvements in AIP was high at 46%. Vascular involvements were found to be closely related to the site of pancreatic inflammation and mass formation.4,5 We speculate that obliterative phlebitis, which is characteristic to AIP, spreads among the vessels around the pancreas, resulting in peripancreatic vascular lesions. The mechanism of encasement of the SMA may be different from that of peripancreatic vascular involvements. This may be a manifestation of retroperitoneal fibrosis. Peripancreatic vascular lesions improved by steroids may represent reversible changes. Patients with AIP with pancreatic pseudocysts are rare.5,6 Yoshida et al2 reported that one of the characteristic features of AIP is the absence of pancreatic cysts. Interestingly, in our study, 5 of the 43 patients exhibited pseudocysts, and these 5 patients
TABLE 1. Imaging and Extrapancreatic Manifestations Observed in 43 Patients With AIP
Peripancreatic vessels involvement Mass around SMA Pancreatic pseudocyst Ascites Renal focal nephritis IgG4-related sialadenitis Lung involvement IgG4-related thyroiditis Hilar sclerosing cholangitis Retroperitoneal fibrosis Ulcerative colitis
No. Patients
%
20
46
3 5 3 15 7 5 5 3 3 1
7 12 7 35 16 12 12 7 7 2.3
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pancreas
&
Volume 43, Number 5, July 2014
Letters to the Editor
FIGURE 1. Radiologic findings of patients with AIP with peripancreatic vascular involvement, pancreatic pseudocysts, massive ascites, and renal involvement. A, Computed tomography shows diffuse enlargement of the pancreas, pseudocysts, and massive ascites. B, Computed tomography shows masses around the SMA (arrow) and ascites. C, Computed tomography shows diffuse enlargement of the pancreas and stenosis of the splenic vein and the portal confluence (arrow). D, Computed tomography shows wedge-shaped lesions (arrow) in the bilateral kidney. E, Computed tomography shows resolution of enlargement of the pancreas and disappearance of pseudocysts and ascites after 12 weeks of steroid therapy. F, Computed tomography shows decrease in size of masses around SMA and disappearance of ascites after 12 weeks of steroid therapy. G, Computed tomography shows resolution of enlargement of the pancreas and improvement of stenosis of the vessels after 12 weeks of steroid therapy. H, Computed tomography shows decrease of renal lesions after 12 weeks of steroid therapy.
all showed involvement of the splenic vein and peripancreatic effusion. Although the exact reason of this finding is unclear, cyst formation in patients with AIP may suggest a highly active inflammatory state. A new finding was the presence of massive ascites in 3 patients with AIP. Autoimmune pancreatitis may involve abdominal visceral or parietal peritoneum with diffuse sclerosing inflammation. The therapeutic options for refractory AIP are steroid pulse therapy or steroidsparing therapy with immunomodulatory drugs.7,8 Our study showed that mycophenolate mofetil may be effective at treating patients with AIP with an incomplete response to steroids. Patients with absent or mild symptoms or undergoing biliary drainage by surgical or endoscopic procedure could be followed up without steroid therapy. In most cases, AIP-related lesions resolved spontaneously. However, the relapse rate of these patients was higher (25%), and AIP-related lesions can occasionally progress, resulting in death. Therefore, steroids are the mainstay of therapy for AIP. ACKNOWLEDGMENT This work was supported by a grant from the Programs for Science and Technology Development of Liaoning Province (no. 2011225020) and from the Social Development Program from Shenyang Science and Technology Bureau (no. F11-262-9-23). The authors declare no conflict of interest. * 2014 Lippincott Williams & Wilkins
Gang Wu, MD, PhD Department of Hepatobiliary and Pancreatic Surgery the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China [email protected]
Xuedan Li, MD Department of Radiology the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China
Tianlong Wang, MD Qi Zhang, MD Hui He, MD Department of Hepatobiliary and Pancreatic Surgery the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China
Mingjun Sun, MD, PhD Department of Gastrointestinal Endoscopy the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China
Yongfeng Liu, MD, PhD Department of Hepatobiliary and Pancreatic Surgery the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China
REFERENCES 1. Sarles H, Sarles JC, Muratore R, et al. Chronic inflammatory sclerosis of the pancreasVan autonomous pancreatic disease? Am J Dig Dis. 1961;6:688Y698.
2. Yoshida K, Toki F, Takeuchi T, et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40:1561Y1568. 3. Shimosegawa T, Chari ST, Frulloni L, et al. International Consensus Diagnostic Criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352Y358. 4. Raina A, Yadav D, Krasinskas AM, et al. Evaluation and management of autoimmune pancreatitis: experience at a large US center. Am J Gastroenterol. 2009;104: 2295Y2306. 5. Ishikawa T, Itoh A, Kawashima H, et al. Peripancreatic vascular involvements of autoimmune pancreatitis. J Gastroenterol Hepatol. 2012;27:1790Y1795. 6. Kawakami H, Kuwatani M, Shinada K, et al. Autoimmune pancreatitis associated with hemorrhagic pseudocysts: a case report and literature review. Intern Med. 2008;47: 603Y608. 7. Sodikoff JB, Keilin SA, Cai Q, et al. Mycophenolate mofetil for maintenance of remission in steroid-dependent autoimmune pancreatitis. World J Gastroenterol. 2012; 18:2287Y2290. 8. Khosroshahi A, Bloch DB, Deshpande V, et al. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62:1755Y1762.
www.pancreasjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
811
Letters to the Editor
after previous therapy with sunitinib and everolimus. The authors declare no conflict of interest. Una Graham, MD, MRCP Regional Centre for Endocrinology and Diabetes Royal Victoria Hospital Belfast, United Kingdom [email protected]
Martin Eatock, MD, FRCP Northern Ireland Cancer Centre Belfast City Hospital Belfast, United Kingdom
Brew Atkinson, MD, FRCP Regional Centre for Endocrinology and Diabetes Royal Victoria Hospital Belfast, United Kingdom
REFERENCES 1. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501Y513. 2. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514Y523. 3. Karhoff D, Sauer S, Schrader J, et al. Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target. Neuroendocrinology. 2007;85:45Y53. 4. Jeong HK, Roh SY, Hong SH, et al. Pancreatic endocrine tumors: a report on a patient treated with sorafenib. J Korean Med Sci. 2011;26:954Y958. 5. Hobday TJ, Rubin J, Holen K, et al. MC044h, a phase II trial of sorafenib in patients with metastatic neuroendocrine tumors (NET): a phase II consortium study. J Clin Oncol. 2007;25:18S.
Review of 43 Patients With Autoimmune Pancreatitis Based on the International Consensus Diagnostic Criteria in China To the Editor:
A
utoimmune pancreatitis (AIP) is a unique type of chronic pancreatitis whose pathogenesis involves an autoimmune component.1,2 Within the past decade in China, many patients with AIP were misdiagnosed with pancreaticobiliary cancer and underwent operations because clinicians were unfamiliar with the concept of AIP or did not recognize its features. Therefore, the aims of this study were to systematically analyze and identify clinical features of the largest cohort of patients with AIP from a single institution in China.
810
www.pancreasjournal.com
MATERIALS AND METHODS A database of patients suspected to have or diagnosed as having AIP (used Japanese Pancreas Society criteria or Mayo Clinic’s histology, imaging, serology, other organ involvement and response to steroid therapy criteria for AIP) was prospectively maintained from January 2007 to December 2012 in our hospital. The medical records of 48 patients were reviewed to obtain information on demographics, clinical presentation, laboratory data, imaging and histologic features, response to treatment, and relapse on follow-up. Fortythree patients fulfilled the International Consensus Diagnostic Criteria3 for AIP.
RESULTS A total of 43 patients had a diagnosis of AIP based on the International Consensus Diagnostic Criteria for AIP (definitive type 1, 34/43 patients; probable type 1, 2/43 patients; type 2, 0/43 patients; and AIP [not otherwise specified], 7/43 patients). The mean age at presentation was 55.8 years (range, 31Y75 years). Three fourths (3/4) of the patients were 50 years and older and male. The most common presenting symptoms included new-onset obstructive jaundice in 77% of the patients, weight loss in 44% of the patients, abdominal pain in 42% of the patients, and hyperamylasemia in 12% of the patients. Serum IgG4 levels were increased to above 135 mg/dL and above 270 mg/dL in 15 and 13 of the 17 patients, respectively. Diffuse and focal pancreatic enlargements were found in 79% and 21% of the patients, respectively. Peripancreatic vessels involvement, masses around the superior mesenteric artery (SMA), pancreatic pseudocysts, and massive ascites were observed in our cases (Table 1, Fig. 1). These lesions were dramatically improved by steroid treatment. Extrapancreatic involvement was observed in 23 patients during the clinical course, and the spectrum is reported in Table 1. Eleven patients had only 1 associated disease, 8 patients had 2 associated diseases, and 4 patients had 3 associated diseases. Renal involvement was observed in 15 patients and was the most frequent extrapancreatic lesion (Fig. 1). Pulmonary inflammatory pseudotumors and interstitial pneumonia were observed in 5 patients. These lesions were partially resolved after steroid therapy. Histologic examination and IgG4 staining in 2 pancreatic resection specimens confirmed the diagnosis of type 1 AIP. The histologic findings of superficial lymph node specimens supported the diagnosis of AIP-related lymphadenopathy with positive IgG4 staining in 5 patients. Two patients with focal AIP in the head underwent a pancreaticoduodenectomy
&
Volume 43, Number 5, July 2014
for suspected pancreatic adenocarcinoma. Thirty patients received steroids as the initial treatment. The usual regimen was 40 mg/d of oral prednisone for 4 weeks followed by a taper of 5 mg/wk. Among the 27 patients with a complete response to steroid, 4 had a recurrence. All 3 patients with an incomplete response eventually responded to the combination of prednisone and mycophenolate mofetil (750 mg twice daily) followed by steroids alone. Among the remaining 11 patients not receiving steroid treatment, 8 patients with obstructive jaundice underwent biliary drainage by surgical or endoscopic procedure. One patient had massive postoperative ascites, and 1 year later, the patient died. Ten patients had spontaneous remission of AIP-related lesions. Two patients had recurrent pancreatic swelling. Two patients were lost to follow-up.
DISCUSSION In this study, the prevalence of peripancreatic vascular involvements in AIP was high at 46%. Vascular involvements were found to be closely related to the site of pancreatic inflammation and mass formation.4,5 We speculate that obliterative phlebitis, which is characteristic to AIP, spreads among the vessels around the pancreas, resulting in peripancreatic vascular lesions. The mechanism of encasement of the SMA may be different from that of peripancreatic vascular involvements. This may be a manifestation of retroperitoneal fibrosis. Peripancreatic vascular lesions improved by steroids may represent reversible changes. Patients with AIP with pancreatic pseudocysts are rare.5,6 Yoshida et al2 reported that one of the characteristic features of AIP is the absence of pancreatic cysts. Interestingly, in our study, 5 of the 43 patients exhibited pseudocysts, and these 5 patients
TABLE 1. Imaging and Extrapancreatic Manifestations Observed in 43 Patients With AIP
Peripancreatic vessels involvement Mass around SMA Pancreatic pseudocyst Ascites Renal focal nephritis IgG4-related sialadenitis Lung involvement IgG4-related thyroiditis Hilar sclerosing cholangitis Retroperitoneal fibrosis Ulcerative colitis
No. Patients
%
20
46
3 5 3 15 7 5 5 3 3 1
7 12 7 35 16 12 12 7 7 2.3
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pancreas
&
Volume 43, Number 5, July 2014
Letters to the Editor
FIGURE 1. Radiologic findings of patients with AIP with peripancreatic vascular involvement, pancreatic pseudocysts, massive ascites, and renal involvement. A, Computed tomography shows diffuse enlargement of the pancreas, pseudocysts, and massive ascites. B, Computed tomography shows masses around the SMA (arrow) and ascites. C, Computed tomography shows diffuse enlargement of the pancreas and stenosis of the splenic vein and the portal confluence (arrow). D, Computed tomography shows wedge-shaped lesions (arrow) in the bilateral kidney. E, Computed tomography shows resolution of enlargement of the pancreas and disappearance of pseudocysts and ascites after 12 weeks of steroid therapy. F, Computed tomography shows decrease in size of masses around SMA and disappearance of ascites after 12 weeks of steroid therapy. G, Computed tomography shows resolution of enlargement of the pancreas and improvement of stenosis of the vessels after 12 weeks of steroid therapy. H, Computed tomography shows decrease of renal lesions after 12 weeks of steroid therapy.
all showed involvement of the splenic vein and peripancreatic effusion. Although the exact reason of this finding is unclear, cyst formation in patients with AIP may suggest a highly active inflammatory state. A new finding was the presence of massive ascites in 3 patients with AIP. Autoimmune pancreatitis may involve abdominal visceral or parietal peritoneum with diffuse sclerosing inflammation. The therapeutic options for refractory AIP are steroid pulse therapy or steroidsparing therapy with immunomodulatory drugs.7,8 Our study showed that mycophenolate mofetil may be effective at treating patients with AIP with an incomplete response to steroids. Patients with absent or mild symptoms or undergoing biliary drainage by surgical or endoscopic procedure could be followed up without steroid therapy. In most cases, AIP-related lesions resolved spontaneously. However, the relapse rate of these patients was higher (25%), and AIP-related lesions can occasionally progress, resulting in death. Therefore, steroids are the mainstay of therapy for AIP. ACKNOWLEDGMENT This work was supported by a grant from the Programs for Science and Technology Development of Liaoning Province (no. 2011225020) and from the Social Development Program from Shenyang Science and Technology Bureau (no. F11-262-9-23). The authors declare no conflict of interest. * 2014 Lippincott Williams & Wilkins
Gang Wu, MD, PhD Department of Hepatobiliary and Pancreatic Surgery the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China [email protected]
Xuedan Li, MD Department of Radiology the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China
Tianlong Wang, MD Qi Zhang, MD Hui He, MD Department of Hepatobiliary and Pancreatic Surgery the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China
Mingjun Sun, MD, PhD Department of Gastrointestinal Endoscopy the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China
Yongfeng Liu, MD, PhD Department of Hepatobiliary and Pancreatic Surgery the First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China
REFERENCES 1. Sarles H, Sarles JC, Muratore R, et al. Chronic inflammatory sclerosis of the pancreasVan autonomous pancreatic disease? Am J Dig Dis. 1961;6:688Y698.
2. Yoshida K, Toki F, Takeuchi T, et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40:1561Y1568. 3. Shimosegawa T, Chari ST, Frulloni L, et al. International Consensus Diagnostic Criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352Y358. 4. Raina A, Yadav D, Krasinskas AM, et al. Evaluation and management of autoimmune pancreatitis: experience at a large US center. Am J Gastroenterol. 2009;104: 2295Y2306. 5. Ishikawa T, Itoh A, Kawashima H, et al. Peripancreatic vascular involvements of autoimmune pancreatitis. J Gastroenterol Hepatol. 2012;27:1790Y1795. 6. Kawakami H, Kuwatani M, Shinada K, et al. Autoimmune pancreatitis associated with hemorrhagic pseudocysts: a case report and literature review. Intern Med. 2008;47: 603Y608. 7. Sodikoff JB, Keilin SA, Cai Q, et al. Mycophenolate mofetil for maintenance of remission in steroid-dependent autoimmune pancreatitis. World J Gastroenterol. 2012; 18:2287Y2290. 8. Khosroshahi A, Bloch DB, Deshpande V, et al. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62:1755Y1762.
www.pancreasjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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