HPB
http://dx.doi.org/10.1016/j.hpb.2015.10.010
ORIGINAL ARTICLE
Intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia is a risk factor for the subsequent development of pancreatic ductal adenocarcinoma Neda Rezaee1, Carlotta Barbon1, Ahmed Zaki1, Jin He1, Bulent Salman1, Ralph H. Hruban2,3, John L. Cameron1, Joseph M. Herman3,4, Nita Ahuja1,3,4, Anne Marie Lennon1,5, Matthew J. Weiss1,3, Laura D. Wood2 & Christopher L. Wolfgang1,2,3 1
Department of Surgery, 2Department of Pathology, 3Department of Oncology, 4Department of Radiation Oncology, and 5Department of Gastroenterology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Abstract Background: Non-invasive intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia and IPMN-associated invasive pancreatic ductal adenocarcinoma (PDAC) are frequently included under the term “malignancy”. The goal of this study is to clarify the difference between these two entities. Methods: From 1996 to 2013, data of 616 patients who underwent pancreatic resection for an IPMN were reviewed. Results: The median overall survival for patients with IPMN with high-grade dysplasia (92 months) was similar to survival for patients with IPMN with low/intermediate-grade dysplasia (118 months, p = 0.081), and superior to that of patients with IPMN-associated PDAC (29 months, p < 0.001). IPMN-associated PDAC had lymph node metastasis in 53%, perineural invasion in 58%, and vascular invasion in 33%. In contrast, no lymph node metastasis, perineural or vascular invasion was observed with high-grade dysplasia. None of the patients with IPMN with high-grade dysplasia developed recurrence outside the remnant pancreas. In stark contrast 58% of patients with IPMN-associated PDAC recurred outside the remnant pancreas. The rate of progression within the remnant pancreas was significant in patients with IPMN with high-grade (24%) and with low/intermediate dysplasia (22%, p = 0.816). Conclusion: Non-invasive IPMN with high-grade dysplasia should not be considered a malignant entity. Compared to patients with IPMN with low/intermediate-grade dysplasia, those with high-grade dysplasia have an increased risk of subsequent development of PDAC in the remnant pancreas. Received 21 July 2015; accepted 16 August 2015
Correspondence Christopher L. Wolfgang, Department of Surgery, Division of Surgical Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 658, Baltimore, MD 21287, USA. Tel: +1 (410) 502 4194. Fax: +1 (410) 955 8110. E-mail: [email protected] Laura D. Wood, Department of pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Hospital, 1550 Orleans Street, CRB2 Room 345, Baltimore, MD 21231, USA. Tel: +1 (410) 614 0671. Fax: +1 (410) 955 8110. E-mail: [email protected]
This study was presented at the Annual Meeting of the AHPBA, 11-15 March 2015, Miami, Florida. Christopher L. Wolfgang and Laura D. Wood are co-senior authors.
HPB 2016, 18, 236–246
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
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Introduction Intraductal papillary mucinous neoplasm (IPMN) is a common cystic neoplasm of the pancreas that is characterized by mucinsecreting intraductal papillary proliferations of neoplastic epithelium.1–4 IPMNs were originally described in 1982 by Ohhashi et al.5 and defining characteristics were outlined by the World Health Organization in 1996.6 Similar to pancreatic intraepithelial neoplasia (PanIN), IPMN is a precursor lesion that can progress to invasive pancreatic ductal adenocarcinoma (PDAC) through a spectrum of dysplastic changes that range from low to high-grade dysplasia. This progression model for the development of PDAC is thought to be analogous to the adenoma-to-carcinoma progression of colorectal cancer.7 One limitation in interpreting the results of the numerous publications on the pathobiology of IPMN is the imprecision in terminology. In particular, the term “malignancy” is used variably and in some reports includes both IPMN-associated PDAC and non-invasive IPMN with high-grade dysplasia, while in other reports malignancy is only used to describe IPMN-associated PDAC. As a result of this discrepancy, there is considerable variability reported for the biological behavior of IPMN as a function of pathological grade. For example, the prevalence of “malignancy” ranges from 6% to 66% in reports of surgically resected IPMNs.8–20 A large part of this variation can be accounted for by the definition of malignancy employed. As a result, variability is observed in the reported survival rates after resection. The 5-year survival rate is reported to be from 77% to 100% for “non-malignant”, and 22% to 62% for “malignant” IPMNs.8,14,15,21–24 In 1996, the WHO established guidelines for the precise nomenclature of IPMN.6 IPMN with an associated invasive carcinoma (IPMN-associated PDAC) is defined by an IPMN with a neoplastic component, which has invaded across the basement membrane of the duct. This represents true “malignancy” as these lesions have the clear potential for systemic spread. In contrast, non-invasive IPMN with high-grade dysplasia is composed of cells with marked nuclear atypia and complex architecture with an unorganized cellular arrangement similar to invasive carcinoma, but the neoplastic cells have not invaded across the basement membrane. The synonymous term of carcinoma in situ is less often used and has been replaced by the more appropriate term high-grade dysplasia. The neoplastic cells of high-grade dysplasia, which presumably lack potential for systemic spread, are considered to be a precursor lesion. In order to document better the differences in biological behavior of IPMN-associated PDAC (true malignancy) and IPMN with high-grade dysplasia, the objective of this study was to demonstrate the disease-specific outcomes of patients who underwent resection of these lesions. Specifically, we performed a retrospective analysis of a large single-institutional series of resected patients in which IPMN-associated PDAC and noninvasive IPMN with high-grade dysplasia were consistently and
HPB 2016, 18, 236–246
precisely defined according to the WHO definitions. We further compared disease-specific local/regional recurrence, systemic recurrence and disease progression in the pancreatic remnant, as well as the disease-specific survival of the patients with IPMNassociated PDAC and non-invasive IPMN with high-grade dysplasia.
Methods Study population This study was approved by the Johns Hopkins Hospital institutional review board (IRB). Review of a prospectively maintained database identified 642 consecutive patients who underwent a pancreatectomy for an IPMN from 1996 to 2013 at Johns Hopkins Hospital. Patients with an unknown grade of dysplasia or those with a concomitant invasive pancreatic ductal adenocarcinoma, coexisting but separate from IPMN, were excluded from the cohort. A total of 616 patients with an IPMN with a clearly defined grade of dysplasia or diagnosis of IPMN with an associated PDAC (IPMN-associated PDAC) formed the population of this study. Clinical information, including patients’ age and gender, pre-operative presenting symptoms; and pathologic data, including tumor size (with the size of the noninvasive IPMN and invasive cancer clearly separated), grade of dysplasia, type of invasive pancreatic cancer, lymph node metastasis, perineural and vascular invasion, and resection margin status were obtained. Pathologic examination of IPMNs In general, all patients were approached with a targeted partial pancreatectomy to resect the index lesion followed by frozen section analysis of margins. The majority of the patients at Johns Hopkins Hospital undergo surgical resection based on the International Consensus Guidelines resection criteria.25 Patients with a presumably benign IPMN undergo resection when there is a strong family history of pancreatic cancer or when the patient has the willing to proceed to operation. IPMN was defined as a mucin-producing cystic neoplasm with tall, columnar epithelial cells, with or without papillary projections that extensively involve the main pancreatic duct or its side branches. Lesions were assigned to only one category consisting of low-grade dysplasia, intermediate-grade dysplasia, high-grade dysplasia or IPMN with invasive carcinoma based on the highest grade of dysplasia/carcinoma encountered in the specimen. IPMN-associated PDAC (pancreatic adenocarcinoma arising in association with an IPMN) were further classified onto two subtypes: tubular adenocarcinoma, composed of predominantly gland-forming neoplastic cells with fibrotic stroma and absence of significant extracellular stromal mucin (i.e. conventional PDAC); and colloid carcinoma (mucinous non-cystic carcinoma), composed of sparsely populated strips, clusters, or individual neoplastic cells residing within extensive pools of extracellular mucin (Fig. 1).
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
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invasive adenocarcinoma at the resection line. A positive margin was further classified based on the highest grade of dysplasia identified at the margin or, in the case of invasive cancer, as R0 (negative margin), R1 (microscopic positive margin) or R2 (macroscopic tumor left at the margin).
Figure 1 a) IPMN with high-grade dysplasia is composed of cells with
marked nuclear atypia and complex architecture with an unorganized cellular arrangement similar to invasive carcinoma but in contrast to invasive cancer lacks invasion of the basement membrane. b) Colloid carcinoma (mucinous non-cystic carcinoma), composed of sparsely populated strips, clusters, or individual neoplastic cells residing within extensive pools of extracellular mucin. These neoplastic cells commonly contain intracytoplasmic mucin. c) IPMN-associated tubular adenocarcinoma composed of predominantly gland-forming neoplastic cells with fibrotic stroma and absence of significant extracellular mucin
When appropriate the nodal status and presence of perineural and vascular invasion were also recorded. The tumor size was evaluated based on the maximal size measured on pathologic examination. The size of only the invasive component in tumors was considered the size of the invasive carcinoma. The resection margins that were routinely assessed included pancreatic neck, uncinate (superior mesenteric artery), bile duct/hepatic duct margin, and enteric resection lines. Margin involvement was defined as presence of IPMN with any grade of dysplasia or
HPB 2016, 18, 236–246
Evaluation of recurrence and survival outcomes Post-operative follow-up data were collected from information obtained during routine surveillance clinic visits. In general, patients were followed for recurrence or progression every 3–6 months if they have IPMN-associated PDAC and 6–12 months if they have non-invasive IPMN with imaging studies that included at least one of the following: computed tomography (CT) scan, magnetic resonance imaging (MRI), or endoscopic ultrasonography (EUS). For patients with non-invasive IPMN, progression in the remnant pancreas was defined as radiologic evidence of a new IPMN, a new solid component within an existing IPMN in the remnant pancreas, a significant increase in the size of the main pancreatic duct in the remnant pancreas, development of a metachronous PDAC in the remnant pancreas or a clinically significant increase in size of an existing cyst in the remnant pancreas. In addition, the presence of a new PDAC in the remnant pancreas with metastatic disease was also counted as progression. In patients with an initial resection of an IPMNassociated PDAC, recurrence was determined by cross-sectional imaging and defined by the typical patterns of recurrence for resected PDAC. That is, local/regional recurrence was defined by the development of soft tissue in the tumor resection bed and systemic recurrence was determined by evidence of liver, lung or peritoneal metastases. In all cases, recurrence or progression was evaluated only among patients who had more than 6 month of follow-up. The time to disease progression was calculated from the time of original diagnoses at pathologic assessment of surgically removed specimens to the time of the progression diagnosed on follow-up imaging evaluations. Survival time was calculated from the time of surgical resection to death, whereas follow-up time was based on time of surgery to the most recent clinic visit. The survival analysis in the study is disease-specific–thus patients who died of causes other than pancreatic cancer were censored along with those who were still alive at last follow-up. Statistical analysis For the purpose of performing a comparative analysis, patients were stratified into 3 groups based on degree of dysplasia as follows: low/intermediate-grade dysplasia, high-grade dysplasia, and IPMN-associated PDAC. In some analyses, IPMNassociated tubular carcinoma and colloid carcinoma were separated as indicated in the results. The clinical and pathologic characteristics of these groups were compared using statistical methods as follows. Continuous variables were presented as median and interquartile range (IQR) and were compared using a Wilcoxon–Mann–Whitney test. To compare the categorical
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
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variables, a chi-squared test or a fisher-exact test were performed. Kaplan–Meier survival estimates and a log-rank test were used to estimate the survival in IPMNs with different grades of dysplasia. To evaluate the independent factors associated with survival we used a cox-proportional hazard regression. Possible factors related to development of PDAC in patients underwent resection for low/intermediate-grade dysplasia or high-grade dysplasia were evaluated using univariate and multivariate regression models. A backward step-wise elimination with a threshold of p = 0.20 was used to select the variables for the final multivariate model. A p-value
http://dx.doi.org/10.1016/j.hpb.2015.10.010
ORIGINAL ARTICLE
Intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia is a risk factor for the subsequent development of pancreatic ductal adenocarcinoma Neda Rezaee1, Carlotta Barbon1, Ahmed Zaki1, Jin He1, Bulent Salman1, Ralph H. Hruban2,3, John L. Cameron1, Joseph M. Herman3,4, Nita Ahuja1,3,4, Anne Marie Lennon1,5, Matthew J. Weiss1,3, Laura D. Wood2 & Christopher L. Wolfgang1,2,3 1
Department of Surgery, 2Department of Pathology, 3Department of Oncology, 4Department of Radiation Oncology, and 5Department of Gastroenterology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Abstract Background: Non-invasive intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia and IPMN-associated invasive pancreatic ductal adenocarcinoma (PDAC) are frequently included under the term “malignancy”. The goal of this study is to clarify the difference between these two entities. Methods: From 1996 to 2013, data of 616 patients who underwent pancreatic resection for an IPMN were reviewed. Results: The median overall survival for patients with IPMN with high-grade dysplasia (92 months) was similar to survival for patients with IPMN with low/intermediate-grade dysplasia (118 months, p = 0.081), and superior to that of patients with IPMN-associated PDAC (29 months, p < 0.001). IPMN-associated PDAC had lymph node metastasis in 53%, perineural invasion in 58%, and vascular invasion in 33%. In contrast, no lymph node metastasis, perineural or vascular invasion was observed with high-grade dysplasia. None of the patients with IPMN with high-grade dysplasia developed recurrence outside the remnant pancreas. In stark contrast 58% of patients with IPMN-associated PDAC recurred outside the remnant pancreas. The rate of progression within the remnant pancreas was significant in patients with IPMN with high-grade (24%) and with low/intermediate dysplasia (22%, p = 0.816). Conclusion: Non-invasive IPMN with high-grade dysplasia should not be considered a malignant entity. Compared to patients with IPMN with low/intermediate-grade dysplasia, those with high-grade dysplasia have an increased risk of subsequent development of PDAC in the remnant pancreas. Received 21 July 2015; accepted 16 August 2015
Correspondence Christopher L. Wolfgang, Department of Surgery, Division of Surgical Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 658, Baltimore, MD 21287, USA. Tel: +1 (410) 502 4194. Fax: +1 (410) 955 8110. E-mail: [email protected] Laura D. Wood, Department of pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Hospital, 1550 Orleans Street, CRB2 Room 345, Baltimore, MD 21231, USA. Tel: +1 (410) 614 0671. Fax: +1 (410) 955 8110. E-mail: [email protected]
This study was presented at the Annual Meeting of the AHPBA, 11-15 March 2015, Miami, Florida. Christopher L. Wolfgang and Laura D. Wood are co-senior authors.
HPB 2016, 18, 236–246
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
237
Introduction Intraductal papillary mucinous neoplasm (IPMN) is a common cystic neoplasm of the pancreas that is characterized by mucinsecreting intraductal papillary proliferations of neoplastic epithelium.1–4 IPMNs were originally described in 1982 by Ohhashi et al.5 and defining characteristics were outlined by the World Health Organization in 1996.6 Similar to pancreatic intraepithelial neoplasia (PanIN), IPMN is a precursor lesion that can progress to invasive pancreatic ductal adenocarcinoma (PDAC) through a spectrum of dysplastic changes that range from low to high-grade dysplasia. This progression model for the development of PDAC is thought to be analogous to the adenoma-to-carcinoma progression of colorectal cancer.7 One limitation in interpreting the results of the numerous publications on the pathobiology of IPMN is the imprecision in terminology. In particular, the term “malignancy” is used variably and in some reports includes both IPMN-associated PDAC and non-invasive IPMN with high-grade dysplasia, while in other reports malignancy is only used to describe IPMN-associated PDAC. As a result of this discrepancy, there is considerable variability reported for the biological behavior of IPMN as a function of pathological grade. For example, the prevalence of “malignancy” ranges from 6% to 66% in reports of surgically resected IPMNs.8–20 A large part of this variation can be accounted for by the definition of malignancy employed. As a result, variability is observed in the reported survival rates after resection. The 5-year survival rate is reported to be from 77% to 100% for “non-malignant”, and 22% to 62% for “malignant” IPMNs.8,14,15,21–24 In 1996, the WHO established guidelines for the precise nomenclature of IPMN.6 IPMN with an associated invasive carcinoma (IPMN-associated PDAC) is defined by an IPMN with a neoplastic component, which has invaded across the basement membrane of the duct. This represents true “malignancy” as these lesions have the clear potential for systemic spread. In contrast, non-invasive IPMN with high-grade dysplasia is composed of cells with marked nuclear atypia and complex architecture with an unorganized cellular arrangement similar to invasive carcinoma, but the neoplastic cells have not invaded across the basement membrane. The synonymous term of carcinoma in situ is less often used and has been replaced by the more appropriate term high-grade dysplasia. The neoplastic cells of high-grade dysplasia, which presumably lack potential for systemic spread, are considered to be a precursor lesion. In order to document better the differences in biological behavior of IPMN-associated PDAC (true malignancy) and IPMN with high-grade dysplasia, the objective of this study was to demonstrate the disease-specific outcomes of patients who underwent resection of these lesions. Specifically, we performed a retrospective analysis of a large single-institutional series of resected patients in which IPMN-associated PDAC and noninvasive IPMN with high-grade dysplasia were consistently and
HPB 2016, 18, 236–246
precisely defined according to the WHO definitions. We further compared disease-specific local/regional recurrence, systemic recurrence and disease progression in the pancreatic remnant, as well as the disease-specific survival of the patients with IPMNassociated PDAC and non-invasive IPMN with high-grade dysplasia.
Methods Study population This study was approved by the Johns Hopkins Hospital institutional review board (IRB). Review of a prospectively maintained database identified 642 consecutive patients who underwent a pancreatectomy for an IPMN from 1996 to 2013 at Johns Hopkins Hospital. Patients with an unknown grade of dysplasia or those with a concomitant invasive pancreatic ductal adenocarcinoma, coexisting but separate from IPMN, were excluded from the cohort. A total of 616 patients with an IPMN with a clearly defined grade of dysplasia or diagnosis of IPMN with an associated PDAC (IPMN-associated PDAC) formed the population of this study. Clinical information, including patients’ age and gender, pre-operative presenting symptoms; and pathologic data, including tumor size (with the size of the noninvasive IPMN and invasive cancer clearly separated), grade of dysplasia, type of invasive pancreatic cancer, lymph node metastasis, perineural and vascular invasion, and resection margin status were obtained. Pathologic examination of IPMNs In general, all patients were approached with a targeted partial pancreatectomy to resect the index lesion followed by frozen section analysis of margins. The majority of the patients at Johns Hopkins Hospital undergo surgical resection based on the International Consensus Guidelines resection criteria.25 Patients with a presumably benign IPMN undergo resection when there is a strong family history of pancreatic cancer or when the patient has the willing to proceed to operation. IPMN was defined as a mucin-producing cystic neoplasm with tall, columnar epithelial cells, with or without papillary projections that extensively involve the main pancreatic duct or its side branches. Lesions were assigned to only one category consisting of low-grade dysplasia, intermediate-grade dysplasia, high-grade dysplasia or IPMN with invasive carcinoma based on the highest grade of dysplasia/carcinoma encountered in the specimen. IPMN-associated PDAC (pancreatic adenocarcinoma arising in association with an IPMN) were further classified onto two subtypes: tubular adenocarcinoma, composed of predominantly gland-forming neoplastic cells with fibrotic stroma and absence of significant extracellular stromal mucin (i.e. conventional PDAC); and colloid carcinoma (mucinous non-cystic carcinoma), composed of sparsely populated strips, clusters, or individual neoplastic cells residing within extensive pools of extracellular mucin (Fig. 1).
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
238
invasive adenocarcinoma at the resection line. A positive margin was further classified based on the highest grade of dysplasia identified at the margin or, in the case of invasive cancer, as R0 (negative margin), R1 (microscopic positive margin) or R2 (macroscopic tumor left at the margin).
Figure 1 a) IPMN with high-grade dysplasia is composed of cells with
marked nuclear atypia and complex architecture with an unorganized cellular arrangement similar to invasive carcinoma but in contrast to invasive cancer lacks invasion of the basement membrane. b) Colloid carcinoma (mucinous non-cystic carcinoma), composed of sparsely populated strips, clusters, or individual neoplastic cells residing within extensive pools of extracellular mucin. These neoplastic cells commonly contain intracytoplasmic mucin. c) IPMN-associated tubular adenocarcinoma composed of predominantly gland-forming neoplastic cells with fibrotic stroma and absence of significant extracellular mucin
When appropriate the nodal status and presence of perineural and vascular invasion were also recorded. The tumor size was evaluated based on the maximal size measured on pathologic examination. The size of only the invasive component in tumors was considered the size of the invasive carcinoma. The resection margins that were routinely assessed included pancreatic neck, uncinate (superior mesenteric artery), bile duct/hepatic duct margin, and enteric resection lines. Margin involvement was defined as presence of IPMN with any grade of dysplasia or
HPB 2016, 18, 236–246
Evaluation of recurrence and survival outcomes Post-operative follow-up data were collected from information obtained during routine surveillance clinic visits. In general, patients were followed for recurrence or progression every 3–6 months if they have IPMN-associated PDAC and 6–12 months if they have non-invasive IPMN with imaging studies that included at least one of the following: computed tomography (CT) scan, magnetic resonance imaging (MRI), or endoscopic ultrasonography (EUS). For patients with non-invasive IPMN, progression in the remnant pancreas was defined as radiologic evidence of a new IPMN, a new solid component within an existing IPMN in the remnant pancreas, a significant increase in the size of the main pancreatic duct in the remnant pancreas, development of a metachronous PDAC in the remnant pancreas or a clinically significant increase in size of an existing cyst in the remnant pancreas. In addition, the presence of a new PDAC in the remnant pancreas with metastatic disease was also counted as progression. In patients with an initial resection of an IPMNassociated PDAC, recurrence was determined by cross-sectional imaging and defined by the typical patterns of recurrence for resected PDAC. That is, local/regional recurrence was defined by the development of soft tissue in the tumor resection bed and systemic recurrence was determined by evidence of liver, lung or peritoneal metastases. In all cases, recurrence or progression was evaluated only among patients who had more than 6 month of follow-up. The time to disease progression was calculated from the time of original diagnoses at pathologic assessment of surgically removed specimens to the time of the progression diagnosed on follow-up imaging evaluations. Survival time was calculated from the time of surgical resection to death, whereas follow-up time was based on time of surgery to the most recent clinic visit. The survival analysis in the study is disease-specific–thus patients who died of causes other than pancreatic cancer were censored along with those who were still alive at last follow-up. Statistical analysis For the purpose of performing a comparative analysis, patients were stratified into 3 groups based on degree of dysplasia as follows: low/intermediate-grade dysplasia, high-grade dysplasia, and IPMN-associated PDAC. In some analyses, IPMNassociated tubular carcinoma and colloid carcinoma were separated as indicated in the results. The clinical and pathologic characteristics of these groups were compared using statistical methods as follows. Continuous variables were presented as median and interquartile range (IQR) and were compared using a Wilcoxon–Mann–Whitney test. To compare the categorical
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
239
variables, a chi-squared test or a fisher-exact test were performed. Kaplan–Meier survival estimates and a log-rank test were used to estimate the survival in IPMNs with different grades of dysplasia. To evaluate the independent factors associated with survival we used a cox-proportional hazard regression. Possible factors related to development of PDAC in patients underwent resection for low/intermediate-grade dysplasia or high-grade dysplasia were evaluated using univariate and multivariate regression models. A backward step-wise elimination with a threshold of p = 0.20 was used to select the variables for the final multivariate model. A p-value
