Evaluation of the Prognostic Significance of ‘High-risk Stigmata’ in the International Consensus Guidelines 2012 for Intraductal Papillary Mucinous Neoplasm

Volume 5 • Issue 3 • 1000234 Surgery Curr Res ISSN: 2161-1076 SCR, an open access journal Evaluation of the Prognostic Significance of ‘High-risk Stigmata’ in the International Consensus Guidelines 2012 for Intraductal Papillary Mucinous Neoplasm Kenjiro Kimura*,1, Ryosuke Amano1, Sadaaki Yamazoe1, Go Ohira1, Kotaro Miura1, Kohei Nishio1, Katsunobu Sakurai1, Takahiro Toyokawa1, Bunzo Nakata2, Akihiro Murata3, Sadatoshi Shimizu3, Sayaka Tanaka4, Masahiko Ohsawa4, Masaichi Ohira1 and Kosei Hirakawa 1Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan 2Department of Surgery, Kashiwara Municipal Hospital, Osaka, Japan 3Department of Surgery, Osaka City General Hospital, Osaka, Japan 4Department of Diagnostic Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan


Introduction
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas arises in the main pancreatic duct or its major branches. The papillary epithelium component, degree of mucin secretion, cystic duct dilatation, and invasiveness are variable. The precancerous nature of IPMN is now widely accepted to imply a sequence of progression to malignancy, as with colonic polyps [1,2].
For the management of IPMN, International Consensus Guidelines (ICG) were first published in 2006 [3]. The 2006 ICG were based on expert opinions rather than clinical evidence, due to the limited number of reports available at that time. Subsequent studies have been performed to identify factors predicting malignancy and indications for surgical resection of IPMNs, resulting in the publication of a second set of guidelines in 2012 [4]. In this version, 'high-risk stigmata' (HRS) and 'worrisome features' (WF) were defined to stratify the risk of malignancy. Contrary to the 2006 ICG, which described predictors of malignancy for BD-IPMN only, the 2012 ICG algorithm analyzes all IPMNs altogether, considering main duct dilatation as indicative of WF or HRS.
Many investigators have attempted to identify factors predictive of malignancy and prognostic factors for IPMN. Each of the following have been suggested to be predictive of malignant IPMN: macroscopic type [5,6]; sizes of the tumor [7] and mural nodule [7]; diameter of the main pancreatic duct [8][9][10]; patulous papilla; cytology of the pancreatic juice; and pathological subtypes [11]. However, no investigations have been conducted on whether WF or HRS represents prognostic factors.
The purpose of this study was to evaluate the prognostic relevance of WF and HRS in the 2012 ICG by analyzing data from 98 consecutive patients with IPMN treated at a single institution.

Patients
A total of 98 patients with IPMN who underwent surgical resection at Osaka City University Hospital were included in this study. Informed consent was obtained from all patients to use specimens for this study in accordance with the institutional rules of the hospital. All patients had a confirmed histopathological diagnosis of IPMN of the pancreas based on World Health Organization (WHO) classifications [12]. Clinical records, radiological data, pathological results, and surgical reports in this study were reviewed retrospectively. The median duration of follow-up for all 98 patients was 55 months (range, 5-210 months).

Definition of radiological type intraductal papillary mucinous neoplasm
IPMNs were classified into three macroscopic types based on preoperative radiological findings. Main duct-type IPMN (MD-IPMN) was defined as showing dilatation of the main pancreatic duct to over 5 mm. Branch duct-type IPMN (BD-IPMN) was defined as showing cystic dilatation of a branch pancreatic duct that communicated with a non-dilated main pancreatic duct. Mixed-type IPMN (MX-IPMN) displayed characteristics of MD-and BD-IPMN. Computed tomography and magnetic resonance cholangiopancreatography were used to determine the radiological type of IPMN, with endoscopic ultrasonography (EUS) added when needed.

Parameters of malignant predictors in the 2012 ICG
Based on the 2012 ICG, a total of nine preoperative clinical and radiological parameters were assessed and cases were then categorized as no criteria (NC), WF, or HRS. HRS was defined as IPMN with at least one of the following factors: obstructive jaundice due to cystic lesion at the head of the pancreas; contrast-enhanced solid component within cyst; or main pancreatic duct ≥ 10 mm. WF was also defined as IPMN with at least one of the following factors: history of acute pancreatitis; cyst diameter ≥ 3 cm; thickened/ enhancing cyst walls; main pancreatic duct size 5-9 mm; non-enhancing mural nodule; or an abrupt change in caliber of pancreatic duct with distal pancreatic atrophy, and lymphadenopathy. Contrary to the 2006 ICG, which described predictors of malignancy for BD-IPMN alone, the 2012 ICG algorithm analyzes all IPMNs together, considering main duct dilatation as indicative of WF or HRS. The present study population thus included BD-IPMNs and MD-/MX-IPMNs both.

Pathology
On the basis of the fourth edition of the WHO classification system, the degree of dysplasia was graded and categorized as low-, intermediate-, or high-grade dysplasia, and IPMN with associated invasive carcinoma [12]. According to the 2012 ICG, low-to high-grade dysplasia was considered as benign, and IPMN with associated invasive carcinomas as malignant. In this study, low-to high-grade dysplasia was classified as 'non-invasive IPMN, and IPMN with associated invasive carcinomas as 'invasive IPMN.

Statistical Analysis
All statistical analyses were performed using JMP statistical software (version 9.0.2; SAS Institute, Cary, NC). The Kaplan-Meier method was used for univariate survival analysis, and log-rank testing was applied. Cox proportional hazard model analysis was used for multivariate survival analysis. Values of p<0.05 were considered statistically significant. Variables with values of p<0.05 after univariate analysis were used in multivariate analysis.

Progression in risk of malignancy across categories
Patients with NC included only two cases of high-grade dysplasia and no cases of invasive IPMNs. Patients with WF included six cases of high-grade dysplasia and two cases of invasive IPMN. On the other hand, patients with HRS included five cases of high-grade dysplasia and 25 cases of invasive IPMN. HRS showed higher rates of invasive lesions than NC (61.0% vs. 0%; p<0.001) and WF (61.0% vs. 5.1%; p<0.001). HRS showed high diagnostic accuracy for invasive IPMN (81.3%), with 92.3% sensitivity, 77.5% specificity, 61.0% positive predictive value, and 96.5% negative predictive value (Figure 2).

Comparison of disease-specific survival between categories
No patients in either NC or WF groups showed disease recurrence  [5,6,11], we did not find that to be the case. WF and HRS are defined in the 2012 ICG as malignant predictor criteria when deciding indications for resection. A number of studies have investigated the validity of that prediction of malignancy, and all concluded that WF and HRS have high ability in that regard [13][14][15]. The present study also demonstrates that HRS has a strong ability to predict malignancy. We showed that 61.0% of HRS cases involve invasive IPMN. HRS was thus proven to have high predictive ability for malignancy and high ability to detect for invasive IPMN.
Interestingly, no deaths occurred due to recurrence in the WF and NC groups, resulting in 5-year survival rates of 100%. Conversely, the prognosis with HRS was poor, with a 3-year survival rate of 65.2% and    Figure 3).

Discussion
The present study analyzed the prognostic meaning of HRS in the 2012 ICG. According to our results, HRS represents a prognostic factor after surgical resection for IPMN. Moreover, HRS showed a high diagnostic ability to detect invasive IPMN. To date, prognostic factors for IPMN have been vigorously investigated, but the current study is the first report to identify HRS as an independent prognostic factor for resected IPMN.
The present study population included BD-IPMN and MD-/ MX-IPMN both. In our series, the malignant ratio was 20.8% for BD-IPMNs and 35.6% for MD-/MX-IPMN. No significant difference was apparent. In the current study, malignant ratio was lower than several past reports, because we defined only invasive IPMN as malignant. But if malignant IPMN will contain IPMN with CIS (carcinoma in situ), malignant ratio of MD-IPMN was 46.7%, and 32.1% in BD-IPMN.
The presence of mural nodule, lymph node metastasis, invasive IPMN, HRS, and high preoperative level of CA19-9 were all significantly associated with poor prognosis in univariate analysis. Moreover, positive lymph node metastasis and HRS independently predicted prognosis on multivariate analysis. Although histological subtype and macroscopic type have previously been reported as prognostic factors   a 5-year survival rate of 49.5%. This strongly indicates that we should assume that HRS has high possibility of invasive IPMN and worse prognosis.
The present study has several limitations. First, this was a retrospective study conducted at a single institution. And the sample size was too small to evaluate the validation of the 2012 ICG. Large scale multicenter cohort study is needed to validate the 2012 ICG in the future. Another significant limitation was that the modality for diagnosing each IPMN varied. In particular, EUS was conducted for 75% of cases. EUS is today considered an essential examination for the diagnosis of IPMN, but it is necessary to note that our patient series includes some cases that predated the use of EUS and were diagnosed and underwent surgery without use of this modality.
In conclusion, the present study identified HRS as an independent prognostic factor after surgical resection for IPMN. Moreover, HRS showed a high diagnostic ability to detect invasive IPMN. Our results strongly indicated that HRS had high possibility of invasive IPMN and worse prognosis.