Clinical validation of the 2017 international consensus guidelines on intraductal papillary mucinous neoplasm of the pancreas

In 1996, intraductal papillary mucinous neoplasm (IPMN) of the pancreas was designated as an independent disease by the World Health Organization (WHO) [1]. Whereas mainduct type IPMN has a high malignant potential and warrants surgical resection, surgical indications for branch-duct type IPMN (BD-IPMN) or mixed-type IPMN remain controversial due to their low malignant potential. The first and second editions of the international consensus guidelines (ICG) for the management of IPMN of the pancreas were introduced in 2006 and 2012, respectively [2, 3]. The 2012 ICG proposed three high-risk stigmata (obstructive jaundice in a patient with a cystic lesion of the head of the pancreas, enhancing mural nodule ≥5 mm, main pancreatic duct [MPD] size ≥10 mm) and five worrisome features (cyst size ≥3 cm, enhancing mural nodule <5 mm, thickened/enhancing cyst walls, 5–9 mm of MPD size, and abrupt change in caliber of the pancreatic duct with distal pancreatic atrophy). Patients who were diagnosed with BD-IPMN under these guidelines were recommended to undergo complete surgical resection. One study reported that the 2012 ICG provided the practical validity for predicting malignant BD-IPMN [4].

In 2015, more conservative guidelines were released by the American Gastroenterological Association (AGA) [5]. They suggested less aggressive resection criteria and more conservative surveillance criteria than the 2012 guidelines. However, some studies questioned the limited evidence of these guidelines and proposed their revision [6, 7, 8].

Recently, the new 2017 ICG were released [9]. Only limited changes have been introduced compared to the 2012 ICG, with the addition of two worrisome features, such as increased serum CA 19-9 and a rapid cyst growth (>5 mm per 2 years) [10, 11, 12]. However, these features have not undergone rigorous clinical validation. Therefore, this study sought to investigate the usefulness of the parameters proposed by the 2017 ICG, clinically validate the 2017 ICG and compare the diagnostic performance between the 2017 and 2012 ICG.

A total of 448 patients were included in this study (Table 1). Mean age was 64.7 years and the male to female ratio was 1.4. The majority of lesions were located on the pancreatic head (55.6%), with a mean cyst size of 32.0 mm, and a mean MPD diameter of 5 mm.

Table 1
Baseline characteristics of patients with branch-duct/mixed type intraductal papi llary mucinous neoplasm

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Out of 448 patients, 148 patients (33.0%) had a pathologically malignant lesion (HGD [n = 58, 12.9%] or IPMN with invasive carcinoma [n = 90, 20.1%]). Compared to patients with benign lesions, their age was typically older (66.3 years vs. 63.9 years, P = 0.008), their cyst sizes were larger (35.0 mm vs. 30.5 mm, P = 0.002), and their MPD diameters were larger (7 mm vs. 4 mm, P = 0.001). Malignant lesions were more frequently located on the pancreatic head versus the benign lesions (62.8% vs. 52.0%, P = 0.001).

Diagnostic parameters predicting malignant BD/mixed type IPMN

Table 2 shows the univariate analysis and the diagnostic values of each parameter. Parameters significantly associated with the malignancy in the univariate analysis included MPD dilatation (>5 mm) (54.7% vs. 22.0%, P = 0.001), the presence of mural nodule (62.8% vs. 12.7%, P = 0.001), thickened cystic wall (38.5% vs. 10.3%, P = 0.001), abrupt change in MPD diameter (19.3% vs. 4.1%, P = 0.001), lymphadenopathy (5.2% vs. 0.4%, P = 0.002), elevated CEA level (>5 ng/mL) (6.8% vs. 2.3%, P = 0.046), and elevated CA 19-9 level (>37 unit/mL) (60.9% vs. 29.7%, P = 0.012). For the 87 patients who underwent imaging surveillance for at least 2 years, lesions showing >5 mm growth over 2 years were more frequently malignant compared to benign lesions (60.9% vs. 29.7%, P = 0.012). The presence of a mural nodule had the highest balanced accuracy (79.2%), followed by elevated CA 19-9 level (72.9%) and thickened cystic wall (72.7%). A cystic growth rate >5 mm over 2 years had a balanced accuracy of 67.8%.

Table 2
Univariate analysis and diagnostic value of each parameter

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In our multivariate analysis, the presence of mural nodule (HR, 9.12; 95% confidence interval [CI], 4.60–18.09; P = 0.001), MPD dilatation (>5 mm) (HR, 5.32; 95% CI, 2.67–10.60; P = 0.001), thickened cystic wall (HR, 3.40; 95% CI, 1.51–7.63; P = 0.003), and elevated CA 19-9 level (>37 unit/mL) (HR, 5.25; 95% CI, 2.05–13.42; P = 0.001) were independent risk factors for malignant branch-duct (BD)/mixed type IPMN (Table 3). Cyst growth rate was removed from the LR model because only 87 patients (19.4%) were evaluated.

Table 3
Predictive factors for malignant branch-duct type intraductal papillary mucinous neoplasm

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After the risk factors for predicting malignant lesion were selected, diagnostic values were calculated according to the number of risk factors (Table 4). Sensitivity, specificity, positive predictive value (PPV), and balanced accuracy increased as the number of risk factors increased.

Table 4
Diagnostic value according to the number of risk factors

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Following the 2006 and 2012 ICG for the management of IPMN [2, 3], research intensified to gather the evidence needed to support these guidelines. Particularly in the case of BD/mixed type IPMN, where large-scaled retrospective studies suggest that the BD/mixed type IPMN has only a 5%–20% likelihood of invasiveness [14, 15, 16, 17, 18, 19], the question of whether surgical resection or regular surveillance is preferable is an important issue. BD/mixed type IPMN without high-risk or worrisome features has been defined by the 2012 guidelines not to warrant surgical resection [3]. The associated decline in unnecessary surgeries had led to a decrease in surgery-related mortality, morbidity, and medical costs.

In 2015, the AGA released new guidelines with lesser aggressive resection criteria and more conservative surveillance criteria than those of the 2012 guidelines [5]. However, these changes were not without controversy. In terms of detecting malignant IPMN, one study reported that 45% of malignant IPMNs were not detected following the AGA guidelines [20]. In regards to the surveillance, new-onset pancreatic cancer [21], and the IPMNs with new-onset high risk stigmata and/or worrisome features were observed beyond 5 years of surveillance [7]. One study recommended continued surveillance beyond 5 years because the overall risk rate of malignancy was 8% during 10 years of surveillance [6]. The present guideline revision was focused on addressing these issues [9].

In 2017, the ICG for IPMN were revised to include 2 new factors: elevated serum CA 19-9 level and cyst growth rate [9]. Although the role of elevated CEA has been controversial, elevated serum CA 19-9 has been reported as a useful predictive marker for malignant IPMNs [12, 15, 22]. In the present study, elevated serum CA 19-9 (>37 U/mL) was strongly associated with malignancy in a multivariate analysis (HR, 5.25; 95% CI, 2.05–13.42; P < 0.001) (Table 3), and had a high diagnostic accuracy (72.9%, Table 2). Laboratory criteria benefit greatly from their relative objectivity compared to preoperative radiologic interpretation. Therefore, the introduction of serum CA 19-9 to the guidelines would be reasonable and improve diagnostic accuracy.

Some studies suggested that a cyst growth rate >2–4 mm per year could be a risk factor for malignant BD/mixed type IPMN [10, 11, 15]. One large-scale study revealed that benign BD-IPMNs observed for >5 years grew slowly at a rate of only 0.8 mm per year [23]. Therefore, growth of 2–4 mm per year is relatively rapid. In the 2017 ICG, the cyst growth rate >5 mm in 2 years was added to the worrisome features. In the present study, the cyst growth rate >5 mm in 2 years was observed more frequently in malignant lesions, and the predictive accuracy was 67.8% in the univariate analysis (Table 2). However, it was not entered into the multivariate analysis due to insufficient data. In order to overcome this limitation, large-cohort studies with long-term surveillance data should be performed.

In our multivariate analysis, mural nodule, dilated MPD, thickened cyst wall, and elevated CA 19-9 level (>37 U/mL) were associated with malignancy (Table 3). The diagnostic validity was evaluated according to the number of risk factors (Table 4). According to these results, if a patient had at least 2 risk factors, the resection would be appropriate because the PPV was over 40% and the balanced accuracy was nearly 80%. Furthermore, the possibility of malignant IPMN was greater than 90% when at least three risk factors were present. Several nomograms able to quantify the possibility of malignancy were released, which combined the risk factors based on the multivariate LR [24, 25]. Therefore, these nomograms can be valuable tools to accurately predict malignant IPMNs.

Whether cystic size is a risk factor or not remains controversial. In the 2017 ICG, a cyst size >3 cm is a worrisome feature [9]. However, recent studies argue that cystic size is not associated with malignant BD-IPMNs [26, 27, 28]. In the present study, cystic size was not associated with malignancy in the univariate analysis, and it had the lowest diagnostic accuracy (54.5%) among the potential risk factors (Table 2). Cyst size alone could not be an absolute indication for resection [4]. However, larger IPMNs tended to have more risk factors and, thus, greater malignant potential [23]. Therefore, larger IPMNs should be observed carefully with standardized protocols.

Jang et al. [4] reported the superior diagnostic performance of the 2012 ICG over the 2006 ICG by using 3 statistical methods (LR, SVM, and RF). In the present study, the same methods were utilized and the AUC values of the 2017 ICG were further improved over the 2012 ICG. The introduction of elevated serum CA 19-9 and a rapid cyst growth rate increased the diagnostic performance of the 2017 ICG.

Despite the strengths of this study, it does have its limitations. It was a single-center retrospective study. All patients had pathologic diagnosis after surgical resection. Many small cysts without worrisome features were excluded due to the lack of a pathologic diagnosis. Only patients who had both postoperative radiologic surveillance data and pathologic results were included in the analysis of cystic growth rate. Therefore, the number of patients available for evaluating cyst growth rate was limited; and therefore, the LR could not include this feature. A future study based on long-term regular surveillance would be needed to more fully address the role of cystic growth rate. Despite of these shortcomings, all the patients in the present study underwent diagnostic examination with standardized protocols, and the radiologic parameters were reviewed again by both a surgeon and a radiologist to improve diagnostic concordance.

In conclusion, the new 2017 ICG for IPMN are clinically valid with improved diagnostic performance over the previous 2012 guidelines. The introduction of elevated serum CA 19-9 level and cyst growth rate to the 2017 guidelines is appropriate.