TYPES OF PANCREATIC CYSTS
Cystic lesions of the pancreas have a large differential diagnosis (Table 2). They can be broadly categorized as neoplastic or non-neoplastic (i.e., pseudocysts) and as mucin-producing (IPMNs or mucinous cystic neoplasms (MCNs)) vs. non-mucin producing. Cystic lesions with malignant potential include IPMNs, MCNs, solid-pseudopapillary tumors, and pancreatic neuroendocrine tumors. The diagnosis of cyst type relies on imaging characteristics and, for some cysts, on the analysis of cyst fluid. Despite high-quality imaging with computed tomography (CT), MRI, and cyst fluid analysis, the correct classification of cyst type can be challenging.
Most pseudocysts occur in patients with a known history of acute or chronic pancreatitis. Neoplastic cysts are much more common than pseudocysts, but it is important to rule out pseudocysts since they have no malignant potential and do not require surveillance or treatment when asymptomatic. One must be careful to consider that a neoplasm can cause unexplained pancreatitis in up to 20% of individuals over the age of 40. Therefore, one must be vigilant to consider that an incidental cyst could be a cystic neoplasm that caused the episode of pancreatitis. When the diagnosis is uncertain, endoscopic ultrasound (EUS) is often helpful in assessing for chronic pancreatitis with fine needle aspiration (FNA) assessing cyst fluid characteristics; pseudocyst aspirates are usually brown in color, have very high cyst fluid lipase or amylase, and have low carcinoembryonic antigen level (CEA). This assessment is not always accurate, given that side-branch IPMNs with connection to the main pancreatic duct also have very high lipase and amylase levels and the CEA may be in the “indeterminate” range. The differentiation of a pseudocyst from a neoplastic cyst in symptomatic patients is critical for an additional reason: most pseudocysts can be treated with endoscopic drainage instead of surgery.
Intraductal papillary mucinous neoplasms
IPMNs may involve side branches only, the main duct, or a combination of both termed mixed IPMN. By far, the most common IPMN, and indeed the most common pancreatic cyst, is a side-branch IPMN. In up to 40% of cases, multiple IPMNs occur; however, there is no evidence that the risk of malignant transformation is higher in multifocal IPMNs (9). Although these are mucin-producing cysts with malignant potential, as discussed previously, the vast majority of side-branch IPMNs will not progress to pancreatic cancer. Main duct IPMN is much less common and appears to have a high risk of malignancy, with 38–68% of main duct IPMNs harboring high-grade dysplasia or pancreatic cancer in resected specimens (10). A patulous, mucin-extruding papillary orifice can be seen in the main duct variety. Both side-branch and main-duct IPMNs may rarely give rise to pancreatitis, presumably due to thick mucin occluding the pancreatic duct orifice. The vast majority of IPMNs are given this diagnosis based on clinical and radiographic parameters rather than tissue diagnosis; when fluid is obtained, the cyst fluid CEA is usually elevated.
Mucinous cystic neoplasms
MCNs occur almost exclusively in women and are most often present in middle age. The most common location is the body or tail of the pancreas. Unlike side-branch IPMNs, there is usually no communication with the pancreatic duct. Their columnar epithelium is surrounded by ovarian-type stroma. MCNs have the potential to develop into pancreatic cancer; however, the risk is lower than previously thought. A recent review of 90 resected MCNs found that only 10% of them contained either high-grade dysplasia or pancreatic cancer (11). In this study, and a large review of 344 MCNs, there were no cases of high-grade dysplasia or pancreatic cancer in MCNs less than 3 cm in size with a normal serum CA 19-9 and no concerning features (11,12).
Serous cystadenomas (SCAs) occur more commonly in women (75%), who usually present in their 50s. A recent multicenter study in over 2,500 SCAs found that the risk of serous cystadenocarcinoma was extremely low at 0.1% (13). Although rare, benign SCAs can cause symptoms because of their size; however, the vast majority of SCAs are asymptomatic. The classic imaging characteristics are microcystic or honeycomb appearance, although macrocystic lesions are not rare. A central scar is a characteristic imaging feature, but is present in less than 30% of SCAs. Cyst fluid analysis reveals very low CEA levels and low viscosity. Most asymptomatic SCAs do not require surveillance.
Solid-pseudopapillary neoplasms (SPNs) are rare lesions, which are more common in women (10:1). They most frequently present in women in their 20s but have a wide age range, and are also described in children and in adults over the age of 50. They can occur in any part of the pancreas. A systematic review of 484 studies showed that the most common presentations were abdominal pain (63%) or were incidental/asymptomatic (38%).(14) Smaller tumors are mostly solid with larger ones having a mixed solid and cystic appearance. Aggressive tumor behavior is found pathologically in ˜10%. Unlike pancreatic adenocarcinoma, outcomes are excellent with a 5-year disease-specific survival of over 98% (14).
Cystic pancreatic neuroendocrine tumors
Pancreatic neuroendocrine tumors are rare and usually non-functioning. They may be solid, cystic, or mixed in morphology. They may occur sporadically or in individuals with multiple endocrine neoplasia type 1. They are equally common in women and men with peak presentation in the 60 s. EUS-guided fine needle aspiration (FNA) is often required for an accurate diagnosis.
Other pancreatic cysts
Other, very rare pancreatic cysts include simple cysts with true epithelia lining, lymphoepithelial cysts, and mucinous non-neoplastic cysts. All of these have no known malignancy risk. Pancreatic ductal adenocarcinoma, and the extremely rare acinar cell adenocarcinoma, may have cystic degeneration on imaging and mimic other pancreatic cysts.
A literature search was performed by a health sciences librarian of Pubmed and Embase through July 2016 using the subject headings pancreatic cyst and pancreatic neoplasm. A second search combined the first one with the imaging modalities of EUS, CT, MRI, and endoscopic retrograde cholangiopancreatography (ERCP). A search was also performed of the MeSH term cyst fluid with a subheading of analysis. The searches were limited to English language, and excluded case reports, comments, editorials, or letters. Additional articles were obtained from review of references from retrieved articles as well as articles that were known to the authors.
The strength of recommendation and the quality of evidence was determined using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology based on study design, study quality, consistency, and directness (15). The strength of recommendation was assigned as “strong” when the evidence shows the benefit of the treatment clearly outweighs any risk, and as “conditional” when uncertainty exists about the risk-benefit ratio. Four levels of evidence were used, high, moderate, low, and very low. The quality of the evidence is graded as follows: “high” if further research is unlikely to change our confidence in the estimate of the effect; “moderate”, if further research is likely to have an impact and may change the estimate; “low”, if further research is very likely to change the estimate; “very low”, if an effect is very uncertain.
PANCREATIC CYST DIAGNOSIS
Question: Is the pancreatic cyst causing symptoms?
1. We recommend caution when attributing symptoms to a pancreatic cyst. The majority of pancreatic cysts are asymptomatic and the nonspecific nature of symptoms requires clinical discernment (Conditional recommendation, very low quality of evidence).
Summary of evidence
Deciding whether a cyst is the cause of symptoms may be straight forward as in the case of biliary obstruction or may be very difficult as in the case of nonspecific abdominal symptoms. Although most pancreatic cysts are incidentally found in asymptomatic patients, symptomatic cysts are reported in 50–84% in surgical case series (16,17,18). Symptomatic pancreatic cysts are more likely to be malignant in surgical series (19) and mucin-producing cysts are the most common type of resected symptomatic pancreatic cyst. A recent meta-analysis of IPMNs evaluated 13 studies in the analysis of symptoms as a risk for malignancy (20). There was a weak association between symptoms and malignancy with an odds ratio (OR) 1.6 (CI 1.0–2.6). The most common symptom in a surgical case series of 134 patients with symptomatic pancreatic cysts was abdominal pain (69%), followed by weight loss (38%), pancreatitis (36%), jaundice (18%), back pain (18%), palpable mass (5%), and postprandial fullness (4%) (16). Abdominal pain or other nonspecific symptoms are usually not attributable to the cyst even if pain was the indication for the abdominal imaging. In this surgical series, 44% of those who had pancreatitis and a neoplastic cyst were initially misdiagnosed as having a pseudocyst. This emphasizes the important point that neoplastic cysts can cause acute pancreatitis, a consideration that must always be considered in patients over the age of 40 with acute pancreatitis and a cyst.
Question: What imaging techniques should be used to characterize a pancreatic cyst? How accurate are the imaging tests?
2. MRI or magnetic resonance cholangiopancreatography (MRCP) are the tests of choice because of their non-invasiveness, lack of radiation, and greater accuracy in assessing communication between the main pancreatic duct and the cyst (which is a characteristic of side-branch IPMNs). Pancreatic protocol CT or EUS are excellent alternatives in patients who are unable to undergo MRI. Indeterminate cysts may benefit from a second imaging modality or cyst fluid analysis via EUS (Conditional recommendation, very low quality of evidence).
3. Use caution when using imaging to diagnose cyst type or concomitant malignancy; the accuracy of MRI or MRCP in diagnosing cyst type is 40–50% and in determining benign vs. malignant is 55–76%. The accuracy for CT and EUS without FNA is similar (Conditional recommendation, very low quality of evidence).
Summary of evidence
The goal of imaging is to characterize the type of cyst and to assess for high-grade dysplasia or pancreatic cancer. A systematic review of imaging modalities for pancreatic cysts concluded that “CT is a good initial investigation” with MRCP being used only when added information is needed (21). Nineteen studies (three prospective) of 1,060 patients with definitive histology results were included. The accuracy of CT for identifying benign from malignant cysts was 71–80%. CT was able to assess communication between the main pancreatic duct and the cyst with 80% sensitivity in distinguishing IPMN vs. other cyst type. The accuracy of MRI or MRCP for differentiating a benign from a malignant cyst ranged from 55 to 76%, with 96% sensitivity for diagnosing an IPMN from other cyst types, presumably due to its high accuracy in identifying main pancreatic duct communication with the cyst. In this systematic review, there were eight studies directly comparing imaging modalities. Three of four studies that compared MRI with CT found them equivalent; one study found MRI superior for the diagnosis of an IPMN. Although this systematic review concluded that CT should be the initial study, they did not take into account the lack of radiation with MRI and the greater accuracy in characterizing IPMNs. A recent review on imaging for pancreatic cysts concluded that MRI has superior sensitivity for detecting cysts, although both modalities are limited by a substantial rate of misdiagnosis for cyst type (22). MRI is better than CT for depicting internal morphology of the cyst, although it has lower spatial resolution, is insensitive for identifying calcification, and can be affected by motion artifact.
EUS imaging alone (without cyst fluid evaluation) was accurate for diagnosing a benign from a malignant cyst 65–96% of the time.(22) This was similar to the accuracy of MRI and CT scan and, given its more invasive nature, we do not recommend it as first-line examination for small cysts with a clear diagnosis and no concerning features. However, EUS is more accurate for identifying a mural nodule than MRI. Contrast-enhanced EUS is helpful for differentiating a mural nodule from mucin; however, it is currently not FDA-approved (23). There are a small number of studies assessing the effect of combining imaging modalities. A multicenter, prospective, observational study found increased sensitivity for identifying IPMNs and MCNs, as well as cysts with high-grade dysplasia or pancreatic cancer, when MRI was combined with EUS compared with either modality alone.(24) Larger, retrospective studies have shown similar findings when combining CT or MRI with EUS (25).
A systematic review evaluated four positron emission tomography (PET) studies to identify benign from malignant pancreatic cysts (21). PET alone was inferior to CT, but when combined with CT it was superior to CT alone. A recent prospective study of 18 F-FDG PET/CT, MDCT, and MRI combined with MRCP in 31 patients with definitive histology found that PET/CT had a diagnostic accuracy of 94% compared with 77% for MDCT and 87% for MR (26). There is insufficient evidence to support the use of PET-CT currently.
Historically, ERCP has been utilized to evaluate pancreatic cysts but, given its procedural risks and the superiority of EUS and MRCP, ERCP is no longer recommended for either cyst diagnosis or surveillance except for a limited role in the evaluation of main duct IPMN.
Other novel imaging techniques include secretin-stimulated MRCP. The addition of secretin to MRCP improves visualization of communication between the main pancreatic duct and a pancreatic cyst, although the communication was visualized solely on the secretin-stimulated study in only 5% of patients (27). This small incremental value may not justify the cost of secretin.
PANCREATIC CYST MANAGEMENT
Question: Which patients should have no further evaluation?
4. Patients who are not medically fit for surgery should not undergo further evaluation of incidentally found pancreatic cysts, irrespective of cyst size (Strong recommendation, low quality of evidence).
5. Patients with asymptomatic cysts that are diagnosed as pseudocysts on initial imaging and clinical history, or that have a very low risk of malignant transformation (such as SCAs) do not require treatment or further evaluation (Conditional recommendation, low quality of evidence).
Summary of evidence
Two studies have evaluated the risk of death from factors other than pancreatic cancer in patients with IPMNs (28,29). Sahora used the Charlson comorbidity index (CACI) in 725 patients with IPMNs, of which 55% underwent resection and 45% underwent surveillance. The CACI scores a total of 22 conditions and each condition is assigned a score of 1, 2, 3, or 6 with the sum of the scores being used to predict mortality (30). After a median follow-up of 5 years, 24% of the patients had died and 78% of the deaths were not related to IPMNs. Multivariate regression analysis showed that the chance of a non-IPMN-related death within 3 years of diagnosis is 11-fold higher for patients with a CACI of 7 or more. The median survival time for patients with a CACI score of ≥7 was 43 months. The authors concluded that the CACI can be used to identify patients who are not likely to benefit from pancreatic resection. Kawakubo et al. used an alternative comorbidity scoring system, the Adult Comorbidity Evaluation 27 (ACE-27) to evaluate 793 patients with IPMN, 6.8% of whom were resected. The ACE-27 grades patients into the following four comorbidity categories: none, mild, moderate, and severe. During a median follow-up of 50 months, 15% died with the cause of death being pancreatic cancer in 26%, extrapancreatic cancer in 38%, other diseases in 32%, and unknown in 3.4%. Both age at diagnosis and an ACE-27 category of moderate or severe significantly increased the risk of a non-pancreatic cancer death. These data suggest that patients with multiple comorbidities have a high risk of dying from causes unrelated to their IPMNs, and are unlikely to benefit from surveillance. The exception to the rule of avoiding further evaluation in inoperable patients is in symptomatic cysts, for example, palliative stenting in patients with jaundice.
If an asymptomatic cyst is diagnosed as a non-neoplastic cyst on initial imaging, no further treatment or evaluation is warranted (Figure 1). The most common non-neoplastic cysts are pseudocysts, which usually present in the setting of acute or chronic pancreatitis. They require no further evaluation when asymptomatic (31). Similarly, if the initial imaging shows classic findings of a SCA—microcystic changes with a central scar—no further evaluation is warranted, given their very low risk of malignancy.(13) Some SCAs are macrocystic, resembling IPMNs or MCNs on imaging, and require cyst fluid analysis to confirm the diagnosis.
Question: What is the role of EUS-FNA and cyst fluid analysis in management decisions?
6.EUS-FNA and cyst fluid analysis should be considered in cysts in which the diagnosis is unclear, and where the results are likely to alter management. Analysis of cyst fluid CEA may be considered to differentiate IPMNs and MCNs from other cyst types, but cannot be used to identify IPMNs and MCNs with high-grade dysplasia or pancreatic cancer (Conditional recommendation, very low quality of evidence).
7.Cyst fluid cytology should be sent to assess for the presence of high-grade dysplasia or pancreatic cancer when the imaging features alone are insufficient to warrant surgery (Conditional recommendation, very low quality of evidence).
8.Molecular markers can help identify IPMNs or MCNs. Their use may be considered in cases in which the diagnosis is unclear and the results are likely to change management (Conditional recommendation, very low quality of evidence).
Summary of the evidence
Identifying cyst type.
EUS-FNA has two potential roles. The first is characterizing the type of pancreatic cyst. The most commonly used marker is cyst fluid CEA, which was found to have a pooled sensitivity of 63% (95% CI 59–67) and specificity of 93% (95% CI 90–95) for identifying IPMNs and MCNs in a systematic review and meta-analysis of 18 papers (32). The most commonly used cutoff level is 192 ng/ml (33). Varying the cutoff level to either a very high (>800 ng/ml), or a very low level (<5 ng/ml), increases the specificity to over 95% for IPMNs or MCNs, and non-mucin-producing cysts, respectively, but at a cost of decreasing sensitivity to 50% (34). Other cyst fluid protein biomarkers have been examined, including CA 72-4, CA 125, CA 19-9, or CA 15-3, but were found to have a lower accuracy than CEA and are, therefore, not routinely used (34). Cyst fluid amylase levels can be useful when trying to exclude the presence of a pseudocyst, with very low levels (<250 IU/l) excluding a pseudocyst in 98% of cases (34). The evaluation of cytological specimens in pancreatic cysts is hampered by the low cellularity of the samples. This is highlighted in a prospective study that found that only 34% of cytology samples had adequate cellular material for evaluation (35). Two systematic reviews and meta-analyses evaluated studies from 937 and 1,438 patients, respectively, and found a pooled sensitivity of 54% (95% CI: 49–59) to 63% (95% CI, 56–70) and specificity of 88% (95% CI, 0.83–0.93) to 93% (95% CI, 90–95%) for identifying IPMNs or MCNs (35,36).
A number of DNA, RNA, protein, and metabolomic markers have been evaluated in cyst fluid (37). The majority of these are still early in development and not yet ready for translation into clinical practice. However, analysis of DNA mutations in cyst fluid has shown promise in identifying IPMNs and MCNs (38). Whole-exome sequencing of the major neoplastic pancreatic cysts identified distinct genetic profiles that can be used diagnostically to classify pancreatic cysts (39). Using highly sensitive techniques, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and/or a guanine nucleotide-binding protein (GNAS) mutation have between 84 and 96% sensitivity and 80 and 100% specificity for identifying an IPMN or MCN (40,41,42,43,44). Recent studies have shown that integrating molecular testing with cyst clinical features increases the sensitivity and specificity for identifying IPMNs or MCNs (41,43,44). Unfortunately, they are costly and have not helped determine cancer risk. In cases in which the diagnosis is unclear, and a change in diagnosis will alter management, analysis of these mutations using highly sensitive techniques may be considered.
Several devices have been developed to improve tissue acquisition, and thus diagnostic yield. A cytology brush (EchoBrush; Cook Endosocpy, Winston-Salem, NC, USA) showed variable results, and was associated with a high rate of adverse events in some studies (45,46,47). We do not recommend its use. A new through the needle micro biopsy forcep (Moray micro forceps; US Endoscopy, Mentor, Ohio) has been developed. Preliminary case reports are promising, but larger, prospective, multicenter studies are required. Needle confocal microscopy (nCLE) probes can be placed directly into pancreatic cysts via a 19-gauge FNA needle and generates an in vivo microscopic image of the cyst epithelium. It has been evaluated in a number of studies showing a sensitivity of 59–69%, with 100% specificity, for differentiating SCAs from other types of pancreatic cysts (48,49,50). A prospective, single center study again had an excellent specificity with 80% sensitivity for differentiating IPMNs and MCNs from other cyst types (51). Although promising, only a small number of cases in these studies were compared with the gold-standard histopathology. We await the results of ongoing studies to provide additional data as to its potential role.
Identifying high-grade dysplasia or pancreatic cancer.
In contrast to determining the type of cyst, cyst fluid CEA is not helpful for identifying the presence of high-grade dysplasia or pancreatic cancer. This was highlighted in a systematic review and meta-analysis of 504 patients, which found a pooled sensitivity of 65% (95% CI, 57–73) and specificity of 66% (95% CI, 59–72) for identifying high-grade dysplasia or pancreatic cancer in IPMNs or MCNs (52). In contrast, cytology can be helpful. A recent systematic review and meta-analysis found that cytology has an excellent pooled specificity for pancreatic cancer of 90.6% (95% CI, 0.81–0.96), but suffers from a low sensitivity of 64.8% (95% CI, 0.44–0.82) (53). There are a large number of studies examining different molecular markers for identifying high-grade dysplasia or pancreatic cancer in IPMNs or MCNs; however, these are still early in development and there is insufficient evidence to recommend their routine use in clinical practice (37,54). Similarly, new devices such as the needle micro biopsy forceps may be helpful, but there are no data currently published to support its use for this indication.
A number of studies have examined whether ethanol alone, or in combination with paclitaxel, can be used to ablate pancreatic cyst epithelium and thus obviate the need for surgery. The results have been varied, with cyst resolution reported in 33–79% of the cases (55,56,57,58,59,60,61,62,63). The reported rate of adverse events (˜12%) is higher than that reported for routine EUS-FNA, and include fever, abdominal pain, pancreatitis, peritonitis, and splenic and portal vein thrombosis. Radiofrequency ablation is an alternative to alcohol or Paclitaxel. A preliminary study of radiofrequency ablation in six cysts reported resolution of the cyst in two cases, and a 49% decrease in size in three cysts (64). To date, it has not been shown that decreasing cyst size in IPMNs or MCNs eradicates the risk of progression to high-grade dysplasia or pancreatic cancer, with one report of pancreatic cancer developing following alcohol ablation (55). Furthermore, patients with IPMNs are at increased risk of pancreatic cancer at a site separate to the cyst, and thus ablation does not remove the need for surveillance. There is insufficient evidence to support the routine use of cyst ablation. It may be considered in patients who refuse, or are not a candidate for surgery. Ideally, these patients should be enrolled in a clinical trial to further evaluate the efficacy of this therapy.
Question: Which patients should enter into a cyst surveillance program?
9.Cyst surveillance should be offered to surgically fit candidates with asymptomatic cysts that are presumed to be IPMN or MCNs (Conditional recommendation, very low quality of evidence).
Summary of evidence
There are several significant clinical questions that surround surveillance of pancreatic cysts. It is unclear whether there is any survival benefit of surveillance over no surveillance, given the relatively low rates of malignancy (15–42%) in surgically resected specimens in the literature. There are currently no prospective studies determining whether cyst surveillance alters mortality; therefore, the utility of surveillance is unproven (3). However, there is strong direct evidence that IPMNs and MCNs are present for years before they progress to pancreatic cancer. Furthermore, patients who do undergo surgery for high-grade dysplasia or very early pancreatic cancer have improved survival rates, suggesting that early detection and intervention may be beneficial (65,66,67). Surveillance of pancreatic cysts, therefore, affords us the opportunity of reducing cancer deaths related to pancreatic cancer (68).
Before embarking on cyst surveillance, the physician should review the patient's risk of developing pancreatic malignancy, their approximate life expectancy, their comorbid conditions, and whether they are a surgical candidate. It is important to convey to the patient that uncertainty remains in the value of surveillance. The risks of pancreatic surgical resection need to be weighed against the risk of malignant transformation of the cyst and the inherent limitations of surveillance. The site of the cystic lesion must also be taken into account; the threshold for a distal pancreatectomy for a lesion in the body or tail may be lower than a pancreaticoduodenectomy for a lesion in the head of the pancreas. Pancreatic cyst surveillance should be offered to surgically fit patients with asymptomatic IPMNs or MCNs.
Patients with non-neoplastic cysts such as pseudocysts do not need surveillance. As discussed previously, patients with SCAs have a tiny risk of malignant transformation (13). If imaging has classic features of a SCA, such as a microcystic appearance with a central stellate scar, then we do not recommend surveillance. If the diagnosis is unclear, EUS-FNA with cyst fluid analysis should be considered to confirm the diagnosis.
Question: Which cysts need increased surveillance or referral to a multidisciplinary group for further evaluation?
10.Patients with IPMNs or MCNs with new onset or worsening diabetes mellitus, or a rapid increase in cyst size (of >3 mm/year) during surveillance, may have an increased risk of malignancy so should undergo a short-interval MRI or EUS±FNA. (Conditional recommendation, very low quality of evidence).
11.Patients with IPMNs or MCNs with any of the following features should undergo EUS±FNA and/or be referred to a multidisciplinary pancreatic group for further evaluation (Strong recommendation, very low quality of evidence):
(a)Any of the following symptoms or signs: jaundice secondary to the cyst, acute pancreatitis secondary to the cyst, significantly elevated serum CA 19-9.
(b)Any of the following imaging findings: the presence of a mural nodule or solid component either within the cyst or in the pancreatic parenchyma, dilation of the main pancreatic duct of >5 mm, a focal dilation of the pancreatic duct concerning for main duct IPMN or an obstructing lesion, IPMNs or MCNs measuring ≥3 cm in diameter.
(c)The presence of high-grade dysplasia or pancreatic cancer on cytology.
12. Patients with a solid-pseudopapillary neoplasm should be referred to a multidisciplinary group for consideration of surgical resection (Strong recommendation, low quality of evidence).
Summary of evidence
IPMNs and MCNs.
Certain features in IPMNs and MCNs are associated with an increased risk of the cyst harboring high-grade dysplasia or pancreatic cancer. This risk varies greatly depending on the clinical and imaging findings. Some features such as a solid component or jaundice are associated with a high risk of malignancy, whereas others, such as a slight increase in cyst size, carry a far lower risk. The decision whether or not to resect a cystic lesion is best determined by a pancreatic team that integrates multiple different factors, such as patient comorbidities and life expectancy, the type of surgery required to remove the lesion, and the estimated morbidity and mortality associated with surgery. In the sections below, we recommend referral to a multidisciplinary group not only for patients with cysts, which clearly require surgical resection, but also for cysts with concerning features. In the latter group many patients may not require surgical resection at that point in time; however, a careful evaluation, and review of the benefits of surveillance vs. surgery, is appropriate. In addition, it is essential to include the patient in the decision-making process. Patients should understand the potential risks and benefits of surgery and surveillance. We therefore recommend referral to a multidisciplinary team with expertise in pancreatic cysts and pancreatic surgery. Input from a pancreatic multidisciplinary group has been shown to alter patient management, including changing the management plan from surgery to careful surveillance in 30% of patients seen (69). If surgery is considered, it should be performed at a tertiary referral center, and by an experienced surgeon, where both the center and the surgeon perform a large number of pancreatic operations. The mortality rate is almost threefold higher when a pancreaticoduodenectomy is performed by an inexperienced surgeon at a low-volume center, as compared with when it is performed by experienced surgeons at high volume centers (˜11–15% vs. ˜1–5%) (70,71).
The presence of obstructive jaundice due to the cyst is concerning for the presence of pancreatic cancer, and these patients should be urgently referred for further evaluation by a multidisciplinary group and consideration of surgical resection (72,73). An elevated CA19-9 (>37 U/ml) has been found in a meta-analysis to have a pooled sensitivity of 40%, a specificity of 89%, and an OR of 4.34 (95% CI, 2.65–7.10) for the presence of high-grade dysplasia or cancer in IPMNs (74). It is important to remember that a number of benign diseases can cause an elevation of CA19-9. Patients with an IPMN and an elevated CA19-9, in whom no benign cause for an elevated CA19-9 is found, should be referred for evaluation at a multidisciplinary clinic. There are a number of other features, which have been shown in some, but not all studies to be associated with an increased risk of high-grade dysplasia or pancreatic cancer. The presence of acute pancreatitis secondary to the cyst is associated with an increased risk of cancer in several (72,75), but not all studies (76). There is also an association between new-onset diabetes mellitus and the risk of pancreatic cancer. Approximately 1% of adults over than 50 years with new-onset diabetes will develop pancreatic cancer within 3 years of diagnosis, whereas almost two-thirds of patients with pancreatic cancer have diabetes mellitus (77). Several studies have shown that patients with IPMNs who have new onset, or worsening control of diabetes mellitus, have an increased risk of high-grade dysplasia or pancreatic cancer (73,78,79). We recommend careful evaluation of patients with pancreatic cysts and new onset, or worsening diabetes mellitus, with consideration of EUS or MRI.
There are a number of features associated with an increased risk of an IPMN or MCN harboring high-grade dysplasia or pancreatic cancer. One of the most concerning features is the presence of a mural nodule, which was associated with an OR 9.3 (CI 5.3–16.1) in a systematic review and meta-analysis of over 1,400 patients (20). A second systematic review found similar results with an OR 7.73 (95% CI, 3.38–17.67) (3). Patients with IPMNs, but not patients with MCNs, are at risk of developing malignancy in the pancreatic parenchyma anatomically separate from the cyst, which is called a “concomitant” pancreatic cancer. In a large, multicenter retrospective study in almost 350 patients 2% of patients developed concomitant pancreatic cancer (80), whereas a smaller prospective study found that 4% of patients with IPMNs developed a concomitant pancreatic cancer over a 17-year period (81). This highlights the importance of evaluating not only the cyst, but also the entire parenchyma on imaging. The presence of a mural nodule or solid component within a cyst or the pancreatic parenchyma warrants referral further evaluation by a multidisciplinary group with consideration of EUS±FNA and surgical resection.
In a systematic review and meta-analysis of 358 IPMNs from eight studies, main pancreatic ductal dilation of >6 mm was associated with an increased risk of high-grade dysplasia or pancreatic cancer with a pooled OR 7.27 (95% CI, 3.0–17.4) (20). Interestingly, a different systematic review of four studies found an increased OR (2.38) but with wide, and not significant CIs (95% CI 0.71–8.00) (3). Large surgical series have consistently reported an increased risk of high-grade dysplasia of ˜60% (range 36–100%), with a rate of pancreatic cancer of ˜44% (range 11–81%) (82,83). There is significant debate as to the optimal diameter of the main pancreatic duct to use as a cutoff. It is clear that the larger the duct diameter, the greater the risk of high-grade dysplasia or pancreatic cancer. We recommend use of a conservative duct diameter, >5 mm, for referring a patient for further evaluation. Similarly, an abrupt change in the caliber of the pancreatic duct with upstream dilation concerning for obstruction also warrants referral for further evaluation. Most patients with only minimal ductal dilation will not require surgical resection; however, early referral is appropriate.
A large cyst diameter is also associated with increased risk of high-grade dysplasia or pancreatic cancer in IPMNs and MCNs. There is ongoing debate as to the optimal size cutoff to use, with some groups reporting a small number cases of high-grade dysplasia and pancreatic cancer in IPMNs measuring less than 3 cm (84); other studies found that a cutoff of >3 cm has a low specificity for high-grade dysplasia or pancreatic cancer (85,86); with still other groups recommending a higher cutoff of ≥4 cm (87,88). Most centers start considering surgical resection when an IPMN or MCN measures >3 cm. This size cutoff is supported by a systematic review of 644 cysts from six studies (OR for high-grade dysplasia or pancreatic cancer of 2.97 (95% CI 1.82–4.85)), as well as by a systematic review and meta-analysis of 1,058 IPMNs from 16 studies (OR 62.4 (95% CI, 30.8-126.3)) (3,20). On the basis of these data, we recommend referral for IPMNs or MCNs measuring ≥3 cm. It may be appropriate for many of these patients to undergo surveillance in the absence of any other concerning features. However, referral is appropriate, so that the pros and cons of surgery vs. surveillance can be discussed.
A rapid increase in cyst size was associated with an increased risk of high-grade dysplasia or pancreatic cancer in two retrospective studies, which found that IPMNs with an increase in cyst size of ≥2 mm/year were associated with a higher risk of high-grade dysplasia or pancreatic cancer. The evidence to support this cutoff is limited. In addition, studies have shown that the interobserver variability in measuring pancreatic cysts may be as high as 4 mm.(89) Despite these limitations, based on the available data, we recommend that IPMNs or MCNs, which rapidly increase in size, should undergo careful surveillance with a short-interval MRI or EUS±FNA within 6 months. If there are concerning features, or ongoing rapid increase in cyst size, patients should be referred for further evaluation.
Cytology has a low sensitivity of 64.8% (95% CI, 0.44–0.82), but has excellent specificity of 90.6% (95% CI, 0.81–0.96) for pancreatic cancer.(53) The presence of high-grade dysplasia or pancreatic cancer warrants urgent referral to a multidisciplinary pancreatic group.
Solid-pseudopapillary neoplasms are rare tumors that occur in young women. They carry a risk of aggressive behavior, with vascular involvement in 4.6%, lymph node in 1.6%, and distant metastases reported in 7.7% of patients.(14) Surgical resection is recommended for these patients and we recommend referral to a high-volume pancreatic center.
Question: Which imaging modality should we use for surveillance?
13.MRCP is the preferred modality for pancreatic cyst surveillance, given the lack of radiation and improved delineation of the main pancreatic duct. EUS may also be the primary surveillance tool in patients who cannot or choose not to have MRI scans (Conditional recommendation, very low quality of evidence).
Summary of evidence
There is no clear best surveillance imaging modality at this time based on the available data. Pancreatic protocol CT or MRI with MRCP are the most commonly utilized methods for evaluating cyst size, morphology, location, internal contents, multiplicity, and communication with the main pancreatic duct (90,91,92,93,94). In general, pancreatic cyst detection is higher with MRI than with CT (19.9% vs. 1.2–2.6%) (95,96,97). A consensus statement by radiologists recommended a dedicated MRI with MRCP as the imaging modality of choice for pancreatic cysts, given its superior contrast resolution that allows excellent evaluation of main duct communication, septae, and mural nodules (98). In addition, MRI has the advantage of avoiding radiation exposure, especially if patients are expected to undergo long-term or frequent surveillance imaging.
One key requirement of surveillance is to identify malignant transformation within a cyst. A recent meta-analysis of 37 studies incorporating 4,073 patients evaluated this question (99). A subset of four studies (159 patients) specifically evaluated the prediction of malignancy by CT and/or MRI by meta-analysis. The pooled sensitivity and specificity of CT or MRI to detect malignancy (compared with resected specimens) was 0.809 (95% CI, 0.71–0.88) and 0.762 (95% CI, 0.65–0.85). The same study evaluated PET in predicting malignancy and the meta-analysis of three studies (106 patients) revealed a pooled sensitivity of 0.968 (95% CI, 0.90–0.99) and specificity was 0.911 (95% CI, 0.81–0.99) (99). We await further studies evaluating PET-CT and there is insufficient evidence to support its routine use currently.
Radiologic imaging studies are less invasive than EUS; however, EUS may be more helpful for the diagnosis and differentiation of pancreatic cystic lesions because of its higher resolution than cross-sectional imaging modalities. EUS also allows for FNA of cystic lesions for biochemical, cytological, and molecular analysis that might be further helpful for diagnosis and differentiation. Overall, EUS has a higher sensitivity for differentiating benign vs. malignant, varying in most studies from 86 to 96%, but a lower specificity of 30 to 99%, when compared with CT or MRI (100,101,102,103). It is favored over other imaging studies when FNA is warranted for cytology, chemical, and/or molecular studies, although EUS is likely more operator-dependent than MRI or CT (80,91,92). EUS allows differentiation between true solid cyst components vs. mucin that appears as a smooth, well-defined hyperechoic rim with a hypoechoic center (104). True mural nodules have ill-defined borders with an isoechoic or hyperechoic center (104). The addition of EUS, with or without FNA, to CT or MRI increased the overall diagnostic accuracy for the diagnosis of pancreatic cystic neoplasms by 36% and 54%, respectively (25).
Question: How often should surveillance occur and what cyst size/characteristics should that depend upon?
14.In the absence of concerning features (Table 3) that warrant increased surveillance or referral for further evaluation, cyst size guides surveillance intervals for presumed IPMNs and MCNs (Figure 2; Conditional recommendation, very low quality of evidence).
Summary of evidence
The goal of surveillance is to identify cysts that are likely to have either high-grade dysplasia or early pancreatic cancer that represent opportunities to intervene and ideally prevent the development of pancreatic cancer. Surveillance is therefore only appropriate for cysts that are presumed to be IPMN or MCNs, and is not indicated for other types of benign cysts. The diagnosis of an IPMN or MCN is usually a presumed diagnosis without actual tissue histology. In a small number of cases the diagnosis may be unclear despite EUS-FNA. In these cases, patients should be followed as presumed IPMNs/MCNs.
The data on which to base decisions on the optimal surveillance intervals are of low quality; however, most published guidelines agree that cyst surveillance intervals should generally be stratified based on cyst features and size. Where the literature does not have evidence to support guideline decisions, we provide practical recommendations. Figure 2 provides an algorithm for surveillance of presumed IPMNs or MCNs. The cyst surveillance strategy is stratified based on cyst size. As previously discussed, cyst size is an imperfect surrogate for high-grade dysplasia or early pancreatic cancer.(3,20,84,105,106,107,108,109,110,111,112,113,114,115) However, at present, cyst size is the most practical surrogate we have. If an experienced radiologist reviews high-quality cross-sectional imaging, and reports no features concerning for malignancy, then radiographic surveillance is appropriate for the majority of IPMNs and MCNs (Figure 2).
As discussed previously, there are a number of clinical, imaging, and cytological features that are associated with an increased risk of high-grade dysplasia or cancer developing in an IPMN or MCN. Imaging features include the development of a mural nodule or solid component either within the cyst or the pancreatic parenchyma, dilation of the main pancreatic >5 mm, a focal dilation of the pancreatic duct concerning for main duct IPMN or an obstructing lesion, or IPMNs or MCNs that measure ≥3 cm in diameter. Many patients with these high-risk features will require close surveillance, rather than surgical resection; however, referral to a multidisciplinary pancreatic center for further evaluation is appropriate. Another high-risk finding, which may be associated with an increased risk of pancreatic cancer, is a rapid increase in cyst size; however, there is less evidence supporting this than the previously mentioned features. Two studies have shown that an increase in size of between 2 and 5 mm/year is associated with an increased risk of pancreatic cancer.(116,117) An important consideration when evaluating either overall cyst size, or increase in cyst size, is that there is considerable variation in the estimation of cyst size by different imaging modalities (CT vs. MRI vs. EUS).(118,119) Even within an imaging modality, such as MRI, the kappa for size agreement among radiologists was only 0.59 with a median s.d. difference of 4 mm.(89) Between multidetector CT and MRI, there was a median size difference of 1.5 mm with an absolute size difference of 2.1±1.8 mm. (120) Consistency in use of imaging modality may help reduce such variability and lead to more meaningful decision-making. On the basis of the current data on cyst growth rates and the interobserver variability in radiographic cyst size evaluation, a cyst growth rate of ≥3 mm/year warrants a shorter follow-up interval, with evaluation with EUS±FNA considered for cysts that undergo a rapid increase in size. There is a higher incidence of pancreatic cancer in patients with newly diagnosed diabetes mellitus. We therefore recommend a shorter surveillance interval of 6 months with either MRI or EUS for these individuals. If there is stabilization of the cyst size, or no concerning features found in the case of a newly diagnosed diabetic, then patients can return to standard surveillance.
Question: When should we stop cyst surveillance?
15.Surveillance should be discontinued if a patient is no longer a surgical candidate (Strong recommendation, very low quality of evidence).
16.It is reasonable to assess the utility of ongoing surveillance in those aged >75 years. An individualized approach for those aged 76–85 years should be considered including an informed discussion about surgery (Conditional recommendation, very low quality of evidence).
Summary of evidence
There are very little data to evaluate whether surveillance intervals can be extended, or whether surveillance should be discontinued if cysts are stable after a specified time period. The current American Gastroenterological Association guidelines are the only guideline that recommends stopping surveillance of pancreatic cysts (3). They recommend that surveillance should stop after 5 years if there are no high-risk features, and size of the cyst is stable. Studies of pancreatic cancer evaluating the progression from a genetic perspective found that it takes between 15 and 20 years for cancer to develop (121). Pancreatic cancer has developed in IPMNs up to 16 years after diagnosis (80,122,123). In contrast, other studies have found that the risk of malignant transformation in a cyst that is stable in size over 3–5 years is low (124). We recommend that surveillance intervals may be increased for cysts with no concerning features that are stable in size (Figure 2). Currently, there is insufficient evidence to support discontinuing surveillance after 5 years in patients who are still surgically fit.
It is appropriate to stop surveillance when the patient is no longer a surgical candidate because of comorbid conditions as previously discussed. The decision to pursue ongoing surveillance must take into account the risks of surgery as the patient ages or acquired comorbid conditions and is a decision that must be tailored to each patient's clinical situation.
A separate question is whether it is appropriate to continue surveillance past a certain age in a healthy individual. There are no studies to guide the decision of when to stop surveillance of pancreatic cysts, nor are cost effectiveness analyses available to estimate the cost-benefit ratio of pancreatic cyst surveillance in an elderly population. The United States Preventive Services Taskforce recommends screening for colon cancer until age 75, with an individualized decision about whether to continue screening in individuals aged between 76 and 85 years (125). It appears reasonable to consider a similar approach to pancreatic cysts. Although there is no evidence to support this, we recommend continuing surveillance in patients until the age of 75 years. For patients between 76 and 85 years, an individualized surveillance plan is appropriate. We recommend having an informed discussion with the patient where their medical comorbidities are reviewed, a discussion of their personal potential morbidity and mortality if surgery was undertaken, and the risk of cyst progression is appraised.
Question: Who should have surveillance after cyst surgery? How often?
17.Patients with a surgically resected SCA, pseudocyst, or other benign cyst do not require any follow-up after resection (Strong recommendation, very low quality if evidence).
18.Resected MCNs without an associated pancreatic cancer do not require postoperative surveillance (Strong recommendation, low quality of evidence).
19.All surgically resected IPMN require postoperative surveillance (Strong recommendation, very low quality of evidence).
20.Patients should be followed on a yearly basis for at least 5 years following resection of a solid-pseudopapillary neoplasm (Conditional recommendation, very low quality of evidence).
Summary of evidence
Benign or very low risk cysts.
If the final surgical pathology demonstrates SCAs, pseudocysts, and other benign cysts, they do not require surveillance.
A recent large systematic review found that there were no cases of MCNs associated with synchronous lesion or recurrence in the absence of invasive carcinoma (126). Therefore, patients with surgically resected MCNs with low-, intermediate-, or high-grade dysplasia do not require surveillance. Patients with a surgically resected MCN with invasive cancer have no risk of developing a new MCN in the remnant pancreas, but they do carry a 25% risk of recurrence of their original cancer. They should therefore undergo standard surveillance-based pancreatic cancer guidelines for 5 years (127,128,129). No surveillance is required after 5 years.
IPMNs, unlike the other cystic neoplasms of the pancreas, are often multifocal. The remnant pancreas after the resection of an IPMN is therefore at risk of developing new IPMNs, progression of pre-existing IPMNs, or development of pancreatic cancers unrelated to an IPMN in the remnant pancreas. The development of any of these is called “recurrence” and the risk of recurrence varies depending on the grade of dysplasia in either the resected pancreas or at the margin. Retrospective studies have reported a high risk of recurrence, 17–65% in IPMNs with pancreatic cancer, and these patients should be followed per pancreatic cancer guidelines (130,131,132,133,134,135,136,137,138).
The second highest risk occurs in patients who have an IPMN with high-grade dysplasia resected, with recurrence rates of 13–31% reported, and these patients warrant careful surveillance (127,128,129,130,131,132,133,134,135). There are little data to guide the optimum surveillance interval; the median time to recurrence varies from 19 to 47 months, with a wide range of 4–180 months. We recommend surveillance with MRI or EUS on a 6-month basis for these patients.
Patients with a surgically resected IPMN with low- or intermediate-grade dysplasia have a lower rate of recurrence of 0–22% (130,131,132,133,134,135,136,137,138). Although some studies show a low risk of high-grade dysplasia or cancer after surgical resection, other studies show conflicting results (82,139,140,141). There is currently insufficient evidence to support no surveillance in these patients, although longer surveillance intervals may be reasonable. In the absence of pancreatic cysts in the remnant, surveillance with MRI every 24 months appears reasonable. If there is an IPMN in the remnant pancreas, then patients should be followed based on the size of the largest IPMN (Figure 2). In these cases, the shortest surveillance interval should be followed (i.e., if there is a 1.5 cm cyst then surveillance would be yearly). The development of concerning features in IPMNs in the remnant warrants further investigation as discussed previously.
Other malignant cysts.
Patients with surgically resected solid-pseudopapillary neoplasm with negative margins have an excellent prognosis. However, recurrence is reported in 4.4% of patients with the median time to recurrence of 50.5 months (14). Surveillance is, therefore, recommended. There is very little evidence to guide the surveillance interval; however, imaging on a yearly basis for at least 5 years, followed by eventual cessation of surveillance, is reasonable.
Pancreatic cysts, and in particular IPMNs, are a common management problem facing gastroenterologists. The majority of incidentally found pancreatic cysts are side-branch IPMNs. The quality of evidence on which guideline recommendations are based is poor. We reviewed the available literature and combined it with expert recommendations to produce a practical management and surveillance approach to pancreatic cysts for the general gastroenterologist. The management algorithms herein do not address every possible clinical scenario and, therefore, it is imperative to tailor management to the individual patient. There is an urgent need for prospective, multicenter studies to provide evidence to guide future guidelines.
This guideline was produced in collaboration with the Practice Parameters Committee of the American College of Gastroenterology. The Committee gives special thanks to Walter G. Park, MD, who served as guideline monitor for this document.
CONFLICT OF INTEREST
Guarantor of the article: Grace H. Elta, MD, FACG.
Specific author contributions: Three authors (Drs. Elta, Enestvedt, and Lennon) planned the guideline, wrote portions of the manuscript, and edited the final version. Dr. Sauer provided the GRADE review.
Financial support: This work was supported by the American College of Gastroenterology.
Potential competing interests: None.
1. de Jong K, Nio CY, Hermans JJ et al
. High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations. Clini Gastroenterol Hepatol 2010;8:806-11.
2. Lee KS, Sekhar A, Rofsky NM et al
. Prevalence of incidental pancreatic cysts in the adult population on MR imaging. Am J Gastroenterol 2010;105:2079-84.
3. Scheiman JM, Hwang JH, Moayyedi P. American gastroenterological association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology 2015;148:824-48.
4. Klibansky DA, Reid-Lombardo KM, Gordon SR et al
. The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol 2012;10:555-8.
5. Gardner TB, Glass LM, Smith KD et al
. Pancreatic cyst prevalence and the risk of mucin-producing adenocarcinoma in US adults. Am J Gastroenterol 2013;108:1546-50.
6. Lennon AM, Ahuja N, Wolfgang CL. AGA guidelines for the management of pancreatic cysts. Gastroenterology 2015;149:825.
7. Fernandez-Del Castillo C, Tanaka M. Management of pancreatic cysts: the evidence is not here yet. Gastroenterology 2015;148:685-7.
8. Choi SH, Park SH, Kim KW et al
. Progression of unresected intraductal papillary mucinous neoplasms of the pancreas to cancer: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017;15:1509-20.
9. Rosenblatt R, Dorfman V, Epelboym I et al
. Demographic features and natural history of intermediate-risk multifocal versus unifocal intraductal papillary mucinous neoplasms. Pancreas 2015;44:478-83.
10. Stark A, Donahue TR, Reber HA et al
. Pancreatic cyst disease: a review. JAMA 2016;315:1882-93.
11. Park JW, Jang JY, Kang MJ et al
. Mucinous cystic neoplasm of the pancreas: Is surgical resection recommended for all surgically fit patients? Pancreatology 2014;14:131-6.
12. Goh BK, Tan YM, Chung YF et al
. A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients. World J Surg 2006;30:2236-45.
13. Jais B, Rebours V, Malleo G et al
. Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas). Gut 2016;65:305-12.
14. Law JK, Ahmed A, Singh VK et al
. A systematic review of solid-pseudopapillary neoplasms: are these rare lesions? Pancreas 2014;43:331-7.
15. Guyatt GH, Oxman AD, Vist GE et al
. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br Med J 2008;336:924-6.
16. Fernández-Del Castillo C, Targarona J, Thayer SP et al
. Incidental pancreatic cysts: clinicopathologic characteristics and comparison with symptomatic patients. Arch Surg 2003;138:427-34.
17. Walsh RM, Henderson JM, Vogt DP et al
. Prospective preoperative determination of mucinous pancreatic cystic neoplasms. Surgery. 2002;132:628-33; discussion 633-4.
18. Parra-Herran CE, Garcia MT, Herrera L et al
. Cystic lesions of the pancreas: clinical and pathologic review of cases in a five year period. J Pancreas 2010;11:358-64.
19. Goh BK, Tan YM, Cheow PC et al
. Cystic lesions of the pancreas: an appraisal of an aggressive resectional policy adopted at a single institution during 15 years. Am J Surg 2006;192:148-54.
20. Anand N, Sampath K, Wu BU. Cyst features and risk of malignancy in intraductal papillary mucinous neoplasms of the pancreas: a meta-analysis. Clin Gastroenterol Hepatol 2013;11:913-21.
21. Jones MJ, Buchanan AS, Neal CP et al
. Imaging of indeterminate pancreatic cystic lesions: a systematic review. Pancreatology 2013;13:436-42.
22. Tirkes T, Aisen AM, Cramer HM et al
. Cystic neoplasms of the pancreas; findings on magnetic resonance imaging with pathological, surgical, and clinical correlation. Abdominal Imaging 2014;39:1088-101.
23. Kamata K, Kitano M, Omoto S et al
. Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of pancreatic cysts. Endoscopy 2016;48:35-41.
24. De Jong K, Van Hooft JE, Nio CY et al
. Accuracy of preoperative workup in a prospective series of surgically resected cystic pancreatic lesions. Scand J Gastroenterol 2012;47:1056-63.
25. Khashab MA, Kim K, Lennon AM et al
. Should we do EUS/FNA on patients with pancreatic cysts? The incremental diagnostic yield of EUS over CT/MRI for prediction of cystic neoplasms. Pancreas 2013;42:717-21.
26. Kauhanen S, Rinta-Kiikka I, Kemppainen J et al
. Accuracy of 18 F-FDG PET/CT, multidetector CT, and MR imaging in the diagnosis of pancreatic cysts: aprospective Single-Center Study. J Nucl Med 2015;56:1163-8.
27. Rastegar N, Matteoni-Athayde LG, Eng J et al
. Incremental value of secretin-enhanced magnetic resonance cholangiopancreatography in detecting ductal communication in a population with high prevalence of small pancreatic cysts. Eur J Radiol 2015;84:575-80.
28. Sahora K, Ferrone CR, Brugge WR et al
. Effects of comorbidities on outcomes of patients with intraductal papillary mucinous neoplasms. Clin Gastroenterol Hepatol 2015;13:1816-23.
29. Kawakubo K, Tada M, Isayama H et al
. Risk for mortality from causes other than pancreatic cancer in patients with intraductal papillary mucinous neoplasm of the pancreas. Pancreas 2013;42:687-91.
30. Charlson M, Szatrowski TP, Peterson J et al
. Validation of a combined comorbidity index. J Clin Epidemiol 1994;47:1245-51.
31. Lenhart DK, Balthazar EJ. MDCT of acute mild (nonnecrotizing) pancreatiis: abdominal complications nd fate of fluid collections. AJR AM J Roentgenol 2008;190:643-9.
32. Thornton GD, McPhail MJ, Nayagam S et al
. Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis. Pancreatology 2013;13:48-57.
33. Brugge WR, Lewandrowski K, Lee-Lewandrowski E et al
. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative Pancreatic Cyst Study. Gastroenterology 2004;126:1330-6.
34. van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc 2005;62:383-9.
35. de Jong K, Poley JW, van Hooft JE et al
. Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides inadequate material for cytology and laboratory analysis: initial results from a prospective study. Endoscopy 2011;43:585-90.
36. Thosani N, Thosani S, Qiao W et al
. Role of EUS-FNA-based cytology in the diagnosis of mucinous pancreatic cystic lesions: a systematic review and meta-analysis. Dig Dis Sci 2010;55:2756-66.
37. Maker AV, Carrara S, Jamieson NB et al
. Cyst fluid biomarkers for intraductal papillary mucinous neoplasms of the pancreas: a critical review from the international expert meeting on pancreatic branch-duct-intraductal papillary mucinous neoplasms. J Am Coll Surg 2015;220:243-53.
38. Guo X, Zhan X, Li Z. Molecular analyses of aspirated cystic fluid for the differential diagnosis of cystic lesions of the pancreas: a systematic review and meta-analysis. Gastroenterol Res Pract 2016;2016; 3546085. doi: 10.1155/2016/3546085.
39. Wu J, Jiao Y, Dal Molin M et al
. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci US A 2011;108:21188-93.
40. Singhi AD, Zeh HJ, Brand RE et al
. American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data. Gastrointest Endosc 2015;83:1107-17.
41. Springer S, Wang Y, Dal Molin M et al
. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology 2015;149:1501-10.
42. Wu J, Matthaei H, Maitra A et al
. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med 2011;3:92ra66.
43. Rosenbaum MW, Jones M, Dudley JC et al
. Next-generation sequencing adds value to the preoperative diagnosis of pancreatic cysts. Cancer Cytopathol 2016;125:41-7.
44. Jones M, Zheng Z, Wang J et al
. Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts. Gastrointest Endosc 2016;83:140-8.
45. Al-Haddad M, Gill KR, Raimondo M et al
. Safety and efficacy of cytology brushings versus standard fine-needle aspiration in evaluating cystic pancreatic lesions: a controlled study. Endoscopy 2010;42:127-32.
46. Thomas T, Bebb J, Mannath J et al
. EUS-guided pancreatic cyst brushing: a comparative study in a tertiary referral centre. JOP 2010;11:163-9.
47. Sendino O, Fernandez-Esparrach G, Sole M et al
. Endoscopic ultrasonography-guided brushing increases cellular diagnosis of pancreatic cysts: a prospective study. Dig Liver Dis 2010;42:877-81.
48. Konda VJ, Aslanian HR, Wallace MB et al
. First assessment of needle-based confocal laser endomicroscopy during EUS-FNA procedures of the pancreas (with videos). Gastrointest Endosc 2011;74:1049-60.
49. Napoléon B, Lemaistre AI, Pujol B et al
. A novel approach to the diagnosis of pancreatic serous cystadenoma: needle-based confocal laser endomicroscopy. Endoscopy 2015;47:26-32.
50. Konda VJ, Meining A, Jamil LH et al
. A pilot study of in vivo
identification of pancreatic cystic neoplasms with needle-based confocal laser endomicroscopy under endosonographic guidance. Endoscopy 2013;45:1006-13.
51. Nakai Y, Iwashita T, Park DH et al
. Diagnosis of pancreatic cysts: EUS-guided, through-the-needle confocal laser-induced endomicroscopy and cystoscopy trial: DETECT study. Gastrointest Endosc 2015;81:1204-14.
52. Ngamruengphong S, Bartel MJ, Raimondo M. Cyst carcinoembryonic antigen in differentiating pancreatic cysts: a meta-analysis. Dig Liver Dis 2013;45:920-6.
53. Suzuki R, Thosani N, Annangi S et al
. Diagnostic yield of EUS-FNA-based cytology distinguishing malignant and benign IPMNs: a systematic review and meta-analysis. Pancreatology 2014;14:380-4.
54. Hata T, Dal Molin M, Suenaga M et al
. Cyst fluid telomerase activity predicts the histologic grade of cystic neoplasms of the pancreas. Clin Cancer Res 2016;22:5141-51.
55. Gomez V, Takahashi N, Levy MJ et al
. EUS-guided ethanol lavage does not reliably ablate pancreatic cystic neoplasms (with video). Gastrointest Endosc 2016;83:914-20.
56. Moyer MT, Dye CE, Sharzehi S et al
. Is alcohol required for effective pancreatic cyst ablation? The prospective randomized CHARM trial pilot study. Endosc Int Open 2016;4:E603-7.
57. Gan SI, Thompson CC, Lauwers GY et al
. Ethanol lavage of pancreatic cystic lesions: initial pilot study. Gastrointest Endosc 2005;61:746-52.
58. Oh HC, Seo DW, Lee TY et al
. New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection. Gastrointest Endosc 2008;67:636-42.
59. Oh HC, Seo DW, Kim SC et al
. Septated cystic tumors of the pancreas: is it possible to treat them by endoscopic ultrasonography-guided intervention? Scand J Gastroenterol 2009;44:242-7.
60. DeWitt J, McGreevy K, Schmidt CM et al
. EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study. Gastrointest Endosc 2009;70:710-23.
61. DiMaio CJ, DeWitt JM, Brugge WR. Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions. Pancreas 2011;40:664-8.
62. Oh HC, Seo DW, Song TJ et al
. Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts. Gastroenterology 2011;140:172-9.
63. Dewitt JM, Al-Haddad M, Sherman S et al
. Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel. Endoscopy 2014;46:457-64.
64. Pai M, Senturk H, Lakhtakia S et al
. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) for cystic neoplasms and neuroendocrine tumors of the pancreas. Gastrointest Endosc 2013;77:AB143-4.
65. Griffin JF, Page AJ, Samaha GJ et al
. Patients with a resected pancreatic mucinous cystic neoplasm have a better prognosis than patients with an intraductal papillary mucinous neoplasm: a large single institution series. Pancreatology 2017;17:490-6.
66. Egawa S, Takeda K, Fukuyama S et al
. Clinicopathological aspects of small pancreatic cancer. Pancreas 2004;28:235-40.
67. Ishikawa O, Ohigashi H, Imaoka S et al
. Minute carcinoma of the pancreas measuring 1 cm or less in diameter—collective review of Japanese case reports. Hepatogastroenterology 1999;46:8-15.
68. Lennon AM, Wolfgang CL, Canto MI et al
. The early detection of pancreatic cancer: What will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res 2014;74:3381-9.
69. Lennon AM, Manos LL, Hruban RH et al
. Role of a Multidisciplinary Clinic in the Management of Patients with Pancreatic Cysts: A Single-Center Cohort Study. Ann Surg Oncol 2014;21:3668-74.
70. de Wilde RF, Besselink MG, van der Tweel I et al
. Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br J Surg 2012;99:404-10.
71. Reames BN, Ghaferi AA, Birkmeyer JD et al
. Hospital volume and operative mortality in the modern era. Ann Surg 2014;260:244-51.
72. Shin SH, Han DJ, Park KT et al
. Validating a simple scoring system to predict malignancy and invasiveness of intraductal papillary mucinous neoplasms of the pancreas. World J Surg 2010;34:776-83.
73. Ingkakul T, Sadakari Y, Ienaga J et al
. Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas. Ann Surg 2010;251:70-5.
74. Wang W, Zhang L, Chen L et al
. Serum carcinoembryonic antigen and carbohydrate antigen 19-9 for prediction of malignancy and invasiveness in intraductal papillary mucinous neoplasms of the pancreas: A meta-analysis. Biomed Rep 2015;3:43-50.
75. Morales-Oyarvide V, Mino-Kenudson M, Ferrone CR et al
. Acute pancreatitis in intraductal papillary mucinous neoplasms: A common predictor of malignant intestinal subtype. Surgery 2015;158:1219-25.
76. Pelletier AL, Hammel P, Rebours V et al
. Acute pancreatitis in patients operated on for intraductal papillary mucinous neoplasms of the pancreas: frequency, severity, and clinicopathologic correlations. Pancreas 2010;39:658-61.
77. Chari ST, Kelly K, Hollingsworth MA et al
. Early detection of sporadic pancreatic cancer: summative review. Pancreas 2015;44:693-712.
78. Leal JN, Kingham TP, D'Angelica MI et al
. Intraductal papillary mucinous neoplasms and the risk of diabetes mellitus in patients undergoing resection versus observation. J Gastrointest Surg 2015;19:1974-81.
79. Mimura T, Masuda A, Matsumoto I et al
. Predictors of malignant intraductal papillary mucinous neoplasm of the pancreas. J Clin Gastroenterol 2010;44:e224-9.
80. Maguchi H, Tanno S, Mizuno N et al
. Natural history of branch duct intraductal papillary mucinous neoplasms of the pancreas: a multicenter study in Japan. Pancreas 2011;40:364-70.
81. Tanno S, Nakano Y, Koizumi K et al
. Pancreatic ductal adenocarcinomas in long-term follow-up patients with branch duct intraductal papillary mucinous neoplasms. Pancreas 2010;39:36-40.
82. Salvia R, Fernandez-del Castillo C, Bassi C et al
. Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg 2004;239:678-85; discussion 685-7.
83. Suzuki Y, Atomi Y, Sugiyama M et al
. Cystic neoplasm of the pancreas: a Japanese multiinstitutional study of intraductal papillary mucinous tumor and mucinous cystic tumor. Pancreas 2004;28:241-6.
84. Fritz S, Klauss M, Bergmann F et al
. Small (Sendai negative) branch-duct IPMNs: not harmless. Ann Surg 2012;256:313-20.
85. Rodriguez JR, Salvia R, Crippa S et al
. Branch-duct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection. Gastroenterology 2007;133:72-9; quiz 309-10.
86. Tang RS, Weinberg B, Dawson DW et al
. Evaluation of the guidelines for management of pancreatic branch-duct intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol 2008;6:815-9; quiz 719.
87. Del Chiaro M, Verbeke C, Salvia R et al
. European experts consensus statement on cystic tumours of the pancreas. Dig Liver Dis 2013;45:703-11.
88. Masica DL, Dal Molin M, Wolfgang CL et al
. A novel approach for selecting combination clinical markers of pathology applied to a large retrospective cohort of surgically resected pancreatic cysts. J Am Med Inform Assoc 2017;24:145-52.
89. Dunn DP, Brook OR, Brook A et al
. Measurement of pancreatic cystic lesions on magnetic resonance imaging: efficacy of standards in reducing inter-observer variability. Abdom Radiol 2016;41:500-7.
90. Kawamoto S, Lawler LP, Horton KM et al
. MDCT of intraductal papillary mucinous neoplasm of the pancreas: evaluation of features predictive of invasive carcinoma. AJR Am J Roentgenol 2006;186:687-95.
91. Nakagawa A, Yamaguchi T, Ohtsuka M et al
. Usefulness of multidetector computed tomography for detecting protruding lesions in intraductal papillary mucinous neoplasm of the pancreas in comparison with single-detector computed tomography and endoscopic ultrasonography. Pancreas 2009;38:131-6.
92. Ohno E, Hirooka Y, Itoh A et al
. Intraductal papillary mucinous neoplasms of the pancreas: differentiation of malignant and benign tumors by endoscopic ultrasound findings of mural nodules. Ann Surg 2009;249:628-34.
93. Sainani NI, Saokar A, Deshpande V et al
. Comparative performance of MDCT and MRI with MR cholangiopancreatography in characterizing small pancreatic cysts. AJR Am J Roentgenol 2009;193:722-31.
94. Waters JA, Schmidt CM, Pinchot JW et al
. CT vs MRCP: optimal classification of IPMN type and extent. J Gastrointest Surg 2008;12:101-9.
95. Laffan TA, Horton KM, Klein AP et al
. Prevalence of unsuspected pancreatic cysts on MDCT. Am J Roentgenol 2008;191:802-7.
96. Spinelli KS, Fromwiller TE, Daniel RA et al
. Cystic pancreatic neoplasms: observe or operate. Ann Surg 2004;239:651-7; discussion 657-9.
97. Zhang XM, Mitchell DG, Dohke M et al
. Pancreatic cysts: depiction on single-shot fast spin-echo MR images. Radiology 2002;223:547-53.
98. Berland LL, Silverman SG, Gore RM et al
. Managing incidental findings on abdominal CT: white paper of the ACR incidental findings committee. J Am Coll Radiol 2010;7:754-73.
99. Sultana A, Jackson R, Tim G et al
. What is the best way to identify malignant transformation within pancreatic IPMN: a systematic review and meta-analyses. Clin Transl Gastroenterol 2015;6:e130.
100. Cellier C, Cuillerier E, Palazzo L et al
. Intraductal papillary and mucinous tumors of the pancreas: accuracy of preoperative computed tomography, endoscopic retrograde pancreatography and endoscopic ultrasonography, and long-term outcome in a large surgical series. Gastrointest Endosc 1998;47:42-9.
101. Kubo H, Chijiiwa Y, Akahoshi K et al
. Intraductal papillary-mucinous tumors of the pancreas: differential diagnosis between benign and malignant tumors by endoscopic ultrasonography. Am J Gastroenterol 2001;96:1429-34.
102. Song MH, Lee SK, Kim MH et al
. EUS in the evaluation of pancreatic cystic lesions. Gastrointest Endosc 2003;57:891-6.
103. Sugiyama M, Atomi Y, Saito M. Intraductal papillary tumors of the pancreas: evaluation with endoscopic ultrasonography. Gastrointest Endosc 1998;48:164-71.
104. Zhong N, Zhang L, Takahashi N et al
. Histologic and imaging features of mural nodules in mucinous pancreatic cysts. Clin Gastroenterol Hepatol 2012;10 (192-198): e2.
105. Kim KW, Park SH, Pyo J et al
. Imaging features to distinguish malignant and benign branch-duct type intraductal papillary mucinous neoplasms of the pancreas: a meta-analysis. Ann Surg 2014;259:72-81.
106. Sadakari Y, Ienaga J, Kobayashi K et al
. Cyst size indicates malignant transformation in branch duct intraductal papillary mucinous neoplasm of the pancreas without mural nodules. Pancreas 2010;39:232-6.
107. Tanaka M. Controversies in the management of pancreatic IPMN. Nat Rev Gastroenterol Hepatol 2011;8:56-60.
108. Wong J, Weber J, Centeno BA et al
. High-grade dysplasia and adenocarcinoma are frequent in side-branch intraductal papillary mucinous neoplasm measuring less than 3 cm on endoscopic ultrasound. J Gastrointest Surg 2013;17:78-84; discussion p 84-5.
109. Shindo K, Ueda J, Aishima S et al
. Small-sized, flat-type invasive branch duct intraductal papillary mucinous neoplasm: a case report. Case Rep Gastroenterol 2013;7:449-54.
110. Koshita S, Fujita N, Noda Y et al
. Invasive carcinoma derived from "flat type" branch duct intraductal papillary mucinous neoplasms of the pancreas: impact of classification according to the height of mural nodule on endoscopic ultrasonography. J Hepatobiliary Pancreat Sci 2015;22:301-9.
111. Genevay M, Mino-Kenudson M, Yaeger K et al
. Cytology adds value to imaging studies for risk assessment of malignancy in pancreatic mucinous cysts. Ann Surg 2011;254:977-83.
112. de Jong K, van Hooft JE, Nio CY et al
. Accuracy of preoperative workup in a prospective series of surgically resected cystic pancreatic lesions. Scand J Gastroenterol 2012;47:1056-63.
113. Sahora K, Mino-Kenudson M, Brugge W et al
. Branch duct intraductal papillary mucinous neoplasms: does cyst size change the tip of the scale? A critical analysis of the revised international consensus guidelines in a large single-institutional series. Ann Surg 2013;258:466-75.
114. Goh BK, Thng CH, Tan DM et al
. Evaluation of the Sendai and 2012 International Consensus Guidelines based on cross-sectional imaging findings performed for the initial triage of mucinous cystic lesions of the pancreas: a single institution experience with 114 surgically treated patients. Am J Surg 2014;208:202-9.
115. Nguyen AH, Toste PA, Farrell JJ et al
. Current recommendations for surveillance and surgery of intraductal papillary mucinous neoplasms may overlook some patients with cancer. J Gastrointest Surg 2015;19:258-65.
116. Kwong WT, Lawson RD, Hunt G et al
. Rapid growth rates of suspected pancreatic cyst branch duct intraductal papillary mucinous neoplasms predict malignancy. Dig Dis Sci 2015;60:2800-6.
117. Kang MJ, Jang JY, Kim SJ et al
. Cyst growth rate predicts malignancy in patients with branch duct intraductal papillary mucinous neoplasms. Clin Gastroenterol Hepatol 2011;9:87-93.
118. Maimone S, Agrawal D, Pollack MJ et al
. Variability in measurements of pancreatic cyst size among EUS, CT, and magnetic resonance imaging modalities. Gastrointest Endosc 2010;71:945-50.
119. Lee YS, Paik KH, Kim HW et al
. Comparison of endoscopic ultrasonography, computed tomography, and magnetic resonance imaging for pancreas cystic lesions. Medicine 2015;94:e1666.
120. Boos J, Brook A, Chingkoe CM et al
. MDCT vs. MRI for incidental pancreatic cysts: measurement variability and impact on clinical management. Abdom Radiol 2016;42:521-30.
121. Yachida S, Jones S, Bozic I et al
. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:1114-7.
122. Farrell JJ, Fernández-Del Castillo C. Pancreatic cystic neoplasms: management and unanswered questions. Gastroenterology 2013;144:1303-15.
123. Khannoussi W, Vullierme MP, Rebours V et al
. The long term risk of malignancy in patients with branch duct intraductal papillary mucinous neoplasms of the pancreas. Pancreatology 2012;12:198-202.
124. Kwong WT, Hunt GC, Fehmi SM et al
. Low rates of malignancy and mortality in asymptomatic patients with suspected neoplastic pancreatic cysts beyond 5 years of surveillance. Clin Gastroenterol Hepatol 2016;14:865-71.
125. Lin JS, Piper MA, Perdue LA et al
. Screening for colorectal cancer: updated evidence report and systematic review for the us preventive services task force. JAMA 2016;315:2576-94.
126. Nilsson LN, Keane MG, Shamali A et al
. Nature and management of pancreatic mucinous cystic neoplasm (MCN): a systematic review of the literature. Pancreatology 2016;16:1028-36.
127. Balaban EP, Mangu PB, Khorana AA et al
. Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016;34:2654-68.
128. Khorana AA, Mangu PB, Berlin J et al
. Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016;34:2541-56.
129. Postlewait LM, Ethun CG, McInnis MR et al
. Association of preoperative risk factors with malignancy in pancreatic mucinous cystic neoplasms: a multicenter study. JAMA Surg 2016;152:19-25.
130. He J, Cameron JL, Ahuja N et al
. Is it necessary to follow patients after resection of a benign pancreatic intraductal papillary mucinous neoplasm? J Am Coll Surg 2013;216:657-65; discussion 665-7.
131. Kang MJ, Jang JY, Lee KB et al
. Long-term prospective cohort study of patients undergoing pancreatectomy for intraductal papillary mucinous neoplasm of the pancreas: implications for postoperative surveillance. Ann Surg 2014;260:356-63.
132. Fujii T, Kato K, Kodera Y et al
. Prognostic impact of pancreatic margin status in the intraductal papillary mucinous neoplasms of the pancreas. Surgery 2010;148:285-90.
133. Kim SC, Park KT, Lee YJ et al
. Intraductal papillary mucinous neoplasm of the pancreas: clinical characteristics and treatment outcomes of 118 consecutive patients from a single center. J Hepatobiliary Pancreat Surg 2008;15:183-8.
134. Rezaee N, Barbon C, Zaki A et al
. Intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia is a risk factor for the subsequent development of pancreatic ductal adenocarcinoma. HPB 2016;18:236-46.
135. Tamura K, Ohtsuka T, Ideno N et al
. Treatment strategy for main duct intraductal papillary mucinous neoplasms of the pancreas based on the assessment of recurrence in the remnant pancreas after resection: a retrospective review. Ann Surg 2014;259:360-8.
136. Marchegiani G, Mino-Kenudson M, Ferrone CR et al
. Patterns of recurrence after resection of IPMN: who, when, and how? Ann Surg 2015;262:1108-14.
137. Miller JR, Meyer JE, Waters JA et al
. Outcome of the pancreatic remnant following segmental pancreatectomy for non-invasive intraductal papillary mucinous neoplasm. HPB 2011;13:759-66.
138. Raut CP, Cleary KR, Staerkel GA et al
. Intraductal papillary mucinous neoplasms of the pancreas: effect of invasion and pancreatic margin status on recurrence and survival. Ann Surg Oncol 2006;13:582-94.
139. Hirono S, Kawai M, Okada K et al
. Long-term surveillance is necessary after operative resection for intraductal papillary mucinous neoplasm of the pancreas. Surgery 2016;160:306-17.
140. Frankel TL, LaFemina J, Bamboat ZM et al
. Dysplasia at the surgical margin is associated with recurrence after resection of non-invasive intraductal papillary mucinous neoplasms. HPB 2013;15:814-21.
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141. Passot G, Lebeau R, Hervieu V et al
. Recurrences after surgical resection of intraductal papillary mucinous neoplasm of the pancreas: a single-center study of recurrence predictive factors. Pancreas 2012;41:137-41.