American Gastroenterological Association Technical Review on the

DO NOT CITE OR REFERENCE 1

American Gastroenterological Association Technical Review on 1

the Diagnosis and Management of Pancreatic Cysts 2

James M. Scheiman,1 Joo Ha Hwang,2 Paul Moayyedi3 3

4 1 University of Michigan Medical School, Department of Internal Medicine and Gastroenterology, 5

Ann Arbor, MI,2 University of Washington, Division of Gastroenterology, Department of 6

Medicine,Seattle, WA, 3 Farncombe Family Digestive Health Research Institute, McMaster 7

University, Division of Gastroenterology, Ancaster, ON. 8

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Conflict of interest disclosure: All members were required to complete a disclosure statement. 10

These statements are maintained at the American Gastroenterological Association Institute 11

(AGA) headquarters in Bethesda, Maryland and pertinent disclosure are published with the 12

report. The authors of the technical review have no conflicts to disclose. 13

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INTRODUCTION 27

Pancreatic cysts are being identified with increasing frequency, related to the increasing 28

utilization of cross sectional imaging, typically for unrelated reasons.1,2 The incidence of 29

pancreatic cysts in the US population is estimated to between 3% and 15% with 30

increasing prevalence with age.3 When a cystic lesion in the pancreas is found, it creates 31

anxiety for both patients and clinicians related to the potential specter of a deadly 32

malignancy. Historically, non-neoplastic inflammatory pancreatic pseudocysts were 33

thought to be the most common pancreatic cyst; however, as imaging has become more 34

sensitive, smaller, neoplastic cysts are more frequently detected. The finding of a 35

pancreatic abnormality with potential association with malignancy is an increasing 36

source of referral to specialists and an important driver of resource utilization, 37

particularly in the US. Imaging studies vary widely in their quality and interpretation, 38

fueling the need for additional investigation. This technical review discusses the 39

challenges in evaluating pancreatic cysts and critically examines the existing data set for 40

evidence based medical decision-making. 41

While the concern for current or future malignancy is justified, a rational, 42

evidence-based, cost effective approach to the patient with a pancreatic cyst remains 43

poorly defined. Despite the high prevalence of these lesions, recent investigators have 44

questioned just how frequent a clinically relevant adverse outcome develops—that is 45

the development of a life threatening malignancy. This is a critical consideration, given 46

the cost of repeat imaging, invasive procedures such as EUS+/- FNA, as well as 47

consideration of major pancreatic resections with their substantial attendant morbidity 48

and mortality, particularly in the aging population with a high rate of prevalent cysts. In 49

a recent analysis, investigators using the SEER database estimated an annual prevalence 50

of 1137 mucin-producing pancreatic adenocarcinomas among a concurrent prevalence 51

of nearly 3.5 million cysts in the same population, concluding that malignant 52

transformation is a very rare event.4 In this clinical context the AGA has commissioned 53

an evidence based review of the diagnosis and management of pancreatic cysts. 54

55


Differential Diagnosis 56

Cystic lesions of the pancreas have a broad differential diagnosis. In general, they 57

can be categorized into non-neoplastic (eg, pseudocysts) and neoplastic cystic lesions. 58

The latter group, often referred to as “cystic neoplasms of the pancreas”, can be broadly 59

sub-categorized into those that produce a mucin-rich fluid (ie, mucin-producing cystic 60

neoplasms) and those that do not. This distinction is important, because an increased 61

risk of pancreatic adenocarcinoma has been attributed to all of the mucin-producing 62

variants, which include “branch duct IPMN”, “main duct IPMN”, and “mixed IPMN” 63

(which has features of branch- and main-duct IPMN). The classic example of a cystic 64

neoplasm that is not mucin producing, to which an increased cancer risk is not 65

attributed, is “serous cystadenoma”. Papillary cystic neoplasms (eg, solid 66

pseudopapillary tumor of the pancreas) and cystic pancreatic neuroendocrine tumors, 67

are additional examples of cystic neoplasms of the pancreas. There are many challenges 68

associated with achieving an accurate diagnosis and, arguably, more importantly, 69

identifying reliable and reproducible methods to stratify cancer risk for these 70

individuals, making clinical decision-making difficult. Several groups, including an 71

international consensus panel, have proposed management recommendations 72

(including algorithms) for patients with suspected cystic neoplasms of the pancreas.5, 6 73

These are commonly used in clinical practice; however, these are consensus guidelines 74

and not necessarily evidence based. Following a basic description of the different types 75

of cystic neoplasms, we provide results from our evidence-based systematic literature 76

review which was designed to assess the strength of the evidence for specific focused 77

clinical questions encountered commonly in the management of patients with 78

pancreatic cysts. The purpose of this document is to assess the existing evidence to 79

address specific clinical questions related to the evaluation and management of 80

pancreatic cysts with a focus on indeterminate cysts. 81

82

Pseudocysts 83


Inflammatory pseudocysts historically were thought to represent up to 90% of all 84

pancreatic cysts, but recent data using high resolution imaging detecting a high 85

prevalence of incidentally noted cysts among individuals without a history or evidence 86

of pancreatitis suggests that neoplastic cysts are likely far more common. The critical 87

patient management issue is differentiating these non-neoplastic lesions from 88

neoplastic ones. When a cyst without an associated solid mass arises in a patient with 89

known chronic pancreatitis, the clinical concern of a neoplasm is minimal. When 90

patients present with unexplained pancreatitis for the first time with a cyst, or have only 91

subtle changes of chronic pancreatitis on EUS imaging alone, the clinician should 92

consider whether the cyst may be a neoplasm and the lesion is the cause of the 93

pancreatitis instead of assuming it is the consequence of pancreatitis. Reviewing 94

imaging performed before the episode of pancreatitis, if available, may address this 95

critical question. 96

97

Serous cystadenomas 98

Serous cystadenomas were originally termed “microcystic adenomas” referring 99

to the small (<2cm) cystic compartments that make up the tumors. The term 100

“microcystic adenoma” is still used synonymously with serous cystadenomas but has 101

gained recent criticism due to reports of macrocystic variants.7 102

Serous cystadenomas occur more commonly in women, who typically present in 103

their sixties. Lesions with serous morphology in a young woman or a man may 104

therefore lead to diagnostic confusion. Although nearly always benign, malignant serous 105

cystadenocarcinomas very rarely have been described.8 They can become symptomatic 106

by increasing in size with “invasive features”, leading to the recommendation by some 107

surgical experts to remove them in younger patients. The low malignancy risk should 108

forestall the need for frequent surveillance. However, if the diagnosis is not confirmed, 109

or if there is concern for local invasiveness, surveillance and management for these 110

cysts remains controversial. 111


Serous cystadenomas generally are slowly growing tumors that are symptomatic 112

in less than half of patients. The pathology of these tumors demonstrate well-113

circumscribed masses enclosed in a fibrous capsule containing numerous, small fluid-114

filled cysts arranged in a classic “honeycomb” pattern.9 Fibrous bands within the lesions 115

often converge centrally forming a stellate scar which may calcify giving a 116

pathognomonic “sunburst” appearance on CT scan.10 117

118

Mucinous cystic neoplasms 119

Mucinous cystic neoplasms (MCNs) represent nearly half of the tumors removed 120

in contemporary surgical series. MCNs occur almost exclusively in women (>98%) and 121

are generally diagnosed in their forties and fifties.11, 12.While the patient may present 122

with pain, an abdominal mass or weight loss, up to one third of series report discovery 123

by cross sectional imaging for unrelated reasons. Ninety percent occur in the pancreatic 124

body or tail.13 125

Mucinous cystic neoplasms are characterized by a thick fibrous capsule that 126

encircles the cystic spaces. A characteristic spindle cell stroma containing epthelioid 127

cells similar to ovarian stroma surrounds the tumor. The cyst lining is comprised of 128

mucin producing duct-like cells frequently exhibiting a papillary architecture. However, 129

the epithelial lining may be denuded, leading to misdiagnosis of “pseudocyst” on limited 130

tissue samples such as operative frozen sections. 131

The prognosis for mucinous cystic neoplasms is defined by the presence or 132

absence of invasive adenocarcinoma. Cancer has been described in approximately one 133

third of operated tumors, and these patients have a variable prognosis, with 5 year 134

survival up to 60% following a cancer operation to poor outcomes similar to ductal 135

adenocarcinoma.14 One explanation for the disparate literature may reflect sampling, 136

because the invasive component may be only a small part of the lesion. 137

138

Intraductal papillary mucinous neoplasm (IPMN) 139


Intraductal papillary mucinous tumors (IPMN) are also mucin producing lesions, 140

which characteristically communicate with the main pancreatic duct as their main point 141

of distinction from MCNs. These increasingly recognized lesions are characterized by 142

intraductal dysplastic epithelium resembling colorectal villous adenomas, with papillae 143

covered by columnar epithelium and the occasional goblet cell with extensive mucin 144

production. This category includes several previously used terms –most commonly 145

referred to as mucinous ductal ectasia in the past. These tumors always exhibit at least 146

low grade dysplasia, and should be considered premalignant in all clinical situations.14 147

However, the natural history with regard to progression to cancer is not well 148

characterized. Gastric, intestinal, pancreatobiliary and oncocytic subtypes of the 149

papillary epithelium have been described with clinicopathological significance.15 150

IPMN’s principally occur in males, with a mean age of diagnosis in the mid 60’s. 151

The lesions are frequently (50%) confined to the head, and if symptomatic, a typical 152

presenting complex is recurrent unexplained pancreatitis with ductal dilation or 153

symptoms similar to chronic pancreatitis, typically without risk factors.14 IPMN’s may 154

involve the main duct and/or side branches, and mixed variants can occur. Pure main 155

duct IPMNs have a dilated main pancreatic duct without an associated “cystic” 156

component, whereas branch duct IPMNs are comprised of cysts that communicate with 157

the main pancreatic duct. Identification of the communication to the main pancreatic 158

duct can be difficult to determine with imaging techniques, which can make it difficult to 159

differentiate a branch duct IPMN from other cystic lesion such as MCNs or serous cysts. 160

It has been proposed that the side branch type has a better prognosis than the variant 161

that involves the main duct. Surgical resection must consider extent of intraductal 162

growth to achieve a negative margin, to prevent recurrence. In the absence of 163

carcinoma, prognosis is excellent with definitive surgical resection.16 A patulous papilla 164

at endoscopy extruding mucous is pathognomonic for the main duct variant. 165

166

Less common neoplastic cystic lesions 167


Cystic pancreatic neuroendocrine tumors (PNETs) are quite rare, and may or may 168

not be associated with symptoms of excess hormone production. If clinical or imaging 169

data suggest this as a relevant diagnostic consideration, attempts to confirm the 170

diagnosis resect localized disease should be undertaken due to its malignant potential 17 171

Papillary cystic tumors of the pancreas have a characteristic appearance on 172

imaging and should not be confused with the far more common lesions which are the 173

focus of this review. The vast majority of papillary cystic neoplasms present in females 174

(~90%), most often in the third decade. 18 While most of these tumors are benign, 175

approximately 15% may be malignant leading to the recommendation for surgical 176

resection when they are identified. 19 177

178

Clinical approach: 179

A detailed history to determine if the patient is experiencing symptoms related 180

to the lesion itself, or a related condition, such as pancreatitis is important. If previous 181

cross sectional imaging is available, it should be reviewed to determine if the lesion was 182

present and evaluate for change in size or appearance. Most asymptomatic patients 183

have small lesions that do not cause symptoms due to their small size. While large cysts 184

may cause vague symptoms of pain, obstructive jaundice is uncommon, even for lesions 185

located in the head. Typical symptoms of malignancy, such as weight loss, epigastric 186

/back pain, nausea, vomiting, and severe malaise, are usually absent. Clinical decision 187

making is driven by an understanding of the differential diagnosis of cyst and in the case 188

of the asymptomatic patient, its likelihood of causing harm with testing and/or 189

treatment. The fundamental issue to be addressed is whether the cyst is neoplastic or 190

not. If the cyst is neoplastic, then what is its risk for malignant progression? More simply 191

stated, is the up-front risk of surgery justified by the long term risk of malignancy, and if 192

so, does it provide a survival benefit to the patient? 193

194

Imaging Studies 195


High resolution CT using thin sections with both enhanced and unenhanced 196

technique provide detailed information about cyst structure and may provide a 197

presumptive diagnosis if characteristic features are present. MRI/MRCP has the 198

potential added advantage of determining communication between the cyst and 199

pancreatic duct as well as lack of ionizing radiation. The presence of a central scar is a 200

highly diagnostic feature of serous lesions, but is seen in only 20% of serous cysts. 201

Despite the high quality of contemporary CT and MRI, their ability to distinguish 202

neoplastic from non-neoplastic cystic pancreatic lesions remains imperfect. Because of 203

this, endoscopic ultrasound (EUS) imaging has emerged a useful tool in evaluating these 204

lesions since its resolution is superior to CT and MRI. While some enthusiastic reports 205

were able to differentiate benign from malignant neoplastic tumors and from non-206

neoplastic cysts with an accuracy of more than 90% based on the endosonographic 207

appearance of the lesion, other reports emphasize that the technique is not sufficiently 208

accurate to differentiate between benign and malignant lesions unless there is evidence 209

of a solid mass or invasive tumor.20, 21 Further, while EUS is quite sensitive in detection 210

and evaluation of cyst morphology, it is highly operator dependent-- as are the 211

performance of all imaging studies. 212

213

Overview 214

This technical review (and the accompanying guideline published as a separate 215

Gastroenterology article) was based on the GRADE framework.22 In developing this 216

technical review, the authors first formulated a series of specific questions that were to 217

be answered by the guideline (appendix 1). The authors then identified the outcomes 218

that were significant to answering each question and rated them as critical or 219

important. Next, the group systematically reviewed and summarized the evidence for 220

each outcome across studies, assessed the quality of evidence for each outcome, and 221

finally integrated the evidence across all the outcomes to answer each specific question. 222

The quality of the evidence was classified into 4 categories: high, moderate, low, and 223

very low. Assessment of the quality for each outcome took into account the study 224


design, risk of bias, inconsistency (or heterogeneity), indirectness, imprecision, and 225

potential publication bias (See glossary of terms in Supplemental Materials for further 226

explanations). GRADE methodology requires clinical questions to be framed in terms of 227

a designated population (P) undergoing a specific intervention or diagnostic test (I) with 228

an explicit comparator (C) and a defined outcome (O) (so called PICO format). When the 229

question does not explicitly state a comparator then the comparison with no 230

intervention is implied. Initially we outlined a total of 7 PICO questions (table 1). The 231

patient populations with pancreatic cysts were further analyzed for risk of malignancy 232

based on imaging findings, cyst fluid analysis, and pathology. In addition, an analysis of 233

the prevalence of pancreatic cysts in the population was performed followed by an 234

estimation of the risk of malignant progression of all pancreatic cysts. We used a 235

consensus decision-making process (http://seedsforchange.org.uk/consensus.pdf) to 236

reach unanimous agreement among the three authors on all statements. 237

238

Table 1: PICO questions 239

Q PICO Question Method.

Population(s) Intervention(s) Comparator Outcome(s)

Initial imaging evaluation of pancreatic cysts

1 Adults with findings of a pancreatic cyst on cross-sectional imaging

Additional MRI imaging

No further investigation

Beneficial Detection of early pancreatic cancer or precancerous cyst Harms Unnecessary surgery/invasive procedures

RCT, observational studies

2 Adults with concerning findings of a pancreatic cyst on MRI

Additoinal EUS-FNA

No further investigation

Beneficial Detection of early pancreatic cancer or precancerous cyst Harms Unnecessary surgery/invasive procedures


Surveillance for pancreatic cysts

3 Adults with low risk pancreatic cysts on imaging

Annual MRI surveillance.

No surveillance Beneficial Detection of early pancreatic cancer


http://seedsforchange.org.uk/consensus.pdf


Harms Unnecessary surgery/invasive procedures

Surgery for pancreatic cysts

4 Adults with pancreatic cyst with concerning features on MRI and EUS-FNA

Surgical pancreatic resection

Continued annual MRI/CT/EUS surveillance.

Beneficial Treatment of early pancreatic cancer and prevention of malignancy developing Harms Unnecessary surgery Morbidity of pancreatic surgery Mortality associated with pancreatic surgery


Surveillance post surgery

5 Patients with successful resection of an early pancreatic malignancy

Annual MRI/CT/EUS surveillance.

No surveillance Beneficial Detection of early pancreatic cancer Harms Unnecessary surgery/invasive procedures


6 Patients with successful resection of a pancreatic cyst with no dysplasia

Annual MRI/CT/EUS surveillance.

No surveillance

Beneficial Detection of early pancreatic cancer Harms Unnecessary surgery/invasive procedures


When to discontinue surveillance

7 Pancreatic cysts with no change after 5 years of surveillance

Continued annual EUS/MRI/CT surveillance.

No surveillance Beneficial Detection of early pancreatic cancer Harms Unnecessary surgery/invasive procedures


240

Outcomes of interest 241

242

When using the GRADE process it is important that the outcomes assessed are patient 243

focused. The most important outcome that would benefit a patient with a pancreatic 244

cyst would be to prevent mortality from cystadenocarcinoma. There are no randomized 245


trials or observational studies that compare screening with no screening in pancreatic 246

cyst patients quantifying mortality from adenocarcinoma as an outcome. There are 247

numerous studies that describe the histology findings of pancreatic cysts in patients that 248

have had surgery to resect a concerning lesion. These studies evaluate a highly selected 249

population in whom surgery has been deemed an appropriate intervention and do not 250

reflect the average patient with pancreatic cyst. Nevertheless, they do give an 251

indication of the histopathology identified in those with “concerning” cystic lesions. 252

These papers often suggest that removal of lesions that contain dysplasia is a successful 253

outcome. Dysplasia is a risk factor for progression to malignancy in other tissues 254

although the majority of patients do not develop invasive cancer.23 Surgical intervention 255

would be appropriate if there was little risk to the patient but this is not the case with 256

pancreatic surgery, which carries a risk of morbidity (approximately 20-40%) and a risk 257

of mortality (less than 1% in high volume centers). 24, 25 An analogous situation would be 258

Barrett’s esophagus where current guidelines do not support surgery when dysplasia is 259

found as the risks of surgery outweigh the benefits.26 260

The literature on findings in patients undergoing surgery is further complicated 261

by the inclusion of those with carcinoma in situ as “malignancy”. Whilst these lesions 262

are of undoubted major concern there is a large body of evidence that this histological 263

lesion does not always progress to invasive adenocarcinoma.27, 28 Indeed these lesions 264

result in an excess of surgery in other screening programs such as breast cancer where it 265

is estimated that 70,000 US women each year undergo surgery for a lesion that would 266

not lead to mortality if left alone.29 This does not mean that surgery is inappropriate for 267

these women as breast surgery still has more benefits than risks but this may not apply 268

to pancreatic cyst surgery where morbidity and mortality are higher. Other outcomes of 269

interest that may be prevented by surgery are episodes of acute pancreatitis due to 270

mucus plugs and obstructive jaundice by cysts in the head, neck and uncinate process. 271

272

All these uncertainties mean that there are a limited number of PICO questions 273

with relevant patient outcomes (survival) that can be answered with any directly 274


relevant data. The initial part of this technical review therefore simply outlines the 275

evidence from these surgical series in a narrative manner to provide the risk of invasive 276

malignancy in this select group according to type of cyst. This will indirectly inform the 277

type of pancreatic cyst that is likely to harbor dysplasia or malignancy. We then 278

evaluated the data according to which imaging modality best diagnosed the type of cyst 279

and malignant risk and then conducted systematic reviews of the literature to address 280

risk of malignant progression in pancreatic cysts that would not undergo initial surgery. 281

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Literature Search 284

285

The literature search is described in detail in the appendix. Medline was searched from 286

1946 to July 2013 and papers evaluating pancreatic cystic neoplasms were identified by 287

combining the exploded MeSH heading pancreatic cyst with text words that contained 288

“pancrea” (e.g. pancreas or pancreatic) and cyst that were separated by two or less 289

adjectives (e.g. such a search would detect “cyst of the pancreas” and “pancreatic 290

cysts”). This was combined with the set operator OR with the exploded MeSH heading 291

pancreatic neoplasm with a similar text word approach described above to identify 292

other pancreatic neoplasms. Case reports, letters and non-English language articles 293

were excluded. 294

295

A second search was carried out to identify diagnostic studies. This identified pancreatic 296

cysts as described in the first section above and combined with MeSH headings and text 297

words that described ultrasonography (including EUS), computerized tomography (CT) 298

scans, magnetic resonance imaging (MRI) and endoscopic retrograde pancreatography 299

(ERCP). Furthermore papers that identified tumor markers and cyst fluid analysis were 300

also identified with exploded MeSH terms and text words (see appendix for details). 301

302


The first search identified over 2000 papers and the second search over 1500 papers 303

with duplicates excluded. These were imported into Endnote version 7.0.1 (Thomson 304

Reuters) and manually assessed for relevance by two reviewers (PM and Cathy Yuan 305

(YY)). The same two reviewers also extracted data relevant for the guideline. 306

307

Results 308

The review identified a literature largely comprised of retrospective case-series. There 309

are no RCTs available. A key limitation of the current literature is that management 310

recommendations are based upon knowledge of the specific cyst histology, which rarely 311

can be determined using current imaging and cyst sampling techniques. This highlights 312

the challenges of providing evidence-based recommendations regarding the 313

management of patients with pancreatic cysts. 314

315

Imaging features of pancreatic cysts predictive of malignancy risk 316

317

To address which patients to offer surgery vs. surveillance once a lesion is identified, the 318

literature was reviewed to identify such predictive features. The evidence for risk 319

factors of malignancy in pancreatic cysts including pancreatic cyst size, dilation of 320

pancreatic duct and solid component associated with the cyst was reviewed. We 321

focused on studies of imaging features where surgical resection was performed so that 322

an accurate diagnosis of the presence or absence of malignancy could be established. 323

Studies that retrospectively selected one type of cyst (e.g. mucinous cystic neoplasm or 324

IPMN) and evaluated risk factors in that type of cyst were excluded since it is not 325

possible to establish the diagnosis with certainty prior to surgery. Therefore, only 326

studies that evaluated all pancreatic cysts that were operated on were included in the 327

analysis, which differs from other reviews in this area that have looked at risk factors in 328


IPMNs specifically.30 Studies that had less than 20 patients were also excluded. We had 329

intended to focus on malignant cysts only but there was insufficient data in some areas 330

so we included studies that reported diagnostic accuracy of imaging studies on both 331

malignant cysts and cysts with high-grade dysplasia. The review found no evidence that 332

multiple cysts were predictive of malignancy risk. 333

334

Size of cyst > 3cm. 335

We identified six studies evaluating 644 patients having surgery that provided 336

information regarding cyst size.31-36 Overall 381/644 (59%) patients had a cyst >3cm and 337

the risk of malignancy was 163/381 (43%) in those with cysts >3cm compared to 57/263 338

(22%) in those < 3cm. The risk of malignancy was significantly increased in cysts > 3cm 339

(OR = 2.97; 95% CI = 1.82 to 4.85) with no significant heterogeneity between studies (I2 340

= 30%; Cochran Q =7.15 [degrees of freedom = 5] p = 0.21). The pooled sensitivity and 341

specificity and positive and negative likelihood ratios (LR) are given in table 2. 342

343

344

Solid component to the cyst 345

346

We identified seven studies evaluating 816 patients having surgery that provided 347

information regarding the presence or absence of a solid component associated with 348

the pancreatic cyst.31-33,36-39 Overall 186/816 (23%) patients had a solid component and 349

the risk of malignancy was 136/186 (73%) in those with as solid component compared 350

to 147/630 (23%) in those without a solid component. The risk of malignancy was 351


significantly increased in those with a solid component (OR = 7.73; 95% CI = 3.38 to 352

17.67) with significant heterogeneity between studies (I2 = 70%; Cochran Q = 20.1 353

[degrees of freedom = 6] p = 0.003). The pooled sensitivity and specificity and positive 354

and negative LR are given in table 2. 355

356

Dilated pancreatic duct 357

We identified four studies evaluating 609 patients having surgery that provided 358

information regarding the presence or absence of a dilated pancreatic duct.33, 36-38 359

Overall 148/609 (24%) patients had a dilated pancreatic duct and the risk of malignancy 360

was 69/148 (47%) in those with a dilated duct compared to 150/461= (33%) in those 361

without a dilated duct. The risk of malignancy was not statistically significantly 362

increased in those with a dilated duct (OR = 2.38; 95% CI = 0.71 to 8.00) with significant 363

heterogeneity between studies (I2 = 84%; Cochran Q = 18.8 [degrees of freedom = 3] p = 364

0.0003). The pooled sensitivity and specificity and positive and negative LR are given in 365

table 2. 366

367


368

Table 2. Summary of pooled data evaluating pancreatic cyst features predictive of malignancy. 369

370

Feature No.

studies

No.

patients

Sensitivity

(95% CI)

Specificity

(95% CI)

LR +ve

(95% CI)

LR –ve

(95% CI)

> 3cm 6 644 74%

(68-80%)

49%

(44-54%)

1.47

(1.24-1.75)

0.53

(0.39-0.72)

Dilated

pancreatic

duct

4 609 32%

(25-38%)

80%

(75-84%)

1.93

(0.78-4.79)

0.85

(0.66-1.10)

Solid

component to

cyst

7 816 48%

(42-54%)

91%

(88-93%)

4.42

(2.42-8.07)

0.60

(0.39-0.94)

371

372

Rate of adenocarcinoma in surgically resected cysts 373

A key limitation of the literature is that among surgical series resecting pancreatic cysts, 374

malignancy is not commonly found.12, 40 While this reflects the goal to prevent cancer, it 375

precludes an assessment of the impact of the intervention, given the lack of a 376

comparison group observed over time (i.e., surgical resection versus surveillance). This 377

is relevant, as removing precancerous lesions in elderly persons may not provide any 378

survival benefit. The benefit of surgery is most evident for pancreatic cysts that are 379

found to harbor invasive malignancy and we have evaluated this in a review of the 380

literature. Surgical case series that reported on unselected pancreatic cysts where 381

surgery was deemed appropriate and reported both the final diagnosis for type of 382


pancreatic and the presence or absence of invasive malignancy were included. Studies 383

that evaluated only one type of cyst (e.g. IPMN) diagnosed after surgery were excluded 384

in this analysis but are discussed later. Studies that combined invasive malignancy with 385

high-grade dysplasia and did not report the results for invasive malignancy only were 386

not included. We did include studies from the same center/group that could have 387

reported on the same patients more than once provided this impact was small. 388

389

We identified 27 studies that fulfilled our criteria reporting on 2796 patients with 390

surgically resected cysts evaluating for the presence of malignancy.32-39, 41-59 Overall 418 391

harbored invasive adenocarcinoma with proportions in each individual study varying 392

between 0 and 32%. The pooled proportion of cysts with invasive adenocarcinoma was 393

15% (95% CI = 12-18%) with marked heterogeneity between studies (I2 = 76.5%, Cochran 394

Q = 111 [df = 26], p < 0.0001). There was also funnel plot asymmetry (Begg-Mazumdar: 395

Kendall's tau = 0.38, p = 0.0045) suggesting publication bias or other small study effects. 396

However, if only the studies that included over 100 patients were selected 32, 33, 35-38, 43-45, 397

47, 48, 50, 52 the pooled proportion with invasive malignancy was still 15% (95% CI = 11 to 398

18%,I2 = 80%, Cochran Q = 61 [df = 12], p < 0.0001) suggesting small study effects were 399

not a major driver of the overall estimate of proportion of patients that had invasive 400

malignancy. 401

402

403

404


405

406

Risk of malignancy in patients having surgery: data specific for IPMN 407

We have shown the overall risk of malignancy found when a patient has surgery for 408

pancreatic cysts is around 15%. However, this does not identify the risk of malignancy 409

for each type of cyst. We have evaluated this in surgical series that have reported on 410

the risk of malignancy in retrospective case series looking at their intraductal papillary 411

mucinous neoplasm (IPMN) data. Studies with less than or equal to 20 patients and 412

those that evaluated only main duct IPMN were excluded. Only studies that reported 413

the presence or absence of invasive malignancy were evaluated. The diagnosis of 414

carcinoma in situ or high-grade dysplasia were not considered to be and invasive 415

malignancy in this analysis; however, these studies were evaluated separately. 416

417

We identified 111 studies involving 10,812 patients with IPMNs identified at surgery 418

that reported on the presence or absence of invasive malignancy. 35, 37-39, 44, 47, 54, 60-163 419

There was significant heterogeneity between studies reporting on the rate of invasive 420

malignancies in IPMNs (Cochran Q = 626 [df = 110], p < 0.0001, I2 = 82%; 95% CI = 79% - 421

85%) with an overall invasive malignancy rate of 25% (95% CI = 23% - 27%) using a 422

random effects model . There was statistically significant funnel plot asymmetry (Begg-423

Mazumdar: Kendall's tau b = 0.26; p < 0.0001) suggesting publication bias or other small 424

study effects. However any effect of this is likely to be small as graphically the data look 425

reasonably symmetrical. 426

427


There were 99 studies assessing 9,249 patients that evaluated both the invasive 428

malignancy rate as well as high grade dysplasia (HGD) and/or carcinoma in situ (CIS) 429

rates in IPMNs. 32, 35, 37-39, 42, 44-48, 54, 81-98, 100-135, 137-169 Again there was significant 430

heterogeneity between studies reporting on the rate of HGD/CIS in IPMNs (Cochran Q = 431

846 [df = 98], p < 0.0001, I2 = 88%; 95% CI = 87% - 90%) with an overall high risk lesion 432

rate of 42% (95% CI = 39% - 45%) using a random effects model. Conversely this means 433

that in these 99 studies of 9,249 patients there were 58% (95% CI = 55 to 61%) that had 434

low risk (e.g. low grade dysplasia) or benign lesions. There was statistically significant 435

funnel plot asymmetry (Begg-Mazumdar: Kendall's tau b = -0.18; P =0.01) suggesting 436

publication bias or other small study effects. However any effect of this is likely to be 437

small as graphically the data look reasonably symmetrical. This latter figure needs to be 438

treated with caution as many papers only reported the high risk group and we inferred 439

that all others were low risk where this may not be the case. 440

441

442


443

444

Risk of malignancy in patients having surgery where the authors report data 445

specifically for mucinous and serous cystic neoplasms 446

We evaluated the risk of malignancy in MCNs and SCNs in retrospective surgical series 447

that reported on the presence or absence of invasive malignancy in these lesions. 448

Studies with less than 20 patients and studies that did not use the term invasive 449

malignancy were excluded from the analysis. Cases of carcinoma in situ or high-grade 450

dysplasia were not considered to be invasive malignancies and were evaluated 451

separately. 452

453

We identified 12 studies 33, 37, 42, 44, 45, 48, 114, 170-174 involving 603 patients with MCNs 454

identified at surgery. 33, 37, 42, 44, 45, 48, 114, 170-174 There was significant heterogeneity 455

between study MCN invasive malignancy proportions (Cochran Q =57 [df = 11], p < 456

0.0001, I2 = 81%; (95% CI = 66% - 88%) with an overall invasive malignancy rate of 15% 457

(95%CI = 9% - 22%) using a random effects model . Test for funnel plot asymmetry was 458

statistically significant (Begg-Mazumdar test, p = 0.02). 459

460

There were 5 studies assessing 295 patients that evaluated the proportion of invasive 461

malignancy in SCNs.175-178 There was heterogeneity between studies (Cochran Q = 8 [df = 462

4], p =0.08, I2 = 52%; 95% CI = 0% - 81%) with an overall high risk lesion rate of 2.2% 463

(95% CI = 0.3% - 5.7%) using a random effects model. 464


Imaging Evaluation 465

466

The rationale for invasive testing and serial imaging of patients with pancreatic cysts is 467

that they will develop pancreatic malignancy at a greater rate than the general 468

population. We found no observational data that addresses this question so this 469

fundamental assumption remains uncertain. We therefore approached the problem 470

from another perspective and modeled the likely risk of a pancreatic cyst progressing to 471

invasive malignancy and causing death. These data are fundamentally necessary to 472

understand the predictive value of diagnostic testing. For example, for conditions with a 473

low risk of invasive malignancy, Bayesian analysis would indicate very high levels of 474

diagnostic test accuracy are need to increase post-test disease probability to a clinically 475

meaningful degree. Therefore, a systematic review to estimate the prevalence of 476

pancreatic cysts in the population and estimated the risk of progression from national 477

cancer statistics on mucinous pancreatic adenocarcinomas was conducted, expanding 478

the approach of Gardner et al.4 These investigators used the “two most rigorous cross-479

sectional imaging studies”. A more objective approach would be to conduct a 480

systematic review and synthesize all prevalence studies. We have therefore conducted 481

a systematic review to estimate the prevalence of pancreatic cysts in the population. 482

483

Overall prevalence of pancreatic cysts in the general population 484

We identified 7 papers1, 2, 179-183 were eligible for inclusion in the review. The 485

characteristics of the studies are summarized in table 3. There were six studies that 486


evaluated pancreatic cysts using MRI and these identified 1021 cysts in 8890 subjects. 487

488

The reported prevalence of pancreatic cysts varied between 2% and 38% with an overall 489

prevalence of 15% (95% CI = 7% - 24%) There were two1, 183 that evaluated pancreatic 490

cysts using CT scan. These studies found 465 cysts in 20,275 subjects with an overall 491

prevalence of 3% (95% CI = 2% - 3%). 492

493

Two studies showed an increase in prevalence with each age band, with a 494

prevalence of 0.5% in those less than 40 years of age, 25% in those 70-79 years and 37% 495

in those aged 80 or over (table 3).2, 182 These data are consistent with a Japanese 496

autopsy study that found cysts in 19% of those 70-79 years and 30% in those 80-89 497

years of age.184 498

499

There were five studies that reported cyst size of >2cm in 25,195 subjects.2, 180-183 500

Overall there were 194 subjects with cysts >2cm giving an overall prevalence of 0.8% 501

(95% CI = 0.5 to 1.1%). 502

503

504

505

506


507

Estimating the risk of malignancy of pancreatic cysts 508

509

We applied the approach used by Gardner et al4 using US population data and SEER 510

cancer statistics. Using the prevelance of cysts from our systematic review and the risk 511

of cystadenocarcinoma mortality from the SEER cancer database the overall risk that a 512

pancreatic cyst is malignant at the time of diagnosis is a maximum of 0.017%. If we 513

assumed that only those cysts over 2cm have malignant potential then the risk that a 514

cyst > 2cm is malignant is a maximum of 0.25%. In addition we modeled what the risk of 515

malignant progression would be assuming that all mucin producing pancreatic 516

adenocarcinomas over the next twenty years arose from cysts. Using these data and 517

incorporating prevalence rates from this systematic review we find the estimate of risk 518

of cancer progression of any cyst over the next twenty years is less than 1%. This is 519

consistent over all age bands as although the risk of cancer progression increases with 520

age so does the prevalence of pancreatic cysts. This extremely low risk of cancer is 521

based on several assumptions that could overestimate or underestimate risk. Risk could 522

be overestimated as we assumed that only cysts visible on imaging would progress to 523

cancer. Although size of cyst is a risk factor, the effect is only modest and it is possible 524

for small cysts not detected by imaging to become malignant. Risk could also be over-525

estimated as the prevalence could be higher than estimated from the systematic review. 526

The screening studies recruited subjects volunteering for screening. Such individuals are 527

usually more affluent and have more healthy lifestyles and this “healthy volunteer 528

effect” reduces their risk of many serious pathologies including cancer.185 529


530

531


532

Table 3. Summary of studies included in the review to estimate the prevalence of pancreas cysts 533

534

Author Country Design Imaging Population

De Jong 2010 Germany Retrospective MRI Subjects paying for MRI as part of a preventative medical exam

Girometti 2011 Italy Retrospective MRI/MRCP Having MRCP to investigate hepatobiliary disease, pancreatic disease not suspected (for this analysis liver transplant patients were excluded)

Ip 2011 US Retrospective CT/MRI All patients undergoing CT or MRI for any reason (78% cases the lesion was not suspected)

Laffan 2008 US Retrospective CT on 16-MDCT

Patients referred for abdominal CT that had known or suspected pancreatic disease excluded

Lee 2010 US Retrospective MRI on 1.5-T units

Patients referred for abdominal MRI that had known or suspected pancreatic disease excluded

Matsubara 2011 Japan Retrospective MRI-RARE and MRCP

Patients referred for abdominal MRI/MRCP that had known or suspected pancreatic disease excluded

Zhang 2002 US Retrospective MRI All patients undergoing MRI of abdomen (suspected pancreatic disease NOT excluded)

535

536

537


538

539

540

Patients with a pancreatic cyst identified on cross-sectional imaging should have 541

further imaging with MRI 542

543

544

Our literature review indicates that accurate initial characterization of the pancreatic 545

cyst as benign or malignant is critical, as the rate of progression of premalignant 546

mucinous lesions is very slow in the absence of features that increase malignancy risk. 547

The initial imaging test should be evaluated for its quality and be reviewed by a 548

radiologist experienced in the accurate assessment of pancreatic cystic lesions. 549

Additional imaging may be necessary if the initial test, such as a CT or MR, was 550

performed to evaluate an unrelated symptom. Either a dedicated pancreatic CT or MR 551

may be performed based upon availability and local expertise, but if high quality MR 552

with MR cholangiopancreatography (MRCP) is available, it offers improved delineation 553

of IPMN from other lesions without radiation exposure since it may be able to 554

determine whether there is a communication between the cyst and the pancreatic 555

duct.186 Although there are no prospective studies, ERCP is not recommended for 556

evaluation of pancreatic cysts to define ductal communication as this can be determined 557

with MRCP without subjecting the patient to the risk of pancreatitis. 558

559

560

Patients with a pancreatic cyst with concerning features on MRI should have further 561

evaluation with EUS and FNA 562


563

Although CT and MR imaging are sensitive for detecting cysts, there is a high rate of 564

misdiagnosis of the etiology of the cyst on cross-sectional imaging even when the 565

operator certainty is high.187 The need for additional studies on a routine basis, including 566

EUS, is not supported for most cysts based on the results of this systematic review as 567

studies suggest the risk of invasive malignancy is very low. However, if there are 568

concerning features then the probability of malignancy may increase to an extent that 569

makes further imaging worthwhile. Our analysis suggests that cyst size >3cm (OR = 570

2.97; 95% CI = 1.82 to 4.85), presence of a solid component (OR = 7.73; 95% CI = 3.38 to 571

17.67) increased the probability of a malignant cyst. In addition a dilated pancreatic 572

duct showed a trend towards increasing risk (OR = 2.38; 95% CI = 0.71 to 8.00) that was 573

not statistically significant. The numbers of papers evaluating this risk factor in 574

undifferentiated cysts was small and another review that specifically evaluated IPMNs 575

(ref 30) did find this to be a risk factor so we included dilated pancreatic duct as a risk 576

factor for malignancy. If any of these features are identified on cross-sectional imaging, 577

then further investigation with EUS ± FNA may provide additional information. However, 578

the performance of EUS ± FNA has not been systematically reviewed in this setting. 579

580

Characterization of the Cyst Fluid 581

While EUS morphology alone has limitations regarding definitive diagnosis of 582

pancreatic cysts, aspiration and characterization of cyst fluid contents has demonstrated 583

somewhat greater value in selected patients.21 EUS guided cyst aspiration is well 584


tolerated and safe in the hands of an experienced operator, with a complication rate of 585

1-2% for bleeding, perforation or infection.188 Most experts use periprocedural 586

antibiotics to reduce the risk of infection, and limit the number of needle passes and 587

remove as much fluid as possible to reduce the risk of bacterial inoculation of the 588

fluid.189 Considerations include the size of the lesion since aspirate volume may be very 589

limited for small lesions. An estimate of the cyst fluid volume can be made from cyst size 590

by the formula 4/3πr3, with ‘r’ being the radius of the cyst. 591

EUS can target any associated solid lesion with the cyst as well as apparent mural 592

nodules. Differentiation of such nodules from adherent mucus can be challenging, and 593

the performance of FNA in excluding malignancy in this setting has not been 594

systematically analyzed. 190 Aspirated fluid has been evaluated by cytology and 595

chemical measurements of amylase and tumor markers. Measurement of cyst fluid CEA 596

levels is useful in differentiating mucinous cysts from non-mucinous cysts. As previously 597

discussed, mucinous cysts include IPMNs and MCNs, both of which have malignant 598

potential; whereas non-mucinous cysts, such as serous cysts and pseudocysts have very 599

low or no malignant potential. Unfortunately, the absolute CEA level is not predictive of 600

current or future malignancy risk. A systematic review of 12 studies comprising data 601

from 450 patients found cysts with an amylase concentration of <250 were serous or 602

mucinous (not pseudoscyt [PC]) with a sensitivity of 44% and specificity of 98%. A CEA 603

<5 suggested PC or serous lesion with a 50% sensitivity and 95% specificity while a CEA 604

>800 suggested a mucinous lesion (sensitivity 48%, specificity 98%). A low CA19-9 in the 605

fluid suggested a PC or serous lesion (sensitivity 19%, specificity 98%) 191 but this test is 606


rarely used as its appears no better than CEA. The largest prospective study concluded 607

CEA was most useful. Using receiver operator curve analysis, the optimal cutoff for cyst 608

fluid CEA was determined to be 192ng/ml. This resulted in a sensitivity of 75% with a 609

specificity of 84% for diagnosing a mucinous cyst. EUS morphology and cytology were 610

also evaluated individually and in combination. Although the combination of EUS 611

morphology, cytology, and CEA had a higher sensitivity than CEA alone (91% vs. 75%, 612

respectively), the combination had a lower specificity than CEA alone and had a smaller 613

area under the ROC curve (p < 0.0001). Therefore, the combination of EUS morphology, 614

cytology, and CEA did not improve the ability to differentiate between a mucinous and 615

non-mucinous cyst.192. 616

617

Cytology 618

Cytology revealed malignancy in only 48% of mucinous cancers in the systematic review 619

noted above. A recent systematic review highlights the limitation of EUS-FNA based 620

cytology for differentiating pancreatic cystic lesions, noting major limitations in a 621

literature characterized by significant heterogeneity.193 Combining 11 studies with 622

confirmed histopathology, the pooled sensitivity and specificity for diagnosing mucinous 623

from non-mucinous lesions was 0.63 (95% CI 0.56-0.70) and 0.88 (95% CI 0.83-0.93) 624

respectively. The positive and negative LRs were 4.46 and 0.46.193 These performance 625

characteristics mandate the selective use of EUS with FNA to obtain a specimen if the 626

purpose for FNA is to confirm if the cyst is mucinous with the understanding that a 627

negative cytology has poor negative predictive value. While the performance of cytology 628


in confirming malignancy is reported higher, the studies are limited by selection bias in 629

that only resected lesions are reported. However, it remains reasonable to perform FNA 630

on solid lesions associated with a cyst to determine if a malignancy is present. 631

632

Molecular testing 633

Testing for molecular alterations in pancreatic cyst fluid is currently available and 634

reimbursed by Medicare under certain circumstances. Case series have confirmed 635

malignant cysts have greater number and quality of molecular alterations, but no study 636

has been properly designed to identify how the test performs in predicting outcome 637

with regard need to surgery, surveillance or predicts interventions leading to improved 638

survival. 194-196 This adjunct to FNA may provide value in distinct clinical circumstances, 639

such as confirmation of a serous lesion due to a lack of KRAS or GNAS mutation in a 640

macrocystic serous cystadenoma, but its routine use is not supported at the present 641

time. 642

EUS-FNA provides additional information for characterizing cystic lesions, but in the 643

absence of positive cytology (rare) or CEA levels at the extremes of the scale, rarely 644

provides absolute diagnostic certainty for lesion type or its risk for malignancy. This 645

leads to an approach to monitor the lesions for change in size or morphology, assuming 646

the lack of worrisome features at initial imaging. 647

648

Post-operative mortality and morbidity for patients undergoing surgery for pancreatic 649

cysts 650


Although patients with pancreatic cysts may harbor malignancy, the only approach to 651

ensure the cyst is not malignant is to resect that portion of the pancreas. However, 652

surgery to resect a pancreatic cyst has associated risks of morbidity and mortality and it 653

is important to balance potential benefits with potential harms. There has been no 654

systematic review on the harms of pancreatic surgery related to resection of cysts. 655

Given the limited data, we were unable to conduct a systematic review of this topic; 656

however, a comprehensive search of the literature and data extraction for this technical 657

review was performed. 658

659

We identified 77 studies evaluating 5,790 patients that reported morbidity and/or 660

mortality data related to surgery performed for resecting pancreatic cysts. 9, 16, 32, 45, 47, 49, 661

54, 62, 64, 66, 67, 69, 76, 77, 80, 82, 90, 96, 98, 100, 104, 115-118, 123, 125-127, 130, 131, 137, 144, 151, 154, 155, 158, 159, 171, 662

175, 176, 178, 197-231 The characteristics of the studies are given in table 4. 663

664

There were 74 studies that reported mortality data involving 5,484 patients. There was 665

significant heterogeneity between study mortality rates (Cochran Q = 155 [df = 73], p < 666

0.0001, I2 = 53%; 95% CI = 37% - 64%) with an overall mortality rate of 2.1% (95%CI = 667

1.5% - 2.7%) using a random effects model. There was statistically significant funnel plot 668

asymmetry (Begg-Mazumdar: Kendall's tau b = 0.49; p < 0.0001) suggesting publication 669

bias or other small study effects. This suggests that the overall mortality is probably 670

underestimated as the overall result is driven by small studies with no mortality. 671

Furthermore, the majority of studies are reported from centers of excellence with high 672


volumes of pancreatic surgery where outcomes are likely to be better. The mortality 673

rate nationally in US is therefore likely to be higher than 2.3%. Indeed it is important to 674

note that the SEER database data that contributed 729 US patients to this review 675

reported an overall mortality of 6.6% that was no different from pancreatic surgery for 676

standard adenocarcinoma of the pancreas.202 677

678

There were 49 studies involving 3,392 patients that reported on morbidity after surgery 679

for pancreatic cysts. Where possible we restricted data to that related to major events 680

such as pancreatic fistula formation. If the authors only reported events we assumed 681

that these did not happen in the same patient when the events were rare (<25%) but 682

not when they were common. There was significant heterogeneity between study 683

morbidity rates (Cochran Q = 403 [df = 48], p < 0.0001, I2 = 88%; 95% CI = 85% - 90%) 684

with an overall morbidity rate of 30% (95% CI = 25% - 35%) using a random effects 685

model. However, there was no statistically significant funnel plot asymmetry (Begg-686

Mazumdar: Kendall's tau b = 0.08; p =0.41) suggesting there was no publication bias or 687

other small study effects. There is substantial variation between study results and the 688

reasons for this are not clear. Some will relate to different thresholds for the authors 689

describing and event as a complication or a major complication. 690

691

Table 4. Characteristics of the included studies for evaluating morbidity and mortality related to 692

surgical resection of pancreatic cysts. 693

694

author Country Cyst type Type of surgery performed Type of complications Total in study

El-Hayek 2013 USA serous cystadenomas Cyst enucleation 2; Distal pancreatectomy with or without splenectomy 16, pancreaticoduodenectomy 6 central

2 major complications (1 pancreatic fistula, 1 aspiration pneumonia), 1 minor (wound

25


pancreatectomy 1 infection)

He 2013 USA IPMNs Pancreaticoduodenectomy 91, distal pancreatectomy with splenectomy 39

N/A 130

Winner 2013 USA IPMNs Pancreaticoduodenectomy 68, distal pancreatectomies 54; 14 were completed laparoscopically 14, 5 converted to open operations. Central pancreatectomies 25, enucleations for benign disease 2

N/A 183

Hwang 2012 Korea serous cystadenoma open pancreatectomy 27, laparoscopic distal pancreatectomy 11

Total 8 Pancreatic fistular 5, delayed gastric emptying 1, pneumonia with AMI 1, and wound failure 1

38

DeMoor 2012 Belgium IPMNs pancreaticoduodenectomy 12, pyloric preserving pancreaticoduodenectomy 30, distal pancreatectomy 7, central pancreatectomy 5, totalisation 1

Total 24 bleeding 3, pancreatic 5 and biliary fistulars 3, collections 6, pulmonary complications 3, wound infection 1, morphinic intoxication 1, spesis 1, gastrojejunal anastomotic ulceration 1

55

Okabayashi 2013

Japan IPMNs total pancreatectomy 6; pancreaticoduodenectomy 58, distal pancreatectomy 34, minimal invasive surgery 10

N/A 100

de Castro 2011

The Netherlands

Serous Cystic Neoplasm 32; Mucinous Cystic Neoplasms 30; IPMNs 26

Distal pancreatectomy 39; Pylorus-preserving pancreatoduodenectomy 41; Resection of uncinate process 1; Kausch-Whipple Procedure 7; Total pancreatectomy 6; Central pancreatectomy 6

Total 39. Surgical 27 (pancreaticojejunostomy leakage 4, hepatico-jejunostomy leakage 2, bleeding 4, abscess 6, wound infection 2, delayed gastric emptying 6, other 9), systemic 15 (pulmonal 9, renal 6)

88

Lahat 2011 Isreal Mucinous tumors 46, IPMT 45, serous cystic tumor 11, cystic islet cell tumor 4, pseudopapillary tumor 10

Whipple operation 46, distal pancreatectomy 64, total pancreatectomy 6

Total 26 Septic complications 17, (of whom 5 had an intra-abdominal abscess), pancreatic fistula 7, reoperated due to bleeding 2

116

Fujii 2011 Japan IPMNs 84, Serous cyst neoplasm 8 (out of 132 surgical patients)

pancreatic head resection with segmental duodenectomy (PHRSD) 77, pylorus-preserving pancreatoduodenectomy (PPPD) 55

55 for all patients (pancreatic fistula 45, delayed gastric emptying 29)

132

Ferrone 2011 USA MCN 35, IPMN 22, serous cystadenomas 23, simple cyst 5

Warshaw Operation for distal pancreatectomy With Preservation of the Spleen

N/A 85

Turrini 2011 USA and France

IPMNs enucleation 7 (IPMN EN), pancreaticoduodenectomy (PD) 100 (IPMN PD) with 17 of these radiographically amenable to EN (PDEN)

Total 39 pancreatic fistula 28, bleeding 2, cardiovascular/pulmonary 8, gastric emptying 6, biliary leak 3, wound infection 4, fascia dehiscence 2, other 6

107

Yopp 2011 USA IPMN with an associated invasive carcinoma

Pancreaticoduodenectomy 42 (10 of these patients undergoing a pylorus-preserving procedure, 32 standard whipple), distal

“major complication” 5, no detailed information

59


pancreatectomy with or without splenectomy 11; total or subtotal pancreatectomy 6

Cone 2011 USA IPMNs Pancreaticoduodenectomy 37, distal pancreatectomy 14, total pancreatectomy 8, bypass 1

N/A 60

Hwang 2011 Korea IPMNs pancreaticoduodenectomy (whipple 32, pylorus-preserving pancreatoduodenectomy 76) 108, total pancreatectomy 5, distal pancreatectomy 65, Spleen preserving DP 20, subtotal pancreatectomy 5, hepatopancreatoduodenectomy 1, median pancreatectomy 12, duodenum-preserving resection of the head of the pancreas 4, pancreatic head resection with segmental duodenectomy 3, excision 14

N/A 237

Turrini 2010 USA Invasive IPMN pancreatoduodenectomy (PD) 62 , distal pancreatectomy (DP) 19, total pancreatectomy (TP) 17

Total 43, no detailed information 98

Lubezky 2010 Isreal IPMNs Pancreaticoduodenectomy 32, subtotal distal pancreatectomy 16, total pancreatectomy 13, palliative bypass 1

Total 31 Major bleeding requiring reoperation 1, pancreatic fistula 6, delayed gastric emptying 6, intra-abdominal collection 6, pseudomembranous colitis 4, pulmonary embolus 5, wound dehiscence or infection 4; pneumonia 3

62

Fan 2010 China IPMNs pancreaticoduodenectomy 23, distal pancreatectomy 14, total pancretectomy 3


Wasif 2010 USA Invasive IPMNs Whipple 541, distal pancreatectomy 109, total pancreatectomy 79

N/A 729

Cheon 2010 Korea IPMN total pancreatectomy 1, extended pancreatoduodenectomy 4, pancreatoduodenectomy 19, medial pancreatectomy 2, distal pancreatectomy 14

N/A 40

Coelho 2010 Brazil Serous cystic tumors 10, mucinous cystic tumors 10, IPMN 4, solid pseudopapillary tumors or Frantz tumor 3

only laparotomy with tumor biopsy 2, cholecystectomy with Roux-en-Y hepaticojejunostomy for jaundice treatment 1, pancreatoduodenectomy 6, partial pancreatectomy 18

Total 7. Pancreatic fistula 5, wound infection 3, incisional hernia 3, pneumonia 1, gastroenteroanastomosis stricture 1, diabetes mellitus 1; necrotizing acute pancreatitis 1

27

Partelli 2010 Italy Invasive intraductal papillary carcinoma

pancreaticoduodenectomy (PD) 69, a distal pancreatectomy (DP) 14 , a total pancreatectomy (TP) 19, a middle pancreatectomy (MP) 2


Correa- USA Cystic neoplasms. In 136 For early surgery, distal pancreatectomy N/A 159


Gallego 2010 early surgical patient: IPMN 61, mucinous cystic neoplasm 25, serous cystadenoma22, solid pseudopapillary neoplasm 9, cystic pancreatic endocrine neoplasm 8, unclear 6 , others 5

60, pancreaticoduodenectomy 56, and a middle pancreatectomy or other atypical resection 20. or delayed surgery, Pancreaticoduodenectomy 11, distal pancreatectomy 11, and 1 middle pancreatectomy 1

Sachs 2009 USA Some of them were cystic lesions: IPMN 19, solid pseudopapillay tumor 2, mucinous cystadenoma 5, serous cystadenoma 15, simple cyst 2, benign multiloculated cyst 2, pseudocyst 2

Distal/subtotal pancreatectomy 42, Whipple 32, central pancreatectomy 7, cyst enucleation 5, total pancreatectomy 3, diagnostic laparotomy/laparoscopy 7, ampullectomy 4, partial gastrectomy 3, retroperitoneal cyst excision 3, excision mass 2, diversion 2

N/A 110

Gumbs 2008 Frances noninvasive IPMN laparoscopically 9, open techniques 13 (laparoscopic duodenopancreatectomy 3, open group 5; total pancreatectomy laparoscopically 2)

Total 14 In laparoscopic: pancreatic fistula 3, postoperative hemorrhage 1, upper GIB 1; In open group: pancreatic fistula 3, postopeative hemorrhage 1, intnraadbominal abscess 3, necrotizing 1, urinary tract infection 1, gastric volvulus 1, billary fistula 1, wound infection 1

22

Schnelldorfer 2008

USA IPMNs partial pancreatectomy 168, total pancreatectomy 40

In-hospital morbidity 77, no detailed information

208

Crippa 2008 Italy Mucinous cystic neoplasms (MCNs)

Distal pancreatic resection 153, (Standard distal pancreatectomy (DP) with splenectomy 119; spleen-preserving DP 28, an extended DP 6); pancreaticoduodenectomies 4, atypical resections (enucleations 3, middle pancreatectomies 2) 5, total pancreatectomy for a large MCN in 1. laparoscopic DP 14.

Total 81. Abdominal complications 54, overall pancreatic fistula 39, Grade B–C pancreatic fistula 15, Intra-abdominal collections/abscess 19, Extra-abdominal complications 39

163

Niedergethmann 2008

Germany IPMNs pylorus-preserving partial pancreaticoduodenectomy (PPPD)/whipple 78, distal pancreatectomy 14, total pancreatectomy 5

Total 55. Leakage pancreatico-jejunostomy 4, leakage hepatico-jejunostomy 2, bleding 8, intra-abdominal Abscess 4, postoperative Pancreatitis 7, delayed gastric emptying 11

97

Nagai 2008 Japan IPMNs pylorus-preserving pancreatoduodenectomy (PPPD) 29, pancreatoduodenectomy (PD) 8 , distal pancreatectomy 20 (including 1 spleen-preserving distal pancreatectomy), total pancreatectomy 10, partial resection of the pancreas 4 , and middle segmental pancreatectomy 1

Total 18. GI anastomotic leakage 1, Pancreatic fistula 4, Intraabdominal abscess 1, Pancreatitis 1, Pancreatic pseudocyst 2, Anastomotic stenosis 2, Cholangitis 2, Delayed gastric emptying 3,

72


Ascites 1, Diarrhea 2, Pneumonia 2

Rodriguez 2007

Italy IPMNs pancreati-coduodenectomies (with pylorus preservation in 28 cases) 97, distal pancreatectomies 29 (14 with splenic preservation), middle pancreatectomies 15, total pancreatectomies 2, enucleation 1, combined pancreaticoduo-denectomy and distal pancreatectomy 1

Total 74 Abdominal complications 39 (Pancreatic fistula 25, Biliary fistula 4, Delayed gastric emptying 9, Intrabdominal collections/ abscess 13); Nonsurgical complications 45

145

Galanis 2007 USA serous cystic Neoplasms of the Pancreas

distal pancreatectomy 75, pancreaticoduodenectomy 65, central pancreatectomy 9, local resection or enucleation 5, total pancreatectomy 4

29 Major complications (defined as defined as pancreatic fistula or anastomotic leak, postoperative bleed, retained operative material, or death). (also reported 52 minor complications)

158

Nakao 2007 Spain IPMNs pancreatic head resection with segmental duodenectomy (PHRSD; Nakao’s technique) 35, pylorus-preserving (pp)-Whipple 32

Total 31 (in PHRSD, 4 pancreatic fistula, 5 delayed gastric emptying, 1 pleural effusions 1 pneumonia, 2 postoperative diabetes mellitus; in pp-Whipple, 7 pancreatic fistula, 10 delayed gastric emptying, 2 postoperative diabetes mellitus)

67

White 2007 USA noninvasive IPMN pancreaticoduodenectom 50 (standard 38, pylorus-preserving 12); distal or subtotal pancreatectomy 23 (splenic-preserving 15, with splenectomy 8); total pancreatectomy 2, enucleation 3. All patients underwent complete gross resection.

N/A 78

Hardacre 2007

USA serous cystic neoplasms 16, mucinous cystic neoplasms (MCNs) 7, IPMNs 37

Pylorus-preserving pancreaticduodenectomy 15; Whipple 8, Distal pancreatectomy and splenectomy 23, Distal pancreatectomy 4, Total pancreatectomy 5, Enucleation 2, Central pancreatectomy 1, Laparoscopic distal pancreatectomy 2

Total 33 Overall pancreatic fistula by operation 8, Delayed gastric emptying by operation 2, Readmission 8 , Wound infection 6, Abscess 6, Urinary tract infection 5, Clostridium difficile colitis 4, Atrial fibrillation 3, Pneumonia 2, Pneumothorax 2, Chylous ascites 1, Reintubation 1, Enterocutaneous fistula 1

60

Allendorf 2007

USA serous cystadenoma 10, mucinous cystadenoma 9, hemorrhagic cyst 2, a solid cystic pseudopapillary tumor of the pancreas (Frantz’s tumor 1, IPMN 1, neuroendocrine neoplasm 2, lymphangioma 1

central pancreatectomy with pancreaticogastrostomy resonstruction

Total 8 Developed fluid collections in the resection bed consistent with a pancreatic leak 2, developed pancreatitis in the remnant distal gland with a peripancreatic phlegmon 2, minor complications: urinary tract infections 2, pneumonia n = 1, clostridium difficile colitis 1

26


Goh 2006 Singapore serous cystic neoplasms (SCN) 33, mucinous cystic neoplasms (MCNs) 21, IPMN 21, solid pseudopapillary neoplasm (SPPN) 14, cystic pancreatic endocrine neoplasms (PEN) 5, ductal adenocarcinoma 5, lymphangioma 2, nonneoplastic cysts 8

Total pancreatectomy 5, Whipple’s 22, minor subtotal 13, minor distal 64, minor enucleation 5

Total 34 Most common complications were pancreatic fistula 11, intra-abdominal abscess or infected collection 11, delayed gastric emptying 4

109

Kang 2006 Korea Solid Pseudopapillary Tumor

pylorus-preserving pancreaticoduodenectomy (PPPD) 5; pancreaticoduodenectomy (PD) 5; Distal pancreatectomy with splenectomy 17; Enucleation 5

N/A 33

Carboni 2006 Italy Serous cystadenomas 13, mucinous cystic neoplasms (MCNs) 12 (9 mucinous cystadenomas, 3 mucinous cystadenocarcinomas), IPMN 4 , solid pseudopapillary neoplasm 1

Curative resections 29 (pancreaticoduodenectomy (PD) 10, 3 with pylorus preservation, distal pancreatectomy (DP) 3, 1 with spllen preservation, Median pancreatectomy (MP) 5, 1 with a concurrent transverse colectomy, TP 1, enucleation (En) 9, duodenum-preserving pancreatic head resection (DPPHR) 1. 2 PD and 1 En were performed laparoscopically); explorative laparotomy (EL) with biopsy 1

Total 12 Pancreatic fistula occurred in 7, delayed hemorrhage in 2, biliary fistula 2, abscess 1, delayed gastric emptying 1, enteric fistula 1

30

Raut 2006 USA IPMNs Pancreaticoduodenectomy 23, Distal pancreatectomy 4, Total pancreatectomy 8 (of them, 15 patients had one or more adjuvant therapy)

N/A 35

Lee 2005 Korea IPMNs Whipple’s operation 17, pylorus preserving pancreatico-duodenectomy 15, total pancreatectomy 11, partial or distal pancreatectomy 13

N/A 56

Sohn 2004 USA IPMNs Pancreaticoduodenectomy 96, total pancreatectomy 21, distal pancreatectomy 16, and central pancreatic resection 3

Total 47 Delayed gastric emptying 18, Pancreatic fistula 15, Intraabdominal abscess 8, Bile leak 6, Wound infection 4 , Pancreatitis 2, Pneumonia 3, Cholangitis 1

136

Salvia 2004 USA IPMNs pancreatoduodenectomy 88, distal pancreatectomy 24, total pancreatectomy 26, middle pancreatectomy 2

Pancreatic fistula 22; Biliary fistula 1; Delayed gastric emptying 11 ; Abdominal collections 9

140

D'Angelica 2004

USA IPMNs total pancreatectomy 6, partial pancreatectomy 56, unresectable 1

Total 31 Majority of complications were gastrointestinal or anastomotic (40%) and infectious (18%). Urinary, cardiovascular, and hemorrhagic complications

63


accounted for 13%, 10%, and 10% of all complications, respectively

Tollefson 2003

USA IPMNs total pancreatectomy 8, pancreatoduodenectomy 7, distal pancreatectomy 1. 5 patients had unresectable disease; 4 of these patients had biliary and/or gastric diversion for symptomatic relief, and 1 underwent biopsy alone

N/A 21

Kiely 2003 USA mucinous cystic neoplasms 16, serous cystadenomas 10, and cystic islet cell tumors 4

Enucleation 11, pancreatoduodenectomy 8, distal pancreatectomy 11

Total 15 enucleation group: fistulas 3, partial small bowel obstruction 1; resection group: pancreatic fistulas 5, abdominal abscess, gastric outlet obstruction, pneumonia, and a urinary tract infection in 4; 2 late complications (small bowel obstruction, pseudocyst)

30

Sheehan 2003 USA serous cystic neoplasms 26, mucinous cystic neoplasms 20 (15 cystadenoma, 5 cystadenocarcinom) , solid pseudopapillary neoplasms 9, and IPMN 18

Whipple procedures 20, distal pancreatectomies 43 (2 without splenectomy), central pancreatectomies 5, total pancreatectomies 2, biliary bypass for a serous cystadenoma (too large for resection) 1

Total 20 pancreatic fistula 7, 2 intra-abdominal abscess, 1 wound infection, 1 hemorrhaged from the cut end, 7 had miscellaneous complications (stroke, deep venous thrombosis, urinary tract infection, delayed gastric emptying, and aspiration pneumonia)

73

Harper 2002 USA serous cystadenoma 14, mucinous cystadenoma 11, mucinous cystadenocarcinoma 5

pylorus sparing or standard pancreaticoduodenectomy 14, distal pancreatectomy with or without splenectomy 15, total pancreatectomy 1.

Total 8 Postoperative pancreatitis 1, new-onset diabetes mellitus 1, wound infection 1, erosive gastritis 1, pancreatic fistular 3, prolonged ileus 1

30

Walsh 2002 USA mucinous neoplasms 18 , serous neoplasms 8, ductal or neuroendocrine carcinomas 4, pseudocysts 3, other 2

distal pancreatectomy 20, pylorus-preserving pancreaticoduodenectomy 9, internal cyst drainage 2, cyst excision without pancreatectomy 3, transduodenal biopsy 1

N/A 35

Maire 2002 France IPMNs pancreaticoduodenectomy 46, distal 14, total pancreatectomy 11, segmentary pancreatectomy 2

Total 18 infection 9, pancreatic fistula 4, haemorrhage 3, abdominal occlusion 2

73

Kalil 2002 Brazil serous cystadenoma 15, mucinous cystadenoma 4, cystadenocarcinoma2

Cephalic gastroduo-denopancreatectomy 4, bodyand tail pancreatectomy 11, only tail pancreatectomy 2, enucleation 2. Internal drainage through cystogastrostomy or cystojejunostomy 3

Total 3 respiratory tract infection, surgical wound infection, large abdominal abscess

21

Sugiura 2002 Japan IPMNs duodenum-preserving pancreatic head resection 12, distal pancreatectomy 8, segmental pancreatectomy 6, conventional pancreaticoduodenectomy 4

Total 8 pancreatic fistula 7, necrosis of the preserved bile due 1

30


Adsay 2002 USA IPMNs Pancreatoduodenectomy 23, distal pancreatectomy 3, total pancreatectomy 2

N/A 28

Tobi 2001 USA IPMNs Whipple’s procedure and modified variants thereof 33, distal 10, total 6, segmental 1

N/A 50

Kanazumi 2001

Japan IPMNs pancreaticoduodenectomies (Whipple's procedure) 10, pylorus-preserving pancreaticoduodenectomies 10, pancreatic head resections with segmental duodenectomies 13, distal pancreatectomies 17, segmental resections of the pancreas 9, duodenum-preserving pancreatic head resections 2, total pancreatectomy 1

Total 2 Major complications: necrosis of the common bile duct and stenosis of that duct due to ischemia after DPPHR

62

Falconi 2001 Italy IPMNs pancreaticoduodenectomy 33 (Whipple resection 15, extended Whipple resection 2, pylorus-preserving pancreaticoduodenectomy 15), splenopancreatectomy 10, total pancreatectomy 5, middle pancreatectomy 3

Total 19 (included Pancreatic fistula 14)

51

Formentini 2000

Germany serous cystic neoplasms (SCN) (serous cystadenoma 22, serous cystadenocarcinoma 3)

Pyloous-preserving duodenopancreatectomy, subtotal left pancreatectomy with splenectomy or segmental pancreatic resection. Concomitant resection of the left adrenal gland in 1

Total 3 (lymph node metastasis, invasion, infiltration of the adjacent adrenal gland, two associated with ductal adenocarcinoma)

25

Cuillerier 2000

Belgium and Frances

IPMNs partial pancreatectomy 35, total pancreatectomy 10

N/A 45

Paye 2000 Frances IPMNs All patients but one underwent a partial pancreatic resection

Total 18 Pancreatic fistula 6; Pancreatitis of remnant pancreas 2 ; Hemorrhage on pancreatic anastomosis 1 ; Transient gastric emptying impairment 2; Small bowel obstruction 1; Biliary fistula (from the cystic duct) 1; Acute cholangitis 2 ; Regressive portal vein thrombosis 1; Pulmonary embolism 1; Transient ischemic cerebral stroke 1

41

Colovic 1999 Serbia Serous cystadenomas 6, mucinous cystadenomas 16

distal pancreatectomy splenectomy 8, splenectomy excision 2, distal pancreatectomy 2, excision 6, distal ancreatectomy and splenectomy 1, resection of tail, tumor excision and splenectomy 1, distal pancreatectomy and distalsplenectomy 1, pancreatectomy and splenectomy 1

Total 4 left subphrenic abscess and left pleyral effusion 1, transient pancreatic fistula 1, malignant alteration 2, melena 1

22

Horvath 1999 USA serous cystadenomas 12, mucinous cystadenomas

curative resections 23, palliative resections 2 (partial pancreatectomy 1;

Total 5 major complications (abscess, bleeding, erosive

25


4, mucinous cystadenocarcinomas 3, intraductal papillary cystic neoplasms 5, serous cystadenocarcinoma 1

distal pancreatectomy 4, distal pancreatectomy with splenectomy 9; pancreatoduodenectomy 11)

gastritis) no pancreatic fistulas, delayed gastric emptying 1, severe erosive gastritis 1 (also reported 5 minor complications- mild pancreatitis, pneumonia, vocal cord injury, diarrhea/ dehydration, delayed gastric emptying)

Wilentz 1999 USA mucinous cystic neoplasms

distal pancreatectomy 32, Whipple resection 26, complete pancreatectomy 2

N/A 60

Paal 1999 USA IPMNs complete surgical resection 7, Whipple procedure 13, biopsy only 2

N/A 22

Siech 1998 Germany serous cystadenoma 30, mucinous cystadenoma 21

Segmental resection (including duodenum-preserving pancreatic head resection) 7; oncological resection 44

Pancreatic fistula 3, sepsis 3, pulmonary complications 4

51

Sugiyama 1998

Japan IPMNs All 41 patients underwent exploratory laparotomy: Tumor resection 39, Total pancreatectomy 5, Pylorus-preserving total pancreatectomy 4, Pancreatoduodenectomy 5, Pylorus-preserving pancreatoduodenectomy 1 3, Distal pancreatectomy 4, Duodenum-preserving pancreatic head resection 3, Spleen-preserving distal pancreatectomy 2, Segmental resection of the pancreatic body 1, Tumor enucleation 2, Bypass operation 2 (Combined resection: Portal vein 3, Stomach 1, Transverse colon 1, Right kidney 1)

Two major postoperative complications occurred: leakage of the pancreatogastrostomy after a duodenum-preserving pancreatic head resection in one case and and a pancreatic fistula after tumor enucleation in another)

41

Talamini 1998 USA mucinous cystadenoma pancreatoduodenectomy or distal pancreatectomy 26. enucleation 10 (4 underwent another concomitant abdominal procedure)

N/A 26

Yasuda 1998 Japan mucin-producing pancreatic tumors 24 (intraductal papillary carcinoma 13, mucinous cystadenocarcinoma 5, intraductal papillary adenoma 3, mucinous cystadenoma 3)

total pancreatectomy 4, pancreateicoduodenctomy (Whipple's procedure) 1, Whipple's procedure with a tranverse colectomy 1, pylorus-preserving pancreaticoduodenectomy (PPPD) 13, duodenum-preserving pancreatic head resection DPPHR 1, resection of the posterior segment of the pancreas (posterior segmentectomy) 1, medial segment of the pancreas 1

Total 2 developed transient duodenal stenosis after DPPHR 1, mucus leaked from the pancreatic duct in the operating filed during pancreatectomy (IPC after PPPD) 1

23

Martin 1998 UK serous cystadenoma (SCA) 6, mucinous cystic adenoma (MCA) 3, mucinous cystadenocarcinoma (MCAC) 10, ductal adenocarcinoma with cystic degeneration 1,

Whipple resection 4, distal pancreatectomy and splenectomy 14, palliative procedures 3

N/A 21


cystic islet cell tumor 1

Cellier 1998 Frances IPMNs partial pancreatectomy 37, Total pancreatectomy 10

N/A 47

Fukushima 1997

Japan intraductal papillary tumor (IDPT) 28, mucinous cystic tumor (MCT) 10

No detailed information for “surgical intervention”

N/A 38

Azar 1996 Belgium IPMNs pancreaticoduodenal resection 17, Caudal and segmental pancreatectomies 6, palliative surgery 1, total pancreatectomy was not performed.

N/A 24

Brenin 1995 USA cystadenocarcinoma 7, serous cystadenoma 10, mucinous cystadenoma 5

Distal pancreatectomy 10, Bypass 4, Open biopsy only 3, Pancreatoduodenectomy 3, Cystenterostomy 1, Enucleation 1

Total 4 pancreaticocutaneous fistula 1, biliary fistula that required reoperation 1, postoperative lower-extremity deep venous hrombosis 4, postoperative pneumonia 3

22

Sessa 1994 Italy IPMNs Whipple resection for tumours involving the pancreas head or head-body and distal pancreatectomy for tumours in the body tail (no other details)

N/A 26

Grieshop 1994

USA mucinous cystic neoplasm-benign 6, mucinous cystic neoplasm-malignant 6, serous cystadenoma 5, ductal adenocarcinoma with cystic degeneration 2, papillary cystic neoplasm 1, intra-ductal mucin hypersecreting neoplasm 1

distal pancreatectomies 14, pancreaticoduodenectomies 5, total pancreatectomy 1

Total 11 Enteric fistula 3, abdominal abscess 3, delayed gastric emptying 2, biliary fistula 1, pseudocyst 1, hemorrhage 1, wound infection 1, ischemic bowel 1, pancreatic fistula 1, pancreatic fistula 1, wound dehiscence 1, fluid collection 1

21

Delcore 1992 USA serous cystadenoma 6, mucinous cystadenomas 2, mucinous cystadenocarcinomas 13

All patients underwent exploratory laparotomy, Benign: excision 2, distal pancreatectomy 5, or pancreatoduodenectomy 1; Malignant: pancreatoduodenectomy 4, distal 4 pancreatectomy, total pancreatectomy 2; palliative procedures 3

no postoperative complications 21

Talamini 1992 USA serous (microcystic) cystadenoma 9, mutinous cystadenoma 14; mutinous cystadenocarcinoma 12; mucin-producing adenocarcinoma 9; adenocarcinoma with an associated pseudocyst or simple cyst 6

Pancreatoduodenectomy 18, Distal pancreatectomy 16 , Palliative bypass 7, Biopsy only 6, Total pancreatectomy 2 , Enucleation 1. 47 patients underwent laparotomy

Total 17 Delayed gastric emptying 8, A pancreatic fistula 5, antibiotic-associated diarrhea 2; wound infection 2, pancreatitis 1, and enterocutaneous fistula 1

50

Pyke 1992 USA serous cystadenoma Radical pancreatoduodenectomy 11; Distal pancreatectomy 17; Enucleation 8; Bypass 2; Biopsy2

Total 15 Pancreatic fistulas developed 6, postoperative bile leak required revision hepaticojejunostomy 1,

40


Other surgical problems requiring reoperation included a revision gastrojejunostomy for gastric stasis, cystoenteric drainage of a postoperative pancreatic pseudocyst, revision of a hepatico-jejunostomy for stenosis, and conversion of an enucleated lesion in the head of the pancreas to a pancreatoduodenectomy for postoperative pancreatitis

Warshaw 1990

USA serous cystic adenomas 18, benign mucinous cystic neoplasms 15, mucinous cystadenocarcinomas 27, papillary cystic tumors 3, cystic islet cell tumors 2, mucinous ductal ectasia 2

distal pancreatectomy 25 patients, by proximal resection 29, by total pancreatectomy 1, explorations with biopsy of cancer unresectable because of local extension of distant metastases 10

N/A 67

Katoh 1989 Japan cystadenoma 26 (serous cystadenoma 17, mucinous adenoma 9), cystadenocarcinoma 19

Cystadenoma: Whipple’s operation 4, distal pancreatectomy 13, total pancreatectomy 3, near total pancreatectomy 2, biopsy with or without bypass 3; autopsy 1, cystadenocarcinoma: Whipple’s operation 6, distal pancreatectomy 5, near total pancreatectomy 1, biopsy with or without bypass 7

N/A 45

695

N/A = not applicable 696

697


698

Patients with pancreatic cysts that are surgical candidates but do not have features 699

that would warrant resection should have surveillance with MRI once per year 700

There are no cohort studies that have analyzed the impact of surveillance and 701

subsequent surgical intervention on the risk of pancreatic cancer among patients with 702

cystic lesions. Given the very low rate of overall malignancy development, it is clear that 703

surveillance imaging in patients should be limited to those who can benefit from major 704

pancreatic resections should the lesion develop cancer. Given the mortality and 705

morbidity of pancreatic resections, this careful determination should be assessed for 706

each patient. Patients who are not surgical candidates because of age or severe 707

comorbidities should not undergo surveillance. However, if the patient is reasonably fit 708

then our review suggest surveillance once per year or once every two years may be 709

reasonable although the evidence base for this is limited. 710

711

The imaging modality and frequency of surveillance imaging has also not been subjected 712

to informative studies in the literature. Current guidelines suggest annual (or more 713

frequent) surveillance, particularly for the lesions near a size cut off associated with 714

malignancy (3cm).6 These recommendations are not evidence based, and should be 715

individualized for every patient. While the literature contains reports of small lesions 716

harboring malignancy, the vast number of these lesions mandates a rational approach 717

to patient care. As cancer is rarely found in resected patients, these size 718


recommendations are likely to be modified upward, particularly as patients’ age and the 719

mortality benefit of surgery remains undefined. 720

721

MRI in expert hands, while more costly than CT and EUS, offers lack of radiation and is 722

an ideal surveillance modality. EUS can be used in those with claustrophobia who 723

require anesthesia for MRI as they are generally equivalent (and can be complementary) 724

and similarly invasive under these circumstances. 725

726

Incidence of invasive malignancy in follow-up of pancreatic cysts 727

International consensus guidelines on the management of pancreatic cysts have 728

suggested follow up of cysts that do not have concerning features. 6, 111, 232 The 729

frequency of follow up depends on the size of the cyst. Guidelines generally do not 730

address whether surveillance can be discontinued at any stage. This has important 731

implications as this could reduce costs of surveillance of pancreatic cysts if this is not a 732

life long commitment. However, it is important to evaluate the risk of malignant 733

progression for pancreatic cysts in determining the interval and duration of surveillance. 734

We have suggested in that the risk of developing malignancy is low based on population 735

data with a lifetime risk of less than 1% provided the cyst has no concerning features at 736

presentation. It remains unclear what the overall risk of malignancy is in cysts 737

identified on imaging but not resected. We conducted a systematic review of the 738

literature to answer this question. 739

740


The search strategy identified 102 potentially relevant papers of which 62 were eligible 741

for this systematic review 16, 32, 45, 47, 49, 54, 64, 66, 67, 76, 77, 80, 82, 90, 96, 98, 100, 104, 115-118, 123, 125-127, 742

137, 144, 151, 154, 155, 158, 171, 176, 178, 199-225 Overall there were 154 invasive malignancies in 743

10,496 patients with a median of 34,460 patient years of follow up. Studies were from 744

Japan, Italy, US, Korea, France, UK and Israel and all were retrospective case series. The 745

characteristics of the patients are summarized in table 5. 746

747

Follow up of suspected IPMNs on imaging 748

There were 37 case series predominantly from Japan and Italy that evaluated suspected 749

IPMNs on imaging studies. 32, 45, 47, 49, 54, 64, 76, 77, 80, 82, 90, 96, 98, 100, 104, 115-118, 144, 151, 154, 155, 158, 750

171, 176, 199-212 Overall 112 invasive cancers were observed in 3,980 patients during 14,830 751

patient years of follow up. The proportion of patients developing invasive neoplasia was 752

2.8% (95% CI = 1.8 to 4.0%) with statistically significant heterogeneity (I2 = 74%, Cocrhan 753

Q = 136 [df = 36], p<0.0001). There was also funnel plot asymmetry. Egger’s bias = 1.33; 754

95% CI = 0.70 - 1.96, p= 0.0001) with smaller studies showing a greater proportion with 755

invasive cancer suggesting publication bias or other small study effects. The proportion 756

of cases developing invasive malignancy is estimated at 0.72% per year (95% CI = 0.48 -757

1.08). This is higher than predicted from the population based data but our analysis 758

included all pancreatic cysts not just suspected IPMNs and this may explain the higher 759

risk seen in this review of the literature. 760

761

762


Follow up of suspected serous cystic neoplasms seen on imaging 763

There were 3 case series from Italy and Canada that evaluated pancreatic cystic lesion 764

that were thought to be serous cystic lesions on imaging. 223-225 Overall there were no 765

invasive cancers were observed in 276 patients during 1,551 patient years of follow up. 766

767

This systematic review suggests the overall rate of conversion to invasive cancer is low 768

and for pancreatic cysts in general is approximately 0.24% per year. The rate of 769

conversion is highest for IPMN but this may be an overestimate as the outliers with the 770

highest conversion rates 45, 104, 116, 202 were somewhat unclear on whether initial cancer 771

cases had been excluded from the cohort or were retrospective and designed to show 772

risk factors of neoplastic progression where we suspect that the case series were 773

enriched with cancer cases to ensure their analyses had sufficient power. 774

775

The limitations of this systematic review are related to the quality of the underlying 776

studies. All were retrospective case series and some presented information whereby it 777

was unclear which patients had invasive malignancy. Whenever this was unclear worst 778

case scenario assumptions were made. The follow up of patients was often poorly 779

described and often the median follow up time was given and for calculation purposes 780

we assumed this was similar to the mean. 781

782


783

Table 5. Summary of eligible studies used to evaluate incidence of malignancy in cysts that are 784

followed by imaging 785

786

Ref Country Patients Diagnostic method

5 Japan Data from clinical records and imaging studies that were collected prospectively. During 2001–2009, 167 consecutive patients with IPMNs underwent EUS, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). The 102 patients whose branch duct IPMNs lacked mural nodules/symptoms and thus did not qualify for resection were followed up by semiannual EUS and annual ultrasonography, CT, and MRI.

With all of the imaging modalities, IPMN was defined as a dilation of the MPD or its branches. To exclude simple cysts, a lesion was suspected to be an IPMN if it was more than 5mm in diameter. IPMN was classified from imaging studies as either main duct or branch duct IPMN according to the new Fukuoka criteria

6 Italy 155 patients with multifocal IPMN of the side branches were examined with MRI and MRCP. Follow-up period shorter than 12 months (n=33) and those with a diagnosis of multifocal IPMN of the side branches without any follow-up (n=14) were excluded from the study

MRI/MRCP- with ≥2 dilated side branches involving any site of the parenchyma; presence of communication with the main pancreatic duct and previous investigations by MRI/MRCP within at least six months

7 Japan Consecutive follow-up of 20 patients with “high-risk stigmata” MPD-IPMN, in whom the diameter of the MPD was > 10 mm, branch duct was < 5 mm, and who underwent clinical follow up for >= 2 years. No past history of pancreatitis

: (i) diameter of MPD was > 10 mm in MRCP or ERCP or EUS, and BD was < 5 mm; (ii) another lesion of MPD obstruction such as pancreatic cancer or pancreatic stone was excluded; and (iii) mucus was identified by ERCP or duodenoscopy, or mucus-like echo detected by EUS.

8 Italy Meeting criteria (Sendai-positive) and not operated. Thirty-five patients enrolled: 40% main-duct, 60% branch-duct IPMN (19 duled out for surgery due to comorbidities, 7 because aged>80, 9 refused surgery)

1. histological diagnosis obtained by EUS fine-needle aspiration or biopsy, 2, cytological diagnosis obtained by EUS FNA, based on the accepted criteria: presence of one or several main pancreatic duct and/or branch duct dilatations and/or pancreatic cystic lesions communicating with pancreatic ducts at CTs, MRCP with


Secretin stimulation, ERCP or EUS,

9 Italy 234 patients with IPMN With a median follow-up of 39.5 months (range, 12-72),

Based on computer file, from the radiological folder and from the MRCP report

10 Japan 142 patients who underwent contrast-enhanced endoscopic ultrasonography for initial diagnosis from January 2001 with more than 12 months of follow-up.

Asymptomatic BD-IPMNs on EUS without any dilatation of the MPD and obvious mural nodules

11 France 53 BD-IPMN had no criteria suggestive of malignancy 60 months after diagnosis and were followed-up beyond that time in a prospective surveillance programme

Based on the presence of one or several BD dilatation(s) or pancreatic cystic lesions clearly communicating with pancreatic ducts seen at CT scan, MRCP, ERCP, or EUS. Confirmed by EUS-FNA or EUS-FNAB

12 France Forty-nine patients with nonoperated BD-IPMN who displayed a low probability for malignancy

Based on radiological criteria whereby unilocular or multilocular lesions, with a grapelike appearance that communicate with MPD; without signs of malignancy; using a minimum of 2 of the conducted morphological examinations (CT, MRCP, EUS, or ERCP), in additionto the extrusion of mucus via the major or minor papilla, or from cytological data

13 US 194 patients with BD-IPMNs

By CT or MRI or EUS or ERCP showed uni or multi-locular lesions with a grape-like appearance communicating with pancreatic ducts, but without any dilatation of the main PD more than 6 mm.

14 Japan 195 patients with IPMNs Ultrasonography,EUS,IDUS, ERCP, CECT, and MRCP

15 Japan 642 pts with IPMNs prospectively followed up Imaging modalities including abdominal US, EUS, contrast-enhanced


for 4.8 years

CT, or MRCP. ERCP and EUS-FNA if necessary. Main-duct IPMNs and branch-duct IPMNs were radiologically defined

16 Japan 100 patients who had branch duct IPMN without mural nodules or who had branch duct IPMN with mural nodules of less than 9 mm

Ultrasound (US), EUS, or CT, and were confirmed by a dilated branch duct with a minimum size of 10 mm and mucus in it on ERCP

17 Japan 349 follow-up BD-IPMN patients who had no MNs on endoscopic ultrasonography at initial diagnosis.

ERCP, EUS, MRCP, CT, histology if surgery; Branch duct IPMN was defined as grapelike multilocular cystic lesion communicating with the MPD less than 10 mm.

18 Japan Long-term outcome in 20 conservatively followed patients with main duct IPMN

CT or MRCP imaging

19 Korea 201 patients with branch duct IPMN, who were followed for more than 3 months with repeated CT at least twice, an initial cyst size of less than 30 mm without MPD dilatation or mural nodules at presentation were enrolled in this study

CT, MRCP, ERCP,

20 US Patients with IPMN, The aim of this preliminary study was to determine if differences in anxiety and quality of life exist between patients who have surgery or undergo surveillance

MRI, CT, EUS, fluid analysis

21 Japan 68 patients with branch duct Intraductal papillary mucinous neoplasm

ERCP

22 Japan 145 patients with branch duct IPMN

Not mentioned except for review of records

23 Japan 103 patients with SB-IPMN and conservatively followed up for at least 2 years

EUS database


24 US 23 consecutive BD-IPMNs patients, who were followed up by MRI with MRCP over a period of more than 9 months after initial MRI examinations

MRI with MRCP

25 Japan 159 patients with BD-IPMN,

IPMN - when a pancreatic cyst with size larger than 1 cm was found to communicate with the main pancreatic duct by EUS and one or more additional imaging studies including CT, MRI, and ERCP, CT and EUS or surgery (histological) or biopsy were used to confirm invasive cancer

26 Korea 190 patients with radiological imaging or histological findings consistent with BD-IPMN, identified retrospectively from the database

(8/190 had acute pancreatitis, history of malignancy n=60)

Diagnosed by CT and pancreatography in 105, two or more imaging studies (CT, MRI, EUS, ERCP) showed one or more pancreatic cysts communicating with the main pancreatic duct but without any dilatation of the main duct.

27 Italy 131 patients had a clinicoradiologic or a histopathologic diagnosis of multifocal BD-IPMN.

Clinicoradiologic or histopathologic diagnosis -The diagnosis of multifocal BD-IPMN was based on the presence of 2 cystic lesions in any part of the pancreatic gland that clearly communicated with the main pancreatic duct. MRCP from 2000, others used EUS and/or ERCP

28 Italy 52 IPMN patients, evaluated serial changes at MRCP

(a) imaging criteria: largest diameter of the mass less than 35 mm; absence of papillary proliferations, calibre of MPD less than 5 mm and (b) clinical criteria: no abdominal symptoms, no evidence of diabetes, no laboratory evidence of biliary obstruction and normal tumour markers

29 Italy Twenty-six patients with multifocal IPMT of ≥ 2 ectasic side branches, presence of communication with the main


the side branches

pancreatic duct, and 2 MRI/MRCP examinations after 6–12 months

30 France Highly suspected IPMNs confined to BD without criteria suggesting a malignant development (mural nodule, cyst wall thickness >2 mm, BD diameter >30 mm, or main pancreatic duct involvement) were followed up prospectively

Diagnosis was highly suspected when patients with normal MPD had 1 or several BD dilatation(s) or pancreatic cystic lesions communicating with pancreatic ducts, observed with at least 2 of the following imaging techniques: CT scan, MRCP, ERCP, or EUS

31 US 147 patients with IPMN-Br of whom 66 underwent surgical resection at diagnosis and 81 were followed conservatively, of whom 11 were resected during follow-up

IPMN-Br was diagnosed when one or more imaging studies (CT, MRI, EUS, ERCP) showed one or more pancreatic cysts ≥ 1cm in size communicating with a main duct < 6 mm in diameter

32 Japan 60 out of 92 cases of branch duct IPMN were followed up for more than 1 year

Diagnosed as branch type IPMN by US, CT, EUS, and MRCP/ERCP

33 Italy 65 branch duct IPMTs, 29 underwent surgery, the other 36 were followed with cross-sectional imaging.

CT, MR, MRCP for observation patients

34 France 106 patients with a diagnosis of highly probable (n=30) or histologically proven (n=76) IPMT, tumor was confined to BD in 53 cases

(1) histologic diagnosis obtained by EUS-FNA or biopsy (EUS-FNAB) or surgical specimen; (2) cytologic diagnosis obtained by EUS-FNA; (3) extrusion of mucus via the major or minor papilla. A high suspicion of IPMT was based on the presence of one or several MPD and/or BD dilatation(s) and/or pancreatic cystic lesions communicating with pancreatic ducts seen at CT, MRCP, ERCP or EUS

35 Japan Eighty-one patients with IPMN were periodically subjected to US (>3 years); 27 were reviewed retrospectively (12 with benign neoplasms [adenoma, borderline] and

histopathology of resected specimens periodically US


15 with malignant tumors [carcinoma in situ, invasive cancer]) and 54 prospectively.

36 Japan Fifty-one patients with IPMN (branch-duct type, 47; main-duct type, 4) who had undergone follow-up study by EUS; excluded Those who had been determined to be inoperable due to advanced disease and had been followed-up

EUS,ERCP, CT

37 Japan Thirty-five patients had branch duct type IPMT underwent initial and follow-up MRCP

over a period of more than 12 months

CT, ERCP, MRCP

38 Japan 26 of 33 pts with branch duct-type IPMT diagnosed by ERCP were prospectively examined with MRCP followed by dynamic gadolinium-enhanced MRI examinations, and patients with no findings suggestive of malignancy, including a solid mass, mural nodules, a main pancreatic duct wider than 5 mm in diameter, and stenosis of the main pancreatic duct, were prospectively followed up with sequential MRI examinations once or twice a year.

ERCP

39 Japan 23 were followed for 1 year or more after the clinical diagnosis (follow-up group), including six who underwent surgery or autopsy after the follow-up period (also included in the confirmed group).

52 patients - transabdominal US (n =52), CT (n =52), ERCP (n= 50), or EUS (n=39). 6 died by autopsy

40 US 356 IPMN patients evaluated for pancreatic cysts. Initial resection was selected for 186 patients 170 patients underwent initial nonoperative management

Radiologic and pathologic confirmation of IPMN and/or cyst fluid carcinoembryonic antigen (CEA) C200 ng/mL

41 US 292 patients were diagnosed with IPMN, with more than 3 months of surveillance

Radiology and cytopathology, serology, clinical


42 US Patients >18 years of age with confirmed PCN from January 2005 to December 2010 in a community-based integrated care setting in Southern California. (excluded acute or chornic pancreatitis)

Diagnosis based on ICD-9 codes

43 Italy Incidentally discovered benign, non-communicating cystic neoplasms (BNCNs) of the pancreas

Incidentally discovered cystic pancreatic neoplasm with non-measurable wall and lack of mural nodules, absence of communication with the pancreatic ductal system and availability of one or more MR/MRCP examinations

44 US 338 asymptomatic pancreatic cystic neoplasms patients underwent evaluation, A total of 63 patients underwent resection.

Cross-sectional imaging studies and EUS-FNA

45 US 62 patients with incidental panceatic cystic lesions who were evaluated by EUS with cystic fluid analysis

EUS

46 Korea 1386 patients diagnosed with pancreatic cysts

All patients underwent radiographic imaging including CT, MRI, or EUS, and radiological findings, Histopathologic results after surgical resection or other diagnostic modalities were recorded

47 Italy 24 of 152 patients with incidental pancreatic cysts were followed

3D turbo spin echo MRCP

48 Korea unilocular or oligolocular cysts, indeterminate cystic lesions that required EUS fine-needle aspiration, and cystic lesions that grew during the observation period, 47 pts who were followed for more than 12 months were analyzed (excluded pseudocyst or overt carcinomas with pancreatic invasion)

UES-FNA

49 US The 539 patients managed from 1995 to 2005 ICD-9 codes of maintained registry


were compared with the 885 patients managed from 2005 to 2010

50 US 942 patients were identified with pancreatic cysts; 350 patients remained with incidental pancreatic cysts. Excluding those with symptoms or pseudocysts. Majority of pancreatic cystic lesions in this study were identified during interpretation of a CT scan performed for staging of a non-pancreatic malignancy-

Database was reviewed for patients with ICD-9 codes for pancreatic cysts; CT and EUS with or withiout FNA, was performed

51 Japan Asymptomatic patients with incidental pancreatic cysts who underwent EUS evaluation ± FNA, 97 / 317 patients underwent EUS for evaluation of pancreatic cysts from 1995 to 2005; 71 of them with < 3 cam lesions were followed.

EUS database

52 US 401 patients with cysts lesions, 117 were symptomatic, 284 were incidental cysts.

Clinical data collected included computed tomography (CT) findings, EUS characteristics, cyst-fluid cytology results, and tumor markers obtained by FNA. Histological diagnosis was obtained from the pathology report in all patients who underwent surgical resection of their cysts

53 US A retrospective analysis of longitudinal medical records of patients with pancreatic cystic neoplasms, 150 patients, excluded small ( < 10 mm) cysts (N = 144) and inadequate clinical follow-up of less than 6 months (N = 79) and those with a clinical diagnosis of pancreatic pseudocysts, serous cystadenoma, main duct intraductal papillary mucinous neoplasm (N = 29), and neuroendocrine tumor (N = 3),

pancreatic cystic lesions were identified retrospectively by searching patient billing records via ICD-9 codes benign neoplasm pancreas (211.6) and pancreatic cyst/pseudocyst (577.2) from 1997 through 2005, independent review by two authors of the reports and digitized images of MRI, CT, and EUS studies. Information was also recorded from FNA and/or surgical pathology reports of these cystic pancreatic lesions whenever available.

54 US 500 patients from the prospective pancreatic cystic neoplasm database

From the prospective database, imaging study, FNS with EUS, resecction, Secretin stimulated MRI was selectively used during the initial evaluation of asymptomatic cysts


suspected to have side-branch IPMN

55 UK 79 patients with Cystic lesions of the pancreas, excluding chronic or acute pancreatitis,

Pathology database and radiology computer coding system, patients with a cystic lesion of the pancreas stated in radiology reports, which included abdominal ultrasonography (USS), CT, MRI, ERCP and EUS

56 Israel patients referred for endoscopic ultrasound (EUS) between 1994 and 2003 because of pancreatic cystic lesions, only asymptomatic patients with an incidental finding of a cystic lesion identified by abdominal imaging; excluded symptomatic or had pancreatic pseudocysts, 14 underwent surgery, 90 patients defined as having indeterminate or mucinous cysts managed conservatively after excluding 8 patients with serous cystadenoma and pseudocysts from the analysis

EUS, medical records, CT records, and images were reviewed

57 Japan 197 patients with pancreatic cystic lesions, 80 with IPMN and 117 with non-IPMN cysts, were followed up for 3.8 years on average, excluded typical pseudocyst or cystic tumor of the pancreas by imaging techniques and clinical signs or resected without follow-up

Lesions were detected by imaging modalities such as US, CT, EUS, and MRCP then evaluated them by CT with injection of contrast material, EUS, and MRCP for differential diagnosis of cystic lesions and for possible existence of pancreatic malignancy. ERCP was performed if needed

58 US Patients with cysts that were 3 cm or smaller at US-guided cyst fluid aspiration and biopsy.

Identified at CT and/or MRI imagine.; (Of the 86 patients, 52 CT only, 20 MR only, and 14 both CT and MR imaging). Imaging findings were compared with surgical and pathology records and with endoscopic US features

59 US 79 patients had small simple pancreatic cysts. 49 had adequate radiologic, clinical, or questionnaire follow-up: 22 patients with radiologic follow-up (mean follow up 9 years); 27 patients with clinical or questionnaire follow-up (mean follow-up, 10 years),18 pts

Diagnosed with one or more small (≤ 2 cm) simple pancreatic cysts on sonography or CT, MRI, endoscopic, pathology, cytology


died within 8 years without adequate radiologic follow-up, 12 were lost to follow up

60 US All radiologic, surgical, and pathology records were reviewed for the presence of pancreatic cysts. Included 79 patients with 103 cysts had more than 1 scan with an average interval of 16 months. Excluded pancratitis or pseudocyst (still 7 with pancreatitis in the surgical group) .only patients with 2 scans more than 1 month apartwere included

Radiology records included CT, MRI. Some pts had ERCP, EUS with FNA and Surgical resection.

61 US 30 patients with cystic pancreatic masses, the majority of whom underwent imaging surveillance. Excluded patients with history of pancreatitis with or without pseudocyst, excluded 35 patients who presented with unilocular masses greater than 4 cm in diameter and underwent immediate surgery

CT report database; underwent 90 CT, 17 MRI, and 9 ERCP examinations

62 Japan 31 among 82 patients that with small and asymptomatic cysts diagnosed as being nonneoplastic by endoscopic ultrasonography, and followed for 3 or more years (excluded pseudocysts, surgical or autopsy cysts, or followed < 3 years)

US and/or CT

63 Korea 112 patients with cystic lesions of the pancreas with additional follow up, received follow-up with repeated imaging studies for more than 3 months.

US and/or CT

64 Italy 145 patients with SCNs; followed up for 7 years

(1) Certain radiological diagnosis: MRI with MR cholangio-pancreatography (MRCP) was employed as the standard, high-resolution imaging modality, (2); availability of serial MRI

65 Canada 31 Serous cystadenomas of the pancreas who had at least 18 months follow up

Diagnostic imaging report database, identified form 1141 pts

66 Italy 100 consecutive cases of pancreatic serous US, CT, MRI, EUS, exploratory needle


cystadenomas

aspiration of the cyst, resection

787

788

789

Patients with pancreatic cysts undergoing surveillance with no or minimal change in 790

cyst characteristics over a five year period should have surveillance discontinued 791

792

When to discontinue surveillance is not defined by the currently literature which 793

indicates a very slow progression to malignancy in a population with mortality defined 794

by age and other comorbidities. It seems reasonable to image selected patients for up 795

to 4 years and if no change in size, surveillance may be discontinued, but this area of 796

uncertainty would benefit from additional study. 797

Our data suggest that the rate of progression to invasive cancer is very low and this is 798

consistent with the earlier analysis we did evaluating the risk of cysts progressing to 799

invasive cancer from the systematic review of pancreatic cyst prevalence and US 800

population statistics on cystic adenocarcinoma. Furthermore the vast majority of 801

surgical resections in these case series were performed within the first two years of 802

surveillance. Therefore, it may be reasonable to propose extending the surveillance 803

period to four years. If there has been no significant change in the cyst characteristics 804

over that time period then the probability the patient will have invasive cancer is very 805

low and it is therefore reasonable to discontinue surveillance. We realize that this 806

approach may be controversial; however, based on the analysis of this review 807


demonstrating the low rate of progression of pancreatic cyst on to malignancy we feel 808

that this view is evidence-based, although the evidence is weak. Of course, such 809

decisions also need to be made on an individual basis and there are circumstances 810

where further surveillance beyond four years may be warranted, particularly for 811

presumed mucinous lesions in fit patients <70 years of age and in patients where there 812

may be equivocal change in cyst apprearance and/or size. 813

814

815


Patients with pancreatic cysts that have concerning features should be offered surgical 816

resection 817

818

Selection of patients with pancreatic cysts for surgical resection continues to be a source 819

of controversy in the absence of confirmed malignancy. This technical review has 820

identified major gaps in the literature to define evidence based decision making in the 821

management of pancreatic cysts. Given the lack of data to support a survival benefit for 822

cyst resection, the approach to proceed with a major pancreatic resection whenever a 823

mucinous lesion is found requires reevaluation. The ability of imaging to accurately 824

define malignancy is poor and indicating surgery on the presence of size alone or a 825

presumed nodule on imaging will subject many low risk patients to surgery with a 826

significant risk of immediate post-operative morbidity and mortality with uncertain 827

long-term benefits. 828

829

The surgical dogma that all mucinous cystic neoplasms be resected is not supported by 830

our literature review. Unfortunately, we cannot make definitive recommendations on 831

when surgery should be offered to patients with pancreatic cysts. It would be 832

reasonable to offer this if there are concerning features that prompted the decision to 833

evaluate the patient with EUS-FNA and this demonstrated malignant cells on cytology 834

and/worrisome imaging features. It is also reasonable to offer surgery on the basis that 835

there is more than one of three features (size >3cm, dilated pancreatic duct, or solid 836

component to the cyst) that suggest concern regarding malignancy. Thus a cyst >3cm 837


alone should usually not warrant surgical resection but a large cyst combined with a 838

dilated pancreatic duct may indicate that there is enough increased risk to justify 839

offering the patient surgery. We should emphasize that there is little evidence that 840

combined risk factors are additive or synergistic but we support this simply based on 841

expert opinion.5, 6 842

Another issue that should be considered with regards to offering resection is the age 843

and health of the patient. Age is a particular issue that argues both for and against 844

offering resection. Young patients are usually healthier and are likely to live for many 845

years so any cancer risk over time is likely to increase. On the other hand on a 846

population level their pre-test probability of having malignancy is much lower so this 847

makes the positive predictive value of any of the above tests even lower. While the 848

anxiety and cost of long term monitoring may sway patients and providers to a surgical 849

intervention, careful consideration of the risks and benefits outlined in this review 850

should be undertaken. 851

852

Surgery for symptomatic patients is another category where the evidence remains 853

unclear. Offering surgery to symptomatic patients may seem reasonable, but again the 854

evidence base for this is weak. There are many case series that show symptoms 855

improve after resection but having surgery is likely to have a strong placebo response 856

and follow up of these cohorts over long periods of time is limited. Given that resection 857

carries a significant risk of morbidity and mortality the literature review does not 858

support surgical resection on the basis of symptoms alone; instead, symptoms should be 859


taken into consideration with other concerning features of the cyst that may tip the 860

balance of benefits versus harm in favor of offering resection. Such decision making 861

should be performed by a multidisciplinary team of physicians. 862

863

62


Proportion meta-analysis plot [random effects]

0.0 0.2 0.4 0.6

combined 0.0210 (0.0155, 0.0274)

Katoh 1989 0.0000 (0.0000, 0.0787)

Warshaw 1990 0.0000 (0.0000, 0.0536)

Pyke 1992 0.1000 (0.0279, 0.2366)

Delcore 1992 0.0000 (0.0000, 0.1611)

Grieshop 1994 0.0000 (0.0000, 0.1611)

Sessa 1994 0.0769 (0.0095, 0.2513)

Brenin 1995 0.0000 (0.0000, 0.1544)

Azar 1996 0.0833 (0.0103, 0.2700)

Fukushima 1997 0.0263 (0.0007, 0.1381)

Cellier 1998 0.0213 (0.0005, 0.1129)

Martin 1998 0.0000 (0.0000, 0.1611)

Yasuda 1998 0.0000 (0.0000, 0.1482)

Talamini 1998 0.0769 (0.0095, 0.2513)

Sugiyama 1998 0.0000 (0.0000, 0.0860)

Seich 1998 0.0000 (0.0000, 0.0698)

Paal 1999 0.1364 (0.0291, 0.3491)

Wilentz 1999 0.0333 (0.0041, 0.1153)

Colovic 1999 0.0000 (0.0000, 0.1482)

Paye 2000 0.0244 (0.0006, 0.1286)

Cuillerier 2000 0.0222 (0.0006, 0.1177)

Formentini 2000 0.0000 (0.0000, 0.1372)

Falconi 2001 0.0196 (0.0005, 0.1045)

Kanazumi 2001 0.0000 (0.0000, 0.0578)

Tobi 2001 0.0200 (0.0005, 0.1065)

Adsay 2002 0.0357 (0.0009, 0.1835)

Sugiura 2002 0.0667 (0.0082, 0.2207)

Kalil 2002 0.0476 (0.0012, 0.2382)

Maire 2002 0.0411 (0.0086, 0.1154)

Walsh 2002 0.0000 (0.0000, 0.1000)

Harper 2002 0.0000 (0.0000, 0.1157)

Sheehan 2003 0.0411 (0.0086, 0.1154)

Kiely 2003 0.0000 (0.0000, 0.1157)

Tollefson 2003 0.1905 (0.0545, 0.4191)

D'Anjelica 2004 0.0635 (0.0176, 0.1547)

Salvia 2004 0.0000 (0.0000, 0.0260)

Sohn 2004 0.0368 (0.0120, 0.0837)

Lee 2005 0.0357 (0.0044, 0.1231)

Raut 2006 0.0000 (0.0000, 0.1000)

Carboni 2006 0.0667 (0.0082, 0.2207)

Kang 2006 0.0000 (0.0000, 0.1058)

Goh 2006 0.0183 (0.0022, 0.0647)

Allendorf 2007 0.0000 (0.0000, 0.1323)

Hardacre 2007 0.0333 (0.0041, 0.1153)

White 2007 0.0128 (0.0003, 0.0694)

Nakao 2007 0.0000 (0.0000, 0.0536)

Galanis 2007 0.0063 (0.0002, 0.0348)

Rodriguez 2007 0.0000 (0.0000, 0.0251)

Nagai 2008 0.0000 (0.0000, 0.0499)

Niedergethmann 2008 0.0103 (0.0003, 0.0561)

Crippa 2008 0.0061 (0.0002, 0.0337)

Schnelldorfer 2008 0.0144 (0.0030, 0.0416)

Gumbs 2008 0.0000 (0.0000, 0.1544)

Sachs 2009 0.0000 (0.0000, 0.0330)

Correa-Gallego 2010 0.0063 (0.0002, 0.0345)

Partelli 2010 0.0000 (0.0000, 0.0348)

Coelho 2010 0.0370 (0.0009, 0.1897)

Cheon 2010 0.0250 (0.0006, 0.1316)

Wasif 2010 0.0658 (0.0489, 0.0864)

Fan 2010 0.0000 (0.0000, 0.0881)

Wbezky 2010 0.0484 (0.0101, 0.1350)

Turnini 2010 0.0306 (0.0064, 0.0869)

Hwang 2011 0.0084 (0.0010, 0.0301)

Cone 2011 0.0333 (0.0041, 0.1153)

Yopp 2011 0.0339 (0.0041, 0.1171)

Turnini 2011 0.0000 (0.0000, 0.0339)

Ferrone 2011 0.0000 (0.0000, 0.0425)

Fujii 2011 0.0000 (0.0000, 0.0430)

Lahat 2011 0.0259 (0.0054, 0.0737)

de Castro 2011 0.0114 (0.0003, 0.0617)

Okabayashi 2013 0.0100 (0.0003, 0.0545)

DeMoor 2012 0.0364 (0.0044, 0.1253)

Hwang 2012 0.0000 (0.0000, 0.0925)

He 2013 0.0000 (0.0000, 0.0280)

El-Hayek 2013 0.0400 (0.0010, 0.2035)

proportion (95% confidence interval)

63


Survival after resection of an invasive/ malignant pancreatic cyst

We have reviewed the potential harms of resection of pancreatic cysts as well as their malignant

potential. It is also important to establish the benefits of removing a pancreatic cyst. There is the

potential benefit of preventing a cyst from becoming malignant. The risk of this is likely to be very low in

benign lesions but there is likely to be some benefit for lesion with high-grade dysplasia (HGD).

Unfortunately, quantifying this benefit is difficult as there are no data on the natural history of cysts with

HGD. This is therefore very difficult to determine.

Another benefit would be that removing an invasive malignant cyst early before spread of the lesion may

lead to long-term survival of the patient. The literature was reviewed to address this question with

studies having < 20 patients and combining invasive cancer and HGD together being excluded. Papers

that did not provide 5 year survival data for patients with invasive cancer (either overall or disease free)

were also excluded. We identified 37 studies evaluating 3842 patients. 16, 64, 66, 68, 75, 77, 87, 89, 90, 92, 94, 97, 104, 106,

116, 117, 119, 121, 128, 143, 150, 152, 158, 201, 204, 206, 216, 233-242 All papers found that survival in those without malignancy

was 80-100% at 5 years. It was not possible to pool the data accurately as very few provided detailed

information required to perform a pooled analysis. The range of 5 year survival was 3% to 68% (table 6)

and most reported on invasive IPMNs.64, 66, 68, 75, 77, 87, 89, 90, 92, 94, 97, 104, 106, 116, 117, 119, 121, 128, 149, 150, 152, 157, 158, 201,

204, 206, 216, 233-236, 238-240, 242 If a simple average is taken then the overall 5 year survival is 28%. This figure is

similar to the most recent SEER data on survival after surgery for a malignant cyst. 234

This is better than

survival for standard pancreatic adenocarcinoma but is still disappointing. There was however one clear

outlying low value that reported from early SEER data, which evaluated IPMNs undergoing surgery 1983-

1991. 240

If this study was excluded on the basis that imaging techniques were not as sophisticated for

that period, then the 5 year survival increases to 36.5%. This is still disappointing but at least more

optimistic for the patient. However, there is a major concern that any apparent benefit of survival may

simply reflect lead and/or length time bias. Indeed the few studies that did report survival longer than 5

years would strongly suggest lead-time bias was a factor as mortality for IPMNs approached that of

64


standard pancreatic adenocarcinoma with longer follow up. There is only one study that reported on 20

invasive mucinous cystic neoplasms. 16

The overall survival in this small group was 33%, which does not

appear better than results for IPMN.

65


Table 6. Summary of studies evaluating 5 year survival of malignant pancreatic cysts

Author Cyst type Number of patients with

invasive malignancy

5 year survival

Kang 2013 IPMN 59 62.7%

Wong 2013 BD-IPMN 39 25.0%

Caponi 2013 IPMN 64 30.0%

Ohtsuka 2012 IPMN 36 31.0%

Worni 2012 IPMN 972 24.1%

De Moor 2012 IPMN 21 25.8%

Kim 2011 IPMN 52 20%

Waters 2011 IPMN 113 31.0%

Mino-Kenudson 2011 IPMN 61 47.0%

Jang 2011 IPMN 41 61.9%

Yamaguchi 2011 IPMN 122 37.0%

Yopp 2011 IPMN 59 68.0%

Shin 2010 IPMN 41 58.3%

Lubezky 2010 IPMN 23 41.0%

Turrini 2010 IPMN 98 30.0%

Sadakari 2010 IPMN 30 32.4%

Partelli 2010 IPMN 104 54.5%

Poultside 2010 IPMN 132 42.0%

Swartz 2010 IPMN 70 45.3%

Crippa 2010 IPMN 62 64%

Schnelldorfer 2008 IPMN 63 31.0%

66


Nara 2008 IPMN 25 38%

Nagai 2008 IPMN 30 57.6%

Nakagohri 2007 IPMN 31 24.0%

Riall 2007 IPMN 992 3.0%

Winter 2006 IPMN 90 48.0%

Wada 2005 IPMN 25 46.0%

Jang 2005 IPMN 51 36.9%

Sohn 2004 IPMN 52 43.0%

Salvia 2004 IPMN 58 60.0%

D'Anjelica 2004 IPMN 30 58.0%

Kitagawa 2003 IPMN 28 44.0%

Chari 2002 IPMN 40 36.0%

Maire 2002 IPMN 51 36.0%

Yamao 2000 IPMN 32 44.0%

Tobi 2001 IPMN 25 62.5%

Wilentz 1999 MCN 20 33.0%

67


Patients should have annual surveillance with MRI after surgical resection if the

resected cyst shows evidence of dysplasia or malignancy

No studies have tested the value of surveillance following pancreatic resection for a

precancerous lesion. Case series have supported the concept a field defect in such

patients with IPMN who may develop tumors due to continued exposure to risk factors

(such as alcohol or smoking) as well as a genetic background promoting tumor

development. No studies define the outcome of such an approach or define the optimal

imaging modality and its frequency. It seems reasonable to follow the principals of

surveillance noted above. However, given such patients likely have a much higher long

term risk for malignancy, discontinuation of surveillance cannot be recommended and

should stop when the patient is no longer a candidate for surgical resection. If non-

surgical treatment of such lesions becomes a viable alternative providing curative

potential these considerations will change.

Patients should not be offered surveillance after surgical resection if the resected cyst

shows no evidence of dysplasia.

Again there is no evidence on this group of patients. However, if the resection shows a

simple mucinous or serous cyst with no evidence of dysplasia then there is unlikely to be

68


a field change and the overall risk of malignancy is this group of patients is likely to be

very low. Given the risk of cystic lesions progressing is low and the patient is currently

free of any concerning lesion it is not appropriate to offer continued surveillance. This

would only add cost to the health care system and anxiety for the patient with little

likelihood of any long-term benefit.

Discussion

In this technical review, we attempted to evaluate the evidence for diagnosing and

managing pancreatic cysts. Unfortunately, there is insufficient evidence to make

definitive recommendations based on defined measures of risk and patient outcomes

(survival benefit).

The approach to the patient with a pancreatic cystic lesion begins with a detailed

history, and consideration of the differential diagnosis to assess the risk of malignancy.

A history to suggest prior pancreatitis or trauma is important since this would increase

the likelihood that the lesion is a pseudocyst without malignant potential. In the

absence of a history of pancreatitis or trauma, pseudocyst is unlikely and the concern of

a cystic neoplasm is paramount. In general, patients with symptomatic lesions should be

evaluated by a multidisciplinary team of physicians to determine if surgical resection is

indicated based on symptoms and other findings, weighing the likelihood of malignancy

against the risk of surgery. If preoperative characterization of the lesion will change

management, EUS + FNA for cytology and fluid analysis may provide information of

69


diagnostic and prognostic value. Risk stratification should occur during the initial

evaluation, as our analysis suggests progression appears rare.

For those patients with benign appearing lesions with low-risk features on

imaging, a decision regarding the patient’s willingness to observe the lesion should be

developed in collaboration with a pancreatic surgeon. In many circumstances,

surveillance with non-invasive imaging typically MRI and selected use of EUS + FNA with

cytology and fluid measurement will allow watchful waiting of a presumed mucinous

lesion including both MCNs and branch duct IPMNs. This approach clearly represents a

trade-off of delayed surgery and a low risk of progression to malignancy with the risk of

morbidity and mortality associated with surgery; however, given the high prevalence of

patients with pancreatic cysts and the low rate of malignant transformation over time,

this appears the most prudent approach to provide patients with the best overall

survival. Given the lack of clear, convincing data, management of patients with

pancreatic cysts should be individualized incorporating the data and recommendations

presented in this review along with the clinical judgment of an experienced

multidisciplinary team.

70


Appendix

AGA guideline: Pancreatic cysts Note there are an initial set of evidence reviews and questions that are not PICO based to establish high-risk pancreatic cyst definitions and also evidence for benefit of detecting pancreatic cancer early.

Appendix. Search strategies

Search to identify risk of malignany

# Searches Results

1 exp Pancreatic Cyst/ use mesz 5937

2 exp pancreas cyst/ use emez 8179

3 (pancrea* adj2 cyst*).ti,ab. 6912

4 or/1-3 17699

5 exp Pancreatic Neoplasms/ use mesz 56348

6 exp pancreas tumor/ use emez 83597

7 (pancrea* adj2 (neoplas* or malignan* or cancer* or tumo?r*)).ti,ab. 74964

8 or/5-7 152666

9 4 and 8 5809

1

0 limit 9 to english language 4317

1

1

limit 10 to (case reports or comment or editorial or letter or note) [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) In-

Process,Embase; records were retained] 721

1

2 Case Report/ use emez 1929266

1

3 10 not (11 or 12) 2976

1

4 remove duplicates from 13 2112

71


Search to identify diagnostic accuracy

Searches Results Search Type

1 exp Pancreatic Cyst/ use mesz 5937

2 exp pancreas cyst/ use emez 0

3 (pancrea* adj2 cyst*).ti,ab. 2801

4 or/1-3 7444

5 exp Ultrasonography/ 243348

6 (ultrasound* or ultrasonic or ultrasonogra* or sonogra* or echotomogra* or endosonogra* or (echo adj2 endoscop*) or echo-

endoscop*).ti,ab. 248057

7 exp Tomography, X-Ray Computed/ 294155

8 ((ct or cat or computed or computer assisted or electron beam) adj (tomograph* or scan* or xray or x-ray)).ti,ab. 186365

9 ((nmr adj tomograph*) or mr imaging or MRI or magnetic resonance imaging).ti,ab. 221516

10 exp Biopsy, Fine-Needle/ 8657

11 (fine needle biops* or fna).ti,ab. 7300

12 exp Cholangiopancreatography, Endoscopic Retrograde/ 12643

13 (endoscopic adj retrograde adj cholangiopancreatograph*).ti,ab. 5094

14 ercp.ti,ab. 6356

15 Antigens, Neoplasm/ 39532

16 exp Tumor Markers, Biological/ 179660

17

(CEA or CA 19-9 or ca-19-9 or CA 72-4 or ca-72-4 or CA-125 or ca 125 or (antigen* adj carcinoembryonic)).mp. or cd66e.ti,ab.

[mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary

concept, rare disease supplementary concept, unique identifier]

23205

18 exp Cyst Fluid/ 374

19 ((imaging or surveillance) adj5 (pancrea* adj2 cyst*)).ti,ab. 78

20 exp Pancreatic Cyst/su [Surgery] 2172

21 ((surgery or surgical or surgeries or operat*) adj5 (pancrea* adj2 cyst*)).ti,ab. 163

22 exp ras Proteins/ or exp Mutation/ 644693

23 (k-ras or kras).ti,ab. 9051

24 or/5-23 1718526

25 4 and 24 4828

26 limit 25 to english language 3305

27 limit 26 to (case reports or comment or editorial or letter) 1511

28 26 not 27

72


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American Gastroenterological Association Technical Review on the