Intraductal Papillary Mucinous Neoplasms of the Pancreas: Challenges and New Insights

Cystic lesions of the pancreas are a common entity with almost a 25% incidence of the general population. These types of lesions are being increasingly diagnosed partly explained due to the technological advances over the past years. The management and treatment varies per cyst type. However, the most threatening cyst lesions are intraductal papillary mucinous neoplasms (IPMNs). These lesions represent nowadays a relatively new clinical entity and in many aspects remain poorly understood. The aim of this ­chapter­is­to­provide­a­comprehensive­review­of­the­classification,­diagnosis,­treatment­ and follow-up strategy.


Introduction
In the face of this new "epidemic of pancreatic cysts," it is clear that we need to be on top of newly emerging changes in our current daily practice.Pancreatic cancer has a fateful prognosis, despite recent improvements in surgery and chemotherapy.However, most cases of intraductal papillary mucinous neoplasms (IPMNs) are considered as premalignant lesions, thusmakingthematargetfordiagnosisandprompttreatment.Ontheotherhand,weshould neverforgettheshort-andlong-termrisksofsurgery.Thisispreciselywhyitissochallenging to adequately manage this pathology.
Biomarkers represent an interesting opportunity, but until they can be used on a regular clinical basis, we are obliged to say knowledgeable on new insights involving radiologic characteristics and potential malignancy prior to deciding, which is the best available individualized option for each patient.

Anatomic classification: involvement of the pancreatic ductal system
Most IPMN arise from the pancreatic main duct or its branch ducts (Figure 1).Most of thesetumorsareunifocal,20-30%aremultifocal,and5-10%oftheIPMNdiffuselyaffect the entire duct system of the pancreas.Depending on the involvement of the pancreatic duct, IPMNs are classified as either main duct IPMN (MD-IPMN) or branch duct IPMN (BD-IPMN).If both, main and branch ducts are involved together, then it is defined as combined-type IPMN (Figure 2).The clinical pathologic behavior of combined-type IPMN is similar to that of MD-IPMN.MD-IPMN is frequently more associated with this malignant transformation than is BD-IPMN, requiring surgical resection in more than a half of the patients, while most patients with BD-IPMN can be observed for a long time after the diagnosis.

World Health Organization (WHO)
TheWorldHealthOrganization(WHO)classifiedIPMNsintothreesubgroupsaccordingto degree of dysplasia: (I) IPMN with low-or intermediate-grade dysplasia; (II) IPMN with highgrade dysplasia (carcinoma in situ); and (III) IPMN with an associated invasive carcinoma.IPMN associated with PDAC (pancreatic ductal adenocarcinoma arising in association with an IPMN) was further classified into two subtypes: tubular adenocarcinoma, composed of predominantlygland-formingneoplasticcellswithfibroticstromaandabsenceof significant extracellular stromal mucin and colloid carcinoma (mucinous noncystic carcinoma), composed of sparsely populated strips, clusters, or individual neoplastic cells residing within extensive pools of extracellular mucin [6].In case of IPMN with low-to intermediate-grade of dysplasia, dysplastic changes in the columnar cells are minimal or absent.The prognosis is usually favorable [7].

Malignancy risk
There has been an increased prevalence of pancreatic cystic neoplasms, frequently being found in elderly asymptomatic patients.This is partially caused by the greater number of cross-sectional studies being performed.Though images obtained through the use of computed tomography (CT-scan) and magnetic resonance imaging (MRI), we are able to estimate the prevalence ofpancreaticcystsin2.5%ofthepopulation.Thisfigureincreasesovertime;aroundtheageof 70 years or older, 10% of the population has pancreatic cysts and 20-50% of them are IPMN [8].
Therealriskofmalignancymaybeverylow,butthediagnosisisassociatedwithanxiety andusuallyleadstofurthermedicaltestinginordertoconfirmmalignancy.Themostfrequentlyusedtestsarelikelytoinclude:consultationscongastroenterologistsand/oroncologists, endoscopic ultrasound with or without percutaneous biopsy, and occasionally surgery [6,8,9].This is one of the reasons why more and more studies are focusing on evaluating the malignancy rate for pancreatic cancer distinct from IPMN and also for pancreatic cancer arisingfromIPMN.Figuresarerathervariable,butoverthecourseofseveralyears,wehave been able to see how the rates for malignancy, especially in SB-IPMN, are found to be lower.
Not only IMPNs are associated with pancreatic malignancies but also it is known that extrapancreatic malignancies are more frequently found in these patients.92% [10][11][12][13].Overall,theprognosisafterresectionisgenerallyfavorableaslongasitsinvasion remains within minimally invasive or in T1a status (depth of stromal invasion <5 mm).

Pathogenesis
IPMNs are mucinous cystic lesions of the pancreas that are characterized by neoplastic, mucin-secreting, and papillary cells projecting from the pancreatic ductal surface.They arise from the epithelial lining of the main pancreatic duct or its side branches.Intraductal proliferation of mucin-producing columnar cells is the main histologic characteristic of IPMNs, and Challenges in Pancreatic Pathology intraluminal growth causes dilatation of the involved duct and its proximal segment.They are usually found in the head of the pancreas as a solitary cystic lesion, but in 20-30% of the cases,theymaybemultifocal,andin5-10%ofcases,theymayinvolvethepancreasdiffusely [18][19][20].InBD-IPMN,malignanttumorscanbefoundin6-46%andinMD-IPMNin57-92%, makingthatMD-IPMNleadstoworseprognosis [5].

Progression to pancreatic cancer
IPMNs are thought to follow an orderly progression from a benign neoplasm to invasive carcinoma of the pancreas, they range from premalignant lesions with low-grade dysplasia to invasive malignancy, and they have a clear tendency to become invasive carcinoma [5,[21][22][23][24].Ithasbeenestimateda5-6yearprogressionrate,dependingonthesubtype.Theyaregraded according to the most atypical area in the lesion as: • Low-grade dysplasia (adenoma).

Risk factors
It has been described that previous history of diabetes, especially with insulin dependency, chronic pancreatitis, or a familial history of pancreatic ductal adenocarcinoma (PDAC), may haveahigherriskforIPMN [25].Also, several studies have noticed that the presence of autoimmune disease in general population is around 5%; however, in patients diagnosed with IPMN, the number rises up to 22%.IPMNs can be associated with systemic diseases such as: systemiclupuserythematousandrheumatoidarthritisaninflammatoryboweldisease,lead-ingtothinkthatIMPNsmaybeonemanifestationofamoresystemicdisease [26].
• Mural nodules: IPMN with >3 mm nodules is highly suggestive of malignancy.Challenges in Pancreatic Pathology

EUS-FNA
This technique has been evolving, and more hospitals are incorporating it into their routine diagnostic tests, helping to introduce its more general application and obtaining information by: • Describing sonographic characteristics: mural nodes and invasion.
• Pancreatic small cyst with worrisome features.
Inconclusion,themostrecentpapersencouragetheuseofEUS-FNAintheinitialdiagnostic tests [15,30] to identify smaller cysts with high grade or invasive pathology [30] and to detect mural nodules otherwise missed on cross-sectional imaging or malignant cytology in lesions >3 cm.The high specificity and accuracy of EUS strongly position it as the optimum tool for diagnosing malignant BD-IPMNs, particularly in patients without worrisome features and with smaller cysts [31].Itisparticularlyimportanttoconsiderthatinherentriskscanbe derived from this test, including complications associated with these endoscopic procedures suchasdifficultyincytologicalinterpretationofsamplesandrelativelylowsensitivity [31].

Biomarkers
DNA analysis of pancreatic cyst fluid demonstrated that KRAS mutation is highly specific (96%) for mucinous cysts, but the sensitivity is only 45%.KRAS is an early oncogenic mutation in the adenoma-carcinoma sequence but cannot discriminate a benign from malignant mucinous cyst.A recent study [32] demonstrated that the "GNAS mutation detectedincystfluidcanseparateIPMNfromMCN,butsimilartoKRASmutations,it does not predict malignancy.The absence of a GNAS mutation also does not correlate with a diagnosis of MCN because not all IPMNs will demonstrate a GNAS mutation [33][34][35].

ERCP
Forsamplingoffluidbrushesinthe2012InternationalConsensusGuidelinesforthemanage-mentofIPMN,routineuseofthistestwasnotrecommendedandwasleftonlyforscientific purposes [28].However, as professionals are becoming more familiarized with it and results are increasingly being more accurate, newer studies are encouraging cytology of the pancreatic juice and it is starting to be considered a reliable predictor of malignancy in IPMN [39].Cytological examination alone is often non-diagnostic due to the low cellularity of the aspiratedfluid.Apositiveornegativediagnosiscanbeobtainedthroughacytologyanalyses witha100%specificity.Moreover,ifahigh-gradeepithelialatypiaisfoundinthecystfluid, it is correlated with an 80% chance of malignancy [40].

Allguidesagreethatduetothehigherriskofmalignancy,allsymptomaticcystsshouldbe
further evaluated or resected, depending on the clinical circumstances.
Invasive carcinoma in patients with asymptomatic cysts is very rare, especially in cysts <10 mm.In such cases, no further work-up will be needed; however, follow-up is still recommended [43][44][45][46].Forbettercharacterizationofthelesions,pancreaticprotocolCTor gadolinium-enhanced MRI with magnetic resonance cholangiopancreatography (MRCP) is recommended for cysts >10 mm [47].The most recent consensus among radiologists [10] suggests that MRI is preferable for evaluating cysts due to its high-contrast resolution, the identificationofseptum,nodules,andductcommunications.Also,MRIisthepreferable follow-up test because it avoids excessive exposure to radiation [47].
-Abrupt change in the MPD caliber with distal pancreatic atrophy. -Lymphadenopathy.
All patients with cysts of 3 cm in size without "worrisome features" should undergo surveillance according the size stratification.Patients with cysts of >3 cm and no "worrisome features"canalsobeconsideredforEUStoverifytheabsenceofthickenedwallsormural nodules, particularly if the patient is elderly.All smaller cysts with "worrisome features" shouldbeevaluatedbyEUStofurtherriskstratifythelesion [48].

Surgery
If surgery is considered for a pancreatic cyst, patients are referred to a center with demonstrated expertise in pancreatic surgery.Surgery is the only treatment option in patients with IPMN of the pancreas with high-grade dysplasia or IPMNs that have progressed to invasive carcinoma (Figure 6).
The most important aspect of resection is to achieve complete removal of a tumor with a negative margin.If a positive margin is found in a high-grade dysplasia, additional resection of the pancreas should be performed.However, there is no consensus regarding further resection in the case of a low-or moderate-grade dysplasia [51,52].
Total pancreatectomy should be contemplated only in younger patients who can manage thecomorbiditiesrelatedtodiabetesandexocrineinsufficiencyorinpatientswithahistory of diabetes [53,54].The choice of surgery will be determined by the location of the tumor and the extent of involvement of the gland.It is not clearly established that multifocality correspondstoahigherriskofinvasivecancer;inmostcaseswithmorethanonelesion,the dominant or concerning lesions are resected; and the others are observed with follow-up imaging [1].
Regarding the BD-IPMN that occurs in elderly patients, the annual malignancy rate is only 2-3%.These factors support a conservative management with follow-up in patients who do not have risk factors predicting malignancy.Younger patients (<65 years) with a cyst size of>2cmmaybecandidatesforresectionowingtothecumulativeriskofmalignancy [27].
BD-IPMN of >3 cm without these signs can be observed without immediate resection, particularly in elderly patients.The decision needs to be individualized and to depend not only on theriskofmalignancybutalsoonthepatient'sconditionsandcystlocation [51].

Follow-up
TheAGArecommendsdiscussingtherisksandbenefitsofamanagementstrategywiththe patient as a good clinical practice for nearly all diseases and interventions.Patients need to receive a full explanation of all therapeutical options so they can choose the best treatment in accordance with the most recent guidelines.Patients who have a limited life expectancy do notderiveanybenefitfromsurveillance,becauseitisinappropriateforpatientswhoarenot surgical candidates due to severe comorbidities.

MD-IPMN
Themanagementdependsonthedegreeofductaldilation,≥10mm,iftheductis(Figure 7) -≥10 mm in diameter: resection of MD-IPMN is recommended for patients who have good performance status with reasonable life expectancy.This recommendation is based on the high rate of malignancy in MD-IPMN [28].
-5-9 mm:weneedadditionalevaluationwithEUSandfine-needleaspiration.Surgeryis then indicated if there is evidence of worrisome features.But the association of malig-
• 10-30 mm: repeat MRCP in 1 year.If the IPMN is stable, continue surveillance with MRCP every 2 years.After 5 years, the surveillance interval can be lengthened to every 3 years.
• <10 mm: repeat in 1 year.If the IPMN is stable, continue surveillance with MRCP every 2 years.After 5 years, surveillance can be discontinued.
MRI is the preferred surveillance imaging modality over computed tomography.The length of surveillance for IPMN is another concern for every clinician.If there is no change in size or characteristics, the AGA suggests that patients without worrisome pancreatic features undergo MRI for surveillance in 1 year and then every 2 years after, for a total of 5 years.The reviewoftheliteraturesuggeststhattheriskofmalignanttransformationofpancreaticcysts isapproximately0.24%peryear.Theriskofcancerincystswithoutasignificantchangeover a 5-year period is lower but this recommendation has very low evidence quality.Therefore, more studies are needed [45].In addition, the Fukuoka consensus suggests for BD-IPMN follow-up:yearlyfollow-upiflesionis<10mminsize,6-12monthlyfollow-upforlesions between 10 and 20 mm, and 3-6 monthly follow-up for lesions >20 mm [28].The optimal surveillance approach, however, remains unclear.
Challenges in Pancreatic Pathology

Surveillance following surgery
• Noninvasive IPMN: the risk of developing a recurrence in the remaining pancreas is at least 5%.So we have to perform the follow-up with MRCP by including a lengthening in the surveillance interval if no changes are detected after several years.If there is another nonresected IPMN, follow-up should continue as stated above [23,61].

Figure 6 .
Figure 6.Proposed algorithm for surgery indications in IPMNs.
Intraductal Papillary Mucinous of the Pancreas: Challenges and New Insights http://dx.doi.org/10.5772/66491nancy with this degree of pancreatic duct dilation has not been well characterized.If the patienthasalongerlifeexpectancy,upto10years,heshouldbeoperated.Forpatients not undergoing surgery, we perform a magnetic retrograde cholangiopancreatography (MRCP) a year later.Surgery should be considered if the duct increases in size or if intramural nodules develop.If the duct is stable, we should repeat imaging every 2 years and continue it as long as the patient is a good surgical candidate.-<5 mm: follow-up with MRCP in 2 years.As with other IPMNs, surgery is indicated if the duct increases in size or if intramural nodules develop.If the duct is stable on repeat imaging, we lengthen the surveillance interval to every 2-3 years and continue surveillance as long as the patient remains a good surgical candidate.