KOK SIU YAN AMYUnited Christian Hospital *

IntroductionClassificationInvestigationIndication for resectionMethods of resection Follow-upPrognosis*

History: 1982Described by Ohashi and his colleagues Incidence ~2.04 per 100 000Autopsy studies 25% of cystic pancreatic lesions30-50% may become invasiveAccounts for 5-7% of all pancreatic neoplasm

*Dtsch Arztebl Int.2011 Nov;108(46):788-94.Intraductal papillary mucinous neoplasia (IPMN) of the pancreas: its diagnosis, treatment, and prognosis.Grtzmann R,Post S,Saeger HD,Niedergethmann

*Dtsch Arztebl Int.2011 Nov;108(46):788-94..Intraductal papillary mucinous neoplasia (IPMN) of the pancreas: its diagnosis, treatment, and prognosis.Grtzmann R,Post S,Saeger HD,Niedergethmann M.

First international consensus guideline in 2006 and was revised in 2012*

Main ductBranch ductMixed *

*

USGCTMRI + MRCPEUS +/- FNACERCPIntraductal USG or pancreatoscopy

*

USGSize and extent

CTDiffusely distended pancreatic duct with mucinous filling defects and cystic space occupying lesionsSensitivity 42%

*

MRI with MRCPEntire pancreatic parenchyma and the intra-abdominal organsMore sensitive to detect mural nodulesSensitivity 88%

*Br J Surg.2009 Jan;96(1):5-20.Preoperativetissuediagnosisfortumoursof thepancreas.Hartwig W,Schneider L,Diener MK,Bergmann F,Bchler MW,Werner J.

*

EUS-FNACEAAmylaseCytologyMolecular analysis

Investigational Small BD-IPMN*

*

MD-IPMN BD-IPMN*

Main duct dilatation1cm Frequency of malignancy: 60-92%No clinical parameters accurately discriminate malignant and non-malignant lesion

RESECT ALL MAIN DUCT AND MIXED VARIANT IPMNIF SURGICALLY FIT *

*

*

*

High-risk stigmata Obstructive jaundice in patient with cystic lesion of the head of pancreasEnhancing solid component within cystMain pancreatic duct 10mm in size

CONSIDER SURGERY IF CLINICALLY APPROPRIATE*

Worrisome featuresClinical: pancreatitisImaging:cyst3cmThickened/enhancing cyst wallsMain duct size 5-9mmNon-enhancing mural noduleAbrupt change in calibre of pancreatic duct with distal pancreatic atrophy

PERFORM ENDOSCOPIC ULTRASOUND*

EUS features:Definite mural noduleMain duct features suspicious for involvementCytology: suspicious or positive for malignancy

CONSIDER SURGERY IF CLINICALLY APPROPRIATE

*

*

MD-IPMNMain duct dilatation5mm5-9mm worrisom features Evaluation No immediate resection

*

According to site and extend of diseasePancreatoduodenectomyDistal pancreatectomyTotal pancreatectomyLimited resection ExcisionEnucleationUncinatectomyLaparoscopy +/- lymph node dissection*

*Non-resected IPMN Surgically resected IPMN

*

Benign:Yearly CT/MRIMalignant6 monthly CT/MRICEA & CA19.9 no value *

*

Surgical margin statusnormal pancreatic tissuenon-dysplastic changes low grade dysplasiamoderate grade dysplasiainvasive carcinoma

*Repeat exam 2-5 yearsHx/PE/MRCP half-yearly Identical to PDAC

Complete resection of noninvasive IPMN5 year survival rate 95%Complete resection of early stage tumors(T1N0)5 year survival rate 60%Advanced or nodal positive tumors5 year survival rate 36%

*

*

*

High-risk stigmata surgerySmaller cyst + worrisome features EUSCyst >3cm + NO worrisome features EUS if elderly Cyst 3cm + NO worrisome features surveillance

*

High incidence of malignant/invasive lesions (61.6%/43.1%)Segmental ectatic type/Diffuse type with focal lesionsDiffuse type without focal lesionsFrozen section Intraductal USG/pancreatoscopy

*

Mean frequency of malignancy/invasive cancer (25.5/17.7%)Elderly Annual malignancy risk 2-3%

High risk factors:Mural nodulesHigh grade dysplasia/Positive cytology Rapidly increasing size

Individual decision

*

One 1st degree relative with PDAC 2.3-fold increased risk

high-quality MRI/MRCP or CT and EUSMalignant stigmata/worrisome features resectionNo malignant stigmata/worrisome features MRI/MRCP or CT at 3-month intervalsEUS annually for first 2 years*

Combination of clinical & imaging characteristics can provide preoperative diagnosis of cyst typeMultidetector CT (MDCT) & MRCP are useful for defining morphology, location, multiplicity, and communication with the MPDDistinguishing features: multiplicity & visualisation of a connection to MPDEUS: delineate malignant characteristics eg mural nodules & invasion but operator dependent Cyst fluid x CEA, amylase & cytology cannot distinguish MCN & IPMN Molecular analysis for GNAS mutations can distinguish MCN from BD-IPMN *

3 morphological patterns:Polycystic Honeycomb Oligocystic

Distinguished from SCN with a polycystic or honeycomb pattern by CT or MRCP

Differentiation between a small oligocystic SCN & a BD-IPMN may require EUS-FNA with cyst fluid CEA determination *

Neoplastic cysts:Non-mucinousSerous cystic neoplasm (SCN)Solid pseudopapillary neoplasm (SPN)MucinousMucinous cystic neoplasm (MCN)Intraductal papillary mucinous neoplasm (IPMN)*

*

Low prevalence of invasive carcinoma (

Apart from imaging, elevated cyst fluid CEA is a marker that distinguishes mucinous from non mucinous cysts, but NOT benign from malignant cystsA cut off of >/=192-200ng/ml is ~80% accurate for diagnosis of mucinous cyst

Cyst fluid amylase is shown to be not uniformly elevated in IPMN

Fluid cytology may add value especially for evaluation of a small BD-IPMN without worrisome features. High grade epithelial atypia recognised in cyst fluid predicted malignancy in a mucinous cyst with 72% sensitivity in one study and detected 30% more cancers in small IPMN without worrisome features in another study

Some studies showed molecular analysis of cyst fluid may be helpful in distinguishing significant mucinous cysts from indolent cysts that can be conservatively managed

However, in view of the inconclusive evidence, this guideline suggests cyst fluid analysis is still investigational, but is recommended for evaluation of small BD-IPMN without worrisome features only in centres with expertise in EUS-FNA and cytological interpretation

*

Synchronous/metachronous malignant diseases in extra-pancreatic organs 20-30%Frequency and location of extra-pancreatic malignancies differsGI cancer is common in AsiaSkin/breast/prostatic cancers common in US

*

This comprehensive guideline has lowered the criterion for characterising MD-IPMN to MPD dilatation of >5mm without losing specificity for radiologic diagnosis-high risk stigmata and worrisome features have been defined to stratify risk of malignancy in BD-IPMN and consider resection or increased freq of surveillance -resection is recommended for all surgically fit patients with MD-IPMN or MCN Indications for resection of BD-IPMN are more conservativeBD IPMN >3cm without high risk stigmata can be observed without immediate resection

*

A previous history of diabetes, especially with insulin use, CP, and family history of PDAC are all relevant risk factors for the development of IPMN.

Am J Gastroenterol.2013 Jun;108(6):1003-9. doi: 10.1038/ajg.2013.42. Epub 2013 Mar 5.Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study.*

Good past healthNo history of pancreatitis No family history of pancreatic cancerPhysical examination: unremarkable *

*

Differential diagnosis

Benign Pseudocyst Serous cystic neoplasm (SCN) Simple cyst, retention cyst, congential, lymphoepithelial cyst

Potentially malignant Intraductal papillary mucinous neoplasm (IPMN) Mucinous cystic neoplasm (MCN) Solid pseudopapillary neoplasm (SPN) Neuroendocrine tumor

Malignant Ductal adenocarcinoma*

Pathological diagnosis (n = 212)

Fernandez-del Castillo et al. Arch Surg 2003*

Intraductal papillary mucinous neoplasm (IPMN)75 (35%)Mucinous cystic neoplasm (MCN)43 (19%)Serous cystadenoma 23 (11%)Pseudocyst 29 (14%)Ductal adenocarcinoma 14 (7%)Others28 (13%)

WHO classification of digestive system 2010IPMN with low or intermediate grade dysplasiaIPMN with high grade dysplasiaIPMN with invasive cancer

*

Criterion for characterising MD-IPMN >5mmMD-IPMN: resection BD-IPMN: high-risk stigmata & worrisome featuresConservative

*

EUS-guided mucosal ablation by ethanol injectionIndication:Cyst >2cmUnilocular/oligolocularNo communication with MPDRefuse surgeryHigh risk surgical candidates*

CT-defined cyst resolution rates 33-79%Variable histopathologic degrees of epithelial ablation

Complication:Acute pancreatitis (4.5-10%)Abdominal pain (

ERCP Washing or brushing for cytology Not recommended *

*

Good morning ladies and gentlemen, the topic of my presentation today is Management of intraductal papillary mucinous neoplasm (IPMN) of pancreas, An update. *In the following presentation, I would like to talk about this important disease entity by giving you a brief introduction, followed by discussing the classification, investigation, indication for resection, methods of resection, follow-up and also its prognosis*IPMN is a cystic, intraductal mucin-producing neoplasm whichdemonstrates significant pancreatic ductal dilatation. It is first described in 1982 with an incidence of around 2 per 100 000. 30-50% may become invasive. It also accounts for 5-7% of all pancreatic neoplasm.

*Apart from those asymptomatic ones, some may present with pain, jaundice, pancreatitis or constitutional symptoms.*The international guideline for the management of IPMN established in 2006 has increased the awareness and improved the management of these entities. During the subsequent 5 yrs, a considerable amount of information was added to literature and thus a revision of guideline was published in 2012. This guideline has given comprehensive recommendations in terms of classification, investigation, indication for resection, operation of choice and FU of this disease entity*MD-IPMN is defined as segmental/ diffuse dilation of the main pancreatic duct (MPD) >5mm without other causes of obstruction. A lower threshold of 5mm (instead of 1cm in 2006) is adopted in the 2012 BD-IPMN is defined as Pancreatic cyst of >5mm that communicates with the MPDFor Mixed type it meets the criteria for both types

*There are considerable differences in the proportions of each type and the frequency of malignancy is 62.2%, 34.4% and 57.6% for main duct, branch duct and mixed type respectively

*There are different types of imaging modality namely USG, CT, MRI+MRCP, EUS +/- FNAC etc*USG can show size and extent of lesion. CT has a sensitivity of 42%*Guideline recommends that risk of invasive carcinoma is uncommon in patients with an asymptomatic pancreatic cyst /=1cm strongly suggests main duct IPMNIt recommends resection of ALL main duct and mixed variant IPMN in view of its high frequency of malignancy *For Branch type IPMN, resection is indicated if size>3cm. For lesion between 1-3cm, if high risk stigmata is present eg MPD diameter >6mm, presence of mural nodules, presence of symptoms, +ve cytology, resection is recommended *There are some changes in the 2012 guideline* for BD-IPMN we need to assess if there is high risk stigmata of malignancy and worrisome features*If imaging shows the cysts with obvious high risk stigmata on CT or MRI ie obstructive jaundice in a patient with a cystic lesion of the pancreatic head, enhanced solid component MPD size >/=10mm, resection is required without further testing. *However, if patient has pancreatitis clinically or imaging shows worrisome features like cyst >/=3cm, thickened enhanced cyst walls, MPD size 5-9mm, non-enhanced mural nodules, abrupt change in MPD caliber with distal pancreatic atrophy and lymphadenopathy, EUS is recommended

*EUS should be arranged to see if there is mural nodule or main duct features suspicious for involvement. EUS FNAC can also be done to see if it is suspicious or positive for malignancy. If yes then surgery is mandated *So in summary for BDIPMN, we need to see if there is high risk stigmata, if yes then surgery is recommended. If no then we need to see if worrisome features are present, if yes then EUS is recommended. If EUS showed worrying features then surgery is reocmmended*In 2012 guideline, main duct dilatation of more than 5mm instead of 1cm in 2006 is defined as main duct type IPMNResection is still recommended for ALL main duct IPMN if duct size is more than 1cm in view of high incidence of malignancyHowever, MPD dilatation of 5-9mm should be considered as one of the worrisome features similar to the case for BD-IPMN with a recommendation of evaluation but no immediate resection*For method of pancreatectomy, it would be stratified according to the site and extent of disease. The aim of resection is complete removal of a tumor with a negative marginPancreatoduodenectomy, distal or total pancreatectomy +/- LN dissection is the standard treatment

Limited resection or focal non-anatomotic resections maybe considered for BD-IPMN However they may be associated with rare, leakage of mucin followed by pseudomyxoma peritonei and also a higher incidence of pancreatic fistule and risk of recurrence from potentially residual neoplasm

Low-grade dysplasia of IPMN maybe good candidate for laparoscopic surgery

*For FU recommendation, there are some changes in 2006 and 2012 guideline. FU recommendation is categorised into non-resected or resected IPMN *For non-resected IPMN, lesion less than 1cm should have FU imaging yearly.1-2cm and 2-3cm should have imaging in 6-12 month and 3-6 month interval respectively. FU can be lengthened if there is no change after 2 year of FU *For resected IPMN, benign pathology should have yearly imaging whereas malignant lesion should have 6 monthly imaging*In 2012, the main difference is that for non resected IPMN 2-3cm or >3cm in size EUS 3-6monthly then lengthen interval alternating MRI with EUS is recommended

*For those resected IPMN, Recurrence rate in the first 5 yrs 0-20%If the resection margin showed normal pancreatic tissue and non-dysplastic changes, it will be considered as negative margins and thus repeat examination at 2 and 5 years may be reasonableFor low grade or moderate grade dysplasia at margin, there is little evidence to guide freq and type of surveillance required to detect recurrence. Hx/PE and MRCP half-yearly is recommended

The FU strategy for invasive IPMN should be identical to that for pancreatic ductal adenoCA

*The 5 year survival rate for complete resection of non invasive IPMN is high up to 95%. For early stage and advanced disease the 5 year survival is 40 and 20% respectively *In conclusion, understanding of IPMN of pancreas continues to evolve. IPMN should be an important diagnosis that we should bear in mind as early investigation and treatment can help curing the disease. Thank you.

*So in summary, if imaging shows high risk stigmata, surgery is required. If smaller cyst with worrisome features or cyst >3cm with NO worrisome features EUS is recommended especially in elderly to verify the absence of thickened walls or mural nodules. If cyst size is 3cm is a weaker indicator of malignancy than the presence of mural nodules and positive cytology.Thus >3cm without these signs can be observed without immediate resection, particularly in elderly patient

Sometimes decision should be individualised as though controversial, patient 2cm maybe candidates for resection owing to the cumulative risk of malignancy

*In patients with 2 or more affected first degree relatives, the risk rapidly escalats and merits aggressive surveillanceWorrisome features are of most concern, if present or FU imaging showed rapidly growing lesion, patient should be considered for resection if surgically fitIf absent, patient should be followed by MRI/MRCP (or CT) at 3-month intervals and EUS annually for the first 2 years.

**Using a combination of clinical history, sex, imaging characteristics, cytology, cyst fluid CEA amylase level, cyst can be characterised as mucinous or non mucinous, and also identified for their subtypes *MCN is defined by the presence of ovarian stroma has a low prevalence of invasive carcinoma