1. KOK SIU YAN AMY United Christian Hospital
Management of intraductal papillary mucinous neoplasm of pancreas (IPMN) An Update
KOK SIU YAN AMY
United Christian Hospital
Good morning ladies and gentlemen, the topic of my presentation today is Management of intraductal papillary mucinous neoplasm (IPMN) of pancreas, An update.

2. IPMN Introduction Classification Investigation
Indication for resection
Methods of resection
Follow-up
Prognosis
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

3. Introduction History: 1982 Incidence ~2.04 per 100 000
Described by Ohashi and his colleagues
Incidence ~2.04 per
Autopsy studies 25% of cystic pancreatic lesions
30-50% may become invasive
Accounts for 5-7% of all pancreatic neoplasm
IPMN is a cystic, intraductal mucin-producing neoplasm which
demonstrates significant pancreatic ductal dilatation.
It is first described in 1982 with an incidence of around 2 per % may become invasive. It also accounts for 5-7% of all pancreatic neoplasm.
Dtsch Arztebl Int. 2011 Nov;108(46):
Intraductal papillary mucinous neoplasia (IPMN) of the pancreas: its diagnosis, treatment, and prognosis.
Grützmann R, Post S, Saeger HD, Niedergethmann

4. Presentation
Apart from those asymptomatic ones, some may present with pain, jaundice, pancreatitis or constitutional symptoms.
Dtsch Arztebl Int. 2011 Nov;108(46):
Intraductal papillary mucinous neoplasia (IPMN) of the pancreas: its diagnosis, treatment, and prognosis.
Grützmann R, Post S, Saeger HD, Niedergethmann M.

5. Management guideline
First international consensus guideline in 2006 and was revised in 2012
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 This guideline has given comprehensive recommendations in terms of classification, investigation, indication for resection, operation of choice and FU of this disease entity

6. classification Main duct Branch duct Mixed
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 MPD
For Mixed type it meets the criteria for both types

7. classification
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

8. Investigation USG CT MRI + MRCP EUS +/- FNAC ERCP
Intraductal USG or pancreatoscopy
There are different types of imaging modality namely USG, CT, MRI+MRCP, EUS +/- FNAC etc

9. investigation USG CT Size and extent
Diffusely distended pancreatic duct with mucinous filling defects and cystic space occupying lesions
Sensitivity 42%
USG can show size and extent of lesion. CT has a sensitivity of 42%

10. investigation MRI with MRCP
Entire pancreatic parenchyma and the intra- abdominal organs
More sensitive to detect mural nodules
Sensitivity 88%
Guideline recommends that risk of invasive carcinoma is uncommon in patients with an asymptomatic pancreatic cyst <1cm and thus no further workup is required.
For cyst greater than 1cm, pancreatic protocol CT or gadolinium-enhanced MRI with MRCP is recommended for better characterisation of the lesion in terms of septae, nodules and duct communications
Br J Surg. 2009 Jan;96(1):5-20.
Preoperative tissue diagnosis for tumours of the pancreas.
Hartwig W, Schneider L, Diener MK, Bergmann F, Büchler MW, Werner J.

11. This is the CT scan showing a markedly dilated main pancreatic duct in a patient with a main duct IPMN with a mural nodule in the body of the pancreas (arrow).
Another CT demonstrating a multilocular cystic lesion in the head of the pancreas (black arrow) and a unilocular cyst in the tail (white arrow), representing multiple branch duct IPMNs.
This is the MRCP showing multifocal BD-IPMN

12. Investigation EUS-FNA Investigational Small BD-IPMN CEA Amylase
Cytology
Molecular analysis
Investigational
Small BD-IPMN
Apart from imaging, EUS guided FNA for CEA, amylase, cytology and molecular analysis are suggested by some studies. However results are inconclusive
Fluid cytology may add value especially for evaluation of a small BD-IPMN
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 another study
However evidence is inconclusive and thus this guideline suggests cyst fluid analysis is still investigational, but is recommended for evaluation of small BD-IPMN only in centres with expertise in EUS-FNA and cytological interpretation

13. investigation
This is the EUS demonstrating a mural nodule in a branch duct IPMN in the head of the pancreas
EUS showed a mural nodule in the dilated MPD with Doppler flow indicating the presence of blood supply

14. INDICATIONS FOR RESECTION
MD-IPMN
BD-IPMN
Concerning indication for resection, we need to take whether it is MD or BD type IPMN into account.
There is change in recommendation in 2006 and 2012 guideline

15. 2006 guideline: MD-IPMN Main duct dilatation≥1cm
Frequency of malignancy: 60-92%
No clinical parameters accurately discriminate malignant and non-malignant lesion
RESECT ALL MAIN DUCT AND MIXED VARIANT IPMN
IF SURGICALLY FIT
In 2006, it states that Main duct dilatation >/=1cm strongly suggests main duct IPMN
It recommends resection of ALL main duct and mixed variant IPMN in view of its high frequency of malignancy

16. For Branch type IPMN, resection is indicated if size>3cm.
2006 guideline: BD-IPMN
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

17. 2012 guideline
There are some changes in the 2012 guideline

18. 2012 guideline: BD-IPMN
for BD-IPMN we need to assess if there is high risk stigmata of malignancy and worrisome features

19. 2012 guideline: BD-IPMN High-risk stigmata
Obstructive jaundice in patient with cystic lesion of the head of pancreas
Enhancing solid component within cyst
Main pancreatic duct ≥10mm in size
CONSIDER SURGERY IF CLINICALLY APPROPRIATE
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.

20. 2012 guideline: BD-IPMN Worrisome features
Clinical: pancreatitis
Imaging:
cyst≥3cm
Thickened/enhancing cyst walls
Main duct size 5-9mm
Non-enhancing mural nodule
Abrupt change in calibre of pancreatic duct with distal pancreatic atrophy
PERFORM ENDOSCOPIC ULTRASOUND
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

21. 2012 guideline: BD-IPMN EUS features: Definite mural nodule
Main duct features suspicious for involvement
Cytology: suspicious or positive for malignancy
CONSIDER SURGERY IF CLINICALLY APPROPRIATE
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

22. 2012 guideline: BD-IPMN
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

23. 2012 guideline: MD-IPMN MD-IPMN Main duct dilatation≥5mm
5-9mm  worrisom features
Evaluation
No immediate resection
In 2012 guideline, main duct dilatation of more than 5mm instead of 1cm in 2006 is defined as main duct type IPMN
Resection is still recommended for ALL main duct IPMN if duct size is more than 1cm in view of high incidence of malignancy
However, 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

24. Method of pancreatectomy
According to site and extend of disease
Pancreatoduodenectomy
Distal pancreatectomy
Total pancreatectomy
Limited resection
Excision
Enucleation
Uncinatectomy
Laparoscopy
+/- lymph node dissection
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 margin
Pancreatoduodenectomy, 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

25. follow-up Non-resected IPMN Surgically resected IPMN
For FU recommendation, there are some changes in 2006 and 2012 guideline. FU recommendation is categorised into non-resected or resected IPMN

26. 2006: non 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

27. 2006: resected IPMN Benign: Malignant Yearly CT/MRI 6 monthly CT/MRI
CEA & CA19.9 no value
For resected IPMN, benign pathology should have yearly imaging whereas malignant lesion should have 6 monthly imaging

28. 2012: Non-resected IPMN
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

29. 2012: Resected IPMN Surgical margin status normal pancreatic tissue
non-dysplastic changes
low grade dysplasia
moderate grade dysplasia
invasive carcinoma
Repeat exam 2-5 years
Hx/PE/MRCP half-yearly
Identical to PDAC
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 reasonable
For 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

30. prognosis Complete resection of noninvasive IPMN
5 year survival rate 95%
Complete resection of early stage tumors(T1N0)
5 year survival rate 60%
Advanced or nodal positive tumors
5 year survival rate 36%
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

31. Conclusion
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.

33. investigation High-risk stigmata surgery
Smaller cyst + worrisome features EUS
Cyst >3cm + NO worrisome features EUS if elderly
Cyst ≤3cm + NO worrisome features surveillance
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 with no worrisome features, only surveillance is recommended

34. Md-ipmn High incidence of malignant/invasive lesions (61.6%/43.1%)
Segmental ectatic type/Diffuse type with focal lesions
Diffuse type without focal lesions
Frozen section
Intraductal USG/pancreatoscopy
In main duct type IPMN, considering its high incidence of malignancy or invasive lesions, surgical resection is recommended for all surgically fit patients
In segmental ectatic type or diffuse type with focal lesions, it is easy to determine the resection side (proximal or distal pancreatectomy) and the transection line
For diffuse dilatation type without focal lesion, FS is useful to decide the resection line, if +ve for high grade dysplasia additional resection of pancreas should be attempted to obtain a negative margin. Thus total pancreatectomy should be discussed prior to the operation
If low-grade or moderate-grade dysplasia is found, further resection is controversial

35. Bd-ipmn Mean frequency of malignancy/invasive cancer (25.5/17.7%)
Elderly
Annual malignancy risk 2-3%
High risk factors:
Mural nodules
High grade dysplasia/Positive cytology
Rapidly increasing size
Individual decision
For Branch duct type IPMN, though resection warrants consideration, these lesions mostly occur in elderly patients and the annual malignancy rate is only 2-3%
These factors support conservative management with FU in patients who do not have risk factors predicting malignancy
Also, in BD-IPMN, a size of >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 <65yo with a cyst size >2cm maybe candidates for resection owing to the cumulative risk of malignancy

36. Family history
One 1st degree relative with PDAC 2.3-fold increased risk
high-quality MRI/MRCP or CT and EUS
Malignant stigmata/worrisome features
resection
No malignant stigmata/worrisome features
MRI/MRCP or CT at 3-month intervals
EUS annually for first 2 years
In patients with 2 or more affected first degree relatives, the risk rapidly escalats and merits aggressive surveillance
Worrisome features are of most concern, if present or FU imaging showed rapidly growing lesion, patient should be considered for resection if surgically fit
If absent, patient should be followed by MRI/MRCP (or CT) at 3-month intervals and EUS annually for the first 2 years.

37. Distinction of BD-IPMN from mcn & other pancreatic cyst
Combination of clinical & imaging characteristics can provide preoperative diagnosis of cyst type
Multidetector CT (MDCT) & MRCP are useful for defining morphology, location, multiplicity, and communication with the MPD
Distinguishing features: multiplicity & visualisation of a connection to MPD
EUS: 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

38. Distinction of BD-IPMN from serous cystic neoplasm (SCN)
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

39. Pancreatic cyst Neoplastic cysts: Non-mucinous Mucinous
Serous cystic neoplasm (SCN)
Solid pseudopapillary neoplasm (SPN)
Mucinous
Mucinous cystic neoplasm (MCN)
Intraductal papillary mucinous neoplasm (IPMN)

40. PANCREATIC CYST
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

41. MCN Low prevalence of invasive carcinoma (<15%)
Resection is recommended
Young
Risk of progression
Locations in body and tail
High cost of long-term FU
Distal pancreatectomy
Parenchymal-sparing resection (middle pancreatectomy)
Laparoscopic
MCN is defined by the presence of ovarian stroma has a low prevalence of invasive carcinoma <15% with no malignancy in MCN <4cm without mural nodules
Observation maybe considered in elderly
However given the relatively young age of most patients, the risk of progression to invasive MCN and their common locations in pancreatic body and tail, surgical resection is recommended for all surgically fit patients since natural hx of MCN is still unknown and non operative management would require yrs of FU based on high resolution imaging associated with high costs
Resection is routinely curative in non-invasive MCN with no recurrence
MCN are usu located in pancreatic body and tail and thus distal pancreatectomy can be performed
MCN <4cm without mural nodules, parenchymal-paring or laparoscopic procedure should be considered
Resection is recommended for all surgically fit patients with MCN

42. EUS-FNA
Apart from imaging, elevated cyst fluid CEA is a marker that distinguishes mucinous from non mucinous cysts, but NOT benign from malignant cysts
A cut off of >/= ng/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

43. prognosis
Synchronous/metachronous malignant diseases in extra-pancreatic organs
20-30%
Frequency and location of extra-pancreatic malignancies differs
GI cancer is common in Asia
Skin/breast/prostatic cancers common in US
No screening recommendation for detecting extrapancreatic malignancies, but once dx is made, consideration of extrapancreatic neoplasm should be undertaken based on freq of malignancy in that country eg 2 reports have recommended screending of colorectal polyps and cancer in US

44. conclusion
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 conservative
BD IPMN >3cm without high risk stigmata can be observed without immediate resection

45. 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): doi: /ajg Epub 2013 Mar 5.
Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study.

46. MR LKF 75/m Good past health No history of pancreatitis
No family history of pancreatic cancer
Physical examination: unremarkable
Let’s start with a case scenrio. Mr Lan Kwai Fong, a 75 year-old gentlman who has good past health with no history of pancreatitis nor family history of pancreatic cancer. Physical examination is unremarkable

47. 2.5cm cystic lesion over pancreas
Ultrasound
He was referred to our clinic for an incidental finding of a 2.5cm hypoechoic cystic lesion over pancreas.
So what will u do next? Ignore it? Resect it? Arrange further investigation?
2.5cm cystic lesion over pancreas
What should we do next?

48. Pancreatic cyst 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
there are a number of differential diagnosis for pancreatic cystic lesion. Some of them are benign but some are of malignant potential that we should pay attention to.

49. Pancreatic cyst 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%)
Others
28 (13%)
According to some previously reported journals, IPMN comprises a high % in final pathology for resected pancreatic cystic lesions

50. introduction WHO classification of digestive system 2010
IPMN with low or intermediate grade dysplasia
IPMN with high grade dysplasia
IPMN with invasive cancer

51. SUMMARY Criterion for characterising MD-IPMN >5mm
MD-IPMN: resection
BD-IPMN:
high-risk stigmata & worrisome features
Conservative

52. Other treatment modality
EUS-guided mucosal ablation by ethanol injection
Indication:
Cyst >2cm
Unilocular/oligolocular
No communication with MPD
Refuse surgery
High risk surgical candidates
Other treatment modality was recently reported for instance EUS guided mucosal ablation by ethanol injection for those patients who refuse or not fit for surgery with a cyst size of >2cm

53. Other treatment modality
CT-defined cyst resolution rates 33-79%
Variable histopathologic degrees of epithelial ablation
Complication:
Acute pancreatitis (4.5-10%)
Abdominal pain (<20%)
Splenic vein obliteration
Study reported that FU CT revealed no evidence of cyst recurrence for a median of 26 mths after cyst resolution
However it is not without complication and thus it is still not recommended for patients with BD-IPMN outside closely monitored research protocol

54. Investigation ERCP Washing or brushing for cytology Not recommended
Few studies suggest that pancreatic juice can be obtained via ERCP by washing and blushing for cytology
One large series showed a significant role of CEA levels of >30ng/ml in diagnosing malignant BD-IPMN
However, routine ERCP for sampling of fluid or brushings in IPMN is not recommended and should only be used in the context of research

55. investigation
Intraductal USG or pancreatoscopy and cytology can be used to obtain additional info of surgical margin in difficult cases. Both are preferrably done preoperatively to avoid leakage of mucin.
This Intraductal USG showed a 25mm mural nodule in main pancreatic duct
This Peroral pancreatoscopy showed a fish egg-like mucosal lesion in MPD