2. Introduction
2nd most common exocrine pancreatic neoplasm,
following only adenocarcinomas
Relatively rare neoplasms
Increased detection in asymptomatic individuals
2.6% of patients undergoing abdominal imaging
25% in autopsy series (73 in 300)
15% of pancreatic tumors
Incidence increases with age
Diagnostic challenge
3. Clinicopathologic Variables
Most common types (90%)
Serous Cystic Neoplasms (SCNs)
Mucinous Cystic Neoplasm (MCNs)
Intraductal Papillary Mucinous Neoplasm (IPMNs)
MCNs and IPMNs are more prevalent and have
malignant potential.
SCNs are almost always benign.
6. Serous Cystic Neoplasms
Compagno and Oertel in 1978
Microcystic adenomas
30% of all cystic neoplasm
Females (M:F – 1:3)
6th – 7th decade of life
Location – Head and uncinate process (>50%)
Each cyst contains glycogen rich, clear, watery fluid.
No mucin
Cysts are lined by single, uniform layer of cuboidal, glycogen
rich cells
7. Few cms to as large as 25 cms (6-10cms)
Usually asymptomatic
When large (>10cms) may cause symptoms
Honeycomb appearance – well demarcated multicystic cluster
of individual small cyst (< 2cms)
Cyst separated by fibrous stroma which is vascular and may be
calcified
Central sunburst, Radial or Stellate scar pattern on CT (30%)
Macrocystic (oligocystic) adenoma – less common, fewer cystic
spaces (>2cms)
No communication with pancreatic duct
8. Generally considered benign
Malignant transformation is very rare (<1%)
Only 25 cases of serous cystadenocarcinoma
Only 9 of 25 had metastasis
Growth rate correlated with tumor size
0.1 cm/year in tumors <4 cm
2 cm/year in tumors >4 cm
In select patients with large (>4 cm) or rapidly growing lesions,
resection is appropriate
9. Mucinous Cystic Neoplasms
Most common type
40 – 50% of all Pancreatic cystic neoplasms
Women (M:F – 1:9)
Mean age – 50 years
Body and tail of pancreas (>95%)
Solitary lesions
Size range from 6 to 35 cms (8 – 10 cms)
Fewer than six separate cysts (>2cm), rarely just one
macrocyst
No communication with pancreatic duct
10. Well encapsulated, spherical in shape
Cysts have septa within them and may have
solid, eccentric component
Content of cyst – usually mucinous, may be
haemorrhagic or watery or necrotic.
MCNs are lined by mucin secreting columnar
epithelium
Ovarian type stroma – pathognomonic of MCNs
Eggshell Calcification – pathognomonic of MCNs
Potentially premalignant lesion – malignant
degeneration after a long period
11. Histological Classification of MCNs (Mayo Clinic)
Mucinous cystadenoma (65%)
Uniform single layer of benign, columnar mucinous
epithelium
Non-invasive proliferative MCNs (30%)
Varying degree of atypia, dysplasia, papillary
endothelial infolding and carcinoma in situ
Mucinous adenocarcinoma (5%)
True invasive tumor
Spectrum of all these changes of epithelium may be found
within the same neoplasm.
12. MCNs frequently contain mutations of
K-ras2 oncogene
p53 tumor suppressor gene
Expression of DPC4 gene product is frequently lost in invasive
MCNs
Incidence of invasive cancer 6 to 20%
Risk factors for malignancy
Large tumor size (>4cm)
Associated mass, mural nodule, asymmetrically thickened wall
Eggshell calcification
Advanced age
Symptomatology – abdo pain, weight loss, jaundice, mechanical
duodenal obstruction
Splenic vein obstruction
13. Intraductal papillary Mucinous Neoplasms
Several names have been given:
Mucin secreting carcinoma (Ohashi et al, 1982)
Villous adenoma of the duct of Wirsung
Diffuse intraductal papillary adenocarcinoma
Intraductal cystadenoma
Mucinous duct ectasia
Intraductal papillary mucinous tumor
14. Formally defined by WHO in 1996 as:
“Intraductal mucin producing neoplasm with tall
columnar, mucin containing epithelium with or without
papillary projections, involving the main pancreatic duct
and/or major side branches and lacking ovarian stroma
characteristics of mucinous cystic neoplasm.”
15. 25% of all pancreatic cystic neoplasm
Pancreatic Head
Older men ( 6th – 7th decade)
The dysplastic lesions within the IPMN are usually
contiguous but on rare occasions can be multicentric
16. Types of IPMNs based on
morphology:
I. Main duct IPMN
II. Branch duct IPMN
III. Mixed type IPMN
17. Main Duct IPMN:
Dilation of main pancreatic duct
Diffuse (generalized) or Segmental (usually involving
body and tail)
Larger with prominent intraductal papillary projections
18. Branch Duct IPMN:
Cystic dilation of side branch of main pancreatic duct
system
Usually in head or uncinate process
Communicating with pancreatic ductal system
Frequently smaller
Indolent course as compared to main duct IPMN
Multifocal (30%), involves multiple non-contiguous side
branches
19. Histologically (WHO) IPMN divided into:
A. Benign
Adenoma without dysplasia
B. Borderline
Adenoma with mild to moderate dysplasia
C. Carcinoma
Non-invasive or invasive
Hyperplastic or dysplastic epithelium may be flat,
micro papillary or grossly papillary
20. Time from IPMN adenoma to invasive cancer – 3 to 6.4
years
25 to 48% IPMN contains invasive carcinoma
IPMN also exhibits different patterns of papillae
Gastric (most commonly branch duct IPMN)
Intestinal (Usually main duct IPMN)
Pancreatobiliary
Oncocytic
Null
21. Intestinal type IPMN are MUC2 positive progress to
invasive colloid carcinoma. Better prognosis
Pancreatobiliary IPMN are MUC1 positive progress to
invasive ductal/tubular adenocarcinoma. Poor
prognosis
Malignant IPMN associated with lower incidence (22%)
of lymph node metastases than ductal
adenocarcinoma and have favourable prognosis
22. Genomic alterations in IPMN – not established
Frequent (50% to 80%) K-ras point mutations
Loss of heterozygosity in 9p21 (p16) and 17p13 (p53)
Increased expression of cyclooxygenase-2
Upregulation of several genes (such as claudin and mesothelin)
Increased expression of matrix metalloproteinase-7, Proliferating-
cell nuclear antigen, and Vascular endothelial growth factor
Increased telomerase activity
23. Unlike SCNs and MCNs, IPMNs are a more aggressive
neoplasm
Approximately 40% at time of diagnosis of main-duct
IPMN have invasive malignancy
Benign main-duct IPMNs are at very high risk of
progressing into invasive cancer
24. Risk factors of underlying malignancy
Main Duct Disease
50 to 90% risk of carcinoma in situ and invasive
cancer
40 to 50% have invasive cancer
MPD dilation > 1cm
Mural nodules > 1cm
Risk of malignancy in branch-duct IPMNs – 25%
Risk of invasive carcinoma in branch-duct IPMNs is
even less (<15%)
Branch-duct dilation more than 3 cm
25. Presence of a mural nodule(s).
Advanced age (older than 70 years).
Presence of symptoms –
Pain (often as result of pancreatitis)
weight loss
Fatigue
Jaundice
30% of patients with malignant IPMNs are asymptomatic
Increased telomerase activity in pancreatic cystic fluid
Elevated CA 19-9 level
26. IPMN may also be accompanied by synchronous and/or
metachronous pancreatic ductal adenocarcinoma (2.5
to 9.2%)
IPMN also associated with synchronous and/or
metachronous malignancy in other organs like
colorectal, gastric and bile duct (23.6 to 32%)
27. Solid Pseudopapillary Neoplasms
Also known as:
Solid papillary epithelial neoplasm
Solid and cystic papillary tumors
Hamoudi tumors
Frantz tumors
5.5 to 12% of pancreatic cystic neoplasm
Young females in thirties
28. Well encapsulate
Typically large lesions (>10cms)
May occur anywhere within pancreas
Start as solid tumors, undergo massive degeneration
giving rise to cystic appearance
Solid and cystic areas and pseudopapillary patterns
seen on histology
Haemorrhage and necrotic cystic degeneration
Low malignant potential
29. SCNs MCNs IPMNs
Incidence 30 % 40 -50 % 25 %
Age 6th – 7th decade 5th decade 6th – 7th decade
Sex Females (M:F – 1:3) Females(M:F - 1:9) Equal/slightly higher
in males
Common location Head & uncinated
process
Body & tail Head (may
multifocal)
Morphology Microcystic Macrocystic Mixed
Imaging Central scar or
sunburst
calcification
Eggshell
calcification
Diffuse or segmental
dilatation of
pancreatic duct
Communication
with pancreatic
duct
Absent Absent (rare) Yes
Incidence of
malignancy
Very rare 6-20 % 25-48 %
30. Diagnostic Evaluation
Clinical Presentation
Asymptomatic – often discovered incidentally on imaging
Non – specific abdominal symptoms
Vague abdominal pain
Nausea and Vomiting
Abdominal fullness or mass
Symptomatic patients have larger lesion (>4cm)
Symptoms - MCNs > SCNs
Weight loss / Back pain / jaundice - ? Malignancy
IPMNs – recurrent episodes of pancreatitis
- misdiagnosed as idiopathic chronic pancreatitis
34. Features in favour of SCN
Indolent course
Lobulated contour
Lack of metastases or local invasion
Lack of peripheral calcification
Location in head of pancreas
35. MCNs
Predominantly macrocystic (80%)
Rarely multilocular (20%)
Spherical in shape
No communication with pancreatic duct
Partial duct obstruction may present
Cysts have thicker, irregular walls.
Usually have papillary excrescences extending into cystic lumen
Peripheral Eggshell calcification – pathognomonic
No pericystic inflammatory component
36. MCNs
Macrocystic form, septum and lack
of inflammatory reaction
Several macrocystic areas (>2cm) in
mid body of pancreas
37. Features of invasive MCN
Eggshell calcification
Eccentrically located mass within cystic
area
Multiple papillary invagination
Invasion of vascular structures
Complex cystic mass with solid intra-
cystic component
38. IPMNs
Cystic dilation of MPD or primary, segmental side branch
Branch duct IPMN – most common in uncinate process
Mucinous globules and malignant lesions – filling defect
Features of malignancy
MPD dilation >1cm
Mural nodules
Dilation of biliary tree
39. IPMNs
Dilation of MPD and atrophy of
parenchyma
Branch duct IPMN: dilation of
secondary branches of ductal
system
40. Endoscopic Ultrasonography
Detailed imaging of cyst morphology
Often detect communication between MPD and cyst
Useful when CT or MRI are equivocal
Aspiration of cyst content, sampling of cyst wall, septa and
mural nodules
Minimizes potential for tumor seeding along needle pathway
Extremely reliable, accurate and safe in experienced hands
Sensitivity, specificity and accuracy for malignant mucinous
tumor is 40%, 100%, and 55% respectively
41. Features of IPMN on EUS
Dilation of MPD
Hypoechoic thickening of duct wall
Mural nodules or papillary projections
Pancreatic atrophy
Multiple cysts communicating with main duct (not dilated) –
Branch duct IPMN
45. SPN
Well demarcated, hypoechoic
Solid appearing mass or mixed solid and cystic lesion or
purely cystic due to haemorrhagic necrosis
46. Problems with EUS
Low availability
Highly operator dependent
Unreliable in distinguishing benign and malignant lesion
Complications specific to EUS-FNA
Pancreatitis (2-3%)
Intracystic haemorrhage (<1%)
Infection (<1%)
47. ERCP
No role for SCN and MCN
Direct communication between pancreatic duct and
cystic lesion
Characteristic features of IPMN:
Patulous papilla resembling ‘Fish mouth’ with mucus
extruding from orifice (30%) – pathognomonic
endoscopic finding
Filling defects in dilated ducts and cystic side
branches
49. ERCP
Main duct ds: filling defects due to
mucin globules
Branch duct ds: continuity with
normal size MPD
50. Differentiate branch duct IPMN from MCN (difficult on non
invasive imaging)
Pancreatic juice for cytology and analysis
Temporary biliary stenting preoperatively – decompression of
jaundiced patient
No role of pancreatic stent in IPMN
Declining diagnostic role
51. MRCP
Non-invasive, diagnostic method with fewer procedure
related risks (compared to ERCP)
More specific than ERCP in imaging pancreatic duct
anatomy
Image fluid collections that do not communicate with the
pancreatic ductal system
Bunch of grapes appearance – Branch duct IPMN
Features suggestive of malignancy
Mural nodules or excrescences
Main-duct IPMNs especially with main pancreatic duct
dilation (>1cm)
Common bile duct dilation
52. MRCP shows both a main-
duct as well as a branch-
duct IPMN
53. PET – CT scan
Diagnosis of malignant lesion
Sensitivity and specificity - 92% and 95% respectively
May be used in differentiating benign versus malignant IPMN
Limited experience
54. Intraductal Ultrasonography
Promising role in differential diagnosis of pancreatic cystic
neoplasm
May be useful in determining the type and extent of
pancreatic resection particularly in main duct IPMN
Branch-duct intraductal papillary mucinous neoplasm located in the pancreatic
head with a mural nodule
56. Fine Needle Aspiration
Endoscopically
EUS guided (most commonly)
Percutaneously
CT guided
US guided
Analysis of aspirates includes:
Cytology
Viscosity
Presence of mucin and glycogen
Enzymes (amylase and lipase)
Antigenic tumor markers
57. Cytology
SCNs
Glycogen containing, low cuboidal cells, clear cytoplasm without
vacuoles
Positive immunostaining for cytokeratin AE1 and AE3
MCNs
Mucin containing columnar cells with rarely papillary sheets
IPMNs
Papillary clusters lined by mucin containing columnar cells
SPN
Branching papillae with myxoid stroma surrounded by monomorphic
neoplastic cells
58. Malignant cells on FNA – highly specific for Mucinous
cystadenocarcinoma or IPMN carcinoma
Accuracy of cytology is poor (59%)
Limitations:
Contamination
Low cellularity of aspirate
EUS guided Tru-cut biopsy – evaluated in small sample
size, appears to be safe.
59. Biochemical Analysis
Positive mucin stain or high viscosity – MCN or IPMN
Amylase levels:
High – IPMN
Low – SCN / MCN
Intra-cystic fluid Tumor markers:
CEA level – differentiates mucinous from non-mucinous lesion
(sensitivity - 75%, specificity - 74%)
>192 ng/ml – Mucinous lesion
< 5 ng/mi – non-mucinous
CA 19-9, CA 72-4, CA 125, CA 15.3 – may be raised in
mucinous lesions
61. Under Trials.
Intra-cystic fluid for Telomerase activity
Mutations
K-ras 2 oncogene
p53
62. Treatment
SCNs
Observation and serial imaging (annually)
Asymptomatic
Small lesion less than 4 cm
Frail or Elderly
Indications for operative intervention:
Symptomatic
Size more than 4 cms
Uncertainty regarding true nature
63. Operative procedure depend on anatomical location
Lesion in Body and tail of pancreas – Distal pancreatectomy
with/without spleen preservation
Lesion in Head of pancreas – pancreaticodudenectomy (pylorus
preserving)
Segmental central pancreatectomy – diminished risk of insulin
dependent diabetes
Enucleation – high morbidity (35%)
No role of extended lymphadenectomy
64. MCNs
Surgery is the treatment of choice
Pancreaticoduodenectomy
Distal pancreatectomy with/ without spleen preservation
Segmental central pancreatectomy
Extended lymph node dissection – not recommended
(incidence of LNs metastases is low)
Frozen section analysis
It is very important not to rupture the cyst during the
procedure
Cyst should be removed intact
65. Rarely, resection of involved adjacent structures or organs
(including portal vein) may be required
however, unlike pancreatic adenocarcinomas, malignant
MCNs tend to be “pushers” rather than “invaders.”
Conservative approach with serial imaging
Presumed low risk of malignancy
High-risk patients with severe comorbidities
Direct injection with ablation agent (alcohol, paclitaxel)
66. IPMNs
Surgical resection is treatment of choice
Extent of pancreatic resection is based on type of ductal
involvement
Localized Branch duct IPMN
Pancreaticodudenectomy
Central/distal pancreatectomy
Watchful waiting - ??
Multifocal Branch duct IPMN
Total pancreatectomy
67. Main duct IPMN localized to body and tail (10 – 25%)
Distal pancreatectomy including splenectomy with frozen
section analysis of proximal margin
Entire pancreatic duct is diffusely dilated
Pancreaticodudenectomy with intra-operative frozen section
analysis of distal margin
Prophylactic Total pancreatectomy – unacceptable and
unnecessary
No role for extended lymphadenectomy
68.
69. Adjuvant/Neoadjuvant Therapy
No randomized clinical trials
Aduvant chemotherapy – Gemcitabine based chemotherapy
with radiation (even after curative resection)
Presence of tissue invasion
Nodal metastases +/-
57% decrease in relative risk of mortality
Neoadjuvant therapy – paucity of evidence
70. Prognosis and follow up
SCNs
Resection ensures cure, no surveillance or adjuvant therapy needed
Excellent survival with 100% cure rates
MCNs
Non-invasive MCN – do not recur after complete resection
Invasive MCN – 5 year survival rate is 15 – 35 %
Six monthly follow up with CT/MRI for 2 years then annually
IPMNs
Non – invasive IPMN – 5 year survival rate >70 %
Invasive IPMN – 5 year survival rate 30 – 50 %
Yearly follow up with CT/MRI
72. References
Shackelford’s Surgery of the Alimentary Tract, 7th edition
Roshan Lall Gupta’s: Recent Advances in Surgery – 13
Blumgart’s Surgery of the Liver, Biliary Tract and Pancreas, 5th edition
Maingot’s Abdominal Operations, 12th edition
Sabiston Textbook of Surgery, 19th edition
Sakorafas GH, Smyrniotis V, Reid-Lombardo KM, Sarr MG. Primary pancreatic
cystic neoplasms revisited: Part I: Serous cystic neoplasms. Surg Oncol.
2011;20(2):e84-92
Sakorafas GH, Smyrniotis V, Reid-Lombardo KM, Sarr MG. Primary pancreatic
cystic neoplasms revisited: Part II: Mucinous cystic neoplasms. Surg Oncol.
2011;20(2):e93-101
Sakorafas GH, Smyrniotis V, Reid-Lombardo KM, Sarr MG. Primary pancreatic
cystic neoplasms revisited: Part III: Intraductal papillary mucinous neoplasms. Surg
Oncol. 2011;20(2):e109-118
Notas del editor
Symptoms – vague abdo pain, local pressure symptom, early satiety, obstructive jaundice
Surrounding tissue usually lack an inflammatory, pericystic reaction except when malignant transformation and tissue invasion have occurred.
Recent studies shows microscopic connection with pancreatic ductal system.
Ovarian stroma – presumed reason that MCNs are almost exclusively found in females.
The proliferative changes often coexist within the same neoplasm as some area show single layer benign columnar epithelium while other area may show changes of atypia, dysplasia, carcinoma in situ and even invasive carcinoma.
There may be focal or patchy area of invasive Ca or carcinoma in situ thus, numerous histological sections are required.
Most MCNs are “pushers” rather than “invaders.” The presence of splenic vein thrombosis in the absence of prior pancreatitis also should heighten the concern of invasive malignancy.
Characterised by – intraductal proliferation of neoplastic mucinous cell, which form micro and macro papillae and lead to cystic dilation of main pancreatic duct and or secondary branches (branch duct).
Interestingly, after resection of pancreatic parenchyma for presumably side-branch IPMN, in a substantial proportion of patients (up to 25%), histology shows concurrent histologic changes also within the main pancreatic duct; therefore, in these patients, the correct diagnosis is IPMN of the mixed type
this classification combines IPMN with carcinoma in situ and invasive IPMN; therefore, when reading the literature, one must be careful to remember this point
Wide spectrum of changes in epithelium can be recognized including normal, hyperplasia, dysplasia and carcinoma in same pancreas
Mucin 1, cell surface associated (MUC1) or polymorphic epithelial mucin (PEM
Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers
Frequent (50% to 80%) K-ras point mutations thereby establishing these mutations as a potential genetic marker for IPMN as with typical pancreatic ductal adenocarcinoma
. Therefore, the absence of symptoms does not guarantee the absence of malignancy
High resolution CT – cyst structure, and Serous or cystic
MRI – communication between MPD and cyst
filling of side-branch ducts at the time of ERCP may be obscured by intraductal plugs of mucin
Promising results in the diagnosis and differential diagnosis of pancreatic cystic neoplasms