pancreatic cystic neoplasms

1. Pancreatic Cystic Neoplasms
Dr Dheeraj Yadav
Armed Forces Medical College

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.

4. WHO Classification
 Serous Cystic Neoplasm
• Serous cystadenoma
• Serous microcystic adenoma
• Serous oligocystic adenoma
• Serous cystadenocarcinoma
 Mucinous Cystic Neoplasm
• Mucinous cystadenoma
• Mucinous cystic neoplasm with moderate dysplasia
• Mucinous cystadenocarcinoma (invasive/non-invasive)
 Intraductal Papillary Mucinous Neoplasm
• Intraductal papillary mucinous adenoma
• Intraductal papillary mucinous neoplasm with moderate dysplasia
• Intraductal papillary mucinous carcinoma (invasive/non-invasive)
 Solid Pseudopapillary Neoplasm

5. Four Morphologic Types of Cystic
Lesions of the Pancreas

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

31.  USG Abdomen – Limited value
 CT Scan/ MRI – Gold standard
 Endoscopic ultrasound
 ERCP
 MRCP
 PET – CT Scan
 Intraductal pancreatoscopy
 Intraductal ultrasonography
 EUS/CT guided FNAC
 Cyst fluid analysis

32. CT Scan / MRI
SCNs
 Accuracy 90 – 95 %
 Three patterns on imaging:
 Polycystic (70%)
 Oligocystic (<10%)
 Honeycomb (20%)
 Central fibrous scar with characteristic Sunburst calcification
(30%) – pathognomonic
 Low attenuation on CT and high signal intensity on T2-
weighted MRI

33. SCNs
Solid appearing lesion with central
sunburst calcification
Microcystic mass in head of pancreas

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

42. EUS criteria for malignant mucinous neoplasm
 Size larger than 2cm
 MPD dilation
 Solid lesion
 Wall calcification
 Mural nodule
 Duct filling defect
 Thickened septa

43. SCNs
 Numerous small cysts
 Thin walled septa
 Calcification of central septa

44. MCNs
 Unilocular or multilocular
 Macrocystic septations and/or adjacent mass

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

48.  Pathognomonic for IPMN on ERCP – “Fish mouth ampulla”

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

55. Intraductal Pancreatoscopy
Main-duct intraductal papillary mucinous neoplasm
(fish-egg-like appearance)

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

60. Analysis of aspirate
SCNs MCNs IPMNs
Cytology Cuboidal, glycogen
rich cells
Columnar cells Columnar cells,
papillary clusters
Fluid appearance Thin, clear Viscous, clear Viscous, clear
Mucin Absent Present Present
Amylase Low Low High
CEA (ng/ml) < 5 >192 >192
Malignant potential No Yes Yes

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

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

71. TAKE HOME …

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