Pancreatic Cystic Neoplasms
Dr Dheeraj YadavArmed Forces Medical College
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
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.
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
Four Morphologic Types of Cystic Lesions of the Pancreas
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
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
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
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
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
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.
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
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
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.”
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
Types of IPMNs based on morphology:
I. Main duct IPMN
II. Branch duct IPMN
III. Mixed type IPMN
Main Duct IPMN:
Dilation of main pancreatic duct Diffuse (generalized) or Segmental (usually involving
body and tail) Larger with prominent intraductal papillary
projections
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
Histologically (WHO) IPMN divided into:
A. Benign Adenoma without dysplasia
B. Borderline Adenoma with mild to moderate dysplasia
C. CarcinomaNon-invasive or invasive
Hyperplastic or dysplastic epithelium may be flat, micro papillary or grossly papillary
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)PancreatobiliaryOncocyticNull
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
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
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
Risk factors of underlying malignancy
Main Duct Disease50 to 90% risk of carcinoma in situ and invasive
cancer40 to 50% have invasive cancerMPD dilation > 1cmMural nodules > 1cmRisk 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
Presence of a mural nodule(s). Advanced age (older than 70 years). Presence of symptoms –
Pain (often as result of pancreatitis)weight lossFatigueJaundice 30% of patients with malignant IPMNs are
asymptomatic Increased telomerase activity in pancreatic cystic fluid Elevated CA 19-9 level
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%)
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
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
SCNs MCNs IPMNsIncidence 30 % 40 -50 % 25 %
Age 6th – 7th decade 5th decade 6th – 7th decadeSex Females (M:F – 1:3) Females(M:F - 1:9) Equal/slightly
higher in malesCommon location Head & uncinated
processBody & tail Head (may
multifocal)
Morphology Microcystic Macrocystic MixedImaging 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 %
Diagnostic EvaluationClinical Presentation Asymptomatic – often discovered incidentally on imaging Non – specific abdominal symptoms
Vague abdominal painNausea and VomitingAbdominal 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
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
CT Scan / MRISCNs 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
SCNs
Solid appearing lesion with central sunburst calcification
Microcystic mass in head of pancreas
Features in favour of SCN Indolent course Lobulated contour Lack of metastases or local invasion Lack of peripheral calcification Location in head of pancreas
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
MCNs
Macrocystic form, septum and lack of inflammatory reaction
Several macrocystic areas (>2cm) in mid body of pancreas
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
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
IPMNs
Dilation of MPD and atrophy of parenchyma
Branch duct IPMN: dilation of secondary branches of ductal system
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
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
EUS criteria for malignant mucinous neoplasm
Size larger than 2cm MPD dilation Solid lesion Wall calcification Mural nodule Duct filling defect Thickened septa
SCNs Numerous small cysts Thin walled septa Calcification of central septa
MCNs Unilocular or multilocular Macrocystic septations and/or adjacent mass
SPN Well demarcated, hypoechoic Solid appearing mass or mixed solid and cystic lesion
or purely cystic due to haemorrhagic necrosis
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%)
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
Pathognomonic for IPMN on ERCP – “Fish mouth ampulla”
ERCP
Main duct ds: filling defects due to mucin globules
Branch duct ds: continuity with normal size MPD
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
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
MRCP shows both a main-duct as well as a branch-duct IPMN
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
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
Intraductal Pancreatoscopy
Main-duct intraductal papillary mucinous neoplasm (fish-egg-like appearance)
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
CytologySCNs 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
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.
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
Analysis of aspirateSCNs 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
Under Trials. Intra-cystic fluid for Telomerase activity Mutations
K-ras 2 oncogenep53
TreatmentSCNs
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
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
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
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)
IPMNs
Surgical resection is treatment of choice Extent of pancreatic resection is based on type of ductal
involvement Localized Branch duct IPMN
PancreaticodudenectomyCentral/distal pancreatectomyWatchful waiting - ??
Multifocal Branch duct IPMNTotal pancreatectomy
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
Adjuvant/Neoadjuvant Therapy
No randomized clinical trials Aduvant chemotherapy – Gemcitabine based chemotherapy
with radiation (even after curative resection)Presence of tissue invasionNodal metastases +/-
57% decrease in relative risk of mortality
Neoadjuvant therapy – paucity of evidence
Prognosis and follow upSCNs 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
TAKE HOME …
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