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