Pancreatic Cystic Lesions

DEFINITION
Often 'incidentalomas' detected on imaging and referred for management.
"Cysts cause consternation for surgeons due to inaccurate diagnostics, ill-defined natural histories and significant consequences from inappropriately performed operations".
Numerous cystic lesions arise in the pancreas, with similar clinical and radiographical appearances.

D E A B M I M


EPIDEMIOLOGY

Incidental detection has led to an epidemic.

Incidence varies by cause
- generally F>M; some exceptions
- generally more common from 7th decade onwards
D E A B M I M
 

AETIOLOGY

Inflammatory
Most common variety - post-pancreatitis
- discussed elsewhere
Tumours
Benign, pre-malignant and malignant

D E A B M I M
 

BIOLOGICAL BEHAVIOUR

3 Categories
i) Serous cysts
- mainly serous cystadenomas (SCA)
- exceedingly uncommon serous cystadenocarcinoma
ii) Mucinous cysts
- mucinous cystadenomas (MCA)
- intraductal papillary mucinous neoplasms (IPMNs)
- non-dysplastic mucinous cysts (NDMCs)
iii) All others
- mainly malignancies with atypical cystic morphology, e.g. neuroendocrine tumours.
- solid pseudopapillary neoplasm (SPN); also called Hamoudi tumours.
- some benign cysts such as simple pancreatic cysts and lymphoepithelial cysts

Serous Cystadenoma
Most common cystic neoplasm
Difficult lesions; too commonly removed inappropriately
F>M; ~older age than the other cystic lesions
Each individual cyst is <2cm, often microscopic, can be massive and involve whole gland.
Are Benign.
But can cause vague abdominal pain due to mass effect if large.
Rarely cause obstructive effects if large, eg on CBD, pancreatic duct, duodenum
Pathology
:
True epithelium (non-mucinous) lined with glycogen-rich clear cuboidal cells that stain positive for periodic acid-Schiff (PAS)
- do not connect with pancreatic ductal system.
Thin walled capsule with a microcystic pattern

Serous Cystadenocarcinoma
Very rare, as in ~10 cases in the literature.

Mucinous Cystadenoma
1/4 of cystic pancreatic neoplasms.
F>M, often in 40s-50s.
Malignant potential or overtly malignant
Dysplastic; follows adenoma to carcinoma degeneration pattern that ends in invasive malignancy.
- however natural history and time course of this progression is uncertain
At resection 50% show high-grade dysplasia; or carcinoma (mucinous cystadenocarcinoma) in 10-15%
- mural nodules, calcification, positive cytology or spread should alert to risk.
Generally asymptomatic but can produce a mass effect.
Pathology

Large (<5cm), single, thick-walled lesions, with septae & papillae.
Cysts are bigger than in SCA, mostly in the body or tail.
Do not communicate with ductal system (distinguishing them from IPMN)
Histo shows discontinuous mucinous epithelium, often proliferative with dysplasia.
- often has an ovarian stromal appearance; hence predilection for women

IPMN
M=F, 60-70 yr olds generally.
- advancing age and men = higher risk of malignancy.
Consider in an older patient with idiopathic pancreatitis and a dilated duct.
By definition, are in continuity with the ductal system.
Definite malignant potential
And, unlike SCA and MCA, usually symptomatic with pain, steatorrhoea, weight loss.
Invasive carcinoma present in 40-50% at time of diagnosis; aggressive biology.
Most common in HOP.
Pathology
Lined with  mucinous papillary epithelium, proliferative tendencies.
- lack the ovarian-type stromal tissue
Site Classification
By relationship to main duct (important for malignant risk stratification)
i) Main duct disease (30%), involve the main duct, with or without secondary side branch involvement; high chance malignancy (30-50%).
- usually in head, but can be located anywhere
ii) Side branch IPMN ('branch-type') (70%); segmental branches involved only; less chance of malignancy (10-15%).
- diverse; may be unifocal, multifocal, segmental or diffuse, and may involve head, neck, body or tail.
- and vary in shape from circular to grapelike clustures
Concomitant GI malignancies in up to 1/3
Grading (degree of dysplasia)
Graded into low-grade, high-grade or invasive.
- low grade vary with papillary epithelium; lowest have flat, columnar, mucinous epithelium
- higher grade have papillary epithelium, higher mitotic activity and may be carcinoma in situ.
- if invasive, may be of colloid type (50% - more indolent) or tubular type (act like adenoCa - aggressive).
Genetics
Like pancreatic Ca; K-ras oncogene, disruption of p53 suppressor.
SMAD4 mutation (in adenoCa) rarely seen

Clinical comments
Usually found incidentally on imaging.
Otherwise usually subtle and vague symptoms.
Vague abdominal pains due to mass effect (50%)
Recurrent pancreatitis (10%)
Endocrine or exocrine pancreas insufficiency (25%)
Symptoms more common if invasive.

Outline

Who
Imaging
SCN
75%F  60-70y (Granny)
Lobulated
Microcystic
20% central scar.
central
Ca++
MCN
99%F  40-50y (Mother)
Macrocystic; us. 1
25% peripheral Ca++
95% in tail and body
Main duct IPMN
M=F 60-80y
Dilated pancreatic duct
Protruding POV
Side branch IPMN
M=F 60-80y
Bunch of grapes;
connected to PD


Others

1. Solid Pseudopapillary tumour
Aka Frantz tumour, Hamoudi tumour.
Third most common cystic neoplasm of the pancreas (10%)
Usually benign but can be aggressive, invasion of local structures, certain malignant and even metastatic potential in 5%
- distant spread to liver, peritoneal cavity; rarely lymph
- rare such that prognostic markers are lacking
Favours young people who show a large pancreatric mass in body or tail (F>M 10:1)
Generally asymptomatic but can cause pain or obstructive features with growth
While they appear cystic, that is false; secondary to necrotic degeneration of mass
4 Cs in diagnosis:
- circumscribed, cystic-appearing lesion, capsule, internally calcified
FNA usually unrewarding
Histology = sheets of polygonal epithelial cells with prominent stalks and incohesive appearance.
crowded sheets of cells around vascular stalks
- cell of origin unclear.
Should be R0 resected due to risk
- usually completely resectable even when large
--> cure rates >90%, but should follow up with imaging.
Aggressive approach to metastatic disease is justified, especially as most young and healthy
- adjuvant chemo used in selective circumstances
image


2. Lymphoepithelial cysts
Exceedingly rare
Totally benign and occasionally cause diagnostic confusion.
FNA shows their hallmark:
- lymphocytes, squamous cells, and cholesterol (cysts contain that and keratin).
Surgical options for those large enough to cause pain or obstruction.

3. Non-neoplastic mucinous cysts
Evolving area where not all mucinous cysts have malignant potential.
Indistinguishable until resection.

4. Autoimmune pancreatitis
(aka lymphoplasmocytic sclerosing pancreatitis)
Important but unusual, as treated medically.
Mimics adenoCa clinically and radiographically.
- hence most diagnosed only at resection.
- but new criteria focused on preventing this.
Often clusters with other autoimmune problems.
Symptoms mimic AdenoCa; overt e.g. jaundice, pancreatitis, endocrine / exocrine dysfunction
Diagnosis
1. Imaging often appears as having a 'full' pancreas resembling a sausage with a rim (loss of acinar pattern).
image
2. ERCP may show duct stricturing
3. Serology shows IgG4 specific to AIP (elevated in 70%)
4. Histology shows plasma cell infiltration with IgG4 positive ductocentric inflammatory destruction.
5. Other organ involvement, e.g. retroperitoneal fibrosis, biliary strictures.
6. Responds to steroids (in 4-6w)

5. Acinar Cell Carcinoma
Rare (<2%) but unique.
Favourable biology cf adenoCa
Often mid 50s, males, large (>5cm)
Look like neuroendocrine tumours but don't express chromogranin
Generate and release lipase, can be used as a tumour marker (some also alpha-fetoprotein)
Generally diagnosed post-operatively, when notable for its better survival

6. Pancreatic Lymphoma
Extremely rare, but needs to be considered as not operated.
Consider if systemic symptoms, associated lymph sites, atypical bulky lesion on scan
- generally proceeds to EUS, FNA is reliable.
Treatment is CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) +/- modern targeted agents
Do not operated: difficult, have complications and unnecessary.

7. Metastatic lesions
Very few cancers go to pancreas
E.g. RCC, melanoma, breast, lung, colon, gynae.
RCC often has long disease intervals and may be worth resecting.


D E A B M I M

MANIFESTATIONS

See Above
Lack of previous pancreatitis suggests neoplasm, not pseudocyst

Often found incidentally on imaging

IPMN
May present with pancreatitis
May have vague pains in epigastrium; possibly local compression
Signs of endocrine or exocrine insufficiency.


D E A B M I M

INVESTIGATIONS

US often ordered first, but CT needed to adequately image disease and pancreas.
Neoplasms usually lack inflammatory changes.

Serous Cystadenoma
Imaging
Thin walled capsule, thin walled septa
Common patterns:
- 'stellate scar': central scar, often calcified, surrounding septa/cysts (30%)
- 'honeycomb': numerous small cysts; more common.
- also the 'macrocystic morphology'
--> this latter form unfortunately confused with mucinous neoplasms; larger, discrete cavities separated by septa; often HOP and males.  Cysts shown on EUS.
- generally >6 cysts/neoplasm but rarely can be single.
image
A=t2MRI,honeycomb; B=stellate scar; C=internal calcification; D=macrocystic
EUS and FNA
Clear serous fluid low in CEA and mucin
Unfortunately, FNA sometimes shows atypia, causing confusion and resection of benign path

Mucinous Cystadenoma

Imaging
Often a rounded,  unilocular lesion, or smaller macrocystic multilocular lesion with septations (generally <6 cysts/neoplasm).
Calcification; may be confused with pseudocysts.
EUS and FNA
Viscous string-like mucinous fluid
- CEA>200 in fluid is strongly indicative of MCA (but not necessarily malignancy).
- low in amylase fluid (cf pseudocyst)
Aspirate cytology will determine if malignant cells or other (e.g. atypical or nondiagnostic; these are not very trustworthy).
image


IPMN
Differentiated by thorough history, imaging and endoscopy
Imaging

US & CT may show dilated duct.
Must differentiate main duct involvement -- malignant risk.
Branch duct disease: main duct normal, but focal multi-cystic lesion can be seen in HOP or throughout the gland.
Less rounded than MCN; often lobulated.
ERCP / MRCP shows ductal communication and MPD involvement
- MRCP is also useful to show mutifocality, ductal continuity and number of lesions.
- probably imaging modality of choice
Solid mass within lesion = suspicious for malignancy.
- as is invasion, associated masses, lymph nodes, peritoneal lesions.
EUS
Now a mainstay of diagnosis
Mucin extruding from an ampulla of Vater is pathognomonic of IPMN
 image
Perform FNA
Mural nodules on EUS >3mm suggests malignancy.
FNA
Send for tumour markers including CEA, K-ras mutation and loss of heterozygosity (all features of tumour)
Amylase level may help show continuity with duct.
ERCP
Useful for visualizing duct structure; limited by inability to fill contrast into side branches
PET
Sensitive for finding invasive malignancy in IPMN

D E A B M I M


MANAGEMENT

What to do with an incidentaloma
image

Serous Cystadenoma

Observation is the rule.
Some will increase in size (0.5cm/year).
- some >4cm can do so rapidly (2cm/yr)
[Growth = serous fluid accumulation, not dysplastic tissue].
Intervention
For symptomatic cysts (typically rapid growth), judged on a case by case basis.
--> anatomic, localized resection; enucleation appears to show more complications.
Far too many get interventions due to misdiagnosis as MCA or side-branch IPMN.
- can be confused in appearance, location, fna; difficult.
- be vigilant for identification of mucin, elevated CEA, scrutiny of clinical data
--> After any resection, surveillance imaging not required
Note:
Patients must understand the risks of imperfect diagnostic accuracy.

Mucinous Cystadenoma
Resection is the rule
All should ideally be removed due to malignant potential (despite unclear understanding of natural hx)
- 40% have at least marked dysplasia requiring an aggressive approach.
- 5 yr survival <50% if tissue invasion present.
Perform a formal anatomical resection
- Often a distal pancreatectomy required as in tail of pancreas
- but small lesions = may be possible to spare parenchyma.
Clear margins convey low recurrence risk
However should be considered for adjuvant therapy if malignant and close surveillance needed.
After resection of benign lesions, surveillance imaging not required

IPMN
Indications
Decision for resection based on patient, symptoms and oncological risk stratification.
Planning rests heavily on preoperative imaging
- essentially operate on all fit pts with MPD involvement
Else weigh surveillance vs surgery as per risk stratification and patient factors.
- strongly considered in side-branch if symptoms, concerning radiology or cytopathology, family hx of pancreas adenoCa, +ve cyst fluid  (e.g. CEA>1000, K-ras and LOH), CA-19-9>100.
- cyst size >3cm is a relative indication.
Some evidence suggests a marked field change here, of all ductal tissue
- hence multifocal IPMN (50%+) is a common and difficult problem.
--> address dominant or most threatening lesions and plan surveillance for the rest.
--> threatening = main duct invovlement, mural nodularity, mass, stricture, or positive cytopathology.
--> options are distal pancreatectomy, pancreaticoduodenectomy or total pancreatectomy

Overall, most treat as follows:

1. Discussion must include:
Cancer risk, treatment, surviellance, post-op progression, possibility of completion pancreatectomy.
Intraoperative conversion to lesser or greater or total operation
Endocrine and exocrine gland function counselling if risk of total resection.
Total pancreatectomy is a morbid procedure with significant long-term degredation of QOL.

2. Main duct disease
Site directed formal anatomic resection
- check margins on frozen section; else if positive and high grade will need to return for further resection.
--> 'creeping' resection if positive'.
If entire main duct involved, total pancreatectomy considered (FDG-PET-CT may help with decision making)
- associated with increased mortality and morbidity so avoid if possible.

3. Side branch
Same.  Enucleation and localized resections are not appropriate.

4. Surveillance protocol
Baseline MRCP, EUS, Ca19-9, Ha1C, alkphos
Surveillance every 3-6m with history / physical, MRCP, Ha1C, and perhaps EUS-FNA every 1-2 y.

After resection
Surveillance is required as recurrence approaches 50% for high grade lesions
- individualized plan as per pt and lesion factors.
- Imaging every 6-12 moths; stepping down at 3 yrs.
Adjuvant chemo-radiotherapy is of unproven benefit.


What if not fit for surgery
?
Endoscopic ablation with alcohol or paclitaxel.

Prognosis
Favourable if all tissue cleared; up to 100% long term disease free
If invasive, drops to 35-60% 5-yr disease-free.
Up to 1/3 of IPMN pts will have a concommitant tumour, e.g. gastric or colonic, however.

D E A B M I M


REFERENCES
Cameron 10th
Sarr & Sakorafas - Surgery of the Pancreas & Spleen; General Surgery Handbooks 2011