Module 2.4: Pancreato-biliary Flashcards
(80 cards)
1
Q
Types of Primary Pancreatobiliary Malignancy
A
• Pancreatic Adenocarcinoma
o Often involves head and neck and the acinar ducts obstruction develops when cancer develops around bile duct that runs through head of pancreas/due to lymph node swelling
o Those with cancer in the body or tail of pancreas are unlikely to present early as bile duct will not be affected no symptoms: jaundice/pale stools/dark urine
• Cholangiocarcinoma
o Cancer of the bile duct may cause obstruction
• Ampullary carcinoma
o Affects ampulla which is where common bile duct and pancreatic duct meet
o Radiologically: double duct sign: dilatation of both ducts is seen (bile duct and pancreatic duct)
• Gallbladder Carcinoma
o Can present with biliary obstruction
2
Q
Causes of Secondary Pancreatobiliary Malignancy
A
o Breast
o Lung
o Lymphoma lymph node swelling can obstruct bile duct
o Melanoma
3
Q
management of Malignant Bile Duct Obstruction
A
- 75-80% carcinoma head of pancreas.
- 15-20% considered for curative surgery.
• The majority managed by:
o Stenting
o Chemotherapy (not curative in pancreatic cancer)
4
Q
Types of stent in bile duct obstruction
A
o Plastic stents
o Self-expanding metal stents (SEMs) allow for better drainage, less occlusion of stents and remodelling of ducts more, can come fully covered/uncovered use depends on whether patient is palliative as well as personal preference (uncovered = reduced migration rate, covered = if clogged up by tumour, there is less tumour ingrowth so it is easier to remove and insert a new one)
5
Q
Describe the types of plastic stents used in bile duct obstruction and their limitation
A
• Two varieties o Pigtail: split the duct open o Straight: allows bile drainage out of the system within stent must ensure stricture is tight enough to secure this, if not use pigtail stent as it allows anchoring (see right) • Limitation: o High occlusion rate
6
Q
Describe the use of SEMs in bile duct obstruction
A
- Flexible come compressed and are deployed once passed through endoscope working channel
- Tensile strength springs open and is able to remodel strictures
- Fully covered metal stents has an inner mesh that prevents it from embedding into the bile duct
• Advantages:
o Patency of SEMs is better than plastic stents
o Plastic stents becomes occluded more quickly à usually within 3 months compared to SEMs = 6 months
o If stents become occluded patients become really sick and septic this can interfere with chemotherapy regime
7
Q
Endoscopic Management of Pancreatic Cancer
A
• Sewnath ME, Ann Surg 2003: Meta-analysis that looked at 5 trials with 302 patients and worked to determine whether pre-op drainage was useful prior to Whipple’s procedure
o Pre-op drainage caused:
Increased complications (ERCP carries its own risks e.g. pancreatitis)
No survival benefit
Prolonged hospital stay
8
Q
How can malignancy of the bile duct be confirmed?
A
• Cross-sectional Imaging
o CT scan is good for mass lesions
o MRCP good for outlining biliary and pancreatic structures
• Tumour Markers – Ca19-9 (not specific, but helpful in the extremes e.g thousands, or single digits)
• Immune Markers
• Histology
• Cytology (tissue diagnosis of C5 indicates cancer)
• Cholangioscopy
9
Q
Types of Benign Hilar Structures
A
• Covera et al 2005: study that showed that not all hilar strictures are malignant
o 22/275 (8%) of resections were confirmed as benign disease due to:
Lymphoplasmacytic sclerosing disease
Primary sclerosing cholangitis
Granulomatous disease
Non-specific fibrosis
Stone disease
10
Q
Uses of Selective MRCP and CT Targeted Drainage
A
Hintze et al 2001, Freeman et al 2003:
o Aim to drain a minimum of 30% of biliary tree
o Optimally to place one stent to achieve drainage
o Two or more stents are placed if:
30% of liver drainage is not achievable
To drain all opacified segments
- Unilateral placement 85%, bilateral in 15%
- Low cholangitis rates
- Clinically successful bile drainage in 75%
- Always must choose to drain the area with the most functioning liver
11
Q
Developments in Endoscopic Palliation
A
• Photodynamic Therapy
• Radiofrequency Ablation via Biliary Catheter
o Sets up heat rim around catheter and burns tumour at repeated points, balloon any necrotic tissue
o Done as often as is required
o Stents can be cleared up using this method
• Removable/Self Absorbing Stents
• Drug Eluting Stents
12
Q
Stenting for Malignant Bile Duct Obstruction - Summarise
A
- Management dependant upon detailed pre intervention assessment.
- Metal stenting in almost all settings.
- Covered stents may be optimum in extrahepatic obstruction.
- Intervention for hilar strictures requires multi disciplinary approach.
- New techniques for improving stent patency /relieving stent occlusion
13
Q
Define Endosonography
A
use of high frequency miniature ultrasound transducer incorporated into the tip of a conventional endoscope resulting in an enhanced resolution of the GI wall and strictures with close proximity to the GI wall.
14
Q
Advantages and disadvantages of endosonography
A
• Advantages
o High intrinsic spatial resolution
o No ionizing radiation
o Inexpensive and easily portable
• Disadvantages
o Gas and bone impede the passage of USS waves, acoustic shadows can also be caused by calcification
o As good as the operator
o Only planar view taken
15
Q
Types of Echoendoscopes
A
o Radial used for upper GI cancers
o Linear allows needles to be placed to take samples, most commonly used
o Miniprobes
16
Q
Indications of endosonoscopy
A
o Staging of malignant GI tumours: ampulla of Vater, extrahepatic bile ducts and pancreas. (see how deep into the tissue the cancer goes)
Assessing the extent of ampullary adenomas/malignancies (adenoma seen on right)
o Obtain FNA/Biopsy of lesions in accessible organs including mediastinal lymph nodes
o Therapeutics: Perform coeliac plexus block – for pain relief; facilitate biliary and pancreatic access when ERCP fails
17
Q
Complications of endosonography
A
o Perforation (1%) o Bleeding (<1%) o Sedation related cardiorespiratory problems o Pancreatitis (0.9%) o Infection (0.1%) must give antibiotics
18
Q
• EUS in Pancreatic Cancer
A
o Post-operative 5 year survival for pancreatic Ca is 20 %
o Incomplete resection and positive nodes carry bad prognosis
o EUS may help to better select patients for curative surgery or to identify the non surgical candidates as it can be used to detect, stage, vascular invasion and resectability of pancreatic cancers. It is also better at defining lesions <2-3cm but more studies are needed to confirm this.
19
Q
Describe the uses of the celiac nerve block
A
- Relatively easy and safe to perform (Alcohol and bupivicane used to ablate the plexus)
- Similar success rate to other methods but less invasive
- Diarrhoea main complication
- Useful in pancreatic Ca related pain but not in CP
20
Q
Clinical Features of CC
A
• Rare before 40 years
• Presenting features depend on location
o Tumours at bifurcation of hepatic ducts or in distal CBD classically present with biliary obstruction:
Painless jaundice
Pale stools
Dark urine
Pruritus
o Peripheral tumours, arising within intrahepatic ducts of the liver parenchyma itself, present with non-specific symptoms:
Malaise
Weight loss
Abdominal pain
• Cholangitis is an unusual presentation
• Most patients have unresectable disease and die in less than 12 months due to:
o Liver failure
o Cancer cachexia
o Recurrent sepsis, secondary to biliary obstruction
21
Q
Explain the poor prognosis in CC
A
- Overall 5-yr survival, including resected patients: <5 %
- This has not changed significantly over the past 30 years
- Possibly due to difficulty in confirming a diagnosis: (no classical imaging features, difficult area to reach with biopsy needle/unaccessible, no tumourmarker to aid diagnosis), patients present very late, risk factors only account for 20% of presentations
22
Q
Classification of CC
A
• 90% are adenocarcinomas
• 50 – 60% are “Peri-Hilar”
arise at bifurcation of hepatic ducts (aka “Klatskin” tumours, usually classified as ICC) (pCCA)
- 20 - 30% in distal common bile duct (CBD)
- 10-20% are intrahepatic (iCCA)
- 5 - 10% are “peripheral”, arising within intrahepatic ducts of liver parenchyma itself
23
Q
Classification of Biliary Structures
A
Bismuth
- Type I: Tumours below the confluence of L and R hepatic ducts
- Type II: Tumours reach confluence but not involving L or R hepatic ducts
- Type III: Tumours occlude the common hepatic duct and either right (IIIa) or left (IIIb) hepatic duct
- Type IV: Tumours that are multi-centric or involving both right and left hepatic ducts
24
Q
Epidemiology of cc
A
o CC makes up 3% of all GI cancers
o 2nd commonest primary hepatic tumour
o Peak age: 7th decade
o Sex incidence: slight male preponderance
o Incidence rates for IHCC vary worldwide, reflecting local geographical risk factors and genetic differences in various populations
o Highest rates in NE Thailand (96/100,000 men), China and other parts of Southeast Asia
Possibly due to liver flukes (environmental exposure)
o Incidence in USA: 1-2 cases/100,000 (3,500 new cases/year); Australia 0.2/100,00 (men)
o Rising incidence rates, paralleled by mortality rates, documented worldwide
• Recent international studies of incidence + mortality rates show that:
o ICC increasing
o ECC decreasing
25
Explain the problems with the CC epidemiological data
Perihilar CC has been misclassified as intra or extrahepatic in different classification methods
ICD-0-1 - intra OR extra
ICD-O-2 - coded as INTRA (1991)
ICD-O-3 - coded as INTRA or EXTRA again
misclassified in all versions, esp 2
Note that pCCA is 50-60% of all CCA
Need International Consistency in Classification of CCA – to allow accurate monitoring of epidemiology
- ICD11 will resolve this
- Proposed:
o 2C18.0 Hilar Cholangiocarcinoma
o 2C12.10 Intrahepatic cholangiocarcinoma
o 2C15.0 Extrahepatic cholangiocarcinoma: Adenocarcinoma of biliary tract, distal bile duct
o Similar needed for ICD-O 4 i.e. three separate topography/morphology codes for iCCA, pCCA and dCCA
26
Aetiology and Risk Factors of CC
* Primary sclerosing cholangitis – biggest RF in the western world
* Parasitic Infection
* Fibropolycystic Liver Disease
* Intrahepatic Biliary Stones
* Chemical Carcinogen Exposure
* Viral Hepatitis
* Cirrhosis, Fatty Liver Disease/Metabolic Syndrome
Unlike with HCC where 90% of patients have cirrhosis, in CC this percentage is much lower (only a minority)
cirrhosis accounts for very few cases of CC.
27
Primary Sclerosing Cholangitis (PSC) in CC
• Commonest predisposing condition for CC in West
o Autoimmune disease that results in inflammation of bile ducts for many years
• CC rates of 8 - 40% reported in PSC pts in f/up studies and explant specimens
• CC in PSC presents earlier, in 30 - 50 year age groups
• 1/3 of PSC patients who develop CC do so within 2 years of PSC diagnosis
• Risk of CC unrelated to the duration of PSC
• 2/3 of PSC patients have IBD (UC): no association between CC risk and presence/severity of IBD
28
Parasitic Infection in CC
• Liver fluke infestation:
o Opisthorcis viverrini
o (Clonorchis sinensis)
• Case-control studies
• Syrian hamsters
• Most data from Thailand
o World’s highest CC rates: 96/100,000 population
o 7 million have opisthorciasis
• Humans infected by eating undercooked fish; adult worms inhabit and lay eggs in biliary tree
• CASCAP: Current strategy for screening is being implemented in those at risk from eating undercooked fish stool samples of patients to check for liver flukes, treat if they flukes present with praziquantel, check bile ducts with USS, if signs of stricturing these patients are sent to have a CT to check for CC
o Problem: people will eat raw fish again and become re-infected (vaccine may be better alternative, has not been developed)
29
Fibropolycystic Liver Disease in CC
• Congenital abnormalities of biliary tree associated with:
o Caroli’s syndrome
o Congenital hepatic fibrosis
o Choledochal cysts
• 15% risk of malignant change after 2nd decade (average 34y)
• Overall incidence of CC in pts with untreated cysts up to 28%
30
Intrahepatic Biliary Stones (Hepatolithiasis)
• Rare in West, relatively common in Asia
o Unsure why this happens
• Associated with peripheral ICC
• Up to 10% of patients with hepatolithiasis develop CC
• Taiwan: up to 70% of CC pts undergoing resection
• Japan: 6 – 18%
• Mechanism: biliary stones cause bile stasis recurrent bacterial infections/inflammation
31
Chemical Carcinogen Exposure in CC
• Promutagenic DNA adducts demonstrated in CC tissue
o Thorotrast: RR X 300 used to be a chemical contrast used in imaging (now banned due to association with CC) [iatrogenic cause]
• Associations with exposure to by-products from the rubber and chemical industries, including:
o Dioxins
o Nitrosamines (also produced by bacteria in fish, foods)
o Alcohol
o Smoking
• Results conflicting: no firm conclusions
32
Cirrhosis and Viral Hepatitis in CC
• Cirrhosis, of any cause, associated with CC
o 10% of all HCCs have mixed features of CC and HCC (known as mixed HCCs)
• Sorenson et al., Hepatology 1998: performed a cohort study on >11000 cirrhotic patients and followed them up for 6 years, found a 10-fold increased risk of CC compared with general population
• Shin et al., Int J Epidemiol 1996: case-control study performed in Korea found that 12.5% of CC cases were HCV+ and 14% HBsAg+ (compared to 3.5% and 2.3% of controls)
• Donato et al., Cancer Causes Control 2001: case-control study in Italy found that 23% of CC patients were HCV+ and 11.5% HBsAg+ (compared with 6% and 5.5% of controls)
• Kobayashi et al., Cancer 2000: performed a prospective control study in Japan and found that risk of CC in HCV-cirrhotic patients were 3.5% in 10 years
• HCV RNA has been detected in CC tissue
33
Molecular Pathogenesis and Markers in CC
* Various oncogene + tumour suppressor gene mutations identified in CC
* Suggests CC arises secondary to cellular, and consequent DNA injury
* K-ras oncogene abnormally expressed in >21% of cases
* p53 tumour suppressor gene mutations in up to 37% archival specimens
* Associated with aggressive phenotype
• Potential molecular markers for biliary malignancy currently under investigation:
o Growth Factors
o DNA Aneuploidy
o Nuclear Morphometry
o Loss of Heterozygosity of Microsatellite markers
o Proteomics?
34
Describe the proposed model of CCgenesis and its problems
Khan et al 2005
see p44
normal cholangiocyte --> initiation (mutation in key gene e.g. p53, k-ras, APC)
due to environmental agents metabolised by or deposited in hepatobiliary system
--> promotion (proliferation of initiated cholangiocyte)
due to persistence of mmutation and cell division despite repair apoptpsis
risk factors for increased cholangiocyte turnover: liver flukes, PSC, etc
--> progression (further DNA mutations ccausing genetic heterogeneity, karyotype instability and selection of clones with growth advantage, angiogenesis)
--> spontaneous events , epigenetic alterations etc. -->
--> clinical cholangiocarcinoma --> metastasis due to further genetic changes
Flaw in proposed model: 70% of CCs are sporadic and hence no risk factors are identifiable presumably there must be other host factors that increase/decrease risk of developing CC (xenobiotics?)
35
Diagnosis and Investigations of CC
• Generally: Hilar Strictures + Jaundice = CC
• But confirming CC difficult due to wide differential:
o Benign strictures
Iatrogenic bile duct injuries,
PSC
Choledocholithiasis
o Other carcinomas e.g. gallbladder
o Hilar nodal metastases
• Need high index of suspicion and multi-investigative approach
36
LTFs in CC
• Obstructive jaundice: rise in
o serum bilirubin
o alkaline phosphatase
o gamma-glutamyl transpeptidase
NB: transaminases also commonly increase
Liver tests are not specific or sensitive lots of reasons why these may be raised e.g. drug induced, hepatitis, will only confirm that liver is irritated
37
Serum Tumour Markers in CC
• None CC-specific
• Carbohydrate Antigen (CA) 19-9
o Used most commonly but low specificity and sensitivity
o Similar % for pancreatic cancer
o Also raised in: colorectal, gastric, gynae malignancies, cholangitis
o M.B: 10% lack Lewis antigen and don’t produce Ca 19-9
o Serum IgG4 must be checked to exclude autoimmune cholangiopathy
• [Carcinoembryonic Antigen (CEA)]
38
Imaging – Transabdominal USS in CC
• Primary investigation for suspected CC
• Highly sensitive for:
o Biliary duct dilatation
Proximal (hilar) lesions: intrahepatic duct dilatation with normal diameter extrahepatic ducts
Distal lesions, both intrahepatic and extrahepatic ducts are dilated
o Localising the site of obstruction
o Excluding gallstones
39
Imaging – Contrast-enhanced, Triple Phase, Helical CT in CC
* Very sensitive for detecting ICCs > 1cm
* Locating level of obstruction wont be able to distinguish between type of cancer
* Presence of lymphadenopathy
* Resectability only established in as few as 60% of cases
40
Imaging – Magnetic Resonance Cholangiopancreatography (MRCP) in CC
* Best imaging option available
* Potential advantages over CT include no radiation
* ID intrahepatic mass lesions, AND gives 3D computerised reconstruction of biliary tree - evaluation of bile ducts above and below a stricture
* Non-invasive cholangiographic images comparable to (invasive) ERCP and PTC
* High +ve and -ve predictive values for detecting the level and features of biliary obstruction
41
Invasive Cholangiography: ERCP and PTC in CC
• Advantages over MRCP:
o Washings, Brushings, Intraductal Bx for cytopathological analysis
o Therapeutic drainage
• Diagnostic yield from cytology obtained is low: sensitivity may be increased by new analysis technique: fluorescent in situ hybridisation (FISH): chromosomal analysis of cells from biliary brushings (polysomy) → sensitivity 467%, specificity, 97% for CC in PSC
• Disadvantage:
o procedural risks e.g. sedation, perforation, biliary leakage, bleeding, pancreatitis
42
Clinical Staging in CC
* Tumour-node-metastasis (TNM) system
| * (Bismuth classification)
43
ILCA Guidelines on iCCA, J Hepatology 2014
p 46-47 LEARN THIS
44
Treatment of CC
```
o Surgical Resection (R0): 5 year survival up to 40%
o Ablation: OS 33m – 39m
o Locoregional, TACE/TARE: OS 16m – 22m
o Cytotoxics: 8 – 12m
o Radiotherapy: 7m – 9m
o Supportive care (inc stenting): 6m
```
• Complete surgical resection with histologically-negative resection margins is the only cure
o Only suitable for 20% patients
o Early liaison with a specialist Surgical Unit
o Nature and extent of the surgery depends on the site
45
Surgical Management in CC
Resectability:
• Commence immediately CC diagnosis considered
• Before instrumentation/stent insertion with ERCP/PTC produces inflammation/infection rendering assessment more difficult
• Exclude
o Metastatic disease causing biliary obstruction by imaging chest/abdomen/pelvis
o CC metastases
46
what does survival post surgery depend on in CC
* Negative resection margins
* Comorbidities (remember the common age is 7th decade so likely to be elderly with lots of comorbidities)
* Hyperbilirubinaemia
* Post-operative liver failure
* Nutritional status
* Hypoalbuminaemia
* ICC: 5-yr survival 9 - 47% highest with negative resection margins
* Distal CC: 5-yr survival 20 - 54% reported in selected patients managed by pancreato-duodenectomy
47
Systemic Chemotherapy for CC
• Best results for Gemcitabine and Cisplatin
o UK ABC Studies (Valle et al, NEJM 2010): Cisplatin + Gemcitabine median OS 11.7m vs Gemcitabine OS 8.1m, no significant evidence 2nd line chemotherapy improves survival
48
Liver Transplantation for Unresectable Cholangiocarcinoma
• Contra-indicated: high recurrence, up to 90% < 2 yrs
• BUT trials in highly selected patients with new adjuvant and neoadjuvant protocols encouraging (Mayo Clinic)
o 70% 5-year survival:
o Pre-op laparoscopy, radiotherapy and chemotherapy
o Only 2% of pts transplanted
49
Palliation in CC
• Important role: 80% of pts unsuitable for resection
• Death is usually secondary to cholangitis or liver failure
• Aims:
o Relieve jaundice and pruritus
o Prevent cholangitis
o Avoid liver failure due to progressive biliary obstruction
o Enhance quality of life
• Median survival: 3m without biliary drainage, 6m with
• Palliation by surgery or endoscopy
o Endoscopic/percutaneous stent placement for majority of patients
50
Describe the Anatomy of Normal Pancreas
• The head of the pancreas is surrounded by the C-shaped duodenum
• Pancreas is split between head, body and tail (where spleen lies)
• The ducts that run through the pancreas include the main pancreatic duct, otherwise known as the duct of Wirsung
• This joins together with the common bile duct at the ampulla of Vater
o N.B.: the common bile duct runs through the pancreas to join the duct of wirsung enters from a superior and posterior pole to travel in at an angle
• The accessory duct to the pancreatic duct is the duct of Santorini, which opens in a separate minor papilla
51
Describe the histology of the pancreas
o Endocrine component: islet of Langerhans
Composed of loosely packed pale-staining cells
o Exocrine component: acinar cells (produce digestive enzymes)
Cytoplasm of these cells is characteristically basophilic at the basal pole and eosinophilic at the apical pole
o Ducts (where exocrine enzymes are deposited)
Small intralobular duct
52
Tumours of the Pancreas
```
• Solid exocrine neoplasms
o Conventional ductal adenocarcinoma (including PAN pancreatic intraepithelial neoplasia which is a precursor to conventional ductal adenocarcinoma)
o Acinar cell carcinoma
o Pancreatoblastoma
Mostly in paediatric populations
```
• Cystic exocrine neoplasms
o Serous cystadenoma
o Mucinous cystic neoplasms (MCN) precursor to pancreatic ductal adenocarcinoma
o Intraductal papillary mucinous neoplasms (IPMN) precursor to pancreatic ductal adenocarcinoma
o Solid pseudopapillary neoplasm
• Endocrine neoplasms
o Well Differentiated Pancreatic endocrine neoplasms
o High Grade Pancreatic endocrine neoplasms
53
Describe Conventional Ductal Adenocarcinoma
• Most common type
• Most fatal of all human cancers
o Recognised at a very late stage
• Incidence rate: 11/100,000
• 4th leading cause of cancer death
• 60-80 year age group
o Disease of old age so age is an important non-modifiable risk factor
• Presentation
o Jaundice (caused by invasion and obstruction of CBD)
o Back pain
o Weight loss
• Risk factors
o Smoking and high dietary fat intake
o Acquired chronic pancreatitis (hence alcohol is a risk factor) and diabetes
o Hereditary chronic pancreatitis
• Most sporadic
• 10% familial
o Genetic basis for most familial cases (80%) unknown
o Heritable genetic syndromes - BRCA2, FAMMM, P-J syndrome, familial pancreatitis, HNPCC
* >75% solid tumours
* 60-70% in head of pancreas
* Typically involve surrounding structures, especially CBD and duodenum
* Tail cancers spread to spleen, kidney, stomach and colon
* 80% unresectable at time of diagnosis
* Encasement of major mesenteric vessels
* Metastases to liver, peritoneum or other distant site
* Often disseminates very early
54
Macroscopic Features of CDA
• Solid firm infiltrative tumour
• Gritty or slightly gelatinous cut surface
o White to yellow appearance
o Ill-defined occupying much of the head of the gland
o Loss of globularity
• Gross areas of necrosis may be present
• Often difficult to distinguish from adjacent areas of fibrosing chronic pancreatitis
• Direct invasion of CBD & duodenum common – head of pancreas
• Recognition that centre of tumour is located within head of pancreas is helpful in distinguishing ductal adenocarcinoma from primary carcinoma of CBD, duodenum or ampulla
55
Microscopic Features of CDA
• Proliferation of small tubular structures lined by cuboidal cells within abundant desmoplastic stroma
o Dissecting going at an angle through the stroma
• Well differentiated growth pattern closely mimics non-neoplastic ductules of chronic pancreatitis
o Can be well-differentiated or poorly-differentiated
• Malignant glands with haphazard growth pattern
• Stratification and irregular papillae of lining epithelium
• Abundant cytoplasm generally containing mucin
• Clear cell change is common
• Loss of nuclear polarity typical
• Nuclei vary in size, shape and intracellular location
• >4x variation in nuclear size (4:1 rule)
• PNI & VI common and diagnostically useful (not commonly detected in core needle biopsies)
• Invasion into peripancreatic fat common
• Immediate juxtaposition of gland with adipose tissue without intervening stroma (‘naked glands in fat’ sign)
• Tumours can be quite aggressive can involve perineural invasion
o Hence why cancer can be quite painful
56
How to differentiate between CDA and chronic pancreatitis
• Invasion of CBD, duodenal mucosa or native pancreatic ducts
o Also invasion of fat (naked glands in fat sign) and vessels
• Colonisation of basement membrane may simulate a pre-invasive neoplasm – duodenal adenoma or PanIN
• Continuity with frankly invasive elements supports colonisation
• Chronic pancreatitis often present in adjacent pancreas
• Lining of native pancreatic ducts may show PanIN
57
Describe the TNM staging for CDA
Primary tumour
• TX – Primary tumour cannot be assessed
• T0 – No evidence of primary tumour
• Tis – Carcinoma in situ (PanIN 3)
• T1 – Tumour limited to pancreas, < or = 20mm
• T2 – Tumour limited to pancreas, >20mm
• T3 – Tumour extends directly into any of the following:
• duodenum, bile duct, peripancreatic tissues
• T4 – Tumour extends into stomach, spleen, colon, adjacent
• large vessels
```
Regional LNs
• NX – Cannot be assessed
• N0 – No regional LN metastases
• N1 – Regional LN metastases
• N1 – Metastases in a group of regional nodes (no 1a/1b)
```
Distant Metastasis
• MX – Cannot be assessed
• M0 – No distant metastases
• M1 – Distant metastases
58
Molecular Basis for Pancreatic Ductal Adenocarcinoma
KRAS
CDKN2A
TP53
SMAD4
59
KRAS in PDA
o One of the earliest and most universal genetic alterations observed in pancreatic cancer is activating mutations in the oncogene KRAS. At least 99% of PanIN 1 lesions harbour mutations in KRAS, suggesting its activation is an important initiating step in carcinogenesis of most pancreatic cancers.
o Point mutations in the KRAS gene result in constitutive activation even in the absence of extracellular signals
o KRAS signalling activates a number of downstream pathways that augment cell growth and survival, including the RAF/mitogen-activated protein (MAP) kinase pathway, as well as into the phosphoinositide-3-kinase (PI3K)/AKT signalling pathway
60
CDKN2A in PDA
o The tumour suppressor gene CDKN2A is inactivated in over 90% of pancreatic ductal adenocarcinomas, with the vast majority of alterations arising as early as the PanIN 2 stage
o This complex locus encodes 2 tumour suppressor proteins:
p16/INK4a, a cyclin dependent kinase inhibitor that antagonises cell cycle progression
p14/ARF, a protein that augments the function of the p53 tumour suppressor gene
61
SMAD4 in PDA
o The SMAD4 tumour suppressor gene is inactivated in 55% of pancreatic adenocarcinomas
o The SMAD4 protein plays a key role in propagating extracellular signals through the transforming growth factor β (TGF-β) signalling pathway
62
Other Pancreatic Carcinomas of Ductal Origin
• Colloid carcinoma / mucinous carcinoma – lots of mucin pools seen in the backgroiund
• Medullary carcinoma – very rare
• Squamous cell carcinoma (SCC) – usual on its own
• Adenosquamous carcinoma
• Hepatoid carcinoma
• Undifferentiated carcinoma – very rare
o Anaplastic giant cell carcinoma
o Carcinosarcoma
• Undifferentiated carcinoma with osteoclast-like giant cells
63
describe Pancreatic Intraepithelial Neoplasia
* Main precursor of ductal adenocarcinoma
* Series of increasingly proliferative changes within the epithelium of pancreatic ducts
* Early lesions with minimal cytologic atypia are now regarded as early neoplastic change
* More recent molecular data shows that most are neoplastic
* Proportion of mucinous metaplasia or mucous cell hypertrophy harbour clonal mutations in KRAS oncogene
* Whole spectrum is referred to as PanIN
64
Grading of PanIN
o PanIN 1A
Tall columnar mucinous cells with well polarised nuclei but without atypia, loss of polarity, papillary or micropapillary formation (previously called mucinous neoplasia or mucous cell hypertrophy)
o PanIN 1B
Characterised by slight nuclear stratification at basal aspect and presence of papillary or micropapillary projections
Still one single layer, no overlapping as above
o PanIN 2
Prominent nuclear stratification (full thickness) associated with focal loss of polarity and mild nuclear atypia (previous atypical hyperplasia / moderate dysplasia)
o PanIN 3
Significant loss of polarity, tufting of cells into the lumen, marked irregularity of nuclei, increased mitotic figures and necrosis (previously called carcinoma in situ or severe dysplasia)
65
Acinar Cell Carcinoma
* Mostly in adults with a mean age of ~60 years
* Very rare
* Large well-circumscribed masses in head or tail of the pancreas (mean 10cm)
* Most architecturally form acinar structures with basally oriented nuclei and granular apical cytoplasm
* Some form solid sheets of cells without well-formed acini
* Nuclei contain single prominent nucleoli
* Salt and pepper chromatin pattern
* Immunolabel for trypsin, chymotrypsin
* Must differentiate from neuroendocrine carcinoma as they look morphologically similar
66
Pancreatoblastoma
* Most, but not all, occur in children
* Very rare
* Associated with Beckwith-Wiedemann syndrome and familial adenomatous polyposis (FAP)
* Large well-circumscribed masses in head or tail of the pancreas (mean 10cm)
* Neoplastic cells with acinar differentiation and squamoid nests
67
Summarise Cystic Exocrine Tumours
* Less common than ductal adenocarcinoma
* 5-10% of all pancreatic neoplasms
* Either benign or low grade (indolent) malignant neoplasms
* Detected more commonly owing to increased use of sensitive imaging techniques
• 3 types:
o Serous cystic neoplasm / serous cystadenomas
o Mucinous cystic neoplasm (MCN)
o Intraductal papillary mucinous neoplasm (IPMN)
o Solid pseudopapillary tumour
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Serous Cystic Neoplasm
• Most common type of ‘true’ cystic neoplasm
• Very benign
• Usually microcystic (microcystic adenoma)
• Numerous small cysts 1-10mm in size
• Forming a well-delineated tumour mass
• Relatively large tumour mass (up to 250mm)
• Mostly in body / tail
• Predominantly in females
o Similar to ovarian cystic neoplasm
• Mean age of 66 years
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Macroscopic Features
• Well circumscribed lesion composed of small cysts
o Honeycomb surface
• Each <10mm
• Separated by thin translucent septa
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Microscopic Features
• Cysts lined by flattened to low cuboidal epithelium
• Clear cytoplasm & well defined cytoplasmic borders
• Small round uniform nuclei with dense homogenous chromatin
• Accumulation of glycogen (PAS+, DPAS -)
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Mucinous Cystic Neoplasm
* Macrocystic
* Almost exclusively in females
* 5-6th decades of life
* Tail of pancreas
* Can develop invasive carcinoma in a number of cases
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Macroscopic Features
• Single multilocular cyst
• Surrounded by thick fibrotic capsule
• Mean size >10cm
• Do not communicate with pancreatic ductal system
• Septa between cysts are thin
• Cyst contents often mucoid
o Thick fluid
• Solid areas may harbour invasive component
• Degenerative changes with haemorrhage
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Microscopic Features
• Similar to ovarian mucinous neoplasm
• Tall columnar cells with abundant apical mucin
• Bland with uniform, basally oriented nuclei
• Minimal architectural complexity
• Some exhibit abundant papillary formations, pseudostratified hyperchromatic nuclei
• Cribriform architecture severe epithelial atypia - may be focal
• Consistent distinctive subepithelial hypercellular spindle cell
• Stroma (ovarian-like) – must be present for diagnosis
o Stroma often contains nests of epithelioid cells suggestive of luteinisation
o Stromal cells express oestrogen and progesterone, as well as inhibin (intense in epithelioid lutea-like cells)
• Epithelium expresses keratin, CEA, CA19.9
• Mucin antibodies can be used to aid diagnosis but not very specific
o MUC 5AC (diffusely)
o MUC 2 (only scattered goblet cells)
o MUC 1 only in invasive carcinoma that arise within these tumours
• Degree of dysplasia - low, moderate or high grade
• Presence or absence of invasive carcinoma should be reported
o MCN with LGD = mucinous cystadenoma
o MCN with HGD = cystadenocarcinoma in situ
o MCN with invasive carcinoma = mucinous cystadenocarcinoma (less aggressive than ductal adenocarcinoma)
• Even benign appearing MCNs have latent malignant potential
• Overall rate of malignancy is ~10%
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Intraductal Papillary Mucinous Neoplasm
• Very distinctive clinical and radiographic findings
• Readily treatable by surgery
• Radiographically cystic
• Distinction from true cystic neoplasm can be difficult
• Spectrum of neoplastic progression
• Clinically detectable unlike PanIN lesions causes symptoms
o Using endoscope: Mucin extrusion through the ampulla diagnostic
• Excellent model of pre-invasive neoplasia
Macroscopic Features
• Characterised by intraductal proliferation of mucinous cells
• Usually arranged in a papillary pattern
o Microscopic or macroscopic papilla forming nodular masses
• Intraluminal mucin deposition
• Cystic dilatation of ducts
• Multilocular cystic mass or abundant papillary nodules
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Background
• Accounts for 5% of all pancreatic neoplasms
• More common than previously recognised
• 7th – 8th decade
• Nonspecific symptoms
• 80% occur in head of pancreas
• Diagnostic features:
o Endoscopic finding of mucin extrusion through the ampulla
o Radiographic finding of ectatic ducts
• 2 Main Types:
o Main duct type
Involves major pancreatic duct
Greater likelihood of intraductal or invasive carcinoma (~35%)
o Branch duct type
Involves secondary ducts
Particularly in uncinate process, body and tail
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Microscopic Features
• Localised, multicentric or entire ductal system (rarely)
• Cystic ducts filled with variably complex papillary projections
• Lined by mucinous cells with various degrees of atypia
• Right: expanding and dilating lumen
• 3 different papillary patterns:
o Intestinal type (50%) – CK20+; MUC2+; CDX2+ more likely to be associated with invasive adenocarcinoma
o Gastric foveolar type (35%) less likely to be associated with invasive adenocarcinoma
o Pancreatobiliary type (15%) – MUC1+ same as intestinal
• Low grade, moderate or high grade dysplasia
• Overall 5 year survival rate relatively good
o >75% free of disease after 5 years
• Even with associated invasive carcinoma, the prognosis is good, particularly if colloid type or small focus
• Most managed by conservative resection
• May recur because of tumour multicentricity
Differential Diagnosis of IPMN
• PanIN – Incidental, microscopic lesions <5mm
o IPMN – Macroscopic masses or cysts >10mm
• MCN – Middle aged female, tail, do not communicate with ductal system, cellular ovarian-like stroma highly specific
o IPMN – Both sexes, older age group, predominantly HOP, involvement of ducts, absence of ovarian-like stroma
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Solid Pseudopapillary Tumour
• Most cases found in young women
• Usually found in the body/(tail) of pancreas
• Mostly benign but has low malignant potential
• Most common clinical sign palpable abdominal pain
• Grossly: large and often contains areas of haemorrhage and necrosis
o Hence they are solid tumours but present in a cystic-like manner due to haemorrhage, so not a true cystic tumour
o Also demonstrate papillae due to fragmentation of solid parts of tumour
• Most cases surrounded by well-developed capsule
• Some cases are predominantly cystic
• Microscopically: very cellular
• Pseudopapilla covered by several layers of epithelial cells
• Nuclei ovoid and folded
• Hyaline globules and foamy macrophages
• Thick fibrovascular stroma with mucinous change
• Genetically: almost always exhibit beta-catenin mutation
o IHC: CK, CD10, PgR, beta-catenin
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Pancreatic Endocrine Neoplasm
* 5-8% of pancreatic tumours
* Majority well differentiated, low to intermediate grade tumours, exhibiting well-developed endocrine differentiation
* Rarely poorly differentiated (high grade) – similar to small and large cell endocrine carcinoma
Well-Differentiated PEN
• 55-60 years
• Functional and non-functional categories
o Functional if symptoms occur, otherwise referred to as non-functional
o Greater proportion non functional
• Presence or absence of para-neoplastic syndrome
• Based on type of hormone secretion (insulinoma, gastrinoma)
• Most non-functional reveal biologic evidence of peptide or bioamine production by serologic or IHC assays
• Non-syndromic (better term)
• Usually present with non-specific symptoms related to mass lesion
• Biliary obstruction and jaundice may occur if in head of pancreas
• May present with symptoms of metastatic disease
• Variety of different classification schemes to help separate benign from malignant cases
• Tumour size – important prognostic factor
• Significant prognostic factors
o Tumours < 5mm max diameter -> benign
o Tumours < 20mm -> low risk malignant behaviour
o Mitotic rate determine grade of tumour
o Necrosis
o Venous invasion
o Extra-pancreatic tissue invasion
• Malignant tumours show metastases to regional LNs and liver
• Slowly progressive indolent tumours
• Once metastases occur, rarely curable
o Survival for many years (even decades)
o Chemotherapy - limited success
o Functional tumours – surgical resection, embolisation of metastases or treatment with somatostatin analogues
Mircroscopic Features
• Well-circumscribed homogeneous tumours
• Soft consistency
• Proliferation of round uniform cells with moderate cytoplasm
• ‘Salt & pepper’ / stippled chromatin
• Distinct nests separated by small thin-walled blood vessels
• Trabeculae, gyrae, pseudo-rosettes or glandular pattern
• Minimal to abundant hyalinised stroma
• Minimal nuclear pleomorphism and indistinct nucleoli
• Sparse mitotic figures
• Staining helps to differentiate cell types
o Chromogranin and synaptophysin usually positive
o NSE and CD56 also generally expressed
o Staining for peptide hormones should be done
o However, functional tumours defined clinically and not by IHC
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Poorly Differentiated PEN
• Rare
• Large cell endocrine carcinoma – large pleomorphic nuclei
• Small cell carcinoma
• Diffuse infiltrative growth pattern
• Numerous mitotic figures (>10/10HPF)
• Abundant tumour necrosis
• Highly aggressive
• Early dissemination and rapidly fatal course
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Cells of the Liver
* Hepatocytes
* Cholangiocytes cell of origin of biliary tumours. These are seen in the portal tract up to the CBD.
* Endothelial cells
* Kupffer cells
* Stellate cells
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Benign Biliary Tumours
1) liver cell adenoma
2) focal nodular hyperplasia
3) bile duct adenoma
4) haemangioma
The most common benign biliary tumour is a bile duct adenoma.
• It not uncommon
• Almost always incidental findings
• Pale, rounded lesion
o Disordered bile ducts
• It can often be misdiagnosed:
o DDx: cholangiocarcinoma, metastatic adenocarcinoma, pancreatic ductal adenocarcinoma, bile duct hamartoma
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Malignant Tumours of the Liver
• The most common malignant tumours include:
o Secondary tumours (more common)
Predominantly adenocarcinomas
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o Primary tumours
Hepatocellular carcinoma
Hepatoblastoma
Haemangiosarcoma
Cholangiocarcinoma
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Most primary and secondary tumours of the liver are adenocarcinomas. 95% of tumours are adenocarcinomas
Important: all adenocarcinomas form mucus secreting glands
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biliary Tumour Characteristics
• Usually well-differentiated adenocarcinomas with marked fibrosis (desmoplastic stromal reaction)
o HCC has no stroma
• Dysplasia may be seen (rarer)
• Haematogenous and lymph node metastases are common
o Hence poor prognosis
• Right: well-differentiated adenocarcinoma showing fibrous stroma and perineural invasion shown (thought to be due to fat around neurones)
• Bile duct dysplasia
o Thought to be a precursor lesion
o Big nucleus, hyperchromatic nuclei
o Usually found with adenocarcinoma also present
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Cytology in biliary tumours
A cytology preparation from bile fluid showing a dissociated cell with a hyperchromatic nucleus and prominent nucleolus on a background indicating tissue necrosis. These features are highly suggestive of an invasive cholangiocarcinoma.
• Diagnosis is confirmed through biopsy however this is not always possible due to sites of cancer. If cancer is in liver then it is easier to biopsy than if in biliary tree. If in biliary tree then only cytology is possible.
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Immunohistochemistry of biliary tumours
• CCAs exhibit
o CK7 and CK19+
o CK20-
• Caution: pancreatic ductal adenocarcinoma also stains the same and metastasises to the liver first hence it may be difficult to confirm CCA without radiology (radiology is needed in order to understand whether this is a primary or secondary)
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mixed HCC/CC phenotype
* 2 main types of cells are present in the liver hepatocyte and cholangiocyte
* Both originate from the same progenitor cell that is originally both K7+ and K19+ (and NCAM- this is a neural cell adhesion molecule)
* Cholangiocytes make mucin and are glandular whilst hepatocytes only produce very little bile hence K7- and K19-, whilst mature cholangiocytes retain K7 and K19 (keratin molecules) as it is needed to make mucin
* Some HCCs have been found to make K19, so there is a spectrum à with some types of cancer in between (HCC with progenitor cell features, intermediate carcinoma, mixed HCC/CC phenotype). Important to understand the difference as treatment for HCC and CC is different so how do we treat the ones in the middle?
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classification of biliary tumours
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Intrahepatic Cholangiocarcinoma
• 1 = peripheral cholangiocarcinoma
• 2a,b = right and left hepatic ducts
• 3 = confluence of right and left hepatic ducts (perihilar, Klatskin tumours)
Extrahepatic
• 4 = common hepatic duct
• 5 = gall bladder
• 6 = cystic duct
• 7 = common bile duct
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see pg 65
