Pancreatic Adenocarcinoma

Anatomy

Anatomy

Arterial Supply

Venous Anatomy

Physiology – Exocrine Pancreas

• Secretion of water and electrolytes originates in the centroacinar and intercalated duct cells

• Pancreatic enzymes originate in the acinar cells

• Final product is a colourless, odourless, and isosmotic alkaline fluid that contains digestive enzymes (amylase, lipase, and trypsinogen)

Physiology – Exocrine Pancreas

• Alkaline pH results from secreted bicarbonate which serves to neutralize gastric acid and regulate the pH of the intestine

• Enzymes digest carbohydrates, proteins, and fats

Enzymes

• Amylase

– only digestive enzyme secreted by the pancreas in an active form

– functions optimally at a pH of 7

– hydrolyzes starch and glycogen to glucose, maltose, maltotriose, and dextrins

• Lipase

– function optimally at a pH of 7 to 9

– emulsify and hydrolyze fat in the presence of bile salts

Endocrine Function: Insulin

• Synthesized in the B cells of the islets of Langerhans

• 80% of the islet cell mass must be surgically removed before diabetes becomes clinically apparent

• Proinsulin, is transported from the endoplasmic reticulum to the Golgi complex where it is packaged into granules and cleaved into insulin and a residual connecting peptide, or C peptide

Insulin

• Major stimulants

– Glucose, amino acids, glucagon, GIP, CCK, sulfonylurea compounds, β-Sympathetic fibers

• Major inhibitors

– somatostatin, amylin, pancreastatin, α-sympathetic fibers

Glucagon

• Secreted by the A cells of the islet

• Glucagon elevates blood glucose levels through the stimulation of glycogenolysis and gluconeogenesis

• Major stimulants – Aminoacids, Cholinergic fibers, β-Sympathetic fibers

• Major inhibitors – Glucose, insulin, somatostatin, α-sympathetic fibers

Somatostatin

• Secreted by the D cells of the islet

• Inhibits the release of growth hormone

• Inhibits the release of almost all peptide hormones

• Inhibits gastric, pancreatic, and biliary secretion

• Used to treat both endocrine and exocrine disorders

Pancreatic adenocarcinoma

Head of Pancreas Tumour Tail of Pancreas Tumour

Pancreatic cancer

• Fourth leading cause of cancer-related death

• > 7000 deaths annually in UK

• Overall 5-year survival approx 1%

• Only approx 13% alive after 1 year

• Often called the “silent disease” because it usually doesn’t cause symptoms in early stages

• M > F (2:1) and 2% of all tumours

• Association with smoking, hypertension, obesity

• Presents in 5th decade

• Risk factors: – Tuberous sclerosis

– Von Hippel-Lindau disease (clear cell)

– Renal transplantation

– Dialysis

Some interesting facts

Aetiology

• Cause unknown

• Smoking & alcohol?

• Diabetes? (5 years greater than 2x increase)

• Hereditary pancreatic cancer – susceptibility locus has been found in relation to chromosome 4q32-34

• Familial breast cancer gene (BRCA2)

• Chronic pancreatitis

Demographics

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Age at diagnosis

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Female cases

Male rates

Female rates

Figure 1.2: Numbers of new cases and age-specific incidence rates,

by sex, pancreatic cancer, UK 2003

Mortality

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males incidence

females incidence

males mortality

females mortality

Figure 1.3: Age standardised (European) incidence and mortality

rates, pancreatic cancer, by sex, GB, 1975-2004

Mortality

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one-year five-year one-year five-year

% s

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1998-2001*

* England only

Figure 3.1: One- and five-year relative survival by sex, adults

diagnosed with pancreatic cancer, England and Wales, 1971-

2001 and followed up to the end of 2003

Males Females

• Renal mass

• Haematuria

• Flank pain

– Complete triad = poor prognosis

• Remember pts often asymptomatic

– Malaise, weight loss, polycythaemia, hypertension can also be seen.

Clinical presentation (triad)

Clinical presentation

• Weight loss

• Anorexia

• Nausea & vomiting

• Abdominal pain

• Obstructive jaundice (head lesions)

• Cachexia

• Very difficult to diagnose in early stage

Investigations

Radiological

• CT – identify renal lesion + involvement of renal vein or IVC

• USS – tell if mass is cystic or solid, and if TCC or RCC

• MRI & MRCP – good for staging

• ERCP

• Endoscopic USS

• Intravenous urogram (IVU)

• CT-PET

Bloods

• ESR usually raised

• LFTs may be abnormal

• FBC

• U&E’s

• Tumour marker: CA 19-9

Laparoscopy

CT

MRCP

ERCP

+ Accuracy of 60%-80 % by imaging alone. - 5%-10% complication rate.

Tissue/Brushings + Diagnostic yield in the range of 40% to 50%. - Up to 11% and 21% complication rate

Double duct sign

Distal CBD stricture

Staging Laparoscopy

1. John et al. Annals of Surg 1995; 221: 156-164

Peritoneal Seedlings

ASCITES

EUS

EUS small tumours

pancreas

Staging and biopsy

CBD: common bile duct; PV: portal vein; HOP: Head of pancreas

Biopsy Needle

Treatment

• Resection possible in only approx 20%

– local invasion

– Metastases

– advanced cachexia

• Resection – Whipple procedure

• Unresectable – biliary bypass + gastric bypass

Allen Oldfather Whipple (1881-1963)

Original paper. Whipple AO, Parsons WB, Mullins CR. Treatment of Carcinoma of the Ampulla of Vater. Ann Surg 1935; 102: 763-769.

Whipple's Procedure

Whipple pancreaticoduodenectom

Pancreatic Anastomosis

Jejunum

Cut end of pancreatic neck

Biliary Anastomosis

Gastric Anastomosis

Staging: TMN T categories

• TX: The main tumour cannot be assessed.

• T0: No evidence of a primary tumour.

• Tis: Carcinoma in situ (very few tumours are found at this stage)

• T1: The cancer has not spread beyond the pancreas and is smaller than 2 cm (about ¾ inch) across.

• T2: The cancer has not spread beyond the pancreas but is larger than 2 cm across.

• T3: The cancer has spread from the pancreas to surrounding tissues near the pancreas but not to major blood vessels or nerves.

• T4: The cancer has extended further beyond the pancreas into nearby large blood vessels or nerves.

N categories

• NX: Regional lymph nodes cannot be assessed.

• N0: Regional lymph nodes (lymph nodes near the pancreas) are not involved.

• N1: Cancer has spread to regional lymph nodes.

M categories

• MX: Spread to distant organs cannot be assessed.

• M0: The cancer has not spread to distant lymph nodes (other than those near the pancreas) or to distant organs such as the liver, lungs, brain, etc.

• M1: Distant metastasis is present.

T Stage

Lymph nodes

Metastases

Stage Grouping Stage 0 (Tis, N0, M0): The tumour is confined to the top layers of pancreatic duct cells and has not invaded deeper

tissues. It has not spread outside of the pancreas. These tumours are sometimes referred to as pancreatic

carcinoma in situ or pancreatic intraepithelial neoplasia III (PanIn III).

Stage IA (T1, N0, M0): The tumour is confined to the pancreas and is less than 2 cm in size. It has not spread to

nearby lymph nodes or distant sites.

Stage IB (T2, N0, M0): The tumour is confined to the pancreas and is larger than 2 cm in size. It has not spread to

nearby lymph nodes or distant sites.

Stage IIA (T3, N0, M0): The tumour is growing outside the pancreas but not into large blood vessels. It has not

spread to nearby lymph nodes or distant sites.

Stage IIB (T1-3, N1, M0): The tumour is either confined to the pancreas or growing outside the pancreas but not

into nearby large blood vessels or major nerves. It has spread to nearby lymph nodes but not distant sites.

Stage III (T4, Any N, M0): The tumour is growing outside the pancreas into nearby large blood vessels or major

nerves. It may or may not have spread to nearby lymph nodes. It has not spread to distant sites.

Stage IV (Any T, Any N, M1): The cancer has spread to distant sites.

5 Year Survival

Stage IA: 37%

Stage IB 21%

Stage IIA 12% Stage

IIB

6% Stage III

2% Stage

IV 1%

Increasing stage = worse 5 year survival

Complications

• Up to 30%

• Include: pancreatic fistula – intraabdominal sepsis – delayed gastric emptying

• Mortality < 5%

Diener et al. Ann of Surg; 2007;245(2);187-200

Mortality

• Resection is only option for cure

• Mortality in high volume centres less than 5%

• Clear evidence that high volume centres have better outcome

Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg. 1997;226:248–257.

Bassi C, Falconi M, Salvia R, et al. Management of complications after pancreaticoduodenectomy in a high volume centre: results on 150 consecutive patients. Dig Surg. 2001;18:453–457.

Gouma DJ, van Geenen RC, van Gulik TM, et al. Rates of complications and death after pancreaticoduodenectomy: risk factors and the impact of hospital volume. Ann Surg. 2000;232:786–795.

Yuman Fong, MD, Mithat Gonen, PhD, David Rubin, MS, Mark Radzyner, MBA, JD, and Murray F. Brennan, MD. Long-Term Survival Is Superior After Resection for Cancer in High-Volume Centers Ann Surg. 2005 October; 242(4): 540–547.

Cystic Lesions of Pancreas

Cystic lesions

• Pseudocyst

• Serous cystadenoma

• Mucinous cystadenoma

• IPMT

• Pseudopapillary cystic tumours

Pancreatic Pseudocyst

Mucinous tumours

• All mucinous pancreatic neoplasms are (believed) to malignant or pre-malignant

• Frankly malignant (invasive + CIS) among resected:

– Main duct IPMN ≈25-80%

– Branch duct IPMN ≈0-30% (series at high end do not have assx pts)

– MCN ≈5-20%

Tanaka et al. Pancreatology 2006

Maybe observe?

• So which CPN are we talking about?

Growing problem

• CT increasing by 9% per yr

• CT abd/pelvis ≈ 30% of all CTs

• ≈1% of abdominal CTs show pancreatic cystic lesion

• up to 70% of CPN referred to 3O centre asymptomatic

Brenner, NEJM 2007

An epidemic of incidental asymptomatic pancreatic cysts.

Diagnostic evaluation

• Cross sectional imaging (CT/MRI) – Modest diagnostic accuracy

• EUS – Morphologic characterization poor

– FNA for cytology and CEA

• PET – Does not appear to discriminate

Visser, AJR 2007

Brugge, Gastro 2004

Sperti, J GI Surg 2005

But why not intervene to prevent cancer?

• Risk of malignancy in small, asymptomatic pancreatic cysts approximates mortality from operative intervention

• i.e. Whipple in expert centres:

– 1-3% mortality

– 40-50% morbidity

Intl Consensus Conference Sedai, Japan 2004

1. Main duct IPMN - resect

2. MCN - generally resect (younger women, usually left sided resection with < morbidity)

3. Branch duct IPMN – Resect if symptomatic, > 3cm, mural nodules, +

cytology, jaundice, ductal dilatation

– Observe if ≤3 cm, no sx, nor worrisome features

Tanaka et al. Pancreatology 2006

Pancreatic Endocrine Tumours

• Insulinoma (B cells)

• Glucagonoma (A cells)

• VIP

• Rare tumours which may give rise to overproduction of peptide products

Malignant Tumours

• Spleen - mostly secondary involvement

• Non-Hodgkin’s Lymphoma - most common malignancy

• Spleen is the primary site

– 10% Hodgkin’s disease

– 30% of resected spleens (staging procedure) have (+) histology

• Hairy cell leukaemia

– Resect for symptomatic splenomegaly

• CML & CLL

– symptomatic splenomegaly (hypersplenism) = splenectomy

Benign Tumours

• Haemangioma

– Risk of rupture + platelet sequestration

– No treatment unless symptomatic

• Hamartoma

• Lymphangioma

• Often haemorrhage associated

• Sheets of clear cells

• Vacuolated cytoplasm

• Pyknotic nuclei (nucleus shrinks & chromatin condenses)

• Cystic in 15%

Clear Cell Carcinoma

• Partial nephrectomy (tumours < 4cm)

• Radical nephrectomy (remove kidneys, ureter, adrenal glad, & hilar lymph nodes)

• Chemotherapy (good for mets)

• Interferon (poorly tolerated, good for mets)

• Radioablation can be used in < 3cm

Treatment

Papillary Carcinoma

• 10% of renal tumours

• 10% cases multifocal/bilateral

• Histo: papillary pattern, cells enclosing “foamy macrophage” clusters

Chromophobe Carcinoma

• 5% of tumours

• Thick cell membrane

• Perinuclear halo

• Decent prognosis

Renal Pelvis Carcinoma

• Vast majority transitional cell carcinomas

Other Tumours

Collecting Duct Carcinoma

• Exophytic tumour

• Poor prognosis, aggressive

• Gland forming

Wilm’s tumour (nephroblastoma)

• Paediatric tumour

• Large abdomen, mass, N&V, haematuria, HTN

• Classic triphasic pattern

Fuhrman Grading

• Grading is based on nuclear size

• Graded between I-IV, with IV having worst prognosis

• I – Small Nuclei IV – Big Nuclei