Pancreatic Cancer

Pancreatic cancer is a highly aggressive malignancy most commonly arising from the exocrine ductal epithelium of the pancreas, often presenting late with obstructive jaundice, weight loss, and pain, carrying a poor prognosis.

1. Definition

Pancreatic cancer refers to malignant neoplasms arising from the pancreas. The overwhelming majority (> 95%) are exocrine tumours, and of those, > 85% are pancreatic ductal adenocarcinoma (PDAC) — the "classic" pancreatic cancer we worry about clinically ^[1]^[2]. The word itself is straightforward: "pancreatic" = of the pancreas (Greek pan = all, kreas = flesh/meat — so named because the gland is "all flesh" with no bone or cartilage), and "carcinoma" (Greek karkinos = crab) denotes an epithelial malignancy.

Unless otherwise specified, "pancreatic cancer" in clinical practice and in exams almost always refers to pancreatic ductal adenocarcinoma (PDAC).

Other exocrine histological subtypes (much rarer) include:

Squamous cell carcinoma
Acinar cell carcinoma
Undifferentiated (anaplastic) carcinoma
Pancreatoblastoma (rare, mainly paediatric)
Adenosquamous carcinoma

Endocrine (neuroendocrine) pancreatic tumours (e.g., insulinoma, gastrinoma) account for < 5% of pancreatic malignancies and have a fundamentally different biology, treatment, and prognosis ^[1]^[2].

Periampullary cancers — a group of cancers arising around the ampulla of Vater — include pancreatic head cancer, ampullary carcinoma, distal cholangiocarcinoma, and duodenal carcinoma. They all present similarly (painless obstructive jaundice) but have different prognoses. Ampullary carcinoma has the best prognosis (5-year survival ~40–60%), while PDAC has the worst (~10%) ^[3].

High Yield Concept

Painless progressive obstructive jaundice is the hallmark presentation of pancreatic head cancer — it is the single most important clinical clue. The differential for painless jaundice with a palpable gallbladder (Courvoisier's sign) is essentially periampullary malignancy until proven otherwise ^[3]^[4].

2. Epidemiology

Global

Pancreatic cancer is the 7th leading cause of cancer death worldwide and one of the most lethal solid malignancies.
Incidence is rising globally.
5-year overall survival remains dismal: ~10–12% across all stages (one of the lowest of any cancer).
Median age at diagnosis: ~70 years — it is predominantly a disease of the elderly ^[1]^[2].
Slight male predominance (M:F ≈ 1.3:1) ^[1].

Hong Kong Context

Pancreatic cancer is the 5th most common cause of cancer death in Hong Kong (2022 data from the Hong Kong Cancer Registry).
Incidence has been steadily increasing, likely related to ageing population, rising obesity, and diabetes prevalence.
Annual incidence: approximately 900–1000 new cases/year in Hong Kong.
Because Hong Kong has a high prevalence of hepatitis B-related HCC and cholangiocarcinoma, pancreatic cancer must be distinguished from other hepatobiliary malignancies presenting with jaundice.

Key Epidemiological Facts

Feature	Detail
Peak incidence	60–80 years
Sex	Male > Female (1.3:1)
5-year survival (all stages)	~10–12%
5-year survival (resected, node-negative)	25–30%
5-year survival (resected, node-positive)	~10%
Median survival (unresectable locally advanced)	~12 months
Median survival (metastatic)	~6 months
% diagnosed at localized stage	Only ~8%
% diagnosed with distant metastases	~53% (majority)

The reason the prognosis is so poor is multifactorial:

Late presentation — the retroperitoneal location means symptoms appear late.
Aggressive biology — dense desmoplastic stroma, early perineural/vascular invasion, early micrometastases.
Chemoresistance — the dense stroma acts as a drug delivery barrier.

Why is pancreatic cancer so deadly?

Think of it as "the perfect storm": located deep in the retroperitoneum (so symptoms come late), surrounded by major vessels (SMA, SMV, celiac axis, portal vein — so even small tumours become unresectable), biologically aggressive (early neural/lymphovascular invasion), and wrapped in dense fibrotic stroma (which shields tumour cells from chemotherapy and immune cells).

3. Risk Factors

Non-Modifiable Risk Factors

Risk Factor	Explanation
Advanced age	Cumulative somatic mutations over time; peak incidence 60–80 years
Male sex	Slight male predominance, possibly related to higher rates of smoking and alcohol use historically ^[1]
Non-O blood group (A, B, AB)	ABO blood group antigens are expressed on pancreatic ductal epithelium; non-O groups have ~30% increased risk. The mechanism is not fully elucidated but may relate to altered inflammatory/immune signaling via ABO glycosyltransferases
Family history (1st-degree relative)	2-fold increased risk with one affected 1st-degree relative; risk increases further with more affected relatives
Hereditary cancer syndromes	See below
Race/Ethnicity	Higher incidence in Black populations (globally); in HK, this is less relevant

Hereditary/Genetic Risk Factors

Approximately 5–10% of pancreatic cancers have a hereditary component. Key syndromes:

Syndrome	Gene	Key Associations
Hereditary breast-ovarian cancer (HBOC)	BRCA1, BRCA2	BRCA2 carriers have ~3.5-fold increased risk of pancreatic cancer; BRCA1 has a smaller but real increase ^[5]^[6]
Lynch syndrome (HNPCC)	MMR genes (MLH1, MSH2, MSH6, PMS2)	Autosomal dominant; ↑ risk of colorectal, endometrial, ovarian, and pancreatic cancer
Peutz-Jeghers syndrome	STK11/LKB1	~130-fold increased risk of pancreatic cancer; mucocutaneous pigmentation + GI hamartomatous polyps
Familial atypical multiple mole melanoma (FAMMM)	CDKN2A (p16)	Multiple atypical naevi + melanoma + ↑ pancreatic cancer risk (13–22-fold)
Hereditary pancreatitis	PRSS1, SPINK1, CFTR	Recurrent pancreatitis from childhood → chronic pancreatitis → malignant transformation (~40% lifetime risk by age 70)
Li-Fraumeni syndrome	TP53	Multiple cancers including pancreatic
Familial pancreatic cancer	PALB2, ATM, and others	≥2 first-degree relatives with PDAC without an identified syndrome

BRCA2 and Pancreatic Cancer

BRCA2 is the most common identifiable germline mutation in familial pancreatic cancer. This is clinically important because BRCA-mutated PDAC responds to platinum-based chemotherapy and PARP inhibitors (e.g., olaparib — maintenance after platinum-based chemo in metastatic disease, based on the POLO trial). The lecture slide on BRCA2 specifically notes: "Increased risk of prostate, laryngeal, bile duct, stomach, colon (minimal), melanoma and pancreatic cancers (~1.5–3 fold risk)" ^[5].

Modifiable Risk Factors

Risk Factor	Mechanism / Explanation
Smoking	~3× increased risk ^[2]; most important modifiable risk factor. Tobacco carcinogens (nitrosamines, polycyclic aromatic hydrocarbons) reach the pancreas via bloodstream and reflux into the pancreatic duct. Dose-dependent; risk decreases after cessation but takes ~10–20 years to normalize
Chronic pancreatitis	Chronic inflammation → repeated injury-repair cycles → accumulation of somatic mutations → malignant transformation. ~2% lifetime risk of pancreatic cancer in chronic pancreatitis patients ^[2]^[7]
Diabetes mellitus	Complex bidirectional relationship: (1) Long-standing T2DM is a modest risk factor (~1.5–2× risk), likely via insulin resistance/hyperinsulinemia promoting growth; (2) New-onset diabetes (within 1–3 years) can be the FIRST manifestation of occult pancreatic cancer — the tumour produces diabetogenic factors (e.g., adrenomedullin, S100A8 calcium-binding protein) that impair β-cell function ^[1]
Obesity	BMI > 30 increases risk by ~20–40%; central adiposity is particularly important. Mechanisms: chronic low-grade inflammation, insulin resistance, altered adipokine signaling
Physical inactivity	Related to obesity and insulin resistance pathway
Heavy alcohol use	Primarily through causing chronic pancreatitis; independent modest risk factor at very high consumption levels
Dietary factors	High saturated fat/protein, processed meat, low fruit/vegetable intake. Western-type diet increases risk
Pancreatic cysts (premalignant)	Intraductal papillary mucinous neoplasm (IPMN) is the most important neoplastic cyst with malignant potential: main-duct IPMN has ~60–70% risk of harbouring malignancy vs. branch-duct IPMN which is lower risk ^[7]^[8]

Premalignant Lesions — The Adenoma-Carcinoma Sequence

Pancreatic cancer develops through a well-characterised stepwise progression:

PanIN = Pancreatic Intraepithelial Neoplasia (the most common precursor lesion)
- PanIN-1: flat (1A) or papillary (1B) mucinous epithelium; KRAS mutation present in >90%
- PanIN-2: moderate dysplasia; p16/CDKN2A inactivation
- PanIN-3: carcinoma in situ; TP53 and SMAD4/DPC4 loss
Other precursor lesions: IPMN and mucinous cystic neoplasm (MCN)

The 'Big Four' Genetic Drivers of PDAC

KRAS (oncogene activation) — present in > 90% of PDAC, the earliest and most universal driver
CDKN2A/p16 (tumour suppressor loss) — ~90%
TP53 (tumour suppressor loss) — ~75%
SMAD4/DPC4 (tumour suppressor loss) — ~55%; loss correlates with widespread metastatic disease

These accumulate in sequence during the PanIN → PDAC progression.

4. Anatomy and Function

Understanding the anatomy is absolutely critical for appreciating why pancreatic cancer presents the way it does and why surgery is so complex.

Gross Anatomy

The pancreas is a retroperitoneal organ lying transversely across the posterior abdominal wall at the level of L1–L2. It is approximately 15–20 cm long and weighs ~80–100 g.

Part	Location	Relations
Head	Nestled within the C-loop of the duodenum (D2)	Anterior: transverse colon, gastrocolic omentum. Posterior: IVC, right renal vein, right crus of diaphragm. The CBD runs through or behind the head of pancreas
Uncinate process	Hook-like projection from inferior head, passes behind SMA and SMV	This is why tumours here can encase the SMA early
Neck	Overlies SMA/SMV junction (portal vein formed here)	Narrowest portion; tumour here can compress the portal vein
Body	Crosses the aorta at L2, behind the stomach	Posterior: aorta, left crus, left adrenal, left kidney, splenic vein
Tail	Extends to the splenic hilum	Intimate relationship with splenic vessels; this is why distal pancreatectomy often requires splenectomy

Key Vascular Relationships (Critical for Resectability)

The relationship of the tumour to major vessels determines resectability — this is the single most important factor in surgical planning ^[3]^[4]:

Superior Mesenteric Artery (SMA) — runs behind the neck/uncinate; involvement = usually unresectable
Superior Mesenteric Vein (SMV) / Portal Vein (PV) — can be resected and reconstructed if involved < 180°
Celiac trunk — involvement usually precludes resection
Common Hepatic Artery (CHA) — limited involvement may be amenable to resection in borderline cases
Splenic artery and vein — course along the superior and posterior border of the body/tail

Ductal Anatomy

The main pancreatic duct (duct of Wirsung) runs the entire length of the pancreas and joins the CBD at the ampulla of Vater (hepatopancreatic ampulla), which opens into D2 via the major duodenal papilla.
The accessory duct (duct of Santorini) drains the uncinate process and opens at the minor duodenal papilla.
Head tumours compress the distal CBD and/or main pancreatic duct → "double duct sign" on imaging (simultaneous dilatation of both CBD and pancreatic duct, with abrupt cutoff at the head) ^[2]^[3].

Why Does Anatomy Matter Clinically?

Anatomical relationship	Clinical consequence
CBD passes through/behind pancreatic head	Head tumours → early biliary obstruction → jaundice (this is why head tumours present earlier than body/tail tumours)
Pancreatic duct drains through head	Head tumours → pancreatic duct obstruction → exocrine insufficiency (steatorrhoea), acute pancreatitis
Retroperitoneal location	(1) Late presentation (no early peritoneal signs), (2) back pain from coeliac/splanchnic nerve plexus invasion
Proximity to SMA, celiac axis, PV/SMV	Even small tumours may be unresectable due to vascular encasement
Tail near splenic hilum	Tail tumours → splenic vein thrombosis → left-sided (sinistral) portal hypertension → gastric varices
Duodenal proximity	Head tumours → duodenal obstruction → gastric outlet obstruction (GOO)

Pancreatic Function

Function	Component	Product	Clinical Implication When Lost
Exocrine (95% of parenchyma)	Acinar cells	Digestive enzymes: lipase, amylase, trypsinogen, chymotrypsinogen	Maldigestion → steatorrhoea, fat-soluble vitamin deficiency (A, D, E, K), weight loss
Exocrine	Ductal cells	Bicarbonate-rich fluid (neutralises gastric acid in duodenum)	Impaired neutralisation
Endocrine (5% — islets of Langerhans)	β-cells	Insulin	Diabetes mellitus
Endocrine	α-cells	Glucagon	Rare clinical consequence
Endocrine	δ-cells	Somatostatin	Rare clinical consequence
Endocrine	PP cells	Pancreatic polypeptide	Rare clinical consequence

Remember

Exocrine insufficiency becomes clinically significant only when > 90% of exocrine function is lost. This is why steatorrhoea is a relatively late manifestation ^[7].

5. Etiology and Pathophysiology

5.1 Pathophysiology of PDAC

PDAC arises from ductal epithelial cells of the pancreas (though some evidence suggests acinar cells can undergo acinar-to-ductal metaplasia as an initiating event).

Step-by-step pathogenesis:

Initiating mutation: KRAS (codon 12) — activating oncogene mutation present in > 90% of PDAC. KRAS is a GTPase molecular switch; the mutation locks it in the "ON" position → constitutive activation of RAS-RAF-MEK-ERK and PI3K-AKT-mTOR proliferative signalling pathways.
Tumour suppressor loss: Sequential inactivation of CDKN2A (p16 → loss of cell cycle G1 checkpoint), TP53 (loss of DNA damage response and apoptosis), and SMAD4/DPC4 (loss of TGF-β growth-inhibitory signalling).
Desmoplastic stromal reaction: A hallmark of PDAC. The tumour elicits a massive fibrotic/inflammatory stromal response (via pancreatic stellate cells) that:
- Creates a hypovascular, hypoxic microenvironment (tumour appears hypoattenuating/hypodense on CT because of poor blood supply — this is a key diagnostic feature) ^[3]
- Acts as a barrier to drug delivery (contributes to chemoresistance)
- Promotes immune evasion (excludes T-cells)
Perineural invasion: PDAC has a striking tropism for nerves (present in >80% of cases). Tumour cells invade perineural spaces of the splanchnic/coeliac nerve plexus → severe, unrelenting back pain.
Early vascular invasion and metastasis: Even small tumours demonstrate lymphovascular invasion. Common sites of distant metastasis:
- Liver (most common)
- Peritoneum
- Lung
- Bone ^[1]^[2]

5.2 Why Does PDAC Present So Late?

Factor	Explanation
Retroperitoneal location	Deep in the abdomen; no peritoneal irritation until very advanced
Body/tail tumours: no ductal obstruction	No jaundice or steatorrhoea → symptoms are only pain and weight loss → non-specific
Head tumours: earlier presentation (relative)	Compression of CBD → jaundice, but by the time jaundice appears, the tumour is often already involving peripancreatic vessels
Dense desmoplastic stroma	Masks the tumour on imaging (makes biopsy yield lower too)
Vague early symptoms	Epigastric discomfort, mild weight loss, new glucose intolerance — often attributed to other causes

5.3 Specific Pathophysiology by Location

Head of Pancreas (70%) [1]

Body and Tail of Pancreas (25–30%) [1]

6. Classification

6.1 Histological Classification (WHO)

Exocrine tumours (> 95%):

Ductal adenocarcinoma (85–90%) — the dominant type
Adenosquamous carcinoma (~1–4%)
Colloid (mucinous non-cystic) carcinoma
Acinar cell carcinoma
Undifferentiated carcinoma
Undifferentiated carcinoma with osteoclast-like giant cells
Pancreatoblastoma (paediatric)
Solid pseudopapillary neoplasm (young women, indolent)

Endocrine (neuroendocrine) tumours (< 5%):

Functional: insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma
Non-functional PanNETs

Precursor lesions:

PanIN (grades 1–3)
IPMN (branch-duct vs. main-duct)
MCN (mucinous cystic neoplasm)

6.2 Anatomical Location

Location	Frequency	Presentation
Head	~70%	Painless obstructive jaundice, steatorrhoea, Courvoisier's sign
Body	~15%	Epigastric pain radiating to back, weight loss
Tail	~10%	Back pain, weight loss, late presentation
Diffuse	5–20%	Combination; very poor prognosis

^[1]^[2]

6.3 TNM Staging (AJCC 8th Edition, 2017)

T Stage	Definition
T1	Tumour ≤ 2 cm (T1a ≤ 0.5 cm, T1b > 0.5–1 cm, T1c > 1–2 cm)
T2	Tumour > 2 cm but ≤ 4 cm
T3	Tumour > 4 cm
T4	Tumour involves celiac axis, SMA, and/or common hepatic artery (regardless of size)

N Stage	Definition
N0	No regional lymph node metastasis
N1	1–3 positive regional lymph nodes
N2	≥ 4 positive regional lymph nodes

M Stage	Definition
M0	No distant metastasis
M1	Distant metastasis present

AJCC Stage	T	N	M	Approximate 5-Year Survival
IA	T1	N0	M0	~34%
IB	T2	N0	M0	~25%
IIA	T3	N0	M0	~15%
IIB	T1–T3	N1	M0	~10%
III	T1–T3 (N2) or T4 (any N)	N2 or any	M0	~3–5%
IV	Any T	Any N	M1	< 3%

6.4 Resectability Classification (NCCN)

This is arguably the most clinically important classification as it directly determines management ^[3]^[4]:

Category	Definition	Management
Resectable	No arterial contact (SMA, celiac, CHA); no venous contact or ≤ 180° contact of SMV/PV without irregularity	Upfront surgery → adjuvant chemotherapy
Borderline resectable	Arterial: ≤ 180° contact with SMA or CHA (without extension to celiac axis); Venous: > 180° contact of SMV/PV, or ≤ 180° with irregular contour, or SMV/PV thrombosis if reconstruction feasible	Neoadjuvant chemotherapy ± CRT → restaging → surgery if response
Locally advanced (unresectable)	Arterial: > 180° contact with SMA or celiac; Venous: unreconstructable SMV/PV	Definitive chemotherapy ± radiation (palliative intent; conversion surgery in select responders)
Metastatic	Distant organ involvement	Palliative systemic chemotherapy

Determining Resectability

A common exam mistake is thinking that "large tumour = unresectable." In reality, it is the relationship to major arteries (SMA, celiac axis, CHA) that determines resectability, NOT the tumour size. A 1.5 cm tumour encasing the SMA is unresectable, whereas a 5 cm tumour that does not contact major vessels may be resectable ^[3]^[4].

7. Clinical Features

Overview Approach

The clinical presentation of pancreatic cancer depends critically on tumour location (head vs. body/tail) and stage (local vs. advanced/metastatic). The key teaching point is:

Head tumours → present earlier (because of biliary obstruction causing jaundice)
Body/tail tumours → present late (no biliary obstruction; only pain and constitutional symptoms)

"Pancreatic cancer is a great mimicker — it can present as back pain, new-onset diabetes, unexplained DVT, or depression before anyone thinks of the pancreas."

7.1 Symptoms

A. Cardinal Symptoms

Symptom	Location	Pathophysiological Basis
Painless progressive obstructive jaundice	Head	Tumour in the head compresses/invades the intrapancreatic portion of the common bile duct (CBD) → progressive obstruction → conjugated hyperbilirubinaemia → jaundice. It is painless because the obstruction is gradual (unlike gallstone impaction which causes colicky pain). This is the classic presentation ^[1]^[2]^[3]^[4]
Severe epigastric pain radiating to the back	Body/Tail (also head)	The pancreas sits on the retroperitoneal structures including the coeliac (solar) plexus and splanchnic nerves. Tumour growth posteriorly invades these nerve plexuses → deep, gnawing, relentless visceral pain radiating to the mid-back. Retroperitoneal infiltration is the key mechanism ^[1]^[2]^[3]
Weight loss / Anorexia	Any	Multifactorial: (1) Cancer cachexia (TNF-α, IL-6 mediated), (2) Exocrine insufficiency → maldigestion/malabsorption, (3) Biliary obstruction → reduced bile salts → fat malabsorption, (4) Anorexia from tumour-derived cytokines, (5) GOO if present

B. Symptoms of Biliary Obstruction

Symptom	Pathophysiological Basis
Pruritus	Bile salt deposition in the skin due to cholestasis. Bile salts activate itch receptors (TGR5 and possibly MRGPRX4 receptor) in cutaneous sensory nerve fibres. Can be extremely distressing and may precede clinical jaundice
Dark urine (tea/cola-coloured)	With CBD obstruction, conjugated bilirubin cannot be excreted into the gut. It backs up into the blood → is filtered by the kidneys (conjugated bilirubin is water-soluble) → dark urine ^[1]
Pale/clay-coloured stools (acholic stools)	Bilirubin cannot reach the gut → no bacterial conversion to stercobilinogen/stercobilin (which normally gives stool its brown colour) → pale, putty-like stools ^[1]
Steatorrhoea	Two mechanisms in head tumours: (1) Bile salt deficiency — obstruction of CBD prevents bile salts from reaching the duodenum → impaired fat emulsification, (2) Pancreatic lipase deficiency — obstruction of the pancreatic duct → loss of exocrine enzyme delivery → fat maldigestion → bulky, pale, foul-smelling, floating stools ^[1]^[2]

C. Symptoms of Pancreatic Insufficiency

Symptom	Pathophysiological Basis
Steatorrhoea and maldigestion	Loss of exocrine pancreatic function (requires > 90% loss to become clinically apparent). Pancreatic duct obstruction by tumour → absence of lipase, amylase, proteases in the duodenum → fat and protein maldigestion
New-onset diabetes mellitus	Tumour destruction of islets of Langerhans → loss of β-cells → insulin deficiency. ALSO, tumour secretes diabetogenic factors (adrenomedullin, S100A8) that impair insulin secretion and signalling. New-onset DM in an elderly patient (especially with weight LOSS rather than gain) should raise suspicion for occult pancreatic cancer ^[1]^[2]

New-Onset DM as a Red Flag

Glucose intolerance is present in ~80% and overt DM in ~50% of pancreatic cancer patients at diagnosis ^[1]. The typical T2DM patient gains weight; a patient with pancreatic cancer-related DM is LOSING weight. New-onset diabetes in a patient > 50 with unexplained weight loss = think pancreatic cancer.

D. Other Symptoms

Symptom	Pathophysiological Basis
Nausea and vomiting	(1) Constitutional/cancer cachexia effect, (2) Gastric outlet obstruction (GOO) — tumour in pancreatic head/uncinate process invades or externally compresses the duodenum (D2/D3) ^[1]^[2]
Fatigue and weakness	Anaemia (chronic disease, malabsorption of iron/B12/folate), cancer cachexia, malnutrition
Acute pancreatitis	Tumour occluding the main pancreatic duct → upstream ductal hypertension → premature activation of pancreatic enzymes → acute pancreatitis. Unexplained acute pancreatitis in a patient > 50 without obvious cause (no gallstones, no alcohol) should prompt imaging to exclude pancreatic cancer ^[1]^[2]
Depression / Psychological disturbance	Pancreatic cancer has a notably high association with depression, even before diagnosis. The mechanism is unclear — possibly related to paraneoplastic neuropsychiatric effects, or cytokine-mediated central effects

E. Pain Characteristics (Detailed)

Feature	Description
Site	Epigastric
Onset	Insidious (weeks to months); rarely acute (pancreatitis)
Character	Deep, gnawing, visceral quality
Radiation	To the sides and back (bilateral, band-like). Severe back pain suggests body/tail tumour invading coeliac/mesenteric plexus ^[1]
Associated symptoms	Jaundice, weight loss, anorexia
Time course	Present for 1–2 months at time of presentation; progressive
Exacerbating factors	Eating, lying supine, nighttime ^[1]
Relieving factors	Curled/fetal position, leaning forward (because this takes pressure off the retroperitoneal structures/coeliac plexus) ^[1]

7.2 Signs

A. Signs of Biliary Obstruction

Sign	Explanation
Jaundice (scleral icterus, skin)	Visible when serum bilirubin > 34–50 μmol/L. Best seen in sclerae (bilirubin has high affinity for elastin). Predominantly conjugated (direct) hyperbilirubinaemia in obstructive jaundice
Courvoisier's sign	Painless jaundice + palpable, distended gallbladder. Courvoisier's law states: "In the presence of obstructive jaundice, a palpable gallbladder is unlikely to be due to gallstones" — because chronic gallstone disease causes a fibrotic, non-distensible gallbladder. A malignant, gradual obstruction of the distal CBD allows the gallbladder to distend progressively ^[1]^[3]^[4]
Scratch marks (excoriations)	From intractable pruritus due to bile salt deposition in skin
Hepatomegaly	Cholestatic liver; back-pressure from biliary obstruction

Courvoisier's Sign — Classic Exam Favourite

Courvoisier's sign: Painless jaundice + palpable, non-tender, distended gallbladder = malignant distal CBD obstruction until proven otherwise. The most common cause is pancreatic head cancer. Remember: gallstones cause a fibrotic, shrunken gallbladder that cannot distend, whereas a slowly growing tumour causes gradual, painless distension ^[3]^[4].

B. Signs of Metastatic / Advanced Disease

Sign	Pathophysiology
Hepatomegaly (nodular/irregular)	Liver metastases — the liver is the most common site of distant spread
Ascites	Peritoneal carcinomatosis → malignant ascites (exudative, high protein, high LDH, may contain malignant cells on cytology)
Virchow's node (left supraclavicular lymphadenopathy)	Metastatic spread via thoracic duct → left supraclavicular (Virchow's) node. Named after Rudolf Virchow. Also called Troisier's sign ^[1]
Sister Mary Joseph's nodule	Palpable periumbilical mass — metastatic deposit at the umbilicus via peritoneal spread along the falciform ligament or direct seeding ^[1]
Blumer's shelf	Palpable mass on rectal exam (drop metastasis to the pouch of Douglas / rectovesical pouch)
Abdominal mass	Palpable epigastric mass = usually advanced disease ^[1]
Cachexia	Profound wasting — temporal wasting, loss of subcutaneous fat, muscle wasting

C. Paraneoplastic Manifestations

Manifestation	Mechanism
New-onset DM	Tumour-secreted diabetogenic factors + islet destruction ^[1]
Trousseau's syndrome (migratory superficial thrombophlebitis)	Tumour-elaborated procoagulants (tissue factor, cancer procoagulant — a cysteine protease that directly activates factor X) and platelet-aggregating factors create a hypercoagulable state. Manifests as migratory thrombophlebitis (different veins at different times) or DVT/PE. Armand Trousseau himself died of gastric cancer with this syndrome ^[1]^[2]
Pancreatic panniculitis	Erythematous subcutaneous nodular fat necrosis, typically on legs. Caused by systemic spillage of excess digestive pancreatic enzymes (especially lipase from acinar cell carcinoma) → autodigestion of subcutaneous fat ^[1]
Paraneoplastic pemphigoid	Autoimmune blistering skin disorder; rare ^[2]
Depression	Occurs with disproportionate frequency; mechanism unclear (cytokine-mediated?)

7.3 Comparison: Head vs. Body/Tail

Feature	Pancreatic Head	Pancreatic Body/Tail
Frequency	~70%	~25–30%
Presenting symptom	Painless obstructive jaundice	Severe epigastric/back pain
Jaundice	Early and common	Late (only with liver mets or direct extension)
Courvoisier's sign	Yes	No
Steatorrhoea	Common (CBD + pancreatic duct obstruction)	Less common
Back pain	Present but may be less severe	Prominent — indicates coeliac/splanchnic plexus invasion ^[1]
GOO	Possible (D2 compression)	Rare
Diagnosis timing	Relatively earlier (jaundice prompts investigation)	Late — most are advanced/metastatic at presentation
Resectability	~15–20% resectable at diagnosis	Rarely resectable
Operation	Pancreaticoduodenectomy (Whipple) ^[3]^[4]	Distal pancreatectomy ± splenectomy ^[1]

^[1]^[2]^[3]^[4]

8. Summary Table: Putting It All Together

Aspect	Key Points
Definition	Malignant epithelial neoplasm of pancreas; > 85% PDAC
Epidemiology	5th cause cancer death in HK; peak age 60–80; M > F; 5-yr survival ~10%
Location	70% head, 15% body, 10% tail, 5–20% diffuse
Risk factors	Smoking (most important modifiable), chronic pancreatitis, DM, obesity, IPMN, BRCA2, Lynch, Peutz-Jeghers, FAMMM
Genetics	KRAS (> 90%), CDKN2A, TP53, SMAD4
Head presentation	Painless obstructive jaundice, Courvoisier's sign, steatorrhoea, dark urine, pale stools
Body/tail presentation	Severe back pain, weight loss, late diagnosis
Metastasis sites	Liver > peritoneum > lung > bone
Paraneoplastic	New-onset DM, Trousseau syndrome, pancreatic panniculitis
Resectability	Determined by arterial involvement (SMA, celiac, CHA), not tumour size

High Yield Summary

Pancreatic cancer ≈ PDAC (> 85%) — retroperitoneal, aggressive, dense desmoplastic stroma, poor prognosis (5-yr survival ~10%).
Painless progressive obstructive jaundice = hallmark of pancreatic head cancer; Courvoisier's sign = painless jaundice + palpable gallbladder.
Body/tail tumours present LATE with severe back pain (coeliac plexus invasion) and are rarely resectable.
Key risk factors: Smoking (~3× risk), chronic pancreatitis, DM (new-onset DM can be the first sign!), obesity, BRCA2 (most common hereditary gene), Lynch syndrome, Peutz-Jeghers, FAMMM, IPMN.
Genetic drivers: KRAS (> 90%), CDKN2A, TP53, SMAD4 — sequential accumulation through PanIN stages.
Resectability is determined by vascular involvement (SMA, celiac axis, CHA, SMV/PV), NOT tumour size.
Trousseau's syndrome (migratory superficial thrombophlebitis) = hypercoagulable paraneoplastic state; pancreatic panniculitis = subcutaneous fat necrosis from enzyme spillage.
New-onset DM in elderly patient + weight loss = suspect pancreatic cancer until proven otherwise.
Sites of metastasis: Liver (most common) > Peritoneum > Lung > Bone.
The "double duct sign" on imaging (dilated CBD + dilated pancreatic duct) is highly suggestive of pancreatic head malignancy.

Active Recall - Pancreatic Cancer (Definition to Clinical Features)

1. A 68-year-old man presents with painless jaundice and a palpable, non-tender gallbladder. What is this sign called, what does it suggest, and why can the gallbladder distend in this scenario but not in gallstone disease?

Your answer

Show mark scheme

Courvoisier's sign. Suggests malignant distal CBD obstruction (most commonly pancreatic head cancer). In gallstone disease, chronic inflammation causes a fibrotic, non-distensible gallbladder. In malignancy, gradual obstruction allows progressive distension of the gallbladder.

2. Name the four most commonly mutated genes in PDAC in order of the PanIN progression sequence and state the approximate frequency of each.

Your answer

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1. KRAS (>90%) - earliest, oncogene activation. 2. CDKN2A/p16 (~90%) - tumour suppressor loss, G1 checkpoint. 3. TP53 (~75%) - loss of DNA damage response. 4. SMAD4/DPC4 (~55%) - loss of TGF-beta signalling; correlates with widespread metastasis.

3. Explain why body/tail pancreatic cancers present later and have a worse prognosis than head tumours.

Your answer

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Body/tail tumours do not obstruct the CBD so they do not cause early jaundice. Symptoms are non-specific (back pain, weight loss). By the time of diagnosis, most are locally advanced (coeliac plexus invasion) or metastatic. Hence rarely resectable.

4. What is Trousseau's syndrome, what is the underlying mechanism, and with which cancers is it classically associated?

Your answer

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Migratory superficial thrombophlebitis (thrombosis in different veins at different times). Caused by tumour-secreted procoagulants (tissue factor, cancer procoagulant activating factor X) and platelet-aggregating factors creating a hypercoagulable state. Classically associated with pancreatic cancer and gastric cancer.

5. A 72-year-old woman with no prior history of diabetes presents with new-onset diabetes and 8 kg weight loss over 3 months. Why should pancreatic cancer be suspected, and what is the pathophysiological mechanism?

Your answer

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New-onset DM in elderly patient with weight loss (rather than weight gain typical of T2DM) is a red flag for occult pancreatic cancer. Mechanism: tumour destruction of islets of Langerhans plus secretion of diabetogenic factors (adrenomedullin, S100A8) impairing beta-cell function and insulin signalling. Glucose intolerance present in ~80% of PDAC patients.

6. What determines resectability in pancreatic cancer, and what are the key vessels assessed? Give one example of a borderline resectable scenario.

Your answer

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Resectability is determined by relationship to major vessels, NOT tumour size. Key vessels: SMA, celiac axis, common hepatic artery (arterial); SMV, portal vein (venous). Borderline resectable example: tumour with 180 degrees or less contact with SMA without extension to celiac axis, or greater than 180 degrees venous contact with SMV/PV but reconstructable.

References

^[1] Senior notes: felixlai.md (Pancreatic cancer section) ^[2] Senior notes: maxim.md (Pancreatic carcinoma section) ^[3] Lecture slides: Malignant biliary obstruction.pdf ^[4] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf ^[5] Lecture slides: The Managment of breast cancer_Prof A Kwong 20_2_2020.pdf (p32 — BRCA2 lifetime risk) ^[6] Lecture slides: GC 202. Surgery may cure your cancer Surgical oncology.pdf ^[7] Senior notes: maxim.md (Chronic pancreatitis / Pancreatic cyst sections) ^[8] Senior notes: maxim.md (Pancreatic cyst — IPMN section)

Differential Diagnosis of Pancreatic Cancer

General Approach to the Differential

The differential diagnosis of pancreatic cancer is broad because the presenting features — epigastric pain, obstructive jaundice, weight loss, new-onset diabetes — are non-specific and shared by many hepatobiliary, pancreatic, and even extra-abdominal conditions ^[1]. The key principle taught in the lectures is:

"Painless progressive obstructive jaundice in elderly is malignant biliary obstruction until proven otherwise" ^[9]

The differential should be structured around two clinical axes:

The presenting syndrome — Are we dealing with obstructive jaundice? Epigastric/back pain? A pancreatic mass? New-onset diabetes?
The imaging appearance — Is the pancreatic lesion cystic or solid? ^[1]

This dual approach is how the senior notes frame it, and it makes clinical sense: you encounter the patient first (history/exam) then refine after imaging.

Framework 1: Differential by Presenting Syndrome

A. Differential Diagnosis of Painless Obstructive Jaundice

This is the most important differential list for exams. The causes can be organised by the anatomical level of obstruction and whether the obstruction is intraluminal, mural, or extramural ^[9]^[3].

The lecture slide explicitly lists the following cancers occurring along the biliary tract ^[3]^[4]:

Cholangiocarcinoma (intrahepatic, perihilar/Klatskin tumour, distal)
Carcinoma of the gallbladder
Carcinoma of the head of pancreas
Periampullary carcinoma (ampulla of Vater)
Carcinoma of the duodenum
Porta hepatis lymphadenopathy (metastatic)

Location of Obstruction	Intraluminal	Mural	Extramural
Proximal / Hilar	Choledocholithiasis (migrated), RPC stones	Cholangiocarcinoma (Klatskin tumour) ^[3]^[4], PSC stricture	Porta hepatis lymphadenopathy ^[4], CA gallbladder invading CHD ^[3]
Mid-CBD	Gallstone (choledocholithiasis)	Cholangiocarcinoma (mid-duct)	Mirizzi syndrome (gallstone in cystic duct/Hartmann's pouch compressing CHD externally)
Distal CBD / Periampullary	Gallstone impacted at ampulla	Distal cholangiocarcinoma, ampullary carcinoma ^[3]^[4]	CA head of pancreas ^[3]^[4], CA duodenum ^[3]^[4], periampullary lymphadenopathy

How to Differentiate Stone vs. Tumour on History

Stone = typically episodic pain (biliary colic), may have fever/rigors (cholangitis — Charcot's triad), fluctuating jaundice (stone ball-valves in and out of the ampulla), history of gallstones/biliary colic.

Tumour = painless, progressive, relentless jaundice (gradual obstruction, no intermittent relief), weight loss, palpable gallbladder (Courvoisier's sign), constitutional symptoms ^[9].

B. Differential Diagnosis of Jaundice + Epigastric Mass

The lecture slide by Prof R Poon explicitly lists the pathology producing jaundice AND epigastric mass ^[4]:

Hepatomegaly secondary to biliary obstruction (back-pressure → enlarged, smooth liver)
Hepatomegaly due to metastases or HCC (nodular, hard liver)
Lymph node metastases to the coeliac axis or porta hepatis
Carcinoma of stomach with metastatic lymph node in the porta hepatis (gastric cancer → coeliac/portal LN → biliary obstruction)
Distended stomach due to duodenal obstruction by tumour which also obstructs the bile duct (i.e., pancreatic head cancer causing both GOO and biliary obstruction simultaneously)

This is high yield because it reminds you that "jaundice + epigastric mass" is not exclusively pancreatic cancer — gastric cancer with portal lymphadenopathy, HCC, and even lymphoma can produce the same constellation.

C. Differential Diagnosis of Epigastric Pain Radiating to Back

Condition	Distinguishing Features
Pancreatic cancer	Insidious onset, progressive weight loss, jaundice (if head), new-onset DM, relieved by leaning forward
Chronic pancreatitis	Difficult to distinguish from CA pancreas! ^[7] History of alcohol/recurrent acute pancreatitis, pancreatic calcifications on imaging, "chain of lakes" on MRCP, may have steatorrhoea triad
Acute pancreatitis	Acute onset, serum lipase/amylase > 3× ULN, obvious aetiology (gallstones, alcohol)
Peptic ulcer disease (posterior DU)	Posterior duodenal ulcer can erode into pancreas → back pain; meal-related, responds to PPI, positive H. pylori
Abdominal aortic aneurysm	Pulsatile epigastric mass, radiates to back, may be asymptomatic or present with rupture
Retroperitoneal lymphoma	Younger patient, B-symptoms, bulky retroperitoneal lymphadenopathy on CT

D. Differential of New-Onset Diabetes + Weight Loss in Elderly

Condition	Clue
Pancreatic cancer	Most important to rule out; associated with obstructive jaundice, back pain
Chronic pancreatitis	Long alcohol history, pancreatic calcifications, exocrine insufficiency preceding endocrine insufficiency ^[7]
Type 1 DM (late-onset/LADA)	Autoantibodies (anti-GAD, anti-IA2), ketosis-prone, lean
Haemochromatosis	Bronze diabetes, liver disease, arthropathy, iron studies

Framework 2: Differential by Imaging Appearance of Pancreatic Mass

This is the framework explicitly provided in the senior notes ^[1]. When imaging shows a pancreatic mass, the first branch point is: is it cystic or solid?

Imaging	Category	Differential Diagnosis	Key Differentiating Features
Cystic	Inflammatory fluid collections	Acute peripancreatic fluid collections (APFC)	Context of recent acute pancreatitis; < 4 weeks
		Pancreatic pseudocyst	> 4 weeks after acute pancreatitis, encapsulated, no solid component, NO epithelial lining (hence "pseudo"), amylase-rich fluid
		Acute necrotic collections (ANC) / Walled-off necrosis (WON)	Necrotising pancreatitis; heterogeneous content (fluid + necrotic debris)
	Non-neoplastic	True cyst, retention cyst, mucinous non-neoplastic cyst, lymphoepithelial cyst	Usually incidental, no worrisome features
	Neoplastic	Serous cystic neoplasm (SCN)	Older women, microcystic/"honeycomb" pattern, central calcified scar, NO malignant potential → observe ^[8]
		Mucinous cystic neoplasm (MCN)	Perimenopausal women, body/tail, ovarian-type stroma, macrocystic, malignant potential ^[8]
		Intraductal papillary mucinous neoplasm (IPMN)	Pancreatic head in old men; main-duct (high malignant risk → resect) vs. branch-duct (observe unless high-risk stigmata: > 4 cm, mural nodules, main duct > 10 mm) ^[8]
Solid	Non-neoplastic	Focal chronic pancreatitis	Very difficult to distinguish from pancreatic cancer! ^[7] History of alcohol, diffuse calcifications, "chain of lakes" duct, IgG4 may help
		Autoimmune pancreatitis (AIP)	Type 1 = IgG4-related disease (diffuse "sausage-shaped" pancreas, multifocal biliary strictures, ↑ serum IgG4, responds dramatically to steroids); Type 2 = associated with IBD. Key DDx because it mimics cancer but is treated medically!
		Solid pseudopapillary neoplasm	Young women (20–30s), large well-encapsulated mass with cystic degeneration, low malignant potential, excellent prognosis after resection
	Neoplastic — Malignant	Pancreatic ductal adenocarcinoma (PDAC)	Hypoattenuating mass, double duct sign, vascular encasement, desmoplastic stroma
		Pancreatic neuroendocrine tumour (PanNET)	Hyperenhancing (hyperdense) on arterial phase CT (contrast with PDAC which is hypo-attenuating!) ± calcifications, chromogranin A positive, somatostatin receptor scintigraphy positive ^[10]
		Lymphoma (pancreatic)	Rare, bulky mass, B-symptoms, responds to chemotherapy, biopsy essential
		Metastasis to pancreas	Most common primary: renal cell carcinoma (RCC) ^[2], also lung, breast, melanoma; usually well-circumscribed, hypervascular, history of prior malignancy

PDAC vs. PanNET on CT — A Classic Distinction

This is a common exam trap. PDAC appears hypoattenuating (hypodense) on CT because of its dense desmoplastic, hypovascular stroma. PanNETs appear hyperenhancing (hyperdense) on arterial phase because they are highly vascular. Also: PDAC = no calcifications, PanNET may have calcifications; PDAC = CA19-9 elevated, PanNET = chromogranin A elevated ^[10]^[2].

Framework 3: The "Periampullary Cancer" Differential

All tumours arising within 2 cm of the ampulla of Vater are termed periampullary cancers. They all present similarly (painless obstructive jaundice) and all require Whipple's procedure for curative resection, but they have different prognoses ^[2]^[3]^[4]:

Tumour	Key Distinguishing Features	5-Year Survival After Resection
CA head of pancreas	Dull aching pain radiating to back, new-onset DM ^[2]; hypoattenuating mass, double duct sign	~10–25%
Distal cholangiocarcinoma	Elderly, cholestatic LFTs, may have PSC history ^[2]	~25–40%
Ampulla of Vater carcinoma	Jaundice (may fluctuate due to tumour necrosis — intermittent obstruction), fat malabsorption; visible on duodenoscopy ^[2]	~40–60%
Periampullary duodenal carcinoma	Rare, except in FAP (familial adenomatous polyposis); Thomas' sign: silver stool (obstructive jaundice → white stool + tumour ulceration → melena → combined appearance) ^[2]	~50–60%

Thomas' Sign

Thomas' sign = silver stool — an uncommon but pathognomonic finding of periampullary duodenal carcinoma. The "silver" colour arises from the combination of pale/clay stool (biliary obstruction) mixed with melaena (GI bleeding from tumour ulceration). White + black = silver ^[2].

The Critical Mimic: Chronic Pancreatitis vs. Pancreatic Cancer

This deserves special emphasis because chronic pancreatitis is notoriously difficult to distinguish from pancreatic cancer ^[7], and getting it wrong has serious consequences (unnecessary Whipple's for pancreatitis, or missed cancer treated as pancreatitis).

Feature	Chronic Pancreatitis	Pancreatic Cancer
History	Long alcohol history, recurrent acute attacks	No prior pancreatic disease; smoking, new-onset DM
Pain pattern	Recurrent, may eventually become "burnt out" (painless)	Progressive, unrelenting
Calcifications	Diffuse pancreatic calcifications	Absent (usually)
Duct	"Chain of lakes" (diffuse alternating stricture-dilatation)	Single focal duct cutoff with upstream dilatation
Mass	May have focal inflammatory mass	Hypoattenuating mass with vascular encasement
CA 19-9	May be mildly elevated (especially if cholangitis)	Usually markedly elevated (but not diagnostic)
IgG4	Elevated in autoimmune pancreatitis (type 1)	Normal
Biopsy	May be needed (EUS-guided) to differentiate	Definitive; but not mandatory if resectable

The Critical Mimic: Autoimmune Pancreatitis (AIP)

Autoimmune pancreatitis is the one condition you absolutely must exclude before committing to Whipple's, because it responds to steroids. The imaging can look identical to PDAC.

Feature	AIP Type 1 (IgG4-related)	PDAC
Age/Sex	Middle-aged to elderly male	Elderly, M > F
Pancreatic imaging	"Sausage-shaped" diffuse enlargement, loss of lobularity, capsule-like rim	Focal hypoattenuating mass
Biliary strictures	Multifocal (intrahepatic + extrahepatic) — mimics PSC/cholangiocarcinoma	Single distal CBD stricture
Serum IgG4	Elevated (> 2× ULN highly specific)	Normal
Other organ involvement	Salivary glands, retroperitoneum, kidneys (systemic IgG4-related disease)	None
Response to steroids	Dramatic response (diagnostic and therapeutic)	No response
EUS-FNA	Lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis	Adenocarcinoma cells

Differential Diagnosis Decision Algorithm

Tumour Markers in the Differential — What They Can and Cannot Tell You

The lecture slide provides a comprehensive table of tumour markers ^[3]:

Marker	Upper Normal	Sensitivity in Pancreatic Cancer	Non-Malignant Causes of Elevation	Key Point
AFP	10 ng/ml	Low (not a pancreatic marker)	Hepatitis, cirrhosis, biliary obstruction	Useful to differentiate HCC from cholangioCA/PDAC
CEA	5 ng/ml	30–70% in pancreatic cancer	Smoking, liver disease, bowel diseases, peptic ulcer, pancreatitis, renal failure ^[3]	Not specific; primarily a CRC marker
CA 19-9	37 U/ml	72–79% in pancreatic cancer	Benign biliary diseases, benign pancreatic diseases (cholangitis, gallstones, chronic pancreatitis) ^[3]	NOT sensitive or specific enough for diagnosis; best used for prognosis and monitoring treatment response/recurrence ^[1]^[2]. Requires Lewis blood group antigen expression (5–10% of population are Lewis-negative and will never elevate CA 19-9)
CA 125	35 U/ml	~60% in pancreatic cancer	Benign pancreatic and liver disease ^[3]	Primarily an ovarian cancer marker
DUPAN-2	150 U/ml	~70% in pancreatic/biliary cancer	Benign hepatobiliary diseases (hepatitis, cholelithiasis) ^[3]	Less commonly used clinically

CA 19-9: Know Its Limitations

CA 19-9 is NOT a screening or diagnostic test for pancreatic cancer. It is elevated in ~75–80% of PDAC but also elevated in cholangitis, choledocholithiasis, chronic pancreatitis, and other GI malignancies. Conversely, 5–10% of the population are Lewis antigen-negative and will NEVER produce CA 19-9 regardless of tumour burden. Its main role is prognostic + monitoring treatment response and detecting recurrence after surgery ^[1]^[2]^[3].

Summary: Key Differential Diagnoses by Clinical Scenario

Clinical Scenario	Top Differentials to Consider
Painless obstructive jaundice + palpable GB	CA head of pancreas, distal cholangioCA, ampullary CA
Painless obstructive jaundice + hepatomegaly	HCC, liver metastases, proximal cholangioCA
Jaundice + epigastric mass	All causes listed by Prof Poon ^[4]: biliary obstruction with hepatomegaly, liver mets/HCC, coeliac/portal LN mets, gastric CA with LN mets, distended stomach from duodenal obstruction
Epigastric pain radiating to back + weight loss	PDAC (body/tail), chronic pancreatitis, AAA, retroperitoneal lymphoma
Pancreatic mass + new-onset DM	PDAC (most important to exclude), chronic pancreatitis
Solid hypoattenuating pancreatic mass	PDAC (most likely), focal chronic pancreatitis, AIP
Solid hyperenhancing pancreatic mass	PanNET, metastasis (RCC, melanoma)
Cystic pancreatic lesion	IPMN, MCN, SCN, pseudocyst, solid pseudopapillary tumour

High Yield Summary — Differential Diagnosis

Painless progressive obstructive jaundice in elderly = malignant biliary obstruction until proven otherwise. Top DDx: CA head of pancreas, distal cholangioCA, ampullary CA, CA duodenum.
Periampullary cancers (within 2 cm of ampulla): pancreatic head, distal CBD, ampullary, duodenal — all present with painless jaundice but have very different prognoses (ampullary best, PDAC worst).
Chronic pancreatitis is notoriously difficult to distinguish from PDAC — look for diffuse calcifications, chain-of-lakes duct, alcohol history; may need biopsy.
Autoimmune pancreatitis (IgG4-related) mimics PDAC but responds dramatically to steroids — check IgG4, look for sausage-shaped pancreas and multiorgan IgG4 disease.
PDAC = hypoattenuating on CT; PanNET = hyperenhancing on arterial phase — a key imaging distinction.
CA 19-9 is NOT diagnostic — use for prognosis and monitoring. Lewis-negative patients (5–10%) will never elevate CA 19-9.
Thomas' sign (silver stool) = pathognomonic of periampullary duodenal carcinoma (white stool from obstruction + melaena from tumour ulceration).
Metastases to pancreas: most commonly from RCC, also lung, breast, melanoma — usually well-circumscribed and hypervascular.

Active Recall - Differential Diagnosis of Pancreatic Cancer

1. List the four periampullary cancers and rank them from best to worst 5-year survival after resection.

Your answer

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1. Periampullary duodenal carcinoma (50-60%). 2. Ampulla of Vater carcinoma (40-60%). 3. Distal cholangiocarcinoma (25-40%). 4. CA head of pancreas (10-25%). PDAC has the worst prognosis.

2. Name three conditions that can elevate CA 19-9 apart from pancreatic cancer, and explain why CA 19-9 cannot be used as a screening test.

Your answer

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Conditions: cholangitis, choledocholithiasis, chronic pancreatitis (also cholangioCA, HCC, gastric CA). CA 19-9 is neither sensitive nor specific for diagnosis. Additionally, 5-10% of the population are Lewis antigen-negative and will never produce CA 19-9 regardless of tumour burden. Its role is prognostic and for monitoring treatment response/recurrence.

3. How do you distinguish autoimmune pancreatitis from pancreatic ductal adenocarcinoma on imaging and biochemistry?

Your answer

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AIP: diffuse sausage-shaped pancreatic enlargement with capsule-like rim, multifocal biliary strictures, elevated serum IgG4 (especially > 2x ULN), other organ involvement (IgG4-related disease), dramatic response to steroids. PDAC: focal hypoattenuating mass, single distal CBD stricture, normal IgG4, no steroid response.

4. What is Thomas' sign, what causes it, and in which specific periampullary cancer is it classically described?

Your answer

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Thomas' sign = silver stool. Caused by combination of pale/clay stool (from obstructive jaundice, no bilirubin reaching gut) and melaena (from ulceration and bleeding of the tumour). Classic for periampullary duodenal carcinoma. White + black = silver appearance.

5. On CT imaging, a solid pancreatic mass is hyperenhancing on arterial phase. What is the most likely diagnosis and how does this differ from PDAC?

Your answer

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Most likely: Pancreatic neuroendocrine tumour (PanNET) or metastasis to pancreas (e.g., RCC). PanNETs are highly vascular so they enhance brightly on arterial phase. PDAC is hypoattenuating/hypodense because of dense desmoplastic, hypovascular stroma. Additional clues: PanNET may have calcifications and positive chromogranin A; PDAC has no calcifications and elevated CA 19-9.

6. According to the lecture by Prof R Poon, list five pathologies that can produce both jaundice AND an epigastric mass simultaneously.

Your answer

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1. Hepatomegaly secondary to biliary obstruction. 2. Hepatomegaly due to liver metastases or HCC. 3. Lymph node metastases to the coeliac axis or porta hepatis. 4. Carcinoma of stomach with metastatic lymph node in the porta hepatis. 5. Distended stomach due to duodenal obstruction by tumour which also obstructs the bile duct.

References

^[1] Senior notes: felixlai.md (Pancreatic cancer section) ^[2] Senior notes: maxim.md (Pancreatic carcinoma section; Periampullary malignancy section) ^[3] Lecture slides: Malignant biliary obstruction.pdf (p5 — cancers along biliary tract; p8 — tumour markers table) ^[4] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p24 — cancers along biliary tract; p32 — pathology producing jaundice and epigastric mass) ^[7] Senior notes: maxim.md (Chronic pancreatitis section) ^[8] Senior notes: maxim.md (Pancreatic cyst section) ^[9] Senior notes: maxim.md (Obstructive jaundice section) ^[10] Senior notes: maxim.md (Pancreatic neuroendocrine tumours section; Non-functioning pNET vs CA pancreas table)

Diagnostic Criteria, Algorithm, and Investigations for Pancreatic Cancer

Why There Are No "Diagnostic Criteria" Like Other Conditions

Unlike acute pancreatitis (which has the classic 2-out-of-3 criteria) or autoimmune pancreatitis (which has the HISORt criteria), pancreatic ductal adenocarcinoma has no universally codified "diagnostic criteria" per se. Instead, the diagnosis is established through a sequential clinical-radiological-pathological approach:

Clinical suspicion — based on symptoms (painless obstructive jaundice, back pain, weight loss, new-onset DM)
Cross-sectional imaging — pancreatic protocol CT is the cornerstone
Tissue diagnosis — required in certain scenarios but NOT mandatory if the tumour is potentially resectable ^[1]^[2]

The overarching principle: once you suspect pancreatic cancer, the primary goal of investigation is not just diagnosis but simultaneously determining resectability — because resectability directly dictates management.

Key Principle

The diagnosis and staging of pancreatic cancer are pursued in parallel, not sequentially. A pancreatic protocol CT scan simultaneously (a) identifies the mass, (b) characterises it, (c) assesses vascular involvement for resectability, and (d) screens for metastatic disease. You do not wait for a biopsy before staging ^[1]^[2]^[3].

The Diagnostic Algorithm — Overview

The approach follows a logical sequence that mirrors real clinical thinking:

Step 1: Clinical suspicion → Baseline bloods
Step 2: Initial imaging (USG) → Pancreatic protocol CT
Step 3: Assess resectability on CT
Step 4: Tissue diagnosis (only if needed)
Step 5: Complete staging (CT TAP ± PET-CT, ± staging laparoscopy)

Investigations — Systematic Breakdown

1. Physical Examination

The examination is not a mere formality — it actively contributes to diagnosis and staging.

Examination	Finding	What It Tells You
General	Jaundice (scleral icterus)	Biliary obstruction — confirms the clinical suspicion
	Cachexia (temporal wasting, muscle loss)	Advanced disease; poor nutritional status — impacts surgical fitness
	Lymphadenopathy	Virchow's node (left supraclavicular) = distant metastatic disease → Stage IV
Abdomen	Scratch marks	Pruritus from cholestasis
	Sister Mary Joseph's nodule (periumbilical)	Peritoneal carcinomatosis with spread via falciform ligament
	Hepatomegaly	Either cholestatic (smooth, non-tender) or metastatic (nodular, hard)
	Epigastric mass	Palpable pancreatic tumour = usually advanced
	Ascites	Peritoneal carcinomatosis or portal hypertension from PV invasion
	Courvoisier's sign	Painless jaundice with palpable gallbladder → points towards malignant biliary obstruction (MBO) ^[1]^[4]^[11]

The lecture by Prof R Poon emphasises Courvoisier's law with its exceptions ^[4]^[11]:

Definition: "In painless jaundice, if the gallbladder is palpable, it is unlikely to be due to gallstones" — points towards malignant biliary obstruction.

Reason: Gallstones develop chronically → chronic cholecystitis → fibrosed/contracted GB that cannot distend. Malignant obstruction develops gradually in a previously normal GB → progressive distension from back-pressure.

Exceptions ^[11]:

Double gallstones: one at CBD (causing jaundice) + another at cystic duct (causing mucocele → GB distension despite fibrosis)

Recurrent pyogenic cholangitis (RPC): pathology is in the bile duct, not the GB → CBD obstruction without chronic cholecystitis → GB can still distend

Courvoisier's Law — Exceptions

Students often state Courvoisier's law as absolute. Remember the two exceptions: double gallstones (CBD + cystic duct) and RPC (bile duct pathology, not GB pathology). Also note that gallstones can sometimes be painless too — the law is about the palpable GB, not the pain ^[11].

2. Biochemical Tests (Blood Investigations)

Investigation	Expected Finding in Pancreatic Cancer	Pathophysiological Basis
CBC with differentials	Anaemia (normocytic, of chronic disease); leukocytosis if concurrent biliary sepsis/cholangitis; thrombocytopenia to check before ERCP ^[1]^[11]	Chronic disease anaemia from cancer cachexia + malabsorption (iron, B12, folate)
Clotting profile (PT/INR)	Prolonged PT/INR	Vitamin K deficiency from obstructive jaundice — bile salts cannot reach the gut → fat-soluble vitamin (K) malabsorption → reduced hepatic synthesis of factors II, VII, IX, X. This MUST be corrected before any invasive procedure (give IV vitamin K) ^[1]^[11]
LFT	↑ ALP and GGT (cholestatic pattern), ↑ conjugated (direct) bilirubin, albumin for nutritional status ^[1]^[2]^[11]	ALP is located on the canalicular membrane of hepatocytes; biliary obstruction causes bile backup → cholestasis → upregulation and leakage of ALP into blood. GGT confirms the ALP is of hepatobiliary origin (vs. bone). Conjugated bilirubin rises because it is formed normally in the liver but cannot be excreted into the bile
RFT	Hyponatraemia, hypokalaemia ^[1]	Secondary to vomiting (especially if GOO present), poor oral intake
Serum glucose / HbA1c	Hyperglycaemia / elevated HbA1c	New-onset DM is both a consequence AND early manifestation of pancreatic cancer. New-onset DM in an older adult should prompt screening for occult pancreatic cancer ^[1]^[2]
Serum amylase and lipase	May be elevated if acute pancreatitis present	Tumour occlusion of pancreatic duct → upstream ductal hypertension → premature enzyme activation → pancreatitis ^[1]
CA 19-9	Elevated in ~75–80% of patients ^[1]^[2]^[3]	See detailed discussion below
CEA	Raised in 30–60% ^[2]	Non-specific; can be elevated in CRC, gastric, lung, breast cancers

CA 19-9 — A Detailed Discussion

CA 19-9 (Carbohydrate Antigen 19-9) is a mucin-bound sialylated Lewis-a blood group antigen (a modified Lewis antigen). Understanding its properties is essential:

Property	Detail
Upper normal limit	37 U/ml ^[3]
Sensitivity in pancreatic cancer	72–79% ^[3]
Specificity	Poor — elevated in many other conditions
NOT useful as a screening/diagnostic tool	Not sensitive and not specific enough to allow early diagnosis of CA pancreas ^[1]^[2]
Primary role	Prognostic marker + monitoring disease activity after surgery/chemotherapy. Serial monitoring of CA 19-9 predicts recurrence and long-term prognosis ^[1]
Lewis antigen requirement	Requires the presence of the Lewis blood group antigen to be expressed — approximately 5–10% of the population are Lewis-negative and will NEVER produce CA 19-9 regardless of tumour burden ^[1]
Non-malignant causes of elevation	Benign biliary diseases, benign pancreatic diseases (chronic pancreatitis, cholangitis, choledocholithiasis) ^[3]
Malignant causes (other than PDAC)	HCC, cholangioCA, CA gallbladder, gastric cancer, CRC, ovarian tumours ^[1]^[3]

The lecture slide tumour marker table ^[3] also lists:

Marker	Upper Normal	Key Cancer Association	Non-Malignant Causes
AFP	10 ng/ml	HCC (70–90%), cholangioCA (10%)	Hepatitis, cirrhosis, biliary obstruction
CEA	5 ng/ml	CRC (30–70%), gastric, pancreatic, lung, breast	Smoking, liver disease, bowel diseases, peptic ulcer, pancreatitis, renal failure
CA 19-9	37 U/ml	Pancreatic cancer (72–79%), biliary cancer (67–73%), gastric (42–62%), CRC (19–41%)	Benign biliary/pancreatic diseases
CA 125	35 U/ml	Ovarian (80%), pancreatic (60%)	Benign pancreatic and liver disease
DUPAN-2	150 U/ml	Pancreatic and biliary cancer (70%)	Benign hepatobiliary diseases (hepatitis, cholelithiasis)

CA 19-9: What It Can and Cannot Do

CA 19-9 CANNOT diagnose pancreatic cancer — it is neither sensitive nor specific. It CAN: (1) Serve as a prognostic marker at diagnosis (very high levels suggest unresectability/metastatic disease), (2) Monitor treatment response (falling levels = good response; rising levels = recurrence/progression), (3) Help detect recurrence after curative resection via serial monitoring ^[1]^[2]^[3].

3. Radiological Investigations

A. Transabdominal Ultrasound (USG) — First-Line Imaging

Aspect	Detail
Role	Initial imaging modality for any patient with suspected pancreatic cancer or obstructive jaundice ^[1]^[2]^[12]
Strengths	High sensitivity for detecting biliary tract dilatation (IHD and CBD), establishing level of obstruction, detecting pancreatic masses > 3 cm, non-invasive, no radiation, cheap, widely available
Limitations	Poor sensitivity for small tumours (< 3 cm), body/tail of pancreas often obscured by bowel gas and body habitus ^[1]^[12]
Typical findings	Focal hypoechoic hypovascular solid mass with irregular margins + dilatation of CBD ^[1]
Normal CBD size	CBD > 0.8 cm is pathological (rule of thumb: 0.1 cm per decade of age is the upper limit, e.g. 6 mm at age 60, 7 mm at age 70) ^[12]
What to assess	Pancreas (mass? duct dilatation?), biliary system (CBD dilatation, level of obstruction, stones?), GB (distended? contracted? stones?), liver (IHD dilatation, liver mets, abscess?) ^[12]

B. Pancreatic Protocol CT — The Gold Standard Investigation

This is the single most important investigation in the workup of pancreatic cancer ^[1]^[2]^[3].

What is "pancreatic protocol CT"?

It is a multidetector, dynamic, thin-sliced (≤ 3 mm), contrast-enhanced CT scan with three specific phases (triphasic) ^[1]^[2]:

Phase	Timing After Contrast	What It Shows	Why It Matters
Arterial phase	~25–30 seconds	Enhancement of celiac axis, SMA, and peripancreatic arteries	Assesses arterial involvement (SMA, celiac trunk, CHA encasement) → determines resectability ^[1]
Pancreatic (venous) phase	~40–50 seconds	Maximum attenuation difference between the hypoattenuating tumour and normal enhancing pancreatic parenchyma	This is the phase where the tumour is most conspicuous — PDAC is hypovascular (dense desmoplastic stroma) so it does NOT enhance, while normal pancreas does → the tumour stands out as a dark (hypoattenuating) area ^[1]^[2]
Portal venous phase	~70–80 seconds	Enhancement of SMV, splenic vein, and portal vein	Assesses venous involvement (SMV/PV encasement, thrombosis) → determines resectability ^[1]

Typical CT findings of pancreatic cancer ^[1]^[2]^[4]:

Finding	Explanation
Ill-defined hypoattenuating mass within the pancreas	The tumour is hypovascular (desmoplastic stroma prevents contrast enhancement) while normal parenchyma enhances brightly → tumour appears darker ^[1]^[2]
Double duct sign	Simultaneous dilatation of both the pancreatic duct AND CBD with abrupt cutoff at the pancreatic head — pathognomonic of pancreatic head malignancy ^[1]^[2]^[4]. This occurs because the tumour compresses both the intrapancreatic CBD and the main pancreatic duct where they converge at the head
Pancreatic duct cutoff	Abrupt termination of pancreatic duct at tumour site
Parenchymal atrophy	Upstream glandular atrophy from chronic duct obstruction
Contour abnormalities	Irregularity of the pancreatic contour at the site of tumour
Vascular encasement	Assessment of tumour contact/encasement of SMA, celiac trunk, hepatic artery, SMV, PV ^[2]^[3]
Liver metastases	Hypodense liver lesions
Ascites	Peritoneal carcinomatosis
Lymphadenopathy	Regional or distant nodes

CT assessment of resectability — the criteria from the lecture ^[3]:

Criteria of Resectability:

No distant metastases

SMA and celiac axis not involved

Patent superior mesenteric-portal venous confluence

PV involvement is NOT an absolute contraindication — venous resection is appropriate to improve resectability and achieve R0 resection

Significant morbidity and mortality

Reasonable survival: median = 13 months, 5-year = 7%

Expanded NCCN resectability assessment:

Category	Arterial Criteria	Venous Criteria
Resectable	No contact with SMA, celiac axis, or CHA	No SMV/PV contact, or ≤ 180° without vein contour irregularity
Borderline resectable	Tumour contact < 180° with SMA; CHA contact without extension to celiac axis	> 180° SMV/PV contact, or ≤ 180° with contour irregularity, or thrombosis if reconstructable ^[2]^[3]
Locally advanced (unresectable)	SMA/celiac trunk encasement > 180°	Unreconstructible SMV/PV due to tumour involvement or thrombus ^[2]^[3]
Metastatic	Any T, any vessels	Distant metastases present

Portal Vein Involvement

PV involvement is NOT an absolute contraindication to surgery. Selected patients with limited PV/SMV involvement can undergo venous resection and reconstruction (segmental resection with primary anastomosis or interposition graft). This achieves R0 resection in borderline cases but carries significant morbidity. The lecture notes: median survival = 13 months, 5-year survival = 7% after venous resection ^[3].

C. Endoscopic Ultrasound (EUS) ± FNAC/Biopsy

Aspect	Detail
Principle	High-frequency ultrasound transducer on the tip of an endoscope placed in the stomach/duodenum → generates high-resolution images of the pancreas from very close range (no bowel gas or body fat interference)
Role in diagnosis	Detects small pancreatic masses that could be missed by CT scan — used when there is high suspicion but no mass on CT ^[1]
EUS-guided tissue sampling	EUS-guided FNAC or biopsy is PREFERRED over percutaneous USG/CT-guided biopsy — less risk of tumour seeding because the needle traverses the GI wall (which will be resected in a Whipple's anyway) rather than crossing the peritoneal cavity ^[1]^[2]
When tissue diagnosis is NOT required	When suspicion of CA pancreas is HIGH and the tumour appears RESECTABLE on CT → proceed directly to surgery without preoperative biopsy ^[1]^[2]. Rationale: resection is both diagnostic and therapeutic; delaying surgery for biopsy provides no benefit and may worsen outcomes
When tissue diagnosis IS required	(1) Locally advanced/unresectable disease (need histology before committing to chemo), (2) Patient unfit for surgery, (3) Neoadjuvant therapy is contemplated, (4) CT failed to show typical features or an alternative diagnosis must be excluded (e.g., lymphoma, autoimmune pancreatitis), (5) Suspected secondary metastasis to pancreas ^[1]^[2]
EUS for chronic pancreatitis vs cancer	Preoperative biopsy is recommended if chronic pancreatitis or autoimmune pancreatitis is suspected since they can closely mimic pancreatic cancer — you do NOT want to do a Whipple's for AIP! ^[1]
Role of EUS in periampullary tumours	EUS helps acquire histological diagnosis of CA head of pancreas (which normally cannot be seen on OGD unless it has invaded through the duodenal wall). EUS has NO role in diagnosing CA ampulla of Vater and CA duodenum (these are visible on duodenoscopy and biopsied directly) ^[12]

When NOT to Biopsy

A very common exam mistake: ordering EUS-biopsy for every pancreatic mass. If the tumour is RESECTABLE on CT and clinical suspicion is HIGH, proceed DIRECTLY to surgery. Biopsy delays treatment, risks tumour seeding, and does not change management — the resected specimen provides the definitive pathology ^[1]^[2].

D. ERCP (Endoscopic Retrograde Cholangiopancreatography)

Aspect	Detail
Current role	Primarily THERAPEUTIC, not diagnostic — its main indication is biliary decompression via stent placement in patients with cholestasis from tumour obstruction ^[1]
Diagnostic capability	Highly sensitive for visualising the biliary tree and pancreatic ducts; can obtain brush cytology or forceps biopsy from the stricture site ^[1]^[2]
NOT all patients need preoperative biliary drainage	Not all patients with biliary obstruction from pancreatic cancer require decompression and stenting if the cancer is potentially resectable — routine preoperative biliary stenting in resectable cases increases infectious complications without clear survival benefit. It is reserved for: (a) severely jaundiced patients needing optimisation before surgery, (b) those with cholangitis, (c) delay to surgery > 2 weeks ^[1]
Complications	Post-ERCP pancreatitis, bleeding, cholangitis, perforation ^[1]
When to use	Symptomatic cholestasis requiring palliation, cholangitis, need for brush cytology when EUS is unavailable or non-diagnostic

E. MRCP (Magnetic Resonance Cholangiopancreatography)

Aspect	Detail
Principle	Non-contrast, T2-weighted MRI that highlights fluid-filled structures (bile and pancreatic ducts appear bright) ^[12]
Role	Superior in delineating the anatomy of the biliary tree especially when the system is not obstructed and there are no therapeutic indications for ERCP ^[1]
Advantage over ERCP	Non-invasive, no risk of pancreatitis/perforation, no sedation required
Limitation	NOT therapeutic (cannot stent, cannot biopsy)
When to use	Equivocal CT findings, need to clarify ductal anatomy, assessment of IPMN and cystic lesions, patients with mild LFT derangement where ERCP is not yet warranted ^[1]^[12]

F. PET-CT

Aspect	Detail
Current evidence	Data remains insufficient to conclude that PET or PET-CT provides useful information above that provided by contrast-enhanced CT ^[1]
Potential use	May help distinguish chronic pancreatitis from CA pancreas (PDAC is FDG-avid; chronic pancreatitis is usually not — but acute inflammation can cause false positives) ^[1]
Other use	Detecting occult distant metastases when CT is equivocal; staging when equivocal CT findings

G. MRI of Pancreas

Aspect	Detail
Current evidence	No evidence that MRI offers a significant diagnostic advantage over triple-phase MDCT. MRI currently provides essentially the same information as CT scan ^[1]
When preferred	Patients with contrast allergy (MRI uses gadolinium instead of iodinated contrast), renal impairment (gadolinium is safer in moderate CKD), pregnant patients, characterisation of indeterminate liver lesions (MRI with liver-specific contrast Primovist is superior for small liver lesions) ^[12]

H. Staging Laparoscopy (Diagnostic Laparoscopy)

Aspect	Detail
Purpose	General exploration of peritoneal surfaces to detect occult peritoneal metastases missed by CT — peritoneal deposits can be very small and are notoriously hard to see on CT ^[1]^[2]
Value	As CT quality has improved, the value of diagnostic laparoscopy has decreased ^[1]. However, it still has an important role in select cases
Indications ^[1]	- Tumours located in body or tail (higher rate of occult peritoneal mets)
	- Large tumours > 4 cm
	- High CA 19-9 level
	- Equivocal findings of metastasis or ascites on CT scan
	- Before resection is attempted for body/tail lesions ^[1]

I. Other Staging Investigations

Investigation	Purpose
CXR / CT thorax	Lung metastases ^[1]
CT abdomen (+ liver)	Liver metastases ^[1]
Bone scan	Bone metastases (only if symptomatic) ^[1]
Staging laparoscopy	Peritoneal metastases ^[1]^[2]
Intra-operative laparoscopy	Peritoneal metastasis is often missed on imaging ^[2]

Putting It All Together — The Complete Investigation Pathway

Key Imaging Signs — Summary Table

Sign	Modality	Meaning
Double duct sign	CT / MRCP	Simultaneous dilatation of CBD + pancreatic duct with cutoff at pancreatic head → highly suggestive of periampullary malignancy ^[1]^[2]^[4]
Hypoattenuating pancreatic mass	CT (pancreatic phase)	PDAC — dense desmoplastic stroma prevents contrast enhancement ^[1]^[2]
Pancreatic duct cutoff	CT / MRCP	Abrupt termination of duct at tumour site
Vascular encasement	CT (arterial + PV phases)	Determines resectability (SMA, celiac, CHA, SMV, PV) ^[2]^[3]
CBD dilatation > 0.8 cm	USG	Suggests distal obstruction ^[12]
Pancreatic duct dilatation > 3 mm	USG / CT	Suggests duct obstruction; in pancreatic head cancer, upstream dilatation
"Sausage-shaped" pancreas	CT	Autoimmune pancreatitis (important mimic!)
Diffuse calcifications	CT / AXR	Chronic pancreatitis (important mimic) ^[7]
Hyperenhancing mass	CT (arterial phase)	PanNET or metastasis (NOT PDAC) ^[10]

Tissue Diagnosis Decision Framework

This is one of the most tested concepts — when do you biopsy and when do you go straight to surgery?

Special Considerations

Correcting Coagulopathy Before Procedures

Why does this matter? Obstructive jaundice → bile salts cannot reach gut → fat malabsorption → vitamin K deficiency → reduced synthesis of coagulation factors II, VII, IX, X → prolonged PT/INR. Before any invasive procedure (ERCP, EUS-FNAC, surgery), you must:

Give IV vitamin K (takes 24–48 hours to work, as the liver needs time to synthesise new factors)
If urgent: give FFP (provides immediate coagulation factors) ^[1]^[11]

Preoperative Biliary Drainage — To Stent or Not to Stent?

This is a nuanced clinical question:

Routine preoperative biliary stenting is NOT recommended for all patients — it increases infective complications (cholangitis, wound infection post-Whipple) without clear survival benefit
Indications for preoperative drainage: (a) bilirubin > 250–300 μmol/L (severe jaundice impairs hepatic function and increases surgical risk), (b) cholangitis, (c) expected delay to surgery > 2–4 weeks, (d) neoadjuvant therapy planned (patient needs biliary decompression during chemo months) ^[1]

High Yield Summary — Diagnosis and Investigations

Pancreatic protocol CT (thin-sliced triphasic) is the GOLD STANDARD for diagnosis AND staging simultaneously.
Triphasic = arterial (arteries/resectability) + pancreatic/venous (tumour conspicuity) + portal venous (veins/resectability).
Classic CT finding: ill-defined hypoattenuating mass + double duct sign + vascular encasement.
Tissue diagnosis (biopsy) is NOT mandatory if the tumour is resectable — proceed to surgery. Biopsy is needed only for unresectable/metastatic disease, atypical features, neoadjuvant planning, or to exclude mimics.
EUS-guided FNAC is preferred over percutaneous biopsy (lower risk of peritoneal tumour seeding).
CA 19-9 is NOT diagnostic — it is prognostic and used for monitoring. Requires Lewis antigen expression.
Resectability criteria: No distant mets, SMA/celiac not encased > 180°, patent SMV-PV confluence (PV involvement is NOT an absolute contraindication if reconstructable).
Staging laparoscopy is indicated for body/tail tumours, large tumours > 4 cm, high CA 19-9, or equivocal CT findings.
Courvoisier's sign: Painless jaundice + palpable GB → malignant biliary obstruction. Exceptions: double gallstones, RPC.
Correct coagulopathy (IV vitamin K) before any invasive procedure in jaundiced patients.

Active Recall - Diagnosis and Investigations of Pancreatic Cancer

1. What are the three phases of a pancreatic protocol CT, and what does each phase specifically assess?

Your answer

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1. Arterial phase (25-30s): enhancement of celiac axis, SMA, peripancreatic arteries — assesses arterial involvement/resectability. 2. Pancreatic/venous phase (40-50s): maximum attenuation difference between hypoattenuating tumour and enhancing normal pancreas — best phase for tumour detection. 3. Portal venous phase (70-80s): enhancement of SMV, splenic vein, portal vein — assesses venous involvement/resectability.

2. In which specific clinical scenarios is tissue diagnosis (biopsy) required before treatment in suspected pancreatic cancer, and in which is it NOT required?

Your answer

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Biopsy REQUIRED: (1) Locally advanced/unresectable disease (before chemo), (2) Metastatic disease (before palliative chemo), (3) Neoadjuvant therapy planned, (4) Atypical CT features or alternative diagnosis must be excluded (e.g. AIP, lymphoma), (5) Patient unfit for surgery. Biopsy NOT required: Resectable tumour with high clinical suspicion — proceed directly to surgery.

3. State the criteria of resectability for pancreatic cancer as outlined in the lecture slides.

Your answer

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Resectable if: (1) No distant metastases, (2) SMA and celiac axis not involved, (3) Patent superior mesenteric-portal venous confluence. PV involvement is NOT an absolute contraindication — venous resection can be performed to achieve R0 resection (median survival 13 months, 5-year survival 7%).

4. Why is EUS-guided FNAC preferred over percutaneous CT-guided biopsy for pancreatic masses, and what are the exceptions to Courvoisier's law?

Your answer

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EUS-FNAC preferred because the needle traverses the GI wall (which is resected during Whipple anyway), so lower risk of peritoneal tumour seeding compared to percutaneous biopsy crossing the peritoneal cavity. Courvoisier exceptions: (1) Double gallstones — CBD stone causing jaundice plus cystic duct stone causing mucocele/GB distension, (2) Recurrent pyogenic cholangitis — pathology is in the bile duct, not the GB, so GB is not fibrosed and can distend.

5. A patient with suspected pancreatic cancer has a prolonged PT/INR. Explain the mechanism and how you would correct it before ERCP.

Your answer

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Mechanism: Obstructive jaundice prevents bile salts from reaching the gut, leading to fat malabsorption including fat-soluble vitamin K. Vitamin K is a cofactor for hepatic synthesis of factors II, VII, IX, and X. Deficiency leads to prolonged PT/INR. Correction: Give IV vitamin K (takes 24-48 hours for effect). If urgent procedure needed, give FFP for immediate coagulation factor replacement.

6. List four specific indications for staging laparoscopy in pancreatic cancer.

Your answer

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(1) Tumours located in body or tail of pancreas (higher rate of occult peritoneal metastases). (2) Large tumours greater than 4 cm. (3) High CA 19-9 level. (4) Equivocal findings of metastasis or ascites on CT scan.

References

^[1] Senior notes: felixlai.md (Pancreatic cancer — Diagnosis section) ^[2] Senior notes: maxim.md (Pancreatic carcinoma — Investigations, Staging, Resectability sections) ^[3] Lecture slides: Malignant biliary obstruction.pdf (p8 — tumour markers table; p23 — criteria of resectability) ^[4] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p41 — CT showing pancreatic head mass and duct dilatation) ^[7] Senior notes: maxim.md (Chronic pancreatitis section) ^[10] Senior notes: maxim.md (Non-functioning pNET vs CA pancreas table) ^[11] Senior notes: felixlai.md (Malignant biliary obstruction — Courvoisier's law, biochemical tests) ^[12] Senior notes: maxim.md (HBP investigations — USG, EUS, MRCP, PTC, ERCP)

Management of Pancreatic Cancer

Overarching Treatment Philosophy

The management of pancreatic cancer is governed by two parallel assessments that must be made before any treatment decision ^[1]^[3]^[4]:

Patient general status — Is the patient fit enough for major surgery? (age, comorbidities, nutrition, organ function)
Tumour status — Is the tumour confined (resectable) or has it spread (unresectable/metastatic)?

The lecture slide by Prof R Poon elegantly summarises this decision framework ^[4]:

General status: good → laparotomy; bad → PTBD or endoprosthesis Tumour status: confined → laparotomy → radical resection if confined, bypass if spread; spread → PTBD or endoprosthesis

The lecture on MBO further distils the approach ^[3]:

MBO → Treat SEPSIS → (1) Assess tumour resectability, (2) Patient general fitness, (3) Liver function reserve → Resectable vs. Non-resectable → Resectable = Surgery; Non-resectable = Palliation

The single most critical teaching point: Surgical treatment is the ONLY potentially curative treatment for pancreatic cancer, but only 15–20% of patients are surgical candidates because the majority present with locally advanced or metastatic disease ^[1]^[2]^[4].

Master Management Algorithm

1. Preoperative Optimisation — Preparing the Patient

Before any surgery for pancreatic cancer, several issues must be addressed. These patients are high-risk because of the combination of cancer cachexia + obstructive jaundice + malnutrition + coagulopathy ^[1]^[11]:

Issue	Problem	Intervention
Cancer cachexia → Malnutrition	Poor wound healing, immunosuppression, increased surgical risk	Nutritional support (enteral preferred: oral supplements, nasojejunal feeding) ^[1]^[11]
Liver derangement → Bleeding tendency	Vitamin K deficiency from bile salt malabsorption → ↓ factors II, VII, IX, X → prolonged PT/INR	IV Vitamin K (takes 24–48h) + FFP during surgery if needed ^[1]^[11]
Superimposed biliary infection	Cholangitis risk from biliary stasis	Antibiotic cover (e.g., Augmentin OR Cefuroxime + Metronidazole) ^[1]^[11]^[13]
Electrolyte abnormalities	Hyponatraemia, hypokalaemia from vomiting/poor intake	Correct preoperatively
Blood products	Major vascular surgery risk	Type and screen / crossmatch

Preoperative Biliary Drainage — A Nuanced Decision

This is one of the most commonly tested management dilemmas:

Aspect	Detail
Methods	ERCP with endoprosthesis (stenting) or PTBD ^[1]^[2]
Target	Serum bilirubin < 50 μmol/L ^[1]^[11]
Theoretically	Do NOT need to drain if no sepsis + early surgery can be offered within 1–2 weeks — preoperative biliary drainage increases risk of serious complications (cholangitis, pancreatitis, perforation) even in expert hands, while surgical-related complications are comparable without drainage ^[1]^[2]^[11]
Practically at QMH	Drain ALL patients since QMH cannot offer early surgery — Whipple operation has to wait 6–8 weeks, and the chance of biliary sepsis will be very high without drainage while waiting ^[1]^[11]
Stent choice	Plastic stent is preferred for preoperative drainage (cf. metal stent which induces inflammation → difficult removal in OT) ^[2]; Metallic stent (SEMS) is preferred if confirmed inoperable since it is more durable ^[1]^[13]
Advantages	Minimise cholangitis risk, relieve jaundice/pruritus, prevent cholestatic complications, allow time for neoadjuvant therapy ^[1]^[11]
Disadvantages	Increase interventions and costs, procedure-related complications (cholangitis, pancreatitis, bleeding, perforation, blocked stent) ^[1]^[11]
Indications for preop drainage	(1) Biliary sepsis/cholangitis, (2) Surgery cannot be arranged within 1–2 weeks, (3) Severe jaundice (bilirubin > 250–300 μmol/L), (4) Neoadjuvant therapy planned ^[1]^[2]

Pre-op ERCP for biliary drainage: NOT routine, only if septic / OT cannot be arranged in 1–2 weeks. Plastic stent is preferred ^[2].

Preoperative Drainage — Theory vs. Practice

In exams, the "textbook" answer is: do NOT drain routinely if early surgery is possible (evidence shows drainage increases infections without improving outcomes). But the practical QMH answer is: drain ALL because surgical wait times are long (6–8 weeks) and the risk of biliary sepsis during this period is unacceptable ^[1]^[11]. Know both perspectives.

2. Curative Treatment — Surgical Resection

Principle: Upfront pancreatectomy (+ local lymphadenectomy) + adjuvant chemotherapy (ALL cases) ± RT ^[2].

A. Resectability Criteria

The lecture slide explicitly states the criteria of resectability ^[3]:

Criteria of Resectability:

No distant metastases

SMA and celiac axis not involved

Patent superior mesenteric-portal venous confluence

PV involvement is NOT an absolute contraindication

Venous resection is appropriate to improve resectability and achieve R0 resection

Significant morbidity and mortality

Reasonable survival: median = 13 months, 5-year = 7% ^[3]

Absolute contraindications to resection ^[2]:

Contraindication	Reason
SMA / celiac trunk encasement > 180°	Cannot safely reconstruct; attempting resection = unacceptably high morbidity
Unreconstructible SMV / portal vein	No suitable vessel proximal and distal for interposition graft
Distant metastasis	Systemic disease — surgery does not improve survival

Borderline resectable (may still be resectable after neoadjuvant therapy) ^[2]:

Tumour contact < 180° with SMA (relative, not absolute contraindication)
SMV/PV involvement but suitable vessel proximal and distal for interposition graft reconstruction

B. Staging Laparoscopy — The Final Check Before Committing

Aspect	Detail
Purpose	No promise of resection until laparotomy/laparoscopy documents absence of spread ^[1]^[11]
Technique	General exploration of peritoneal surfaces; look for peritoneal nodules → send for frozen section to rule out malignancy if suspicious ^[1]^[11]
Indications	Body/tail tumours, large tumours > 4 cm, high CA 19-9, equivocal CT findings ^[1]
Intra-op USG	Used to rule out liver metastases not seen on preop imaging ^[2]
If metastases found	Surgery should be aborted → convert to palliative management ^[1]

C. Whipple's Operation (Pancreaticoduodenectomy) — For Head/Uncinate Tumours

The lecture explicitly states: "Whipple operation for carcinoma of pancreas, distal CBD cholangiocarcinoma, CA duodenum and CA ampulla" ^[3].

Prof R Poon's slide: "Line of resection of pancreatic head cancer — Whipple operation or pancreaticoduodenectomy" ^[4].

What Gets Removed?

Structure Resected	Reason
Pancreatic head	Contains the tumour
Duodenum (D1–D4 or D2–D4)	Shares blood supply with pancreatic head (via pancreaticoduodenal arteries); cannot survive without pancreatic head blood supply
First 15 cm of jejunum	Distal to ligament of Treitz, included for oncological margin
Common bile duct	Runs through/behind pancreatic head; must be transected and reconstructed
Gallbladder + cystic duct	Removed with CBD
Partial gastrectomy (classic Whipple) OR preservation of pylorus (PPPD)	See below
Regional lymphadenectomy	Take at least 12 LN for accurate staging ^[2] — LN around SMA, para-aortic

Pylorus-Preserving (PPPD) vs. Classic Whipple

Feature	PPPD (Standard, preferred)	Classic Whipple
What is preserved	Gastric antrum, pylorus, proximal 3–6 cm of duodenum ^[1]^[2]	Antrectomy + truncal vagotomy
When to use classic Whipple	—	Only when entire duodenum must be removed (e.g. FAP) or PPPD cannot achieve clear margin (tumour encroaches on D1/distal stomach) ^[2]
Survival/recurrence	No difference vs. classic Whipple ^[2]	Same
Operative advantage	Less blood loss, shorter operative time ^[2]	—
Dumping syndrome	Lower rate ^[1]^[2]	Higher (post-gastrectomy dumping)
Marginal ulceration	Lower rate ^[1]^[2]	Higher (mucosal erosion at GJ)
Bile reflux gastritis	Lower rate (difficult to manage) ^[1]^[2]	Higher
Delayed gastric emptying	Similar or slightly higher (controversial) ^[2]	Similar
Nutritional outcomes	Improved post-operative nutrition ^[1]	Poorer

Reconstruction — The Triple Anastomosis

After resection, GI continuity is restored via Roux-en-Y reconstruction with three anastomoses (performed in this specific order) ^[2]:

Anastomosis	Abbreviation	What It Connects	Key Points
1. Pancreaticojejunostomy (PJ)	PJ	Pancreatic remnant → jejunum	Highest risk of leak (30%) due to digestive enzymes + small/soft duct ^[2]. Done FIRST because it is deepest in the operative field
2. Choledochojejunostomy (CJ)	CJ	Remaining bile duct → jejunum	Restores biliary drainage
3. Gastrojejunostomy (GJ) or Duodenojejunostomy (DJ)	GJ/DJ	Stomach/duodenal stump → jejunum	Restores alimentary continuity; DJ in PPPD, GJ in classic Whipple

Why this order? The PJ is the deepest (most posterior) anastomosis — you do the deepest one first because it becomes inaccessible once the more superficial ones are done.

Why Is PJ Leak the Most Dangerous Complication?

The pancreatic remnant leaks activated digestive enzymes (lipase, trypsin, elastase) into the peritoneal cavity or retroperitoneum. These enzymes can: (1) Erode blood vessels → GDA pseudoaneurysm → catastrophic haemorrhage, (2) Cause portal/splenic vein thrombosis, (3) Create pancreatic fistula → dehydration, malnutrition, metabolic acidosis (loss of HCO₃⁻-rich pancreatic juice). Risk factors: high BMI, soft pancreas, narrow duct ^[2]^[14].

Methods to reduce PJ leakage ^[2]^[14]:

Only proven method: high-volume centre with high case load ^[14]
Possible options explored: octreotide, prophylactic stenting, Blumgart technique (duct-to-mucosa anastomosis), small bowel invagination ^[14]

D. Distal Pancreatectomy ± Splenectomy — For Body/Tail Tumours

Aspect	Detail
Indication	Lesions of the body or tail ^[1]^[2]
Procedure	Resection of pancreas lateral to SMV + splenectomy + local lymphadenectomy ^[2]
Why splenectomy?	The splenic artery and vein run intimately along the superior and posterior border of the pancreas body/tail; en-bloc removal provides oncological margin. Splenic vessel preservation is sometimes attempted (Warshaw technique) but not for cancer
Post-splenectomy care	Vaccination for encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis) — ideally ≥ 2 weeks before elective splenectomy or ASAP postop ^[2]
Staging laparoscopy first	In the rare patient with potentially resectable body/tail disease, laparoscopic exploration should be performed FIRST to rule out occult metastasis missed by CT ^[1]
Prognosis	Poor — most body/tail cancers are advanced at presentation; higher anastomotic leak rate compared to Whipple's ^[2]

E. Total Pancreatectomy

Aspect	Detail
Indications	Multifocal tumour (e.g. main-duct IPMN) or when body/tail of pancreas is too inflamed to achieve a safe anastomosis with bowel ^[2]
Consequence	Complete exocrine and endocrine insufficiency → lifelong pancreatic enzyme replacement + insulin therapy (brittle diabetes)
Advantage	Eliminates risk of PJ leak (no pancreatic remnant to anastomose)

Summary of surgery by tumour location — from the lecture ^[3]:

"Whipple operation for carcinoma of pancreas, distal CBD cholangiocarcinoma, CA duodenum and CA ampulla" "Radical cholecystectomy for CA gallbladder" "Major hepatectomy + caudate lobectomy together with confluence of hepatic ducts for Klatskin tumour" ^[3]

3. Adjuvant Chemotherapy — After Curative Resection

Aspect	Detail
Indication	ALL resected CA pancreas — no exceptions ^[2]
Timing	Start within 12 weeks post-op ^[2]
Regimens	FOLFIRINOX (folinic acid + 5-FU + irinotecan + oxaliplatin) — preferred if fit (PRODIGE-24 trial showed superior OS); OR Gemcitabine + capecitabine × 6 months (ESPAC-4 trial) ^[1]^[2]
Rationale	Evidence suggests adjuvant therapy increases survival ^[1]. Even after R0 resection, micrometastatic disease is presumed present — adjuvant chemo targets these microscopic deposits
Benefit	Clear benefit to adjuvant therapy in CA pancreas ^[1]; mFOLFIRINOX increases median OS from ~35 months to ~54 months in selected patients (PRODIGE-24)

Adjuvant Chemo Is Non-Negotiable

Every single patient who undergoes curative resection for pancreatic cancer should receive adjuvant chemotherapy. This is one of the strongest evidence-based recommendations in pancreatic surgery. Even node-negative patients benefit ^[2].

4. Neoadjuvant Therapy — For Borderline Resectable Disease

Aspect	Detail
Goal	Downstage patients with borderline resectable disease to make R0 resection achievable ^[1]
Regimens	FOLFIRINOX or Gemcitabine + nab-paclitaxel ± chemoradiation
Duration	Typically 4–6 months → restage with CT → surgery if response/stable disease
Tissue diagnosis	Required before neoadjuvant therapy — EUS-guided biopsy ^[1]^[2]
Evidence	Growing evidence that neoadjuvant approach may be superior to upfront surgery even for resectable disease (PREOPANC-2, NEONAX trials), but current standard remains upfront surgery for clearly resectable tumours

5. Palliative Treatment — For Unresectable / Metastatic Disease

The three pillars of palliation (from the lecture) ^[1]^[3]:

Palliative care:

Treat sepsis

Relieve obstruction (enteric / biliary)

Pain control ^[3]

Scenario A: Tumour Found Unresectable DURING Laparotomy

When you open the abdomen expecting to resect but find unresectable disease (occult mets/vascular invasion) ^[2]:

Action	Purpose	Details
Double bypass surgery	Prevent future obstruction	Performed prophylactically because the patient is already open
→ Gastric bypass: Gastroenterostomy	Relieve / prevent duodenal obstruction	Connects stomach to jejunum, bypassing the duodenum
→ Biliary bypass: Choledochoenterostomy	Relieve jaundice	Connects CBD to jejunum, bypassing the distal obstruction
Transduodenal trucut biopsy	Obtain tissue for histological confirmation and guide chemotherapy	DDx includes lymphoma (which has completely different treatment) ^[2]
± Celiac plexus block	Pain control	Inject alcohol/phenol into celiac plexus under direct vision while abdomen is open ^[2]

Why not choledochoduodenostomy? Choledochoduodenostomy is NOT advised because of the proximity of the duodenum to the tumour — the tumour will eventually grow into and obstruct the anastomosis ^[1].

Scenario B: Tumour Found Unresectable on Imaging (Never Goes to OR)

Action	Details
ERCP stenting (SEMS preferred)	Biliary stent ± duodenal stent to relieve jaundice and GOO without surgery ^[2]
PTBD if ERCP fails or is contraindicated	External or external-internal drainage ^[1]^[2]
Systemic chemotherapy	First obtain EUS-guided biopsy for tissue diagnosis (must exclude lymphoma) ^[2]
Chemotherapy regimens	FOLFIRINOX (folinic acid + 5-FU + irinotecan + oxaliplatin) if fit; Gemcitabine + nab-paclitaxel if borderline fit; Gemcitabine monotherapy if poor PS ^[1]^[2]

Biliary Drainage — ERCP Stenting vs. PTBD

ERCP with endoprosthesis is ALWAYS 1st line regardless of the level of obstruction especially for periampullary carcinoma ^[13], except:

ERCP Contraindication	Then Use PTBD
Structural upper GI abnormalities (oesophageal diverticulum, stricture, paraesophageal hernia)	PTBD
Gastric surgery (Billroth II, Roux-en-Y — altered anatomy makes endoscopic access to ampulla impossible)	PTBD
Multiple stenting required / difficulty reaching intrahepatic bile ducts	PTBD
Failed ERCP	PTBD

ERCP is preferred over PTBD because ^[13]:

PTBD is technically more difficult
PTBD has risk of bleeding from puncture of hepatic artery or portal vein (portal triad traversed during puncture)
If bleeding occurs: stabilise → clamp PTBD catheter → cholangiogram via catheter to identify location → remove catheter slowly to control bleeding → do NOT remove immediately (converts to free haemoperitoneum) ^[13]

Types of stents ^[1]^[13]^[14]:

Stent Type	When to Use	Properties
Plastic stent	Preoperative drainage (temporary, removable)	Cheaper but shorter patency (~3 months), tends to occlude with sludge
Self-expandable metallic stent (SEMS)	Confirmed inoperable (long-term palliation)	Longer patency (~6–12 months), cannot be removed; uncovered stents preferred (lower risk of occluding branch bile ducts) ^[14]

Stent complications ^[1]^[13]^[14]:

Stent occlusion (sludge, tumour ingrowth, tumour overgrowth) → managed by sweeping or placing new stent
Stent migration
Cholangitis / Cholecystitis

PTBD Subtypes [13]

Type	Indication	Detail
Simple external PTBD	Short-term drainage to bridge to surgery	Catheter drains bile externally; prone to electrolyte and fluid loss due to bile output
External-internal PTBD	Long-term palliation	Catheter pushed past the obstruction and internalized → bile drains into duodenum

Duodenal Obstruction Management

Option	When
Endoscopic duodenal wall stenting	Non-surgical candidate; provides immediate relief
Gastrojejunostomy (double bypass)	During laparotomy (prophylactic or therapeutic) ^[1]
Percutaneous endoscopic gastrostomy (PEG)	For gastric decompression in patients unfit for any procedure ^[1]

C. Symptomatic / Supportive Palliation

Symptom	Management	Mechanism
Pain	Narcotics (e.g. morphine) — WHO analgesic ladder; Celiac plexus neurolysis (block) — EUS-guided or CT-guided injection of alcohol/phenol into celiac plexus, destroys pain fibres; Short-course RT for local pain control ^[1]^[2]	Celiac plexus carries visceral pain afferents from the pancreas — chemical ablation interrupts pain transmission
Exocrine insufficiency	Pancreatic enzyme replacement therapy (PERT) — e.g. Creon (pancrelipase) taken with meals	Replaces missing lipase/protease/amylase for digestion
Endocrine insufficiency	OHA / insulin ^[2]	Replaces lost β-cell function
Nutritional support	Dietary counselling, oral supplements, NJ feeding if needed	Counteracts cachexia and malabsorption
Thromboembolic disease	Anticoagulation (LMWH) for Trousseau syndrome / VTE	Addresses hypercoagulable state
Pruritus	Cholestyramine (bile acid sequestrant), rifampicin, biliary drainage	Removes bile salts from skin/circulation

6. Chemotherapy Regimens — Summary

Setting	Regimen	Notes
Adjuvant (post-resection)	FOLFIRINOX (preferred if fit) or Gemcitabine + capecitabine × 6 months ^[2]	Start within 12 weeks postop
Neoadjuvant (borderline resectable)	FOLFIRINOX or Gemcitabine + nab-paclitaxel ± CRT	4–6 months → restage
First-line palliative (fit, PS 0–1)	FOLFIRINOX ^[2]	Superior OS vs. gemcitabine alone; significant toxicity
First-line palliative (borderline fit)	Gemcitabine + nab-paclitaxel	Better tolerated than FOLFIRINOX
First-line palliative (poor PS)	Gemcitabine monotherapy ^[1]	Results in symptomatic improvement, improved pain control, performance status and weight gain ^[1]
BRCA-mutated PDAC (maintenance)	Olaparib (PARP inhibitor)	After ≥ 16 weeks of platinum-based chemo without progression (POLO trial)

FOLFIRINOX Explained

FOLFIRINOX = FOLinic acid (leucovorin) + Fluorouracil (5-FU) + IRINotecan (topoisomerase I inhibitor) + OXaliplatin (platinum agent). This is the most active regimen for PDAC but carries significant toxicity (myelosuppression, diarrhoea, neuropathy). Reserved for fit patients with good performance status ^[2].

7. Prognosis — Long-Term Survival Data

From the lecture by Prof R Poon ^[4]:

Long-term survival of pancreatic head cancer:

1-year 5-year
After radical resection 66% 27%
Palliative bypass 10% 0%

This starkly illustrates why resection is pursued so aggressively when possible — it is the only chance of meaningful long-term survival.

Additional survival data ^[1]:

5-year survival after pancreaticoduodenectomy, node-negative = 25–30%
5-year survival after pancreaticoduodenectomy, node-positive = ~10%
Median survival for unresectable locally advanced = 12 months
Median survival for metastatic disease = 6 months

Surgical Complications — Whipple's Operation

Timing	Complication	Detail
Early	Haemorrhage	Intraoperative vascular injury or postop GDA pseudoaneurysm erosion from PJ leak
	Anastomotic leak	Risk: PJ (30%) > CJ > GJ ^[2]; PJ highest because of digestive enzymes + small/soft duct
	Pancreatic fistula	Drain output after postop D3 with amylase > 3× ULN ^[14]; classified by ISGPF: Biochemical leak (asymptomatic) → Grade B (persistent drainage > 3 weeks, infection, no organ failure) → Grade C (unstable, re-operation, organ failure)
	Delayed gastric emptying (common)	Especially in PPPD; mechanisms: injury to nerve of Latarjet, disrupted pacemaker cells, reduced CCK (high in duodenum) ^[2]
	Wound infection	Especially if preop biliary stenting (contaminated bile)
	Intra-abdominal abscess	From leak or infection
	Post-ERCP pancreatitis	If preop stenting performed
Late	Exocrine insufficiency	Malabsorption and steatorrhoea → PERT ^[1]
	Endocrine insufficiency	DM (16% new-onset) ^[2] → insulin/OHA
	Gastric stasis	Especially in PPPD patients ^[1]
	Marginal ulceration	Mucosal erosion at GJ (more common in classic Whipple)
	Dumping syndrome	More common in classic Whipple (removed pylorus)

Pancreatic Fistula Management [14]

Grade	Management
Biochemical leak	Maintain oral feeding, drain in situ for 3 weeks
Grade B (symptomatic)	NPO, NJ feeding, correct fluid and electrolytes, drain in situ, antibiotic prophylaxis, somatostatin analogue
Persistent/Grade C	Endoscopic transpapillary stent; surgical repair; embolization for bleeding

Complete Management Summary Table

Stage	Treatment	Key Points
Resectable	Upfront surgery → Adjuvant chemo (ALL cases)	Whipple (head), distal pancreatectomy (body/tail); PPPD preferred; take ≥ 12 LN
Borderline resectable	Neoadjuvant chemo ± CRT → Restage → Surgery if response	FOLFIRINOX or Gem/nab-paclitaxel; tissue diagnosis required first
Locally advanced	Definitive chemo ± RT; palliative stenting	Conversion surgery in exceptional responders
Metastatic	Palliative chemo + symptom control	FOLFIRINOX (fit) or Gem-based; biliary/duodenal stenting; celiac plexus block
All stages	Symptom management: pain (opioids, celiac block), jaundice (stent), GOO (duodenal stent/GJ), exocrine insufficiency (PERT), DM (insulin)	Multidisciplinary team approach

High Yield Summary — Management

Only 15–20% of patients are surgical candidates — surgery is the only potentially curative treatment.
Assessment framework: General status (fit/unfit) + Tumour status (confined/spread) → determines surgery vs. palliation.
Resectability criteria: No distant mets, SMA/celiac not involved, patent SMV-PV confluence. PV involvement is NOT an absolute contraindication (venous resection for R0: median 13 months, 5-year 7%).
Whipple operation: For head/periampullary tumours. PPPD preferred (less dumping, less marginal ulcer, less bile reflux, better nutrition). Triple anastomosis: PJ → CJ → GJ/DJ.
Adjuvant chemotherapy is given to ALL resected patients — FOLFIRINOX (preferred) or Gemcitabine + capecitabine × 6 months. Start within 12 weeks.
Preop biliary drainage: NOT routine if early surgery possible; practically at QMH: drain ALL (long wait times). Plastic stent preop; SEMS if confirmed inoperable.
Palliative triad: Treat sepsis + Relieve obstruction (biliary stent/bypass, duodenal stent/GJ) + Pain control (opioids, celiac plexus block).
Unresectable at laparotomy → Double bypass (GJ for GOO + choledochoenterostomy for jaundice) + biopsy + celiac plexus block.
ERCP stenting is 1st line for biliary palliation (over PTBD). SEMS preferred for palliation (longer patency). PTBD if ERCP fails.
PJ leak is the most feared complication of Whipple (30% risk) → can cause GDA pseudoaneurysm, haemorrhage, pancreatic fistula.
Long-term survival after radical resection: 1-year 66%, 5-year 27%. Palliative bypass: 1-year 10%, 5-year 0%.

Active Recall - Management of Pancreatic Cancer

1. State the three criteria of resectability for pancreatic cancer as per the lecture slides. Is portal vein involvement an absolute contraindication?

Your answer

Show mark scheme

Criteria: (1) No distant metastases, (2) SMA and celiac axis not involved, (3) Patent superior mesenteric-portal venous confluence. PV involvement is NOT an absolute contraindication — venous resection is appropriate to improve resectability and achieve R0 resection. Survival after venous resection: median 13 months, 5-year 7%.

2. Name the three anastomoses performed during a Whipple operation in the correct order, and explain why PJ leak is the most dangerous complication.

Your answer

Show mark scheme

Order: (1) Pancreaticojejunostomy (PJ), (2) Choledochojejunostomy (CJ), (3) Gastrojejunostomy/Duodenojejunostomy (GJ/DJ). PJ done first because it is deepest. PJ leak (30% risk) is most dangerous because: activated digestive enzymes leak into peritoneum causing vessel erosion (GDA pseudoaneurysm, catastrophic haemorrhage), portal/splenic vein thrombosis, and pancreatic fistula with dehydration, malnutrition, and metabolic acidosis.

3. A patient with unresectable pancreatic head cancer is found to have both biliary obstruction and duodenal obstruction during laparotomy. What surgical procedure should be performed and what additional interventions?

Your answer

Show mark scheme

Double bypass surgery: (1) Biliary bypass — choledochoenterostomy (relieve jaundice), (2) Gastric bypass — gastroenterostomy (relieve duodenal obstruction). Additional: Obtain transduodenal trucut biopsy for tissue diagnosis (DDx lymphoma) and perform celiac plexus block for pain control. Note: choledochoduodenostomy is NOT advised due to proximity of duodenum to tumour.

4. Compare PPPD and classic Whipple operation. List four advantages of PPPD and state when classic Whipple should be used instead.

Your answer

Show mark scheme

PPPD advantages: (1) Lower rate of post-gastrectomy dumping syndrome, (2) Lower rate of marginal ulceration, (3) Lower rate of bile reflux gastritis, (4) Improved post-operative nutrition, with less blood loss and shorter operative time. No difference in survival/recurrence. Classic Whipple used when: entire duodenum must be removed (e.g. FAP) or PPPD cannot achieve clear resection margin (tumour encroaches on D1 or distal stomach).

5. When should preoperative biliary drainage be performed, and why is the practical approach at QMH different from the theoretical recommendation?

Your answer

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Theoretical: Do NOT drain if no sepsis and early surgery within 1-2 weeks (drainage increases complications without improving outcomes). Practical at QMH: Drain ALL patients because Whipple has 6-8 week wait time and risk of biliary sepsis is unacceptable. Indications: biliary sepsis/cholangitis, surgery delayed beyond 1-2 weeks, severe jaundice (bilirubin > 250-300), neoadjuvant therapy planned. Use plastic stent preop (removable); use SEMS if confirmed inoperable (longer patency).

6. State the adjuvant chemotherapy principle for resected pancreatic cancer including indication, timing, and two regimen options.

Your answer

Show mark scheme

Indication: ALL resected CA pancreas (no exceptions). Timing: Start within 12 weeks post-op. Regimens: (1) FOLFIRINOX (folinic acid + 5-FU + irinotecan + oxaliplatin) — preferred if fit, or (2) Gemcitabine + capecitabine for 6 months. Clear evidence that adjuvant therapy increases survival.

References

^[1] Senior notes: felixlai.md (Pancreatic cancer — Treatment section, Preoperative biliary drainage, Whipple operation, Distal pancreatectomy, Prognosis) ^[2] Senior notes: maxim.md (Pancreatic carcinoma — Curative treatment, Whipple operation, PPPD, Distal pancreatectomy, Adjuvant chemotherapy, Palliative treatment) ^[3] Lecture slides: Malignant biliary obstruction.pdf (p18 — MBO management framework; p21 — surgical operations by tumour type; p23 — criteria of resectability; p30 — palliative care) ^[4] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p9 — Whipple line of resection; p54 — general status/tumour status flowchart; p76 — long-term survival data) ^[11] Senior notes: felixlai.md (Malignant biliary obstruction — Preoperative measures, Courvoisier's law, ERCP/PTBD section) ^[13] Senior notes: felixlai.md (MBO treatment — ERCP vs PTBD, stent types, palliative bypass, PTBD complications) ^[14] Senior notes: maxim.md (Pancreatic fistula — ISGPF classification, management; methods to reduce PJ leakage; stent types for cholangioCA)

Complications of Pancreatic Cancer

Complications of pancreatic cancer can be categorised into three broad groups: (A) complications of the disease itself (from tumour progression), (B) complications of treatment (surgical and non-surgical), and (C) causes of mortality. Understanding these from first principles is critical — every complication traces back to either the tumour's anatomical effects, its systemic biological impact, or the consequences of removing/manipulating vital structures.

A. Complications of the Disease (Untreated / Progressive Pancreatic Cancer)

These occur as the tumour grows locally, invades adjacent structures, metastasises, or exerts systemic paraneoplastic effects.

1. Biliary Complications

Complication	Pathophysiology	Clinical Consequence
Progressive obstructive jaundice	Head tumour gradually compresses/invades the intrapancreatic CBD → complete biliary obstruction	Conjugated hyperbilirubinaemia → jaundice, pruritus, dark urine, pale stools. If untreated: coagulopathy (vitamin K malabsorption), malabsorption, malnutrition, and immune dysfunction ^[3]
Acute cholangitis ^[1]	Biliary stasis proximal to obstruction → bacterial colonisation of static bile (normally bile is sterile, but stasis allows ascending infection from duodenum) → suppurative infection of the biliary tree	Charcot's triad (fever/rigors, jaundice, RUQ pain) → can progress to Reynolds' pentad (+ hypotension + confusion) = biliary sepsis. Biliary sepsis is a leading cause of mortality in MBO ^[3]^[15]
Secondary biliary cirrhosis	Prolonged biliary obstruction → chronic cholestasis → periductal fibrosis → eventually cirrhosis	Rare (requires months–years of obstruction); liver failure in advanced cases

Why Is Cholangitis Dangerous in Pancreatic Cancer?

In a normal biliary system, the sphincter of Oddi prevents reflux of duodenal bacteria into the bile duct. When a tumour obstructs the distal CBD, bile stagnates → bacteria ascend from the duodenum into the stagnant bile → multiply → cholangitis. If not treated urgently with antibiotics + biliary decompression (ERCP stenting or PTBD), this progresses to biliary sepsis — one of the three major causes of death in MBO ^[3]^[15].

2. Pancreatic Complications

Complication	Pathophysiology	Clinical Feature
Acute pancreatitis ^[1]	Tumour occludes the main pancreatic duct → upstream ductal hypertension → premature activation of pancreatic enzymes (trypsinogen → trypsin) → autodigestion of pancreatic parenchyma	Acute epigastric pain radiating to back, ↑ amylase/lipase > 3× ULN. Unexplained pancreatitis in an elderly patient without obvious cause (no gallstones, no alcohol) should prompt imaging for occult pancreatic cancer
Exocrine insufficiency	Pancreatic duct obstruction → loss of exocrine enzyme delivery (lipase, amylase, proteases) to duodenum; clinically significant when > 90% function is lost	Steatorrhoea (bulky, pale, foul-smelling, floating stools), maldigestion, malabsorption, fat-soluble vitamin deficiency (A, D, E, K), weight loss
Endocrine insufficiency	Tumour destroys islets of Langerhans + secretes diabetogenic factors (adrenomedullin, S100A8)	New-onset DM — present in ~50% at diagnosis ^[1]

3. Gastrointestinal Complications

Complication	Pathophysiology	Presentation
Gastric outlet obstruction (GOO)	Head/uncinate tumour invades or externally compresses the duodenum (D2/D3) → mechanical obstruction of gastric outflow	Persistent vomiting (often non-bilious if obstruction above ampulla, bilious if below), abdominal distension, succession splash, dehydration, hypokalaemic hypochloraemic metabolic alkalosis (from loss of HCl in vomit), aspiration pneumonia risk ^[1]^[2]
GI bleeding	Tumour erosion into duodenal mucosa or peripancreatic vessels (GDA, splenic artery)	Melaena, haematemesis, iron-deficiency anaemia
Duodenal obstruction	Direct invasion	Similar to GOO; managed by duodenal stenting or gastrojejunostomy ^[2]

4. Vascular Complications

Complication	Pathophysiology	Clinical Feature
Venous thromboembolism (Trousseau syndrome)	Tumour-elaborated procoagulants (tissue factor, cancer procoagulant — a cysteine protease that directly activates factor X) + platelet-aggregating factors → hypercoagulable state	Migratory superficial thrombophlebitis, DVT, PE. ↑ Risk of both arterial and venous thromboembolic events ^[1]
Portal vein / SMV thrombosis	Direct tumour invasion or compression of PV/SMV	Portal hypertension → splenomegaly, ascites, variceal bleeding. Can cause mesenteric ischaemia (SMV thrombosis → compromise bowel perfusion)
Splenic vein thrombosis	Body/tail tumours directly invade or compress the splenic vein (runs along posterior/superior border of pancreatic body)	Left-sided (sinistral) portal hypertension → isolated gastric varices (NOT oesophageal) → risk of upper GI bleeding
GDA pseudoaneurysm	Pancreatic enzyme leak (from tumour erosion or post-op fistula) erodes into the GDA wall → weakening → pseudoaneurysm formation	Sentinel bleed → catastrophic intra-abdominal haemorrhage or UGIB. Three signs suggestive of pseudoaneurysm: unexplained GI bleeding, unexplained drop in Hb/Hct, sudden expansion of a pancreatic fluid collection ^[15]

5. Metastatic Complications

Site	Complication	Pathophysiology
Liver (most common)	Hepatomegaly, liver failure, ascites, jaundice (from intrahepatic mets even without head tumour)	Tumour replaces functional hepatic parenchyma → synthetic failure (↓ albumin, ↓ clotting factors), portal hypertension
Peritoneum	Malignant ascites, bowel obstruction	Peritoneal carcinomatosis → exudative ascites (high protein, high LDH, positive cytology), serositis, and adhesions causing mechanical small bowel obstruction
Lung	Dyspnoea, cough, haemoptysis, pleural effusion	Haematogenous spread; malignant pleural effusion (exudative)
Bone	Pathological fractures, bone pain, hypercalcaemia	Osteolytic/osteoblastic metastases

6. Paraneoplastic Complications

Complication	Mechanism
Trousseau syndrome	Discussed above under vascular complications ^[1]
Pancreatic panniculitis	Systemic spillage of excess digestive pancreatic enzymes (especially lipase, particularly in acinar cell carcinoma variant) → autodigestion of subcutaneous fat → erythematous subcutaneous nodular fat necrosis, typically on legs ^[1]
Depression	Occurs with disproportionate frequency even before diagnosis; mechanism unclear (cytokine-mediated central effects, IL-6/TNF-α)

7. Nutritional / Systemic Complications

Complication	Mechanism
Cancer cachexia	Tumour-derived cytokines (TNF-α, IL-6, IL-1) → proteolysis-inducing factor → skeletal muscle wasting, adipose tissue loss, anorexia. Cancer cachexia is a leading cause of mortality in MBO ^[15]^[16]
Malnutrition	Combination of: (1) maldigestion/malabsorption (exocrine insufficiency + bile salt deficiency), (2) anorexia from cytokines, (3) GOO preventing adequate intake
Fat-soluble vitamin deficiency	Vitamin K → coagulopathy; Vitamin D → osteomalacia; Vitamin A → night blindness; Vitamin E → neuropathy

B. Complications of Treatment

1. Whipple's Operation (Pancreaticoduodenectomy) — Specific Surgical Complications

This is one of the most technically demanding operations in surgery, with a perioperative mortality of 2–5% in high-volume centres and a morbidity rate of 30–50%.

Early Complications

Complication	Incidence	Pathophysiology	Management
Pancreaticojejunostomy (PJ) leak	~30% ^[2]	Highest leak risk of the three anastomoses because: (1) pancreatic enzymes actively digest the anastomosis, (2) the pancreatic duct is often small and soft (normal pancreas without upstream dilatation), (3) the parenchyma is friable. Leak of activated digestive enzymes causes local tissue destruction	Biochemical leak (asymptomatic): maintain oral feeding, drain in situ for 3 weeks. Symptomatic (Grade B): NPO, NJ feeding, correct fluids/electrolytes, drain in situ, antibiotics, somatostatin analogue. Grade C: re-operation, may require completion distal pancreatectomy ^[2]^[14]
Pancreatic fistula	Related to PJ leak	Definition: drain output of any volume after post-op day 3 with drain amylase > 3× ULN ^[2]^[14]. Risk factors: high BMI, soft pancreas, narrow duct ^[2]	As above (ISGPF classification — biochemical leak, Grade B, Grade C) ^[14]
GDA pseudoaneurysm	Rare but lethal	PJ leak → pancreatic enzymes (elastase) erode into GDA stump → pseudoaneurysm → rupture → catastrophic intra-abdominal haemorrhage or UGIB ^[2]^[14]^[15]	Angiography (diagnostic + therapeutic embolisation); if unstable → emergency re-laparotomy
Portal / splenic vein thrombosis		PJ leak → local inflammation → venous thrombosis ^[2]^[14]	Anticoagulation; monitor for mesenteric ischaemia
Biliary anastomotic leak (CJ)	Less common than PJ	Bile leak from choledochojejunostomy → bile peritonitis	Percutaneous drainage ± re-operation
Delayed gastric emptying (DGE)	Common ^[1]^[2]	Especially in PPPD. Mechanisms: (1) Injury to nerve of Latarjet (anterior vagal branch supplying pylorus/antrum), (2) Disruption of duodenal pacemaker cells (interstitial cells of Cajal in the resected duodenum normally coordinate gastric emptying), (3) Reduced CCK (cholecystokinin — high concentration in duodenal mucosa, now resected) ^[2]	Prokinetics (metoclopramide, erythromycin), NJ feeding to maintain nutrition, usually self-resolving over weeks
Haemorrhage		Intra-operative vascular injury or post-op from anastomotic site / pseudoaneurysm	Re-operation or angiographic embolisation
Pancreatitis		Manipulation of pancreatic remnant → inflammation	Supportive; usually mild
Wound infection		Especially if preop biliary stenting → bile colonised with bacteria → contaminated operative field	The lecture slide notes: "Pre-op biliary stenting → bacterial contamination, inflammation, procedure-associated complications" ^[3]
Pancreatic ascites		Pancreatic juice leaks into peritoneal cavity ^[14]	Drainage, somatostatin analogue
Multi-organ failure		SIRS from pancreatic enzyme spillage → MOF (kidneys, lungs, bowels)	ICU support ^[1]

The Dreaded PJ Leak Cascade

The PJ leak is the most dangerous complication of Whipple's because it triggers a cascade: leak of pancreatic enzymes → erosion of GDA pseudoaneurysm → catastrophic haemorrhage, AND/OR → portal vein thrombosis → mesenteric ischaemia, AND/OR → pancreatic fistula → dehydration + metabolic acidosis (loss of HCO₃⁻-rich pancreatic juice). This is why surgeons place abdominal drains around the pancreatic and biliary anastomosis to monitor for leaks early ^[1]^[2].

Somatostatin analogue (e.g. octreotide) does NOT reduce the risk of PJ leak — it only reduces the volume of output in established fistulae ^[2].

Only proven method to reduce PJ leakage: high-volume centre with high case load ^[14].

Late Complications

Complication	Pathophysiology	Management
Exocrine insufficiency → Malabsorption and steatorrhoea ^[1]	Loss of pancreatic head parenchyma → reduced enzyme production (though some function remains from body/tail remnant)	Pancreatic enzyme replacement therapy (PERT) — e.g. Creon (pancrelipase) taken with meals
Endocrine insufficiency → DM	Loss of islets of Langerhans in resected head; new-onset DM in ~16% ^[2]	OHA / insulin
Gastric stasis	Especially in PPPD (preserved pylorus, but loss of duodenal coordination) ^[1]	Prokinetics, dietary modification (small frequent meals)
Dumping syndrome	More common in classic Whipple (loss of pylorus → rapid gastric emptying of hyperosmolar contents into jejunum → fluid shifts → vasomotor symptoms)	Dietary modification (small meals, avoid simple sugars), rarely octreotide
Marginal ulceration	Mucosal erosion at the gastrojejunostomy (GJ) site — exposure of jejunal mucosa to acid without buffering by duodenal bicarbonate	PPI therapy
Bile reflux gastritis	Bile reflux through GJ into gastric remnant → chemical gastritis (difficult to manage) ^[2]	Sucralfate, cholestyramine; surgical revision rarely needed
Tumour recurrence	Micrometastatic disease despite R0 resection; most recurrences are distant (liver, peritoneum)	Adjuvant chemotherapy reduces risk; surveillance with CT + CA 19-9

The lecture slide on tissue loss after resection explicitly notes ^[16]:

"Just adequate resection → No diabetes mellitus, No steatorrhoea" "Excessive resection → Diabetes mellitus, Steatorrhoea"

This highlights that the extent of pancreatic resection directly determines the severity of metabolic consequences. The surgical principle is to remove enough for oncological clearance while preserving as much functional parenchyma as possible.

2. Distal Pancreatectomy ± Splenectomy — Specific Complications

Complication	Detail
Pancreatic fistula / anastomotic leak	Higher anastomotic leak rate compared to Whipple's ^[2] — the cut surface of the pancreatic body/neck is large and the stump closure is under tension
Post-splenectomy complications	Overwhelming post-splenectomy infection (OPSI): lifelong risk of fulminant sepsis from encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis) → vaccination required ^[2]
Post-splenectomy thrombocytosis	Loss of splenic sequestration → reactive thrombocytosis → risk of thrombosis
Endocrine/exocrine insufficiency	Variable — depends on extent of resection

3. Biliary Stent / ERCP Complications

Complication	Mechanism
Stent occlusion	Sludge, tumour ingrowth (through mesh of metallic stent), tumour overgrowth (tumour grows over ends of stent) ^[13] → recurrent jaundice. Managed by sweeping or placing new stent ^[14]
Stent migration	Stent moves distally into duodenum or proximally into bile duct ^[13]
Cholangitis / Cholecystitis	Bacterial contamination of obstructed bile; stent dysfunction → re-obstruction → cholangitis ^[13]
Post-ERCP pancreatitis	Traumatic instrumentation at the ampulla → papillary oedema → pancreatic duct obstruction → acute pancreatitis
Perforation	Sphincterotomy too deep, or scope-related duodenal perforation
Bleeding	Post-sphincterotomy

The lecture slide on preoperative biliary drainage complications notes ^[3]:

"Pre-op biliary drainage has increased risk of serious complications — Pancreatitis (7%), cholangitis (26%), blocked stent (15%), bleeding (2%), perforation (2%)" "Surgery-related complications were comparable" "Routine pre-op biliary drainage in patients undergoing surgery for CA pancreas increases rate of complications"

4. PTBD-Specific Complications

Complication	Mechanism
Haemobilia / bleeding	Puncture of hepatic artery or portal vein before reaching bile duct (portal triad) ^[13]
Electrolyte / fluid loss	External PTBD → bile output is lost externally → loss of bile salts, fluid, electrolytes (Na⁺, K⁺, HCO₃⁻)
Catheter dislodgement	Accidental removal → bile peritonitis
Bacteraemia	Needle traverses skin and liver → risk of introducing infection

5. Chemotherapy Complications

Regimen	Key Toxicities
FOLFIRINOX	Myelosuppression (neutropaenia), diarrhoea, peripheral neuropathy (oxaliplatin — cumulative, dose-limiting), mucositis, fatigue. Significant toxicity — reserved for fit patients
Gemcitabine	Myelosuppression (thrombocytopaenia predominant), flu-like symptoms, hepatotoxicity, interstitial pneumonitis (rare)
Capecitabine	Hand-foot syndrome (palmar-plantar erythrodysaesthesia — capecitabine is preferentially activated in tumour tissue via thymidine phosphorylase, but also activates in palms/soles), diarrhoea, mucositis

C. Causes of Mortality in MBO / Pancreatic Cancer

The lecture slide explicitly lists the three major causes of mortality ^[15]:

Cause of mortality in MBO:

Biliary sepsis

Cancer cachexia

Liver failure

And from the surgical oncology lecture ^[16]:

Causes of mortality related to cancer:

Cancer invasion of organ of origin, adjacent organs or distant sites leading to loss of organ function

Cancer cachexia

Examples: Oesophageal cancer, Pancreatic cancer, Liver cancer

Cause of Death	Mechanism
Biliary sepsis	Biliary stasis → ascending cholangitis → overwhelming sepsis → septic shock → multi-organ failure. This is why biliary decompression (stenting/PTBD) is a priority in palliation ^[15]
Cancer cachexia	Progressive wasting driven by tumour-derived cytokines (TNF-α/cachectin, IL-6, IL-1, proteolysis-inducing factor) → loss of skeletal muscle and adipose tissue → immune dysfunction → death from infection or cardiac failure ^[15]^[16]
Liver failure	(1) Hepatic metastases replace functional liver parenchyma → synthetic failure, or (2) prolonged biliary obstruction → secondary biliary cirrhosis → hepatic decompensation ^[15]

Prognosis — Final Summary

Scenario	Survival
After radical resection: 1-year	66% ^[4]
After radical resection: 5-year	27% ^[4]
Palliative bypass: 1-year	10% ^[4]
Palliative bypass: 5-year	0% ^[4]
Node-negative resection: 5-year	25–30% ^[1]
Node-positive resection: 5-year	~10% ^[1]
Unresectable locally advanced: median	12 months ^[1]
Metastatic disease: median	6 months ^[1]
Diagnosed at localised stage	Only 8% ^[1]
Diagnosed with distant metastases	53% (majority) ^[1]

High Yield Summary — Complications

Disease complications: Acute cholangitis (biliary sepsis), acute pancreatitis, GOO, obstructive jaundice with coagulopathy/malnutrition, Trousseau syndrome (migratory thrombophlebitis), new-onset DM.
Three leading causes of death in MBO: Biliary sepsis, cancer cachexia, liver failure.
PJ leak (~30%) is the most feared complication of Whipple's — triggers cascade of GDA pseudoaneurysm, haemorrhage, PV thrombosis, pancreatic fistula.
Pancreatic fistula definition: Drain output after postop D3 with amylase > 3× ULN. Risk factors: high BMI, soft pancreas, narrow duct.
DGE in PPPD: Injury to nerve of Latarjet + disrupted pacemaker cells + reduced CCK.
Only proven method to reduce PJ leak: High-volume centre with high case load.
Preop biliary drainage increases complications: Pancreatitis 7%, cholangitis 26%, blocked stent 15% — but practically necessary at QMH due to long surgical wait times.
Post-splenectomy: Lifelong risk of OPSI from encapsulated organisms → vaccination essential.
Just adequate resection → no DM, no steatorrhoea; excessive resection → DM + steatorrhoea — balance oncological clearance with functional preservation.
Radical resection: 1-year 66%, 5-year 27%. Palliative bypass: 1-year 10%, 5-year 0%.

Active Recall - Complications of Pancreatic Cancer

1. Name the three leading causes of mortality in malignant biliary obstruction as stated in the lecture slides.

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(1) Biliary sepsis (ascending cholangitis leading to overwhelming sepsis). (2) Cancer cachexia (tumour-derived cytokines cause progressive wasting). (3) Liver failure (hepatic metastases replacing functional parenchyma or secondary biliary cirrhosis from prolonged obstruction).

2. Define pancreatic fistula according to the ISGPF classification, state its risk factors, and describe the three-grade classification.

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Definition: drain output of any volume after post-op day 3 with drain amylase level greater than 3 times the upper limit of normal. Risk factors: high BMI, soft pancreas, narrow duct. Grades: Biochemical leak (asymptomatic, drain amylase elevated but no clinical consequence). Grade B (persistent drainage greater than 3 weeks, change in management required, signs of infection but no organ failure). Grade C (unstable, requires re-operation, risk of organ failure).

3. Explain three mechanisms by which delayed gastric emptying occurs after pylorus-preserving pancreaticoduodenectomy.

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(1) Injury to nerve of Latarjet (anterior vagal branch supplying pylorus and antrum, disrupted during dissection). (2) Disruption of duodenal pacemaker cells (interstitial cells of Cajal in the resected duodenum that coordinate gastric emptying). (3) Reduced CCK (cholecystokinin normally produced in high concentration in duodenal mucosa which is now resected, impairing coordinated gastric motility).

4. A patient develops unexplained GI bleeding, a drop in haemoglobin, and sudden expansion of a peripancreatic fluid collection two weeks after a Whipple operation. What is the most likely complication, what caused it, and how should it be managed?

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Most likely: GDA pseudoaneurysm rupture. Caused by PJ leak with pancreatic enzymes (especially elastase) eroding into the GDA stump, weakening the arterial wall and forming a pseudoaneurysm. Management: urgent angiography (both diagnostic and therapeutic via embolisation). If haemodynamically unstable, emergency re-laparotomy.

5. The lecture slide states the complications of preoperative biliary drainage. List the five specific complications and their stated incidence rates.

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Pancreatitis (7%), cholangitis (26%), blocked stent (15%), bleeding (2%), perforation (2%). Despite this, routine preop drainage is practiced at QMH because Whipple has a 6-8 week wait time and biliary sepsis risk without drainage is unacceptable.

6. Compare the metabolic consequences of 'just adequate resection' versus 'excessive resection' of the pancreas as stated in the surgical oncology lecture slide.

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Just adequate resection: No diabetes mellitus, No steatorrhoea (sufficient endocrine and exocrine tissue preserved). Excessive resection: Diabetes mellitus (loss of islets of Langerhans) and steatorrhoea (loss of exocrine tissue producing lipase and other digestive enzymes). Principle: balance oncological clearance with functional preservation.

References

^[1] Senior notes: felixlai.md (Pancreatic cancer — Complications, Prognosis, Clinical manifestation sections) ^[2] Senior notes: maxim.md (Pancreatic carcinoma — Whipple complications, Distal pancreatectomy, Adjuvant chemotherapy, Palliative treatment sections) ^[3] Lecture slides: Malignant biliary obstruction.pdf (p24 — preop biliary drainage complications; p26 — drainage complication rates; p29 — causes of mortality in MBO) ^[4] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p76 — long-term survival data) ^[13] Senior notes: felixlai.md (MBO treatment — ERCP stent complications, PTBD complications) ^[14] Senior notes: maxim.md (Pancreatic fistula — ISGPF classification, management, methods to reduce PJ leakage; stent complications) ^[15] Lecture slides: Malignant biliary obstruction.pdf (p29 — causes of mortality in MBO) ^[16] Lecture slides: GC 202. Surgery may cure your cancer Surgical oncology.pdf (p15 — causes of mortality related to cancer; p44 — adequate vs excessive resection)

Pancreatic Cancer

Active Recall - Pancreatic Cancer (Definition to Clinical Features)

Active Recall - Differential Diagnosis of Pancreatic Cancer

Active Recall - Diagnosis and Investigations of Pancreatic Cancer

Active Recall - Management of Pancreatic Cancer

Active Recall - Complications of Pancreatic Cancer

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