Gallbladder Cancer

Definition

Gallbladder cancer (GBC) is a primary malignancy arising from the gallbladder wall, most commonly adenocarcinoma (~90%). The name itself tells you everything: "gall" = bile, "bladder" = a hollow sac — so it's cancer of the bile-storage sac.

It is an uncommon but highly lethal malignancy because it tends to present late, often discovered incidentally during cholecystectomy for presumed benign gallstone disease. By the time symptoms appear, the cancer has usually already spread. ^[1][2]

Key statistics at presentation ^[1]:

• 25% localized to gallbladder wall
• 35% have regional nodal involvement or extension into adjacent liver
• 40% have distant metastasis

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Epidemiology

Global Perspective

• GBC is the most common biliary tract malignancy and the 5th most common GI malignancy worldwide
• Incidence varies dramatically by geography and ethnicity:
  • High incidence regions: Chile, Bolivia, northern India, Pakistan, Japan, Korea, Eastern Europe (particularly among indigenous populations)
  • Low incidence regions: Western Europe, North America, Australia
• Very rare in Hong Kong ^[2]
• Female predominance with M:F ratio of approximately 1:2–3 ^[1][2]
  • Why? Women have a higher prevalence of gallstones (estrogen increases cholesterol secretion into bile → cholesterol supersaturation → stone formation). Since gallstones are the strongest risk factor, the female predominance follows logically.
• Peak incidence in the 6th–7th decade of life
• 5-year overall survival < 5% with a median survival of ~6 months for all comers ^[1][2]

Hong Kong Context

• GBC is uncommon in Hong Kong relative to HCC and colorectal cancer
• However, given the relatively high prevalence of gallstones in the ageing population and the endemic presence of Clonorchis sinensis (liver fluke) in southern China, awareness is important
• Most cases are discovered late and are unresectable at diagnosis ^[2]

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Anatomy and Function

Understanding GBC requires a thorough understanding of gallbladder anatomy because the pattern of tumour spread is dictated entirely by the anatomy.

Gross Anatomy [1]

The gallbladder is a pear-shaped, hollow viscus located on the inferior surface of the liver, sitting in the gallbladder fossa between hepatic segments IVb and V.

It is divided into:

Histology — The Key to Understanding GBC Behaviour

The gallbladder wall is composed of (from lumen outward):

1. Mucosa (columnar epithelium + lamina propria)
2. Muscularis propria (smooth muscle — single, thin layer)
3. Perimuscular connective tissue (also called subserosa/adventitia)
4. Serosa (visceral peritoneum) — only on the peritoneal side (the side facing away from the liver)

Lymphovascular Drainage [1]

Arterial supply:

• Cystic artery — branch of the right hepatic artery (found in Calot's triangle)

Venous drainage:

• Cystic veins → drain directly into the gallbladder fossa (liver segments IVb and V) via small veins that traverse the gallbladder bed into the right hepatic vein
• This is why direct venous tumour invasion into the liver (segments IVb and V) is so common — the venous blood literally flows from gallbladder straight into these segments

Lymphatic drainage (follows a predictable, stepwise pattern):

1. Cystic duct node (node of Calot/Lund) — first echelon
2. Pericholedochal and hilar nodes — second echelon
3. Peripancreatic, periduodenal, periportal nodes — third echelon
4. Celiac and superior mesenteric artery (SMA) nodes — considered distant (not locoregional), hence incurable by surgery ^[1]

Nerve supply:

• Sympathetic innervation from the T9 segment and the celiac plexus
• This explains referred pain to the epigastrium and right shoulder (phrenic nerve via diaphragmatic irritation)

Function of the Gallbladder [1]

• Storage and concentration of bile produced by the liver
• Bile is released into the duodenum via the cystic duct → common bile duct → ampulla of Vater
• Cholecystokinin (CCK) — released from duodenal I-cells in response to fat and amino acids in the duodenum — is the major hormone that stimulates gallbladder contraction and pancreatic enzyme secretion
• Bile contains bile salts, cholesterol, phospholipids, and bilirubin; it emulsifies dietary fat for absorption

Routes of Tumour Spread

Understanding the anatomy makes the spread patterns intuitive:

Sites of distant metastasis: lung, pleura, and peritoneum ^[1]

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Etiology and Risk Factors

The etiology of GBC revolves around chronic inflammation → dysplasia → carcinoma sequence, analogous to the adenoma-carcinoma sequence in colorectal cancer but driven predominantly by chronic biliary irritation.

Mnemonic: "4P" risk factors [2]

• Polyps
• Porcelain gallbladder (and other gallstone diseases)
• Primary sclerosing cholangitis
• Pancreatobiliary duct anomalous junction

Below is an expanded and comprehensive discussion of each risk factor:

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1. Gallstones (Cholelithiasis) — The Strongest Risk Factor [1][2]

• 95% of patients with GBC have gallstones ^[1]
• Larger stones (> 3 cm) and symptomatic gallstones carry higher risk
  • Stones > 3 cm have a ~10× increased risk compared to stones < 1 cm
• Pathophysiology: Chronic mechanical irritation of the gallbladder mucosa by gallstones → chronic inflammation → mucosal hyperplasia → metaplasia → dysplasia → carcinoma
• However, the absolute risk of GBC in patients with gallstones remains low (~0.3–0.5% over a lifetime), so prophylactic cholecystectomy for all patients with gallstones is NOT indicated ^[3]

High Yield: The association between gallstones and GBC is strong but the absolute risk is low. This is why we do NOT recommend prophylactic cholecystectomy for asymptomatic gallstones UNLESS other risk factors are present (e.g., porcelain gallbladder, large stones > 3 cm, polyps > 1 cm).

2. Gallbladder Polyps [1][2]

Gallbladder polyps are classified as:

A. Benign Non-neoplastic (no malignant potential):

• Cholesterol polyps (cholesterolosis) — ~60% of all polyps ^[1]
  • Deposits of cholesterol esters in the submucosal macrophages
  • Usually small (< 10 mm), pedunculated, multiple
• Adenomyomatosis (adenomyoma) — ~25% ^[1]
  • Characterized by intramural diverticula called Rokitansky-Aschoff sinuses ^[2]
  • Hypertrophy of the muscularis with invagination of mucosa
• Inflammatory polyps — ~10% ^[1]
  • Granulation tissue from chronic cholecystitis

B. Benign Neoplastic (premalignant potential):

• Adenoma — ~4% ^[1]
  • True neoplasm with malignant potential (like colonic adenomas)
  • Risk of malignant transformation increases with size
• Leiomyoma, Fibroma, Lipoma — rare

C. Malignant:

• Adenocarcinoma — ~80% of malignant polyps ^[1]
• Squamous cell carcinoma, mucinous cystadenoma, adenoacanthoma — rare

Risk stratification by size ^[1]:

Key features suggesting malignancy in polyps ^[1][2]:

• Sessile (broad-based) morphology — malignant polyps tend to be sessile
• Echogenic on USG
• Solitary
• Rapidly growing on serial imaging
• No gravity dependence and no acoustic shadow (differentiating from gallstones on USG) ^[2]

Indications for cholecystectomy for gallbladder polyps ^[2]:

• Symptomatic polyps (e.g., RUQ pain)
• Adenomatous polyps ≥ 1 cm (or ≥ 8 mm if underlying PSC) ^[2]
• Rapidly growing polyps on serial imaging
• Polyps > 2 cm may need extended cholecystectomy with LN dissection and partial hepatic resection ^[2]

3. Porcelain Gallbladder [1][2]

• An uncommon manifestation of chronic cholecystitis characterized by intramural calcification of the gallbladder wall
• "Porcelain" → because the calcified wall appears bluish-white and brittle, resembling porcelain
• Associated with gallstones and chronic gallbladder inflammation ^[1]
• Historically thought to carry a very high malignancy risk (up to 25%), but more recent data suggests the risk is lower (~2–3%), particularly with selective mucosal calcification (which carries higher risk than complete intramural calcification) ^[2]
• Subtypes ^[2]:
  • Complete intramural calcification — lower malignancy risk
  • Selective mucosal calcification — higher malignancy risk (because incomplete calcification suggests ongoing active inflammation)
• ALL porcelain gallbladders should be removed even if patients are asymptomatic — this is an absolute indication for cholecystectomy ^[1][3]

4. Primary Sclerosing Cholangitis (PSC) [1][2]

• An autoimmune inflammatory disorder of the biliary tree leading to fibrosis and stricturing of intrahepatic and extrahepatic bile ducts
• Strongly associated with ulcerative colitis ^[4]
• Chronic inflammation and biliary stasis → increased risk of both cholangiocarcinoma and GBC
• Patients with PSC should have a lower threshold for cholecystectomy when polyps are found (≥ 8 mm rather than the usual 1 cm cutoff) ^[2]

5. Abnormal Pancreaticobiliary Duct Junction (APBDJ) [1][2]

• A rare congenital anatomical variation in which the pancreatic duct joins the common bile duct outside the duodenal wall, creating an abnormally long common channel (> 15 mm)
• Associated with choledochal cysts ^[2]
• Pathophysiology: The sphincter of Oddi cannot regulate the long common channel → reflux of pancreatic juice into the biliary tree → chronic chemical inflammation from activated pancreatic enzymes → mucosal injury → metaplasia → dysplasia → carcinoma
• Represents failure of the embryological ducts to migrate fully into the duodenum ^[1]
• GBC is the most common malignancy associated with APBDJ
• Prophylactic cholecystectomy is recommended ^[1]

6. Choledochal Cysts [1][4]

• Congenital cystic dilatation of the bile ducts
• Most diagnosed before 10 years of age (60%) ^[2]
• Classified by the Todani classification (most commonly Type I) ^[2]
• Risk of cholangiocarcinoma and GBC via:
  • Biliary stasis
  • Chronic inflammation from reflux of pancreatic juice
  • Abnormalities in bile salt transporter proteins
• Management: Radical excision of cyst + biliary tract reconstruction using a Roux-en-Y loop of jejunum (hepaticojejunostomy) — to prevent development of cholangiocarcinoma ^[2]

7. Mirizzi Syndrome [1][5]

• Common hepatic duct obstruction caused by extrinsic compression from an impacted stone in the cystic duct or Hartmann's pouch ^[1][5]
• Chronic inflammation and biliary stasis → predisposes to GBC ^[5]
• One of the exceptions to Courvoisier's Law (jaundice with palpable gallbladder due to a benign cause) ^[5]

8. Chronic Cholecystitis [3][6]

• Result of recurrent acute cholecystitis or persistent mechanical irritation by gallstones → fibrosis and thickening of GB wall
• The dysplasia-carcinoma sequence in GBC is thought to parallel the chronic inflammation → metaplasia → dysplasia → carcinoma pathway seen in Barrett's oesophagus and other chronic inflammatory conditions
• Chronic cholecystitis is associated with CA gallbladder and porcelain gallbladder ^[6]

9. Other Risk Factors

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Pathophysiology

The Inflammation → Dysplasia → Carcinoma Sequence

The dominant paradigm for GBC carcinogenesis is:

This sequence takes 15–20 years on average, explaining why GBC typically presents in the 6th–7th decade.

An Alternative Pathway — Adenoma-Carcinoma Sequence

A smaller proportion of GBCs (~5–10%) arise from pre-existing adenomatous polyps through the traditional adenoma → carcinoma pathway (similar to colorectal cancer). This is less common but explains why adenomatous polyps > 1 cm should be removed.

Molecular Pathogenesis

• p53 mutations — common in GBC; tumour suppressor gene on chromosome 17p
• KRAS mutations — oncogene activation; more common in the setting of APBDJ
• CDKN2A/p16 inactivation — cell cycle checkpoint loss
• Microsatellite instability (MSI) — found in a subset, relevant for immunotherapy
• ERBB2 (HER2) amplification — potential therapeutic target
• PI3K/AKT/mTOR pathway activation
• EGFR overexpression

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Classification

Histological Classification [1][2]

Adenocarcinoma subtypes ^[1]:

• Papillary — bulky, intraluminal growth; associated with the most favourable outcome because it tends to grow into the lumen rather than invading the wall early
• Nodular — constricting, annular pattern
• Tubular — glandular pattern; most common subtype

TNM Staging (AJCC 8th Edition, 2017) [1]

Primary Tumour (T):

Regional Lymph Nodes (N):

Distant Metastasis (M):

Overall Stage Grouping:

High Yield: T1a (lamina propria only) → simple cholecystectomy is curative. T1b and beyond → extended cholecystectomy with lymph node dissection is needed. This staging-to-surgery mapping is commonly tested.

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Clinical Features

GBC is notoriously difficult to diagnose early because its symptoms mimic benign gallbladder disease ^[2]. Most patients present with symptoms attributable to coexisting gallstones rather than the cancer itself.

Symptoms

Signs

Courvoisier's Law — Applied to GBC [5][8]

"In the presence of painless obstructive jaundice, a palpable gallbladder is unlikely to be due to gallstones" — Courvoisier

Why? A gallbladder that has been chronically inflamed by gallstones becomes fibrosed and shrunken — it cannot distend. Therefore, if you find painless jaundice + a distended, palpable gallbladder, think of a malignant cause of distal biliary obstruction (e.g., pancreatic head cancer, ampullary cancer, distal cholangiocarcinoma) ^[8].

In GBC specifically: Despite being a malignancy, GBC often does NOT produce a palpable gallbladder because:

• The cancer arises FROM the gallbladder wall → the wall is rigid and infiltrated → cannot distend
• Coexisting gallstones → chronic cholecystitis → fibrosed wall

Exceptions to Courvoisier's Law (jaundice with palpable gallbladder from benign causes) ^[5]:

• Double impaction (gallstone in cystic duct + CBD simultaneously)
• Mirizzi syndrome ^[5]
• Recurrent pyogenic cholangitis (RPC)

Incidental Discovery

• A significant proportion of GBC is found incidentally during or after cholecystectomy for presumed benign disease
• The surgeon may notice:
  • An abnormal gallbladder wall (thickened, mass-like)
  • Suspicious findings on frozen section of the cystic duct margin
  • Unexpected pathology report showing carcinoma in the cholecystectomy specimen
• Intraoperative frozen section of the cystic duct is critical — a positive margin mandates further surgery ^[1]

Presentation by Tumour Location

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Paraneoplastic Phenomena

GBC does not commonly produce paraneoplastic syndromes (unlike HCC), but when present:

• Trousseau syndrome (migratory thrombophlebitis) — mucin-producing adenocarcinomas can activate the coagulation cascade
• Leser-Trélat sign — explosive onset of seborrhoeic keratoses (rare, non-specific)

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Key Pathological Features Linking Anatomy to Clinical Behaviour

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Active Recall - Gallbladder Cancer (Definition to Clinical Features)

1. Why does gallbladder cancer spread to the liver so readily? Explain the anatomical basis.

Your answer

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Three reasons: (1) No serosa on the hepatic side of the gallbladder — only loose connective tissue separates GB from liver segments IVb and V, allowing direct invasion. (2) Venous drainage via cystic veins goes directly into the liver (gallbladder fossa). (3) Lack of submucosa means tumour traverses the wall rapidly to reach the subserosa and liver bed.

2. What is the '4P' mnemonic for GBC risk factors? List them and briefly explain each.

Your answer

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Polyps (adenomatous polyps > 1cm have malignant potential), Porcelain gallbladder (intramural calcification from chronic cholecystitis), Primary sclerosing cholangitis (chronic biliary inflammation), Pancreatobiliary duct anomalous junction (reflux of pancreatic juice into biliary tree via long common channel). Additionally, gallstones are the strongest overall risk factor (95% of GBC patients have gallstones).

3. Why is early gallbladder cancer so difficult to diagnose clinically?

Your answer

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Early GBC presents with biliary colic and RUQ pain — symptoms identical to gallstone disease (which coexists in 95% of cases). There are no pathognomonic early symptoms. Most GBC is discovered incidentally during cholecystectomy for presumed benign disease or at late stage when obstructive jaundice or a mass develops.

4. Explain why the T2 stage in gallbladder cancer is subdivided into T2a and T2b. What is the prognostic significance?

Your answer

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T2a = perimuscular connective tissue invasion on the peritoneal side (has serosa as a barrier). T2b = perimuscular connective tissue invasion on the hepatic side (NO serosa, only loose connective tissue abutting liver). T2b has worse prognosis because the tumour has a more direct route to invade the liver.

5. A patient with painless jaundice is found to have a palpable, non-tender gallbladder. Apply Courvoisier's Law. Is gallbladder cancer a likely cause? Why or why not?

Your answer

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Courvoisier's Law states that painless jaundice with palpable gallbladder is unlikely due to gallstones (fibrosed wall cannot distend) and suggests malignant distal biliary obstruction (e.g., pancreatic head CA, ampullary tumour, distal cholangiocarcinoma). GBC is actually LESS likely to produce a palpable gallbladder because: (1) the cancer arises from the GB wall itself making it rigid, and (2) coexisting gallstones cause chronic cholecystitis and fibrosis. Exceptions to Courvoisier's Law include Mirizzi syndrome, double impaction, and RPC.

6. What is the pathophysiology of abnormal pancreaticobiliary duct junction (APBDJ) leading to gallbladder cancer?

Your answer

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APBDJ is a congenital anomaly where the pancreatic duct joins the CBD outside the duodenal wall, creating a long common channel (> 15mm). The sphincter of Oddi cannot regulate this long channel, leading to reflux of pancreatic juice (containing activated enzymes) into the biliary tree. This causes chronic chemical inflammation of the gallbladder mucosa, leading to metaplasia, dysplasia, and eventually carcinoma. It represents failure of embryological duct migration into the duodenum.

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References

^[1] Senior notes: felixlai.md (Gallbladder cancer section, pages 563–571) ^[2] Senior notes: maxim.md (Section 5.7 — Cancers of gallbladder and biliary tree) ^[3] Senior notes: maxim.md (Cholecystectomy indications section) ^[4] Senior notes: felixlai.md (Cholangiocarcinoma etiology section, page 548) ^[5] Senior notes: maxim.md (Mirizzi syndrome section, pages 131–132) and felixlai.md (Mirizzi syndrome section, pages 572–573) ^[6] Senior notes: maxim.md (Chronic cholecystitis section, page 130) ^[7] Senior notes: maxim.md (Clonorchis sinensis section, page 138) ^[8] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf

Differential Diagnosis of Gallbladder Cancer

Why is Differential Diagnosis Challenging in GBC?

Before diving into the list, let's understand why the differential is broad and clinically important. GBC presents in two fundamentally different clinical scenarios, and the differential changes depending on the presentation:

1. Early presentation — biliary colic, RUQ pain → indistinguishable from benign gallstone disease (GBC is found in 95% of patients with concurrent gallstones) ^[1][2]
2. Late presentation — obstructive jaundice, palpable mass, constitutional symptoms → overlaps with all causes of malignant biliary obstruction (MBO) ^[8][9]

The differential must therefore be structured around these two clinical presentations, and additionally around the level of biliary obstruction seen on imaging.

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Structured Differential Diagnosis

A. Differential Diagnosis When Presenting as RUQ Pain / Biliary Colic (Early/Incidental)

These are conditions that mimic the gallstone-like presentation of early GBC:

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B. Differential Diagnosis When Presenting as Obstructive Jaundice / Mass (Late)

This is the more common exam scenario: a patient presents with painless progressive obstructive jaundice — and the question is: what is causing the biliary obstruction?

The differential here overlaps with all causes of malignant biliary obstruction. The lecture slides from Prof R Poon provide a clear framework ^[8][9]:

Pathology causing malignant biliary obstruction ^[8]:

• Carcinoma of gallbladder — via cystic duct LN compression, direct infiltration of CBD, or tumour fragments in the duct
• Cholangiocarcinoma (including Klatskin tumour at hilum)
• Carcinoma of head of pancreas
• Periampullary carcinoma (carcinoma of the ampulla of Vater)
• Carcinoma of duodenum
• Lymphoma
• HCC — direct infiltration, compression, or tumour fragments in CBD ^[8][9]
• Porta lymphadenopathy (metastatic nodes at the porta hepatis compressing the bile duct) ^[9]

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C. Differential Diagnosis Based on Level of Biliary Obstruction

This is a critical concept for imaging interpretation. When you see biliary dilatation on USG or CT, the level at which the ducts transition from dilated to non-dilated tells you where the obstruction is — and narrows the differential dramatically ^[10]:

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D. Benign Causes of Obstructive Jaundice to Exclude

While GBC enters the differential for malignant causes, always remember benign causes of obstructive jaundice that can mimic the presentation ^[7]:

High Yield Exam Point: "Painless progressive obstructive jaundice in an elderly patient is malignant biliary obstruction until proven otherwise" ^[7]. The key word is "progressive" — gallstone jaundice tends to be intermittent and fluctuating (the stone moves), while malignant jaundice is relentlessly progressive (the tumour only grows).

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Differential Diagnosis — Visual Framework

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Key Differentiating Features Among Major Malignant Causes

Let's compare the "big five" malignant causes of biliary obstruction side by side — this is extremely high yield for exams ^[8][9]:

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Distinguishing Gallstone Disease (Benign) from GBC (Malignant) on History

This is one of the most commonly tested clinical reasoning exercises ^[7]:

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Differentials for Gallbladder Mass on Imaging

When imaging reveals a gallbladder wall mass or thickening, the differential includes:

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Active Recall - Differential Diagnosis of Gallbladder Cancer

1. List the major malignant causes of biliary obstruction as mentioned in the lecture slides. For each, state the mechanism by which it causes obstruction.

Your answer

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CA gallbladder (cystic duct LN, direct CBD infiltration, tumour fragments), Cholangiocarcinoma/Klatskin tumour (mural stricture), CA head of pancreas (extrinsic compression of distal CBD), Periampullary carcinoma (ampullary mass), CA duodenum (mass at duodenal wall), Lymphoma (porta lymphadenopathy), HCC (direct infiltration, compression, tumour fragments in CBD), Porta lymphadenopathy (extrinsic compression).

2. A 65-year-old woman presents with progressive painless jaundice. USG shows intrahepatic duct dilatation with normal calibre CBD below the hilum. What is the level of obstruction and what are the top 3 malignant differentials?

Your answer

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Level = hilar obstruction. Top 3: (1) Klatskin tumour (perihilar cholangiocarcinoma), (2) CA gallbladder (neck tumour compressing CHD, or cystic duct LN), (3) HCC (direct invasion or compression at hilum). Also consider porta lymphadenopathy from metastatic disease.

3. Why does gallstone-related jaundice tend to be fluctuating while GBC-related jaundice is progressive? Explain from first principles.

Your answer

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Gallstone jaundice: stone moves within the CBD, intermittently obstructing and then partially or fully releasing the obstruction, so bilirubin levels fluctuate. GBC jaundice: caused by tumour growth (either direct infiltration of CBD or progressive lymph node enlargement compressing the duct), which only increases over time, causing relentless progressive jaundice.

4. What is xanthogranulomatous cholecystitis and why is it an important differential for gallbladder cancer?

Your answer

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Xanthogranulomatous cholecystitis is a benign destructive inflammatory condition characterised by foamy (xanthoma) macrophages and giant cells in the GB wall. It mimics GBC on imaging (irregular wall thickening, loss of fat planes with liver, local lymphadenopathy) and even at surgery. Important because: (1) may lead to unnecessary radical surgery if misdiagnosed as GBC, (2) frozen section can be misleading, (3) definitive diagnosis often requires full histopathology.

5. Explain how GBC causes biliary obstruction by three distinct mechanisms, as described in the lecture slides.

Your answer

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Three mechanisms: (1) Cystic duct lymph node enlargement compressing the CHD/CBD from outside, (2) Direct infiltration of the CBD by tumour growing from the gallbladder wall, (3) Tumour fragments detaching and falling into the biliary lumen (rare, similar to HCC tumour thrombus).

References

^[1] Senior notes: felixlai.md (Gallbladder cancer section, pages 563–571) ^[2] Senior notes: maxim.md (Section 5.7 — Cancers of gallbladder and biliary tree; Gallbladder polyps) ^[3] Senior notes: felixlai.md (Biliary colic differential diagnosis section, page 511) ^[5] Senior notes: felixlai.md (Mirizzi syndrome section, pages 572–574) ^[6] Senior notes: maxim.md (Chronic cholecystitis section) ^[7] Senior notes: maxim.md (Obstructive jaundice section, page 125) ^[8] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p23–24) ^[9] Lecture slides: Malignant biliary obstruction.pdf (p5) ^[10] Senior notes: felixlai.md (Malignant biliary obstruction — causes by level of obstruction, page 500)

Diagnostic Criteria and Approach

Does GBC Have Formal "Diagnostic Criteria"?

Unlike some medical conditions (e.g., rheumatoid arthritis with ACR/EULAR criteria, or diabetes with specific glucose thresholds), GBC does not have a standardised set of clinical diagnostic criteria. The diagnosis is ultimately histopathological — you need tissue to confirm adenocarcinoma of the gallbladder.

In practice, GBC is diagnosed in one of three clinical scenarios:

1. Incidental discovery — found on histopathology of a cholecystectomy specimen performed for presumed benign disease (most common scenario, ~50–70% of cases) ^[1][2]
2. Preoperative suspicion — clinical features + imaging findings raise suspicion → tissue confirmation sought before definitive surgery
3. Advanced/unresectable disease — diagnosed on imaging ± percutaneous/EUS-guided biopsy when the tumour is clearly inoperable

The diagnostic approach therefore centres on: clinical assessment → laboratory investigations → imaging → tissue diagnosis → staging ^[1][11]

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Diagnostic Algorithm

The approach to diagnosing GBC can be divided into two pathways depending on the clinical scenario:

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Investigation Modalities

A. Physical Examination

Physical examination is the first step and provides crucial information about disease extent and operability.

General Examination [1][10][11]

Abdominal Examination [1][10][11]

Courvoisier's Law — Applied to Diagnosis [1][10]

"ALWAYS look for a palpable gallbladder in malignant biliary obstruction" ^[10]

• Definition: "In painless jaundice if the gallbladder is palpable, it is unlikely to be due to gallstones" — points towards malignant biliary obstruction ^[1][10]
• Why? Gallstones → chronic cholecystitis → GB wall fibrosed and contracted → cannot distend. Malignant obstruction develops over a shorter time → GB wall is still compliant → distends from back-pressure ^[1]
• In GBC specifically: Courvoisier's sign is usually ABSENT because the cancer arises in the GB wall itself (rigid) + coexisting gallstones cause chronic fibrosis
• Exceptions ^[1][10]:
  • Double impaction (stone in cystic duct + CBD)
  • Recurrent pyogenic cholangitis (RPC) — pathology in bile duct, not GB → no chronic cholecystitis → GB not fibrosed, can distend
  • Mirizzi syndrome

Signs of Inoperability [10][11]

These findings at physical examination indicate unresectable/incurable disease — crucial to assess before planning surgery:

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B. Laboratory Investigations (Biochemical Tests)

Complete Blood Count with Differentials [1][10]

Clotting Profile [1][10]

Liver Function Tests [1][10][11]

The overall pattern is a cholestatic picture: ↑↑ ALP, ↑↑ GGT, ↑ conjugated bilirubin, with relatively preserved transaminases initially ^[2][10]

Tumour Markers [1][10][12]

Tumour markers are NOT very useful for MBO as a screening tool and are not included in the initial testing ^[10]

Other Blood Tests

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C. Radiological Investigations

1. Ultrasound (USG) Abdomen — First-line Imaging [1][10][11][12]

USG is the initial imaging modality for any patient presenting with RUQ pain, jaundice, or suspected biliary pathology. It is cheap, non-invasive, widely available, and provides critical information.

Why USG first? Because it can quickly answer three key questions ^[12]:

1. What is the size of the bile duct — is there any dilatation? (Normal intrahepatic ducts are < 2–3 mm and typically not visible on USG; CBD > 0.8 cm is pathological) ^[10]
2. What is the level of obstruction?
3. What is the cause of obstruction — stone or mass?

USG findings suggestive of GBC ^[1]:

2. Endoscopic Ultrasound (EUS) [1][10]

• More accurate for imaging the gallbladder than transabdominal USG ^[1] because the transducer is placed in the duodenum, directly adjacent to the gallbladder and bile ducts — eliminates the problem of bowel gas and body habitus
• Roles in GBC:
  • Detailed assessment of GB wall layers → accurate T-staging
  • Evaluation of regional lymph nodes (porta hepatis, peripancreatic)
  • EUS-guided FNA/biopsy — for tissue diagnosis when percutaneous biopsy is risky or when the lesion is not accessible percutaneously ^[10]
• Limitations: Operator-dependent; limited availability; cannot assess distant metastases

3. CT Thorax and Abdomen with Contrast — The Key Staging Investigation [1][11][12]

CT with IV contrast is the workhorse for staging GBC. It answers the critical question: is this tumour resectable?

Key imaging protocol: Contrast-enhanced CT with arterial phase images to determine the anatomic course of the hepatic artery relative to the tumour, which is necessary to determine resectability ^[1]

CT findings consistent with GBC ^[1]:

CT thorax is essential to detect distant metastases to the lung and pleura ^[1]

4. MRI Abdomen + MRCP [1][2]

5. ERCP (Endoscopic Retrograde Cholangiopancreatography) [1][10]

ERCP indications in GBC:

• Preoperative biliary drainage when jaundice is severe and surgery needs to be delayed
• Palliative stenting for inoperable disease
• Differentiation from benign stricture (with brush cytology)

6. PTC (Percutaneous Transhepatic Cholangiography) [10][14]

• Preferred over ERCP for obstruction at or above the level of confluence of hepatic ducts (i.e., hilar obstruction — because ERCP cannot reliably opacify ducts above a complete hilar obstruction) ^[14]
• Provides cholangiogram from above the obstruction
• Can place percutaneous transhepatic biliary drainage (PTBD) catheter for decompression
• Complications: bacteraemia (requires antibiotic prophylaxis), haemobilia ^[14]

7. PET/CT Scan [1][2]

Listed in staging investigations: PET/CT, laparoscopy ^[2]

8. Staging Laparoscopy — Critical Pre-operative Step [1]

This is one of the most important and commonly overlooked investigations in GBC workup.

Why is it needed?

• GBC frequently involves regional LNs or extends directly to adjacent structures which may preclude curative resection but may NOT be detectable by preoperative imaging such as CT or MRI scan ^[1]
• Mainly to confirm the absence of liver or peritoneal metastatic disease ^[1]
• Diagnostic staging laparoscopy identifies metastatic disease or other findings that contraindicate tumour resection ^[1]

What the surgeon looks for during staging laparoscopy:

1. Peritoneal nodules (send for frozen section if suspicious)
2. Liver surface metastases (not seen on CT if small/superficial)
3. Omental disease
4. Suspicious lymph nodes

When to perform: Before committing to a formal laparotomy for radical resection, particularly for T2 or higher disease

No promise of resection until laparotomy findings document absence of spread ^[10]

9. Tissue Diagnosis (Biopsy) [1][2][11]

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Summary of Investigation Modalities — Quick Reference Table

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Assessment of Resectability — Putting It All Together

The ultimate goal of the diagnostic workup is to determine: can this tumour be resected with curative intent?

Absolute contraindications for radical resection ^[1]:

This framework — assessment of patient status (good/bad) + assessment of tumour status (confined/spread) — is directly from the lecture slides ^[10]:

• Patient status good + Tumour confined → Laparotomy (radical resection)
• Patient status bad OR Tumour spread → PTBD or endoprosthesis (palliation)

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Active Recall - Diagnosis of Gallbladder Cancer

1. What is the most common way gallbladder cancer is diagnosed? Why?

Your answer

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Most commonly diagnosed incidentally on histopathology of a cholecystectomy specimen performed for presumed benign gallstone disease (50-70% of cases). This is because early GBC is asymptomatic or presents with gallstone symptoms, and there are no reliable screening tools. The diagnosis is histopathological — you need tissue.

2. A patient with suspected GBC has a potentially resectable tumour on CT. Should you perform a percutaneous biopsy before surgery? Explain your reasoning.

Your answer

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No. Percutaneous biopsy is NOT performed for potentially resectable tumours because of: (1) risk of tumour seeding along the needle tract, (2) risk of bile/tumour spillage causing peritoneal dissemination. The diagnosis will be confirmed on the surgical specimen. Biopsy is reserved ONLY for unresectable cases where histological confirmation is needed before palliative chemotherapy.

3. Explain why staging laparoscopy is critical before laparotomy in GBC. What specifically are you looking for?

Your answer

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GBC frequently has peritoneal or liver surface metastases that are NOT detectable on preoperative CT or MRI (too small, flat peritoneal implants). Staging laparoscopy avoids an unnecessary, morbid laparotomy. Looking for: (1) peritoneal nodules (send for frozen section), (2) liver surface metastases, (3) omental disease, (4) suspicious lymph nodes. If found, abandon resection and proceed to palliative care.

4. What is the expected LFT pattern in GBC causing obstructive jaundice? Explain the pathophysiology of each finding.

Your answer

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Cholestatic pattern: (1) Markedly elevated ALP — cholestasis solubilises ALP from canalicular membrane + induces ALP gene transcription. (2) Elevated GGT — confirms hepatobiliary origin of ALP. (3) Elevated conjugated bilirubin — conjugated bilirubin cannot drain into duodenum, refluxes into blood. (4) Initially normal or mildly elevated AST/ALT — rises later when chronic obstruction causes secondary hepatocyte damage. (5) Prolonged PT/INR — Vitamin K malabsorption from lack of bile salts in gut.

5. List 5 absolute contraindications for radical resection of gallbladder cancer.

Your answer

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Any 5 of: (1) Liver metastasis, (2) Peritoneal metastasis, (3) Malignant ascites, (4) Encasement/occlusion of hepatic artery or portal vein, (5) Para-aortic/pericaval/SMA/celiac artery lymph node involvement (considered distant, not locoregional), (6) Extensive involvement of the hepatoduodenal ligament by tumour or nodes.

6. Why is CA 19-9 not a reliable diagnostic marker for GBC? When is it useful?

Your answer

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CA 19-9 lacks both sensitivity and specificity. It is elevated in many other cancers (pancreatic 72-79%, biliary 67-73%, gastric, CRC) and also in benign conditions (cholangitis, cholelithiasis, pancreatitis). Also requires Lewis blood group antigen expression — ~5-10% of population are Lewis-negative and will never produce CA 19-9. Its main utility is serial monitoring after resection to detect persistent or recurrent disease.

References

^[1] Senior notes: felixlai.md (Gallbladder cancer — Diagnosis and Treatment sections, pages 568–571) ^[2] Senior notes: maxim.md (Section 5.7 — Gallbladder carcinoma investigation and treatment) ^[10] Senior notes: felixlai.md (Malignant biliary obstruction — Diagnosis section, pages 501–503) ^[11] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p2) ^[12] Lecture slides: Malignant biliary obstruction.pdf (p7–8, p10) ^[13] Senior notes: felixlai.md (Mirizzi syndrome — Diagnosis section, page 574) ^[14] Senior notes: maxim.md (HBP investigations — MRCP and PTC sections)

Management of Gallbladder Cancer

Guiding Principles

The management of GBC is dictated by two fundamental assessments that must be made before any treatment decision ^[10][15][16]:

1. Assessment of patient status (good / bad) ^[15]
2. Assessment of tumour status (confined / spread) ^[15]

This framework — directly from the lecture slides — is the backbone of all hepatobiliary surgical oncology decision-making:

Why surgery? ^[16]

• Removal of tumour (oncological clearance)
• Relief of obstruction
• Pain control

The role of surgery in MBO has three goals ^[17]:

• R0 resection (absence of microscopic residual tumour — the gold standard)
• Relieve obstruction (jaundice, duodenal obstruction)
• Pain control (celiac plexus block)

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Master Management Algorithm

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Preoperative Assessment

Before any surgical intervention, a systematic assessment is required ^[10][15]:

A. Assessment of Patient Status [10]

B. Assessment of Tumour Status [10]

Clinical assessment — Signs of inoperability ^[10]:

• Irregular surface hepatomegaly (liver metastases)
• Troisier's sign (Virchow's node) — left supraclavicular LN
• Blumer's shelf — peritoneal metastasis palpable on DRE
• Sister Mary Joseph nodules — periumbilical metastasis
• Ascites — peritoneal carcinomatosis

Radiological assessment — Signs of inoperability ^[10]:

• LN metastasis (para-aortic, celiac, SMA nodes)
• Distant metastasis (liver, lung, peritoneum)
• Arterial involvement (SMA / celiac axis)
• Venous involvement (SMV / PV)

Criteria of resectability ^[18]:

• 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 ^[10][18]
• However: significant morbidity and mortality; reasonable survival: median = 13 months, 5-year = 7% ^[18]

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Preoperative Optimisation

Before proceeding to surgery, several conditions must be addressed ^[10][19]:

1. Treat Biliary Sepsis [16]

The first step in managing any MBO is to TREAT SEPSIS ^[16]

• Antibiotics: Augmentin OR Cefuroxime (Zinacef) + Metronidazole (Flagyl) ^[10]
• Biliary drainage to decompress the infected, obstructed biliary tree

2. Preoperative Biliary Drainage [19]

3. Nutritional and Haemostatic Optimisation [19]

• Cancer cachexia → Malnutrition → Nutritional support (enteral preferred)
• Liver derangement → Bleeding tendency → IV Vitamin K and FFP during surgery ^[19]
• Superimposed biliary infection → Antibiotic cover ^[19]

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Surgical Treatment — Curative Intent

Surgical treatment is the ONLY potentially curative treatment for GBC.

The specific operation depends entirely on the T-stage, which is determined either:

• Preoperatively on imaging, OR
• Intraoperatively on frozen section (for incidentally discovered GBC)

Overview of Surgery by Stage [1][2][7]

"In general... Radical cholecystectomy for CA gallbladder" ^[17]

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Open vs Laparoscopic Approach [1][3]

Indications for open cholecystectomy (rather than laparoscopic) ^[3]:

• CA gallbladder (extensive adhesions, risk of rupture and tumour seeding)
• Cannot tolerate pneumoperitoneum (cardiopulmonary comorbidities)
• Refractory coagulopathy
• Multiple abdominal surgeries

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Simple Cholecystectomy [1][2]

Indication: Tis and T1a tumours

• Very early stage tumours including Tis and T1a can be cured with simple cholecystectomy alone ^[1]
• Why is this sufficient?
  • T1a invades only the lamina propria. Lymphatics reside in the subserosal layer — the tumour has not yet reached the lymphatic highway. Therefore, the risk of nodal metastasis is < 2.5%
  • Cystic duct margin is checked — if positive, further resection is needed
• Stage I disease (confined to mucosa, T1N0): no further treatment required ^[2]
• 5-year survival for T1a: ~85–100%

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Extended (Radical) Cholecystectomy [1][2]

Indication: T1b and higher (when resectable)

The concept: "Open cholecystectomy with intra-op frozen section" ^[2] → if T1b or higher on histology, extend the operation.

Extended cholecystectomy involves ^[1][2]:

1. En-bloc removal of gallbladder + rim of liver

   • Rim of liver at ≥ 2 cm adjacent to the gallbladder bed OR a formal central liver resection (Segment IVb and V) ^[1]
   • Why? The gallbladder body is directly adherent to liver segments IVb and V via loose connective tissue with no serosa — tumour invades directly into these segments. You must resect the liver beneath the gallbladder bed to ensure clear margins
   • Patients with tumours of the fundus or body: tumour is generally far enough from the inflow structures to allow a negative-margin resection with ≥ 2 cm non-anatomical wedge resection or anatomic resection of segment IVb and V ^[1]
   • More aggressive surgery may be necessary including resection of additional liver segments if there is evidence of tumour infiltration beyond segments IVb/V ^[1]

2. Regional lymphadenectomy ^[1][2]

   • Porta hepatis LN ^[2]
   • Proper LN dissection involves removing ALL LNs in the porta hepatis and along the hepatoduodenal ligament (cystic duct, CBD, hepatic artery, portal vein), paraduodenal, peripancreatic, and celiac LNs ^[1]
   • At least 6 lymph nodes should be removed for proper staging ^[1]
   • Why 6? This is the minimum needed to accurately stage N disease. Inadequate lymph node harvest leads to understaging and potentially undertreating

3. ± Extrahepatic bile duct resection ^[1][2]

   • Only performed when gross tumour extends into CBD or when a negative cystic duct margin cannot be obtained by intraoperative frozen section ^[1]
   • If cystic duct margin positive → Regional LN dissection + Extrahepatic bile duct resection with reconstruction by Roux-en-Y hepaticojejunostomy ^[1]
   • If cystic duct margin negative → Regional LN dissection only ^[1]

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Intraoperative Frozen Section — The Pivotal Decision Point [1][2]

Intraoperative frozen section of the cystic duct is performed during every cholecystectomy for GBC (or when GBC is suspected):

Why? A positive cystic duct margin means tumour extends into the CBD — leaving this behind guarantees local recurrence and makes the surgery non-curative.

Roux-en-Y hepaticojejunostomy ("Roux" = named after surgeon César Roux; "en-Y" = the shape of the bowel loop; "hepatico-" = hepatic duct; "jejunostomy" = anastomosis to jejunum):

• A loop of jejunum is divided
• The distal limb is brought up and anastomosed to the residual hepatic duct(s) — this restores bile drainage from the liver into the gut
• The proximal limb is anastomosed to the side of the Roux limb downstream — creating the "Y" shape
• This is the standard reconstruction after bile duct resection

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Management of Incidental GBC Found After Laparoscopic Cholecystectomy

This is one of the most commonly tested scenarios in exams.

Scenario: Patient undergoes elective laparoscopic cholecystectomy for gallstones. Final histopathology unexpectedly shows adenocarcinoma.

Why excise port sites? During laparoscopic cholecystectomy, the gallbladder is extracted through a port (usually umbilical). If there was bile spillage or direct contact of the tumour with the port site, tumour cells may have implanted there. Excision of all port sites is standard practice for incidental GBC.

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Absolute Contraindications for Radical Resection [1]

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Non-Surgical / Palliative Treatment

The majority of patients with GBC have unresectable disease at the time of diagnosis ^[1]. For these patients, the goals shift from cure to symptom palliation and quality of life.

Three main indications for palliation ^[10][20]:

1. Biliary obstruction → relieve jaundice
2. Duodenal obstruction → relieve gastric outlet obstruction
3. Pain → control cancer-related pain

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1. Relief of Obstructive Jaundice

a) ERCP with Endoprosthesis (Endoscopic Stenting) — ALWAYS 1st line [10]

ERCP with endoprosthesis is ALWAYS 1st line regardless of the level of obstruction ^[10], except:

• Contraindications for ERCP (structural upper GI abnormalities, post-Billroth II or Roux-en-Y anatomy)
• Multiple stenting required or difficulty reaching intrahepatic bile ducts (e.g., hilar obstruction → may need PTC)

b) Percutaneous Transhepatic Biliary Drainage (PTBD) [10]

ERCP is preferred over PTBD because ^[10]:

• PTBD is technically more difficult
• Bleeding is common due to puncture of hepatic artery or portal vein before reaching the bile duct (portal triad) ^[10]

Approaches to biliary drainage ^[21]:

• Internal drainage: ERCP + stenting
• External drainage: PTBD
• Internal-external drainage: PTBD pushed past obstruction → internalised

If PTBD catheter causes bleeding ^[10]:

1. Stabilise and resuscitate
2. Clamp the PTBD catheter
3. Perform cholangiogram by injecting contrast into PTBD to determine whether catheter is in hepatic artery or portal vein
4. Remove catheter slowly to control bleeding — do NOT attempt to remove immediately as it will convert into free haemoperitoneum

c) Palliative Surgical Bypass [1][2]

• Reserved for patients who undergo laparotomy but are found to have unresectable disease
• Bypass if spread ^[15]
• Biliary bypass: Hepaticojejunostomy or choledochojejunostomy (NOT choledochoduodenostomy — duodenum is too close to tumour) ^[20]
• Advantage: long-term relief without risk of stent occlusion; but requires laparotomy

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2. Relief of Duodenal Obstruction [1][2][20]

GBC can directly invade the duodenum (body of GB abuts D1/D2) causing gastric outlet obstruction.

Double bypass (biliary + gastric bypass) — performed when inoperable disease is found at laparotomy ^[20]:

• Biliary bypass: choledochojejunostomy (relieves jaundice)
• Gastric bypass: gastrojejunostomy (relieves GOO)
• Also: obtain transduodenal trucut biopsy ± celiac plexus block ^[20]

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3. Pain Control [10][17][20]

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Adjuvant and Systemic Therapy

Adjuvant Chemotherapy

• Indication: All patients with T2 or higher GBC who undergo R0/R1 resection (especially node-positive disease)
• The BILCAP trial (2019) established capecitabine as the standard adjuvant chemotherapy for resected biliary tract cancers (including GBC), showing improved overall survival ^[1]
• Other options:
  • Gemcitabine + cisplatin (extrapolated from ABC-02 trial for advanced biliary cancers)
  • Gemcitabine + capecitabine
• Adjuvant chemotherapy should be started within 8–12 weeks of surgery

Palliative Chemotherapy

• For unresectable, locally advanced, or metastatic GBC
• First-line: Gemcitabine + cisplatin (ABC-02 trial) — the standard of care for advanced biliary tract cancers
• Alternatives: FOLFOX, capecitabine, 5-FU/leucovorin
• Newer options (biomarker-driven):
  • Pembrolizumab/Durvalumab (immune checkpoint inhibitors) — for MSI-high or PD-L1 positive tumours (TOPAZ-1 trial: durvalumab + gemcitabine/cisplatin improved OS)
  • HER2-targeted therapy (trastuzumab deruxtecan) — for ERBB2-amplified tumours
  • IDH1 inhibitors (ivosidenib) — for IDH1-mutated tumours (more relevant to cholangiocarcinoma)
  • FGFR inhibitors (pemigatinib, futibatinib) — for FGFR2 fusion/rearrangement (more relevant to intrahepatic cholangiocarcinoma)

Adjuvant Radiotherapy

• Role is controversial and not established as standard
• May be considered for positive margins (R1 resection) or locally advanced disease
• Often combined with chemotherapy as chemoradiation

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Prognosis [1]

Majority of patients with gallbladder cancer have unresectable disease at the time of diagnosis ^[1] 5-year survival for all patients with gallbladder cancer is < 5% with a median survival of 6 months ^[1]

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Active Recall - Management of Gallbladder Cancer

1. A patient with GBC has a T1a tumour on final histopathology after cholecystectomy. What further treatment is required and why?

Your answer

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No further treatment required. T1a invades only the lamina propria. Lymphatics are in the subserosal layer, so T1a has minimal risk of nodal disease (less than 2.5%). Simple cholecystectomy alone is curative for Tis and T1a. 5-year survival 85-100%.

2. Describe the components of an extended (radical) cholecystectomy for GBC. Why is each component necessary?

Your answer

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Three components: (1) En-bloc removal of gallbladder + rim of liver at least 2cm from GB bed or formal segment IVb/V resection — because GB is directly adherent to liver with no serosa on hepatic side, tumour invades directly. (2) Regional lymphadenectomy of porta hepatis, hepatoduodenal ligament, paraduodenal, peripancreatic LNs (minimum 6 nodes) — for accurate staging and oncological clearance. (3) Extrahepatic bile duct resection ONLY if cystic duct margin positive on frozen section — to achieve R0 margin; reconstructed with Roux-en-Y hepaticojejunostomy.

3. Why is the open approach recommended over laparoscopic for known or suspected gallbladder cancer?

Your answer

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Three reasons: (1) Port-site metastasis — tumour cells seed along trocar tracks (up to 10-20%). (2) Bile spillage — pneumoperitoneum and gallbladder manipulation risk perforation, spilling tumour-containing bile into peritoneal cavity causing carcinomatosis. (3) Inadequate resection — difficult to perform en-bloc liver resection and formal lymphadenectomy laparoscopically.

4. A patient with GBC is found to have unresectable disease at staging. What are the three main palliative goals and the treatment options for each?

Your answer

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Three goals: (1) Relieve obstructive jaundice — ERCP with endoprosthesis (1st line, metallic stent preferred if confirmed inoperable), PTBD if ERCP fails, or surgical biliary bypass. (2) Relieve duodenal obstruction — endoscopic duodenal stenting or gastrojejunostomy. (3) Pain control — analgesics (WHO ladder), celiac plexus neurolysis (EUS or CT-guided). Palliative chemotherapy: gemcitabine + cisplatin +/- durvalumab.

5. During cholecystectomy for GBC, intraoperative frozen section of the cystic duct shows a positive margin. What is the next step and why?

Your answer

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Positive cystic duct margin means tumour extends into the CBD. Next step: extrahepatic bile duct resection + regional LN dissection + reconstruction with Roux-en-Y hepaticojejunostomy. This is to achieve R0 resection (clear margins). A positive margin left behind guarantees local recurrence. Routine bile duct resection is NOT recommended if margin is negative (no survival benefit, risk of bile leak and anastomotic stricture).

6. State the absolute contraindications for radical resection in GBC.

Your answer

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Six contraindications: (1) Liver metastasis, (2) Peritoneal metastasis, (3) Malignant ascites, (4) Encasement or occlusion of hepatic artery or portal vein, (5) Involvement of para-aortic, pericaval, SMA or celiac artery LNs (considered distant, not locoregional), (6) Extensive involvement of the hepatoduodenal ligament by tumour or LN. Note: portal vein involvement alone is NOT an absolute contraindication in some centres — venous resection may be considered.

References

^[1] Senior notes: felixlai.md (Gallbladder cancer — Treatment and Prognosis sections, pages 569–571) ^[2] Senior notes: maxim.md (Section 5.7 — Gallbladder carcinoma treatment) ^[3] Senior notes: maxim.md (Cholecystectomy — Indications and approach) ^[7] Senior notes: felixlai.md (Gallbladder cancer — Treatment by stage, page 569) ^[10] Senior notes: felixlai.md (Malignant biliary obstruction — Treatment section, pages 503–505) ^[15] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p48, p54) ^[16] Lecture slides: Malignant biliary obstruction.pdf (p18) ^[17] Lecture slides: Malignant biliary obstruction.pdf (p19, p21) ^[18] Lecture slides: Malignant biliary obstruction.pdf (p23) ^[19] Senior notes: felixlai.md (Malignant biliary obstruction — Preoperative biliary drainage and surgical treatment, pages 505–507) ^[20] Senior notes: felixlai.md (Pancreatic cancer — Palliative treatment, page 598) ^[21] Senior notes: maxim.md (Cholangiocarcinoma — Palliative care, stenting)

Complications of Gallbladder Cancer

Complications of GBC can be organised into three major categories:

1. Complications of the disease itself (from tumour growth and spread)
2. Complications of surgical treatment (from cholecystectomy and extended resection)
3. Complications of palliative interventions (from stenting, PTBD, and chemotherapy)

Understanding these from first principles means linking each complication back to the anatomy, the natural history of GBC, and the specific physiological insults of each treatment.

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I. Complications of the Disease Itself

These arise from the local invasion, biliary obstruction, metastatic spread, and systemic effects of GBC.

A. Obstructive Jaundice and Its Sequelae

GBC causes biliary obstruction by three mechanisms (cystic duct LN compression, direct CBD infiltration, tumour fragments) ^[8]. Once bile flow is obstructed, a cascade of complications follows:

The lecture slide summarises these consequences neatly: "Jaundice → coagulopathy, malabsorption, malnutrition and immune dysfunction" ^[22]

B. Biliary Sepsis (Acute Cholangitis)

• When bile stasis occurs proximal to a malignant obstruction, the stagnant bile becomes a fertile medium for bacterial growth
• Bacteria ascend from the duodenum or reach the bile via the portal circulation
• Common organisms: E. coli, Klebsiella, Enterococcus faecalis (same as for any cholangitis)
• Presents as Charcot's triad (fever + jaundice + RUQ pain) or Reynolds' pentad (adds hypotension + altered mental status)
• Biliary sepsis is one of the leading causes of mortality in MBO ^[23]

C. Direct Tumour Invasion — Local Complications

The anatomy of the gallbladder means that as tumour grows, it invades neighbouring structures in a predictable pattern ^[1]:

D. Metastatic Complications

Sites of distant metastasis include lung, pleura, and peritoneum ^[1]

E. Systemic Complications

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II. Complications of Surgical Treatment

These are divided by the specific operation performed.

A. Simple Cholecystectomy — Specific Complications [3][24]

Even simple cholecystectomy carries risks. Since GBC requires an open approach, the complication profile differs slightly from elective laparoscopic cholecystectomy.

Immediate:

• Conversion to open surgery (if started laparoscopically — 5% elective, 25% emergency) — NOT an indication of failure ^[24]
• GA risks, haemorrhage
• Damage to neighbouring structures ^[24]:
  • Bile duct injury → bile leakage (the most feared complication of any cholecystectomy)
  • Cystic artery bleeding
  • Duodenal, transverse colon, or hepatic flexure injury (especially during difficult dissection in inflamed Calot's triangle)

Early (days to weeks):

Late (weeks to months):

B. Extended (Radical) Cholecystectomy — Additional Complications

Extended cholecystectomy adds liver resection + lymphadenectomy ± bile duct resection, each contributing specific complications:

C. Incidental GBC After Laparoscopic Cholecystectomy — Specific Complications

When GBC is discovered incidentally after laparoscopic cholecystectomy:

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III. Complications of Palliative Interventions

A. ERCP with Stenting [10][21]

Pre-op biliary drainage has increased risk of serious complications — pancreatitis (7%), cholangitis (26%), blocked stent (15%), bleeding (2%), perforation (2%) ^[22]

B. PTBD [10]

C. Chemotherapy-Related Complications

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IV. Disease Recurrence After Curative Resection

Even after apparently curative R0 resection, GBC has a high recurrence rate:

Serial CA 19-9 monitoring after resection can aid in detection of persistent or recurrent disease — a rising trend is concerning even if imaging is negative ^[1]

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V. Summary Table — Complications by Category

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Active Recall - Complications of Gallbladder Cancer

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

Your answer

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Three causes: (1) Biliary sepsis — infection of stagnant bile proximal to obstruction leads to bacteraemia and septic shock. (2) Cancer cachexia — tumour-derived cytokines cause progressive wasting and multi-organ failure. (3) Liver failure — secondary biliary cirrhosis from chronic obstruction, or direct tumour invasion destroying liver parenchyma.

2. Explain the pathophysiology of coagulopathy in obstructive jaundice from GBC. Why must you give Vitamin K intravenously rather than orally?

Your answer

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Biliary obstruction prevents bile salts from reaching the gut. Without bile salts, dietary fat cannot be emulsified, so fat-soluble vitamins (including Vitamin K) cannot be absorbed. Vitamin K is essential for hepatic synthesis of clotting factors II, VII, IX, X. Deficiency causes prolonged PT/INR and bleeding tendency. Must give IV (not oral) because oral Vitamin K also requires bile salts for absorption, which are absent in the obstructed patient.

3. A patient develops recurrent jaundice 4 months after palliative ERCP stenting for unresectable GBC. What are the possible causes of stent failure and how would you manage?

Your answer

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Causes of stent failure: (1) Stent occlusion by sludge (bile deposits), (2) Tumour ingrowth (tumour grows through metallic stent mesh), (3) Tumour overgrowth (tumour grows over stent ends), (4) Stent migration. Management: ERCP with sweeping (mechanical cleaning) of the occluded stent or placement of a new stent through the old one. If ERCP fails, consider PTBD.

4. Why is port-site recurrence a specific concern after laparoscopic cholecystectomy for incidental GBC? What should be done about it during re-resection?

Your answer

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During laparoscopic cholecystectomy, the GB is extracted through a port site (usually umbilical). If there is bile spillage or direct tumour contact with the port, tumour cells implant in the abdominal wall. Reported in 10-20% of incidental GBC. During re-resection (extended cholecystectomy), ALL port sites from the index operation must be excised to remove any implanted tumour cells.

5. What are the three reasons that MBO is high risk for surgery, and what preoperative measures address each?

Your answer

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Three reasons and their countermeasures: (1) Cancer cachexia causing malnutrition — addressed by nutritional support (enteral/parenteral). (2) Liver derangement causing bleeding tendency — addressed by IV Vitamin K and FFP during surgery. (3) Superimposed biliary infection — addressed by antibiotic cover (Augmentin or Cefuroxime plus Metronidazole). Also: preoperative biliary drainage to target bilirubin below 50 micromol/L.

References

^[1] Senior notes: felixlai.md (Gallbladder cancer — Overview, Treatment, and Prognosis sections, pages 563–571) ^[3] Senior notes: maxim.md (Cholecystectomy — Indications, approach, and complications) ^[8] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p24) ^[10] Senior notes: felixlai.md (Malignant biliary obstruction — Treatment section, pages 503–507) ^[19] Senior notes: felixlai.md (Malignant biliary obstruction — Preoperative biliary drainage, pages 505–507) ^[21] Senior notes: maxim.md (Cholangiocarcinoma — Palliative care, stenting, and complications) ^[22] Lecture slides: Malignant biliary obstruction.pdf (p24, p26) ^[23] Lecture slides: Malignant biliary obstruction.pdf (p29) ^[24] Senior notes: maxim.md (Cholecystectomy — Specific complications)