Theory and latest guidelines on carcinoma gallbladder

1. Carcinoma Gallbladder
YUGAL JYOTY NEPAL

2. INTRODUCTION
• Rare – Most common biliary tract malignancy
• F > M (3-4 : 1)
• Higher rate of cholelithiasis and inflammation
• Generally, disease of older age (6th-7th decade)

3. • Aggressive malignant disease
• Poor prognosis
• Late presentation
• Higher incidence in India and Pakistan

4. Etiology
Chronic inflammation
• Cholelithiasis
• 75-90% of Ca GB associated with GB
stones
• Incidence of Ca GB – 0.3-3%
• ABPJ
• PSC
• Biliary-enteric fistulae
• Typhoid infection
• Porcelain GB
• Calcification due to chronic
inflammation
• GB polyp
• > 10 mm

5. Anatomic considerations
• GB – partially intraperitoneal – attached to undersurface
of liver on segments IVb andV
• On liver side – no peritoneal covering, but fibrous lining known as
cystic plate
• During cholecystectomy – plane between muscularis of GB and cystic
plate dissected – inadequate for malignancy

7. • Segment IVb andV resection – adequate for tumors of fundus and
body
• Tumors of infundibulum and cystic duct – may require bile duct
resections or major hepatic resections

8. Lymphatic drainage

9. Pattern of spread
• Lymphatics
• Hematogenously
• Into peritoneal cavity
• Along biopsy or surgical wound tracts

10. • Ca GB seems to invade and metastasize early – due to anatomy
• Thin wall
• Narrow lamina propria
• Single muscular layer
• No serosal covering between GB and liver

11. • Thin wall – early hematogenous and lymphatic spread
• Once through muscular layer – access to major lymphatics and
vascular channels – early dissemination

12. Clinical presentation
• Varies depending on geographic location
• Study (Duffy et al, 2008) of 435 patients with Ca GB treated at MSKCC
during 10-year period
• 47% discovered incidentally at routine laparoscopic cholecystectomy
• 53% presented with locally advanced (16%) or disseminated (37%) disease

13. • Asymptomatic in early stages
• Symptomatic – similar presentation to biliary colic or chronic
cholecystitis
• Constant RUQ pain
• Jaundice – usually representative of locally advanced disease
• Weight loss
• Anemia

14. Presentation
• Three common clinical scenarios
1. Identified by final pathology after routine cholecystectomy
2. Discovered intraoperatively
3. Suspected before surgery

15. Laboratory investigation
• Generally not helpful except for typical signs of advanced disease
• Anemia
• Hypoalbuminemia
• Leukocytosis
• Elevated ALP or bilirubin

16. Tumor markers
• Only tumor markers studied
• Carcinoembryonic antigen (CEA)
• CarbonicAnhydrase 19-9 (CA 19-9)
• Elevated CEA
• Specificity 90%
• Sensitivity 50%
• Elevated CA 19-9 – more consistent marker
• Sensitivity and specificity ~75% if >20 U/mL

17. Tumor markers
Helpful in following patient for recurrence if elevated before treatment
and normalize after treatment

18. Radiologic investigation
• Ultrasonography
• Excellent imaging modality for GB
• Direct extension of Ca GB
• Limitation in identifying LN metastases
• Most common finding – Heterogeneous mass replacing all or part of GB

19. Cross-sectional imaging
CT or MRI
• Important for preoperative assessment
• Local extent and metastases
• Most common finding – mass involving all or part of GB
• Assessment of lymph node
• Size >1 cm
• Ring-like heterogeneous enhancement 80% accuracy

20. • CT
• 71-84% accurate inT-staging
• T1 vsT2 : 79%
• T2 vsT3 : 93%
• T3 vsT4 : 100%
• MRI
• Utility improved in recent years
• Sensitivity 70-100% for hepatic invasion & 60-75% for LN metastases
• No added information than CT

21. • First test – USG
• Suspicion or proven malignancy – CT or MRI
• Role of PET
• In searching metastatic disease when CT or MRI provides equivocal information
Blumgart's Surgery of the Liver, Biliary Tract, and Pancreas, 6th edition

22. Staging

25. Surgical management

26. Polyps
• Polyp with malignant potential – Adenomatous polyps
• Most common polyp – Cholesterol polyp – no malignant potential
• USG
• Diagnostic modality of choice to measure and characterize polyps
• Any suspicion of malignancy – Cross-sectional imaging

27. • Polyps found in context of abdominal symptoms
• Another cause of pain is sought
• No other cause found – Cholecystectomy
• Polyps <1cm
• USG follow up at 12-month intervals for 2-3 years
• No additional imaging if polyp stable and no new or suspicious symptoms

28. • Polyps >1cm
• Cholecystectomy
• Laparoscopic method if no suspicion of malignancy and availability of frozen
section biopsy
• Low threshold for open conversion

29. NCCN guidelines

30. 1. Incidental finding at surgery
• If expertise available – definitive resection
• Radical cholecystectomy with segments IV b andV with lymphadenectomy
• If diagnosis not clear – frozen section biopsies

32. 2. Incidental finding on pathology
• Pathologic re-review by hepatobiliary pathology expert
• Diagnostic laparoscopy – but low yield unless advanced disease
• Cross-sectional imaging of chest, abdomen and pelvis

33. 2. Incidental finding on pathology contd..
• Initial exploration
• To rule out distant LN metastases in celiac axis or aortocaval groove
• If present – defer surgery
• Hepatic resectin of IV b andV or extended resections
• Lymphadenectomy
• Port site resection – not effective – surrogate marker of underlying
disseminated disease

35. Neoadjuvant therapy
• Outside the setting of clinical trial, neoadjuvant therapy – not
recommended for surgically resectable ca GB
Gallbladder Cancer in the 21st Century, Rani Kanthan, 2015

36. 3. Mass on imaging
• Staging with cross-sectional imaging of chest, abdomen and pelvis
• Biopsy not necessary – definitive resection
• Diagnostic laparoscopy – recommended
• Diagnosis not clear – cholecystectomy – frozen section biopsy –
followed by definitive resection if pathology report confirms
malignancy

38. Terms
• Wedge resection – Liver resection around GB taking 2 cm margin
• Extended/Radical cholecystectomy – Resection of segments IV b andV
with dissection of LN within hepatoduodenal ligament
• Extended radical cholecystectomy – Resection of lymphatics within
hepatoduodenal ligament, posterosuperior head of pancreas with
dissection around portal vein, and common hepatic artery with GB, rim of
liver and extrahepatic bile duct
• Extended right hepatectomy – Resection of segments 4,5,6,7,8

39. Extent of resection
• T1a – Simple cholecystectomy
• T1b – liver resection and lymph node dissection
• T2,T3 – complete resection of tumor en bloc with segments IVb andV
• If tumor invasion of hepatic inflow vascular structures – extended right
hepatectomy
• LN dissection of hepatoduodenal ligament

41. Representation of the extent of
dissection in an extended
cholecystectomy. (©2015, Memorial
Sloan Kettering Cancer Center)

42. Liver resection
• Goal:To ensure a margin of resection ~1-2 cm
• Standard resection – anatomic resection of segments IV b andV
• But smaller wedge resection for early-stage cancers with no radiographic
disease in liver
• Inflow pedicles to segments IV b andV
• Generally taken within liver substance
• But segment IV b pedicles can be dissected in umbilical fissure –
divided before parenchymal dissection

43. • Extended right hepatectomy
• Large tumors invading right portal pedicle
• Tumors of lower end of GB encroaching porta hepatis – may require bile duct
resection
• Isolated invasion of local organs (stomach, duodenum, and colon)
• Local resection

44. Lymph node dissection
• First maneuver – mobilization of duodenum to assess aortocaval and
retropancreatic LNs – assessment of celiac node
• Suspicious – Frozen section analysis
• If positive –Termination of procedure
• Regional lymphadenectomy
• All N1 LNs
• American Joint Committee on Cancer (AJCC) recommendation
• Resection of a minimum of three regional lymph nodes

46. Adjuvant therapy
• Meta-analysis favors adjuvant therapy –
• High risk patients – node-positive gallbladder cancer
• Question remains unsolved in low risk patients
• ChemoradiotherapyVS chemotherapy alone – unsolved
Gallbladder Cancer in the 21st Century, Rani Kanthan, 2015

47. • NCCN
• Adjuvant fluoropyrimidine chemoradiation or
• Fluoropyrimidine or gemcitabine chemotherapy
For >T1N0 following curative surgery
• European Society of Medical Oncology (ESMO) guidelines
• Also suggest postoperative chemoradiotherapy in patients with high risk
gallbladder cancer
• Optimal adjuvant therapy – unknown
• Though six months duration of adjuvant therapy can be considered
Gallbladder Cancer in the 21st Century, Rani Kanthan, 2015

48. Post resection

50. Targeted therapies
• Common mutations
• KRAS 10-67%
• EGFR 63%
• BRAF 0-33%
• erbB2/HER2 16-64%
• Phase III Korean trial evaluated gemcitabine and oxaliplatin with/out
erlotinib (oral tyrosine kinase inhibitor)
• Improvement in median progression-free survival (PFS)

51. • VEGF – overexpressed in biliary tract cancers
• Proposed as therapeutic target
• Efficacy of bevacizumab in combination of erlotinib – assessed in a
phase II trial

52. Radiation
• Poorly described in literature
• Conflicting and largely disappointing results
• Combination of EBRT with fluorouracil – encouraging results
• But further investigation required
• External radiation – may be considered in palliative patients

53. Conclusion
• Ca GB – high case fatality rate
• Most ca GB – discovered incidentally or present as advanced stage
disease
• Adenocarcinomas – majority of ca GB
• Surgery – only curative therapy, however, at diagnosis, ~20% are
candidates for curative surgery
• Extent of surgical resection depends onTNM stage

54. • Regional nodal status andT status – two most important prognostic
factors
• Role of adjuvant therapy – not well defined
• T2 or higher or node positive disease – 6 months of gemcitabine or
fluoropyrimidine-based chemotherapy considered
• Due to high risk of recurrence
• Targeted therapy – limited role
• “Orphan disease”

55. ThankYou