from blumgart,AJCC 2018

1. Gall Bladder Carcinoma
Presentor – Dr
Arjun Raja A
Moderator – Dr
S.Opendro

2. OUTLINE
• Introduction
• Epidemiology
• Etiology/Pathophysiology
• Pathology
• Histology
• Presentation
• Workup
• Treatment
• Follow Up

3. INTRODUCTION
• Gallbladder carcinoma –
first described by Maximilian Stoll
in 1777 and more than 200 years later it is still
considered to be a highly malignant disease with
a poor survival rate
• G.B cancer is relatively uncommon but it is the 5th most
common GIT malignancy(worldwide)
• Most frequent malignant tumor of the biliary tract
• 90 % Adenocarcinomas.

4. INTRODUCTION
• Most common sites -fundus and the neck; 20% lateral
walls.
• Most important risk factor -gallstones (cholelithiasis)
90% of cases
• Only 0.5% of patients with gallstones develop
gallbladder cancer after twenty or more years

5. INTRODUCTION
Premalignant Lesions
Adenomatous polyps
– Papillary adenomas grow as pedunculated, complex,
branching tumors projecting into the gallbladder lumen.
– Tubular adenomas arise as a flat, sessile neoplasm.
– Size > 1cm, age> 50, solitary polyp, symptomatic polyp
Porcelain gall bladder
• Associated with 10-50 % risk of malignancy.

6. EPIDEMIOLOGY
• incidence of GC  1 to 23 per 100,000 worldwide
• over the last three decades there is decrease in incidence in
developed and increase in incidence in developing countries
• The highest incidence of gallbladder carcinoma is reported
more recently from the Indian-Subcontinent including India
and Pakistan (18-23/100,000) mirror image of worldwide
distribution of gall stones.
• Most common cause of gastrointestinal cancer related
mortality in females in subcontinent.

7. EPIDEMIOLOGY
• Rise in incidence of GC from Northern India and Southern
Pakistan over the past two decades
• Frequency of gallbladder cancer in Pakistan varies between
6-7%.
• Highest incidence is found in Chelians American Indian and in
parts of Northern India where it accounts for 9% of all biliary
tract diseases.
• Female to male ratio is 3:1
• Peak incidence is in 7th decade of life.

8. ETIOLOGY/PATHOPHYSIOLOGY
• Risk factors include
– Chronic inflamation and Cholelithiasis.
– Porcelain Gallbladder
– Typhoid carrier
– Adenomatous polyp (size of the polyp is strongest
predictor of malignant transformation)
– Advanced age(>55 yr)
– Multiparity(>5)
– Presence of gallstone larger than 3cm.
– Anomalous pancreatobiliary junction
– Drugs :OCP, methyldopa

9. • Occupational exposure to rubber, cigarette smoking.
Bile acid composition.
Diet: low fibre, low calories. High CHO, low protein.
ETIOLOGY/PATHOPHYSIOLOGY

10. PRESENTATION
• Usually asymptomatic at the time of diagnosis
• Symptoms if present are similar to benign diseases such
as cholecystitis or biliary colic.
• Jaundice and anorexia are late features
• Palpable mass is a late sign
• less than 50% of gallbladder cancers are diagnosed
preoperatively.
• Commonly diagnosed incidentally in gallbladders removed for
biliary colic or cholecystitis.

11. CLASSIFICATION
Adenocarcinoma
• Well differentiated
• Papillary
• Intestinal type
• Pleomorphic giant cell
• Poorly differentiated
• Signet ring cell
• Mucinous
• Clear cell
• Colloid
• Choriocarcinoma like
• Squamous cell carcinoma
• Adenosquamous cell
carcinoma
Mesenchymal Tumours
• Embryonal
rhabdomyosarcoma
• Leiomyosarcoma
• Malignant fibrous
histiocytoma
• Angiosarcoma.
Other tumours
• Melanoma
• Carcinoid

12. PATHOLOGY
Based on Gross Morphology
• Infiltrative
• Nodular
• Papillary
• Combined nodular-infiltrative
• Combined papillary-infiltrative.

13. PATHOLOGY
Infiltrating pattern
• More common
• Poorly defined area of diffuse thickening and induration
or may involve the entire gallbladder.
• Deep ulceration can cause direct penetration of the
gallbladder wall or fistula formation to adjacent viscera
into which the neoplasm has grown.
• Mainly spreads in subserosal plane

14. PATHOLOGY
Nodular pattern
• More circumscribed mass
• Despite invasion into liver, easily resectable (because
less diffuse)
Papillary Pattern
• Polypoid lesions with front like extensions giving a
cauliflower like appearance.
• Luminal portion may be necrotic, haemorrhagic,
and ulcerated

15. The opened gallbladder contains a large, exophytic
tumor that virtually fills the lumen

16. GALLBLADDER POLYPS
• Most common polyp – Cholesterol polyp
• Only polyp associated with risk of malignancy-
adenomatous polyp.
Other benign lesions-
• Fibromas.
• Lipomas.
• Hemangiomas
• Inflammatory polyp
• Adenomyomas.

17. HISTOLOGY
Based on histologic
appearance
• Adenocarcinoma
• Squamous/Adenosquamo
us
• Neuroendocrine
• Sarcoma/Adenosarcoma
• Melanoma
• Unspecified
Based on metaplastic
changes
• Metaplastic
Pseudopyloric/Intestinal
• Non metaplastic

18. HISTOLOGY
• Most carcinomas of the gallbladder are
adenocarcinomas.
• Some are papillary in architecture and are well to
moderately differentiated; others are infiltrative and
poorly differentiated to undifferentiated
• About 5% are squamous cell carcinomas or have
adenosquamous differentiation

19. HISTOLOGY
NORMAL ADENOCARCINOMA

20. HISTOLOGY
MALIGNANT GLANDULAR STRUCTURES ARE
PRESENT WITHIN A DENSELY FIBROTIC
GALLBLADDER WALL.
PAPILLARY PATTERN

21. Work Up
• Laboratory studies are generally nonspecific for gallbladder
cancer.
• In the later stages, liver function enzyme levels may be slightly
elevated. These levels are generally not elevated in stages I
and II.
• An elevated bilirubin or alkaline phosphate level generally
indicates advanced or obstructive disease.
*Found in 80% of the cases
Tumour Marker Sensitivity Specificity
CA 19-9 * 79.4 % 79.5%
CEA 50 % 93%

22. SPREAD
• Early spread via lymphatics
• Other means-hematogenous, peritoneal metastasis, and
implantion along biopsy tracts.
• Factors attributing to early invasion and metastasis
- Gallbladder wall is thin.
- Narrow lamina propria.
- Only a single muscular layer.
- No serosal covering between gallbladder and liver.
- Connection between subserosal lymphatics and
subcapsular lymphatics of liver.
- Pericholedochal lymphnodes can go to interaortocaval
group

23. PRINCIPLES OF IMAGING
• Detection of early stage gallbladder cancer difficult
• MC incidental discovery at surgery or pathology
• If gallbladder cancer suspected preoperatively
then Multiphase CT of abdomen, pelvis and chest CT
along with MRCP done.
• MRI – preferred for mass within Gallbladder and to
demonstrate duct involvement.
• Careful evaluation of nodes needed, especially porta hepatis,
left gastric , aortocaval.
• When equivocal finding in CT/MRI, PET/CT can be used.
• CT Chest and Multiphasic CECT of abdomen and pelvis used
for follow up imaging.

24. IMAGING STUDIES
Ultrasonography
• Polypoid lesions
• Cholesterol polyps (benign) - pedunculated lesions.
• Ultrasonographic findings that indicate possible malignancy
– a thick gallbladder wall,
– vascular polyp
– a mass projecting into the lumen or invading the wall,
multiple masses or a fixed mass in the gallbladder,
– a porcelain gallbladder, and an extracholecystic mass.
Invasion of the liver can also be seen on ultrasonograms.

25. This image demonstrates heterogeneous thickening
of the gallbladder wall (arrows). The diagnosis was
primary papillary adenocarcinoma of the
gallbladder.

26. Computed tomography (CT) scanning and magnetic resonance
imaging (MRI)
• extent of invasion and resectability of gall bladder tumors.
asymmetrical wall thickening or gallbladder mass with or
without invasion into the liver.
CT scanning of the chest, abdomen, and pelvis
• staging modality
• presence of distant metastases and involvement of other
organs and vascular structures.
• Positron emission tomography (PET) scanning has a
sensitivity of 75% and a specificity of 88% in gallbladder
cancer but is not used routinely.

27. PARTIALLY CALCIFIED GALLBLADDER
(ARROW). AT
LAPAROTOMY AND HISTOLOGY,
AN INFILTRATING
ADENOCARCINOMA OF THE
GALLBLADDER WAS CONFIRMED.
CT SCAN SHOWING SQUAMOUS CELL
CARCINOMA OF GALL BLADDER
SHOWING LIVER METASTASIS

28. DIAGNOSTIC PROCEDURES
• Percutaneous CT scan – guided biopsy
avoided (risk of peritoneal seeding)
• Percutaneous CT scan – guided biopsy is a useful diagnostic
tool in patients who appear to have a nonresectable tumor.
Tissue diagnosis is necessary for palliative treatment.
• Endoscopic ultrasonography with fine-needle aspiration
Biopsy can be used to evaluate for peripancreatic and
periportal lymphadenopathy.

29. STAGING

30. PRINCIPLES OF SURGERY AND
PATHOLOGY
INCIDENTAL FINDING AT SURGERY
• If expertise unavailable-document all findings , refer to higher
centres
• If suspicious mass seen – Biopsy not advised (peritoneal
dissemination)
• If expertise available
1)if clinical evidence is adequate –definitive resection
2)if clinically not clear – frozen section biopsies before resection

31. PRINCIPLES OF SURGERY AND
PATHOLOGY
INCIDENTAL FINDING ON PATHOLOGIC REVIEW
• Consider pathologic re-review by hepatobiliary
pathology expert.
• Diagnostic laparoscopy can be done.
• Repeat CT of chest, abdomen & pelvis
• Initial exploration to rule out metastasis in coeliac axis,
aortocaval groove ( contraindication )
• Hepatic resection/extended resections/bile duct
resection with lymphadenectomy.
• Port site resection not effective(indicates disseminated
disease.)

32. PRINCIPLES OF SURGERY AND
PATHOLOGY
MASS ON IMAGING
• Staging done with CT chest, abdomen, pelvis.
• Biopsy not necessary, definitive resection done.
• Diagnostic laparoscopy recommended prior to surgery.
• If diagnosis not clear, reasonable to do cholecystectomy
(with intraoperative frozen section) and definitive resection
in same setting if pathology confirms cancer.
PRESENTS AS JAUNDICE
• Jaundice –a poor prognosis
• If expertise available, can attempt curative resection if
resectable .

33. SURGICAL MANAGEMENT
• Cholecystectomy recommended in
– polyps larger than 1 cm or with polyps in the setting of primary sclerosing
cholangitis
– porcelain gallbladder.
• Diagnostic Laproscopy
– In order to exclude the presence of undetected intra-abdominal metastases
prior to curative laparotomy.
– Surgery is contraindicated in the presence of distant metastases.
• Exploratory Laparotomy
– The initial exploration focuses on the presence of metastatic disease that was
not detected by preoperative imaging and staging laparoscopy.(15%)
– Aortocaval nodal metastases are considered distant metastatic disease.

34. GB cancer as Incidental finding in intra op/Post
Cholecystectomy
For T1a lesions-
Cholecystectomy +/- cystic plate resection.
For T1b lesions-
1)with negative cystic duct margins
Cholecystectomy +/- cystic plate resection
2)with perineural , lymphatic and vascular invasions.
Extended Cholecystectomy
(i) 2cm wedge resection of Liver parenchyma
(ii) Resection of cystic duct/CBD margin to
univolved mucosa.
(iii) Removal of pericholedochal, periportal,
hepatodeodenal, right celiac, posterior
pancreatico deodenal.
(iv) Roux-en-y hepatico jejunostomy.

35. For T2 lesions-
Extended / Radical cholecystectomy(Extended
cholecystectomy including segment IVb and V) .
GB cancer diagnosed preoperatively
For T3 and T4 lesions-
Radical Cholecystectomy
+/- Central Hepatectomy ( segment IV,V,VIII)
+/- Right Trisegmentectomy (segment IV,V,VI,VII,VIII)

36. Intraoperative ultrasonography (IOUS)
• To evaluate the extent of involvement of the liver, as well as
the portal and intrahepatic vasculature.
• This information is especially useful when ligating the pedicle
to segment V and avoiding injury to the right anterior portal
pedicle or segment VIII pedicle. Extended right hepatectomy
may be necessary to achieve tumor clearance if the tumor
involves the right portal pedicles

37. A schematic drawing of the
extent of lymphadenectomy for
gallbladder cancer, especially
when the extrahepatic biliary
tree is resected.
Gallbladder tumors.
A schematic
drawing of the
extent of resection
of liver segments
IV-b and V for
gallbladder cancer.

38. • Surgical exploration
– will determine the need to resect other organs that may
be involved, such as the stomach, duodenum, pancreas
and colon.
– If tumor is suspected on the bile duct based on a previous
pathology report or operative exploration, the presence of
tumor on the right hepatic duct must be evaluated.
– Suspicion of tumorous involvement of the right hepatic
duct will require an extended right hepatectomy, excision
of the extrahepatic biliary tree, and Roux-en-Y
hepaticojejunostomy to the left hepatic duct.

39. No standard adjuvant treatment protocol has been
defined for gall bladder cancer.
– A 2008 study found that only 20% of patients with gall
bladder cancer received adjuvant treatment.
– In the report, no benefit from adjuvant therapy could
be demonstrated, but only a small number of patients
received this treatment.
– Generally, fluoropyrimidine-based chemoradiotherapy
or single-agent chemotherapy with fluoropyrimidines
or gemcitabine is used.
– Because of the high cure rate with surgery alone for
T1N0 lesions, adjuvant therapy is not commonly
offered to these patients.

40. NCCN GUIDELINES 2018

41. NCCN GUIDELINES 2018

42. NCCN GUIDELINES 2018

43. NCCN GUIDELINES 2018

44. NCCN GUIDELINES 2018

45. Complications
• The overall complication and morbidity rate is
approximately 25%.
• Complications are similar to those experienced with
cholecystectomy and include infection, hematoma, and bile
leaks.
• Complication rates are higher in patients
undergoing more extensive resections.
• Liver failure can occur following extended hepatectomy,
especially if jaundice is present preoperatively.

46. Non surgical Management
• Small gallbladder tumors -safely followed with serial
ultrasonographic examination. (polyps of less than 1 cm are
safe to follow)
• Chemotherapy is used in the adjuvant and palliative
treatment of gallbladder cancer. Phase II studies have shown
that the use of single- agent chemotherapy (with
gemcitabine or 5-fluorouracil) in the palliative setting can be
beneficial.
• Combination chemotherapy - based on gemcitabine,
capecitabine, and 5-fluorouracil used in combination with
cis-platinum or oxaliplatinum.
• Fluoropyrimidine-based chemoradiotherapy is commonly
employed in the palliative and adjuvant setting as well.

47. Patients with unresectable disease have a median survival of 2-4 months
PROGNOSIS [5][11]
STAGE 5 YEAR SURVIVAL RATE
T1b 100% especially with hepatectomy
T2 38% to 77% after extended
cholecystectomy
III and IV 25 % with extended resection
Unresectabe disease < 5% ( 1 year survival rate)

48. Follow Up
• No data to support aggressive surveillance following resection
of gall bladder cancer, because treatment of recurrences is not
generally effective.
• However, many clinicians and patients prefer follow-up
imaging every 6 months for 2 years if clinically indicated,then
annualy upto 5 years.
• CEA and CA-19-9