2. INTRODUCTION
• The most common of biliary tract malignancy. Sixth most
common cancer of GIT
• often discovered incidentally after cholecystectomy performed
for presumed benign disease.
• For surgeons whose specialty includes gallbladder cancer, it is
important to understand the outcome and limitations of surgical
resection so that a complete understanding of the risks and
benefits can be analyzed, presented to patients, and result in a
rational treatment strategy.
• overall 5-year survival of 20% with median survival of just 16
months for patients with resectable disease. For advanced,
untreated gallbladder cancer, the median survival is generally 2
to 5 months.
• Systemic chemotherapy remains limited in its effectiveness.
• Complete surgical removal of gallbladder cancer is the only
potentially curative therapy
3. EPIDEMIOLOGY
• Incidence of gallbladder cancer varies significantly by
geographic region and racial group.
• Women are affected two to four times more often than
men(higher rate of cholelithiasis and inflammation).
• Disease of older age with the incidence steadily
increasing to a plateau at about 60 years.
• Obesity, a risk factor for increased death rates from many
cancers, is similarly associated with increased risk of
developing gallbladder cancer.
• epidemiologic associations with gallbladder cancer
include : inflammatory bowel disease and primary
sclerosing cholangitis, history of typhoid infection, and
polyposis coli.
4. ETIOLOGY
• Most consistent etiologic factor in the development of
gallbladder cancer is cholelithiasis (90% of gallbladder cancer
specimens contain stones) and chronic inflammation .
• 75% to 90% occur in the setting of cholelithiasis.
• More stones, heavier stones, and increased stone volume in
the patients who had gallbladder cancer.
• Most patients with gallstones never develop cancer(incidence
of gallbladder cancer in the population of patients with stones is
(0.3% to 3%). and a definitive cause-and-effect relationship has
not been established.
• It is possible that stones and cancer share similar risk factors
or simply that stones prompt a radiologic workup or
cholecystectomy, increasing recognition in this group of
patients.
5. • Other epidemiologic associations, such as anomalous
pancreatobiliary duct junction, biliary-enteric fistulae, and
typhoid infection, also represent conditions in which the
mucosa of the gallbladder is exposed to the effects of
chronic inflammation.
• Bacterial colonization often accompanies chronic
cholecystitis, it has been proposed that bacteria may play
an important role in carcinogenesis.
6. • calcification in the wall (porcelain gallbladder) increase
risk of gallbladder cancer due long-standing inflammation.
• The risk of malignancy within a porcelain gallbladder was
previously reported to be extremely high (10%-50%);
modern series, however, have shown a much lower
incidence (<10%).
• type of calcification seems to be associated with the
degree of risk, with stippled calcification of the mucosa
representing a higher risk than diffuse intramural
calcification.
• In porcelain gallbladder: cholecystectomy in medically fit
patients is supported.
7. • The composition of bile in patients with gallbladder cancer
has been studied in attempts to identify carcinogenic
agents. Higher concentrations of free radical oxidation
products and secondary bile acids were found in
gallbladders harboring cancer compared with gallbladders
with gallstones alone.
• Some chemicals have been implicated in gallbladder
carcinogenesis, including methyldopa, oral contraceptives
, isoniazid , and occupational exposure in the rubber
industry. None of these associations has been definitively
proven.
8. pathology
• Similar to many GI malignancies, progression from
dysplasia to carcinoma in situ to frank invasive carcinoma
is seen in gallbladder epithelium.
• patients with multiple gallbladder polyps appear to have
no increased risk of malignancy (Unlike colorectal cancer
: adenoma to carcinoma progression).
• the incidence of malignancy in gallbladder polyps may be
higher in the patient with primary sclerosing cholangitis.
• polyps have been noted in 3% to 6% of patients
undergoing ultrasonography. Most are cholesterol polyps
with no malignant potential .The incidence of carcinoma in
nonadenomatous polyps (cholesterol polyps(most
common GB polyp) , inflammatory polyps, and
hyperplastic polyps) is close to zero.
9. • Early-stage gallbladder cancers are difficult to distinguish from
the findings typical of chronic cholecystitis(both often present
as a thickened gallbladder wall in the face of inflammation).
• The overall incidence of gallbladder cancer discovered during
cholecystectomy for presumed benign disease is less than 1%
• The gallbladder may become distended with tumor or become
contracted and collapsed.
• Tumors in the lower end of the gallbladder may obstruct the
neck or cystic duct, leading to hydrops.
• Approximately 60% of tumors originate from the fundus, 30%
from the body, and 10% from the neck.
• Advanced tumors of the neck, infundibulum, or cystic duct may
infiltrate the porta hepatis, resulting in major vascular invasion,
jaundice, and potentially hepatic atrophy. This presentation is
often indistinguishable from a hilar cholangiocarcinoma.
10. • Grosslly gallbladder cancer have been grouped into
infiltrative, nodular, combined nodular-infiltrative, papillary,
and combined papillary-infiltrative forms.
• Most tumors have an infiltrative pattern as at least part of
their presentation, causing diffuse thickening and
induration of the gallbladder wall. These types of tumors
seem to spread in a subserosal plane and can invade the
whole gallbladder wall and even invade into the porta
hepatis, causing jaundice from diffuse biliary involvement.
These types of tumor can also diffusely invade the liver.
11. HISTOLOGY
• 90% with gallbladder cancer are adenocarcinomas.
• Most gallbladder tumors can be characterized
histologically, but typically there is more than one
histologic pattern in each tumor. The only histologic
subtype that seems to have prognostic significance is the
papillary tumor, which has a better prognosis related to its
tendency to be less invasive .When papillary gallbladder
cancers become invasive, however, they can metastasize
and have a prognosis typical of the pathologic stage.
• Gallbladder cancers grouped into metaplastic and
nonmetaplastic types. types of metaplasia that are
precursors to malignancy in the gallbladder mucosa are
pseudopyloric and intestinal,The intestinal type has a
higher rate of carcinoma
12. • Histologically, gallbladder cancers are graded into four
categories ranging from well differentiated to poorly
differentiated. This differentiation does not have a
significant impact on prognosis.
• Although it is clear that gallbladder cancers can be
differentiated based on histologic type and grade, the
most important prognostic factor is the stage at
presentation, making grade and type prognostically
unimportant.
13.
14. Pattern of Spread
• Gallbladder cancer spreads via lymphatics, hematogenously,
and into the peritoneal cavity or along biopsy or surgical wound
tracts.
• Invade and metastasize early; this attributable to the anatomy
of the gallbladder.(wall is thin, narrow lamina propria, and
single muscular layer, no serosal covering between the
gallbladder and liver.
• Tumors invade the liver at a thickness where in many organs a
second muscular layer would be encountered.
• The thin wall of the gallbladder may be responsible for early
hematogenous and lymphatic spread.
• Gallbladder tumors, once through the muscular layer, have
access to major lymphatic and vascular channels, providing
these tumors with early opportunities for dissemination.
15.
16.
17. • The only common extraabdominal site of distant
metastases is the lung, but lung metastases are rarely
seen in the absence of advanced intraabdominal disease.
• In an attempt to define sites of first recurrence after
complete resection : only 15% of patients developed
locoregional recurrence as the only site of recurrence,
and most (85%) had recurrence involving a distant site.
This finding shows the minimal potential utility of adjuvant
locoregional strategies and underscores the importance of
effective adjuvant systemic therapies.
18. CLINICAL PRESENTATION
• There are three common clinical scenarios for gallbladder
cancer: (1) identified by final pathology after routine
cholecystectomy; (2) discovered intraoperatively; and (3)
suspected before surgery
• high percentage of patients diagnosed with gallbladder cancer
after routine cholecystectomy for presumed benign gallbladder
disease, it is reasonable practice for the surgeon to inspect the
gallbladder mucosa at the completion of a cholecystectomy.
• try to remove the gallbladder intact (without perforation) if there
is any suspicion of gallbladder cancer.
• Frozen-section analysis should be used to examine any
suspicious areas if further surgery is planned, or if these
biopsies would substantially change the stage of disease.
19. • Asymptomatic in early stages.
• Constant right upper quadrant pain
• Weight loss, anorexia, and particularly jaundice are signs
of advanced disease.
• The presence of a palpable mass also is clearly an
ominous finding and predicts a high rate of irresectability
and advanced disease.
• LABS : anemia, hypoalbuminemia, leukocytosis, and
elevated alkaline phosphatase or bilirubin
• Tumor markers: CEA, CA19-9 : serum tumor markers are
of minimal clinical value compared with clinical
awareness, helpful in following a patient for recurrence.
20. RADIOLOGIC INVESTIGATION
• US : excellent imaging modality for the gallbladder, good
modality for evaluating the direct extension of gallbladder
cancer, limited, in identifying lymph node metastases in
pericholedochal and peripancreatic nodes. Because most
cases are advanced, the most common finding in
gallbladder cancer is a heterogeneous mass replacing all
or part of the gallbladder.
• CT : most common finding is a mass involving all or part
of the gallbladder. Assess local extent of disease and
whether distant metastases are present. Assessment of
regional and distant lymph nodes(regional nodal status
can vary, This may be improved by using criteria such as
size greater than 1 cm and a ringlike heterogeneous
enhancement (80% accuracy)).
21. • In CT : false-negative examinations continue to be a
problem because many involved lymph nodes can be
small with minimal tumor in them.
• CT is 71% to 84% accurate in T-staging gallbladder
cancer. The overall accuracy improved from 72% to 85%
when multiplanar reconstructions were added to
conventional axial imaging.
• PET: differentiate between benign and malignant tumors
and diagnose extrahepatic spread. limited in
differentiating between benign inflammatory states and
malignancy. more accurate in diagnosing metastatic
disease than CT scan. more useful in evaluating primary
gallbladder cancer rather than recurrent disease.
22.
23. • Mid–bile duct stricture, Mirizzi syndrome, distortion, or
nonfilling of the segment V or VI bile ducts can be caused
by gallbladder tumors. (assessed by CT or MRI)
• Invasive cholangiography(PTC OR ERCP) : part of the
palliation of advanced gallbladder cancer(stenting).
24. PREOPERATIVE PATHOLOGIC
DIAGNOSIS
• Unnecessary.
• Dangerous in patients with disease that is amenable to
resection (tendency to seed the peritoneum, biopsy tracts, and
surgical wounds).
• Negative biopsy result cannot be trusted because of significant
false-negative rates.
• Unwise to perform a diagnostic cholecystectomy to make the
diagnosis.
• surgeon and patient also must be prepared for the possibility of
performing a liver resection for benign disease.
• Unresectable or metastatic disease, a percutaneous biopsy
has an accuracy of almost 90%, and the falsepositive rate is
negligible
25. • Bile cytology: Sensitivity of bile cytology has been
reported to be approximately 75%. Done only if the
patient need PTC or ERCP . deliberate attempt to make
the diagnosis this way is unwarranted.
26. STAGING
• The layers of the gallbladder consist of mucosa, a
muscular layer, perimuscular connective tissue, and
serosa on one side (serosa is lacking on the side of the
gallbladder embedded in the liver).GB lacks a
submucosal layer.
• It is recommended that at least six lymph nodes be
harvested and evaluated, all nodes removed at operation
should be assessed for metastasis.
27. AJCC 8TH edition changes
***There is no longer a distinction between T3 and T4 tumors based on
the depth of liver invasion.
28.
29.
30.
31.
32. Staging Laparoscopy
• Two studies demonstrated that DL could prevent
nontherapeutic laparotomy in 33% to 55% of patients with
metastatic disease. Laparoscopy was more accurate than
CT in detecting peritoneal disease in patients with locally
advanced tumors, suggesting that patients with T3 and T4
lesions may benefit from DL prior to surgery.
33. SURGICAL MANAGEMENT
• 1-Benign Polyps:
• current practice recommendations are to perform lap.
cholecystectomy for gallbladder polyps greater than 1 cm in
size. (>0.8 cm in PSC )
• IF < 1 cm : Ultrasound follow-up at 12-month intervals for 2 to 3
years, then consideration of no additional imaging if the polyp
is stable and there are no new or suspicious clinical symptoms.
• WHY lap not open ? : (1) the overall low risk of malignancy, (2)
simple cholecystectomy is curative for T1a tumors, (3)
laparoscopically resected early-stage tumors do not appear to
have a worse outcome if a definitive resection is performed
subsequently and there is no perforation of the gallbladder
34. 2-GB Ca Incidentally Discovered
During or After Routine Cholecystectomy
• If cancer diagnosed by frozen section during surgery a curative
resection or no further dissection then transfer to experienced
hepatobiliary surgeon (This strategy does not appear to affect
outcomes).
• If cancer diagnosed after cholecystectomy:
• prior to undertaking a second operation, high-quality crosssectional
imaging (CT/MRI) should be obtained to appropriately stage the
disease.
• Postoperative inflammatory changes may be indistinguishable from
tumour and thus may necessitate bile duct resection or a more
aggressive hepatic resection to ensure complete tumour eradication.
• Re-resection is recommended for all patients who are medically fit
with T1b or greater level of invasion.
• Routine resection of the bile duct has not been associated with
improvements in survival but is generally required for a complete
resection in patients with a positive cystic duct stump
margin(examined with frozen section).
35.
36. Liver Resection
• If the tumor invade hepatic inflow vascular structures, an
extended right hepatectomy may be necessary to clear all
tumor, also consider systemic chemotherapy in advance.
• The goal of the liver resection is to ensure a margin of
resection of approximately 1 to 2 cm because there is no
serosal surface on the liver side of the gallbladder.
• The standard resection is an anatomic resection of
segments IVb and V, but it is possible to do a smaller
wedge resection for early-stage
37. Lymph Node Dissection
• The most common site of spread from gallbladder cancer
is to the periportal lymph nodes (LN) and then to
aortocaval LN. Celiac LN can also be involved.
• Long-term survival has not been demonstrated for
patients who undergo resection in the setting of positive
extraregional (para-aortic, celiac, or SMA) lymph nodes
(N2).
• The most recent AHPBA/SSAT/SSO/ASCO Consensus
Conference published a consensus statement
recommending aortocaval, retropancreatic and/or coeliac
LN sampling at the initiation of intended resection for
gallbladder cancer. If these LN are positive on frozen
section, there is no benefit to proceeding with radical
resection.
38. • Lymphatic drainage of
the gallbladder as
studied by dye
injections. When injected
into the lymphatics of the
gallbladder, dye was
shown never to ascend
into the proximal porta
hepatis lymphatics.
• Lymphatic channels from
the gallbladder lead first
to the cystic and
pericholedochal nodes.
39. • With locally advanced lesions it has been found that on
progression of T stage from T2 to T4, nodal and distant
metastases increased from 16% to 79% and from 33% to
69%, respectively.
• The presence of any nodal disease is associated with
poor survival.
40.
41. PORT SITE RECURRENCES
• port site seeding after laparoscopic cholecystectomy
• exacerbated by spillage of bile or stones inside the
peritoneal cavity.
• it is rare for port site recurrences to occur as the sole site
of disease.
• Given that port site recurrence is more a marker of
aggressive disease, the practice does not include empiric
resection of port sites during reexploration for gallbladder
cancer.
42. Obstructive jaundice
• Obstructive jaundice is a poor prognostic indicator and a
marker of advanced disease in patients with gallbladder
cancer.
• Patients presenting with obstructive jaundice and a
gallbladder malignancy have tumour involvement of the
porta hepatis by either direct extension of the tumour,
diffuse invasion of the porta hepatis or extensive nodal
disease.
• In 240 patients at MSKCC who presented with gallbladder
cancer, 82 (34%) were jaundiced and were more likely to
have advanced-stage disease; only six patients
underwent resection with curative intent, and only four
had an R0 resection.
43. Adjuvant therapy
• Sixty-six per cent of patients with gallbladder cancers who
underwent a potentially curative resection recurred within
a median follow-up of 24 months.
• Only 15% of patients developed a locoregional recurrence
as the first site of failure, while the majority of patients
(85%) had recurrence that involved a distant site.
• Thus, local therapies targeted at locoregional disease,
such as radiotherapy, are unlikely to significantly impact
the course of this disease, further emphasising the
importance of developing effective systemic adjuvant
therapies.
44. • One phase III multi-institutional trial of adjuvant chemotherapy
was performed in Japan as reported by Takada et al.103 It
should be noted that this trial included 508 patients with biliary
and pancreatic cancers. However, on subset analysis, this
study included 140 patients with gallbladder cancer who were
randomised to undergo surgical resection alone or resection
plus adjuvant mitomycin and 5FU. In considering only the
patients with gallbladder cancer, the actuarial 5-year disease-
free survival favoured the adjuvant chemotherapy group in
comparison to the surgeryalone group (20.3% vs 11.6%). From
these data, it is reasonable to offer adjuvant chemotherapy with
5FU and mitomycin; however, no consensus has been reached
regarding routine use of adjuvant chemotherapy.
45. • The contemporary drug gemcitabine was compared to
best supportive care and 5-FU in a three-arm trial for
patients with unresectable gallbladder cancer.
Gemcitabine significantly improved median overall
survival compared to both 5-FU and best supportive care.
• Currently, gemcitabine-based regimens, often combined
with a platinum agent, have become the most common
choice for treating gallbladder cancer.
46. • It is reasonable to consider patients with high-risk lesions
(i.e., T4 tumors, node positive, R1 resection) for both
neoadjuvant and adjuvant therapy and to offer
consultation with a medical oncologist to discuss
treatment options.
• Treatment efficacy demonstrated in the unresectable or
metastatic patient may not translate into improved
outcomes when used as an adjuvant to resection.
47. PALLIATIVE MANAGEMENT
• Most treatment options in patients with gallbladder cancer
are palliative because most patients are unresectable at
presentation.
• The most common symptoms to palliate include pain,
jaundice, and bowel obstruction.
• Palliation of jaundice: endoscopic or percutaneous
interventions are the preferred approach for palliation and
minimizing morbidity. These palliative procedures were
successful in alleviating pruritus, but there was no
improvement in quality of-life.
48. • The high risk of morbidity and mortality precludes
recommending these treatments in the absence of
symptoms or a specific reason to treat jaundice, such as
allowing administration of chemotherapy.
• Intestinal bypass can also be performed in patients with
symptomatic bowel obstruction. Percutaneous feeding
tubes or drains and endoscopic stents are favored over
surgical bypass because of the extremely poor prognosis.
49. • Chemotherapy has been used to palliate unresectable
disease but often offers little benefit.
• Clinical trials ofgemcitabine and oxaliplatin have showed
response rates of 40% to 50%
• Radiation therapy may be an effective palliative therapy
for locally advanced disease.
• Radiation therapy is generally well tolerated, may have an
impact on local symptoms, and is usually combined with
chemotherapy
50. Key Points:
• In gallbladder cancer, a cholecystectomy should be performed
for adenomatous polyps >1 cm, or those that are smaller but
growing and changing in character. Cholesterol polyps and
• Adenomyomatosis are not premalignant conditions.
• Complete surgical resection is the goal, whether the diagnosis
is made preoperatively, intraoperatively or after a non-curative
laparoscopic cholecystectomy.
• In patients with invasion into the common bile duct,
consideration should be given to neoadjuvant chemotherapy
prior to surgical exploration in an attempt to best select patients
for potentially curative resection.
• Obstructive jaundice in the setting of gallbladder carcinoma
portends poor survival and systemic therapy should be
considered prior to entertaining surgical resection.
