Download Carcinoma Gall Bladder

CARCINOMA GALL BLADDER
-An Update
Dr Sanjay De Bakshi
MS; FRCS (Eng; Edin -ad eundem)
Division of Surgical Gastroenterology
Calcutta Medical Research Institute
PREAMBLE
• Gallbladder cancer is the most common malignant
tumour of the biliary tract worldwide .
• It is also the most aggressive cancer of the biliary tract
with the shortest median survival from the time of
diagnosis.
• This poor prognosis is due, in part, to an aggressive
biologic behaviour and a lack of sensitive screening
tests for early detection - resulting in delayed diagnosis
and presentation at an advanced stage.
C. H. E. Lai and W. Y. Lau, “Gallbladder cancer—a comprehensive review,” Surgeon, vol. 6,
no. 2, pp. 101–110, 2008.
X. Zhu, T. S. Hong, A. F. Hezel, and D. A. Kooby, “Current management of gallbladder
carcinoma,” The Oncologist, vol. 15, no. 2, pp. 168–181, 2010.
U. Dutta, “Gallbladder cancer: can newer insights improve the outcome?” Journal of
Gastroenterology and Hepatology, vol. 27, no. 4, pp. 642–653, 2012.
INCIDENCE
• Gallbladder carcinoma is the fifth most
common gastrointestinal tumour.
• Well- to moderately differentiated
adenocarcinoma accounts for the most
common form of gallbladder carcinoma.
Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and
Treatment Options. Alessandro Furlan et al American Journal of Roentgenology.
2008;191: 1440-1447
RISK FACTORS
Demographic factors
Gall bladder pathologies/ abnormalities
RISK
FACTORS
Chronic inflammation
Infections
Exposures
Adapted from -Gallbladder Cancer in the 21st Century. Rani Kanthan, Jenna-Lynn Senger,
Shahid Ahmed, and Selliah Chandra Kanthan Journal of Oncology; Volume 2015 (2015),
RISK FACTORS
• Demographic factors:
(a)advanced age,
(b)female gender,
(c)obesity,
(d)geography: South American, Indian, Pakistani,
Japanese, and Korean,
(e)ethnicity: Caucasians, Southwestern Native
American, Mexican, and American Indians,
(f)genetic predisposition.
GEOGRAPHICAL VARIATION
GEOGRAPHICAL VARIATION
in Gall Stone Disease
RISK FACTORS
• Gallbladder pathologies/abnormalities:
(a) cholelithiasis, (Kaushik 2001; Rustagi and Dasanu
2014)
(b) porcelain gallbladder, (Hundal and Schaffer 2014)
(c) gallbladder polyps,
(d) congenital biliary cysts *,
(e) pancreaticobiliary maljunction anomalies.
In Todani 's series of 154 cancers associated with bile duct cysts, 62 were in
the gall-bladder, 1 in the liver and 2 in the pancreas.*
RISK FACTORS
• Gallbladder pathologies/abnormalities:
 The issue of microlithiasis
 Gallbladder metaplastic changes appear to be more
frequent in cases of micro-lithiasis and seem to be
associated with a chronic thickening of the gallbladder
wall.
 Further studies are needed to evaluate a possible role of
prophylactic cholecystectomy in this population to
prevent the long term evolution of these early changes
to cancerous lesions.
Metaplastic Changes in Chronic Cholecystitis: Implications for Early Diagnosis and
Surgical Intervention to Prevent the Gallbladder Metaplasia-Dysplasia-Carcinoma
Sequence. Charalampos Seretis et al; J Clin Med Res. 2014 Feb; 6(1): 26–29.
RISK FACTORS
• Chronic inflammation associated with
(a)Primary sclerosing cholangitis (Bernstein 2001)
(b)Ulcerative colitis (Bernstein 2001)
RISK FACTORS
• Infections
(a)Liver flukes (R. Hundal and E. A. Shaffer 2014),
(b)Chronic Salmonella typhi and paratyphi infections
(Nath 1997; Shukla 2000; Randi 2006; Nagaraja
2014) and
(c)Helicobacter infection (Matsukura 2002; Kobayashi
2005).
• Exposures
RISK FACTORS
(a)Ingestion of certain medications (eg, oral contraceptives,
INH, methyldopa) can increase the risk of gallbladder
cancer.
(b)Likewise, certain chemical exposures (eg, pesticides,
rubber, vinyl chloride) and
(c)Occupational exposures associated with working in the
textile, petroleum, paper mill, and shoemaking industries
increase the risk of gallbladder cancer.
(d) Smoking
(e)Exposures through
water pollution (organopesticides, eg,
dichlorodiphenyltrichloroethane and benzene hexachloride);
heavy metals (eg, cadmium, chromium, lead); and
radiation exposure (eg, radon in miners) are associated with
gallbladder cancer.
PATHOGENESIS
• Gallbladder cancer may arise in the gallbladder’s
fundus (60%), body (30%), or neck (10%).
• The development of gallbladder cancer is
proposed to occur over a span of 5–15 years,
with tissue alterations including metaplasia,
dysplasia, carcinoma in situ, and invasive cancer
K. S. Lim, C. C. Peters, A. Kow, and C. H. Tan, “The varying faces of gall bladder
carcinoma: pictorial essay,” Acta Radiologica, vol. 53, no. 5, pp. 494–500, 2012.
R. Hundal and E. A. Shaffer, “Gallbladder cancer: epidemiology and outcome,” Clinical
Epidemiology, vol. 6, no. 1, pp. 99–109, 2014.
MOLECULAR PATHOGENESIS
• Biologic pathways
• Two distinct pathways proposed:(1) a dysplasia-carcinoma sequence arising from
metaplastic epithelium and
(2) an adenoma-carcinoma sequence
MOLECULAR PATHOGENESIS
• Genetic
mutations
• The genetic
mutagenesis of
Gall Bladder
Carcinoma is ill
understood.
• Genes that have been studies
– Oncogenes
– Tumour Suppressor genes
– Adhesion molecules and
mucins
– Angiogenesis
– Cell cycle regulators
– Apoptosis inducers
IMAGING
• Sonography has a relatively high sensitivity for
the detection of tumor at advanced stages, it is
limited in the diagnosis of early lesions and is
unreliable for staging.
• Therefore, CT and, increasingly, MRI are more
widely used for further characterization of
potentially malignant gallbladder lesions and
metastatic survey.
Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and
Treatment Options. Alessandro Furlan et al American Journal of Roentgenology.
2008;191: 1440-1447
IMAGING
• On sonography, CT, or
MRI, the presence of a
large gallbladder mass
that nearly fills or
replaces the lumen, often
directly invading the
surrounding liver
parenchyma, is highly
suggestive of gallbladder
carcinoma.
Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and
Treatment Options. Alessandro Furlan et al American Journal of Roentgenology.
2008;191: 1440-1447
IMAGING
• On sonography,
heterogeneous,
predominantly
hypoechoic tumor fills
much or all of the
gallbladder lumen.
Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and
Treatment Options. Alessandro Furlan et al American Journal of Roentgenology.
2008;191: 1440-1447
IMAGING
• Primary gallbladder
carcinoma is usually
hypodense on
unenhanced CT, with up
to 40% of lesions showing
hypervascular foci of
enhancement equal to or
greater than that of liver
after IV contrast
administration
Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and
Treatment Options. Alessandro Furlan et al American Journal of Roentgenology.
2008;191: 1440-1447
IMAGING
• On MRI, gallbladder
carcinoma usually shows
hypo- to isointense signal
characteristics on T1weighted and moderately
hyperintense signal
characteristics on T2weighted sequences
Axial fast spin-echo T2-weighted MR image shows
hyperintense mass (arrow) occupying gallbladder
lumen and extending into adjacent liver parenchyma
(arrowheads) with similar signal intensity.
Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and
Treatment Options. Alessandro Furlan et al American Journal of Roentgenology.
2008;191: 1440-1447
IMAGING
• Gallbladder carcinoma
may present as focal or
diffuse asymmetric wall
thickening in 20–30% of
cases
Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and
Treatment Options. Alessandro Furlan et al American Journal of Roentgenology.
2008;191: 1440-1447
IMAGING
• The initial detection of
gallbladder carcinoma as a
polypoid lesion occurs in
15–25% of cases.
• Malignant lesions are
usually larger than 1 cm in
diameter and may have a
thickened implantation
base .
Gallbladder Carcinoma Update: Multimodality Imaging Evaluation, Staging, and
Treatment Options. Alessandro Furlan et al American Journal of Roentgenology.
2008;191: 1440-1447
IMAGING
• Xanthogranulomatous
cholecystitits presents
usually with a
– Symmetric thickening of the
wall,
– Continuous contrast—
enhanced mucosal line.
– Hypoattenuating nodules
These represent abscesses
or foci of inflammation.
– Absence of any infiltration of
surrounding tissues
http://www.radiologyassistant.nl/en/p43a074
6accc5d/gallbladder-wall-thickening.html
GB CA vs XGC
IMAGING
Xanthogranulomatous Cholecystitis Masquerading as Gallbladder Cancer: Can It Be
Diagnosed Preoperatively?
Ashwin Rammohan, Sathya D. Cherukuri, Jeswanth Sathyanesan, Ravichandran
Palaniappan, and Manoharan Govindan; Gastroenterology Research and Practice
Volume 2014 (2014), Article ID 253645,
IMAGING
• PET-CT in the assesment of Gall Bladder
cancers.
• Of value in detecting unsuspected distant
metastases.
Impact of integrated positron emission tomography and computed tomography on
staging and management of gall bladder cancer and cholangiocarcinoma. Petrowsky
et al J Heptol 2006 Jul; 45: 43-50.
Clinical usefulness of 18-EDG PET-CT for patients with gall bladder cancer and
cholangiocarcinoma. J Gastroenterol. 2010 May;45(5): 560-6.
IMAGING
• Contrast-enhanced
ultrasonography with
perflubutane has been
described in which
gallbladder cancer
shows continuous
staining throughout the
tumour and an
“eruption sign”
The efficacy of contrast-enhanced harmonic endoscopic ultrasonography in diagnosing
gallbladder cancer. Mitsuru Sugimoto et al Sci Rep. 2016; 6: 25848.
IMAGING
Contrast Enhanced US Scan
Upper LeftPolypoid
Upper MiddleThick wall type
Upper RightMass forming
type
Lower LeftScattered blood
vessels
Lower MiddleLinear blood
vessels
Lower RightLinear blood
vessels
Contrast-Enhanced Ultrasound in the Diagnosis of Gallbladder Diseases: A Multi-Center
Experience. Lin-Na Liu, Hui-Xiong Xu et al October 31,
http://dx.doi.org/10.1371/journal.pone.0048371
ROLE OF ADJUVANT THERAPY
• Currently (2014), no adjuvant therapy that has
been agreed upon as standard of care.
Williams et al; Defining the role of adjuvant therapy;
cholangiocarcinoma and gall bladder cancer. Semin Radial
Oncol 2014 Apr; 24(2):94-104
ROLE OF NEO-ADJUVANT THERAPY
• Of the 38 pts 33patients were treated with Gem-P
(oxaliplatin, cisplatin; cetuximab-Gem-P) based therapy
and 5 pts received chemoradiotherapy (CTRT) with
wkly gemcitabine 300mg/m2.
• Site of disease was
–
–
–
–
liver in 22 pts,
nodal in 12,
adjacent organ in 9 &
other in 3 pts..
• Neoadjuvant therapy in Indian patients with locally advanced gall bladder
cancer: Tata Memorial Centre (TMC) experience. Bhawna Sirohi, Vipul
Sheth, Ashish Singh, Reena Engineer, Mukta Ramadvar, Mahesh Goel,
Shailesh V. Shrikhande2014 Gastrointestinal Cancers Symposium
ROLE OF NEO-ADJUVANT THERAPY
• Response rate to NA therapy was
–
–
–
–
–
5 (13%) complete response (CR),
17(45%) partial response (PR),
9 stable disease (SD),
5 (13%) progressive disease and
not assessed in 2 patients (1 pt died post CTRT and 1 was
inoperable at surgery).
• Neoadjuvant therapy in Indian patients with locally advanced gall bladder
cancer: Tata Memorial Centre (TMC) experience. Bhawna Sirohi, Vipul
Sheth, Ashish Singh, Reena Engineer, Mukta Ramadvar, Mahesh Goel,
Shailesh V. Shrikhande2014 Gastrointestinal Cancers Symposium
ROLE OF NEO-ADJUVANT THERAPY
• Overall clinical benefit rate (CR+PR+SD) was 82%.
• Of the 24 pts who underwent surgery,
– 21 (87%) had curative resection and
– 3 were inoperable.
• Of 9 pts with SD, 6 received 2nd –line NA therapy as
they were not downstaged enough to undergo
surgery– 4 CTRT, 1 gemcitabine-cape, 1 cape-Ox.
• Perioperative morbidity (biliary leak) was higher post
CTRT. Overall, 7 pts have relapsed.
• Neoadjuvant therapy in Indian patients with locally advanced gall bladder
cancer: Tata Memorial Centre (TMC) experience. Bhawna Sirohi, Vipul
Sheth, Ashish Singh, Reena Engineer, Mukta Ramadvar, Mahesh Goel,
Shailesh V. Shrikhande2014 Gastrointestinal Cancers Symposium
ROLE OF NEO-ADJUVANT THERAPY
• This is the first report of the use of
neoadjuvant chemotherapy in patients with
LA GB cancer.
• CONCLUSION- preoperative chemotherapy is
feasible with acceptable toxicity and
perioperative morbidity.
• Neoadjuvant therapy in Indian patients with locally advanced
gall bladder cancer: Tata Memorial Centre (TMC) experience.
Bhawna Sirohi, Vipul Sheth, Ashish Singh, Reena Engineer,
Mukta Ramadvar, Mahesh Goel, Shailesh V. Shrikhande2014
Gastrointestinal Cancers Symposium
ROLE OF ADJUVANT & NEO-ADJUVANT
THERAPY
• Kaplan–Meier analysis
demonstrates that neither
neoadjuvant (a log rank
p=0.59) nor adjuvant (b log
rank p=0.16) therapy is
associated with an
improved probability of
survival.
• However, adjuvant
chemotherapy is associated
with a significant decrease
in survival (b p=0.04)
M. D. Anderson Cancer Center.
ROLE OF ADJUVANT & NEO-ADJUVANT
THERAPY
• Kaplan–Meier analysis
demonstrates that neither
neoadjuvant (a log rank
p=0.59) nor adjuvant (b log
rank p=0.16) therapy is
associated with an
improved probability of
survival.
• However, adjuvant
chemotherapy is associated
with a significant decrease
in survival (b p=0.04)
M. D. Anderson Cancer Center.
ROLE OF ADJUVANT & NEO-ADJUVANT
THERAPY
• Early surgical resection of biliary tract
malignancies with 1 cm tumor-free
margins or segmentectomy with
lymph node dissection provides the
best probability for long-term
survival.
• Currently available neo-adjuvant or
adjuvant therapy does not improve
survival.
• Neither neoadjuvant nor adjuvant therapy increases
survival after biliary tract cancer resection with
wide negative margins. Glazer ES et al. J
Gastrointest Surg. 2012 Sep;16(9):1666-71. M. D.
Anderson Cancer Center.
TARGETED THERAPIES IN
GALL BLADDER CANCER
• Common mutations reported in gallbladder cancer are
KRAS (10%–67%), EGFR (63%), BRAF (0% to 33%), and
erbB2/HER2 (16%–64%).
• Early data suggest possible benefit from blockade of
the epidermal growth factor receptor by the oral
tyrosine kinase inhibitor erlotinib or anti-EGFR
monoclonal antibody cetuximab.
• Vascular endothelial growth factor (VEGF) is
overexpressed in biliary tract cancers and has been
proposed as a therapeutic target. The efficacy of
bevacizumab, a monoclonal antibody targeting VEGF, in
combination with erlotinib was assessed in a phase II
trial showed onlty a modest benefit.
PROGNOSIS
• A disease of very poor
prognosis.
• Surgery, the only curative
therapy. (<20% operable)
• Techniques of early
diagnosis evolving.
• Regional nodal status and
the depth of tumor
invasion (T status) are the
two most important
prognostic factors.
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