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Early View Article: Online published version of an accepted article before
publication in the final form.
Journal Name: International Journal of Hepatobiliary and Pancreatic
Diseases
doi: To be assigned
Early view version published: December 22, 2017
How to cite the article: Sagar PV, Rao KS. Synchronous
cholangiocarcinoma and gallbladder cancer: A rare presentation.
International Journal of Hepatobiliary and Pancreatic Diseases. Forthcoming
2017.
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Manuscript Accepted Early View Article
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TYPE OF ARTICLE: Case Report 1
2
TITLE: Synchronous cholangiocarcinoma and gallbladder cancer: A rare 3
presentation 4
5
AUTHORS: 6
Dr. Puppala Venkata Sagar1, 7
Dr. Kanchustambam Subba Rao, M.B.B.S, D.N.B, FRCS, ASTS 8
9
AFFILIATIONS: 10
1M.B.B.S., M.S. Senior Specialist/Jr. Consultant, Department of Surgical 11
Gastroentrology & HPB, Transplant, Care Hospitals, Visakhapatnam, Andhra 12
Pradesh, India, [email protected] 13
2M.B.B.S, D.N.B,FRCS, ASTS, Senior Consultant, Department of Surgical 14
Gastroentrology & HPB, Transplant, Care Hospitals, Visakhapatnam, Andhra 15
Pradesh, India, [email protected] 16
17
CORRESPONDING AUTHOR DETAILS 18
Venkata Sagar Puppala 19
49-36-16/5, F2, Galaxy Apartment, NGGO’s Colony, Akkayyapalem, sakhapatnam, 20
Andhra Pradesh, INDIA, 530016 21
Email: [email protected] 22
23
Short Running Title: Synchronous Biliary tree Tumours. 24
25
Guarantor of Submission : The corresponding author is the guarantor of 26
submission. 27
28
29
30
31
32
Manuscript Accepted Early View Article
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ABSTRACT 33
34
Introduction 35
Synchronous biliary tree and gall bladder cancers are rarely encountered and appear 36
in the literature. In this article ,we report an extremely rare presentation of a patient 37
with Distal common hepatic duct(CHD) ,proximal common bile duct(CBD) and 38
gallbladder(GB) cancer associated with anamolous pancreaticobiliary duct junction 39
(APBDJ) as primary tumours. 40
41
Case Report 42
A 40yrs male referred to us with RUQ pain, fever, jaundice and pruritis since 43
2weeks. PET-CT showed hypermetabolic polypoidal mass in the fundus of GB and a 44
periportal node. ERCP was done but guide wire couldn't be passed beyond mid 45
CBD. Impression of thight stricture at mid CBD ?Malignant.The patient planned for 46
surgery and the findings were neoplastic mass in fundus of the GB with 47
pericholedochal lymphadenopathy. There was another neoplastic mass in the CBD. 48
An extended cholecystectomy with extrahepatic CBD excision with a 49
pancreaticoduodenectomy with radical lymphadenectomy was performed. Intra-50
operative ultrasonography was done to rule out other lesions in the pancreas and 51
liver. Histopathology shows well defferentiated adenocarcinoma of GB and 52
adenocarcinoma of proximal CBD and Distal CHD ,stagging pT2 pN0 pMx. 53
54
Conclusion 55
Synchronous extra hepatic and gall bladder tumors are extremely rare ,their 56
etiopathogenesis has not been properly undestood and defined. Fujii et al reported 57
that 62.5% of synchronous double cancers and 100% of metachronous double 58
cancers of the biliary tract were associated with PBM. Biliary cancers with PBM are 59
thought to develop multicentrally, due to the effect of pancreatic juice reflux on the 60
mucosa of the biliary tract. 61
62
Keywords : Synchronous, biliary tree, adenocarcinoma, anomalous 63
pancreaticobiliary maljunction 64
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INTRODUCTION 65
Synchronous biliary tree and gall bladder cancers are rarely encountered and appear 66
in the literature. Cholangiocarcinoma is a malignant neoplasm arising from the 67
epithelium of the biliary tract, histologically described by Durand-Fardel in 1840. 68
Cholangiocarcinomas are anatomically classified as originating from the intra- and 69
extrahepatic biliary epithelium[1]. Extrahepatic cholangiocarcinomas are further 70
separated into upper-third or perihilar (including the confluence of the right and left 71
biliary ducts) tumors; middle-third tumors; and distal bile duct tumors. About 5% of 72
cholangiocarcinomas may be multifocal[2]. Different histologies, tumor locations, and 73
treatment techniques all affect the ultimate outcome. In this article, we report an 74
extremely rare presentation of a patient with Distal common hepatic duct (CHD), 75
proximal common bile duct (CBD) and gallbladder (GB) cancer as primary tumours 76
77
CASE REPORT 78
A 40-year-old male presented with a 2-weeks history of right upper quardrant pain, 79
fever, history of weight loss exceeding 20 pounds. Initial evaluation revealed 80
obstructive jaundice with intractable pruritus. Physical examination was significant 81
for scratch marks, jaundice in the absence of hepatomegaly or 82
splenomegaly but there was palpable globular mass propably distended gall bladder. 83
Murphy’s sign was negative. 84
85
Diagnostic work-up 86
Initial laboratory data revealed a white blood cell count of 5,280 mm³, hemoglobin 87
concentration of 10g/dL, platelet count of 286,000 mm³, total bilirubin 88
level of 16.7 mg/dL (direct bilirubin level = 13 mg/dL), albumin level of 3.2 g/dL, 89
aspartate aminotransferase level of 119 U/L, alanine aminotransferase level of 99 90
U/L, alkaline phosphatase level of >700 U/L, γ-glutamyl transpeptidase level 91
of 374 U/L, and lactate dehydrogenase level of 783 U/L. The remainder of the 92
chemistry panel, renal function tests, and electrolytes were normal. The patient had 93
normal coagulation studies, a prothrombin time of 13.2 seconds, a partial 94
thromboplastin time of 34.6 seconds, and an international normalized ratio of 1.12. 95
His tumor markers revealed a CA19.9 level of >500 U/mL. 96
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A ultra sound revealed distended gall bladder with fundal mass and dilated intra 97
hepatic biliary radicles. A CT scan of the patient’s abdomen revealed evidence of 98
moderate-to-severe, right and left intrahepatic ductal dilatation; a mass in the fundus 99
of gall bladder 3-4 cm, portacaval lymph node compressing cbd and pancreatic 100
head; and no evidence of intrapancreatic duct dilatation. A work-up for metastatic 101
disease, which included a PET scan revealed (1)hypermetabolic polypoidasl mass 102
in fundus of gall bladder,(2)Hypermetabolic periportal node- metatastic nature 103
(Figure 1,2,3). Endoscopic retrograde cholangio-pancreaticogram was attempted but 104
it was failed as the guide wire couldn’t be progress in the common bile duct(Figure 105
4), and a differential diagnosis of periportal node obstructing CBD or malignant 106
stricture was made. 107
108
Treatment 109
The patient planned Radical cholecystectomy and peri portal nodal dissection. Right 110
Hockey stick incision given and it was found that there is neoplastic hard mass in 111
fundus of the gall bladder with pericholedochal lymphadenopathy. There was 112
another neoplastic mass in the Common bile duct (Figure 5). Portal vein was 113
adherent to the common bile duct (Figure 6). Intra-operative ultrasonography was 114
done to rule out other lesions in the pancreas and liver. Common bile duct 115
mobilization done from the portal vein and hepatic artery. Extended Duodenum 116
kocherization done. Dodenum mobilized till jejunum. Superior mesenteric vein 117
dissection done from pancreas. Finally a extended cholecystectomy including liver 118
segment 4b &5, along with excision of extrahepatic Common bile duct with a 119
pancreaticoduodenectomy and radical lymphadenectomy was performed. Finally 120
hepatico jejunostomy and pancreaticojejuostmy can be seen in figure 6. Final 121
resected specimen is seen in figure 7,8 grossly showed the fowling findings: 122
• Gall bladder with nodular exo-phytic tumour having a broad based 123
attachment spread over a base of about >4-5sq cm, surface nodular 124
• Cystic duct is normal smooth 125
• Irregularly elliptical/ oval tumour mass, with nodular surface, obstructing the 126
CHD & Proximal CBD, causing dilatation of both tubes. 127
• The distal CBD & prox. CHD are free from deposits, & showed normal surface 128
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• No deposits seen in attached piece of liver, pancreas, pancreatic duct, and 129
distal D & J. 130
• The other part of the specimen ie, nodal mass surrounding HA, para- aortic 131
LNs – are grossly red brown in colour, no macroscopic evidence of deposits. 132
Histology of the specimen:(Figure 10-16) 133
• Tumor: Well differentiated adenocarcinoma 134
• The tumor histo- morphology is similar in both locations, ie in Gall bladder & 135
Common Hepatic Duct (CHD)+Common Bile Duct (CBD) lesions 136
• MARGINS: The tumor mass seen invading up to the muscle layer, not 137
invading the serosa of the gall bladder. The second mass in the CBD& CHD 138
also showed invasion up to the muscular layer, no invasion detected in the 139
serosa. 140
• The gall bladder mucosa near to the tumour & CBD+CHD mucosa showed 141
dysplastic changes 142
• The cystic duct, LNs at cystic duct, the attached liver, head of pancreas, 143
distal CBD, proximal CHD are free from tumor deposits. 144
• The nodal mass surrounding HA, para-aortic LNs, nodal mass all are free 145
from tumor deposits. 146
No lympho-vascular, perineural deposits detected. 147
Histological Diagnosis and staging: 148
• Synchronous well differentiated adenocarcinoma of gall bladder, (intestinal 149
type, multi-focal adeno Ca), with 2nd focus in distal CHD & proximal CBD- 150
(pT2) 151
• Invasion of the tumor seen up to the muscular layer, no deposits/ penetration 152
of the serosa seen. 153
• The distal CBD, proximal CHD, attached portion of liver, head pf pancreas, 154
pancreatic duct, ampulla of Vater, duodenum jejunum are free from tumor 155
deposits. 156
• All the LNs sent from different locations are free from deposits, (pN0). 157
Histological staging, (TNM): pT2, pN0, pMx. 158
Post operative period was uneventful and patient discharged from hospital in 8 days 159
after surgery. 160
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On 6 months followup two abdominal ultra sound was done twice and found to be 161
normal. 162
163
DISCUSSION 164
Synchronous extra hepatic and gall bladder tumors are extremely rare, their 165
etiopathogenesis has not been properly understood and defined. Fujii et al reported 166
that 62.5% of synchronous double cancers and 100% of metachronous double 167
cancers of the biliary tract were associated with anamolous pancreaticobiliary duct 168
junction but not established in this patient. Biliary cancers with anamolous 169
pancreaticobiliary duct junction are thought to develop multicentrally, due to the 170
effect of pancreatic juice reflux on the mucosa of the biliary tract. However, there are 171
increasing reports suggesting that they are more common than earlier reported, 172
probably due to inadequate sampling of the gall bladder when performing a resection 173
for extrahepatic bile duct malignancies. Their occurrence is seen to be approximately 174
5-7.4% , in Japan, where anamolous pancreaticobiliary duct junction is an important 175
etiology. This association with APBDJ is not an absolute necessity or rule 176
Gertsch et al. have suggested that the best way to say synchronicity by applying the 177
following criteria, viz.: 1) No direct continuity between the two tumors, 2) a growth 178
pattern typical of a primary tumor, 3) and clear histologic differences between the 179
two tumors. These criteria, however, may not be sufficient to confirm synchronicity, 180
especially in malignancies of the extrahepatic biliary tree. Kurosaki et al. have in fact 181
advised the mapping technique to confirm the distinctness of the two lesions. 182
Allelic loss or deletions at the TP53 locus (17p13) reported ranging from 58% to 92% 183
in gallbladder cancer have been noted at histologically normally appearing 184
epithelium near gallbladder cancer. The p53 gene mutations have been closely 185
associated with determination of clonality . Hori et al. concluded that more studies 186
on p53 mutations are needed in synchronous malignancies unrelated to APBDJ. 187
While studying chromosome 3p, Riquelme et al., too, have demonstrated a very high 188
frequency of GBC methylation in SEMA3B (92%) and FHIT (66%). The time thus 189
seems opportune to explore the role of epigenetics in field cancerization of 190
gallbladder cancer. 191
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By newer imaging technique, intraductal ultrasonography, has the ability to visualize 192
the bile ducts and evaluate the degree of nodal involvement[3] Cholangiographic 193
techniques, such as magnetic resonance cholangiography, endoscopic retrograde 194
cholangiopancreatography (ERCP), and percutaneous transhepatic cholangiography 195
(PTC), are used for detailed bile-duct imaging and (in combination with magnetic 196
resonance angiography) accurate staging, as well as evaluation of vascular invasion 197
by the tumor[2]. ERCP demonstrates the site of obstruction by direct retrograde dye 198
injection and excludes ampullary pathology by endoscopic evaluation. Brush 199
cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide 200
material for histologic studies. Palliative stent placement relieves biliary obstruction 201
and can be performed at the time of evaluation. In proximal lesions, in which both the 202
right and left hepatic ducts are obstructed, PTC may provide access to the lesion, 203
drainage of the obstruction, and a means of obtaining material for cytologic 204
studies[3,4,5]. 205
Surgical resection gives the better outcome and is associated with a survival benefit, 206
especially when resection margins are free from cancerous infiltration [6,7]. Adjuvant 207
radiotherapy is given to improve local tumor control after complete resection and has 208
a variable effect on the overall survival rate. Several series have shown an increase 209
in the duration of median survival, from 8 months with surgery alone to more than 19 210
months with postoperative irradiation. Intraluminal brachytherapy and intraoperative 211
radiotherapy have provided a survival advantage and significant palliation over stent 212
placement or bypass surgery alone in patients with medically inoperable or 213
unresectable tumors[8,9]. The rate of margin-negative resection increases to 100% 214
with preoperative chemoradiation, compared with 54% without preoperative 215
chemoradiation therapy, suggesting that preoperative chemoradiation therapy 216
produces a significant antitumor response and improvement in tumor-free resection 217
margins [10,11]. 218
Objective response rates with 5-fluorouracil (5-FU) and 5-FU–based combination 219
therapies range from 0% to 34%, and median survival is less than 6 months. Higher 220
response rates are seen with either infusional administration of 5-FU or leucovorin-221
modulated 5-FU therapy, but whether such treatment translates 222
into better survival is unclear. Gemcitabine (Gemzar) combined with cisplatin 223
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as first-line chemotherapy has been evaluated as well. Overall response rates with 224
gemcitabine alone range from 13% to 60%, but median survival is only 8 months[2]. 225
More favorable results are seen when gemcitabine is combined with cisplatin, 226
capecitabine (Xeloda), irinotecan, or oxaliplatin (Eloxatin)[12,13,14].12–14 In two 227
representative published studies with a total of 72 patients (60 with 228
cholangiocarcinoma), the overall objective response rates were 28% and 35%, and 229
median survival was 9 and 11 months, respectively[12,15]. 12,15 In a group of 33 230
untreated patients with advanced biliary cancer and a good performance status, 231
using gemcitabine (1,000 mg/m2) on day 1 every 2 weeks and oxaliplatin (100 232
mg/m2) on day 2, resulted in a response rate of 36% and a median overall survival 233
of 15.4 months. The patients generally tolerated the regimen well [7,13]. 234
Orthotopic liver transplantation is considered for some patients with proximal tumors 235
who are not candidates for resection because of the extent of tumor spread in the 236
liver[12].Liver transplantation may have a survival benefit over palliative 237
treatments, especially for early-stage tumors. A 5-year survival rate greater 238
than 80% has been seen in selected transplant patients[8]. It is essential that 239
complete removal of the tumor should be the goal in patients capable of withstanding 240
a major resection. 241
242
CONCLUSION 243
Common risk factors for occurrence of synchronous Ca. In biliary tree are Gallstones 244
disease, anomalous pancreatic bile duct junction (APBDJ), Hepato-biliary infections 245
by parasites, (liver flukes). The Possible explanations for synchronous occurrence 246
could be Local spread, Metastasis, Multi focal origin. The majority of cases of 247
synchronous malignancies reported are from Japan, where malignancies are usually 248
associated with anomalous pancreatic bile duct junction (APBDJ). This association 249
with APBDJ is not an absolute necessity or rule. There are no very well approved 250
criteria for differentiating between “synchronous primaries and metastasis” these are 251
still being developedThe good method of differentiating the above possibilities are, 252
by applying the following criteria, 253
• No direct continuity between the two tumors being described 254
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• A growth pattern, in all the ways esp. histological appearance criteria, 255
typical of a primary tumor 256
• Presence of predisposing factors in the site involved 257
In the case of field cancerization, the phenotype is a result of a molecular event 258
affecting multiple cells separately and independently of each other, or a single 259
molecular event in a single clonal progenitor that leads to widespread clonal 260
expansion or an alternative means of undergoing lateral spread across the mucosa. 261
The p53 gene mutations have been closely associated with determination of 262
clonality. Allelic loss or deletions at the TP53 locus (17p13) reported ranging from 263
58% to 92% in gallbladder cancer more studies on p53 mutations are needed in 264
synchronous malignancies unrelated to APBDJ. 265
Coming back to present case, as both lesions are morphologically, histologically look 266
alike, and occur in the biliary tree in close proximity. The gall bladder mucosa and 267
CBD mucosa showed “dysplasia”, indicating field cancerization – giving chance for 268
occurrence of multiple primary tumors. It is concluded as “synchronous multifocal 269
origin”. 270
271
CONFLICT OF INTEREST 272
There is no conflict of interest in the given article. 273
274
AUTHOR’S CONTRIBUTIONS 275
Author 1 has been the sole responsible for the management of the patient and the 276
article has been written by the author 1. Author 2 has made corrections needed in 277
the article. 278
279
REFERENCES 280
1. Boris R.A. Blechacz, et.al.Cholangiocarcinoma. Clin Liver Dis 2008;12: 131–281
150. 282
2. Seema Naik, et.al. Synchronous hilar cholangiocarcinoma and gallbladder 283
cancer. COMMUNITY ONCOLOGY. August 2008; vol 5 (8): 447-451. 284
3. Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ. The utility of CA 19-285
9 in the diagnoses of cholangiocarcinoma in patients without primary 286
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sclerosing cholangitis. Am J Gastroenterol 2000; 95:204–207. 287
4. Ahrendt SA, Cameron JL, Pitt HA. Current management of patients with 288
perihilar cholangiocarcinoma. Adv Surg 1996; 30:427–452. 289
5. Rumalla A, Baron TH. Evaluation and endoscopic palliation of 290
cholangiocarcinoma: management of cholangiocarcinoma. Dig Dis 1999; 291
17:194–200. 292
6. Chamberlain RS, Blumgart LH. Hilar cholangiocarcinoma: a review and 293
commentary. Ann Surg Oncol 2000;7:55–66. 294
7. Anderson C, Pinson SC, Berlin J, et al. Diagnosis and treatment of 295
cholangiocarcinoma. Oncologist 2004;9:43–47. 296
8. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinoma: 297
postoperative radiotherapy does not improve survival. Ann Surg 1995; 298
221:788–797. 299
9. McMasters KM, Tuttle TM, Leach SD, et al. Neoadjuvant chemoradiation for 300
extrahepatic cholangiocarcinoma. Am J Surg 1997; 174:605–608. 301
10. Lillemoe KD, Cameron JL. Surgery for hilar cholangiocarcinoma: the Johns 302
Hopkins approach. J Hepatobil Pancreat Surg 2000; 7:115–121. 303
11. Serafini FM, Sachs D, Bloomston M, Carey LC, Murr MM, Rosemurgy AS. 304
Location, not staging, of cholangiocarcinoma determines the role for adjuvant 305
chemoradiation therapy. Am Surg 2001; 67:839–843. 306
12. Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann Oncol 307
2005;16(suppl 2):93–96. 308
13. Andre T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with 309
oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR 310
study. Ann Oncol 2004; 15:1339–1343. 311
14. Knox J, Hedley D, Oza A, et al. Combining gemcitabine with capecitabine in 312
patients with advanced biliary cancer: a phase II trial. J Clin Oncol 2005; 313
23:2332–2338. 314
15. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with 315
oxaliplatin compared with gemcitabine alone in locally advanced or metastatic 316
pancreatic cancer: results 317
318
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FIGURE LEGENDS 319
320
Figure 1: PET CT Sagital showing hyperechoic mass in the fundus of gall bladder 321
and Intra hepatic biliary dilatation. 322
323
Figure 2: PET CT Axial showing hyperechoic mass in gall bladder. 324
325
Figure 3: PET CT showing high SUV value uptake in Gall bladder fundus. 326
327
Figure 4: Endoscopic retrograde cholngiogram showing guide wire which is getting 328
coiled in distal common bile duct due to further ? malignan stricture or ? perinodal 329
mass obstructing common bile duct. 330
331
Figure 5: Intra operative finding showing distended all bladder and dilated common 332
bile duct with mass. 333
334
Figure 6: Intra operative finding of Portal vein adherent to common bile duct. 335
336
Figure 7: Final Anastomosis after resection showing hepaticojejunostomy and 337
pancreatico jejunostomy 338
339
Figure 8: Resected Specimen showing gall bladder with mass and wedge resected 340
liver and dilated common bile duct with mass , duodenum with head os pancreas 341
and proximal jejunum. 342
343
Figure 9: Specimen(cut section) showing mass arising from fundus of gall blabber 344
and mass in common dile duct. There is a anomalous pancreatico-biliary duct 345
junction small in length and diameter is also small. 346
347
Figure 10: Histology slide showing Gall bladder mucosa with dysplasia. 348
349
Figure 11: Microscopic pictures- gallbladder mass, 5x 350
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Figure 12: Microscopic pictures- gallbladder mass, 10x 351
352
Figure 13: Histology slide showin Common bile duct mucosa showing dysplasia 353
354
Figure 14: Microscopic pictures- CBD mass, 5x 355
356
Figure 15: Microscopic pictures- CBD mass, 10x 357
358
Figure 16: Serosa of CBD & pancreas 5x 359
360
Figure 17: Lymphnode at cystic duct 361
362
FIGURES 363
364
365
366
Figure 1: PET CT Sagital showing hyperechoic mass in the fundus of gall bladder 367
and Intra hepatic biliary dilatation. 368
369
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370
371
Figure 2: PET CT Axial showing hyperechoic mass in gall bladder. 372
373
374
375
Figure 3: PET CT showing high SUV value uptake in Gall bladder fundus. 376
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377
378
Figure 4: Endoscopic retrograde cholngiogram showing guide wire which is getting 379
coiled in distal common bile duct due to further ? malignan stricture or ? perinodal 380
mass obstructing common bile duct. 381
382
383
Figure 5: Intra operative finding showing distended all bladder and dilated common 384
bile duct with mass. 385
386
387
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388
389
Figure 6: Intra operative finding of Portal vein adherent to common bile duct. 390
391
392
393
Figure 7: Final Anastomosis after resection showing hepaticojejunostomy and 394
pancreatico jejunostomy 395
396
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397
398
Figure 8: Resected Specimen showing gall bladder with mass and wedge resected 399
liver and dilated common bile duct with mass , duodenum with head os pancreas 400
and proximal jejunum. 401
402
403
404
Figure 9: Specimen (cut section) showing mass arising from fundus of gall blabber 405
and mass in common dile duct. There is a anomalous pancreatico-biliary duct 406
junction small in length and diameter is also small. 407
408
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409
410
Figure 10: Histology slide showing Gall bladder mucosa with dysplasia. 411
412
413
414
Figure 11: Microscopic pictures- gallbladder mass, 5x 415
416
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417
418
Figure 12: Microscopic pictures- gallbladder mass, 10x 419
420
421
422
Figure 13: Histology slide showin Common bile duct mucosa showing dysplasia 423
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424
425
Figure 14: Microscopic pictures- CBD mass, 5x 426
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427
428
Figure 15: Microscopic pictures- CBD mass,10x 429
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430
431
Figure 16: Serosa of CBD & pancreas 5x 432
433
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435
436
437
438
439
440
441
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443
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444
445
Figure 17: Lymphnode at cystic duct 446