Journal Name: International Journal of Hepatobiliary and ... Sajid Muhammad Tanveer 1, 7 Hussain...

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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 (IJHPD)

Type of Article: Original Article

Title: Incidental gall bladder cancer; missing links in Pakistani population

Authors: Sajid Muhammad Tanveer, Hussain Syed Mukarram, Hashmi Shoaib Nayyar,

Mustafa Qurat Ul Ain, Shaheen Neelofar

doi: To be assigned

Early view version published: June 22, 2016

How to cite the article: Tanveer SM, Mukarram HS, Nayyar HS, Ain MQU, Neelofar S.

Incidental gall bladder cancer; missing links in Pakistani population. Forthcoming 2016.

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TYPE OF ARTICLE: Original Article 1

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TITLE: Incidental gall bladder cancer; missing links in Pakistani population 3

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AUTHORS: 5

Sajid Muhammad Tanveer 1, 6

Hussain Syed Mukarram2, 7

Hashmi Shoaib Nayyar3, 8

Mustafa Qurat Ul Ain4, 9

Shaheen Neelofar5 10

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AFFILIATIONS 12

1MBBS, FCPS, Assistant Professor & Classified surgical specialist, Department of 13

General and Laparoscopic surgery, Combined Military Hospital Rawalpindi, Punjab, 14

Pakistan, [email protected] 15

2MBBS, FCPS, Associate professor & Head of department, Department of General 16

and Laparoscopic surgery, Combined Military Hospital Rawalpindi, Punjab, Pakistan, 17

[email protected] 18

3MBBS, FCPS, FRCP, Professor & Head of department, department of 19

histopathology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, 20

[email protected] 21

4MBBS, Senior Registrar, department of chemical pathology, Armed Forces Institute 22

of Pathology, Rawalpindi, Pakistan, [email protected] 23

5MBBS, Senior medical officer, Department of General and Laparoscopic surgery, 24

Combined Military Hospital Rawalpindi, Punjab, Pakistan, [email protected] 25

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CORRESPONDING AUTHOR DETAILS 27

Muhammad Tanveer Sajid 28

C/o Hafiz Ghulam Mustafa Ezzy traders Hakeem jee building Jinnah road 29

Abbottabad, KPK, Pakistan, 22010 30

Email: [email protected] 31

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Short Running Title: Incidental gallbladder cancer in Pakistan 33

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ABSTRACT 67

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Aims 69

To determine frequency of incidental gallbladder cancer (IGBC) in Pakistani 70

population, its demographic/histopathological features and type of surgical 71

resections performed. 72

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Methods 74

This Observational study was conducted at Combined Military Hospital (CMH)/ 75

Armed Forces Institute of Pathology (AFIP) Rawalpindi, Pakistan from July 2009 to 76

July 2015. Clinical as well as pathological records of all patients who underwent 77

laparoscopic (LC) / open cholecystectomy (OC) were reviewed and data was 78

obtained regarding IGBC and benign gall bladder pathology (BP). Patients 79

diagnosed with cancer underwent staging investigations and were offered definitive 80

surgery. Overall frequency and clinicopathological features of IGBC were studied. 81

82

Results 83

One hundred and sixty four patients out of 10549 had IGBC (1.55%). Mean age of 84

presentation in IGBC and BP patients was 59.23 ± 12.17 and 45.73±13.11 years 85

respectively (p value <0.001). Cancer patients had significantly more comorbid 86

(73.17% vs. 39.43%, p value <0.001) and larger stones (p value <0.001). 87

Histopathology revealed adenocarcinoma in 148 (90.24%), adenosquamous 88

carcinoma in 08 (4.88%), undifferentiated in 04 (2.44%), squamous cell carcinoma in 89

02 (1.22%), sarcoma and melanoma in one patient each (0.61%). Most of the tumors 90

were well differentiated (36.59%) and liver was most commonly infiltrated organ 91

(52.44%). Thirty four patients had stage I, 38 stage II, 49 stage III and 43 had stage 92

IV cancer (20.73%, 23.17%, 29.88%, 26.22% respectively). Surgical resection 93

included no further treatment in 31 patients as cholecystectomy proved adequate 94

vis-à-vis stage, extended cholecystectomy in 03 patients (1.83%), radical 95

cholecystectomy in 17 (10.37%), pancreaticoduodenectomy (Whipple) in 06 (3.66%), 96


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palliation/symptomatic management in 42 patients (25.61%) while 65 patients 97

(39.63%) refused surgery. Adequate lymphadenectomy was performed only in 50 98

(30.49%) patients while 44 (26.83%) showed positive resection margins. 99

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Conclusion 101

IGBC must be kept in mind while performing cholecystectomy and every specimen 102

should undergo routine histopathological examination. Radical surgery should be 103

offered and may improve outcome in carefully selected cases. 104

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Keywords: Incidental gall bladder cancer, cholecystectomy, Radical 106

cholecystectomy, benign pathology. 107

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INTRODUCTION 131

Gallbladder cancer (GBC), a highly lethal disease, is the 3rd most prevalent 132

gastrointestinal tract cancer with multifactorial etiology [1]. Strikingly distinct ethnic, 133

gender and geographical variations superimpose vague clinical picture, leading to 134

late diagnosis at advance stage usually in 7th decade and disastrous clinical course 135

with dismal survival rates, in spite of growing awareness and recent advances in 136

medical sciences [2]. 137

Global rates for GBC exhibit striking variability closely following worldwide 138

prevalence of gallstones, reaching epidemic levels for Mapuche Indians of Chile 139

(35/100000) followed by Hispanics, North American Indians and Japan [3]. Asian 140

subcontinent exhibits extraordinarily high disease incidence, where an increased 141

frequency of GBC occurs in northern Indian females (21.5/100000), Pakistani 142

females (13.8/100000) and Korean males [4]. 143

Adenoma-carcinoma sequence and dysplasia-carcinoma sequence are the most 144

common theories as exact etiology of GBC is still not known. Intrinsic genetic 145

predisposition orchestrated by environmental triggers play critical role in eliciting 146

cancer [5]. Gallstones represent most significant risk factor being present in 85% 147

cases [6]. Progression is frequently rapid and silent with early spread through 148

Vascular, lymphatic, intraperitoneal, neural and intraductal routes, most common 149

route being lymphatics. Metastases usually occur in liver, adjacent organs and 150

peritoneum, liver being involved in 76%-86% cases [7]. 151

Significant overlap between BP and GBC defies early detection leading to incidental 152

diagnosis in majority at advanced stage. Persistent right upper quadrant pain, 153

jaundice, anorexia, nausea and weight loss are most common symptoms while 154

palpable gallbladder is present in few only. Deranged liver functions represent most 155

common laboratory finding [8]. Though ultrasonography (USG) is most widely used 156

initial screening as well diagnostic tool, it lacks sensitivity and specificity for early 157

cancer. Other preferred investigations are endoscopic US (EUS), computerized 158

tomography (CT) scan, magnetic resonance cholangiopancreatography (MRCP) and 159

Fluorodeoxyglucose positron emission tomography (FDG-PET) [9]. Although there is 160


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currently no single tumor marker helping clinch diagnosis, promising one include 161

cancer antigen (CA) 242, CA125, and CA19-9. 162

Clinical and pathological staging is most important determinant dictating treatment 163

strategy and outcome. Adenocarcinoma is most common histopathological type and 164

immunohistochemistry helps differentiate difficult cases [10]. Early diagnosis and 165

radical surgical resection offers only chance of long-term survival. Unfortunately, 166

only 10% or so are resectable at the time of diagnosis. IGBC may be defined as a 167

malignancy detected only on histopathological examination without prior pre-168

operative suspicion of malignancy. Current study was performed to determine 169

frequency of IGBC in Pakistani population, its demographic as well as 170

histopathological features and type of surgical resections performed. 171

172

MATERIALS AND METHODS 173

After approval of Hospital Ethical Committee, clinical as well as pathological records 174

of all patients who underwent LC / OC at hepatobiliary department CMH / AFIP 175

Rawalpindi, a tertiary care referral center, from July 2009 till December 2015, were 176

studied. IGBC was defined as a malignancy detected only on histopathological 177

examination without prior pre-operative suspicion of malignancy. Only those cases 178

having complete clinical as well as pathological record were included. 179

Gall bladder disease was confirmed through history, physical examination, laboratory 180

tests and USG. Choledocholithiasis was treated with pre-operative endoscopic 181

retrograde cholangiopancreatography (ERCP) and sphincterotomy/stenting after 182

confirmation of diagnosis with MRCP/CT scan while gallstone pancreatitis was also 183

treated with LC in the same admission after settlement of acute pancreatitis. LC was 184

initial procedure and converted to open when indicated or felt appropriate. Patients 185

diagnosed with IGBC on histopathological examination underwent staging 186

investigations and were staged according to 7th edition of the American Joint 187

Committee on Cancer (AJCC) Manual, 2010 [11]. Second stage surgical resection 188

was offered to those patients having stage II/III disease if R0 was deemed possible 189

while simple cholecystectomy was considered sufficient for Tis/T1a disease and 190

palliative care offered for stage IV disease. Extended cholecystectomy comprising of 191

cholecystectomy, resection of 2 cm non neoplastic liver tissue and skeletonization of 192


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hepatoduodenal ligament was performed in patients having T1b lesions. Radical 193

cholecystectomy consisting cholecystectomy, excision of medial liver segments 4b/5 194

and regional lymphadenectomy was carried out in T2 lesions while T3 lesions 195

underwent removal of additional extra hepatic bile ducts or other organs as dictated 196

by tumor spread. Palliation involved nonsurgical/surgical biliary drainage and 197

symptomatic relief accordingly [12]. Definitive surgery was performed by same 198

surgical team comprising two consultants and 05 registrars. 199

Analysis was carried out on formalin fixed and paraffin embedded (FFPE) tissue 200

specimens by single consultant over the period of the study as per college of 201

American pathologist (CAP) protocol version 3.1.0.2. Immunohistochemistry (IHC) 202

help was sought in difficult cases and Leica Microsystems®, USA Cytokeratin (CK) 7 203

and 20 were employed. CK 7 positivity while CK 20 negativity confirmed GBC [13]. 204

Cases diagnosed with IGBC were discussed in multidisciplinary team (MDT) meeting 205

comprising operating surgeon, histopathologist, gastroenterologist and oncologist. 206

All the data reviewed was entered into Statistical Package for Social Sciences 207

(SPSS) software version 21 for windows (SPSS Inc., Chicago, IL, USA) and 208

analyzed through its statistical package. Mean ± SD was used for quantitative data 209

like age while frequency and percentage was calculated for qualitative data. Chi-210

square and t-test were applied for categorical and numerical variables respectively. 211

P-value of less than < 0.05 was taken as significant. 212

213

RESULTS 214

Clinical as well as pathological records of 12578 patients were reviewed with regard 215

to demographic/ histopathological features and surgical intervention performed. 216

Complete data was available in 10549 (83.87%) patients and were included in 217

analysis. One hundred and sixty four patients out of 10549 had IGBC (1.55%). Mean 218

age of presentation in IGBC and BP patients was 59.23 ± 12.17 and 45.73±13.11 219

years respectively (p value <0.001). Male: female ratio was 1: 2.3 in IGBC and 1: 3.2 220

In BP patients (p value .042). Significantly more patients had concomitant disease in 221

cancer group (73.17% vs. 39.43%, p value <0.001). BMI was also significantly high 222

in cancer patients (29.73±3.44 IGBC & 28.19±3.99 BP, p value <0.001). Higher ASA 223

status was found in cancer patients which may be due to presence of comorbid/ 224


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advance age (p value <0.001). Single stone was present in 61(37.2%) patients while 225

multiple stones inflicted 91 (55.49%) cancer patients. Size of stone was significantly 226

larger in IGBC patients (2.23±1.36 cm vs 1.27±0.66 cm p value <0.001). Most of the 227

surgeries were performed by consultants while acute cholecystitis and symptomatic 228

cholelithiasis were most common presenting pathologies as depicted in Table 1. 229

One hundred and sixty four patients (114 female and 50 male) were diagnosed 230

histologically with IGBC. Among them, 93 (56.71%) patients presented with acute 231

cholecystitis while 64 (39.02%) with symptomatic cholelithiasis and 07 (4.27%) had 232

polyps. Majority had acute presentation while in 18 patients, length of disease was 233

not known. Anorexia was most common sinister symptom present in 53 (32.32%) 234

patients followed by weight loss in 52 (31.71%) and jaundice in 19 (11.59%) patients. 235

Family history of cancer was more commonly found in female patients. Significantly 236

more smokers with cancer were diagnosed as males (p value <0.001). Simple 237

cholecystectomy was performed in 72.81% while rest underwent biopsy only due to 238

intraoperative suspicion (Figure 1) as shown in Table 2. 239

Histopathological analysis revealed adenocarcinoma in 148 (90.24%) patients, 240

adenosquamous carcinoma in 08 (4.88%), undifferentiated in 04 (2.44%), squamous 241

cell carcinoma in 02 (1.22%), sarcoma and melanoma in one patient each (0.61%). 242

Fundus (42.1%) of gallbladder was most common site followed by Body and neck. 243

Most of tumors were well differentiated (36.59%) while 33.54% had poorly 244

differentiated tumors. IHC was performed in 65 (39.63%) patients to reach at correct 245

diagnosis. Thirty four patients had stage I (31 patients Tis / T1a while 03 had T1b 246

lesion), 38 stage II, 49 stage III and 43 had stage IV cancer (20.73%, 23.17%, 247

29.88%, 26.22% respectively) according to AJCC 7th edition. Surgical resection 248

included no further treatment in 31 patients, extended cholecystectomy in 03 249

(1.83%), radical cholecystectomy in 17 (10.37%), pancreaticoduodenectomy 250

(Whipple) in 06 (3.66%), palliation/symptomatic management in 42 (25.61%) patients 251

while 65 (39.63%) patients refused any sort of surgical intervention. Liver was most 252

common organ to be involved by tumor (86 subjects 52.44%). Only 50 patients 253

(30.49%) had adequate number of lymph node sent while in majority (55.49%) no 254

comment was found in histopathology report. Resection margins were positive in 44 255


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(26.83%) specimens while in 48 (29.27%) patients, margin status was not mentioned 256

(Table 3). 257

258

DISCUSSION 259

GBC is a highly lethal disease harboring dismal outcome. Cancer epidemiology 260

(frequencies, pattern of distribution and determinants) are of immense importance as 261

identification of risk factors provides insight into pathogenesis thus establishing 262

platform for effective preventive and treatment strategies [14]. Early diagnosis and 263

radical surgical resection is the only effective weapon in treatment armamentaria at 264

present [15]. 265

IGBC is a realistic hope allowing considerable leverage of tactical maneuverability as 266

disease stage is the most important determinant of surgical success [16]. Diagnosis 267

of IGBC remains enigma due to paucity of clinical features and inability of 268

investigations to identify the disease [17]. Recognizing important risk factors and 269

associated clinical jargons may provide clue for picking IGBC early [18]. 270

Current study focuses on frequency of IGBC at tertiary care referral center, its 271

demographic/histopathological variables and overview of definitive surgeries 272

performed. Clinical as well as pathological record of 10549 patients was studied. 273

IGBC was found in 164 patients (1.55%). Patients with IGBC were significantly older 274

than those having BP (59.23 ± 12.17 Vs. 45.73±13.11 years, p value <0.001). 275

Figures are in concordance with international literature as cancer usually affects 276

elderly female in 7/8th decade while cholelithiasis is a disease of 4th decade [19]. 277

Significantly more patients had concomitant disease in cancer group (p <0.001), 278

higher ASA status (p <0.001) and larger stones (p <0.001) conforming to reports of 279

various other authors [20]. Acute cholecystitis (56.7%) was most common 280

presentation while anorexia was most frequent sinister symptom present in 32.3% of 281

IGBC patients. Significantly more smokers with cancer were diagnosed as males (p 282

value <0.001); however, family history was more frequently found in female patients 283

which may confer to more prevalence of gallstones in females worldwide. Majority of 284

females were multipara (95.6%). Simple cholecystectomy was most frequent 285

operation performed while biopsy was performed in those having suspicion of 286

malignancy per operative. Histological diagnosis of malignancy was followed by 287


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staging investigations, discussion in MDT meeting and then treatment as per stage. 288

Number of cases increased with advancing years which may be due to more 289

surgeries being performed at our center. Histopathological analysis was performed in 290

all specimens regardless of diagnosis as per guidelines [21]. 291

Most common tumor found was adenocarcinoma (90.24%) followed by 292

adenosquamous carcinoma. Zhou et al. quoted that 93.1% patients in their series 293

had adenocarcinoma [22]. Most of tumors in our series were well differentiated and 294

fundus was most common site, the results are in concordance with study conducted 295

by Cui et al [23]. Majority of the patients had either stage II or III disease. 296

Surprisingly, most of the patients (36.6%) refused second stage surgery while radical 297

cholecystectomy was most common definitive surgical procedure performed in 17 298

patients (10.37%). Other surgeries performed included pancreaticoduodenectomy in 299

06, extended cholecystectomy in 03 and palliation in 42 patients. Simple 300

cholecystectomy proved adequate in 31 patients. IHC was performed in 62 (37.8%) 301

patients to reach at diagnosis. Liver was most common organ infiltrated by tumor. 302

Lymph node analysis revealed that majority had either none sent or inadequate 303

number which is also in concordance with international data [24]. Resection margins 304

were found negative in majority (37.8%), however, no comment was found in case of 305

48 (29.3%) patients. 306

Our results are consistent with international figures quotes worldwide [25, 26, 27]. A 307

study conducted by Zhou et al [22] showed a frequency of 2.06% while another 308

study by He et al [12] revealed higher age but similar findings as for as stage and 309

treatment strategies are concerned. Haq et al [28] conducted a study at Fauji 310

Foundation hospital, Rawalpindi Pakistan and showed frequency of 0.68%. A review 311

performed by Piccolo et al [24] showed that frequency of IGBC varied from 0.25%-312

3%. They also revealed that in most studies proper number of lymph nodes were 313

either not resected or not sent which is case with our study as well. A meta-analysis 314

involving 986 articles by Choi et al [8] found that most important clinical dilemma with 315

IGBC is decision of second stage surgery both at clinician as well as patient end. 316

Same dilemma is visible in our series where majority of patients refused definitive 317

surgery in spite of thorough counselling. Most of cancer patients had acute 318


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cholecystitis which is consistent with results quoted by You et al [13]. Most of female 319

cancer patients in our cohort were multipara as also reported by Chan et al [29]. 320

IGBC represent an important area of research as early diagnosis will considerably 321

affect morbidity as well as mortality. Alterations in oncogenes, tumor suppressor 322

genes, microsatellite instability and methylation of gene promoter areas act in 323

synergy with recurrent or chronic mucosal inflammation to induce cancer although 324

exact cause in not known [30]. Gallstones especially chronic one pose most 325

significant risk although other suspected culprits [31] are advance age, female sex, 326

positive family history, cholelithiasis, obesity (BMI>30), parasitic infestations, chronic 327

bacterial cholangitis especially by salmonella & helicobacter [32], porcelain 328

gallbladder, large polyps >10 mm, heavy metals exposure and abnormal 329

pancreaticobiliary duct junction [33] Clinical features are ominous but those 330

harboring clue include persistent right upper quadrant pain, jaundice, nausea and 331

weight loss [8]. Biochemical investigations are nonspecific. Ultrasound features that 332

may give rise to suspicion include Wall thickness >3 mm and enhanced vascularity. 333

Currently EUS along with fine needle aspiration cytology (FNAC) has become 334

modality of choice to distinguish benign from malignant lesion and stage disease [34] 335

CT Diagnostic features of GBC are heterogeneously enhanced wall area, irregular 336

distorted GB filled with mass and it determines accurately possibility of surgical 337

resection (93% for T stage). Multiplanar and 3D volume rendered CT is current 338

addition to diagnostic battery [35]. All-in-on MRI protocol (MRCP, MR angiography) 339

quite accurately detects bile duct or vascular invasion, with sensitivity and specificity 340

approaching 100%. Diffusion-weighted imaging (DWI) is revolutionizing the use of 341

MR [36]. PET/CT may have a promising role in the diagnosis of unsuspected 342

metastases thus changing staging and treatment early in the disease course [37]. 343

Although no current tumor marker is available but most promising is CA 242 which 344

may be regarded as marker of early infiltration [38]. Histopathology is current gold 345

standard for diagnosis and provides framework for future management options [21] 346

Staging is the most significant factor determining treatment and prognosis in short as 347

well as long term [39]. A minimum of three regional lymph nodes are required for 348

accurate “N” staging while adequate clearance requires at least 06 as per SEER 349

guidelines [3]. 350


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Surgery is the only cure available at present and options include simple 351

cholecystectomy (stage1/Tis, T1a), extended cholecystectomy (stage 1/T1b), radical 352

cholecystectomy (stage II/T2), major hepatic/ bile duct resection or 353

pancreaticoduodenectomy (stage III/T3) and palliation (surgical/nonsurgical) for 354

stage IV disease [27,40]. Regional lymphadenectomy is a must but currently 355

neglected part of oncological clearance [41]. Factors that may point towards sinister 356

diagnosis during surgery include thick wall, stiff uneven pale surface, miliary nodules, 357

enlarged regional lymph nodes, plastered atrophied GB, intraluminal nodules/mass 358

or local GB wall thickening and necrotic tissue/blood clot found in GB lumen [42] 359

There is still no effective adjuvant or neoadjuvant chemo radiotherapy for GBC 360

although combination chemotherapies and targeted molecular therapies are rapidly 361

emerging [43, 44]. 362

The results of this study should be interpreted with care as it was single center 363

study. Although small number of patients limited the accuracy of the study but low 364

incidence of GBC makes it difficult to acquire larger cohorts. Moreover, there was no 365

data reported regarding results of definitive surgery and patient survival thus missing 366

extremely important aspect. Larger multicenter studies are required to further extend 367

the results of our work. Various aspects of IGBC like risk factors, tumor markers and 368

survival rates need to be studied further. The results of current study will help us to 369

identify at risk patients and formulate guidelines for appropriate surgical intervention 370

in conjunction with oncologist/gastroenterologist feedback. 371

372

CONCLUSION 373

The clinical and radiologic diagnosis of GBC at early stage is challenging despite 374

recent advances in technology. A detailed clinical history, high index of suspicion, 375

good USG and competent histopathologist is the linchpin for early diagnosis. The 376

surgical strategy and prognosis differ strikingly according to T-stage and R0 377

resection is still the only chance of cure. Interdisciplinary collaboration among 378

surgeon, ultrasonologist, oncologist, endoscopy expert and histopathologist is 379

hallmark of improved vigilance and better long term outcome [45]. Prognosis is very 380

ominous due to high recurrence, morbidity and mortality. 381

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CONFLICT OF INTEREST 383

None disclosed. 384

385

Author Contribution 386

Muhammad Tanveer Sajid 387

Group 1-Conception and design, Acquisition of data, Analysis and interpretation of 388

data, 389

Group 2- Drafting the article, Critical revision of the article, 390

Group 3-Final approval of the version to be published 391

392

Syed Mukarram Hussain 393

Group 1-Conception and design, Acquisition of data, Critical revision of the article, 394


396

Shoaib Nayyar Hashmi 397

Group 1-Conception and design, Acquisition of data, Critical revision of the article, 398


400

Qurat ul Ain Mustafa 401

Group 1- Acquisition of data, Analysis and interpretation of data, 402

Group 2- Drafting the article 403


405

Neelofar Shaheen 406

Group 1-Acquisition of data, Critical revision of the article, 407


409

ACKNOWLEDGEMENTS 410

We are thankful to Dr Salman registrar histopathology and Dr Azhar for their kind 411

support. 412

413

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542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

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TABLES 572

573

Table 1: Demographic variables of IGBC and BP patients 574

575

Characteristics

Incidental gall bladder

cancer

(IGBC)

Benign Pathology

(BP)

P

value

Frequency Percentage Frequency Percentag

e

Male

Female

Male :female ratio

50

114

30.5

69.5

2457

7928

23.66

76.34

.042

1 : 2.3 1 : 3.2

Age in years 59.23 ± 12.17 45.73±13.11 .000

Concomitant

disease

Diabetes

mellitus

Hypertension

Ischemic heart

disease

Respiratory

disease

73.17% 39.43%

.000

71

34

14

01

43.3

20.7

8.5

0.6

1575

1890

420

210

14.88

17.86

3.97

1.98

Surgeon

Consultant

Resident

115

49

70.1

29.9

7151

3234

68.86

31.14

.729

BMI 29.73±3.44 28.19±3.99 .000

ASA status

I/II

III/IV

91

73

55.5

44.5

9305

1080

89.6

10.4

.000

Surgical anatomy

Single stone

61

37.2

1134

10.92

.000


of 27

Multiple stone

Size of the stone

91 55.48 6689 64.41

.000

2.23±1.36

1.27±0.66

Pre Op diagnosis

Ac cholecystitis

Symptomatic

cholelithiasis

Polyp

Other

93

64

07

0

56.7

39

4.3

0

1638

8117

105

525

15.77

78.16

1.01

5.06

.000

576

Abbreviations: Incidental gallbladder cancer IGBC, benign pathology BP, Body mass 577

index BMI 578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597


of 27

Table 2: Clinical features of IGBC patients with respect to gender 598

599

Characteristics Male Female P

valu

e

Frequenc

y

Percentag

e

Frequenc

y

Percentag

e

Clinical Presentation

Acute cholecystitis

Symptomatic cholelithiasis

Polyp

27

21

02

54

42

04

66

43

05

57.89

37.72

4.39

0.87

Duration of cholelithiasis

< 10 years

>10 years

Not Known

27

17

06

54

34

12

65

37

12

57

32.46

10.53

0.92

Sinister symptoms

Anorexia

Jaundice

Weight loss

15

06

15

30

12

30

38

13

37

33.33

11.40

32.46

0.67

0.91

0.76

Family history

Yes

No

04

46

08

92

27

87

23.68

76.32

0.18

Parity

Nulliparous

Multipara

05

109

4.39

95.61

Smoking

Yes

No

42

8

84

16

13

101

11.4

88.6

.000

Surgical procedure

Simple cholecystectomy

38

6

83

72.81

0.67


of 27

Biopsy 12 24 31 27.19

Suspicion of cancer during

surgery

No

Yes

38

12

6

24

83

31

72.81

27.19

0.67

Year wise cancer case

2009

2010

2011

2012

2013

2014

2015

3

4

4

6

9

12

12

6

8

8

12

18

24

24

12

16

15

16

15

17

23

10.53

14.03

13.16

14.03

13.16

14.91

20.18

0.39

600

Abbreviations: Incidental gallbladder cancer IGBC 601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617


of 27

Table 3: Histopathological features of IGBC with respect to gender 618

619

Characteristics Male Female P

value Frequency Percentag

e

Frequency Percentag

e

Tumor type

Adenocarcinoma

Adenosquamous

Undifferentiated

SCC

sarcoma

Melanoma

43

03

02

0

01

01

86

06

04

0

02

02

105

05

02

02

0

0

92.11

4.39

1.75

1.75

0

0

0.26

Tumor Site

Body

Fundus

Neck

21

20

09

42

40

18

39

49

26

34.21

42.98

22.81

0.59

Wall of gallbladder

Normal

Thick contracted

Proximal

Circumferential

Cystic duct margin

09

21

01

18

01

18

42

02

36

02

22

29

11

48

04

19.30

25.44

9.65

42.11

3.51

0.16

Type of growth

Ulcerated

Papillary

Polipoidal

17

16

17

34

32

34

50

29

35

43.86

25.44

30.70

0.47

Mucosa of gallbladder

Normal

Ulcerated

Hemorrhagic

15

19

16

30

38

32

27

46

41

23.68

40.35

35.96

0.68

Grade of tumor


of 27

Well differentiated

Moderately

differentiated

Poorly

differentiated

18

14

18

36

28

36

42

35

37

36.84

30.70

32.46

0.89

Stage of the disease

I

II

III

IV

12

13

14

11

24

26

28

22

22

25

35

32

19.3

21.93

30.70

28.07

0.72

Second stage surgery

None

Radical/extended

cholecystectomy

Whipple

Palliation

Refused by patient

10

05

03

11

21

20

10

6

22

42

21

15

03

31

44

18.42

13.58

2.63

27.19

38.60

0.75

Invasion

Lymphovascular

Perineural

Liver

23

29

23

46

58

46

48

56

63

42.11

49.12

55.26

0.64

0.29

0.27

Lymph node status

Not sent

<3

>3

Negative

27

11

4

8

54

22

8

16

64

25

10

15

56.14

21.93

8.77

13.16

0.64

Resection margins

Positive

Negative

Not mentioned

10

25

15

20

50

30

34

47

33

29.82

41.23

28.95

0.39

Immunohistochemistry


of 27

Yes

No

21

29

42

58

44

70

38.60

61.40

0.68

620

Abbreviations: Incidental gallbladder cancer IGBC 621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649


of 27

FIGURE LEGEND 650

651

Figure 1: (A, B, C) - Laparoscopic view of advance gallbladder cancer involving 652

peritoneum and liver. Biopsy performed that revealed poorly differentiated 653

adenocarcinoma. 654

655

FIGURE 656

657

658

659

660

Figure 1: (A, B, C) - Laparoscopic view of advance gallbladder cancer involving 661

peritoneum and liver. Biopsy performed that revealed poorly differentiated 662

adenocarcinoma. 663

Journal Name: International Journal of Hepatobiliary and ... Sajid Muhammad Tanveer 1, 7 Hussain...

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