Garcia P, Leal P, Alvarez H, et al.
Connective tissue growth factor immunohistochemical expression is associated with gallbladder cancer progression.
Arch Pathol Lab Med. 2013; 137(2):245-50 [PubMed]

CONTEXT: Gallbladder cancer (GBC) is an aggressive neoplasia associated with late diagnosis, unsatisfactory treatment, and poor prognosis. Molecular mechanisms involved in GBC pathogenesis remain poorly understood. Connective tissue growth factor (CTGF) is thought to play a role in the pathologic processes and is overexpressed in several human cancers, including GBC. No information is available about CTGF expression in early stages of gallbladder carcinogenesis. Objective.- To evaluate the expression level of CTGF in benign and malignant lesions of gallbladder and its correlation with clinicopathologic features and GBC prognosis.
DESIGN: Connective tissue growth factor protein was examined by immunohistochemistry on tissue microarrays containing tissue samples of chronic cholecystitis (n = 51), dysplasia (n = 15), and GBC (n = 169). The samples were scored according to intensity of staining as low/absent and high CTGF expressers. Statistical analysis was performed using the χ(2) test or Fisher exact probability test with a significance level of P < .05. Survival analysis was assessed by the Kaplan-Meier method and the log-rank test.
RESULTS: Connective tissue growth factor expression showed a progressive increase from chronic cholecystitis to dysplasia and then to early and advanced carcinoma. Immunohistochemical expression (score ≥2) was significantly higher in advanced tumors, in comparison with chronic cholecystitis (P < .001) and dysplasia (P = .03). High levels of CTGF expression correlated with better survival (P = .04).
CONCLUSIONS: Our results suggest a role for CTGF in GBC progression and a positive association with better prognosis. In addition, they underscore the importance of considering the involvement of inflammation on GBC development.

Sharma S, Bansal R, Agrawal N, et al.
Tuberculosis of the gall bladder clinically mimicking carcinoma--a case report.
J Indian Med Assoc. 2012; 110(6):402-3 [PubMed]

Gall bladder tuberculosis is very rare and curable but, sometimes can be confused with the clinical diagnosis like carcinoma. A 32-year-old male presented with acute pain in right abdomen for one month and fever off and on for two months. CT scan (whole abdomen) showed features suggestive of lymphadenopathy although peroperatively no significant lymph node could be identified but there were multiple white patches on gastrohepatic ligament and neck of gall bladder probably which were identified as lymph nodes on scanning. On the basis of peroperative findings clinician diagnosed it as a case of carcinoma gall bladder and was subjected to cholecystectomy. On histopathological examination it turned out to be tuberculosis gall bladder. Therefore tuberculosis of gall bladder can mimic carcinoma clinically.

Jain D, Chopra P
Metastatic renal cell carcinoma of gall bladder.
Saudi J Kidney Dis Transpl. 2013; 24(1):100-4 [PubMed]

Renal cell carcinoma (RCC) is well known for its propensity to metastasize to unusual sites. Metastasis to the gall bladder (GB) has been reported in the literature rarely. We herein report an interesting case of metastatic RCC, which presented with cholecystitis. Gall bladder is a rare site of metastasis of RCC. Polypoid lesions of the GB in patients who have a synchronous or a prior history of RCC should be considered as metastatic lesions. It needs to be differentiated from primary clear cell carcinoma of the GB with the help of immunohistochemistry.

Rai R, Sharma KL, Tiwari S, et al.
DCC (deleted in colorectal carcinoma) gene variants confer increased susceptibility to gallbladder cancer (Ref. No.: Gene-D-12-01446).
Gene. 2013; 518(2):303-9 [PubMed]

BACKGROUND AND AIM: GBC is a lethal and multifaceted disease. Deleted in colorectal carcinoma (DCC) is a well known tumor suppressor gene. Recently a small genome-wide association study (GWAS) identified DCC to be significantly associated with gallbladder cancer (GBC) susceptibility in a Japanese population sample. However, the study sample size was small and lacked independent replication. Therefore, the present study was carried out to replicate the association of two GWAS identified DCC SNPs (A>Grs4078288, C>Trs7504990) and two other SNPs (C>Grs2229080 and A>Grs714) previously associated with various cancers.
METHODOLOGY: The study was accomplished in 406 GBC cases and 260 healthy control samples from North India. Genotyping was carried out by PCR-RFLP and Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16 and functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP).
RESULT: We did not observe association with GWAS-identified SNPs of DCC but other SNPs showed significant association. In addition, a DCC haplotype Grs2229080-Ars4078288-Crs7504990-Ars714 conferred high risk of GBC in India. The haplotype associated risk was independent of gallstone, sex or tobacco usages which are well-known modifiers of GBC risk. Further analysis suggested DCC A>Grs714 as a major risk conferring SNP in the Indian population.
CONCLUSION: This study re-affirms the role of plausible tumor suppressor DCC variants, in gallbladder carcinogenesis and the risk haplotype may be explored as a useful marker for GBC susceptibility.

Russo S, Russo F, Maiello FM, et al.
Biphasic large cell neuroendocrine carcinoma--pure mucinous carcinoma of the gallbladder (MANEC): a unique combination.
Pathologica. 2012; 104(4):185-9 [PubMed]

INTRODUCTION: We report a case of primary combined large cell neuroendocrine carcinoma (LCNEC)--pure mucinous carcinoma of the gallbladder (MANEC)--which represents the first description of this entity.
METHODS: The patient is a 59-year-old Italian male who underwent cholecystectomy under a preoperative diagnosis of cholecystitis with gallstones and gallbladder tumour. During laparotomy, cholecystectomy, liver wedge resection and regional lymph node dissection were performed. The resected gallbladder showed a thickened wall, gallstones and a 4 cm gelatinous, cauliflower-like soft tissue mass.
RESULTS: Following surgery, the gallbladder tumour was diagnosed as a mixed endocrine-exocrine carcinoma. There was evidence of lymph node metastasis or direct liver invasion. The mucin-producing carcinoma was composed of poorly differentiated glandular cells with mucin lakes. The LCNEC was characterized by large cells with prominent nucleoli, coarse chromatin and a high mitotic rate. The cells showed an "organoid" growth pattern with rosette formation and frequent areas of necrosis. Chromogranin A, synaptophysin and CD56 were diffusely and strongly expressed.
DISCUSSION: This case may provide helpful insights regarding the histogenesis of this unusual combination of tumors: the concept of a collision tumor between two neoplasms that have arisen in adjacent areas may be the best explanation for its pathogenesis.

Li ML, Wang XF, Tan ZJ, et al.
Ethyl pyruvate administration suppresses growth and invasion of gallbladder cancer cells via downregulation of HMGB1-RAGE axis.
Int J Immunopathol Pharmacol. 2012 Oct-Dec; 25(4):955-65 [PubMed]

High mobility group box B1 (HMGB1)-receptor for advanced glycation end products (RAGE) axis has been previously known to be involved in carcinogenesis and development of multiple malignancies. Some studies have confirmed that Ethyl pyruvate (EP), a potent inhibitor of HMGB1, exerts the therapeutic effects on metastatic live tumor from gastric cancer. However, the effects and possible molecular mechanisms of EP on gallbladder cancer (GBC) need to be further explored. In the present study, human GBC cell lines (GBC-SD and SGC-996) were treated with different concentrations of EP. Then, the expression levels of HMGB1, RAGE and some transcription factors were identified by Real-time PCR and Western blot assays. Cell proliferative activities indicated by MTT assay, invasive potential by Transwell assay and cell apoptosis and cycle distribution were performed for functional analysis of GBC cell lines in vitro. As a result, EP decreased the expression of HMGB11, RAGE, PCNA and matrix metallopeptidase-9 (MMP-9), while it increased the expression of p53. Moreover, EP administration decreased GBC cell proliferation, inhibited the invasive potential, and induced apoptosis and cycle arrest in S phase in GBC cells. In conclusion, EP administration inhibits growth and invasion of gallbladder cancer cells possibly via down-regulation of the HMGB1-RAGE axis, suggesting that EP may play a critical role in the treatment of cancer in conjunction with other therapeutic agents.

Hughes NR, Bhathal PS
Adenocarcinoma of gallbladder: an immunohistochemical profile and comparison with cholangiocarcinoma.
J Clin Pathol. 2013; 66(3):212-7 [PubMed]

AIM: Cholangiocarcinomas display intestinal and pyloric gland metaplasia-cell phenotypes. Those that arise in chronically inflamed (fluke infested) bile ducts more frequently express the intestinal metaplasia-cell phenotype and p53 than sporadic cholangiocarcinomas. We wished to determine if adenocarcinomas of the gallbladder display a similar profile.
METHODS: Adenocarcinoma, adenoma, and dysplastic and metaplastic epithelia were studied in 55 gallbladders. Serial paraffin sections were stained for five foregut antigens characteristically present in pyloric gland metaplasia, three intestinal-specific antigens and p53. Antigen expression was compared with that shown by 65 fluke-associated and 47 sporadic cholangiocarcinomas.
RESULTS: Pyloric gland metaplasia in gallbladders with chronic cholecystitis invariably displayed the five foregut antigens. The frequency of expression of these five antigens by the gallbladder cancers and cholangiocarcinomas did not differ significantly. An intestinal goblet-cell marker and p53 were more frequently expressed by gallbladder carcinoma (59% and 45%, respectively) and fluke-associated cholangiocarcinoma (45% and 46%) than by sporadic cholangiocarcinoma (17% and 23%). K20 was more frequently expressed by gallbladder carcinoma (52%) than either fluke-associated (21%) or sporadic (17%) cholangiocarcinoma. Dysplastic epithelium and adenomas also displayed the pyloric gland and intestinal metaplasia-cell phenotypes. Cells staining for pyloric gland metaplasia-cell phenotypes were distinct from the intestinal metaplasia-cell phenotypes when present together in a gallbladder carcinoma, cholangiocarcinoma, dysplastic epithelium or adenoma.
CONCLUSIONS: Adenocarcinomas of gallbladder generally arise from a foregut cell lineage via a metaplasia-dysplasia-carcinoma sequence. A background of chronic inflammation increases the frequency of expression of an intestinal goblet-cell phenotype and p53 in the cancers.

Rossi M, Bencini L, Calistri M, et al.
Gallbladder neoplasm: a single institution experience according to the standard current management.
Minerva Chir. 2012; 67(5):389-97 [PubMed]

AIM: The aim of this paper was to determine if an aggressive surgical approach, with an increase in R0 resections, has resulted in improved survival for patients with gallbladder cancer. Gallbladder cancer is a silent disease, despite the efforts, the prognosis remains dismal. Consensus among surgeons regarding the indications for the extent of resection, lymph node dissection, port site resection, bile duct management has not been reached.
METHODS: A retrospective review of all patients with gallbladder cancer admitted during 12 years period was conducted. Sixteen patients were identified. Cases were divided into 2 cohorts surgical treated group (STG, N.=10) and non surgical treated group (NSTG, N.=6).
RESULTS: In NSTG the disease was metastatic (stage IV): liver (33.3%), peritoneum (50%), liver and peritoneum (16.7%). In STG 13 procedures were performed, 6 liver resection (2 en bloc resection, 2 bisegmentectomy, 2 wedge resection) 7 cholecystectomies. 6 R1, 7 R0 resections. All the liver resections were R0. 0% mortality, 30.7% of morbidity, all the complications were managed conservatively. Length of stay was 10 days for the STG, and 5 days for the NSTG. The median overall survival was 10 months (Std Error 2.381 CI 5.333-14.667), while in the STG 16 months (Std Error 6.275 CI 3.701-28.299) and in the NSTG was 7 months (Std Error 2.381 CI 5.337-14.667)
CONCLUSION: Whenever is possible radical resection with free margin (R0) must be achieved, being the only chance to treat efficiently.

Song W, Chen W, Zhang S, et al.
Successful treatment of gallbladder mixed adenoneuroendocrine carcinoma with neo-adjuvant chemotherapy.
Diagn Pathol. 2012; 7:163 [PubMed] Free Access to Full Article

Mixed adenoneuroendocrine carcinoma (MANEC) carcinomas rarely occur in the gallbladder. Here we reported a case of giant gallbladder unresectable mass with local liver invasion and omentum metastasis, which proved to be neuroendocrine carcinoma (NEC) by biopsy, received successful radical operation after neo-adjuvant chemotherapy plus somatostatin treatment. The patient showed good response as the neoplasm diminished dramatically and showed clear margin after 6 courses of treatment. A radical operation including cholecystectomy, hepatic wedge resection of the gallbladder fossa segment and lymph node of group 8a and 8p resection was performed successfully. Postoperative histopathological examination revealed neuroendocrine carcinoma mixed with adenocarcinoma in the gallbladder wall. Followed up showed no evidence of recurrence after 7 months of the operation. We suggest that neo-adjuvant chemotherapy may be beneficial to gallbladder mixed neuroendocrine carcinomas in an advanced stage which could also be advantageous to NEC of other organs. VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/2731892837743787.

Pedersen MR, Dam C, Rafaelsen SR
Ultrasound follow-up for gallbladder polyps less than 6 mm may not be necessary.
Dan Med J. 2012; 59(10):A4503 [PubMed]

INTRODUCTION: The management of ultrasound (US) detected gallbladder (GB) polyps remains a dilemma. The aim of this study was to assess the size distribution and the outcome of US follow-up of GB polyps.
MATERIAL AND METHODS: The study was approved by the Danish Data Protection Agency. US reports from patients examined with abdominal US in our department from January 2008 to the end of December 2009 were reviewed with a view to including all patients with GB polyps. Patients with GB polyps are routinely recommended a 2-year follow-up with US every six months. The GB polyp size was recorded at baseline and at subsequent US reports. Pathology reports were finally reviewed for all patients with GB polyps to check who underwent cholecystectomy and to register the histological diagnosis.
RESULTS: A total of 203 patients (median age 54 years; range 19-95 years) with GB polyps were included; 89 (44%) men and 114 (56%) women. The mean polyp size was 5 mm (range 2-40 mm). In 143 patients (70%) the GB polyp diameter was less than 6 mm. The first US follow-up was performed in 120 patients (59%), and only 31 (15%) completed the full 2-year US follow-up programme. Polyp size was stable in 100 patients, decreased in five patients, increased in eight and resolved in 15 patients. A total of 13 patients (6%) underwent cholecystectomy. Of the 203 patients, none showed neoplastic or malignant GB polyps.
CONCLUSION: We recommend that follow-up US of patients with GB polyps < 6 mm is avoided. Alternatively, the intervals between US follow-up of GB polyps < 6 mm may be extended.
FUNDING: not relevant.
TRIAL REGISTRATION: not relevant.

Kang MJ, Song Y, Jang JY, et al.
Role of radical surgery in patients with stage IV gallbladder cancer.
HPB (Oxford). 2012; 14(12):805-11 [PubMed] Article available free on PMC after 01/12/2013

OBJECTIVES: The role of surgery in stage IV gallbladder (GB) cancer is not well established. This study analyses prognostic factors in patients with stage IV GB cancer following surgical resection with the aim of identifying a subgroup of patients who might benefit from surgical resection.
METHODS: Clinicopathological details were analysed for 94 patients who were surgically treated for stage IV GB cancer at Seoul National University Hospital.
RESULTS: Median survival was 8 months in patients with either stage IVa or IVb disease. Sixteen patients (17.0%) underwent resection with curative intent, which increased overall survival over that in patients undergoing palliative surgery (P < 0.001). No survival benefit was seen following surgery with curative intent in patients with stage IVa disease (P = 0.764). Surgery with curative intent resulted in a survival benefit in patients with stage IVb disease, patients with an isolated liver metastasis near the GB bed (median survival: 31 months vs. 9 months; P < 0.001) and patients with limited numbers of peritoneal implantations (median survival: 20 months vs. 6 months; P = 0.002). Preoperative serum carcinoembryonic antigen (CEA) (P = 0.018), surgery with curative intent (P = 0.045) and adjuvant chemotherapy (P = 0.002) were independent prognostic factors in patients with stage IV GB cancer.
CONCLUSIONS: Surgery in combination with systemic chemotherapy may be beneficial in carefully selected patients with stage IVb GB cancer.

Ray R, Dey R, Chatterjee S, Guha P
Gallbladder adenomyomatosis with tubercular portal lymphadenopathy masquerading as gallbladder carcinoma.
Arab J Gastroenterol. 2012; 13(3):150-2 [PubMed]

Gallbladder carcinoma is more likely to occur in elderly females and the presence of periportal adenopathy often signifies advanced disease. Such patients are generally not taken up for surgery and are treated palliatively. Isolated periportal tuberculosis without the evidence of disease elsewhere is in itself a rarity. Here we present a case study of gallbladder mass suspected of being gallbladder carcinoma with portal lymphatic metastasis actually turning out to be that of gallbladder adenomyoma with periportal tuberculosis. This case illustrates how mass lesions of the gallbladder are commonly and falsely interpreted to be malignant.

Dursun N, Escalona OT, Roa JC, et al.
Mucinous carcinomas of the gallbladder: clinicopathologic analysis of 15 cases identified in 606 carcinomas.
Arch Pathol Lab Med. 2012; 136(11):1347-58 [PubMed]

CONTEXT: There are virtually no data in the literature regarding the incidence, patterns, and clinicopathologic characteristics of mucinous carcinomas (MCs) of the gallbladder (GB).
OBJECTIVE: To determine the incidence of mucinous differentiation in invasive GB carcinomas and the clinicopathologic characteristics of those that qualify as MC.
DESIGN: Primary invasive GB carcinomas (n  =  606) were reviewed for mucinous differentiation. Some degree of mucin production was identified in 40 cases (6.6%); however, only 15 (2.5%) were qualified for the World Health Organization definition of MC (stromal mucin deposition constituting >50% of the tumor).
RESULTS: The mean age was 65 years, and the female to male ratio was 1.1 (versus 3.9 for conventional pancreatobiliary-type GB adenocarcinomas; P  =  .04). A significant proportion of the cases (8 of 12, 67%) presented with the clinical picture and intraoperative findings that were interpreted as acute cholecystitis. Mean and median tumor sizes were larger than those of conventional adenocarcinomas (4.8 and 3.4 cm versus 2.9 and 2.5 cm, respectively; P  =  .01). Most (13 of 15, 87%) cases presented with pT3 tumors (versus 48% for ordinary GB carcinomas; P  =  .01). Two cases had almost an exclusive colloid pattern (>90% composed of well-defined stromal mucin nodules that contained scanty carcinoma cells, most of which were floating within the mucin). Eight cases were of mixed-mucinous type, showing a mixture of colloid and noncolloid patterns. Five others had prominent signet-ring cells, both floating within the mucin (which constituted >50% of the tumor by definition) and infiltrating into the stroma as individual signet-ring cells in some areas. Immunohistochemical analysis performed on the 7 cases that had available tissue revealed CK7 in 4 of 7 (57%), CK20 in 2 of 7 (29%), MUC1 in 4 of 7 (57%), MUC2 in 6 of 7 (86%), CDX2 in 1 of 7 (14%), MUC5AC in 6 of 7 (86%), MUC6 in 0 of 7 (0%), and loss of E-cadherin in 6 of 7 (86%). The MLH1 and MSH2 were retained in 6 of 7 cases (100%). Follow-up information was available for 13 cases: 11 (85%) died of disease (1-37 months) and 2 (15%) were alive (23 months and 1 month). Overall survival of MCs was significantly worse than that of conventional adenocarcinomas (13 versus 26 months; P  =  .01); however, that did not seem to be independent of stage.
CONCLUSIONS: Mucinous carcinomas constitute 2.5% of GB carcinomas. They present with an acute cholecystitis-type picture. Most MCs are a mixed-mucinous, not pure colloid, type. They are typically large and advanced tumors at the time of diagnosis and thus exhibit more-aggressive behavior than do ordinary GB carcinomas. Immunophenotypically, they differ from conventional GB adenocarcinomas by MUC2 positivity, from intestinal carcinomas by an often inverse CK7/20 profile, from pancreatic mucinous carcinomas by CDX2 negativity, and from mammary colloid carcinomas by a lack of MUC6. Unlike gastrointestinal MCs, they appear to be microsatellite stable.

Shi J, Liu H, Wang HL, et al.
Diagnostic utility of von Hippel-Lindau gene product, maspin, IMP3, and S100P in adenocarcinoma of the gallbladder.
Hum Pathol. 2013; 44(4):503-11 [PubMed]

Our recent study demonstrated the up-regulation of maspin, IMP3, and S100P and down-regulation of von Hippel-Lindau gene product (pVHL) in ductal adenocarcinoma of the pancreas. Distinction of adenocarcinoma of the gallbladder from benign/reactive glandular epithelium can be challenging if based on hematoxylin and eosin-stained sections alone. Immunohistochemical stains for pVHL, maspin, IMP3, and S100P were performed on 82 gallbladder specimens, including adenocarcinoma (n = 33) and normal/reactive gallbladder (n = 49). The results demonstrated (1) only 6.0% of adenocarcinoma cases were focally positive for pVHL, and all normal and most reactive cases (85%) were diffusely positive for pVHL; (2) maspin, IMP3, and S100P were positive in 100%, 81.8%, and 75.8% of adenocarcinoma cases, respectively; in contrast, 53.1%, 12.2%, and 30.6% of normal/reactive cases were only focally and weakly positive for maspin, IMP3, and S100P, respectively; and (3) 90.3% of adenocarcinoma cases were pVHL-negative and positive for 2 or more positive markers, whereas none of the benign/reactive cases showed this staining profile. This study demonstrates that the immunostaining profile of pVHL-/IMP3+/maspin+/S100P+ is useful in the distinction of adenocarcinoma of the gallbladder from normal/reactive conditions.

Jindal R, Jain A, Mittal A, Shirazi N
Sweet's syndrome as the presenting manifestation of gall bladder adenocarcinoma.
BMJ Case Rep. 2012; 2012 [PubMed]

Sweet's syndrome is a neutrophilic inflammatory dermatosis presenting with sudden onset tender red to purple papules and nodules, fever and neutrophilia. Gastrointestinal and urinary tract infections, pregnancy, inflammatory bowel disease, drugs and malignancy are some of the known aetiological factors. Paraneoplastic Sweet's syndrome accounts for 15-20% cases and thus forms an important subset. At times its onset helps in suspecting an underlying malignancy, thus making timely intervention possible. In the present case report Sweet's syndrome was the presenting feature of gall bladder adenocarcinoma; an association that has been rarely reported before.

Li J, Yang ZL, Ren X, et al.
ILK and PRDX1 are prognostic markers in squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder.
Tumour Biol. 2013; 34(1):359-68 [PubMed]

Although the incidence of gallbladder cancers is low, they are highly aggressive tumors. Squamous cell/adenosquamous carcinoma (SC/ASC) is a rare subtype of gallbladder cancer. The clinical characteristics of SC/ASC have not been well documented, and no prognosis marker has been identified. In this study, we examined integrin-linked kinase (ILK) and peroxiredoxin-1 (PRDX1) expression in 46 SC/ASCs and 80 adenocarcinomas (ACs) by using immunohistochemistry and analyzed their correlations with clinicopathological characteristics. We demonstrated that positive ILK and PRDX1 expressions were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and invasion of SC/ASC and AC. Univariate Kaplan-Meier analysis showed that positive ILK and PRDX1 expressions were closely associated with decreased overall survival in both SC/ASC (p < 0.001 and p = 0.005, respectively) and AC (p < 0.001) patients. Multivariate Cox regression analysis showed that positive ILK and PRDX1 expressions were an independent poor prognostic predictor in both SC/ASC and AC patients. We also revealed a similar significance of differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical curability with survival in SC/ASC and AC patients. Our study suggested that positive ILK and PRDX1 expressions are closely related to the progression and poor prognosis of gallbladder cancer.

Shen CM, Niu GC, Cui W, et al.
The improvement of surgical treatment for patients with gallbladder cancer: analysis of 208 consecutive cases over the past decade.
J Gastrointest Surg. 2012; 16(12):2239-46 [PubMed]

OBJECTIVES: The aim of this study was to determine if there has been improvement in survival for patients with gallbladder cancer treated with surgical procedures.
METHODS: A retrospective review of all patients with gallbladder cancer admitted during the past 11 years was conducted. The patients were categorized into two periods: period 1, from 1 January 2000 to 31 December 2005 (group 1, n = 77); and period 2, from 1 January 2006 to 31 December 2010 (group 2, n = 131).
RESULTS: The two groups have similar age, sex distribution, and symptoms. There were more patients with advanced stage in group 2 (P = 0.001). And patients in group 2 were treated with more aggressive surgical procedures compared with group 1. Patients of group 2 had a better surgical outcomes and longer 5-year overall survival (9 % vs. 19 %, P = 0.040) and disease-free survival (P = 0.017). Median survival in group 1 was 14.7 months, while in group 2 it was 22.3 months. Patients underwent R0 resection in group 2 had better survival than that in group 1 (P = 0.009), while they had similar survival for those who underwent non-R0 resection in both periods (P = 0.108).
CONCLUSIONS: A significant improvement of disease-free survival and long-term survival results was observed in the past decade.

Adsay NV, Bagci P, Tajiri T, et al.
Pathologic staging of pancreatic, ampullary, biliary, and gallbladder cancers: pitfalls and practical limitations of the current AJCC/UICC TNM staging system and opportunities for improvement.
Semin Diagn Pathol. 2012; 29(3):127-41 [PubMed]

Tumors of the ampulla-pancreatobiliary tract are encountered increasingly; however, their staging can be highly challenging due to lack of familiarity. In this review article, the various issues encountered in staging of these tumors at the pathologic level are evaluated and possible solutions for daily practice as well as potential improvements for future staging protocols are discussed. While N-stage parameters have now been well established (the number of lymph nodes required in pancreatoduodenectomies is 12), the T-staging has several issues: for the pancreas, the discovery of small cancers arising in intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) necessitates the creation of substages of T1 (as T1a, b, and c); lack of proper definition of "peripancreatic soft tissue" and "common bile duct involvement" (as to which part is meant) makes T3 highly subjective. Increasing resectability of main vessels (portal vein) brings the need to redefine a "T" for such cases. For the ampulla, due to factors like anatomic complexity of the region and the under-appreciation of three-dimensional spread of the tumors in this area (in particular, the frequent extension into periduodenal soft tissues and duodenal serosa, which are not addressed in the current system and which require specific grossing approaches to document), the current T-staging lacks reproducibility and clinical relevance, and therefore, major revisions are needed. Recently proposed refined definition and site-specific subclassification of ampullary tumors highlight the areas for improvement. For the extrahepatic bile ducts, the staging schemes that use the depth of invasion may be more practical to circumvent the inconsistencies in the histologic layering of the ducts; better definition of terms like "periductal spread" is needed. For the gallbladder, since many gallbladder cancers are "unapparent" (found in clinically and grossly unsuspected cholecystectomies), establishing proper grossing protocols and adequate sampling are crucial. Since the gallbladder does not have the distinct layering of the other gastrointestinal organs, the definitions of Tis/T1a/T1b lack practicality, and therefore, "early gallbladder carcinoma" category proposed in high-risk regions may have to be recognized instead. Involvement of the Rokitansky-Aschoff sinuses should be a part of the evaluation and management of these early gallbladder cancers; for advanced cancers, documentation of hepatic versus serosal involvement is necessary. In summary, T-staging of ampulla-pancreatobiliary tract tumors has many challenges. Proper grossing and appreciation of histo-anatomic subtleties of this region are crucial in addressing these issues and achieving more applicable and clinically relevant staging systems in the future.

Al-Rawi H, Al-Jafari M, Mathew H
Metastatic breast cancer mimicking cholecystitis. A rare clinical presentation.
Saudi Med J. 2012; 33(10):1128-30 [PubMed]

We report a case of a 61-year-old lady who presented with central chest and epigastric pain. A clinical diagnosis of cholecystitis was established, and a cholecystectomy was carried out. Microscopic examination of the gallbladder showed chronic cholecystitis and metastatic carcinoma of probable breast lobular carcinoma origin. The report was followed by further clinical and mammographic examination, which showed a focal area of thickening in the left breast. Core biopsy of this lesion confirmed the diagnosis of lobular carcinoma of the breast. Her tumor was treated with surgery followed by chemo/hormone therapy. The patient died 5 years after the cholecystectomy from disseminated breast malignancy.

Boutros C, Gary M, Baldwin K, Somasundar P
Gallbladder cancer: past, present and an uncertain future.
Surg Oncol. 2012; 21(4):e183-91 [PubMed]

Although gallbladder cancer (GBC) is the most common malignancy of the biliary tract, its relatively low incidence and confounding symptomatology result in advanced disease at the time presentation, contributing to the poor prognosis and decreased survival associated with this disease. It is therefore increasingly important to understand its pathogenesis and risk factors to allow for the earliest possible diagnosis. To date, gallbladder cancer is poorly understood compared to other malignancies, and is still most commonly discovered incidentally after cholecystectomy. Moreover, while much is known about biliary neoplasms as a whole, understanding the clinical and molecular nuances of GBC as a separate disease process will prove a cornerstone in the development of early intervention, potential screening and overall more effective treatment strategies. The present work reviews the most current understanding of the pathogenesis, diagnosis, staging and natural history of GBC, with additional focus on surgical treatment. Further, review of current adjuvant therapies for unresectable and advanced disease as well as prognostic factors provide fertile ground for the development of future studies which will hopefully improve treatment outcomes and affect overall survival for this highly morbid, poorly understood malignancy.

Al-Abed Y, Elsherif M, Firth J, et al.
Simultaneous xanthogranulomatous cholecystitis and gallbladder cancer in a patient with a large abdominal aortic aneurysm.
Korean J Intern Med. 2012; 27(3):338-41 [PubMed] Article available free on PMC after 01/12/2013

There have been reports of the coexistence of abdominal aortic aneurysm (AAA) with intra-abdominal malignancy including gastric, colonic, pancreatic, and renal. We herein report a case of a previously undiagnosed AAA and a presenting complaint consistent with acute cholecystitis. Following cholecystectomy, this was noted to be a rare form of chronic cholecystitis: xanthogranulomatous cholecystitis. There is a known possible association of this uncommon condition with gallbladder cancer. The management of concomitant pathologies can present a real challenge to the multidisciplinary team, especially with large aneurysms.

Pudasainin S, Subedi N, Prasad KB, et al.
Signet ring cell carcinoma of the gallbladder: a case report.
Nepal Med Coll J. 2011; 13(4):308-10 [PubMed]

Carcinoma of the gall bladder is the most common biliary tract tumor with higher incidence in females and increasing age. The risk is significantly higher in cholelithiasis. Signet ring cell carcinoma is a rare form of mucinous adenocarcinoma and has a worse prognosis. Early diagnosis is rare. We report a case of signet ring cell carcinoma of the gall bladder in a 70 years old female patient. The gross finding was yellowish white mass measuring 4 x 3.5 cm on cut surface of the gall bladder along with thickened wall. Histopathological examination of the specimen shows the sheets of signet ring cells with lateral spread through the lamina propria and large amount of extracellular mucin. There was metastasis in the retroperitoneum and mesenteric lymph node. The tumor was stage IV (according to TNM staging). Patient died 20th post operative day. Since very few cases have been reported, information regarding the behavior and prognosis of gall bladder carcinoma is limited. However it has been seen that stage III and IV carcinoma usually have worse prognosis.

Croitoru A, Gramaticu I, Dinu I, et al.
Fluoropyrimidines plus cisplatin versus gemcitabine/gemcitabine plus cisplatin in locally advanced and metastatic biliary tract carcinoma - a retrospective study.
J Gastrointestin Liver Dis. 2012; 21(3):277-84 [PubMed]

AIM: This is a retrospective study of patients with advanced biliary tract carcinoma (BTC), who were treated with different regimens of chemotherapy.
METHODS: We studied patients with advanced BTC registered at the Department of Oncology at the Fundeni Clinical Institute between 2004 and 2008. The following data were analyzed: rate of response, progression free survival (PFS) to first and second line of chemotherapy, overall survival (OS) and drug toxicity. Ninety-six patients were eligible having either advanced intra or extrahepatic cholangiocarcinoma, or gallbladder cancer with no prior chemotherapy.
RESULTS: Out of 96 patients, 57 (59.4%) received fluoropyrimidines (FP)+cisplatin and 39 (40.6%) gemcitabine (Gem)+/-cisplatin. The median PFS for FP+cisplatin was 5.9 months (95%CI 5-6.9) and for Gem+/-cisplatin 6.3 months (95%CI 5.4-7.1), p=0.661. Median OS for FP+cisplatin was 10.3 months (95%CI 7.5-13.1) and for Gem+/-cisplatin 9.1 months (95%CI 7.0-11.2), p=0.098. On disease progression, 46 patients received second line CT (Gem or FP+/-platinum compounds). Median OS for patients with FP based first line and Gem+/-cisplatin in second line was 19 months (95%CI 8.9-29) higher than for the reverse sequence: 13.2 months (95%CI 12-14.4), but not statistically significant (p=0.830). All patients were evaluated for toxicities. Most patients (75.5%) reported at least one adverse event.
CONCLUSION: Our results through direct comparison of FP+cisplatin with Gem+/-cisplatin as first line treatment did not show any statistical differences in terms of rate of response, PFS and OS. However, our study showed that FP+cisplatin as first line and Gem based second line therapy gave a better OS rate.

Kapoor S
CD146 expression and its close relationship to tumor progression in systemic malignancies besides gall bladder carcinomas.
Tumour Biol. 2013; 34(2):1273-4 [PubMed]

Recent data suggest that CD146 may be involved in tumor development and may influence tumor prognosis in a number of systemic tumors besides gall bladder carcinomas. For instance, CD146 augments the development and progression of gastric carcinomas. It performs this function by accentuating epithelial mesenchymal transition (Liu et al., Int J Mol Sci 13:6399-6406, 2012). CD146 thus points towards a poor clinical outcome in gastric malignancies. An increase in gastric tissue vimentin is seen with an increase in CD146 levels. Similarly, around 8.7 % of lung adenocarcinomas express CD146. A decreased 5-year overall survival rate is seen following lung resection of pulmonary adenocarcinomas in male patients who express CD146 (Zeng et al., Proc Natl Acad Sci USA 109:1127-1132; 2012).

Basu S, Priya R, Singh TB, et al.
Role of nicotine in gallbladder carcinoma: a preliminary report.
J Dig Dis. 2012; 13(10):536-40 [PubMed]

OBJECTIVE: To assess the role of nicotine in gallbladder carcinoma and its association with the stage and degree of cancer differentiation.
METHODS: Tissue samples from gallbladder were obtained from 20 patients with gallbladder cancer and 20 age- and gender-matched patients with cholelithiasis who served as the control group. Gallbladder tissue (2 g) was extracted and analyzed for nicotine content using capillary gas chromatography. Nitrogen was used as the carrier gas. Standard curves of nicotine in methanol were made by injecting the internal standards.
RESULTS: A significantly higher tissue nicotine concentration was observed in the gallbladder carcinoma group than that in the control group (179.63 ng/mg vs 6.00 ng/mg, P < 0.001). The stage and degree of cancer differentiation did not seem to affect the nicotine levels. Gallbladder tissue contained a significantly higher nicotine concentration in smokers with cancer compared with those in the control group (1570.00 ng/mg vs 232.25 ng/mg, P < 0.001). Interestingly, non-smokers in cancer group also had a higher nicotine concentration than the control group (161.50 ng/mg vs 4.00 ng/mg, P = 0.002).
CONCLUSION: Nicotine is selectively concentrated in malignant gallbladder tissue irrespective of smoking status, showing its strong association with gallbladder cancer.

Zhai G, Yan K, Ji X, et al.
LAPTM4B allele *2 is a marker of poor prognosis for gallbladder carcinoma.
PLoS One. 2012; 7(9):e45290 [PubMed] Article available free on PMC after 01/12/2013

BACKGROUND: Lysosomal protein transmembrane 4 beta (LAPTM4B) is a novel cancer-related gene which has two alleles designated LAPTM4B*1 and LAPTM4B*2. In this study we investigated the correlation of LAPTM4B genotype with prognosis and clinicopathologic features in patients who had undergone curative resection for gallbladder carcinoma (GBC).
METHODOLOGY/PRINCIPAL FINDINGS: PCR assay was performed to determine the LAPTM4B genotype in 85 patients. The correlation of LAPTM4B genotype with clinicopathologic parameters was assessed with the Chi-squared test. Differences in patient survival were determined by the Kaplan-Meier method. Multivariate analysis of prognostic factors was carried out with Cox regression analysis. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both P<0.001). Multivariate analysis showed that LAPTM4B genotype is a prognostic factor for OS and DFS (both P<0.001).
CONCLUSIONS/SIGNIFICANCE: LAPTM4B allele *2 is a risk factor associated with poor prognosis in patients with resected GBC, and LAPTM4B status may be therefore be useful preoperatively as an adjunct in evaluation of the operability of GBC.

Ishiguro S, Onaya H, Esaki M, et al.
Mucin-producing carcinoma of the gallbladder: evaluation by magnetic resonance cholangiopancreatography in three cases.
Korean J Radiol. 2012 Sep-Oct; 13(5):637-42 [PubMed] Article available free on PMC after 01/12/2013

We report three cases of mucin-producing carcinoma of the gallbladder, along with the magnetic resonance (MR) findings, especially the findings on a MR cholangiopancreatography. In our cases, linear or curvilinear streaks were detected running along the long axis of an enlarged gallbladder (mucus thread sign). When such findings were seen, a mucin-producing carcinoma of the gallbladder should be included as a differential diagnosis. Thus, gadolinium-enhanced MR imaging is mandatory for the precise diagnosis of the mucin-producing carcinoma of the gallbladder.

Wang RT, Xu XS, Liu J, Liu C
Gallbladder carcinoma: analysis of prognostic factors in 132 cases.
Asian Pac J Cancer Prev. 2012; 13(6):2511-4 [PubMed]

OBJECTIVE: To evaluate the prognostic factors of gallbladder carcinoma.
METHODS: Presentation, operative data, complications, and survival outcome were examined for 132 gallbladder carcinoma patients who underwent gallbladder surgery in our unit during 2002-2007, and follow-up results were obtained from every patient for univariate and multivariate survival analysis.
RESULTS: The univariate analysis showed that gallbladder lesion history, tumor cell differentiation, Nevin staging, preoperative lymph node metastasis and the surgical approach significantly correlated with the prognosis of the patients (p <0.05). The results of the multivariate analysis (Cox regression) showed that gallbladder lesion history, Nevin staging and the surgical approach were independent predicators with relative risks of 6.9, 4.4, 2.8, respectively (p=0.002, 0.003, 0.008).
CONCLUSION: Gallbladder lesion history, Nevin staging and the surgical approach are independent prognostic factors for gallbladder carcinoma, a rapidly fatal disease. Therefore, early diagnosis, anti-infective therapy and radical surgery are greatly needed to improve the prognosis of gallbladder carcinoma.

Raznatović ZJ, Zarić ND, Galun DA, et al.
Multiple port-site metastasis of incidental gallbladder carcinoma after laparoscopic cholecystectomy.
Acta Chir Iugosl. 2012; 59(1):105-9 [PubMed]

Laparoscopic cholecystectomy is a surgical procedure of choice for benign gallbladder diseases. In about 1-2% of cases histopathological examination demonstrate incidental gallbladder cancer (GBCA). We report a case of a 61 year old woman who developed port site metastases after laparoscopic cholecystectomy for adenocarcinoma of the gallbladder. Metastases appeared on all four port sites. Review of literature regarding incidental GBCA an port site metastases was also performed. We conclude that the retrieval bag should be routinely used in laparoscopic cholecystectomy; the procedure should be performed with minimal trauma; in cases of incidental GB carcinoma, full thickness excision of the abdominal wall of the port sites demands additional studies; additional liver bed excision and local lymphadenectomy for T1b carcinoma are yet to be considered.

Cavallaro A, Piccolo G, Panebianco V, et al.
Incidental gallbladder cancer during laparoscopic cholecystectomy: managing an unexpected finding.
World J Gastroenterol. 2012; 18(30):4019-27 [PubMed] Article available free on PMC after 01/12/2013

AIM: To evaluate the impact of incidental gallbladder cancer on surgical experience.
METHODS: Between 1998 and 2008 all cases of cholecystectomy at two divisions of general surgery, one university based and one at a public hospital, were retrospectively reviewed. Gallbladder pathology was diagnosed by history, physical examination, and laboratory and imaging studies [ultrasonography and computed tomography (CT)]. Patients with gallbladder cancer (GBC) were further analyzed for demographic data, and type of operation, surgical morbidity and mortality, histopathological classification, and survival. Incidental GBC was compared with suspected or preoperatively diagnosed GBC. The primary endpoint was disease-free survival (DFS). The secondary endpoint was the difference in DFS between patients previously treated with laparoscopic cholecystectomy and those who had oncological resection as first intervention.
RESULTS: Nineteen patients (11 women and eight men) were found to have GBC. The male to female ratio was 1:1.4 and the mean age was 68 years (range: 45-82 years). Preoperative diagnosis was made in 10 cases, and eight were diagnosed postoperatively. One was suspected intraoperatively and confirmed by frozen sections. The ratio between incidental and nonincidental cases was 9/19. The tumor node metastasis stage was: pTis (1), pT1a (2), pT1b (4), pT2 (6), pT3 (4), pT4 (2); five cases with stage Ia (T1 a-b); two with stage Ib (T2 N0); one with stage IIa (T3 N0); six with stage IIb (T1-T3 N1); two with stage III (T4 Nx Nx); and one with stage IV (Tx Nx Mx). Eighty-eight percent of the incidental cases were discovered at an early stage (≤ II). Preoperative diagnosis of the 19 patients with GBC was: GBC with liver invasion diagnosed by preoperative CT (nine cases), gallbladder abscess perforated into hepatic parenchyma and involving the transversal mesocolon and hepatic hilum (one case), porcelain gallbladder (one case), gallbladder adenoma (one case), and chronic cholelithiasis (eight cases). Every case, except one, with a T1b or more advanced invasion underwent IVb + V wedge liver resection and pericholedochic/hepatoduodenal lymphadenectomy. One patient with stage T1b GBC refused further surgery. Cases with Tis and T1a involvement were treated with cholecystectomy alone. One incidental case was diagnosed by intraoperative frozen section and treated with cholecystectomy alone. Six of the nine patients with incidental diagnosis reached 5-year DFS. One patient reached 38 mo survival despite a port-site recurrence 2 years after original surgery. Cases with non incidental diagnosis were more locally advanced and only two patients experienced 5-year DFS.
CONCLUSION: Laparoscopic cholecystectomy does not affect survival if implemented properly. Reoperation should have two objectives: R0 resection and clearance of the lymph nodes.