Early-stage Gallbladder Cancer Research Articles

Somatic Mutations of PI3K in Early and Advanced Gallbladder Cancer: Additional Options for an Orphan Cancer

Gallbladder cancer (GBC) is the second-leading cause of death from malignant tumors in Chilean women. The phosphatidylinositol 3-kinase (PI3K) pathway is involved in proliferation, cell survival, and growth. We investigated mutations in exons 9 and 20 of the PI3K gene in GBC. Mutations in exons 9 (E542K, E545G, E545K) and 20 (H1047L and H1047R) of PI3K were determined by direct sequencing in 130 cases of GBC. The patient group consisted of 110 women and 20 men, and mutations were found in 22 cases (16.9%). Of these, 14 cases had mutations in exon 9 (63.6%) (E542K, 64%; E545K, 29%; and E545G, 7%) and 8 in exon 20 (37.4%; H1047L, 50%; H1047R, 50%). No differences were noted in the frequency and type of mutations analyzed by sex, age, or histologic features. We observed mutations in 22% of the early-stage GBC and 14.6% of the advanced cases. In this series of GBC, 17% of cases were noted as having mutations in either exons 9 or 20 of PI3K. These results suggest that therapeutic testing of inhibitors of the PI3K/AKT pathway may be of benefit in advanced GBC patients.

Is Laparoscopy Contraindicated for Gallbladder Cancer? A 10-Year Prospective Cohort Study

Laparoscopic treatment for gallbladder cancer (GBC) has long been contraindicated, but few studies have demonstrated the oncologic outcomes of this treatment. The purpose of this study was to evaluate long-term survival after intended laparoscopic surgery for early-stage GBC based on our 10 years of experience. Between May 2004 and April 2014, eighty-three patients suspected of having early-stage GBC with no evidence of liver invasion were enrolled in the prospective protocol for laparoscopic surgery. Data for 45 of these patients with pathologically proven GBC were analyzed to determine the safety and oncologic outcomes of a laparoscopic approach to GBC. Twenty-six patients whose postoperative follow-up exceeded 5 years were investigated to determine the 5-year actual survival outcomes. Extended cholecystectomy, including laparoscopic lymphadenectomy, was performed in 32 patients and simple cholecystectomy in 13 patients. The T stages based on final pathologic results were Tis (n = 2), T1a (n = 10), T1b (n = 8), and T2 (n = 25). After a median follow-up of 60 months after surgery, recurrence was detected in 4 patients as distant metastases. There was no local recurrence around the gallbladder bed or lymphadenectomy. Disease-specific 5-year survival rate of the 45 patients was 94.2%. Disease-specific actual survival rate of 26 patients whose postoperative follow-up period exceeded 5 years was 92.3% at 5 years. The favorable long-term oncologic results shown in this study confirm the oncologic safety of laparoscopic cholecystectomy, including laparoscopic lymphadenectomy in selected patients with GBC.

Clinical Characteristics of Early-Stage Gallbladder Cancer

Background/Aims: Early detection of gallbladder (GB) cancer is essential for better survival rates. Most cases of GB cancer are diagnosed incidentally via pathology of the cholecystectomy specimen. Data on the clinical characteristics of early GB cancer are lacking. The aim of the current study was to investigate the clinical characteristics of early GB cancer to aid earlier diagnosis. Methods: Sixty-four patients who were diagnosed with early GB cancer after surgical resection at the Samsung Medical Center were enrolled in this study. Clinical characteristics, preoperative diagnoses, preoperative tumor size, laboratory findings including carbohydrate antigen 19-9 (CA19-9) levels, imaging features, and survival rate were investigated. Results: Clinical symptoms and serum tumor markers such as carcinoembryonic antigen and CA19-9 levels were not helpful indicators of early GB cancer. Radiologic modalities showed abnormal findings in every case of early GB cancer; a polypoid mass was the most common feature. Less common features included GB wall thickening, cholecystitis, and GB stones. The clinical outcome of early GB cancer was excellent. Conclusions: Screening with imaging modalities such as computed tomography (CT) or ultrasonography (US) is helpful in detecting early GB cancer. Even in the presence of GB wall thickening, cholecystitis, or GB stones on the CT or US, any abnormal findings should prompt careful examination and intensive follow up, considering the possibility of occult gallbladder cancer. (Korean J Med 2015;88:161-167)

A rare finding during a common procedure: xanthogranulomatous cholecystitis.

Xanthogranulomatous cholecystitis is a rare variant of chronic cholecystitis characterized by severe proliferative fibrosis and accumulation of lipid-laden macrophages in regions of destructive inflammation. Xanthogranulomatous cholecystitis clinically and radiologically mimics early-stage gallbladder cancer, with wall thickening on computed tomography. The study included 14 xanthogranulomatous cholecystitis patients that were identified following retrospective analysis of the records of 1248 patients that underwent cholecystectomy between 2005 and 2011. Mean age of the 5 male and 9 female patients was 56.7 years. All 14 patients had gallbladder stones; 10 had a history of acute cholecystitis, 1 had cholangitis, and 2 presented with obstructive jaundice. A right-upper quadrant mass was palpable in 2 patients. All patients underwent cholecystectomy. Open surgery was planned and performed in 6 of the 14 patients, and laparoscopic cholecystectomy was planned in 8 patients, but was converted to open surgery in 1 case. In total, 1 patient developed wound infection, 1 patient had postoperative pneumonia, and 1 patient developed intraabdominal hematoma. None of the patients in the series died. Xanthogranulomatous cholecystitis is difficult to diagnose, both preoperatively and intraoperatively, and definitive diagnosis depends exclusively on pathological examination. Xanthogranulomatous cholecystitis should be a consideration in all difficult cholecystectomy cases.

Tu1946 From Miami to Paris: Validation of Refined Probe-Based Confocal Microscopy Classification of Indeterminate Biliary Strictures

Background and study aim: The prognosis of gallbladder cancer (GBC) is poor because it is typically diagnosed at an advanced stage and cannot be surgically treated. Moreover, even with advanced cancer, it is difficult to distinguish between malignant and benign disease. Therefore, pathological examination is indispensable for an appropriate diagnosis before surgery. Furthermore, a majority of tumors are diffusely infiltrating (flat-type). The diagnostic performance of various modalities is low for the flat-type GBC. We believe that cytology of gallbladder lavage-fluid (CGLF) contributes to definitive diagnosis and endoscopic doublecontrast cholangiography (EDCC) aids in the discovery in the infiltrating (flat-type) GBC. This study aimed to evaluate the efficacy of EDCC and CGLF by endoscopic transpapillary gallbladder drainage. Patients and methods: Between January 2005 and December 2011, 251 patients [men, 111; women, 140; mean age, 67 years (range 40-90 years)] suspected of GBC (an elevated lesion, thickening of the gallbladder wall, or gallbladder debris), were examined by EDCC and CGLF to confirm the diagnoses. Results: Of the 251 patients, 130 were diagnosed with benign disease on the basis of the results of follow-up examinations conducted for at least one year. Of the patients whose tissues were subjected to histopathological examination after surgery, 30 and 91 had GBC and benign gallbladder disease, respectively. The diagnoses of the 91 patients with benign disease included 62 with chronic cholecystitis, 11 with adenomyomatosis, 3 with hyperplasia, 3 with dysplasia, 11 with polyps, and 1 with xanthogranuloma cholecystitis. Of the 30 patients, 15 (50.0%) had earlystage GBC (pT1a, n = 11; pT1b, n = 4). The diagnostic accuracy of EDCC and CGLF was 87.3% and 96.4%, respectively. Of the 15 early-stage GBC, 9 (60.0%) were flat-type GBC. Conclusions: CGLF and EDCC using ETGD proved to be effective techniques for cytological diagnosis of GBC and were suitable for diagnostic imaging of infiltrating (flat-type) GBC. These techniques enhance surgical treatment and thus improve the prognosis of GBC.

Tu1945 Efficacy of Endoscopic Double-Contrast Cholangiography and Cytology of Gallbladder Lavage-Fluid for Diagnosing Gallbladder Cancer

Background and study aim: The prognosis of gallbladder cancer (GBC) is poor because it is typically diagnosed at an advanced stage and cannot be surgically treated. Moreover, even with advanced cancer, it is difficult to distinguish between malignant and benign disease. Therefore, pathological examination is indispensable for an appropriate diagnosis before surgery. Furthermore, a majority of tumors are diffusely infiltrating (flat-type). The diagnostic performance of various modalities is low for the flat-type GBC. We believe that cytology of gallbladder lavage-fluid (CGLF) contributes to definitive diagnosis and endoscopic doublecontrast cholangiography (EDCC) aids in the discovery in the infiltrating (flat-type) GBC. This study aimed to evaluate the efficacy of EDCC and CGLF by endoscopic transpapillary gallbladder drainage. Patients and methods: Between January 2005 and December 2011, 251 patients [men, 111; women, 140; mean age, 67 years (range 40-90 years)] suspected of GBC (an elevated lesion, thickening of the gallbladder wall, or gallbladder debris), were examined by EDCC and CGLF to confirm the diagnoses. Results: Of the 251 patients, 130 were diagnosed with benign disease on the basis of the results of follow-up examinations conducted for at least one year. Of the patients whose tissues were subjected to histopathological examination after surgery, 30 and 91 had GBC and benign gallbladder disease, respectively. The diagnoses of the 91 patients with benign disease included 62 with chronic cholecystitis, 11 with adenomyomatosis, 3 with hyperplasia, 3 with dysplasia, 11 with polyps, and 1 with xanthogranuloma cholecystitis. Of the 30 patients, 15 (50.0%) had earlystage GBC (pT1a, n = 11; pT1b, n = 4). The diagnostic accuracy of EDCC and CGLF was 87.3% and 96.4%, respectively. Of the 15 early-stage GBC, 9 (60.0%) were flat-type GBC. Conclusions: CGLF and EDCC using ETGD proved to be effective techniques for cytological diagnosis of GBC and were suitable for diagnostic imaging of infiltrating (flat-type) GBC. These techniques enhance surgical treatment and thus improve the prognosis of GBC.

Gallbladder Cancer, Treatment Failure and Relapses: the Peritoneum in Gallbladder Cancer

This study aims to review gallbladder cancer (GBC) and present current management strategies, factors influencing prognosis, recurrence and areas of consideration. Literature search in PubMed was made and restricted to articles published from 2002 to 2013 using the following keywords: (GBC + peritoneum and GBC + surgery + metastasis/recurrence); abstract evaluation narrowed results to 53 articles. Twenty-six single-institution reports with 2,097 patients among 36 large-scale retrospective studies were obtained and focused on surgical outcomes. GBC presents late and recurs early with a poor prognosis. There is no definitive time for curative re-resection following incidental diagnosis. Effective surgical strategies for each disease stage remain unclear. Management guidelines are not universally standardised, most institutions utilise protocols based on individual experiences and limitations. Early-stage GBC is curable with complete resection but invisible metastases at unobvious sites remain problematic. In this study, at least 450 patients relapsed, most had peritoneal metastasis. The peritoneum is a common metastatic site, its microenvironment is intrinsically hypoxic, well vascularized and lined with mesothelium overlaying immune aggregates, which express pro-angiogenic and adhesion molecules that are highly selective for tumour growth and evolution. There are no medical/molecular antagonists to inhibit peritoneal carcinomatosis. Peritonectomies have been successfully undertaken; furthermore, GBC responds to some chemotherapy combinations. This review focused on GBC surgery. Peritoneal carcinomatosis is common. In carefully selected patients, the incorporation of peritoneal disease in cytoreductive surgery and intraperitoneal chemotherapy will inhibit a vehicle for dissemination, eliminate future relapse sites and improve survival. Areas for consideration include universally standardised protocols, clear management guidelines for each stage, effective re-resection timings with guidance on where or how to identify additional disease.

Full-thickness Cholecystectomy with Limited Lymphadenectomy for Gallbladder Cancer

Aggressive radical resection is advocated for gallbladder cancer. However, this is a disease of the elderly and some patients have comorbid disease(s) and/or a debilitated condition that may preclude such an aggressive treatment strategy. Here, we describe a minimum radical procedure for gallbladder cancer, termed as "full-thickness cholecystectomy with limited lymphadenectomy". This procedure comprises full-thickness resection of the gallbladder (cholecystectomy combined with removal of the entire cystic plate) and removal of the first-echelon lymph nodes (the pericholedochal and cystic duct node groups). Since 1992, 12 consecutive patients underwent the described procedure for tumors confined to the gallbladder wall and with no gross evidence of distant metastases/nodal disease, resulting in no in-hospital mortality or recurrent disease. The median overall survival was 229 months with a cumulative 5-year survival of 100%. In conclusion, the minimal radical resection procedure is safe and effective for early-stage gallbladder cancer. This less invasive procedure can be applied to patients with advanced age and/or comorbid disease(s), provided that the tumor is apparently confined to the gallbladder wall and has no gross evidence of distant metastases/nodal disease.

Early-Stage Gallbladder Cancer in the Surveillance, Epidemiology, and End Results Database

Extended surgical resection (ESR) may improve survival in patients with early-stage primary gallbladder cancer. Retrospective analysis of findings in the Surveillance, Epidemiology, and End Results (SEER) database. Academic research. Individuals with potentially surgically curable gallbladder cancer (Tis, T1, or T2) who underwent a surgical procedure. Overall survival, number of lymph nodes (LNs) excised, and results of simple cholecystectomy vs ESR. We identified 3209 patients with early-stage gallbladder cancer (11.7% Tis, 30.1% T1, and 58.2% T2). On multivariate analysis, decreased survival was noted among patients older than 60 years (hazard ratio, 1.57; 95% confidence interval, 1.30-1.90), among patients with more advanced cancer (1.99; 1.46-2.70 for T1; 3.29; 2.45-4.43 for T2), and among patients with disease-positive LNs (1.65; 1.39-1.95 for regional; 2.58; 1.54-4.34 for distant) (P < .001 for all), while increased survival was observed among female patients (0.82; 0.70-0.96; P = .02) and among patients undergoing ESR (0.59; 0.45-0.78; P < .001). The survival advantage of ESR was seen only in patients with T2 lesions (0.49; 0.35-0.68; P < .001). Lymph node excision data were available for a subset of 2507 patients, of whom 68.2% had no LN excised, 28.2% had 1 to 4 LNs excised, and 3.6% had 5 or more LNs excised. On multivariate analysis, patients with 1 to 4 LNs excised had a survival benefit over those with no LN excised (HR, 0.55; 95% CI, 0.46-0.66; P < .001), and patients with 5 or more LNs excised had a survival benefit over patients with 1 to 4 LNs removed (0.63; 0.40-0.96; P = .03). Lymph node excision improved survival in patients with T2 lesions (0.42; 0.33-0.53; P < .001 for patients with 1-4 LNs excised). Extended surgical resection, LN excision, or both may improve survival in certain patients with incidentally discovered gallbladder cancer.

Distinguishing Xanthogranulomatous Cholecystitis from the Wall-Thickening Type of Early-Stage Gallbladder Cancer

Xanthogranulomatous cholecystitis (XGC) mimics early-stage gallbladder (GB) cancer with wall thickening on computed tomography (CT), both clinically and radiologically. Preoperative differentiation of XGC from early-stage GB cancer is important for selecting the most appropriate surgical management. Therefore, we evaluated the clinical features and multidetector CT (MDCT) findings of XGC to determine whether it can be distinguished from early-stage GB cancer. We retrospectively evaluated 25 patients with XGC and 56 patients with the wall-thickening type of T1- and T2-stage GB cancer, where all of the diagnoses were pathologically confirmed by surgical treatment. All of the patients underwent preoperative MDCT. The clinical symptoms, laboratory findings, and CT findings were compared. Abdominal pain, fever, and jaundice were noted more frequently in the patients with XGC. Serum aspartate aminotransferase and alanine aminotransferase levels were more elevated in patients with XGC, whereas carbohydrate antigen (CA 19-9) was higher in the patients with GB cancer. When the T-category cancer staging of XGC and early-stage GB cancer were compared, diffuse GB wall thickening, intramural hypoattenuated nodule, gallstone, and pericholecystic infiltration were consistent significant findings associated with XGC, regardless of the cancer staging. MDCT findings such as diffuse GB wall thickening, intramural hypoattenuated nodule, gallstone, and pericholecystic infiltration together with the clinical symptoms, can provide clues for physicians to differentiate XGC from early-stage GB cancer with wall thickening on CT.

Laparoscopic completion radical cholecystectomy for T2 gallbladder cancer

The role of minimally invasive surgery in the surgical management of gallbladder cancer is a matter of controversy. Because of the authors' growing experience with laparoscopic liver and pancreatic surgery, they have begun offering patients laparoscopic completion partial hepatectomies of the gallbladder bed with laparoscopic hepatoduodenal lymphadenectomy. The video shows the steps needed to perform laparoscopic resection of the residual gallbladder bed, the hepatoduodenal lymph node nodes, and the residual cystic duct stump in a setting with a positive cystic stump margin. The skin and fascia around the previous extraction site are resected, and this site is used for specimen retrieval during the second operation. To date, three patients have undergone laparoscopic radical cholecystectomy with hepatoduodenal lymph node dissection for gallbladder cancer. The average number of lymph nodes retrieved was 3 (range, 1-6), and the average estimated blood loss was 117 ml (range, 50-200 ml). The average operative time was 227 min (range, 120-360 min), and the average hospital length of stay was 4 days (range, 3-5 days). No morbidity or mortality was observed during 90 days of follow-up for each patient. Although controversy exists as to the best surgical approach for gallbladder cancer diagnosed after routine laparoscopic cholecystectomy, the minimally invasive approach seems feasible and safe, even after previous hepatobiliary surgery. If the previous extraction site cannot be ascertained, all port sites can be excised locally. Larger studies are needed to determine whether the minimally invasive approach to postoperatively diagnosed early-stage gallbladder cancer has any drawbacks.

Planned Laparoscopic Approach for Early-Stage Gallbladder Cancer: The Glass Is One-Third Full

Planned Laparoscopic Approach for Early-Stage Gallbladder Cancer: The Glass Is One-Third Full

Laparoscopic Radical Cholecystectomy

Controversy exists as to the role of minimally invasive techniques in the management of early gallbladder cancer. The majority of early gallbladder cancers are diagnosed upon final pathology after laparoscopic cholecystectomy. For stage pT1a tumors, no further surgery is warranted; however, for pT1b or greater lesions, patients usually undergo port-site excisions and completion of open radical cholecystectomy involving a partial hepatectomy of segments IV and V and a lymphadenectomy of the hepatoduodenal ligament. Presented in this paper is a totally laparoscopic radical cholecystectomy performed for suspected early gallbladder cancer. Despite the fact that a preoperative serum IgG4 level was within normal limits, final pathology was consistent with autoimmune cholecystitis. As a result, the laparoscopic radical cholecystectomy may be useful in select patients with a preoperative suspicion of early-stage gallbladder cancer by sparing them the necessity of a second-stage open procedure.

A Critical Analysis of the Surgical Management of Early-Stage Gallbladder Cancer in the United States

BackgroundRadical resection is recommended for selected patients with gallbladder (GB) cancer. We sought to determine whether radical resection improves survival for patients with early-stage cancer and to evaluate surgeon compliance with current treatment recommendations. Patients and methodsPatients with stage 0, I, or II GB cancer who underwent surgical resection were identified from the Surveillance, Epidemiology, and End Results (SEER) tumor registry from 1988 through 2004. Patients were classified by surgical procedure performed (simple vs. radical resection) and adjuvant treatment given (radiation therapy [RT] vs. no RT). Unadjusted and adjusted overall survival (OS) and cancer-specific survival (CSS) were compared. ResultsOf the 4,631 patients who underwent surgery for early-stage GB cancer from 1988 through 2004, 4,188 (90.4%) underwent cholecystectomy alone and 443 (9.6%) underwent radical surgery including hepatic resection. The proportion of patients having radical surgery for T1b, T2, and T3 cancers was 4.5%, 5.6%, and 16.3%, respectively. For patients with T1b/T2 cancer, radical resection was associated with significant improvement in adjusted CSS (p = 0.01) and OS (p = 0.03). For patients with T3 cancers, we noted no improvement in CSS or OS. Survival for patients with node-positive disease (stage 2b) was universally poor and not improved by radical resection. For all patients who underwent radical resection, node negativity, female sex, age <70, low grade, and RT predicted improved CSS and OS. ConclusionsDespite a significant survival advantage for patients with T1b/T2 GB cancer who undergo radical resection, this treatment is significantly underutilized. Ensuring delivery of recommended surgical treatment is vital to improving outcomes for patients with this disease.

Laparoscopic cholecystectomy for treatment of unexpected early‐stage gallbladder cancer

Laparoscopic cholecystectomy (LC) may result in the incidental diagnosis of early stage (T1 and T2) gallbladder cancer. LC is useful for T1 patients, however, its role in T2 patients remains controversial. We sought to determine the effect of initial LC on patient outcome in early-stage gallbladder cancer. Twenty-nine patients with T1 or T2 disease were reviewed retrospectively to assess preoperative diagnosis, intraoperative findings, and outcomes. Diagnoses included gallbladder stones (5), gallstones with polyps (5), and gallbladder polyps (19). Malignancy was suspected in 15 patients (14 polyp lesions and 1 gallbladder stone with wall thickening). After frozen sections, two T2 patients were immediately treated with radical operation owing to positive margins. Of 14 patients diagnosed by pathology, 4 T2 patients with positive margins underwent a second radical operation. Five-year survival rate was 100% and 49.6 % (T1 and T2 patients). No mortality or recurrence was detected in T1 patients (mean follow-up, 45.8 months; range, 6-98 months). Three T2 patients died, and one T2 patient relapsed after LC. No port site metastasis was detected. LC for T1a and T1b gallbladder cancer needs no additional treatment, however, radical operation for T2 patients is recommended, regardless of the margin condition.