Background

Carcinoma of the gallbladder is rare but a devastating disease. The majority of malignant epithelial tumors are adenocarcinomas and account for 60% to 80% of all malignant tumors of the gallbladder.

OUTLINE

Pathogenesis
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
GENERAL
Immunohistochemical and genetic analysis of non-small cell and small cell gallbladder carcinoma and their precursor lesions. Parwani AV, Geradts J, Caspers E, Offerhaus GJ, Yeo CJ, Cameron JL, Klimstra DS, Maitra A, Hruban RH, Argani P. Departments of Pathology (AVP, AM, RHH, PA), Surgery (CJY, JLC), and Oncology (CJY, RHH), The Johns Hopkins Hospital, Baltimore, Maryland.	Mod Pathol 2003 Apr;16(4):299-308 Abstract quote Gallbladder carcinomas can be highly lethal neoplasms. Relatively little is known about the genetic abnormalities that underlie these tumors, particularly with respect to their timing in neoplastic progression. The authors evaluated 5 noninvasive dysplasias and 33 invasive gallbladder carcinomas (6 small cell carcinomas, 27 non-small cell carcinomas, of which 16 were accompanied by an in situ carcinoma component) for expression of the protein products of the p16, p53, Dpc4, and pRB tumor suppressor genes by immunohistochemistry. Neoplasms were also evaluated for the presence of activating K-ras oncogene mutations. Seventy-five percent of non-small cell gallbladder carcinomas demonstrated loss of p16 expression, whereas 63% accumulated high levels of p53. Loss of Dpc4 and pRB expression was less frequent, seen in 19% and 4% of the neoplasms, respectively. Thirty percent of neoplasms harbored activating K-ras mutations. In contrast, 100% of the small cell carcinomas of the gallbladder demonstrated inactivation of the pRB/p16 pathway; 67% showed loss of pRB expression, and the other 33% lost p16 expression. Eighty-three percent of small cell carcinomas accumulated high levels of p53, whereas loss of Dpc4 expression and activating K-ras mutations were not found. Among 15 evaluable in situ components, 13 harbored the same alterations found in the invasive component. Inactivation of p16 and p53 occur in the majority of non-small cell gallbladder carcinomas. Dpc4 inactivation and K-ras mutations occur in a significant minority of cases. pRB loss is uncommon in non-small cell gallbladder carcinoma, but virtually all small cell carcinomas inactivate the p16/pRB pathway, usually by retinoblastoma protein loss. It is noteworthy that all of these alterations occur at the level of carcinoma in situ.
BETA CATENIN
Mutation and altered expression of beta-catenin during gallbladder carcinogenesis. Chang HJ, Jee CD, Kim WH. Department of Pathology, Seoul National University College of Medicine, Korea.	Am J Surg Pathol 2002 Jun;26(6):758-66 Abstract quote Gallbladder carcinoma has two main morphologic developmental pathways: a dysplasia-carcinoma sequence and an adenoma-carcinoma sequence. beta-Catenin is a key regulator of the cadherin-mediated cell adhesion system, and altered expression and mutation of beta-catenin have been identified in many human malignancies. To clarify its role in gallbladder carcinogenesis, we investigated mutation and immunohistochemical expression of beta-catenin in adenomas, dysplasias, and carcinomas. We classified adenomas according to the expression of apomucins and cytokeratin and compared the mutational and expression pattern among each type. beta-Catenin mutations were identified in 58% (14 of 24) of the adenomas, and they were absent from all carcinomas (37 cases) and dysplasias (13 cases). Altered expression of beta-catenin, such as nuclear or cytoplasmic expression and loss of membranous expression, was also significantly higher in adenomas than in dysplasias or carcinomas (p <0.001). Of the adenomas, papillary adenomas and tubular adenomas of intestinal type showed infrequent beta-catenin abnormality, which was similar to the carcinomas. The cytoplasmic and nuclear expression of beta-catenin in carcinomas was correlated with less aggressive tumor behavior; in particular, cytoplasmic expression was associated with improved patient outcome (p = 0.028). Gallbladder adenoma may be a heterogeneous entity, and the majority of adenomas are not responsible for carcinoma progression.
BRAF MUTATIONS
The V599E BRAF mutation is uncommon in biliary tract cancers. Goldenberg D, Rosenbaum E, Argani P, Wistuba II, Sidransky D, Thuluvath PJ, Hidalgo M, Califano J, Maitra A. 1Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.	Mod Pathol. 2004 Nov;17(11):1386-91. Abstract quote   Activating point mutations of the BRAF oncogene have been identified in several solid tumors, most commonly in cutaneous melanomas and papillary carcinomas of the thyroid. A specific point mutation-V599E-accounts for the overwhelming majority of these mutational events. We explored the frequency of the V599E BRAF mutation in biliary tract cancers. In all, 62 archival biliary tract cancers, including 15 gallbladder cancers, 15 extrahepatic, and 10 intrahepatic cholangiocarcinomas from the United States, and 22 gallbladder carcinomas from Chile were analyzed for the V599E mutation of the BRAF gene using three distinct methods: direct sequencing, a primer extension method (Mutector((R)) assay), and the highly sensitive quantitative Gap Ligase Chain Reaction. The common V599E mutation was not identified in any of the 62 biliary cancer samples using these three methods of detection. The V599E somatic mutation of the BRAF gene is absent in biliary tract cancers, at least in the two geographic populations (United States and Chile) examined. Activation of the RAS/RAF/MAP kinase pathway in biliary tract cancers is likely to be secondary to oncogenic RAS mutations, or due to mutations of the BRAF gene at nucleotide positions not explored in the current study.
LOSS OF HETEROZYGOSITY
Loss of heterozygosity in clonal evolution with genetic progression and divergence in spindle cell carcinoma of the gallbladder. Arakawa A, Fujii H, Matsumoto T, Hirai S, Suda K. First Department of Pathology, Juntendo University, School of Medicine, Tokyo, Japan.	Hum Pathol. 2004 Apr;35(4):418-23. Abstract quote   Spindle cell carcinoma (SpCC) of the gallbladder is a rare neoplasm that shows carcinoma with a variable component of sarcomatoid spindle cells. The clinical and pathological features of this neoplasm have been well documented, but the histogenesis has long been a matter of speculation. In an attempt to clarify the clonality and genetic relationships involved in the evolution of this neoplasm, we microdissected a total of 18 carcinomatous and sarcomatous foci from 2 gallbladder SpCCs and analyzed the allelic status with 42 microsatellite markers on chromosomal arms 1p, 1q, 3p, 4q, 5q, 6q, 8p, 9p, 10q, 11p, 11q, 13q, 16q, 17p, 17q, 18q, and 22q. The 2 cases examined had a polypoid tumor in the gallbladder, in which both adenocarcinomatous and sarcomatoid spindle cell components were identified histologically. In both SpCCs, homogenous allelic losses were identified in both the carcinomatous and sarcomatous components; 17p, 18q, and 5q in case 1 and 17p and 11q in case 2. These indicated that both SpCCs had a single clonal origin. In case 1, additional loss of heterozygosity (LOH; 6q) consisting of genetic progression occurred in both the carcinomatous and sarcomatoid components. In case 2, there was additional LOH (9p) in the carcinomatous components and additional microsatellite instability at D5S644 in both the carcinomatous and sarcomatoid components, indicating a monoclonal neoplasm with genetic progression and divergence. In the 2 cases, the genetic changes indicated that an original clone of a pure adenocarcinoma apparently acquired sarcomatoid spindle cell phenotype by successive genetic changes. On the other hand, we saw no evidence of tumors in which a sarcomatoid spindle cell appeared to give rise to a carcinomatous subclone in the examined cases. In conclusion, the current study includes the first LOH analyses of SpCC of the gallbladder. Our data support the concept that gallbladder SpCC is derived from a single clone originating from a carcinoma. Furthermore, we showed genetic heterogeneity accompanying the phenotypic divergence, with patterns of genetic alterations that are consistent with both the progression and divergence within the individual tumors.
MICROSATELLITE INSTABILITY
Microsatellite Instability in Chronic Cholecystitis Is Indicative of an Early Stage in Gallbladder Carcinogenesis Nobuyuki Yanagisawa, MD, Tetuo Mikami, MD, Kazuya Yamashita, PhD, and Isao Okayasu, MD	Am J Clin Pathol 2003;120:413-417 Abstract quote The study of microsatellite instability (MSI) in cases of severe chronic cholecystitis and gallbladder carcinomas, to cast light on its significance for tumorigenesis, revealed MSI in 9 (30%) of 30 cases of cholecystitis and 7 (41%) of 17 carcinomas, respectively. In addition, 5 (33%) of 15 samples of background mucosa of carcinoma were positive. Respective figures for loss of heterozygosity were 3 (10%) of 30 cases of cholecystitis, 6 (35%) of 17 carcinomas, and 1 (7%) of 15 samples of adjacent nonneoplastic mucosa. No correlation was observed among MSI state, immunohistochemical hMLH1 or hMSH2 expression, and any clinicopathologic factors. MSI was observed not only in gallbladder tumors but also in severe chronic cholecystitis and background mucosa, suggesting that it may have an important role in early-stage gallbladder carcinogenesis.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General
In Situ and Invasive Adenocarcinomas of the Gallbladder Extending Into or Arising From Rokitansky-Aschoff Sinuses: A Clinicopathologic Study of 49 Cases. Albores-Saavedra J, Shukla D, Carrick K, Henson DE. *Department of Pathology, LSU Health Sciences Center School of Medicine, Shreveport, LA; daggerDepartment of Pathology, University of Texas Southwestern Medical Center; and double daggerDepartment of Pathology, Office of Cancer Prevention and Control, George Washington University Cancer Institute, Washington, DC.	Am J Surg Pathol. 2004 May;28(5):621-628. Abstract quote   We report 49 cases of gallbladder carcinomas that extended into or originated from Rokitansky-Aschoff sinuses (RAS), all of which were resected by laparoscopic cholecystectomy. Twenty-one tumors were in situ carcinomas that extended along RAS; six in situ carcinomas arose in adenomyomatous hyperplasia and 22 were invasive adenocarcinomas with extension into RAS. Thirty-seven patients were women and 12 men. Forty patients had cholelithiasis. The age of the patients ranged from 55 to 84 years (mean 67 years). All in situ carcinomas were incidental microscopic findings in gallbladders removed for cholelithiasis and/or cholecystitis. No patient with in situ carcinoma died as a result of the tumor, including two with in situ carcinoma that originated in adenomyomatous hyperplasia and showed microinvasion. In contrast, of 15 patients with invasive well to moderately differentiated adenocarcinoma extending into RAS and invading the muscle layer or subserosal connective tissue, 8 died 2 to 4 years after surgery. Seven patients survived 1 to 8 years after cholecystectomy. Useful clues to separate RAS with in situ carcinoma from tubular neoplastic invasive glands were the following: connection of the epithelial invaginations to the surface epithelium, recognition of normal biliary epithelium admixed with neoplastic epithelium, presence of inspissated bile in long dilated spaces, and lack of invasion to the smooth muscle bundles. In situ carcinoma spreading along RAS consisted of long tubular often dilated structures extending through the intermuscular connective tissue, whereas neoplastic glands were usually small or of medium size that invaded smooth muscle bundles or intermuscular connective tissue. Perineural invasion was seen only in invasive glands located in the subserosal connective tissue. Two cases of in situ carcinoma that arose in adenomyomatous hyperplasia and three invasive adenocarcinomas that were composed predominantly of tall columnar mucin containing cells similar to gastric foveolar cells with varying degrees of atypia and cells with biliary phenotype bear some resemblance to intraductal papillary mucinous carcinoma of the pancreas or to mucinous cystic pancreatic neoplasm. Metaplastic pyloric glands often seen in the muscle layer and subserosal connective tissue maintain their lobular pattern and should not be confused with invasive glands. Our findings indicate that distinction of in situ carcinoma spreading into RAS from tubular neoplastic glands of invasive adenocarcinomas is crucial to determine prognosis in this group of patients with gallbladder carcinoma.
VARIANTS
DYSPLASIA
Putative precursors of gallbladder dysplasia: a review of 400 routinely resected specimens. Mukhopadhyay S, Landas SK. Department of Pathology, State University of New York Upstate Medical University, Syracuse 13210, USA.	Arch Pathol Lab Med. 2005 Mar;129(3):386-90. Abstract quote   CONTEXT: Dysplasia is thought to be a precursor of invasive gallbladder carcinoma, but it is unsettled whether dysplasia arises from other precursor lesions. OBJECTIVE: To ascertain the presence and nature of precursors of dysplasia in the gallbladder. DESIGN: Four hundred consecutive cholecystectomy specimens were processed and stained routinely for diagnosis. We retrospectively reviewed these cases to look for the presence of epithelial changes, including antral-type metaplasia, intestinal metaplasia, and dysplasia. RESULTS: Antral-type metaplasia, intestinal metaplasia, and dysplasia were found in 238 (59.5%), 39 (9.8%), and 20 (5.0%) cases, respectively. The mean patient age was 47.7 years (range, 15-93 years). The mean ages for patients with antral-type metaplasia, intestinal metaplasia, and dysplasia were 49.4, 50.9, and 52.6 years, respectively. Statistically significant associations were found between antral-type metaplasia and intestinal metaplasia (P = .007, chi2 test) and between intestinal metaplasia and dysplasia (P < .001, chi2 test). CONCLUSION: These associations, along with the age gradient from antral-type metaplasia to dysplasia, suggest a progression from antral-type metaplasia to dysplasia via intestinal metaplasia.
LARGE CELL NEUROENDOCRINE
Large Cell Neuroendocrine Carcinoma of the Gallbladder Report of Two Cases Mauro Papotti, M.D.; Paola Cassoni, M.D.; Anna Sapino, M.D.; Giorgio Passarino, M.D.; Jo Ellen Krueger, M.D.; Jorge Albores-Saavedra, M.D. From the Department of Pathology, University of Turin, Turin, Italy (M.P., P.C., A.S., G.P.); and the Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. (J.E.K., J.A.S.).	Am J Surg Pathol 2000;24:1424-1428 Abstract quote We report two cases of primary large cell neuroendocrine carcinoma (LCNEC) of the gallbladder, which, to the best of our knowledge, represent the first description of this entity. One of the tumors consisted entirely of LCNEC, whereas the second tumor was composed of LCNEC and the more common intestinal-type adenocarcinoma. Both tumors were morphologically similar to their pulmonary counterpart and were 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. Panendocrine markers were expressed in a variable proportion of tumor cells in both cases, and one of the cases also showed focal positivity for type 2 somatostatin receptors. One of the tumors followed a rapidly fatal course despite aggressive surgical treatment and chemotherapy administration, and the second patient is still alive and disease-free 12 months after surgery. The description of these two cases of LCNEC of the gallbladder is significant for two reasons. From an academic standpoint, we now know that all the neuroendocrine tumors described in other organs can arise de novo in the gallbladder. More importantly, however, the recognition of this rare tumor type carries important clinical implications in regard to the use of chemotherapeutic agents and supplemental treatments (for example, somatostatin analogs).
PAPILLARY
Papillary carcinomas of the gallbladder: analysis of noninvasive and invasive types. Albores-Saavedra J, Tuck M, McLaren BK, Carrick KS, Henson DE. Department of Pathology, Louisiana State University Health Sciences Center, Shreveport 71130, USA.	Arch Pathol Lab Med. 2005 Jul;129(7):905-9. Abstract quote   CONTEXT: Although papillary carcinomas have been recognized as distinct morphologic variants of gallbladder neoplasms, they have been lumped together in a single group despite the recognition of noninvasive and invasive types. As a result, the biologic behavior of each type remains undescribed. OBJECTIVE: To compare the biologic behavior of noninvasive and invasive papillary carcinomas of the gallbladder. DESIGN: The clinical and morphologic features of 16 noninvasive papillary carcinomas (>1 cm) of the gallbladder were analyzed, and their clinical behavior was compared with that of 370 invasive papillary carcinomas recorded in the Survey Epidemiology and End Results (SEER) Program of the National Cancer Institute from 1973 through 2001. The biologic behavior of invasive papillary carcinomas was compared with that of invasive nonpapillary carcinomas of the gallbladder recorded in SEER. Hematoxylin-eosin-stained sections were available for review in the 16 noninvasive papillary carcinomas. The number of slides examined per case varied from 3 to 16, with an average of 7. RESULTS: The 16 patients with noninvasive papillary carcinomas included 11 women and 5 men, aged 34 to 83 years (mean age, 61 years). Thirteen patients had cholelithiasis. Laparoscopic cholecystectomy was performed on 12 patients and open cholecystectomy on 4. The tumors measured from 1.3 to 8.6 cm and were well to moderately differentiated. Fourteen noninvasive papillary carcinomas showed biliary phenotype, and 2 showed intestinal phenotype. Follow-up was obtained in 11 patients; 6 were asymptomatic 5 to 11 years after surgery, 2 were symptom free 9 months to 4 years following cholecystectomy, and 3 died of unrelated causes 2 to 3 years after surgery. Three hundred seventy cases of invasive papillary carcinomas were recorded in SEER. The 10-year relative survival rate for 225 patients with invasive papillary carcinomas confined to the gallbladder wall was 52%, while the 10-year relative survival rate for 83 patients with papillary carcinomas that had spread to the lymph nodes was less than 10%. Of the remaining 62 invasive papillary carcinomas, 58 had distant metastases and 4 were not staged. The 10-year relative survival rate for invasive nonpapillary carcinomas confined to the gallbladder wall was 30%. CONCLUSION: Noninvasive papillary carcinomas of the gallbladder-regardless of size, cell phenotype, and degree of differentiation-do not metastasize, and a simple cholecystectomy appears to be a curative procedure. In contrast, invasive papillary carcinomas do metastasize and are associated with a poor prognosis (10-year relative survival rate for tumors confined to the gallbladder wall was 52%, while the 10-year relative survival rate for tumors with lymph node metastasis was <10%). The separation of papillary carcinomas into noninvasive and invasive types is clinically relevant and therefore fully justified.
SMALL CELL
Small cell carcinoma of the gallbladder: a case report and review of 53 cases in the literature. Fujii H, Aotake T, Horiuchi T, Chiba Y, Imamura Y, Tanaka K. Second Department of Surgery, Fukui Medical University, Matsuoka-Cho, Yoshida-Gun, Fukui, 910-1193 Japan	Hepatogastroenterology 2001 Nov-Dec;48(42):1588-93 Abstract quote Although small cell carcinoma of the gallbladder is rare, the prognosis of this tumor type is poorer than that of differentiated carcinomas. We report herein the case of a 62-year-old man with small cell carcinoma of the gallbladder. The operative findings showed an unresectable large tumor of the gallbladder and multiple metastases involving the liver and lymph nodes. Pathological findings revealed small sized carcinoma cells, round or oval in shape which displayed a cord-like or solid appearance. Diagnosis was confirmed by ultrastructural study that showed the presence of neurosecretory-type cored granules. He was treated by intraarterial chemotherapy with cisplatin and etoposide. Six months later, abdominal computed tomography scan confirmed loss of the large mass. A complete response to the chemotherapy was noted over a period of six months, suggesting the efficacy of intraarterial chemotherapy for this disease. Fifty-three cases of small cell carcinoma reported in the English literature are reviewed. In most cases, including ours, a radical operation was not indicated and the prognosis was extremely poor, due to the difficulty of early diagnosis and the rapid progression of the disease. Chemotherapy is effective in general and intraarterial chemotherapy performed in the present case may be particularly useful to improve survival.
Small Cell Carcinoma of the Gallbladder A Clinicopathologic, Immunohistochemical, and Molecular Pathology Study of 12 Cases Anirban Maitra, etal.	Am J Surg Pathol 2001;25:595-601 Abstract quote Small cell carcinomas of the gallbladder are unusual neoplasms that have been characterized only recently. The authors describe the clinical, histopathologic, immunohistochemical, and molecular features of 12 small cell carcinomas of the gallbladder. The mean age at diagnosis was 69 years, and the male-to-female ratio was 5:7. The neoplasms had an average size of 3 cm, and 90% showed invasion of the muscularis propria and perimuscular connective tissue. Seventy-five percent of the carcinomas had metastasized or extended locally beyond the gallbladder at surgery. Survival was uniformly poor, with a mean survival of 10.7 months (range, 3–25 months). Half the small cell carcinomas were combined with other neoplasms. Four had foci of adenocarcinoma, one contained areas of squamous differentiation, and another had a component of carcinosarcoma. Immunohistochemical analysis showed focal reactivity for chromogranin (six of six cases), neuron-specific enolase (six of six cases), and Leu-7 (three of three cases). The molecular changes in small cell carcinomas were similar to those of adenocarcinomas occurring at this site, with a high frequency of p53 (75%) and p16INK4a (33%) abnormalities, and a low frequency of deleted in pancreatic carcinoma-4 inactivation (0%) and K-ras codon 12 mutations (17%). In contrast to pulmonary small cell carcinomas, p16INK4a function appears to be abrogated more frequently in these carcinomas.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
CARCINOID TUMOR
Clear cell carcinoid tumor of the gallbladder. A case without von Hippel-Lindau disease. Konishi E, Nakashima Y, Smyrk TC, Masuda S. Department of Laboratory Medicine, Saiseikai Kyoto Hospital, Nagaokakyo, Japan	Arch Pathol Lab Med 2003 Jun;127(6):745-7 Abstract quote A golden yellow polyp was detected in the gallbladder of a 64-year-old man who presented with epigastric pain. The lesion was composed of clear polygonal cells arranged in a trabecular and glandular pattern. The tumor invaded through the wall into the perimuscular subserosal layer. Immunohistochemical stains showed that neoplastic cells were positive for chromogranin A, synaptophysin, somatostatin, gastrin, and pancreatic polypeptide and negative for glucagon, serotonin, insulin, S100 protein, and inhibin. This tumor resembles the recently described clear cell endocrine tumors of the gallbladder and pancreas that are associated with von Hippel-Lindau disease. Our patient, however, had neither personal nor family history indicative of von Hippel-Lindau disease. Furthermore, published accounts of clear cell endocrine tumors in von Hippel-Lindau disease describe immunoreactivity for inhibin; the current case was negative for the disease. There may be a subtype of clear cell carcinoid tumor not associated with von Hippel-Lindau disease, which is characterized by its lack of immunoreactivity against inhibin.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Carcinoma of the gallbladder. Histologic types, stage of disease, grade, and survival rates. Henson DE, Albores-Saavedra J, Corle D. National Cancer Institute, Division of Cancer Prevention and Control, Bethesda, MD 20892	Cancer 1992 Sep 15;70(6):1493-7 Abstract quote Data on patients with gallbladder cancer listed in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were reviewed. Between 1977 and 1986, 3038 patients were recorded in the Program. Histologic grade, histologic type, stage of disease, and vascular invasion were correlated with outcome. Compared with all other histologic types of cancer, papillary carcinomas had the most favorable prognosis. The 2-year survival rate for patients with papillary carcinoma was 47%. A correlation with survival existed between grade, stage of disease, and vascular invasion. The study confirmed that cancers of the gallbladder occur more often in older age groups and are more common in women. Almost 40% of cases are found at an advanced stage. For patients whose enolase tumor was limited to the gallbladder at the time of surgery, the 2-year survival rate was 45% and the 5-year rate was 32%.
Long-term results after curative resection for carcinoma of the gallbladder. French University Association for Surgical Research. Benoist S, Panis Y, Fagniez PL. Service de Chirurgie Digestive, Hopital Henri-Mondor, Creteil, France.	Am J Surg 1998 Feb;175(2):118-22 Abstract quote BACKGROUND: The surgical management of gallbladder carcinoma is controversial, especially as regards the indications for radical resection. The aim of this study was to evaluate the results of surgical treatment for gallbladder carcinoma with special reference to the extent of its histological spread. METHODS: Eighty-six patients from 25 French centers underwent resection for cure and were included in this study. They comprised 65 women and 21 men (mean age 65 +/- 21 years). Resection included radical resection in 21 patients (partial hepatectomy, regional lymphadenectomy, and common bile duct resection) and simple cholecystectomy in 65. RESULTS: There were 3 postoperative deaths (3.5%). The mean follow-up period was 25 +/- 24 months. The overall 5-year actuarial survival rate was 26%. The 5-year actuarial survival rate was 27% for patients who had radical resection. Eight patients with nodal metastasis had a 5-year survival rate of 0%, but the rate for 13 patients without such metastasis was 43% (P <0.05). For patients undergoing simple cholecystectomy, the 5-year actuarial survival rate was 44% for stage I disease, 22% for stage II, and 0% for stage III (P <0.05). CONCLUSIONS: In patients with stage I gallbladder carcinoma, outcome is good after cholecystectomy only. In stages II to IV, radical resection should only be considered in the absence of regional lymph node metastasis.
Prognostic factors for adenocarcinoma of the gallbladder: an analysis of 162 cases. North JH Jr, Pack MS, Hong C, Rivera DE. Department of Surgery, Eisenhower Army Medical Center, Fort Gordon, Georgia 30905, USA	Am Surg 1998 May;64(5):437-40 Abstract quote Carcinoma of the gallbladder is a rare neoplasm and is associated with a dismal prognosis. To analyze the natural history of this disease and prognostic factors, a large tumor registry database was accessed. During the period 1972 to 1995, 214 patients were entered. Adequate follow-up was available on 162 patients, and this group forms the basis of this review. There were 54 males and 108 females with a median age of 62 years. Median follow-up was 7 months. Right upper quadrant abdominal pain was the most frequent presenting symptom. Fifteen patients had an incidental finding of carcinoma after cholecystectomy. Overall, 5-year survival was 25 per cent, with a median survival time of 9.7 months. Survival was improved for patients with local disease compared with those with regional or metastatic disease. One hundred nine patients underwent surgical therapy. Complete resection was possible in 36 patients, whereas 44 patients had residual disease. Median survival time for patients with no residual disease was 67.2 months, whereas those for patients with microscopic residual tumor and gross residual tumor were 8.9 and 3.8 months, respectively (P < 0.000001). Gallbladder cancer is often diagnosed at an advanced stage and is associated with a poor prognosis. In patients with localized disease, surgical treatment provides the opportunity for long-term survival only when a complete resection can be performed. Prognosis for patients with microscopic residual and gross residual disease is similar.
Liver metastasis from gallbladder carcinoma: anatomic correlation with cholecystic venous drainage demonstrated by helical computed tomography during injection of contrast medium in the cholecystic artery. Yoshimitsu K, Honda H, Kuroiwa T, Irie H, Aibe H, Tajima T, Chijiiwa K, Shimada M, Masuda K. Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.	Cancer 2001 Jul 15;92(2):340-8 Abstract quote BACKGROUND: The current study evaluated whether the sites of liver metastasis from gallbladder carcinoma are correlated with areas of cholecystic venous drainage (CVD) utilizing helical computed tomography (CT) during the injection of contrast medium into the cholecystic artery (cholecystic artery CT). METHODS: Cholecystic artery CT scans were performed in 26 patients with gallbladder carcinoma. Liver metastases were examined retrospectively in these patients on CT, and the sites of liver metastasis and CVD were compared closely. The patients were divided into concurrent (those who had metastasis at the time of cholecystic artery CT), early postoperative metastasis (those who developed metastasis within 6 months after surgery), and late postoperative metastasis (those who developed metastasis more than 6 months after surgery) groups. The frequency of metastasis related to CVD was compared between the three groups. RESULTS: A total of 32 metastases were identified in 11 patients, 21 of which were related to CVD. Six patients were included in the concurrent metastasis group; 18 of 20 tumors were found to be related closely to CVD. There were two patients in the early postoperative metastasis group; all three of the tumors detected were found to be closely related to CVD. Three patients were subclassified as being in the late postoperative metastasis group; none of the nine tumors detected appeared to be in areas associated with CVD. CONCLUSIONS: The sites of liver metastases were found to be well correlated with the areas with CVD, particularly in the concurrent and early postoperative metastasis groups. CVD may be a useful marker of potential areas of liver metastasis from gallbladder carcinoma, particularly in patients with early stage metastasis.
Clinical significance of lymph node micrometastasis in gallbladder carcinoma. Nagakura S, Shirai Y, Yokoyama N, Hatakeyama K. Department of Surgery, Niigata University School of Medicine, 1-757 Asahimachi-dori, Niigata City, 951-8510 Japan.	Surgery 2001 Jun;129(6):704-13 Abstract quote BACKGROUND: This retrospective study was intended to define the clinical significance of lymph node micrometastasis in gallbladder carcinoma. METHODS: A total of 1136 regional lymph nodes taken from 63 consecutive patients undergoing radical resection were examined histologically. Micrometastasis was defined as a metastasis missed on routine histologic examination with hematoxylin-and-eosin but detected by immunohistochemical examination with an antibody against cytokeratins 8 and 18. RESULTS: None of 9 patients (0%) with pT1 disease and 19 of 54 patients (35%) with pT2-4 disease had nodal micrometastases. Univariate analysis identified nodal micrometastasis, type of radical resection, M classification, pT classification, perineural invasion, pTNM stage, timing of radical resection, lymphatic vessel invasion, and pN classification as significant variables. Multivariate analysis revealed that nodal micrometastasis (P =.0003) and type of radical resection (P=.0044) were independent prognostic factors. Nodal micrometastasis affected survival adversely, despite the absence (P=.0002) or presence (P <.0001) of overt nodal metastasis. Nodal micrometastasis correlated significantly with invasive characteristics: lymphatic vessel invasion, perineural invasion, and distant metastasis. CONCLUSIONS: Lymph node micrometastasis is the strongest independent predictor of worse survival regardless of the overt nodal status and may indicate aggressive tumor biology among patients undergoing curative resection for gallbladder carcinoma.
Prognostic factors and long-term results after surgery for gallbladder carcinoma: a retrospective study of 127 patients. Schauer RJ, Meyer G, Baretton G, Schildberg FW, Rau HG. Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilian University, 81377 Munich, Germany.	Langenbecks Arch Surg 2001 Mar;386(2):110-7 Abstract quote BACKGROUND: The surgical management of gallbladder cancer is controversial, especially as to the indications for reoperation, extended resection, and aggressive treatment in advanced tumor stages. METHODS: Records and follow-ups of 127 patients with gallbladder carcinoma who underwent surgery between 1980 and 1997 were examined according to the pTNM and Nevin staging systems. Factors predictive for survival were obtained from histopathologic staging and surgical procedures. RESULTS: Surgery for gallbladder cancer was associated with an overall 5-year survival rate of 6.6%. Curative resection was possible in 35.5% of cases, which resulted in 5-year survival rates of 20%. Noncurative surgery revealed poor prognosis, with median survival time limited to 3.2 months, independently of macroscopic or microscopic tumor residues. None of the latter patients survived longer than 24 months. Surgery of stage I/II cancer showed a 5-year survival rate of 64.5%. In stage III/IV tumors, resectability was only 20.4%. However, curative surgery in advanced stages significantly increased median survival from 3.2 to 19.4 months. CONCLUSIONS: Only complete tumor resection can provide long-term survival, even in advanced stages. Because negative surgical margins and UICC stage are the strongest predictors for survival, reoperation is required with all incidental findings above the T1b stage.
TREATMENT
Appraisal of surgical resection of gallbladder carcinoma with special reference to hepatic resection. Paquet KJ. Department of Surgery, University of Bonn, D-53127 Bonn Heinz Kalk-Hospital, D-97688 Bad Kissingen and Johanniter-Hospital, D-39576 Stendal, Germany.	J Hepatobiliary Pancreat Surg 1998;5(2):200-6 Abstract quote Carcinoma of the gallbladder a gastrointestinal malignancy with an extraordinarily poor prognosis. However, aggressive surgery, with special reference to hepatic resection, may improve survival. To prove this, we performed a retrospective analysis over an 18-year period to investigate the experience of a center that began employing liver resection in patients with gallbladder cancer in 1978. The analysis was based on patients' documentation and regular follow-up to January 1996. The standard procedures were extended cholecystectomy (cholecystectomy with lymphadenectomy and wedge hepatic resection), anatomic segmentectomy of segments IVa and V, and extended hepatectomy. Significance was assessed by the log-rank test. Thirty-nine patients were resected, curatively in 41% (n = 22; group I) and palliatively in 31% (n = 17; group 2). In 28% (n = 15; group 3) a palliative or no operation was performed. Only curatively resected patients were analyzed and followed up to January 1996. No patients in group 1 died postoperatively. The actuarial 5-year survival rate of the patients with curative resection was 55%. Four patients had stage I, two had stage II, four had stage III, and two had stage IV disease according to TNM-classification. Six of the 16 patients without lymph node metastasis survived more than 5 years. A significant difference in long-term survival was recognised between stage II and stage IV patients and between stage (pT1a)- and (look table 1b) (pT1b)-patients (P < 0.01). Diagnostic efforts should focus on detecting early stages I and II gallbladder cancer. In advanced cases, aggressive surgery, particularly with hepatic resection, is the method of choice and is successful even in patients 70 years and older.
Outcomes of aggressive treatment of stage IV gallbladder cancer and predictors of survival. Todoroki T, Takahashi H, Koike N, Kawamoto T, Kondo T, Yoshida S, Kashiwagi H, Otsuka M, Fukao K, Saida Y. Department of Surgery, University of Tsukuba, Japan.	Hepatogastroenterology 1999 Jul-Aug;46(28):2114-21 Abstract quote BACKGROUND/AIMS: Stage IV gallbladder carcinoma patients are rarely considered treatable by resection. They resign themselves to palliation because there is no long-term survival data available on the risks of morbidity and mortality following aggressive treatment. The aim of this study was to evaluate predictors of survival following aggressive resection surgery for stage IV gallbladder carcinoma. METHODOLOGY: In this retrospective study, we examined 93 patients with stage IV gallbladder carcinoma who had undergone resections. Of the 93 patients, 69 had undergone liver resection to various extents together with hepaticocholedochus resection (HCR); 2 had undergone pancreaticoduodenectomy (PD) both with and without HCR; 31 had undergone hepatopancreaticoduodenectomy (HPD); 7 had undergone cholecystectomy together with HCR; 12 had undergone cholecystectomy; and 3 had undergone extended cholecystectomy. Fifty of the 93 patients had also undergone adjuvant radiotherapy. Using univariate and multivariate analyses, 13 clinicopathologic risk factors were analyzed to predict survival. RESULTS: Operative morbidity and mortality rates were 17.2% and 5.4%, respectively. Overall, the 5-year survival rate and median survival time were 9.8% and 243 days, respectively. The 5-year survival rate was significantly higher in stage IVA (n = 17) than in stage IVB (n = 76), at 42.8% and 4.9%, respectively. Multivariate analysis revealed that sex, histopathologic type, lymph node involvement (N), subgroup of stage IV, post-resection residual tumors, and adjuvant radiotherapy were significant predictors of survival. CONCLUSIONS: Long-term survival, with acceptable mortality and morbidity, can be expected in female patients who have stage IVA gallbladder cancer consisting of well-differentiated adenocarcinoma and who undergo either complete microscopic resection or grossly complete resection followed by adjuvant radiotherapy.
Benefits of combining radiotherapy with aggressive resection for stage IV gallbladder cancer. Todoroki T, Kawamoto T, Otsuka M, Koike N, Yoshida S, Takada Y, Adachi S, Kashiwagi H, Fukao K, Ohara K. Department of Surgery and Radiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-shi, Japan	Hepatogastroenterology 1999 May-Jun;46(27):1585-91 Abstract quote BACKGROUND/AIMS: The efficacy of combining resection and radiation in the management of advanced gallbladder cancer has not yet been defined. In this study, effects of combining radiation therapy on survival, local control and the pattern of recurrences were analyzed as a retrospective review. METHODOLOGY: From October 1976 to May 1996, 85 patients with stage IV (pTNM) gallbladder cancer underwent various aggressive resection modalities in our institute, including 34 liver resections, 30 hepatopancreaticoduodenectomies. Intra-operative, external or intracavitary radiation therapy was supplemented to resection in 47 patients. RESULTS: The 30-day operative mortality rate was 5.9% and the overall 5-year survival rate of stage IV disease patients was 6.3%; 3 patients are living well more than 6 years after surgery. Adjuvant radiotherapy yielded a significantly (p=0.0023) higher 5-year survival rate (8.9%) than resection alone (2.9%). The local control rate was significantly (p=0.0467) higher in the adjuvant radiation group than in the resection alone group (59.1% vs. 36.1%). However, there was no statistical difference in the frequency of distant metastasis between the two groups. Significant improvement (p=0.0028) of long-term survival was exhibited when radiation was used appropriately on patients with microscopic residues only. Those with macroscopic or without microscopic residues failed to improve. The 5-year survival rate and median survival time of patients receiving adjuvant radiation therapy for microscopic residues were 17.2% and 463 days, respectively. CONCLUSIONS: Adjuvant radiation therapy following aggressive resection, in certain circumstances, improves prognosis with acceptable operative mortality for stage IV gallbladder cancer.

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