Gallbladder Tumors

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Gallbladder tumors are recognized with increasing frequency, as a consequence of improvements in imaging techniques and increased utilization of these studies. Approximately 5% of patients evaluated with ultrasonography for abdominal pain will have a gallbladder polyp. Cancer of the gallbladder is uncommon, though it is the fifth most common gastrointestinal (GI) malignancy.

It is possible to cure gallbladder cancer when tumors are treated surgically at an early stage. Given that gallbladder polyps are common, it is important to identify those that carry a high risk of malignancy. The size of a gallbladder polyp is generally the strongest predictor of malignant transformation. ^[1]

Benign lesions of the gallbladder are relatively common, but only adenomatous polyps are considered to have malignant potential. Although ultrasonography can be useful in evaluating these lesions, considerable difficulty may be encountered in establishing the diagnosis preoperatively.

In 1924, Blalock suggested avoiding surgery on patients with gallbladder cancer if the diagnosis could be made preoperatively. ^[2] Therapeutic nihilism continued to define the approach to gallbladder cancer through most of the 20th century. Although most patients with gallbladder cancer continue to present with advanced disease, advances in imaging and hepatobiliary surgical techniques have made curative surgery possible in a greater number of cases.

The surgical approach to gallbladder cancer includes prevention, early detection, appropriate staging, and curative resection.

The gallbladder is a saccular structure located at the inferior surface of the liver, at the division of the right and left hemilivers, just below segments IV and V. It is composed of four different areas: the fundus, body, infundibulum, and neck. The gallbladder is approximately 7-10 cm long and about 2.5-3.5 cm wide. It normally contains approximately 30-50 mL of fluid, but it can distend and hold as much as 300 mL of fluid.

Gallbladder cancer generally spreads via the lymphatic channels and venous drainage, and peritoneal metastasis is common. Because the gallbladder is immediately adjacent to the liver, bile duct, portal vein, hepatic artery, duodenum, and transverse colon, involvement of these structures is common.

The cystic plate is the reflection of the visceral peritoneum between the liver and the gallbladder. The dissection between the gallbladder and the liver during cholecystectomy divides the plane between the cystic plate and the muscle layer of the gallbladder. This is the anatomic basis for the improved survival in patients undergoing liver resection for T1b gallbladder cancer.

The lymphatic drainage of the gallbladder proceeds from the cystic node to the pericholedochal nodes and then to the regional nodal basins, including the superior mesenteric, retropancreatic, retroportal, and celiac. Interestingly, direct drainage from the gallbladder to the aortocaval nodes has been demonstrated. For this reason, exposure of this region is a necessary step in the operative staging of gallbladder cancer. ^[3]

Cholesterol polyps

Cholesterol polyps account for approximately 50% of all polypoid lesions of the gallbladder. These lesions are thought to originate from a defect in cholesterol metabolism. They appear as yellow spots on the mucosal surface of the gallbladder and are identified histologically as epithelial-covered macrophages laden with triglycerides and esterified sterols in the lamina propria of the mucosal layer of the gallbladder. As a rule, cholesterol polyps exist as multiple lesions and are usually smaller than 10 mm. They are generally asymptomatic.

Inflammatory polyps

These lesions result from chronic inflammation. They extend into the gallbladder lumen by a narrow vascularized stalk.

Adenomyomatosis

Adenomyomatosis is characterized by extensions of Rokitansky-Aschoff sinuses through the muscular wall of the gallbladder. Ultrasonography reveals a thickened gallbladder wall with intramural diverticula. Although adenomyomatosis is generally considered a benign condition, serial ultrasonographic evaluation is indicated to rule out enlarging adenomatous polyps and gallbladder cancer. Some authors have reported gallbladder cancer occurring in localized adenomyomatosis and have suggested a more aggressive approach to these benign lesions.

Adenomatous polyps

Adenomatous polyps are benign epithelial neoplasms with malignant potential. Papillary adenomas grow as pedunculated, complex, branching tumors projecting into the gallbladder lumen. Tubular adenomas arise as flat, sessile neoplasms. Consequently, it can be difficult to distinguish some adenomas from other gallbladder polyps by means of ultrasonography. As in many GI tumors, an adenoma-carcinoma sequence is generally thought to occur in these lesions.

Others 

Other rare, benign lesions found in the gallbladder include fibromas, leiomyomas, lipomas, hemangiomata, granular cell tumors, and heterotropic tissue, including gastric, pancreatic, and intestinal epithelium.

Chronic inflammation from a variety of stimuli has been implicated in the pathogenesis of gallbladder cancer. Numerous studies have investigated genetic abnormalities in gallbladder cancer and have shown that approximately 39-59% of these cancers are associated with the K-ras mutation, whereas more than 90% are associated with a p53 mutation. Other studies have identified higher levels of microsatellite instability and loss of heterozygosity when gallbladder cancers develop against a background of chronic cholecystitis.

A number of other genetic abnormalities have been associated with gallbladder cancer, including overexpression of the c-erb-2 gene, upregulation of cyclin D1, p16, p27, and MSH2. ^[4]

The most common risk factor for gallbladder cancer is gallstones, which are present in 75-90% of gallbladder cancer cases. The size of the gallstones plays a role in the risk of developing of gallbladder cancer. Gallbladders containing gallstones that are greater than 3 cm in diameter have a 10-fold greater risk for developing malignancy than do those containing gallstones that are 1 cm in diameter.

Causality is difficult to establish, but other chronic inflammatory conditions, such as cholecystoenteric fistula, primary sclerosing cholangitis, pancreaticobiliary maljunction, and chronic infection with Salmonella typhi, have also been associated with an increased risk of gallbladder cancer.

Modern series report about a 10% incidence of gallbladder cancer in porcelain gallbladders (in which the gallbladder wall is calcified), a much lower rate than that reported in older series. Stippled calcification of the mucosa is thought to carry a higher risk of gallbladder cancer than does generalized calcification of the gallbladder wall. ^{[5, 6]}  On the basis of these associations, chronic inflammation is postulated to be involved in the pathogenesis of gallbladder cancer.

Gallbladder cancer is often discovered incidentally during a workup for gallstone disease, and about 50% of gallbladder cancer cases are diagnosed incidentally in cholecystectomy specimens. Unfortunately, about 35% of patients have distant metastases at the time of diagnosis. Gallbladder cancer spreads early via lymphatic, hematogenous, and transcoelomic dissemination. Local invasion into the liver and surrounding organs is common.

As noted, an adenoma-carcinoma sequence is thought to be involved in many cases of gallbladder cancer. Histologically, adenocarcinoma is found in 90% of gallbladder cancer cases, and squamous cell carcinoma is found in 2% of cases. A number of histologic subtypes of adenocarcinoma have been described, but papillary adenocarcinoma represents about 5% of gallbladder cancers; it tends to be well-differentiated and carries a more favorable prognosis.

Rare types of gallbladder cancer include sarcoma, adenosquamous carcinoma, oat cell carcinoma, carcinoid, lymphoma, melanoma, and metastatic tumors. 

Gallstones are present in 75-90% of gallbladder cancer cases, but an etiologic influence remains unproven. Risk factors for developing gallbladder cancer include the inflammatory conditions listed above, advanced age, and the presence of a gallstone larger than 3 cm. Anomalous pancreatobiliary junction also may be a risk factor for the development of gallbladder cancer.

Some authors have implicated bile acid composition, methyldopa, oral contraceptives, and occupational exposure to rubber, but these associations remain unproven. A 2008 study found evidence that excess body weight in women, specifically a 5 kg/m² increase in the body-mass index (BMI), is strongly associated with an increased risk of gallbladder cancer. ^[7]

Approximately 5% of patients evaluated with ultrasonography for abdominal pain will have a gallbladder polyp. Adenomatous polyps are found in about 1% of cholecystectomy specimens.

The American Cancer Society estimated that 11,740 new cases of gallbladder or other biliary cancer would be diagnosed in 2017 and that there would be 3830 deaths from the disease. ^[8]  The incidence of gallbladder cancer is 1.2 cases 100,000 persons in the United States ^[9] ; the frequency is much higher in Mexican Americans and Native Americans, though the highest incidence is found in the indigenous peoples of the Andes Mountains, in northeastern Europeans, and in Israelis.

The female-to-male ratio for gallbladder cancer is about 3:1; the incidence of the disease peaks in the seventh decade of life. ^{[8, 4]}

The overall survival rate for adenocarcinoma of the gallbladder depends on the stage at presentation. For T1 lesions, many studies report 5-year survival rates of 100%, especially when hepatectomy is used routinely for T1b or deeper lesions.

The 5-year survival rates following extended cholecystectomy for T2 lesions range in the literature from 38% to 77%. Tumor location may affect survival for T2 lesions. In a study that included 252 patients who underwent curative resection for T2 disease, those with tumors on the hepatic side had higher rates of vascular invasion, neural invasion, and nodal metastasis and lower 3- and 5-year survival rates than patients with tumors on the peritoneal side. ^[10]

Extended resection is necessary for stage III and IV tumors and results in a 5-year survival rate of about 25%.

Patients with unresectable disease have a median survival of 2-4 months and a 1-year survival rate of less than 5%. ^{[4, 11]}

A study by Li et al indicated that the tumor-stroma ratio (TSR) may be an important prognostic indicator for gallbladder cancer. ^[12]  In their study of 51 patients who underwent operations for gallbladder carcinoma, who were classified on the basis of the TSR as either stroma-poor or stroma-rich, the latter had a worse prognosis than the former. Univariate analysis found the TSR to have a statistically significant relation to overall survival.

D’Hondt M, Lapointe R, Benamira Z, Pottel H, Plasse M, Letourneau R, et al. Carcinoma of the gallbladder: Patterns of presentation, prognostic factors and survival rate. An 11-year single centre experience. Eur J Surg Oncol. 2013 Jun. 39(6):548-53. [Medline].

Blalock AA. A statistical study of 888 cases of biliary tract disease. Johns Hopkins Hospital Bulletin. 1924. 35:391-409.

Shirai Y, Yoshida K, Tsukada K, et al. Identification of the regional lymphatic system of the gallbladder by vital staining. Br J Surg. 1992 Jul. 79(7):659-62. [Medline].

Davis JL, Kingham TP. Tumors of the gallbladder. Jarnagin WR, Allen PJ, Chapman WC, et al, eds. Blumgart’s Surgery of the Liver, Biliary Tract, and Pancreas. 6th ed. Philadelphia: Elsevier; 2017. 786-804.

Kwon AH, Inui H, Matsui Y, et al. Laparoscopic cholecystectomy in patients with porcelain gallbladder based on the preoperative ultrasound findings. Hepatogastroenterology. 2004 Jul-Aug. 51(58):950-3. [Medline].

Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery. 2001 Jun. 129(6):699-703. [Medline].

Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008 Feb 16. 371(9612):569-78. [Medline].

Cancer Facts and Figures 2017. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. 2017; Accessed: May 30, 2017.

Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review (CSR) 1975-2014. National Cancer Institute. Available at https://seer.cancer.gov/csr/1975_2014/. April 14, 2017; Accessed: May 30, 2017.

Shindoh J, de Aretxabala X, Aloia TA, et al. Tumor location is a strong predictor of tumor progression and survival in T2 gallbladder cancer: an international multicenter study. Ann Surg. 2015 Apr. 261(4):733-9. [Medline].

Okada K, Kijima H, Imaizumi T, et al. Wall-invasion pattern correlates with survival of patients with gallbladder adenocarcinoma. Anticancer Res. 2009 Feb. 29(2):685-91. [Medline].

Li H, Yuan SL, Han ZZ, Huang J, Cui L, Jiang CQ, et al. Prognostic significance of the tumor-stroma ratio in gallbladder cancer. Neoplasma. 2017 May 9. 64:[Medline]. [Full Text].

Okuyama Y, Fukui A, Enoki Y, Morishita H, Yoshida N, Fujimoto S. A Large Cell Neuroendocrine Carcinoma of the Gall Bladder: Diagnosis with 18FDG-PET/CT-guided Biliary Cytology and Treatment with Combined Chemotherapy Achieved a Long-term Stable Condition. Jpn J Clin Oncol. 2013 May. 43(5):571-4. [Medline].

Dehdashti F, Laforest R, Gao F, Shoghi KI, Aft RL, Nussenbaum B, et al. Assessment of cellular proliferation in tumors by PET using 18F-ISO-1. J Nucl Med. 2013 Mar. 54(3):350-7. [Medline].

Gallbladder cancer treatment (PDQ®)–health professional version. National Cancer Institute. Available at https://www.cancer.gov/types/gallbladder/hp/gallbladder-treatment-pdq#section/_6. February 2, 2017; Accessed: May 31, 2017.

Zielinski MD, Atwell TD, Davis PW, et al. Comparison of surgically resected polypoid lesions of the gallbladder to their pre-operative ultrasound characteristics. J Gastrointest Surg. 2009 Jan. 13(1):19-25. [Medline].

Park JO, Oh DY, Hsu C, Chen JS, Chen LT, Orlando M, et al. Gemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer: A Systematic Review. Cancer Res Treat. 2015 Jul. 47 (3):343-61. [Medline].

Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol. 2008 Dec 1. 98(7):485-9. [Medline].

Hepatobiliary cancers. NCCN Clinical Practice Guidelines in Oncology™. Available at http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed: June 17, 2015.

Mitin T, Enestvedt CK, Jemal A, Sineshaw HM. Limited Use of Adjuvant Therapy in Patients With Resected Gallbladder Cancer Despite a Strong Association With Survival. J Natl Cancer Inst. 2017 Jul 1. 109 (7):[Medline].

Reddy SK, Clary BM. Surgical management of gallbladder cancer. Surg Oncol Clin N Am. 2009 Apr. 18(2):307-24. [Medline].

Wiles R, Thoeni RF, Barbu ST, Vashist YK, Rafaelsen SR, Dewhurst C, et al. Management and follow-up of gallbladder polyps : Joint guidelines between the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), European Association for Endoscopic Surgery and other Interventional Techniques (EAES), International Society of Digestive Surgery - European Federation (EFISDS) and European Society of Gastrointestinal Endoscopy (ESGE). Eur Radiol. 2017 Feb 9. [Medline]. [Full Text].

He XD, Li JJ, Liu W, et al. Surgical procedure determination based on tumor-node-metastasis staging of gallbladder cancer. World J Gastroenterol. 2015 Apr 21. 21(15):4620-6. [Medline].

Ito H, Ito K, D’angelica M, et al. Accurate staging for gallbladder cancer: implications for surgical therapy and pathological assessment. Ann Surg. 2011 Aug. 254(2):320-5. [Medline].

Tumor (T), Node (N), Metastasis (M)

Description

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor invades lamina propria (T1a) or muscle layer (T1b)

T2

Tumor invades the perimuscular connective tissue; no extension beyond the serosa or into the liver

T3

Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or 1 other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts

T4

Tumor invades the main portal vein or hepatic artery or invades multiple extrahepatic organs or structures

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein

N2

Metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes

MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

AJCC Stage

TNM

0

Tis, N0, M0

I

T1 (a or b), N0, M0

II

T2, N0, M0

IIIA

T3, N0, M0

IIIB

T1-3, N1, M0

IVA

T4, N0-1, M0

IVB

Any T, N2, M0

Any T, any N, M1

Thomas J VanderMeer, MD Assistant Professor of Surgery, State University of New York Upstate Medical University; Chief, Section of General Surgery, Program Director of General Surgery Residency Program, Guthrie Health System

Thomas J VanderMeer, MD is a member of the following medical societies: American College of Surgeons, American College of Surgeons Oncology Group, Americas Hepato-Pancreato-Biliary Association, Association for Surgical Education, Association of Program Directors in Surgery, Society for Surgery of the Alimentary Tract

Disclosure: Nothing to disclose.

Michael Kent McLeod, MD, MBA, FACE, FACS Associate Chair, Professor of Surgery and Program Director, Integrated General Surgery Program, Department of Surgery, Michigan State University College of Human Medicine

Michael Kent McLeod, MD, MBA, FACE, FACS is a member of the following medical societies: American Association of Clinical Endocrinologists, American Association of Endocrine Surgeons, American College of Surgeons, American Medical Association, Association for Academic Surgery, Central Surgical Association, International Association of Endocrine Surgeons, Michigan State Medical Society, Midwest Surgical Association, National Medical Association, Society of American Gastrointestinal and Endoscopic Surgeons, Western Surgical Association

Disclosure: Nothing to disclose.

Tara Mancl, MD Staff Physician, Department of Surgery, Michigan State University, Kalamazoo Center for Medical Studies

Tara Mancl, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Family Physicians, American College of Surgeons, American Medical Student Association/Foundation

Disclosure: Nothing to disclose.

Michel M Murr, MD Professor, Department of Surgery, Director of Bariatric Surgery, University of South Florida

Michel M Murr, MD is a member of the following medical societies: American College of Surgeons, Americas Hepato-Pancreato-Biliary Association, American Society for Metabolic and Bariatric Surgery, Association for Academic Surgery, International College of Surgeons US Section, Society for Surgery of the Alimentary Tract, Southeastern Surgical Congress

Disclosure: Received consulting fee from Covidien for consulting.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John Geibel, MD, DSc, MSc, AGAF Vice Chair and Professor, Department of Surgery, Section of Gastrointestinal Medicine, Professor, Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director of Surgical Research, Department of Surgery, Yale-New Haven Hospital; American Gastroenterological Association Fellow

John Geibel, MD, DSc, MSc, AGAF is a member of the following medical societies: American Gastroenterological Association, American Physiological Society, American Society of Nephrology, Association for Academic Surgery, International Society of Nephrology, New York Academy of Sciences, Society for Surgery of the Alimentary Tract

Disclosure: Nothing to disclose.

Michael A Grosso, MD Consulting Staff, Department of Cardiothoracic Surgery, St Francis Hospital

Michael A Grosso, MD is a member of the following medical societies: American College of Surgeons, Society of Thoracic Surgeons, and Society of University Surgeons

Disclosure: Nothing to disclose.

Gallbladder Tumors

Research & References of Gallbladder Tumors|A&C Accounting And Tax Services
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