Gallbladder cancer: Historical treatment and new management options

Table 1 Risk factors for gallbladder cancer[35]

Patient predisposition	Environmental factors	Patient factors/conditions
Female sex	Chronic bacterial infections	Diabetes
Age	Aflatoxins	High body mass index
Race/ethnicity	Ochratoxin	Primary sclerosing cholangitis
Genetics (variants)	Arsenic	Porcelain gallbladder
	Liver fluke	Gallbladder polyps
	Geography	Crohn’s disease
		Anomalous biliary ductal insertion
		Gallstones
		Sjogren’s syndrome

Table 2 Staging of gallbladder cancer

T stage	Primary tumor
Tx	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor invades the lamina propria or muscular layer
T1a	Tumor invades lamina propria
T1b	Tumor invades muscle layer
T2	Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum) or tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver
T2a	Tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum)
T2b	Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver
T3	Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts
T4	Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures
N stage	Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis to one to three regional lymph nodes
N2	Metastasis to four or more regional lymph nodes
M stage	Distant metastasis
M0	No distant metastasis
M1	Distant metastasis

Table 3 Cancer stage grouping

Stage	T	N	M	Description
0	Tis	N0	M0	Cancer in situ
I	T1	N0	M0	Tumor is only in the gallbladder and has not spread
II	T2	N0	M0	Tumor has extended to the perimuscular connective tissue but has not spread elsewhere
IIIA	T3	N0	M0	Tumor has spread beyond the gallbladder but not to nearby arteries or veins. It has not spread to any lymph nodes or other parts of the body
IIIB	T1-3	N1	M0	Tumor of any size has spread to nearby lymph nodes but not to nearby arteries and/or veins or to other parts of the body
IVA	T4	N0 or N1	M0	Tumor has spread to nearby arteries, veins, and/or nearby lymph nodes, but it has not spread to other parts of the body
IVB	Any T	Any N	M1	Any tumor that has spread to other parts of the body
	Any T	N2	M0	Any tumor that has distant lymph node spread, even if it has not spread to distant organs

Table 4 Surgical procedures performed for gallbladder cancer

Procedure	Description	Indications
Curative procedures
Simple cholecystectomy	Dissection, ligation, and transection of cystic duct and artery at the level of Calot triangle and dissection of the cystic plate	Benign gallbladder conditions, gallbladder polyps, porcelain gallbladder, GBC (T0, Tis, and T1a)
Extended cholecystectomy	Simple cholecystectomy + hepatic wedge resection at the level of gallbladder fossa (2-3 cm in depth)	T1b and higher GBC
IVb/V hepatic bisegmentectomy	Resection of liver segments IVb and V en bloc with the gallbladder with intra-parenchymal transection of the middle hepatic vein	GBC invading liver parenchyma
Extended liver resections	Most commonly right hepatectomy, rarely left hepatectomy	GBC invading structures of porta hepatis
Bile duct resection	Resection of the extrahepatic bile duct + Roux-en-Y hepaticojejunostomy	GBC invading extrahepatic bile ducts or positive cystic duct margin at frozen section pathology
Lymphadenectomy	Removal of lymph nodes from N1 and N2 zones	T1b and higher GBC, N+ GBC
Multivisceral resection	May involve right colectomy, pancreaticoduodenectomy, resection of abdominal wall, etc.	Locally advanced GBC
Palliative procedures
Biliodigestive anastomoses	Roux-en-Y hepaticojejunostomy	Locally advanced unresectable GBC presenting with jaundice
Digestive anastomoses	Gastro-enteric anastomosis, ileo-transverse colon anastomosis	Locally advanced unresectable GBC presenting with intestinal obstruction

GBC: Gallbladder cancer.

Table 5 Historical prognosis of gallbladder cancer

Ref.	n	Year	Status	Survival time (mo)
Gall et al[96], 1991	113	1970-1989	Curative resection	42
			Non-curative resection (metastasis +)	12.5
Cubertafond et al[97], 1994	724	1980-1989	Curative resection 25%	Overall 3
			Non-curative resection 75%
Jarnagin et al[98], 2003	97	1990-2001	Curative resection	31.3
Hawkins et al[29], 2004	240	1995-2002	Curative resection	34
			Non-curative resection	8
Nishio et al[99], 2007	166	1977-2004	Curative resection	12
			Non-curative resection	6
Duffy et al[28], 2008	206	1995-2005	Overall	10.3
			Incidental GBC	15.7
			Curative surgery	30.3
			Curative surgery + adjuvant therapy	23.4
D’Hondt et al[25], 2013	102	1998-2008	Overall	7.2
			Incidental GBC	25.8
			Non-Incidental GBC	4.4
Butte et al[100], 2011	261	1999-2007	Overall	DSS 16.97
Ito et al[55], 2011	122	1992-2007	R0 resection	DSS 41
Butte et al[101], 2014	135	1998-2009	Overall	DFS 25.9
			Residual disease	11.2
			Non-residual disease	93.4
Ethun et al[18], 2017	449	2000-2014	Incidental GBC	27.6
Zhang et al[102], 2018	1422	2010-2014	Resection	13
Yu et al[86], 2019	81	2006-2015	T3 Anatomical resection	54
			T3 Wedge resection	49
Ref.	n	Year	Status	Survival rate (%)
Ogura et al[103], 1991	1686	1979-1988	Radical resection	66.2 (3 yr) 50.7 (5 yr)
			Non-radical resection	14.1 (3 yr) 6.2 (5 yr)
Cubertafond et al[97], 1994	724	1980-1989	Curative resection 25%	Overall 14 (1 yr) 5 (5 yr)
			Non-curative resection 75%
Carriaga and Henson[104], 1995	4412	1973-1987	Overall	12.3 (5 yr)
Bartlett et al[105], 1996	149	1985-1993	Resection	51 (5 yr)
Fong et al[17], 2000	410	1986-2000	Resection	38 (5 yr)
			Non-resection	4 (5 yr)
Nakeeb et al[106], 2002	140	1990-2001	Resection	31 (5 yr)
Pawlik et al[107], 2007	115	1984-2006	Resection	12 (5 yr)
Kayahara and Nagakawa[57], 2007	4770	1988-1997	Overall	39 (5 yr)
Shih et al[108], 2007	107	1995-2004	Overall	15 (5 yr)
			Incidental GBC	33 (5 yr)
D’Angelica et al[59], 2009	109	1988-2002	Overall	42 (5 yr)
Fuks et al[15], 2011	218	1998-2008	Incidental GBC	41 (5 yr)
Hari et al[109], 2013	1115	1988-2008	Cholecystectomy	50 (5 yr)
			Cholecystectomy + LN dissection	70 (5 yr)
			Radical cholecystectomy	79 (5 yr)
Barreto et al[110], 2014	163	2003-2010	Overall	DFS 79.6 (2 yr)
Shindoh et al[42], 2015	252	1981-2011	T2	42.6 (5 yr)

DSS: Disease specific survival; DFS: Disease free survival; LN: Lymph node.