Cystic duct cancer: Should it be deemed as a type of gallbladder cancer?

Table 1 Comparison of clinical characteristics between cystic duct cancer, gallbladder cancer and extrahepatic cholangiocarcinoma, n (%)

Variable	No. (%) of patients			P value
	GC (n = 4878)	EC (n = 3295)	CC (n = 36)	CC vs GC	CC vs EC
Sex				< 0.001a	0.067
Male	1528 (31.3)	1880 (57.1)	26 (72.2)
Female	3350 (68.7)	1415 (42.9)	10 (27.8)
Age at diagnosis (median)	71	69	66.5	0.059	0.161
Year of diagnosis				0.487	0.492
2006 to 2010	2041 (41.8)	1377 (41.8)	13 (36.1)
2011 to 2015	2837 (58.2)	1918 (58.2)	23 (63.9)
Marital status				0.269	0.948
Not married	2348 (48.1)	1264 (38.4)	14 (38.9)
Married	2530 (51.9)	2031 (61.6)	22 (61.1)
Race				0.703	0.330
White	3604 (73.9)	2529 (76.8)	25 (69.4)
Black	683 (14.0)	246 (7.5)	5 (13.9)
Others	591 (12.1)	520 (15.8)	6 (16.7)
Tumor size (median)	33	25	25.5	0.005a	0.195
SEER historical stage				< 0.001a	0.326
Localized	1934 (39.6)	522 (15.8)	3 (8.3)
Regional	1150 (23.6)	2098 (63.7)	27 (75.0)
Distant	1794 (36.8)	675 (20.5)	6 (16.7)
Surgical procedure				< 0.001a	0.047a
No operation	1014 (20.8)	1468 (44.6)	8 (22.2)
Biopsy/partial resection	833 (17.1)	535 (16.2)	10 (27.8)
Total resection	2490 (51.0)	417 (12.7)	6 (16.7)
Radical resection	541 (11.1)	875 (26.6)	12 (33.3)
Region				0.928	0.865
Alaska	10 (0.2)	6 (0.2)	0 (0.0)
East	1705 (35.0)	1104 (33.5)	14 (38.9)
Northern plains	441 (9.0)	301 (9.1)	5 (13.9)
Pacific coast	1858 (51.1)	1346 (41.9)	16 (44.4)
Southwest	149 (4.1)	86 (3.4)	1 (2.8)
Histology				0.042a	0.725
Adenocarcinoma	4152 (85.1)	3086(93.7)	35 (97.2)
Others	726 (14.9)	209 (6.3)	1 (2.8)

CC: Cystic duct cancer; GC: Gallbladder cancer; EC: Extrahepatic cholangiocarcinoma; SEER: Surveillance, Epidemiology, and End Results.

^aP < 0.05.

Table 2 The COX multivariate analysis for cystic duct cancer, gallbladder cancer, and extrahepatic cholangiocarcinoma

Variable	OS			CSS
	HR	95%CI	P value	HR	95%CI	P value
Sex
Male	Ref			Ref
Female	0.886	0.838 to 0.938	< 0.001a	0.895	0.838 to 0.957	0.001a
Age at diagnosis	1.025	1.022 to 1.027	< 0.001a	1.022	1.019 to 1.025	< 0.001a
Year of diagnosis
2006 to 2009	Ref			Ref
2010 to 2013	0.938	0.889 to 0.990	0.019a	0.927	0.870 to 0.987	0.018a
Marital status
Married	Ref			Ref
Unmarried	0.839	0.794 to 0.887	< 0.001a	0.855	0.801 to 0.912	< 0.001a
Race			0.110			0.258
White	Ref			Ref
Black	0.929	0.857 to 1.007	0.074	0.941	0.856 to 1.033	0.200
Other	1.042	0.956 to 1.135	0.347	1.048	0.948 to 1.158	0.359
Tumor size	1.002	1.001 to 1.002	< 0.001a	1.003	1.002 to 1.004	< 0.001a
SEER historical stage			< 0.001a			< 0.001a
Distant	Ref			Ref
Regional	0.342	0.316 to 0.370	< 0.001a	0.277	0.252 to 0.306	< 0.001a
Localized	0.642	0.599 to 0.668	< 0.001a	0.613	0.566 to 0.664	< 0.001a
Surgical procedure			< 0.001a			< 0.001a
No operation	Ref			Ref
Partial resection	0.412	0.378 to 0.449	< 0.001a	0.395	0.356 to 0.438	< 0.001a
Total resection	0.403	0.373 to 0.435	< 0.001a	0.383	0.350 to 0.419	< 0.001a
Radical resection	0.359	0.330 to 0.391	< 0.001a	0.352	0.318 to 0.388	< 0.001a
Region			0.934			0.883
Alaska	Ref			Ref
East	1.081	0.623 to 1.878	0.781	1.055	0.593 to 1.878	0.855
Northern Plains	1.127	0.646 to 1.967	0.673	1.116	0.623 to 2.001	0.711
Pacific coast	1.088	0.628 to 1.885	0.764	1.052	0.593 to 1.867	0.863
Southwest	1.090	0.619 to 1.920	0.766	1.06	0.584 to 1.926	0.847
Histology
Adenocarcinoma	Ref			Ref
Others	1.186	1.094 to 1.285	< 0.001a	1.215	1.107 to 1.334	< 0.001a
Disease			< 0.001a			< 0.001a
CC	Ref			Ref
GC	1.494	0.980 to 2.279	0.062	1.348	0.845 to 2.151	0.210
EC	1.238	0.813 to 1.884	0.320	1.124	0.706 to 1.789	0.623

OS: Overall survival; CCS: Cancer-specific survival; HR: Hazard ratio; CC: Cystic duct cancer; GC: Gallbladder cancer; EC: Extrahepatic cholangiocarcinoma; SEER: Surveillance, Epidemiology, and End Results, CI: Confidence interval.

^aP < 0.05.

Table 3 Three models to differentiate between gallbladder cancer and extrahepatic cholangiocarcinoma, and categorize cystic duct cancer cases

	Fisher’s linear discriminant	Binary logistic	ANN
	Coefficient in structure matrix	P value	Normalized importance (%)
Variable
Sex	0.479b	< 0.001a	26.1
Age at diagnosis	-0.091	< 0.001a	44.1
Year of diagnosis	0.018	0.508	12.4
Martial status	0.164	0.088	7.1
Race	-0.011	0.426	22
Tumor size	-0.215	< 0.001a	71.8c
SEER historical stage	0.665b	< 0.001a	80.4c
Surgical procedure	-0.238b	< 0.001a	100.0c
Region	0.011	0.315	25.9
Histology	0.221	< 0.001a	26.6
Model performance
Accuracy (%)
Training sample (n = 5743)	70.1	72.7	82.2
Testing sample (n = 2430)	69.3	73.6	81.9
Whole (n = 8173)	69.9	73.0	82.1
AUROC (95% CI)	0.781 (0.771-0.791)	0.785 (0.775-0.795)	0.902 (0.895-0.908)
Categorization in CC cases
Categorized as GC (%)	8 (22.2)	9 (25.0)	8 (22.2)
Categorized as EC (%)	28 (77.8)	27 (75.0)	28 (77.8)

^aP < 0.05;

^bTop 3 variables with the highest absolute values in the Fisher’s linear discriminant model;

^cThe most important three variables in the artificial neuron network mode. ANN: Artificial neuron network; SEER: Surveillance, Epidemiology, and End Results; AUROC: Area under the receiver operating characteristic curve; CI: Confidence interval; CC: Cystic duct cancer; GC: Gallbladder cancer; EC: Extrahepatic cholangiocarcinoma.