Regional variation in routes to diagnosis of cholangiocarcinoma in England from 2006 to 2017

Table 1 Definition of cholangiocarcinoma: World Health Organization International Classification of Diseases codes included

Sub-type	ICD10 topography code	ICDO2 histology code
Intrahepatic (iCCA)	C221 (Intrahepatic bile duct carcinoma)	All
Extrahepatic (eCCA)	C240 (Extrahepatic bile duct carcinoma)	All
CCA other	C248 (Overlapping lesion of biliary tract), C249 (Biliary tract, unspecified)	All
	C220, C222, C223, C224, C227, C229	8160

iCCA: Intrahepatic cholangiocarcinoma; eCCA: Extrahepatic cholangiocarcinoma; CCA: Cholangiocarcinoma; ICD: International Classification of Disease; ICDO2: International Classification of Disease second edition.

Table 2 Cohort description

Characteristics		Patients, n (%)
Total patients (n, %)1		23632 (100.0)
Age at diagnosis (yr)	0-44	488 (2.1)
	45-54	1282 (5.4)
	55-64	3466 (14.7)
	65-74	6315 (26.7)
	75-84	7606 (32.2)
	> 84	4475 (18.9)
Gender	Male	11466 (48.5)
	Female	12166 (51.5)
Yr of diagnosis	2006	1585 (6.7)
	2007	1540 (6.5)
	2008	1732 (7.3)
	2009	1867 (7.9)
	2010	1952 (8.3)
	2011	1977 (8.4)
	2012	1997 (8.5)
	2013	2110 (8.9)
	2014	2060 (8.7)
	2015	2217 (9.4)
	2016	2262 (9.6)
	2017	2333 (9.9)
Stage at diagnosis	1	377 (1.6)
	2	873 (3.7)
	3	430 (1.8)
	4	4918 (20.8)
	Unstaged	17034 (72.1)
Tumour sub-type	CCA Other	1500 (6.3)
	eCCA	4400 (18.6)
	iCCA	17732 (75.0)
Tumour morphology	Adenomas and adenocarcinomas	21831 (92.4)
	Other	1801 (7.6)
English Index of Multiple Deprivation, income component	Quintile 1 (least deprived)	4491 (19.0)
	Quintile 2	4966 (21.0)
	Quintile 3	4823 (20.4)
	Quintile 4	4742 (20.1)
	Quintile 5 (most deprived)	4610 (19.5)
Charlson Comorbidity Index	0	17491 (74.0)
	1	2906 (12.3)
	2	1630 (6.9)
	3 +	1605 (6.8)
Underlying liver disease	No	21967 (93.0)
	Yes	1665 (7.0)
Cancer Alliance at diagnosis	Cheshire and Merseyside	1218 (5.2)
	East Midlands	2164 (9.2)
	East of England - North	1298 (5.5)
	East of England - South	1352 (5.7)
	Greater Manchester	1278 (5.4)
	Humber, Coast and Vale	862 (3.6)
	Kent and Medway	664 (2.8)
	Lancashire and South Cumbria	853 (3.6)
	North Central London	408 (1.7)
	North East London	498 (2.1)
	North West and South West London	1109 (4.7)
	Northern	1835 (7.8)
	Peninsula	950 (4.0)
	Somerset, Wiltshire, Avon and Gloucestershire	1191 (5.0)
	South East London	497 (2.1)
	South Yorkshire and Bassetlaw	655 (2.8)
	Surrey and Sussex	1354 (5.7)
	Thames Valley	590 (2.5)
	Wessex	1225 (5.2)
	West Midlands	2573 (10.9)
	West Yorkshire and Harrogate	1058 (4.5)

¹The cohort contains cholangiocarcinoma patients diagnosed between January 2006 and December 2017 inclusive. If a patient received two cholangiocarcinoma diagnoses in the study time, their first cohort-relevant tumour was selected.

iCCA: Intrahepatic cholangiocarcinoma; eCCA: Extrahepatic cholangiocarcinoma; CCA: Cholangiocarcinoma; ICD: International Classification of Disease.

Table 3 Estimated proportions diagnosed via Two Week Wait referral (as opposed to any other route): Results from linear probability models

	Model 1: Unadjusted		Model 2: Demographic-adjusted1		Model 3: Adjusted2
	Estimate	95%CI	Estimate	95%CI	Estimate	95%CI
Population average (intercept)	13.77	13.33-14.20	13.77	13.33-14.20	13.77	13.33-14.20
Cheshire and Merseyside	-4.16	-5.79--2.53	-4.08	-5.72--2.45	-3.66	-5.28--2.04
East Midlands	1.25	-0.18-2.68	1.07	-0.35-2.50	1.02	-0.38-2.43
East of England -North	1.87	-0.04-3.79	1.83	-0.09-3.75	1.71	-0.20-3.62
East of England -South	-2.67	-4.31--1.03	-2.85	-4.49--1.21	-3.01	-4.64--1.38
Greater Manchester	-2.11	-3.83--0.39	-1.92	-3.65--0.19	-1.78	-3.50--0.06
Humber, Coast and Vale	2.13	-0.26-4.52	1.93	-0.46-4.33	2.06	-0.31-4.43
Kent and Medway	-1.72	-4.17-0.73	-1.55	-3.98-0.89	-1.80	-4.24-0.64
Lancashire and South Cumbria	1.36	-1.00-3.72	1.37	-0.99-3.72	1.49	-0.84-3.82
North Central London	-4.70	-7.48--1.91	-4.57	-7.36--1.78	-4.48	-7.27--1.68
North East London	-1.92	-4.74-0.90	-1.32	-4.14-1.51	-1.04	-3.84-1.76
North West and South West London	-5.38	-6.99--3.77	-5.15	-6.76--3.53	-4.91	-6.51--3.30
Northern	3.62	1.97-5.27	3.6	1.94-5.25	3.66	2.02-5.30
Peninsula	-0.40	-2.52-1.73	-0.39	-2.52-1.74	-0.64	-2.76-1.49
Somerset, Wiltshire, Avon and Gloucestershire	1.18	-0.79-3.15	1.03	-0.94-2.99	1.18	-0.76-3.13
South East London	-0.49	-3.44-2.47	-0.02	-2.97-2.93	0.27	-2.67-3.20
South Yorkshire and Bassetlaw	1.50	-1.21-4.22	1.82	-0.89-4.54	1.93	-0.76-4.63
Surrey and Sussex	-0.99	-2.72-0.74	-1.20	-2.94-0.54	-1.41	-3.15-0.34
Thames Valley	0.81	-2.00-3.63	0.45	-2.37-3.27	0.30	-2.48-3.09
Wessex	5.17	3.05-7.30	4.89	2.76-7.02	4.73	2.63-6.83
West Midlands	-1.37	-2.58--0.16	-1.30	-2.51--0.09	-1.55	-2.76--0.35
West Yorkshire and Harrogate	2.68	0.50-4.86	2.91	0.73-5.08	3.12	0.96-5.28
Age 0-44	-8.44	-10.44--6.43	-7.76	-9.77--5.75	-8.76	-10.78--6.74
Age 45-54	-1.13	-2.90-0.65	-0.84	-2.62-0.93	-1.37	-3.14-0.40
Age 55-64	1.12	0.03-2.21	1.25	0.16-2.33	1.03	-0.06-2.13
Age 65-74	2.32	1.57-3.08	2.29	1.53-3.05	2.16	1.41-2.91
Age 75-84	0.42	-0.22-1.06	0.33	-0.31-0.97	0.56	-0.08-1.20
Age 85+	-3.62	-4.44--2.80	-3.67	-4.50--2.84	-3.46	-4.30--2.61
Female	-0.17	-0.60-0.26	0.04	-0.39-0.46	-0.27	-0.70-0.16
Male	0.18	-0.27-0.63	-0.04	-0.49-0.42	0.29	-0.17-0.74
Quintile 1 (least deprived)	0.91	-0.02-1.83	0.74	-0.20-1.67	0.42	-0.51-1.35
Quintile 2	0.59	-0.27-1.46	0.49	-0.38-1.35	0.28	-0.57-1.14
Quintile 3	0.29	-0.58-1.17	0.32	-0.56-1.20	0.33	-0.55-1.20
Quintile 4	-0.44	-1.31-0.43	-0.31	-1.18-0.56	-0.20	-1.06-0.67
Quintile 5 (most deprived)	-1.38	-2.24--0.52	-1.26	-2.15--0.37	-0.86	-1.74-0.03
2006	-3.86	-5.30--2.42			-4.4	-5.84--2.97
2007	-3.64	-5.11--2.16			-4.17	-5.64--2.69
2008	-3.31	-4.72--1.91			-3.90	-5.29--2.51
2009	-2.84	-4.21--1.47			-3.07	-4.44--1.69
2010	-1.93	-3.31--0.55			-2.15	-3.53--0.77
2011	-1.98	-3.35--0.61			-2.12	-3.49--0.75
2012	0.66	-0.82-2.13			0.73	-0.72-2.18
2013	1.07	-0.37-2.51			1.13	-0.30-2.56
2014	0.22	-1.21-1.65			0.54	-0.88-1.96
2015	2.52	1.07-3.97			3.00	1.57-4.44
2016	2.99	1.54-4.44			3.39	1.95-4.82
2017	6.04	4.52-7.55			6.42	4.92-7.93
Adenomas and adenocarcinomas	0.20	0.08-0.32			0.04	-0.08-0.16
Other morphology	-2.44	-3.86--1.02			-0.49	-1.99-1.02
eCCA	-0.38	-1.29-0.53			-0.52	-1.45-0.40
iCCA	0.12	-0.13-0.37			0.07	-0.19-0.33
Other subtype	-0.30	-1.97-1.38			0.72	-0.97-2.42
Charlson 0	1.64	1.40-1.87			1.68	1.44-1.92
Charlson 1	-2.93	-4.00--1.85			-2.88	-3.95--1.81
Charlson 2	-4.87	-6.23--3.51			-5.03	-6.40--3.67
Charlson 3 +	-7.60	-8.78--6.42			-7.98	-9.19--6.77
Liver disease -No	0.32	0.22-0.43			0.34	0.23-0.44
Liver disease -Yes	-4.28	-5.65--2.90			-4.44	-5.86--3.02

¹Adjustment for: Age, gender, income deprivation quintile.

²Adjustment for: Age, gender, income deprivation quintile, Charlson comorbidity index, underlying liver disease at diagnosis, diagnosis year, tumour morphology, tumour sub-type.

Apart from intercept, estimates represent the percentage-point difference from the weighted cohort average probability of each route. If 95%CI does not contain zero, the percentage-point difference from average will be more than 2 SD and indicates variation that is unlikely to be due to chance. Bold indicates a difference that is > 2 SD above or below average. iCCA: Intrahepatic cholangiocarcinoma; eCCA: Extrahepatic cholangiocarcinoma.

Table 4 Estimated proportions diagnosed via emergency presentation (as opposed to any other route): Results from linear probability models

	Model 1: Unadjusted		Model 2: Demographic-adjusted1		Model 3: Adjusted2
	Estimate	95%CI	Estimate	95%CI	Estimate	95%CI
Population average (intercept)	49.57	(48.94, 50.21)	49.57	(48.95, 50.20)	49.57	(48.95, 50.19)
Cheshire and Merseyside	2.81	(0.08, 5.54)	2.39	(-0.31, 5.10)	2.26	(-0.44, 4.96)
East Midlands	-2.30	(-4.3, -0.29)	-1.76	(-3.74, 0.22)	-1.69	(-3.66, 0.29)
East of England -North	1.81	(-0.83, 4.46)	1.79	(-0.82, 4.40)	2.35	(-0.26, 4.97)
East of England -South	1.46	(-1.12, 4.05)	2.55	(0.00, 5.10)	2.82	(0.27, 5.38)
Greater Manchester	5.36	(2.70, 8.01)	4.59	(1.96, 7.22)	4.75	(2.12, 7.39)
Humber, Coast and Vale	3.44	(0.17, 6.72)	3.57	(0.37, 6.78)	3.50	(0.29, 6.71)
Kent and Medway	-1.98	(-5.73, 1.77)	-2.78	(-6.42, 0.85)	-2.66	(-6.29, 0.97)
Lancashire and South Cumbria	2.83	(-0.46, 6.12)	2.59	(-0.63, 5.82)	2.32	(-0.90, 5.54)
North Central London	-1.29	(-6.11, 3.53)	-1.97	(-6.77, 2.83)	-1.82	(-6.60, 2.97)
North East London	4.85	(0.51, 9.18)	3.44	(-0.89, 7.77)	3.32	(-1.02, 7.66)
North West and South West London	0.02	(-2.85, 2.90)	0.47	(-2.35, 3.28)	0.58	(-2.24, 3.40)
Northern	-0.53	(-2.72, 1.67)	-1.26	(-3.43, 0.91)	-1.34	(-3.51, 0.82)
Peninsula	-11.47	(-14.5, -8.44)	-12.11	(-15.12, -9.09)	-12.44	(-15.44, -9.44)
Somerset, Wiltshire, Avon and Gloucestershire	0.39	(-2.38, 3.15)	1.32	(-1.39, 4.03)	0.61	(-2.10, 3.32)
South East London	2.74	(-1.61, 7.10)	2.78	(-1.51, 7.07)	2.53	(-1.77, 6.82)
South Yorkshire and Bassetlaw	9.36	(5.64, 13.08)	7.67	(3.99, 11.34)	7.74	(4.06, 11.41)
Surrey and Sussex	-3.41	(-5.99, -0.83)	-2.08	(-4.61, 0.45)	-1.97	(-4.49, 0.56)
Thames Valley	-3.81	(-7.79, 0.17)	-1.23	(-5.16, 2.70)	-1.67	(-5.57, 2.22)
Wessex	-3.86	(-6.58, -1.14)	-2.94	(-5.61, -0.27)	-3.39	(-6.04, -0.73)
West Midlands	-2.16	(-3.98, -0.34)	-2.80	(-4.58, -1.02)	-2.58	(-4.36, -0.79)
West Yorkshire and Harrogate	5.15	(2.22, 8.09)	4.33	(1.45, 7.21)	4.56	(1.68, 7.43)
Age 0-44	-5.72	(-10.09, -1.35)	-6.46	(-10.82, -2.10)	-5.66	(-10.06, -1.27)
Age 45-54	-8.39	(-11.01, -5.76)	-8.83	(-11.44, -6.23)	-8.16	(-10.78, -5.53)
Age 55-64	-10.85	(-12.35, -9.35)	-10.98	(-12.47, -9.49)	-10.46	(-11.97, -8.95)
Age 65-74	-6.82	(-7.86, -5.77)	-6.61	(-7.65, -5.57)	-6.32	(-7.36, -5.28)
Age 75-84	3.66	(2.74, 4.58)	3.65	(2.74, 4.56)	3.35	(2.44, 4.27)
Age 85+	14.83	(13.56, 16.10)	14.87	(13.59, 16.14)	14.28	(12.98, 15.57)
Female	1.91	(1.29, 2.53)	0.94	(0.32, 1.55)	1.11	(0.49, 1.72)
Male	-2.02	(-2.68, -1.37)	-0.99	(-1.64, -0.34)	-1.17	(-1.83, -0.52)
Quintile 1 (least deprived)	-4.93	(-6.24, -3.62)	-4.91	(-6.21, -3.60)	-4.61	(-5.92, -3.31)
Quintile 2	-2.69	(-3.93, -1.46)	-2.65	(-3.87, -1.43)	-2.50	(-3.71, -1.28)
Quintile 3	-0.66	(-1.92, 0.60)	-0.44	(-1.69, 0.80)	-0.41	(-1.65, 0.83)
Quintile 4	3.11	(1.84, 4.38)	3.00	(1.74, 4.25)	2.86	(1.61, 4.11)
Quintile 5 (most deprived)	5.20	(3.91, 6.49)	5.02	(3.70, 6.33)	4.67	(3.36, 5.99)
2006	1.72	(-0.66, 4.10)			1.85	(-0.49, 4.19)
2007	0.49	(-1.92, 2.91)			1.40	(-0.98, 3.79)
2008	1.58	(-0.68, 3.85)			2.50	(0.28, 4.71)
2009	2.38	(0.21, 4.56)			2.47	(0.33, 4.61)
2010	0.79	(-1.34, 2.91)			0.64	(-1.43, 2.71)
2011	-0.26	(-2.37, 1.85)			-0.05	(-2.13, 2.02)
2012	-1.10	(-3.20, 1.00)			-1.38	(-3.42, 0.66)
2013	1.28	(-0.76, 3.32)			1.24	(-0.74, 3.22)
2014	1.01	(-1.05, 3.07)			0.32	(-1.70, 2.33)
2015	-0.81	(-2.79, 1.17)			-1.37	(-3.31, 0.57)
2016	-1.83	(-3.79, 0.13)			-2.22	(-4.15, -0.30)
2017	-3.58	(-5.50, -1.66)			-3.27	(-5.16, -1.38)
Adenomas and adenocarcinomas	-0.56	(-0.74, -0.37)			-0.38	(-0.58, -0.19)
Other morphology	6.73	(4.52, 8.93)			4.64	(2.31, 6.97)
eCCA	-3.41	(-4.74, -2.08)			-2.84	(-4.16, -1.53)
iCCA	0.80	(0.43, 1.17)			0.81	(0.44, 1.18)
Other subtype	0.56	(-1.89, 3.01)			-1.26	(-3.74, 1.22)
Charlson 0	-2.09	(-2.46, -1.71)			-1.28	(-1.66, -0.90)
Charlson 1	3.97	(2.27, 5.67)			1.95	(0.29, 3.62)
Charlson 2	5.21	(2.88, 7.55)			2.74	(0.45, 5.02)
Charlson 3 +	10.24	(7.92, 12.56)			7.63	(5.31, 9.95)
Liver disease -No	0.07	(-0.11, 0.24)			-0.19	(-0.36, -0.01)
Liver disease -Yes	-0.86	(-3.18, 1.45)			2.45	(0.10, 4.70)

¹Adjustment for: Age, gender, income deprivation quintile.

²Adjustment for: Age, gender, income deprivation quintile, Charlson comorbidity index, underlying liver disease at diagnosis, diagnosis year, tumour morphology, tumour sub- type.

Apart from intercept, estimates represent the percentage- point difference from the weighted cohort average probability of each route. If 95%CI does not contain zero, the percentage- point difference from average will be more than 2 SD and indicates variation that is unlikely to be due to chance. Bold indicates a difference that is > 2 SD above or below average. iCCA: Intrahepatic cholangiocarcinoma; eCCA: Extrahepatic cholangiocarcinoma.