Risk prediction model for cutaneous squamous cell carcinoma in adult cardiac allograft recipients

Table 1 Patient characteristics and predictive variables

	Total (n = 23736)	Derivation group (n = 18989)	Validation group (n = 4747)	P value for derivation vs validation groups	cSCC positive (n = 1827)	cSCC negative (n = 21909)	P value for cSCC positive vs cSCC negative
Age	52.1 (12.6)1	52.1 (12.6)1	52.3 (12.6)1	0.293	59.1 (7.76)1	51.6 (12.7)1	< 0.001
Female	24.5	24.7	23.7	0.159	9.58	25.8	< 0.001
HLA mismatch level	4.67 (1.02)1	4.67 (1.02)1	4.68 (1.01)1	0.966	4.59 (1.05)1	4.68 (1.01)1	< 0.001
PRA against Class I antigens	5.36 (16.3)1	5.41 (16.4)1	5.16 (15.6)1	0.960	3.61 (13.2)1	5.51 (16.5)1	< 0.001
PRA against Class II antigens	3.95 (14.3)1	3.98 (14.4)1	3.83 (14.0)1	0.404	2.85 (12.2)1	4.04 (14.5)1	0.003
Race
White	71.4	71.4	71.6	0.716	97.0	69.3	< 0.001
Black	17.6	17.6	17.5	0.906	0.712	19.0	< 0.001
Hispanic	7.26	7.26	7.27	0.989	1.81	7.72	< 0.001
Other	3.70	3.74	3.54	0.514	0.493	3.97	< 0.001
Diagnosis
Dilated myopathy	82.1	82.1	82.0	0.884	81.5	82.1	0.515
Restrictive myopathy	2.22	2.27	2.00	0.261	2.24	2.21	0.932
Heart re-transplant	2.63	2.58	2.84	0.301	2.68	2.62	0.883
Coronary artery disease	4.47	4.43	4.61	0.582	6.51	4.30	< 0.001
Hypertrophic myopathy	1.92	1.90	2.00	0.636	1.70	1.94	0.475
Valvular heart disease	2.01	2.10	1.69	0.0716	2.35	1.99	0.282
Congenital heart defect	2.46	2.48	2.42	0.835	0.985	2.59	< 0.001
Other	2.23	2.18	2.44	0.272	2.03	2.25	0.532
Donor cancer history
No	98.1	98.1	98.0	0.566	98	98.1	0.764
Yes	1.60	1.56	1.73	0.422	1.81	1.58	0.457
Unknown	0.282	0.29	0.253	0.669	0.164	0.292	0.322
Malignancy at listing
No	92.7	92.8	92.5	0.476	90.3	92.9	< 0.001
Yes	5.83	5.80	5.94	0.708	7.72	5.67	< 0.001
Unknown	1.45	1.42	1.58	0.416	1.97	1.41	0.055
Malignancy at transplant
No	98.1	98.1	97.8	0.15	97.4	98.1	0.039
Yes	0.421	0.416	0.442	0.802	0.712	0.397	0.046
Unknown	1.51	1.45	1.75	0.136	1.86	1.48	0.204
Donor skin cancer history
No	97.4	97.4	97.2	0.571	97.6	97.3	0.518
Yes	0.139	0.147	0.105	0.486	0.164	0.137	0.764
Unknown	2.50	2.46	2.65	0.454	2.24	2.52	0.462
Patient status at transplant
Status 1A	46.4	46.6	45.5	0.213	38.2	47.0	< 0.001
Status 1B	37.6	37.4	38.3	0.268	40.6	37.3	0.006
Status 2	16.0	16.0	16.2	0.817	21.2	15.6	< 0.001
Induction with thymoglobulin	14.6	14.7	14.1	0.335	14.4	14.6	0.819
Induction with ATGAM	5.02	5.11	4.66	0.201	5.15	5.01	0.795
Induction with OKT3	2.32	2.29	2.44	0.517	5.42	2.06	< 0.001
Induction with daclizumab	8.30	8.43	7.77	0.142	12.2	7.98	< 0.001
Induction with basiliximab	17.5	17.4	18.0	0.321	12.6	17.9	< 0.001
Induction with alemtuzumab	1.56	1.56	1.81	0.116	1.48	1.57	0.771

¹Continuous variables are expressed as mean (SD). The rest of the values are categorical variables expressed as percentages. cSCC: Cutaneous squamous cell carcinoma; HLA: Human leukocyte antigen; PRA: Panel-reactive antibody.

Table 2 Univariate analysis of predictive variables associated with incidence probability of post-transplant cutaneous squamous cell carcinoma

Covariates	Hazard ratio (95%CI)	P value
Age	1.08 (1.07-1.09)	< 0.001
Female	0.310 (0.260-0.370)	< 0.001
HLA mismatch level	0.914 (0.870-0.960)	< 0.001
PRA against Class I antigens	0.994 (0.990-0.998)	0.006
PRA against Class II antigens	0.994 (0.989-0.999)	0.012
Race
White	1	-
Black	0.0390 (0.0221-0.068)	<0.001
Hispanic	0.178 (0.120-0.265)	<0.001
Other	0.108 (0.0512-0.226)	<0.001
Diagnosis
Dilated myopathy	1	-
Restrictive myopathy	1.38 (0.985-1.93)	0.061
Heart re-transplant	1.12 (0.807-1.55)	0.500
Coronary artery disease	1.49 (1.22-1.82)	< 0.001
Hypertrophic myopathy	0.923 (0.630-1.35)	0.681
Valvular heart disease	1.16 (0.842-1.59)	0.368
Congenital heart defect	0.393 (0.232-0.666)	0.001
Other	1.01 (0.695-1.47)	0.951
Donor cancer history
No	1	-
Yes	1.28 (0.883-1.84)	0.195
Unknown	0.997 (0.321-3.10)	0.997
Malignancy at listing
No	1	-
Yes	1.72 (1.43-2.09)	< 0.001
Unknown	0.983 (0.667-1.45)	0.930
Malignancy at transplant
No	1	0
Yes	2.55 (1.48-4.41)	0.001
Unknown	0.791 (0.528-1.18)	0.255
Donor skin cancer history
No	1	-
Yes	1.06 (0.265-4.24)	0.935
Unknown	0.631 (0.439-0.906)	0.013
Patient status at transplant
Status 1A	1	-
Status 1B	1.07 (0.950-1.20)	0.274
Status 2	0.983 (0.854-1.13)	0.805
Induction with thymoglobulin	1.05 (0.911-1.22)	0.481
Induction with ATGAM	0.980 (0.784-1.22)	0.857
Induction with OKT3	1.59 (1.27-2.01)	< 0.001
Induction with daclizumab	1.16 (0.995-1.36)	0.057
Induction with basiliximab	1.08 (0.927-1.26)	0.322
Induction with alemtuzumab	1.18 (0.773-1.80)	0.444

HLA: Human leukocyte antigen; PRA: Panel-reactive antibody; CI: Confidence interval.

Table 3 Risk factors selected from multivariate analysis

Covariates	Hazard ratio (95%CI)	P value
Age	1.068 (1.062-1.075)	< 0.001
Female	0.412 (0.344-0.494)	< 0.001
HLA mismatch level	0.951 (0.905-0.999)	0.043
Race
White	1	-
Black	0.124 (0.059-0.261)	< 0.001
Hispanic	0.058 (0.033-0.102)	< 0.001
Other	0.229 (0.154-0.340)	< 0.001
Diagnosis
Dilated myopathy	1	-
Restrictive myopathy	1.869 (1.333-2.619)	< 0.001
Heart re-transplant	1.711 (1.231-2.378)	0.001
Coronary artery disease	1.144 (0.935-1.400)	0.192
Hypertrophic myopathy	1.596 (1.087-2.345)	0.017
Valvular heart disease	1.159 (0.842-1.596)	0.364
Congenital heart defect	1.106 (0.649-1.886)	0.710
Other	1.381 (0.9477-2.012)	0.093
Malignancy at listing
No	1	-
Yes	1.593 (1.315-1.930)	< 0.001
Unknown	0.982 (0.666-1.448)	0.926
Induction with OKT3	1.380 (1.095-1.739)	0.006
Induction with daclizumab	1.371 (1.173-1.603)	< 0.001

HLA: Human leukocyte antigen; CI: Confidence interval.

Table 4 Risk score for the 5-yr development of cutaneous squamous cell carcinoma after transplantation

Covariates	Category	Score
Age	18-40	0
	40-60	1
	> 60	2
Sex	Female	0
	Male	2
HLA mismatch level	> 5	0
	≤ 5	1
Race	White	2
	Other	0
Diagnosis	Restrictive myopathy	1
	Heart re-transplant	1
	Hypertrophic myopathy	1
	Other	0
Malignancy at listing	No	0
	Yes	1
	Unknown	0
Induction with OKT3	No	0
	Yes	1
Induction with daclizumab	No	0
	Yes	1

HLA: Human leukocyte antigen.

Table 5 Log-rank test to compare the cumulative incidence of post-transplant cutaneous squamous cell carcinoma between risk groups

Group	P value	Hazard ratio (95%CI)
Low vs very low	< 0.001	4.19 (3.66-4.78)
Medium vs very low	< 0.001	7.12 (6.18-8.21)
Medium vs low	< 0.001	1.69 (1.52-1.88)
High vs very low	< 0.001	9.16 (6.23-13.5)
High vs low	< 0.001	2.18 (1.74-2.72)
High vs medium	0.004	1.28 (1.07-1.54)

CI: Confidence interval.

Table 6 Risk factors selected from multivariate analysis without OKT3 and daclizumab

Covariates	Hazard ratio (95%CI)	P value
Age	1.068 (1.062-1.075)	< 0.001
Female	0.412 (0.344-0.494)	< 0.001
HLA mismatch level	0.948 (0.903-0.996)	0.034
Race
White	1	-
Black	0.126 (0.060-0.265)	< 0.001
Hispanic	0.058 (0.033-0.102)	< 0.001
Other	0.228 (0.154-0.339)	< 0.001
Diagnosis
Dilated myopathy	1	-
Restrictive myopathy	1.897 (1.354-2.658)	< 0.001
Heart re-transplant	1.703 (1.226-2.366)	0.002
Coronary artery disease	1.135 (0.927-1.389)	0.219
Hypertrophic myopathy	1.589 (1.082-2.334)	0.018
Valvular heart disease	1.156 (0.840-1.592)	0.373
Congenital heart defect	1.098 (0.645-1.872)	0.730
Other	1.329 (0.913-1.935)	0.138
Malignancy at listing
No	1	-
Yes	1.589 (1.312-1.925)	< 0.001
Unknown	0.983 (0.666-1.449)	0.930

HLA: Human leukocyte antigen; CI: Confidence interval.

Table 7 Risk score without OKT3 and daclizumab for the 5-yr development of cutaneous squamous cell carcinoma after transplantation

Covariates	Category	Score
Age	18-40	0
	40-60	1
	> 60	2
Sex	Female	0
	Male	2
HLA mismatch level	> 5	0
	≤ 5	1
Race	White	2
	Other	0
Diagnosis	Restrictive myopathy	1
	Heart re-transplant	1
	Hypertrophic myopathy	1
	Other	0
Malignancy at listing	No	0
	Yes	1
	Unknown	0

HLA: Human leukocyte antigen.

Table 8 Log-rank test to compare the cumulative incidence of post-transplant cutaneous squamous cell carcinoma between different risk groups where patients were divided using the scoring system without OKT3 and daclizumab

Group	P value	Hazard ratio (95%CI)
Low vs very low	< 0.001	3.97 (3.51-4.50)
Medium vs very low	< 0.001	6.80 (5.86-7.90)
Medium vs low	< 0.001	1.70 (1.52-1.90)
High vs very low	< 0.001	10.1 (5.41-18.8)
High vs low	< 0.001	2.48 (1.78-3.47)
High vs medium	0.003	1.41 (1.09-1.83)

CI: Confidence interval.