Tumor infiltrating lymphocyte grade in Merkel cell carcinoma: relationships with clinical factors and independent prognostic value

Figures & data

Table 1. Baseline patient, tumor and treatment details.

	Overall cohort		No TIL		TIL no-brisk		TIL brisk
	N	%	N	%	N	%	N	%	p Value
	1594		1175	73.7%	300	18.8%	119	7.5%
Radiation treatment									.2368
No	803	50.4%	605	51.5%	138	46.0%	60	50.4%
Yes	791	49.6%	570	48.5%	162	54.0%	59	49.6%
Chemotherapy									.0446
No	1495	93.8%	1111	94.6%	272	90.7%	112	94.1%
Yes	99	6.2%	64	5.4%	28	9.3%	7	5.9%
Age									.5588
40–59	161	10.1%	119	10.1%	28	9.3%	14	11.8%
60–69	356	22.3%	250	21.3%	72	24.0%	34	28.6%
70–79	523	32.8%	391	33.3%	98	32.7%	34	28.6%
80+	554	34.8%	415	35.3%	102	34.0%	37	31.1%
Sex									.0995
Male	992	62.2%	721	61.4%	202	67.3%	69	58.0%
Female	602	37.8%	454	38.6%	98	32.7%	50	42.0%
Charlson/Deyo comorbidity score									.1542
0	1207	75.7%	888	75.6%	236	78.7%	83	69.7%
>0	387	24.3%	287	24.4%	64	21.3%	36	30.3%
Diagnosis year									.0010
2010	249	15.6%	206	17.5%	32	10.7%	11	9.2%
2011	314	19.7%	244	20.8%	52	17.3%	18	15.1%
2012	308	19.3%	228	19.4%	53	17.7%	27	22.7%
2013	399	25.0%	283	24.1%	85	28.3%	31	26.1%
2014	324	20.3%	214	18.2%	78	26.0%	32	26.9%
Positive nodes									.0100
None positive	781	49.0%	^a	59.0%		47.2%		59.2%
1–3 positive	344	21.6%		29.5%		38.4%		34.4%
4–8 positive	51	3.2%		7.4%		9.5%		5.0%
9 or more positive	16	1.0%		4.0%		4.9%		1.5%
Unknown	402	25.2%
Extracapsular extension									<.0001
No ECS	266	16.7%		26.0%		37.0%		36.5%
ECS	125	7.8%		14.9%		15.8%		4.4%
No positive nodes	781	49.0%		59.0%		47.2%		59.2%
Unknown	422	26.5%
Tumor size									.4599
0.1–2.0 cm	999	62.7%		67.8%		65.0%		69.7%
2.1–5.0 cm	424	26.6%		27.2%		31.6%		25.2%
5+ cm	70	4.4%		5.0%		3.4%		5.0%
Unknown	101	6.3%
Surgical margins									.8929
No residual tumor	1438	90.2%		91.5%		89.7%		89.9%
Residual tumor	141	8.8%		8.5%		10.3%		10.1%
Unknown	15	0.9%
Subsite									.9945
Head/neck	669	42.0%	494	42.0%	127	42.3%	48	40.3%
Trunk	162	10.2%	118	10.0%	31	10.3%	13	10.9%
Limbs/other	763	47.9%	563	47.9%	142	47.3%	58	48.7%
Vascular invasion									<.0001
Not present	859	53.9%		73.0%		60.2%		59.6%
Present	387	24.3%		27.0%		39.8%		40.4%
Unknown	348	21.8%
Immunosuppression									.0287
None	997	62.5%		91.0%		82.9%		91.9%
Suppressed	100	6.3%		9.0%		17.1%		8.1%
Unknown	497	31.2%

ECS: extracapsular extension; residual tumor: final surgical margin status after definitive surgical resection as residual tumor NOS, microscopic residual tumor or macroscopic residual tumor.

^a Variables with unknown status were imputed using multiple imputation, the percentage values stratified by TIL grade are based on the imputed datasets and felt to better represent population averaged proportions for these factors.

Figure 1. Kaplan–Meier’s curve of OS depicted for the cohort stratified by TIL grade.

Table 2. Multivariable Cox proportional hazards regression model for predictors of overall survival.

	Adj HR	95% CI		p Values
TIL type				.0031
None	Reference
Non-brisk	0.77	0.60	0.98		.0370
Brisk	0.55	0.36	0.83		.0052
Radiation treatment				.1396
No	Reference
Yes	0.87	0.72	1.05		.1396
Chemotherapy				.0068
No	Reference
Yes	1.64	1.15	2.35		.0068
Age				<.0001
40–59	Reference
60–69	1.11	0.72	1.72		.6398
70–79	1.76	1.18	2.64		.0059
80+	3.69	2.47	5.51		<.0001
Sex				<.0001
Male	Reference
Female	0.64	0.53	0.78		<.0001
Charlson/Deyo comorbidity score				.0979
0	Reference
>0	1.19	0.97	1.45		.0979
Diagnosis year				.7901
2010	Reference
2011	0.99	0.76	1.29		.9619
2012	0.93	0.70	1.23		.5947
2013	0.85	0.64	1.13		.2750
2014	1.00	0.72	1.37		.9771
Positive nodes				^a
None positive	Reference
1–3 positive	1.51	1.20	1.91		.0005
4–8 positive	1.79	1.26	2.56		.0013
9 or more positive	2.14	1.40	3.27		.0005
Extracapsular extension				<.0001
No ECS	Reference
ECS	2.00	1.54	2.58		<.0001
No positive nodes	NA
Tumor size				.0047
0.1–2.0 cm	Reference
2.1–5.0 cm	1.38	1.12	1.69		.0022
5+ cm	1.49	1.03	2.18		.0363
Surgical margins				.0006
No residual tumor	Reference
Residual tumor	1.65	1.24	2.20		.0006
Subsite				.3408
Head/neck	Reference
Trunk	0.87	0.64	1.18		.3586
Limbs/other	0.85	0.70	1.05		.1319
Vascular invasion				.2229
Not present	Reference
Present	1.15	0.92	1.43		.2229
Immunosuppression				<.0001
None	Reference
Suppressed	2.29	1.62	3.23		<.0001

ECS: extracapsular extension; residual tumor: final surgical margin status after definitive surgical resection as residual tumor NOS, microscopic residual tumor or macroscopic residual tumor.

^a An overall variable test for nodes is not considered because the category of ‘None positive’ is also considered as part of the ECS variable. We cannot independently assess this impact of the number of positive nodes in the presence of the ECS variable.

Table 3. Multinomial, multivariable logistic regression model of clinical factors and likelihood of TIL grade.

	Overall effect	Non-brisk to no TIL				Brisk to no TIL
	p Value	OR	LCI	UCI	p Value	OR	LCI	UCI	p Value
Age	.5240
40–59		Reference				Reference
60–69		1.18	0.71	1.94	.5251	1.19	0.61	2.32	.6147
70–79		0.96	0.59	1.57	.8850	0.72	0.37	1.42	.3435
80+		0.98	0.61	1.60	.9491	0.76	0.39	1.48	.4127
Sex	.0670
Male		Reference				Reference
Female		0.73	0.55	0.97	.0324	1.12	0.75	1.66	.5907
Charlson/Deyo comorbidity score	.0582
0		Reference				Reference
>0		0.77	0.56	1.06	.1133	1.40	0.91	2.15	.1213
Positive nodes	^a
None positive		Reference				Reference
1–3 positive		1.61	1.15	2.26	.0051	1.40	0.88	2.24	.1569
4–8 positive		1.74	0.91	3.30	.0930	1.05	0.31	3.51	.9389
9 or more positive		1.62	0.70	3.73	.2610	0.13	0.00	Inf	.9899
Extracapsular extension	.0023
No ECS		Reference				Reference
ECS		0.75	0.47	1.19	.2214	0.21	0.07	0.59	.0034
No positive nodes		NA				NA
Tumor size	.2669
0.1–2.0 cm		Reference				Reference
2.1–5.0 cm		1.11	0.81	1.50	.5201	0.80	0.50	1.27	.3503
5+ cm		0.54	0.26	1.14	.1062	0.91	0.36	2.33	.8511
Subsite	.9724
Head/neck		Reference				Reference
Trunk		0.87	0.54	1.39	.5616	0.99	0.50	1.94	.9744
Limbs/other		1.04	0.78	1.38	.8122	1.00	0.65	1.52	.9833
Vascular invasion	.0002
Not present		Reference				Reference
Present		1.72	1.27	2.33	.0005	2.05	1.31	3.21	.0016
Immunosuppression	.0434
None		Reference				Reference
Suppressed		1.90	1.12	3.22	.0165	0.78	0.34	1.82	.5671

ECS: extracapsular extension; residual tumor: final surgical margin status after definitive surgical resection as residual tumor NOS, microscopic residual tumor or macroscopic residual tumor.

^a An overall variable test for nodes is not considered because the category of ‘None positive’ is also considered as part of the ECS variable. We cannot independently assess this impact of the number of positive nodes in the presence of the ECS variable.

The p values which are italicized are considered statistically significant with alpha ≤.05.