Evaluation of tumor budding, desmoplastic reaction, and lymphocytic infiltration in predicting survival for pancreatic ductal adenocarcinoma

Table 1 Correlation of intratumoral budding, peritumoral budding, desmoplastic reaction, and tumor-infiltrating lymphocytes with clinicopathological parameters in pancreatic adenocarcinoma, n (%)

Factor	n	PTB1	PTB2	PTB3	ITB1	ITB2	ITB3	DR1	DR2	DR3	↓pTILs	↑pTILs	↓sTILs	↑sTILs
Age, years
< 61.75 ± 12.40	40	10 (55.6)	10 (33.3)	20 (38.5)	5 (31.3)	11 (61.1)	24 (36.4)	8 (30.8)	14 (51.9)	18 (38.3)	24 (35.3)	16 (50.0)	27 (37.5)	13 (46.4)
≥ 61.75 ± 12.40	60	8 (44.4)	20 (66.7)	32 (61.5)	11 (68.8)	7 (39.9)	42 (63.6)	18 (69.2)	13 (48.1)	29 (61.7)	44 (64.7)	16 (50.0)	45 (62.5)	15 (53.6)
Sex
Female	46	8 (44.4)	10 (33.3)	28 (53.8)	6 (37.5)	7 (38.9)	33 (50.0)	10 (38.5)	14 (51.9)	22 (46.8)	32 (47.1)	14 (43.8)	33 (45.8)	13 (46.4)
Male	54	10 (55.6)	20 (66.7)	24 (46.2)	10 (62.5)	11 (61.1)	33 (50.0)	16 (61.5)	13 (48.1)	25 (53.2)	36 (52.9)	18 (56.3)	39 (54.2)	15 (53.6)
Location
Head	55	10 (55.6)	14 (46.7)	31 (59.6)	10 (62.5)	7 (38.9)	38 (57.6)	14 (53.8)	11 (40.7)	30 (63.8)	35 (51.5)	20 (62.5)	42 (58.3)	13 (46.4)
Corpus	27	5 (27.8)	12 (40.0)	10 (19.2)	5 (31.3)	7 (38.9)	15 (22.7)	8 (30.8)	7 (25.9)	12 (25.5)	18 (26.5)	9 (28.1)	16 (22.2)	11 (39.3)
Tail	18	3 (16.6)	4 (13.3)	11 (21.2)	1 (6.2)	4 (22.2)	13 (19.7)	4 (15.4)	9 (33.4)	5 (10.6)	15 (22.0)	3 (9.4)	14 (19.4)	4 (14.3)
Diameter, cm
< 1.43 ± 0.60	56	13 (72.2)	12 (40.0)	31 (59.6)	9 (56.2)	9 (50.0)	38 (57.6)	12 (46.2)	16 (59.3)	28 (59.6)	34 (50.0)	22 (68.8)	40 (55.6)	16 (57.1)
≥ 1.43 ± 0.60	44	5 (27.8)	18 (60.0)	21 (40.4)	7 (43.8)	9 (50.0)	28 (42.4)	14 (53.8)	11 (40.7)	19 (40.4)	34 (50.0)	10 (31.2)	32 (44.4)	12 (42.9)
RM
R0	81	16 (88.9)	22 (73.3)	43 (82.7)	22 (84.6)	20 (74.1)	39 (83.0)	22 (84.6)	20 (74.1)	39 (83.0)	54 (79.4)	27 (84.4)	59 (81.9)	22 (78.6)
R1	19	2 (11.1)	8 (26.7)	9 (17.3)	4 (15.4)	7 (25.9)	8 (17.0)	4 (15.4)	7 (25.9)	8 (17.0)	14 (20.6)	5 (15.6)	13 (18.1)	6 (21.4)
Invasion
T1	28	11 (61.1)	4 (13.3)	13 (25.0)a	5 (31.3)	4 (22.2)	19 (28.8)	7 (26.9)	5 (18.6)	16 (34.0)	14 (20.6)	14 (43.8)b	20 (27.8)	8 (28.6)
T2	42	6 (33.3)	15 (50.0)	21 (40.4)	8 (50.0)	10 (55.6)	24 (36.4)	11 (42.3)	11 (40.7)	20 (42.6)	29 (42.6)	13 (40.6)	27 (37.5)	15 (53.6)
T3	26	1 (5.6)	11 (36.7)	14 (26.9)	3 (18.8)	3 (16.7)	20 (30.3)	7 (26.9)	10 (37.0)	9 (19.1)	21 (30.9)	5 (15.6)	22 (30.5)	4 (14.2)
T4	4	0	0	4 (7.7)	0	1 (5.5)	3 (4.5)	1 (3.9)	1 (3.7)	2 (4.3)	4 (5.9)	0	3 (4.2)	1 (3.6)
Node status
N0	56	14 (77.8)	20 (66.7)	22 (42.3)b	13 (81.2)	13 (72.2)	30 (45.4)	17 (65.4)	14 (51.9)	25 (53.2)	32 (47.0)	24 (75.0)b	35 (48.6)	21 (75.0)b
N1	22	2 (11.1)	7 (23.3)	13 (25.0)	1 (6.3)	2 (11.1)	19 (28.8)	3 (11.5)	7 (25.9)	12 (25.5)	18 (26.5)	4 (12.5)	16 (22.2)	6 (21.4)
N2	22	2 (11.1)	3 (10.0)	17 (32.7)	2 (12.5)	3 (16.7)	17 (25.8)	6 (23.1)	6 (22.2)	10 (21.3)	18 (26.5)	4 (12.5)	21 (29.2)	1 (3.6)
LNM
Absent	56	14 (77.8)	20 (66.7)	22 (42.3)a	13 (81.3)	13 (72.2)	30 (45.5)b	17 (65.4)	14 (51.9)	25 (53.2)	32 (47.1)	24 (75.0)a	35 (48.6)	21 (75.0)b
Present	44	4 (22.2)	10 (33.3)	30 (57.7)	3 (18.8)	5 (27.8)	36 (54.5)	9 (34.6)	13 (48.1)	22 (48.6)	36 (52.9)	8 (25.0)	37 (51.4)	7 (25.0)
Metastasis
Absent	88	17 (94.4)	27 (90.0)	44 (84.6)	15 (93.8)	16 (88.9)	57 (86.4)	21 (80.8)	23 (85.2)	44 (93.6)	58 (85.3)	30 (93.8)	62 (86.1)	26 (92.9)
Present	12	1 (5.6)	3 (10.0)	8 (15.4)	1 (6.2)	2 (11.1)	9 (13.6)	5 (19.2)	4 (14.8)	3 (6.4)	10 (14.7)	2 (6.3)	10 (13.9)	2 (7.1)
Stage
I	29	9 (50.0)	7 (23.3)	13 (25.0)b	9 (56.3)	5 (27.8)	15 (22.7)	7 (26.9)	6 (22.2)	16 (34.0)	14 (20.6)	15 (46.9)a	20 (27.8)	9 (32.1)b
II	25	5 (27.8)	12 (40.0)	8 (15.4)	3 (18.8)	7 (38.9)	15 (22.7)	8 (30.8)	9 (33.2)	8 (17.0)	15 (22.1)	10 (31.3)	13 (18.1)	12 (42.9)
III	34	3 (16.6)	8 (26.7)	23 (44.2)	3 (18.8)	4 (22.2)	27 (40.9)	6 (23.1)	8 (29.6)	20 (42.6)	29 (42.6)	5 (15.6)	29 (40.2)	5 (17.9)
IV	12	1 (5.6)	3 (10.0)	8 (15.4)	1 (6.3)	2 (11.1)	9 (13.6)	5 (19.2)	4 (14.8)	3 (6.4)	10 (14.7)	2 (6.3)	10 (13.9)	2 (7.1)
Grade
G1	35	6 (33.3)	12 (40.0)	17 (32.7)	9 (56.3)	5 (27.8)	21 (31.8)	11 (42.3)	9 (33.3)	15 (31.9)	24 (35.3)	11 (34.4)	23 (31.9)	12 (42.9)
G2	54	10 (55.6)	14 (46.7)	30 (57.7)	6 (37.5)	10 (55.6)	38 (57.6)	12 (46.2)	16 (59.3)	26 (55.3)	39 (57.4)	15 (46.9)	39 (54.2)	15 (53.5)
G3	11	2 (11.1)	4 (13.3)	5 (9.6)	1 (6.2)	3 (16.7)	7 (10.6)	3 (11.5)	2 (7.4)	6 (12.8)	5 (7.4)	6 (18.8)	10 (13.9)	1 (3.6)
LVI
Absent	55	15 (83.3)	18 (60.0)	22 (42.3)a	11 (68.8)	13 (72.2)	31 (40.0)	16 (61.5)	13 (48.1)	26 (55.3)	32 (47.1)	23 (71.9)b	34 (47.2)	21 (75.0)b
Present	45	3 (16.7)	12 (40.0)	30 (57.7)	5 (31.2)	5 (27.8)	35 (53.0)	10 (38.5)	14 (51.9)	21 (44.7)	36 (52.9)	9 (28.1)	38 (52.8)	7 (25.0)
PNI
Absent	25	7 (38.9)	10 (33.3)	8 (15.4)	6 (37.5)	6 (33.3)	13 (19.7)	7 (26.9)	7 (25.9)	11 (23.4)	15 (22.1)	10 (31.3)	17 (23.6)	8 (28.6)
Present	75	11 (61.1)	20 (66.7)	44 (84.6)	10 (62.5)	12 (66.7)	53 (80.3)	19 (73.1)	20 (74.1)	36 (76.6)	53 (77.9)	22 (68.8)	55 (76.4)	20 (71.4)
Survival
Deceased	68	6 (33.3)	18 (60.0)	44 (84.6)a	0	13 (72.2)	55 (83.3)a	15 (57.7)	20 (74.1)	33 (70.2)	50 (73.5)	18 (56.3)	57 (79.2)	11 (39.3)a
Alive	32	12 (66.7)	12 (40.0)	8 (15.4)	16 (100)	5 (27.8)	11 (16.7)	11 (42.3)	7 (25.9)	14 (29.8)	18 (26.5)	14 (43.8)	15 (20.8)	17 (60.7)
PTB
PTB1	18	-	-	-	10 (62.5)	3 (16.7)	5 (7.6)	7 (26.9)	2 (7.4)	9 (19.1)b	7 (10.3)	11 (34.4)b	11 (15.3)	7 (25.0)b
PTB2	30	-	-	-	5 (31.2)	14 (77.8)	11 (16.5)	12 (46.2)	8 (29.6)	10 (21.3)	20 (29.4)	10 (31.3)	18 (25.0)	12 (42.9)
PTB3	52	-	-	-	1 (6.3)	1 (5.5)	50 (75.9)	7 (26.9)	17 (63.0)	28 (59.6)	41 (60.3)	11 (34.4)	43 (59.7)	9 (32.1)
ITB
ITB1	16	-	-	-	-	-	-	10 (38.5)	1 (3.7)	5 (10.6)a	7 (10.3)	9 (28.1)b	6 (8.3)	10 (37.5)a
ITB2	18	-	-	-	-	-	-	5 (19.2)	6 (22.2)	7 (14.9)	11 (16.2)	7 (21.9)	10 (13.9)	8 (28.6)
ITB3	66	-	-	-	-	-	-	11 (42.3)	20 (74.1)	35 (74.5)	50 (73.5)	16 (50.0)	56 (77.8)	10 (35.7)
DR
DR1	26	-	-	-	-	-	-	-	-	-	15 (22.1)	11 (34.4)	19 (26.4)	7 (25.0)
DR2	27	-	-	-	-	-	-	-	-	-	19 (27.9)	8 (25.0)	17 (23.6)	10 (34.7)
DR3	47	-	-	-	-	-	-	-	-	-	34 (50.0)	13 (40.6)	36 (50.0)	11 (39.3)
Total	100	18	30	52	16	18	66	26	27	47	68	32	72	28

^aP < 0.005.

^bP < 0.05.

DR: Desmoplastic reaction; ITB: Intratumoral budding; LNM: Lymph node metastasis; LVI: Lymphovascular invasion; PNI: Perineural invasion; PTB: Peritumoral budding; pTILs: Tumor infiltrating lymphocytes (according to median value); RM: Resection margins; sTILs: Tumor infiltrating lymphocytes (according to scoring).

Table 2 Univariate and multivariate analyses of clinicopathological characteristics on overall survival

Factors	n	Univariate survival analysis				Univariate Cox regression			Multivariate Cox regression
		Mean survival		Median survival		P value	HR	P value	95%CI	P value
		Estimate ± SE	95%CI	Estimate ± SE	95%CI
Age, years
< 61.75 ± 12.40	40	39.5 ± 2.8	33.900-45.000	44.0 ± 6.4	31.400-56.500	0.220	1.232	0.483	0.688-2.207	0.184
≥ 61.75 ± 12.40	60	45.8 ± 2.6	40.700-51.000	47.0 ± 1.8	43.400-50.500
Sex
Male	46	43.0 ± 3.6	35.900-50.200	47.0 ± 7.2	32.800-61.100	0.810	0.863	0.616	0.485-1.535	0.592
Female	54	44.4 ± 2.5	39.500-49.300	46.0 ± 1.5	42.900-49.000
Diameter, cm
< 1.43 ± 0.60	56	44.0 ± 38.6	38.600-49.400	47.0 ± 1.8	43.400-50.500	0.730	0.850	0.606	0.246-1.528	0.541
≥ 1.43 ± 0.60	44	42.2 ± 3.0	36.300-48.100	44.0 ± 3.0	38.000-49.900
Location
Head	55	29.1 ± 3.0	23.000-35.100	21.0 ± 2.9	15.100-26.800	0.590	1.523	0.582	1.081-2.404	0.053
Corpus	27	36.6 ± 28.8	28.800-44.400	37.0 ± 6.5	24.100-49.000
Tail	18	21.7 ± 3.5	14.800-28.600	17.0 ± 6.3	4.500-29.400
RM
R0	81	15.1 ± 3.6	8.000-22.100	6.0 ± 1.3	3.200-8.700	0.640	0.396	0.253	0.179-1.877	0.071
R1	19	8.6 ± 1.4	5.700-11.440	8.0 ± 2.9	2.300-13.700
Invasion
T1	28	33.0 ± 3.5	26.000-40.000	32.0 ± 3.1	25.700-38.200	0.320	0.739	0.116	0.507-1.078	0.197
T2	42	33.5 ± 2.9	27.700-39.200	36.0 ± 3.1	29.800-42.200
T3	26	42.0 ± 4.0	34.100-49.900	49.0 ± 9.3	30.600-67.300
T4	4	29.0	29.000-29.000	29.0	-
Node status
N0	56	19.0 ± 5.7	7.800-30.200	5.0 ± 1.0	3.000-6.900	0.550	1.585	< 0.020	0.523-2.096	0.961
N1	22	9.6 ± 1.1	7.300-11.900	9.0 ± 1.5	5.900-12.000
N2	22	7.6 ± 1.1	5.300-9.900	8.0 ± 1.8	4.400-11.600
LNM
Absent	56	45.8 ± 2.3	41.300-50.400	48.0 ± 1.6	44.800-51.100	< 0.001	1.388	< 0.049	0.874-12.741	0.821
Present	44	38.1 ± 4.3	29.600-46.600	36.0 ± 2.3	31.400-40.500
Metastasis
Absent	88	43.2 ± 2.0	39.100-47.300	46.0 ± 1.4	43.100-48.900	0.680	1.968	0.137	0.244-13.121	0.802
Present	12	41.1 ± 6.1	29.000-53.200	-	-
Stage
I	29	42.3 ± 2.9	36.500-48.000	45.0 ± 1.5	41.900-48.000	0.350	1.102	0.041	0.321-1.602	0.212
II	25	48.5 ± 3.7	41.100-55.900	48.0 ± 2.7	42.600-53.300
III	34	38.2 ± 4.9	28.400-47.900	36.0 ± 3.9	28.300-43.600
IV	12	41.1 ± 6.1	29.000-53.200	-	-
Grade
Low	35	47.3 ± 3.1	41.100-53.600	47.0 ± 1.5	43.900-50.000	0.140	0.748	0.210	0.475-1.177	0.265
Moderate	54	42.5 ± 2.8	37.000-48.000	48.0 ± 2.9	42.300-53.700
High	11	35.3 ± 5.2	24.900-45.600	36.0 ± 5.0	26.100-45.900
LVI
Absent	55	45.9 ± 2.4	41.100-50.600	47.0 ± 2.0	42.800-51.100	0.001	2.011	0.030	0.438-89.230	0.176
Present	45	38.6 ± 3.8	31.200-46.100	36.0 ± 4.8	26.400-45.500
PNI
Absent	25	42.9 ± 2.6	37.800-48.100	47.0 ± 1.0	45.000-48.900	0.950	0.095	0.950	0.891-4.182	0.143
Present	75	43.5 ± 2.7	38.200-48.800	45.0 ± 3.2	38.600-51.300
PTB
PTB1	18	51.8 ± 4.3	43.400-60.300	56.0 ± 3.8	48.500-63.400	< 0.001	3.065	< 0.001	1.561-5.334	< 0.001
PTB2	30	37.0 ± 2.4	32.300-41.700	35.0 ± 2.3	30.400-39.500
PTB3	52	15.9 ± 1.9	12.100-19.6	14.0 ± 0.8	12.000-15.900
ITB
ITB1	16	44.4 ± 3.6	37.300-51.500	46.0 ± 1.8	42.400-49.500	< 0.001	5.558	< 0.001	2.905-10.634	< 0.001
ITB2	18	40.2 ± 2.3	35.500-44.900	44.0 ± 6.4	31.400-56.500
ITB3	66	29.1 ± 2.6	23.900-34.200	28.0 ± 3.2	21.600-34.300
DR
DR1	26	43.7 ± 3.3	37.100-50.300	45.0 ± 6.5	32.100-57.800	0.680	1.445	0.075	0.964-2.168	0.340
DR2	27	40.3 ± 3.1	34.200-46.500	48.0	-
DR3	47	44.7 ± 3.3	38.200-51.300	48.0 ± 4.6	38.800-57.100
pTILs
↓pTILs	68	27.5 ± 2.6	22.300-32.700	21.0 ± 4.8	11.600-30.400	0.630	1.681	0.349	0.567-4.987	0.403
↑pTILs	32	35.3 ± 3.7	28.100-45.500	37.0 ± 9.8	17.700-56.300
sTILs
↓sTILs	72	23.6 ± 2.2	19.400-27.900	19.0 ± 1.4	16.400-21.500	< 0.001	0.476	0.022	0.205-1.105	0.044
↑sTILs	28	47.7 ± 4.1	39.200-55.600	27.0 ± 4.5	18.200-35.800

DR: Desmoplastic reaction; HR: Hazard ratio; ITB: Intratumoral budding; LNM: Lymph node metastasis; LVI: Lymphovascular invasion; PNI: Perineural invasion; PTB: Peritumoral budding; pTILs: Tumor infiltrating lymphocytes (according to median value); RM: Resection margins; SE: Standard error; sTILs: Tumor infiltrating lymphocytes (according to scoring).