Prognostic impact of tertiary lymphoid structures and other pathological features in intrahepatic cholangiocarcinoma

doi:10.3877/cma.j.issn.1674-0793.2026.02.004

Abstract

Abstract:

Objective

To investigate the prognostic values of tertiary lymphoid structures (TLS), perineural invasion, lymph node metastasis, and other pathological features in patients with intrahepatic cholangiocarcinoma (ICC) after curative resection.

Methods

Clinicopathological and follow-up data of 302 patients with pathologically confirmed ICC who underwent curative resection from June 2009 to April 2021 were retrospectively analyzed. TLS in tumor and liver tissues were evaluated by hematoxylin-eosin staining and classified as lymphoid aggregates (Agg), primary follicles (FL-1), and secondary follicles (FL-2). Survival was analyzed using the Kaplan-Meier method and Cox regression model.

Results

The median recurrence-free survival (RFS) and overall survival (OS) were 9.9 months (95% CI: 7.14-11.83) and 29.5 months (95% CI: 21.39-36.63), respectively. Intratumoral TLS were observed in 124 patients (41.06%). Multivariate analysis showed that intratumoral TLS positivity was an independent protective factor for RFS (P=0.015) and OS (P=0.006). Perineural invasion was an independent risk factor for RFS (P=0.006) and OS (P<0.001). Lymph node metastasis was also an independent risk factor for OS (P<0.001) and RFS (P<0.001). TLS in liver tissue and TLS maturation were not significantly associated with RFS or OS.

Conclusions

Intratumoral TLS positivity is an independent protective factor for OS and RFS in patients with ICC after surgery, while perineural invasion and lymph node metastasis are independent risk factors. These pathological features may provide valuable references for postoperative prognostic evaluation in ICC.

Key words: Intrahepatic cholangiocarcinoma, Tertiary lymphoid structures, Perineural invasion, Lymph node metastasis, Prognosis

Liwang Deng, Yuxi Huang, Shiyi Liu, Bin Li. Prognostic impact of tertiary lymphoid structures and other pathological features in intrahepatic cholangiocarcinoma[J]. Chinese Archives of General Surgery(Electronic Edition), 2026, 20(02): 91-97.

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Figures/Tables 6

References 22

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项目	总例数	TLS阴性组	TLS阳性组	统计值	P值
例数	302	178	124
年龄(岁) ^a	58 (51~66)	58 (48~65)	58 (52~66)	-0.804	0.421
性别				-	1.000
男	175 (57.95)	103 (57.87)	72 (58.06)
女	127 (42.05)	75 (42.13)	52 (41.94)
白细胞(×10⁹/L) ^a	7.09 (5.85~8.77)	7.83 (6.19~9.95)	6.55 (5.69~7.67)	3.920	<0.001
中性粒细胞(×10⁹/L) ^a	4.39 (3.43~6.02)	5.08 (3.69~6.62)	4.08 (3.16~5.07)	3.747	<0.001
白蛋白(g/L) ^a	39.75 (36.40~42.20)	40.15 (36.90~42.60)	38.70 (35.20~41.60)	2.506	0.012
总胆红素(μmol/L) ^a	12.30 (9.60~19.00)	12.00 (9.50~17.20)	14.00 (9.65~28.85)	-2.188	0.029
HBsAg				-	0.113
阴性	222 (73.51)	137 (76.97)	85 (68.55)
阳性	80 (26.49)	41 (23.03)	39 (31.45)
肝硬化				-	0.574
否	235 (77.81)	136 (76.40)	99 (79.84)
是	67 (22.19)	42 (23.60)	25 (20.16)
AFP (μg/L)				-	0.006
≤20	276 (91.39)	156 (87.64)	120 (96.77)
>20	26 (8.61)	22 (12.36)	4 (3.23)
CA19-9 (U/ml)				-	0.395
≤37	108 (35.76)	60 (33.71)	48 (38.71)
>37	194 (64.24)	118 (66.29)	76 (61.29)
肿瘤直径(cm)				-	0.100
≤5	129 (42.72)	69 (38.76)	60 (48.39)
>5	173 (57.28)	109 (61.24)	64 (51.61)
肿瘤个数				-	0.134
单发	230 (76.16)	130 (73.03)	100 (80.65)
多发	72 (23.84)	48 (26.97)	24 (19.35)
肿瘤分化程度				-	0.554
高	20 (6.62)	10（5.62）	10（8.06）
中	250（82.78）	147（82.58）	103（83.06）
低	32 (10.60)	21 (11.80)	11 (8.87)
微血管浸润				-	0.045
无	238 (78.81)	133 (74.72)	105 (84.68)
有	64 (21.19)	45 (25.28)	19 (15.32)
淋巴结转移				-	0.188
无	186 (61.59)	104 (58.43)	82 (66.13)
有	116 (38.41)	74 (41.57)	42 (33.87)
TNM分期				-	0.076
Ⅰ~Ⅱ	176 (58.28)	96 (53.93)	80 (64.52)
Ⅲ~Ⅳ	126 (41.72)	82 (46.07)	44 (35.48)
瘤内纤维化程度				-	0.015
高	95 (31.46)	46 (25.84)	49 (39.52)
中	83 (27.48)	48 (26.97)	35 (28.23)
低	124 (41.06)	84 (47.19)	40 (32.26)
肿瘤坏死				-	0.021
无	45 (14.90)	19 (10.67)	26 (20.97)
有	257 (85.10)	159 (89.33)	98 (79.03)
神经浸润				-	<0.001
无	163 (53.97)	115 (64.61)	48 (38.71)
有	139 (46.03)	63 (35.39)	76 (61.29)
包膜侵犯				-	0.497
无	261 (86.42)	156 (87.64)	105 (84.68)
有	41 (13.58)	22 (12.36)	19 (15.32)

项目	总例数	TLS阴性组	TLS阳性组	统计值	P值
例数	302	178	124
年龄(岁) ^a	58 (51~66)	58 (48~65)	58 (52~66)	-0.804	0.421
性别				-	1.000
男	175 (57.95)	103 (57.87)	72 (58.06)
女	127 (42.05)	75 (42.13)	52 (41.94)
白细胞(×10⁹/L) ^a	7.09 (5.85~8.77)	7.83 (6.19~9.95)	6.55 (5.69~7.67)	3.920	<0.001
中性粒细胞(×10⁹/L) ^a	4.39 (3.43~6.02)	5.08 (3.69~6.62)	4.08 (3.16~5.07)	3.747	<0.001
白蛋白(g/L) ^a	39.75 (36.40~42.20)	40.15 (36.90~42.60)	38.70 (35.20~41.60)	2.506	0.012
总胆红素(μmol/L) ^a	12.30 (9.60~19.00)	12.00 (9.50~17.20)	14.00 (9.65~28.85)	-2.188	0.029
HBsAg				-	0.113
阴性	222 (73.51)	137 (76.97)	85 (68.55)
阳性	80 (26.49)	41 (23.03)	39 (31.45)
肝硬化				-	0.574
否	235 (77.81)	136 (76.40)	99 (79.84)
是	67 (22.19)	42 (23.60)	25 (20.16)
AFP (μg/L)				-	0.006
≤20	276 (91.39)	156 (87.64)	120 (96.77)
>20	26 (8.61)	22 (12.36)	4 (3.23)
CA19-9 (U/ml)				-	0.395
≤37	108 (35.76)	60 (33.71)	48 (38.71)
>37	194 (64.24)	118 (66.29)	76 (61.29)
肿瘤直径(cm)				-	0.100
≤5	129 (42.72)	69 (38.76)	60 (48.39)
>5	173 (57.28)	109 (61.24)	64 (51.61)
肿瘤个数				-	0.134
单发	230 (76.16)	130 (73.03)	100 (80.65)
多发	72 (23.84)	48 (26.97)	24 (19.35)
肿瘤分化程度				-	0.554
高	20 (6.62)	10（5.62）	10（8.06）
中	250（82.78）	147（82.58）	103（83.06）
低	32 (10.60)	21 (11.80)	11 (8.87)
微血管浸润				-	0.045
无	238 (78.81)	133 (74.72)	105 (84.68)
有	64 (21.19)	45 (25.28)	19 (15.32)
淋巴结转移				-	0.188
无	186 (61.59)	104 (58.43)	82 (66.13)
有	116 (38.41)	74 (41.57)	42 (33.87)
TNM分期				-	0.076
Ⅰ~Ⅱ	176 (58.28)	96 (53.93)	80 (64.52)
Ⅲ~Ⅳ	126 (41.72)	82 (46.07)	44 (35.48)
瘤内纤维化程度				-	0.015
高	95 (31.46)	46 (25.84)	49 (39.52)
中	83 (27.48)	48 (26.97)	35 (28.23)
低	124 (41.06)	84 (47.19)	40 (32.26)
肿瘤坏死				-	0.021
无	45 (14.90)	19 (10.67)	26 (20.97)
有	257 (85.10)	159 (89.33)	98 (79.03)
神经浸润				-	<0.001
无	163 (53.97)	115 (64.61)	48 (38.71)
有	139 (46.03)	63 (35.39)	76 (61.29)
包膜侵犯				-	0.497
无	261 (86.42)	156 (87.64)	105 (84.68)
有	41 (13.58)	22 (12.36)	19 (15.32)

项目	HR	95% CI	P值
年龄	0.99	0.98~1.00	0.204
性别	0.94	0.71~1.23	0.640
白细胞	1.11	1.06~1.15	<0.001
中性粒细胞	1.12	1.07~1.16	<0.001
白蛋白	0.96	0.93~0.99	0.005
总胆红素	1.00	1.00~1.00	0.127
HBsAg（阳性）	1.00	0.73~1.36	0.994
肝硬化（是）	1.13	0.82~1.54	0.463
AFP（>20 μg/L）	1.63	1.00~2.65	0.048
CA19-9（>37 U/ml）	1.80	1.34~2.42	<0.001
肿瘤大小（>5 cm）	1.60	1.21~2.11	0.001
肿瘤个数（多发）	1.58	1.16~2.17	0.004
肿瘤分化程度
中 vs 高	1.49	0.85~2.61	0.168
低 vs 高	2.29	1.15~4.55	0.019
微血管浸润	1.81	1.31~2.49	<0.001
淋巴结转移	2.47	1.87~3.26	<0.001
TNM分期（Ⅲ-Ⅳ期）	2.34	1.78~3.09	<0.001
瘤内纤维化程度
中 vs 高	0.81	0.57~1.16	0.256
低 vs 高	1.06	0.78~1.46	0.695
肿瘤坏死	1.85	1.19~2.88	0.006
神经浸润	1.33	1.01~1.75	0.041
包膜侵犯	1.01	0.68~1.49	0.965
肿瘤内TLS（阳性）	0.77	0.58~1.01	0.059
肝组织内TLS（阳性）	0.99	0.73~1.33	0.926

项目	HR	95% CI	P值
年龄	0.99	0.98~1.00	0.204
性别	0.94	0.71~1.23	0.640
白细胞	1.11	1.06~1.15	<0.001
中性粒细胞	1.12	1.07~1.16	<0.001
白蛋白	0.96	0.93~0.99	0.005
总胆红素	1.00	1.00~1.00	0.127
HBsAg（阳性）	1.00	0.73~1.36	0.994
肝硬化（是）	1.13	0.82~1.54	0.463
AFP（>20 μg/L）	1.63	1.00~2.65	0.048
CA19-9（>37 U/ml）	1.80	1.34~2.42	<0.001
肿瘤大小（>5 cm）	1.60	1.21~2.11	0.001
肿瘤个数（多发）	1.58	1.16~2.17	0.004
肿瘤分化程度
中 vs 高	1.49	0.85~2.61	0.168
低 vs 高	2.29	1.15~4.55	0.019
微血管浸润	1.81	1.31~2.49	<0.001
淋巴结转移	2.47	1.87~3.26	<0.001
TNM分期（Ⅲ-Ⅳ期）	2.34	1.78~3.09	<0.001
瘤内纤维化程度
中 vs 高	0.81	0.57~1.16	0.256
低 vs 高	1.06	0.78~1.46	0.695
肿瘤坏死	1.85	1.19~2.88	0.006
神经浸润	1.33	1.01~1.75	0.041
包膜侵犯	1.01	0.68~1.49	0.965
肿瘤内TLS（阳性）	0.77	0.58~1.01	0.059
肝组织内TLS（阳性）	0.99	0.73~1.33	0.926

项目	HR	95% CI	P值
白蛋白	0.96	0.93~0.99	0.022
肿瘤大小（>5 cm）	1.46	1.09~1.94	0.010
淋巴结转移	2.04	1.51~2.73	<0.001
神经浸润	1.52	1.13~2.05	0.006
AFP（>20 μg/L）	1.57	0.95~2.59	0.080
微血管浸润	1.40	0.99~1.98	0.057
肿瘤分化程度
中 vs. 高	1.75	0.98~3.14	0.059
低 vs. 高	2.90	1.41~5.96	0.004
肿瘤内TLS	0.69	0.51~0.93	0.015

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