Neural Invasion is an Independent Prognostic Factor in Young and Lymph Node Negative Gastric Cancer Patients Underwent Curative Gastrectomy

Figures & data

Figure 1. A consort diagram of the patients enrolled in this study.

Figure 2. (A) The representative microphotographs of neural invasion (NI) in gastric cancer assessed by HE staining (magnification: ×200, scale bar: 10 μm). NI was assessed as positive if the cancer cells presented along the sides of nerves and/or inside the epineurial, perineurial and endoneurial spaces of the neuronal sheath. (B) The nerve fiber was confirmed with the immunohistochemistry of a specific neuronal marker (PGP9.5).

Table 1. Association of neural invasion (NI) status and other clinical-pathological characteristics.

Characteristic	NI negative		NI positive		Total	p value
	n	%	n	%
Patients	322	54.39%	270	45.61%	592
Gender						0.965
Male	238	54.34%	200	45.66%	438
Female	84	54.55%	70	45.45%	154
Age						0.880
<60	120	54.79%	99	45.21%	219
≥60	202	54.16%	171	45.84%	373
Tumor Size (cm)						<0.001
<3	172	75.77%	55	24.23%	227
≥3	150	41.10%	215	58.90%	365
Tumor Site						<0.001
upper 1/3	100	45.87%	118	54.13%	218
middle 1/3	50	48.54%	53	51.46%	103
lower 1/3	172	63.47%	99	36.53%	271
Invasion Depth						<0.001
pT1	142	95.95%	6	4.05%	148
pT2	70	75.27%	23	24.73%	93
pT3	51	42.86%	68	57.14%	119
pT4	59	25.43%	173	74.57%	232
Lymph Node Metastasis						<0.001
Negative (pN0)	190	76.00%	60	24.00%	250
Positive (pN1-3)	132	38.60%	210	61.40%	342
TNM Stage						<0.001
I	167	93.30%	12	6.70%	179
II	80	59.70%	54	40.30%	134
III	75	26.88%	204	73.12%	279
D dissection						<0.001
D1+	96	96.97%	3	3.03%	99
D2	226	45.84%	267	54.16%	493
Tumor Differentiation						<0.001
Well-moderate	116	81.12%	27	18.88%	143
Poor-signet	206	45.88%	243	54.12%	449
Lauren Classification						<0.001
Diffuse	68	38.86%	107	61.14%	175
Mixed	158	69.91%	68	30.09%	226
Intestinal	96	50.26%	95	49.74%	191
Blood Vessel Invasion						<0.001
Negative	263	69.76%	114	30.24%	377
Positive	59	27.44%	156	72.56%	215
ECOG PS						0.209
0	182	52.15%	167	47.85%	349
1	140	57.61%	103	42.39%	243
BMI
<23	159	55.99%	125	44.01%	284	0.455
≥23	163	52.92%	145	47.08%	308

Figure 3. Kaplan–Meier curves for overall survival according to the positivity of NI.

Table 2. Univariate and Multivariate Cox regression analysis of overall survival in 592 GC patients, *p < 0.05, ** p < 0.01, ***p < 0.001.

	Overall Survival
	Univariate analysis		Multivariate analysis
Clinical-pathological Characteristic	HR (95% CI)	p value	HR (95% CI)	p value
Gender (Female vs Male)	0.872 (0.617-1.234)	0.441
Age (≥60 years vs <60 years)	1.973 (1.398-2.783)	<0.001***	1.842 (1.303-2.604)	<0.001***
Tumor Size (≥3cm vs <3cm)	3.192 (2.175-4.685)	<0.001***	1.612 (1.068-2.434)	0.023*
Tumor Site (Proximal vs Non-proximal)	0.769 (0.570-1.039)	0.087
Invasion Depth (Advanced (pT2-4) vs Early (pT1))	5.479 (3.048-9.850)	<0.001***	2.330 (1.225-4.430)	0.009**
Lymph Node Metastasis (pN1-N3 vs pN0)	4.008 (2.743-5.857)	<0.001***	2.415 (1.587-3.675)	<0.001***
TNM Stage (III vs I-II)	4.099 (2.919-5.758)	<0.001***
D dissection (D2 vs D1+)	6.994 (4.823-10.14)	<0.001***
Tumor Differentiation (Poor-signet vs Well-moderate)	2.854 (1.791-4.548)	<0.001***
Lauren Classification (Diffuse vs Non-diffuse)	1.466 (1.079-1.996)	0.015*
Neural Invasion (Positive vs Negative)	2.600 (1.904-3.550)	<0.001***
Blood Vessel Invasion (Positive vs Negative)	2.609 (1.936-3.517)	<0.001***	1.430 (1.038-1.970)	0.029*
ECOG PS (1 vs 0)	1.663 (1.227-2.255)	<0.001***
BMI (≥23 vs <23)	0.880 (0.654-1.184)	0.398

Table 3. Univariate survival analysis according to NI status, stratification for different clinical-pathological variable, *p < 0.05, **p < 0.01, ***p < 0.001.

	NI negative		NI positive		p value
	N	5-yr. Survival	n	5-yr. Survival
Total	322	80.0%	270	56.5%	<0.001
Gender
Male	238	77.8%	200	56.9%	<0.001
Female	84	86.2%	70	55.3%	<0.001
Age
	120	92.2%	99	64.1%	<0.001
≥60	202	72.6%	171	52.2%	<0.001
Tumor Size (cm)
	172	86.8%	55	79.4%	0.141
≥3	150	72.5%	215	50.7%	<0.001
Tumor Site
Proximal	100	78.0%	118	55.0%	<0.001
Non-proximal	222	80.9%	152	57.7%	<0.001
Invasion Depth
Early (pT1)	142	90.8%	6	100.0%	0.447
Advanced (pT2-4)	180	71.5%	264	55.5%	<0.001
Lymph Node Metastasis
Negative (pN0)	190	89.8%	60	74.3%	0.002
Positive (pN1-3)	132	65.9%	210	51.3%	0.007
TNM Stage
I/II	247	86.5%	66	77.5%	0.077
III	75	59.3%	204	49.7%	0.198
Tumor Differentiation
Well-moderate	116	88.9%	27	65.6%	0.008
Poor-signet	206	75.0%	243	55.4%	<0.001
Lauren Classification
Diffuse	68	80.6%	107	51.7%	<0.001
Mixed	158	79.0%	68	62.1%	0.007
Intestinal	96	80.3%	95	56.1%	<0.001
Blood Vessel Invasion
Negative	263	83.1%	114	67.4%	<0.001
Positive	59	66.1%	156	48.5%	0.035
BMI
<23	159	75.6%	125	57.1%	<0.001
≥23	163	84.4%	145	55.9%	<0.001

Figure 4. Multivariate Cox regression survival analysis according to NI status, stratification for different clinical-pathological variable, * p < 0.05, ** p < 0.01, *** p < 0.001. ^# the proportion of NI positive patients in early stage subgroup was too small for analysis.

Table 4. Multivariate Cox regression survival analysis according to the combination of NI status with other clinical-pathological variables, *p < 0.05, **p < 0.01, ***p < 0.001. NI: Neural invasion, LNM: Lymph node metastasis, BVI: Blood vessel invasion. ^#The sample size of early GC (pT1) & NI + subgroup was not enough for analysis.

		Hazard Ratio (95% CI)	p value
Age	<60 & NI+	0.798 (0.542-1.176)	0.254
	≥60 & NI+	1.260 (0.908-1.748)	0.167
Tumor Size	<3cm & NI+	0.543 (0.293-1.006)	0.052
	≥3cm & NI+	1.517 (1.083-2.127)	0.015*
Tumor Site	Proximal & NI+	0.901 (0.635-1.278)	0.559
	Non-proximal & NI+	1.163 (0.835-1.620)	0.371
Invasion Depth	Early GC (pT1) & NI+^#	–	–
	Advanced GC (pT2-4) & NI+	1.174 (0.808-1.706)	0.400
Lymph Node Metastasis	Negative (pN0) & NI+	0.791 (0.454-1.376)	0.406
	Positive (pN1-3) & NI+	1.178 (0.806-1.721)	0.398
TNM Stage	I/II & NI+	0.725 (0.410-1.283)	0.270
	III & NI+	1.528 (1.090-2.143)	0.014*
Tumor Differentiation	Well-moderate & NI+	0.727 (0.354-1.493)	0.386
	Poor-signet & NI+	1.191 (0.842-1.686)	0.324
Lauren Classification	Diffuse & NI+	1.614 (1.156-2.253)	0.005**
	Non-diffuse & NI+	0.783 (0.561-1.093)	0.150
Blood Vessel Invasion.	Negative & NI+	0.841 (0.578-1.224)	0.366
	Positive & NI+	1.302 (0.936-1.813)	0.118

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.