Protective effects of female reproductive factors on gastric signet-ring cell carcinoma

Table 1 Characteristics of 1431 gastric cancer patients with signet ring cells

Characteristics	Overall (n = 1431, %)	Male (n = 935, 65.3%)	Female (n = 496, 34.7%)	P value1
Age (yr)
mean ± SD	56.3 ± 11.3	57.5 ± 10.7	54.2 ± 12.1	< 0.01
< 50	386 (27.0)	213 (55.2)	173 (44.8)	< 0.01
≥ 50, < 60	444 (31.0)	303 (68.2)	141 (31.8)
≥ 60	601 (42.0)	419 (69.7)	182 (30.3)
BMI (kg/m2)
mean ± SD	23.8 ± 3.4	24.3 ± 3.4	22.9 ± 3.3	< 0.01
> 24	659 (46.1)	501 (76.0)	158 (24.0)	< 0.01
≤ 24	772 (54.0)	434 (56.2)	338 (43.8)
Smoke				< 0.01
No	822 (57.4)	346 (42.1)	476 (57.9)
Yes	609 (42.6)	589 (96.7)	20 (3.3)
Drink				< 0.01
No	821 (57.4)	354 (43.1)	467 (56.9)
Yes	610 (42.6)	581 (95.3)	29 (4.8)
Tumor site2				< 0.01
Upper	334 (23.3)	271 (81.1)	63 (18.9)
Middle	345 (24.1)	205 (59.4)	140 (40.6)
Lower	662 (46.3)	416 (62.8)	246 (37.2)
Others	90 (6.3)	43 (47.8)	47 (52.2)
Histology differentiation				0.23
Well-/moderately differentiated	29 (2.1)	22 (75.9)	7 (24.1)
Poorly/undifferentiated	1326 (97.9)	864 (65.2)	462 (34.8)
Signet-ring cell proportion (%)				0.02
≤ 10	155 (10.8)	117 (75.5)	38 (24.5)
> 10, ≤ 50	954 (66.7)	616 (74.6)	338 (35.4)
> 50, ≤ 90	235 (16.4)	143 (60.9)	92 (39.2)
> 90	87 (6.1)	59 (67.8)	28 (32.2)
Lauren type				< 0.01
Intestinal	73 (5.1)	61 (83.6)	12 (16.4)
Diffused	910 (63.6)	557 (61.2)	353 (38.8)
Mixed	353 (24.7)	261 (73.9)	92 (26.1)
Unknown	95 (6.6)	56 (59.0)	39 (41.0)
T stage				0.02
T1	411 (28.7)	246 (59.9)	165 (40.2)
T2	172 (12.0)	119 (69.2)	53 (30.8)
T3	322 (22.5)	227 (70.5)	95 (29.5)
T4	526 (36.8)	343 (65.3)	183 (34.8)
N stage				0.54
N0	573 (40.0)	365 (63.7)	208 (36.3)
N1	192 (13.4)	130 (67.7)	62 (32.3)
N2	219 (15.3)	150 (68.5)	69 (31.5)
N3	447 (31.2)	290 (64.9)	157 (35.1)
Metastasis				< 0.01
No	1348 (94.2)	892 (66.2)	456 (33.8)
Yes	83 (5.8)	43 (51.8)	40 (48.2)
Adjuvant chemotherapy				0.51
No	924 (64.6)	598 (64.7)	326 (35.3)
Yes	507 (35.4)	337 (66.5)	170 (33.5)
Neoadjuvant chemotherapy				0.72
No	1315 (91.9)	861 (65.5)	454 (34.5)
Yes	116 (8.1)	74 (63.8)	42 (36.2)
Nerve invasion				0.02
No	313 (21.9)	184 (58.8)	129 (41.2)
Yes	714 (49.9)	477 (66.8)	237 (33.2)
Unknown	404 (28.2)	274 (67.8)	130 (32.2)
Lymphovascular invasion				0.02
No	416 (29.1)	249 (59.9)	167 (40.1)
Yes	554 (38.7)	373 (67.3)	181 (32.7)
Unknown	461 (32.2)	313 (67.9)	148 (32.1)
HER-2				0.28
Negative	1082 (85.3)	702 (64.9)	380 (35.1)
Positive	187 (14.7)	129 (69.0)	58 (31.0)
Lymph nodes removed				< 0.01
≤ 16	171 (12.0)	131 (76.6)	40 (23.4)
> 16, ≤ 30	585 (40.9)	395 (67.5)	190 (32.5)
> 30	675 (47.2)	409 (60.6)	266 (39.7)

¹The P values for age and BMI (continuous variables) were calculated from Wilcoxon–Mann–Whitney test; The P value for other categorical variables were calculated from χ² test.

²Tumor site was divided by upper (cardia, fundus, gastroesophageal junction), middle (body, lesser/greater curvature), lower (antrum, pylorus) and other (gastric remnant, anastomosis, linitis plastica) parts of the stomach.

P < 0.05 indicates statistical significance. Row percentage was reported for the overall sample. BMI: Body mass index; HER-2: Human epidermal growth factor receptor 2.

Table 2 Multivariate analysis for mortality risk in gastric cancer patients with signet ring cells

Variable	HR (95%CI)1	P value
Sex disparity
Male	Ref
Menstrual female	0.58 (0.42–0.82)	< 0.01
Menopausal female	0.91 (0.72–1.14)	0.42
BMI (kg/m2)
> 24	Ref
≤ 24	1.24 (1.02–1.51)	0.03
Signet-ring cell proportion (%)
≤ 10	Ref
> 10, ≤ 50	0.97 (0.72–1.32)	0.86
> 50, ≤ 90	0.79 (0.53–1.17)	0.25
> 90	1.03 (0.63–1.70)	0.90
T stage
T1	Ref
T2	1.58 (0.87–2.88)	0.13
T3	4.20 (2.57–6.84)	< 0.01
T4	5.96 (3.67–9.69)	< 0.01
N stage
N0	Ref
N1	1.30 (0.87–1.93)	0.195
N2	1.92 (1.34–2.75)	< 0.01
N3	3.29 (2.38–4.55)	< 0.01
Adjuvant chemotherapy
No	Ref
Yes	0.75 (0.62–0.91)	< 0.01
Neoadjuvant chemotherapy
No	Ref
Yes	2.34 (1.79–3.04)	< 0.01
Nerve invasion
No	Ref
Yes	1.50 (0.93–2.43)	0.10
Unknown	1.47 (0.88–2.46)	0.14
Lymphovascular invasion
No	Ref
Yes	1.39 (1.02–1.90)	0.04
Unknown	1.26 (0.89–1.80)	0.19

¹The Cox model included gender, BMI, signet-ring cell proportion, T stage, N stage, adjuvant chemotherapy, neoadjuvant chemotherapy, nerve invasion, and lymphovascular invasion.

P < 0.05 indicates statistical significance. BMI: Body mass index.

Table 3 Associations of sex and risk of mortality among gastric cancer patients with signet-ring cells by subgroups

Variable	Male		Menstrual female		Menopausal female		P-interaction3
	n1 (%)	HR (95%CI)2	n1(%)	HR (95%CI)2	n1 (%)	HR (95%CI)2
BMI (kg/m2)							0.014
> 24	501 (53.6)	Ref	41 (22.7)	0.56 (0.27–1.16)	117 (37.1)	1.04 (0.72–1.50)
≤ 24	434 (46.4)	Ref	140 (77.4)	0.58 (0.39–0.85)	198 (62.9)	0.84 (0.62–1.12)
Signet-ring cell proportion (%)							0.038
≤ 50	733 (78.4)	Ref	129 (71.3)	0.56 (0.38–0.82)	247 (78.4)	0.94 (0.74–1.21)
> 50	202 (21.6)	Ref	52 (28.7)	0.73 (0.33–1.61)	68 (21.6)	0.74 (0.40–1.35)
Adjuvant chemotherapy							< 0.001
No	598 (64.0)	Ref	119 (65.8)	0.38 (0.22–0.65)	207 (65.7)	1.01 (0.75–1.36)
Yes	337 (36.0)	Ref	62 (34.3)	0.83 (0.53–1.29)	108 (34.3)	0.80 (0.56–1.16)
Neoadjuvant chemotherapy							< 0.001
No	861 (92.1)	Ref	165 (91.2)	0.53 (0.36–0.77)	289 (91.8)	0.80 (0.35–1.82)
Yes	74 (7.9)	Ref	16 (8.8)	0.97 (0.76–1.25)	26 (8.3)	0.65 (0.33–1.26)
Nerve invasion							0.0294
No	184 (19.7)	Ref	54 (29.8)	0.36 (0.07–1.86)	75 (23.8)	0.78 (0.27–2.27)
Yes	477 (51.0)	Ref	87 (48.1)	0.60 (0.40–0.89)	150 (47.6)	0.91 (0.69–1.21)
Unknown	274 (29.3)	Ref	40 (22.1)	0.65 (0.31–1.39)	90 (28.6)	0.95 (0.60–1.49)
Lymphovascular invasion							< 0.004
No	249 (26.6)	Ref	70 (38.7)	0.89 (0.40–1.95)	97 (30.8)	1.13 (0.61–2.11)
Yes	373 (39.9)	Ref	56 (30.9)	0.49 (0.30–0.80)	125 (39.7.2)	0.81 (0.59–1.10)
Unknown	313 (33.5)	Ref	55 (30.4)	0.68 (0.37–1.23)	93 (29.5)	1.23 (0.80–1.91)

¹Column percentage was reported for the overall sample; percentage can differ slightly from 100% because of rounding.

²The Cox proportional hazards model included gender, BMI, signet-ring cell proportion, T stage, N stage, adjuvant chemotherapy, neoadjuvant chemotherapy, nerve invasion, and lymphovascular invasion.

³Wald test was used to examine the interaction term between sex (male, menstrual female, and menopausal female) and BMI, signet-ring cell proportion, adjuvant chemotherapy, neoadjuvant chemotherapy, nerve invasion, and lymphovascular invasion.

⁴The P value shows the outcome of interaction test between sex difference and nerve invasion (no vs yes) and lymphovascular invasion (no vs yes).

BMI: Body mass index. P < 0.05 indicates statistical significance.