Novel predictors for lymph node metastasis in submucosal invasive colorectal carcinoma

Table 1 Univariate analysis of clinicopathological and histological parameters for lymph node metastasis

	LNM		P value
	No (n = 221)	Yes (n = 31)
Age (yr)	61.81 ± 11.40	61.35 ± 10.63	0.8334
	63.0 (31.0, 86.0)	66.0 (38.0, 78.0)
Sex
Male	115 (88.46)	15 (11.54)	0.7205
Female	106 (86.89)	16 (13.11)
Tumor location
Ascending colon	34 (89.48)	4 (10.52)	0.6018
Transverse colon	12 (85.71)	2 (14.29)
Descending colon	6 (100.00)	0 (0.00)
Sigmoid colon	73 (91.25)	7 (8.75)
Rectosigmoid colon	14 (93.33)	1 (6.67)
Rectum	78 (82.98)	16 (17.02)
Cecum	3 (75.00)	1 (25.00)
Vermiform appendix	1 (100.00)	0 (0.00)
Tumor size (cm)	2.05 ± 1.67	2.07 ± 1.27	0.6902
	1.8 (0.2, 6.5)	2.0 (0.4, 6.5)
Tumor type
Pedunculated type	84 (93.33)	6 (6.67)	0.0424
Sessile type	137 (84.57)	25 (15.43)
Depth of submucosal invasion
by JSCCR (μm)	2473.94 ± 2003.78	3777.42 ± 2167.10	0.0002
	2200.0 (0.0, 13500.0)	3500.0 (1050.0, 12000.0)
< 1000	46 (100.00)	0 (0.00)	0.0021
≥ 1000	175 (84.95)	31 (15.05)
by Kitajima (μm)	1944.3 ± 1885.18	3380.65 ± 2390.28	0.0002
	1900.0 (0.0, 13500.0)	3000.0 (500.0, 12000.0)
< 1000	76 (95.00)	4 (5.00)	0.0218
≥ 1000	145 (94.30)	27 (15.70)
by Ueno (μm)	2671 ± 1898.39	3908.06 ± 2147.17	0.0002
	2300.0 (50.0, 13500.0)	3500.0 (1050.0, 12000.0)
< 1000	34 (100.00)	0 (0.00)	0.0113
≥ 1000	187 (85.78)	31 (14.22)
Width of submucosal invasion (μm)	5831.45 ± 4724.02	9261.29 ± 4692.03	< 0.0001
	5000.0 (50.0, 31000.0)	8000.0 (1900.0, 21000.0)
< 4000 μm	87 (96.67)	3 (3.33)	0.0010
≥ 4000 μm	134 (82.72)	28 (17.28)
Depth multiplied by width
by JSCCR (mm2)	20.22 ± 35.07	38.91 ± 36.50	< 0.0001
	11.6 (0.0, 303.8)	26.6 (2.0, 163.8)
< 6.5	84 (98.82)	1 (1.18)	< 0.0001
≥ 6.5	137 (82.04)	30 (17.96)
by Kitajima (mm2)	16.79 ± 34.52	36.42 ± 37.97	< 0.0001
	8.8 (0.0, 303.8)	23.1 (2.0, 163.8)
< 6.5	100 (95.24)	5 (4.76)	0.0017
≥ 6.5	121 (82.31)	26 (17.69)
by Ueno (mm2)	20.91 ± 34.82	40.12 ± 36.52	< 0.0001
	12.8 (0.0, 303.8)	26.6 (2.0, 163.8)
< 6.5	76 (98.70)	1 (1.30)	0.0001
≥ 6.5	145 (82.86)	30 (17.14)
Tumor differentiation
Well and moderately	211 (87.92)	29 (12.08)	0.6470
Poorly	10 (83.33)	2 (16.67)
Lymphatic invasion
No	190 (95.96)	8 (4.04)	< 0.0001
Yes	31 (57.41)	23 (42.59)
Venous invasion
No	215 (87.76)	30 (12.24)	1.0000
Yes	6 (85.71)	1 (14.29)
Perineural invasion
No	219 (87.60)	31 (12.40)	1.0000
Yes	2 (100)	0 (0.00)
Inflammation
No	100 (87.72)	14 (12.28)	1.0000
Yes	121 (87.68)	17 (12.32)
Desmoplasia
No	106 (92.17)	9 (7.83)	0.0550
Yes	115 (83.94)	22 (16.06)
Tumor budding
Ueno
Grade 0, 1	158 (95.18)	8 (4.82)	< 0.0001
Grade 2, 3	63 (73.26)	23 (26.74)
Present or absent
No	119 (100)	0 (0.00)	< 0.0001
Yes	102 (76.69)	31 (23.31)
PDCs
No	110 (100.00)	0 (0.00)	< 0.0001
Yes	111 (78.17)	31 (21.83)

Data are presented as n (%) and as mean ± SD, median (range). P value of significant difference between present/absent of LMN, by χ², Fisher's exact, Wilcoxon rank sum test. LNM: Lymph node metastasis; JSCCR: Japanese Society for Cancer of the Colon and Rectum; PDCs: Poorly differentiated clusters.

Table 2 Predictive powers of histopathological factors for lymph node metastasis

	Sensitivity	Specificity	Accuracy	Positive P value	Negative P value
Depth of submucosal invasion
by JSCCR	100.00%	20.81%	30.56%	15.05%	100.00%
by Kitajima	87.10%	34.39%	40.87%	15.70%	95.00%
by Ueno	100.00%	15.38%	25.79%	14.22%	100.00%
Width of submucosal invasion	90.32%	39.37%	45.63%	17.28%	96.67%
Depth multiplied by width
by JSCCR	96.77%	38.01%	45.24%	17.96%	98.82%
by Kitajima	83.87%	45.25%	50.00%	17.69%	95.24%
by Ueno	96.77%	34.39%	42.06%	17.14%	98.70%
Lymphatic invasion	74.19%	85.97%	84.52%	42.59%	95.96%
Tumor budding
by Ueno	74.19%	71.49%	71.83%	26.74%	95.18%
Present or absent	100.00%	53.84%	59.52%	23.31%	100.00%
PDCs	100.00%	49.77%	55.95%	21.83%	100.00%

JSCCR: Japanese Society for Cancer of the Colon and Rectum; PDCs: Poorly differentiated clusters.

Table 3 Comparison of histopathological factors for predicting of lymph node metastasis by multivariate analysis

Model	AUC	SE	95%CI	Difference AUC	95%CI	P value
Crude (unadjusted)	0.640	0.046	(0.549, 0.730)
JSCCR (depth)	0.666	0.041	(0.585, 0.747)	0.026	(0.009, 0.043)	0.0022
Kitajima (depth)	0.650	0.044	(0.565, 0.736)	0.011	(-0.022, 0.043)	0.5103
Ueno (depth)	0.664	0.042	(0.582, 0.746)	0.024	(0.009, 0.040)	0.0024
Width	0.692	0.040	(0.613, 0.771)	0.053	(-0.007, 0.112)	0.0829
JSCCR (depth × width)	0.703	0.038	(0.629, 0.776)	0.063	(0.024, 0.103)	0.0017
Kitajima (depth × width)	0.681	0.042	(0.599, 0.763)	0.042	(-0.002, 0.085)	0.0612
Ueno (depth × width)	0.699	0.038	(0.624, 0.775)	0.060	(0.020, 0.099)	0.0030
Budding (ueno)	0.768	0.044	(0.682, 0.853)	0.128	(0.043, 0.214)	0.0033
Lymphatic invasion	0.843	0.041	(0.763, 0.924)	0.204	(0.114, 0.294)	< 0.0001
Budding present itself	0.830	0.0277	(0.776, 0.884)	0.190	(0.106, 0.274)	< 0.0001
PDCs	0.811	0.0296	(0.753, 0.870)	0.172	(0.087, 0.256)	< 0.0001

Crude: Tumor type, desmoplasia each model was adjusted to the tumor type and desmoplasia. AUC: Area under curve; JSCCR: Japanese Society for Cancer of the Colon and Rectum; PDCs: Poorly differentiated clusters.