Predicting lymph node metastasis in colorectal cancer: An analysis of influencing factors to develop a risk model

Table 1 Clinicopathological characteristics of the study population (%)

Variable	Training set (n = 188)	Validation set (n = 70)	P value
Age (yr)			0.86
mean ± SD	60.4 ± 13.1	60.6 ± 13.5
Median (range)	61 (18-95)	61 (20-93)
Sex			0.91
Male	112 (59.6)	42 (60)
Female	76 (40.4)	28 (40)
Tumor location			0.97
Right colon	60 (31.9)	22 (31.4)
Left colon	60 (31.9)	23 (32.9)
Rectum	68 (36.2)	25 (35.7)
Tumor size (cm)			0.83
mean ± SD	4.2 ± 2.1	4.2 ± 2.0
Median (range)	4 (1-15)	4 (1-12)
Tumor differentiation			0.99
Well/moderate	162 (86.2)	60 (85.7)
Poor/undifferentiated/others1	26 (13.8)	10 (14.3)
Tumor invasion depth			0.98
Tis	3 (1.6)	1 (1.4)
T1	14(7.4)	5(7.1)
T2	32 (17)	11 (15.7)
T3	121 (64.4)	45 (64.3)
T4a	15 (8)	6 (8.6)
T4b	3 (1.6)	2 (2.9)
Lymphovascular invasion			0.95
Negative	147 (78)	55 (78.6)
Positive	41 (21.7)	15 (21.4)
Indeterminate2	N/A	N/A
Perineural invasion			0.96
Negative	168 (89.4)	63 (90)
Positive	20 (10.3)	7 (10)
Indeterminate	N/A	N/A
Tumor budding			0.09
Absent3	121 (64.3)	38 (54.3)
Low	44 (23.7)	19 (27.1)
High	23 (12)	13 (18.6)
LNM status			0.90
Negative	141 (74.9)	52 (74.3)
Positive	47 (25.1)	18 (25.7)

¹Others included mucinous, signet-ring cell, neuroendocrine differentiation, medullary carcinoma, mixed adenoneuroendocrine carcinoma, micropapillary carcinoma, and serrated adenocarcinoma.

²Indeterminate means that the presence or absence of lymphovascular invasion or perineural invasion cannot be determined.

³Absent: No tumor budding; Low: ≤ 10 tumor buds per high-power field; High: > 10 tumor buds per high-power field.

LNM: Lymph node metastasis; N/A: Not applicable; Tis: Carcinoma in situ; T1: Tumor invades submucosa; T2: Tumor invades muscularis propria; T3: Tumor invades through muscularis propria into pericolorectal tissues; T4a: Tumor penetrates to the surface of the visceral peritoneum; T4b: Tumor directly invades or is adherent to other organs or structures.

Table 2 Representative patches of tumor tissue for each of the top 10 clusters

Cluster	Description
1	Poorly differentiated tumor cells with a high nuclear-cytoplasmic ratio, irregular glandular formation, and sparse stroma
2	Well-differentiated tumor cells with low nuclear-cytoplasmic ratio, regular glandular formation, and abundant stroma
3	Tumor cells with moderate differentiation, moderate nuclear-cytoplasmic ratio, and moderate stroma
4	Tumor cells with signet-ring cell differentiation, high nuclear-cytoplasmic ratio, and mucin production
5	Tumor cells with neuroendocrine differentiation, high nuclear-cytoplasmic ratio, and rosette-like structures
6	Tumor cells with serrated adenocarcinoma differentiation, low nuclear-cytoplasmic ratio, and serrated glandular formation
7	Tumor cells with mucinous differentiation, low nuclear-cytoplasmic ratio, and abundant extracellular mucin
8	Tumor cells with medullary carcinoma differentiation, high nuclear-cytoplasmic ratio, and solid growth pattern
9	Tumor cells with micropapillary carcinoma differentiation, high nuclear-cytoplasmic ratio, and papillary projections
10	Tumor cells with mixed adenoneuroendocrine carcinoma differentiation, high nuclear-cytoplasmic ratio, and dual expression of neuroendocrine and epithelial markers

Table 3 Coefficients and odds ratios of the predictors in the final model

Predictor	Coefficient	Odds ratio	P value
Age (yr)	0.02	1.02	0.01a
Tumor location			< 0.001b
Right colon	Reference	Reference
Left colon	-0.65	0.52
Rectum	-1.04	0.35
Tumor size	0.17	1.19	< 0.001a
Tumor differentiation	-0.48	0.62	0.02a
Tumor invasion depth			< 0.001b
Tis	Reference	Reference
T1	1.32	3.74
T2	2.12	8.34
T3	3.45	31.49
T4a	4.67	106.71
T4b	5.89	361.23
Lymphovascular invasion	1.23	3.42	< 0.001a
Perineural invasion	1.01	2.75	< 0.001a
Tumor budding	0.87	2.38	< 0.001a
Frequency of cluster 1	0.05	1.05	< 0.001a
Frequency of cluster 2	-0.04	0.96	0c
Frequency of cluster 3	0.03	1.03	0.02a
Frequency of cluster 4	-0.02	0.98	0.04a
Frequency of cluster 5	0.04	1.04	0.01a
Frequency of cluster 6	-0.03	0.97	0.03a
Frequency of cluster 7	0.02	1.02	0.05a
Frequency of cluster 8	-0.01	0.99	0.06c
Frequency of cluster 9	0.01	1.01	0.07c
Frequency of cluster 10	-0.01	0.99	0c

^aP < 0.05, statistically significant.

^bP < 0.001, highly statistically significant.

^cP > 0.05, not statistically significant.

Table 4 Performance of the risk prediction model and the existing models in the validation set

Model	NRI	IDI	Brier score
Our model	0.28	0.11	0.10
Kikuchi’s model	-0.04	-0.03	0.17
Ueno’s model	-0.01	-0.01	0.15
Krogue’s model	0.12	0.05	0.12

NRI: Net reclassification improvement; IDI: Integrated discrimination improvement.

Table 5 Distribution of patients and lymph node metastasis in each risk group in the validation set (%)

Risk group	Predicted probability of LNM	Number of patients	Number of LNMs
Low risk	< 10	27 (38.6)	1 (5.6)
Intermediate risk	10-30	26 (37.1)	6 (33.3)
High risk	> 30	17 (24.3)	11 (61.1)

LNM: Lymph node metastasis.