Clinicopathological parameters predicting recurrence of pT1N0 esophageal squamous cell carcinoma

Table 1 Summary of clinical, endoscopic, and histopathological characteristics of the 199 pT1N0 esophageal squamous cell carcinoma patients n (%)

Characteristic		Patients
Clinical variable
Sex	Male	142 (71)
	Female	57 (29)
Age (yr)	< 60	121 (61)
	≥ 60	78 (39)
Symptoms	No	13 (7)
	Yes	186 (93)
Endoscopic variable
Tumor location	Upper thoracic	31 (16)
	Middle thoracic	143 (72)
	Lower thoracic	25 (13)
Tumor size (measured endoscopically)	< 2 cm	59 (30)
	≥ 2 cm	140 (70)
Macroscopic tumor type	Erosive	73 (37)
	Papillary	26 (13)
	Plaque-like	79 (40)
	Ulcerative	9 (5)
	Intraluminal mass	12 (6)
Standard histopathological variable
Tumor invasion depth level	m2	21 (11)
	m3	26 (13)
	sm1	18 (9)
	sm2	45 (23)
	sm3	89 (45)
Degree of differentiation	Well	39 (20)
	Moderate	76 (38)
	Poor	56 (28)
	Basaloid	19 (10)
	Spindle cell/sarcomatoid	9 (5)
Angiolymphatic invasion	No	172 (86)
	Yes	27 (14)
Multicentric invasive lesions	No	183 (92)
	Yes	16 (8)
Number of lymph nodes dissected	< 14	90 (45)
	≥ 14	109 (55)
Measured histopathological variables
Tumor thickness	< 3000 μm	85 (43)
	≥ 3000 μm	114 (57)
Submucosal invasion thickness	0	47 (24)
	0-2000 μm	85 (43)
	≥ 2000 μm	67 (34)
Diameter of the largest single tongue of invasion	< 2 cm	134 (67)
	≥ 2 cm	65 (33)
Immunohistochemical staining1
P53	Complete loss	50 (39)
	Weak, patchy	41 (32)
	Diffuse, strong	37 (29)
Cyclin D1	-	38 (30)
	1+	39 (31)
	2+	49 (39)
EGFR	-	52 (41)
	1+	44 (34)
	2+	32 (25)
VEGF	-	54 (44)
	1+	34 (28)
	2+	35 (28)

¹Available in tissue microarray cases.

Table 2 Sites of recurrence in the 199 pT1N0 esophageal squamous cell carcinoma patients n (%)

Site of recurrence	Total patients with recurrence	Patients by tumor location			Patients by macroscopic tumor type
		Upper thoracic (n = 31)	Middle thoracic (n = 143)	Lower thoracic (n = 25)	Ulcerative or intraluminal (n = 21)	Erosive, papillary, or plaque-like (n = 178)
Local-regional recurrences1	33 (17)	15 (48)	14 (10)	4 (16)	8 (38)	25 (14)
Anastomosis	3 (2)	3 (10)	0	0	2 (10)	1 (1)
Cervical node	19 (10)	10 (32)	7 (5)	2 (8)	4 (19)	15 (8)
Mediastinal node	21 (11)	9 (29)	9 (6)	3 (12)	8 (38)	13 (7)
Abdominal node	0	0	0	0	0	0
Distant recurrences1	16 (8)	5 (16)	8 (6)	3 (12)	4 (19)	12 (7)
Lung	7 (4)	2 (6)	5 (3)	0	1 (5)	6 (3)
Liver	2 (1)	1 (3)	0	1 (4)	0	2 (1)
Bone	6 (3)	0	4 (3)	2 (8)	2 (10)	4 (2)
Brain	1 (0)	1 (3)	0	0	0	1 (1)
Pleura	3 (2)	2 (6)	1 (1)	0	1 (5)	2 (1)
Distant node	0	0	0	0	0	0
Multiple site recurrences	15 (8)	7 (23)	6 (4)	2 (8)	5 (24)	10 (6)
Mediastinal node and bone	2 (1)	0	1 (1)	1 (4)	1 (5)	1 (1)
Mediastinal node, cervical node, and bone	1 (1)	0	0	1 (4)	0	1 (1)
Mediastinal node, pleura, and bone	1 (1)	0	1 (1)	0	0	1 (1)
Mediastinal node and cervical node	3 (1)	2 (6)	1 (1)	0	1 (5)	2 (1)
Cervical node and lung	1 (1)	0	1 (1)	0	0	1 (1)
Mediastinal node, cervical node, and anastomosis	1 (1)	1 (3)	0	0	1 (5)	0
Mediastinal node, cervical node, anastomosis, and pleura	1 (1)	1 (3)	0	0	1 (5)	0
Mediastinal node, cervical node, and lung	2 (1)	1 (3)	1 (1)	0	1 (5)	1 (1)
Cervical node, bone, and lung	1 (1)	0	1 (1)	0	0	1 (1)
Mediastinal node, liver, and lung	1 (1)	1 (3)	0	0	0	1 (1)
Mediastinal node and brain	1 (1)	1 (3)	0	0	0	1 (1)
Unknown sites	10 (5)	1 (3)	8 (6)	1 (4)	1 (5)	9 (5)
Total recurrences	47 (24)	16 (52)	25 (17)	6 (24)	10 (48)	37 (21)

¹Including the patients with multiple site recurrences.

Table 3 Relationship of clinicopathological parameters with recurrence-free survival and tumor recurrence in the 199 pT1N0 esophageal squamous cell carcinoma patients n (%)

Parameter		Total	Recurrences	Kaplan-Meier analysis			Univariate Cox proportional hazards analysis
				5-yr RFS (%)	10-yr RFS (%)	P-value	HR	95%CI	Global P	P-for-trend
Clinical variable
Sex	Male	142	33 (23)	81	71.6	0.97	1
	Female	57	14 (25)	80	72.7		1.011	0.54-1.89	0.97
Age (yr)	< 60	121	28 (23)	79.2	74.1	0.6	1
	≥ 60	78	19 (24)	82.9	66.4		1.17	0.65-2.10	0.6
Symptoms	No	13	0	100	100	0.03	1
	Yes	186	47 (25)	79.2	69.8		23.54	0.28-2017	0.16
Endoscopic variable
Tumor location	Upper thoracic	31	15 (48)	55.9	44.7	< 0.001	3.46	1.83-6.54	< 0.001
	Middle thoracic	143	26 (18)	85.2	78.5		1
	Lower thoracic	25	6 (24)	86.5	65.4		1.49	0.61-3.63	0.38
Tumor size (endoscopically)	< 2 cm	59	16 (27)	79.3	69.7	0.53	1
	≥ 2 cm	140	31 (22)	81.2	73		0.82	0.45-1.51	0.53
Macroscopic	Erosive	73	12 (16)	87.2	78	0.001	1
tumor type	Papillary	26	4 (15)	90.2	90.2		0.98	0.32-3.06	0.98
	Plaque-like	79	21 (27)	75.8	68.6		1.64	0.81-3.25	0.13
	Ulcerative	9	6 (67)	53.3	26.7		6.06	2.26-16.26	< 0.001
	Intraluminal mass	12	4 (33)	74.1	49.4		3.94	1.26-12.32	0.02
Standard histopathological variable
Tumor invasion depth level	m2	21	1 (5)	94.1	94.1	0.04	1.52	1.14-1.97		0.004
	m3	26	3 (12)	96.2	88.1
	sm1	18	4 (22)	81.4	81.4
	sm2	45	11 (25)	83.8	74.8
	sm3	89	28 (31)	70.6	58.6
Degree of differentiation	Well	39	10 (26)	79.5	65	0.02	1
	Moderate	76	15 (20)	84.7	82		0.73	0.33-1.63	0.44
	Poor	56	13 (23)	80.7	67.8		0.92	0.40-2.11	0.92
	Basaloid	19	8 (42)	58.3	35		2.88	1.13-7.38	0.03
	Spindle cell/sarcomatoid	9	1 (11)	88.9	88.9		0.54	0.07-4.21	0.55
Angiolymphatic invasion	No	172	33 (19)	84.6	75.3	< 0.001	1
	Yes	27	14 (52)	55.4	49.9		3.48	1.85-6.52	< 0.001
Multicentric invasive lesions	No	183	45 (25)	80.2	70.9	0.42	1
	Yes	16	2 (13)	86.5	86.5		0.56	0.14-2.32	0.42
Number of lymph nodes dissected	< 14	90	24 (27)	72.7	70.2	0.25	1
	≥ 14	109	23 (21)	87.2	73.8		0.72	0.41-1.27	0.26
Measured histopathological variable
Tumor thickness	< 3000 μm	85	13 (15)	90	79.3	0.005	1
	≥ 3000 μm	114	34 (30)	73.2	65.7		2.41	1.27-4.56	0.007
Submucosal	0	47	4 (9)	95.5	90.5	0.001	2.24	1.44-3.46		< 0.001
invasion thickness	1-2000 μm	85	19 (22)	82.8	74.4
	≥ 2000 μm	67	24 (36)	67.4	56.4
Diameter of the	< 2 cm	134	27 (20)	85.5	75.7	0.008	1
largest single tongue of invasion	≥ 2 cm	65	20 (31)	70.1	64.1		2.15	1.20-3.85	0.01
Immunohistochemical staining1
P53	Complete loss	50	19 (38)	64.8	59.5	0.33	2.43	1.02-5.79	0.045
	Weak, patchy	41	7 (17)	81.8	81.8		1
	Diffuse, strong	37	12 (33)	88.6	78.2		1.88	0.74-4.77	0.19
Cyclin D1	-	38	14 (37)	71.3	56.4	0.88	0.93	0.64-1.36		0.72
	1+	39	11 (28)	80.7	73.7
	2+	49	14 (29)	68.7	68.7
EGFR	-	52	13 (25)	82.9	75.6	0.27	1.15	0.78-1.69		0.49
	1+	44	17 (39)	65.6	51.3
	2+	32	9 (28)	70.2	68
VEGF	-	54	15 (28)	76	67.3	0.59	1.05	0.72-1.54		0.79
	1+	34	12 (35)	74.1	59.6
	2+	35	10 (29)	72.2	72.2

¹Available in tissue microarray cases. HR: Hazard ratio; CI: Confidence interval; 5-yr RFS: 5-year recurrence free survival; 10-yr RFS: 10-year recurrence free survival; NA: Not associated.

Table 4 Multivariate Cox proportional hazard models for tumor recurrence in the 199 pT1N0 esophageal squamous cell carcinoma patients

Parameter		HR	95%CI	Global P	P-for-trend
Tumor location	Upper thoracic	3.26	1.70-6.27	< 0.001
	Middle thoracic	1
	Lower thoracic	1.05	0.43-2.59	0.91
Angiolymphatic invasion		3.42	1.80-6.52	< 0.001
Submucosal invasion thickness		2.06	1.30-3.27		0.002

HR: Hazard ratio; CI: Confidence interval.

Table 5 Relationship between clinicopathological parameters and distant tumor recurrence in the 189 informative patients¹

Univariate Cox proportional hazards analysis
Parameter		Total	Distant recurrences (%)	HR	95%CI	Global P	P-for-trend
Clinical variables
Sex	Male	136	14 (10)	1
	Female	53	2 (4)	0.33	0.07-1.44	0.14
Age (yr)	< 60	118	8 (7)	1
	≥ 60	71	8 (11)	2.18	0.79-6.02	0.13
Symptoms	No	13	0	1
	Yes	176	16 (9)	23.59	0.01-40030	0.41
Endoscopic variables
Tumor location	Upper thoracic	30	5 (17)	3.56	1.15-11.07	0.03
	Middle thoracic	135	8 (6)	1
	Lower thoracic	24	3 (13)	2.37	0.63-8.94	0.2
Tumor size (measured endoscopically)	< 2 cm	55	6 (11)	1
	≥ 2 cm	134	10 (8)	0.76	0.27-2.09	0.59
Macroscopic type	Erosive	71	5 (7)	1
	Papillary	26	2 (8)	1.11	0.21-5.75	0.9
	Plaque-like	72	5 (7)	0.95	0.27-3.31	0.94
	Ulcerative	8	2 (25)	5.58	1.06-29.32	0.04
	Intraluminal mass	12	2 (17)	5.41	1.02-28.68	0.047
Standard histopathological variable
Tumor invasion depth level	m2	21	0	1.42	0.91-2.21		0.13
	m3	26	2 (8)
	sm1	16	1 (6)
	sm2	43	4 (9)
	sm3	83	9 (11)
Degree of differentiation	Well	36	1 (3)	1
	Moderate	73	5 (7)	2.19	0.25-18.98	0.48
	Poor	54	6 (11)	3.93	0.47-32.89	0.21
	Basaloid	17	3 (18)	12.4	1.27-121.08	0.03
	Spindle cell/sarcomatoid	9	1 (11)	5.73	0.35 -92.90	0.22
Angiolymphatic invasion	No	166	11 (7)	1
	Yes	23	5 (22)	3.38	1.15-9.93	0.03
Multicentric invasive lesions	No	173	15 (9)	1
	Yes	16	1 (6)	0.92	0.12-7.00	0.93
Number of lymph nodes dissected	< 14	85	7 (8)	1
	≥ 14	104	9 (9)	0.95	0.36-2.57	0.93
Measured histopathological variable
Tumor thickness	< 3000 μm	82	6 (7)	1
	≥ 3000 μm	107	10 (9)	1.53	0.56-4.21	0.42
Submucosal	0	47	2 (4)	1.88	0.91-3.90		0.09
invasion thickness	< 2000 μm	80	7 (9)
	≥ 2000 μm	62	7 (11)
Diameter of the	< 2 cm	126	9 (7)	1
largest invasive lesion	≥ 2 cm	63	7 (11)	2.56	0.92-7.15	0.07
Immunohistochemical staining2
P53	Complete loss	47	6 (13)	1.78	0.44-7.16	0.42
	Weak, patchy	40	3 (8)	1
	Diffuse, strong	34	6 (18)	2.31	0.58-9.25	0.24
Cyclin D1	-	35	5 (14)	0.94	0.51-1.74		0.84
	+	37	5 (14)
	++	47	5 (11)
EGFR	-	52	9 (17)	0.63	0.31-1.28		0.2
	+	40	4 (10)
	++	29	2 (7)
VEGF	-	50	6 (12)	0.95	0.50-1.81		0.88
	+	33	3 (9)
	++	33	4 (12)
Multivariate Cox proportional hazards analysis
Parameter
Tumor location	Upper thoracic			3.83	1.23-11.96	0.02
	Middle thoracic			1
	Lower thoracic			1.95	0.50-7.54	0.34
Angiolymphatic invasion				3.55	1.17-10.77	0.03

¹Excluding 10 patients with an unknown site of recurrence;

²Available in tissue microarray cases. HR: Hazard ratio; CI: Confidence interval; 5-yr RFS: 5-year recurrence free survival; 10-yr RFS: 10-year recurrence free survival; NA: Not associated.

Table 6 Relationship between clinicopathological parameters and the likelihood of having early recurrence (≤ 24 mo) in the 199 pT1N0 esophageal squamous cell carcinoma patients n (%)

Univariate logistic regression
Parameter		Total	Early recurrence	Odds ratio	95%CI	Global P	P-for-trend
Clinical variable
Sex	Male	142	12 (9)	1
	Female	57	6 (11)	1.28	0.45-3.58	0.65
Age (yr)	< 60	121	15 (12)	1
	≥ 60	78	3 (4)	0.28	0.08-1.01	0.052
Endoscopic variable
Tumor location	Upper thoracic	31	9 (29)	7.95	2.68-23.54	< 0.001
	Middle thoracic	143	7 (5)	1
	Lower thoracic	25	2 (8)	1.69	0.33-8.64	0.53
Tumor size (endoscopically)	< 2 cm	59	4 (7)	1
	≥ 2 cm	140	14 (10)	1.53	0.48-4.85	0.47
Macroscopic	Erosive	73	4 (6)	1
tumor types	Papillary	26	1 (4)	0.69	0.07-6.47	0.75
	Plaque-like	79	7 (9)	1.68	0.47-5.98	0.43
	Ulcerative	9	3 (33)	8.63	1.55-47.86	0.01
	Intraluminal mass	12	3 (25)	5.75	1.10-29.95	0.04
Standard histopathological variable
Tumor invasion depth level	m2	21	0	1.78	1.05-3.01		0.03
	m3	26	1 (4)
	sm1	18	2 (11)
	sm2	45	2 (4)
	sm3	89	13 (15)
Degree of differentiation	Well	39	3 (8)	1
	Moderate	76	6 (8)	1.03	0.24-4.35	0.97
	Poor	56	4 (7)	0.92	0.20-4.38	0.92
	Basaloid	19	4 (21)	3.2	0.64-16.07	0.16
	Spindle cell/sarcomatoid	9	1 (11)	1.5	0.14-16.36	0.74
Angiolymphatic invasion	No	172	10 (6)	1
	Yes	27	8 (30)	6.82	2.40-19.38	< 0.001
Multicentric invasive lesions	No	183	17 (9)	1
	Yes	16	2 (13)	0.65	0.08-5.24	0.69
Number of lymph nodes dissected	< 14	90	11 (12)	1
	≥ 14	109		0.49	0.18-1.33	0.16
Measured histopathological variable
Tumor thickness	< 3000 μm	85	2(2)	1
	≥ 3000 μm	114	16(14)	6.78	1.51-30.33	0.01
Submucosal invasion thickness	0	47	1(2)	4.02	1.66 -9.73		0.001
	0-2000 μm	85	4(5)
	≥ 2000 μm	67	13(19)
Diameter of the largest single tongue of invasion	< 2 cm	134	5(4)	1
	≥ 2 cm	65	13(20)	6.45	2.19-19.00	0.001
Immunohistochemical staining1
P53	Complete loss	50	7 (14)	1.34	0.36-4.98		0.66
	Weak, patchy	41	5 (12)	1
	Diffuse, strong	37	4 (11)	1.15	0.28-4.63		0.85
Cyclin D1	-	38	4 (11)	1.32	0.69-2.54		0.4
	1+	39	4 (10)
	2+	49	8 (16)
EGFR	-	52	4 (8)	1.32	0.69-2.54		0.4
	1+	44	8 (18)
	2+	32	4 (13)
VEGF	-	54	4 (7)	1.59	0.83-3.04		0.16
	1+	34	5 (15)
	2+	35	6 (17)
Multivariate logistic regression
Tumor location	Upper thoracic			7.73	2.15-27.78	0.002
	Middle thoracic			1
	Lower thoracic			1.18	0.20-6.86	0.85
Angiolymphatic invasion				5.75	1.63-20.24	0.006
Submucosal invasion thickness				2.64	0.92-7.60	0.07
Diameter of the largest single tongue of invasion				4.13	1.17-14.56	0.03

¹Available in tissue microarray cases. OR: Odds ratio; CI: Confidence interval; NA: Not associated.