Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

Table 1 Tumour regression scoring according to Mandard et al[14]

Grade	Definition
TRG 1	No residual cancer
TRG 2	Rare residual cancer cells
TRG 3	Fibrosis outgrowing residual cancer
TRG 4	Residual cancer outgrowing fibrosis
TRG 5	Absence of regressive changes

TRG: Tumour Regression Grade.

Table 2 Clinical and pathological characteristics of the 218 patients operated on for esophageal and gastro-esophageal adenocarcinoma, according to treatment n (%)

Characteristic		Surgery only 82 (37.6)	Neoadjuvant chemotherapy and surgery 136 (62.4)	Pvalue
Preoperative status
Age (range)1 yr		74.32 (42.08-85.41)	63.76 (32.77-81.28)	< 0.0001
Sex ratio (M:F)1		68 (82.9):14 (17.1)	118 (86.8):18 (13.2)	0.439
cT stage	1	17 (20.7)	0 (0.0)	< 0.0001
	2	30 (36.6)	16 (16.0)
	3	34 (41.5)	114 (84.0)
	4	1 (1.2)	6 (4.4)
cN stage	0	36 (43.9)	19 (14.0)	< 0.0001
	1	46 (56.1)	117 (86.0)
cM stage	0	80 (97.6)	134 (98.5)	0.613
	1	1 (2.4)	2 (1.4)
Performance status	0	8 (11.6)	35 (25.7)	0.001
	1	51 (73.9)	96 (70.6)
	2	10 (14.5)	5 (3.7)
ASA	1	3 (3.7)	11 (8.1)	0.005
	2	56 (68.3)	106 (78.5)
	3	23 (28)	18 (13.3)
O-POSSUM		18 (12-30)	16 (12-26)	< 0.0001
Tumour site	Middle 1/3	1 (1.2)	1 (0.7)	0.418
	Lower 1/3	32 (39)	57 (41.9)
	GEJ-S1	19 (23.2)	23 (16.9)
	GEJ-S2	18 (22.0)	34 (25.0)
	GEJ-S3	12 (14.6)	20 (14.7)
Operative outcomes
Length of operation (min)1		255 (120-480)	261 (120-471)	0.409
Blood loss (mL)1		300 (0-2200)	318 (0-3000)	0.429
Clavien Dindo Max	0	26 (31.7)	53 (39.3)	0.59
	1	5 (6.1)	8 (5.9)
	2	35 (42.7)	40 (29.6)
	3	6 (7.3)	17 (12.6)
	4	6 (7.3)	17 (12.6)
	5	4 (4.9)	0 (0)
Anastomotic leaks		8 (9.8)	9 (6.7)	0.413
Pathological outcomes
pT or ypT	0	3 (3.6)	8 (5.9)	0.692
	1	23 (28)	23 (16.9)
	2	17 (20.7)	34 (25)
	3	34 (41.5)	66 (48.5)
	4	5 (6.1)	5 (3.7)
pN or ypN	0	40 (48.8)	73 (53.7)	0.758
	1	20 (24.4)	21 (15.4)
	2	11 (13.4)	25 (18.4)
	3	11 (13.4)	17 (12.5)
pM or ypM	0	82 (100)	136 (100)	1.00
Tumour regression grade	1	-	8 (5.8)	n/a
	2	-	28 (20.6)
	3	-	20 (14.7)
	4	-	45 (33.1)
	5	-	35 (25.7)
Nodal downstaged (cN1 to p or ypN1)		13 (15.9)	60 (44.1)	< 0.0001
Positive nodes1		1 (0-21)	0 (0-24)	0.789
Nodal yield1		18 (4-49)	18 (3-53)	0.242
Resection clearance	R0	65 (79.3)	110 (80.9)	0.772
Vascular invasion		24 (29.3)	41 (30.1)	0.891
Lymphatic invasion		9 (11)	22 (16.2)	0.28
Perineural invasion		8 (9.8)	20 (14.7)	0.291
Maximum tumour diameter (mm)1		25 (0-90)	25 (0-155)	0.998
Morphology	Ulcer	48 (60)	96 (74.4)	0.029
	Polypoid	22 (27.5)	23 (17.8)
	Fungating	2 (2.5)	3 (2.3)
	Diffuse infiltrating	8 (10)	7 (5.4)
Grade	G1	6 (7.3)	16 (11.8)	0.669
	G2	30 (36.6)	37 (27.2)
	G3	46 (56.1)	82 (60.3)
	G4	0 (0)	1 (0.7)
Sites of recurrence	Local	3 (3.7)	8 (5.9)	0.461
	Nodal	5 (6.1)	14 (10.4)	0.281
	Distant	18 (22.0)	44 (32.6)	0.093

Values in parentheses are percentages unless indicated.

¹Values in parentheses are range. ASA: American society of anesthesiologists classification; O-POSSUM: Oesophagogastric surgery-physiological and operative severity score for the enumeration of mortality and morbidity; GEJ-S1-3: Gastro-esophageal junction-Siewert type 1-3.

Table 3 Clinical and pathological characteristics of the 136 patients treated with neoadjuvant chemotherapy for esophageal and gastro-esophageal adenocarcinoma, classified as responders Tumour regression grade 1-2 or non-reponders tumour regression grade 3-5 n (%)

		TRG 1-2 36 (26.5)	TRG 3-5 100 (73.5)	Pvalue
Preoperative status
Age (range) yr1		65.27 (26.99-76.04)	63.51 (32.77-81.28)	0.410
Sex ratio (M:F)1		32 (88.9):4 (11.1)	86 (86):14 (14)	0.662
cT stage	1	0 (0)	0 (0)	0.396
	2	2 (5.6)	14 (14)
	3	33 (91.7)	81 (81)
	4	1 (2.8)	5 (5)
cN stage	0	5 (13.9)	14 (14)	0.987
	1	31 (86.1)	86 (86)
cM stage	0	35 (97.1)	99 (99)	0.456
	1	1 (2.8)	1 (1)
Performance status	0	12 (33.3)	23 (23)	0.225
	1	23 (63.9)	73 (73)
	2	1 (2.8)	4 (4.0)
ASA	1	2 (5.6)	9 (9.1)	0.408
	2	32 (88.9)	74 (74.7)
	3	2 (5.6)	16 (16.2)
O-POSSUM		15 (12-23)	16 (12-26)	0.476
Tumour site	Middle 1/3	1 (2.8)	0 (0)	0.738
	Lower 1/3	15 (41.7)	42 (42)
	GEJ-S1	7 (19.4)	16 (16)
	GEJ-S2	9 (25)	25 (25)
	GEJ-S3	4 (11.1)	16 (16)
Operative outcomes
Length of operation (min)1		262 (163-427)	260 (120-471)	0.513
Blood loss (mL)1		300 (0-3000)	325 (0-1700)	0.673
Clavien Dindo Max	0	14 (38.9)	39 (39.4)	0.531
	1	2 (5.6)	6 (6.1)
	2	14 (38.9)	26 (26.3)
	3	4 (11.1)	13 (13.1)
	4	2 (5.6)	15 (15.2)
	5	0 (0)	0 (0)
Anastomotic leaks		1 (2.8)	8 (8.1)	0.276
Pathological outcomes
yPT	0	8 (22.2)	0 (0)	< 0.0001
	1	11 (30.6)	12 (12)
	2	9 (25)	25 (25)
	3	8 (22.2)	58 (58)
	4	0 (0)	5 (5)
yPN	0	34 (94.4)	39 (39)	< 0.0001
	1	0 (0)	21 (21)
	2	2 (5.6)	23 (23)
	3	0 (0)	17 (17)
yPM	0	36 (100)	100 (100)	0.579
Nodal downstaged (cN1 to ypN0)		30 (83.3)	30 (30)	< 0.0001
Positive nodes1		0 (0-5)	1 (0-24)	< 0.0001
Nodal yield1		18 (4-25)	18 (3-53)	0.984
Resection clearance	R0	35 (97.2)	75 (75)	0.004
Vascular invasion		4 (11.1)	37 (37)	0.004
Lymphatic invasion		4 (11.1)	18 (18)	0.338
Perineural invasion		2 (5.6)	18 (18)	0.072
Maximum tumour diameter1	(mm)	15 (0-110)	30 (0-155)	< 0.0001
Morphology	Ulcer	30 (93.8)	66 (68)	0.003
	Polypoid	2 (6.3)	21 (21.6)
	Fungating	0 (0)	3 (3.1)
	Diffuse infiltrating	0 (0)	7 (7.2)
Grade	G1	8 (22.2)	8 (8)	0.104
	G2	9 (25)	28 (28)
	G3	19 (52.8)	63 (63)
	G4	0 (0)	1 (1)
Sites of recurrence	Local	0 (0)	8 (8.1)	0.080
	Nodal	1 (2.8)	13 (13.1)	0.082
	Distant	2 (5.6)	42 (42.4)	< 0.0001

Values in parentheses are percentages unless indicated.

¹Values in parentheses are range. TRG: Tumour Regression Grade; ASA:American Society of Anesthesiologists classification; O-POSSUM: Oesophagogastric surgery-physiological and operative severity score for the enumeration of mortality and morbidity; GEJ-S1-3: Gastro-esophageal junction-Siewert type 1-3.

Table 4 Univariate and multivariate Cox regression analyses of patient and tumour factors with disease free survival for patients undergoing neoadjuvant chemotherapy (n = 136)

		Univariate			Multivariate
		HR	95%CI	Pvalue	HR	95%CI	Pvalue
Patient factors
Age		0.972	(0.944-1.00)	0.054
Sex	Female	1.000	Ref
	Male	0.953	(0.453-2.005)	0.899
ASA	1	1.000	Ref
	2	0.696	(0.313-1.548)	0.374
	3	0.947	(0.352-2.546)	0.914
Performance status	0	1.000	Ref
	1	1.016	(0.578-1.789)	0.955
	2	0.950	(0.218-4.129)	0.945
O-POSSUM
Tumour response
TRG	1	1.000	Ref
	2	1.099	(0.099-12.148)	0.939
	3	8.404	(1.071-65.929)	0.043
	4	7.829	(1.054-58.163)	0.044
	5	15.422	(2.083-114.189)	0.007
TRG grouped	1-2	1.000	Ref		1.000	Ref
	3-5	9.504	(2.973-30.380)	< 0.0001	6.315	(1.261-31.616)	0.025
Lymph node response
Lymph nodes downstaged	Yes	1.000	Ref		1.000	Ref
	No	5.784	(3.064-10.919)	< 0.0001	6.161	(1.683-22.554)	0.006
Tumour factors
ypT stage	0	1.000	Ref		1.000	Ref
	1	2.085	(0.232-18.711)	0.512	0.281	(0.020-3.928)	0.345
	2	5.214	(0.687-39.549)	0.110	0.286	(0.022-3.705)	0.338
	3	9.490	(1.293-69.635)	0.027	0.469	(0.034-6.460)	0.571
	4	52.907	(6.008-465.873)	< 0.0001	1.519	(0.087-26.389)	0.774
ypN stage	0	1.000	Ref		1.000	Ref
	1	4.791	(2.434-9.431)	< 0.0001	0.476	(0.133-1.700)	0.253
	2	4.102	(2.005-8.392)	< 0.0001	0.254	0.070-0.927)	0.038
	3	7.449	(3.522-15.756)	< 0.0001	0.476	(0.129-1.755)	0.265
ypM stage	0	1.000	Ref		1.000	Ref
	1	3.172	(1.253-8.031)	0.015	2.693	(0.924-7.847)	0.069
Vascular invasion	No	1.000	Ref		1.000	Ref
	Yes	3.444	(2.080-5.702)	< 0.0001	1.929	(1.034-3.600)	0.039
Lymphatic invasion	No	1.000	Ref		1.000	Ref
	Yes	2.201	(1.268-3.821)	0.005	1.253	(0.637-2.462)	0.514
Perineural invasion	No	1.000	Ref		1.000	Ref
	Yes	5.073	(2.896-8.886)	< 0.0001	2.766	(1.444-5.300)	0.002
Resection clearance	R0	1.000	Ref		1.000	Ref
	R1	3.869	(2.272-6.588)	< 0.0001	1.805	(0.940-3.468)	0.076

TRG: Tumour Regression Grade; ASA: American Society of Anesthesiologists classification; O-POSSUM: Oesophagogastric surgery-physiological and operative severity score for the enumeration of mortality and morbidity.

Table 5 Clinical and pathological characteristics of the 113 patients with pathological N0 stage, according to treatment n (%)

		pN0 Surgery alone 40 (35.4)	ypN0 Neoadjuvant chemotherapy and surgery 73 (64.6)	Pvalue
Preoperative status
Age (range) yr1		73.62 (56.73-85.41)	65.59 (32.77-78.43)	< 0.0001
Sex ratio (M:F)1		31 (77.5):9 (22.5)	66 (90.4):7 (9.8)	0.061
cT stage	1	13 (32.5)	0 (0)	< 0.0001
	2	17 (42.5)	9 (12.3)
	3	10 (25)	61 (83.6)
	4	0 (0)	3 (4.1)
cN stage	0	27 (67.5)	13 (17.8)	< 0.0001
	1	13 (32.5)	60 (82.2)
cM stage	0	40 (100)	71 (97.3)	0.293
	1	0 (0)	2 (2.8)
Performance status	0	3 (9.4)	16 (21.9)	0.045
	1	25 (78.1)	54 (74)
	2	4 (12.5)	3 (4.1)
ASA	1	2 (5)	6 (8.2)	0.268
	2	31 (77.5)	59 (80.8)
	3	7 (17.5)	8 (11)
O-POSSUM1		17 (14-29)	16 (12-26)	0.015
Tumour site	Middle 1/3	0 (0)	1 (1.4)	0.190
	Lower 1/3	15 (37.5)	35 (47.9)
	OGJ-S1	11 (27.5)	12 (16.4)
	OGJ-S2	8 (20)	16 (21.9)
	OGJ-S3	6 (15)	9 (12.3)
Operative outcomes
Length of operation (min)1		240 (120-360)	278 (120-471)	0.082
Blood loss (mL)1		200 (0-2200)	350 (0-3000)	0.167
Clavien Dindo Max	0	14 (35)	24 (32.9)	0.709
	1	1 (2.5)	3 (4.1)
	2	17 (42.5)	27 (37)
	3	4 (10)	10 (13.7)
	4	2 (5)	9 (12.3)
	5	2 (5)	0 (0)
Anastomotic leaks		4 (10)	7 (9.6)	0.944
Pathological outcomes
TRG 1-2		-	34 (46.6)	NA
TRG 3-5		-	39 (53.4)
pT or ypT	0	2 (5)	11 (15.1)	0.224
	1	22 (55)	20 (27.4)
	2	5 (12.5)	20 (27.4)
	3	10 (25)	24 (32.9)
	4	0 (0)	1 (1.4)
Nodal Downstaged (cN1 to p or ypN0)		15 (37.5)	61 (83.6)	< 0.0001
Nodal yield1		16 (4-49)	18 (3-52)	0.150
Resection clearance	R0	35 (87.5)	69 (94.5)	0.189
Vascular invasion		7 (17.5)	10 (13.7)	0.590
Lymphatic invasion		2 (5)	6 (8.2)	0.525
Perineural invasion		2 (5)	5 (6.8)	0.698
Maximum tumour diameter (mm)1		24 (0-50)	24 (0-110)	0.324
Morphology	Ulcer	25 (65.8)	53 (79.1)	0.135
	Polypoid	10 (26.3)	11 (16.4)
	Fungating	1 (2.6)	1 (1.5)
	Diffuse infiltrating	2 (5.3)	2 (3)
Grade	G1	4 (10)	13 (17.8)	0.811
	G2	17 (42.5)	20 (27.4)
	G3	19 (47.5)	40 (54.8)
	G4	0 (0)	0 (0)
Site of recurrence	Local	0 (0)	2 (2.7)	0.293
	Nodal	1 (2.5)	4 (5.5)	0.463
	Distant	3 (7.5)	12 (16.4)	0.182

Values in parentheses are percentages unless indicated.

¹Values in parentheses are range. ASA: American society of anesthesiologists classification; O-POSSUM: Oesophagogastric surgery-physiological and operative severity score for the enumeration of mortality and morbidity; NA: Not available.