Mesenterico-portal vein invasion should be an important factor in TNM staging for pancreatic ductal adenocarcinoma: Proposed modification of the 8th edition of the American Joint Committee on Cancer staging system

doi:10.3748/wjg.v25.i46.6752

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Retrospective Cohort Study

World J Gastroenterol. Dec 14, 2019; 25(46): 6752-6766
Published online Dec 14, 2019. doi: 10.3748/wjg.v25.i46.6752

Table 1 Characteristics of patients enrolled in this study, n (%)

Characteristic	SEER database			West China Hospital database
Characteristic	MPV- group	MPV+ group	P value	MPV- group	MPV+ group	P value
Sample size, n	6825	714		579	110
Sex			0.041^a			0.353
Male	3458 (50.7)	333 (46.6)		368 (63.6)	75 (68.2)
Female	3367 (49.3)	381 (53.4)		211 (36.4)	35 (31.8)
Age at diagnosis (± SEM)	66.4 (± 0.13)	65.4 (± 0.38)	0.019^a	58.4 (± 0.41)	58.35 (± 0.88)	0.998
Tumor diameter			0.000^a			0.003^a
≤ 2 cm	1232 (18.1)	62 (8.7)		130 (22.5)	12 (10.9)
> 2 cm but ≤ 4 cm	4377 (64.1)	482 (67.5)		373 (64.4)	73 (66.4)
> 4 cm	1216 (17.8)	170 (23.8)		76 (13.1)	25 (22.7)
Positive lymph nodes			0.161			0.001^a
0	1900 (27.8)	214 (30.0)		345 (59.6)	46 (41.8)
1-3	2893 (42.4)	311 (43.6)		195 (33.7)	48 (43.6)
≥ 4	2032 (29.8)	189 (26.5)		39 (6.7)	16 (14.5)
AJCC 8^th stage			0.000^a			0.000^a
IA	500 (7.3)	22 (3.1)		89 (15.4)	4 (3.6)
IB	1162 (17.0)	19 (20.9)		219 (37.8)	31 (28.2)
IIA	238 (3.5)	43 (6.0)		37 (6.4)	11 (10.0)
IIB	2893 (42.4)	311 (43.6)		195 (33.7)	45 (43.6)
III	2032 (29.8)	189 (26.5)		39 (6.7)	16 (14.5)
Perineural invasion			N/A			0.016^a
Absent	N/A	N/A		165 (28.3)	19 (17.3)
Present	N/A	N/A		415 (71.7)	91 (82.7)
Intravascular tumor emboli			N/A			0.971
Absent	N/A	N/A		494 (85.3)	94 (85.5)
Present	N/A	N/A		85 (14.7)	16 (14.5)
Grade¹			0.605			0.984
Well differentiated	632 (9.3)	59 (8.3)		5 (0.9)	1 (1.0)
Moderately differentiated	3397 (49.8)	314 (44.0)		215 (38.1)	37 (37.4)
Poorly/undifferentiated	2489 (36.5)	251 (35.1)		344 (61.0)	61 (61.6)
Unknown	307 (4.5)	90 (12.6)		0 (0.0)	0 (0.0)
Margin status²			N/A			0.000^a
R0	N/A	N/A		427 (73.7)	61 (55.5)
R1	N/A	N/A		152 (26.3)	49 (44.5)
R2	N/A	N/A		0 (0.0)	0 (0.0)

¹Row "Unknown" was excluded from the crosstab chi-square analysis.

²The last row was excluded from the crosstab chi-square analysis since the expected frequencies were equal to 0.

^aP < 0.05. SEER: Surveillance, epidemiology, and end results; MPV: Mesenterico-portal vein; SEM: Standard error of the mean; N/A: Not available.

Table 2 Univariate and multivariate analyses of the survival of patients with pancreatic ductal adenocarcinoma

Univariate	SEER database			West China Hospital database
Univariate	Hazard ratio (95%CI)		P value	Hazard ratio (95%CI)		P value
Sex
Male	1.000	Reference		1.000	Reference
Female	0.931	(0.879, 0.987)	0.017^a	0.861	(0.709, 1.046)	0.132
Tumor diameter			0.000^a			0.000^a
≤ 2 cm (T1)	1.000	Reference		1.000	Reference
> 2 cm but ≤ 4 cm (T2)	1.375	(1.267, 1.492)	0.000^a	1.466	(1.145, 1.878)	0.002^a
> 4 cm (T3)	1.796	(1.629, 1.982)	0.000^a	2.466	(1.789, 3.397)	0.000^a
Positive lymph nodes			0.000^a			0.000^a
0 (N0)	1.000	Reference		1.000	Reference
1-3 (N1)	1.527	(1.419, 1.644)	0.000^a	1.676	(1.378, 2.039)	0.000^a
> 4 (N2)	1.940	(1.791, 2.100)	0.000^a	2.466	(1.774, 3.429)	0.000^a
MPV invasion	1.170	(1.059, 1.293)	0.002^a	1.708	(1.352, 2.159)	0.000^a
Multivariate	SEER database			West China Hospital database
Multivariate	Hazard ratio (95%CI)		P	Hazard ratio (95%CI)		P
Sex
Male	1.000	Reference
Female	0.937	(0.887, 0.989)	0.018^a
Tumor diameter			0.000^a			0.000^a
T1	1.000	Reference		1.000	Reference
T2	1.299	(1.203, 1.404)	0.000^a	1.361	(1.060, 1.746)	0.015^a
T3	1.611	(1.468, 1.768)	0.000^a	2.079	(1.500, 2.880)	0.000^a
Positive lymph nodes			0.000^a			0.000^a
N0	1.000	Reference		1.000	Reference
N1	1.454	(1.358, 1.557)	0.000^a	1.573	(1.290, 1.916)	0.000^a
N2	1.842	(1.710, 1.984)	0.000^a	2.127	(1.523, 2.971)	0.000^a
MPV invasion	1.178	(1.071, 1.290)	0.000^a	1.423	(1.120, 1.807)	0.004^a

^aP < 0.05. SEER: Surveillance, epidemiology, and end results; MPV: Mesenterico-portal vein.

Table 3 Differences in survival functions between American Joint Committee on Cancer TNM stages in patients stratified according to whether there was mesenterico-portal vein invasion

	SEER database		West China Hospital database
	MPV- group	MPV+ group	MPV- group	MPV+ group
Stage IA
Median survival	38 (± 3.6)	19 (± 3.4)	32 (± 5.3)	21
1-yr survival rate	84.7% (± 1.7%)	85.7% (± 7.6%)	84.2% (± 4.0%)	100.0%
3-yr survival rate	51.7% (± 2.5%)	26.8% (± 10.9%)	45.4% (± 6.6%)	0.0% (±0.0%)
5-yr survival rate	39.4% (± 2.7%)	26.8% (± 10.9%)	36.0% (± 7.1%)	0.0% (± 0.0%)
Stage IB
Median survival	27 (± 1.3)	22 (± 2.3)	24 (± 1.6)	17 (± 2.3)
1-yr survival rate	78.0% (± 1.3%)	76.6% (± 3.7%)	79.0% (± 2.9%)	72.5% (± 8.3%)
3-yr survival rate	40.1% (± 1.6%)	34.1% (± 4.6%)	27.9% (± 3.8%)	8.55% (± 5.7%)
5-yr survival rate	27.6% (± 1.6%)	23.7% (± 4.4%)	20.9% (± 4.0%)	4.35% (± 4.2%)
Stage IIA
Median survival	20 (± 1.1)	19 (± 6.6)	18 (± 3.7)	15 (± 3.7)
1-yr survival rate	69.8% (± 3.1%)	71.6% (± 7.3%)	59.3% (± 8.5%)	55.6% (± 16.6%)
3-yr survival rate	24.7% (± 3.1%)	32.8% (± 8.5%)	13.7% (± 8.4%)	0.0% (± 0.0%)
5-yr survival rate	13.4% (± 2.7%)	18.4% (± 8.1%)	6.95% (± 6.4%)	0.0% (± 0.0%)
Stage IIB
Median survival	20 (± 0.5)	17 (± 1.1)	18 (± 1.0)	15 (± 4.8)
1-yr survival rate	68.7% (± 0.9%)	63.6% (± 2.8%)	66.7% (± 3.5%)	63.3% (± 7.1%)
3-yr survival rate	26.3% (± 0.9%)	15.3% (± 2.3%)	14.1% (± 3.1%)	7.95% (± 4.3%)
5-yr survival rate	15.9% (± 0.8%)	9.25% (± 2.1%)	5.65% (± 2.9%)	0.0% (± 0.0%)
Stage III
Median survival	16 (± 0.4)	13 (± 1.2)	15 (± 2.8)	15 (± 4.8)
1-yr survival rate	60.0% (± 1.1%)	53.1% (± 3.9%)	53.3% (± 8.4%)	53.9% (± 14.1%)
3-yr survival rate	17.6% (± 1.0%)	8.65% (± 2.6%)	10.4% (± 6.1%)	0.0% (± 0.0%)
5-yr survival rate	8.15% (± 0.8%)	6.55% (± 2.4%)	0.0% (± 0.0%)	0.0% (± 0.0%)
IA vs IB
Survival function	P = 0.000^a	P = 0.917	P = 0.044^a	P = 0.382
1-yr survival rate	P = 0.002^a	P = 0.282	P = 0.293
3-yr survival rate	P = 0.000^a	P = 0.537	P = 0.022^a	P = 0.136
5-yr survival rate	P = 0.000^a	P = 0.792	P = 0.064	P = 0.306
IB vs IIA
Survival function	P = 0.000^a	P = 0.486	P = 0.003^a	P = 0.264
1-yr survival rate	P = 0.015^a	P = 0.541	P = 0.028^a	P = 0.363
3-yr survival rate	P = 0.000^a	P = 0.893	P = 0.124	P = 0.136
5-yr survival rate	P = 0.000^a	P = 0.565	P = 0.064	P = 0.306
IIA vs IIB
Survival function	P = 0.622	P = 0.136	P = 0.523	P = 0.500
1-yr survival rate	P = 0.733	P = 0.306	P = 0.421	P = 0.670
3-yr survival rate	P = 0.620	P = 0.047^a	P = 0.964	P = 0.066
5-yr survival rate	P =0.375	P = 0.272	P = 0.853
IIB vs III
survival function	P = 0.000^a	P = 0.053	P = 0.033^a	P = 0.418
1-yr survival rate	P = 0.000^a	P = 0.029^a	P = 0.141	P = 0.552
3-yr survival rate	P = 0.000^a	P = 0.054	P = 0.589	P = 0.066
5-yr survival rate	P = 0.000^a	P =0.397	P = 0.053

Values in parentheses are the standard error of median survival or standard error of survival rate.

^aP < 0.05. SEER: Surveillance, epidemiology, and end results; MPV: Mesenterico-portal vein.

Table 4 The 8^th edition of the American Joint Committee on Cancer staging system and the modified staging scheme

AJCC staging of pancreatic cancer (8^th edition)	Stage
Primary tumor size and extension (T)
T1: Tumor ≤ 2 cm in the greatest dimension, without involvement of the CA, SMA, and CHA.	IA: T1N0M0
	IB: T2N0M0
T2: Tumor > 2 cm and ≤ 4 cm in the greatest dimension, without involvement of the CA, SMA, and CHA.	IIA: T3N0M0
	IIB: T1-3N1M0
T3: Tumor > 4 cm in the greatest dimension, without involvement of the CA, SMA, and CHA.	III: (1) TxN2M0;
T4: Tumor involves the CA, SMA, or CHA, regardless of size.	(2) T4NxM0
Regional lymph node (N)	IV: TxNxM1
N0: No positive regional lymph node
N1: 1-3 positive regional lymph nodes
N2: 4 or more positive regional lymph nodes
Distant metastasis (M)
M0: No distant metastasis
M1: Distant metastasis
Modified staging of pancreatic cancer
Primary tumor size and extension (T)
T1: Tumor ≤ 2 cm in the greatest dimension, without involvement of the CA, SMA, CHA, and MPV	IA: T1N0M0
	IB: T2N0M0
T2: Tumor > 2 cm and ≤ 4 cm in the greatest dimension, without involvement of the CA, SMA, CHA, and MPV	IIA: T1N1M0
	IIB: T3N0M0;
T3: Tumor involves the MPV, or > 4 cm in the greatest dimension, without involvement of the CA, SMA, and CHA	T2N1M0
	III: (1) T3N1M0;
T4: Tumor involves the CA, SMA, or CHA, regardless of size	(2) TxN2M0;
Regional lymph node (N)	(3) T4NxM0
N0: No positive regional lymph node	IV: TxNxM1
N1: 1-3 positive regional lymph nodes
N2: 4 or more positive regional lymph nodes
Distant metastasis (M)
M0: No distant metastasis
M1: Distant metastasis

AJCC: American Joint Committee on Cancer; CA: Celiac artery; SMA: Superior mesenteric artery; CHA: Common hepatic artery; MPV: Mesenterico-portal vein.

Table 5 Verification of the modified staging system in predicting prognosis

Stage	SEER database				West China Hospital database
Stage	Median survival	1-yr survival rate, % (±%)	3-yr survival rate, % (±%)	5-yr survival rate, % (±%)	Median survival	1-yr survival rate, % (±%)	3-yr survival rate, % (±%)	5-yr survival rate, % (±%)
Prognostic comparison of different 8^th edition AJCC T classifications
AJCC T1	27 (± 1.1)	78.7 (± 1.2)	39.7 (± 1.5)	27.0 (± 1.5)	25 (± 2.2)	82.6 (± 3.3)	32.9 (± 4.8)	24.4 (± 4.9)
AJCC T2	20 (± 0.3)	68.9 (± 0.7)	26.0 (± 0.7)	16.1 (± 0.7)	19 (± 0.9)	72.0 (± 2.2)	21.5 (± 2.4)	11.4 (± 2.2)
AJCC T3	15 (± 0.5)	61.7 (± 1.4)	18.7 (± 1.2)	9.9 (± 1.0)	15 (± 1.6)	53.5 (± 5.3)	10.4 (± 4.1)	3.1 (± 2.8)
T1 vs T2	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.002^a	P = 0.008^a	P = 0.034^a	P = 0.016^a
T2 vs T3	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.001^a	P = 0.019^a	P = 0.020^a
Prognostic comparison of different modified T classifications
Modified T1	28 (± 1.2)	78.7 (± 1.2)	41.1 (± 1.6)	27.8 (± 1.6)	26 (± 2.6)	82.6 (± 3.4)	35.7 (± 5.1)	26.5 (± 5.2)
Modified T2	20 (± 0.4)	69.2 (± 0.7)	26.6 (± 0.8)	16.4 (± 0.7)	21 (± 1.1)	72.8 (± 2.4)	21.8 (± 2.8)	13.8 (± 2.7)
Modified T3	16 (± 0.4)	60.5 (± 1.2)	19.1 (± 1.0)	10.7 (± 0.9)	15 (± 0.8)	61.1 (± 3.7)	7.7 (± 2.5)	2.6 (± 1.6)
T1 vs T2	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.004^a	P = 0.019^a	P = 0.017^a	P = 0.030^a
T2 vs T3	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.008^a	P = 0.000^a	P = 0.000^a
Prognostic comparison of different 8^th edition AJCC stages
AJCC IA	38 (± 3.4)	84.8 (± 1.6)	50.7 (± 2.5)	38.9 (± 2.6)	30 (± 4.6)	84.9 (± 3.9)	43.9 (± 6.5)	34.8 (± 7.0)
AJCC IB	27 (± 1.1)	77.8 (± 1.2)	39.4 (± 1.5)	27.2 (± 1.5)	23 (± 1.8)	78.2 (± 2.7)	25.6 (± 3.6)	18.3 (± 3.5)
AJCC IIA	20 (± 1.0)	70.0 (± 2.8)	25.8 (± 2.9)	14.1 (± 2.6)	16 (± 2.0)	58.4 (± 7.6)	9.9 (± 6.3)	5.0 (± 4.7)
AJCC IIB	19 (± 0.4)	68.2 (± 0.9)	25.2 (± 0.9)	15.3 (± 0.8)	17 (± 0.9)	66.1 (± 3.1)	12.7 (± 2.6)	4.5 (± 2.3)
AJCC III	16 (± 0.4)	59.4 (± 1.1)	16.8 (± 0.9)	7.9 (± 0.7)	15 (± 2.7)	53.3 (± 7.2)	6.8 (± 4.3)	0.0
IA vs IB	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.014^a	P = 0.158	P = 0.014^a	P = 0.035^a
IB vs IIA	P = 0.000^a	P = 0.010^a	P = 0.000^a	P = 0.000^a	P = 0.001^a	P = 0.014^a	P = 0.030^a	P =0.023^a
IIA vs IIB	P = 0.958	P = 0.541	P = 0.843	P = 0.659	P = 0.425	P = 0.348	P = 0.681	P = 0.924
IIB vs III	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.000^a	P = 0.018^a	P = 0.102	P = 0.240	P = 0.050
Prognostic comparison of different modified stages
Modified IA	38 (± 3.6)	84.7 (± 1.7)	51.7 (± 2.5)	39.4 (± 2.7)	32 (± 5.3)	84.2 (± 4.0)	45.4 (± 6.6)	36.0 (± 7.1)
Modified IB	27 (± 1.3)	80.7 (± 1.2)	40.1 (± 1.6)	27.6 (± 1.6)	24 (± 1.6)	79.0 (± 2.9)	28.6 (± 4.0)	20.9 (± 4.0)
Modified IIA	25 (± 1.4)	75.6 (± 2.0)	36.3 (± 2.3)	22.5 (± 2.2)	21 (± 3.3)	77.3 (± 7.1)	22.1 (± 7.6)	14.7 (± 6.6)
Modified IIB	20 (± 0.5)	69.7 (± 1.0)	25.4 (± 1.0)	15.7 (± 0.9)	18 (± 1.1)	67.1 (± 3.4)	10.5 (± 2.8)	4.1 (± 2.2)
Modified III	16 (± 0.3)	60.0 (± 0.9)	17.4 (± 0.8)	8.6 (± 0.7)	15 (± 1.0)	56.2 (± 4.5)	7.8 (± 2.8)	0.0 (± 0.0)
IA vs IB	P = 0.000^a	P = 0.055	P = 0.000^a	P = 0.000^a	P = 0.044^a	P = 0.293	P = 0.029^a	P = 0.064
IB vs IIA	P = 0.008^a	P = 0.029^a	P = 0.175	P = 0.061	P = 0.425	P = 0.825	P = 0.449	P = 0.422
IIA vs IIB	P = 0.000^a	P = 0.008^a	P = 0.000^a	P = 0.004^a	P = 0.043^a	P = 0.195	P = 0.152	P = 0.128
IIB vs III	P = 0.000^a	P =0.000^a	P = 0.000^a	P = 0.000^a	P = 0.004^a	P = 0.053	P = 0.495	P = 0.062

Values in parentheses are the standard error of median survival or standard error of survival rate.

^aP < 0.05. SEER: Surveillance, epidemiology, and end results; AJCC: American Joint Committee on Cancer.

Citation: Chen HY, Wang X, Zhang H, Liu XB, Tan CL. Mesenterico-portal vein invasion should be an important factor in TNM staging for pancreatic ductal adenocarcinoma: Proposed modification of the 8^th edition of the American Joint Committee on Cancer staging system. World J Gastroenterol 2019; 25(46): 6752-6766
URL: https://www.wjgnet.com/1007-9327/full/v25/i46/6752.htm
DOI: https://dx.doi.org/10.3748/wjg.v25.i46.6752