Stage migration vs immunology: The lymph node count story in colon cancer

Table 1 Factors with influence on lymph node harvest in colorectal cancers

Surgery	Pathology	Patient	Tumor	Other
Experience	Experience	Age	Location	Specimen length
Volume	Technique	Gender	T-stage	Hospital status
		BMI	N-stage	Year of operation
			Lymph node size
			MSI

BMI: Body mass index; MSI: Microsatellite instability.

Table 2 Prognostic relevance of lymph node harvest in stage II colon cancers

First author	Year	n	Insuff.-rate	pT3/4	Prognostic	Endpoints	Cut off	Survival
Swanson	2003	35787	60%	100%	Yes	5yOS	No cut off	linear increase of 5yOS-rate
Law	2003	115	NA	100%	Yes	5yOS, 5yDFS	≥ 7	5yOS: < 7LN 69% vs > 6LN 89%
Bui	2006	4531	NA	NA	Yes	OS	1-3 vs 10-36	HR = 0.6 (CI: 0.4-1.0), P = 0.03
Bilimoria	2008	142009	NA	59%	Yes	5yOS	≥ 12	HR = 0.75 (CI: 0.71-0.8), P < 0.0001
Maggard	2009	11263	NA	69%	Yes	5yOS	4 (T1) and 10 (T2)	T1: HR = 0.76 (CI: 0.641-0.902), P = 0.002
								T2: 0.853 (CI: 0.776-0.937), P = 0.001
Stocchi	2011	901	NA	100%	Yes	OS, DFS, CsS	≥ 12	< 12 LN: HR = 1.93 (1.27-2.94), P = 0.002
Sato	2011	1476	56%	100%	Yes	5yOS	> 12	ACT: improved 5yOS for LNs ≤ 12

¹Sub-group of the study collection. NA: No available data; 5yOS: 5 years overall survival; 5yDFS: 5 years disease-free survival; OS: Overall survival; CsS: Cancer specific survival; ACT: Adjuvant chemotherapy; LN: Lymph node.

Table 3 Prognostic relevance of lymph node harvest in stage II and III colon cancers

First author	Year	n	N+	Insuff rate	pT3/4	Endpoints	Cut off	Prognostic stage II	Prognostic stage III
Prandi1	2002	3491	48%	501%	n.m.	OS, PFS	8-12 (RR = 0.46) vs 13-17 (RR = 0.76) vs > 17 (RR = 0.79)	Yes	No
Le Voyer2	2003	3411	81%	NA	89%	CsS	N1: ≥ 12 vs > 10 vs > 40; N2: > 35; N0: ≥ 12 vs≥ 12 vs > 20 and < 35	Yes	Yes
Jestin	2004	3735	31%	NA	NA	OS	≥ 12	Yes	/3
Johnson	2006	20702	100%	NA	92%	5yCsS	< 4 neg LN vs > 12 neg LN	/	Yes
Kelder	2009	2281	32.4%	79%	79%	5yOS	< 6; 6-11; > 11	Yes	N
Tsikitis	2009	329	100%	49%	NA	CsS/DFS	> 12	/	N
Vather	2009	4309	NA	NA	NA	5yOS	4 LN wide steps	Yes	Yes
Dillman	2009	574	NA	NA	NA	OS	≥ 12	Yes	No
Shanmugam	2011	490	46.9%	24%	NA	5yCsS/CsS	≥ 20	Yes	Yes
Chang	2012	9644	41%	27.7%	80.2%	5yOS	≥ 12	Yes	Yes
Gleisner	2013	154208	34%4	NA	69.4%	OS	Linear risk reduction up to 25 LN in N- and up 10 LN in N+	Yes	Yes
Khan	2014	194459	NA	41%	NA	CsS	≥ 12 LN	Yes	Yes

¹Intergroup Trial INT-0089;

²INTAC-Trail;

³Lymph node ratio is prognostic;

⁴Mean out of two collectives. NA: No available data; 5yOS: 5 year overall survival; 5yDFS: 5 year disease-free survival; OS: Overall survival; CsS: Cancer specific survival; HR: Hazard rate; ACT: Adjuvant chemotherapy; LN: Lymph node; PFS: Progression-free survival; DFS: Disease-free survival; N-: Node negative; N+: Node positive.

Table 4 Prognostic relevance of lymph node harvest in stage II colorectal cancers

First author	Year	n	Insuff rate	pT3/4	Prognostic	Endpoint	Cut off	Survival
Cserni	2002	8574	NA	100%	Yes	OS	No cut off	Continuously improved survival
Cianchi	2002	140	min 40%1	n.m.	Yes	5yOS	≥ 9	54.9% vs 79.9%, P < 0.001
Wong	2002	345	NA	NA	≥ 68	DFS	22.6 vs 11.32	40% vs 90%1, P < 0.001
Berberoglu	2004	301	53.5%1	69%	Yes	5yOS	≤ 10	RR = 2.8 (CI: 1.6-5.2), P = 0.0008
Yoshimatsu	2005	94	35%	100%	Yes	5yOS	≥ 9	66.7% vs 86.7%
Tsai	2007	180	NA	70%	Yes	OS	≥ 18	5yOS: 70 vs 98%1, P = 0.015
Norwood	2009	2449	NA	NA	Yes	OS	< 12	about 15% difference1, P = 0.001
Ishizuka	2010	205	min 36%1	100%	Yes	CsS	≤ 9 vs > 9	44.5 mo vs 66 mo, P = 0.0042
Nir	2010	117	28%	100%	No	5yOS, 5yDFS	≥ 12	No difference
La Torre	2012	204	16%	100%	Yes	5yDFS, 5yCsS, and 5yOS	> 12	5yOS 78.5% vs 53.1%, P = 0.001
Iachetta	2013	657	22%	100%	Yes	CsS/PFS	< 12 vs≥ 20	HR = 0.49 (CI: 0.30-0.79), P = 0.003
Xingmao	2013	729	NA	100%	Yes	OS	> 12	88.7% vs 64.9%, P = 0.000

¹Estimated based on Kaplan-Meier-curve;

²Comparision of different cohorts. NA: No available data; 5yOS: 5 year overall survival; 5yDFS: 5 year disease-free survival; OS: Overall survival; CsS: Cancer specific survival; HR: Hazard rate; LN: Lymph node; PFS: Progression-free survival.

Table 5 Prognostic relevance of lymph node harvest in stage II and III colorectal cancers

First author	Year	n	N+	Insuff-rate	pT3/4	Endpoints	Cut off	Stage II	Stage III
Caplin	1998	377	NA	NA	NA	OS	> 6	Yes	No
Sarli	2005	1040	NA	NA	100%	5yOS	< 10	Yes	No
Wong	2005	21491	37%	NA	67%	OS	> 13	Yes	1
George	2006	3592	NA	79%	NA	5yOS	0-4; 5-10; > 10	Yes	Yes
Edler	2007	125	51%	87%	NA	OS	0-11 vs > 11	Yes	Yes1
Evans	2008	381	45.3%	47%1	82%	5yOS	≥ 9	Yes	2
Choi	2010	664	NA	NA	100%	DFS	> 20	Yes	No
Desolneux	2010	362	NA	NA	72.4%	OS	< 8 vs≥ 8 and < 12 vs≥ 12	Yes	No
Ogino	2010	716	38%	63%1	68.3%	CsS/OS	0-3 negative LN, 7-12 and > or = 13 negative LN	Yes	Yes
Fretwell	2010	351	48%	min 20%	95%	5yOS	≥ 9 (Dukes B); > 9 (Dukes C)	Yes	Yes
Wong	2011	8521	About 30%	32%	66%	CsS	medians: 4 vs 8 vs 10	Yes	No
Kotake	2011	16865	46%	24%1	100%	5yOS	< 10 vs > 27	Yes	Yes
Kritsanasakul	2012	533	43%	59.1%	82%	5yOS	≥ 12	Yes	1
Moro-Valdezate	2013	11662	39.7%	65%1	79.7%	5yOS/5yCsS	≥ 12	No	No
Zhang	2013	265	42.3%	75.1%	79.2%	OS	< 12	Yes	Yes
Onitilo	2013	1397	37%	26%	67%	OS	≥ 12	Yes	Yes
Duraker	2014	461	NA	51%	74%	CsS	≥ 12	Yes	No1

¹Survival analysis only in the nodal negative sub group (n = 1348);

²Based on cases with available survival data (n = 359). NA: No available data; 5yOS: 5 year overall survival; 5yDFS: 5 year disease-free survival; OS: Overall survival; CsS: Cancer specific survival; HR: Hazard rate; LN: Lymph node; PFS: Progression-free survival.

Table 6 Lymph node positivity rates of the five largest studies

First author	Year	n	Register	N+ rate	Insuff rate	Rate T3/4
Gleisner	2013	154208	SEER	34%	NA	69.4%
Baxter	2010	110444	SEER	41%	53.6%	100%
Ricciardi	2006	106900	SEER	34%	57%	73%
Gonsalves	2011	19240	VACCR	30%	NA	61.1%
Chang	2012	9644	Taiwan Cancer Database	41%	27.7%	80.2%

SEER: Surveillance, Epidemiology and End Results cancer registry; VACCR: Veteran's Affairs Central Cancer Registry; NA: No available data.

Table 7 Upstaging rates after re-evaluation

First author	Year	n	Mean LN before	Mean LN after	UpstagingN0/N+	Up-rate	Location	Technique	Comment
Scott	1989	103	6.2	12.4	Yes	8.6%	CR	Fat clearing	5yFU available
Haboubi	1992	41	6.7	58.2	Yes	28%1	CR	Fat clearing	Based on HE; higher up-staging with ICH1
Cohen	1994	41	13	17	?1	1	CR	Xylene	Upstaging in 1 single case; primary N-stage (N0/1) not given; %tage N+ not given1
Koren	1997	30	2.6	8.6	Yes	31%	CR	Fat clearing
Brown	2005	15	20.8	89.6	Yes	1	CR	ESMT	1 of 7; however unclear wether it was a LN metastasis or a deposit1
Kim	2007	48	19.4	43	No	/	CR	ESMT
Richter	2007	188	n.m.	n.m.	Yes	min 4%	CR	Fat clearing	Initinal insuff rate 59; after 9
Vogel	2008	80	6.9	11.3	Yes	2%	CR	Fat clearing
Märkl	2008	30	17	25	Yes	3%	C	Fat clearing	Primarily conventional technique
Märkl	2008	30	35	40	No	/	C	Fat clearing	Primarily methylen technique
Fan	2010	115	9.1	14.2	Yes	5%-10%1	CR	Re-evaluation	Insuff Rate 79%; Up Staging rate not exactly calculatable
Hernanz	2010	50	13.9	23.9	Yes	4%1	CR	Fat clearing	based on own calculation
Chapman	2012	94	22.5	29	Yes	1	CR	Schwartz-clearing	1 single case upstaged1
Chen	2014	83	7.2	14.1	No	/	CR	Re-evaluation: partly Fat clearing
Ma	2014	55	9.8	18.4	Yes1	1	CR	GEWF	Upstaging in cases with primary insufficient LNY; 3 cases N0 to N+1

¹See comment in the same row. CR: Colorectal; C: Colon; ESMT: Entire submission of mesenteric tissue; GEWF: Glacial acetic acid, ethanol, distilled water, formaldehyde; LN: Lymph node.

Table 8 Results of advanced pathological lymph node dissection techniques in colorectal cancers

First author	Year	n	Mean/median LN-Conv	Mean/median LN-Spec	N+ Konv	N+ Spec	T3/4 Konv	T3/4 Spec	Technique	P value
										N+ rates
Ratto	1999	801	11.4%	29.4%	30.2%	37.5%	76.9%	84.5%	Fixing Technique	< 0.05
Newell	2001	67	6.8%	10.2%	31%	46%	81%	85%	GEWF	NS
Kukreja	2009	701	12.8%	17.3%	36.9%	32.4%	65.8%	62.8%	Fat clearance	NS
Törnroos	2009	32	22%	61%	56.3%	37.5%	100%	100%	MB	NS
van Steenbergen	2010	170	11%	14%	42%	41%	80%	79%	mesent. Patent Blue Injection	ND
Frasson	2012	473	20.6%	37.1%/47.6%	38.9%	48%	80.9%	72%	MB	NS
Jepsen	2012	428	24%	37%	9.4%1	26.7%1	82%	81%	MB	0.040
Märkl	2013	1332	13%	34%	37%	37%	65%	63%	MB	ND
Kir	2014	180	21.5%	24.5%	28%	47.9%	91.6%	84.9%	MB	0.006
Borowski	2014	100	15%	23%	34%12	40%12	NA	NA	MB	NS
Iversen	2015	120	9.5%	16.5%	44%	36%	81%	71%	GEWF	NS

¹Subgroup of T1/2 cases;

²Based on the number of % Dukes C cases. LN-Conv.: Lymph node harvest of conventional dissected cases; LN–Spec: Lymph node harvest of cases using advanced techniques; NA: No data available; GEWF: Glacial acetic acid. ethanol. distilled water. formaldehyde; MB: Methylene blue assisted lymph node dissection; NS: Not significant; ND: No difference.