Systematic review of risk factors, prognosis, and management of colorectal signet-ring cell carcinoma

Table 1 Overview of articles eligible for data extraction with methodological details

Ref.	Type of article	Time of inclusion	% (SRC/total study population)	Database	Compared to
Tawadros et al[13], 2015	Retrospective cohort study	2004-2010	< 40 yr: 3%, > 40 yr: 0.87% (NA)	SEER	MA and OA of the rectum
Song et al[25], 2017	Retrospective cohort study (pT1 cancer)	1988-2011	62/21463 (0.3%)	SEER	MA and OA
Wei et al[41], 2016	Retrospective case series (SRC component)	11/2008-01/2015	39 group A, 22 group B	NA	Group A (> 50% SRC) and group B (< 50% SRC, but with SRC component)
Wu et al[9], 2018	Retrospective cohort study	1988-2012	4402 colon + 853 rectum/24171 overall SRC	SEER	Other SRCC locations (bladder, breast, esophagus, gallbladder, lung, pancreas, small intestine)
Hartmann et al[16], 2013	Retrospective case series	2002-2012	53/4760 (1.1%)	NA	40 (75%) mucin-rich SRCC vs 13 (25%) mucin-poor SRCC and 23 (43%) MSI-H SRCC vs 30 (57%) MSS SRCC
Pande et al[54], 2008	Retrospective cohort study (SRC component < 50%)	01/2002-05/2006	39/753 (5.1%)	NA	MA, CMA, > 50% SRRC, < 50% SRC component, OA in a random sample size of 100 patients
van Oudheusden et al[59], 2015	Retrospective cohort study	04/2005-12/2013	20/351 (5.7%): CRS + HIPEC in 16/20 (80%)	NA	CRS + HIPEC in SRCC vs CRS + HIPEC in other differentiation (252/331)
Wu et al[10], 2019	Retrospective cohort study	2004-2015	4140/399791 (1.0%)	SEER	MA and NMA
Hyngstrom et al[19], 2012	Retrospective cohort study	1998-2002	2260/244794 (1%)	NA	MA and OA
Hugen et al[17], 2015	Retrospective cohort study	1989-2010	1972/196757 (1.0%)	NA	MA and OA
Shi et al[61], 2019	Retrospective cohort study	2010-2014	1932/173460	SEER	Non-SRCC
Kang et al[12], 2005	Retrospective cohort study	1991-2000	1522/164628 (0.9%)	NA	MA and OA
Ciarrocchi[4], 2014	Retrospective cohort study	2004-2009	1484	NA	Rectal SRCC vs non-rectal colonic SRCC
Huang et al[26], 2016	Retrospective cohort study (<35/>35 y with SRCC)	01/1988-12/2011	NA	SEER	NA
Ling et al[50], 2017	Retrospective cohort study	1988-2011	622/69543 (0.9%)	NA	MA and OA of the rectum
Simkens et al[38], 2016	Retrospective cohort study	01/2005-12/2014	385/5516 (7%)	NA	MA and OA with peritoneal metastases
Razenberg et al[62], 2015	Retrospective cohort study (peritoneal metastases +)	01/2005-12/2012	311/4277 (7%)	NA	MA and OA with peritoneal metastases
Wu et al[11], 2017	Retrospective case series	1988-2012	292 (stage II and III rectal SRCC)	NA	NA
Thota et al[30], 2014	Retrospective cohort study	01/1995-12/2008	206/36260 (0.6%)	VACCR	MA and NMA
Tamhankar et al[51], 2016	Retrospective case series	01/2011-12/2013	170/1487 (11.4%)	NA	NA
Nitsche et al[33], 2013	Retrospective cohort study	1998-2012	160/28056 (0.6%)	SEER	MA and OA
Fu et al[58], 2016	Retrospective cohort study	1998-2010	94/3568 (2.6%)	NA	Resectable metastatic SRRC vs resectable metastatic non-SRCC
Kakar and Smyrk[44], 2005	Retrospective case series	1985-2000	72	NA	NA
Yun et al[63], 2017	Retrospective cohort study (+ propensity score matching)	09/1994-12/2013	71/12631 (0.56%)	NA	OA
Sung et al[21], 2008	Retrospective cohort study	01/1995-12/2006	65	NA	MA
Chen et al[6], 2004	Retrospective cohort study	01/1979-07/2001	61/2619 (2.3%)	NA	MA and NMA of the rectum
Wang et al[43], 2016	Retrospective case series	09/2008-07/2014	59/6625 (0.89%)	NA	NA
Nissan et al[18], 1999	Retrospective case matched study/cohort study	1986-1997	40/5350 (0.7%)	NA	CG/non-signet-ring CRC
Liang et al[31], 2018	Retrospective case series	01/1990-12/2010	37/2643 (1.4%)	NA	NA
Korphaisarn et al[46], 2019	Retrospective cohort study (metastatic CRC)	03/1994-11/2015	35/665 (5.3%), 28(4.2%) SRC component	NA	OA with SRC component and OA
Lee et al[52], 2007	Retrospective cohort study	10/1996-12/2005	35/5022 (0.7%)	NA	MA and poorly differentiated OA
Bittorf et al[8], 2004	Retrospective cohort study	01/1978-12/1999	34/4458 (0.8%)	NA	Non-SRCC
Messerini et al[32], 1995	Retrospective case series	01/1985-12/1993	34/2995 (1.1%)	NA	NA
Bademci et al[28], 2019	Retrospective case series	2009-2018	34/3180 (1.06%)	NA	NA
Chua et al[53], 2009	Retrospective case series (peritoneal carcinomatosis)	01/1997-12/2008	33	NA	NA
Kakar et al[45], 2012	Retrospective cohort study	NA	33	NA	MA and OA
Barresi et al[27], 2016	Retrospective case series	2003-2014	32/3248	NA	NA
Chew et al[22], 2010	Retrospective cohort study	01/1999-12-2005	30/2764 (1.1%)	NA	MA and OA
Nitsche et al[1], 2016	Retrospective cohort study	01/1982-10/2012	30/3479 (0.9%)	NA	MA and OA
Anthony et al[7], 1996	Retrospective case series	09/1971-12/1993	29/3690 (0.8%)	NA	NA
Song et al[64], 2009	Retrospective cohort study	08/1994-03/2007	25/2079 (1.2%)	NA	MA and NMA
Belli et al[20], 2014	Retrospective case series	03/2007-06/2013	22/842 (2.6%)	NA	NA
Zhang et al[65], 2020	Retrospective cohort study	2006-2013	21 vs 90	NA	MA
Wang et al[39], 2019	Retrospective cohort study	2004-2013	21/90 (SRC/SRC + MAC)	NA	MA
Song et al[66], 2019	Retrospective cohort study	2000-2010	20/299	NA	Predominant SRCC (> 50% SRCC) vs mixed SRC vs cluster predominant vs strip predominant
Mizushima et al[36], 2010	Retrospective cohort study	1993-2007	19/5884 (0.32%)	NA	Well or moderately differentiated OA and poorly differentiated MA
Foda et al[42], 2018	Retrospective cohort study	01/2007-12/2011	19/150 (12.6%)	NA	MA, OA, OA with mucinous component
Lee et al[29], 2015	Retrospective case matched study	01/2003-12/2011	15 vs 75 NMA	NA	NMA
Imai et al[67], 2013	Retrospective cohort study	04/1998-03/2000	15/250 (6%)	NA	Well or moderately differentiated OA, poorly differentiated OA and MA
Psathakis et al[15], 1999	Retrospective case matched study/cohort study	01/1979-12/1997	14/1600 (0.88%)	NA	Non-SRCC
Pozos-Ochoa et al[37], 2018	Retrospective cohort study	1995-2015	12	NA	MA with SRC component
Sasaki et al[14], 1998	Retrospective cohort study	01/1963-12/1996	11/1595 (0.7%)	NA	Mucinous adenocarcinoma (KRAS mutation screening in 30 control advanced colorectal carcinomas)
Ooi et al[23], 2001	Retrospective case series	1989-1999	9/3000 (0.3%)	NA	NA
Secco et al[68], 1994	Retrospective cohort study	01/1979-12/1986	4/352 (1.1%)	NA	MA and OA

SRC: Signet-ring cell; SRCC: Signet-ring cell cancer; MA: Mucinous adenocarcinoma; OA: Ordinary/conventional adenocarcinoma; NMA: Non-mucinous adenocarcinoma; CMA: Component of mucinous adenocarcinoma; CRS: Cytoreductive surgery; HIPEC: Hyperthermic intraperitoneal chemotherapy; MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; NA: Not applicable; CG: Control group; SEER: Surveillance, Epidemiology and End Results program database; VACCR: Veterans Affairs Central Cancer Registry; CRC: Colorectal cancer; MAC: Mucinous adenocarcinoma.

Table 2 Overview of articles reporting on tumor characteristics at the time of diagnosis

Ref.	Mean tumor size (cm)	LNM	Stage III or IV	% M+
Tawadros et al[13], 2015	5.2 vs 4.8 MA vs 4 OA (P < 0.001)	60.8% vs 51.4% MA vs 35% OA (P < 0.001)	NA	24.3% vs 15.2% MA vs 12.3% OA (P < 0.001)
Song et al[25], 2017	NA	35.5% vs 11.6% MA vs 18.4% AC (P < 0.001)	NA	NA
Wei et al[41], 2016	NA	NA	54/61 (88.5%)	NA
Wu et al[9], 2018	NA	NA	NA	NA
Hartmann et al[16], 2013	NA	NA	57% mucin-rich vs 100% mucin-poor (P = 0.005); 44% MSI-H vs 87% MSS (P = 0.0012)	NA
Pande et al[54], 2008	NA	NA	74.2% vs 65% MA vs 70.5 CMA vs 63% OA (P = 0.75)	17/39 (43.6%) vs 30% MA vs 32.4% CMA vs 35% OA
van Oudheusden et al[59], 2015	NA	N2: 62.5% vs 36.1% (P = 0.04)	NA	NA
Wu et al[10], 2019	NA	63.3% vs 45.1% MA vs 36.1% OA (P < 0.001)	3231 (78%) vs 52.3% MA vs 44.7% OA (P < 0.001)	1595 (38.5%) vs 20.3% vs 19% (P < 0.001)
Hyngstrom et al[19], 2012	NA	NA	80% vs 52% MA vs 44% OA (P < 0.01)	NA
Hugen et al[17], 2015	NA	NA	75.2% vs 47.7% (MA) vs 43.6% OA P < 0.0001	NA
Shi et al[61], 2019	NA	60.8% vs 35.1% (P < 0.001)	76.04 vs 44.05% (P < 0.001)	39.13% vs 19.08% (P < 0.001)
Kang et al[12], 2005	NA	NA	80.9 % vs 52.8% (MA; P < 0.0001) vs 49.5% OA (P < 0.0001)	NA
Ciarrocchi[4], 2014	5.6 ± 3.1 (5.4 ± 4.9 rectum vs 5.7 ± 2.7 colon; P = 0.235)	NA	1123 (76%) (144 (72%) vs 979 (76%; P = 0.193)	NA
Huang et al[26], 2016	> 4 cm: 67.9%	74.90%	III: 74.9%	NA
Ling et al[50], 2017	> 5 cm: 45.3% vs 43.2% MA vs 31.1% OA (P = 0.372 vs MA. P < 0.001 vs OA)	NA	Stage III: 79.4% vs 57.1 MA (P < 0.001) vs 52.8 OA (P < 0.001)	NA
Simkens et al[38], 2016	NA	NA	NA	NA
Razenberg et al[62], 2015	NA	62% vs 60% MA vs 59% OA. Nx: 30% vs 25% MA vs 28% OA (P < 0.0001)	100%	NA
Wu et al[11], 2017	53.5 ± 25.1	NA	Stage III: 241/292 (82.5%)	NA
Thota et al[30], 2014	NA	46.5% vs 38% MA vs 27% NMA. Unknown: 32.5% vs 14% MA vs 29% NMA	61.2% vs 44.6% MA vs 44.5% NMA. Unknown: 22.3% vs 16% MA vs 32% NMA	NA
Tamhankar et al[51], 2016	NA	NA	91.20%	39.40%
Nitsche et al[33], 2013	NA	71% vs 44% (P < 0.001)	86% vs 48% (P < 0.001)	35% vs 18% (P < 0.001)
Kakar and Smyrk[44], 2005	> 5 cm: 52/72 (72%)	NA	55/72 (76.4%)	NA
Yun et al[63], 2017	NA	NA	69% vs 43% (P < 0.001)	NA
Sung et al[21], 2008	6.64 ± 2.4 vs 10.35 ± 55.2 MA (P = 0.608)	57/65 (88%) vs 130/266 (49%) (P < 0.0001)	58/65 (89%) vs 138/266 (52%) MA (P < 0.0001)	NA
Chen et al[6], 2004	5.7 ± 3.8 vs 4.3 ± 1.8 MA vs 3.8 ± 1.7 (NMA; P < 0.001)	NA	90% vs 69% (MA; P = 0.013) vs 49% (NMA; P < 0.001)	25/61 (41%) vs 44/144 (30%; MA) vs 311/2414 (13%) NMA
Wang et al[43], 2016	NA	52/59 (88.1%)	NA	14/59 (23.7%)
Nissan et al[18], 1999	NA	NA	60% vs 60% CG vs 45% CRC	30%
Liang et al[31], 2018	NA	26 (70.3%)	33/37 (89.2%)	16/37 (43%)
Korphaisarn et al[46], 2019	NA	NA	NA	100%
Lee et al[52], 2007	NA	NA	79.9% vs 55% MA vs 64.7% poorly differentiated OA (P = 0.003)	37.1% vs 15% MA vs 25% poorly differentiated OA
Bittorf et al[8], 2004	NA	NA	20/24 (83%) resected specimens vs 2089/4231 (49%) resected specimens (P = 0.002)	15/34 (44%) vs 912/4458 (21%; P = 0.002)
Messerini et al[32], 1995	> 5 cm: 22/34 (64.7%)	NA	Dukes stage C: 21/34 (61.8%). D: 3/34 (8.8%). Combined: 24/34 (70.6%)	NA
Bademci et al[28], 2019	4.6 ± 1.8	17 (68%)	22 (64.7%)	NA
Chua et al[53], 2009	NA	Colorectal: 13/15 (87%). Appendiceal: 11/18 (61%)	NA	NA
Kakar et al[45], 2012	NA	NA	79% vs 62% MA vs 34% OA (P < 0.001)	NA
Barresi et al[27], 2016	NA	NA	28/32	NA
Chew et al[22], 2010	NA	25 (89%) vs 101 (61%) MA vs 1320 (52%) OA (P = 0.002)	38 (94%) vs 112 (67%) MA vs 1426 (56%) (P < 0.001)	13 (43%) vs 45 (27%) MA vs 520 (20%) (P = 0.009)
Nitsche et al[1], 2016	NA	NA	26/30 (87%) vs 48% MA vs 55% OA (P < 0.001)	12/30 (40%) vs 25% MA vs 22% OA (P = 0.015)
Anthony et al[7], 1996	6 (0.8-15)	13/29 (45%)	21/29 (72%)	8/29 (28%)
Song et al[64], 2009	5.52 ± 3.36 vs 5.52 ± 1.823 MA vs 4.62 ± 268 NMA (P < 0.001)	18 (72%) vs 59% MA vs 51% NMA	20 (75%) vs 59% MA vs 52% NMA (P < 0.01)	NA
Belli et al[20], 2014	7 ± 3.6	NA	20/22 (91%)	10/22 (45%)
Zhang et al[65], 2020	SRCC + MA: > 5 cm: 50%	SRCC + MAC: 74.4%	SRCC + MAC: 83.3%	SRCC + MAC: 23.3%
Wang et al[39], 2019	NA	NA	NA	38% vs 20%
Song et al[66], 2019	NA	80% vs 65.1 mixed vs 47.1 cluster vs 32.1% strip (P < 0.001)	85% vs 65.1% mixed vs 48.4% cluster vs 35.8% strip (P = 0.006)	15% vs 7.0% mixed vs 9.0% cluster vs 6.2% strip (P = 0.603)
Mizushima et al[36], 2010	7.2 ± 3.8 vs 4.4 ± 2.2 (well/moderately differentiated) vs 5.6 ± 2.7 (poorly differentiated/MA)	14/19 (73.7%)	16/19 (84.21%) (SRC differentiation)	7/19 (36.8%) vs 14.5% well/moderately differentiated vs 29.9% (poorly differentiated/mucinous) (SRC differentiation)
Foda et al[42], 2018	NA	84.2% vs 57.2 MA vs 60.7% OA with mucinous component vs 42.6% OA	84.2% vs 57.1% MA vs 60.7% AWNC vs 44.7% OA	NA
Lee et al[29], 2015	7.59 ± 2.9 vs 5.37 ± 2.19 (P = 0.003)	12/15 (80%) vs 60/75 (80%; P = 0.994)	80% vs 80%	NA
Imai et al[67], 2013	NA	9/15 (64.3%) vs 46.8% MA vs 78.4% poorly differentiated OA vs 54% well or moderately differentiated OA	11/15 (73.3%) vs 50% vs 81.1% vs 54%	NA
Psathakis et al[15], 1999	NA	NA	13/14 (92.8%) vs 30/56 (50%; P < 0.05)	NA
Pozos-Ochoa et al[37], 2018	NA	75% vs 50% (P = 0.040)	91.7% vs 75% (P = 0.248)	NA
Sasaki et al[14], 1998	> 8 cm: 11/11 (100%) vs 6/29 (21.4%; P < 0.00001)	NA	9/22 (81.8%) vs 17/29) (58.6%) (stages I-III/stage IV P < 0.01)	NA
Ooi et al[23], 2001	NA	NA	Dukes stage C or D: 9/9 (100%)	2/9 (22%)
Secco et al[68], 1994	NA	NA	Duke C/D: 100% vs 56.4% MA vs 42.4% OA	NA

LNM: Lymph node metastases; SRCC: Signet-ring cell cancer; MA: Mucinous adenocarcinoma; OA: Ordinary/conventional adenocarcinoma; NA: Not applicable; NMA: Non-mucinous adenocarcinoma; CMA: Component of mucinous adenocarcinoma; MAC: Mucinous adenocarcinoma; CRC: Colorectal cancer; AWNC: Adenocarcinoma with mucinous component.

Table 3 Overview of studies describing rate of lymphovascular invasion or molecular features

Ref.	LVI +	MSI-H	KRAS	E-cadherin expression
Wei et al[41], 2016	NA	NA	9/54 (16.7%) KRAS. 3/54 (5.6%) NRAS. 2/54 (3.7%) BRAF
Hartmann et al[16], 2013	L: 55% mucin-rich vs 100% mucin-poor (P = 0.002); 56% MSI-H vs 73% MSS (P = 0.25); V: 8% mucin-rich vs 46% mucin-poor (P = 0.004); 4% MSI-H vs 27% MSS (P = 0.06)	23/53 (43%)	16/53 (30%)	NA
Nitsche et al[33], 2013	L: 79% vs 36% (P < 0.001). A: 38% vs 18.37% (P < 0.001)	20% vs 30% (P = 0.644), 155/160 and 15368/25172 missing data	NA	NA
Kakar and Smyrk[44], 2005	NA	22/72 (31%)	NA	NA
Yun et al[63], 2017	L: 60.6% vs 24.8% (P < 0.001). V: 36.6% vs 13.4% (P < 0.001)	NA	NA	NA
Sung et al[21], 2008	Vascular invasion: 58/65 (89%) vs 137/266 (52%; P < 0.0001)	12/63 (19%) vs 21/95 (22%)	NA
Wang et al[43], 2016	NA	NA	NA	23/59 (39%) E-cadherin+ vs 36 (61%) E-cadherin- (P = 0.010)
Nissan et al[18], 1999	Blood vessel invasion: 7.5% vs 22.5% vs 11.9%; LVI: 42.5% vs 2.5% vs 3.5% (P < 0.001); neural invasion: 17.5% vs 7.5% control group vs 4.7% CRC (P < 0.001)	NA
Korphaisarn et al[46], 2019	NA	Deficient MMR: 12.1% vs 9.5% OA with SRC component vs 4.9% (P = 0.10)	Wild type: OR = 7.7, 95%CI: 2.7-22 (P < 0.001)	NA
Lee et al[52], 2007	56% vs 17.4% MA vs 43.3% poorly differentiated OA (P < 0.001)	NA	NA	NA
Bittorf et al[8], 2004	V: 75% vs 34 % and L: 92% vs 54% (P < 0.001)	NA
Bademci et al[28], 2019	22 (88%)	NA	NA	NA
Kakar et al[45], 2012	NA	24% vs 27% MA vs 12% OA (P = 0.52)	52% vs 27% MA vs 40% OA (P = 0.04)	NA
Barresi et al[27], 2016	17/32	7/32	NA	NA
Chew et al[22], 2010	Vascular emboli: 18 (60%) vs 33 (20%) MA vs 587 (23%; P < 0.001)	NA
Nitsche et al[1], 2016	L: 20/30 (67%) vs 23% vs 25% (P < 0.001). Angio-invasion: 5/30 (17%) vs 5% vs 9% (P = 0.18)	1/2 (50%) (P = 0.006) (data only on 251 patients available)
Belli et al[20], 2014	19/22 (86%)	NA
Zhang et al[65], 2020	SRCC + MA: 45.5%	NA	NA	NA
Song et al[66], 2019	75% vs 30.2% mixed vs 21.3% cluster vs 8.6% strip (P < 0.001)	11.1% vs 34.2% mixed vs 23.7% cluster vs 34.2% strip (P = 0.110)	NA	NA
Foda et al[42], 2018	89.5% vs 62.5% MA vs 60.7% OA with mucinous component vs 59.6% OA	NA	NA	26.3% E-cadherin + vs 78.6% MA vs 85.7% OA with mucinous component vs 89.4% OA
Lee et al[29], 2015	7/15 (46.7%) vs 25/75 (33.3%) (P = 0.336)	3/11 (27.3%) vs 10/6 (16.7%; P = 0.486)
Pozos-Ochoa et al[37], 2018	58.3% vs 65% (P = 0.706)	NA	NA	NA
Sasaki et al[14], 1998	NA	NA	4/11 (36.4%) vs 11/29 (37.9%) vs 18/30 (60%) OA

LVI: Lymphovascular invasion; L: Lymphatic invasion; V: Vascular invasion; SRC: Signet-ring cell; SRCC: Signet-ring cell cancer; MA: Mucinous adenocarcinoma; OA: Ordinary/conventional adenocarcinoma; MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; NA: Not applicable; CRC: Colorectal cancer.

Table 4 Overview of articles reporting on survival outcomes for colorectal signet-ring cell carcinoma

Report	5-yr OS (SRC vs other)	5-yr OS in stage III tumors	5-yr DFS % (SRC vs other)
Song et al[25], 2017	5-yr CSS: 85.6% (colon: 89.2%, rectum: 73.3%) vs 90.7% MA (P = 0.17) (colon: 90.5%; rectum: 91.6%) vs 93.3% AC (P = 0.013) (colon: 93.8%; rectum: 92.2%)	NA	NA
Wu et al[9], 2018	5-yr CSS: Colon: 33.2%; rectum: 28.1%	NA	NA
Hartmann et al[16], 2013	66% mucin-rich vs 19% mucin-poor (P = 0.0035); 75% MSI-H vs 48% MSS	NA	66% mucin-rich vs 0% mucin-poor (P = 0.0001); 73% MSI-H vs 31% MSS
van Oudheusden et al[59], 2015	3-yr OS: 0% vs 44%	NA	NA
Wu et al[10], 2019	26.8% vs 50.6% MA vs 60.2% OA (HR: 1.592, 95%CI: 1.558-1.627, P < 0.001)	NA	NA
Hyngstrom et al[19], 2012	NA	Relative survival: Colon IIIa: 0.81 vs 0.87 MA vs 0.86 OA; IIIb: 0.49 vs 0.66 MA vs 0.65 OA; IIIc: 0.21 vs 0.42 MA vs 0.45 OA; rectum IIIa: 0.91 vs 0.82 MA vs 0.86 OA; IIIb: 0.55 vs 0.56 MA vs 0.64 OA; IIIc: 0.3 vs 0.44 MA vs 0.48 OA	NA
Hugen et al[17], 2015	Relative survival: Colon: 31% vs 58% MA vs 57% OA; rectum: 20% vs 54% MA vs 57% OA	Relative survival: Colon: 36% vs 54% MA vs 57% OA; rectum: 25% vs 45% MA vs 54% OA	NA
Kang et al[12], 2005	26.8% vs 58.1% MA (P < 0.0001) vs 62.9% OA (P < 0.0001)	IIIa: 68.3% vs 87.3% MC vs 83.8% OA; IIIb: 46% vs 64.3% MC (P = 0.0002) vs 63.6% OA (P <0.0001); IIIc: 19% vs 29.2% MC (P <0.0001) vs 30% OA (P <0.0001)	NA
Ciarrocchi[4], 2014	32% (32% rectum vs 33% colon)	NA	NA
Huang et al[26], 2016	5-yr CSS: 52.2% (< 35 yr poorer CSS than > 35 yr, P < 0.001 at cutoff of 30 y, P < 0.001 at cutoff of 35 y, P = 0.015 at cutoff 40 yr)	NA	NA
Ling et al[50], 2017	NA	34.% vs 53.9% (MA) vs 63.1% (OA; P = 0.001)	NA
Wu et al[11], 2017	39%	NA	NA
Thota et al[30], 2014	NA	19% vs 41% MA vs 47% (P = 0.0002)	NA
Nitsche et al[33], 2013	40.3% (95%CI: 32.1-48.5) vs 58.7% (95%CI: 58.0-59.3)	NA	NA
Fu et al[58], 2016	9.66% vs 24.04% (non-SRCC)	NA	NA
Kakar and Smyrk[44], 2005	41% MSI-H vs 34% MSS (P = 0.3)	NA	NA
Sung et al[21], 2008	3-yr CSS: 33% vs 74% MA (P < 0.0001)	NA	NA
Chen et al[6], 2004	23.3 % vs 40.3% (MA) vs 54.5 % (NMA) (P < 0.001)	32.5% vs 38.3% (MA) vs 41.5% (NMA)	NA
Wang et al[43], 2016	3-yr OS: 62.7%	NA	NA
Liang et al[31], 2018	10.80%	Mean survival time in stage III tumors: 37.1 ± 3.9 (22-80) mo	NA
Lee et al[52], 2007	25.3% vs 68.6% MA vs 53.7% poorly differentiated OA (P < 0.001)	14.5% vs 61.5% MA vs 46.3% (P < 0.001)	12.3% vs 59.9% MA vs 46.8% poorly differentiated OA (P < 0.001)
Bittorf et al[8], 2004	14.7% vs 53.6% (P < 0.001)	20.8% vs 62.6%	NA
Messerini et al (1995)[32]	9.10%	NA	NA
Bademci et al[28], 2019	NA	NA	16 (47%) disease-free during follow-up
Kakar et al[45], 2012	33% vs 50% MA vs 63% (P = 0.09)	III/IV: 27% vs 43% MA vs 57% OA (P = 0.03)	NA
Chew et al[22], 2010	5-yr CSS: 11.1% (0-22.9%) vs overall 57.4% (55.4%-59.4%; P <0.001)	NA	No statistical difference (P = 0.356)
Nitsche et al[1], 2016	5-yr CSS: 21% ± 8% vs 61% ± 3% MA vs 67% ± 1% OA (P < 0.001)	5-yr CSS for stage III: 15% ± 10% vs 60% ± 5% MA vs 65% ± 2% OA (P < 0.001)	NA
Anthony et al[7], 1996	22%	NA	NA
Song et al[64], 2009	27% vs 51% MA vs 69% (P < 0.01)	NA	NA
Zhang et al[65], 2020	31.3% ± 12.9% vs 58.1% ± 7.7% (P = 0.018)	NA	NA
Wang et al[39], 2019	37.3% (95%CI: 14.4%-61.2%) vs 62.9% (95%CI: 48.5%-74.3%; P = 0.021)	NA	NA
Song et al[66], 2019	SRCC predominant MAC with worse survival (P < 0.001)	NA	NA
Mizushima et al[36], 2010	24.1% vs 77.5% well/moderately differentiated vs 57.7% poorly differentiated/MA	NA	NA
Foda et al[42], 2018	10.5% vs 23.2% MA vs 42.9% AWMC vs 55.3% OA	NA	3-yr DFS: 11.1% vs 28.3% MA vs 60.7% OA with SRC component vs 63% OA
Lee et al[29], 2015	46% vs 88.7% (P > 0.001)	NA	NA
Pozos-Ochoa et al[37], 2018	3-yr CSS: 28.6% vs 80.7% (P = 0.017) (II, III, and IV: 100%, 33%, and 0% vs 100%, 78%, and 73%, P = 0.017)	NA	NA
Sasaki et al[14], 1998	0% vs 76.5 % (3 mo-85 mo) (P < 0.0001)	NA	NA
Ooi et al[23], 2001	12%	NA	NA
Secco et al[68], 1994	0% vs 28% MA vs 45% OA	NA	NA

SRC: Signet-ring cell; SRCC: Signet-ring cell cancer; MA: Mucinous adenocarcinoma; OA: Ordinary/conventional adenocarcinoma; NMA: Non-mucinous adenocarcinoma; MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; NA: Not applicable; CSS: Cause-specific survival; AWMC: Adenocarcinoma with mucinous component.