World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Review

Volume 14, Number 6, December 2023, pages 447-456

Malignant Transformation of Long-Standing Ileal Crohn’s Disease Likely Favors Signet Ring Cell Adenocarcinoma Histology

Figure 1. PRISMA study selection flow chart. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

**Table 1.** Data Extraction From Included Studies in the Systematic Review
Age, sex	Crohn’s duration (years)	Surgical indication	Histology (location)	Pathological features	Postoperative treatment	Follow-up (f/u) or survival time	Country, year	Reference
M: male; F: female; FOLFOX: folinic acid, fluorouracil, and oxaliplatin; MMR: mismatch repair; LVI: lymphovascular invasion; PNI: perineural invasion; WT: wild type; SBA: small bowel adenocarcinoma; CD: Crohn’s disease; SRCC: signet ring cell adenocarcinoma; TI: terminal ileum; SD: standard deviation; TNF: tumor necrosis factor; mo: month; NED: no evidence of disease.
36, M	7	Obstruction	SRCC, adjacent high-grade dysplasia (ileum)	pT4N0M0	-	42 mo f/u (alive, with recurrence)	USA, 1987	[9]
SBA in CD median 43 (range 33 - 72)	-		CD: SRCC 7/20 (19/20 ileum, 1/20 jejunum)	-	-		France, 2005	[10]
SBA de novo median 68 (range 41 - 95)			De novo: SRCC 0/40 (12/40 ileum, 16/40 jejunum, 12/40 mid bowel)
31, F	15	Complex fistulae and large abscess unresponsive to conservative treatment	SRCC (distal ileum)	2/7 positive lymph nodes	FOLFOX	13 mo f/u (alive)	South Korea, 2007	[11]
55, M	31	TI obstruction	SRCC, villous adenoma (ileum)	16/16 positive lymph nodes, proficient MMR	Chemotherapy	-	Israel, 2011	[12]
64, M	15	Symptomatic CD	SRCC (ileum)	pT4N1M0	-	-	France, 2012	[13]
40, F	19	Crohn’s flare with medically refractory symptoms	SRCC (TI)	pT4N0M1G3; proficient MMR; KRAS mutant	Chemotherapy	-	Germany, 2013	[14]
59, M	28	No surgery due to widespread metastasis on diagnosis; diagnosed due to symptoms of Crohn’s flare	SRCC (11 cm proximal to ileocecal valve)	-	Cisplatin monotherapy	6 mo (died from disease)	Italy, 2013	[15]
Three cases, mean age 50.6 (range 31 - 76)	Mean 23.4 (range 1 - 47)	-	Two cases: SRCC (small bowel)	pT4bN2aMx; + LVI	-	Recurred and died	Italy, 2014	[16]
				pT3NxMx; + LVI		Alive
			One case: SRCC (at site of prior anastomosis)	pT4b.NxM1 + LVI		Recurred and died (f/u unknown)
64, M	8	Ileal obstruction	SRCC (ileum)	Multiple mitoses, PNI, pseudopyloric metaplasia	-	-	Spain, 2014	[17]
47, F	0, diagnosed at presentation	2 weeks: abdominal pain, watery diarrhea, SRCC found on colonoscopy	SRCC (distal ileum)	pT3N1M0R0	FOLFOX	1 mo f/u (alive)	Portugal, 2016	[18]
51, M	0, diagnosed at presentation	6 months: bloody diarrhea, pain, tenesmus, weight loss; started on systemic therapy for Crohn’s and perforated	SRCC (ileum)	pT4N1M0R0	FOLFOX	1 mo f/u (alive)	Portugal, 2016	[18]
58, F	0, diagnosed at presentation	TI stenosis without complete obstruction, SRCC found on colonoscopy biopsies	SRCC (TI, invading adjacent sigmoid)	PNI, pseudopyloric metaplasia, pT4N2M0	FOLFOX	5 mo f/u (alive)	Portugal, 2018	[19]
46, M	15	Obstruction	SRCC, villous dysplasia (distal ileum)	G3, T4N1M1; proficient MMR, BRAF/KRAS WT	-	11 mo (died from disease)	France, 2017	[20]
64, M	32	Obstructive symptoms and low-grade dysplasia on preoperative colonoscopy biopsy	SRCC, adenomatous dysplasia (distal ileum)	G3, T4N0M0; germline mutation of HLML1 and PMS2, BRAF/KRAS WT	-	66 mo f/u (alive)	France, 2017	[20]
63, M	32	Symptomatic CD refractory to steroids and TNF blockade	SRCC (ileum), with carcinomatosis	pT4aN2M1; 12/15 positive nodes; proficient MMR; + LVI, + PNI	-	-	USA, 2018	[21]
68, M	0, diagnosed at presentation	Perforation	SRCC (40 cm from ileocecal valve)	pT4N0M0	Referred to medical oncology	9 mo f/u (alive, NED)	Algeria, 2019	[22]
44, F	-	Hematochezia, SRCC diagnosed on endoscopy	SRCC (TI)	pT4aN1M0; RAS/RAF WT	FOLFOX	-	USA, 2019	[23]
67, M	44	SRCC on colonoscopy biopsy after medically managed flare	SRCC, tubulovillous adenoma (distal ileum)	G3, pT2N1M0	FOLFOX	-	USA, 2020	[24]
64, M	3	Acute abdomen, TI perforation	SRCC (distal ileum)	G2, pT4N1Mx. 9/25 positive lymph nodes	Chemotherapy	-	Romania, 2021	[25]
53.73 ± 14.52 (mean ± SD); 4/15, F	-	11/15 cases CD	SRCC, 66.7% ileum, 20% duodenum, 13.3% jejunum	pT3 in 46.7% and pT4 in 53.3%; positive nodes; 93.3% proficient MMR; 53.3%; + LVI 93.3%; + PNI 93.3%	-	-	Italy, 2022	[26]
68, F	0, diagnosed at presentation	Newly diagnosed Crohn’s, colonoscopy biopsy positive for cancer	SRCC (arising from tubulovillous adenoma of TI)	pT4 (no other information)	FOLFOX	3 mo f/u (alive)	USA, 2022	[27]
41, M	Suspected new diagnosis of Crohn’s	Anemia, weight loss, fistula to buttock	SRCC (TI)	pT4bN2b, MMR proficient; + LVI; + PNI; KRAS WT, negative for NTRK, BRAF, TNB, HER-2, PIK3 and PDL1	FOLFOX	3 mo f/u (alive)	USA, 2022	[28]

Table 1. Data Extraction From Included Studies in the Systematic Review

Age, sex

Crohn’s duration (years)

Surgical indication

Histology (location)

Pathological features

Postoperative treatment

Follow-up (f/u) or survival time

Country, year

Reference

M: male; F: female; FOLFOX: folinic acid, fluorouracil, and oxaliplatin; MMR: mismatch repair; LVI: lymphovascular invasion; PNI: perineural invasion; WT: wild type; SBA: small bowel adenocarcinoma; CD: Crohn’s disease; SRCC: signet ring cell adenocarcinoma; TI: terminal ileum; SD: standard deviation; TNF: tumor necrosis factor; mo: month; NED: no evidence of disease.

36, M

Obstruction

SRCC, adjacent high-grade dysplasia (ileum)

pT4N0M0

42 mo f/u (alive, with recurrence)

USA, 1987

[9]

SBA in CD median 43 (range 33 - 72)

CD: SRCC 7/20 (19/20 ileum, 1/20 jejunum)

France, 2005

[10]

SBA de novo median 68 (range 41 - 95)

De novo: SRCC 0/40 (12/40 ileum, 16/40 jejunum, 12/40 mid bowel)

31, F

Complex fistulae and large abscess unresponsive to conservative treatment

SRCC (distal ileum)

2/7 positive lymph nodes

FOLFOX

13 mo f/u (alive)

South Korea, 2007

[11]

55, M

TI obstruction

SRCC, villous adenoma (ileum)

16/16 positive lymph nodes, proficient MMR

Chemotherapy

Israel, 2011

[12]

64, M

Symptomatic CD

SRCC (ileum)

pT4N1M0

France, 2012

[13]

40, F

Crohn’s flare with medically refractory symptoms

SRCC (TI)

pT4N0M1G3; proficient MMR; KRAS mutant

Chemotherapy

Germany, 2013

[14]

59, M

No surgery due to widespread metastasis on diagnosis; diagnosed due to symptoms of Crohn’s flare

SRCC (11 cm proximal to ileocecal valve)

Cisplatin monotherapy

6 mo (died from disease)

Italy, 2013

[15]

Three cases, mean age 50.6 (range 31 - 76)

Mean 23.4 (range 1 - 47)

Two cases: SRCC (small bowel)

pT4bN2aMx; + LVI

Recurred and died

Italy, 2014

[16]

pT3NxMx; + LVI

Alive

One case: SRCC (at site of prior anastomosis)

pT4b.NxM1 + LVI

Recurred and died (f/u unknown)

64, M

Ileal obstruction

SRCC (ileum)

Multiple mitoses, PNI, pseudopyloric metaplasia

Spain, 2014

[17]

47, F

0, diagnosed at presentation

2 weeks: abdominal pain, watery diarrhea, SRCC found on colonoscopy

SRCC (distal ileum)

pT3N1M0R0

FOLFOX

1 mo f/u (alive)

Portugal, 2016

[18]

51, M

0, diagnosed at presentation

6 months: bloody diarrhea, pain, tenesmus, weight loss; started on systemic therapy for Crohn’s and perforated

SRCC (ileum)

pT4N1M0R0

FOLFOX

1 mo f/u (alive)

Portugal, 2016

[18]

58, F

0, diagnosed at presentation

TI stenosis without complete obstruction, SRCC found on colonoscopy biopsies

SRCC (TI, invading adjacent sigmoid)

PNI, pseudopyloric metaplasia, pT4N2M0

FOLFOX

5 mo f/u (alive)

Portugal, 2018

[19]

46, M

Obstruction

SRCC, villous dysplasia (distal ileum)

G3, T4N1M1; proficient MMR, BRAF/KRAS WT

11 mo (died from disease)

France, 2017

[20]

64, M

Obstructive symptoms and low-grade dysplasia on preoperative colonoscopy biopsy

SRCC, adenomatous dysplasia (distal ileum)

G3, T4N0M0; germline mutation of HLML1 and PMS2, BRAF/KRAS WT

66 mo f/u (alive)

France, 2017

[20]

63, M

Symptomatic CD refractory to steroids and TNF blockade

SRCC (ileum), with carcinomatosis

pT4aN2M1; 12/15 positive nodes; proficient MMR; + LVI, + PNI

USA, 2018

[21]

68, M

0, diagnosed at presentation

Perforation

SRCC (40 cm from ileocecal valve)

pT4N0M0

Referred to medical oncology

9 mo f/u (alive, NED)

Algeria, 2019

[22]

44, F

Hematochezia, SRCC diagnosed on endoscopy

SRCC (TI)

pT4aN1M0; RAS/RAF WT

FOLFOX

USA, 2019

[23]

67, M

SRCC on colonoscopy biopsy after medically managed flare

SRCC, tubulovillous adenoma (distal ileum)

G3, pT2N1M0

FOLFOX

USA, 2020

[24]

64, M

Acute abdomen, TI perforation

SRCC (distal ileum)

G2, pT4N1Mx. 9/25 positive lymph nodes

Chemotherapy

Romania, 2021

[25]

53.73 ± 14.52 (mean ± SD); 4/15, F

11/15 cases CD

SRCC, 66.7% ileum, 20% duodenum, 13.3% jejunum

pT3 in 46.7% and pT4 in 53.3%; positive nodes; 93.3% proficient MMR; 53.3%; + LVI 93.3%; + PNI 93.3%

Italy, 2022

[26]

68, F

0, diagnosed at presentation

Newly diagnosed Crohn’s, colonoscopy biopsy positive for cancer

SRCC (arising from tubulovillous adenoma of TI)

pT4 (no other information)

FOLFOX

3 mo f/u (alive)

USA, 2022

[27]

41, M

Suspected new diagnosis of Crohn’s

Anemia, weight loss, fistula to buttock

SRCC (TI)

pT4bN2b, MMR proficient; + LVI; + PNI; KRAS WT, negative for NTRK, BRAF, TNB, HER-2, PIK3 and PDL1

FOLFOX

3 mo f/u (alive)

USA, 2022

[28]

**Table 2.** Baseline Demographics and Clinical Characteristics of Small Bowel Cancers From SEER
Location	Small bowel	Duodenum	Jejunum	Ileum
Incidence rates per 1 million. CSS: cause-specific survival; CI: confidence interval.
N (%)	6,111 (100)	327 (100)	-	3,702 (60.6)	151 (46.2)	-	959 (15.7)	29 (8.9)	-	670 (11.0)	92 (28.1)	-
Age (years) (%)
0 - 14	0 (0)	0 (0)	< 0.001	0 (0)	0 (0)	0.02	0 (0)	0 (0)	0.35	0 (0)	0 (0)	0.13
15 - 29	42 (0.7)	5 (1.5)		17 (0.5)	2 (1.3)		13 (1.4)	1 (3.4)		8 (1.2)	2 (2.2)
30 - 49	794 (13.0)	55 (16.8)		344 (9.3)	19 (12.6)		206 (21.5)	8 (27.6)		106 (15.8)	17 (18.5)
50 - 69	2,533 (41.4)	157 (48.0)		1,416 (38.2)	71 (47.0)		476 (49.6)	9 (31.0)		295 (44.0)	50 (54.3)
70 - 85	2,129 (34.8)	90 (27.5)		1,465 (39.6)	47 (31.1)		221 (23.0)	9 (31.0)		197 (29.4)	18 (19.6)
> 85	613 (10.0)	20 (6.1)		460 (12.4)	12 (7.9)		43 (4.5)	2 (6.9)		64 (9.6)	5 (5.4)
Mean (SD)	66.4 (14.5)	62.7 (14.3)	< 0.001	68.9 (13.8)	64.7 (14.2)	< 0.001	60.2 (14.5)	60.7 (16.8)	0.81	64.6 (14.9)	60.7 (14.0)	0.02
Sex (%)
Male	3,244 (53.1)	185 (56.6)	0.22	1,941 (52.4)	88 (58.3)	0.16	538 (56.1)	13 (44.8)	0.23	345 (51.5)	55 (59.8)	0.14
Female	2,867 (46.9)	142 (43.4)		1,761 (47.6)	63 (41.7)		421 (43.9)	16 (55.2)		325 (48.5)	37 (40.2)
Race (%)
White	4,521 (74.0)	263 (80.4)	0.01	2,733 (73.8)	112 (74.2)	0.31	686 (71.5)	24 (82.8)	0.25	540 (80.6)	84 (91.3)	0.04
Black	1,136 (18.6)	39 (11.6)		637 (17.2)	21 (13.9)		225 (23.5)	3 (10.3)		93 (13.9)	6 (6.5)
Other	454 (7.4)	25 (7.6)		332 (9.0)	18 (11.9)		48 (5.0)	2 (6.9)		37 (5.5)	2 (2.2)
Detection stage (%)
In situ	32 (0.5)	0 (0)	< 0.001	25 (0.7)	0 (0)	0.21	0 (0)	0 (0)	0.04	5 (0.7)	0 (0)	< 0.001
Localized	1,237 (20.2)	33 (10.1)		617 (16.7)	19 (12.6)		247 (25.8)	4 (13.8)		211 (31.5)	5 (5.4)
Regional	2,100 (34.4)	142 (43.4)		1,223 (33.0)	61 (40.4)		382 (39.8)	16 (55.2)		268 (40.0)	49 (53.3)
Distant	2,227 (36.4)	132 (40.4)		1,383 (37.4)	57 (37.7)		314 (32.7)	7 (24.1)		177 (26.4)	38 (41.3)
Unstaged	515 (8.4)	20 (6.1)		454 (12.3)	14 (9.3)		16 (1.7)	2 (6.9)		9 (1.3)	0 (0)
Grade differentiation (%)
Well	453 (7.4)	0 (0)	< 0.001	266 (7.2)	0 (0)	< 0.001	58 (6.0)	0 (0)	< 0.001	78 (11.6)	0 (0)	< 0.001
Moderate	2,559 (41.9)	16 (4.9)		1,427 (38.5)	7 (4.6)		519 (54.1)	3 (10.3)		296 (44.2)	6 (6.5)
Poor	1,880 (30.8)	229 (70.0)		1,124 (30.4)	103 (68.2)		294 (30.7)	10 (62.1)		228 (34.0)	71 (77.2)
Undifferentiated	62 (1.0)	9 (2.8)		28 (0.8)	5 (3.3)		10 (1.0)	1 (3.4)		14 (2.1)	3 (3.3)
Unknown	1,157 (18.9)	73 (22.3)		857 (23.1)	36 (23.8)		78 (8.1)	7 (24.1)		54 (8.1)	12 (13.0)
Surgery (%)
Yes	3,671 (60.1)	219 (67.0)	0.01	1,579 (42.7)	67 (44.4)	0.68	865 (90.2)	23 (79.3)	0.06	632 (94.3)	87 (94.6)	0.93
No	2,440 (39.9)	109 (33.0)		2,123 (57.3)	84 (55.6)		94 (9.8)	6 (20.7)		38 (5.7)	5 (5.4)
Radiotherapy (%)
Yes	604 (9.9)	34 (10.4)	0.76	510 (13.8)	28 (18.5)	0.1	37 (3.9)	1 (3.4)	0.91	27 (4.0)	1 (1.1)	0.16
No	5,507 (90.1)	293 (89.6)		3,192 (86.2)	123 (81.5)		922 (96.1)	28 (96.6)		643 (96.0)	91 (98.9)
Chemotherapy (%)
Yes	2,452 (40.1)	160 (48.9)	0.002	1,380 (37.3)	63 (41.7)	0.27	483 (50.4)	15 (51.7)	0.89	254 (37.9)	55 (59.8)	< 0.001
No	3,659 (59.9)	167 (51.1)		2,322 (62.7)	88 (58.3)		476 (49.6)	14 (48.3)		416 (62.1)	37 (40.2)
Incidence rate (95% CI)	5.29 (5.18 - 5.41)	0.27 (0.24 - 0.29)	-	3.15 (3.07 - 3.24)	0.14 (0.12 - 0.15)	-	0.77 (0.73 - 0.82)	0.02 (0.01 - 0.03)	-	0.59 (0.55 - 0.63)	0.07 (0.06 - 0.08)	-
CSS (%) (95% CI)
1-year	56.2 (54.9 - 57.5)	53.7 (48.0 - 59.1)	-	47.5 (45.8 - 49.1)	42.0 (33.9 - 49.8)	-	76.9 (74.0 - 79.6)	58.7 (35.5 - 76.1)	-	72.7 (69.0 - 76.0)	72.3 (61.8 - 80.4)	-
2-year	42.3 (41.0 - 43.7)	30.1 (24.7 - 35.6)		33.6 (31.9 - 35.3)	22.5 (15.7 - 30.0)		62.8 (59.5 - 66.0)	24.5 (9.0 - 44.0)		59.9 (55.8 - 63.8)	38.6 (27.9 - 49.2)
5-year	28.2 (26.7 - 29.3)	16.4 (12.0 - 21.3)		22.7 (19.5 - 22.6)	17.8 (11.6 - 25.1)		41.5 (37.9 - 45.1)	24.5 (9.0 - 44.0)		46.3 (42.0 - 50.5)	7.9 (3.0 - 15.8)
10-year	23.8 (22.5 - 25.1)	13.8 (9.7 - 18.8)		18.8 (16.0 - 19.1)	16.2 (10.0 - 23.6)		40.9 (32.6 - 40.0)	16.3 (3.6 - 37.2)		41.7 (37.1 - 46.2)	5.9 (1.8 - 13.6)
Median (Months)	16.5	14.2		10.9	5.7		40.9	13.3		39.3	20.0

Table 2. Baseline Demographics and Clinical Characteristics of Small Bowel Cancers From SEER

Location

Small bowel

Duodenum

Jejunum

Ileum

Adenocarcinoma

Signet ring

P value

Adenocarcinoma

Signet ring

P value

Adenocarcinoma

Signet ring

P value

Adenocarcinoma

Signet ring

P value

Incidence rates per 1 million. CSS: cause-specific survival; CI: confidence interval.

N (%)

6,111 (100)

327 (100)

3,702 (60.6)

151 (46.2)

959 (15.7)

29 (8.9)

670 (11.0)

92 (28.1)

Age (years) (%)

0 - 14

0 (0)

< 0.001

0 (0)

0.02

0 (0)

0.35

0 (0)

0.13

15 - 29

42 (0.7)

5 (1.5)

17 (0.5)

2 (1.3)

13 (1.4)

1 (3.4)

8 (1.2)

2 (2.2)

30 - 49

794 (13.0)

55 (16.8)

344 (9.3)

19 (12.6)

206 (21.5)

8 (27.6)

106 (15.8)

17 (18.5)

50 - 69

2,533 (41.4)

157 (48.0)

1,416 (38.2)

71 (47.0)

476 (49.6)

9 (31.0)

295 (44.0)

50 (54.3)

70 - 85

2,129 (34.8)

90 (27.5)

1,465 (39.6)

47 (31.1)

221 (23.0)

9 (31.0)

197 (29.4)

18 (19.6)

> 85

613 (10.0)

20 (6.1)

460 (12.4)

12 (7.9)

43 (4.5)

2 (6.9)

64 (9.6)

5 (5.4)

Mean (SD)

66.4 (14.5)

62.7 (14.3)

< 0.001

68.9 (13.8)

64.7 (14.2)

< 0.001

60.2 (14.5)

60.7 (16.8)

0.81

64.6 (14.9)

60.7 (14.0)

0.02

Sex (%)

Male

3,244 (53.1)

185 (56.6)

0.22

1,941 (52.4)

88 (58.3)

0.16

538 (56.1)

13 (44.8)

0.23

345 (51.5)

55 (59.8)

0.14

Female

2,867 (46.9)

142 (43.4)

1,761 (47.6)

63 (41.7)

421 (43.9)

16 (55.2)

325 (48.5)

37 (40.2)

Race (%)

White

4,521 (74.0)

263 (80.4)

0.01

2,733 (73.8)

112 (74.2)

0.31

686 (71.5)

24 (82.8)

0.25

540 (80.6)

84 (91.3)

0.04

Black

1,136 (18.6)

39 (11.6)

637 (17.2)

21 (13.9)

225 (23.5)

3 (10.3)

93 (13.9)

6 (6.5)

Other

454 (7.4)

25 (7.6)

332 (9.0)

18 (11.9)

48 (5.0)

2 (6.9)

37 (5.5)

2 (2.2)

Detection stage (%)

In situ

32 (0.5)

0 (0)

< 0.001

25 (0.7)

0 (0)

0.21

0 (0)

0.04

5 (0.7)

0 (0)

< 0.001

Localized

1,237 (20.2)

33 (10.1)

617 (16.7)

19 (12.6)

247 (25.8)

4 (13.8)

211 (31.5)

5 (5.4)

Regional

2,100 (34.4)

142 (43.4)

1,223 (33.0)

61 (40.4)

382 (39.8)

16 (55.2)

268 (40.0)

49 (53.3)

Distant

2,227 (36.4)

132 (40.4)

1,383 (37.4)

57 (37.7)

314 (32.7)

7 (24.1)

177 (26.4)

38 (41.3)

Unstaged

515 (8.4)

20 (6.1)

454 (12.3)

14 (9.3)

16 (1.7)

2 (6.9)

9 (1.3)

0 (0)

Grade differentiation (%)

Well

453 (7.4)

0 (0)

< 0.001

266 (7.2)

0 (0)

< 0.001

58 (6.0)

0 (0)

< 0.001

78 (11.6)

0 (0)

< 0.001

Moderate

2,559 (41.9)

16 (4.9)

1,427 (38.5)

7 (4.6)

519 (54.1)

3 (10.3)

296 (44.2)

6 (6.5)

Poor

1,880 (30.8)

229 (70.0)

1,124 (30.4)

103 (68.2)

294 (30.7)

10 (62.1)

228 (34.0)

71 (77.2)

Undifferentiated

62 (1.0)

9 (2.8)

28 (0.8)

5 (3.3)

10 (1.0)

1 (3.4)

14 (2.1)

3 (3.3)

Unknown

1,157 (18.9)

73 (22.3)

857 (23.1)

36 (23.8)

78 (8.1)

7 (24.1)

54 (8.1)

12 (13.0)

Surgery (%)

Yes

3,671 (60.1)

219 (67.0)

0.01

1,579 (42.7)

67 (44.4)

0.68

865 (90.2)

23 (79.3)

0.06

632 (94.3)

87 (94.6)

0.93

2,440 (39.9)

109 (33.0)

2,123 (57.3)

84 (55.6)

94 (9.8)

6 (20.7)

38 (5.7)

5 (5.4)

Radiotherapy (%)

Yes

604 (9.9)

34 (10.4)

0.76

510 (13.8)

28 (18.5)

0.1

37 (3.9)

1 (3.4)

0.91

27 (4.0)

1 (1.1)

0.16

5,507 (90.1)

293 (89.6)

3,192 (86.2)

123 (81.5)

922 (96.1)

28 (96.6)

643 (96.0)

91 (98.9)

Chemotherapy (%)

Yes

2,452 (40.1)

160 (48.9)

0.002

1,380 (37.3)

63 (41.7)

0.27

483 (50.4)

15 (51.7)

0.89

254 (37.9)

55 (59.8)

< 0.001

3,659 (59.9)

167 (51.1)

2,322 (62.7)

88 (58.3)

476 (49.6)

14 (48.3)

416 (62.1)

37 (40.2)

Incidence rate (95% CI)

5.29 (5.18 - 5.41)

0.27 (0.24 - 0.29)

3.15 (3.07 - 3.24)

0.14 (0.12 - 0.15)

0.77 (0.73 - 0.82)

0.02 (0.01 - 0.03)

0.59 (0.55 - 0.63)

0.07 (0.06 - 0.08)

CSS (%) (95% CI)

1-year

56.2 (54.9 - 57.5)

53.7 (48.0 - 59.1)

47.5 (45.8 - 49.1)

42.0 (33.9 - 49.8)

76.9 (74.0 - 79.6)

58.7 (35.5 - 76.1)

72.7 (69.0 - 76.0)

72.3 (61.8 - 80.4)

2-year

42.3 (41.0 - 43.7)

30.1 (24.7 - 35.6)

33.6 (31.9 - 35.3)

22.5 (15.7 - 30.0)

62.8 (59.5 - 66.0)

24.5 (9.0 - 44.0)

59.9 (55.8 - 63.8)

38.6 (27.9 - 49.2)

5-year

28.2 (26.7 - 29.3)

16.4 (12.0 - 21.3)

22.7 (19.5 - 22.6)

17.8 (11.6 - 25.1)

41.5 (37.9 - 45.1)

24.5 (9.0 - 44.0)

46.3 (42.0 - 50.5)

7.9 (3.0 - 15.8)

10-year

23.8 (22.5 - 25.1)

13.8 (9.7 - 18.8)

18.8 (16.0 - 19.1)

16.2 (10.0 - 23.6)

40.9 (32.6 - 40.0)

16.3 (3.6 - 37.2)

41.7 (37.1 - 46.2)

5.9 (1.8 - 13.6)

Median (Months)

16.5

14.2

10.9

5.7

40.9

13.3

39.3

20.0

**Table 3.** Derived Univariate and Multivariable Cox-Proportional Hazard Ratios of Mortality Comparing Signet Ring Cell Adenocarcinomas to Conventional Adenocarcinomas
Location	Univariate (95% CI)	Multivariable (95% CI)
Multivariable hazard ratios were corrected for age, sex, race, detection stage, grade differentiation, surgery, radiotherapy, and chemotherapy. CI: confidence interval.
Small bowel	1.35 (1.18 - 1.54)	1.23 (1.06 - 1.41)
Duodenum	1.25 (1.02 - 1.52)	1.19 (0.97 - 1.46)
Jejunum	1.94 (1.24 - 3.04)	1.87 (1.19 - 2.95)
Ileum	2.23 (1.71 - 2.90)	1.25 (0.93 - 1.69)

Table 3. Derived Univariate and Multivariable Cox-Proportional Hazard Ratios of Mortality Comparing Signet Ring Cell Adenocarcinomas to Conventional Adenocarcinomas

Location

Univariate (95% CI)

Multivariable (95% CI)

Multivariable hazard ratios were corrected for age, sex, race, detection stage, grade differentiation, surgery, radiotherapy, and chemotherapy. CI: confidence interval.

Small bowel

1.35 (1.18 - 1.54)

1.23 (1.06 - 1.41)

Duodenum

1.25 (1.02 - 1.52)

1.19 (0.97 - 1.46)

Jejunum

1.94 (1.24 - 3.04)

1.87 (1.19 - 2.95)

Ileum

2.23 (1.71 - 2.90)

1.25 (0.93 - 1.69)