ORIGINAL CONTRIBUTION

Adenocarcinoma of the Rectum in Patients Under

Age 40 Is Increasing: Impact of Signet-Ring Cell
Histology
Patrick S. Tawadros, M.D., Ph.D., F.R.C.S.C.1 Ian M. Paquette, M.D.2
Ann M. Hanly, M.D., M.Sc.3 Anders F. Mellgren, M.D., Ph.D.4
David A. Rothenberger, M.D.1 Robert D. Madoff, M.D.1
1 Division of Colon and Rectal Surgery, University of Minnesota, Minneapolis, Minnesota
2 Division of Colon and Rectal Surgery, University of Cincinnati, Cincinnati, Ohio
3 Center for Colorectal Disease, St Vincents University Hospital, Dublin, Ireland
4 Division of Colon and Rectal Surgery, University of Illinois, Chicago, Illinois

BACKGROUND: Overall, the incidence of colorectal

cancer appears to be stable or diminishing. However,
based on our practice pattern, we observed that the
incidence of rectal cancer in patients under 40 is
increasing and may be associated with a prominence of
signet-ring cell histology.
OBJECTIVE: The aim of this study was to verify the rising
trend in rectal cancer in patients under 40 and describe
the histology prominent in that cohort.
DESIGN: This is a retrospective cohort study.
SETTING AND PATIENTS: We performed a retrospective

cohort study of all patients diagnosed with rectal

adenocarcinoma from 1980 to 2010 using the Surveillance,
Epidemiology, and End Results cancer registry.
MAIN OUTCOME MEASURES: Rectal cancer incidence,
histology, and associated staging characteristics were the
primary outcomes measured.
RESULTS: Although the incidence of rectal cancer for all
ages remained stable from 1980 to 2010, we observed an
annual percent change of +3.6% in the incidence of rectal
Financial Disclosures: None reported.
Drs Tawadros and Paquette are first authors for this article.
Presented at the meeting of the Surgical Forum of the American College
of Surgeons, San Francisco, CA, October 23 to 27, 2011 (an earlier version of this article with older data [up to 2007 only]).
Correspondence: Patrick S. Tawadros, M.D., Ph.D., F.R.C.S.C.,
420 Delaware St, SE, MMC 450, Minneapolis, MN 55455. E-mail:
ptawadro@umn.edu
Dis Colon Rectum 2015; 58: 474478
DOI: 10.1097/DCR.0000000000000318
The ASCRS 2015

474

cancer in patients under 40. The prevalence of signet cell

histology in patients under 40 was significantly greater
than in patients over 40 (3% vs 0.87%, p < 0.01). A
multivariate regression analysis revealed an adjusted odds
ratio of 3.6 (95% CI, 2.65.1) for signet cell histology in
rectal adenocarcinoma under age 40. Signet cell histology
was also significantly associated with a more advanced
stage at presentation, poorly differentiated tumor grade,
and worse prognosis compared with mucinous and
nonmucinous rectal adenocarcinoma.
LIMITATIONS: The study was limited by its retrospective
nature and the information available in the Surveillance,
Epidemiology, and End Results database.
CONCLUSIONS: Despite a stable incidence of rectal
cancer for all ages, the incidence in patients under 40
has quadrupled since 1980, and cancers in this group are
3.6 times more likely to have signet cell histology. Given
the worse outcomes associated with signet cell histology,
these data highlight a need for thorough evaluation of
young patients with rectal symptoms.
KEY WORDS: Rectal cancer; Young adults; Signet-ring cell

histology.

olorectal cancer remains the second leading cause

of cancer-related death in North America. Although
improved adherence to screening guidelines with
early detection of colorectal cancer and polypectomy have
resulted in reduced overall mortality,1 recent studies suggest a rising incidence of rectal cancer in young adults.24
This patient population is typically below the screening
age; furthermore, there is a tendency for rectal cancer in
young patients to present with more advanced disease,5,6
making this trend all the more concerning.
Diseases of the Colon & Rectum Volume 58: 5 (2015)

475

Diseases of the Colon & Rectum Volume 58: 5 (2015)

10

Rectal cancer incidence (all ages)

APC = 0%

8
7
6
5

All ages

4
3
2
1
1980

1985

1990

1995

2000

2005

2010

Figure 1. Rectal cancer incidence (all ages). Rectal cancer incidence, in all ages, from 1980 to 2010, in cases per 100,000, using the SEER-9
database. The annual percentage change (APC) is zero. SEER = Surveillance, Epidemiology, and End Results.

The signet-ring cell variety of adenocarcinoma has

been shown to present at a younger average age, to present
at a more advanced stage of disease, and to carry a worse
prognosis in comparison with its more common mucinous and nonmucinous adenocarcinoma counterparts.7,8
Signet-ring cell adenocarcinoma histology is defined by a
greater than 50% presence of tumor cells with prominent
intracytoplasmic mucin accumulation and a lack of cellto-cell adhesion molecules.9 In gastric adenocarcinoma, a
link to E-cadherin CDH1 gene mutation has been shown
to correlate with signet-ring cell histology,10,11 which also
tends to occur in younger patients.
We hypothesized that the incidence of rectal cancer in
patients under 40 is increasing and may be associated with
a prominence of signet-ring cell histology.

associated demographic, histologic, and TNM staging

data. This period of time was chosen because complete
TNM staging was available during this period. Univariate and multivariate logistic regression analyses were performed by using Stata version 12.1 (College Station, TX)
to identify factors associated with rectal cancer in patients
under 40 as well as to discern the differences in characteristics of different histologic patterns. 2 tests were used
to compare categorical variables. Mean values of normally
distributed continuous variables were compared by using
the Student t test, or 1-way ANOVA with the Bonferroni
modification where appropriate. Median values of abnormally distributed continuous variables were compared by
using the Wilcoxon rank-sum test or the Kruskal-Wallis
test where appropriate. All p values are 2-tailed.

METHODS

RESULTS

The Surveillence, Epidemiology, and End Results (SEER)

database of the National Cancer Institute reflects 28% of
the American population, and contains data on cancer incidence and patient demographics, as well as tumor stage
and histology. SEERStat version 8.2 (National Cancer Institute) was used to calculate the incidence of rectal cancer
for all ages and in patients aged 20 to 39. The SEER-9 database was used because it was available for all years from
1980 to 2010. Rectal cancer was defined by International
Classification of Diseases, Ninth Revision code 154, whereas SEERStat software was used to select cases defined as
rectosigmoid junction cancer for exclusion. Histology
codes were used to select for adenocarcinoma, mucinous
adenocarcinoma, and signet cell carcinoma. The annual
percent change (APC) statistic was calculated by using the
weighted least-squares method.
The SEER-18 database was used to retrieve all cases of
rectal cancer from 2004 to 2010 (n = 38,351) and analyze

The overall incidence of rectal cancer has remained stable

since 1980, with an APC of 0% (p < 0.05; Fig.1). In contrast, the incidence of rectal cancer in patients age 20 to
39 has steadily increased from 0.3 cases per 100,000 to 1.2
cases per 100,000, representing a quadrupling in incidence
over the same time period, with APC of 3.6 % (p < 0.05;
Fig.2).
A systematic comparison of patients age 20 to 39 (under 40) and patients age 40 and older (over 40) is demonstrated in Table1. Younger patients had more aggressive
tumors as demonstrated by worse tumor grade, stage, tumor size, and histology. Notably, 3% of younger patients
(under 40) presented with signet cell histology in comparison with 0.87% of older patients (over 40). The median
survival in the under 40 group is also statistically shorter
than in the over 40 group (28 vs 31 months, p < 0.001).
A multivariate regression analysis (Table2) revealed
that race other than black or white (OR, 1.46; 95% CI,

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TAWADROS ET AL: INCIDENCE OF RECTAL CANCER UNDER AGE 40

Rectal cancer incidence (Age 20-39)

Table 1. Patient characteristics (SEER 18, 20042010, N = 38,351)

Variable

2.5
2
1.5

20-39
APC = 3.6%

1
0.5

1980

1985

1990

1995

2000

2005

2010

Figure 2. Rectal cancer incidence (ages 2039). Rectal cancer

incidence, in patients aged 20 to 39, from 1980 to 2010, in cases
per 100,000, using the SEER-9 database. The incidence quadruples
and the annual percentage change (APC) is 3.6% (p < 0.05). SEER =
Surveillance, Epidemiology, and End Results.

1.231.73), mucinous histology (OR, 1.77; 95% CI, 1.45

2.15), and signet cell histology (OR, 3.62; 95% CI, 2.57
5.1) were associated with rectal cancer under 40.
A comparison of characteristics of different histologic
subtypes is presented in Table3. Patients with signet cell
carcinoma were younger and more likely to be from a race
other than black or white. Substantial differences were
noted detailing the more aggressive behavior of signet cell
tumors as 70% were poorly differentiated, 23% were T4
tumors, 61% were node positive, and 24% had metastases.
Median overall survival was 14 months in patients with
signet cell histology vs 27 months in patients with mucinous or nonmucinous adenocarcinoma (p < 0.001).

DISCUSSION
With the use of a large American cancer registry, this
study demonstrates a rising trend in rectal cancer among
patients under 40 years of age, despite an overall stable
incidence of rectal cancer. Although this trend has been
suggested in other studies, our study confirms the trend in
more recent years, and offers a detailed comparison of histologic characteristics revealing an overall more aggressive
disease presentation along with a 3.6-fold increased risk of
signet-ring cell histology in the under 40 cohort.
By comparison, Meyer et al3 demonstrated an annual
percent increase in rectal cancer under 40 of 2.6% between
1973 and 2005. That study also used the SEER database
and identified 1984 as the transition year marking the
beginning of the increasing trend. In this study, we confirmed a continued rising trend up to 2010 at an annual
percent increase of 3.6% per year between 1980 and 2010.
There remains no clear explanation for this finding. Granted, despite the rising trend, we are still referring to a small incidence (1.2 rectal cancers under 40 per

n
Age, y
Male, %
Race, %
White
Black
Other
Married, %
Tumor characteristics
Grade, %
Well differentiated
Moderately differentiated
Poorly differentiated
Undifferentiated/anaplastic
Unknown
Stage (AJCC 6th)
I
IIA
IIB
IIIA
IIIB
IIIC
IV
T3 or T4 tumor, %
Tumor size, cm
Histology< %
Adenocarcinoma
Mucinous
Signet cell
Median survival, mo

Age 2039

Age >40

1274
35
56.20

37,077
65
59.60

77.60
10.20
12.20
53.50

82.60
8.60
8.80
57.70

7
59.10
21.10
1.70
11.20

8.20
66.50
13.30
1
11

22.60
15.60
2.10
5.70
20.70
14.40
18.40
66.60
4.6cm

35.70
21.30
2.90
4.60
15
8.20
12.30
56
4.0cm

87.80
9.20
3
28

93.60
5.60
0.87
31

p
<0.001
0.016
<0.001

0.003

<0.001

<0.001

<0.001
<0.001
<0.001

<0.001

AJCC = American Joint Committee on Cancer; SEER = Surveillance, Epidemiology,

and End Results.

100,000). However, when considering that this represents

a quadrupled incidence compared with merely 30 years
ago, the trend requires attention. Improved detection has
been hypothesized as an underlying cause. Greater access
to screening, greater understanding of genetic colorectal disorders prompting earlier screening, and improved
methods of cancer detection for IBD patients could all
contribute to the rise in rectal cancer incidence in patients
under 40. Improved awareness of cancer in general may
also contribute to this rising trend because more young
patients with rectal bleeding can potentially get an endoscopic evaluation than previously. However, if any of these
reasons were responsible, we should also have observed
a concurrent rise in colon cancer under 40. Yet the incidence of colon cancer in patients under 40 appears stable.3
Table 2. Logistic regression of factors associated with rectal
cancer under age 40
Variable
Race other
Mucinous
Signet cell

Adjusted OR

95% CI

1.46
1.77
3.62

1.231.73
1.452.15
2.575.1

<0.001
<0.001
<0.001

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Diseases of the Colon & Rectum Volume 58: 5 (2015)

Table 3. Characteristics of different histological subtypes

Variable
Age
Race, %
White
Black
Other
Tumor grade, %
Well differentiated
Moderately differentiated
Poorly differentiated
Anaplastic
Unknown
T stage
T1
T2
T3
T4
N stage, %
N0
N1
N2
Metastasis, %
Tumor size, cm
Median survival, mo

Adenocarcinoma

Mucinous

Signet cell

65 (5475)

64 (5475)

62 (4973)

0.006
0.001

82.60
8.60
8.90

82.10
10.20
7.80

77.40
8.80
13.80

8.20
67.50
12.70
0.90
10.80

6
56.70
18.70
2.30
13.70

0.30
3.90
70.20
7.50
18.20

26.50
18.60
47.30
7.50

9.30
12.70
63.70
14.30

15.50
6.60
55
22.90

48.70
28.20
23.20
15.20
4.8
27 (1350)

39.20
24.60
36.20
24.30
5.2
14 (732)

<0.001

<0.001

<0.001
65
24.20
10.80
12.30
4
27 (1149)

Therefore, none of these hypotheses can adequately account for the specific rise in rectal cancer.
The higher incidence of signet-ring cell histology is
also noteworthy. Signet-ring cell histology is known to be
more aggressive because the cellular abnormality involves
the lack of cell-to-cell adhesions, which results in greater
spreading tendency.8,9 This is reflected in our histologic
comparison data and correlates with outcomes seen in
other studies of colon and rectal cancers.7,12 There is a rationale from the gastric cancer literature to suggest that
signet-ring cell histology has an underlying genetic basis.13
In diffuse gastric signet-ring cell carcinoma, a mutation
in the CDH-1 gene leads to E-cadherin deficiency and
initiates the signet-ring cell histology. Carriers of CDH1 germline mutations are predisposed to hereditary diffuse gastric cancer (70% lifetime risk) and are treated with
close surveillance and sometimes prophylactic gastrectomies.14 Richards et al15 investigated whether germline
CDH-1 mutations could also predispose to colorectal cancer in a small cohort of 8 known British and Irish families
with this germline mutation. Of interest, 6 gastric cancers
and 1 rectal cancer at age 30 were identified within that cohort. With signet-ring cell histology being more aggressive
and more prominent in young patients, further research is
required to identify the potential underlying genetic susceptibility traits specifically related to rectal cancer.
It is interesting to note that the multivariate regression analysis singled out race other than black or white as
an independent risk factor for rectal cancer under 40. A
limitation of the SEER database is that it does not provide
a longitudinal breakdown of the ethnicities within the

<0.001
<0.001
<0.001

other category. However, because the ethnic mix of the

American population has changed over the past 30 years,
perhaps the rising trend of rectal cancer under 40 is reflecting a heretofore unknown underlying genetic susceptibility within a subset of Americans, further supporting
the need for research in this area.
Another significant limitation of the SEER database
is that it does not have records of family history. Such information would be a valuable addition to these data and
would help characterize and understand the risk factors
associated with rectal cancer in patients under 40.

CONCLUSION
With the use of data from the SEER registry, this study
confirms and updates reports of a rising trend in rectal
adenocarcinoma in patients under 40. Furthermore, it
identifies a 3.6-fold increased risk of signet-ring cell
histology within that group. Given the significantly worse
outcomes associated with this histology, these data highlight a need for thorough evaluation of young patients
with rectal symptoms.
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