Combined Loss of E-cadherin and Aberrant -Catenin Protein Expression Correlates With a Poor Prognosis for Small Intestinal Adenocarcinomas

Article (PDF Available)inAmerican Journal of Clinical Pathology 139(2):167-76 · February 2013with13 Reads
DOI: 10.1309/AJCPS54RTFCTHGWX · Source: PubMed
Abstract
Small intestinal adenocarcinomas (SIACs) are rare, and their molecular pathogenesis is largely unknown. To define the roles of E-cadherin and β-catenin, we performed immunohistochemistry for E-cadherin and β-catenin in 194 surgically resected SIACs with tissue microarrays and compared the data with clinicopathologic factors, including survival rates of patients with SIAC. Loss of E-cadherin expression and aberrant β-catenin expression were observed in 41.8% (81/194 cases) and 40.7% (79/194 cases) of SIACs, respectively. Combined loss of E-cadherin and aberrant β-catenin expression was observed in 24.2% (47/194 cases) of SIACs, and this feature was most frequently observed in mucinous adenocarcinomas and signet ring cell carcinomas (P < .001), poorly differentiated and undifferentiated carcinomas (P < .001), and tumors with advanced pT classification (P = .03). Survival times for patients with SIAC with both loss of E-cadherin and aberrant β-catenin expression (median, 13.9 months) were significantly shorter than those for patients without aberrant expression of both proteins (49.9 months), as determined by univariate (P < .001) and multivariate (P = .01) analyses. In conclusion, loss of E-cadherin and aberrant β-catenin expression correlate with poorly differentiated tumors, advanced T classification, and decreased patient survival time; therefore, it could be a prognostic factor in patients with SIAC.
Am J Clin Pathol 2013;139:167-176 167
167 DOI: 10.1309/AJCPS54RTFCTHGWX 167
© American Society for Clinical Pathology
Anatomic Pathology / E-  b-C  S I A
Combined Loss of E-cadherin and Aberrant β-Catenin
Protein Expression Correlates With a Poor Prognosis
for Small Intestinal Adenocarcinomas
Hee Jin Lee, MD, PhD,
1
Ok-Jun Lee, MD, PhD,
2
Kee-Taek Jang, MD, PhD,
3
Young Kyung Bae, MD, PhD,
4
Joon-Yong Chung, PhD,
5
Dae Woon Eom, MD, PhD,
6
Joon Mee Kim, MD, PhD,
7
Eunsil Yu, MD, PhD,
1
and Seung-Mo Hong, MD, PhD
1
Key Words: Small intestine; Adenocarcinoma; E-cadherin; b-catenin; Immunohistochemistry; Prognosis
DOI: 10.1309/AJCPS54RTFCTHGWX
Abstract
Small intestinal adenocarcinomas (SIACs) are rare,
and their molecular pathogenesis is largely unknown.
To define the roles of E-cadherin and β-catenin, we
performed immunohistochemistry for E-cadherin
and β-catenin in 194 surgically resected SIACs with
tissue microarrays and compared the data with
clinicopathologic factors, including survival rates of
patients with SIAC. Loss of E-cadherin expression and
aberrant β-catenin expression were observed in 41.8%
(81/194 cases) and 40.7% (79/194 cases) of SIACs,
respectively. Combined loss of E-cadherin and aberrant
β-catenin expression was observed in 24.2% (47/194
cases) of SIACs, and this feature was most frequently
observed in mucinous adenocarcinomas and signet
ring cell carcinomas (P < .001), poorly differentiated
and undifferentiated carcinomas (P < .001), and
tumors with advanced pT classification (P = .03).
Survival times for patients with SIAC with both loss of
E-cadherin and aberrant β-catenin expression (median,
13.9 months) were significantly shorter than those for
patients without aberrant expression of both proteins
(49.9 months), as determined by univariate (P < .001)
and multivariate (P = .01) analyses. In conclusion,
loss of E-cadherin and aberrant β-catenin expression
correlate with poorly differentiated tumors, advanced
T classification, and decreased patient survival time;
therefore, it could be a prognostic factor in patients
with SIAC.
The small intestine is the longest organ of the gastro-
intestinal (GI) tract, extending from the duodenum to the
ileum, with a mucosal surface that covers about 90% of the
absorptive surface area of the entire GI tract. Despite its
length and large mucosal surface area, only 5% of malig-
nant neoplasms of the GI tract occur in the small intestine.
It is estimated that 8,070 Americans will be diagnosed with,
and 1,150 people will die from, small intestinal cancers in
2012.
1
The global age-adjusted incidence of small intestinal
carcinoma is generally less than 1.0 per 100,000, ranging
from 0.3 to 2.0 per 100,000.
2
Adenocarcinomas are pre-
dominantly found in the duodenum and proximal jejunum,
whereas neuroendocrine tumors (previously called carci-
noid tumors) and lymphomas most commonly occur in the
distal jejunum and ileum.
2
Recent advances in imaging techniques and endoscopic
modalities have improved the detection of small intestinal
neoplasms.
3
Small intestinal adenocarcinomas (SIACs) are
diagnosed at an advanced disease state, and the 5-year surviv-
al rate is 41.2%.
4
Lymph node metastasis and distal location
of these tumors (in the jejunum and ileum) are reported to be
the most important independent prognostic factors.
4
Several
molecular alterations have been reported to be correlated with
carcinogenesis of SIACs. These include K-ras mutations,
overexpression or mutation of p53, overexpression of cyclin
D1 and p27, mutation of deleted pancreatic carcinoma 4
(DPC4), and microsatellite instability.
5-9
However, compared
with our knowledge of cancers of other GI tract organs,
such as stomach and colorectal cancers, our knowledge of
the molecular pathogenesis of SIACs is limited. Therefore,
identification of new biomarkers for early detection and/or
development of new therapeutic regimens based on a better
168 Am J Clin Pathol 2013;139:167-176
168 DOI: 10.1309/AJCPS54RTFCTHGWX
© American Society for Clinical Pathology
Lee et al / E-  b-  S I A
understanding of the biological mechanisms are essential for
this rare but aggressive disease.
E-cadherin is a transmembrane glycoprotein that serves
as the prime mediator of epithelial cell adhesion.
10
The cyto-
plasmic domains of E-cadherin molecules are tethered to the
actin fibers of the cytoskeleton via a complex that comprises
α-catenin, β-catenin, axin, and glycogen synthase kinase
(GSK3β).
10
Loss of E-cadherin from the plasma membrane
releases β-catenin, which then migrates to the nucleus, associ-
ates with Tcf/Lef transcription factors, and induces expression
of several genes orchestrating the epithelial-mesenchymal
transition.
11
In addition, inactivation of the degradation com-
plex protein APC stabilizes nuclear β-catenin, which acti-
vates transcription by binding to Tcf/Lef proteins. Reduced
β-catenin expression without associated APC abnormality,
as well as large deletions and insertions in the β-catenin gene
(CTNNB1), has both been identified in SIACs.
6,12
Previously,
a few case studies reported aberrant E-cadherin and β-catenin
protein expression in SIACs with small numbers of cases.
6,12-15
However, to the best of our knowledge, prognostic implica-
tions of E-cadherin and β-catenin expression have never
been analyzed in the context of SIACs. In the current study,
we analyzed E-cadherin and β-catenin expression in a large
number of SIAC cases and demonstrated that E-cadherin and
β-catenin expression in SIACs constitute prognostic factors in
patients with SIAC.
Materials and Methods
Case Selection
This study focused on primary solitary adenocarcinomas
originating in the mucosa of the small intestine. Carcinomas
extending into the small intestines from surrounding organs of
the GI tract, including the ampulla of Vater, appendix, cecum,
pancreas, or stomach, were excluded. Tumors were regarded
as having arisen by metastatic cancer to the small intestine
when the epicenter of the tumor was located in the subserosa,
multiple small intestinal tumors, or serosa of the intestine
without an involvement of mucosa by histologic examination.
Metastatic tumors were excluded from the study. Instead, the
tumor was considered a primary SIAC when the tumor was
solitary or predominantly involved the mucosa inconsiderate
extension into the serosa, regardless of the presence of peritu-
moral dysplasia as 1 recent study reported.
16
Appropriate measures were taken to protect the rights
of all human subjects, and the necessary approvals were
received from the institutional review boards of each hospital
participating in the Korean Small Intestinal Cancer Study
Group. Overall, 194 cases of surgically resected SIACs
were collected from the surgical pathology archives of 22
South Korean institutions, as previously described.
17
Data
collected by reviewing the medical records of patients with
SIAC included the age and sex of patients; diagnoses of prior
or current malignancies; additional prior or current treatment
modalities, including chemotherapy and/or radiation therapy;
most recent follow-up dates; and survival status.
Data obtained from the gross examination included the
growth pattern, location, and size of the tumor, as well as the
operation date. Microscopic characteristics that were evaluated
included the depth of invasion, degree of differentiation, and
histologic subtype. Other features noted included lymphatic
invasion, metastasis to the regional lymph node, metastasis
to the pancreas and other intestinal loops, perineural invasion,
peritoneal seeding, tumor size, and vascular invasion.
Tissue Microarray Construction
Tissue microarrays were constructed from archival for-
malin-fixed, paraffin-embedded tissue blocks, as previously
described.
17
Briefly, a representative tumor area was carefully
selected for each tumor from an H&E-stained section of a
donor block. Each case was represented by four 1-mm diam-
eter cores, including matched normal small intestine.
Immunohistochemical Staining and Scoring
Immunohistochemistry was performed on 4-μm-thick
tissue microarray sections as previously described.
17
Briefly,
tissue sections were deparaffinized in xylene and hydrated in
serially diluted ethanol. Endogenous peroxidase was blocked
by incubation in 3% H
2
O
2
for 10 minutes. Antigen retrieval
was performed in a steam pressure cooker with preheated
antigen retrieval buffer, pH 6 (DAKO, Glostrup, Denmark),
at 95°C for 10 minutes. Nonspecific binding of antibodies was
minimized by incubating sections with Protein Block (DAKO)
for 15 minutes. Microarrays were incubated at room tempera-
ture for 36 minutes with antibodies against E-cadherin (4A2C7;
1:200 dilution; Invitrogen, Carlsbad, CA) and β-catenin (CAT-
5H10, 1:200 dilution; Invitrogen). Sections were labeled using
an automated immunostaining system with an I-View detec-
tion kit (Benchmark XT; Ventana Medical Systems, Tucson,
AZ). Immunostained sections were lightly counterstained with
hematoxylin, dehydrated in ethanol, and cleared in xylene.
Normal intestinal epithelial cells included in tissue microar-
rays were used as positive controls for both E-cadherin and
β-catenin. For validation of immunohistochemical staining on
tissue microarray slides, we selected 10 conventional slides
from 10 included cases in this study, performed immunohisto-
chemical staining for E-cadherin and β-catenin, and compared
the staining pattern of tissue microarray slides and matched
conventional slides from the same case. Both tissue microarray
slides and matched conventional slides showed similar staining
patterns for E-cadherin and β-catenin staining. To be included
for analysis, each cancer had to have sufficient numbers of
Am J Clin Pathol 2013;139:167-176 169
169 DOI: 10.1309/AJCP S54RTFCTHGWX 169
© American Society for Clinical Pathology
Anatomic Pathology / O A
E-cadherin–labeled cells to permit quantification of the per-
centage of cells with E-cadherin labeling (>100 cancer cells).
E-cadherin expression was evaluated primarily according to
the percentage of cells that labeled, although we also evaluated
if labeling intensity was an important variable. The results of
membranous immunohistochemical staining for E-cadherin
and β-catenin were scored with a previously described his-
tologic score (also known as “histoscore”) scheme.
18-20
The
intensity of staining was categorized as 0 (negative), 1 (weak),
2 (moderate), or 3 (strong). In addition, the results of abnormal
cytoplasmic catenin were scored the same way. We counted
the proportion of labeled cancer cells of approximately 100
cancer cells in each tissue microarray core. The percentage of
positive epithelial cells was scored as 0 (<5%), 1 (6%-25%),
2 (26%-50%), 3 (51%-75%), or 4 (>76%). A histoscore was
generated as the product of the intensity and the area of stain-
ing. The histoscore was then dichotomized into loss of expres-
sion (histoscore, 0-6) and intact expression (histoscore, 8-12).
We arbitrarily selected a histoscore of 8 as the cutoff point for
intact expression because histoscores of 8 or more matched
with cases with diffuse (>51%) and strong or moderate inten-
sity. We did not compare other cutoff points in this study. For
β-catenin, nuclear staining was also evaluated as present or
absent, separately from evaluation of cytoplasmic expression
of each specimen. Aberrant β-catenin expression of defined
tumor cells showed either cytoplasmic or nuclear expression
of β-catenin.
Statistical Analysis
Statistical analyses were performed using SPSS version
17 (SPSS, Chicago, IL). Associations between categorical
variables were examined using the Pearson c
2
and Fisher
exact tests. Survival curves were calculated by the Kaplan-
Meier method, and statistical significance was evaluated
using the log-rank test and the Cox proportional hazards
regression model. A P value less than .05 was considered
statistically significant.
Results
Clinicopathologic Characteristics of Cases
Clinicopathologic characteristics of the cases in this
study are summarized in Table 1. Patient ages ranged from
23 to 86 years (mean, 59.0 years). Of the 194 patients, 121
were men and 73 were women. Tumor sizes ranged from 0.8
to 16 cm (mean, 4.4 cm). Chemotherapy and radiation therapy
were performed in 74 (38.2%) and 25 (12.9%) cases, respec-
tively. The length of patient follow-up time ranged from 1 to
158 months, and median survival time at last follow-up was
28 months.
E-Cadherin and β-Catenin Expression
In normal small intestinal epithelia, moderate to strong sig-
nals related to E-cadherin and β-catenin were identified in the
cytoplasmic membranes in all 194 cases Image 1A and Image
1B
. Representative expression of E-cadherin and β-catenin in
SIAC tumor specimens is also depicted Image 1C and Image
1D
. Loss of E-cadherin expression, resulting in either complete
elimination of or simply a decrease in E-cadherin expression,
was observed in 41.8% (81/194 cases) of SIACs. As shown
in Table 2, mucinous adenocarcinomas (7/9 cases, 77.8%),
Table 1
Clinicopathologic Characteristics of the 194 Cases
Characteristics No. of Patients (Except as Noted)
Mean age 59.0 y
Sex
M 121
F 73
Mean tumor size 4.4 cm
Tumor location
Proximal (duodenal) 105
Distal (jejunal/ileal) 89
Growth pattern
a
Polypoid 35
Nodular 12
Infiltrative 139
Histologic subtype
Tubular adenocarcinoma 176
Mucinous adenocarcinoma 9
Signet ring cell carcinoma 4
Undifferentiated carcinoma 5
Differentiation
Well 42
Moderate 105
Poor 42
Undifferentiated 5
pT classification
pTis 4
pT1 7
pT2 9
pT3 63
pT4 111
Lymph node metastasis
b
Present 90
Absent 85
Pancreatic invasion
Present 68
Absent 126
Other loop invasion
Present 5
Absent 189
Retroperitoneal seeding
Present 13
Absent 181
Perineural invasion
Present 62
Absent 132
Vascular invasion
Present 51
Absent 143
Lymphatic invasion
Present 96
Absent 98
a
Calculated only 186 cases with available information of growth pattern.
b
Calculated only 175 cases with available information of examined lymph nodes.
170 Am J Clin Pathol 2013;139:167-176
170 DOI: 10.1309/AJCPS54RTFCTHGWX
© American Society for Clinical Pathology
Lee et al / E-  b-  S I A
signet ring cell carcinomas (4/4 cases, 100.0%), and undiffer-
entiated carcinomas (4/5 cases, 80.0%) were all characterized
by a significantly greater reduction in levels of E-cadherin
expression than tubular adenocarcinoma (66/176 cases, 37.5%;
P = .001, c
2
test). Poorly differentiated cancers (26/42 cases,
61.9%) demonstrated more loss of E-cadherin expression than
well-differentiated (17/42 cases, 40.5%) or moderately differ-
entiated (34/105 cases, 32.4%) tumors (P = .002).
Changes in patterns of β-catenin expression were also
observed at the subcellular level, with decreased expres-
sion in membranes, increased expression in the cytoplasm,
and abnormal expression in the nucleus. Combined loss of
β-catenin from membranes and accumulation of β-catenin
in the cytoplasm was observed in 39.2% (76/194 cases) of
SIACs. Abnormal nuclear β-catenin expression was found in
9.3% (18/194 cases) of SIACs. Three cases were character-
ized by aberrant accumulation of nuclear β-catenin only with-
out accompanying increased cytoplasmic labeling. Therefore,
aberrant β-catenin expression, characterized by a combination
of loss of membranous β-catenin and aberrant accumulation
of nuclear β-catenin, was present in 40.7% (79/194 cases) of
SIACs. The frequency of aberrant β-catenin expression was
higher in tumors with infiltrative growth patterns (65/139
cases, 46.8%) than in those with polypoid (8/35 cases, 22.9%)
or nodular patterns (3/12 cases, 25.0%; P = .02). Poorly dif-
ferentiated (24/42 cases, 57.1%) and undifferentiated (4/5
cases, 80.0%) cancers showed significantly more abnormal
β-catenin expression than well differentiated (10/42 cases,
A
B
C D
Image 1Representative images of normal and cancer cells following E-cadherin and b-catenin immunohistochemical
staining. Both E-cadherin (A, ×100) and b-catenin (B, ×100) were stained in the cytoplasmic membrane in normal small intestinal
epithelia. Cancer cells show a loss of E-cadherin labeling (C, ×200) and aberrant nuclear and cytoplasmic staining of b-catenin
(D, ×200).
Am J Clin Pathol 2013;139:167-176 171
171 DOI: 10.1309/AJCP S54RTFCTHGWX 171
© American Society for Clinical Pathology
Anatomic Pathology / O A
23.8%) and moderately differentiated (41/105 cases, 39.0%)
cancers (P = .04). The frequency of aberrant β-catenin expres-
sion was higher in more deeply invasive cancers (pT3 cancers
[26/63 cases, 41.3%] and pT4 cancers [53/111 cases, 47.7%])
than in superficially invasive tumors (pTis-T2 cancers [0/20
cases, 0%]; P < .001). Aberrant β-catenin expression was
observed more frequently in SIACs with other loop invasion
(5/5 cases, 100%) than those without other loop invasion
(74/189 cases, 39.2%; P = .01). Abnormal β-catenin expres-
sion was also observed more frequently in SIACs with lym-
phovascular invasion (49/100 cases, 49.0%) than those with-
out lymphovascular invasion (30/94 cases, 31.9%; P = .019).
A combined loss of E-cadherin and aberrant β-catenin
expression was observed in 24.2% (47/194 cases) of SIACs.
Simultaneous loss of E-cadherin and aberrant β-catenin
expression was more frequently observed in mucinous adeno-
carcinomas (7/9 cases, 77.8%), signet ring cell carcinomas
(4/4 cases, 100%), and undifferentiated carcinomas (3/5
cases, 60%) than in tubular adenocarcinomas (33/176 cases,
18.8%; P < .001). Moreover, SIACs with combined decreased
E-cadherin and aberrant β-catenin expression were more
associated with poorly differentiated (21/42 cases, 50.0%)
or undifferentiated (3/5 cases, 60.0%) cancers than well-
differentiated (6/42 cases, 18.8%) or moderately differenti-
ated (17/105 cases, 16.2%) cancers (P < .001). Concomitant
loss of E-cadherin and aberrant β-catenin expression in SIACs
were mainly observed in more deeply invaded tumors (pT3
tumors [18/63 cases, 28.6%] and pT4 tumors [29/111 cases,
Table 2
E-cadherin and β-Catenin Expression and Association With Clinicopathologic Characteristics in Patients With Small Intestinal
Adenocarcinoma
Loss of E-cadherin Aberrant β-catenin Loss of E-cadherin
Case Expression, Expression, and Aberrant β-catenin
Characteristics No. No. (%) P Value No. (%) P Value Expression, No. (%) P Value
Sex
M 121 50 (41.3) .882 57 (47.1) .024
a
35 (28.9) .058
F 73 31 (42.5) 22 (30.1) 12 (16.4)
Location
Proximal (duodenal) 105 39 (37.1) .189 40 (38.1) .465 21 (20.0) .178
Distal (jejunal/ileal) 89 42 (47.2) 39 (43.8) 26 (29.2)
Growth pattern
b
Polypoid 35 16 (45.7) .93 8 (22.9) .018
a
7 (20.0) .826
Nodular 12 5 (41.7) 3 (25.0) 3 (25.0)
Infiltrative 139 57 (41.0) 65 (46.8) 35 (25.2)
Histologic subtype
Tubular adenocarcinoma 176 66 (37.5) .001
a
64 (36.4) .001
a
33 (18.8) <.001
a
Mucinous adenocarcinoma 9 7 (77.8) 7 (77.8) 7 (77.8)
Signet ring cell carcinoma 4 4 (100.0) 4 (100.0) 4 (100.0)
Undifferentiated carcinoma 5 4 (80.0) 4 (80.0) 3 (60.0)
Differentiation
Well 42 17 (40.5) .002
a
10 (23.8) .04
a
6 (14.3) <.001
a
Moderate 105 34 (32.4) 41 (39.0) 17 (16.2)
Poor 42 26 (61.9) 24 (57.1) 21 (50.0)
Undifferentiated 5 4 (80.0) 4 (80.0) 3 (60.0)
pT classification
pTis-pT2 20 5 (31.3) .729 0 (0.0) <.001
a
0 (0.0) .029
a
pT3 63 27 (42.9) 26 (41.3) 18 (28.6)
pT4 111 47 (42.3) 53 (47.7) 29 (26.1)
Lymph node metastasis
c
Present 90 35 (38.9) .76 43 (47.8) .064 26 (28.9) .071
Absent 85 35 (41.2) 28 (32.9) 14 (16.5)
Pancreatic invasion
Present 68 23 (33.8) .127 32 (47.1) .221 15 (22.1) .726
Absent 126 58 (46.0) 47 (37.3) 32 (25.4)
Other loop invasion
Present 5 2 (40.0) 1 5 (100.0) .010
a
2 (40.0) .596
Absent 189 79 (41.8) 74 (39.2) 45 (23.8)
Retroperitoneal seeding
Present 13 8 (61.5) .154 5 (38.5) 1 4 (30.8) .52
Absent 181 73 (40.3) 74 (40.9) 43 (23.8)
Perineural invasion
Present 62 3 (48.4) .215 29 (46.8) .274 18 (29.0) .287
Absent 132 51 (38.6) 50 (37.9) 29 (22.0)
Lymphovascular invasion
Present 100 45 (45.0) .384 49 (49.0) .019
a
30 (30.0) .065
Absent 94 36 (38.3) 30 (31.9) 17 (18.1)
a
Significant at the level of less than .05.
b
Calculated only 186 cases with available information of growth pattern.
c
Calculated only 175 cases with available information of examined lymph nodes.
172 Am J Clin Pathol 2013;139:167-176
172 DOI: 10.1309/AJCPS54RTFCTHGWX
© American Society for Clinical Pathology
Lee et al / E-  b-  S I A
26.1%]) than less deeply invaded cancers (pTis-pT2 cancers,
0/20 cases, 0%; P = .03).
Survival Analysis
Median survival time in patients with SIAC with either
no or reduced E-cadherin expression (median survival, 22.6
months) trended shorter than that in patients with intact
expression (median survival, 48.4 months; P = .054, log-rank
test) Figure 1A.
Median survival in patients with aberrant β-catenin
expression (20.1 months) was significantly worse than that
in patients with an intact β-catenin expression pattern (50.1
Figure 1Survival of small intestinal adenocarcinomas (SIAC) patients based on E-cadherin and b-catenin labeling. A, Median
survival in patients with SIAC with loss of E-cadherin expression (median survival, 22.6 months) trended lower than that in
patients with intact E-cadherin expression (median survival, 48.4 months; P = .054, log-rank test). B, Median survival in patients
with SIAC with aberrant b-catenin expression (20.1 months) was significantly worse than that in patients with intact b-catenin
expression pattern (50.1 months; P = .003). C, Survival of patients with SIAC according to combined E-cadherin and b-catenin
expression. The median survival times of patients with SIAC with intact expression of both E-cadherin and b-catenin (n = 81),
loss of E-cadherin expression only (n = 34), aberrant b-catenin expression only (n = 32), and combined loss of E-cadherin and
aberrant b-catenin expression (n = 47) were 48.5 months, 74.1 months, 41.6 months, and 13.9 months, respectively. There was
a significant survival difference among the 4 groups by overall comparison (P < .001). When compared in a pairwise manner,
patients with SIAC with combined loss of E-cadherin and aberrant b-catenin expression had significantly shorter survival
times than those with intact expression of both E-cadherin and b-catenin expression (P < .001), those with loss of E-cadherin
expression only (P = .004), and those with aberrant b-catenin only (P = .04). However, no differences in survival were apparent
from other group comparisons. D, Median survival in patients with SIAC with combined loss of E-cadherin and aberrant
b-catenin expression (13.9 months) was significantly lower than those without combined decreased E-cadherin and aberrant
b-catenin expression (49.9 months; P < .001).
0
25
50
0244872
Survival (mo)
Survival Probability (%)
96 120 144 168
75
E-cadherin expression
100
Intact
Loss
0
25
50
0244872
Survival (mo)
Survival Probability (%)
96 120 144 168
75
Combined E-cadherin/
β-cadherin expression
100
Loss of E-cadherin/
aberrant β-cadherin
Intact any or both
0
25
50
0244872
Survival (mo)
Survival Probability (%)
96 120 144 168
75
Combined E-cadherin/
β-cadherin expression
100
Loss of E-cadherin and
aberrant β-cadherin
Loss of E-cadherin only
Aberrant β-cadherin only
Both intact
0
25
50
0244872
Survival (mo)
Survival Probability (%)
96 120 144 168
75
β-cadherin expression
100
Intact
Aberrant
A B
C D
Am J Clin Pathol 2013;139:167-176 173
173 DOI: 10.1309/AJCP S54RTFCTHGWX 173
© American Society for Clinical Pathology
Anatomic Pathology / O A
Aberrant E-cadherin and β-catenin expression (P = .01),
pN classification (P = .01), and retroperitoneal seeding (P
= .02) were all independently prognostic in our model. The
hazard ratio for SIAC with reduced E-cadherin and aberrant
β-catenin expression was 1.82 (95% confidence interval, 1.15-
2.87) compared with those of intact E-cadherin and β-catenin
Table 4.
Because cases with pT3 and pT4 composed about 90% of
the cases, additional multivariate analysis was performed with
pT3 and pT4 cases. Again, aberrant E-cadherin and β-catenin
expression (P = .008), pN classification (P = .02), and retroper-
itoneal seeding (P = .02) remained as independent prognostic
factors after stratifying with pT3 and pT4 classifications.
Discussion
We observed abnormal expression of the E-cadherin
and β-catenin proteins in a large number of SIACs. Loss of
E-cadherin was observed in 41.8% (81/194 cases) of SIACs,
and aberrant β-catenin was observed in 40.7% (79/194
cases) of SIACs. Combined loss of E-cadherin and aberrant
β-catenin expression was observed in 24.2% (47/194 cases)
of SIACs. Only a few previous studies analyzed abnormal
β-catenin expression in SIACs, with frequencies of 19% to
81% reported with small numbers (fewer than 32 cases) of
SIACs.
6,12-15
A study concerning aberrant E-cadherin expres-
sion reported that 38% of SIACs had decreased membranous
expression of E-cadherin,
6
which is similar to the percentage
frequency we observed.
Although a few previous studies reported aberrant
E-cadherin and β-catenin protein expression in SIACs, they
did not compare rates of aberrant expression of E-cadherin
and β-catenin protein owing to small sample sizes.
6,12-15
In the current study, we observed more common loss of
E-cadherin expression in poorly differentiated or undif-
ferentiated carcinomas than in moderately differentiated
or well-differentiated carcinomas. Signet ring cell carcino-
mas, undifferentiated carcinomas, and mucinous carcinomas
showed more frequent reduced or no E-cadherin expression
than conventional tubular adenocarcinomas. It is reasonable
to deduce that reduced E-cadherin expression was more fre-
quent in poorly differentiated or undifferentiated carcinomas
because the main function of E-cadherin involves adhe-
sion of epithelial cells. Wheeler et al
6
previously observed
decreased membrane expression of E-cadherin in 38% (8/21
cases) of SIACs and did not find an association between
reduced E-cadherin expression and differentiation of SIACs
owing to the small number of examined cases. Loss of
E-cadherin expression was associated with loss of intercel-
lular junctional or cellular polarity of cancer cells, which are
characteristics of poorly cohesive or noncohesive cancer cell
phenotypes, such as undifferentiated carcinomas or signet
months; P = .003, log-rank test) Figure 1B. The 1-, 3-,
and 5-year survival rates in the aberrant β-catenin expression
group were 62%, 37%, and 29%, respectively, whereas the
corresponding rates in the retained membranous β-catenin
expression group were 79%, 59%, and 46%.
The survival differences were compared after combining
E-cadherin and β-catenin expression patterns. The median sur-
vival times for patients with SIAC with both intact E-cadherin
and β-catenin expression (n = 81), reduced E-cadherin expres-
sion only (n = 34), aberrant β-catenin only (n = 32), and both
reduced E-cadherin and aberrant β-catenin (n = 47) were 48.5
months, 74.1 months, 41.6 months, and 13.9 months, respec-
tively. There was a significant survival difference among the
4 groups (P < .001, log-rank test, overall comparison) Figure
1C
. When compared in a pairwise manner, patients with SIAC
with both reduced E-cadherin and aberrant β-catenin had sig-
nificantly shorter survival than those with intact expression of
both E-cadherin and β-catenin (P < .001), those with reduced
E-cadherin expression only (P = .004), and those with aberrant
β-catenin expression only (P = .04). However, there was no
difference in survival between other group comparisons.
Median survival in patients with SIAC with combined
reduced E-cadherin and aberrant β-catenin expression (13.9
months) was significantly lower than in those without com-
bined decreased E-cadherin and aberrant β-catenin expression
(49.9 months; P < .001) Figure 1D.
Univariate Analysis of Other Clinicopathologic Factors
The relationships between other clinicopathologic vari-
ables and survival are summarized in Table 3. The clinico-
pathologic factors associated with shorter patient survival by
univariate survival analysis were tumor location (P = .03),
pT classification (P = .02), lymph node metastasis (P < .001),
other loop invasion (P = .025), retroperitoneal seeding (P <
.001), perineural invasion (P = .008), lymphovascular inva-
sion (P < .001), and radiation therapy (P = .002). In contrast,
survival was not associated with sex, growth pattern, histologic
subtype, differentiation, pancreatic invasion, or chemotherapy.
Multivariate Analysis of Clinicopathologic Factors
The independent prognostic significance of a combined
reduced E-cadherin and aberrant β-catenin expression as
well as other clinicopathologic parameters were determined
by applying the Cox proportional hazards model. Although
β-catenin expression, pT classification, and lymphovascular
invasion were significant by univariate analyses, they were
not included for the Cox regression model because β-catenin
expression was associated with other factors, such as com-
bined reduced E-cadherin and aberrant β-catenin expression.
Similarly, loop invasion and retroperitoneal seeding, which
were components of pT classification as well as lymphovas-
cular invasion, were closely linked with pN classification.
174 Am J Clin Pathol 2013;139:167-176
174 DOI: 10.1309/AJCPS54RTFCTHGWX
© American Society for Clinical Pathology
Lee et al / E-  b-  S I A
Combined loss of E-cadherin and aberrant β-catenin
expression was more commonly seen in poorly differenti-
ated or undifferentiated SIACs than in moderately differenti-
ated or well-differentiated SIACs. The incidence of aberrant
β-catenin expression was higher in signet ring cell carcino-
mas, undifferentiated carcinomas, and mucinous carcinomas
ring cell carcinomas, which were previously described in
stomach and pancreatic cancers.
21-23
Likewise, the poorly
cohesive phenotype of poorly differentiated or undifferenti-
ated SIACs and signet ring cell carcinomas in the present
study was associated with complete loss or a reduced level
of E-cadherin expression.
Table 3
Univariate Analysis of Clinicopathologic Factors
Characteristics Median Survival, mo 95% Confidence Interval P Value
Sex
M 36.4 23.2-49.8 .998
F 47.6 13-82.2
E-cadherin expression
Loss 22.6 9.4-35.7 .054
Intact membranous pattern 48.4 38.7-58
b-Catenin expression
Aberrant cytoplasmic and/or nuclear pattern 20.1 8.1-32.1 .003
a
Intact membranous pattern 50.1 33.4-66.9
E-cadherin and b-catenin expression
Loss of E-cadherin and aberrant b-catenin expression 13.9 10.3-17.4 <.001
a
Loss of E-cadherin only, aberrant b-catenin only, or intact 49.9 33.8-66
both E-cadherin and b-catenin
Location
Proximal (duodenal) 48.5 22.8-74.2 .030
a
Distal (jejunal/ileal) 24.5 16.1-32.9
Growth pattern
Polypoid 48.5 20.1-76.9 .623
Nodular 36.2
Infiltrative 30.7 17.8-43.6
Histologic subtype
Tubular adenocarcinoma 40 24.7-55.2 .31
Mucinous adenocarcinoma 21 18.5-23.5
Signet ring cell carcinoma 4.2 1.8-6.7
Undifferentiated carcinoma 7.6 0-20.1
Differentiation
Well 50.1 40.5-59.8 .294
Moderate 32 11.8-52.2
Poor 28.4 19.2-37.5
Undifferentiated 7.6 0-20.1
pT classification
pTis-pT2 71.2 30.3-112.1 .020
a
pT3 41.7 26-57.3
pT4 22.5 18.1-26.9
Lymph node metastasis
Present 23.9 20-27.8 <.001
a
Absent 71.2 42.8-99.6
Pancreatic invasion
Present 38.5 5.6-71.5 .737
Absent 36.2 21.5-50.9
Other loop invasion
Present 5.1 0-23 .025
a
Absent 39.7 26-53.5
Retroperitoneal seeding
Present 15 4.6-25.5 <.001
a
Absent 41.7 28.1-55.2
Perineural invasion
Present 22 14.5-29.6 .008
a
Absent 50.1 26.8-73.5
Lymphovascular invasion
Present 21.1 14.9-27.4 <.001
a
Absent 71.2 42.5-99.9
Chemotherapy
Present 30.7 24-53 .114
Absent 41.7 8.9-74.4
Radiotherapy
Present 22 6.7-37.4 .002
a
Absent 47.6 31.2-63.9
a
Significant at the level of less than .05.
Am J Clin Pathol 2013;139:167-176 175
175 DOI: 10.1309/AJCP S54RTFCTHGWX 175
© American Society for Clinical Pathology
Anatomic Pathology / O A
patients with ampullary carcinomas.
25,26
Similarities between
these studies and ours in the extent of the loss of E-cadherin,
the extent of aberrant β-catenin expression, and correlation
of both parameters with worse survival suggest that common
molecular profiles may exist between patients with SIAC and
ampullary carcinoma.
In the present study, we observed that β-catenin expres-
sion and a combination of reduced E-cadherin and aberrant
β-catenin expression were both associated with a worse prog-
nosis in patients with SIAC. Combined abnormal E-cadherin
and β-catenin expression has been reported as a prognostic
indicator in cancers from other organs, including colorectal
cancers,
27,
28
as well as head and neck squamous cancers.
29
In summary, loss of E-cadherin and aberrant β-catenin
expression are commonly observed in surgically resect-
ed SIACs. Loss of membranous E-cadherin and aberrant
β-catenin expression are more frequently observed in tumors
with poorly cohesive phenotypes, including poorly differ-
entiated, undifferentiated, and signet ring cell carcinomas.
Combined abnormalities in both E-cadherin and β-catenin
expression are negatively correlated with patient survival,
thus providing a prognostic factor for patients with SIAC.
From the
1
Department of Pathology, Asan Medical Center,
University of Ulsan College of Medicine, Seoul, South Korea;
2
Department of Pathology, Chungbuk National University College
of Medicine, Cheongju, South Korea;
3
Department of Pathology,
Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul, Korea;
4
Department of Pathology, Yeungnam
University College of Medicine, Daegu, South Korea;
5
Applied
Molecular Pathology Laboratory & Tissue Array Research
Program, Laboratory of Pathology, National Cancer Institute,
National Institutes of Health, Bethesda, MD;
6
Department of
Pathology, Gangneung Asan Hospital, University of Ulsan College
of Medicine, Gangneung, South Korea;
7
Department of Pathology,
Inha University College of Medicine, Incheon, South Korea.
Dr H. J. Lee and Dr O.-J. Lee equally contributed to this work.
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) and funded by the Ministry of Education, Science, and
than in conventional tubular adenocarcinomas. We also
observed that SIACs with aberrant β-catenin expression were
associated with increased depth of invasion and invasion of
other intestinal loops and the lymphovascular system. To
the best of our knowledge, ours is the first study to evaluate
β-catenin expression in the context of clinicopathologic vari-
ables, including survival of patients with SIAC.
Murata et al
24
first reported that SIACs occasionally
carry mutations of CTNNB1, which encodes β-catenin. They
observed somatic interstitial deletion of exon 3 in CTNNB1
and deduced that an activating mutation of CTNNB1 is
involved in the carcinogenesis of SIACs.
24
Wheeler and
colleagues
6
evaluated the roles of mutation of APC and
used immunohistochemistry to characterize E-cadherin and
β-catenin levels in 21 cases of SIAC. They did not find any
APC mutation but observed frequent abnormal expression of
E-cadherin and β-catenin, which led them to conclude that
SIACs have a distinct genetic pathway with colorectal can-
cers. Likewise, Blaker et al
14
examined 21 SIACs and identi-
fied the CTNNB1 mutation in 1 case and abnormal β-catenin
expression in 5 cases. They insisted that accumulation of
nuclear β-catenin following the activation of Wnt signaling
is important in the carcinogenesis of SIACs and concluded
that nuclear accumulation of β-catenin may not be caused by
mutations that either inactivate APC or activate CTNNB1.
14
We did not include any case of ampullary carcinoma in
the present study because ampullary carcinomas may have
combined features of carcinomas of the small intestine (espe-
cially duodenal cancers), distal bile duct, or pancreas. Interest-
ingly, the prognostic significance of reductions in the levels
of either E-cadherin or β-catenin was reported in 2 previous
studies of ampullary carcinomas.
25,26
Loss of E-cadherin
expression was reported for 34% to 63% of the tested cases,
and aberrant β-catenin expression was reported for 41% to
60%.
25,26
The proportion of loss of E-cadherin and the extent
of aberrant β-catenin expression were both similar to those
seen in the current study. Loss of E-cadherin and aberrant
β-catenin expression was associated with worse survival in
Table 4
Multivariate Analysis for Prognosis
Variable P Value Hazard Ratio 95% Confidence Interval
Loss of E-cadherin and aberrant b-catenin expression .01
a
1.82 1.15-2.87
Location (proximal vs distal) .27 1.26 0.83-1.90
pN classification .01
a
pN0 (no lymph node metastasis) 1
pN1 (1-3 lymph nodes metastasis) .01
a
1.86 1.16-2.98
pN2 (>4 lymph nodes metastasis) .01
a
2.15 1.21-3.84
Other intestinal loop invasion .57 1.56 0.34-7.26
Perineural invasion .07 1.49 0.97-2.28
Retroperitoneal seeding .02
a
2.48 1.17-5.23
Radiotherapy .06 1.7 0.98-2.93
a
Significant at the level of less than .05.
176 Am J Clin Pathol 2013;139:167-176
176 DOI: 10.1309/AJCPS54RTFCTHGWX
© American Society for Clinical Pathology
Lee et al / E-  b-  S I A
13. Svrcek M, Jourdan F, Sebbagh N, et al. Immunohistochemical
analysis of adenocarcinoma of the small intestine: a tissue
microarray study. J Clin Pathol. 2003;56:898-903.
14. Blaker H, Helmchen B, Bonisch A, et al. Mutational
activation of the RAS-RAF-MAPK and the Wnt pathway
in small intestinal adenocarcinomas. Scand J Gastroenterol.
2004;39:748-753.
15. Zhang MQ, Chen ZM, Wang HL. Immunohistochemical
investigation of tumorigenic pathways in small intestinal
adenocarcinoma: a comparison with colorectal
adenocarcinoma. Mod Pathol. 2006;19:573-580.
16. Estrella JS, Wu TT, Rashid A, et al. Mucosal colonization by
metastatic carcinoma in the gastrointestinal tract: a potential
mimic of primary neoplasia. Am J Surg Pathol. 2011;35:563-
572.
17. Chung JY, Hong SM, Choi BY, et al. The expression of
phospho-AKT, phospho-mTOR, and PTEN in extrahepatic
cholangiocarcinoma. Clin Cancer Res. 2009;15:660-667.
18. Koorstra JB, Hong SM, Shi C, et al. Widespread activation
of the DNA damage response in human pancreatic
intraepithelial neoplasia. Mod Pathol. 2009;22:1439-1445.
19. Maitra A, Ashfaq R, Gunn CR, et al. Cyclooxygenase 2
expression in pancreatic adenocarcinoma and pancreatic
intraepithelial neoplasia: an immunohistochemical
analysis with automated cellular imaging. Am J Clin Pathol.
2002;118:194-201.
20. Hansel DE, Rahman A, Hermans J, et al. Liver metastases
arising from well-differentiated pancreatic endocrine
neoplasms demonstrate increased VEGF-C expression. Mod
Pathol. 2003;16:652-659.
21. Fiocca R, Luinetti O, Villani L, et al. Molecular mechanisms
involved in the pathogenesis of gastric carcinoma: interactions
between genetic alterations, cellular phenotype and cancer
histotype. Hepatogastroenterology. 2001;48:1523-1530.
22. Winter JM, Ting AH, Vilardell F, et al. Absence of E-cadherin
expression distinguishes noncohesive from cohesive pancreatic
cancer. Clin Cancer Res. 2008;14:412-418.
23. Hong SM, Li A, Olino K, et al. Loss of E-cadherin expression
and outcome among patients with resectable pancreatic
adenocarcinomas. Mod Pathol. 2011;24:1237-1247.
24. Murata M, Iwao K, Miyoshi Y, et al. Molecular and biological
analysis of carcinoma of the small intestine: beta-catenin
gene mutation by interstitial deletion involving exon 3 and
replication error phenotype. Am J Gastroenterol. 2000;95:1576-
1580.
25. Park S, Kim SW, Lee BL, et al. Expression of E-cadherin and
beta-catenin in the adenoma-carcinoma sequence of ampulla
of Vater cancer. Hepatogastroenterology. 2006;53:28-32.
26. Hsu HP, Shan YS, Jin YT, et al. Loss of E-cadherin and
beta-catenin is correlated with poor prognosis of ampullary
neoplasms. J Surg Oncol. 2010;101:356-362.
27. Ozguven BY, Karacetin D, Kabukcuoglu F, et al.
Immunohistochemical study of E-cadherin and beta-catenin
expression in colorectal carcinomas. Pol J Pathol. 2011;62:19-
24.
28. Matsuoka T, Mitomi H, Fukui N, et al. Cluster analysis of
claudin-1 and -4, E-cadherin, and beta-catenin expression in
colorectal cancers. J Surg Oncol. 2011;103:674-686.
29. Liu LK, Jiang XY, Zhou XX, et al. Upregulation of vimentin
and aberrant expression of E-cadherin/beta-catenin complex
in oral squamous cell carcinomas: correlation with the
clinicopathological features and patient outcome. Mod Pathol.
2010;23:213-224.
Technology (2010-0004807) and a grant (2013-554) from the
Asan Institute for Life Sciences, Seoul, South Korea.
Address reprint requests to Dr Hong: Dept of Pathology,
Asan Medical Center, University of Ulsan College of Medicine,
388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea;
smhong28@gmail.com.
Acknowledgments: We thank the members of the Korean
Small Intestinal Cancer Study Group: Dr Hee-Kyung Chang, Kosin
University College of Medicine, Pusan; Dr Eun Sun Jung, The
Catholic University of Korea College of Medicine, Seoul; Drs Ghil
Suk Yoon and Han-Ik Bae, Kyungpook National University, Dague;
Dr Young-Ha Oh, Hanyang University College of Medicine, Seoul;
Dr Gwangil Kim, Bundang CHA Medical Center, CHA University,
Seongnam; Dr Soo Jin Jung, Inje University College of Medicine,
Busan; Dr Mi Jin Gu, Fatima Hospital, Daegu; Dr Jung Yeon Kim,
Inje University Sanggye Paik Hospital, Seoul; Dr Kyu Yun Jang,
Chonbuk National University Medical School, Jeonju; Dr Kye Won
Kwon, Bundang Jesaeng General Hospital, Seongnam; Dr Gyeong
Hoon Kang, Seoul National University College of Medicine, Seoul;
Dr Jae Bok Park, Catholic University of Daegu, Daegu; Dr Soon
Won Hong, Yonsei University College of Medicine, Seoul; and Dr Ji
Shin Lee, Chonnam National University Medical School, Gwangju,
South Korea.
References
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA
Cancer J Clin. 2012;62:10-29.
2. Schottenfeld D, Beebe-Dimmer JL, Vigneau FD. The
epidemiology and pathogenesis of neoplasia in the small
intestine. Ann Epidemiol. 2009;19:58-69.
3. Cobrin GM, Pittman RH, Lewis BS. Increased diagnostic
yield of small bowel tumors with capsule endoscopy. Cancer.
2006;107:22-27.
4. Chang HK, Yu E, Kim J, et al. Adenocarcinoma of the small
intestine: a multi-institutional study of 197 surgically resected
cases. Hum Pathol. 2010;41:1087-1096.
5. Sutter T, Arber N, Moss SF, et al. Frequent K-ras mutations in
small bowel adenocarcinomas. Dig Dis Sci. 1996;41:115-118.
6. Wheeler JM, Warren BF, Mortensen NJ, et al. An insight into
the genetic pathway of adenocarcinoma of the small intestine.
Gut. 2002;50:218-223.
7. Arber N, Hibshoosh H, Yasui W, et al. Abnormalities in the
expression of cell cycle-related proteins in tumors of the small
bowel. Cancer Epidemiol Biomarkers Prev. 1999;8:1101-1105.
8. Blaker H, von Herbay A, Penzel R, et al. Genetics of
adenocarcinomas of the small intestine: frequent deletions
at chromosome 18q and mutations of the SMAD4 gene.
Oncogene. 2002;21:158-164.
9. Planck M, Ericson K, Piotrowska Z, et al. Microsatellite
instability and expression of MLH1 and MSH2 in carcinomas
of the small intestine. Cancer. 2003;97:1551-1557.
10. Thiery JP. Epithelial-mesenchymal transitions in tumour
progression. Nat Rev Cancer. 2002;2:442-454.
11. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and
cadherin pathways. Science. 2004;303:1483-1487.
12. Breuhahn K, Singh S, Schirmacher P, et al. Large-scale
N-terminal deletions but not point mutations stabilize
beta-catenin in small bowel carcinomas, suggesting
divergent molecular pathways of small and large intestinal
carcinogenesis. J Pathol. 2008;215:300-307.
    • "(Svrcek et al, 2003), 2 out of 21 (23%) (Blaker et al, 2004), 79 out of 194 (40.7%) (Lee et al, 2013) to 10 out of 21 (48%) (Wheeler et al, 2002). One study reported a shorter survival in the case of combined loss of E-cadherin and aberrant b-catenin expression (Lee et al, 2013). The accumulation of b-catenin could occur either in the case of APC gene mutation preventing b-catenin degradation or by gain-of-function mutations (Murata et al, 2000; Blaker et al, 2004). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking. Methods: Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated. Results: We obtained samples from 63 SBA patients (tumour stages: I–II: 30% III: 35% IV: 32% locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9–72.2). For all patients, in univariate analysis, stages I–II (P<0.001), WHO PS 0–1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0–1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0–1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS. Conclusion: This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.
    Full-text · Article · Nov 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Small bowel cancers account for 3% of all gastrointestinal malignancies and small bowel adenocarcinomas represent a third of all small bowel cancers. Rarity of small bowel adenocarcinomas restricts molecular understanding and presents unique diagnostic and therapeutic challenges. Better cross-sectional imaging techniques and development of enteroscopy and capsule endoscopy have facilitated earlier and more-accurate diagnosis. Surgical resection remains the mainstay of therapy for locoregional disease. In the metastatic setting, fluoropyrimidine and oxaliplatin-based chemotherapy has shown clinical benefit in prospective non-randomized trials. Although frequently grouped under the same therapeutic umbrella as large bowel adenocarcinomas, small bowel adenocarcinomas are distinct clinical and molecular entities. Recent progress in molecular characterization has aided our understanding of the pathogenesis of these tumours and holds potential for prospective development of novel targeted therapies. Multi-institutional collaborative efforts directed towards cogent understanding of tumour biology and designing sensible clinical trials are essential for developing improved therapeutic strategies. In this Review, we endeavour to outline an evidence-based approach to present-day management of small bowel adenocarcinoma, describe contemporary challenges and uncover evolving paradigms in the management of these rare 'orphan' neoplasias.
    Article · Jul 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Due to the rarity of small intestine adenocarcinoma (SIAC), estimating the prognosis for patients with surgically resected SIAC is difficult. Overexpression of S100A4 has been linked to worse patient survival in several malignant neoplasms, but its significance in SIAC has not been determined. S100A4 protein expression was assessed in 197 surgically resected SIAC cases and compared with clinicopathological factors, including patient survival. A progressive increase in S100A4 labelling was observed in normal intestinal epithelium, adenoma and adenocarcinoma (p<0.001), and 50 SIAC cases (26.2%) showed strong S100A4 expression. Patients with SIAC with strong S100A4 expression had a higher pT classification (p=0.05), as well as increased lymph node metastasis (p=0.009) and perineural invasion (p=0.002). Patients with SIAC with strong S100A4 expression had significantly worse survival (median survival, 21 months) than those with weak/no S100A4 expression (42.5 months) by univariable (p=0.04) and multivariable (p=0.01) analyses. S100A4 overexpression is observed in a subset of SIACs, is associated with advanced disease and can be used as a prognostic indicator of poor prognosis in patients with SIAC.
    Article · Sep 2013
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