Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis.

Abstract

Progression of colorectal cancer may follow either of two main genetic routes: the chromosome- or microsatellite-instability pathways. Association between the patients' prognosis and microsatellite instability has been questioned. Improved survival has previously been found in patients with expression of HLA-DR antigens on their tumour cells. In this study, the expression of HLA-DR antigen was investigated by immunohistochemistry in 357 large bowel carcinomas stratified by microsatellite instability status. Sixteen per cent of the tumours showed strong HLA-DR expression and 35% had weak DR expression. We confirmed that patients with strong positive HLA-DR staining had improved survival (P<0.001) compared to patients with no HLA-DR expression. Strong epithelial HLA-DR staining was significantly associated with high level of microsatellite instability (P<0.001). In the subgroup of tumours with characteristics typical of the chromosomal instability phenotype, i.e. in microsatellite-stable tumours, the patients positive for the HLA-DR determinants showed better survival than those without HLA-DR expression. The protective effect of HLA-DR expression on survival was confirmed by multivariate analysis, both in the whole patient group and in the microsatellite-stable/microsatellite instability-low group. This might be explained by enhanced T-cell mediated anti-tumour immune responses against tumour cells in the HLA-DR positive tumours. The finding of better patient survival in the subgroup of strong HLA-DR positive microsatellite-stable tumours may have clinical implications for these patients.

Full text

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Strong HLA-DR expression in microsatellite stable carcinomas of
the large bowel is associated with good prognosis
T Løvig*,1, SN Andersen1, L Thorstensen2, CB Diep2, GI Meling1, RA Lothe2and TO Rognum1
1Institute of Forensic Medicine, The National Hospital, University of Oslo, 0027 Oslo, Norway;2Department of Genetics, Institute for Cancer Research, The
Norwegian Radium Hospital, 0310 Oslo, Norway
Progression of colorectal cancer may follow either of two main genetic routes: the chromosome- or microsatellite-instability
pathways. Association between the patients’ prognosis and microsatellite instability has been questioned. Improved survival has
previously been found in patients with expression of HLA-DR antigens on their tumour cells. In this study, the expression of
HLA-DR antigen was investigated by immunohistochemistry in 357 large bowel carcinomas stratified by microsatellite
instability status. Sixteen per cent of the tumours showed strong HLA-DR expression and 35% had weak DR expression. We
confirmed that patients with strong positive HLA-DR staining had improved survival (P50.001) compared to patients with no
HLA-DR expression. Strong epithelial HLA-DR staining was significantly associated with high level of microsatellite instability
(P50.001). In the subgroup of tumours with characteristics typical of the chromosomal instability phenotype, i.e. in
microsatellite-stable tumours, the patients positive for the HLA-DR determinants showed better survival than those without
HLA-DR expression. The protective effect of HLA-DR expression on survival was confirmed by multivariate analysis, both in
the whole patient group and in the microsatellite-stable/microsatellite instability-low group. This might be explained by
enhanced T-cell mediated anti-tumour immune responses against tumour cells in the HLA-DR positive tumours. The finding
of better patient survival in the subgroup of strong HLA-DR positive microsatellite-stable tumours may have clinical
implications for these patients.
British Journal of Cancer (2002) 87, 756–762. doi:10.1038/sj.bjc.6600507
ª 2002 Cancer Research UK
www.bjcancer.com
Keywords: colorectal neoplasms; HLA-DR; immunohistochemistry; microsatellite instability; survival
Primary colorectal tumours may be divided into two main groups
related to the genetic profile of the tumour (Kinzler and Vogel-
stein, 1996). Tumours with chromosome instability (CIN) reveal
high rates of chromosome losses and gains, whereas tumours with
microsatellite instability (MSI) show genome-wide changes in
repetitive sequences due to defects in the DNA mismatch repair
system. Most tumours in hereditary non-polyposis colorectal
cancer (HNPCC), and about 15% of sporadic colorectal carcino-
mas show MSI (Aaltonen et al, 1993; Lothe et al, 1993). MSI
leads to the accumulation of deletion and insertion of nucleotides
at simple repeat sequences. The clinical and pathological features
of colorectal cancers showing high degree of MSI (MSI-H) are
proximal location, poor differentiation, mucinous phenotype, high
density of lymphocyte infiltration, diploid DNA content, reduced
invasiveness, female preponderance and multiplicity (Lothe et al,
1993; Kim et al, 1994; Ruschoff et al, 1995; Messerini et al,
1997; Jass et al, 1998; Thibodeau et al, 1998). High density of
tumour infiltrating lymphocytes (TIL) are found in MSI-H color-
ectal cancers, whereas it is only infrequently observed in MSI-L
and MSS tumours (Jass et al, 1998; Smyrk et al, 2001). Recently,
two studies have identified significantly more cytotoxic lympho-
cytes (CD3, CD8 and TIA-1) and a higher rate of cells
undergoing apoptosis in MSI-H colorectal carcinomas than in
MSI-L and MSS (Dolcetti et al, 1999; Michael-Robinson et al,
2001). Furthermore, patients with MSI-H tumours and a high
content of activated cytotoxic lymphocytes showed improved
overall survival (Guidoboni et al, 2001). Some studies have
reported improved survival among colorectal cancer patients with
microsatellite unstable tumours (Lothe et al, 1993; Thibodeau et
al, 1993; Bubb et al, 1996; Lukish et al, 1998; Halling et al,
1999; Johannsdottir et al, 1999; Massa et al, 1999; Elsaleh et al,
2000; Gryfe et al, 2000; Hemminki et al, 2000; Wright et al,
2000; Ward et al, 2001; Watanabe et al, 2001), while others have
not (Messerini et al, 1997; Senba et al, 1998; Feeley et al, 1999;
Salahshor et al, 1999; Curran et al, 2000).
The major histocompatibility complex (MHC) in humans plays
an important role in various kinds of immune reactions, including
antigen presentation, cytotoxic response, and immune recognition.
The MHC encodes for three classes of cell antigens: class I (HLA-A,
-B, -C), class II (HLA-DR, -DQ, -DP) and class III (Klein and Sato,
2000). HLA-DR antigen expression is usually not present in the
epithelium of the large bowel, but may be turned on in inflamma-
tory disorders, such as ulcerative colitis (Rognum et al, 1987),
Crohn’s disease and in colorectal tumours (Rognum et al, 1983;
Gutierrez et al, 1987; Norheim Andersen et al, 1993; Chang and
Sohn, 1995; Lazaris et al, 1995; Morita et al, 1995; Kunihiro et
al, 1998). HLA-DR antigen expression on tumour cells is a marker
of good prognosis in large bowel carcinomas (Gutierrez et al, 1987;
Norheim Andersen et al, 1993; Lazaris et al, 1995; Morita et al,
1995; Kunihiro et al, 1998).
In a large series of primary colorectal carcinomas, stratified as
MSI-H and MSS/MSI-L, we have analysed the epithelial expression
Molecular and Cellular Pathology
Received 4 February 2002; revised 31 May 2002; accepted 25 June 2002
*Correspondence: T Løvig; E-mail: tone.lovig@labmed.uio.no
British Journal of Cancer (2002) 87, 756–762
ª 2002 Cancer Research UK All rights reserved 0007–0920/02$25.00
www.bjcancer.com

Page 2

of HLA-DR and addressed the association with clinical and patho-
logical variables.
MATERIALS AND METHODS
Patients
The study was based on two series of tumours collected from
hospitals in the Oslo and Akershus region. The first series of
100 large bowel carcinomas from 100 patients were operated
on between 1978 and 1982, and have previously been studied
according to HLA-DR expression (Norheim Andersen et al,
1993). The second consecutive series of tumours from 257
patients with primary colorectal cancer were collected during
the period 1987–1989. The clinicopathological characteristics of
the patients are given in Table 1. The median age at diagnosis
was 67 years for males (range 26–94) and 69 years for females
(range 24–92). Survival was recorded from the date of resection
of the tumour until death or until the censor date (1 July 1995
for the first series of 100 patients and 1 July 1999 for the second
series of 257 patients). Patients that died within 30 days after
operation were censored and cancer-specific deaths have been
recorded from hospital and post-mortem reports. All of the
patients underwent surgery alone as the curative treatment,
except for a few patients with rectal cancers who also received
postoperative radiation therapy. Two patients in the second series
of tumours fulfil the Amsterdam criteria for HNPCC, one case
being MSS and the other MSI-H. For the first series of tumours
information about Amsterdam criteria is not available.
HLA-DR immunohistochemistry
Tissue slices from each of the 257 tumours in the second series
were fixed in cold 96% ethanol and processed for paraffin embed-
ding as previously described (Brandtzaeg, 1974). Sections cut at
6 mm were dewaxed and subjected to immunofluorescence staining
and one section was stained by a routine method (HAS) containing
haematoxylin, azofloxin and saffron. A murine monoclonal anti-
body to a non-polymorphic human HLA-DR antigen was applied
in an indirect three-step immunofluorescence method as described
previously (Norheim Andersen et al, 1993). The method included
affinity purified biotinylated horse anti mouse IgG and fluorecein
isothiocyanate (FITC)-labelled avidin.
The epithelial staining for HLA-DR antigens in the carcinomas
was evaluated by a Leitz Aristoplan fluorescence microscope
(Leica). The tumours were divided into four groups according
to the percentage of positive tumour epithelium, 0–5, 5–20,
20–50 and 450%, respectively. In the further analysis, the
samples with 0–5% positive cells were considered negative,
whereas samples with 5–50% positive cells were classified as
weak HLA-DR positive, and those 450% as strong HLA-DR
positive. Three sections from 97 tumours and two sections from
224 tumours were investigated, while only one section was inves-
tigated in the remaining 36 cases. The same investigator (SNA)
was responsible for the fluorescence scoring throughout both
series of tumours studied. The HLA-DR staining was scored
blindly in view of MSI status of the tumour. Since the scoring
procedure showed good inter- and intra-observer reproducibility
in the first study of 100 carcinomas (Norheim Andersen et al,
Molecular and Cellular Pathology
Table 1
in 357 primary colorectal carcinomas
Epithelial HLA-DR expression in relation to clinicopathological variables and MSI status
HLA-DR expressiona
Total numberNegative (%)Weak (%) Strong (%)P
Age (mean+S.D.) 35767.4+12.268.2+12.667.1+13.80.924c
Sex
Females
Males
173
184
77 (45)
99 (54)
65 (38)
58 (32)
31 (18)
27 (15)0.214b
Tumour site
Right colon
Left colond
Rectum
108
93
156
42 (39)
53 (57)
81 (52)
35 (32)
31 (33)
57 (37)
31 (29)
9 (10)
18 (12)
0.001b
Dukes’ stage
A
B
C
D
6026 (43)
71 (47)
49 (49)
30 (65)
20 (33)
56 (37)
33 (33)
14 (30)
14 (23)
24 (16)
18 (18)
2 (4)
151
100
46 0.141b
Histological grade
Well differentiated
Moderately differentiated
Poorly differentiated
2615 (58)
136 (49)
25 (48)
11 (42)
104 (37)
8 (15)
0 (0)
279
52
39 (14)
19 (37)
50.001b
TIL count
(mean+s.d.)
Median
25416.7+9.6
14.0
18.1+11.1
15.0
32.3+25.6
25.5
50.001c
Ploidy
Diploid
Aneuploid
MSI statuse
MSS/MSI-L
MSI-H
132
225
56 (42)
120 (53)
39 (30)
84 (37)
37 (28)
21 (9)
50.001b
306
40
158 (52)
11 (28)
113 (37)
8 (20)
35 (11)
21 (53)
50.001b
Total357176 (49)123 (35) 58 (16)
aPer cent of cells showing epithelial staining; negative 0–5%, weak 5–50% and strong more than 50%.
bPearson’s w2test.cKruskal–Wallis test.dSigmoideum, descendens and left flexure.eData missing on 11
tumours.
HLA-DR and MSI in large bowel carcinomas
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1993), such tests were not included in the evaluation of the 257
tumours.
Histopathological analysis of the tumours
For all tumours, histopathological type and degree of differentiation
(WHO classification (Jass and Sobin, 1989)), as well as clinicopatho-
logical stage, have been published previously (Meling et al, 1991;
Rognum, 1991). In the second series of tumours, tumour infiltrating
lymphocytes (TIL) were identified by light microscopy on HAS-
stained sections as cells with the morphology of lymphocytes, seen
within the tumour epithelium. TIL’s were counted in 10 high power
fields from each tumour, since a stable mean of number of TIL per
high power field was achieved in the tumours after counting 10
fields. Enumeration of TIL’s was performed by the same experienced
investigator (SNA) throughout the study.
MSI status
The MSI status of the 100 tumours in the first series were
analysed by the two mononucleotide repeats, BAT-25 and BAT-
26, which are robust markers for MSI-H detection (Loukola et
al, 2001; Zhou et al, 1998). Tumours with mutation in both
markers were defined MSI-H (10 cases) and the rest were put
in the MSS/MSI-L group.
MSI status in the second series was available in 246 of the 257
tumours (Lothe et al, 1993; Thorstensen et al, 2001; Diep et al,
2002, unpublished). The tumours have been analysed with BAT-
25 and BAT-26, in addition to a total of 19 dinucleotide repeats.
DNA from each tumour, except from five tumours, was informa-
tive in at least five (median 18, range 5–21) of the loci analysed
(Thorstensen et al, 2001; Diep et al, 2002, unpublished). The 30
tumours with instability in 530% of the microsatellite loci
analysed, or with mutation in both BAT-25 and BAT-26 were
defined as MSI-high (MSI-H). The 32 tumours with instability in
at least one locus and less than 30% of the loci was MSI-low
(MSI-L), whereas the 184 tumours without microsatellite instability
was classified as microsatellite stable (MSS), according to the
consensus criteria for classification of MSI (Boland et al, 1998).
Statistics
Statistical analyses were conducted using the SPSS software v10.0.
Comparisons between categorical variables were performed using
Pearson’s w2analysis. Continuous variables (age and TIL count)
were analysed using the non-parametric Kruskal–Wallis test.
Survival curves were estimated by the Kaplan-Meier method, and
differences were assessed using the log rank test. To estimate the
effect of different factors on survival, a multivariate analysis was
performed using the Cox proportional-hazards method. The
following variables were included in the analysis: age, sex, Dukes’
stage, tumour site, histological grade, DNA ploidi pattern, HLA-
DR staining and MSI status. A probability value of less than 0.05
was considered statistically significant.
RESULTS
HLA-DR expression in relation to MSI status and
clinicopathological variables
Epithelial HLA-DR expression in varying degrees was found in 181
of the 357 (51%) tumours investigated (Figure 1). Fifty-eight
(16%) showed strong HLA-DR expression, whereas 123 (35%)
had weak DR expression. HLA-DR expression in relation to MSI
status and clinicopathological variables is shown in Table 1. Strong
HLA-DR expression occurred in 21 of 40 (53%) of MSI-H
tumours, whereas the same was found in only 35 of 306 (11%)
MSS/MSI-L tumours (P50.001). Furthermore, tumours with DR
expression were related to other variables typical for MSI-H
tumours. That is, tumours with strong HLA-DR expression were
significantly more often poorly differentiated (P50.001), had more
often a diploid DNA pattern (P50.001) and were more frequent
Molecular and Cellular Pathology
Figure 1
HLA-DR determinants.
Moderately differentiated large bowel carcinoma with strong HLA-DR expression. (A) HAS staining and (B) adjacent section stained green for
HLA-DR and MSI in large bowel carcinomas
T Løvig et al
758
British Journal of Cancer (2002) 87(7), 756–762
ª 2002 Cancer Research UK

Page 4

located in the right colon than in the left colon or rectum
(P=0.001) (Table 1). Left-sided and rectal tumours had an equal
distribution of strong DR expression. Strong DR positive tumours
had significantly higher number of TIL than tumours with weak or
no DR-staining (P50.001). There was no association with HLA-
DR expression according to Dukes’ stages (P=0.141).
HLA-DR expression and survival analysis
During the follow-up period of 10–13 years there were 138 cancer
specific deaths in the group of 357 patients included in the study.
Dukes’ stage is significantly associated with patient survival
(P50.001, log rank test for trend). There is a better patient survival
in MSI-H tumours compared to MSS/MSI-L tumours, as shown by
both univariate Kaplan–Meier method (P=0.004, log rank test for
trend) and by multivatiate analysis (HR 0.44, 95% CI: 0.20–0.96,
data not shown). Analysis of survival according to HLA-DR in the
whole group of patients showed significant differences between the
three patterns of tumour HLA-DR expression (P50.001) (Figure
2). Survival was significantly better in patients with tumours show-
ing HLA-DR expression compared to those with no DR expression,
both in the weak- and strong DR expression group (P=0.025 and
P50.001, respectively). Stratified survival analysis according to sex
showed that both males and females with DR-positive tumours
had better survival compared to those without (P50.001, data
not shown). According to tumour site, stratified analysis showed
that patients with HLA-DR positive tumours located in colon had
better survival, whereas for patients with rectal tumours DR expres-
sion had no influence on patient survival (P50.001 and P=0.421,
respectively; data not shown). Stratified survival analysis according
to tumour MSI status, histological grade and ploidi showed that
expression of HLA-DR in tumours was associated with better survi-
val in the subgroups of patients with characteristics typical for the
chromosome instability (CIN) phenotype, i.e. MSS/MSI-L tumours.
Patients with tumours expressing HLA-DR showed significantly
better survival when the tumours were MSS/MSI-L (P=0.001)
(Figure 3). The same was true for patients with tumours that had
aneuploid DNA content (P=0.003) or were moderately differen-
tiated (P=0.002) (Figure 3). The good prognosis in the patients
with strong HLA-DR positive MSS tumours is not due to higher
TIL count in these tumours, as they had a median TIL count of 16.
Survival analysis stratified according to Dukes’ stage showed an
overall significant difference in survival (P=0.003, data not shown).
Multivariate analysis using Cox proportional hazard regression
analysis confirmed that both weak and strong HLA-DR expression
Molecular and Cellular Pathology
Rate of surviving patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Survival time (months)
050100150200250
Strong DR
Weak DR
DR neg.
P=0.0004
Figure 2
tients with different degrees of HLA-DR expression. n=58 with strong
DR expression, n=123 with weak DR expression and n=176 DR negative.
Survival analyses (cancer-related Kaplan–Meier plots) of pa-
Rate of surviving patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00
50100150200 250
Strong DR, n=35
Weak DR, n=113
DR neg., n=158
P=0.0013
MSS/MSI-L
050100150 200250
Survival time (months)
0 50 100150 200250
Aneuploid DNA pattern
Moderately differentiated
Strong DR, n=21
Weak DR, n=84
DR neg., n=120
P=0.0032
Strong DR, n=39
Weak DR, n=104
DR neg., n=136
P=0.0018
Rate of surviving patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Rate of surviving patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
A
B
C
Figure 3
tients in relation to HLA-DR expression and different variables. (A) Pa-
tients with MSS/MSI-L tumours, (B) patients with aneuploid tumours and
(C) patients with moderately differentiated tumours. When considering
strong DR expression compared to no expression, the P-value for MSS/
MSI-L tumours was P=0.0024, P=0.0050 for aneuploid tumours, and
P=0.0006 for moderately differentiated tumours.
Survival analysis (cancer-related Kaplan–Meier plots) of pa-
HLA-DR and MSI in large bowel carcinomas
T Løvig et al
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had an overall protective effect on survival (Table 2). When analys-
ing only the MSS/MSI-L group, the protective effect of DR-
expression is still significant (strong HLA-DR expression: HR
0.38, 95% CI: 0.175–0.812 and weak HLA-DR expression: HR
0.68, 95% CI: 0.458–0.998; data not shown).
DISCUSSION
In the present study we found that strong epithelial HLA-DR
expression was highly associated with the MSI-H phenotype. Thus,
53% of the MSI-H tumours were strong HLA-DR positive, vs 11%
in the MSS/MSI-L group. Because of the strong association between
MSI-H tumours and HLA-DR expression, significant correlation
was also demonstrated between DR expression and tumours with
right-sided location, poor differentiation and diploid DNA pattern,
which are the characteristics typical for colorectal tumours following
the MSI pathway (Lothe et al, 1993; Kim et al, 1994; Ruschoff et al,
1995; Messerini et al, 1997; Jass et al, 1998; Thibodeau et al, 1998).
Strong HLA-DR positive tumours also had a higher TIL count than
the other two groups. The presence of an inflammatory reaction in
the form of TIL is most frequently found in MSI-H carcinomas (Jass
et al, 1998; Smyrk et al, 2001). No association was found between
Dukes’ stage and HLA-DR expression, which is consistent with
previous studies (Lazaris et al, 1995; Kunihiro et al, 1998).
The MSI-H tumour phenotype is caused by defects in the DNA
mismatch repair machinery, and stretches of repetitive sequences
are prone to mutations. When such repeats are present in the
coding region, mutations may cause disturbances in normal cellular
control. Indeed, frameshift mutations in MSI-H tumours have been
reported for several downstream target genes (Ionov et al, 1993;
Thorstensen et al, 2001). The resulting shift in the reading frame
of the genes gives rise to syntheses of truncated proteins that have
lost all or part of their function. These antigenic peptides could
elicit specific anti-tumour immune responses potentially effective
in limiting tumorigenesis. This hypothesis is supported by the fact
that there is a significant increase of the pronounced inflammatory
reaction in the MSI-H tumours. Recently, two studies have identi-
fied the majority of TIL in MSI-H tumours as CD8+ T-cells, the
number being higher than in MSS tumours (Dolcetti et al, 1999;
Michael-Robinson et al, 2001). The number and distribution of
infiltrating CD4+ lymphocytes were similar in MSI and MSS
tumours (Dolcetti et al, 1999). However, our finding of HLA-DR
expression in 53% of the MSI-H tumours, indicate that this might
be an important part of the ongoing immune activation supposed
to be present in MSI-H tumours. The abnormal peptides produced
by MSI-H tumours may be presented to CD4+ T-cells by the HLA-
DR molecules expressed on the cell surface. In fact, one recent
study has identified a patient with an HLA-DR restricted CD4+
T-cell response against a TGFbRII frameshift peptide (Sæterdal et
al, 2001). The tumour had heterogeneous HLA-DR expression with
prominent CD4+ T-cell infiltration in areas positive for HLA-DR
antigen, whereas relatively few cytotoxic CD8+ T-cells were present.
This indicates local cytokine production and may be a direct mani-
festation of immune surveillance.
Patients with HLA-DR positive carcinomas showed significantly
better overall survival than in patients with DR negative carcino-
mas, which is consistent with several other studies (Gutierrez et
al, 1987; Norheim Andersen et al, 1993; Lazaris et al, 1995; Morita
et al, 1995; Kunihiro et al, 1998). Quite surprisingly, stratified
analyses of survival with respect to MSI status, differentiation, ploi-
di and tumour localisation disclosed that in MSS/MSI-L tumours,
in tumours with aneuploid DNA pattern and in moderately differ-
entiated tumours, strong HLA-DR expression turned out to be a
marker for favourable prognosis (Figure 3A,B,C). However, HLA-
DR expression in the poorly differentiated, diploid, MSI-H
tumours had no influence on survival. The overall protective effect
of the HLA-DR expression on survival was confirmed by the multi-
variate analysis. Also, when analysing only patients with MSS/MSI-
L tumours by multivariate analysis, HLA-DR expression had a
positive impact on patient survival.
Tumours with the CIN phenotype (usually MSS) represent the
majority of sporadic colorectal cancers and are characterised by
high rates of chromosome losses and gains. The HLA complex is
located on chromosome 6p21, a region infrequently gained in
colorectal carcinomas (Bardi et al, 1993; de Angelis et al, 1999;
Rooney et al, 1999). The increased level of HLA- DR expression
detected in 11% of the MSS tumours is not likely to be explained
by a gain of chromosome 6p.
Most studies report that there is an association between MSI-H
tumours and improved disease outcome (Lothe et al, 1993; Thibo-
deau et al, 1993; Bubb et al, 1996; Lukish et al, 1998; Halling et al,
1999; Johannsdottir et al, 1999; Massa et al, 1999; Elsaleh et al,
2000; Gryfe et al, 2000; Hemminki et al, 2000; Wright et al,
2000; Ward et al, 2001; Watanabe et al, 2001). Furthermore, several
studies have found that the degree of lymphocyte infiltration corre-
lates with a better patient survival (Jass, 1986; di Giorgio et al,
1992; Ropponen et al, 1997; Naito et al, 1998). A recent study
found that patients with MSI-H tumours with a high content of
activated intra-tumour cytotoxic lymphocytes had better prognosis
(Guidoboni et al, 2001). This finding supports the presence of an
anti-tumour immune response in the MSI-H tumours, which
probably explains the better prognosis in these patients. Patients
with MSI-H tumours in the present study showed better survival
than patients with MSS/MSI-L tumours. However, HLA-DR
expression did not turn out to be of prognostic significance in
the MSI-H tumours, although about half of the MSI-H tumours
showed HLA-DR expression.
In conclusion, HLA-DR expression is most frequently found in
carcinomas with MSI phenotype. However, it is also highly
expressed in a small subgroup among tumours with the CIN
phenotype. These patients have prolonged survival, indicating that
HLA-DR expression may be an important part of the anti-tumour
immune responses in colorectal carcinomas.
ACKNOWLEDGEMENTS
The authors wish to thank Kari Thorsdalen for excellent technical
assistance. T Løvig is a Research Fellow and L Thorstensen is a Post
Doctoral Fellow of the Norwegian Cancer Society (NCS). This
study was also supported by additional grants from the NCS (RA
Lothe, TORognum)anda
Foundation for Health and Rehabilitation (CB Diep).
grantfrom theNorwegian
Molecular and Cellular Pathology
Table 2
confidence interval (95% CI) for death from colorectal cancer in accor-
dance with different factors
Cox proportional hazard model. Hazard ratio (HR) with 95%
VariableHR 95% CIP-value
Age at surgery
Sex, female vs male
Dukes’ stage B vs A
Dukes’ stage C vs A
Dukes’ stage D vs A
Localisation, right colon vs left
Histological grade, poorly
differentiated vs mod./well
Diploid vs aneuploid
Weak DR expression vs none
Strong DR expression vs none
MSI-H vs MSS+MSI-L
1.01
0.99
1.43
2.87
20.88
0.85
1.65
0.99–1.03
0.70–1.45
0.73–2.83
1.47–5.61
10.24–42.57
0.59–1.23
1.04–2.64
ns
ns
ns
50.01
50.01
ns
0.04
1.18
0.67
0.42
0.71
0.77–1.82
0.45–0.98
0.22–0.82
0.46–1.10
ns
0.04
0.01
ns
ns: not significant.
HLA-DR and MSI in large bowel carcinomas
T Løvig et al
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British Journal of Cancer (2002) 87(7), 756–762
ª 2002 Cancer Research UK