Increased tissue factor expression and poor nephroblastoma prognosis.

Abstract

There is potential interaction between malignant cell growth and the coagulation pathway. Recent studies suggest that tissue factor, a primary initiator of the extrinsic coagulation pathway, is expressed in various solid tumors in association with increased angiogenesis. To our knowledge we report for the first time the detection of tissue factor expression by immunohistochemistry in Wilms tumors and its correlation with clinical outcomes.
Tissue factor expression detected by immunohistochemistry was assessed in 41 formalin fixed, paraffin embedded Wilms tumor cases treated at university hospitals. We correlated findings with tumor recurrence and cancer specific survival.
Positive immunohistochemistry detection of tissue factor was observed in 88.3% of the tumors analyzed. Tissue factor on immunohistochemistry was associated with tumor recurrence and survival (p = 0.01 and 0.02, respectively). Increased immunohistochemical detection of tissue factor was the most important risk factor for recurrence and mortality in our population on bivariate and multivariate analysis.
Tissue factor is a promising research subject as a prognostic factor for Wilms tumor. More studies are needed to clarify the mechanisms by which tissue factor affects cancer progression and outcome, and its potential role as a therapeutic target.

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Increased Tissue Factor Expression and Poor
Nephroblastoma Prognosis
Elinês O. Maciel, Gustavo F. Carvalhal,* Vinícius D. da Silva, Eraldo L. Batista, Jr.
and Bernardo Garicochea
From the Departments of Pediatric Surgery (EOM), Urology (GFC), Pathology (VDS, ELB) and Clinical Oncology (BG), Pontifícia Universidade
Católica, Porto Alegre, Brazil
Abbreviations
and Acronyms
NWTS ? National WT Study
SIOP ? Societé Internationale
d’Urologie Pédiatrique
TF ? tissue factor
WT ? Wilms tumor
Submitted for publication December 26, 2008.
Study received approval from the ethical com-
mittee at the 2 university hospitals.
* Correspondence: Pontifícia Universidade
católica do Rio Grande do Sul, Rua Sto. Inácio
500 Apt. 501, Porto Alegre, RS, Brazil, CEP 90570-
150 (telephone: 55 51 99589025; FAX: 55 51
33463939; e-mail: gcarvalhal@terra.com.br).
Purpose: There is potential interaction between malignant cell growth and the
coagulation pathway. Recent studies suggest that tissue factor, a primary initi-
ator of the extrinsic coagulation pathway, is expressed in various solid tumors in
association with increased angiogenesis. To our knowledge we report for the first
time the detection of tissue factor expression by immunohistochemistry in Wilms
tumors and its correlation with clinical outcomes.
Material and Methods: Tissue factor expression detected by immunohistochem-
istry was assessed in 41 formalin fixed, paraffin embedded Wilms tumor cases
treated at university hospitals. We correlated findings with tumor recurrence and
cancer specific survival.
Results: Positive immunohistochemistry detection of tissue factor was observed
in 88.3% of the tumors analyzed. Tissue factor on immunohistochemistry was
associated with tumor recurrence and survival (p ? 0.01 and 0.02, respectively).
Increased immunohistochemical detection of tissue factor was the most impor-
tant risk factor for recurrence and mortality in our population on bivariate and
multivariate analysis.
Conclusions: Tissue factor is a promising research subject as a prognostic factor
for Wilms tumor. More studies are needed to clarify the mechanisms by which
tissue factor affects cancer progression and outcome, and its potential role as a
therapeutic target.
Key Words: kidney, Wilms tumor, thromboplastin, prognosis, mortality
WILMS tumor or nephroblastoma is
the most common renal malignancy
and the second most common ab-
dominal solid tumor in childhood.1,2
Known preoperative and postopera-
tive factors help define the prognosis
in each individual, such as anapla-
sia, and clinical and pathological
stage. Although the NWTS-V Group
stated that overall 4-year survival
exceeds 90% for favorable histology
tumors, a subgroup of patients expe-
riences relapse and responds poorly
to second line therapy.3,4Therefore,
there is a continuous search for
novel potential prognostic markers
of poor outcomes to improve thera-
peutic strategies.5,6
TF, also known as thromboplas-
tin, is a transmembrane glycopro-
tein that was originally recognized
as important for initiating the ex-
trinsic pathway of coagulation.
Weak TF expression on immunohis-
tochemistry was observed in various
tissue lines.7However, it is strongly
detected in the adventitia of blood
vessels and in tissues surrounding
1594
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0022-5347/09/1824-1594/0
THE JOURNAL OF UROLOGY®
Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 182, 1594-1599, October 2009
Printed in U.S.A.
DOI:10.1016/j.juro.2009.06.011

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most internal organs, presumably acting as a nat-
ural hemostatic barrier. When exposed, TF acts as
a specific cofactor for plasma factor VII and sub-
sequently TF activated factor VIIa activates fac-
tors IX and X, resulting in fibrin formation.8–10TF
expression was also identified by immunohisto-
chemistry in cells of various tissues during embryo-
genesis, when coagulation factors are not present
or are incapable of crossing the placental barrier.8
Studies in knockout mice models revealed that TF
deficiency is lethal to embryos due to defective
development of the blood vessel subendothelial
layer.7,8,11More recently TF was related to metas-
tasis, possibly due to interference with cell signal-
ing pathways and the proteolytic activity of TF/
factor VII activated complex.12TF also correlates
with a worse prognosis of various tumors.
To our knowledge TF expression detected by
immunohistochemistry has not previously been
studied in WT. We evaluated TF expression de-
tected by immunohistochemistry in 41 patients
with WT treated at tertiary hospitals in Porto
Alegre, Brazil. We correlated findings with vari-
ables such as patient age, stage, histology, tumor
recurrence and cancer specific survival.
MATERIALS AND METHODS
We evaluated the records of 45 patients with WT treated
from 1993 to 2003 at 2 university affiliated institutions in
southern Brazil, including Hospital São Lucas and Hospi-
tal da Criança Conceição. All patients underwent surgery
despite the use of neoadjuvant or adjuvant treatment and
were followed until death or the latest evaluation up to
June 2007. Three patients were excluded from analysis
because paraffin blocks were unavailable and 1 missed
followup evaluations after surgery. Thus, our final study
group consisted of 41 patients. Variables were patient age
at diagnosis, histology, tumor stage and TF expression on
immunohistochemistry. Tumor recurrence and overall
survival were chosen as outcome measures.
Histological criteria defined by NWTS-V were consid-
ered in analysis, including favorable or unfavorable his-
tology depending on the presence of focal or diffuse
anaplasia. The same pathologist (VDS) reviewed all
conventional pathology slides. The staging system pro-
posed by SIOP-9 was used since 34 patients (82.9%)
were operated on after neoadjuvant chemotherapy with
different schemes, consisting mostly of combinations of
vincristine, dactinomycin and doxorubicin. Occasionally
other chemotherapeutic agents were used. The surgical
approach was determined by the attending surgeon.
Profiles of patients who did and did not receive neoad-
juvant chemotherapy were similar in preoperative age,
gender, stage and histology.
Immunohistochemistry
Immunohistochemical analysis was performed in formalin
fixed, paraffin embedded tumor tissue. Sections (5 ?) were
mounted on coated slides and deparaffinized by routine tech-
niques. TF expression was analyzed in blinded fashion using
an Axioskop 40 optical microscope (Carl Zeiss, Jena, Ger-
many) at 100? magnification and Image Pro Plus image
analysis software (MediaCybernetics®). Two observers in-
dependently assessed each slide and classified TF ex-
pression into 4 grades, including grade I—0% to 25%,
grade II—26% to 50%, grade III—51% to 75% and grade
IV—greater than 76% of cancer cells with intense stain-
ing for TF. Immunohistochemical TF expression was
evaluated in the overall tumor and in the different
histological components of tumors (blastematous, epi-
thelial and stromal). Figures 1 and 2, A show examples
of low (grade I) and high (grade IV) TF expression,
respectively, as detected by immunohistochemistry in
WTs.
Prostatic carcinoma samples served as positive and as
negative controls since a previous study showed that TF
expression on immunohistochemistry was almost univer-
sally observed in focal areas of prostatic carcinoma.13Nega-
tive controls were obtained by suppressing the specific anti-
body from the reaction.
Statistical Analysis and Ethics
We used the median and range for continuous variables,
and frequency and percent for categorical variables. We
?
?
Figure 1. WT staining for TF. A, low intensity staining (grade I). B, high intensity staining (grade IV) in blastematous and epithelial
components. Reduced from ?100.
TISSUE FACTOR EXPRESSION AND NEPHROBLASTOMA PROGNOSIS
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used the nonparametric Wilcoxon/Mann-Whitney test to
compare continuous variables and the chi-square or
Fisher exact test to compare categorical variables. For
survival analysis Kaplan-Meier curves were compared
using the log rank test. To evaluate the effect of poten-
tial confounders on survival curves we used Cox propor-
tional hazards model. Significance was considered at
? ? 5% (p ?0.05). Data were analyzed using SPSS®,
version 11.5. The study protocol was approved by the
ethical committee at the 2 university hospitals.
RESULTS
Table 1 lists clinical and pathological variables in
our 41 patients. Of the patients 23 (56.1%) were
female. The tumor affected the left kidney in 22
cases (53.7%). Histology was favorable in 38 cases
(92.7%) and cases were distributed across all
SIOP-9 stages.
Median followup was 4.4 years (range 0 to 12).
In 18 patients (43.9%) recurrence developed dur-
ing followup. The lungs were the most common
sites of recurrence, followed by local recurrence at
the primary tumor site. Nine recurrences (50.0%)
developed at multiple sites with liver metastasis
occurring exclusively in this scenario. A total of 14
patients (34.1%) died of the disease, including 1
(7.1%) of postoperative complications, while 13
were related to tumor progression. The 2-year sur-
vival rate after surgery was 78%, and the 5 and
10-year survival rates were 66%. Figure 2, A
shows the overall survival curve in our patients.
Survival was not affected by patient age at di-
agnosis (p ? 0.68). There was a strong correlation
between histology by the NTWS classification and
patient mortality. All patients with unfavorable
NWTS histology had tumor recurrence and died
but only 28.9% with favorable NWTS histology
died (p ? 0.03). SIOP-9 tumor stage was an im-
portant predictor of survival. The higher the
stage, the greater the probability of death with 9
deaths occurring in stages III and IV cases, 5 in
stage II cases and none in stage I cases (p ? 0.02).
Figure 2, B shows survival curves by tumor stage.
Considering the risk categories proposed by
SIOP-9, 11 and 30 patients were classified as be-
ing at high and intermediate/low risk, respec-
tively. Recurrence and survival rates were not sta-
tistically associated with risk categories (p ? 0.49 and
0.2, respectively).
TF immunohistochemistry staining was ob-
served mainly in the cytoplasm of blastematous
component cells, and in the cell membrane and
cytoplasm of epithelial component cells. Stromal
component cells did not stain significantly for TF.
Only 6 patients showed weak TF expression in the
stroma on immunohistochemistry. There was a
positive correlation between total TF staining and
TF staining at the blastematous component (Pear-
son’s test p ?0.001). Overall 38 of 41 cases (88.3%)
expressed TF at various levels on immunohisto-
Figure 2. Overall survival curve. A, overall. B, by SIOP-9 stage. C, by low and high TF expression
Table 1. Clinical and pathological characteristics in 41 patients
Median yrs age (range)
Ratio females/males
No. laterality (%):
Lt kidney
Rt kidney
Bilat
No. NWTS histology (%):
Favorable
Unfavorable
No. SIOP-9 stage (%):
I
II
III
IV
V
No. tumor recurrence (%):
Overall
Pulmonary
Local
Multiple
2.6 (0.33–7.25)
1.3:1
22
17
(53.7)
(41.5)
(4.9)2
38(92.7)
(7.3)3
8 (19.5)
(36.6)
(29.3)
(9.7)
(4.9)
15
12
4
2
18(43.9)
(33.3)
(16.7)
(50.0)
6
3
9
TISSUE FACTOR EXPRESSION AND NEPHROBLASTOMA PROGNOSIS
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chemistry. Of the 41 cases TF expression was
graded by immunohistochemistry staining inten-
sity as grades I to IV in 8 (19.5%), 13 (31.7%), 17
(41.5%) and 3 (7.3%), respectively.
There was no statistical correlation between
median total TF expression grade on immunohis-
tochemistry and patient age (p ? 0.64), favorable/
unfavorable histology (p ? 0.21) or SIOP stage
(p ? 0.13). There was a positive association be-
tween median total TF expression grade on immu-
nohistochemistry and tumor recurrence (p ? 0.01,
table 2). Increased intensity of total TF expression
and of blastematous TF expression were also pos-
itively associated with death (p ? 0.02 and ?0.01,
respectively, table 2).
For survival analysis we divided patients into 2
main groups according to TF expression on immuno-
histochemistry, including low intensity—grades I plus
II and high intensity—grades III plus IV. On immu-
nohistochemistry low and high TF expression inten-
sity was noted in 21 (51.2%) and 20 patients (48.8%),
respectively. Increased TF expression on immunohis-
tochemistry was statistically associated with de-
creased survival (fig. 2, C).
Since in our sample the TF expression score on
immunohistochemistry was a significant predictor
of mortality, we performed multivariable regres-
sion analyses adjusted for some of the main known
prognostic factors of WT, such as patient age at
diagnosis, stage and SIOP-9 risk categories. In the
multivariate models increased TF expression on
immunohistochemistry remained the most impor-
tant independent prognostic factor for recurrence
and increased mortality in our sample (table 3).
DISCUSSION
Although WT is generally curable, the survival
rate in our series was 78% at 2 years and 66% at
final evaluation. In Brazil the national WT study
group, Grupo Cooperativo Brasileiro para o Trata-
mento do Tumor de Wilms, described results sim-
ilar to ours, that is a 2 and 4-year survival rate of
80% and 73%, respectively.14In the international
literature survival rates are directly related to
prognostic factors, especially histology and stage.
The SIOP-9 study showed a 71% 2-year disease-
free rate for stages II and III with anaplasia, and
for stages II and III with favorable histology but
positive lymph nodes as well as 71% and 85%
5-year overall survival with and without anapla-
sia, respectively.15NWTS-3 showed a 4-year sur-
vival rate of 92.2% for stage II, 86.9% for stage III,
and 73% for stage IV and favorable histology.16A
Japanese cooperative study showed a 2-year survival
rate of 95.5% for stages I and II, and a 66.7% rate for
stages III and IV.17Our relatively high mortality rate
was probably related to the significant proportion of
stage III and IV cases (39%). Survival results in our
series were similar to those in the literature for early
stages but our mortality rate was higher than in coop-
erative studies of SIOP, NWTS and the United King-
dom Children’s Cancer Study Group for more ad-
vanced stages. The reasons are uncertain but it could
be tentatively explained by a greater proportion of
Table 2. Tumor recurrence and death by patient age and TF grade
Variable
Yes No
p Value
Mann-Whitney U TestNo. Pts Median Grade (range)No. PtsMedian Grade (range)
Recurrence:
Age (yrs)
Total TF
Blastematous TF
Epithelial TF
Stromal TF
Death:
Age (yrs)
Total TF
Blastematous TF
Epithelial TF
Stromal TF
18
18
16
14
17
2.7 (1.3–7.3)
III (I–IV)
III (I–III)
III (I–IV)
I (I–IV)
23
23
20
17
23
2.6 (0.3–7.0)
II (I–IV)
II (I–IV)
II (I–IV)
I (I–II)
0.58
0.01
0.06
0.97
0.23
14
14
13
10
13
2.6 (1.3–6.9)
III (I–IV)
III (II–III)
II (I–IV)
I (I–IV)
27
27
23
21
27
2.8 (0.3–7.3)
II (I–IV)
II (I–IV)
II (I–IV)
I (I–II)
0.92
0.02
?0.01
0.11
0.20
Table 3. Recurrence and death risk factors
Bivariate Analysis Cox Regression Model
Risk FactorRR (95% CI)p ValueHR (95% CI)p Value
Recurrence:
TF III ? IV
Stages III ? IV (SIOP-9)
Age greater than 2.6 yrs
SIOP risk category I
Death:
TF III ? IV
Stages III ? IV (SIOP-9)
Age greater than 2.6 yrs
SIOP risk category I
3.8 (1.3–10.7)
4.1 (1.5–11.0)
0.9 (0.4–2.4)
1.8 (0.7–4.8)
0.01
0.005
0.90
0.22
3.9 (1.3–11.8)
2.9 (0.9–9.0)
0.8 (0.2–2.3)
3.0 (0.3–27.9)
0.02
0.07
0.64
0.34
5.1 (1.4–18.3)
3.7 (1.2–11.1)
0.8 (0.3–2.3)
2.0 (0.7–6.9)
0.01
0.02
0.69
0.21
5.6 (1.4–21.6)
2.9 (1.0–9.0)
0.8 (0.3–2.2)
2.5 (0.8–8.3)
0.01
0.06
0.60
0.12
TISSUE FACTOR EXPRESSION AND NEPHROBLASTOMA PROGNOSIS
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malnutrition and delayed diagnosis in our patients
since the chemotherapy and radiotherapy that we
used were strictly in accordance with SIOP-9 protocol
recommendations.
Some groups reported that older age at diagnosis
correlated with a worse WT prognosis.1Although in
our patients age at diagnosis was similar to that in
published studies, we did not find any correlation
between age and stage, histology, recurrence or
death.
In our series there was a slight preponderance
of the female gender (56.1% of patients). This is in
agreement with the North American literature, in
which females are slightly more common than
males (1.0:0.92 in NWTS). Regarding tumor loca-
tion, our findings were also similar to those in the
published literature with the left kidney affected
slightly more often.17
Traditionally histology is a major prognostic
factor for WT and the NWTS classification is the
most widely used. As in NWTS,18most of our
patients had favorable histology. Likewise, unfa-
vorable histology was an important determinant
of poor outcome in our series. However, on multi-
variate analysis histology was incorporated into
the SIOP-9 risk categories and was not an inde-
pendent predictor of mortality in our study.
We used the SIOP-9 system for tumor staging
because most patients received neoadjuvant che-
motherapy. Tumor stage remained an important
prognostic factor for recurrence and survival in
our series. Of the 18 cases of recurrence 12 were
stages III and IV, and only 6 were stages I and II.
The higher the stage at diagnosis, the greater the
probability of death with 9 deaths in stages III and
IV, 5 in stage II and none in stage I cases. Our
survival curves show greater than 80% 10-year
survival for stages I and II with less than 50%
10-year survival for stages III and IV, confirming
the assumption that stage at diagnosis is a key
prognostic factor for WT. However, tumor stage
was not an independent predictor of mortality on
multivariate analysis. This might be explained by
the important relative weight of other prognostic
factors, eg TF, to predict survival. SIOP-9 risk
categories (low, intermediate or high) were not
determinants of recurrence or death. Our small
sample size could be a reason.
To our knowledge our study shows for the first
time the immunohistochemical expression of TF in
WT. On immunohistochemistry TF was expressed
more frequently in tumor blastematous and epi-
thelial components, and sparsely in the stromal
component. Despite the relatively small number of
patients increased TF expression on immunohis-
tochemistry showed a significant association with
recurrence and death. Increased immunohisto-
chemistry detection of TF expression was the most
important prognostic factor for recurrence and
death, and the only independent predictor of death
in our series on multivariate analysis.
Increased TF expression on immunohistochemistry
was an adverse prognostic factor in other studies. Ab-
dulkadir et al noted increased TF expression on im-
munohistochemistry in 73% of 67 patients with pros-
tate carcinoma and found that TF expression on
immunohistochemistry correlated positively with pre-
operative serum prostate specific antigen.13Callander
et al reported that at least 60% of epithelial malignant
neoplasms expressed TF on immunohistochemistry.19
The percent of gastrointestinal carcinomas expressing
TF on immunohistochemistry was particularly high,
up to 100% in gastric and pancreatic carcinomas. More
recently researchers defining a possible role for TF as
a tumor marker noted that it can be measured in blood
and urine. Lwaleed et al studied urinary TF in pa-
tients with bladder and prostate cancer.20In that se-
ries increased urinary TF was related to poorly differ-
entiatedtumorsanddeath.Furtherstudiesinthefield
may prove the usefulness of TF as a diagnostic and
followup tool. Therapies against TF, eg TF protein
inhibitor, may be tested in laboratory and clinical set-
tings, which could allow advances in the management
of many tumors.
Despite the interesting positive correlation between
increased TF expression on immunohistochemistry
and prognosis in our study we acknowledge some ca-
veats that may limit the generalization of our findings.
1) We performed a retrospective study in a relatively
small sample, which should be put into perspective.
2) Our patients were treated at 2 university hospitals
by different groups of pediatric surgeons. Al-
though all surgeons who treated these children
were experienced with pediatric oncology, we can-
not truly ascertain the importance of this fact.
3) Most patients received chemotherapy preoper-
atively and at this time it is impossible to evaluate
the effects of this treatment on TF expression, as
detected by immunohistochemistry. 4) We cannot
overemphasize the limitations of immunohisto-
chemistry. TF staining intensity was measured
according to a semiquantitative score based on
quartiles with the problems of subjectivity inher-
ent to this methodology. We also must consider
that many slides were obtained from paraffin em-
bedded samples in stock more than 10 years at the
pathology laboratory. A prospective study would the-
oretically be more useful since it could minimize techni-
cal biases.
CONCLUSIONS
TFexpressiononimmunohistochemistrywasthemost
important independent prognostic factor for survival
TISSUE FACTOR EXPRESSION AND NEPHROBLASTOMA PROGNOSIS
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in a cohort of patients with WT. However, the limita-
tions of our study do not allow us to do more than
generate hypotheses. Further studies are needed to
determine the real usefulness of these findings and
identify possible roles of TF as a clinical marker and a
therapeutic target.
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