Histopathology 2004, 44, 109–115

WT-1 assists in distinguishing ovarian from uterine serous

carcinoma and in distinguishing between serous and
endometrioid ovarian carcinoma
M Al-Hussaini, A Stockman,1 H Foster1 & W G McCluggage
Department of Pathology, Royal Group of Hospitals Trust and 1Department of Pathology, Belfast City Hospital Trust,
Belfast, UK

Date of submission 23 January 2003

Accepted for publication 20 May 2003

Al-Hussaini M, Stockman A, Foster H & McCluggage W G

(2004) Histopathology 44, 109–115
WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing
between serous and endometrioid ovarian carcinoma

Aims: It has been suggested that WT-1 is helpful in
distinguishing a primary ovarian serous carcinoma
(OSC) from a primary uterine serous carcinoma (USC).
Since both neoplasms are often disseminated at diag-
nosis and since USC often spreads to the ovary and vice
versa, it may be difficult to ascertain the primary site.
This is important, since adjuvant therapies for OSC and
USC may differ. WT-1 staining patterns also differ
between OSC and ovarian endometrioid carcinoma and
so it is possible that WT-1 may assist in the distinction
of these two neoplasms, which is sometimes problem-
atic, especially with poorly differentiated tumours. This
study aims to document the value of WT-1 in these
settings. Cases of ovarian borderline serous tumour,
primary peritoneal serous carcinoma (PPSC) and uter-
ine endometrioid carcinoma were also studied.
Methods and results: Cases of OSC (n ¼ 38), USC (n ¼ 25)
(in five of these cases there was also a component of
endometrioid adenocarcinoma), ovarian endometrioid
carcinoma (n ¼ 13), uterine endometrioid carcinoma
Keywords: ovary, serous carcinoma, uterine serous carcinoma, endometrioid carcinoma, serous borderline tumour,
primary peritoneal serous carcinoma, WT-1, immunohistochemistry
Abbreviations: OSC, ovarian serous carcinoma; PPSC, primary peritoneal serous carcinoma;
USC, uterine serous carcinoma
(n ¼ 7), ovarian borderline serous tumour (n ¼ 16) and
PPSC (n ¼ 6) were stained with WT-1. Cases were scored
on a scale of 0–3, depending on the percentage of posit-
ive cells. The intensity of staining was scored as weak,
moderate or strong. There was positive nuclear staining
of 36 of 38 (94.7%) OSC with WT-1. In most OSC
(68.4%), >50% of cells stained positively and staining
was usually strong. Five of 25 (20%) USC were positive
with only two cases exhibiting staining of >50% of cells.
All primary ovarian and uterine endometrioid carcino-
mas were negative. All PPSC were positive, usually with
diffuse strong immunoreactivity. Fourteen of 16 border-
line serous tumours exhibited positivity with WT-1.
Conclusions: WT-1 is useful in distinguishing OSC
(characteristically diffuse strong nuclear positivity)
from USC (characteristically negative). However, rarely
OSC is negative and occasional cases of USC are
positive. WT-1 may also be helpful in differentiating
poorly differentiated OSC from poorly differentiated
ovarian endometrioid carcinoma.

endometrial carcinoma.1 It is a highly aggressive,

Introduction
generally non-oestrogen-dependent neoplasm, usually
Uterine serous carcinoma (USC), also known as papil- arising in elderly women from an atrophic endo-
lary serous carcinoma, is the prototype of type II metrium. It is often high stage at diagnosis, commonly

Address for correspondence: Dr W G McCluggage, Department of Pathology, Royal Group of Hospitals Trust, Grosvenor Road, Belfast BT12 6BL,
Northern Ireland. e-mail: glenn.mccluggage@bll.n-i.nhs.uk

2004 Blackwell Publishing Limited.

110 M Al-Hussaini et al.

with extrauterine spread and subsequently the overall
prognosis is poor.1 Histologically, USC is identical to
ovarian serous carcinoma (OSC) and primary peritoneal
serous carcinoma (PPSC), and in cases of USC with
tumour deposits in the ovary or peritoneum it may be
impossible to ascertain whether the ovarian and ⁄ or
peritoneal disease represents metastatic spread from the
primary uterine neoplasm or whether these represent
independent primary tumours. It is a not uncommon
scenario for widespread extrauterine disease to be
present with a small primary USC, which may even be
confined to an endometrial polyp without myometrial
infiltration.2–4 Additionally, OSC may result in wide-
spread uterine involvement, potentially mimicking a
primary uterine neoplasm. Although in such cases the
neoplasm is usually preferentially located in the outer
aspect of the uterus, tumour may also involve the
endometrium, rarely even in the absence of myometrial
disease, resulting in diagnostic difficulties regarding the
site of tumour origin. The distinction between a primary
uterine and ovarian neoplasm is of significance since
adjuvant therapies may differ depending on the primary
site and on whether two independent neoplasms are
present. For example, although the chemotherapy
regime for a USC and an OSC might be identical, in
some institutions radiotherapy is also given for a uterine
primary.
A recent study has suggested that the Wilms’
tumour-1 (WT-1) antibody may be of value in distin-
guishing between a primary USC and OSC, since the
latter usually exhibits nuclear reactivity while the
former is generally negative.5 This study aimed to
investigate WT-1 immunoreactivity in a series of
primary USC and OSC to ascertain whether this antibody
does exhibit differing staining patterns between these
two neoplasms. We also studied cases where tumour was
present in both the uterus and ovary. PPSC was also
studied to ascertain whether the WT-1 staining pattern
of this neoplasm is similar to that of OSC. Endometrioid
carcinomas of the ovary were included since a previous
study has shown them to be largely negative for WT-1.6
Therefore, we hoped that this antibody would be of value
in distinguishing an OSC from an ovarian endometrioid
carcinoma. Uterine endometrioid carcinomas and ovar-
ian borderline serous neoplasms were also investigated
as part of the study.
Materials and methods
cases
Cases were retrieved from the files of the Departments of
Pathology, Royal Group of Hospitals Trust, Belfast and
the Belfast City Hospital Trust. Cases included in the
study are shown in Table 1. In two cases of primary USC
there was involvement of an ovary (n ¼ 1) or the
omentum (n ¼ 1). In five cases of primary OSC and one
PPSC there was involvement of the uterus. Five of the
USC cases also had a definite component of endometrioid
adenocarcinoma, as opposed to glandular areas within
USC. The cases were reviewed by pathologists involved
in the study and the diagnoses confirmed.

Table 1. Cases included in

WT-1 immunohistochemical score and percentage
study together with results
0 1+ 2+ 3+ of immunohistochemistry

Ovarian serous carcinoma 2 (5.3%) 4 (10.5%) 6 (15.8%) 26 (68.4%)

(n ¼ 38) 4w 3 w, 3 m 1 w, 5 m, 20 s

Ovarian endometrioid 13 (100%) 0 (0%) 0 (0%) 0 (0%)

adenocarcinoma (n ¼ 13)

Uterine serous carcinoma* 20 (80%) 3 (12%) 0 (0%) 2 (8%)

(n ¼ 25) 2 w, 1 m 1 m, 1 s

Uterine endometrioid 7 (100%) 0 (0%) 0 (0%) 0 (0%)

adenocarcinoma (n ¼ 7)

Ovarian serous borderline 2 (12.5%) 6 (37.5%) 2 (12.5%) 6 (37.5%)

tumour (n ¼ 16) 6w 1 w, 1 m 2 m, 4 s

Primary peritoneal serous 0 (0%) 1 (16.7%) 0 (0%) 5 (83.3%)

carcinoma (n ¼ 6) 1w 5s

w, Weak; m, moderate; s, strong.

*In five of these cases there was also a component of endometrioid adenocarcinoma.

2004 Blackwell Publishing Ltd, Histopathology, 44, 109–115.


All cases had been routinely fixed in formalin and
processed in paraffin wax. One or two blocks from each
case were selected for immunohistochemistry.
immunohistochemistry
Sections of 4 lm thickness were cut from paraffin wax-
embedded blocks. These were floated onto sialinized
glass slides and dried out at 37C overnight, before
deparaffinization in xylene and rehydration through
graded ethanols. All sections were subjected to micro-
wave heating at 850 W for 22 min in pH 6.0 citrate
buffer and cooled rapidly in running water. WT-1
monoclonal antibody (Dako, Ely, UK), was added and
immunohistochemistry was carried out using a per-
oxidase envision method (Dako). Diaminobenzidine
(Dako) was used as the chromogen and sections were
counterstained in Harris’ haematoxylin.
Positive controls were performed with each batch of
immunostaining. The positive control comprised a
primary OSC with known diffuse immunoreactivity
for WT-1. Negative controls, using mouse IgG at a
comparable concentration in place of the primary
antibody, were included.
im m u n o h i s t o c h em i c a l an a l ys i s
Cases were considered positive when they exhibited
nuclear staining of tumour cells. Cytoplasmic staining
was not assessed as previous studies have revealed
nuclear staining in OSC.5,6 Cases were scored as 0
(totally negative or only occasional scattered positive
cells), 1+ (<10% cells positive), 2+ (10–50% of cells
positive) or 3+ (>50% of cells positive). The intensity of
WT-1 staining was also subjectively evaluated with
cases classified as showing weak, moderate or strong
nuclear staining. The most strongly staining areas
were selected to evaluate the staining intensity. The
immunohistochemical scoring was evaluated by two
participants (M.A. and W.G.M.) looking at the cases
together at a double-headed microscope.
Results
The immunohistochemistry results are shown in
Table 1. In almost all cases, positivity was nuclear,
although in occasional cases weak cytoplasmic stain-
ing was present (as mentioned previously, this was not
assessed as positive). Of the 25 cases of USC, 20 (80%)
were completely negative with WT-1, including the five
cases with an endometrioid component. Two cases
showed weak positivity in <10% of nuclei, one case
exhibited moderate positivity in <10% of nuclei, while

2004 Blackwell Publishing Ltd, Histopathology, 44, 109–115.
WT-1 assists in distinguishing OSC from USC 111
Figure 1. Case of uterine serous carcinoma where tumour cells
are negative with WT-1 but where there is positive nuclear staining
of endometrial stromal cells.
two cases showed moderate positivity in >50% of
nuclei. However, on further analysis of these two cases,
one had a large tumour mass in a fallopian tube and so
it was not possible to exclude totally a tubal primary.
The other case (which was diagnosed on endometrial
curettings) did not have definitive surgery since
imaging revealed widespread disease. It is theoretically
possible that this did not represent a primary uterine
neoplasm. In some of the cases of USC, there was
positive nuclear staining of the residual non-neoplastic
endometrial stromal cells with WT-1 (Figure 1). In two
cases of USC, ovarian and omental metastatic deposits
were stained with WT-1. Both were negative, similar to
the primary neoplasm.
Thirty-six of 38 (94.7%) cases of OSC were positive
with WT-1, with only two being completely negative.
There were no discernible morphological differences
between the positive and negative cases. Thirty-two
cases showed positivity in 10% or more of the tumour
cell nuclei, with 26 cases exhibiting staining in >50%
of cells (Figure 2). In many of these cases, almost 100%
of cells stained positively. In five cases of OSC there was
extensive involvement of the uterus by tumour and in
these cases, all of which were positive with WT-1 in
>50% of cells, the uterine tumour was also diffusely
positive (Figure 3). In one case of OSC, a small
superficial focus of what was considered to be coexist-
ing USC was present in the endometrium. This showed
strong positivity with WT-1, comparable to that of the
primary ovarian carcinoma (Figure 4). The signifi-
cance of this is discussed later, but it is probable that
this represented a true metastasis and not a small
independent USC.
All primary ovarian endometrioid carcinomas were
negative with WT-1, as were all primary uterine
112 M Al-Hussaini et al.
Figure 2. Diffuse strong positive nuclear staining with WT-1 in
ovarian serous carcinoma.
Figure 3. Ovarian serous carcinoma involving myometrium where
tumour cells are strongly positive with WT-1.
Figure 4. Metastatic ovarian serous carcinoma involving
endometrium exhibiting strong positivity with WT-1. Initially this
was thought to represent a coexistent uterine serous carcinoma.
endometrioid carcinomas. Sixteen cases of primary
ovarian borderline serous tumour were included in the
study, with two cases exhibiting a prominent micro-
Figure 5. Strong WT-1 immunoreactivity in ovarian borderline
serous tumour with a prominent micropapillary growth pattern.
Figure 6. Primary peritoneal serous carcinoma exhibiting diffuse
strong nuclear positivity with WT-1.
papillary growth pattern. Fourteen of 16 cases
were positive with WT-1. Interestingly, of the six
cases which exhibited 3+ positivity, two were
neoplasms with a prominent micropapillary growth
pattern (Figure 5). All PPSC were positive with WT-1
(Figure 6), all but one case exhibiting diffuse
3+ positivity. The uterine metastasis in one PPSC also
exhibited 3+ postivity.
All positive control cases exhibited diffuse strong
immunoreactivity and there was no staining of negative
controls. There was positive nuclear staining of myo-
metrial smooth muscle in many cases. There was also
positive cytoplasmic staining of endothelial cells. There
was no staining of non-neoplastic endometrial glands.
Discussion
The WT-1 gene is a tumour suppressor gene located on
the short arm of chromosome 11 at p13. It was first
reported as a candidate for the main gene implicated in

2004 Blackwell Publishing Ltd, Histopathology, 44, 109–115.

Wilms’ tumour development.7 In normal human tissues,
expression of WT-1 protein is thought to be restricted to
the kidney, ovary, testis, spleen and mesothelium.8,9
However, in this study we also found nuclear positivity of
endometrial stromal cells and of myometrial smooth
muscle and cytoplasmic positivity of endothelial cells,
suggesting that expression of WT-1 may be more
widespread than hitherto reported. Positive staining of
endothelial cells has been noted previously.5 WT-1
expression has also been documented in a number of
human malignancies, including malignant mesotheli-
oma,10,11 intra-abdominal desmoplastic small round cell
tumour,12,13 and breast cancer.14
In ovarian neoplasms, it has previously been shown
that WT-1 expression is characteristic of the serous
phenotype with much lesser degrees of staining of other
morphological subtypes of ovarian carcinoma.6 Some
investigators have evaluated the use of WT-1, in
both histological and cytological material, as a marker
of ovarian carcinoma to distinguish it from adeno-
carcinoma arising at other sites.15,16 In the current
study, 94.7% of OSC were positive with WT-1 and most
exhibited moderate to strong positivity in >50% of the
tumour cells. PPSC unsurprisingly showed a similar
pattern of WT-1 immunoreactivity, although the number
of these neoplasms was small. Expression of WT-1 in
PPSC has been noted previously.17
Only one previous study has compared WT-1
immunoreactivity of OSC and USC.5 In that study,
97% of OSC were positive while all USC were negative.
Our results are in broad agreement, although in our
study small numbers of USC were positive with WT-1,
illustrating that this antibody is not totally specific in
distinguishing between serous carcinomas of ovarian
and uterine origin. However, when combined carefully
with the clinical features, including the pattern of
spread of the neoplasm, and with close morphological
examination, staining with WT-1 may be useful.
Interestingly, of the two presumed USC which exhibited
3+ positivity with WT-1, one had tumour within a
fallopian tube, raising the possibility of a primary tubal
neoplasm. The other was diagnosed on endometrial
curettings and had widespread disease on imaging.
Definitive surgery was not performed and therefore the
possibility that this did not represent a primary uterine
neoplasm cannot be excluded.
It is a not uncommon scenario to be faced with a
serous carcinoma involving the ovaries and the
endometrium simultaneously. This is because USC
and its precursor lesion, endometrial intraepithelial
carcinoma (EIC),18,19 may disseminate widely to
involve the ovaries, omentum and peritoneum even
in the presence of a small superficial uterine

2004 Blackwell Publishing Ltd, Histopathology, 44, 109–115.
WT-1 assists in distinguishing OSC from USC 113
neoplasm.20,21 Conversely, OSC may exhibit wide-
spread uterine involvement. Although in such cases
tumour usually preferentially involves the outer aspect
of the uterus, often with extensive myometrial vascular
involvement, in some cases there may be involvement
of the endometrium, even in the absence of myometrial
tumour. Such cases may raise the possibility of
independent primaries within the ovary and endo-
metrium, the so-called ‘field change’ effect. Indeed, it is
possible that some of these cases do represent inde-
pendent primaries. In one case in the present study, an
OSC was associated with a small focus of serous
carcinoma involving the endometrium which was
initially interpreted as an independent stage IA USC.
However, both the ovarian and endometrial neoplasms
exhibited diffuse strong positivity with WT-1, suggest-
ing that the endometrial tumour was a secondary from
the ovary, although one cannot exclude a small WT-
1+ uterine primary. When faced with this situation,
the presence of moderate to strong nuclear staining
with WT-1, especially if widespread, favours an ovarian
origin of serous carcinoma although, as already stated,
occasional USC are positive. This has important thera-
peutic implications, especially in influencing the need
for adjuvant chemotherapy or radiotherapy. Chemo-
therapy is the mainstay of treatment for OSC, while
radiotherapy is usually given for USC.
The histopathological distinction between an ovar-
ian serous and an endometrioid carcinoma is usually
straightforward. However, when a tumour is poorly
differentiated the distinction may be difficult. The
presence of areas of squamous differentiation or of
associated endometriosis is helpful in supporting an
endometrioid carcinoma, while the presence of micro-
papillae and psammoma bodies is more in favour of
OSC. In poorly differentiated tumours, however, such
features may not be obvious. In our study, all primary
ovarian endometrioid carcinomas were negative with
WT-1, suggesting that WT-1 positivity within a poorly
differentiated ovarian neoplasm, especially if wide-
spread, may be a pointer towards serous carcinoma.
This is of importance, since chemoresponsiveness may
differ between different morphological subtypes of
ovarian cancer,22 although it is doubtful whether this
is so in poorly differential carcinomas which are
difficult to type on purely morphological grounds. In
the study investigating WT-1 staining of ovarian
neoplasms referred to above, ovarian endometrioid
carcinomas exhibited a very low rate of staining with
WT-1,6 in agreement with our study in which all
ovarian endometrioid carcinomas were negative. The
different WT-1 staining patterns between OSC and
ovarian endometrioid carcinoma support the view that
114 M Al-Hussaini et al.
the underlying genetic events and the pathogenesis of
these two neoplasms are different. OSC, in most cases,
probably arises directly from the ovarian surface
epithelium or from cortical inclusion cysts.23 Since
ovarian surface epithelium is in reality a specialized
form of mesothelium, which is itself WT-1+, this
provides an explanation for WT-1 positivity of OSC.
In contrast, many ovarian endometrioid carcinomas
probably arise from ovarian endometriosis.
Ovarian borderline serous tumours have a different
pathogenesis from invasive serous carcinoma.23 As
already stated, it is probable that most OSCs arise
de novo from the ovarian surface epithelium or from
inclusion cysts rather than through progression from a
borderline tumour. However, it has been proposed that
ovarian borderline serous tumours with a pronounced
micropapillary growth pattern should be termed low-
grade carcinomas rather than borderline neo-
plasms.24,25 One reason for this is that these neoplasms
are often associated with invasive peritoneal or omental
disease and subsequently have a worse prognosis than
ordinary borderline serous tumours which, in this
scheme, would be called benign since they have an
excellent prognosis.24,25 However, not all authorities
agree with this, pointing out that the worse prognosis of
micropapillary borderline serous neoplasms is entirely
due to the increased prevalence of invasive implants and
that in those cases without invasive implants the
prognosis is excellent.26,27 It has also been shown that
genetic alterations within micropapillary borderline
serous neoplasms are similar to those found in some
low-grade invasive serous carcinomas.28,29 This has
been put forward as an additional argument for regard-
ing borderline serous tumours with a micropapillary
growth pattern as low-grade carcinomas. Interestingly,
our study showed diffuse strong staining with WT-1 in
the two micropapillary borderline serous tumours with a
pattern comparable to that of most OSC. Most of the more
common type of serous borderline tumours were either
completely negative or exhibited focal weak staining of
<50% of nuclei. Although the numbers are small, these
findings lend support to the argument that, genetically at
least, micropapillary borderline serous neoplasms are
more akin to serous carcinomas than ordinary border-
line serous tumours without a micropapillary growth
pattern.
In conclusion, WT-1 is useful in distinguishing OSC
from USC and in cases with widespread disease this
antibody may be valuable in ascertaining the likely
primary site. The differences in WT-1 staining between
OSC and USC illustrate that although morphologically
these neoplasms are identical, the underlying genetic
events are likely to be different.
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