Gun et al.

Diagnostic Pathology 2012, 7:80

http://www.diagnosticpathology.org/content/7/1/80

RESEARCH

Open Access

Clinicopathological significance of fascin and

CD44v6 expression in endometrioid carcinoma
Banu Dogan Gun*, Burak Bahadir, Sibel Bektas, Figen Barut, Gamze Yurdakan, Nilufer Onak Kandemir
and Sukru Oguz Ozdamar

Abstract
Background: Fascin and CD44v6 may have significant roles as biomarkers in tumour progression and metastasis.
In endometrioid carcinomas, the fascin expression profile is less defined, and the significance of CD44v6 is
uncertain. We aimed to investigate the expressions of both fascin and CD44v6 in endometrioid carcinomas and to
evaluate their inter-relation with clinicopathological parameters.
Methods: Fascin and CD44v6 expressions were evaluated, individually and in combination, in a series of
47 endometrioid carcinomas and 10 proliferative endometrium samples. The staining extent and intensity of both
markers in tumour cells were scored semiquantitatively. The relationship between immunoexpressions and
clinicopathological variables was assessed.
Results: The expression rates of fascin and CD44v6 in endometrioid carcinoma were 72.34% and 46.80%,
respectively. Although these expression rates were higher than those in proliferative endometrial samples,
fascin expression showed a statistically significant difference from the normal group (p = 0.02), but CD44v6 did not
differ (p = 0.54). Fascin expression was significantly correlated with tumour grade (p = 0.003) and neural invasion
(p = 0.036) in a univariate analysis. In contrast, no significant correlation was found between CD44v6 and any of the
clinicopathological parameters.
Conclusions: Our findings suggest that fascin might be an independent prognostic indicator in the different steps
of extracellular matrix invasion. On the other hand, CD44v6 was not a predictive factor in endometrioid cancer.
Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/
vs/8511594927206899.
Keywords: Fascin, CD44v6, Endometrioid carcinoma, Immunohistochemistry

Background
Endometrial carcinoma is the most common invasive
neoplasm in the female genital tract. Based on clinicopathological and molecular genetic features, it can be
divided into two major groups referred to as type I
and type II. The endometrioid subtype, which is the
prototype of type I carcinoma, is associated with unopposed estrogenic stimulation, as well as endometrial
hyperplasia. Prognosis is dependent on some wellaccepted clinical and pathological parameters, including
the histological type and grade of the tumour, the depth
* Correspondence: [email protected]
Department of Pathology, Faculty of Medicine, Bulent Ecevit University,
67100 Kozlu, Zonguldak, Turkey

and pattern of myometrial invasion, the degree of disease

extension beyond the uterine corpus, adnexal involvement, and pelvic and para-aortic lymph node metastasis
[1]. Although several common molecular alterations have
been identified in the pathogenesis of endometrial cancer
[2-4], additional molecular factors need to be defined to
predict the specific behaviour of the tumour.
The interaction between epithelial tumour cells and
their stroma is very crucial in tumour progression and
metastatic cascade. To escape from the primary tumour
and invade adjacent tissues, cancer cells must interact
with the extracellular matrix at several stages [5]. Invasive cancer cells are believed to breach the basal membrane using specialised protrusions called invadopodia
[6-8]. The forces that drive tumour cell migration and

2012 Gun et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Gun et al. Diagnostic Pathology 2012, 7:80

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invasion are provided by the actin cytoskeleton underlying the membrane protrusions [9,10]. Fascin is a
55 kDa actin-bundling protein and is an important regulatory element in the maintenance and stability of parallel bundles of filamentous actin in a variety of cellular
contexts. The ability of fascin to bind and bundle actin
plays a central role in the regulation of cell adhesion, migration, and invasion [11].
CD44 is a transmembrane receptor protein that
belongs to the family of adhesion molecules and is
expressed on the surface of diverse cell types [12]. This
glycoprotein has a critical role in extracellular matrix adhesion and is implicated in a series of cellular events,
such as lymphocyte homing, leukocyte activation, lymphopoiesis, embryogenesis, and wound healing [13].
CD44 is encoded by a single gene containing 20 exons,
10 of which (v1v10) are variant exons [14]. The overexpression of the variant form, CD44v6, which contains
sequences encoded by exon 6, has been proposed as a
potential prognostic marker in many epithelial and nonepithelial malignancies in both early and metastatic phases
of carcinogenesis [13].
Fascin expression has been evaluated in several
human neoplasia, and recently in epithelial tumours
[15-30], but to our knowledge only two studies have
been conducted on the significance of fascin expression
in endometrioid carcinomas [31,32]. With regard to
CD44 and its variants, several studies have investigated
its expressions in endometrial pathologies, including
adenocarcinomas, yielding different results [31-41]. Our
purpose was to evaluate the possible roles of these two
molecular markers, fascin and CD44, in the invasive
and metastatic behavior of endometrioid carcinoma and
to analyse their association with clinicopathological
features.

Methods
Patients

We studied 47 well-documented cases of endometrioid

adenocarcinoma for which archival material of surgical
specimens from primary tumour resections were available between 2006 and 2011 at the Pathology Department of Bulent Ecevit University Hospital. Tumours
were staged according to the 2010 FIGO (The International Federation of Gynecology and Obstetrics)
staging system. The hematoxylin and eosin stained sections were reviewed to determine the FIGO grade, the
depth of myometrial invasion (if present), and the
presence or absence of lymphovascular invasion and
neural invasion. The macroscopic sizes and the FIGO
stage of all tumours were also noted. Proliferative
phase endometrium tissue samples were obtained from
10 cases.

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Immunohistochemical staining

The sections (45 m) obtained from representative tissue sample blocks were deparaffinised with xylene, rehydrated in graded alcohols, and placed in 0.5% hydrogen
peroxide in methanol for 10 min to block endogeneous
peroxidase activity. Antigen retrieval was carried out by
incubation in 0.01 M citrate buffer (ph 6.0) for 5 min in
a pressure cooker. The sections were exposed to the primary antibody for 60 min at room temperature. The
standard streptavidin-biotin-peroxidase complex method
was used for fascin (IM20, Novocastra, Newcastle, UK,
1:400) and CD44v6 (VVF-7, Novocastra, Newcastle, UK,
1:50) by employing diaminobenzidine (DAB) as the
chromogen. Human tonsil was used as a positive control, while negative controls were obtained by omitting
the primary antibody.
Evaluation of immunohistochemical staining

We calculated the immunohistochemical score (IHS)

of fascin and CD44v6 for each case. The scoring system
used for both fascin and CD44v6 was similar to previously published methods [20,40]. The extent of positively
stained epithelial cells was estimated and classified on a
four-point scale as follows: no staining = 0%, 1 = 1%
10%, 2 = 11%25%, 3 = 26%50%, and 4 = 51%100%.
The intensity of the immunoexpression was categorised
into three groups: weak (+1), moderate (+2), and strong
(+3). A final IHS score was obtained by multiplying the
score for extent and the score for intensity. Therefore,
the combined immunoreactivity score ranged from 0 to
12. According to this, cases were categorised into three
groups: 0 (absent), IHS 10, and IHS 11.
Statistical analysis

Statistical analysis was conducted with SPSS 18.0 software (SPSS, Inc., Chicago, IL). Continuous variables
were expressed as mean standard deviation, and categorical variables were expressed as frequency and
percentage. Pearsons chi-square test was used to determine the difference between groups. A p value of less
than 0.05 was considered statistically significant for all
tests.

Results
Immunohistochemical expression of fascin

The median age of the patients was 58.60 (SD 11.16)

years, with a range of 3479 years. The macroscopic
tumour sizes varied from 1 to 9, with a mean size of
4.41 cm (SD 11.16). According to the FIGO staging
system, 19 tumours were in stage 1A, 11 in stage 1B, 11
in stage 2, 3 in stage 3, and 4 in stage 4. Histopathologically, there were 16 grade 1, 16 grade 2, and 15 grade 3
tumours.

Gun et al. Diagnostic Pathology 2012, 7:80

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Fascin was detected in 72.34% (34 out of 47) of the

cases in the tumour cell cytoplasm. Also, microvessel
endothelium was stained with fascin in all carcinoma
cases. In the tumour stroma only a few inflammatory
cells including histiocytes showed weak fascin immunoreactivity. Epithelial staining was heterogeneous; while a
score 10 was detected in 56.25% (27) of the cases, a
score 11 was only seen in 16.66% (7) of the cases. The
positively stained epithelial cells with fascin revealed
various staining patterns, such as diffuse expression in
a gland, patchy staining in a gland, or aggregation at
the peripheral portion of a gland [Figures (a)1(c)].
There was no obvious micro-anatomical distribution of

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fascin expression in terms of superficial portion and conventional invasive areas. In our series, only one case
(grade 2) exhibited a microcystic, elongated, and fragmented (MELF)-type invasion pattern and fascin was
expressed strongly in the neoplastic epithelium within
these areas [Figure 1(d)]. The foci of squamous/morular
differentiation were all strongly stained with fascin
[Figure 1(e)].
In the proliferative endometrium, the stroma stained
diffusely and homogeneously in all samples. However,
glandular epithelium stained weakly in three (30%) of
the samples [Figure 1(f )]. A statistically significant difference with fascin expression was found between

Figure 1 Immunohistochemical staining for fascin. (a) Strong fascin expression in tumour glands. (b) Heterogeneous expression was seen in
the same gland. (c) Areas where immunoreactivity was seen at the peripheral portion of the glands. (d) The expression in an MELF-type area in a
grade 2 tumour. (e) The expression in the areas of squamous differentation. (f) Diffuse staining of stroma in proliferative endometrium. B-SA
peroxidase, DAB: [(a) and (c)] 200, [(b), (e), and (f)] 100, and (d) 400.

Gun et al. Diagnostic Pathology 2012, 7:80

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Table 1 Comparison of cases with endometrioid

carcinoma and proliferative endometrium
IHS
score

Endometrioid
carcinoma
(n = 47)

Proliferative
endometrium
(n = 10)

P value

13 (27.7%)

7 (70.0%)

p = 0.023

10

27 (57.4%)

3 (30.0%)

Fascin

CD44v6

11

7 (14.2%)

0 (0%)

25 (53.2%)

6 (60.0%)

10

19 (40.4%)

4 (40%)

11

3 (6.4%)

0 (0%)

p = 0.542

IHS: immunohistochemical score.

endometrioid carcinoma cases and proliferative endometrial samples (p = 0.023) (Table 1).
Fascin expression was found to be significantly correlated with tumour grade (p = 0.003) and with neural invasion (p = 0.036) (Table 2). This finding was only seen
on a univariate analysis. As these variables were highly
correlated (multicollinearity), binary logistic regression
analysis did not fit the model and couldnt be done.
However, no correlation was detected between fascin

expression and tumour size, degree of myometrial invasion, lymphovascular invasion, and tumour stage
(p > 0.05).
Immunohistochemical expression of CD44v6

The neoplastic glands in 46.80% (22 out of 47) of the

cases showed cytoplasmic and membranous CD44v6 reactivity. The CD44v6 staining pattern was observed as
cytoplasmic and/or membranous in tumour cells [Figure 2(a) and 2(b)], but cytoplasmic expression was the
predominant pattern. In squamous/morular differentiation areas, however, membranous expression was
strong and widespread [Fig. 2(c)]. The staining was not
diffuse, and the total IHS score was calculated as 11 in
only three tumours. No CD44v6 expression was seen
within the MELF-type neoplastic epithelium, and no
special micro-anatomical distribution was observed. Also
stromal tumour cells were not stained with CD44v6. In
four (40%) of the proliferative endometrial samples,
CD44v6 expression was weak only in the glandular epithelium [Fig. 2(d)]. Statistically, no difference was found
between endometrioid carcinoma cases and proliferative
endometrial samples (p = 0.542).

Table 2 Correlation of clinicopathological parameters with fascin and CD44v6 expressions in 47 endometrioid
carcinoma
Variables

Fascin

CD44v6

Absent
n = 13 (%)

IHS 10
n = 27 (%)

IHS 11
n = 7 (%)

P value

7 (53.8%)

13 (48.1%)

3 (42.9%)

0.889

6 (46.2%)

14 (51.9%)

4 (57.1%)

Absent
n = 25 (%)

IHS 10
n = 19 (%)

IHS 11
n = 3 (%)

P value

0.814

Mass size
12 (48.0%)

9 (47.4%)

2 (66.7%)

13 (52.0%)

10 (52.6%)

1 (33.3%)

Grade
G1

9 (69.2%)

7.(25.9%)

0 (0%)

11 (44.0%)

5 (26.3%)

0 (0%)

G2

3 (23.1%)

11 (40.7%)

2.(28.6%)

0.003

7 (28.0%)

8 (42.1%)

1.(33.3%)

G3

1 (7.7%)

9 (33.3%)

5 (71.4%)

7 (28.0%)

6 (31.6%)

2 (27.7%)

0.322

Depth of MI
Absent

2 (15.4%)

0 (0%)

0 (0%)

2 (8.0%)

0 (0%)

0 (0%)

Superficial

5 (38.5%)

13 (48.1%)

3 (42.9%)

0.244

10 (40.0%)

9 (47.4%)

2 (66.7%)

Deep

6 (46.2%)

14 (51.9%)

4 (57.1%)

13 (52.0%)

10 (52.6%)

1 (33.3%)

Absent

9 (69.2%)

17 (63.0%)

2 (28.6%)

Present

4 (30.8%)

10 (37.0%)

5 (71.4%)

Absent

11(84.6%)

26 (96.3%)

4 (57.1%)

Present

2 (15.4%)

1 (3.7%)

3 (42.9%)

8 (61.5%)

18 (66.7%)

3 (42.9%)

3 (23.1%)

6 (22.2%)

2 (28.6%)

1 (7.7%)

2 (7.4%)

0 (0%)

1 (7.7%)

1 (3.7%)

2 (28.6%)

0.527

LVI
0.182

13 (52.0%)

12 (63.2%)

3 (100.0%)

12 (48.0%)

7 (36.8%)

0 (0%)

22 (88.0%)

16 (84.2%)

3 (100.0%)

3 (12.0%)

3 (15.8%)

0 (0%)

17 (68.0%)

10 (52.6%)

2 (66.7%)

3 (12.0%)

8(42.1%)

0 (0%)

2 (8.0%)

0 (0%)

1 (33.3%)

3 (12.0%)

1 (5.3%)

0 (0%)

0.150

NI
0.036

0.613

Stage
0.597

IHS: immunohistochemical score, MI: myometrial invasion, LVI: lymphovascular invasion, NI: neural invasion.

0.084

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Figure 2 Immunohistochemical staining for CD44v6. (a) Cytoplasmic expression in tumour glands. (b) Focal membranous staining in the
tumour. (c) Squamous differentation areas showing strong expression. (d) Weak expression in the glands of proliferative endometrium. B-SA
peroxidase, DAB: [(a)(c)] 200 and (d) 100.

Additionally, no significant correlation was detected between the expression of CD44v6 and any clinicopathological
features of endometrioid carcinoma cases, such as tumour
size, tumour grade, depth of myometrial invasion, lymphovascular invasion, neural invasion, and stage (p > 0.05).

Discussion
Fascin and CD44 are proteins involved in different steps
in the extracellular matrix invasion. The interaction between epithelial and stromal cells is important in tumour
progression and metastasis; cancer cells use invasive fingerlike protrusions called invadopodia to invade the
basal membrane and to degrade the extracellular matrix
[6]. These protrusions carry actin bundles under the
membrane [6,9,10]. At that point, fascin, the so-called
actin-bundling protein, becomes a part of this process
and is essential for the stability of actin microfilaments.
It also facilitates the invasion [9].
Experimental studies demonstrated that CD44 was
strongly associated with the actin cytoskeleton in an indirect position, and this interaction is mediated by ERM
(ezrin-radixin-moesin) proteins [14,42,43]. ERM adapts
CD44 to the actin-based cytoskeleton and organises the
membrane and cytoskeleton interaction. However, little
knowledge is known about the relationship between

fascin and CD44 in solid tumours. In the present study,

we examined fascin along with CD44v6 in 47 endometrioid carcinoma and 10 proliferative endometrium samples. We demonstrated that the expression of these two
molecular proteins did not correlate with each other.
Fascin has recently received considerable attention as a
new prognostic marker in several solid neoplasms. In the
present study, we detected fascin in 72.34% of endometrioid carcinoma, and the expression was significantly
different from the normal group. Among the studies
about fascin in endometrial carcinomas, Kabukcuoglu
et al. revealed positive staining in 74% of the carcinoma
specimens and in 39% of the non-neoplastic endometrial
samples [31]. They also indicated that higher-grade endometrial carcinoma cases revealed a significant increase in
the total epithelial fascin expression. These results are
considerably compatible with our findings that fascin
was significantly correlated with histological grade.
Stewart et al. also demonstrated strong fascin immunoreactivity in the neoplastic epithelium of MELF-type invasion areas in contrast to negative or weakly stained
conventional tumour glands in low-grade uterine endometrioid adenocarcinoma. In addition, prominent staining within the peripheral epithelial cell and in the foci of
squamous/morular-type differentiation was observed [32].

Gun et al. Diagnostic Pathology 2012, 7:80

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Of the 47 cases, only one (a grade 2 tumour) showed

an MELF-type invasion pattern and revealed strong fascin expression. In a unique study determining the exact
nature of the MELF pattern of invasion, the immunprofile in MELF areas was found to be consistent with the
features of epithelial-mesenchymal transition [44].
Although areas of squamous or morular differentiation are frequently observed in endometrioid carcinomas, their pathogenesis remain unclear. In studies that
investigated the precise nature of squamous differentiation in endometrial carcinoma, these areas were found
to express beta catenin [45-47]. In our series, areas with
squamous and morular differentation expressed both
fascin and CD44v6 strongly. CD44v6 expression can be
detected in a subset of squamous cell carcinoma in different locations and in the foci of squamous differentation [41,48,49]. This finding was attributed to the fact
that the cells were packed tightly in these foci, as seen
in squamous cell carcinoma of any organ or in solid
nests within an otherwise adenocarcinoma [49]. Meanwhile the presence of fascin expression in squamous
and morular differentiation was explained by the activation of the Wnt signalling pathway and the upregulation
of fascin via nuclear translocation of beta catenin [32].
The immunoexpression of fascin and CD44v6 was predominantly heterogeneous, while diffuse and strong
expressions were seen in 6.4% and 14.2% of cases,
respectively. Fascin immunostaining was sometimes
restricted to the periphery of the neoplastic glands. However, no special staining distribution was seen between
the glands in the superficial portion of the tumour and in
the deep invasive conventional areas. Being a dynamic
process, carcinogenesis might be responsible for the heterogeneity of protein expressions.
CD44v6 has been implicated in the malignant transformation and metastatic potential of several tumours
and in endometrial carcinomas. Among the previous
analyses of CD44 in endometrial adenocarcinoma, some
investigators found no relation between CD44v6 and
clinicopathological parameters and thought that CD44v6
was not an adverse predictive factor [33-35]. However,
the others indicated that CD44v6 was inversely correlated with adverse prognostic factors [37,38]. In this
study, CD44v6 was demonstrated in 46.80% of carcinoma
specimens and in 40% of the proliferative phase. Meanwhile, no correlation was found between any of the clinicopathological features. The expression of CD44v6 may
be seen as a result of disregulation and is not primarly
implicated in the progression of endometrial cancer.

Conclusions
Our findings suggest that fascin may become a novel
marker in the prognosis of endometrial cancer. However,
further detailed studies in a larger series that should

Page 6 of 7

include prospective clinicopathological analyses and

menstrual cycle phases are neccessary to determine the
significance of these molecules in physiological conditions and in endometrial tumors as a prognostic indicator or a molecular target for treatment.
Abbreviations
IHS: Immunohistochemical score; MELF: Microcystic, elongated, and
fragmented; FIGO: The International Federation of Gynecology and
Obstetrics.
Competing interests
The authors declare that they have no competing interests.
Acknowledgement
We would like to sincerely thank Firuzan Kokturk for her assistance in the
statistical analyses.
Authors contributions
BDG conducted the study design, performed microscopic evaluation, and
drafted the manuscript. BB participated in the design of the study and
helped to draft the manuscript. SB participated in the design of the study
and performed microscopic evaluation. FB, GY, and NOK participated in the
microscopic and immunohistochemical evaluation. SOO participated in the
study design and coordination. All authors read and approved the final
manuscript.
Received: 27 April 2012 Accepted: 11 July 2012
Published: 11 July 2012
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doi:10.1186/1746-1596-7-80
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and CD44v6 expression in endometrioid carcinoma. Diagnostic Pathology
2012 7:80.

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