Correlation of FOXL2 with Inhibin and Calretinin in the Diagnosis of Ovarian Sex Cord Stromal Tumors
Ruchi RATHORE, Deepshikha ARORA, Sarla AGARWAL, Sonal SHARMA
Department of Pathology, University College of Medical Sciences, NEW DELHI, INDIA
Keywords: FOXL2, Inhibin, Calretinin, Ovarian neoplasms, Sex cord stromal tumor
Alpha-inhibin and calretinin have been traditionally used as immunomarkers for sex cord stromal tumors. However, the
variation in their immunoreactivity and their lack of specificity for sex cord stromal tumor makes the search for a more sensitive and specific
immunohistochemical marker essential in routine diagnosis of sex cord stromal tumor. This study was conducted to correlate the diagnostic
utility of FOXL2 with inhibin and calretinin in the diagnosis of sex cord stromal tumors of ovary.
Material and Method: The study was conducted in the department of pathology. 31 cases of sex cord tumors received in past eight years
(2002-2010) were included in this study. Immunostaining for inhibin, calretinin and FOXL2 was performed and compared on the basis of
staining intensity and percentage positivity on all the cases.
Results: Calretinin was found to be positive in 29/31 sex cord stromal tumors with variable intensities and was negative in two cases of sex cord
stromal tumors, inhibin was positive in 28/31 and only three cases had no cytoplasmic staining. All the 31 cases included in this study were
positive for FOXL2 with variable staining intensities and percentage positivity. Ten cases of each surface epithelial and germ cell tumors were
also negatively stained with FOXL2.
Conclusion: In contrast to inhibin and calretinin, FOXL2 had a sensitivity and specificity of 100% for all the cases of sex cord stromal tumors
included in this study.
Sex cord stromal tumors (SCST) constitute 8% of all
the ovarian neoplasms comprising those that contain
granulosa cells, theca cells, and their luteinized derivatives,
Sertoli cells, Leydig cells and fibroblast of gonadal stromal
origin singly or in various combinations with varying
degrees of differentiation1
. These tumors as known for
their hormonal activity are slow growing tumors and have
a tendency of late recurrence. Since the patients are often
young and most tumors are unilateral, accurate diagnosis is
necessary for proper treatment and maintenance of fertility
Although the mainstay for diagnosing these SCST
remains gross and microscopic features, the presence
of diverse morphological variations makes the use of
immunohistochemistry essential in their diagnosis.
The widely varied appearance of SCST and the fact that
some of them are uncommon can lead to difficulties
in their diagnosis. Some of them may show atypical or unconventional microscopic patterns and, therefore,
morphology alone may not be reliable for an unequivocal
classification. In these cases, immunohistochemistry can be
of value. Alpha-inhibin2-6 and calretinin7,8 have been
traditionally used as immunomarkers of SCST. However
due to the variation in their immunoreactivity and a lack
of specificity for SCST, the search for a more sensitive and
specific immunohistochemical marker becomes essential
in routine diagnosis of SCST.
In the recent past, FOXL2 mutations have been consistently
found in adult granulosa cell tumors9,10. Currently
there are increasing numbers of studies eliciting the role
of FOXL2 in the diagnosis of adult granulosa cell tumors
but there is paucity of literature on its diagnostic utility in
comparison to inhibin and calretinin in the diagnosis of the
entire spectrum of SCST of the ovary. The aim of this study
was to evaluate the role of FOXL2 and its correlation with
inhibin and calretinin in the diagnosis of entire spectrum
The study was conducted in the department of pathology
of our institute. Thirty-one cases of SCST received in
past eight years (2002-2010) were included in this study.
These consisted of 17 adult granulosa cell tumors, 1
juvenile granulosa cell tumor, 7 fibrothecoma, 1 fibroma,
1 fibrosarcoma, 1 SCST of uncertain histogenesis, 1 poorly
differentiated tumor possibly granulosa cell tumor and
2 cases of Sertoli-Leydig cell tumor. For all the cases,
Hematoxylin and Eosin (H&E) stained slides were retrieved
from archives and reviewed by expert pathologists. Ten
cases each of surface epithelial and germ cell tumors were
also included in the study for FOXL2 staining.
The blocks were selected for immunohistochemical
demonstration of inhibin, calretinin and FOXL2. Then
3-4 micrometer thick sections were taken from each block
on poly-L-lysine-coated slides. These were stained with
monoclonal antibody against α subunit of inhibin, antibody
to calretinin and polyclonal antibody to C-terminal
hexadecapeptide of the human FOXL2 protein respectively
using the avidin biotin method. The primary antibody for
FOXL2 used in this study was polyclonal FOXL2-antiserum
(1:200; Imgenex, San Diego, CA, USA). For calretinin and
inhibin the primary antibodies used were monoclonal
anticalretinin (RTU, Spring Biosciences, CA, USA) and
monoclonal anti-inhibin (1:50; Spring biosciences, CA,
USA) respectively. Serial dilutions of antibody were tested
to avoid background staining and to find optimal staining
before the entire series was processed. Sections from normal
ovary with graffian follicles were used as positive control.
For negative controls, primary antibody was replaced by
The slides were examined at 40x magnification. Positive
reaction was characterized by cytoplasmic (inhibin),
nuclear and cytoplasmic (calretinin), nuclear (FOXL2)
staining showing variable intensities with the distribution
of staining approximated for variable intensity levels. The
presence of any nuclear staining of FOXL2, regardless of
intensity or focality, was considered to be positive.
Sensitivity, specificity, negative predictive value, and
positive predictive value for inhibin, calretinin and
FOXL2 were determined taking histopathology as the gold
standard. Ten cases each of malignant surface epithelial tumors and germ cell tumors were included in this study
to determine the specificity of antibodies for SCST. The
exact binomial method (Clopper-Pearson) was applied
to calculate the confidence interval of diagnostic indices.
SPSS version 17-statistic software was used for data analysis
Comparison of Immunostaining for FOXL2, Inhibin
Immunostaining for FOXL2, inhibin and calretinin were
compared on the basis of staining intensity and percentage
positivity in all the cases. The staining intensity was graded
as -weak (1+), moderate (2+), strong (3+). The percentage
of tumor cells labeled by FOXL2, inhibin and calretinin
were semiquantitatively scored as <5% (negative), 5-25%
(1+), 26-50 % (2+), 51-75% (3+), >75% (4+).
Inhibin was positive in the majority of the SCST i.e. 28/31
and only 3 cases had no cytoplasmic staining (Table I
Of all negatively stained tumors, two were granulosa cell
tumors which included a cystic granulosa cell tumor and the
other was a granulosa cell tumor with postchemotherapy
changes (bizarre cells), and the remaining case was a SCST
of uncertain histogenesis (Figure 1A-D
) (Table I
Click Here to Zoom
|Figure 1: Granulosa cell tumor: A) H&E staining section (H&E; x400) B) Cytoplasmic positivity for inhibin (Inhibin; x400) C) Nuclear
and cytoplasmic positivity for calretinin (Calretinin; x400). D) Nuclear positivity for FOXL2 (FOXL2; x400).
Click Here to Zoom
|Table I: Inhibin, calretinin and FOXL2 immunoanalysis for sex cord stromal tumors.
Taking H&E stained sections as the gold standard, the
sensitivity of inhibin was 90.3% and the specificity was
100% for SCST. The positive predictive value for inhibin in
our study was 100% and the negative predictive value was
Calretinin was found to be positive in 29/31 SCST
with variable intensities and was negative in 2 cases of
SCST including 1 case of fibrothecoma and the other of
fibrosarcoma (Table I). Both the above stated cases were
also found to be negative, when the percentage positivity
of all the 31 cases was seen. The remaining 29/31 cases
had variable staining intensities ranging from 1(+) to 4(+)
The sensitivity of calretinin in this study was 93.5% while
the specificity was 100%. The negative predictive value
of calretinin for this study was 90.9% and the positive
predictive value was 100%. H&E stained sections were
taken as the gold standard for the analysis. (Figure 1A-D)
Thirty-one cases of SCST were stained using a polyclonal
antibody against FOXL2, which is a nuclear protein. Ten
cases each of surface epithelial and germ cell tumors were also stained with FOXL2. All negative controls as well as
surface epithelial and germ cell tumors were negative.
Positive control had a nuclear pattern of staining in the
granulosa cells of normal ovary (Figure 1A-D).
FOXL2 was positive with variable staining intensities
and percentage positivity in all the cases included in this study. While 16/31 SCST had mild intensity of staining,
6/31 had strong staining intensity and 9/31 had moderate
intensity of staining. Tumors, which were strongly
positive included 4/17 adult granulosa cell tumors and
1/7 fibrothecomas. One tumor which was signed out as
poorly differentiated tumor possibly granulosa cell tumor and was positive for inhibin and calretinin also had strong
intensity of staining with FOXL2 (Figure 2A,B). Tumors
showing moderate intensity of staining included 4/17 adult
granulosa cell tumor, 2/7 cases of fibrothecoma, 1/1 of
fibrosarcoma and 1/2 Setoli-Leydig cell tumor. 1/1 SCST
of uncertain histogenesis included in this study was also
moderately positive for FOXL2 (Table I). The remaining
cases, including 9/17 adult granulosa cell tumors, 1 /1 case
of juvenile granulosa cell tumor, 4/7 fibrothecomas, 1/1
fibroma and 1/2 Sertoli-Leydig cell tumors, were mildly
positive for FOXL2 (Table I).
Click Here to Zoom
|Figure 2: A) Nuclear FOXL2 staining in fibrothecoma (Immunohistochemistry; x400). B) Adult Granulosa Cell Tumor (FOXL2; x400).
C) Sertoli-Leydig cell tumor (FOXL2; x400). D) Juvenile granulosa cell tumor (FOXL2; x400).
Comparing the percentage positivity for all the 31 cases
of SCST, it was seen that of the three cases having 4(+)
percentage positivity, 2 were granulosa cell tumors
with diffuse microscopic patterns and one was a poorly
differentiated tumor. 8/31 cases that had 3(+) positivity,
which included 5/17 adult granulosa cell tumors followed by
1/7 fibrothecomas, 1/1 fibrosarcoma and 1 case of Sertoli-
Leydig cell tumors. The only case of juvenile granulosa cell
tumor included in the study had 2(+) percentage positivity
while SCST of uncertain histogenesis had 1(+) percentage positivity. 3/7 fibrothecomas had 1(+) and 3/7 had 2(+)
percentage positivity respectively (Table I).
Taking H&E sections as the gold standard, the sensitivity
and specificity of FOXL2 was 100% and negative predictive
values as well as positive predictive value were also 100%
in our study. Moreover, ten cases each of surface epithelial
tumors and germ cell tumors were negative for FOXL2.
Comparison of FOXL2, Inhibin and Calretinin
In contrast to inhibin and calretinin, FOXL2 had a
sensitivity and specificity of 100% for all the cases of SCST
included in the study (Table II).
Click Here to Zoom
|Table II: Comparison of immunohistochemical staining sensitivity, specificity, negative predictive value and positive predictive value
of inhibin, calretinin and FOXL2
Inhibin is a dimeric 32 KDa peptide hormone composed of
an α subunit and a β subunit. Apart from being produced
normally by granulosa cells and testicular Sertoli cells, its
extragonadal expression in the placenta, adrenal gland,
pituitary gland and liver has also been demonstrated in
. Most studies have shown that
inhibin is expressed in nearly all granulosa cell tumors, juvenile and adult types, most Sertoli and Leydig cell tumors,
SCST with annular tubules, gynandroblastomas, and
steroid cell tumors17,18-21
. However, Matias-Guiu et al.
demonstrated that it is less frequently expressed in fibromas,
fibrothecomas and unclassified SCST and is absent in
. In our study it was seen that inhibin was
positive in the majority of the SCST i.e. 28/31 (90.3%) and
only 3 cases had no cytoplasmic staining. As opposed to the
previous studies, all 7/7 cases of fibrothecoma and 1/1 cases
of fibroma (moderate intensity) were positive for inhibin.
In fact, a single case of fibrosarcoma included in our study
demonstrated moderate intensity of staining with inhibin.
However, in accordance with the described literature, the only case of SCST of uncertain histogenesis included in our
study was negative for inhibin immunoreactivity.
Calretinin, a 29-kd calcium-binding protein, has been
shown in human ovarian surface epithelial cells, theca
interna cells, stromal cells, hilar cells, and certain types
of ovarian SCST by various research groups22-25.
Calretinin, initially used for the diagnosis of mesothelioma,
has been shown to be highly sensitive but a less specific
marker than inhibin for SCST of the ovary. In studies
conducted by Movahedi et al. and Shah et al., it was seen
that calretinin has a sensitivity of 97% and specificity
of 85% (except in granulosa cell tumors with extensive
luteinization, which less frequently express calretinin) compared with inhibin having 71% sensitivity and 97%
specificity26,27. However, the sensitivity of calretinin in
this study was 93.5% while the specificity was 100%. The
negative predictive value of calretinin for this study was
90.9% and the positive predictive value was 100%.
In contrast to inhibin, calretinin is more frequently
expressed in epithelial ovarian tumors including serous,
mucinous, clear cell, and endometroid carcinomas (as many
as 22% of cases in one series) and is therefore less reliable
in the differential diagnosis of SCST and endometroid
carcinoma20,26. It has been noted in various studies that
fibromas are frequently positive for calretinin and negative
for inhibin and the sole use of calretinin in this setting is
more discriminatory26,28,29. In our study it was seen
that in the single case of SCST of uncertain histogenesis
where inhibin was found to be negative, calretinin staining
gave a 1(+) percentage positivity in cells whereas the only
case of a poorly differentiated tumor possibly granulosa
cell tumor on morphology had strong positivity for both
inhibin as well as calretinin. Moreover, it was seen that in
the case of cystic granulosa cell tumor and granulosa cell
tumor with postchemotherapy changes where inhibin
was negative, calretinin was strongly positive. Our study
supports that calretinin is more sensitive than inhibin for
the diagnosis of SCST as described in the literature.
FOXL2, a forkhead transcription factor is a key factor
in proper differentiation of granulosa cells during
folliculogenesis and its expression persists in the ovary after
birth30. Shah et al. identified a single recurrent somatic,
missense mutation in FOXL2 (C402G), which was present
in almost all morphologically identified adult type granulosa
cell tumours9. Kalfa et al. studied the underexpression
of FOXL2 in juvenile ovarian granulosa cell tumors with
an aggressive pattern of progression and it thus may be
a prognostic factor for these tumors31. Rosario et al.
concluded that FOXL2 mutations target the deregulation
of TGF-β signaling genes, a key antiproliferative pathway
in the pathogenesis of adult-type GCTs32. However, its
exact role in the pathogenesis of these tumors is still under
evaluation. FOXL2 immunostaining gives a nuclear pattern
of staining due to the nuclear location of FOXL2 protein, a
transcription factor antibody.
Recently a study conducted by Osama et al. demonstrated
that FOXL2 is a robust immunohistochemical marker for
SCST that works in formalin-fixed, paraffin-embedded
tissue sections and is highly expressed in both FOXL2-
mutant SCST and a subset of SCST without a (402C-G)
mutation in FOXL2. FOXL2 immunostaining is both
sensitive and highly specific for SCST, performing better than α inhibin and calretinin. A subset of SCST is typically
negative for FOXL2 on immunostaining (retiform or
poorly differentiated SLCT), but these tumors usually
express α inhibin and/or calretinin. In most of the FOXL2
positive cases in this study, FOXL2 demonstrated a nuclear
pattern of staining and stained a high proportion of tumor
cells leading to easy interpretable staining33.
A single study conducted by McCluggage et al. on the
expression of FOXL2 in fibromas and its diagnostic utility as
an adjunct in the differential diagnosis of diffuse granulosa
cell tumors concluded that FOXL2 mutations are absent in
ovarian fibromas in contrast to granulosa cell tumors and
are thus a useful diagnostic adjunct in distinction from
diffuse adult granulosa cell tumors34.
In our study it was seen that all the cases including 100%
of adult granulosa cell tumors, 100% of juvenile granulosa
cell tumors, all the cases of fibrothecoma, fibrosarcoma,
fibroma, SCST of uncertain histogenesis and poorly
differentiated tumor possibly granulosa cell tumor on
morphology were positive for FOXL2. McCluggage et al.
detected no FOXL2 mutation in ovarian fibroma. The
importance of detection of FOXL2 expression in ovarian
fibroma is not clear because FOXL2 expression was
detected in only one case in our study. This finding should
be investigated in large case series and compared with
FOXL2 mutation and expressions in the tumor34. All
the cases that were negative for inhibin or calretinin were
positive for FOXL2 in our study. Taking H&E sections as
the gold standard, the sensitivity and specificity of FOXL2
was 100% and negative predictive values as well as positive
predictive value were also 100% in our study. Though the
pattern of immunoreactivity in our study was in accordance
with the literature, the limited number of cases included
in our study was a major setback in studying the role of
FOXL2 in the whole range of SCST. No case of steroid
cell tumor, Leydig cell tumor or female adnexal tumor of
probable Wolffian origin and only a single case of fibroma
in which FOXL2 has been shown to be negative in earlier
studies was included in our study.
However, it was demonstrated that most cases of SCSTs were
positive for FOXL2 as compared to inhibin or calretinin
in this study. Our results also suggested that FOXL2 had a
better percentage positivity of cells as compared to earlier
well-established markers such as calretinin and inhibin. As
only a limited number of cases were included in this study,
the whole range of sex cord stromal tumors could not be
evaluated for immunohistochemical analysis and further
studies with a wider range of these tumors are required for
the validation of our study.
In conclusion, testing for FOXL2 immunoexpression
can serve to distinguish between SCST and non-SCST.
However, we acknowledge that the smaller number of cases
included in our study was a major limitation and further
validation with a larger number of cases is still required.
CONFLICT of INTEREST
No financial support of any form has been taken from any
agency for this study.
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