cERBB-2/Her-2 Neu Overexpression and Prognostic Significance in Uterine Carcinosarcoma
Huseyin Salih SEMIZ1, Emel Ebru PALA2, Behzat CAN3, Elif ATAG4, Hatice GUNGOR4, Muzaffer SANCI3
1Department of Medical Oncology, Dokuz Eylül University Institute of Oncology, IZMIR, TURKEY
2Department of Pathology, Health Science University, Tepecik Education and Research Hospital, IZMIR, TURKEY
3Department of Gynecological Oncology, Health Science University, Tepecik Education and Research Hospital, IZMIR, TURKEY
4Department of Medical Oncology, Health Science University, Istanbul Haydarpaþa Numune Education and Research Hospital, ISTANBUL, TURKEY
Keywords: Carcinosarcoma, Her-2/neu, Prognosis, Uterine cancer
There is not enough data in the literature regarding Her-2 overexpression in uterine carcinosarcomas or its association with the
prognosis. The aim of this study was to determine the Her-2 overexpression rate in uterine carcinosarcoma and to evaluate its relationship with
Material and Method: Her-2 protein and gene status were evaluated by immunohistochemistry (IHC) and fluorescence in situ hybridization
(FISH), respectively, in hysterectomy specimens from 51 patients with uterine carcinosarcoma.
Results: Her-2 protein expression in the epithelial component was negative in 42 patients (score 0 in 33 cases, score (+1) in 9 cases), score (+2)
in 7 patients and score (+3) in 2 patients. None of the patients had Her-2 protein expression within the sarcomatous component of the tumors.
Her-2 gene was not amplified in epithelial or mesenchymal tumor areas according to the FISH method. There was no difference between the
Her-2 overexpression negative and positive groups in terms of disease-free survival (DFS) and overall survival (OS). Her-2 overexpression was
significantly higher in tumors of patients diagnosed at 65 years or older (p=0.046).
Conclusion: In our study, no relationship could be shown between Her-2 overexpression and prognosis in uterine carcinosarcoma. More
comprehensive studies are needed to illustrate the relationship between Her-2 overexpression and carcinosarcoma prognosis.
Carcinosarcomas (CS) constitute 5% of all uterine
cancers and have a poor prognosis (1). They have both
mesenchymal and epithelial components. Histology of the
epithelial component can be endometrioid, serous, clear
cell, or undifferentiated. The mesenchymal component can
be homologous, as in endometrial stromal sarcoma (ESS),
leiomyosarcoma (LMS), or undifferentiated sarcoma, or
heterologous as in rhabdomyosarcoma, osteosarcoma,
chondrosarcoma, liposarcoma, or fibrosarcoma (2).
Carcinosarcomas are considered to develop from an
epithelial origin. It is known that the epithelial and
mesenchymal components of carcinosarcomas have many
common features, both immunohistochemically and
genomically. In addition, carcinosarcomas have similar
characteristics to uterine carcinomas rather than uterine
sarcomas in terms of the clinical course and risk factors (3).
Approximately 70% of patients are at locally advanced or
metastatic stage at the time of diagnosis (4).
The most important prognostic factor in carcinosarcomas
is the stage of the disease. While 5-year survival is around
60% in stage 1 disease, this rate decreases to below 10%
in stage 4 (5). Other prognostic factors are depth of
myometrial invasion, presence of lymphovascular invasion,
advanced age, ethnicity (poor prognosis in black race),
and late menopause (6). The poor prognosis of the disease
and the lack of treatment options other than conventional
chemotherapies, especially in advanced stage disease, have
led to the search for new biomarkers and treatments.
ERBB-2 (Her-2 / neu) is a member of the epidermal growth
factor receptor (EGFR) family. In many types of cancer, especially
in breast carcinoma, overexpression of Her-2 is associated
with poor prognosis, and it is also associated with
poor prognosis in endometrial serous carcinoma (7-9).
However, there is not enough data in the literature regarding
Her-2 overexpression in uterine carcinosarcomas or its
association with the prognosis. In this study, we aimed to
determine Her-2 overexpression/amplification rates in uterine
carcinosarcomas and its relationship with the prognosis.
Sixty consecutive uterine carcinosarcoma cases diagnosed
in our center between 2013 and 2020 provided consent and
were selected for the study. Paraffin blocks with samples
for nine patients were insufficient for examination and
therefore excluded from the study. Samples for a total
of fifty-one patients were examined. Since our study was
cross-sectional and carcinosarcoma cases are seen much
less than other uterine malignancies, the sample size was
not calculated. All cases in the specified date range were
included in the study.
Her-2 overexpression was determined by immunohistochemistry
(IHC) and consequently fluorescence in situ
hybridization (FISH), and scoring was done as either negative
(score 0 and score (+1), score (+2) and score (+3). IHC
score (+2) and score (+3) cases were accepted as positive
for Her-2 overexpression. The correlation between Her-2
overexpression and survival (DFS and OS) was examined.
We also studied the correlation between Her-2 overexpression
and prognostic parameters for carcinosarcoma such
as necrosis, atypia, FIGO stage, LVI, PNI, and histological
Her-2 Immunohistochemistry Staining Procedure
Formalin-fixed, paraffin-embedded tissues from hysterectomy
specimens were processed according to standardized
protocols. Paraffin blocks containing both epithelial and
mesenchymal areas were chosen. Her-2 protein expression
was evaluated by IHC, and Her-2 gene amplification was
evaluated by FISH method. To determine the Her-2 protein
expression, polyclonal rabbit Her-2 antibody (1/300
dilution) (A0485 clone, DAKO) was used. The whole procedure
was performed on a DAKO Autostainer Link 48.
Her-2 staining was evaluated according to the College of
American Pathologists (CAP) 2018 protocols for breast
cancer Her-2 scoring (10).
Fluorescence in Situ Hybridization Procedure of Her-2
DAKO instant quality FISH kit was used for determining
the Her-2 gene copy numbers. Deparaffinization of slides
was started on the incubator at 60 °C for one hour, then run
through two xylol series. After rehydration with ethanol,
slides were pretreated with pretreatment solution for 10
minutes at 99 °C in a water bath. Ready-to-use pepsin
was used for enzymatic digestion for 4 min at 37 °C on
the hybridizer. Her-2/CEN17 probe mix was applied (10
μL) to each slide. After denaturation at 66 °C for 10 min,
hybridization was performed at 45 °C for 2 hours. At the
end of the hybridization, the slides were washed with wash buffer at 63 °C for 10 min. Then 15 μL of fluorescence
mounting medium was applied to the dehydrated slides
and cover slipped.
Interpretation of Her-2 FISH method
Epithelial and mesenchymal areas were evaluated with an
Olympus BX51 fluorescence microscope equipped with
red/green/DAPI filter set under oil immersion objective
(100x). CAP 2018 recommendations were used for
evaluation of Her-2 gene status (10).
The data was analyzed with the SPSS 24.0 package program.
Numerical data analysis was done with Fisher’s Exact test
and the Chi-Square test. The Mann-Whitney U Test was
used for independent group analysis. The Kaplan-Meier
test was used for survival analysis. Survival curves were
compared using Log Rank analysis. Statistical significance
level was accepted as p <0.05.
Fifty-one uterine CS patients diagnosed between January
2013 and December 2020 were enrolled in this study. The
median age was 63.4 years (range: 43-81) and only 3 of the
patients were premenopausal at the time of diagnosis. While
15 patients had no comorbidity (29.4%), all the remaining
patients (70.6%) had at least one comorbid disease (type
2 diabetes, hypertension, etc.). Patient sociodemographic
and clinicopathological characteristics are shown in Table
Twenty-two patients were diagnosed with carcinosarcoma
by probe curettage and proceeded to cytoreductive surgery.
Operation materials were also found to be compatible
with carcinosarcoma. Histopathological findings of probe
curettages are shown in Table II. The histological subtypes
of the mesenchymal component in the operation materials
are given in Table III. Thirty-seven patients received
carboplatin and paclitaxel, while six patients received
ifosfamide and paclitaxel as adjuvant chemotherapy after
frontline cytoreductive surgery. Four patients did not
receive adjuvant chemotherapy due to a poor performance
score (ECOG performance score >2) and three patients
for unknown reasons. At the time of diagnosis, 3 of 51
patients were inoperable. Optimal cytoreductive surgery
was performed in these 3 patients after neoadjuvant
carboplatin and paclitaxel chemotherapy. After adjuvant
chemotherapy, 8 patients received brachytherapy, 4
patients received external radiotherapy, and 13 patients
received both brachytherapy and external radiotherapy. A
total of 22 patients did not receive adjuvant radiotherapy.
IHC and FISH were carried out on hysterectomy specimens
of 51 patients. Biphasic tumor areas with high-grade
epithelial and sarcomatous components (HE, 10x) are
shown in Figure 1. Her-2 protein expression in epithelial
areas was score (0) in 33, score (+1) in 9, score (+2) in 7, and score (+3) in 2 cases by A0485 IHC. Her-2 expression
in mesenchymal areas was negative according to IHC in all
cases. None of the cases showed Her-2 gene amplification
in epithelial or mesenchymal areas according to the FISH
method (Figures 2-4).
Click Here to Zoom
|Figure 1: Biphasic tumor areas with high grade epithelial and
mesenchymal components (HE, 10x).
Click Here to Zoom
|Figure 2: A) Carcinosarcoma case showing incomplete membranous staining (1(+) score) in epithelial component by HER2
immunohistochemistry is B) non-amplified by HER2 fluorescence in situ hybridization.
Click Here to Zoom
|Figure 3: A) Carcinosarcoma case showing mild/moderate complete membranous staining (2(+) score) in carcinoma component by
HER2 immunohistochemistry is B) non-amplified by HER2 fluorescence in situ hybridization.
Click Here to Zoom
|Figure 4: A) Carcinosarcoma case showing complete membranous staining (3(+) score) in 20% of epithelial tumor component by HER2
immunohistochemistry is B) non-amplified by HER2 fluorescence in situ hybridization.
At the time of data cut-off, 31 patients were alive, and
12 patients had no evidence of disease. Median followup
period was 16 months. Median DFS was 18 months,
and median OS was 27 months. There was no significant
difference between the histological subtypes of epithelial
components in terms of the Her-2 positivity rate (p=0.9)
Click Here to Zoom
|Table IV: Her-2 positivity according to histological subtypes of epithelial components.
The median age was 69.31 in the Her-2 score (+2) and
(+3) groups (n=9) and 62.88 in Her-2 score (0) and (+1)
groups (n=42) (p=0.04) The estimated mean DFS did not
differ between Her-2 negative and positive groups (p=0.59) (Figure 5). There was no difference between the Her-2
negative and positive groups in terms of overall survival
(39.8 vs. 38.3 months, p=0.698) (Figure 6). There was no
relationship between Her-2 expression scores and any of
the parameters (necrosis, atypia, FIGO stage, LVI, PNI,
histological grade) with negative prognostic value for
carcinosarcoma. However, the probability of recurrence
was higher in patients with cervical involvement than in
patients without cervical involvement (p=0.016) (Table V).
Click Here to Zoom
|Table V: Crosstabulation of clinical characteristics of uterine carcinosarcoma patients.
The frequency of Her-2 [score (+2) and (+3)] was significantly
higher in patients 65 years of age and older (29.1%
positivity) than patients under 65 years of age (7.4% positivity)
(p=0.04). Although not statistically significant, the
median age in patients with disease recurrence was higher
than in patients without recurrence (p=0.247) (62.58
vs. 69.04) (Table V). Also, the estimated mean DFS (42.2
months vs. 56.5 months, p = 0.037) and OS (29.6 months
vs. 50.4 months, p=0.025) was shorter in the patient group
aged ≥ 65 compared to the group aged <65.
Carcinosarcomas are tumors with aggressive behavior and
the disease has poor prognosis. However, there is no treatment
available other than cytoreductive surgery followed
by adjuvant systemic chemotherapy and radiotherapy in
early-stage disease and a limited number of systemic chemotherapy
regimens in advanced stage. Therefore, the
search for targetable biomarkers/molecules in carcinosarcomas
Since Her-2 overexpression was shown to play an important
role in treatment and prognosis of serous endometrial
carcinomas and the survival advantage of anti-Her-2 treatment was established, we wanted to investigate whether
this biomarker could also be a game changer for carcinosarcomas
In our study, we did not observe Her-2 protein overexpression
in any mesenchymal component from 51 patients. In
contrast, we detected score [(+2) and (+3)] Her-2 expression
in the epithelial component in 9 (17.6%) of 51 carcinosarcoma
Her-2 overexpression in uterine carcinosarcoma samples
was reported in a range between 0% and 65% by IHC (12,13). Her-2 gene amplification according to the FISH
method varied from <1% to 20% of cases in different
case series (14,15). Saglam et al. investigated Her-2
immunoexpression in 37 uterine carcinosarcoma cases
(16). They found Her-2 score (+3) in only one case (1/37),
both in epithelial and mesenchymal areas of the tumor, and
(+2) expression in three cases (3/37); however, they did not
correlate IHC results with any ISH method.
Sawada et al. and Raspollini et al. also reported higher
expression rates of 56% and 29.2% respectively in uterine
carcinosarcomas (17,18). Both studies considered (+2) and
(+3) results as overexpression. Sawada et al. examined 16
uterine carcinosarcoma cases with Her-2 IHC and reported
overexpression in 9/16 cases with 8 of them in the epithelial
component, and only 1 of them in the mesenchymal
component. They also performed FISH in 6 cases; the
epithelial component was examined in 4 cases and the
mesenchymal component in 1 case, while the remaining
1 case was undetermined as to whether the component
was epithelial or mesenchymal. In 4 cases with Her-2
overexpression, only 1 case had low-level Her-2 DNA
amplification (Her-2/CEP17 ratio 2.0), and the remaining
5 cases were either not amplified or the Her-2/CEP17
ratio was <2.0. We also considered score [(+2) and (+3)]
results as overexpression (17.6%) based on IHC but protein
expression could not be correlated with gene amplification
by the FISH method. In our series, Her-2 expression was
observed only in the epithelial component of the tumors,
compatible with the previous studies.
Her-2 overexpression by IHC and gene amplification by
FISH were in perfect concordance in (+3) cases both in
breast and gastric carcinomas. Equivocal cases with 20–
28% amplification rates need to be clarified by molecular
methods. Because of the conflicting results about Her-2
status in uterine carcinosarcomas, we analyzed all our
cases both with IHC and FISH methods regardless of their
scoring. None of the negative, equivocal, or positive cases
according to IHC showed Her-2 amplification based on
FISH. We did not observe centromere 17 (CEP17) region
amplification. In a study by Yoshida et al. on 89 patients
diagnosed with uterine carcinosarcoma, Her-2 staining
patterns and what should be used as evaluation criteria
were emphasized (19). In this study, Her-2 examination
was performed by considering tumor samples as a single
histological type without distinction as epithelial and
mesenchymal. At the same time, Her-2 staining was
examined and compared according to both breast cancer
criteria (10) and gastric cancer criteria (20) of the ASCO/
CAP guideline. In this study, it was concluded that in the
evaluation of Her-2 in uterine carcinosarcoma, the lateral/
basolateral staining pattern gave more accurate results
instead of the complete membranous staining pattern,
and therefore it would be more appropriate to perform
the evaluation according to gastric cancer criteria rather
than breast cancer criteria. In the study of Yoshida et al.,
the frequency of Her-2 positive staining was found to be
higher than our study. In a study conducted by Rottmann
et al. on 80 patients diagnosed with ovarian and uterine carcinosarcoma, the most common staining pattern of Her-
2 was found to be incomplete-basal or basolateral staining
pattern (21). In this study, which was evaluated according
to both 2007 and 2013 breast cancer guidelines of ASCO/
CAP, the Her-2 positivity rate was found to be 16%. In our
study, the rate of (+1) patients was 17.6%, and the rate of
(+2 or +3) patients was 17.7%. The studies of Yoshida and
Rottmann provide very important information because,
according to these studies the Her-2 staining patterns in
uterine carcinosarcomas show significant differences from
The reasons for inconsistencies between Her-2 protein
products and Her-2 gene amplification can either be due to
tissue fixation/processing problems, aggressive antigen retrieval
methods, protein overexpression in transcriptional
or posttranslational steps, or chromosome 17 centromere
amplification (10). Although there were no cases of false
negativity with IHC, we noted score (+3) Her-2 expression
without amplification in two cases. Possible reasons for the
discordance between IHC and FISH could be the usage of
polyclonal antibodies, posttranslational modifications, fixation/
processing problems, and aggressive antigen retrieval
In a preclinical study conducted by Nicoletti et al. in the
carcinosarcoma cell line, the Her-2 expression level was
found to be 25%. In addition, they obtained an antitumoral
response with trastuzumab and trastuzumab emtansine (TDM1),
which is a combination of chemotherapy (emtansine)
with trastuzumab, in the Her-2 expressing cell group (22).
In a study by Raspollini et al., 28 carcinosarcoma cases were
examined. In this study, the Her-2 expression level was
found to be 32%, and it was concluded that the presence
of expression was not related to the prognosis, similar to
our research (18). In the study conducted by Livasy et al.
with 55 carcinosarcoma cases, the Her-2 expression rate
was found to be 25% in the epithelial component and 4%
in the mesenchymal component. In addition, this study
concluded that Her-2 overexpression had no prognostic
Age was a significant parameter between Her-2 score [(0)/
(+1)] and score [(+2)/ (+3)] results in our study. Although
survival rates were found to be worse in patients aged
≥65 years than in patients under 65 years of age, it is not
possible to directly correlate these survival differences with
Her-2 expression. The Her-2 score [(+2)/ (+3)] IHC results
and gene amplification (FISH test) do not seem to have
prognostic significance. Therefore, there is a need to carry
out more comprehensive studies.
In our study, Her-2 overexpression was examined by both
IHC and FISH methods in all cases to verify the accuracy
of the results. Her-2 overexpression in mesenchymal
components in our study was also consistent with the
literature, in that Her-2 overexpression in other studies was
found to be very low-level or negative in the mesenchymal
component of carcinosarcomas. Our study has some
limitations: we only included a low number of patients with
short follow-up period, and therefore the median survival
time was not reached in all cases.
The literature about Her-2 overexpression in carcinosarcomas
has quite conflicting results. This may be related to
the fact that carcinosarcomas are much less common than
other uterine malignant tumors and contain highly heterogeneous
components. For this reason, it is difficult to
obtain large case series and ensure a uniform study. More
comprehensive studies and Her-2 mutation analysis are
needed to clarify the matter further.
In our study, we did not observe Her-2 protein
overexpression in any mesenchymal component in the
tumors. In contrast, we detected score [(+2)/ (+3)] Her-
2 expression in the epithelial component in 17.6% of
carcinosarcoma samples. The Her-2 gene was not amplified
in both epithelial and mesenchymal tumor areas according
to the FISH method. A relationship between Her-2
overexpression and prognosis in uterine carcinosarcoma
could not be detected. More comprehensive studies
are needed to show the relationship between Her-2
overexpression and carcinosarcoma prognosis.
The authors thank Prof. Dr. Hulya Ellidokuz for her valuable support
in statistical analysis.
The Turkish Society of Medical Oncology funded this study with
project number 458 on the date 26/11/2020.
Conflict of Interest
I certify that all of my affiliations with or without financial involvement,
within the past 5 years and foreseeable future, and any organization
or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript are completely
disclosed (e.g., employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents received or
pending, and royalties).
Concept: HSS, MS, Design: HSS, EEP, Data collection or processing:
EA, HG, BC, Analysis or Interpretation: HSS, Literature search: BC,
MS, HSS, Writing: HSS, EA, BC, Approval: HSS.
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