Malignant mixed mullerian tumors are very rare genital tumors. They are biphasic neoplasms composed of an admixture of malignant epithelial and mesenchymal elements. In descending order of frequency they originate in the uterus, ovaries, fallopian tubes, cervix and vagina. Also they arise denovo from peritoneum. They are highly aggressive and tend to occur in postmenopausal low parity women. Because of rarity, there is as such no treatment guidelines available. Multimodality treatment in the form of radical surgery followed by adjuvant chemotherapy or radiotherapy or combined chemoradiation gives a better prognosis & outcome. Two case reports of such tumors, one from ovary and other from penitoneum are presented along with the review of literature.
2. Review Article
INTRODUCTION
MALIGNANT mixed mullerian tumors (MMMT) are highly
aggressive tumors, usually diagnosed in advanced stage and
have an extremely poor long term prognosis. MMMTs
include both malignant epithelial and mesenchymal or
stromal elements. MMMT arising from the endometrium
are the most common sarcomas of genital tract. However
they may arise from other tissues derived from mullerian
system such as cervix, vagina, tubes and ovary. Also they
may arise from extra genital sites like denovo peritoneal.
MMMTs are subdivided into homologous and hetrologous
tumors. In homologous tumors, both the carcinomatous and
sarcomatous elements present arise from normal
components of the mullerian system. Where as, in
heterologous tumors, sarcomatous elements arising from
tissue not normally found in mullerian system like skeletal
muscle, bone, cartilage etc are present. The prognosis
depends on the degree of the carcinomatous component.
Because of rarity, we report 2 cases of MMMT, one arising
from ovary and one arising denovo from peritoneum.
CASE REPORT 1
A sixty seven years, old lady P4 obese, hypertensive,
diabetic with interstitial lung disease was admitted to the
hospital with the diagnosis of a pelvic mass diagnosed on
CECT abdomen outside hospital. Initially she had loss of
appetite and irritable bowel habits for which she was
investigated and CECT of whole abdomen was done which
revealed a large complex adnexal mass. Her upper GI
endoscopy and colonoscopy were normal. Her CA125 was
133.2 μ/mL and other tumor markers were normal. USG
whole abdomen revealed a right adnexal mass of 24.9×9.5
cm size, cystic with internal septations with high resistance
flow in septal vessels. X ray chest showed interstitial
pneumonitis for which, she was treated. Keeping in mind,
the diagnosis of malignant ovarian tumor, she underwent
staging laparotomy.At laparotomy, uterus and left tube and
ovary were grossly normal. There was a large friable solid
cum cystic mass seen arising from right adnexa adharent to
omentum and intestine. Omentum and pelvic peritoneum
were studded with metastatic deposits. Moderate ascities
was present. Total abdominal hysterectomy, bilateral
salpingo oophorectomy, omentectomy bilateral pelvic and
para-aortic lymphadenectomy and resection of peritoneal
metastatic deposits were carried out and optimal
cytoreduction achieved. With an established blood loss of
1200cc, the patient received 3 units of PRC. Her
postoperative period was uneventful and she was
discharged on 8th post operative day.
Histopathology
The sections of ovarian cyst showed partial linning by
low cuboidal cells.Most of cyst linning was lost and
replaced by necrotic slough. The cyst wall was thickened
and replaced by tumor showing two distinct morphological
appearances. Most areas were showing a polymorphic
infiltrate with round to spindle cells admixed with
227 Apollo Medicine, Vol. 6, No. 3, September 2009
MALIGNANT MIXED MULLERIAN TUMOR – CASE REPORTSAND REVIEW ARTICLE
Shakti Bhan Khanna*, Kiranabala Dash** and Deep Shikha Arora***
*Senior Consultant & Clinical Coordinator, Obstetrics & Gynaecology & Gynae. Oncosurgeon, **Associate Consultant,
Department of Obstetrics and Gynaecology, ***Senior Consutlant Histopathology,
Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
Correspondence to: Prof (Dr) Shakti Bhan Khanna, Senior Consultant & Clinical Coordinator, Obstetrics & Gynaecology
& Gynae. Oncosurgeon, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
e-mail: sbkhanna@yahoo.com
Malignant mixed mullerian tumors are very rare genital tumors. They are biphasic neoplasms composed of an
admixture of malignant epithelial and mesenchymal elements. In descending order of frequency they originate
in the uterus, ovaries, fallopian tubes, cervix and vagina. Also they arise denovo from peritoneum. They are
highly aggressive and tend to occur in postmenopausal low parity women. Because of rarity, there is as such
no treatment guidelines available. Multimodality treatment in the form of radical surgery followed by adjuvant
chemotherapy or radiotherapy or combined chemoradiation gives a better prognosis & outcome. Two case
reports of such tumors, one from ovary and other from penitoneum are presented along with the review of
literature.
Key words: Malignant Mixed Mullerian Tumors, Mullerian system, Radical surgery, Chemotherapy.
3. Apollo Medicine, Vol. 6, No. 3, September 2009 228
Review Article
lymphohistiocystic cells. Mild nuclear pleomorphism was
seen in this component. Other smaller areas showed single
cell infiltration, cords and nests of round epithelial cells.
Moderate nuclear plemorphism was seen. A few mitoses
were present. Large areas of necrosis and mixed
inflammatory cell infiltrate was seen (Fig .1).
Sections of cervix, uterus, left tube and ovary were
unremarkable and peritoneal deposits showed fibro-
vascular and adipose tissue with a tumor deposits of spindle
cell component with fibrohistiocytic appearance. No
evidence of metastasis was seen in the lymphnodes.
On immunohistochemistry the epithelial and spindle
cells showed positivity with CK7 & CA125.The tumor was
negative for CK20. Scattered reactive cells showed
positivity with LCA(Lymphocyte marker) and CD 68
(histiocytic marker) (Fig. 2).
With the diagnosis of malignant mixed mullerian tumor
of ovary with metastatic deposits showing sarcomatous
component (Stage III C) she was given 6 cycles of
chemotherapy with carboplatin and intaxel. She was
disease free for 18 months, but did not turn up for follow up
after that.
CASE REPORT 2
A fifty nine years, P2 postmenopausal for 15 years,
obese, normotensive, non diabetic, presented with pain in
lower abdomen, frequency of micturition and dyspepsia.
She had ultrasound of abdomen done which revealed a
large complex pelvic mass of ? uterine? ovarian origin. On
examination, there was a firm to hard large mass filling
whole of the pelvis probably in continuation with uterus.
Her repeat USG whole abdomen revealed a large 13×7.7cm
mass in right side of pelvis with poor visualization of
intervening fat plane with uterus and intralesional
vascularity. Both ovaries could not be visualized.
Endometrial thickness was 8.9mm. Her Sr. CA 125 was
463.3μ/mL. Her endometrial aspiration cytology revealed
inactive endometrium. So, with a provisional diagnosis of
ovarian tumor, she was taken up for laparotomy.
At operation, moderate haemorrhagic ascitic fluid was
seen which was sent for cytology. Large fungating,
irregular, friable and necrotic mass of around 12×10cm was
seen in the pelvis adherent to sigmoid colon and left
fallopian tube. Uterus and ovaries were atrophic and
healthy looking. Tumor was separate from the ovaries. No
deposits were seen on ovaries. Multiple tumor deposits
were found on the omentum, over the pancreas and gall
bladder area. No metastatic deposits felt on the liver and
undersurfaces of diaphragm. Mass sent for frozen section
which was suggestive of high grade malignancy.
In view of atrophic endometriunm, normal looking
uterus and ovaries, tumor debulking and total omentectomy
was done. Her post operative period was uneventful and she
was discharged from the hospital on 7th post operative day.
Histopathology
Section showed multiple fragments infiltrated by a
tumor exhibiting biphasic morphology. Many areas showed
epithelioid appearance and were composed of round to
Fig.1. H&E (4x;20x,40x): The tumor show complex tubulo
papillary architecture (A) The lining cuboidal cells show
stratification and nuclear atypia (B) The cyst wall shows
cords & nests of epitheloid cells (C) and cellular
mitotically active spindle cells area (D).
Fig.2. Immunohistochemistry the tumor shows epithelial
component positive for CA 125 & CK 7. The stromal
component is positive for vimentin & weakly positive
for CK 7.
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229 Apollo Medicine, Vol. 6, No. 3, September 2009
polygonal cells, lying in solid sheets, nests, forming
complex glandular to papillary structures at places showing
prominent nuclear palisading. These were closely admixed
with the other components which composed of spindle
shaped cells, arranged in sheets and fascicles. Foci of
cartilaginous differentiation were also seen.These spindle
cells also exihibited moderate to marked nuclear
pleomorphism. Frequent mitoses were seen in both the
areas. Many bizzare cells and tumor giant cells were also
seen (Figs. 3 & 4). Sections from the omental nodule also
showed metastatic deposits of a high grade malignancy of
similar morphology.
Fig. 3. H & E (10x;20x) The tumours shows variable
morphological appearances. These include tubulopillary
architecture (A) nuclear palisading (B) and cartilaginous
differentiation (C&D).
Fig.5. Immunohistochemistry. The mesenchymal component
shows endometrial stromal (CD10 positive) and skeletal
muscle (Desmin positive) differentiation. The epithelial
component is positive for cytokeratin (CK).
Fig.4. H&E (40x): The tumor shows biphasic growth (A) with
nuclear atypia & mistosis in both components (B). Many
hyaline globules are seen (C ). Nuclear pleomorphism
is marked with many bizzare forms and tumor giant cells
(D)
On immunohistochemistry, the round cell areas in the
tumor showed strong positivity with cytokeratin, while the
spindle cell areas were positive for vimentin and showed
patchy positivity with CD 10 and desmin. The tumor cells
was negative for caldesmon (Fig. 5).
A diagnosis of primary peritoneal MMMT was made.
After case discussion in tumor board she was advised
chemotherapy with ifosfamide and cisplatin.She
completed 6 cycles of chemotherapy and is doing well at
present with 13 months follow up. Her follow up CECT
whole abdomen at one year showed no recurrence.
DISCUSSION
MMMT was described by Weber in the year 1867 [1]. In
the year 1970, MMMTs were further classified by
Kempson and Bare as heterogenous or homologous on the
basis of the type of sarcomatous elements [1]. Although
little is known about their pathogenesis, more recent
clinicopathological, immuno histochemical and cell
culture studies suggest that these malignant elements are
not distinct in their origin. Malignant epithelial cells have
been shown to differentiate into either malignant epithelial
or stromal tumor and terms biphasic carcinoma and
carcinosarcoma have been used.
Four theories have been proposed regarding
histogenesis of MMMT [2].
(i) Collision theory or biclonal theory
(ii) Combination theory or monoclonal theory
(iii) Composition theory
5. Apollo Medicine, Vol. 6, No. 3, September 2009 230
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(iv) Metaplastic carcinoma theory
(i) Collision theory:- The collision theory suggests that
tumor has a biclonal origin where two distinct,
neoplastic, separate, synchronous proliferations or
clones fuse to form one tumor.
(ii) Combination or monoclonal theory:- This theory
postulates that the epithelial and sarcomatous
components share the same originating stem cell and
represent an extreme manifestation of phenotypic
diversity.
(iii) Composition theory:- This suggests monoclonal
origin postulating that sarcomatoid component
originates from the epithelial component during a
metaplastic transformation. It again postulates that
the sarcomatoid component is reactive and not
neoplastic, developing as a consequence of paracrine
factors secreted by epithelial component.
(iv) Metaplastic carcinoma:- This theory favours a
common cell of origin, claiming that the carcinoma
precedes and gives rise to the sarcomatous
component by metaplasia of a subclonal population.
This theory is favoured currently.
MMMT of uterus
The incidence of MMMT is very low accounting for about
2-5% of all tumors arising from the uterus [3]. These are
highly aggressive tumors with five years survival rates of
about 30-40% in stage 1 disease and much lesser rates are
seen in advanced disease [3]. MMMT of uterus usually
arise from endometrium with predominent epithelial
component. Endometriod adenocarcinoma is the most
common epithelial component. The mesodermal compo-
nent is the most commonly undifferentiated sarcoma in
homologous tumors and rhabdomyosarcoma in hetero-
logous tumors. The majority of the patients present in their
5th and 7th decade of life and most of them are
postmenopausal [3]. Macasaet and Williamson have
reported association of obesity in 20% to 31% of cases
[4,5]. Nulliparity has been reported to occur in from 0-
32% of patients [3-5]. Previous pelvic radiation is a
recognized predisposing factor in some [3-6]. Uterine
MMMT has also been reported in women who have
received estrogen replacement therapy or unopposed
estrogen stimulation or long term tamoxifen [7-9]. The
majority of patients present with vaginal bleeding. Uterine
enlargement is by far the commonest finding in these
patients. Histopathological diagnosis from endometrial
curettage can be made only in 50-70% of cases [10,11].
Ho and Ho in 2002 have reported 26 patients of uterine
MMMTs and in most of the cases diagnosis was obtained
from endometrial curettings [3].
Piver and Lurian reviewed 19 studies including 610
patients [12]. They found the average 5 years survival for
all stages to be 21% only. 70-90% of tumor related deaths
occur within 18 months of diagnosis. This was because of
the fact that most of the patients presented at an advanced
stage and highly aggressive character of the tumor. The
most important prognostic factor in uterine MMMT is the
extent of the tumor at the time of diagnosis and treatment.
Di Saia, et al in 1973 studied 94 patients and found that
patients with stage 1 disease had a 53 % two year survival
rate, where as survival decreased to 8.5% in stage II and
stage III when disease had extended to cervix,vagina or
parametrium [13]. In the series of Ho and Ho in 2002,
50% of patients had presented at an advanced stage and all
of them died within 2 years of diagnosis [3]. The other
important prognostic factor is the depth of myometrial
invasion. Increasing depth of myometrial invasion is
associated with poorer survival [8]. Whether the presence
of heterologous component has any association with
prognosis is controversial. According to some authors,
prognosis is poorer in the heterologous tumors [14].
However others did not find any differences in survival
[3,14]. Positive peritoneal washings are associated with a
poorer prognosis reflecting the advanced stage of the
disease.
Staging of MMMTs of the uterus is same as for
endometrial carcinoma. Tumor spread occurs by direct
extension to cervix, vagina and other pelvic organs.
Lymphatic spread occurs to local & regional lymphnodes
and is more common. Usually 1/3rd of patients have
lymph node metastasis at the time of diagnosis
Hematogenous spread is also seen and usually involves
lung, liver and bone.
Treatment
Because of aggressiveness of the tumor, and poor
prognosis various therapeutic modalities have been used.
Surgery in the form of abdominal hysterectomy and
bilateral salpingo-oopherectomy remains as the principal
treatment. Adjuvant radiotherapy is beneficial when
disease is limited to pelvis. Chemotherapy has been shown
to have beneficial effect. Kohorn, et al have reported an
80% survival of 3-5 yrs in 5 patients treated by a
combination of surgery, radiotherapy and chemotherapy
[15]. Ho & Ho also observed an improved survival by
adjuvant chemotherapy and also combined
chemoradiation [3]. Few studies have demonstrated the
expression of estrogen and progesteron receptors in
MMMT [16]. The apparent link between excessive
estrogen exposure, MMMT and expression of hormonal
receptors indicate that antiestrogen therapy may be
effective in uterine MMMT. Wang, et al in 2005 reported
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231 Apollo Medicine, Vol. 6, No. 3, September 2009
the use of Letrozole( aromatose inhibitor ) in the treatment
of recurrent high grade uterine MMMT and observed a
partial response till 11months after treatment [16].
MMMT of ovary
MMMT of ovary otherwise known as ovarian
carcinosarcoma is extremely rare constituting 1 to 2 % of
all ovarian malignancies [17]. They are one of the most
highly malignant forms of ovarian cancer. These patients
also present in their 5th & 7th decade of life, though its
occurance in younger age group is also reported [17].
They are usually seen among postmenopausal nullipara .
An association with abnormal 5th chromosome has been
described [18]. These tumors are usually asymptomatic till
they become very large in size and may present with
abdominal pain, altered bowel habit, urinary symptoms,
abdominal distention and occasionally vaginal bleeding.
More than 80% of patients have an extra-ovarian
abdominal spread [17].
The tumors are usually unilateral, soft and fleshy, often
with areas of haemorrhage and necrosis filling whole of
the pelvis and even abdomen. The tumor consists of
carcinomatous component and homologus or heterologus
sarcomatous component. The carcinomatous components
commonly consist of adenocarcinoma (serous, mucinous
or papillary). On the other hand most common are
homologous sarcomas (fibrosarcoma, angiosarcoma and
leiomyosarcoma) although heterologous sarcomas are
also seen.In our case the sarcomatous component was
homologus containing spindle cells.
The largest series of 382 patients of ovarian MMMT is
annalysed by Barnholtz-sloan, et al and compared with
14025 women with epithelial ovarian cancer. They found
women with ovarian MMMT had a significant increased
risk of death from any cause compared with the other
group.
They observed a 60% increased risk of death in
advanced ovarian MMMT compared to advanced stage
epithelial ovarian cancer. There was no difference in risk
of death for these two groups of women with early stage
disease [19].
Like other ovarian malignancies treatment of all stage
tumors includes Total abdominal hysterectomy, bilateral
salpingo oophorectomy, omentectomy, bilateral pelvic &
paraortic lymphadenectomy and excision of all resectable
tumor. This should be followed by chemotherapy. Most
significant prognostic factors is the stage and residual
disease following cytoreduction.
Several combination chemotherapy regimens have
been studied in ovarin MMMT.
Le, et al. treated 29 patients of MMMT of the ovary
with cisplatin and doxorubacin as adjuvant therapy
resulting in a survival of 35% at 5 years and a median
survival of 16 to 18 months [20]. A phase to II GOG trial
however, observed only a 3.6% complete response and
14.3% partial response in patients with recurrent MMMT
of the ovary treated with ifosfamide and mesna after
platinum based chemotherapy [21]. Sit, et al reported a
median survival of 23 months in patients treated with
platinum/ ifosfamide and a median survival of 19 months
in patients treated with paclitaxel/carboplatin [22]. In the
present case report, the patient had received carboplatin
and intaxel and remained disease free at least up to 18
months. It seems that optimal chemotherphy regimen for
the disease remains to be determined. However Platinum
based chemotherapy in combination with ifosfamide or
paclitaxel may be active against these rare malignancies.
MMMT of fallopian tube
Primary malignant tumor of the fallopian tube are
uncommon and malignant mixed mullerian tumor
(MMMT) of the fallopian tube are extremely rare. Only
approximately 64 cases have been reported so far [23].
Most patients had the disease in their 5th or 6th decade of
life.
Approximately all patients with tubal MMMT are
postmenopausal. The usual presentation includes a watery
or bloody vaginal discharge, abdominal pain or both.
Grossly, the tumors spread to pelvis or abdomen.
Lumen of tube is usually filled with solid neoplastic tissue
that contains areas of hemorrhage and necrosis.
Microscopically distinct carcinomatous and sarcomatous
components resemble those of MMMT found elsewhere
in genital tract. Presence of mesenchymal element which
is an essential requiste for MMMT has been found to be
heterologous in more than half of the cases. Treatment
includes cytoreductive surgery as in case of ovarian
malignancy followed by platinum based chemotherapy.
MMMT of Cervix
MMMT of the cervix is extremely rare. It was first
described in 1951 by Ferriera [24]. Approximately 50
cases has been reported so far [25]. All the reported cases
of cervical MMMT are tabulated in Table 1 [25-29].
Cervical MMT usually occurs in postmenopausal women
in their 6th decade of life though the age range varies from
12-93 years.The commonest clinical features include
vaginal bleeding and polypoidal cervical mass.
Maheshwari, et al in 2006 reported a case of Cervical
MMMT who presented with large pelvic mass [25].
Diagnosis is made by Histopathology. These tumors
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usually arise in the endocervical polyp and histologically
resemble endometrial stromal sarcoma. The islands of
squamous differentiation is clue to diagnosis . Clement, et
al reported the largest single series of nine cases of
cervical MMMT [35]. Cervical MMMT is more often
confined to the cervix and uterus at the time of
presentation. Behavior of this tumor is dominated by the
carcinomatous component.
Due to rarity of these tumors, no evidence based
management guidelines are available. Radical surgery is
the principal modality of treatment. Although adjuvant
chemotherapy and radiotherapy have been used with good
results, their role is not well defined. Commonly used
chemotherapeutic agents are cisplatin, doxorubicin,
ifosfamide or cyclophophamide. Radiotherapy is
beneficial for locally advanced disease. Grayson, et al
studied HPV status in 8 patients with cervical MMMT.
Though on PCR all eight were positive for HPV, using in
situ hybridization technique they demonstrated HPV 16
DNA in the nucleus of both epithelial and sarcomatous
components in 3 cases suggesting metaplastic theory of
histogenesis in cervical MMMT [36].
MMMT of vagina
Primary MMMT of the vagina is very rare. The first
case of vaginal MMMT was described by Davis &
Franklin in the year 1975 [40]. Till date only 10 cases of
vaginal MMT have been reported in literature. Table 2
describes all the reported cases of vaginal MMMT and
their outcome [40-46]. Squamous cell carcinoma is by far
the commonest epithelial component. The age of these
patients varied from 57 to 74 years. Prior history of
radiation was found to be associated with such tumor [42-
46]. The diagnosis of primary MMMT of vagina is made
on the following evidences.
(a) location in vagina without involvment of cervix or
vulva.
(b) mixed histological appearance of carcinoma and
sacromatous component.
(c) lack of evidence of any other primary tumor which
metastasizes to vagina.
Treatment includes surgery in the form of wide
excision or total vaginectomy and radiation. Prognosis
remains to be very poor. Six out of ten patients. reported so
far have died of the disease. Sebenik, et al have reported
presence of integrated High risk HPV DNA in both
epethelial and sarcomatous component of vaginal
MMMT, thus it may suggests that at least some of these
cases are probably HPV related and this also favours the
metaplastic theory of histogenesis [46].
Primary peritoneal/Extragenital MMMTs
This was first described by Ober & Black in 1955
[47]. Till date only 32 cases have been reported in
literature and ours may be the 33rd case [47-48]. Table 3
shows all the reported cases of primary peritoneal
MMMTS.
Though the origin is not known, various authors have
found endometriosis to be associated with such type of
tumor suggesting that primary peritoneal MMMTs may
originate from a pre existent foci of endometriosis
[47,53,54,65]. There are also reports of primary MMMT
of peritoneum not associated with endometriosis. In such
cases mullerian duct remnants have been postulated to be
potential proginators. Some patients may have a history of
prior gynaecologic cancer [50,51,56,60,62]. Additionally
few studies have shown that patients also had prior pelvic
radiation therapy [47,54,59,62,65]. BRCA I gene is
supposed to be some how involved with this malignancy
[64]. The case reported from our institution did not have
any such history.
Most of these tumor are heterologous in type so also
was our case. Primary MMMT of the peritoneum is a rare
tumor occurring in elderly postmenopausal women. Most
common clinical presentation is presence of abdomino
pelvic mass. Usually the prognosis is very poor. Though
experience with surgical and post operative treatment is
limited, cytoreductive surgery and adjuvant
chemotherapy like that of ovarian MMMT have been
advocated. The present case report probably had sub
optimal cytoreduction. This was due to the fact that the
origin and type of malignancy was not known at the time
of surgery. Frozen section showed only high grade
malignancy. Endometrial aspiration showed atrophic
endometrium and at the operation sites uterus and ovaries
looked atrophic without any suspicious of malignancy.
However, after histopathological report was received,
patient was given six cycles of chemotherapy.
As ifosfamide & cisplatin have been identified to be
the most active agents for uterine MMMTs by Gynae
oncology group, these agents are choosen for primary
MMMT of the peritoneum also. Role of radiotherapy
remains controversial. Ma-Lee Ko, et al suggested a
multimodality treatment by optimal cytoreduction, a
combination chemotherapy with ifosfamide and cisplatin
followed by pelvic irradiation. They reported a longest
disease free interval of 48 months [70].
Other extragenital MMMTs involving stomach &
esophagus( 30 cases), colon ( 9 cases ) and spleen (2
cases) have also been reported in literature [71].
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239 Apollo Medicine, Vol. 6, No. 3, September 2009
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