Gynecologic Oncology 103 (2006) 1164 – 1168

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Case Report
Synchronous ovarian granulosa cell tumor and uterine serous carcinoma:
A rare association of a high-risk endometrial cancer with an
estrogenic ovarian tumor
Joseph T. Rabban a,⁎, Divya Gupta b , Charles J. Zaloudek a , Lee-may Chen b
a
Department of Pathology, University of California, San Francisco, CA, USA
b
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA, USA
Received 10 July 2006
Available online 10 October 2006

Abstract

Background. Ovarian granulosa cell tumors are often associated with endometrial hyperplasia or carcinoma. The endometrial carcinoma is
thought to occur under the influence of the estrogen receptor pathway and is typically a low-grade, low-stage endometrioid adenocarcinoma.
Case. We present a case of a woman with a granulosa cell tumor of the ovary and a synchronous serous carcinoma of the endometrium.
Immunohistochemical stains for estrogen receptors, progesterone receptors, and p53 protein were performed on both tumors.
Conclusions. Not all uterine tumors associated with ovarian granulosa cell tumors have low-risk histology. Preoperative evaluation of the
uterus with attention to tumor subtyping is important for optimum staging and therapy.
© 2006 Elsevier Inc. All rights reserved.

Keywords: Uterine serous carcinoma; Granulosa cell tumor; High-risk histology; p53

Introduction through a different histologic precursor known as endometrial

Granulosa cell tumors are the most common estrogenic
ovarian tumors and may be associated with a wide spectrum of
estrogen-related endometrial pathology, ranging from polyps to
endometrial hyperplasia with or without atypia to carcinoma
[1]. Endometrial carcinoma has been reported in up to
approximately 15% of such patients [2–4]. Although the
histologic subtype of the endometrial pathology has not been
described in detail, most studies indicate that these are generally
well-differentiated adenocarcinomas of low stage, which is
consistent with low-grade endometrioid adenocarcinoma
[2,3,5]. This is the expected subtype since endometrioid
adenocarcinomas typically evolve via an estrogen-driven
pathway that progresses through a histologic precursor stage
of endometrial hyperplasia. In contrast to this so-called type 1
pathway, type 2 uterine cancers, of which serous carcinoma is
the prototype, appear unrelated to estrogen stimulation, arise
⁎ Corresponding author. UCSF Department of Pathology, M-551, 505
Parnassus Avenue, San Francisco, CA 94143, USA. Fax: +1 415 353 1200.
E-mail address: joseph.rabban@ucsf.edu (J.T. Rabban).
0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2006.09.005
intraepithelial carcinoma, and exhibit more aggressive behavior.
Mutation of the p53 tumor suppressor gene is uncommon in
endometrioid carcinoma, but it appears to be a critical early
event in the evolution of serous carcinoma [6]. We report a
unique case of synchronous uterine serous carcinoma and
ovarian granulosa cell tumor, an unusual association of a high-
risk histologic subtype of endometrial cancer with an estrogen-
producing ovarian tumor.
Case report
Clinical presentation
The patient was an 80-year-old gravida one, para one
Caucasian woman who presented with uterine bleeding.
Menarche was at age 14, and she had regular menses until
menopause at age 52. She had not taken oral contraceptive pills
or hormone therapy. Other than uterine bleeding, she described
no other symptoms. Her body mass index was 24.7. Her
gynecologic evaluation revealed a 12 cm globular uterus. An
abdominopelvic computed tomography scan revealed a fibroid
 J.T. Rabban et al. / Gynecologic Oncology 103 (2006) 1164–1168 1165

uterus containing a 5.9 cm mass in the right posterolateral

uterine wall. The radiologic differential diagnosis was a
pedunculated leiomyoma versus an adnexal mass. An endome-
trial biopsy was performed and demonstrated a high-risk
histology adenocarcinoma. Clinically she was managed as if
she had either a synchronous ovarian and uterine carcinoma or a
uterine carcinoma metastatic to the adnexa. The patient
underwent an exploratory laparotomy, total abdominal hyster-
ectomy, bilateral pelvic and periaortic lymphadenectomy,
omentectomy, peritoneal biopsies, and pelvic washings. Intrao-
perative findings included a 16-week leiomyomatous uterus and
a 7.9 cm right ovarian mass.

Pathological findings

The endometrial biopsy contained a villoglandular adeno-

carcinoma with high-grade nuclear features, including enlarged
hyperchromatic nuclei, marked nuclear pleomorphism, promi-
nent nucleoli, nuclear crowding and loss of polarity, and
numerous mitotic figures. The differential diagnosis was a
serous carcinoma growing in a predominantly tubuloglandular
pattern versus a villoglandular endometrioid adenocarcinoma
with high nuclear grade. Tissue was not available to perform an
immunohistochemical stain for p53 or estrogen receptors.
The hysterectomy specimen included a 7.9 cm solid tan-
yellow right ovarian mass with a smooth surface. The uterus
contained several endometrial polyps measuring up to 1.2 cm
each and multiple well-circumscribed white whorled myometrial
nodules compatible with leiomyomas ranging up to 7 cm each.
Microscopically, the right ovarian tumor displayed the
diffuse growth pattern of adult granulosa cell tumor (Fig. 1A).
The tumor cells had uniform plump basophilic nuclei and scanty
cytoplasm. Nuclear grooves were noted in many nuclei (Fig.
1B). No significant nuclear pleomorphism was present. Mitotic
activity averaged 2 mitoses per 10 high-power fields. No
surface involvement was present. Immunohistochemical stains
for inhibin and calretinin were strongly positive in the tumor
cells while staining for epithelial membrane antigen was
negative (Fig. 1C). The morphologic features and immunophe-
notype were diagnostic of an adult granulosa cell tumor.
The nonneoplastic endometrium showed atrophy, cystic
hyperplasia and polyps. The main finding was an exophytic
papillary and tubuloglandular proliferation of high-grade tumor
cells similar to those seen in the biopsy (Fig. 2A). The carcinoma
also involved polyps and replaced atrophic endometrium (Fig.
2D). There was marked nuclear enlargement, crowding, loss of
polarity, hyperchromasia, and pleomorphism. Numerous mitotic
figures were present (>30 mitoses per 10 high power fields), many
of which were atypical (Figs. 2B and E). There was no resemblance
to the tumor cells in the ovary. Immunohistochemical staining for
p53 showed diffuse intense nuclear reactivity in essentially all of
the endometrial tumor cells (Figs. 2C and F). Immunohistochem-
ical staining for estrogen receptors was negative except in a focal
minority of tumor cells that showed minimal weak patchy nuclear
reactivity. The morphology and immunophenotype were diagnos-
tic of uterine serous carcinoma. The carcinoma was confined to the
endometrium; no myometrial or lymphovascular space invasion
Fig. 1. (A) The ovarian granulosa cell tumor grows in diffuse solid sheets. (B)
Grooves, folds, and irregular contours characterize granulosa cell tumor nuclei.
(C) Tumor cells express calretinin by immunohistochemical staining.
was identified and the cervix was not involved. At the periphery of
the carcinoma, the background atrophic endometrium and a polyp
were involved by endometrial intraepithelial carcinoma. In these
areas, the surface endometrium and glands were lined by tumor
cells that did not invade the surrounding stroma (Fig. 3A). These
foci strongly expressed p53 by immunohistochemistry (Fig. 3B).
In contrast, the ovarian tumor cells did not express p53. The foci of
endometrial hyperplasia were also negative for p53. Strong
immunohistochemical staining for progesterone receptors was
present in approximately half of the serous carcinoma cells and in
many endometrial cells lining hyperplastic glands. Immunohisto-
chemical staining for estrogen receptors was weak and focal in the
serous carcinoma tumor cells but strong and diffuse in the
background benign endometrial glands and in hyperplastic glands
(Fig. 3C).
The myometrium contained multiple leiomyomas. Pelvic
and para-aortic lymph nodes were all free of tumor, as were
multiple peritoneal biopsies and the omentum. The uterine
serous carcinoma was staged as FIGO stage IA as was the
ovarian granulosa cell tumor.
Follow-up
The patient's post-operative course was uncomplicated. She
was recommended for pelvic radiation but did not receive any
1166 J.T. Rabban et al. / Gynecologic Oncology 103 (2006) 1164–1168

Fig. 2. (A) The uterine serous carcinoma grows in an exophytic papillary and tubuloglandular pattern replacing the atrophic endometrial surface. Endometrial cystic
hyperplasia can be seen in the lower right corner of the image. (B) High magnification of the main tumor shows high-grade cytology, including nuclear enlargement,
hyperchromasia, crowding, pleomorphism, and brisk mitotic activity. (C) Immunohistochemical expression of p53 is intense and diffuse throughout the main tumor.
(D) Serous carcinoma focally colonizes the surface of an atrophic endometrial polyp. (E) Compared to the small, orderly columnar cells of a benign endometrial gland
(right edge of image), serous carcinoma cells are enlarged, hyperchromatic, crowded, pleomorphic and mitotically active, similar to the cytology of the main tumor. (F)
Immunohistochemical expression of p53 is intense and diffuse throughout the tumor colonizing the polyp, similar to the main tumor.

adjuvant treatment. At the time of this report, the patient is alive
without any evidence of disease 56 months following her
hysterectomy.
Discussion
The case that we report is unique in that an ovarian granulosa
cell tumor, an estrogen secreting ovarian neoplasm, is
associated with a serous endometrial carcinoma, a type of
endometrial cancer that appears to initially develop along a
pathway that is unrelated to estrogenic stimulation. Granulosa
cell tumor is the most common estrogen producing ovarian
tumor followed by thecoma [1]. Endometrial effects of estrogen
secreting ovarian neoplasms range from cystic hyperplasia to
atypical hyperplasia to adenocarcinoma. The first report of a
concurrent ovarian granulosa cell tumor and a uterine
carcinoma is attributed to Schroeder in 1922 [7]. Early
observers combined ovarian granulosa cell tumors and
thecomas together as so-called feminizing mesenchymomas of
the ovary or feminizing ovarian tumors and reported a spectrum
of endometrial pathologies related to hyperestrogenism [8–12].
Large follow-up studies of ovarian granulosa cell tumors have
found that approximately two-thirds of patients present with
menstrual cycle abnormalities or post-menopausal uterine
bleeding; approximately two-thirds have endometrial hyperpla-
sia in biopsy material or at hysterectomy; up to one-third may
have atypical endometrial hyperplasia; and up to one-fifth have
an endometrial carcinoma [2–5,13]. A causal relationship is
thought to exist between estrogen production by granulosa cell
tumors and development of endometrial carcinoma. Recently, a
dualistic model of the pathogenesis of endometrial carcinoma
has been proposed based on clinical, morphologic, immuno-
phenotypic, and molecular observations. Hyperestrogenism
is a hallmark of a so-called type 1 carcinomas, of which endo-
metrioid adenocarcinoma is the prototype. Type 1 carcinomas
arise in a background of endometrial hyperplasia, usually
express estrogen and progesterone receptors, and are associated
with elevated serum estradiol levels [6]. Thus, it would be
expected that endometrial carcinomas that arise in association
with ovarian granulosa cell tumors would be of the endome-
trioid subtype. The histologic type of uterine carcinomas arising
in women with ovarian granulosa cell tumors has not been
explicitly described in the literature. Most studies use the
general term “adenocarcinoma” without further specification
[2–5,13]. Some authors describe adenocarcinomas with squa-
mous differentiation [4]. Of those who report a tumor grade and
stage, most find that the carcinomas are low-grade and low-
stage; rare cases of carcinosarcoma and endometrial sarcoma
 J.T. Rabban et al. / Gynecologic Oncology 103 (2006) 1164–1168
have been noted [2,3], Thus, most uterine tumors that develop
in women with granulosa cell tumors are low-grade, early-stage
endometrioid adenocarcinomas.
Fig. 3. (A) Endometrial cystic hyperplasia (left half of image), consisting of
crowded small simple endometrial glands mixed with large dilated glands, is
adjacent to serous carcinoma (right half of image), growing in a glandular
pattern. (B) The nuclei of the serous carcinoma cells strongly express p53 by
immunohistochemistry, whereas the hyperplastic glands do not. (C) Conversely,
the nuclei of the hyperplastic glands strongly express estrogen receptor by
immunohistochemistry, whereas the serous carcinoma does not. Elsewhere (not
shown), patchy weak estrogen receptor expression was noted in some serous
carcinoma nuclei.
1167
Type 2 carcinomas (serous and clear cell carcinomas and
carcinosarcoma) comprise 10% to 20% of all endometrial
carcinomas and differ from type 1 tumors in that they appear to
be unrelated to hyperestrogenism, do not arise in a background
of endometrial hyperplasia, uncommonly express estrogen and
progesterone receptors, are of high histologic grade, and are
clinically aggressive [6]. Serous carcinoma is the most
important tumor in this category. The molecular pathogenesis
of type 2 carcinomas also appears to differ from that of type 1
carcinoma. Alterations in the tumor suppressor gene PTEN,
which codes for a tyrosine kinase protein, appear to be critical
early events in the pathogenesis of most endometrioid
adenocarcinomas. Microsatellite instability and K-ras altera-
tions are also associated with the early development of some
type 1 uterine carcinomas [6]. In contrast, these alterations are
uncommon in type 2 carcinomas. Instead, mutations in the
tumor suppressor gene p53 appear to be important in the early
pathogenesis of uterine serous carcinoma. Most uterine serous
carcinomas harbor p53 mutations, and the accumulation of the
altered protein in the tumor cell nuclei can be detected
immunohistochemically, serving a helpful diagnostic role.
Unlike endometrioid adenocarcinoma, whose precursor lesion
is atypical hyperplasia, mounting evidence suggests that
endometrial intraepithelial carcinoma (EIC) is the precursor to
serous carcinoma. In pure EIC, tumor cells similar to those of
serous carcinoma replace the surface epithelium or the lining of
superficial endometrial glands without invading the stroma.
Pure EIC typically arises in atrophic endometrium or endome-
trial polyps and can also be found adjacent to invasive serous
carcinoma. EIC harbors the same rate of p53 mutations as
serous carcinoma, and the immunohistochemical expression of
p53 is also similar. Thus, two distinct phenotypic and genetic
classes of endometrial carcinoma have been proposed [6].
In this case, the endometrial carcinoma exhibited the
tubuloglandular and papillary morphology of serous carcino-
ma. EIC was present adjacent to the serous carcinoma, and both
the carcinoma and the EIC showed strong positive nuclear
staining for p53 protein. These are histologic features of a so-
called type 2 carcinoma. There were, however, some findings
that were more in keeping with a type 1 carcinoma, such as the
focal expression of estrogen and progesterone receptors and the
focal presence of endometrial hyperplasia, which are typically
associated with type 1 carcinomas. Two different possible
pathways could explain how this endometrial tumor developed.
This could be an entirely de novo serous carcinoma arising
initially independently of the estrogen pathway; the focal
expression of estrogen receptors may have allowed the hyper-
estrogenic environment of the ovarian tumor to promote
growth of the endometrial tumor. Alternatively, the serous
morphology could represent tumor progression from what was
initially an endometrioid adenocarcinoma. Features favoring
the former pathway include the presence of EIC flanking the
serous carcinoma and the lack of atypical hyperplasia or
component of endometrioid adenocarcinoma. However, we
cannot definitively distinguish between these two possibilities.
From a clinical perspective, this case demonstrates that not all
uterine tumors associated with ovarian granulosa cell tumors are
1168 J.T. Rabban et al. / Gynecologic Oncology 103 (2006) 1164–1168
low-grade endometrioid adenocarcinomas. Regardless of how
this serous carcinoma developed, this is a high-risk endometrial
cancer with a propensity for aggressive behavior even in the
absence of a large primary or deep myometrial invasion.
Treatment typically involves complete surgical staging and
consideration of adjuvant therapy. This patient had complete
surgical staging and was FIGO stage IA. Her good clinical
outcome at 56 months of follow-up is consistent with the
literature on surgically staged early uterine serous carcinoma.
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