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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
Pathological findings
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 bleeding; approximately two-thirds have endometrial hyperpla-
without any evidence of disease 56 months following her sia in biopsy material or at hysterectomy; up to one-third may
hysterectomy. have atypical endometrial hyperplasia; and up to one-fifth have
an endometrial carcinoma [2–5,13]. A causal relationship is
Discussion thought to exist between estrogen production by granulosa cell
tumors and development of endometrial carcinoma. Recently, a
The case that we report is unique in that an ovarian granulosa dualistic model of the pathogenesis of endometrial carcinoma
cell tumor, an estrogen secreting ovarian neoplasm, is has been proposed based on clinical, morphologic, immuno-
associated with a serous endometrial carcinoma, a type of phenotypic, and molecular observations. Hyperestrogenism
endometrial cancer that appears to initially develop along a is a hallmark of a so-called type 1 carcinomas, of which endo-
pathway that is unrelated to estrogenic stimulation. Granulosa metrioid adenocarcinoma is the prototype. Type 1 carcinomas
cell tumor is the most common estrogen producing ovarian arise in a background of endometrial hyperplasia, usually
tumor followed by thecoma [1]. Endometrial effects of estrogen express estrogen and progesterone receptors, and are associated
secreting ovarian neoplasms range from cystic hyperplasia to with elevated serum estradiol levels [6]. Thus, it would be
atypical hyperplasia to adenocarcinoma. The first report of a expected that endometrial carcinomas that arise in association
concurrent ovarian granulosa cell tumor and a uterine with ovarian granulosa cell tumors would be of the endome-
carcinoma is attributed to Schroeder in 1922 [7]. Early trioid subtype. The histologic type of uterine carcinomas arising
observers combined ovarian granulosa cell tumors and in women with ovarian granulosa cell tumors has not been
thecomas together as so-called feminizing mesenchymomas of explicitly described in the literature. Most studies use the
the ovary or feminizing ovarian tumors and reported a spectrum general term “adenocarcinoma” without further specification
of endometrial pathologies related to hyperestrogenism [8–12]. [2–5,13]. Some authors describe adenocarcinomas with squa-
Large follow-up studies of ovarian granulosa cell tumors have mous differentiation [4]. Of those who report a tumor grade and
found that approximately two-thirds of patients present with stage, most find that the carcinomas are low-grade and low-
menstrual cycle abnormalities or post-menopausal uterine stage; rare cases of carcinosarcoma and endometrial sarcoma
J.T. Rabban et al. / Gynecologic Oncology 103 (2006) 1164–1168 1167
have been noted [2,3], Thus, most uterine tumors that develop Type 2 carcinomas (serous and clear cell carcinomas and
in women with granulosa cell tumors are low-grade, early-stage carcinosarcoma) comprise 10% to 20% of all endometrial
endometrioid adenocarcinomas. 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
Fig. 3. (A) Endometrial cystic hyperplasia (left half of image), consisting of
morphology could represent tumor progression from what was
crowded small simple endometrial glands mixed with large dilated glands, is initially an endometrioid adenocarcinoma. Features favoring
adjacent to serous carcinoma (right half of image), growing in a glandular the former pathway include the presence of EIC flanking the
pattern. (B) The nuclei of the serous carcinoma cells strongly express p53 by serous carcinoma and the lack of atypical hyperplasia or
immunohistochemistry, whereas the hyperplastic glands do not. (C) Conversely, component of endometrioid adenocarcinoma. However, we
the nuclei of the hyperplastic glands strongly express estrogen receptor by
immunohistochemistry, whereas the serous carcinoma does not. Elsewhere (not cannot definitively distinguish between these two possibilities.
shown), patchy weak estrogen receptor expression was noted in some serous From a clinical perspective, this case demonstrates that not all
carcinoma nuclei. uterine tumors associated with ovarian granulosa cell tumors are
1168 J.T. Rabban et al. / Gynecologic Oncology 103 (2006) 1164–1168
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