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Androgenic adult granulosa cell tumor with secondary amenorrhea and elevated luteinizing hormone

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Granulosa cell tumors (GCTs), adult type, are the most common type of ovarian sex cord tumors. Menstrual irregularity, even secondary amenorrhea is frequently observed in premenopausal women bearing GCTs with hormonal activity. We present here in an extremely rare case of adult GCT in a patient presenting with secondary amenorrhea and serum testosterone (Test) and luteinizing hormone (LH) elevations, and decreased estradiol (E 2). A 32-year-old woman visited our hospital complaining of secondary amenorrhea two years after second delivery. Signs of virilisatoin, such as increased pubic hair and clitoromegaly were present. A pelvic ultrasound scan revealed a right adnexal solid mass measuring 2.9x3.9 cm. Under the working diagnosis of sex-cord tumor, the woman underwent a laparoscopic surgery of a right salpingo-oophorectomy and the tumor was collected from the Douglas' pouch. The tumor was diagnosed as an adult-type GCT stage IA. Spontaneous menstruation occurred and serum levels of Test, LH, FSH and E 2 showed normal ranges one month after surgery. The patient is now healthy without evidence of a recurrence 30 months after the surgery. Although s-Test and LH elevations in patients with GCT is rare and its mechanism is not clearly understood, monitoring of s-Test and LH may provide an additional tumor marker after conservative surgery in such patients.
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Pathology Discovery
ISSN 2052-7896
Case report Open Access
Androgenic adult granulosa cell tumor with secondary amenorrhea
and elevated luteinizing hormone
Kenji Niwa1*, Ryuichiro Yano2, Sakae Mori3, Yoshio Yamaguchi3, Nozomi Narikawa3 and Takuji Tanaka4
*Correspondence: kniwa.gujo913@gmail.com
1Department of Obstetrics and Gynecology, Gujo City Hospital, Gujo-city, Gifu Pref, Japan.
2Department of Obstetrics and Gynecology, Gifu University Post-graduate School of Medicine, Gifu-city, Gifu Pref, Japan.
3Section of Laboratory Medicine, Gujo City Hospital, Gujo-city, Gifu Pref, Japan.
4Director of The Tohkai Cytopathology Institute, Minami-Uzura, Gifu-city, Gifu Pref, Japan.
Abstract
Granulosa cell tumors (GCTs), adult type, are the most common type of ovarian sex cord tumors. Menstrual irregularity, even
secondary amenorrhea is frequently observed in premenopausal women bearing GCTs with hormonal activity. We present here
in an extremely rare case of adult GCT in a patient presenting with secondary amenorrhea and serum testosterone (Test) and
luteinizing hormone (LH) elevations, and decreased estradiol (E2). A 32-year-old woman visited our hospital complaining of
secondary amenorrhea two years aer second delivery. Signs of virilisatoin, such as increased pubic hair and clitoromegaly were
present. A pelvic ultrasound scan revealed a right adnexal solid mass measuring 2.9x3.9 cm. Under the working diagnosis of sex-
cord tumor, the woman underwent a laparoscopic surgery of a right salpingo-oophorectomy and the tumor was collected from the
Douglas’ pouch. e tumor was diagnosed as an adult-type GCT stage IA. Spontaneous menstruation occurred and serum levels of
Test, LH, FSH and E2 showed normal ranges one month aer surgery. e patient is now healthy without evidence of a recurrence
30 months aer the surgery. Although s-Test and LH elevations in patients with GCT is rare and its mechanism is not clearly
understood, monitoring of s-Test and LH may provide an additional tumor marker aer conservative surgery in such patients.
Keywords: Granulosa cell tumor (GCT), ovary, androgenic, luteinizing hormone (LH), laparoscopic surgery
© 2013 Niwa et al; licensee Herbert Publications Ltd. is is an Open Access article distributed under the terms of Creative Commons Attribution License
(http://creativecommons.org/licenses/by/3.0). is permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Granulosa cell tumors
(
GCTs), adult type are the most common
type of ovarian sex cord tumors and account for 1-2% of
all ovarian tumors and 3-5% of all ovarian malignancies [
1
].
GCTs are usually diagnosed in early clinical stage and are also
renowned for late recurrences.
GCTs exhibits endocrine activity and many features of normal
granulosa cells, including FSH-binding, a response to FSH, and
the secretion of estrogen, inhibin [2], progesterone, androgen
[1,3,4] and Müllerian inhibiting substance [5]. The presentation
of an adult GCTs accompanied by endocrinological symptoms
is often related to hyperestrogensim and varies according
to the age of patient. In premenopausal women, menstrual
irregularity, menorrhagia, or even secondary amenorrhea may
be the initial manifestation of GCTs [6].
We report here an extremely rare case of GCT associated
with secondary amenorrhea and elevated LH and testosterone.
Case report
A 32-year-old Japanese woman, gravida 2 para 2, visited our
hospital complaining of secondary amenorrhea two years after
second delivery. Signs of virilisataion, such as increased pubic
hair and clitoromegaly were present. A pelvic ultrasound scan
revealed a right adnexal solid mass measuring 2.9x3.9 cm. As
shown in (Table 1), her serum LH and Test were elevated to 18.1
mIU/ml (normal range: 1.76-10.24 in follicular phase) and 2.09
ng/ml (normal range: 0.11-0.47) respectively; meanwhile her
serum estradiol was relatively low: 33 pg/ml (normal range: 19-
226). Other hormones, such as FSH (5.13 mIU/ml) progesterone
(1.23 ng/ml) and prolactin were within normal range. Findings
of other routine laboratory tests and tumor markers [CA125,
6.0, CA19-9, 3.3 and CA72-4, 0.9 (ng/ml)] were also within
normal limits. Magnetic resonance image (MRI) showed a well-
circumscribed solid tumor producing high-intensity signals on
T2-weighted (Figure 1). Whole body CT examinations showed
no abnormal signs other than pelvic tumor.
Under the working diagnosis of sex-cord tumor, the
woman underwent a laparoscopic surgery of a right salpingo-
oophorectomy and the tumor was collected from the Douglas’
pouch, using by an Endopouch
®
. A small amount of ascites
was also collected. Cytology of the cut-surface of the resected
tumor suggested a sex-cord tumor (Figure 2). Macroscopically,
the resected ovarian tumor was solid and yellow (Figure 3).
Microscopically, the tumor consisted of monomorphilic small
cells with a trabecular pattern separated by a fibrothecomatous
stroma and coffee-bean like nuclei were frequently seen
(
Figure 4
). The tumor cells had small amounts of cytoplasm,
and pale and uniform nuclei with high cellular density and
without cellular atypia. Cytology of ascites was negative. On
immunohistocehmical evaluation, the tumor cells expressed
Niwa et al.
Pathology Discovery
2013,
http://www.hoajonline.com/journals/pdf/2052-7896-1-9.pdf
2
doi: 10.7243/2052-7896-1-9
Figure 1. A well-circumscribed solid tumor (3.9x2.9 cm)
producing high-intensity signals on T2-weighted.
Figure 2. Cytology of the cut-surface of the resected tumor
suggested a sex-cord tumor (Papanicolaou stain, original
magnication: x 400).
Figure 3. Macroscopically, the resected ovarian tumor was
solid and yellow.
Figure 4. e tumor consisted of monomorphilic small cells
with a trabecular pattern separated by a brothecomatous
stroma (hematoxylin-eosin, original magnication: x 200).
strong and diffuse staining for androgen receptor (Dako). The
tumor cells showed positive staining for estrogen receptor
(Dako) and focally positive for inhibin (Dako). Based on these
findings, the tumor was diagnosed as an adult-type GCT
stage IA (FIGO).
The changes of hormonal data are present in (Table 1). On
the 5th day after the surgery, s-Test decreased to the normal
range, and the s-E2 increased to 60 pg/dl level. One month
after the surgery, the hormonal levels showed normal womens’
Pre-operative D5 aer
surgery
One month
aer surgery
luteinizing hormone (mIU/mL) 18.124.42.93
Follicle stimulating hormone
(mIU/mL)
5.13 19.5↑↑ 2.46
Estradiol (ng/mL) 33↓ ↓ 60171
Progesterone (ng/mL) 1.23 0.15 ND*
Testosterone (ng/mL) 2.09<0.16 <0.16
ones. Spontaneous menstruation occurred one month after
the surgery. The patient showed no signs of recurrence and
normal menstrual cycles 30 months after the surgery.
Table 1. Change of hormones.
*ND, not detremined.
Niwa et al.
Pathology Discovery
2013,
http://www.hoajonline.com/journals/pdf/2052-7896-1-9.pdf
3
doi: 10.7243/2052-7896-1-9
Discussion
We report here an extremely rare case of GCT associated with
secondary amenorrhea. GCTs typically produce estrogen,
however, in rare instances, they produce androgen. The clinical
manifestations may be related to an excess androgen produced
by GCTs. There have been several case reports of GCTs in
which patients have presented with secondary amenorrhea
[2,6]. Most of these cases were associated with baseline FSH
levels and high inhibin levels, but serum LH and E
2
levels were
normal in many cases [2]. There have been only three cases
of GCTs associated with high LH levels. The present case has
shown clinically virilised and the pre-operatively elevated
s-Test levels return to normal range following the removal of
the ovarian tumor. In our case, an elevation of LH was thought
be have interfered with normal follicular development and
ovulation. LH levels returned to normal range and regular
menstruation occurred after the surgery.
In polycystic ovary syndrome (PCO) cases, serum LH levels
are high and secondary amenorrhea may occur. In the present
case, the presence of hormonal disorders, such as PCOs were
ruled out by the findings that the contralateral ovary showed
a normal appearance and the LH level decreased immediately
after the surgery.
The reason for the elevation of LH levels in the present case
is not clear. Immunohistochemical examination of the GCT
cells revealed the presence of androgen receptors. Based on
the two-cell hypothesis of estrogen production, granulosa
cells produce estradiol if the precursor Test is secreted by
adjacent theca cells. However, in androgenic GCTs, few theca
cells are present and it has been suggested that the granulosa
cells lack aromatase activity to varying degrees. It has been
reported that amenorrhea is the result of suppression of
gonadotropins by the high levels of Test [7].
In the present case, high level of LH and normal level of FSH
were present. The discrepancy of the LH and FSH levels, inhibin,
a glycoprotein hormone suppress pituitary FSH production
[
2
]. It can be suggested that the high s-Test induced atresia
of follicles in the normal ovary, GCT replacing in the ovarian
tissue, and resulted in secondary amenorrhea [8].
Unilateral oophorectomy is recommended treatment for
women with GCT who wish to preserve their productive
capacity [9]. GCTs are low potential malignant neoplasms with
the capacity for local or lymphatic extension, particularly to
the para-aortic lymph nodes [9]. Therefore, it is important to
have a circulating marker as an early predictor or recurrent
disease. Because an inhibin cannot be available in the clinical
use, the serum LH may be a good marker for a recurrence in
the present case.
Conclusion
An extremely rare case of adult type, granulosa cell tumor in
a 32-year-old patient presenting with secondary amenorrhea
and serum Test and LH elevations, and decreased E2 is reported.
After a laparoscopic surgery of a right salpingo-oophorectomy,
Authors’ contributions KN RY SM YY NN TT
Research concept and design -- -- -- -- --
Collection and/or assembly of data ✓ ✓ ✓ ✓ --
Data analysis and interpretation ✓ ✓ ✓ ✓ --
Writing the article -- -- -- -- --
Critical revision of the article -- -- -- --
Final approval of article ✓ ✓ ✓ ✓
Statistical analysis -- -- -- -- -- --
spontaneous menstruation soon occurred and serum levels
of Test, LH and E2 showed normal ranges. The patient is now
healthy without evidence of a recurrence 30 months after the
surgery. Monitoring of s-Test and LH may provide an additional
tumor marker after conservative surgery in such patients.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
Acknowledgement
We thank the editor and reviewers for their constructive
comments, which helped us to improve the manuscript.
Publication history
Editor: Jingsong Yuan, The University of Texas, USA.
EIC: Markus H. Frank, Harvard Medical School, USA.
Received: 03-Nov-2013 Revised: 26-Nov-2013
Accepted: 10-Dec-2013 Published: 21-Dec-2013
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Citation:
Niwa K, Yano R, Mori S, Yamaguchi Y, Narikawa N
and Tanaka T. Androgenic adult granulosa cell tumor
with secondary amenorrhea and elevated luteinizing
hormone. Pathol Discov. 2013; 1:9.
http://dx.doi.org/10.7243/2052-7896-1-9
... Previously, these tumors typically produce oestrogens and therefore abnormal vaginal bleeding is the norm. However, there are some cases that presented with secondary amenorrhea too [2,3]. In these cases, we found that most of the hormonal profiles were deranged and associated with raised Inhibin, causing the low FSH level and therefore a state of pseudo-FSH deficiency [4]. ...
... Our case was differ from the others with the estradiol level markedly elevated instead of low or normal [2,5,6]. So far there was no report that presented with secondary amenorrhea yet with such elevated oestrogens and pseudo FSH deficiency with normal luteinizing hormone. ...
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... Se reporta una incidencia de 0.5 a 1.6 casos/100,000 mujeres al año 3,4 . De acuerdo con sus características clínicas e histológicas, se dividen en TCG del adulto (TCGA) y juvenil (TCGJ) 5 . Los TCGA son más comunes y usualmente se observan en mujeres peri y posmenopáusicas, con un pico de incidencia a los 50-55 años de edad. ...
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Case reportA 29 year old woman attended at our clinic complainingof secondary amenorrhoea. She was found to have anandrogenic adult granulosa cell tumour without androgenicmanifestations. Signs of virilisation (increased facial orabdominal hair, hirsutism or clitoromegaly) were absent.Concentrations of luteinising hormone, follicle stimulatinghormone, prolactin, dehydroepiandesterone sulphate, dehy-droepiandesterone and cortisol were all within theirreference ranges. The patient was initially treated withclomiphene citrate to induce menstruation; however, whenshe did not respond, she was treated with monophasic oralcontraceptive pills. The amenorrhoea persisted for the nextthree months; a pelvic ultrasound scan revealed a rightadnexal mass measuring 7.5 6.4 4.8 cm, with cysticand solid components. Her plasma testosterone waselevated to 192 ng/dL (normal range: 10–85 ng/dL);however, her plasma oestradiol was within normal limitsat 41 pg/mL (normal range: 12–49 pg/mL). Her activatedpartial thromboplastin time (APTT) was 76.1 s (normalrange: 29.7–47.4 s). Her prothrombin time, clotting factorsVIII, IX, XI, XII, fibrinogen, lupus anticoagulant, glycopro-tein 1 complex anti-cardiolipin h2 and tests of fibrinolysiswere normal. Plasma factor VIII procoagulant activitiesand plasma factor IX procoagulant activities were normal.The mixing test using 25%, 50%, and 75% normal pooledplasma did not completely correct the elevated APTT(56, 45.5 and 37 s). The possibility of a mild coagulationfactor inhibitor was considered; however, she did notexhibit thrombotic or haemorrhagic phenomena.The woman underwent a wedge resection of the leftovary and right salpingo-oophorectomy. The right ovariantumour measured 7.0 cm in its greatest diameter. No othergross evidence of disease was noted. Microscopic exam-ination of the right ovarian tumour revealed the typicalfeatures of an adult granulosa cell tumour. It was composedof thin, fibrous septa separating sheets of small cellscontaining nuclei with prominent grooving. OccasionalCall–Exner bodies were present (Fig. 1). The granulosacells in the tumour were strongly positive for testosterone(Fig. 2). Peritoneal washings were negative for tumourcells. On the first post-operative day, the APTT was inAB
Article
Adult granulosa cell tumors (GCTs) are the most common type of ovarian sex cord tumors. Menstrual irregularity, menorrhagia, or even secondary amenorrhea is frequently observed in premenopausal women bearing GCTs with hormonal activity. We report herein a case of GCT in a patient presenting with secondary amenorrhea and serum luteinizing hormone elevation. A 28-year-old primigravid Japanese woman was admitted complaining of secondary amenorrhea of 2 years' duration. Pelvic examination, transvaginal ultrasonography, and magnetic resonance imaging demonstrated a left ovarian tumor 4 cm in diameter. Serum hormone assays revealed a follicle-stimulating hormone level of 4.8 mIU/ml, luteinizing hormone (LH) of 35.8 mIU/ml, estradiol of 24 pg/ml, progesterone of 1.6 ng/ml, and testosterone of 40 ng/dl. A left salpingo-oophorectomy was performed. The tumor was diagnosed as an adult-type GCT stage IIb (FIGO [International Federation of Obstetricians and Gynecologists], 1988). Spontaneous menstruation occurred soon after the surgery. Serum levels of LH also decreased to normal levels and showed cyclic changes during the menstrual cycle. Subsequently, the patient conceived and delivered a healthy female baby. The tumor recurred in the pelvis 50 months after the initial conservative surgery, with elevated serum LH levels of 36.0 mIU/ml and amenorrhea. The patient was treated by hysterectomy, right salpingo-oophorectomy, omentectomy, paraaortic and pelvic lymphadenectomy, and low anterior resection of the recto-sigmoid colon. Her hormone levels progressed to the postmenopausal state after this surgery. Although LH elevation in patients with GCT is rare and its mechanism is unknown, monitoring of serum LH may provide an additional tumor marker after conservative surgery in such patients.