Investigation of the Cause of Precocious Puberty in an 8-Year-Old Girl Ended up in Juvenile Granulosa and Theca Cell Tumor of the Ovary

doi:10.4236/jct.2013.48165

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Journal of Cancer Therapy, 2013, 4, 1391-1394

http://dx.doi.org/10.4236/jct.2013.48165 Published Online October 2013 (http://www.scirp.org/journal/jct)

1391

Investigation of the Cause of Precocious Puberty in an

8-Year-Old Girl Ended up in Juvenile Granulosa and

Theca Cell Tumor of the Ovary

Mahtab Ordooei1, Mojgan Karimi-Zarchi2*, Golnaz Malekzadeh3, Mansour Moghimi4

1Department of Pediatrics, Pediatric Endocrinologist, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 2Gynecology

Oncology Department, Shahid Sadoughi Hospital, Yazd, Iran; 3Shahid Sadoughi University of Medical Sciences, Yazd, Iran;

4Department of Pathology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Email: *[email protected]

Received March 6th, 2013; revised April 5th, 2013; accepted April 14th, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Isosexual precocious puberty in girls has several etiologies. Juvenile granulose cell tumor is one of the rarest causes that

only stands for 1.5% of ovarian cancers. This tumor mostly encounters in first 2 decades of life. This paper is a report of

an 8-year-old girl with precocious puberty that within five months developed breast enlargement followed by menarche.

Works which are done to find the underlying cause of precocious puberty revealed juvenile granulosa cell tumor in her

left ovary. She then under went laparoscopic surgery and 3 courses of chemotherapy. She did not experience any vagi-

nal bleeding after that and the serum level of estradiol lay among its normal ranges, but after that the tumor relapsed and

presented as abdominal pain and a huge mass which under went resection of all afflicted tissues. After 2 courses of che-

motherapy, her status deteriorated and unfortunately she died after 6 months from the time of diagnosis. Treatment for

this disease is consists of resection surgery and chemotherapy. If this tumor is diagnosed in its early stages, it will be

curable, but in its advanced stages, up to 80% of patients die from recurrent tumors. The reported patient was diagnosed

at stage IIIC that had poor prognosis.

Keywords: Precocious Puberty; Juvenile Granulosa Cell Tumor; Ovary

1. Introduction

Juvenile granulosa cell tumor of the ovary (JGCT) is a

subset of ovarian cancers and stands for almost 5% of all

ovarian malignancies [1]. It can be distinct from its adult

type that mostly occurs in post menopausal women due

to different clinical and pathological features such as

hirsutism, abdominal discomfort and abnormal vaginal

bleeding. Juvenile type has higher mitotic activity and

nuclear atypicality as well as the expression of PCNA

and p53, but has poor prognosis in comparison to adult

type [2]. This tumor has the potential to produce hor-

mones that lead to early presentation and diagnosis [3].

The complaint that is common among these patients is a

palpable mass in lower abdomen. Ascites in 10% of them

is reported [4]. This tumor can present in divers ages

from infancy to teenage but it mostly presents in the age

of 8 or 9 years old [5].

This tumor is rarely reported before [6-15], this paper

is a report of an 8-year-old girl who presented iso sexual

precocious puberty and works which are done to find the

underlying cause ended up in Juvenile granulosa and

theca cell tumor of the ovary.

2. Case Presentation

The patient was an 8 year old girl from Yazd in an only

child family from high socioeconomic level with the

height of 142 cm and weight of 34 kg, who presented

breast enlargement compatible with Tanner III. About

five months from first bud of breasts, she started vaginal

bleeding but no presentation of pubic or auxiliary hair.

She was referred to pediatric endocrinologist to investi-

gate the cause of precocious puberty. In physical exam

the vital sign was stable everything was normal but a

large mass in left side of abdomino pelvic cavity was

palpated. No peripheral lymphadenopathy or organo-

megaly was detected. She had no complaint of pain or

nausea, vomiting or other complaint of any kind. The lab

*Corresponding author.

Investigation of the Cause of Precocious Puberty in an 8-Year-Old Girl Ended up in Juvenile Granulosa

and Theca Cell Tumor of the Ovary

1392

results indicated normal thyroid function and Cell Blood

Count (CBC) but impaired serum level of gonadal hor-

mones. Folicle stimulating hormone (FSH) was 0.2 (0.1 -

4.3 IU/lit), luteinizing hormone was 1.9 (0.1 - 5 IU/lit),

stradiol was 120.9 (6 - 27 pg/ml), serum cortisol of 8 AM

was 15 μg/dl (5 - 23 μg/dl). Advanced bone age was also

detected that was around 12 years old. Other lab tests

consist of liver function test was normal but a high Lac-

tate dehyrogenase was reported which was 1040 U/l (up

to 580 U/l). Alkaline phosphatase was 664 U/l (180 -

1200) and urine analysis showed moderate amorph urate

crystal. Electrolytes consist of Na, K, Ca, P were all in

their normal ranges. In the sequence order abdominopel-

vic sonography was done. It showed a lobulated echo-

genic solid mass in left part of abdomen with the diame-

ter of 4 cm and free fluid in abdomen especially in pelvis

and under the liver. For further assessment CT scan with

intravenous contrast was done. The result showed a large

20 * 11 cm multiloculated cystic mass with marked sep-

tation and loculation in left side of abdomino pelvic cav-

ity that has the pressure effect on the pelvic and abdomi-

nal content. Ovarian cystadenoma, mucinous cystade-

noma or other pelvic masses were suggested. Some of

tumor markers also were elevated. Carbohydrate antigen

19-9 was 6.2 U/ml (up to 39), carbohydrate antigen 125

was 469 U/ml (up to 35), carcinoembryonic antigen

(CEA) was 0.44 ng/ml (0.0 - 5), beta HCG (beta Human

Chorionic Gonadotropin) was 0.1 mIU/ml (up to 5.3),

alpha feoto protein was 1.2 IU/ml (0.0 - 5.8) and inhibin

A was 320 pg/ml (<2.2 pg/ml). Patient was referred to

gynecologist and the tumor was resected by Laparo-

scopic surgery. Histopathology and ascites fluid cytology

confirmed the rare ovarian tumor of Juvenile granulosa

and theca cell. High mitotic activity with wide necrotic

parts and calcified and bizarre nuclei was seen (Figures

1 and 2). In immunohisto chemistry CD99 (Cluster of

Differentiation 99), BCL2 (B-cell lymphoma 2), PR

(progesterone receptor), CKAE1/AE3 (Cytokeratin AE1/

AE3) was reported positive which is compatible with

juvenile granulose cell tumor (Figures 3 and 4). Then

Figure 1. JGCT with high mitotic rate and moderate to

abundant eosinophilic to vacuolated cytoplasm and round,

hyperchromatic nuclei lacking grooves (H & E 40X).

Figure 2. JGCT with pseudopapillary architecture (H & E

4X).

Figure 3. JGCT, Diffuse membranous CD99 positivity is

characteristic (IHC 40X).

Figure 4. JGCT, patchy weak cytoplasmic staining for

CKAE1/AE3 (IHC 40X).

chemotherapy of BEP consists of Bleomycin, Etoposide

and Cisplatin started for her. After the third course of

chemotherapy the tumor relapsed with the presentation of

abdominal pain and huge mass. Because of the relapse of

tumor patient went under complete resection of tumor,

left oophorectomy, appendectomy and resection of intes-

tine and peritonea which the tumor adhered to them.

Only uterine, right ovary and fallopian tube were pre-

served. The stage of the tumor was equivalent to III C.

Chemotherapy of BEP continued for her but after the

second course, her status deteriorated. She had dyspnea

which then hospitalized and metastasis to lungs was de-

tected. Despite all procedures done on her unfortunately

she died after 6 months passed from diagnosis.

3. Discussion

Ovarian juvenile granulosa cell tumors are rare malignant

Investigation of the Cause of Precocious Puberty in an 8-Year-Old Girl Ended up in Juvenile Granulosa

and Theca Cell Tumor of the Ovary

1393

tumors afflict young girls. As this tumor mostly secreted

hormones, the most common presentation is precocious

puberty, premature thelarche and vaginal bleeding [16]

that all goes along with this reported patient’s presenta-

tion. Due to tumor derived estradiol, she had advanced

bone age compatible with the age of 12 years old.

On CT scan and sonography, JGCT most typically

appears as large, multilocular mass [17]. In this case, also

a large multi loculated cystic mass with marked septation

and loculation in left side of abdomino pelvic cavity was

seen.

Diagnosis of JGCT in pathology may be confused with

other ovarian tumors with pseudopapillary pattern; im-

munohistochemistry can be used in more problematic

cases [18]. These tumors are characteristically positive

for inhibin, calretinin, Vimentin and keratin [19]. In this

patient, CD99 and Cytokeratin AE1/AE3 were reported

positive. In 6 cases reviewed by Kavuri et al, diffuse

positivity for vimentin in all of them was reported but the

staining for cytokeratin (AE1/AE3) and calretinin was

negative. Four cases expressed CD99 and 1 case was

positive for inhibin [20].

The most important prognostic factor is tumor stage.

The tumors with the size of more than 5 cm, mitotic fig-

ures more than 10 in hpf and The more degree of nuclear

atypia have poor prognosis [21,22]. The treatment is also

related to the stage of the tumor, but selective treatment

in early stages is unilateral salpingo oophorectomy and

then starting the chemotherapy [23]. Cisplatin had shown

good results in treatment of these patients [24]. BEP

(Bleomycin, Etoposide and Cisplatin) is also recom-

mended for chemotherapy [24] but if the tumor excised

completely in early stages, adjuvant therapy may not be

necessary [25].

Inhibin is dimeric glycoprotein secreted from ovarian

granulose cells. It is a good marker to follow up patients

and diagnose any recurrence [26-28]. In previous studies,

Activin B was also reported as a good marker to monitor

the patients [29].

As this tumor mostly presented in juveniles, preserva-

tion of fertility in patients is an important issue which

can be reached by early diagnosis, tumor resection, che-

motherapy and strict follow up. The patient’s disease was

diagnosed less than 5 months and went under surgery

twice and 5 courses of BEP chemotherapy which lead to

regression in breast size and decrease in the serum estra-

diol level but unfortunately the tumor outnumbered all

treatments and she expired after 6 months.

4. Conclusion

According to the high prevalence of functional cysts in

comparison to neoplastic masses in childhood, malign-

nancies may be underdiagnosed and mismanaged. So

consideration of the clinical features along with preclini-

cal investigations can result in earlier diagnosis and a

better prognosis.

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