Metachronous benign ovarian tumors are not uncommon in children

Seppo Taskinen, Alda Urtane, Riitta Fagerholm, Jouko Lohi, MerviTaskinen

PII: S0022-3468(13)00738-0DOI: doi: 10.1016/j.jpedsurg.2013.09.019Reference: YJPSU 56496

To appear in: Journal of Pediatric Surgery

Received date: 14 June 2013Revised date: 3 September 2013Accepted date: 7 September 2013

Please cite this article as: Taskinen Seppo, Urtane Alda, Fagerholm Riitta, Lohi Jouko,Taskinen Mervi, Metachronous benign ovarian tumors are not uncommon in children,Journal of Pediatric Surgery (2013), doi: 10.1016/j.jpedsurg.2013.09.019

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Metachronous benign ovarian tumors are not uncommon in children

Running title: Metachronous benign ovarian tumors in children

Seppo Taskinen, Department of Pediatric Surgery, Children’s Hospital, University of Helsinki

Alda Urtane Department of Pediatric Surgery, Children’s Hospital, University of Helsinki

Riitta Fagerholm Department of Pediatric Surgery, Children’s Hospital, University of Helsinki

Jouko Lohi Department of Pathology, University of Helsinki,

Mervi Taskinen, Department of Hematology, Oncology and Stem Cell Transplantation, Children’s

Hospital, University of Helsinki

Correspondence:

Seppo Taskinen

tel: +358 504272542

e-mail: seppo.taskinen@hus.fi

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ACCEPTED MANUSCRIPTMetachronous benign ovarian tumors are not uncommon in children

Purpose. To evaluate the risk for metachronous ovarian tumor in pediatric patients with mature ovarian

teratoma.

Methods. During 1981-2011, 22 children underwent oophoretomy for mature teratoma at the median

age of 11.4 (range 1.5-15.3) years. The patients were followed-up in median 4.4 (range 0.5-25.5) years.

Results. None of the patients had synchronous bilateral tumor at the time of primary operation, but

during follow-up five patients (23%) got metachronous contralateral ovarian tumor. The contralateral

tumor was observed in median 3.6 (range 1-8.8) years after the primary operation. According to

Kaplan-Meier analysis the risk for contralateral tumor was 14± 8% (SE) within five years and 66± 26%

(SE) within 10 years. In this series, the contralateral tumor was operated by ovary preserving surgery.

Three of the metachronous tumors were mature teratomas and two were seromucinous infantile

cystadenomas. One patient had a second teratoma recurrence 14 years after the first recurrence.

Conclusions. More than one fifth of the children with ovarian mature teratoma get metachronous be-

nign tumor to the contralateral ovary. Therefore a yearly ultrasound follow-up is needed for these pa-

tients up to potential pregnancy to enable early diagnosis, ovary preserving surgery and maintenance of

fertility in the case of metachronous tumor.

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Ovarian masses are rare in children. Approximately one half of them are neoplastic [1]. The

majority of the ovarian neoplastic tumors are benign, the most common diagnosis being a mature

teratoma [2-4]. Benign teratomas have been reported to be bilateral in 11-17% of the adult and

pediatric patients occurring most frequently synchronously and only occasionally metachronous

appearance has been reported [5-7].

The focus in research and publications concerning patients with benign teratomas has been in mini-

invasive and ovary sparing surgery [3,4]. However, the exact risk of recurrence on the contralateral

side is unknown, and the role of follow-up after primary surgery has not been investigated in detail

[8]. Our clinical follow-up has revealed some metachronous contralateral benign ovarian tumors in

children and adolescents operated on mature ovarian teratoma. In this study we wanted to evaluate

the frequency of subsequent benign tumors in the contralateral ovary in this patient group to see if

follow-up of these patients is really needed. The major clinical implication of follow-up and eaely

diagnosis of recurrence would be the option to ovary preserving surgery .

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1. Methods

This retrospective study was performed in the Children’s Hospital of Helsinki University Central

Hospital. We identified from the hospital database altogether 46 patients operated for an ovarian

neoplastic tumor during 1981-2011 . Twenty-two (48%) of them had mature teratoma.

The clinical data of the diagnostic and operative procedures as well as follow-up data were

collected from the hospital medical and surgical records. The ovarian tissue samples were re-

evaluated by one of the researchers (JL). During the last 20 years the patients have been

followed up yearly with abdominal ultrasonography and tumor markers (serum alpha-

fetoprotein (AFP), human chorionic gonadotropin (hCG) and CA-125) for five years after the

primary operation . After five years the follow-up had not been so systematic.

Kaplan-Meier analysis was performed to evaluate the development of metachronous tumors.

(Statview®

5.0.1, SAS Institute Inc.). The study was approved by the institutional Ethical Review

Committee.

2. Results

The median age of the 22 patients with mature teratoma was 11.4 (range 1.5-15.3) years at primary

surgery. Preoperative diagnostic evaluation was done with ultrasonography for all 22 patients, with

confirmation by magnetic resonance imaging for 11 patients and with computed tomography for 4

patients. None of the patients had tumor on the contralateral ovary either in preoperative imaging or

in peroperative examination. Contralateral ovarian biopsy was performed to one patient during the

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primary operation due to multiple cysts with negative results, but the patient was later diagnosed

with a tumor also in the contralateral tumor. All the patients were primarily treated with

oophorectomy. The histology of the primary tumor was mature teratoma in all 22 cases also in the

re-examination (JL).

The median follow-up time was 4.5 (range 1.0-25.5) years. Five out of the 22 patients (23%) were

observed to have a neoplastic tumor in the contralateral ovary in median of 3.6 (range 1-8.8) years

after the primary surgery. At the time of re-operation all the measured tumor markers were

normal (s-CA-125 in all five patients, s-AFP and -hCG in four patients). The primary operation

was done at the median age of 11.3 (range 1.5-14.6) years for the 17 patients without metachronous

tumor and at the age of 13.7 years (range 3.6-15.3) for the five patients with metachronous tumor

(p=0.531). Two patients were detected to have preoperative tumor rupture during the primary

operation. The other of them got contralateral recidive after one year follow-up. The estimated risk

for contralateral ovarian tumor was 14± 8% (SE) at 5 years and 66± 26% (SE) at 10 years in

Kaplan-Meier analysis (Fig. 1).

The recurrent tumors were operated by ovary preserving surgery. One patient was detected to have

second mature teratoma recurrence in the remaining ovary during pregnancy, 14 years after the first

recurrence. The second recurrence was treated with oophorectomy at the time of caesarean section.

In three cases the recurrent contralateral tumor was also mature teratoma, but in two cases it was

infantile seromucinous cystadenoma (Table 1). One additional patient was operated because of

metachronous non-neoplastic polycystic ovary.

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3. Discussion

In this retrospective study, we observed that the patients operated for ovarian mature teratomas

during childhood are in a substantial risk of having benign neoplastic tumors in the contralateral

ovary later in life.

Ovarian neoplasms are rare in children. In our 30 years’ material, 46 patients with ovarian

neoplasms were diagnosed in a population of about 18 000 newborns yearly. Almost half of the

primary tumors were mature teratomas, fitting to the previous observations [9, 10]. In our study,

23% of the patients with ovarian mature teratoma had a neoplastic tumor in the contralateral ovary

during a median follow-up time of 4 years. None of them had had any signs or findings of neoplasm

in the contralateral ovary at the time of the primary surgery.

Bilateral simultaneous ovarian teratomas have been reported in adult patients with a prevalence of

10.8-13.2% [5,6,11]. However, in adults we did not succeed to find proper follow-up series

evaluating the risk for metachronous tumors.

In children the reported patient series have been small and usually no follow-up information has

been provided. In the study of Al Jama et al [4] one out of 28 pediatric ovarian teratoma patients

was operated because of synchronous mature teratoma in the contralateral ovary, but no follow-up

data was given. In another study of 30 patients with mature teratoma, two developed multiple

recurrent cysts and lesions to the remaining ovary resulting in removal of the ovary because of

severe pain [3]. Unfortunately, neither the histology, nor the length of the follow-up were reported.

In the study of DeBacker et al three out of nine patients with immature teratoma were diagnosed

with contralateral tumor after 3-6 months’ follow-up [12]. However, no metachronous tumors were

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reported in the 45 patients with mature teratoma [12]. In a recent study from Paris, 5 out of the 30

(17%) pediatric patients with (mature) ovarian teratoma had bilateral tumor [7]. One patient had a

syncronous bilateral tumor and four patients developed metachronous tumor after a median follow-

up of 3 (range 1-14) years. This is in line with our findings.

Multifocal origin of ovarian teratomas has previously been reported [13]. In adult patients, bilateral

tumors have usually been macroscopically evident, but some patients have had covert tumors

identified only by a peroperative biopsy of the contralateral ovary [5,6]. A Chinese study suggests

that metachronous appearance of benign ovarian tumors could be a particular feature in young

females [14]. The 20 patients with a subsequent tumor in the contralateral ovary were younger than

the 40 patients without tumor in the remaining ovary (26 vs. 30 years, p<0.05). Our hypothesis is

that in adult patients with bilateral ovarian teratomas, the neoplasm has had time to develop into a

macroscopic tumor on both sides. In contrast, in pediatric patients the niche of the neoplasm may be

covert in the other ovary at the time of primary surgery , and more time is needed for the tumor to

become macroscopically detectable on the contralateral side.

Tumor spillage before or during the primary operation is a potential but unlike explanation for

metachronous appearance of ovarian tumors. In our material, two patients were detected to have

preoperative tumor ruptures and the other was detected to have contralateral tumor at follow-up.

However, the role of tumor spillage in the development of contralateral ovarian tumors is not

supported by the observation that none of the 27 patients with mature cystic teratoma and tumor

spillage had tumor recurrence or tumor in the contralateral ovary [8].

In our material two out of the five patients with metachronous tumor develped infantile

seromucinous cystadenoma to the contralateral ovary. In adults mucinous epithelial neoplasms have

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rarely been reported in association with mature teratomas [15]. Recently one pediatric patient has

been reported to have a metchronous ipsilateral mucinous cystadenoma three years after ovary-

sparing surgery of mature teratoma [16]. In a study of Massicot et al [10] 7 out of 31 patients with

infantile seromucinous cystadenoma had bilateral involvement. In their series one patient had also

bilateral mature ovarian teratoma and unilateral cystadenoma. It was discussed that the epithelial

tumour could also originate from the differentiation of potentially totipotent teratoma cells.

In this series one fifth of the young females with mature ovarian teratoma developed contralateral

tumor during follow-up. We conclude that yearly ultrasound follow-up of pediatric patients

with ovarian teratoma is justified to enable the early detection of the contralateral or

ipsilateral tumor, and consequently giving the option to ovary sparing surgery and preserving

fertility. The lenght of follow-up should propably be continued up to the first pregnancy.

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[11] Comerci JT Jr, Licciardi F, Bergh PA, et al: Mature cystic teratoma: a clinicopathologic evalu-

ation of 517 cases and review of the literature. Obstet Gynecol. 1994;84:22-8.

[12] De Backer A, Madern GC, Oosterhuis JW, et al: Ovarian germ cell tumors in children: a clini-

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[13] Bournas N, Varras M, Kassanos D, et al: Multiple dermoid cysts within the same ovary: our

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cases. Zhonghua Yi Xue Za Zhi 2007;87:1184-1186.

[15] McKenney JK, Soslow RA, Longacre TA : Ovarian mature teratomas with mucinous epithelial

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Pathol 2008;32:645-655.

[16] Parmentier B, Vaz E, Chabaud-Williamson M, et al: Mucinous cystadenoma arising 3 years

after ovarian-sparing surgery for mature teratoma in a child. J Pediatr Surg 2010;45:E9-12.

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ACCEPTED MANUSCRIPTFigule legend

Fig. 1 Appearance of contralateral benign ovarian tumor after ophorectomy because of mature terato-

ma.

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0

,2

,4

,6

,8

1

Recurr

ence-f

ree S

urv

ival

0 2 4 6 8 10Follow-up (years)

n= 22 21 16 6 2 1

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Table 1. Patients with mature ovarian teratoma and metchronous neoplastic contralateral ovarian tumor

Patient

No

Primary operation

age (year)

Metachronous contralateral tumor

Diagnosis Operation

age (year)

1 3 Seromucinous

cystadenoma

5

2 8 Mature teratoma* 14; 28

3 13 Seromucinous

cystadenoma

17

4 14 Mature teratoma 22

5 15 Mature teratoma 16

* the patients had two teratoma recurrences in the remaining ovary