Gynecologic Adnexal Tumors and Tumor-Like Lesions in Children and Adolescents: Experience at a Cancer Center

Abstract

Introduction. Tumors and tumor-like lesions of the uterine adnexa in children and adolescents are uncommon but may carry devastating consequences. Methods. We conducted an observational retrospective cohort study, to describe patients aged 0 to 19 years diagnosed with tumors and tumor-like lesions of the uterine adnexa at our institution between 2000 and 2018. Results. Eighty-nine patients with 105 adnexal lesions were included. Thirty-seven (42%) patients presented with benign tumors, 13 (15%) with borderline tumors, 25 (28%) with malignant tumors and 14 (16%) with tumor-like lesions. Germ cell tumors (n = 45|43%) were the most frequent, followed by epithelial tumors (n = 30|29%). No significant differences were found in the age distribution of the lesions by malignant potential or histologic group. Most patients (n = 80|90%) were treated primarily with conservative surgery, including cystectomy (n = 25|28%) and unilateral oophorectomy/adnexectomy (n = 54|61%). Thirty-four (38%) underwent surgical staging (partial omentectomy and peritoneal biopsies). Twenty (23%) patients with borderline and malignant tumors were submitted to chemotherapy. Four (5%) patients with borderline or malignant tumors relapsed, one of whom died from disease. Conclusion. Gynecological lesions in children and adolescents encompass a wide range of rare histological tumor subtypes, requiring evaluation by experienced pathologists. Most tumors were diagnosed at early stages, with low relapse and mortality rates. Conservative management, with fertility sparing surgery and limited use of adjuvant chemotherapy, is of utmost importance.

Keywords

genital neoplasms female gynecology pediatrics children adolescent

Introduction

Gynecological tract lesions in children and adolescents are rare, representing less than 5% of all pediatric tumors.¹ The most common primary site is the ovary (46-87.5%), followed by the vagina and cervix (8.4%-43%), uterus (2.5%-16%), and the vulva (1.6%-4%).^1‐3 Ovarian tumors mostly occur in adults and are rare in the pediatric population, with an estimated annual incidence of 2.6/100 000.⁴ Among ovarian tumors, 10% to 30% are malignant⁵ and, by some estimates, account for 60% to 70% of all pediatric gynecological malignancies.⁵ When compared with adults, germ cell and sex-cord and stromal tumors, are more frequent in this age range, and require experienced pathologic evaluation.^2,6

Several lesions in the pediatric setting may mimic ovarian tumors, both clinically and by imaging studies. These include ovarian torsions, massive ovarian edema, and follicular cysts. Ovarian torsions, for instance, are reported to have an estimated incidence of 4.9/100 000 patients in the pediatric age.⁷ Follicular cysts have 2 peaks of incidence in the pediatric age: in the neonatal period and during menarche.^8,9 Pre-surgical distinction between tumor and tumor-like lesions may be very difficult and judicious intra-operative management is essential.

There is a paucity of descriptive studies regarding pediatric gynecologic tumors due to its rarity, and, consequently, little prospective research to guide recommendations. The main goal of this study was to describe the clinicopathological features of a series of children and adolescents with uterine adnexal tumors and tumor-like lesions diagnosed at a cancer center.

Materials and Methods

Patient Identification

We conducted an observational cross-sectional retrospective cohort study, in accordance with the STROBE guidelines.¹⁰ This study was approved by the Ethics Committee of the Portuguese Oncology Institute of Porto (IPOP)—CES52/019. Patients were identified using the IPOP Pathology Department's database and the Oncological Registry of the Northern Regions of Portugal (RORENO). Patients were included if they presented the following criteria: (a) Female patients aged 0 to 19 years old, to include children and adolescents (Word Health Organization's [WHO] adolescence age definition: 10-19 years); (b) Histological diagnosis of a tumor or tumor-like lesion in the uterine adnexa; (c) Follow-up at IPOP between Jan 1st, 2000 and 31st 2018. Both databases were crosschecked and queried using topography instead of morphology, to ensure identification of all patients. Patients were excluded if histological data was unavailable.

Data Collection and Database Construction

We searched physical and electronic patient records and collected data regarding demographic factors, clinical presentation, pathological findings, treatment, follow-up, and outcome.

Pathology reports, including gross and microscopic features were reviewed. All available histological and immunohistochemical slides were reviewed by a gynecological pathologist (CB). Tumors were classified according to the latest WHO classification, regarding histologic group (eg, epithelial, germ cell, sex cord-stromal, and other), histological subtype and biological behavior (benign, borderline, malignant).⁹ In bilateral tumors, each lesion was recorded as a separate finding. Data regarding symptoms at presentation, surgical interventions, chemotherapy, and radiotherapy was also collected. All borderline and malignant tumors were re-staged using the latest International Federation of Gynecology and Obstetrics (FIGO) system. Patients were classified as dead of disease, alive with disease and alive with no evidence of disease, according to their status at the date of Dec 13th, 2022.

Statistical Analysis

Statistical analysis was conducted using the IBM SPSS Statistics, version 25.0. Categorical variables were described using absolute and relative frequencies. All percentages reported excluded missing values. Considering the small sample size, continuous variables were characterized using median, minimum, and maximum. Comparisons between continuous variables were conducted using Mann–Whitney U-test and Kruskal–Wallis test, with correction for multiple comparisons using the Bonferroni adjustment. Follow-up time was calculated using the reverse Kaplan–Meier estimator. The end date of follow-up was considered Dec 13th, 2022. Statistical significance was considered at the level of P < .05.

Results

Combined search of databases yielded 107 patients. Eighteen patients were excluded: 15 due to absence of complete histological data, 2 due to miscoded age, and 1 due to miscoded topography. In total, 89 patients with 105 adnexal tumors or tumor-like lesions were included for analysis.

General Characteristics

Table 1 presents data regarding age, distribution of patients by age group, clinical behavior, malignancy rate by age group, and histopathological group type. Germ cell tumors (Figures 1 and 2) were the most common type in the 0 to 4 y/o (n = 4; 57%) and 10 to 14 y/o (n = 16; 55%) age groups. Epithelial tumors were the most common type in the 15 to 19 age group (n = 26; 41%), followed by germ cell tumors (n = 23; 36%). No significant differences were found when comparing age distribution between tumor-like lesions, benign, borderline, and malignant tumors (P = .085) or different histologic groups (P = .054). Malignant tumors had a significantly larger size (14.4 cm [range: 0.5;29]) than tumor-like lesions (6.5 cm [range: 1.7;11.5]; P = .045). No other differences in size between groups were found.

Table 1.

General Characteristics of Uterine Adnexal Tumors and Tumor-Like Lesions.

Age	15 (1-19) years^a
Age category (n = 89 patients)
0-4 y/o	6 (7%)
5-9 y/o	5 (6%)
10-14 y/o	25 (28%)
15-19 y/o	53 (60%)
Clinical behavior (n = 105 tumors and tumor-like lesions)
Benign tumors	44 (42%)
Borderline tumors	13 (12%)
Malignant tumors	25 (24%)
Tumor-like lesions	23 (22%)
Malignancy rate by age group (n = 89 patients)
0-4 y/o	50%
5-9 y/o	60%
10-14 y/o	24%
15-19 y/o	25%
Histopathological group (n = 82 tumors)
Germ cell	45 (55%)
Epithelial	30 (37%)
Sex cord-stromal	6 (7%)
Other	1 (1%)

^aMedian (minimum-maximum).

Benign adnexal tumors and tumor-like lesions (Table 2)

Fifty-one (57%) patients presented benign tumors (n = 37; 42%) or tumor-like lesions (n = 14; 16%). Sixteen (31%) patients had bilateral lesions: 7 bilateral benign tumors, 3 bilateral tumor-like lesions, 3 benign tumors with a tumor-like lesion in the contralateral ovary; and 3 tumor-like lesions in the contralateral ovary of a borderline/malignant tumor.

Table 2.

Gynecologic Adnexal Benign Tumors and Tumor-like Lesions.

Category	Histologic group	Diagnosis	Count	Age at diagnosis	Treatment
Benign tumors	Epithelial	Hydatid of Morgagni	2 (3.0%)	15 (14; 16)	Cystectomy (2; 100%)
		Mucinous cystadenoma	5 (7.5%)	16 (14; 18)	Adnexectomy (2; 40.0%); Oophorectomy (1; 20.0%); Cystectomy (2; 40.0%)
		Serous cystadenoma	11 (16.4%)	17 (13; 18)	Adnexectomy with contralateral cystectomy (1; 12.5%); Oophorectomy (1; 12.5%); Bilateral cystectomies (2; 25.0%); Cystectomy (4; 50.0%)
	Germ cell	Mature teratoma	23 (34.3%)	16 (6; 19)	Adnexectomy with contralateral cystectomy (1; 4.8%); Adnexectomy (3; 14.3%); Oophorectomy (7; 33.3%); Bilateral cystectomies (2; 9.5%); Cystectomy (8; 38.1%)
	Sex cord-stromal	Fibroma	2 (3.0%)	18 (17; 19)	Adnexectomy (2; 100%)
	Sex cord-stromal	Thecoma	1 (1.5%)	15	Oophorectomy
Tumor-like lesions		Adnexal torsion	7 (10.4%)	12 (3; 18)	Adnexectomy (6; 85.7%) \| Oophorectomy (1; 14.3%)
		Cystic corpus luteum	1 (1.5%)	18	Cystectomy
		Endometrial cyst	4 (6.0%)	17 (12; 19)	Adnexectomy (1; 33.3%); Bilateral cystectomies (1; 33.3%); Salpingectomy (1; 33.3%)
		Follicular cyst	9 (13.4%)	16 (3; 19)	Adnexectomy (1; 12.5%); Bilateral cystectomies (1; 12.5%); Cystectomy (6; 75.0%)
		Hemorrhagic corpus luteum	1 (1.5%)	15	Cystectomy
		Massive ovarian oedema	1 (1.5%)	9	Oophorectomy

Counts include bilateral tumors and findings in the contralateral adnexum, and are presented as absolute and relative frequencies (in parenthesis) considering the total number of tumors. Age is presented as median age (minimum; maximum), in years. Treatment types are presented as absolute and relative frequencies (in parenthesis) for the specific morphology, excluding missing values.

Among benign tumors (n = 44; 42%), 23 (52%) were of germ cell origin, 18 (41%) were epithelial tumors, and 3 (7%) were sex cord-stromal tumors. The most common benign tumor was mature teratoma (n = 23; 52%), followed by serous cystadenoma (n = 11; 25%). Three patients had bilateral mature teratomas. Among tumor-like lesion (n = 23; 22%), the most frequent were follicular cysts (n = 9; 39%) and adnexal torsions (n = 7; 30%). Median size for benign adnexal tumors was 7.5 cm (range: 0.9; 41) and 6.5 (range: 1.7; 11.5) cm for tumor-like lesions.

Data on presenting signs and symptoms was available for 18 patients with benign tumors: 4 (22%) with pain/discomfort, 3 (17%) with sensation of mass, 2 (11%) with amenorrhea, and 2 (11%) with bloody discharge. Two (11%) patients had signs of hyperandrogenism. Four patients (22%) were diagnosed incidentally, one during an emergency appendectomy. Within patients solely with tumor-like lesions, data on presenting signs and symptoms was available for 6: 3 (50%) with pain/discomfort, 1 (17%) with sensation of mass, 1 (17%) with bloody discharge, and 1 (17%) with amenorrhea.

Surgical treatment of patients with benign tumors and/or tumor-like lesion included 16 (31%) unilateral cystectomies, 7 (14%) bilateral cystectomies, 10 (20%) unilateral oophorectomies, 9 (18%) unilateral adnexectomies, 8 (16%) oophorectomies/adnexectomies plus contralateral cystectomy or contralateral biopsy, and 1 (2%) salpingectomy. Ten patients (20%) also performed limited omental and peritoneal biopsies, ± appendicectomy. Patient follow-up showed no clinical/radiological evidence of relapse (median follow-up time 152 months [95% confidence interval: 108; 196]).

Borderline and malignant adnexal tumors (Tables 3 and 4)

Thirty-eight patients presented with borderline (n = 13; 15%) or malignant tumors (n = 25; 28%). Six (16%) patients had bilateral tumors (2 bilateral borderline serous tumors, 1 bilateral neuroectodermal tumor, 1 bilateral dysgerminoma, 1 bilateral gonadoblastoma, and 1 dysgerminoma with a gonadoblastoma in the contralateral ovary).

Table 3.

Patients With Gynecologic Adnexal Borderline Tumors.

Histologic group	Diagnosis	Age at diagnosis	FIGOstage	Treatment			Relapse	Status
Histologic group	Diagnosis	Age at diagnosis	FIGOstage	Surgery	CT	RT	Relapse	Status
Epithelial	Borderline mucinous tumor	15	I	Adnexectomy	No	No	No	NED
	Borderline mucinous tumor	17	I	Adnexectomy	No	No	No	NED
	Borderline mucinous tumor^b	13	I	Adnexectomy with contralateral ovarian biopsy + partial omentectomy + peritoneal biopsies	No	No	No	NED
	Borderline mucinous tumor	19	I	Adnexectomy with contralateral ovarian biopsy	No	No	No	NED
	Borderline mucinous tumor	19	I	Adnexectomy + peritoneal biopsies + appendicectomy	No	No	No	NED
	Borderline serous tumor^a	18	I	1st Oophorectomy with contralateral cystectomy + partial omentectomy + peritoneal biopsies; 2nd adnexectomy	No	No	No	NED
	Borderline serous tumor	17	I	1st Adnexectomy with contralateral cystectomy; 2nd omentectomy + peritoneal biopsies	No	No	Yes^e	NED
	Borderline serous tumor	17	I	Bilateral adnexectomy with hysterectomy + omentectomy + peritoneal biopsies	Yes^c	No	No	NED
	Borderline serous tumor	15	NA	Adnexectomy + partial omentectomy + peritoneal biopsies + lymph node sampling	No	No	No	NED
	Borderline serous tumor^a	19	I	Bilateral adnexectomy + partial omentectomy + peritoneal biopsies	No	No	No	NED
Germ cell	Gonadoblastoma^a	4	I	Bilateral adnexectomy	No	No	No	NED
Sex cord-stromal	Juvenile granulosa cell tumor	3	I	Oophorectomy + partial omentectomy + peritoneal biopsies + lymph node sampling	No	No	No	NED
Sex cord-stromal	Sertoli-Leydig cell tumor	5	III	1st Oophorectomy; 2nd Omentectomy + salpingectomy	Yes^d	No	No	NED

Primary surgery's and second-look surgery's procedures are identified as 1st and 2nd, respectively.

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; NA, not available; CT, chemotherapy; RT, radiotherapy; NED, no evidence of disease.

^aBilateral lesion.

^bContralateral follicular cyst (accounted in Table 1).

^c6 cycles of paclitaxel and carboplatin.

^d4 cycles of bleomycin, etoposide, and platinum.

^eContralateral adnexectomy due to recurrence of serous borderline tumor.

Table 4.

Patients With Malignant Gynecologic Adnexal Tumors.

Histologic type	Diagnosis	Age at diagnosis	FIGOstage	Treatment			Relapse	Status
Histologic type	Diagnosis	Age at diagnosis	FIGOstage	Surgery	CT	RT	Relapse	Status
Epithelial	Endometrioid carcinoma	18	I	Adnexectomy + lymph node sampling + omentectomy + appendicectomy	No	No	No	NED
Epithelial	Mucinous adenocarcinoma^b	16	I	1st Adnexectomy; 2nd Contralateral ovarian biopsy + omentectomy + peritoneal biopsies	Yes^c	No	No	NED
Germ cell	Choriocarcinoma	6	I	1st Adnexectomy; 2nd Post-chemotherapy surgery for residual disease: No pathological findings	Yes^d	No	No	NED
	Dysgerminoma^e	12	II	1st Adnexectomy; 2nd Adnexectomy + hysterectomy + peritoneal biopsies	Yes^f	No	No	NED
	Dysgerminoma	15	I	Adnexectomy + partial omentectomy	No	No	No	NED
	Dysgerminoma	15	I	Adnexectomy with contralateral ovarian biopsy + partial omentectomy + peritoneal biopsies	Yes^f	No	No	NED
	Dysgerminoma^a	18	I	Bilateral adnexectomy	No	No	No	NED
	Dysgerminoma	17	II	Adnexectomy + peritoneal biopsies	Yes^f	No	No	NED
	Immature teratoma	18	I	1st Oophorectomy; 2nd Omentectomy + peritoneal biopsies, lymph node sampling;	No	No	No	NED
	Immature teratoma	12	III	1st Adnexectomy + partial omentectomy; 2nd Post-chemotherapy surgery for residual disease: Mature teratoma	Yes^f	No	No	NED
	Immature teratoma	13	I	1st Oophorectomy; 2nd Post-chemotherapy surgery for residual disease: No pathological findings	Yes^f	No	No	NED
	Immature teratoma^g	13	I	Adnexectomy + partial omentectomy + peritoneal biopsies + lymph node sampling	Yes^f	No	No	NED
	Immature teratoma^g,h	6	I	Adnexectomy + partial omentectomy + peritoneal biopsies + lymph node sampling + appendicectomy	No	No	No	NED
	Immature teratoma	17	I	Adnexectomy with contralateral ovarian biopsy + partial omentectomy + peritoneal biopsies	No	No	No	NED
	Immature teratoma	15	I	1st Cystectomy; 2nd Oophorectomy with contralateral ovarian biopsy	No	No	Yesⁱ	NED
	Mixed germ cell tumor^g	18	I	1st Cystectomy; 2nd Adnexectomy with contralateral ovarian biopsy + omentectomy + lymphadenectomy	Yes^j	No	Yes^k	NED
	Mixed germ cell tumor	12	I	Adnexectomy + partial omentectomy + peritoneal biopsies	Yes^f	No	No	NED
	Neuroectodermal tumor^a	14	IV	1st Bilateral adnexectomy; 2nd Post-chemotherapy surgery for residual disease including hysterectomy	Yes^l	No	Yes^m	DOD
	Yolk sack tumor	17	II	Bilateral adnexectomy with hysterectomy + peritoneal biopsies	Yesⁿ	No	No	NED
	Yolk sack tumor^b	17	I	Adnexectomy + partial omentectomy + peritoneal biopsies + lymph node sampling	Yes^f	No	No	NED
	Yolk sack tumor	1	III	Tumorectomy	Yes^f	No	No	NED
	Yolk sack tumor	1	IV	Post-chemotherapy tumorectomy	Yes^o	No	No	NED
	Yolk sack tumor	2	IV	No surgery	Yes^p	No	No	NED
Sex cord-stromal	Sertoli-Leydig cell tumor	15	NA	Oophorectomy + nephrectomy	Yes^q	No	No	NED
Other	Acute lymphoblastic leukemia^r	7	NA	Adnexectomy	Yes^r	No	No	NED

Primary and second-look surgery's procedures are identified as 1st and 2nd, respectively.

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; CT, chemotherapy; RT, radiotherapy; NED, no evidence of disease; DOD, dead of disease; NA, not available/applicable.

^aBilateral lesions.

^bContralateral follicular cyst.

^cSix cycles of paclitaxel and carboplatin.

^dFour cycles of etoposide and cisplatin.

^eContralateral gonadoblastoma.

^fFour cycles of bleomycin, etoposide, and platinum.

^gPeritoneal gliomatosis.

^hNodal gliomatosis.

ⁱSix cycles of bleomycin, etoposide, and platinum.

^jThree cycles of bleomycin, etoposide, and platinum and 1 cycle of etoposide and cisplatin.

^kThree cycles of bleomycin, etoposide, and platinum and 1 cycle of etoposide and cisplatin in the first relapse; metastasectomy and RT in second relapse.

^lSix cycles of carboplatin, etoposide, and bleomycin sulfate.

^mFour cycles of cisplatin, etoposide, and ifosfamide in first relapse; 2 cycles of paclitaxel and ifosfamide plus 3 cycles of carboplatin and etoposide, followed by autologous bone marrow transplant in second relapse.

ⁿSix cycles of bleomycin, etoposide, and platinum and 4 cycles of etoposide, ifosfamide, and cisplatin.

^o6 cycles of bleomycin, etoposide, and platinum and 1 cycle of dactinomycin.

^p6 cycles of bleomycin, etoposide, and platinum and 2 cycles of etoposide, ifosfamide, and cisplatin.

^q4 cycles of etoposide, ifosfamide, and cisplatin, with bleomycin in the last 3 cycles.

^rOvarian mass due to secondary involvement of acute lymphoblastic leukemia diagnosed at 4 years of age. Treated with protocol 58951 of the European Organization for Research and Treatment of Cancer's Children's Leukemia Group and protocol INTREALL SR 2010.

The most common histologic type was germ cell (n = 22; 58%), followed by epithelial (n = 12; 32%) and sex cord-stromal (n = 3; 8%). The majority of borderline tumors were serous (n = 5; 39%) and mucinous (n = 5; 39%) tumors. The most common malignant tumor was immature teratoma (n = 7; 28%): 2 grade 1, 2 grade 2, and 3 grade 3. Gliomatosis was found in 3 patients, 2 with an immature teratoma (peritoneal and nodal gliomatosis) and 1 with a mixed germ cell tumor (nodal gliomatosis). Median size was 9.5 cm (range: 5.8; 33) for borderline tumors and 14.4 (range: 0.5; 29.0) cm for malignant tumors.

Data on presenting signs and symptoms was available for 9 patients with borderline tumors: 5 (56%) with sensation of mass, 2 (22%) with pain/discomfort, 2 (22%) with bloody discharge, and 2 (22%) with signs of early puberty. Data on presenting signs and symptoms was available for 17 patients with malignant tumors: 9 (53%) with sensation of mass, 5 (29%) with pain/discomfort, and 5 (29%) with bloody discharge.

First approach for surgical treatment of patients with borderline tumors included 2 (15%) unilateral oophorectomies, 4 (31%) unilateral adnexectomies, 2 (15%) bilateral adnexectomies, 1 (8%) bilateral adnexectomy with hysterectomy, and 4 (31%) oophorectomies/adnexectomies plus contralateral cystectomy or contralateral ovarian biopsy. Initial surgical treatment of patients with malignant tumors included: 2 (8%) cystectomies, 3 (12%) unilateral oophorectomies, 12 (48%) unilateral adnexectomies, 2 (8%) bilateral adnexectomies, 1 (4%) bilateral adnexectomy with hysterectomy, 2 (8%) oophorectomies/adnexectomies plus contralateral cystectomy or contralateral biopsy, and 2 (8%) tumorectomies. Nine (69%) patients with borderline tumors and 15 (60%) patients with malignant tumors also underwent surgical staging including omentectomy/partial omentectomy and peritoneal biopsies ± lymph node sampling ± appendicectomy. Two (15%) patients with borderline tumors and 18 (72%) patients with malignant tumors were submitted to chemotherapy. Twenty-six (72%) patients were classified as FIGO stage I, 3 (8%) as stage II, 3 (8%) as stage III, and 3 (8%) as stage IV.

Overall median follow-up time was 125 months (95% confidence interval: 90.4; 159.6). Thirty-seven (97%) patients showed no evidence of disease, and 4 (11%) patients relapsed, 1 (3%) of which died from disease (a stage IV neuroectodermal tumor). The 3 other patients who relapsed had a stage I serous borderline tumor, a stage I mixed germ cell tumor, and stage I immature teratoma. Four patients who underwent cisplatin chemotherapy developed bilateral sensorineural hearing loss. One patient developed a Hodgkin lymphoma, nodular sclerosis type, stage IIB 18 years after the adnexal tumor diagnosis.

Discussion

In this study, over half of patients presented benign tumors and tumor-like lesions. It should be emphasized that our institution is a referral cancer center, and thus, there may be a bias towards underestimation of benign tumors and tumor-like lesions rates for this population. Nonetheless, our results regarding the age distribution and histopathological types are in line with current evidence in literature. The median age of diagnosis was 15 years and the malignancy rate tended to decrease with age. The most common histologic group were germ cell tumors. Germ cell tumors tended to be diagnosed at earlier ages than epithelial tumors, but this difference was not statistically significant. Surgical treatment, in most cases, was conservative and allowed for fertility preservation. Nearly a third of patients with borderline and malignant tumors were submitted to a second surgery to complete staging or remove suspected lesions. Most patients with borderline and malignant tumors were diagnosed in early stages of the disease. A small percentage of patients relapsed and 1 patient died from disease.

The number of cases increased exponentially with age, as expected. Several studies point to a higher frequency of malignancy of ovarian tumors in early ages (0-6 years), with a decrease in the malignancy rate from 7 to 12 years onward.¹¹ In our cohort, epithelial tumors tended to have a higher median age of onset when comparing to other histological types, but this difference was not statistically significant. Young et al studied 1563 ovarian tumors in patients aged 0 to 24 years and reported a bimodal distribution for germ cell and epithelial ovarian tumors in patients aged between 0 and 24 years, showing a transition period in the ages of 20 to 24 years, with an increased incidence of carcinoma and a decreased incidence of germ cell tumors.¹² Other authors also reported a higher proportion of ovarian germ cell tumors in younger children, when comparing to late pediatric ages,¹³ while epithelial ovarian are reported to be infrequent in children and adolescents, increasing in incidence with age.^6,14,15 It is important to note that variations exist in the definition of pediatric age across studies. The WHO pediatric age definition is 0 to 18 years old, but some healthcare institutions or countries extend the upper age limit to 19 years. The American Academy of Pediatrics (AAP) defines the pediatric age range as birth to 21 years, and the scope of adolescent medicine may also go up to 24 years.

The distribution of histological subtypes in our cohort of children and adolescents is in accordance with the literature. Germ cell tumors predominate (43%), followed by 29% epithelial tumors and 6% sex cord-stromal tumors. Several studies reported that 35% to 87% of ovarian lesions were of germ cell origin.^2,13–16 Epithelial tumors were reported as 19% of all ovarian tumors and sex cord-stromal tumors as 10% of all ovarian malignancies in the pediatric age.⁵ Mature teratomas have consistently been reported as the most common benign ovarian tumor.^14,15,17,18

Bilaterality was more frequent in mature teratomas and dysgerminomas. In addition, one case of dysgerminoma had a contralateral gonadoblastoma, and we identified 1 patient with bilateral gonadoblastomas. Pediatric mature teratomas are described as being bilateral in 10% of patients.^5,19 Dysgerminomas are described as the most commonly bilateral at presentation of all malignant germ cell tumors, in 10% to 20% of cases.^20,21 Several cases in literature report the coexistence between gonadoblastomas and dysgerminomas.^22–25 Gonadoblastomas develop in patients with gonadal dysgenesis, including Turner syndrome and androgen insensitivity syndrome, and were shown to coexist with dysgerminoma in more than half of patients.^9,24

The overall malignancy rate in our cohort was 28%. Most studies in literature report a 9% to 33% malignancy rate for ovarian lesions,^5,14,17 while others report 40% to 60% malignancy rates.^11,26 Inclusion of ovarian cysts and differences in classification between studies might explain these differences. Overestimation of the overall malignancy rate might have occurred in this study given that our hospital is a tertiary referral center and only lesions with a histological diagnosis were included.

Most borderline and malignant adnexal tumors in our cohort were FIGO stage I and II. Several studies estimate that the proportion of pediatric patients with ovarian malignancies diagnosed with localized disease is around 50% to 70%.^2,4,12,13 Young et al reported that the proportion of patients diagnosed at higher stages was larger in children aged 0 to 4 years compared to 15 to 24 years, possibly due to the differences in histologic types that occur in each age group.¹²

Surgical and adjuvant treatment of adnexal tumors in this age may have everlasting effects on fertility and lead to premature menopause.^27,28 Great care must be taken in the balancing act of treatment/fertility. The initial treatment in our study, in most patients, consisted in surgical exploration, with unilateral salpingo-oophorectomy or cystectomy. Extensive staging procedures and bilateral adnexectomies and hysterectomies were conducted in a minority of patients. Re-intervention to complete staging was only performed in a small number of cases. Conservative surgery has been shown to have little impact on pediatric patients’ recurrence and prognosis (even in patients at advanced stages).⁴ This observation might be the result of the high proportion of germ cell tumors, the main histologic group found in the pediatric population, which have a good prognosis, as well as the excellent response to chemotherapy. Little data exists on fertility outcomes after treatment of adnexal tumors in these ages. One study reported a 15% fertility deficit in adult patients who survived gynecological cancers in the pediatric age.²⁹ Alkylating agents have been associated with higher rates of ovarian failure in childhood cancer survivors.³⁰ Higher rates of ovarian failure after chemotherapy and radiotherapy have also been reported in post-pubertal girls versus pre-pubertal girls³⁰ and several options are under study for fertility preservation.^27,28

In our cohort, 4 patients with borderline and malignant tumors relapsed and 1 died from disease. Death and relapse rates found in literature are, in most cases, low.¹¹ You et al reported, for ovarian malignancies, 96% 5-year survival rate for localized disease, 92% for regional disease, and 64% for distant metastasis.² You et al also reported crude mortality rates of 0.1/100 000 for 15 to 19 years old with ovarian carcinoma.² Brookfield et al reported a 97.1% 5-year survival rate for ovarian tumors and found that disease stage, tumor grade, and treatment were independent predictors for survival. The large proportion of germ cell and borderline tumors, detection in early stages and good response to chemotherapy might affect these outcomes.

No patients with benign tumors or tumor-like lesions relapsed in our cohort. In contrast, 10% to 30% recurrence rate is reported in literature for ovarian-sparing surgery in benign tumors and tumor-like lesions.³¹ These recurrence rates have been associated with functional cysts, benign tumors, large size, and incompleteness of resection.³¹

Ovarian torsion is a rare event in childhood and adolescence, most occurring in 20 to 40 years of age.⁷ Ovarian torsions are often treated surgically, either through oophorectomy or ovarian detorsion. Oophorectomy is the most common procedure performed (one study reported 78% of patients underwent oophorectomy and only 6% underwent detorsion).³² Increasing evidence points to the benefit of detorsion over oophorectomy, with little evidence supporting the risk of non-complete excision of neoplasms and thromboembolism, as well as an increased number of patients demonstrating ovarian viability after detorsion.⁷ Despite the evidence, the rate of oophorectomy has not changed in recent years.³³ In our cohort, 7 patients were diagnosed with ovarian torsion, 6 were treated with adnexectomies, and 1 was treated with oophorectomy. In the setting of referral, these torsions were submitted to surgery sometime after the acute event, which might have decreased the likelihood of ovarian viability and made the case for oophorectomy.

The rare occurrence of pediatric adnexal tumors is reflected in the paucity of data in literature, with a small number of cohorts studied and few reports on larger databases. To our knowledge, this is the largest cohort of adnexal tumors described in a Portuguese institution. Only 1 study, by Carvalho et al, described a Portuguese cohort of 16 patients with ovarian lesions aged between 5 and 15 years, 6 with tumor-like lesions, and 10 with neoplastic lesions.³⁴ Limitations of our study mainly relate to missing information, classification, and treatments differences in referring hospitals, which proved to be a challenge in information gathering.

Conclusion

Gynecologic adnexal tumors, although rare, should be considered in young girls who report abdominal pain and present abdominal palpable masses. Histologic subtypes and biological behavior in the pediatric age is different from adults. Most cases are benign, including tumors and tumor-like lesions. Malignancy rate is higher than in adults, but most tumors are diagnosed in early stages, have low recurrence potential and high cure rates. Conservative treatment with preservation of fertility can be performed in most patients.

Footnotes

Author Contributions

All authors contributed to the study conception and design. Data collection was performed by JC. Pathological review of the cases and data analysis were performed by JC and CB. The first draft of the manuscript was written by JC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

The research was conducted ethically in accordance with the Declaration of Helsinki. This study was approved by the Ethics Committee of the Portuguese Oncology Institute of Porto (CES52/019).

Informed Consent

Not applicable, because this article does not contain any studies with human or animal subjects.

Trial Registration

Not applicable, because this article does not contain any clinical trials.

ORCID iD

João Costa

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