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Diagnosis, Pathology, Staging, Treatment, and Outcome of Epithelial Ovarian Neoplasia in Patients Age < 21 Years
Josephine Y. Tsai, M.D.1,2 Patricia E. Saigo, M.D.1,2 Carol Brown, M.D.1,2 Michael P. La Quaglia, M.D.1,2
1

BACKGROUND. Epithelial ovarian neoplasms are rare in patients under the age of 21
years. This is a report of a series of such patients documenting their presentation, histologic type, stage of disease, treatment, and outcome. METHODS. Clinical ndings, histology, stage, treatment, and outcomes of 19 patients with epithelial ovarian neoplasia are reported. All histology was rereviewed. RESULTS. The median age at the time of diagnosis was 19.7 years (range, 14.121.8 years), and the median follow-up was 5.6 years (range, 0.219.5 years). The most common presenting symptom was dysmenorrhea (100%) followed by abdominal pain (68%), and the initial diagnosis usually was made ultrasonographically. There were nine (47%) serous tumors, 7 (37%) mucinous tumors, 2 (11%) small cell carcinomas, and 1 (5%) endometrioid carcinoma. Seventy-nine percent of tumors were unilateral, and 84% were low malignant potential or well differentiated tumors. Surgical treatment included unilateral salpingo-oophorectomy in 12 patients (63%), total abdominal hysterectomy and bilateral salpingo-oophorectomy in 6 patients (32%), and ovarian cystectomy in 1 patient (5%). Fifteen patients (79%) had Stage I disease, and 4 patients (21%) had Stage III disease at the time of diagnosis. There were two deaths in this series, and both occurred in patients with small cell anaplastic carcinoma. CONCLUSIONS. Epithelial ovarian neoplasias are rare in patients in this age group but must be included in the differential diagnosis of an ovarian mass. Most patients present with Stage I tumors of low malignant potential. In these patients, good survival is achieved with unilateral salpingo-oophorectomy and preservation of fertility. In contrast, small cell carcinomas are very aggressive, and patients with this variant require intensive therapy. Cancer 2001;91:206570. 2001 American Cancer Society.

Department of Surgery (Pediatric Surgery, Gynecologic Oncology), Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.

KEYWORDS: ovary, carcinoma, childhood, adolescence, treatment, histology, staging, International Federation of Gynecology and Obstetrics.

Address for reprints: Michael P. La Quaglia, M.D., F.A.A.P., Department of Surgery, Memorial SloanKettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: 212-717-3373; E-mail: laquaglm@mskcc.org. Received January 17, 2000; revisions received September 25, 2000 and January 23, 2001; accepted January 26, 2001. 2001 American Cancer Society

alignant ovarian tumors are rare in childhood and adolescence, comprising approximately 1% of all malignant neoplasms.1 However, ovarian neoplasms constitute 60 70% of all gynecologic malignancies in patients in this age group.2 Epithelial ovarian neoplasias are even more uncommon in young patients, and few series have reported primarily on epithelial ovarian tumors in children. Earlier series have been complicated by a lack of standardized histologic typing and by combining nonneoplastic and malignant tumors.1,3,4 Recent papers on epithelial tumors in children usually have been isolated case reports.5,6 We report our experience with 19 patients who were diagnosed at age 21 years with epithelial ovarian

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FIGURE 1. The staging of ovarian carcinoma according to the International Federation of Gynecology and Obstetrics (FIGO). Asterisks indicate that, to evaluate the impact on prognosis with the different criteria for allotting patients to Stage IC or IIC, it would be of value to know whether rupture of the capsule was spontaneous or was caused by the surgeon and whether the source of malignant cells detected was peritoneal washings or ascites (adapted from Young et al.7 and FIGO8).

neoplasia to document clinical presentation, histology, staging, treatment, and outcome.

MATERIALS AND METHODS

The initial patient data base included all female patients who were diagnosed with ovarian neoplasms at age 21 years at Memorial Sloan-Kettering Cancer Center (MSKCC) from January 1, 1973 to August 15, 1996. One hundred thirty-four patients were accrued. Patients with germ cell tumors, gonadal stromal tumors, nongonadal stromal tumors, and two patients with benign cystadenomas were excluded. According to the World Health Organization classication, germ cell tumors included teratoma, dysgerminoma, endodermal sinus tumor, choriocarcinoma, mixed germ cell tumor, and embryonal carcinoma.7 Gonadal stromal tumors included granulosa-stromal cell tumor, SertoliLeydig tumor, and gynandroblastoma. Other ovarian tumors excluded from this study included sarcoma and lymphoma. Staging was done after surgery, as dened by the International Federation of Gynecology and Obstetrics classication system shown in Figure 1.7,8 Of the 134 patients in this age group who were diagnosed with ovarian tumors, 26 patients (19%) had epithelial ovarian neoplasia. The charts on four pa-

tients with epithelial ovarian neoplasia were not available. Three patients with epithelial ovarian tumors only sought second opinions and were not treated or followed at our institution. These 7 patients were excluded from our analysis, leaving 19 patients available for review. Slides were rereviewed, and the diagnosis of epithelial ovarian neoplasia was conrmed by a single pathologist (P.E.S.). In two patients, the initial slides were unavailable, and a diagnosis was obtained by MSKCC pathology reports. This retrospective analysis focused on clinical presentation, pathology, staging, treatment, and outcome. We report mean values with the standard deviation.

Surgical Approach
All patients in this report underwent a full staging laparotomy through a midline incision except for Patient 9 in Table 1. This included the primary tumor resection, as listed in Table 1 or 2, as well as omentectomy or omental biopsy, peritoneal washings/and or biopsies (including the subdiaphragmatic surface and pelvis), and para-aortic or pericaval lymph node sampling. The infundibulopelvic ligament was dissected as high as possible, and accompanying lymph nodes were removed. A normal appearing, contralateral ovary was not biopsied. In one patient with a low

Epithelial Ovarian Neoplasia in the Young/Tsai et al. TABLE 1 Demographic, Staging, Pathology, Treatment, and Outcome of Patients with Low Malignant Potential Neoplasia (n
Age at diagnosis (yrs) 20.2 19.0 18.1 18.9 20.7 15.9 20.9 15.0 19.1 17.8 Size (cm) 5 13.8 18.5 20 20 15 25 5 Surgery/ chemotherapy Uso/no Uso/no Uso/no Uso/no Uso/no Uso/no Tah,Bso/no Uso/no Ovarian cystectomy/no Uso/no

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10 patients)
Follow-up (yrs) 14.2 2.2 0.8 9.2 14.9 6.5 0.2 4.6 5.7 2.9

Patient 1 2 3 4 5 6 7 8 9 10

Side Right Right Right Right Right Right Bilateral Left Right Right

Symptoms Pain, distension Pain, recurrent ovarian cyst Distension Pain Pain Mass Bloating, emesis Pain Asymptomatic Pain (rlq)

Histology and grade Mucinous/lmp neoplasia Serous lmp neoplasia Serous lmp neoplasia Serous lmp neoplasia Serous lmp neoplasia Mucinous lmp neoplasia Serous lmp neoplasia Mucinous lmp neoplasia Serous lmp neoplasia Serous lmp neoplasia

Stage IA IA IA IA IA IA IB IC IC IC

Status ned ned ned ned ned ned ned ned ned ned

Uso: unilateral salpingo-oophorectomy; lmp: low malignant potential; ned: no evidence of disease; Tah: total abdominal hysterectomy; Bso: bilateral salpingo-oophorectomy; rlq: right lower quadrant.

TABLE 2 Demographic, Staging, Pathology, Treatment, and Outcome Patients with Invasive Carcinomaa
Age at diagnosis (yrs) 20.4 19.7 Size (cm) 8.0 10.0 Surgery/ chemotherapy Tah, Bso/no Uso/no Follow-up (yrs) 12.1 16.7

Patient 1 2

Side Left Left

Symptoms Pain (pressure) Amenorrhea Pain, nausea, emesis, diarrhea Pain Vaginal discharge Pain Pain (pressure), dyspareunia, vaginal discharge Pain, distension Pain, distension

Histology and grade Mucinous/wd Mucinous/wd

Stage IA IA

Status ned ned

3 4 5 6

14.1 20.5 20.2 17.3

Left Left Right Bilateral

18.0 22.0 12.0

Uso/yes Uso/yes Uso/yes Tah, Bso/yes

Mucinous/wd Mucinous/wd Endometrioid Serous/wd

IA IA IA III

ned ned ned ned

16.2 19.8 10.7 1.5

7 8 9

21.8 20.2 20.7

Bilateral Bilateral Left

9.5

Tah, Bso/yes Tah, Bso/yes Tah, Bso/yes

Serous/wd Small cell anaplastic Small cell anaplastic

III III III

ned dod dod

1.4 0.9 0.6

Tah: total abdominal hysterectomy; Bso: bilateral salpingo-oophorectomy; wd: well differentiated; ned: no evidence of disease; Uso: unilateral salpingo-oophorectomy; dod: died of progressive disease.

malignant potential (LMP) neoplasia, a laparoscopic approach was employed.

RESULTS
Patient Characteristics and Presentation
The patient data are summarized in Tables 1 and 2. The overall median age at the time of diagnosis was 19.7 years, with a range of 14.121.8 years (mean, 19.0 2.1 years). Patients with LMP tumors had a mean age of 18.6 1.9 years, whereas those with invasive tumors presented at a mean age of 19.4 2.3 years. The majority of patients were Caucasians, and 18 pa-

tients were gravida 0 and para 0. The median age at menarche was 13.0 years and ranged from 11 years to 15 years (n 12 patients), and none of the patients was premenarchal at the time of diagnosis. The family histories were unremarkable for gynecologic malignancies, except for two patients who had maternal aunts with ovarian and uterine carcinoma, respectively. In addition, one patients mother had a history of cervical carcinoma. Past medical histories also were unremarkable. The median interval from the onset of symptoms to the time of diagnosis was 0.7 months and ranged

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from 10 days to 3.5 months (n 11 patients). The most common symptoms, in descending order, were dysmenorrhea or amenorrhea in 19 patients (100%), abdominal pain in 13 patients (68%), abdominal distension in 5 patients (26%), nausea and emesis in 3 patients (16%), and vaginal discharge in 2 patients (15%). In addition, diarrhea, difculty with urination, dyspareunia, and a mass were each reported in one patient. Physical examination revealed an abdominal or pelvic mass that was conrmed by ultrasound.

Staging, Pathology, Treatment, and Outcome

Of the patients with LMP neoplasms, six had Stage IA disease, one had Stage IB disease, and three had Stage IC disease at the time of diagnosis (Table 1). Five of the invasive tumors were Stage IA, and four were Stage III (Table 2). Overall, nine tumors were right-sided (47%), six were left-sided (32%), and four were bilateral (21%). The median maximal tumor dimension was 14.4 cm and ranged from 5 cm to 25 cm. (n 14; mean, 14.4 6.4 cm). The median greatest dimension of LMP neoplasms was 15.3 7.2 cm, and that for the invasive tumors was 13.3 5.5cm. Two ovarian tumors weighed approximately 800 grams each, and 8.4 liters of cystic uid were removed from one additional tumor. Another was described as extending from the pelvis to the xiphoid. Seven of the 10 LMP neoplasms were serous tumors, and 3 were mucinous. Four of the nine invasive tumors had mucinous characteristics, one was endometrioid, and two were small cell anaplastic tumors. Eight of 10 patients with LMP neoplasms were treated with unilateral salpingo-oophorectomy, one with ovarian cystectomy, and one patient underwent a total abdominal hysterectomy and bilateral salpingooophorectomy (Table 1). The ovarian cystectomy was done laparoscopically, and a follow-up staging laparoscopy was also performed. The one patient undergoing bilateral salpingo-oophorectomy underwent the initial surgery at an outside institution and was referred for follow-up. None of these patients received systemic chemotherapy, and all were alive and without evidence of disease at last follow-up. Data for patients with invasive tumors are summarized in Table 2. Unilateral salpingo-oophorectomy was performed in four of the nine patients with invasive neoplasms, and ve patients were treated with total abdominal hysterectomy and bilateral salpingooophorectomy. This was done at an outside center in one patient with Stage IA disease who received all subsequent follow-up at our institution. Complete resection was accomplished in all patients with Stage I disease but not in patients with Stage III disease at the time of diagnosis. All but two patients with invasive

tumors received adjuvant chemotherapy. Patient 6 (Table 2) had residual disease at second-look laparotomy and underwent further debulking and more chemotherapy. She had no evidence of disease at a third exploration. Patient 7 had no evidence of disease at second-look laparotomy that was done after chemotherapy. Patient 8 had a negative second-look laparotomy but experienced disease recurrence 6 months later and expired from progressive disease. Patient 9 had progressive disease at second-look and subsequently died from disease. The other patients in this group are alive and without evidence of disease 1.4 19.8 years after diagnosis. The overall survival of all patients from the time of diagnosis is shown in Figure 2.

DISCUSSION
Epithelial ovarian neoplasia in adolescent girls and young women is very rare but remains part of the differential diagnosis of any ovarian mass. Deprest et al.9 reviewed 10 published series of benign and malignant ovarian tumors in children ages 20 years and younger. Those authors reported that 19.3% of all ovarian tumors were epithelial in origin, and the majority of these, 15.9% of tumors in all patients from the 10 series, were malignant. This is consistent with our observed rate of 19% (26 of 134 patients). Because ovarian malignancy rates in children may be overestimated by reports originating from referral centers, Diamond et al.10 looked at ovarian malignancy rates for girls ages 20 years from ve community hospitals: They cited a 9.8% malignancy rate for all subtypes of ovarian tumors and an even lower rate of 2.4% for malignant epithelial carcinomas. This may be a more accurate estimate of the proportion of malignant epithelial carcinomas in all young patients with ovarian neoplasms. Epithelial ovarian neoplasias in children occur almost exclusively after menarche.1,3,4,10 12 In our series, none of the patients was premenarchal. We found four reported cases of epithelial ovarian carcinoma in premenarchal girls, the youngest of which were two patients both age 4 years.5,6,13 Many authors have postulated that hormonal stimulation may trigger the development of epithelial ovarian tumors. In one report, all epithelial tumors in patients ages 14 years were benign, whereas the eight malignant epithelial tumors in this series occurred in patients ages 15 years.4 We found a median age at the time of diagnosis of 19 years, consistent with other reports. For instance, Abell and Holtz14 noted an average age of 17 years for patients with epithelial tumors, whereas Breen and Maxson1 noted that 65% of epithelial neoplasms occurred in patients ages 18 19 years. Epithelial ovarian neoplasias in children are frequently LMP tumors and/or well differentiated tumors

Epithelial Ovarian Neoplasia in the Young/Tsai et al.

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FIGURE 2. Chart showing the overall

survival of patients with epithelial ovarian carcinoma.

in an early stage. Hong et al.6 reported that epithelial tumors occur at a frequency of 1719% in children and adolescents compared with 70 80% in adults. This suggests (but does not prove) that LMP epithelial tumors in children may be precursors of ovarian carcinoma in adults.6,12 The rate of LMP ovarian neoplasia in reports of epithelial ovarian malignancy in childhood and adolescence has varied from 30% to 45%.9,12 In the current report, 53% of patients had LMP tumors of the ovary. These rates contrast with the 10 20% rate reported in adults.15 The greater frequency of LMP ovarian neoplasia in children correlates with a longer overall survival compared with adults with epithelial ovarian neoplasia. For instance, the 10-year survival rate for 13 patients ages 20 years with malignant epithelial ovarian carcinoma was 73% in a report by Norris and Jensen.4 None of the 10 patients in our series with LMP tumors died from disease, despite one patient who presented with Stage III disease. This contrasts with an overall survival rate of about 35% at 5 years for all stages of adult-onset epithelial ovarian malignancies.15 In addition to histologic grade, surgical stage also affects survival. Patients with Stage I disease comprised 78% of the patients in our series, and overall survival was 100%. The four patients who presented with Stage III disease had an overall survival of 50%. Others reported a 100% survival rate among nine patients with Stage I disease and a 33% survival rate

among three patients with Stage II disease.4 In contrast, 65% of adults with ovarian carcinoma have Stage III disease at the time of diagnosis, and only 20% have Stage I disease.15 The rate of malignant mucinous tumors has varied from 39% to 77% in reported series,10,13 and we found that 37% of our patients had mucinous neoplasia of the ovary. In contrast, 12% of tumors are mucinous in adults. Based on this nding, some believe that epithelial tumors in children may be of germ cell origin, representing monodermal teratomas with gastric or intestinal differentiation. This hypothesis does not account for the equally high numbers of serous tumors found and the lack of teratomatous elements identied histologically. Deprest et al.9 reported that 43.9% were malignant serous tumors versus 39.4% mucinous tumors in a review of 18 series. In our series, 42% of tumors were serous, and 37% were mucinous. In our series, 10 patients presented with Stage I LMP ovarian tumors. Of these, eight were treated with unilateral salpingo-oophorectomy, one with total abdominal hysterectomy and bilateral salpingo-oophorectomy, and one patient underwent a simple laparoscopic ovarian cystectomy. The survival rate was 100% in this group of patients, supporting use of unilateral salpingo-oophorectomy alone, completely resected LMP tumors. Chemotherapy is not required in patients with LMP tumors that have undergone complete resection. It is noteworthy that Piver and Patton2

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noted a 30% rate of bilaterality for Stage I serous tumors and a 10% rate of bilaterality for Stage I mucinous LMP tumors. Three patients who presented with invasive, Stage I, well differentiated, mucinous cystadenocarcinoma underwent unilateral salpingo-oophorectomy with negative biopsies of the contralateral ovary. Two of these patients received adjuvant chemotherapy, and the third patient received no chemotherapy: All three patients survived without evidence of disease. A fourth patient who underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy without adjuvant chemotherapy also remains alive. Although single-agent, alkylator-based chemotherapy was used until 1979 in patients with epithelial ovarian carcinoma, cisplatin-based, multiagent chemotherapy is recommended today. Barber15 noted that 10% of patients with Stage I neoplasias may present with metastases between the liver and diaphragm, and adjuvant chemotherapy is recommended for patients with Stage I disease who have evidence of peritoneal dissemination.16 Most authors recommend some form of cisplatin-based, multiagent chemotherapy for patients with high grade Stage II, III, and IV disease after radical surgery. Intraperitoneal 32P also is effective if macroscopic disease is eradicated rst. Raney et al.16 described two young patients who presented with Stage II endometrioid carcinoma and Stage III cystadenocarcinoma, respectively. Those patients were treated with cisplatin, doxorubicin, and cyclophosphamide. The second patient also received intraperitoneal 32P. Both patients are without evidence of disease at 6 years and 2 years, respectively. The two patients in our series with Stage III, well differentiated serous cystadenocarcinoma underwent radical surgery for bilateral disease and received adjuvant chemotherapy. They were without evidence of disease at second- and third-look laparotomies, respectively. Our one patient with Stage I endometrioid carcinoma followed a favorable course with unilateral salpingo-oophorectomy and single-agent chemotherapy. Endometrioid ovarian carcinoma is rare in children, and disease stage determines their treatment.17,18 Both patients in our series with small cell carcinoma presented with advanced disease and died within 1 year of diagnosis despite undergoing aggressive surgery and chemotherapy. Patsner et al.19 reported two children who presented with advanced disease and expired within 6 months of diagnosis. Progress against small cell carcinoma will require more effective adjuvant therapy. In summary, we report 19 patients with primary LMP and malignant epithelial ovarian neoplasias who were age 21 years at the time of diagnosis. Epithelial ovarian tumors in the young usually are of low grade

and stage despite the large sizes of the primary tumors. To preserve reproductive capacity, conservative treatment for young patients with localized tumors is recommended. Patients with small cell carcinomas have a poor prognosis.

REFERENCES
1. 2. 3. 4. 5. Breen JL, Maxson WS. Ovarian tumors in children and adolescents. Clin Obstet Gynecol 1977;20(3):60723. Piver MS, Patton T. Ovarian cancer in children. Semin Surg Oncol 1986;2(3):1639. Abell MR. Ovarian neoplasms in childhood and adolescence. J Ark Med Soc 1967;63(8):279 -85. Norris HJ, Jensen RD. Relative frequency of ovarian neoplasms in children and adolescents. Cancer 1972;30(3):7139. Blom GP, Torkildsen EM. Ovarian cystadenocarcinoma in a 4-year-old girl: report of a case and review of the literature. Gynecol Oncol 1982;13(2):242 6. Hong SJ, Lurain JR, Tsukada Y, Piver MS, Humbert JR, Freeman AI. Cystadenocarcinoma of the ovary in a 4-year-old: benign transformation during therapy. Cancer 1980;45(8):222730. Young RC, Perez CA, Hoskins WJ. Cancer of the ovary. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology, vol 1, 4th ed. Philadelphia: JB Lippincott Company, 1993;1226 63. International Federatoin of Gynecology and Obstetrics. Changes in denitions of clinical staging for carcinoma of the cervix and ovary. Am J Obstet Gynecol 1987;156:236. Deprest J, Moerman P, Corneillie P, Ide P. Ovarian borderline mucinous tumor in a premenarchal girl: review on ovarian epithelial cancer in young girls. Gynecol Oncol 1992; 45(2):219 24. Diamond MP, Baxter JW, Peerman CG Jr., Burnett LS. Occurrence of ovarian malignancy in childhood and adolescence: a community-wide evaluation. Obstet Gynecol 1988; 71(6 Pt 1):858 60. La Vecchia C, Morris HB, Draper GJ. Malignant ovarian tumours in childhood in Britain, 19621978. Br J Cancer 1983;48(3):36374. Morris HB, La Vecchia C, Draper GJ. Malignant epithelial tumors of the ovary in childhood: a clinicopathological study of 13 cases in Great Britain 19621978. Gynecol Oncol 1984;19(3):290 7. Moen MD, Cliby WA, Wilson TO. Stage III papillary serous cysteadenocarcinoma of the ovary in a 15-year-old female. Gynecol Oncol 1994;53:274 6. Abell MR, Holtz F. Ovarian neoplasms in childhood and adolescence. II. Tumors of non-germ cell origin. Am J Obstet Gynecol 1965;93(6):850 66. Barber HRK. Ovarian carcinoma: etiology, diagnosis, and treatment. New York: Springer-Verlag, 1992. Raney RB Jr., Sinclair L, Uri A, Schnaufer L, Cooper A, Littman P. Malignant ovarian tumors in children and adolescents. Cancer 1987;59(6):1214 20. Fink D, Plaxe SC, Brown JF, Baergen RN. Endometrioid ovarian carcinoma in a premenarchal girl: report of a case. Gynecol Oncol 1997;67(2):2225. Grosso G, Raspagliesi F, Baiocchi G, Di Re E, Colavita M, Cobellis L. Endometrioid carcinoma of the ovary: a retrospective analysis of 106 cases. Tumori 1998;84(5):5527. Patsner B, Piver MS, Lele SB, Tsukada Y, Bielat K, Castillo NB. Small cell carcinoma of the ovary: a rapidly lethal tumor occurring in the young. Gynecol Oncol 1985;22(2):2339.

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