Malignant lesions of the ovary in childhood

Seminars in Pediatric Surgery (2005) 14, 100-105

Malignant lesions of the ovary in childhood Daniel von Allmen, MD From the Division of Pediatric Surgery, University of North Carolina, Chapel Hill, North Carolina. INDEX WORDS Ovarian; Pediatric; Germ cell; Epithelial; Stromal; Malignant

Approximately half of all lesions of the ovary in childhood are neoplastic, yet only a small fraction of neoplastic lesions contain malignant elements. Overall, malignancies of the ovary account for 10% of all ovarian masses and 1% of childhood cancers. Primary ovarian malignancies fall into three broad categories based on the cell type of origin. Germ cell tumors predominate and may be further subdivided based on the differentiation of the malignant cells. Epithelial cell tumors, which are most common in adults, and sex-cord stromal tumors each make up 15% of the total in children. Rare malignant lesions and metastatic disease account for the small remaining group of tumors. Regardless of tumor type, the majority of patients present with localized disease, but proper surgical staging is important to determine the need for adjuvant therapy. The development of platinum-based chemotherapeutic regimens has resulted in significant improvements in long-term survival, even for children who present with advanced stage disease. © 2005 Elsevier Inc. All rights reserved.

Malignant tumors of the ovary are uncommon in childhood and can arise from all three of the major tissue components of the ovary. They do not follow the same histologic distribution as those seen in adults. Germ cell tumors predominate while epithelial tumors, the most common histology in adults, constitute a much smaller percentage of tumors seen in children. Stromal tumors including granulose–thecal cell tumors and Sertoli–Leydig cell tumors are also uncommon but significant in their propensity to present with precocious puberty. Leukemia, lymphoma, and metastatic disease from other locations account for the remaining cases. There are multiple subclassifications within these broad categories (Table 1), and an understanding of the distinctions between groups is important for proper staging and treatment. The incidence of all ovarian masses in childhood is approximately 2.6 cases/100,000 girls per year1 and malignancy is reported in 16% to 55% of cases. The incidence of

Address reprint requests and correspondence: Daniel von Allmen, MD, CB# 7223, 3010 Old Clinic Building, UNC-CH, Chapel Hill, NC 27599-7223. E-mail address: [email protected].

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ovarian masses overall and the relative number of neoplastic lesions is highlighted in a recent series from The Children’s Hospital of Philadelphia.2 In a 14-year review of pathology specimens, 251 ovarian lesions were identified. Slightly less than half of these lesions (48.8%) were neoplastic in nature. Only 20% of the neoplastic lesions contained malignant elements. Cass and coworkers3 reported malignancy in only 10% of 102 patients with ovarian masses identified over a 15-year period at The Texas Children’s Hospital. The variation in the incidence of malignancy between different series is likely influenced by the referral population, age cut-offs and inclusion of nonneoplastic lesions. When all ages and all lesions are considered, the incidence of malignancy is low. Malignant lesions of the ovary make up approximately 1% of all pediatric cancers.4

Germ cell tumors Germ cell tumors account for 75% to 80% of all neoplastic ovarian masses in most studies.1 The tumors are divided into five subgroups based on the degree of differentiation and the cellular components involved. Dysgerminomas are

von Allmen Table 1

Malignant Lesions Ovarian tumors

Germ cell tumors Undifferentiated Dysgerminoma Embryonic Teratoma Embryonal carcinoma Extraembryonal Endodermal Sinus Tumor Choriocarcinoma Sex Cord-Stromal Tumors Granulosa–thecal cell Sertoli–Leydig Cell Epithelial Tumors Serous Cystadenoma/cyadenocarcinoma Mucinous Cystadenoma/cystadenocarcinoma Miscellaneous Lymphoma Leukemia Polyembryoma Ovarian myxoma Mesothelioma Gonadoblastoma

the least differentiated tumors and are comparable to the seminoma in males. Germ cells that undergo some degree of differentiation before becoming neoplastic yield the embryonic tumors (embryonal carcinoma or teratoma) or the extraembryonic tumors (endodermal sinus tumors or choriocarcinoma). Although each of the tumor types arises from the primordial germ cell, they express different tumor markers (Table 2) and have different malignant potential. There may be significant differences in the biology of ovarian teratomas versus those found in the testicle in males. Ovarian germ cell tumors are thought to arise in germ cells that have entered meiosis in contrast to the mitotic arrest seen in testicular germ cell tumors.4 The biology of ovarian tumors is more complex than that of testicular tumors and it has recently been proposed that the majority of ovarian germ cell tumors arise from benign germ cells while the majority of testicular germ cell tumors arise from a malignant transformed germ cell. Most postadolescent testicular teratomas are malignant and they are more commonly aneuploid and exhibit the presence of isochromosome 12p. Ovarian teratomas are characteristically diploid and benign. The presence of i(12p) is uncommon. However, malignant ovarian germ cell tumors are more likely to be aneuploid and some contain i(12p). Ulbright has postulated that malignant ovarian teratomas may follow a path through a malignant transformed germ cell similar to the majority of postadolescent testicular germ cell tumors. This might account for the similarities between the genetics of malignant ovarian and testicular tumors compared with the majority of benign ovarian germ cell tumors.5 This review will focus only on the malignant forms of ovarian germ cell neoplasms as benign disease is considered elsewhere in this issue.

101 Teratomas are the most common lesions and may be mature, immature or malignant. Although not a true malignancy, immature teratomas have been treated as such because of their propensity to recur. Immature tumors are graded from I to III based on the amount of immature neuroepithelium or other immature elements of the mass.6-8 The more immature the neural tissue, the higher the grade and more aggressive the behavior of the neoplasm in adults. In the past, high grade immature teratomas were treated with chemotherapy to reduce the recurrence rate noted in adult series. However, an intergroup study between the Children’s Oncology Group and the Pediatric Oncology Group examined the need for adjuvant therapy in the pediatric and adolescent population. In that study immature teratomas were treated with surgery alone regardless of the histologic grade. Forty-four patients were evaluated and 31 were found to have pure ovarian teratoma after central review of the pathology. Thirteen others were found to have microscopic foci of yolk sac tumor. All patients were treated with tumor resection followed by observation. One child recurred with yolk sac tumor and was salvaged with chemotherapy. The authors concluded that surgery alone is adequate treatment for an immature teratoma, even with elevated AFP levels to suggest possible microscopic foci of yolk sac tumor.9 While this study clearly points out the efficacy of surgical treatment, it also points out the importance of careful pathologic evaluation of these frequently large tumors to identify foci of malignant tissue that might be missed on cursory review. Dysgerminomas arise from germ cells with suppressed differentiation and are comparable to seminomas in males. Pure dysgerminomas are malignant but highly responsive to chemotherapy and radiation, and fortunately, the majority of cases present as stage I disease.10,11 They are the most common pure germ cell malignancy and account for 26% to 31% of malignant ovarian germ cell tumors.3,12,13 Unlike other germ cell tumors, dysgerminomas are bilateral in 10% to 15% of cases.14 Serum lactic dehydrogenase (LDH-1) can be elevated in dysgerminoma and may be a useful tumor marker. A number of other tumor markers have also been reported to be positive in dysgerminoma, including neuronspecific enolase, ␤-HCG, and CA-125.15 Endodermal sinus tumor, also know as yolk sac tumor, is the second most common type of pure tumor reported in most series.12 Endodermal sinus tumor is nearly always associated with elevations of AFP16 and is a more aggres-

Table 2

Ovarian tumor markers

Tumor

Markers

Bilaterality

Teratoma Dysgerminoma Endodermal sinus tumor Choriocarcinoma Epithelial tumors

⫾AFP LDH-1 AFP ␤-HCG CA-125

10% 15% Low Low 15%

102 sive tumor that can metastasize within the peritoneum and to liver, lung and brain.17,18 Embryonal carcinoma is rarely seen in isolation and is most often present with other malignant cell types. The tumor may produce ␤-HCG and precocious puberty has been reported. Similarly, choriocarcinoma is quite rare but also produces ␤-HCG. Both cell types are much more commonly seen in mixed tumors which make up approximately 30% of malignant ovarian germ cell tumors.12 Mixed lesions contain multiple malignant cell types and commonly contain elements of endodermal sinus tumor. Patients may have elevated levels of AFP, ␤-HCG, or both. Gonadoblastoma is a rare germ cell variant that is seen in patients with dysgenetic gonads and male pseudohermaphroditism.4 The tumor itself usually exhibits benign behavior but it may be associated with a yolk sac tumor in some cases. Frasier syndrome is the combination of male pseudohermaphroditism with nephropathy and gonadoblastoma.19,20 Bilateral oophrectomy is indicated to prevent the development of malignant change in the ovary. Polyembryoma is an extremely rare germ cell tumor that can present in childhood and most often occurs as a component of a mixed lesion.21 It is a very malignant neoplasm that is not radiosensitive.22 It has been reported to produce AFP and can present with precocious puberty.22

Sex cord stromal tumors The sex-cord tumors, granulosa cell tumors and Sertoli– Leydig cell tumors arise from stromal components of the ovary and frequently produce hormones that may result in clinically apparent changes in the patient. Granulosa cell tumors account for 1% to 10% of ovarian malignancies in girls under age 20.23-25 Ninety-five percent of granulosa cell tumors develop in postpubertal women; however, in 80% of the tumors that develop in patients under the age of 20, the tumors exhibit different histologic features and clinical behavior.26 They are referred to as juvenile granulosa cell tumors, may be associated with pseudoprecocious puberty in as many as 80% of prepubertal girls,27,23 and galactorrhea has been reported.28 Menstrual irregularities, swelling and pain are the presenting symptoms in postpubertal girls. Fortunately, the vast majority of lesions are limited to the ovary at presentation and the outcome from surgical resection is good. Platinum-based chemotherapy is used in more advanced stages. Sertoli–Leydig cell tumors (arrhenoblastomas) are rare tumors that account for approximately 20% of ovarian sex cord-stromal tumors.29 In a large pathology series of 207 cases, 52% of patients were under the age of 20 and approximately 40% of patients had either definite or suspected evidence of androgen excess.30 Serum testosterone metabolites can be elevated and, curiously, elevated AFP levels have also been noted.31 Several histologic patterns have been described with the less well differentiated and retiform

Seminars in Pediatric Surgery, Vol 14, No 2, May 2005 patterns found most commonly in children. The tumors can have cystic and solid components and, as with the granulosa cell tumors, they are most often localized to the ovary.

Epithelial tumors Less than 20% of ovarian tumors in childhood are derived from the surface epithelium of the ovary and such tumors are extremely rare before menarche.32,33 By contrast, in adults, epithelial neoplasms represent the majority of ovarian tumors.34 Although there are numerous classes of epithelial ovarian cancer in adults, the histologic subtypes of epithelial ovarian tumors in children include only serous and mucinous tumors.35 Each of these tumor types may be further characterized as benign, malignant, or of low malignant potential. Tumors in the latter category are also referred to as borderline tumors. In a recent series from the Children’s Hospital of Philadelphia, 19 epithelial tumors were identified over 15 years, representing 16% of all ovarian neoplasms.2 Eighty-four percent of the lesions were either benign or of low malignant potential consistent with results reported in a similar series from Memorial Sloan Kettering Cancer Center.36 Adenocarcinoma of the ovary in children is a rare entity. A 43-year review of pediatric malignant ovarian tumors in Toronto found only two cases of adenocarcinoma.12 A similar review from Indiana in 1993 reported only one patient in 17 years with cystadenocarcinoma.37 Recently, Shankar and coworkers described three cases of ovarian adenocarcinoma in premenarchal girls, all with poor outcomes.38 Borderline epithelial ovarian tumors are defined as epithelial neoplasms of varying levels of nuclear atypia that lack stromal invasion of the ovary.39,40 The incidence of such tumors is reported as up to three times higher in the pediatric age group than in adults.41,42 These are indolent tumors that have a high incidence of bilaterality and local spread within the pelvis. The majority of cases are limited to one ovary but they may be locally extensive and resection of all tumor sometimes requires procedures that might leave the patient infertile. Proper workup of these tumors requires knowledge of the differences in proper operative staging of epithelial tumors using adult guidelines and germ cell tumors using pediatric guidelines.

Staging Proper tumor staging at the time of operation plays an important role in determining the need for postoperative chemotherapy. There are two staging systems used for pediatric ovarian tumors: the International Federation of Gynecology and Obstetrics (FIGO) staging system (Table 3) and the Children’s Oncology Group staging system (Table 4). In general, intraoperative staging involves collection of ascites for cytology, lymph node sampling, omentectomy, peritoneal biopsies and assessment of the contralateral

von Allmen Table 3

Malignant Lesions

103

FIGO staging system for primary carcinoma of the ovary

Stage I: Growth limited the ovaries IA: Growth limited to one ovary; no ascites; no tumor on the external surface; capsule intact IB: Growth limited to both ovaries; no ascites; no tumor on the external surface; capsule intact IC: Tumor either stage IA or IB, but with ascites or peritoneal washings containing malignant cells; tumor on the surface or capsule ruptured Stage II: Growth involving one or both ovaries with pelvic extension IIA: Extension to the uterus or tubes IIB: Extension to other pelvic tissues IIC: Tumor either IIA or IIB, but with ascites or peritoneal washings containing malignant cells; tumor on the surface or capsule ruptured Stage III: Tumor involving one or both ovaries with peritoneal implants outside the pelvis or positive retroperitoneal or inguinal lymph nodes; superficial liver metastasis equals stage III; tumor is limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum IIIA: Tumor grossly limited to the true pelvis with negative nodes but histologically proven microscopic seeding of the peritoneal surfaces IIIB: Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative IIIC: Abdominal implants greater than 2 cm in diameter or positive retroperitoneal or inguinal lymph nodes Stage IV: Growth involving one or both ovaries with distant metastases; if pleural effusion present, there must be positive cytology to allot a case to stage IV; parenchymal liver metastasis equals stage IV

ovary (Table 5). The adult staging protocol dictates mandatory lymph node dissections, biopsies of the peritoneal surfaces and omentectomy. These procedures are frequently omitted in pediatric germ cell cases unless gross metastatic disease is present, but this does not appear to have an adverse impact on survival. In the most recent report from the COG, only 3 of 131 patients were staged according to the guidelines outlined above.43 The most frequent protocol violations included failure to biopsy bilateral retroperitoneal lymph nodes, failure to biopsy the contralateral ovary, and failure to perform omentectomy. Survival was excellent and the new protocol guidelines omit the need for these steps in the absence of gross disease. However, these guidelines apply only to germ cell lesions. Epithelial tumors should be staged according to the adult staging guidelines since lymph nodes are positive in as many as 38% of FIGO stage I tumors.44 Bilateral biopsies are important since the lymph node metastases are frequently not clinically evident.

Surgery Ovarian lesions can be approached from either a midline incision or a pfannensteil approach depending on the size of the lesion and the likelihood of malignancy. Regardless of

Table 4

the approach, one must be prepared to do a cancer operation since it is frequently impossible to know at the time of surgery whether the lesion is malignant or not. The use of laparoscopy is controversial. The recommendations of the Germ Cell Committee of the Children’s Oncology Group specifically discourage this approach and stress the importance of removing the tumor intact. Violating the capsule laparoscopically or rupturing the tumor intraoperatively can result in up staging of malignant lesions. If the mass is large, a midline incision that can be extended sufficiently to remove the tumor without rupture may be necessary. Resection of the actual tumor is frequently very straightforward. The tumors are commonly large and amenable to a unilateral salpingo-oophrectomy. If the tumor is an encapsulated teratoma, the ipsilateral fallopian tube can be preserved. In the case of bilateral teratomas, it is frequently possible to enucleate the lesions on at least one ovary to preserve fertility. Cass and coworkers have advocated fertility sparing operations in all patients with clinically benign-appearing lesions and normal tumor markers.3 Extensive germ cell tumors should be biopsied for diagnosis without resecting vital structures. Current chemotherapy regimens are very effective in treating these tumors and a second look procedure is often undertaken after the fourth

Pediatric germ cell staging: Pediatric Oncology Group

Stage I: Limited to ovary (ovaries) peritoneal washings negative; Tumor markers normal after appropriate half-life decline (AFP, 5 days; ␤-hcg, 16 hours) Stage II: Microscopic residual disease or disease in lymph nodes ⬍2 cm; peritoneal washings normal; tumor markers positive or negative Stage III: Gross residual disease or biopsy only; lymph nodes ⬎2 cm; contiguous spread to other organs (omentum, intestine, bladder); peritoneal washings positive for malignant cells; markers negative or positive Stage IV: Metastatic disease, including liver

104

Seminars in Pediatric Surgery, Vol 14, No 2, May 2005

Table 5

Intraoperative staging procedure

1. Send ascites or peritoneal washings for cytology 2. Biopsy peritoneal surfaces 3. Inspect contralateral ovary - wedge biopsy suspicious lesions 4. Bilateral retroperitoneal lymph node sampling 5. Omentectomy

course of chemotherapy to achieve a complete response following an initial biopsy.

Chemotherapy Chemotherapy is indicated for any ovarian tumor that has spread beyond the confines of the ovary. Early protocols used combination therapy with vincristine, actinomycin, and cyclophosphamide (VAC). However, results in higher stage tumors were discouraging with a 68% failure rate.45 Subsequent protocols employed cisplatin, vincristine, and bleomycin with improved outcome,46 although for 30 children with ovarian tumors, the estimated 4-year survival was 67% and event-free survival (EFS) was 63%. More recently, the combination of bleomycin, etoposide, and cisplatin has been used with vastly improved success.47-49 Patients with stage I tumors had an EFS and overall survival (OS) of 95.1% and 95.1%, respectively, and patients with stage II disease had EFS and OS of 87.5% and 93.8% when treated with 4 cycles of standard cisplatin, etoposide, and low dose bleomycin.48 Patients with stage III and IV disease were randomized to high dose and standard dose cisplatin. There was no difference in overall survival (91.7% versus 86%), but there was significantly more toxicity associated with the high dose therapy.49 In an effort to reduce cisplatin associated toxicity, carboplatin has been substituted for cisplatin in a small study of germ cell tumors with an OS and EFS of 91% and 87%, respectively.50 Long term toxicities appeared to be minimal. Overall, the treatment of germ cell tumors of the ovary is very successful even in advanced cases, marking a dramatic improvement in survival over the past 30 years. Stromal cell tumors are frequently limited to the ovary and are treated effectively with surgery alone while more advanced disease is treated with cisplatin-based adjuvant therapy similar to that used for germ cell tumors.51 Patient outcome correlates with tumor stage and mitotic activity. Tumors with ⱖ20 mitoses per 10 high power field (HPF) had an EFS of 0.48 compared with an EFS of 1.0 for those with ⬍20 mitoses per HPF.29 In a recent study from MD Anderson Cancer Center, the efficacy of taxanes in conjunction with cisplatin-based therapy was evaluated in a small group of patients with stromal tumors and showed some promise.52 The majority of patients with stromal tumors present at low tumor stage and the prognosis in these patients is excellent, but tumors characterized by high proliferative activity remain a challenge to treat.

The treatment of epithelial tumors is based on adult protocols. Patients with adenocarcinoma are also treated with platinum-based regimens and outcome correlates with the amount of residual disease after primary surgical debulking. Survival in a recent report of 463 women at 5 years was 21%, at 10 years was 13.5%, and at 15 years was 12%.53 Fortunately these tumors are extremely rare in children. The management of borderline malignant lesions (tumors of low malignant potential) is somewhat more challenging. Adult experience has shown that these tumors nearly always present early and that they have an excellent prognosis with 20-year survival of all borderline tumors estimated to be as high as 89%.54 The population of patients with borderline epithelial tumors is clearly heterogeneous and requires individualized management decisions. Patients with large lesions with peritoneal spread may require total abdominal hysterectomy/bilateral salpingooophorectomy. In most cases the disease is limited and fertility sparing procedures should be attempted.2 In summary, malignant ovarian neoplasms in children arise predominantly from the germ cell element of the ovary in contrast to the predominance of epithelial tumors seen in adults. Tumors of epithelial or stromal cell origin each account for 15% to 20% of the other malignancies. Although the specific characteristics of each tumor type differ, the majority of malignant ovarian tumors in children present at a low stage and can be treated with fertility sparing surgery. Significant advances in platinum-based adjuvant chemotherapy regimens has improved the outcome for the minority of patients that present with advanced stage disease. Proper staging and identification of the tumor type are key elements to a successful treatment plan for patients with malignant tumors of the ovary.

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