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Epithelial ovarian tumors in children: A retrospective analysis
Epithelial Ovarian Tumors in Children: A Retrospective Analysis By Michael Morowitz, Dale Huff, and Daniel von Allmen Philadelphia, Pennsylvania
Background/Purpose: Epithelial tumors of the ovary account for about 15% of pediatric ovarian masses. The authors reviewed a 14-year experience with ovarian masses to understand the spectrum of pathology, presentation, and outcome of children with epithelial lesions. Methods: All ovarian masses resected or biopsied at the authors’ institution from 1988 to the present were reviewed retrospectively. Patient age, presenting symptoms, operative procedures, postoperative treatment, and outcome were obtained from the medical record. Results: A total of 240 cases were identified. A total of 123 (51.2%) were nonneoplastic in nature. Of the 117 neoplastic masses, 79 (67.5%) were germ cell tumors and nineteen (16.2%) were epithelial-derived tumors. Patients with epithelial tumors had a mean age of 13.9 ⫾ 4 years. Ten patients (52.6%) presented with abdominal pain, and 9 (47.4%) presented with an asymptomatic mass. Eleven underwent oophorectomy, 6 underwent cystectomy, and 2 had biopsy alone. Four patients (21%) had ascites, and 1 (5.3%) had a
C
HILDHOOD OVARIAN masses represent a heterogeneous group of lesions with many etiologies. It has been reported that up to 64% of these masses are neoplastic, and it is well established that the majority of such neoplasms arise from germ cells.1,2 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.1,2 By contrast, in adults, epithelial neoplasms represent the majority of ovarian tumors.3 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.4 Each of these tumor types may be further characterized as benign, malignant, or of low malignant potential. Tumors in the latter category also are referred to as borderline tumors. The staging and management of epithelial lesions differ somewhat from the more prevalent pediatric germ cell tumors. In this study, we report our experience with epithelium-derived ovarian tumors in pediatric patients identified at our institution between 1988 and 2001.
pleural effusion. The histopathologic diagnoses for the epithelial tumors included 9 serous cystadenomas (47%) and 3 mucinous cystadenomas (16%), 3 mucinous cystadenocarcinomas (16%), and 4 serous tumors of borderline malignancy (21%). Two patients (11%) had bilateral disease. Four patients (21%) underwent a subsequent laparotomy for either staging or recurrence, and 2 patients (11%) required chemotherapy. One patient (5.3%) died of ovarian adenocarcinoma. Conclusions: Epithelial tumors comprise a small but significant proportion of pediatric ovarian masses. The pediatric surgeon must understand the biologic characteristics, operative management, and follow-up treatment of these tumors, and how these differ from germ cell lesions. J Pediatr Surg 38:331-335. Copyright 2003, Elsevier Science (USA). All rights reserved. INDEX WORDS: Epithelial ovarian tumors, serous cystadenoma, mucinous cystadenoma, mucinous cystadenocarcinoma.
tion, treatment, tumor histology, and outcome were collected from the medical record. This retrospective analysis was performed with the approval of the Institutional Review Board at this institution.
RESULTS
The computerized search of our surgical pathology database identified 240 patients with ovarian masses evaluated at our institution during the 14-year period from 1988 through 2001, an average of 17.1 cases per year. This total includes 12 specimens sent to our hospital for pathologic consultation only. These 240 patients had a total of 251 ovarian masses. Figure 1 illustrates the relative incidence of various types of ovarian masses during these years. In our experience, nonneoplastic ovarian masses were slightly more common (51.2%) than neoplasms (48.8%). Germ cell tumors represented 33% of all masses and 67.5% of all neoplasms. The 19 tumors of epithelial origin represented 8% of all masses
Cases were identified through a computerized search of the hospital surgical pathology database. All cases in which ovarian tissue was submitted for pathologic review between 1988 and 2001 were characterized, and patients with a diagnosis of an epithelial neoplasm then were selected for further evaluation. Data regarding clinical presenta-
From the Departments of Surgery and Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA. Presented at the 33rd Annual Meeting of the American Pediatric Surgical Association, Phoenix, Arizona, May 19-23, 2002. Address reprint requests to Daniel von Allmen, MD, Children’s Hospital of Philadelphia, 34th St & Civic Center Blvd, Wood Bldg, 5th Floor, Philadelphia, PA 19104. Copyright 2003, Elsevier Science (USA). All rights reserved. 0022-3468/03/3803-0011$35.00/0 doi:10.1053/jpsu.2003.50103
Journal of Pediatric Surgery, Vol 38, No 3 (March), 2003: pp 331-335
331
MATERIALS AND METHODS
332
MOROWITZ, HUFF, AND VON ALLMEN
Table 1. Associated Complaints and Findings With Epithelial Ovarian Tumors
Fig 1.
Incidence of ovarian tumor subtypes.
and 16.2% of all neoplasms. There were no epithelial tumors among the 12 specimens evaluated in consultation. The remaining neoplastic masses included 13 ovarian stromal tumors and 6 miscellaneous tumors, such as metastatic Ewing’s sarcoma and Burkitt’s lymphoma. Figure 2 shows the relative incidence of each of the histologic subtypes of epithelial tumors observed in this series. Benign cystadenomas (9 serous and 3 mucinous) were the most frequently encountered epithelial tumors in this series. There were 3 patients with invasive mucinous cystadenocarcinoma. Finally, there were 4 serous tumors of borderline malignancy. The mean age at diagnosis of patients with epithelial tumors was 13.9 ⫾ 4 years. Presenting signs and symptoms observed in these patients are summarized in Table 1. Ten of these patients (52.6%) presented with pain, whereas 9 (47.4%) were referred with an asymptomatic mass. Four patients (21%) had ascites, and one patient (5.3%) had a pleural effusion requiring thoracentesis. One patient presented with ovarian torsion. Eleven of the patients with epithelial neoplasms underwent oophorectomy, 6 patients had a cystectomy, and 2 patients had biopsy only. Two patients (11%) had bilateral disease, and each of these patients had serous
Fig 2.
Incidence of epithelial ovarian tumors.
Abdominal Pain
10/19 (52.6%)
Aymptomatic mass Ascites Bilateral disease Torsion Pleural effusion
9/19 (47.3%) 4/19 (21%) 2/19 (11%) 1/19 (5.3%) 1/19 (5.3%)
borderline tumors. Five incidental appendectomies were performed. Four patients (21%) underwent a subsequent laparotomy for either complete staging or recurrence, including one for a total abdominal hysterectomy and bilateral salpingooophorectomy and one for a contralateral salpingooophorectomy. Two patients (11%) received chemotherapy; one of these patients died of metastatic ovarian adenocarcinoma. DISCUSSION
Although primary ovarian neoplasms are relatively uncommon in the pediatric population, there have been several large reviews on the topic. In 1992, Lack et al4 published a comprehensive review of the cumulative literature on pediatric ovarian neoplasms dating back to 1904. This review indicated that the reported percentage of epithelial tumors among all ovarian tumors has been relatively similar in many published series. For example, in 1984, Lack and Goldstein5 published a retrospective analysis of 148 patients treated for primary ovarian neoplasms at the Children’s Hospital of Boston between 1928 and 1982; 13.5% of these patients had epitheliumderived tumors.5 Previously, in 1977, Breen and Maxson searched the literature, tabulated 1,002 cases, and found that 17% of these tumors were epithelial neoplasms.1 Similarly, in 1972, Norris and Jensen2 reported their analysis of 353 pediatric ovarian neoplasms at the Armed Forces Institute of Pathology, and they found that 19% of these tumors were epithelium derived. In this study, we sought to compare our recent experience with epithelial ovarian neoplasms at the Children’s Hospital of Philadelphia with the existing literature. Our observations regarding the incidence of these tumors correlate very well with previously published results; we encountered 19 epithelial tumors, representing 16% of all ovarian neoplasms. The most common type of epithelial neoplasm encountered in our series was the benign cystadenoma. Of these tumors, 9 were serous cystadenomas and 3 were mucinous cystadenomas. Figure 3 shows the histologic appearance of a benign serous cystadenoma of the ovary. This observed distribution of the benign epithelial tumors also correlates well with the existing literature. Norris and Jensen2 found that 59 of 67 observed epithelial neoplasms were benign cystadenomas. Furthermore,
EPITHELIAL OVARIAN TUMORS
Fig 3. Benign serous cystadenoma. (H&E, original magnification ⴛ60.) The cyst is lined by a single layer of well-oriented serous epithelium, which mimics tubal epithelium with scattered ciliated cells. The basement membrane is intact. Other areas may show simple papillary projections.
this and other studies have indicated that epithelial ovarian masses in children are more commonly serous than mucinous.4,6 Of the 12 cystadenomas in our series, 5 were treated with cystectomy alone, whereas the remainder of patients underwent unilateral oophorectomy. Three patients with invasive mucinous adenocarcinoma of the ovary were identified in this series, and one of these patients was premenarchal. Figure 4 illustrates the histologic appearance of this tumor subtype, which is similar to the commonly observed epithelial carcinoma of the ovary in adults. One of the patients in our series had a history of abdominal complaints, which was attributed preoperatively to inflammatory bowel disease. At laparotomy, carcinomatosis was observed, and a diagnosis of stage IIIC ovarian adenocarcinoma was made. She received postoperative chemotherapy but died of progressive disease one year after diagnosis. The second patient initially underwent a left salpingooophorectomy for diagnosis. A second laparotomy was required to complete appropriate staging. No spread of the tumor was identified, but subsequent surveillance imaging showed the presence of a right ovarian mass. A benign cyst was found at surgery without evidence for tumor. She has remained disease free since that time without further treatment. The third patient had stage I adenocarcinoma and was treated by unilateral salpingooophorectomy alone with close postoperative surveillance. Adenocarcinoma of the ovary in children is a rare entity. A 43-year review of pediatric malignant ovarian tumors in Toronto found only 2 cases of adenocarcinoma.7 A similar review from Indiana in 1993 reported only one patient in 17 years with cystadenocarcinoma.8 Recently, Shankar et al9 described 3 cases of ovarian
333
adenocarcinoma in premenarchal girls, all with poor outcome. It is clear that the mortality rate of patients with ovarian adenocarcinoma is high when diagnosed at an advanced stage. However, the sporadic cases referred to above, in addition to 2 of the 3 cases of adenocarcinoma in this series, presented with early disease and fortunately experienced long-term survival. Borderline epithelial ovarian tumors are defined as epithelial neoplasms of varying levels of nuclear atypia, which lack stromal invasion of the ovary.10,11 Previous accounts have reported that the incidence of such tumors is up to 3 times higher in the pediatric age group than in adults.1,12,13 Similarly, our data suggest that these tumors are slightly more common than invasive ovarian carcinoma in children, although not nearly as common as benign cystadenomas. We encountered 4 borderline serous neoplasms but no borderline mucinous tumors. An example of the histologic appearance of a borderline serous neoplasm is shown in Fig 5. 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%.14 Unlike adenocarcinoma, which must be managed aggressively according to surgical staging, the management and follow-up of borderline tumors presents more of a clinical challenge. One of the patients with a borderline serous tumor in this series was found at laparotomy to have a large fungating pelvic mass, which was biopsied initially and subsequently treated with a total abdominal hysterectomy/ bilateral salpingooophorectomy and premarin therapy. A second patient initially underwent a left salpingooophorectomy and right wedge biopsy. Pathologic review found a borderline serous tumor with microinvasion on
Fig 4. Ovarian mucinous cystadenocarcinoma metastatic to omentum. (H&E, original magnification ⴛ60.) The omental serosal surface is on the left. The omentum is replaced by nests and islands of malignant epithelial cells floating in a sea of mucin. The malignant epithelium forms glandular structures.
334
MOROWITZ, HUFF, AND VON ALLMEN
Fig 5. Borderline serous neoplasm of the ovary. (H&E, original magnification ⴛ60.) The cyst is lined by several layers of disorganized, poorly oriented epithelial cells with atypical nucle; all of these features indicates a low malignant potential (compare with Fig 3). The basement membrane, however, remains intact and indicates that the lesion is not frankly malignant. Invasion through the basement membrane, not present here, is the earliest histologic evidence of malignancy.
the left and tumor without invasion on the right. Because of the presence of microinvasion as well as omental spread of tumor, she was treated with a course of chemotherapy and then subsequently underwent a secondlook laparotomy with right salpingooophorectomy and lymph node dissection. The remaining 2 patients received a unilateral salpingoophorectomy only; one of these patients was found to have a small focus consistent with a borderline tumor in her contralateral ovary, but this has been followed nonoperatively to date. The population of patients with borderline epithelial tumors is clearly heterogeneous and requires individualized management decisions. The relation between epithelial ovarian neoplasms in children and adult ovarian carcinoma is unclear. Still, treatment of pediatric epithelial ovarian tumors is guided by experience with adults in the context of attempting to preserve reproductive capability whenever possible. The diagnosis and staging of epithelial ovarian lesions is
based on adult algorithms that differ in some aspects from those used to evaluate pediatric ovarian germ cell tumors. Proper workup and staging of these tumors requires knowledge of these subtle differences. In contrast to germ cell tumors, epithelial ovarian tumors frequently cause elevation of the serum level of the CA-125 tumor antigen. Although some have questioned the positive predictive value of this test in premenopausal women,3 the appropriate workup for an epithelial ovarian mass should ideally include measurement of this level. In our series, this test was performed preoperatively in 6 patients with epithelial tumors, of whom, 4 had elevated serum levels. Intraoperatively, adult staging protocols dictate mandatory lymph node dissections and biopsies of the peritoneal surfaces. These procedures frequently are omitted along with omentectomy in pediatric cases unless gross metastatic disease is present. Careful inspection of the contralateral ovary with biopsy of suspicious areas also is mandatory given the significant incidence of bilateral disease in patients with epithelial tumors. Careful follow-up of these patients by routine surveillance pelvic imaging is critical to observe for disease recurrence or progression. CA-125 levels also should be monitored postoperatively in patients with borderline and malignant tumors, although the utility of following this test result for patients with borderline tumors remains a source of debate in the adult literature. In our experience, from 1988 through 2001, 16% of all ovarian neoplasms were derived from the surface epithelium of the ovary. A fraction of these cases are frankly invasive carcinomas, and these tend to carry poor prognoses unless detected early. We found borderline tumors to be slightly more prevalent, and this class of tumors is more heterogeneous and requires a comprehensive multidisciplinary approach to both treatment and future surveillance for recurrence. Most common of all are benign cystadenomas, which are effectively treated by unilateral cystectomy. Knowledge of the classification and biology of this class of tumors allows for prompt and effective treatment.
REFERENCES 1. Breen JL, Maxson WS: Ovarian tumors in children and adolescents. Clin Obstet Gynecol 20:607-623, 1977 2. Norris HJ, Jensen RD: Relative frequency of ovarian neoplasms in children and adolescents. Cancer 30:713-719, 1972 3. Abu-Rustum NR, Chi DS, Curtin JP: Epithelial ovarian cancer. Curr Prob Surg 36:5-53, 1999 4. Lack EE, Young RH, Scully RE: Pathology of ovarian neoplasms in childhood and adolescence. Pathology Annual 27:281-356, 1992 5. Lack E, Goldstein D: Primary ovarian tumors in childhood and adolescence, in Leventhal J (ed): Current Problems in Obstetrics and Gynecology. Chicago, IL, Year Book, 1984, pp 1-90 6. Abell M, Holtz F: Ovarian neoplasms in childhood and adoles-
cence. I. Tumors of non-germ cell origin. Am J Obstet Gynecol 93:850, 1965 7. Gribbon M, Ein SH, Mancer K: Pediatric malignant ovarian tumors: A 43-year review. J Pediatr Surg 27:480-484, 1992 8. Skinner MA, Schlatter M, Heifetz S, et al: Ovarian neoplasms in children. Arch Surg 128:849-854, 1993 9. Shankar KR, Wakhlu A, Kokai GK, et al: Ovarian adenocarcinoma in premenarchal girls. J Pediatr Surg 36:511-515, 2001 10. Eltabbakh GH, Natarajan N, Piver S, et al: Epidemiologic differences between women with borderline ovarian tumors and women with epithelial ovarian cancer. Gynecol Oncol 74:103-107, 1999
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11. Gershenson D, Silva E, Levy L, et al: Ovarian serous borderline tumors with invasive peritoneal implants. Cancer 82:1096-1103, 1998 12. Fotiou S: Ovarian malignancies in adolescence. Ann N Y Acad Sci 816:338-346, 1997 13. Deprest J, Moerman P, Corneillie P, et al: Ovarian borderline
mucinous tumor in a premenarchal girl: Review on ovarian epithelial cancer in young girls. Gynecol Oncol 45:219-224, 1992 14. Leake J, Currie JL, Rosenshein NB, et al: Long-term follow-up of serous ovarian tumors of low malignant potential. Gynecol Oncol 47:150-158, 1992
Discussion From the Floor: I think the most important sentence you said is that these patients need to be treated with a proper cancer operation, and sticking a laparoscope in and poking a cyst or using a small Pfannenstiel and then discovering that you have had a malignancy is actually upstaging the patient. I would urge against biopsy of ovarian lesions that do appear suspicious. I would urge that a patient undergo a unilateral oophorectomy with a frozen section of that tumor and use that as your biopsy, because if you open the capsule of a malignant tumor you actually do upstage the patient. Furthermore, I would encourage these be done through a vertical incision, because proper surgical staging includes diaphragmatic scrapings and random systematic peritoneal samplings that have to go up into the upper abdomen as well as a periaortic node dissection. That cannot be done through a small pfannenstiel. I would caution you about your use of simple cystectomy alone on borderline tumors because borderline tumors, although they do have a good survival rate of 89%, if treated with cystectomy alone, that drops significantly. So I think you need to alert your pathologist that you have an ovarian tumor that is coming to him or her and get their input, because it does change intraoperative management of these patients. D. Cass (Houston, TX): When we reviewed our experience with the management of children with ovarian lesions at Texas Children’s Hospital, we found several patients with epithelial tumors but none with epithelial malignancies. Indeed, over 95% of children with ovarian
cancer can be detected by elevations in beta-HCG and AFP. I suggest that for a child with an ovarian mass and normal serology, we should attempt ovary-preserving resections of tumor, unless there are other obvious signs of cancer. In the very rare event that a mistake is made and pathology shows adenocarcinoma, then prompt reoperation and salpingo-oophorectomy, omentectomy, pelvic washings, and lymph node sampling can be performed. Provided the tumor was not ruptured in the first operation, it is unlikely that there will be any adverse sequelae for the patient. M. Morowitz (response): All of these points are very well taken. One point from a practical standpoint is one common scenario involving cystectomy of a lesion that you do not suspect is malignant and then turns out to be a borderline neoplasm on pathologic review. The issue at hand then because you did not get a frozen section is how to proceed. One option would be to proceed with an oophorectomy; however, you could certainly counsel the patient and her family that conservative management with observation may be adequate. B. Benjamin (Amarillo, TX): My only comment is that I am hearing a divergence here between suggesting that you may be able to do an ovarian cystectomy, and I agree that that may be inadequate, with the alternative being a salpingo-oophorectomy. I think that there is an alternative to that and that is the oophorectomy, leaving the tube because that may be important for preservation of reproduction later.
Background/Purpose: Epithelial tumors of the ovary account for about 15% of pediatric ovarian masses. The authors reviewed a 14-year experience with ovarian masses to understand the spectrum of pathology, presentation, and outcome of children with epithelial lesions. Methods: All ovarian masses resected or biopsied at the authors’ institution from 1988 to the present were reviewed retrospectively. Patient age, presenting symptoms, operative procedures, postoperative treatment, and outcome were obtained from the medical record. Results: A total of 240 cases were identified. A total of 123 (51.2%) were nonneoplastic in nature. Of the 117 neoplastic masses, 79 (67.5%) were germ cell tumors and nineteen (16.2%) were epithelial-derived tumors. Patients with epithelial tumors had a mean age of 13.9 ⫾ 4 years. Ten patients (52.6%) presented with abdominal pain, and 9 (47.4%) presented with an asymptomatic mass. Eleven underwent oophorectomy, 6 underwent cystectomy, and 2 had biopsy alone. Four patients (21%) had ascites, and 1 (5.3%) had a
C
HILDHOOD OVARIAN masses represent a heterogeneous group of lesions with many etiologies. It has been reported that up to 64% of these masses are neoplastic, and it is well established that the majority of such neoplasms arise from germ cells.1,2 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.1,2 By contrast, in adults, epithelial neoplasms represent the majority of ovarian tumors.3 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.4 Each of these tumor types may be further characterized as benign, malignant, or of low malignant potential. Tumors in the latter category also are referred to as borderline tumors. The staging and management of epithelial lesions differ somewhat from the more prevalent pediatric germ cell tumors. In this study, we report our experience with epithelium-derived ovarian tumors in pediatric patients identified at our institution between 1988 and 2001.
pleural effusion. The histopathologic diagnoses for the epithelial tumors included 9 serous cystadenomas (47%) and 3 mucinous cystadenomas (16%), 3 mucinous cystadenocarcinomas (16%), and 4 serous tumors of borderline malignancy (21%). Two patients (11%) had bilateral disease. Four patients (21%) underwent a subsequent laparotomy for either staging or recurrence, and 2 patients (11%) required chemotherapy. One patient (5.3%) died of ovarian adenocarcinoma. Conclusions: Epithelial tumors comprise a small but significant proportion of pediatric ovarian masses. The pediatric surgeon must understand the biologic characteristics, operative management, and follow-up treatment of these tumors, and how these differ from germ cell lesions. J Pediatr Surg 38:331-335. Copyright 2003, Elsevier Science (USA). All rights reserved. INDEX WORDS: Epithelial ovarian tumors, serous cystadenoma, mucinous cystadenoma, mucinous cystadenocarcinoma.
tion, treatment, tumor histology, and outcome were collected from the medical record. This retrospective analysis was performed with the approval of the Institutional Review Board at this institution.
RESULTS
The computerized search of our surgical pathology database identified 240 patients with ovarian masses evaluated at our institution during the 14-year period from 1988 through 2001, an average of 17.1 cases per year. This total includes 12 specimens sent to our hospital for pathologic consultation only. These 240 patients had a total of 251 ovarian masses. Figure 1 illustrates the relative incidence of various types of ovarian masses during these years. In our experience, nonneoplastic ovarian masses were slightly more common (51.2%) than neoplasms (48.8%). Germ cell tumors represented 33% of all masses and 67.5% of all neoplasms. The 19 tumors of epithelial origin represented 8% of all masses
Cases were identified through a computerized search of the hospital surgical pathology database. All cases in which ovarian tissue was submitted for pathologic review between 1988 and 2001 were characterized, and patients with a diagnosis of an epithelial neoplasm then were selected for further evaluation. Data regarding clinical presenta-
From the Departments of Surgery and Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA. Presented at the 33rd Annual Meeting of the American Pediatric Surgical Association, Phoenix, Arizona, May 19-23, 2002. Address reprint requests to Daniel von Allmen, MD, Children’s Hospital of Philadelphia, 34th St & Civic Center Blvd, Wood Bldg, 5th Floor, Philadelphia, PA 19104. Copyright 2003, Elsevier Science (USA). All rights reserved. 0022-3468/03/3803-0011$35.00/0 doi:10.1053/jpsu.2003.50103
Journal of Pediatric Surgery, Vol 38, No 3 (March), 2003: pp 331-335
331
MATERIALS AND METHODS
332
MOROWITZ, HUFF, AND VON ALLMEN
Table 1. Associated Complaints and Findings With Epithelial Ovarian Tumors
Fig 1.
Incidence of ovarian tumor subtypes.
and 16.2% of all neoplasms. There were no epithelial tumors among the 12 specimens evaluated in consultation. The remaining neoplastic masses included 13 ovarian stromal tumors and 6 miscellaneous tumors, such as metastatic Ewing’s sarcoma and Burkitt’s lymphoma. Figure 2 shows the relative incidence of each of the histologic subtypes of epithelial tumors observed in this series. Benign cystadenomas (9 serous and 3 mucinous) were the most frequently encountered epithelial tumors in this series. There were 3 patients with invasive mucinous cystadenocarcinoma. Finally, there were 4 serous tumors of borderline malignancy. The mean age at diagnosis of patients with epithelial tumors was 13.9 ⫾ 4 years. Presenting signs and symptoms observed in these patients are summarized in Table 1. Ten of these patients (52.6%) presented with pain, whereas 9 (47.4%) were referred with an asymptomatic mass. Four patients (21%) had ascites, and one patient (5.3%) had a pleural effusion requiring thoracentesis. One patient presented with ovarian torsion. Eleven of the patients with epithelial neoplasms underwent oophorectomy, 6 patients had a cystectomy, and 2 patients had biopsy only. Two patients (11%) had bilateral disease, and each of these patients had serous
Fig 2.
Incidence of epithelial ovarian tumors.
Abdominal Pain
10/19 (52.6%)
Aymptomatic mass Ascites Bilateral disease Torsion Pleural effusion
9/19 (47.3%) 4/19 (21%) 2/19 (11%) 1/19 (5.3%) 1/19 (5.3%)
borderline tumors. Five incidental appendectomies were performed. Four patients (21%) underwent a subsequent laparotomy for either complete staging or recurrence, including one for a total abdominal hysterectomy and bilateral salpingooophorectomy and one for a contralateral salpingooophorectomy. Two patients (11%) received chemotherapy; one of these patients died of metastatic ovarian adenocarcinoma. DISCUSSION
Although primary ovarian neoplasms are relatively uncommon in the pediatric population, there have been several large reviews on the topic. In 1992, Lack et al4 published a comprehensive review of the cumulative literature on pediatric ovarian neoplasms dating back to 1904. This review indicated that the reported percentage of epithelial tumors among all ovarian tumors has been relatively similar in many published series. For example, in 1984, Lack and Goldstein5 published a retrospective analysis of 148 patients treated for primary ovarian neoplasms at the Children’s Hospital of Boston between 1928 and 1982; 13.5% of these patients had epitheliumderived tumors.5 Previously, in 1977, Breen and Maxson searched the literature, tabulated 1,002 cases, and found that 17% of these tumors were epithelial neoplasms.1 Similarly, in 1972, Norris and Jensen2 reported their analysis of 353 pediatric ovarian neoplasms at the Armed Forces Institute of Pathology, and they found that 19% of these tumors were epithelium derived. In this study, we sought to compare our recent experience with epithelial ovarian neoplasms at the Children’s Hospital of Philadelphia with the existing literature. Our observations regarding the incidence of these tumors correlate very well with previously published results; we encountered 19 epithelial tumors, representing 16% of all ovarian neoplasms. The most common type of epithelial neoplasm encountered in our series was the benign cystadenoma. Of these tumors, 9 were serous cystadenomas and 3 were mucinous cystadenomas. Figure 3 shows the histologic appearance of a benign serous cystadenoma of the ovary. This observed distribution of the benign epithelial tumors also correlates well with the existing literature. Norris and Jensen2 found that 59 of 67 observed epithelial neoplasms were benign cystadenomas. Furthermore,
EPITHELIAL OVARIAN TUMORS
Fig 3. Benign serous cystadenoma. (H&E, original magnification ⴛ60.) The cyst is lined by a single layer of well-oriented serous epithelium, which mimics tubal epithelium with scattered ciliated cells. The basement membrane is intact. Other areas may show simple papillary projections.
this and other studies have indicated that epithelial ovarian masses in children are more commonly serous than mucinous.4,6 Of the 12 cystadenomas in our series, 5 were treated with cystectomy alone, whereas the remainder of patients underwent unilateral oophorectomy. Three patients with invasive mucinous adenocarcinoma of the ovary were identified in this series, and one of these patients was premenarchal. Figure 4 illustrates the histologic appearance of this tumor subtype, which is similar to the commonly observed epithelial carcinoma of the ovary in adults. One of the patients in our series had a history of abdominal complaints, which was attributed preoperatively to inflammatory bowel disease. At laparotomy, carcinomatosis was observed, and a diagnosis of stage IIIC ovarian adenocarcinoma was made. She received postoperative chemotherapy but died of progressive disease one year after diagnosis. The second patient initially underwent a left salpingooophorectomy for diagnosis. A second laparotomy was required to complete appropriate staging. No spread of the tumor was identified, but subsequent surveillance imaging showed the presence of a right ovarian mass. A benign cyst was found at surgery without evidence for tumor. She has remained disease free since that time without further treatment. The third patient had stage I adenocarcinoma and was treated by unilateral salpingooophorectomy alone with close postoperative surveillance. Adenocarcinoma of the ovary in children is a rare entity. A 43-year review of pediatric malignant ovarian tumors in Toronto found only 2 cases of adenocarcinoma.7 A similar review from Indiana in 1993 reported only one patient in 17 years with cystadenocarcinoma.8 Recently, Shankar et al9 described 3 cases of ovarian
333
adenocarcinoma in premenarchal girls, all with poor outcome. It is clear that the mortality rate of patients with ovarian adenocarcinoma is high when diagnosed at an advanced stage. However, the sporadic cases referred to above, in addition to 2 of the 3 cases of adenocarcinoma in this series, presented with early disease and fortunately experienced long-term survival. Borderline epithelial ovarian tumors are defined as epithelial neoplasms of varying levels of nuclear atypia, which lack stromal invasion of the ovary.10,11 Previous accounts have reported that the incidence of such tumors is up to 3 times higher in the pediatric age group than in adults.1,12,13 Similarly, our data suggest that these tumors are slightly more common than invasive ovarian carcinoma in children, although not nearly as common as benign cystadenomas. We encountered 4 borderline serous neoplasms but no borderline mucinous tumors. An example of the histologic appearance of a borderline serous neoplasm is shown in Fig 5. 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%.14 Unlike adenocarcinoma, which must be managed aggressively according to surgical staging, the management and follow-up of borderline tumors presents more of a clinical challenge. One of the patients with a borderline serous tumor in this series was found at laparotomy to have a large fungating pelvic mass, which was biopsied initially and subsequently treated with a total abdominal hysterectomy/ bilateral salpingooophorectomy and premarin therapy. A second patient initially underwent a left salpingooophorectomy and right wedge biopsy. Pathologic review found a borderline serous tumor with microinvasion on
Fig 4. Ovarian mucinous cystadenocarcinoma metastatic to omentum. (H&E, original magnification ⴛ60.) The omental serosal surface is on the left. The omentum is replaced by nests and islands of malignant epithelial cells floating in a sea of mucin. The malignant epithelium forms glandular structures.
334
MOROWITZ, HUFF, AND VON ALLMEN
Fig 5. Borderline serous neoplasm of the ovary. (H&E, original magnification ⴛ60.) The cyst is lined by several layers of disorganized, poorly oriented epithelial cells with atypical nucle; all of these features indicates a low malignant potential (compare with Fig 3). The basement membrane, however, remains intact and indicates that the lesion is not frankly malignant. Invasion through the basement membrane, not present here, is the earliest histologic evidence of malignancy.
the left and tumor without invasion on the right. Because of the presence of microinvasion as well as omental spread of tumor, she was treated with a course of chemotherapy and then subsequently underwent a secondlook laparotomy with right salpingooophorectomy and lymph node dissection. The remaining 2 patients received a unilateral salpingoophorectomy only; one of these patients was found to have a small focus consistent with a borderline tumor in her contralateral ovary, but this has been followed nonoperatively to date. The population of patients with borderline epithelial tumors is clearly heterogeneous and requires individualized management decisions. The relation between epithelial ovarian neoplasms in children and adult ovarian carcinoma is unclear. Still, treatment of pediatric epithelial ovarian tumors is guided by experience with adults in the context of attempting to preserve reproductive capability whenever possible. The diagnosis and staging of epithelial ovarian lesions is
based on adult algorithms that differ in some aspects from those used to evaluate pediatric ovarian germ cell tumors. Proper workup and staging of these tumors requires knowledge of these subtle differences. In contrast to germ cell tumors, epithelial ovarian tumors frequently cause elevation of the serum level of the CA-125 tumor antigen. Although some have questioned the positive predictive value of this test in premenopausal women,3 the appropriate workup for an epithelial ovarian mass should ideally include measurement of this level. In our series, this test was performed preoperatively in 6 patients with epithelial tumors, of whom, 4 had elevated serum levels. Intraoperatively, adult staging protocols dictate mandatory lymph node dissections and biopsies of the peritoneal surfaces. These procedures frequently are omitted along with omentectomy in pediatric cases unless gross metastatic disease is present. Careful inspection of the contralateral ovary with biopsy of suspicious areas also is mandatory given the significant incidence of bilateral disease in patients with epithelial tumors. Careful follow-up of these patients by routine surveillance pelvic imaging is critical to observe for disease recurrence or progression. CA-125 levels also should be monitored postoperatively in patients with borderline and malignant tumors, although the utility of following this test result for patients with borderline tumors remains a source of debate in the adult literature. In our experience, from 1988 through 2001, 16% of all ovarian neoplasms were derived from the surface epithelium of the ovary. A fraction of these cases are frankly invasive carcinomas, and these tend to carry poor prognoses unless detected early. We found borderline tumors to be slightly more prevalent, and this class of tumors is more heterogeneous and requires a comprehensive multidisciplinary approach to both treatment and future surveillance for recurrence. Most common of all are benign cystadenomas, which are effectively treated by unilateral cystectomy. Knowledge of the classification and biology of this class of tumors allows for prompt and effective treatment.
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cence. I. Tumors of non-germ cell origin. Am J Obstet Gynecol 93:850, 1965 7. Gribbon M, Ein SH, Mancer K: Pediatric malignant ovarian tumors: A 43-year review. J Pediatr Surg 27:480-484, 1992 8. Skinner MA, Schlatter M, Heifetz S, et al: Ovarian neoplasms in children. Arch Surg 128:849-854, 1993 9. Shankar KR, Wakhlu A, Kokai GK, et al: Ovarian adenocarcinoma in premenarchal girls. J Pediatr Surg 36:511-515, 2001 10. Eltabbakh GH, Natarajan N, Piver S, et al: Epidemiologic differences between women with borderline ovarian tumors and women with epithelial ovarian cancer. Gynecol Oncol 74:103-107, 1999
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11. Gershenson D, Silva E, Levy L, et al: Ovarian serous borderline tumors with invasive peritoneal implants. Cancer 82:1096-1103, 1998 12. Fotiou S: Ovarian malignancies in adolescence. Ann N Y Acad Sci 816:338-346, 1997 13. Deprest J, Moerman P, Corneillie P, et al: Ovarian borderline
mucinous tumor in a premenarchal girl: Review on ovarian epithelial cancer in young girls. Gynecol Oncol 45:219-224, 1992 14. Leake J, Currie JL, Rosenshein NB, et al: Long-term follow-up of serous ovarian tumors of low malignant potential. Gynecol Oncol 47:150-158, 1992
Discussion From the Floor: I think the most important sentence you said is that these patients need to be treated with a proper cancer operation, and sticking a laparoscope in and poking a cyst or using a small Pfannenstiel and then discovering that you have had a malignancy is actually upstaging the patient. I would urge against biopsy of ovarian lesions that do appear suspicious. I would urge that a patient undergo a unilateral oophorectomy with a frozen section of that tumor and use that as your biopsy, because if you open the capsule of a malignant tumor you actually do upstage the patient. Furthermore, I would encourage these be done through a vertical incision, because proper surgical staging includes diaphragmatic scrapings and random systematic peritoneal samplings that have to go up into the upper abdomen as well as a periaortic node dissection. That cannot be done through a small pfannenstiel. I would caution you about your use of simple cystectomy alone on borderline tumors because borderline tumors, although they do have a good survival rate of 89%, if treated with cystectomy alone, that drops significantly. So I think you need to alert your pathologist that you have an ovarian tumor that is coming to him or her and get their input, because it does change intraoperative management of these patients. D. Cass (Houston, TX): When we reviewed our experience with the management of children with ovarian lesions at Texas Children’s Hospital, we found several patients with epithelial tumors but none with epithelial malignancies. Indeed, over 95% of children with ovarian
cancer can be detected by elevations in beta-HCG and AFP. I suggest that for a child with an ovarian mass and normal serology, we should attempt ovary-preserving resections of tumor, unless there are other obvious signs of cancer. In the very rare event that a mistake is made and pathology shows adenocarcinoma, then prompt reoperation and salpingo-oophorectomy, omentectomy, pelvic washings, and lymph node sampling can be performed. Provided the tumor was not ruptured in the first operation, it is unlikely that there will be any adverse sequelae for the patient. M. Morowitz (response): All of these points are very well taken. One point from a practical standpoint is one common scenario involving cystectomy of a lesion that you do not suspect is malignant and then turns out to be a borderline neoplasm on pathologic review. The issue at hand then because you did not get a frozen section is how to proceed. One option would be to proceed with an oophorectomy; however, you could certainly counsel the patient and her family that conservative management with observation may be adequate. B. Benjamin (Amarillo, TX): My only comment is that I am hearing a divergence here between suggesting that you may be able to do an ovarian cystectomy, and I agree that that may be inadequate, with the alternative being a salpingo-oophorectomy. I think that there is an alternative to that and that is the oophorectomy, leaving the tube because that may be important for preservation of reproduction later.