eMedicine Specialties > Obstetrics and Gynecology > Gynecologic Oncology

Borderline Ovarian Cancer

Andrew E Green, MD, BA, BS, Consulting Staff, Southeastern Gynecologic Oncology, LLC, Northeast Georgia Medical Center

Updated: Jan 15, 2008

Introduction

Borderline ovarian tumors are a subset of epithelial ovarian tumors that have a very favorable prognosis. The accepted initial treatment is surgical removal of the tumor and biopsies. However, the postoperative management protocol is far from clear. To date, no medical therapy has been shown to clearly improve outcomes.

History of the Procedure

In 1929, Taylor first described a subset of ovarian tumors that he termed semimalignant. These lesions had a more favorable outcome than other ovarian cancers, but they were not separately classified by the Federation of Gynecology and Obstetrics (FIGO) and the World Health Organization (WHO) until the early 1970s.

Frequency

One woman in 55 (1.8%) develops some form of ovarian cancer in her lifetime. Approximately 90% of these cancers are tumors of epithelial origin. If benign lesions are included, epithelial tumors account for 60% of all ovarian tumors.

Borderline tumors comprise approximately 15% of all epithelial ovarian tumors. The mean age of occurrence is approximately 10 years younger than that of women with frankly malignant ovarian cancer. Factors reportedly linked with borderline tumors include oral contraceptive use, menarche, age at first pregnancy, age at first delivery, menstrual history, smoking, and family history of ovarian cancer, although none of these has been shown to be statistically significant.

Borderline ovarian cancer is staged according to the FIGO classification of ovarian cancer. Many clinicians group stages II-IV together for prognostic consideration. Another common component of staging is the description of the type of implants, as these have significant prognostic value. As opposed to its true malignant counterpart, epithelial ovarian carcinoma, borderline ovarian cancers are often found at early stages.

Etiology

The etiology of this disease remains unclear because of the small number of cases and the lack of randomized controlled studies. Based on molecular studies, some mucinous borderline tumors of the ovary may actually represent metastasis from the appendix.

Pathophysiology

The 2 major histologic tumor subtypes are serous and mucinous, with serous being more common. Serous tumors are presumed to originate from the germinal epithelium. Mucinous tumors do not have a clearly defined origin. Substantial information indicates that many tumors may actually originate from the appendix; thus, this organ should be removed at time of surgery.

Presentation

These tumors, as with other ovarian tumors, are difficult to detect clinically until they are advanced in size or stage. In one study, the most common presenting symptoms were abdominal pain, increasing girth or abdominal distension, and abdominal mass. Approximately 23% of patients were asymptomatic.

Indications

When a complex ovarian mass is discovered, surgery is often, if not always, indicated. Preoperatively, borderline tumors are often presumed to be either benign or malignant ovarian masses; regardless, surgery is required to determine the type of mass.

Contraindications

Contraindications to surgery include medical reasons (ie, the patient is too great a surgical risk secondary to other medical problems) or patient refusal. Otherwise, the masses should be surgically removed.

Workup

Laboratory Studies

Cancer antigen 125 (CA-125) levels are not shown to aid in the diagnosis or follow-up care of patients with borderline tumors.

Imaging Studies

Preoperative transvaginal color Doppler ultrasound has been used to assess the possibility of malignancy of ovarian masses. The rate of detection of intratumoral blood flow in borderline tumors is similar to that of malignant neoplasms: 90% and 92%, respectively. The resistance and pulsatility indexes are also significantly reduced in carcinoma and borderline ovarian tumors compared to benign tumors. While useful in some situations, this medium is not currently part of the standard workup. It is neither sensitive enough nor specific enough to be used as a screening tool in the normal populations.
Some authors use CT scans in their presurgical workup; however, laparotomy is still required.

Histologic Findings

According to Dietel and Hauptmann, the histology of borderline tumors is characterized by the following features:¹

Epithelial multilayering of more than 4 cell layers
Not more than 4 mitoses per 10 high-power field
Mild nuclear atypia
Increase in nuclear/cytoplasmic ratio
Slight-to-complex branching of epithelial papillae and pseudopapillae
Epithelial budding and cell detachment into the lumen
No destructive stromal invasion - A major component in differentiating malignant from borderline tumors

Mucinous tumors look grossly similar to their benign counterparts, having large multilocular cysts with smooth surfaces. The epithelial layer is characterized by stratification of 2-3 layers. Nuclear atypia, enlarged nuclei, and mitotic figures are observed.

Approximately 25% of borderline tumors have cell proliferations on the outer surface of the lesion with no evidence of growth from the inner surface. Of these, approximately 90% develop peritoneal implants. Only 4% of cases with peritoneal implants do not have surface proliferation.

Peritoneal implants are described as invasive or noninvasive. Noninvasive implants are glandular or papillary proliferations with cell detachments.

Psammoma bodies, cellular atypia, and desmoplastic fibrosis are observed in some instances. The appearance of invasive implants is similar, but they have epithelial cells infiltrating the stroma.

Staging

As with other ovarian masses, staging is performed surgically. Many sources recommend complete staging if a borderline tumor is found. Current guidelines include biopsy specimens of the pelvic peritoneum (cul-de-sac, pelvic wall, and bladder peritoneum), abdominal peritoneum (paracolic gutters and diaphragmatic surfaces), omentum, intestinal serosa and mesentery, and retroperitoneal lymph nodes (pelvic and para-aortic).

Treatment

Medical Therapy

No consensus has been reached concerning treatment of patients with stage II-IV disease. While they still have high 5-year survival rates compared to their malignant counterparts, an increased stage is associated with a worse prognosis. However, stage (II vs III vs IV), type of surgery, postoperative treatment, postoperative platinum-based chemotherapy, and even the number of noninvasive implants have no effect on progression-free survival. Only age at diagnosis and the presence of invasive implants are shown to influence prognosis.

Various chemotherapy regimens have been used, but evidence is insufficient to determine exactly which therapy is indicated. Many authors have used platinum-based agents but with varying results. Some authors recommend platinum-based therapy for patients with invasive peritoneal implants because of their worse prognosis. Standard chemotherapy regimens for invasive ovarian cancer are used if any medical therapy is given.

Surgical Therapy

Complete excision of the disease must be achieved if at all possible. Comprehensive staging, as described above, should be a part of every operation. Although stage may or may not affect future treatment, it is of significant prognostic value and therefore is of value to both clinician and patient. In one study, 77% of patients with invasive peritoneal implants also had noninvasive implants. Comprehensive debulking and staging decreases the chance of a sampling error that could result in an inaccurate diagnosis and prognosis.

In most instances, surgery is curative for patients with confirmed stage I disease. If the tumor is unilateral and adjacent to normal tissue, unilateral cystectomy can be performed; however, inspection of the capsule for signs of rupture should be performed before resection. If no normal adjacent tissue is present, oophorectomy or salpingo-oophorectomy should be performed. If the contralateral ovary is normal in appearance, a biopsy should not be performed on the adjacent ovary because of the risk of ovarian failure if fertility is an issue.

Owing to the high association between surface proliferations and peritoneal implants, exploration of the peritoneum should be extensive and thorough. If possible, carefully evaluate and remove the implants. The type of implant (ie, invasive, noninvasive) should be noted by pathology. The type of implant has significant prognostic value.

Postoperative Details

While not routine, static DNA cytometry can be performed on the specimens. Approximately 95% of tumors have diploid DNA. This finding is almost always associated with excellent prognosis. If the tumor is aneuploid, the recurrence rate is high. Some authors suggest treating these as low-grade invasive carcinoma (aka, micropapillary carcinoma).

With the advent of microarray technology, the actual characterization of the tumor genome can now be studied. Some preliminary work is starting to emerge in the invasive forms of ovarian cancer; however, little has been done on borderline ovarian cancer, mostly because of its low incidence and good prognosis. Some data suggest that invasive tumors discovered at low stages and borderline tumors, especially those with invasive implants, share genetic expression profiles. However, the significance of this has not been determined.

Conflicting data exist with respect to overexpression of various oncogenes and tumor suppressor genes. While p53 positivity and Her-2 overexpression in invasive cancer were associated with a worse prognosis, the same gene profile conferred a survival advantage in borderline tumors.

Complications

Most of the complications of this disease are caused by the operation itself, subsequent therapy, or recurrence. Without comprehensive surgical staging, the prognosis for an individual patient is difficult to predict.

In one study of stage I disease, all recurrences appeared in patients who were inadequately staged. Many, if not all, of these patients probably did not actually have stage I disease.

Pathologic diagnosis is difficult to confirm by frozen section. Borderline tumors are correctly diagnosed 58-86% of the time by frozen section, depending on the experience of the pathologist and the site of the operation (eg, tertiary care vs community hospital). However, in one study at a tertiary referral center, benign disease was excluded in 94% of cases subsequently diagnosed as borderline tumor. Thus, the proper operation and staging procedures could have been performed during the initial operation in most cases even though the diagnosis by frozen section was not completely accurate.

Another major source of complications is that of postoperative chemotherapy. In one series of 28 borderline tumor–related deaths, 2 patients died of radiation-associated complications, 9 of chemotherapy-associated complications, 8 of bowel obstruction, and 8 of invasive carcinoma. This led the authors to suggest that most patients with borderline tumors died with the disease rather than of the disease.

Outcome and Prognosis

Patients with stage I disease confirmed by comprehensive staging have an approximate 15% recurrence rate. The 5-year survival rate for such patients approaches 100%. However, the 10-year survival rate is 90-95% depending on histologic findings.

In patients with stage II-IV disease, the prognosis is different. In women with serous tumors with noninvasive peritoneal implants, a mean 20% recurrence rate and a mean 7% death rate were found in reported series. In patients with recurrence, a median time to diagnosis of 3.1 years was reported if the recurrence was of the borderline type. In patients whose recurrence was invasive carcinoma, the median time to diagnosis was 8.3 years. It is believed that the former was a recurrence but that the latter was probably a new primary tumor. The CA-125 level was normal in 65% of the recurring cases. Death was noted only when invasive carcinoma was noted in the recurrence.

In patients with serous borderline tumors with invasive implants, the relapse rate was 31-45%. The median time from diagnosis to recurrence was 24 months, although the time to progression of disease was significantly longer in patients who had no macroscopic disease remaining at time of initial operation. Additionally, patients who received postoperative platinum-based chemotherapy had a significantly worse progression-free survival rate. However, the authors of this study believed that this finding might have been due to selection bias. Gershenson and colleagues' research indicated that age, stage, type of surgery, postoperative treatment, coexistence with noninvasive implants, and number of invasive implants had no effect on progression-free survival.²

No statistically significant differences are found in survival between mucinous and serous tumors. Mucinous tumors are most often stage I at time of diagnosis, and it is quite unusual to find extraovarian disease in tumors of mucinous origin.

Given the excellent prognosis of patients with stage I disease and its occurrence in women of reproductive age, fertility-sparing surgery is of great interest. In patients diagnosed with stage I disease who were treated with fertility-sparing surgery of any type, a higher recurrence was found in patients who had a cystectomy (with or without contralateral oophorectomy) as opposed to patients treated with oophorectomy (58% and 23%, respectively). However, only half of these patients underwent complete staging. When comprehensive staging was performed, no statistical difference was found in recurrence in confirmed cases of stage I disease. Thus, fertility-sparing surgery is an acceptable option in confirmed stage I disease. This again emphasizes the need for comprehensive staging in all cases.

Of patients who attempted pregnancy after fertility-sparing operations, a 50% conception rate was achieved among 24 patients who were studied. At the endpoint of the study, 16 live births, 4 spontaneous abortions, 3 ectopic pregnancies, and 2 ongoing pregnancies were found. No fetal anomalies were reported. All authors, nevertheless, indicate that this is an area that needs further research because, in the literature, only 48 patients were found to have conceived after having conservative surgery for borderline tumors. Another study looked at 25 women who underwent fertility-sparing surgery. No recurrences took place in the study period, although the range of follow-up varied widely (4-157 months). Of the 6 patients who attempted to become pregnant, 5 were successful, resulting in 5 live births and one patient had a miscarriage who underwent assisted reproductive techniques.

Patient Education:

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Ovarian Cancer.

Future and Controversies

Patients with borderline tumors have an excellent overall prognosis. Patients have a 60% chance of having stage I disease when diagnosed. Postoperative treatment for any stage is controversial; therefore, recommending reoperation for surgical staging alone is difficult. This being said, adequate staging is essential for determining the prognosis.

One study found that only 12% of patients were adequately staged at initial operation. Of these patients, 78% were operated on by general obstetrician/gynecologists, 10% by gynecologic oncologists, and 6% by general surgeons. When gynecologic oncologists were asked about surgical staging for borderline tumors, 97% recommend some type of staging procedure, although opinions varied significantly about which samples should be taken.³

Currently, an important area of research is postoperative chemotherapy. Little advantage has been reported after postoperative chemotherapy, but the number of patients studied is small and the chemotherapeutic regimens used were varied. The general consensus is that borderline tumors with noninvasive implants do not require any further therapy and should be observed. However, the benefit of treating tumors with invasive implants has been discussed. To date, no randomized data show a benefit.

References

Dietel M, Hauptmann S. Serous tumors of low malignant potential of the ovary. 1. Diagnostic pathology. Virchows Arch. May 2000;436(5):403-12. [Medline].
Gershenson DM, Silva EG, Levy L, et al. Ovarian serous borderline tumors with invasive peritoneal implants. Cancer. Mar 15 1998;82(6):1096-103. [Medline].
Lin PS, Gershenson DM, Bevers MW, et al. The current status of surgical staging of ovarian serous borderline tumors. Cancer. Feb 15 1999;85(4):905-11. [Medline].
Chan JK, Lin YG, Loizzi V, et al. Borderline ovarian tumors in reproductive-age women. Fertility-sparing surgery and outcome. J Reprod Med. Oct 2003;48(10):756-60. [Medline].
Eltabbakh GH, Natarajan N, Piver MS, Mettlin CJ. Epidemiologic differences between women with borderline ovarian tumors and women with epithelial ovarian cancer. Gynecol Oncol. Jul 1999;74(1):103-7. [Medline].
Emoto M, Udo T, Obama H, et al. The blood flow characteristics in borderline ovarian tumors based on both color Doppler ultrasound and histopathological analyses. Gynecol Oncol. Sep 1998;70(3):351-7. [Medline].
Harris R, Whittemore AS, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. III. Epithelial tumors of low malignant potential in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. Nov 15 1992;136(10):1204-11. [Medline].
Houck K, Nikrui N, Duska L, et al. Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis. Obstet Gynecol. Jun 2000;95(6 Pt 1):839-43. [Medline].
Menzin AW, Gal D, Lovecchio JL. Contemporary surgical management of borderline ovarian tumors: a survey of the Society of Gynecologic Oncologists. Gynecol Oncol. Jul 2000;78(1):7-9. [Medline].
Menzin AW, Rubin SC, Noumoff JS, LiVolsi VA. The accuracy of a frozen section diagnosis of borderline ovarian malignancy. Gynecol Oncol. Nov 1995;59(2):183-5. [Medline].
Morris RT, Gershenson DM, Silva EG, et al. Outcome and reproductive function after conservative surgery for borderline ovarian tumors. Obstet Gynecol. Apr 2000;95(4):541-7. [Medline].
Nielsen JS, Jakobsen E, Holund B, et al. Prognostic significance of p53, Her-2, and EGFR overexpression in borderline and epithelial ovarian cancer. Int J Gynecol Cancer. Nov-Dec 2004;14(6):1086-96. [Medline].
Sherman ME, Mink PJ, Curtis R, et al. Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis. Cancer. Mar 1 2004;100(5):1045-52. [Medline].
Tamakoshi K, Kikkawa F, Nakashima N, et al. Clinical behavior of borderline ovarian tumors: a study of 150 cases. J Surg Oncol. Feb 1997;64(2):147-52. [Medline].

Keywords

borderline ovarian tumors, ovarian tumors of low malignant potential, epithelial ovarian tumors of low malignant potential, ovarian masses, cancer antigen 125, CA125, CA-125, mucinous tumors, serous tumors, fertility-sparing surgery, oophorectomy, salpingo-oophorectomy, cystectomy, epithelial ovarian tumors, epithelial ovarian carcinoma

Contributor Information and Disclosures

Author

Andrew E Green, MD, BA, BS, Consulting Staff, Southeastern Gynecologic Oncology, LLC, Northeast Georgia Medical Center
Andrew E Green, MD, BA, BS is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society of Clinical Oncology, and Society of Gynecologist Oncologists
Disclosure: Nothing to disclose.

Medical Editor

Bryan D Cowan, MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi College of Medicine; Consulting Staff, Department of Obstetrics and Gynecology, Veterans Affairs Medical Center; Medical Director, Wiser Hospital for Women, University of Mississippi Medical Center
Bryan D Cowan, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Gynecological and Obstetrical Society, American Medical Association, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Endocrine Society, Sigma Xi, Society for Assisted Reproductive Technologies, Society for Gynecologic Investigation, Society for the Study of Reproduction, and Society of Laparoendoscopic Surgeons
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Michel E Rivlin, MD, Associate Professor, Coordinator, Quality Assurance/Quality Improvement, Department of Obstetrics and Gynecology, University of Mississippi School of Medicine
Michel E Rivlin, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Mississippi State Medical Association, and Royal College of Surgeons of Edinburgh
Disclosure: Nothing to disclose.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Assumption Community Hospital
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Laszlo Sogor to the development and writing of this article.

Further Reading

See Borderline Ovarian Cancer on Medscape.

See Treatment for Borderline Ovarian Cancer on Medscape.