Borderline Ovarian Cancer

Last Updated: July 7, 2005

Synonyms and related 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
AUTHOR INFORMATION Section 1 of 10
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Author: Andrew E Green, MD, Fellow, Section of Gynecologic Oncology, Department of

Obstetrics and Gynecology, Cleveland Clinic Foundation

Coauthor(s): Laszlo Sogor, MD, PhD, Chief, Division of Gynecology, Acting Chairman,
Department of Obstetrics and Gynecology, University MacDonald Women's Hospital; Associate
Professor, Department of Reproductive Biology, Case Western Reserve University
Andrew E Green, MD, is a member of the following medical societies: American College of
Obstetricians and Gynecologists
Editor(s): Bryan D Cowan, MD, Director, Division of Reproductive Endocrinology, Professor,
Department of Obstetrics and Gynecology, University of Mississippi College of Medicine;
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michel E Rivlin,
MD, Coordinator, Quality Assurance/Quality Improvement, Associate Professor, Department of
Obstetrics and Gynecology, University of Mississippi Medical Center; Frederick B Gaupp,
MD, Consulting Staff, Department of Family Practice, Assumption Community Hospital; and
Lee P Shulman, MD, Professor of Obstetrics and Gynecology, Feinberg School of Medicine,
Northwestern University; Chief, Division of Reproductive Genetics, Department of Obstetrics
and Gynecology, Prentice Women's Hospital, Northwestern Memorial Hospital

INTRODUCTION Section 2 of 10
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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.

Pathophysiology: The 2 major histologic tumor subtypes are serous and mucinous, with serous
being more common. Other much less common tumors include clear cell and endometrioid.
Serous tumors are presumed to originate from the germinal epithelium. Mucinous tumors do not
have a clearly defined origin. Many authorities consider borderline tumors to occupy an
intermediate position between their benign and frankly malignant counterparts.

Clinical: 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 Section 3 of 10
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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.

Section 4 of 10
RELEVANT ANATOMY AND CONTRAINDICATIONS
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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 Section 5 of 10
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Lab Studies:

Cancer antigen 125 (CA125) 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:

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 paraaortic).

TREATMENT Section 6 of 10
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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, explore the
peritoneum thoroughly when they are discovered. 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 patients 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.

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 Section 7 of 10
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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 tumorrelated 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 Section 8 of 10

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Prognosis Future And Controversies Bibliography

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 CA125 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.

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 Section 9 of 10

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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.

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. However, when deciding on postoperative
therapy, one should remember that patients may have more complications than benefits from the
therapy.

BIBLIOGRAPHY Section 10 of 10
Author Information Introduction Indications Relevant Anatomy And Contraindications Workup Treatment Complications Outcome And
Prognosis Future And Controversies Bibliography

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