Borderline Ovarian Cancer

INTRODUCTION ¡@

Borderline ovarian tumors are a subset of epithelial ovarian tumors that have a very favorable prognosis. They often are responsive to surgery. However, postoperative management is far from clear. To date, no medical therapy has been shown to clearly improve outcomes.

History of the Procedure:
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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. However, it was not until the early 1970s that these entities were classified separately by the Federation of Gynecology and Obstetrics (FIGO) and by the World Health Organization (WHO).

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Frequency:
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One woman in 55 (1.8%) will develop some form of ovarian cancer in her lifetime. Of these, approximately 90% are tumors of epithelial origin. If benign lesions are included, epithelial tumors account for 60% of all ovarian tumors.

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

Borderline ovarian cancer is staged according to the FIGO classification of ovarian cancer. However, many clinicians group stages II-IV together for prognostic consideration. Another component of staging that has become common is the description of the type of implants, as these have significant prognostic value.

Etiology:
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Due to the small number of cases and the lack of randomized controlled studies, the etiology of this disease remains unclear.

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Pathophysiology:
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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, however, do not have a clearly defined origin. Many consider borderline tumors to occupy an intermediate position between their benign and frankly malignant counterparts.

Clinical:
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These tumors, as with other ovarian tumors, are difficult to detect clinically until 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% were asymptomatic.

RELEVANT ANATOMY AND CONTRAINDICATIONS ¡@

Contraindications: When an ovarian mass is found, surgery is often, if not always, indicated. Preoperatively, borderline tumors often are presumed to be either benign ovarian masses or malignant ones; regardless, surgery is required to determine the type of mass. Contraindications to surgery would be either for medical reasons (ie, the patient is too great a surgical risk secondary to other medical problems) or because the patient refuses therapy for one reason or another. Otherwise, the masses should be surgically removed.

WORKUP ¡@

Lab Studies:
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Imaging Studies:
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Histologic Findings: According to Dietel, the histology of borderline tumors is characterized by the following:

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Mucinous tumors grossly look 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 seen.

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 the tumor. 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 seen 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 done 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 ¡@

Medical therapy: There still is no consensus for treatment of patients with stage II-IV disease. While they still have high 5-year survival as 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 regimes have been used; however, not enough evidence is available 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 due to their worse prognosis.

Surgical therapy: Complete excision of the disease must be achieved if at all possible. Make comprehensive staging, as described above, a part of every operation. While 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 that a sampling error will occur, which could result in an inaccurate diagnosis and prognosis.

In patients with confirmed stage I disease, surgery is curative in most instances. If the tumor is unilateral and adjacent to normal tissue, unilateral cystectomy can be performed. However, before resection inspect the capsule for signs of rupture. If no normal adjacent tissue is present, perform oophorectomy or salpingo-oophorectomy. If normal in appearance, the adjacent ovary should not be biopsied due to the risk of ovarian failure.

Due to the high association between surface proliferations and peritoneal implants, when they are found, explore the peritoneum thoroughly. Carefully evaluate and remove the implants, if possible. The type of implant (ie, invasive or noninvasive) should be noted by pathology. The type of implant found has significant prognostic value.

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

COMPLICATIONS ¡@

Most of the complications of this disease are caused by the operation itself, by subsequent therapy, or from 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. Most likely, many, if not all, of these patients were not actually stage I.

Pathologic diagnosis is difficult to make at frozen section. Borderline tumors are correctly diagnosed 58-86% of the time at 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 the vast majority of cases even though the diagnosis at 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 died of chemotherapy-associated complications, 8 died from bowel obstruction, and 8 died 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 for such patients approaches 100%.

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 was found in reported series. In patients with recurrence, a median time to diagnosis of 3.1 years was reported if the recurrence was borderline type. In patients whose recurrence was invasive carcinoma, the median time to diagnosis was 8.3 years. It is felt that the former was a recurrence but that the latter probably was 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. However, the time to progression of disease was significantly longer in patients who had no macroscopic disease remaining at time of initial operation. Also, patients who received postoperative platinum-based chemotherapy had a significantly worse progression-free survival. However, the authors of this study felt this finding might be due to selection bias. Gershenson’s 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 most often are stage I at time of diagnosis. It is quite unusual to find extraovarian disease in tumors of mucinous origin.

Given the excellent prognosis of 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 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 stage I disease. This again confirms 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. However, all authors indicate that this is an area that needs further research as a total of only 48 patients are found in the literature to have conceived after having conservative surgery for borderline tumors.

FUTURE AND CONTROVERSIES ¡@

Borderline tumors have an excellent prognosis overall. There is a 60% chance of having stage I disease, and postoperative treatment for any stage is controversial; therefore, it is difficult to recommend reoperation for surgical staging alone. 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; however, opinions varied significantly about which samples needed to 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 regimes used were varied.

BIBLIOGRAPHY ¡@