Correspondence *Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

Email chid@mskcc.org

The case

A 30-year-old woman underwent a routine sonogram at 6 weeks of gestation during her first pregnancy and was found to have a 6 cm complex right-ovarian mass, thought to be a dermoid cyst. She had no remarkable gynecologic history or significant family history of cancer. Because of the pregnancy, surgery was not performed; however, she was followed conservatively, and went on to have a normal pregnancy and vaginal delivery at full term. The adnexal cyst did not grow appreciably; however, it persisted and 3 months postpartum the patient underwent a laparoscopic ovarian cystectomy. Preoperative serum cancer antigen 125 (CA125) was within the normal range (0–35 U/ml) at 23.6 U/ml. The ovarian cyst was removed intact, placed in a laparoscopic bag and aspirated for decompression. The ovarian aspirate was negative for malignant cells, but pathologic evaluation of the cyst revealed a clear-cell ovarian carcinoma. Following surgery, the patient underwent a CT scan of the abdomen and pelvis, which revealed no evidence of metastatic disease. She was referred to a large cancer center in the northeastern US for further management.

Review of the pathologic slides from the cystectomy confirmed the diagnosis of clear-cell epithelial carcinoma of the ovary. The patient then underwent dilation and curettage, laparotomy, right SALPINGO-OOPHORECTOMY and comprehensive surgical-staging pro-cedures, including INFRACOLIC OMENTECTOMY, multiple peritoneal biopsies, peritoneal washings, appendectomy, and bilateral pelvic and para-aortic lymphadenectomy. The left adnexa appeared grossly normal and, therefore, the uterus, left fallopian tube and ovary were not removed in order to preserve fertility. No residual carcinoma was noted in the right adnexal specimen, and all other specimens, including 31 resected lymph nodes, were negative for malignancy.

Although the patient was diagnosed with surgical stage IA disease (Table 1), because of the high recurrence rate associated with the clear-cell histology of the tumor, adjuvant chemotherapy was indicated and the patient was treated with systemic paclitaxel (175 mg/m²) and carboplatin (area under the curve = 6.0) every 3 weeks for six cycles.

Table 1 Staging of carcinoma of the ovary

Full tableFigures & Tables indexDownload Power Point slide (286K)

The patient was followed up with periodic serum CA125 blood tests every 3–6 months, pelvic sonograms every 6–12 months, and CT scans of the abdomen and pelvis annually for 2 years. She showed no evidence of recurrent disease and, 2 years after completing chemotherapy, became pregnant with her second child. The pregnancy was uneventful and the patient was delivered of a healthy baby by cesarean section, during which no gross evidence of recurrent disease was noted by the obstetrician.

Currently, 4 years after completing her therapy, the patient has no evidence of recurrent malignancy, with a stable serum CA125 level of 6 U/ml, and is pregnant with her third child. After delivery, she will be followed up with serum CA125 tests and pelvic sonograms yearly, and CT scans of the abdomen and pelvis every few years.

Discussion of diagnosis

Ovarian tumors are divided into histologic subtypes that present differently and harbor diverse prognoses. The main subclassifications are epithelial, germ-cell and sex-cord-stromal tumors. This patient was diagnosed with an epithelial ovarian cancer (EOC) with clear-cell histology. Surface epithelial tumors account for over half of all ovarian neoplasms.¹ These tumors are classified according to cell type and are stratified as benign, borderline or malignant. Grading of these tumors should also be reported by the pathologist. Poorly differentiated tumors and those with clear-cell histology are predictive of a higher chance of recurrence in stage I patients than other subtypes.

Incidence of EOC increases with advancing age and peaks in the seventh decade of life, with 60–70 cases per 100,000 women.² Incidence is higher in industrialized Western countries, and lower in Africa and Asia. In 2005, an estimated 22,220 women will be diagnosed with EOC in the US, and 16,210 women will die from the disease.³ This places ovarian cancer as one of the leading causes of death from cancer in women, after lung, breast and colon cancers.

A total of 90% of EOCs are sporadic. The remaining 10% are hereditary.⁴ The most common genetic syndrome associated with hereditary cases is hereditary breast and ovarian cancer (HBOC) syndrome, which accounts for 90% of hereditary cases and is linked with inherited mutations in the BRCA1 or BRCA2 gene. HBOC syndrome is more prevalent in women of Ashkenazi Jewish heritage, as a result of founder mutations in these genes. The lifetime risk of breast cancer is 60–85% for carriers of mutations in either gene. The lifetime risk of ovarian cancer has been estimated as 40–65% for BRCA1-mutation carriers and 10–15% for BRCA2-mutation carriers.⁵ Hereditary non-polyposis colorectal cancer syndrome (HNPCC) accounts for 2% of hereditary ovarian cancer cases, and other single-gene mutations account for the remaining 8%.

Other factors have also been shown to influence the risk of EOC in women. Parity decreases the risk of developing EOC, with a reduction in risk with each birth. Oral contraceptive use also decreases the risk in both low-risk and high-risk women. The effects of fertility drugs and environmental and dietary factors remain controversial.

Adnexal neoplasms diagnosed during pregnancy are malignant only in about 5% of cases. Pregnancy does not seem to alter the prognosis of ovarian malignancies, but complications (such as torsion of the ovary and rupture) might increase the risk of spontaneous abortion or preterm delivery. Ovarian masses should be evaluated similarly in both pregnant and non-pregnant patients, and diagnosis should be based on symptomatology and the appearance of the mass on ultrasound. The ovarian cancer serum marker CA125 is of no value during pregnancy, and CT is generally not utilized because of radiation-induced risks to the fetus.

EOC is diagnosed at an advanced stage (International Federation of Gynecology and Obstetrics (FIGO) stage III–IV) in approximately 75% of cases, with disease spread outside the pelvis or abdomen at the time of diagnosis (Table 1). Patients diagnosed with advanced disease have a reported 5-year-survival rate of 35%.² Symptoms are vague and include pelvic pain or pressure, mild gastrointestinal symptoms, and changes in urinary patterns. These nonspecific symptoms cause women to delay seeking medical attention, and the opportunity for early diagnosis is missed. Late diagnosis has a direct influence on prognosis, and educating both women and physicians to evaluate these symptoms promptly and appropriately is of the utmost importance. Patients diagnosed with early-stage disease (FIGO stage I–II) have a much better prognosis, with reported 5-year-survival rates of 70–90%.⁶ Investigations should include pelvic sonography and evaluation of serum markers for ovarian tumors. If advanced disease is suspected, abdominal and pelvic CT scans should be performed. Complex ovarian masses, including those with thick capsules, septations and papillary projections, should raise suspicion for malignancy.

Differential diagnosis

Ovarian masses are often functional and benign. When the probability of malignancy is low, a repeat pelvic ultrasound after the next menstrual cycle should be performed before surgery. Levels of CA125 might also be elevated in benign conditions, such as endometriosis, which can present as an endometrioma or complex ovarian cyst. CA125 is more sensitive and less specific in premenopausal women. Germ-cell tumors occur more frequently in younger women, and sex-cord-stromal tumors present in women of all ages. Other serum tumor markers, such as -fetoprotein, lactate dehydrogenase, human chorionic gonadotropin and inhibin, can assist in preoperative diagnosis and in differentiating between tumor subtypes.

Treatment and management

Patients with stage IA or IB disease and well-differentiated tumors have an excellent prognosis with surgical therapy alone, and are usually spared adjuvant chemotherapy. Patients with stage IC or II disease, poorly differentiated tumors and high-risk histologies (such as clear-cell carcinomas) of any stage have up to a 50% rate of recurrence.⁶ Recent research has shown that this group of patients derives significant benefit from adjuvant chemotherapy, with improvements in overall and recurrence-free survival.^{7, 8, 9}

The importance of determining the exact surgical stage in apparent early-stage EOC patients is clear—it has both prognostic and therapeutic implications. Staging should ideally be performed by a trained gynecologic oncologist and should usually include peritoneal washings for cytology, total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, pelvic and para-aortic lymph-node sampling, and multiple peritoneal biopsies. Of course, removal of both the ovaries and the uterus results in total infertility, and can be devastating for young women still wishing to conceive.

Conservative therapy should be considered only in comprehensively staged patients. Although hysterectomy and bilateral oophorectomy are part of the staging procedure, they can be omitted in well-selected patients in order to preserve fertility. In young patients diagnosed with what seems to be early-stage disease, it is prudent to postpone the decision regarding hysterectomy and resection of the contralateral ovary until a final diagnosis is made. Further surgery can be performed on a young patient if necessary, either to complete the staging procedure or to carry out a hysterectomy at a later time. Several retrospective trials have demonstrated the safety of fertility-sparing surgical staging in selected women with early-stage EOC who wished to conserve fertility.^{10, 11} In patients with stage IA or IC disease, it is possible to remove only the affected adnexa and perform a thorough staging procedure without removing the contralateral ovary or the uterus. After staging, if adjuvant therapy is required, platinum-based chemotherapy is recommended. Following this outline of therapy, many women have been reported to regain ovarian function, conceive, and deliver healthy children.

The treatment of advanced-stage ovarian cancer (FIGO stage III–IV) in patients of all ages includes surgery aimed at maximizing tumor debulking or minimizing residual disease—including total hysterectomy, bilateral salpingo-oophorectomy and resection of all tumor nodules—and adjuvant platinum-based chemotherapy.

In this case, the surgical staging procedure was performed through a large vertical incision to afford sufficient access to the whole peritoneal cavity. With advances in surgical instrumentation and technique, however, recent reports have demonstrated that comprehensive surgical staging procedures can now be performed safely and effectively via minimally invasive laparoscopic surgery.¹²This is particularly appealing in cases such as this, where diagnosis was made during initial surgery but secondary surgery for staging was necessary.

Conclusion

Ovarian cancer is not frequently diagnosed at an early stage or in women of childbearing age; however, the outcomes for patients in either situation can be improved by prompt diagnosis and correct management. Physicians should be vigilant about exploring vague symptoms, and women at high risk should be followed closely. When apparent early-stage EOC is diagnosed, comprehensive surgical staging should be performed to determine the appropriate postoperative treatment and prognosis. Studies demonstrating the safety and efficacy of performing surgical staging with minimally invasive surgical techniques are now emerging. Postoperative therapy should be specifically tailored to individual patients with early-stage disease, and adjuvant chemotherapy should be given to all women with high-risk early-stage disease. As in this case, after careful consultation, fertility-sparing surgery is an option for women with stage I disease, and pregnancies can be successfully achieved even after the administration of cytotoxic chemotherapy.

References

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Subject areas under which this article appears: Surgical Oncology