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Cancer in Pregnancy: Ovarian Tumors and Pregnancy

Introduction
Ovarian cancer is the second most frequent gynecologic cancer complicating pregnancy1. Although the overall incidence of ovarian cancer in pregnancy is low, the increased use of ultrasound in early fetal evaluation has led to more frequent findings of adnexal mass in pregnancy. The average estimated incidence of ovarian tumors in pregnancy is approximately 1 in 1000 deliveries.2,3 The vast majority of tumors detected during pregnancy are benign. Approximately 2 to 5 percent of adnexal masses are true malignant neoplasms.2,4-6

Diagnosis
A significant number of patients are asymptomatic and are found to have an adnexal mass on physical examination, during routine ultrasound, or at the time of cesarean delivery 7. However, other presentations include abdominal pain, increasing abdominal girth, obstructed labour and emergency laparatomy due to torsion or rupture of the mass.7-9

Adnexal masses during pregnancy are managed according to characteristics of the mass and sonographic appearance, gestational age and patient symptomatology. High resolution transabdominal ultrasound is the initial imaging tool and essential diagnostic method10. It is best used in combination with high-frequencytransvaginal transducer applied transabdominally11. Observation and repeat ultrasound at 14 to 16 weeks gestational age to document resolution is appropriate for those masses < 6 cm that are unilateral, unilocular, mobile and asymptomatic. In contrast, laparotomy has been traditionally recommended if the mass is > 6 cm, solid or of complex appearance, bilateral or persists into the second trimester. Elective surgery for removal of these masses is preferable since urgent procedures for adnexal torsion or rupture have been associated with higher rates of spontaneous abortion and premature delivery 12.

Elective surgery should be delayed until the second trimester to decrease the chance of fetal complications. Intervention may be delayed until after delivery when an asymptomatic mass is detected in the third trimester13. Careful examination of the adnexal mass and intraoperative confirmation of pathology is mandatory. If benign pathology is confirmed, a simple cystectomy is usually sufficient 14. Management of malignant pathology depends on the tumor type, gestational age and patient wishes. Although serum tumor markers remain important in the preoperative assessment of all women with adnexal mass, their interpretation in pregnancy is not always reliable since they are often elevated and fluctuate with gestational age13.

Staging
Stages referred to in this article are similar to those defined by the International Federation of Gynaecology and Obstetrics (FIGO) 1999 for ovarian epithelial carcinoma.

Most of the patients with ovarian cancer diagnosed during pregnancy have disease confined to the pelvis or abdomen. Staging is primarily surgical. Laparoscopy may be a reasonable initial approach to explore adnexal masses in patients who do not show evidence of extra-ovarian pathology. Despite concerns regarding fetal risk, uterine injury and restricted operative field, the safety of this technique is growing15,16.As mentioned previously, ultrasound is an effective tool to evaluate adnexal masses and can be done serially with little risk to the fetus or mother. Magnetic Resonance Imaging (MRI) (with its multiplanar capability and improved tissue characterization), is a valuable adjunct. Also, MRI is not associated with ionizing radiation exposure 17,18. In general, decisions regarding the use of radiological investigations must take into account the age of the fetus and the estimated dose of radiation delivered with the respective imaging study.

Pathology and biology
The vast majority of adnexal masses are benign and are diagnosed at an early stage when the disease is still confined to the ovary. Of those that are malignant, the following tumor types have been described: epithelial, germ cell, sex-cord stromal and much less commonly, metastatic involvement of the ovary from another primary site (Krukenberg tumor). The relative frequency of tumor types reflects the young age of presentation. Depending on the series, germ cell tumors are either the most common or second only to epithelial tumors 2,19,20.

The epithelial tumors tend to be early stage and low grade although advanced stage tumors have been reported 4,8,21.

In the germ cell category, dysgerminomas are the most frequently encountered in pregnancy. Endodermal sinus tumors have also been reported 2. Both tumor types tend to be confined to the ovary (approximately 80 percent) at the time of diagnosis in pregnancy. Ten retrospective cases of serous neoplasms of low malignant potential resected during pregnancy, were reported with clinical and microscopic features suggesting aggressive behavior. However, these features subsided significantly after delivery and years after, all patients are still alive with no evidence of disease22.

Sex cord-stromal tumor types that have been described include granulosa, Sertoli-Leydig and 'unclassified'5. The differential diagnosis of sex cord stromal tissues includes other benign conditions which can mimic malignancy. These include luteoma of pregnancy, luteinized follicular cyst, granulosa cell proliferations, hilus cell hyperplasia and ectopic decidua 6,19. These conditions are characterized by regression after pregnancy.

There is no evidence that pregnancy alters the course or affects the prognosis of pure dysgerminoma23,24. However, the prognosis of non-dysgerminomatous germ cell tumors associated with pregnancy may be uncertain, since two fatal cases of rapidly progressive disease during the second trimester were described in the literature24.

Treatment

Surgery
Surgical exploration using a midline incision at 16 -18 weeks gestation is recommended. For benign pathology, cystectomy is warranted. A frozen section diagnosis must be made to guide further decisions. Careful examination of both ovaries is essential as well as standard surgical exploration and staging for more advanced cancers.

This may include omental biopsy/sampling, peritoneal biopsies and pelvic washings for cytology. In cases of ovarian dysgerminoma, pelvic/paraaortic lymph node biopsy is mandatory, since the tumor spreads predominantly through the lymphatics. Under-staging is common if lymphadenectomy is omitted13. Contralateral ovarian biopsy is warranted only if the ovary appears to be involved with the tumor. Routine biopsy or wedge resection of a normal-appearing contralateral ovary is no longer recommended25.

Germ cell tumors confined to the ovary may be managed with conservative surgery, ie. oophorectomy/salpingo - oophorectomy. This allows for preservation of the uterus and contralateral ovary. It is often possible to continue the pregnancy after surgical staging and tumor debulking. One case report described successful outcomes of a 9-week pregnancy managed by bilateral salpingo-oophorectomy for ovarian cancer26.

Similarly, low malignant potential and sex cord-stromal tumors with early stage disease can be managed with adnexectomy or oophorectomy.

Epithelial ovarian cancers are staged in a similar manner to the non-pregnant population. If fertility preservation is an issue, unilateral salpingo oophorectomy may be used to treat patients with stage IA, low grade tumors. The literature describes successful pregnancy and preservation of normal ovarian function, in cases of advanced-stage metastatic, low malignant potential tumors treated by successful tumor debulking27,28. All higher stage tumorsshould undergo standard surgery with debulking, i.e. total abdominal hysterectomy, salpingo oophorectomy, omentectomy, lymph node sampling, perioneal cytology and careful inspection of the liver and diaphragm. For those patients with advanced disease, decisions regarding debulking procedures should take into account fetal viability, patient health and patient desires at the time of surgery. Hysterectomy during pregnancy is rarely indicated unless it contributes significantly to tumor debulking. A recently published retrospective study of 174 patients undergoing adnexal surgery during pregnancy showed no evidence of increasing risk of fetal loss when surgery was performed after the seventh week of gestation29.

Chemotherapy
Cancer chemotherapeutic drugs are very potent teratogens. Currently, there is very little information on the effect of cancer chemotherapy on the fetus 30. The risk of malformations when chemotherapy is administered in the first trimester has been estimated to be around 10% for single agent chemotherapy31 and 25% for combination chemotherapy32. It is generally suggested that chemotherapy be avoided during the first trimester, when cells are actively dividing. Use of these agents in the second and third trimesters has been associated with an increased risk of stillbirth, intrauterine growth retardation and low birth weight30,33,34. When chemotherapy is administered during pregnancy, timing of delivery of the infant should take into account the expected bone marrow depression and potential problems such as bleeding or infections. Self limiting fetal haematopoetic depression has been described and the neonate should be monitored for complications of this 35. Long term neurodevelopmental complications of in utero chemotherapy exposure have not been extensively studied. Limited data exist to suggest that this may be normal in the offspring of patients with haematologic malignancies treated during various stages of the pregnancy 36.

Post operative observation with chemotherapy reserved for relapse is a reasonable option for patients with stage IA pure dysgerminoma. With the exception of Stage IA grade I immature teratoma, and low malignant potential epithelial cancer, both ovarian germ cell and epithelial invasive tumors are usually considered for adjuvant chemotherapy. Cure rates for ovarian germ cell tumors are high - on average, 95% for stage I and 75% for the advanced disease37. Recent evidence suggests that survival may not be compromised if stage I tumors are managed by surveillance, reserving chemotherapy for relapse38. It is unclear whether maternal outcome would be compromised by a delay in adjuvant therapy until after delivery. Although limited, there are case reports of cytotoxic treatment for germ cell tumors in the second and third trimesters using agents such as vincristine, vinblastine, actinomycin-D, cyclophosphamide, bleomycin, cisplatinum and etoposide. Fetal outcome was good 39-45. Long term toxicity information is generally lacking.

Epithelial tumors of low malignant potential are known for their indolent disease course and good prognosis. Even in late-stage disease, chemotherapy is apparently not needed.

Patients with poor prognosis stage I (high grade tumors or stage IC) or more advanced invasive epithelial ovarian cancers are considered candidates for post operative therapy - usually cisplatin-based chemotherapy plus paclitaxel. There are isolated reports of favorable fetal outcome after treatment with cisplatin based therapy for advanced epithelial cancers 46-49. Cases of adjuvant cisplatin and cyclophosphamide therapy initiated in the second trimester of pregnancy are described in the literature, with good response to therapy and subsequent delivery of a healthy baby50.

There is no published data regarding the use of Taxol during human pregnancy.

Prognosis
There is no evidence that pregnancy alters the prognosis of ovarian tumors compared to the non-pregnant population when patients are matched for tumor histology and stage. In general, pregnant patients with ovarian cancer have a better prognosis overall due to the age related tumor distribution and early stage of diagnosis in a significant number of patients.

Lactation
Cytotoxic agents administered systemically may reach significant levels in breast milk and thus breastfeeding while on chemotherapy is contraindicated. A similar situation exists for the use of radioiodine. See also Breastfeeding and anti-cancer chemotherapy.

References

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