Although the occurrence of ovarian masses in pregnancy is relatively common, the majority of them is functional and resolve spontaneously; nevertheless, ovarian cancer is the fifth most common malignancy diagnosed in pregnancy. If malignancy is suspected, treatment should be decided on the basis of gestational age, stage of the disease and patient preferences. In early stage, ovarian cancer surgery may be planned preferably after 16 weeks of pregnancy, and chemotherapy can be administered from the second trimester if indicated as in non-pregnant patients. In advanced-stage disease, when complete cytoreduction is not achievable, neoadjuvant chemotherapy could be administered even in pregnancy. Chemotherapy should be a combination of carboplatin and paclitaxel in epithelial ovarian cancer patients and a combination of cisplatin, vinblastin and bleomycin in non-epithelial ovarian cancer. The outcome of patients with ovarian cancer diagnosed in pregnancy is similar to non-pregnant patients, and stage of the disease is the most important prognostic factor.
Highlights
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Ovarian cancer in pregnancy is an uncommon event.
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Diagnosis may be challenging due to the modifications induced by pregnancy.
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Surgery can be performed after 16 weeks of gestation.
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Chemotherapy can be administered in the second and third trimesters.
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The treatment aims at adequately curing patients and achieving full-term delivery.
Introduction
A small proportion of pregnant women (∼0.2–2%) are diagnosed with adnexal masses, mostly in the first trimester by routine obstetrical ultrasound. The vast majority are benign, pregnancy-related masses and will resolve spontaneous within the first 16 weeks of pregnancy. However, malignancy rate of adnexal masses in pregnancy is 1–6%, which makes ovarian cancer the fifth most common tumour in pregnancy . Awareness on the possibility of ovarian cancer in pregnancy is important and careful evaluation of (persisting) adnexal masses in pregnancy is required to avoid delay in diagnosis.
This chapter will give an overview of the diagnostic and therapeutic possibilities in pregnant patients with adnexal masses and ovarian cancer.
Diagnosis
Adnexal masses in premenopausal women are often found incidentally and are mostly of little clinical relevance. Because of the extensive use of obstetrical ultrasound, the number of masses diagnosed in pregnancy has increased over the past decades and it is therefore important to identify those who need further evaluation. Adnexal masses in pregnancy can be categorized into ovarian and non-ovarian as well as pregnancy-related and non-pregnancy-related. Non-pregnancy related masses can change morphology due to pregnancy, and proper diagnostic evaluation by an experienced specialist is important to identify those women who are in need of therapy.
Non-ovarian masses include hydrosalpinx, pedunculated fibroids and para-ovarian cysts. The most common ovarian masses in pregnancy are functional cysts, resembling a follicular cyst of corpus luteum. These masses are hormonally influenced and resolve spontaneously within weeks or sometimes months in most of the cases. Because of the changing characteristic, their morphology on ultrasound can vary widely especially when intracystic bleeding occurs. Non-functional masses such as dermoid cysts, endometriomas and epithelial masses do not resolve spontaneously . In pregnancy, making a proper diagnosis by imaging can be challenging because of the enlarged uterus and pregnancy-related morphological changes in the ovarian masses.
Ultrasound
Transvaginal and abdominal ultrasound is the preferred imaging technique to evaluate pelvic masses in pregnancy, because it is safe, widely assessable and has a high sensitivity and specificity . Over the last years, different algorithms have been developed to stratify the risk of malignancy using elements such as tumour size, morphology and colour Doppler flow . In 2010, Timmerman et al. published the IOTA simple rules, a model to characterize ovarian pathology. They demonstrated up to 75% correctly classified ovarian masses, in hands of examiners with different levels of ultrasound expertise. The use in specific populations like pregnant women, however, has not been established.
When evaluating adnexal masses in pregnancy, it must be considered that ovarian masses can undergo pregnancy-related morphological changes and that pregnancy-related masses can occur. When a symptomatic unilateral adnexal mass is diagnosed in early pregnancy, when no intrauterine gravidity is (yet) to be seen, an ectopic pregnancy must be ruled out. The most common pregnancy-specific masses are the corpus luteum of pregnancy and the theca lutein cysts, both will resolve mostly after 16 weeks of pregnancy but can persist until after delivery . With regard to endometriomas, because of the high levels of progesterone, decidualization of the walls can occur, making it difficult to distinguish between a benign and malignant lesion . When diagnosis remains unclear, even after re-evaluation by an experienced sonographer, further imaging is needed.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) can be safely used throughout pregnancy. The use of the MRI contrast agent gadolinium is discouraged, as it crosses the placenta and is excreted by the foetal kidney into the amniotic fluid. The possibility of gadolinium becoming toxic in the amniotic fluid by dissociating the ion from the chelating molecule makes its use in pregnancy reserved for those cases where the maternal benefit outweighs the potential foetal risks .
The use of MRI in evaluation of adnexal masses is particularly useful in differentiating between bone and muscular tissue, like leiomyomas, endometriomas and complex masses with solid compounds . When ultrasound is not conclusive, when masses are too large to fully assess with ultrasound or when there is a high risk of malignancy, MRI can add value in making the proper diagnosis. The use of new imaging techniques like diffusion-weighted imaging (DWI) can potentially reduce the need of gadolinium contrast. Especially in evaluating potential peritoneal disease spread and nodal metastases, a good diagnostic performance of whole-body MRI with DWI has been proven, regardless of lesion size, compared with contrast-enhanced MRI or computed tomography (CT) and Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET)/CT .
Other imaging techniques
Exposure to ionizing radiation should be avoided in pregnancy where possible, or at least the ALARA principle (as low as reasonably achievable) should be followed. CT scan is not absolutely contraindicated in pregnancy, but should be considered only if maternal benefits from the scan are higher than the risk of foetal radiation exposure .
18F-FDG PET has little application in pregnancy. Radioactive nuclides could affect the foetal health depending on the tracer pharmacokinetics, proximity of the foetus to maternal bladder and gestational age. Few experiences described a radiopharmaceutical dose reduction in pregnant patients .
Tumour markers
The tumour markers should be used with care in the diagnosis of ovarian cancer in pregnancy. During normal pregnancy, especially in the first and last trimesters, decidua and granulosa cells produce CA 125, reducing its diagnostic value for ovarian cancer. This is also the case for other tumour makers for ovarian cancer like alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (β-hCG) for germ cell tumours. The use of these markers may however be useful in the evaluation of therapy . Inhibin B and anti-mullerian hormone (AMH) for granulosa cell tumours and human epididymis protein 4 (HE4) are not elevated in normal pregnancy and can be used in both diagnosis and therapy evaluation .
Diagnosis
Adnexal masses in premenopausal women are often found incidentally and are mostly of little clinical relevance. Because of the extensive use of obstetrical ultrasound, the number of masses diagnosed in pregnancy has increased over the past decades and it is therefore important to identify those who need further evaluation. Adnexal masses in pregnancy can be categorized into ovarian and non-ovarian as well as pregnancy-related and non-pregnancy-related. Non-pregnancy related masses can change morphology due to pregnancy, and proper diagnostic evaluation by an experienced specialist is important to identify those women who are in need of therapy.
Non-ovarian masses include hydrosalpinx, pedunculated fibroids and para-ovarian cysts. The most common ovarian masses in pregnancy are functional cysts, resembling a follicular cyst of corpus luteum. These masses are hormonally influenced and resolve spontaneously within weeks or sometimes months in most of the cases. Because of the changing characteristic, their morphology on ultrasound can vary widely especially when intracystic bleeding occurs. Non-functional masses such as dermoid cysts, endometriomas and epithelial masses do not resolve spontaneously . In pregnancy, making a proper diagnosis by imaging can be challenging because of the enlarged uterus and pregnancy-related morphological changes in the ovarian masses.
Ultrasound
Transvaginal and abdominal ultrasound is the preferred imaging technique to evaluate pelvic masses in pregnancy, because it is safe, widely assessable and has a high sensitivity and specificity . Over the last years, different algorithms have been developed to stratify the risk of malignancy using elements such as tumour size, morphology and colour Doppler flow . In 2010, Timmerman et al. published the IOTA simple rules, a model to characterize ovarian pathology. They demonstrated up to 75% correctly classified ovarian masses, in hands of examiners with different levels of ultrasound expertise. The use in specific populations like pregnant women, however, has not been established.
When evaluating adnexal masses in pregnancy, it must be considered that ovarian masses can undergo pregnancy-related morphological changes and that pregnancy-related masses can occur. When a symptomatic unilateral adnexal mass is diagnosed in early pregnancy, when no intrauterine gravidity is (yet) to be seen, an ectopic pregnancy must be ruled out. The most common pregnancy-specific masses are the corpus luteum of pregnancy and the theca lutein cysts, both will resolve mostly after 16 weeks of pregnancy but can persist until after delivery . With regard to endometriomas, because of the high levels of progesterone, decidualization of the walls can occur, making it difficult to distinguish between a benign and malignant lesion . When diagnosis remains unclear, even after re-evaluation by an experienced sonographer, further imaging is needed.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) can be safely used throughout pregnancy. The use of the MRI contrast agent gadolinium is discouraged, as it crosses the placenta and is excreted by the foetal kidney into the amniotic fluid. The possibility of gadolinium becoming toxic in the amniotic fluid by dissociating the ion from the chelating molecule makes its use in pregnancy reserved for those cases where the maternal benefit outweighs the potential foetal risks .
The use of MRI in evaluation of adnexal masses is particularly useful in differentiating between bone and muscular tissue, like leiomyomas, endometriomas and complex masses with solid compounds . When ultrasound is not conclusive, when masses are too large to fully assess with ultrasound or when there is a high risk of malignancy, MRI can add value in making the proper diagnosis. The use of new imaging techniques like diffusion-weighted imaging (DWI) can potentially reduce the need of gadolinium contrast. Especially in evaluating potential peritoneal disease spread and nodal metastases, a good diagnostic performance of whole-body MRI with DWI has been proven, regardless of lesion size, compared with contrast-enhanced MRI or computed tomography (CT) and Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET)/CT .
Other imaging techniques
Exposure to ionizing radiation should be avoided in pregnancy where possible, or at least the ALARA principle (as low as reasonably achievable) should be followed. CT scan is not absolutely contraindicated in pregnancy, but should be considered only if maternal benefits from the scan are higher than the risk of foetal radiation exposure .
18F-FDG PET has little application in pregnancy. Radioactive nuclides could affect the foetal health depending on the tracer pharmacokinetics, proximity of the foetus to maternal bladder and gestational age. Few experiences described a radiopharmaceutical dose reduction in pregnant patients .
Tumour markers
The tumour markers should be used with care in the diagnosis of ovarian cancer in pregnancy. During normal pregnancy, especially in the first and last trimesters, decidua and granulosa cells produce CA 125, reducing its diagnostic value for ovarian cancer. This is also the case for other tumour makers for ovarian cancer like alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (β-hCG) for germ cell tumours. The use of these markers may however be useful in the evaluation of therapy . Inhibin B and anti-mullerian hormone (AMH) for granulosa cell tumours and human epididymis protein 4 (HE4) are not elevated in normal pregnancy and can be used in both diagnosis and therapy evaluation .
Surgical treatment
Surgery can be seen as the least controversial type of oncologic treatment in pregnancy because of the frequent application of surgery for non-oncological reasons with no reported adverse effects. Non-obstetrical surgery is performed in one to four of 200 pregnant patients. Surgery can be performed throughout pregnancy, provided specific measures are taken. If the expected delivery date is forthcoming, the general condition of the patient good and disease is not quickly progressive, and one could consider delaying surgery until postpartum. In pregnancy, besides an optimal surgical outcome, the main objectives to consider are also the maternal and foetal safety . In case of ovarian cancer, special attention is required because of the abdominal approach. Fortunately not all ovarian masses require acute resection. Simple cysts smaller than 5 cm, or with unequivocal benign features, can be easily resolved. Therefore, thorough follow-up in pregnancy is recommended . A careful decision must be made between operating too early (risk of miscarriage and loss of luteal function before the fourth month of pregnancy) and too late (complications such as torsion/rupture or bleeding, progression in case of malignancy and premature labour) .
The incidence of a malignant adnexal mass in pregnancy is reported to be four to eight in 100,000 pregnancies, of which the most frequent are the non-epithelial tumours (germ-cell and sex-cord), borderline tumours and epithelial ovarian cancers .
According to the International Federation of Gynecology and Obstetrics (FIGO), for early-stage (I–II) ovarian cancer, standard surgical procedure involving hysterectomy, bilateral adnexectomy, omentectomy, cytology, biopsies and lymphadenectomy should be aimed for . Fertility- and pregnancy preserving-treatment (removal of the adnex and surgical staging – cytology, peritoneal biopsies, omentectomy, appendectomy (in mucinous tumours)) can only be considered in selected cases. For a FIGO stage IA, grade 1, epithelial ovarian cancer, and in every cases where occult extra-ovarian disease cannot be adequately assessed in pregnancy, a restaging after delivery may be considered .
A midline laparotomy, performed through midline vertical incision with minimal uterine manipulations is preferred for optimal exposure. Laparoscopy is safe and feasible when specific guidelines are followed . Preferably a laparoscopic approach is scheduled between 16 and 20 weeks, to optimize the visualization of the mass in contrast to the enlarged uterus and to decrease the ratio of preterm labour . The location of the first trocar should be at least 3–4 cm above the uterine fundus. Next to these measures, four prerequisites were recommended by experts on a consensus meeting on gynaecologic malignancies in pregnancy: a maximal laparoscopic procedure time of 90 min, a pneumoperitoneum with a maximal intra-abdominal pressure of 10–13 mmHg, open introduction (Hasson technique, to avoid Verees needle injury) and an experienced surgeon . A total of 48 pregnant women treated with laparoscopy in first ( n = 17), second ( n = 27) and third trimesters ( n = 4) were reported by Mathevet et al. showing minimal risk for both the mother and foetus considering the possible technical problems and correct approach by the surgeon and his specialized team.
Next to these preventive measures for laparoscopic procedures, general guidelines for surgery in pregnancy need to be considered. To avoid hypovolemia, hypotension and hypoxemia, the position of the patient should be slowly changed to Trendelenburg allowing only mild inclination, and from 20 weeks onwards, the left lateral position should be used. Oxygen consumption increases till term because of the increasing oxygen requirements of the uterus, placenta and foetus. By contrast, the functional residual capacity decreases up to 20% at term. This leads more rapidly to significant desaturation after apnoea; thus, a thorough pre-oxygenation is critical . Moreover, maintaining normal maternal oxygenation is important as the foetal well-being is directly related to the maternal condition. Continuous monitoring of foetal heart rate during surgery (laparoscopy) is therefore advisable (depending on gestational age, local policy and parent’s consent). Because the uterus is manipulated, tocolytic agents are indicated . Antibiotic prophylaxis depends on the specific procedure, but cephalosporins, penicillins, erythromycin and clindamycin can be safely used in pregnancy. Pregnancy, surgery, immobilization and malignancy are all independent risk factors for the development of thrombo-embolic events. Prophylaxis with either unfractionated or low molecular weight heparin is advisable . Postoperative analgesia and antiemetics can be prescribed.
For advanced-stage ovarian cancer (FIGO stage III and IV), cytoreduction to no residual disease is not possible. A biopsy or adnexectomy should be performed, followed by neoadjuvant chemotherapy with completion of cytoreductive surgery after delivery. Because the incidence and thus the experience are limited, termination of pregnancy is mostly reported . If the patient considers to proceed the pregnancy, standard chemotherapeutic treatment (carboplatin-paclitaxel) from the second trimester onwards can be safely administered, until foetal maturity. A vaginal delivery is should be aimed for.
Chemotherapy for epithelial ovarian cancers
Chemotherapy should be offered after primary surgery in all cases of epithelial ovarian cancer. As in non-pregnant patients, only stage IA, grade 1 and 2 patients can avoid chemotherapy and be carefully monitored. When the diagnosis of advanced epithelial ovarian cancer is made preoperatively, neoadjuvant chemotherapy could be proposed as complete cytoreduction including hysterectomy, which cannot be achieved if pregnancy has to be preserved.
To avoid maternal hematopoietic nadir and neonatal myelosuppression, the last cycle of chemotherapy should be scheduled at least 3 weeks before delivery .
The standard first-line chemotherapy for epithelial ovarian cancer includes platinum derivatives and paclitaxel. Preclinical data suggest that cisplatin is highly embryolethal and teratogenic in mice and rats during the period of rapid DNA replication in early organogenesis . Similar effects have been reported for carboplatin. In human, there are five reports on cisplatin administered in the first trimester, with one major (blepharophimosis, microcephaly and hydrocephalus) and one minor malformation (microphtalmos) ; no case of carboplatin administration during the first trimester has been reported to date. Therefore, administration of platinum derivatives in the first trimester is not recommended. Despite the high percentage of platinum compounds bound to plasma protein, when administered in the second and third trimesters, it has been shown to cross the placental barrier, as both cisplatin and carboplatin adducts can be measured in the amniotic fluid and in the umbilical cords of the newborn. These observations confirm the reported data on mice and baboons . However, no detrimental effect on the newborn has been observed, as only one foetus out of 98 patients receiving cisplatin and none out of 17 patients receiving carboplatin had a major malformation possibly related to drug exposure (ventriculomegaly and cerebral atrophy) . Because of its nephrotoxicity, when cisplatin is administered in the third trimester, newborn renal function should be thoroughly assessed. Carboplatin is less nephrotoxic than cisplatin and should be preferentially used in pregnancy.
There are less data available about paclitaxel administered in pregnancy. The placental transfer in human is unknown; however, data reported on a baboon model suggest that foetus are exposed to low level of paclitaxel but that the exposure is long lasting . Preclinical data show that paclitaxel is embryolethal in mice and rats and teratogenic in rats when administered in early pregnancy. It has been hypothesized that embryotoxicity is associated with Cremophor EL, the vehicle used for drug administration. In humans, there is no report on the effect of paclitaxel administration in the first trimester. In the second and third trimesters, paclitaxel was administered to 36 pregnant women, in the majority of cases as polytherapy. The only major malformation reported has been a pyloric stenosis in a foetus exposed to paclitaxel, doxorubicin and cytarabine. The most common pregnancy complications were oligohydramnios, which occurred in two patients and preeclampsia in three patients .
Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, prolonged progression-free survival in advanced-stage ovarian cancer when administered with standard chemotherapy and as maintenance treatment. VEGF plays a crucial role in pregnancy, stimulating trophoblastic vessels invasion and foetal growth, as well as enhancing amniotic fluid production . Preclinical data suggest that anti-VEGF agents inhibit organogenesis and foetal development in mice models, and their use in pregnancy is not recommended. In humans, no cases of systemic administration of bevacizumab in pregnancy have been reported to date. Intravitreal injection of bevacizumab has been reported in 15 patients , with two experiencing early pregnancy loss. Thus, even if data remain scanty, the standard doublet with carboplatin and paclitaxel seems to give the best results in terms of foetal safety and maternal outcome. Nonetheless, further comprehensive pharmacokinetic and safety studies on these drugs are warranted.
Chemotherapy for non-epithelial ovarian cancers
Non-epithelial ovarian cancer is usually diagnosed as stage I and surgery is, in the majority of cases, adequate to treat these patients. However, adjuvant chemotherapy should be administered in women with advanced-stage tumours, following the same indications used for non-pregnant patients. The standard chemotherapy for non-epithelial ovarian cancer is the combination of bleomycin, etoposide and cisplatin. Preclinical data suggest that bleomycin has a teratogenic effect in animals when administered during the first trimester. In humans, the majority of pregnant patients treated with bleomycin in pregnancy had Hodgkin and non-Hodgkin lymphoma. Bleomycin administration has been reported in 15 patients during the first trimester, with one major malformation (floating thumb) , resulting in a 7% malformation rate. A total of 80 patients received bleomycin during the second and third trimesters, with four major malformations reported , but only one judged possibly related to drug exposure . The most commonly reported pregnancy complications associated with bleomycin administration were intra-uterine growth restriction in five patients and preeclampsia in four patients . The neonatal adverse effects reported are generally linked to prematurity instead of drug administration.
Etoposide is a semi-synthetic antineoplastic agent used to treat Hodgkin lymphoma, ovarian, testicular and lung cancer. Embryolethal and teratogenic effects of etoposide in animals exposed during the organogenesis have been reported . Because of the well-known risk of secondary leukaemia , a recent consensus suggested replacing etoposide in pregnancy . Reasonable alternatives would be combinations of paclitaxel and carboplatin or cisplatin, vinblastin and bleomycin.
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