Robert Fruscio1, Lorenzo Ceppi1, Giovanni Codacci-Pisanelli2 and Fedro Alessandro Peccatori2
(1)
Clinic of Obstetrics and Gynecology, University of Milan Bicocca, San Gerardo Hospital, Monza, Italy
(2)
Fertility & Procreation Unit, Division of Gynecologic Oncology, European Institute of Oncology, Milan, Italy
Fedro Alessandro Peccatori
Email: Fedro.peccatori@ieo.it
Introduction
Ovarian masses may complicate 2.3–4.1 % [1] of all pregnancies. Due to the extensive use of transvaginal ultrasound (US) in the first trimester for the assessment of fetal viability, growth, and anomalies, the diagnosis of ovarian masses during pregnancy has increased in the last decades. Most of these are asymptomatic and undergo spontaneous resolution without treatment [2]. Pain related to mass torsion, enlargement, or rupture occurs in 3–28 % of cases. Most persistent ovarian masses diagnosed during pregnancy are benign tumors, with only 1–3 % [3] being malignant. After cervical cancer, ovarian cancer (OC) is the second most frequent gynecologic cancer complicating pregnancy, with an incidence rate of 1:12.000–47.000 pregnancies. Updated INCIP (International Network on Cancer, Infertility and Pregnancy) registration study described the frequency of cancer in pregnancy in European countries [4]: among more than 1000 cases of diagnosed cancer during pregnancy, ovarian cancer accounts for 5 % of all cases.
Histological subtypes are similar to those reported for young nonpregnant women. Most common benign tumors are teratomas and serous cystadenomas, whereas most common malignant histology is epithelial invasive and borderline cancer. Eighty percent of malignancies are diagnosed at early stage. Germ cell tumors are less frequent, with few cases reported in several series [5]. Table 13.1 describes a summary of ovarian cancer cases reported in literature so far.
Table 13.1
Epithelial and non-epithelial ovarian cancer in pregnancy published reports
|
Authors |
Year |
Total |
Epithelial |
Non-epithelial |
|||||||
|
BL |
BL |
BL |
Malignant |
Malignant |
Malignant |
||||||
|
Total |
ES |
AS |
Total |
ES |
AS |
Total |
ES |
AS |
|||
|
Whitecar M |
1999 |
8 |
4 |
4 |
1 |
1 |
3 |
2 |
1 |
||
|
Sood AK |
2001 |
1 |
1 |
1 |
|||||||
|
Sayedur M |
2002 |
9 |
7 |
6 |
1 |
2 |
2 |
||||
|
Sherard GB |
2003 |
8 |
5 |
N/A |
N/A |
3 |
N/A |
N/A |
|||
|
Mendez LE |
2003 |
1 |
1 |
1 |
|||||||
|
Zanetta G |
2003 |
2 |
2 |
2 |
|||||||
|
Picone O |
2004 |
1 |
1 |
1 |
|||||||
|
Ferrandina G |
2005 |
1 |
1 |
1 |
|||||||
|
Zhao XY |
2006 |
22 |
6 |
5 |
11 |
||||||
|
Machado F |
2007 |
13 |
4 |
2 |
2 |
6 |
6 |
3 |
3 |
||
|
Modares M |
2007 |
1 |
1 |
1 |
|||||||
|
Hubalek M |
2007 |
1 |
1 |
||||||||
|
Mantovani G |
2007 |
1 |
1 |
1 |
|||||||
|
Behtash N |
2008 |
23 |
5 |
5 |
4 |
1 |
3 |
14 |
12 |
2 |
|
|
Rouzi AA |
2009 |
1 |
1 |
1 |
|||||||
|
Doi D |
2009 |
1 |
1 |
1 |
|||||||
|
Palmer J |
2009 |
1 |
1 |
1 |
|||||||
|
Gezginc K |
2011 |
11 |
4 |
4 |
4 |
3 |
1 |
3 |
2 |
1 |
|
|
Li X |
2011 |
13 |
8 |
8 |
3 |
3 |
2 |
2 |
|||
|
Serkies K |
2011 |
1 |
1 |
1 |
|||||||
|
Dobashi M |
2012 |
10 |
2 |
2 |
6 |
6 |
2 |
2 |
|||
|
Fauvet R |
2012 |
40 |
40 |
38 |
2 |
||||||
|
He S |
2012 |
1 |
1 |
1 |
|||||||
|
Smith E |
2013 |
1 |
1 |
1 |
|||||||
|
Gottheil S |
2013 |
1 |
1 |
1 |
|||||||
|
Akhter N |
2013 |
1 |
1 |
1 |
|||||||
|
Morikawa A |
2014 |
41 |
25 |
24 |
1 |
8 |
7 |
1 |
8 |
8 |
|
|
Total |
215 |
105 |
89 |
5 |
58 |
38 |
15 |
52 |
33 |
4 |
|
BL borderline, ES early stage, AS advanced stage, N/A not available
Diagnosis
The radiological evaluation of ovarian masses during pregnancy is hampered by uterine growth and limited by the potential detrimental effects on the fetus due to radiation exposure. In the first trimester, the most reliable diagnostic tool is vaginal ultrasound, while magnetic resonance imaging (MRI) may be used at higher gestational age (GA) [6].
Sonographic malignancy criteria are the same as for nonpregnant patients, and IOTA group risk prediction scores demonstrated sensitivity and specificity of 95 % and 98 %, respectively [7]. Ultrasound (US) is more accurate when performed by a specialized gynecologic oncologist.
Aggarwal et al. reviewed ten studies describing US assessment and treatment of pregnancy-associated ovarian masses [3]. The diagnosis was made in the first or second trimester in almost half of the 940 women studied. The diagnosis was occasional in most patients, whereas it was due to pain or other symptoms (bleeding/obstruction/rupture) in 25 % of cases. Successful conservative treatment was reported in 69.4 % of prospectively followed cases, with spontaneous mass resolution or surgical removal during cesarean section or in the postpartum period. Taking into account the low rate of malignancy and the high rate of spontaneous resolution, an expectant management is deemed reasonable [8], unless malignancy is suspected or symptoms mandate surgical intervention. A specific challenge of pregnancy-related ovarian mass is the decidualization of ovarian endometriomas due to the hormonal changes of pregnancy. In this case, sonographic features can be erroneously interpreted as malignant, and a close follow-up is needed.
MRI can be used after the first trimester to better evaluate a persistent ovarian mass and differentiate degenerating leiomyoma from ovarian neoplasm. The European Society of Urogenital Radiology states that when there is a strong indication for contrast-enhanced MRI, the smallest possible dose of one of the stable gadolinium contrast agents should be used. No neonatal tests are necessary after delivery [9].
CT scan is not recommended [10] during pregnancy due to possible fetal harm. The fetal radiation exposure is reported between 20 and 40 mGy. This diagnostic method should be considered only when the life of the woman is at risk.
18F-FDG PET has little application in pregnancy. Radioactive nuclides could affect the fetal health depending on the tracer pharmacokinetics, proximity of the fetus to maternal bladder, and gestational age. Few experiences described a radiopharmaceutical dose reduction in pregnant patients [11].
Serum tumor markers, including AFP, CA125, and beta-HCG, are not reliable tools to assess ovarian masses during pregnancy. Studies demonstrated that CA125 has a lower positive predictive value during pregnancy, with variations based on gestational age [12]. CA125 rises in the first trimester, with normalization during the second and third trimester, and remains elevated at the time of delivery and 48 h thereafter [13]. On the other hand, AFP and beta-HCG increase rapidly during the first and second trimester, but are mainly secreted by the trophoblast and thus may not be used as tumor markers. Accordingly, biomarker assessment should only be performed at least 2–10 weeks postpartum in order to obtain reliable information.
Surgical Treatment
Preoperative Considerations
To successfully treat ovarian cancer during pregnancy, a multidisciplinary evaluation should take place. The multidisciplinary team should include a gynecological oncologist, an obstetrician, a pathologist, a neonatologist, a psychologist, and an anesthesiologist. The patient and her family should be informed of the different options and the possible fetal risks. It is highly recommended to refer these cases to specialized centers where specific competences are present and care of pregnant patients with cancer is common practice.
So far, no evidences have demonstrated the benefit of medically induced abortion followed by standard treatment of pregnancy-associated ovarian cancer. This decision should be carefully discussed with the parents as a potential option, especially in the first trimester.
Pregnant women can perceive abdominal surgery as a violation of their maternal status. When a surgical approach is indicated, appropriate information and supportive care considerations are critical in the preoperative assessment.
Timing of Surgery
Surgery during the first trimester may be associated with a higher incidence of miscarriage [14], due to corpus luteum disruption or direct uterine manipulation. Whenever possible, delaying surgery between 14 and 20 weeks of gestation is a safer option. In the third trimester, the risk of preterm delivery should be taken into account.
If surgery is planned in the first trimester, intramuscular (IM) daily injection of progesterone is suggested. For surgery occurring between 24 and 34 weeks, corticosteroid for fetal lung maturation should be administered 48 h prior to operation. Prophylactic tocolysis might be administered for the same reason in the third trimester, even if this indication remains controversial. In a series of 28 patients undergoing surgery in the third trimester [15], tocolytic agents (indomethacin or terbutaline) were administered, and no obvious uterine contractions were reported in 86 % of cases, even if a control arm without tocolysis was not present.
Intraoperative Care
During anesthesia, the patient should be placed in left lateral oblique position to prevent inferior vena cava compression and supine hypotension syndrome as well as to improve uterine perfusion. The placenta is not able to self-regulate the blood flow; thus, particular care should be taken to control maternal vital parameters in order to keep constant blood pressure and avoid life-threatening fetal hypoxia (maternal hypotension, hemorrhage, and hypovolemia).
Fetal assessment by cardiotocography is indicated before and after the surgical procedure, but continuous monitoring is not considered necessary. Immunoprophylaxis with anti-Rh serum is recommended for Rh-negative mothers after surgery [16]. Thromboprophylaxis is mandatory for an adequate period in order to cover the risk of thromboembolic events related to pregnancy and cancer diagnosis.
Access Technique: Laparoscopy or Laparotomy
Two retrospective studies compared maternal and fetal outcome after laparoscopy or laparotomy performed during pregnancy for different indications [17, 18]. Sixty-eight laparoscopies and 78 laparotomies were compared, without any significant difference in terms of fetal and maternal outcomes. A population registry-based Swedish study [19] compared patients undergoing abdominal surgery in pregnancy. Fetal outcomes were compared in 2181 laparoscopies and 1522 laparotomies. An increased risk of birth weight <2500 g, preterm delivery, and intrauterine growth restriction was described in both groups compared to the general population. No difference in fetal outcome was reported.
Considering the low incidence of ovarian cancer in pregnant patients with an adnexal mass, a laparoscopic starting approach is advisable to minimize perioperative complications. Intra-abdominal pressure should be kept between 10 and 12 mmHg, to preserve maternal cardiac output and to avoid the hypoxic effect of CO2 on the fetus. Laparoscopic procedure should be adjusted to overcome uterus size and to avoid fetal and genital tract accidental injuries. An open technique is preferred [17], and the first trocar should be placed in a supraumbilical position. The operative trocars should be placed in cranial positions to allow a more comfortable movement in the abdomen. Nonetheless, systematic reviews highlight the risk of intraoperative cyst rupture, tumor tissue spread, and port site metastases when laparoscopy is used in early-stage malignant ovarian cancer [20]. Thus, a laparotomic conversion should be considered in any case of malignancy, taking into consideration gestational age and the necessity of accurate tumor staging. In these situations, a midline incision can offer wide exposure of the pelvis and should be considered.
Staging Procedures
Pelvic surgery during pregnancy may be hampered by several technical limitations, including the increased uterine volume due to pregnancy and the limited manipulations needed to preserve the pregnancy. Frozen section should be available to guide the surgical management. Definitive pathologic diagnosis should be performed by well-trained pathologist in the field of gynecologic malignancy since it is necessary to interpret histological aspects in the context of the physiologic changes that may appear in hormone-sensitive tissues.
Recent data demonstrate that borderline ovarian tumors occurring during pregnancy have a more aggressive behavior [21]. Intraepithelial carcinoma, microinvasion, micropapillary features, and invasive implants were described in a higher proportion of cases, compared to the nonpregnant patients. Restaging surgery was necessary in 52 %, with upstaging in 24 % of patients [21]. The recurrence rate among this small group was 7.5 %, not different from other series of nonpregnant cases. In order to avoid spillage and to perform staging procedures, a midline laparotomy with unilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies, and appendectomy should be performed. A laparoscopic approach can be preferred in selected cases with limited disease.
Early-stage epithelial ovarian cancer should be accurately staged with open surgery, including intraperitoneal and retroperitoneal staging. For stages IA to IIA, pelvic and para-aortic lymph node dissection is recommended. Large series showed the feasibility to offer a comprehensive staging procedure with fertility-sparing surgery [22] outside pregnancy.
Forty-four cases were reported in the literature with a diagnosis of early-stage ovarian cancer in pregnancy (Table 13.1). Most of these cases underwent a conservative surgery in pregnancy with secondary radical surgery after delivery. If a complete staging primary surgery is not feasible during pregnancy, postpartum restaging should be considered.
The diagnosis of advanced-stage epithelial ovarian cancer in pregnancy is a rare situation, with only 16 cases reported in the literature (Table 13.1). If the patient is willing to preserve the pregnancy, radical debulking surgery is not feasible during pregnancy. Alternative approaches include primary debulking surgery with pregnancy termination or delivery, expectant management until delivery, or surgery during pregnancy followed by chemotherapy. To allow the fetus to reach a viability condition, a reasonable treatment plan could be a comprehensive surgical diagnostic procedure, as a diagnostic laparoscopy, adjuvant chemotherapy, and radical surgery after delivery.
A fertility-sparing surgical approach is recommended in non-epithelial ovarian cancers patients: almost 90 % of cases published during pregnancy cases were at an early stage. Usually a peritoneal staging is sufficient and lymph node dissection is not recommended.
A summary of proposed management is reported in Table 13.2.
Table 13.2
Proposed management of OC in pregnancy
|
First trimester |
Second trimester |
Third trimester |
|
|
Borderline ovarian cancer |
Close observation until second trimester |
Surgery, frozen section diagnosis and intraperitoneal sampling |
Close observation and postpartum treatment |
|
Early-stage epithelial ovarian cancer |
Close observation until second trimester |
Surgery, frozen section diagnosis and chemotherapy (according to grade of nuclear differentiation and stage) |
Close observation and postpartum treatment or surgery and postpartum chemotherapy |
|
Advanced-stage epithelial ovarian cancer |
Close observation until second trimester |
Debulking surgery and postoperative chemotherapy or diagnostic surgery and neoadjuvant chemotherapy (carboplatin and paclitaxel) |
Neoadjuvant chemotherapy or preterm delivery and debulking surgery |
|
Non-epithelial ovarian cancer |
Close observation until second trimester |
Surgery and chemotherapy (according to disease stage) |
Close observation and postpartum treatment |
Carboplatin AUC 6, Paclitaxel 175 mg/sqm q 21 days
Systemic Chemotherapy
Epithelial Ovarian Cancers
Platinum derivatives and taxanes represent the backbone of first-line chemotherapy of epithelial ovarian cancer. Platinum derivates are known to be teratogenic in rodents during the first trimester, and historic series [23] reported the same effect in humans. When fetuses were exposed to platinum compounds in the second and third trimester, platinum-DNA adducts were detected, but no detrimental effects were reported. The largest revision of ovarian cancer patients treated with platinum derivates was made by Mir et al. [24]. These Authors identified 2/43 newborns with major malformations including ventriculomegaly and microphthalmos after platinum exposure. Both mothers had been treated with cisplatin during the first trimester. When cisplatin is administered in the third trimester, newborn renal function should be thoroughly assessed. As carboplatin is less nephrotoxic than cisplatin and animal data report a fetal plasma concentration of 50 % compared to maternal plasma concentration, this drug should be preferentially used during pregnancy [25]. Consistent experience now also exists concerning the use of paclitaxel use during pregnancy [26, 27].
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 vessel invasion and fetal growth, as well as enhancing amniotic fluid production [28]. Anti-VEGF agents inhibit organogenesis and fetal development in mice models, and their use during pregnancy is not recommended. The standard doublet with carboplatin and paclitaxel seems to give the best results in terms of fetal safety and maternal outcome [29].
Non-epithelial Ovarian Cancers
The standard chemotherapy for non-epithelial ovarian cancer is the association of bleomycin, etoposide, and cisplatin. A recent consensus suggested replacing etoposide during pregnancy: reasonable alternatives would be paclitaxel-carboplatin or cisplatin-vinblastine-bleomycin [30].
Delivery Considerations
Delivery should be planned according to the obstetrical situation aiming at term vaginal delivery. If the patient has received chemotherapy, white blood cell nadir should be avoided possibly waiting 3–4 weeks after last cycle to allow blood values to rise.
Conclusions
The occurrence of ovarian malignancies during pregnancy is rare, and most of the ovarian masses diagnosed in the first trimester are benign. Nonetheless, when ovarian cancer is diagnosed during pregnancy, the clinical management should take into consideration maternal and fetal well-being with careful evaluation of the best surgical management and the most appropriate systemic treatment. Surgery is best performed during the second trimester, and either a laparoscopic or laparotomic approach can be considered, according to the clinical characteristic of the tumor. Carboplatin- and paclitaxel-based chemotherapy may be used after the first trimester, when indicated. Patients should be referred to specialized centers where surgical, oncological, obstetrical, and neonatological competences are present, and each case should be reported within international registries to better understand the biology and outcome of this rare situation.
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