Gwyn Richardson, MD
• Management of Preinvasive Diseases During Pregnancy
• Management of Invasive Cervical Cancer
BACKGROUND
Cancer in pregnancy is a rare and life-changing event. It brings significant challenges for the patient, patient’s family, and her physicians. Fortunately, cancer in pregnancy has an estimated incidence of only about 1:1000 pregnancies.1
Pregnancy-associated cancer is defined as cancer diagnosed during pregnancy or within 12 months of delivery.2,3 The reason to include the immediate postpartum period is a frequent delay in diagnosis for certain types of cancers due to physiologic changes of pregnancy and reluctance to perform most radiologic procedures.
No precise information is available on incidence of cancer during pregnancy as most of the data are based on case reports and small case series. Therefore, the literature varies significantly in regard to incidence of cancer in pregnancy by the disease site. The number of new cases of cancer diagnoses during pregnancy in the United States is reported to range from 3500 to 6000 per year.1,4–6 Most authors agree that common malignancies diagnosed during pregnancy include breast cancer (1:3000-10,000), cervical cancer (1.2:10,000), malignant melanoma (2.6:10,000), lymphoma (1:1000-6000), and leukemia (1:75,000-100,000). Less frequent are ovarian cancer (1:10,000-100,000) and colorectal cancer (1:130,000).6,8
Because the incidence of most cancers increases with age, the incidence of cancer in pregnancy is slowly increasing in recent years.7–9 This trend is partially related to a general tendency to postpone childbearing and also to the fact that pregnancy requires a thorough physical examination including ultrasound and regular care. In fact, some malignancies, including cervical and ovarian cancer are diagnosed early solely due to state of pregnancy.
The first International consensus meeting was held in Leuven, Belgium; in 2008. The main goal of this consensus meeting was to evaluate the current state of diagnosis and management of cancer during pregnancy.10 The task force reviewed all available literature excluding that of endometrial cancer and gestational trophoblastic disease. They noted that there were no randomized trials or prospective trials available and emphasized urgent need to gain more experience in the field. Because this first consensus meeting an international organization was created (http://cancerinpregnancy.org) and more publications about cancer in pregnancy are emerging.
OVARIAN CANCER IN PREGNANCY
Due to the fact that most common types of ovarian cancer are of the epithelial type and usually occur in peri- and postmenopausal women,6 ovarian cancer is a rare event during pregnancy with a reported incidence of 1:10,000 to 100,000.6,8 Most of the epithelial ovarian tumors diagnosed during pregnancy are of low malignant potential.
Palmer and colleagues performed a worldwide literature review of publications about epithelial ovarian cancer during pregnancy.10 They identified 28 publications and excluded 5 due to lack of information. From 1958 to 2007, 41 reported cases of invasive epithelial ovarian cancer had adequate information for the review. In their review, 28% of women were older than 40 years and 69% were older than 30 years.
The tumors that are most frequently diagnosed during pregnancy are benign teratomas and cystadenomas. Because germ cell and stromal ovarian tumors are, in general, more prevalent in younger women, it is more common to identify these types of tumors during pregnancy. Dysgerminomas and malignant teratomas are the most common malignant ovarian tumors during pregnancy.11,12
Diagnosis
Imaging studies
Increased use of ultrasound in pregnancy has led to increased diagnosis of adnexal masses early in gestation with a reported incidence of 0.2% to 2%; however, only 1% to 6% of these masses are malignant.11–13
Palmer and colleagues reported that detection of asymptomatic adnexal masses was the most common presentation of ovarian cancer during pregnancy. In their analysis, more than 50% of patients with ovarian cancer diagnosed during pregnancy were asymptomatic and had an incidental adnexal mass found during imaging studies.10 Only 30% of patients with ovarian cancer had pain, 15% had an abdominal distention or a palpable mass, and 4% had masses found during cesarean section.
Ovarian cancer outside of pregnancy is often associated with nonspecific symptoms, especially in the early stages, including abdominal bloating, indigestion, and changes in bladder and bowel habits.14 Unfortunately, similar symptoms are present during normal pregnancy. Other presenting symptoms might be a palpable adnexal mass found during routine pelvic examination or pain associated with adnexal torsion. Once a pelvic mass is identified, it will require diagnostic evaluation.
Imaging studies during pregnancy, especially those that use ionizing radiation, present a significant source of anxiety for physicians and patients. Expert opinion suggests that staging in pregnancy should not be compromised and necessary diagnostic tests should be performed.15–17 When possible, tests should be chosen to minimize ionizing radiation or substituted for a less harmful test (ultrasound, MRI). Abdominal shield use is required to decrease fetal exposure during radiologic images. Specific guidelines for imaging in pregnancy are beyond the scope of this chapter and presented by the American College of Obstetricians and Gynecologists (ACOG) committee opinion16 and in the compendium of National Guidelines for Imaging the Pregnant Patient.17
Since most of the adnexal masses during pregnancy are benign, one of the goals during initial evaluation is to determine the size and morphology of the adnexal mass and possible differentiate between a benign and malignant mass.
Benign masses usually have simple sonographic appearance: anechoic fluid, thin walls, and an absence of septations or excrescencies.18 Ekerhovd and colleagues compared ultrasonographic findings with pathologic diagnosis of adnexal masses.19 They found that the incidence of borderline or malignant tumors on final diagnosis with reported normal ultrasound findings was 3 in 413 (0.73%). All three were larger than 7.5 cm and the worrisome findings were most likely simply overlooked.
Internal echoes or homogeneous low-to-medium level echoes may be associated with either endometriomas or hemorrhagic cysts.20,21 Color Doppler might be helpful in differentiating the two since hemorrhagic cysts usually do not exhibit blood flow.21 In addition, hemorrhagic cysts usually decrease in size, which can be seen by repeating the ultrasound after several weeks. Hyperechoic nodules, fluid-fluid levels, and calcifications are the most common ultrasonographic findings associated with teratomas.20,22–24
The presence of thick septations (greater than 2-3 mm), solid components with nodular or papillary appearance, or ascites are worrisome findings that may require additional evaluation and/or intervention.25,26 Since septations are relatively frequent findings in cases of hemorrhagic cysts or endometriomas, septations alone are not as worrisome as the presence of a solid component or excrescences.26 Another source of adnexal masses might be paratubal and paraovarian cysts.27 The most common is a paramesonephric cyst, in particular, hydatid cyst of Morgagni, which is usually a benign cyst. At the present time, only 11 malignant tumors and 3 tumors of low malignant potential arising from paratubal cyst have been reported.28,29
Solid appearing masses can represent pedunculated fibroids, a common finding in women who are older and have an enlarged uterus. In many instances, ovaries cannot be well visualized and leiomyomas are perceived to be an ovarian mass.20,21 During pregnancy, cystic degeneration of the fibroid due to hormonal influences might create an appearance of a complex mass.
In most cases, ultrasound provides adequate information to proceed with certain clinical decisions; however, no specific finding is highly useful to differentiate between benign and malignant masses. In cases when the diagnosis is unclear, magnetic resonance imaging (MRI) can provide additional information without exposing the patient and fetus to ionizing radiation. MRI is especially helpful in evaluation of endometriomas and solid masses.30 Because there are no safety data regarding the use of Gadolinium-based contrast during pregnancy, it is recommend to avoid contrast-based material during pregnancy if possible. Risks and benefits have to be discussed with the patient and family.
Computer tomography is generally avoided in pregnancy if any other imaging method can provide sufficient information. Tumor markers commonly used among nonpregnant individuals are less useful during pregnancy.
CA 125—Serum levels of cancer antigen #125 are routinely used in the management of epithelial ovarian cancer. This tumor marker is nonspecific, and is secreted by the endothelial lining of the abdominal cavity. Mild-to-moderate changes in values are not a reliable indicator even in nonpregnant premenopausal women. During pregnancy, especially in early gestation or immediately postpartum, serum levels of CA 125 can be markedly elevated. Values more than 1000 U/mL might be suggestive (but not diagnostic) of a malignant process.31
HUMAN CHORIONIC GONADOTROPIN—Human chorionic gonadotropin (B-HCG) has been used reliably in follow-up of choriocarcinoma and other germ cell tumors. It cannot be used in pregnancy due to its natural physiologic increase during pregnancy.
LACTATE DEHYDROGENASE—Lactate dehydrogenase (LDH) is a marker for diagnosis and follow-up of ovarian dysgerminomas.32 Except for cases involving HELLP syndrome, LDH levels are normally not influenced by pregnancy status.
ALPHA-FETOPROTEIN—Alpha-fetoprotein (AFP) levels change during pregnancy and are used during pregnancy to detect neural tube defects and chromosomal anomalies in the fetus. Maternal serum AFP (MSAFP) is routinely used for fetal screening and is expressed in multiples of mean (MoM) for each gestational week. For screening purposes, MSAFP levels higher than 2.0 to 2.5 MoM are considered abnormal. In cases of reported germ cell tumors during pregnancy, MoM levels were 12.5 and higher.33,34 With significant elevation of MSAFP, performing ultrasound to evaluate fetal anatomy and ovaries is imperative.
INHIBIN—Either inhibin A or B can be elevated in granulosa cell tumors. Inhibin A is also elevated during pregnancy and is one of the markers that have been used for evaluation of Down syndrome. If elevated with no clear explanation, it is recommended that the ovaries be thoroughly evaluated with a detailed ultrasound.35,36
Management
Once an adnexal mass is diagnosed in pregnancy, further management is defined by the appearance and size of the mass and gestational age. The ultimate goal is to make an appropriate diagnosis and to avoid complications of pregnancy and harm to the fetus. About 70% to 90% of asymptomatic simple appearing adnexal masses diagnosed during the first trimester will spontaneously resolve by the second trimester.37,38 Masses larger than 5 cm in size with complex morphology are less likely to resolve.39
If accidental removal of the corpus luteum occurs during the first trimester, progesterone support should be initiated immediately. After 10 weeks of gestation, the placenta is usually developed enough to provide adequate progesterone to support the pregnancy.
Accepted management of adnexal masses during pregnancy is defined by maximal safety. If a mass persists into the second trimester, the chances of pregnancy complications or abnormal pathology are higher (although the total risk is usually low). The generally accepted indications for intervention of an adnexal mass during pregnancy are persistence into the second trimester, size greater than 10 cm, and complex morphology (suggestive of malignancy). All efforts are made to avoid emergency surgery, which is usually associated with a higher rate of complications.40
It is well accepted that the optimal time of intervention is during the early second trimester for the following reasons:
• Almost all functional cysts have been resolved by the second trimester; thus, avoiding unnecessary procedures.
• If a suspicious mass is a persistent corpus luteum, the placenta has developed enough and is secreting adequate progesterone to support the pregnancy.
• Organogenesis is complete and the risks of teratogenic effects from anesthetic agents are lower.
• Spontaneous pregnancy losses are more frequent in the first trimester and if occur will not be attributed to the surgery as an only cause.
The safety of surgical intervention during the second trimester has been well documented.12,41,42 The procedure should be performed early in second trimester (around 18 weeks) since a smaller uterine size allows for better exposure and mass manipulation without affecting the uterine corpus. Early second trimester pregnancy is also remote from viability. Guintoli and colleagues suggested that if pregnancy is beyond 20 weeks of gestation, delaying surgery until viability is preferable if circumstances permit.43 The sole presence of a mass that persists into the second trimester or that is larger than 10 cm or that appears “complex” on ultrasound imaging is not an absolute indication for surgical removal during pregnancy. Individualization of each case is mandatory, and overall the likelihood of malignancy is 5% or less. Patients may opt for removal after delivery.
A midline incision is recommended if laparotomy is performed. Using “hands-off” technique whenever possible is recommended (minimize uterine manipulation). If malignancy is suspected before surgery, a careful exploration should be performed at the entry to the peritoneal cavity:
• Peritoneal washings should be obtained immediately upon entry into the abdomen.
• Suspicious adnexa should be sent for frozen section.
As mentioned above, the most common findings at surgery are usually benign teratomas and benign cystadenomas. If the mass is determined to be malignant or of low-malignant potential, adequate staging procedures will need to be completed. It is particularly important to complete formal staging procedures for what appears to be stage I disease, as it will be a determining point for future treatment decisions. Adequate staging procedures for an ovarian malignancy include:
• Collect peritoneal washings, if it has not already been done.
• Inspect the opposite adnexa carefully, if it is suspected to be involved with cancer, proceed with biopsy or resection.
• Perform a systematic exploration of the pelvis and abdomen: All organs need to be visualized and palpated; biopsy of all suspected areas or adhesions should be performed.
• If no suspicious areas are apparent, biopsies from multiple areas of the peritoneal lining should be obtained. These include bladder, cul-de-sac, paracolic gutters, intestinal mesentery, and diaphragm. The diaphragm can also be scraped, if it cannot be reached for adequate biopsy.
• Perform an infracolic omentectomy.
• Send suspicious lymph nodes for frozen section.
• Perform pelvic and para-aortic lymph node dissection. The para-aortic lymph nodes should be resected above the inferior mesenteric artery.
Borderline tumors need to be staged in the same fashion as malignant epithelial tumors to determine the presence of possible invasive implants. If a patient has an advanced malignancy at exploration (stage IIIB or IIIC), the staging procedure is of less importance, as the patient will require adjuvant chemotherapy.
In nonpregnant patient’s optimal cytoreduction is the ultimate goal (tumor debulking); however, in pregnant patients, fetal safety should be taken into consideration and the procedure modified accordingly. If it is not possible to perform optimal cytoreduction (for instance if the uterine corpus is involved), an option is to proceed with chemotherapy and perform an interval cytoreductive surgery after the pregnancy is completed since the majority of epithelial ovarian tumors are sensitive to platinum-based chemotherapy. In general, survival is poor in patients with an advanced ovarian cancer.
Dysgerminomas comprise about 30% of all ovarian malignant neoplasms during pregnancy. Dysgerminomas are usually solid masses and often present as torsion or cause obstruction of labor. These tumors are unique since they are bilateral in 10% to 15% of cases. Dysgerminomas tend to spread via lymphatics and, therefore, pelvic and para-aortic lymph node dissection is imperative. In appropriately staged patients with true stage IA disease, chemotherapy is not required.44 The same is true for immature teratomas.
Sex cord-stromal tumors in pregnancy usually present in early stage and have an indolent course. A few of these present with hemorrhage and hemoperitoneum. Diagnosis is often difficult to make, especially on frozen section due to cellular changes related to the pregnant state.45 Therefore, appropriate staging procedures are need for future treatment planning.
Laparoscopy
Until recently, laparoscopy was contraindicated in pregnancy as the effects of pneumoperitoneum were unknown. Major concerns of laparoscopic surgery included potential direct or indirect effects to the fetus due to carbon dioxide insufflation.
Several studies in animal models documented transient changes in the fetus, including fetal heart rate changes and changes in blood pressure. Most of these resolved once insufflation was discontinued. Changes in pH were related to maternal serum pH changes during surgery. None of the studies demonstrated harm to the fetus.46–49
No prospective randomized trials exists comparing laparotomy to laparoscopy in humans; however, multiple case series reported the safety of laparoscopic procedures during pregnancy. Laparoscopy is now considered as safe as laparotomy during pregnancy. In their small series, Candaini and colleagues did not detect any changes in feto-maternal blood flow during laparoscopy.50 Several others reported good outcomes in patients undergoing laparoscopy during pregnancy.51,52 Most of the patients in these reports have been in the first or second trimester of their pregnancies. Reedy and colleagues reviewed surgical cases in pregnancy through the Swedish Health registries with a total of 2181 laparoscopies and 1522 laparotomies.42 Most of the cases were performed at less than 20 weeks of gestation, and there was no difference in fetal outcome or pregnancy complications.
All patients undergoing laparoscopic surgery are at risk of trocar injury. The gravid uterus, especially with increasing gestational age can inadvertently be damaged during the Veress needle or trocar placement.53 The preferred location of trocar placement during pregnancy is either supraumbilical (at least 6 cm above the uterine fundus) or left upper quadrant. The Veress needle approach requires blind entry and might result in uterine injury.53 Most surgeons recommend an open technique to assure safety.51,54,55 In general, the surgeon should use his or her surgical experience and common sense depending on specific gestational age, size of the mass, and maternal anatomy.
It is recommended that intra-abdominal pressures during laparoscopy be maintained between 8 and 12 mmHg. If visualization is problematic, a slight increase in intra-abdominal pressure is accepted. Pressures more than 15 mmHg should be avoided in order to avoid uterine hypoperfusion.53,56 Several studies reported that monitoring CO2 levels is adequate to avoid respiratory acidemia. It is recommended to maintain levels of end-tidal CO2 are between 32 and 34 mmHg to avoid fetal acidemia.57,58
The standard of care treatment for ovarian cancer includes surgical debulking (to no visible disease if possible) and chemotherapy except for a few cases of stage IA disease (grade 1 epithelial ovarian cancer, dysgerminoma, malignant teratoma, and early granulosa cell tumors).
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