Cancer and Other Neoplasms in Pregnancy



Cancer and Other Neoplasms in Pregnancy


Gautam Gorantla Rao



Introduction

In the United States, benign gynecologic masses, known as myomas, account for more than 1 million hospital admissions per year.1 Benign masses may occur in pregnancy, and their management is complicated by the possible risk to the fetus. Knowledge of the natural history of these masses during pregnancy is essential to their proper management. Cancer during pregnancy is unusual. As a result of physiologic changes that normally occur in pregnancy, cancer during pregnancy may be more advanced because the diagnosis is not recognized as early as it might otherwise have been. However, stage-for-stage, cancer during pregnancy is no more virulent than cancer occurring in the nonpregnant state. The routine interruption of pregnancy to influence cancer progression has not been established.


Benign Masses in Pregnancy


Uterine Myomas


Epidemiology and Etiology

Myomas are very common in the general population, especially in nonwhite women.1 They are a frequent cause of infertility and are less prevalent among pregnant women than among the same age group of nonpregnant women. Myomas which cause hospitalization are mostly seen in women aged 40 to 45 years. Complications occur in about 10% of pregnancies with uterine myomas.2,3,4,5,6,7,8

Several hormone receptors become amplified in myomas, the most notable of which are estrogen receptors.6 Estrogen is thought to stimulate the growth of uterine myomas, but the precise mechanism is not well understood. Traditionally, it was believed that uterine myomas grow during pregnancy due to elevated levels of estrogen produced, but this has been challenged by several prospective studies.7,8,9


Clinical Presentation

Myomas can cause pain through degenerative changes or by direct compression of adjacent organs. Nongrowing myomas can cause symptoms during pregnancy as a result of the enlarging uterus which displaces them out of the pelvis. Symptoms may develop as asymptomatic myomas compress abdominal organs.

Uterine myomas can undergo central necrosis and degeneration, causing localized pain at the site. Degenerating myomas can provide a culture medium for pathogenic organisms with occasional leukocytosis and superimposed infection. Myomas are thought to increase the frequency of preterm labor and premature rupture of membranes. They have been implicated in first-trimester spontaneous abortions,10,11 and large cervical and lower uterine segment myomas can cause obstructed labor and infertility.9,12

Placental abruption, postpartum hemorrhage, and retained placenta are thought to be complications of uterine myomas during pregnancy. However, several studies failed to show statistically different rates of these complications compared with the general population.9,12 One study showed that women with leiomyomata are at increased risk of second-trimester spontaneous abortion.13


Management of Myomas in Pregnancy

Preconception myomectomy may be considered based on the patient’s age, reproductive history, size and location of the myomas, and symptoms. However, there is no good evidence that myomectomy will improve fertility or fecundity rates.5
Most of the symptoms can be managed medically in pregnant women. Surgical management is usually avoided during pregnancy. There are very few studies and no randomized trials available on the safety of myomectomy in pregnancy.14,15,16 Myomectomy during pregnancy is best avoided in all but the most extreme circumstances, such as torsion of a pedunculated myoma or when a malignancy is suspected. The 2013 Committee Opinion by the American College of Obstetricians and Gynecologists recommends that women with previous myomectomy which caused significant compromise of the uterine integrity undergo cesarean delivery rather than a trial of labor and vaginal delivery due to small but catastrophic risk of uterine rupture.17



Pharmacologic Treatment

Symptomatic treatment with acetaminophen or opioid analgesics usually provides relief. Several studies have shown that nonsteroidal anti-inflammatory drugs can be used successfully in pregnancy for management of the symptoms.2,18 However, these drugs have known fetal risks and should be used with caution during pregnancy.19 Hydration and antibiotics can be used if infection is suspected.


Adnexal Masses in Pregnancy

Benign adnexal tumors are sometimes associated with normal pregnancies, but adnexal masses can be malignant (discussed later). The most common benign pelvic masses in pregnancy are persistent corpus luteum cysts, benign cystic teratomas, paratubal cysts, cystadenomas, and pedunculated myomas. Although the majority of benign pelvic neoplasms discovered during pregnancy are present before the beginning of the pregnancy, the hormonal changes of pregnancy, particularly the production of human chorionic gonadotropin (hCG), are associated with luteomas, theca lutein cysts, hyperreactio luteinalis, and large solitary luteinized follicular cyst of pregnancy.

Clinical features suspicious for malignancy, particularly ovarian cancer, include the presence of a fixed mass, lymphadenopathy, ascites, and constitutional symptoms such as pain, abdominal distention, dyspareunia, frequency, or constipation.20,21 Sonographic features of adnexal masses suspicious for malignancy include size greater than 6 cm, thick septations, papillary projections, complex echogenicity, and the presence of ascites.22,23 The negative predictive value of sonography as a method of excluding malignancy appears to improve in pregnancy.24 Magnetic resonance imaging (MRI) has been used to distinguish benign from malignant ovarian masses in pregnancy. This modality may prove particularly useful in the evaluation of adenopathy and tumor invasion. To date, there is little evidence to link exposure to diagnostic MRI with adverse fetal effects.25,26


Corpus Luteum Cysts


Clinical Presentation

The corpus luteum is the most common hormone-producing functional unit of pregnancy. These unilateral, sonolucent structures contiguous with the ovary arise when granulosa-lutein cells in the postovulatory ovarian follicle are stimulated by the production of placental chorionic gonadotropin and, subsequently, produce progesterone. The corpus luteum maintains progesterone production until approximately 9 weeks’ gestation, when placental progesterone production is sufficient to maintain the pregnancy and the placenta becomes the primary site of progesterone production from week 12 onward. Corpus luteum cysts can complicate pregnancy if they undergo torsion or spontaneous rupture.



Nonpharmacologic Treatment

Asymptomatic corpus luteum cysts typically regress during the second trimester and are completely absent by the third trimester. If a corpus luteum cyst is removed before 9 weeks’ gestation, exogenous progesterone is administered.


Luteoma


Clinical Presentation

Luteomas of pregnancy are solid tumors that are characterized by hypertrophy of ovarian stroma. This hypertrophy may be secondary to stimulation by hCG. They are frequently bilateral and multinodular. Elevated levels of testosterone accompany luteomas in at least 25% of cases, although other hormones may be responsible for maternal virilization.27,28,29 When maternal virilization is present, female fetuses are at risk of virilization. The female fetus is usually not at significant risk of labioscrotal fusion because placental aromatization of maternal androgens is not usually overwhelmed by androgen production until fusion is complete.30,31 There does not appear to be any association between luteomas and multifetal gestation or gestational trophoblastic disease.




Nonpharmacologic Treatment

Expectant management is recommended.32 Luteomas can occasionally recur; therefore, preconception counseling is necessary for women with a history of luteoma.33


Hyperreactio Luteinalis


Clinical Presentation

Hyperreactio luteinalis is a benign, nonneoplastic enlargement of theca lutein cysts, most likely due to stimulation by hCG.34 Hyperreactio luteinalis is strongly associated with conditions that produce abnormally elevated hCG, such as multifetal gestation, gestational trophoblastic disease, and ovarian hyperstimulation syndrome.35 Hyperreactio luteinalis is usually bilateral and multicystic with stromal edema. Ovarian enlargement can be massive. Although maternal androgen excess is occasionally present, virilization of female fetuses rarely occurs.36,37 Life-threatening ascites, electrolyte abnormalities, thromboembolism, intravascular depletion, hemoconcentration, renal failure, and pleural effusion with respiratory difficulties may be present when hyperreactio luteinalis complicates ovarian hyperstimulation syndrome or gestational trophoblastic disease.



Nonpharmacologic Treatment

In addition to supportive measures, uterine evacuation may be necessary to reverse hCG-induced ovarian stimulation in such cases. In milder cases, expectant management is appropriate because hyperreactio luteinalis and theca lutein cysts usually resolve shortly after delivery.


Cancers in Pregnancy


Incidence

Data reflecting the incidence of cancers during pregnancy are scant because of a lack of information accrued by population-based tumor registries. Estimates of cancer during pregnancy vary considerably (Table 42.1). The most common neoplasms in pregnancy include melanoma, breast cancer, cervical cancer, lymphomas, and leukemias.39,40

Between 1994 and 2008, Lee et al50 examined the incidence and outcomes of pregnancy-associated cancer in Australia. The authors found an overall crude incidence of 137.3 per 100,000 pregnancies. A total of 1767 women had 1785 cancer-affected pregnancies and 1798 new cancer diagnoses, including 499 during pregnancy and 1299 during the postpartum period. From 1994 to 2007, the crude incidence rate of pregnancy-associated cancer increased from 112.3 to 191.5 per 100,000 pregnancies (P < .001). During this period, maternal age also increased; the percentage of women aged 35 years and over increased from 13.2% to 23.6% (with women aged 40 years and over increasing from 1.9% to 4.0%). Cancer diagnosis was more common than expected in women aged 15 to 44 years (observed-to-expected ratio 1.49; 95% confidence interval [CI] 1.42-1.56). In order of decreasing frequency, the most common cancers found were melanoma, breast cancer, thyroid cancer, lymphohematopoietic cancer, and cervical cancer. Women with cancer diagnosed during pregnancy had high rates of labor induction (28.5%), caesarean delivery (40.0%), and planned preterm birth (19.7%).










Screening

Serum tumor markers are an essential tool for diagnosing and monitoring patients with cancer, but use of these markers should be done with caution during pregnancy. Levels of tumor markers, such as members of the cancer antigen (CA) family, may be affected by the pregnancy and may vary due to gestational age and pregnancy-related conditions. For example, variations by trimester have been noted for CA 15-3, with a sharp increase in the third trimester. Additionally, CA 15-3 concentration is higher among women with gestational diabetes, intrahepatic cholestasis of pregnancy, or heart disease than among those without any risk factors.51 Alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (β-hCG) levels rise significantly during pregnancy and cannot be used as tumor markers.


Management of Cancer in Pregnancy

Termination of a pregnancy affected by maternal neoplasia is rarely indicated. Although a fear expressed by pregnant patients is that the cancer might spread to the placenta and fetus, information collected during the past 2 decades suggests that transplacental metastasis is extremely unusual, and metastases to the fetus are rare. The most common malignancy to be associated with fetal and placenta metastases is malignant melanoma. However, the reported number of cases in the literature of such an event is fewer than 30.52

Occasionally, iatrogenic preterm birth should be considered as an alternative management strategy in treating pregnant patients with cancer. This strategy requires that sophisticated newborn special care units be available for maintaining premature infants. Antenatal corticosteroid therapy has been shown to decrease complications related to organ immaturity such as respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. Fetal interventions to promote maturation are most effective if delivery occurs from 2 to 7 days after the initiation of therapy. Tests of fetal lung maturity, such as the lecithin/sphingomyelin (L/S) ratio, could be considered in determining the timing of delivery.53



Nonpharmacologic Treatment


Surgery in Pregnancy

Patients may undergo successful surgical procedures when they are pregnant without jeopardizing the fetus. The timing of surgery for malignancy in pregnancy is based upon the balance of potential risks and benefits for mother and baby. In general, surgery should be delayed until the second trimester, which seems to be the safest time in terms of avoiding patients going into labor. Spontaneous abortion sometimes occurs when surgery is performed in the first trimester. After viability, fetal heart rate should be documented by Doppler or ultrasound just before and after the procedure.

Maternal surgery in the third trimester may be associated with a risk of premature labor and altered uteroplacental perfusion, putting the fetus at risk of hypoxia, brain injury, intrauterine fetal demise, and premature delivery which is, itself, associated with significant short-term and long-term risks to the neonate, including mortality. A systematic review of 12,452 women who underwent nonobstetric surgical intervention during pregnancy found no increase in the rate of miscarriage or major birth defects compared with the general obstetric population.54

In preparing the patient for a surgical procedure, simple technical considerations may have an important impact on the success of the operation. For example, placing the patient in a lateral position to avoid vena cava and aortic compression is an important factor in considering the anesthetic consequences of surgery.55,56 In addition, there are many concerns about general anesthesia during pregnancy (see Chapter 26). The US Food and Drug Administration (FDA) suggests minimizing time under general anesthesia, minimize the dose and concentration of agent and to avoid inhalational anesthetics, propofol, and midazolam.57 Anesthesiologists must always act as if a pregnant woman has a full stomach, as progesterone relaxes the gastroesophageal sphincter, and pyloric displacement by the gravid uterus impedes gastric emptying.58

Laparoscopic surgery, if indicated, can be performed safely during pregnancy. General recommendations include auscultation of fetal heart tones before and after the procedure, use of pneumatic compression devices for thromboprophylaxis, left lateral tilt of the patient to relieve pressure on the aorta and vena cava from the gravid uterus, lateral tilt of the operating table and/or use of a sponge stick in the vagina to improve visualization for pelvic procedures, careful peritoneal entry with use of Hasson technique or entry at Palmer point, lowering
the insufflation pressure during surgery, avoidance of touching the uterus within the peritoneal cavity, and avoidance of routine use of tocolytics.59


Radiation in Pregnancy

Radiation is commonly employed in the diagnosis and management of cancers that may occur in pregnancy. Diagnostic imaging to investigate signs and symptoms of cancer malignancy should be performed during pregnancy if necessary and should not be delayed. The imaging modality should be chosen to minimize fetal radiation exposure but not at the cost of a poor study. Ultrasound is the ideal mode of imaging in pregnancy given its lack of ionizing radiation; however, ultrasound has limits as a diagnostic tool for a suspected neoplasm due to maternal body habitus and the gravid uterus. MRI with magnet strength of 3 T or less in any trimester is not associated with increased risk of harm to the fetus or in early childhood. However, maternal exposure to gadolinium, a common MRI contrast agent, should be avoided in pregnancy as it is associated with increased risk of stillbirth and neonatal death, as well as an increased risk of childhood inflammatory, rheumatologic, and infiltrative skin lesions.60

Deleterious effects that the fetus may experience from being exposed to radiation therapy have been recognized for many years (see Chapter 9).61,62,63 Production of genetic mutations by radiation in the laboratory was documented as early as 1927, but data directly applicable to humans are scant.64 Three phases of pregnancy must be considered with regard to radiation damage.65 The preimplantation phase lasts for approximately 7 to 10 days and represents the time from fertilization to the implantation of the blastocyst into the uterine wall. Spontaneous abortion is the most likely consequence of an embryo being exposed to radiation in the preimplantation phase. For many patients, the pregnancy may not be clinically recognized.41 Organogenesis, the period from the first to the 10th week of gestation, represents the most sensitive time for the fetus with regard to radiation injury.65 This is the time of major organ formation and the time when the fetus is most susceptible to teratogenic agents. However, the central nervous system (CNS), the eyes, and the hematopoietic system remain highly sensitive to the effects of radiation throughout the entire pregnancy. Radiation has been associated with microcephaly, the most common malformation observed in humans exposed to high-dose radiation during pregnancy, and mental retardation.66 In general, such effects are seen in fetuses exposed to amounts greater than 0.5 Gray (Gy) of low energy transfer radiation. Embryonic exposure to 0.05 Gy or less is rarely associated with anomalies.66 The actual radiation dose rates are extremely important in assessing the risks to the fetus for developing growth restriction, malformations, or death.

Pregnant women exposed to radiation therapy of 2.5 Gy or greater during the first 2 to 3 weeks of gestation have an increased risk of spontaneous abortion but not a dramatic risk of severe congenital anomalies.67 However, once patients are exposed to such radiation during the third to 10th weeks of gestation, multiple congenital anomalies including low birth weight, microcephaly, mental retardation, retinal degeneration, cataracts, and genital and skeletal malformations have been reported.67 Radiation exposure between the 11th and 20th weeks has been associated with a significant decline in anomalies. Exposure after the 20th week of gestation is usually limited to anemia, skin pigmentation changes, and dermal erythema. The risks of growth restriction and abnormalities of the eye and CNS increase throughout the latter period of fetal radiation exposure. It has been suggested that fetuses exposed to radiation doses higher than 0.1 Gy should be considered for therapeutic abortion.65

Pelvic irradiation for the management of malignancies, particularly cervical lesions in pregnancy, will result in fetal demise and will usually lead to spontaneous abortion. The fetus may receive only minor exposure when supradiaphragmatic irradiation is given, particularly if such radiation is tapered so that the internal scatter is minimal during the first trimester of pregnancy. Proper shielding equipment can significantly reduce the radiation dose to the fetus.68 However, as the fetus grows, its exposure to supradiaphragmatic radiation increases. Such radiation may not be appropriate in the more advanced stages of pregnancy.



Pharmacologic Treatment


Chemotherapy and Pregnancy

Prior experience supported the concept that cytotoxic chemotherapy should not be administered to patients, especially during the first trimester of pregnancy. This was because of the high incidence of spontaneous abortion following exposure to
chemotherapy and the teratogenic effects of these agents on the developing fetus.69,70 However, as anecdotal and small series reports have accumulated, it appears that, although certain drugs must be avoided during early pregnancy, others might be life-saving and might not cause congenital anomalies in the fetus71,72,73,74 (Table 42.2).








Prematurity and low birth weight are frequent complications of chemotherapy exposure in any trimester of pregnancy. However, the fear of exposure in the second and third trimesters of pregnancy resulting in congenital anomalies no longer appears to be a major concern, provided that the selection of drugs is appropriate.69,70 The long-term neurologic consequences of intrauterine exposure to chemotherapeutic agents are yet to be established. Children who have been born after in utero exposure to chemotherapeutic agents during the second and third trimesters have not been noted to have significant congenital abnormalities. One study of 17 children exposed in utero to chemotherapy for the management of maternal acute leukemia revealed no fetal malformations. The children’s growth and development, school performance, intelligence tests, neurologic examinations, and hematologic evaluations (with a follow-up period ranging from 4 to 22 years) were normal.74 Another study of 16 pregnant women treated for non-Hodgkin lymphoma reported similar results.72


Physiologic effects of pregnancy may have an impact on the efficacy and toxicity of chemotherapeutic agents. For example, renal blood flow, glomerular filtration rate, and creatinine clearance increases may lead to increased clearance of drugs from the body.75 It has been suggested that amniotic fluid may act as a pharmacologic third space for such drugs as methotrexate, analogous to ascites or pleural effusions, which may then increase methotrexate toxicity.76 Gastrointestinal absorption of drugs may be decreased owing to delayed gastric motility. The distribution and kinetics of antineoplastic agents may be substantially affected by the physiologic increase in body water in a pregnant woman in association with a 15% increase in plasma volume and changes in plasma protein concentrations.77 Drugs that cross the placenta have low molecular weight, have high lipid solubility, are nonionized, and are loosely bound to plasma proteins.76,78,79

Congenital anomalies have been noted in patients treated with alkylating agents in the first trimester of pregnancy but not in the second and third trimesters.69 Cisplatin has become the most important drug in the management of gynecologic malignancies.80

Antimetabolites are cell cycle-specific and interfere with DNA, RNA, and some coenzymes. Aminopterin and methotrexate act as abortifacients for patients when administered during the first trimester.39,69 Only one congenital anomaly was observed in 56 patients exposed to other antimetabolites during pregnancy.70 Second- and third-trimester exposure to a variety of antimetabolites resulted in no congenital anomalies in 37 fetuses. Thus, antimetabolites other than amethopterin and aminopterin may be relatively safely used in the management of cancer during pregnancy.

Antibiotics such as actinomycin D, doxorubicin, daunorubicin, bleomycin, mitomycin C, and mithramycin have been used relatively safely in the second and third trimesters of pregnancy. Recent data suggest that doxorubicin and daunorubicin may be relatively safe when used in the first trimester of pregnancy, but the follow-up information on children exposed in utero remains extremely limited.81,82

Vinca alkaloids are cell phase-specific agents that cause mitotic (cell division) arrest. These agents include vincristine, vinblastine, etoposide (VP-16), and teniposide (VM-26). A limited experience with exposure to vinca alkaloids suggests that only 1 of 15 pregnancies exposed during the first trimester was associated with a congenital anomaly. No anomalies were seen in 11 patients treated later in pregnancy.69,70

The reported rate of fetal malformations when exposed to combination chemotherapy in the first trimester (16%) is similar to that of single-agent therapy.69,83,84,85 Theoretically, the incidence could be reduced to 6% by removing folate antagonists in common with radiation therapy.71 Doll and colleagues71 summarized the findings of 71 patients treated with single-agent therapy in the last two trimesters and of 79 patients treated with combination therapy; they identified one child in each treatment group with a congenital anomaly. Thus, second- and third-trimester chemotherapy appears to be safe with regards to teratogenicity in the fetus.71 Nevertheless, a 40% incidence of low birth weight was reported by Nicholson69 when fetuses were exposed to chemotherapy in utero. Other complications may occur in the fetus exposed to cytotoxic chemotherapy in addition to teratogenicity, stunted growth, and death.86 Anemia, leukopenia, and thrombocytopenia also may occur in the fetus as a result of bone marrow suppression and leukopenia, or immune suppression may lead to secondary infection.73

Timing of chemotherapy in relation to the anticipated delivery must be carefully assessed. Deliveries should occur when the mother is not bone marrow suppressed. Breastfeeding is discouraged in patients who are receiving cytotoxic chemotherapy, although the data supporting this are weak.86 To date, there have been no reports of children developing leukemia after in utero exposure to chemotherapeutic agents.

In assessing the teratogenic effects of chemotherapeutic agents administered in pregnancy, it must be kept in mind that up to 3% of children have associated major congenital anomalies and 9% have minor anomalies in pregnancies not complicated by cancer treatments or exposure to a chemotherapeutic agent.87


Cervical Cancer


Incidence

The cervix remains the most common site for precancerous and cancerous changes in pregnancy (see Table 42.1). The current International Federation of Gynecology and Obstetrics (FIGO) staging
system for cervical cancer is seen in Table 42.3. Invasive cervical cancer is on the decline in the United States. Effective Pap smear screening techniques in combination with colposcopy for directed biopsies have allowed physicians to recognize the presence of malignancy early and to treat patients with simple office procedures. Although the decline in invasive cancer is evident in the United States, an increase in cervical intraepithelial neoplasia (CIN) has occurred as a result of widescale cytologic screening.88,89 Epidemiologic studies suggest that women who develop CIN and invasive cancer in pregnancy tend to be married at an earlier age, have an earlier age of diagnosis of CIN and invasive
cancer, and have a higher parity than a control population.90,91,92 The most common histologic types of cancer occurring in the cervix are squamous cell. Four case reports of a small cell neuroendocrine carcinoma arising in the uterine cervix in pregnancy have also been reported.93,94










Pharmacologic and Nonpharmacologic Treatment

The identification of invasive cancer of the cervix requires prompt treatment, except for patients in the late second or third trimester, when one may briefly delay therapy until fetal viability is established. Sood et al95 reported on 11 women with cervical cancer diagnosed in pregnancy who underwent surgical treatment in the third trimester with a mean planned delay in therapy of 16 weeks. None of these patients experienced a recurrence.

Patients with stage IB and stage IIA cervical cancer recognized in the first trimester of pregnancy are routinely recommended to be treated with a type III radical hysterectomy and bilateral deep pelvic lymphadenectomies. This approach affords the patient the opportunity to preserve ovarian function and have a more pliable vagina compared with patients treated with radiation therapy.

Patients with more advanced cervical cancer are routinely recommended to be treated with radiation therapy concurrent with weekly cisplatin.96,97,98 Intracavitary radiation follows completion of the external beam radiation regimen. At some institutions, the treatment for locally advanced cervical cancer in pregnancy is to use external beam radiation first and not to attempt to deliver the fetus prior to initiation of therapy. There are no data to suggest that delivering the fetus through an irradiated cervix affects the course of the disease. However, 13 pregnant women with squamous cell carcinoma who delivered vaginally were subsequently diagnosed to have the same type of malignancy in episiotomy sites.99,100

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  4. Fetal Malpresentation

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Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Cancer and Other Neoplasms in Pregnancy

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