Management of the Obstetric Patient With Malignancy

A malignancy complicates as many as 1 of every 1000 pregnancies.¹ Half of these involve tumors of the uterine cervix, breast, or thyroid. When the diagnosis of a malignancy is suspected during pregnancy, the patient is confronted simultaneously with the responsibilities of being a new mother and the fear of her own mortality. As her obstetrician, gynecologist, and oncologist, it is important for the physicians and patient to discuss how the pregnancy may affect the diagnosis, treatment, and prognosis of the malignancy, and the potential effects the malignancy may have on the patient, her fetus, her prognosis, and side effects of treatment.

Cancers that complicate pregnancy and lactation are generally defined as those that occur during gestation or within 1 year postpartum. It is the consensus estimate that approximately 3500 new malignancies will be diagnosed during pregnancy each year (1/1000 pregnancies).² However, a recent 6-year review of epidemiological data from a Californian cohort demonstrated a lower rate of pregnancies associated with malignancies than previously thought, .71 per 1000 live singleton births.³ In this population, the most common malignancy complicating pregnancy was cancer of the breast, followed by thyroid, uterine cervix, Hodgkin lymphoma, ovary, and leukemia (Table 1). Less commonly encountered malignancies during pregnancy include carcinomas of the stomach, central nervous system, vulva, melanoma, colon, and uterus. In this chapter, the most common malignancies occurring during pregnancy and the postpartum period are discussed. Specific topics include the incidence of each malignancy associated with pregnancy, the options for and timing of treatment, the side effects, and the prognosis for the specific malignancies associated with gestation. Rarer malignancies of particular interest to the practicing obstetrician/gynecologist are also discussed.

Table 1. Incidence of Malignancy During Pregnancy

*Malignancies per pregnancy

Cervical cancer commonly occurs during the reproductive years. A small percentage of women with cervical cancer will also be pregnant, with an incidence from 1.2 to 10.6 per 10,000 women, depending on the population.⁴ There were 13,000 new cervical carcinomas expected to be diagnosed in the United States in 2002.⁵ Many studies have documented that cervical cancer is one of the most common malignancy affecting pregnant women. As many as 5% of women with cervical cancer will be pregnant or postpartum at the time of diagnosis.⁶ Hacker and associates⁷ reviewed 14 reports published since 1960 and estimated that cervical carcinoma is diagnosed in 1 in 2205 pregnancies, and that 2.9% of all invasive cervical cancers are diagnosed during pregnancy or within 12 months postpartum.

The principles of detection, diagnosis, staging, and treatment for cervical cancer are largely the same in the pregnant and nonpregnant patient. However, certain diagnostic maneuvers and management decisions are altered or delayed by the presence of a concomitant gestation, depending on the gestational age and degree of disease at the time of diagnosis.

Because most women seek prenatal care, pregnancy provides a window of opportunity to diagnose cervical cancer. Pregnancy may also contribute to an earlier diagnosis of cervical cancer. Women with cervical cancer during pregnancy are 3-times more likely to have stage I disease than nonpregnant age-matched controls with cervical cancer.⁷ Patients with cervical cancer may be asymptomatic, or they may present with symptoms mistakenly attributed to pregnancy, such as vaginal bleeding, pelvic pressure, or increased vaginal discharge. Cervical cancer is an uncommon source of bleeding during pregnancy, but it should always be considered in the differential diagnosis of a gravid woman with vaginal bleeding. The patient should be evaluated with a speculum examination of the cervix and vagina. Lesions suspicious for carcinoma should undergo biopsy, regardless of the gestational age.

Asymptomatic cervical cancer may be detected by cervical cytology. Most physicians perform a Papanicolaou (Pap) smear at the first prenatal visit. Pap smears suggestive of dysplasia during pregnancy should be further evaluated with colposcopy, as with nonpregnant women. Colposcopically directed biopsy specimens should be taken from areas suggestive of high-grade dysplasia or invasive carcinoma. Experienced colposcopists may choose to follow lesions consistent with mild degrees of dysplasia, without performing a biopsy.⁸ Some authors suggest that conservative management of high-grade lesions is also warranted during pregnancy.^9,10 Other investigators, however, do not recommend this policy, stating that colposcopy alone has a significant risk of underestimating the severity of the lesion.¹¹ Endocervical curettage is not routinely advised during pregnancy because it has been associated with bleeding, infection, spontaneous abortion, and preterm labor. A cytobrush of the canal is safe during pregnancy and as sensitive as endocervical curettage.

An unsatisfactory colposcopic examination is uncommon during pregnancy because ectropion often occurs with advancing gestational age. If the transformation zone is not entirely seen, the colposcopy may be repeated in several weeks. Frequently, as pregnancy progresses, the cervix enlarges and the transformation zone becomes more visible. The primary goal of colposcopy in the pregnant patient is to exclude invasive cancer. If the examination remains inadequate and the possibility of an invasive cancer cannot comfortably be excluded, a conization or partial wedge resection of the cervix can be safely performed.^12,13 If the index of suspicion for an invasive cervical carcinoma is low, others have found it safe to avoid conization and to reevaluate these patients postpartum.⁸ Because conization in the first trimester can be associated with a 17% to 33% risk of spontaneous abortion, it can be delayed until the second trimester when it is associated with less complications.¹² Some authors suggest routinely placing a cerclage immediately after a cone biopsy in the second trimester of pregnancy to prevent cervical incompetence.¹⁴

The Society of Gynecologic Oncologists endorses a definition of microinvasive cervical cancer that is limited to microscopic lesions invading less than or equal to 3 mm without lymphovascular space invasion. If microinvasive cervical cancer is diagnosed on cone biopsy during pregnancy, it is reasonable to delay further therapy until after delivery. Vaginal delivery is not contraindicated in the setting of microinvasive cervical cancer. Because data on the management of pregnant women with microinvasive cervical cancer are very limited, once childbearing has been completed, a postpartum extrafascial hysterectomy is usually recommended. Alternatively, a cesarean hysterectomy may be performed at term or after fetal pulmonary maturity is demonstrated. Although cesarean hysterectomy is associated with greater blood loss, it may be the preferred treatment when patient compliance is an issue. Preservation of the uterus after the diagnosis of microinvasive carcinoma is controversial in the nonpregnant patient. Patient compliance and close follow-up are crucial when hysterectomy is refused.

When microinvasive carcinoma is suspected on the basis of colposcopically directed biopsy specimens obtained in the third trimester, enthusiasm for conization is diminished. Morbidity caused by bleeding and preterm labor is significantly increased in the third trimester. Alternatives to conization include wedge biopsy encompassing the abnormal area, postponing conization to the postpartum period, or performing a conization followed by cesarean delivery and radical or extrafascial hysterectomy, depending on evaluation of the conization specimen.^7,12

Frankly, invasive carcinomas of the cervix require more aggressive treatment. During pregnancy, the treatment is determined by the gestational age of the fetus, the size and stage of the tumor, and the patient's willingness to accept a therapeutic abortion. Before fetal viability (less than 24 weeks' gestation), the cervical carcinoma is generally treated without regard to the fetus. Radical abdominal hysterectomy and pelvic lymphadenectomy are performed for stage I and stage IIA lesions of a reasonable diameter. Most gynecologic oncologists limit radical hysterectomy to lesions up to 4 to 5 cm in diameter in otherwise medically healthy patients. Hysterotomy before radical hysterectomy may improve visualization and facilitate surgical dissection after 20 weeks' gestational age but should be avoided unless absolutely necessary. Radical hysterectomy has the advantage over radiation therapy of preserving ovarian and vaginal function. In association with pregnancy, a radical hysterectomy has a high cure rate and an acceptable morbidity rate.^15,16

Pelvic radiotherapy is the preferred treatment for advanced stage cervical cancer or early stage carcinomas with a large tumor volume.¹⁷ The previable fetus will usually abort during the first several weeks of external beam irradiation. If abortion has not occurred before brachytherapy, surgical evacuation, either by hysterotomy or by dilatation and curettage, should be performed to decrease the volume of the uterus and improve radiation dosimetry. Alternatively, if abortion does not occur, external beam irradiation can be followed by vaginal irradiation using colpostats alone, and then followed by a modified radical hysterectomy and pelvic lymphadenectomy.¹⁸ Dosages of teletherapy and brachytherapy should be tailored to the size and stage of the tumor, as in the nonpregnant patient.

If cervical cancer is diagnosed in the third trimester, antenatal maternal corticosteroid prophylaxis and amniocentesis to assess fetal lung maturation after 32 weeks' gestation can be considered if a preterm delivery is desired to initiate maternal treatment.^15,19 There is a paucity of data to determine optimal route of delivery. Small cervical tumors do not preclude vaginal delivery. However, for large, bulky cervical tumors, the fetus should be delivered by cesarean section to prevent cervical hemorrhage, lacerations, or dystocia.²⁰ A classical uterine incision has been recommended in the past because of concerns that a low cervical transverse incision may increase the risk of tumor dissemination or hemorrhage.²¹ Cesarean section is followed immediately by either radical abdominal hysterectomy and pelvic lymphadenectomy or pelvic irradiation for advanced disease. Vaginal delivery through an enlarged cervix containing macroscopically evident carcinoma has been associated with a few reports of recurrence at episiotomy scars.^{22,23,24,25,26,27,28,29} Although cesarean delivery has been advocated in women with large cervical tumors, incisional recurrence has also been reported.^30,31,32 Several large retrospective reviews, however, have failed to reveal a negative impact on survival based on either route of delivery.^7,33,34 If positive lymph nodes are identified at the time of radical hysterectomy, postoperative pelvic radiotherapy with chemosensitization is advised.^17,35

When cervical cancer is diagnosed in the late second trimester or early third trimester, the decision to proceed with therapy or await fetal maturity is more difficult. One study examined the average treatment delay between nonpregnant and pregnant patients with stage IB cervical cancer.³⁶ In the five pregnant patients who postponed treatment to improve neonatal outcome, delay ranged from 6 to 17 weeks. In 60 comparable, nonpregnant patients with stage IB cervical cancer, an average delay of 28 days (range, 6–74 days) was observed. As expected, a marked improvement in neonatal outcome was observed as gestational age increased. Similar reports have not demonstrated an adverse maternal outcome in patients who opt for treatment delay to improve neonatal outcome.^6,19,37 If the patient does decide to delay treatment for this reason, reasonable assurance of fetal maturity should be obtained before proceeding with delivery.

Cervical cancer staging as defined by the International Federation of Gynecologists and Obstetricians (FIGO) is predominantly determined by palpation and inspection of the cervix and parametria. During pregnancy, however, the presence of the fetus may hinder accurate physical examination. If clinically indicated, magnetic resonance imaging or computerized tomography can provide images of the urinary tract and retroperitoneum during pregnancy. Bipedal lymphangiography is an alternative method to assess nodal metastasis that is rarely used. In the third trimester, if lymphangiography is indicated, it is usually performed after delivery and immediately before planned radiotherapy to limit fetal exposure to fluoroscopic irradiation.³⁸ Limited intravenous urography poses little danger to the fetus. During chest radiography, abdominal shielding is recommended. In the first and second trimester, radiographic and/or surgical assessment of the extent of disease should be similar to that used in the nonpregnant patient, with greater emphasis on magnetic resonance imaging (MRI).

Survival of patients with cervical cancer is not affected by pregnancy when controlled for stage, lymph node metastasis, or histology.^7,33,34,39 Senekjian and coworkers⁴⁰ found comparable actuarial survival rates in pregnant versus nonpregnant patients with clear cell adenocarcinoma of the cervix and vagina.

Breast cancer is the most common malignancy in women. It complicates pregnancy more often than any other malignancy except possibly cervical cancer. It is estimated that 203,500 new cases of breast cancer will have been diagnosed in 2002.⁵ Approximately 1 in 3000 women will have breast cancer diagnosed during pregnancy. This includes women with diagnoses up to 1 year postpartum and any woman who is lactating.⁴¹ Because the incidence of breast cancer increases with increasing age, breast cancer may become more prevalent during pregnancy, because there is a trend among women to delay childbirth.

Women with breast cancer diagnosed while pregnant have a worse prognosis than those with it diagnosed while in the nonpregnant state. Investigators reported pregnant women with breast cancer were 2.5-times more likely to present with metastatic disease and less likely to have stage I disease.⁴² This may be caused by a delay in diagnosis, as well as the influence of pregnancy-associated hormones on tumor growth and biology.^41,43 Furthermore, unlike cervical cancer, breast cancer diagnosed during pregnancy is often more advanced than in nonpregnant women. This poorer prognosis is closely related to stage and age at diagnosis. Multivariate analysis of disease-free and overall survival has demonstrated that younger women have a worse prognosis that is independent of other factors such as tumor site, nodal status, grade, hormone receptor status, locoregional treatment, and adjuvant systemic therapy.⁴⁴ However, stage for stage, women with breast cancer diagnosed during pregnancy have a similar prognosis as those not pregnant.^41,42 Pregnant women with breast cancer are more likely to have lymph node involvement and tumors larger than 2 cm, compared with their nonpregnant counterparts.⁴¹ In Japanese women, those with pregnancy-associated breast cancer were found to have a longer duration of symptoms, larger tumor size, more frequent vascular invasion, and a higher rate of lymph node metastasis than nonpregnant women.⁴⁵ In Nigeria, however, pregnant or lactating women with breast cancer had clinical presentations similar to those of nonpregnant women, but most of both groups of Nigerian women had stage IV disease, longer duration of symptoms, and a low survival rate.⁴⁶ Guinee and colleagues⁴⁷ demonstrated that women aged 20 to 29 years with pregnancy-associated breast cancer had a significantly greater risk of dying than similarly aged women with breast cancer who had never been pregnant. It is likely that the gestational breast may camouflage an otherwise clinically evident lesion. There also may be some reluctance on the part of the physician to proceed with diagnostic procedures or suspect that a breast mass detected during pregnancy is malignant. Patients with suspected cancer, pregnant or not, should receive the same recommendations designed to quickly and accurately determine the extent of disease. If the informed patient chooses to delay treatment because of pregnancy considerations, the clinician must still be supportive of her decision.

Delay in diagnosis no doubt contributes to the poorer outlook of the pregnant breast cancer patient. Dominant breast masses in pregnant women must be evaluated and not ignored. Mammography with abdominal shielding can be performed safely during pregnancy. Mammography, however, may provide limited information, as a result of increased water density and hyperemia in the pregnant breast. Ultrasound can be used to discriminate between a solid and a cystic lesion. Dominant masses should be evaluated with aspiration or biopsy. In a study by Gupta,⁴⁸ 214 pregnant women with breast masses underwent fine needle aspiration (FNA). Cytologic diagnosis of breast cancer was confirmed in all cases. Women with benign masses were followed-up throughout pregnancy and the postpartum period and showed no progression to cancer. One large series of breast tumors diagnosed during pregnancy and lactation found three-times as many benign tumors as malignant tumors.⁴⁹

Staging studies in pregnant women with breast cancer are modified. Bone scans are generally not recommended unless significant therapeutic decisions would depend on their outcome. Similarly, radionucleotide brain and liver scans are generally not indicated in these patients. If localizing neurologic symptoms develop, a brain computerized tomographic scan with abdominal shielding or MRI can be performed. If symptoms or laboratory values suggest liver involvement, a right upper quadrant ultrasound should detect significant abnormalities.

Treatment depends on the stage of the cancer and the gestational age of the fetus (Table 2). Modified radical mastectomy is the treatment of choice during pregnancy for stage I and stage II disease. Breast-conserving procedures, such as lumpectomy and axillary dissection, are usually followed-up by whole-breast irradiation after delivery. During pregnancy, this would expose the fetus to high levels of irradiation. At or near term, a woman may choose a breast-conserving operation and then delay radiation therapy until after delivery. The effect of treatment delay in this manner is not well studied. Alternatively, in early pregnancy, the patient may elect to undergo induced abortion followed by lumpectomy and radiation. Although breast-conserving surgery and radiation are comparable with modified radical mastectomy in the nonpregnant woman, data are lacking to support or refute a similar outcome in the pregnant or postpartum woman. Recently, investigators compared the outcomes breast-conserving surgery versus modified radical mastectomy and reported no difference between the two approaches in progression-free survival or disease-free survival.⁵⁰ Subsequently, the same authors reported the use of neoadjuvant chemotherapy followed by surgery in four pregnant women with locally advanced breast cancer, and reported no recurrence with a median follow-up of 44 months.⁵¹ However, the authors note that larger studies will be necessary to evaluate the safety of these treatments.

Table 2. Breast Cancer Staging Based on the American Joint Commission on Cancer (AJCC)

(Beahrs OH, Henson De, Hutter RVP, Kennedy BJ: Handbook for Staging or Cancer, p 164. Philadelphia, JB Lippincott, 1993)

Rarely, termination of pregnancy may need to be considered in women with more advanced tumors that would normally require chemotherapy and radiation. Termination can be performed in first-trimester by dilation and curettage or in the third-trimester by induction of labor or cesarean delivery. In the second trimester, the issues are more complex. If radiation therapy is administered during pregnancy, it must be performed with adequate abdominal-pelvic shielding. A thermoluminescent dosimeter in an anatomic phantom can be used to estimate fetal radiation exposure. During the period of organogenesis, fetal exposure to more than 10 cGy is associated with an increased risk of congenital anomalies. Delaying therapy may not always be reasonable in the face of recurrent or progressive disease. The relative risks to the mother and fetus should be weighed by the patient with health care providers' input.

In the presence of positive lymph nodes, adjuvant chemotherapy is generally recommended for premenopausal patients. In certain circumstances, adjuvant chemotherapy is also advised in premenopausal women with negative nodes, particularly those with estrogen-receptor negative tumors and tumors greater than 1 cm.⁵² As more data are accumulated and additional prognostic factors are elucidated, the role and timing of adjuvant chemotherapy for node-negative women during pregnancy will hopefully become clearer. If possible, chemotherapy should be delayed until the second trimester of pregnancy after completion of organogenesis. Short-term delays may be acceptable without adverse effect on survival; however, the length of acceptable delay is unknown. Therapeutic abortion has not been shown to have a beneficial effect on breast cancer outcome.^53,54 When the treatment is expected to have a high likelihood of damaging the fetus, abortion is often elected; however, these treatments are rarely indicated today.

Many case reports and case series of pregnant women undergoing chemotherapy can be found in the medical literature. Because of the retrospective and uncontrolled nature of the studies, the information is somewhat anecdotal and must be interpreted cautiously. Doll and coworkers⁵⁵ summarized the literature in 1988, detailing the chemotherapeutic experience in pregnancy. They reported a 17% incidence of fetal malformations in patients treated in the first trimester with single chemotherapeutic agents. When patients who also received irradiation or folate antagonists were excluded, the incidence of fetal malformations after treatment with single agents decreased to 6%, which is approximately the incidence of fetal anomalies in the general population, which is 2% to 5%. No increased risk of fetal teratogenesis was noted when chemotherapy was administered in the second and third trimesters. However, antineoplastic agents have been associated with low birth weight, intrauterine growth retardation, spontaneous abortion, premature birth, and myocardial toxicity.⁵⁵ A review of 217 pregnant patients reported on the outcomes of 14 women with breast cancer who were treated with chemotherapeutic or hormonal agents.⁵⁶ In this series, two had spontaneous abortions, one had a stillborn infant, and three infants had congenital anomalies. The remaining eight women had normal fetuses without congenital abnormalities; however, one infant had intrauterine growth restriction and three infants were born prematurely. Highly teratogenic chemotherapeutic agents, such as methotrexate and aminopterin, should be avoided during pregnancy, especially during the first trimester. In general, the risk of congenital anomalies is highest when a chemotherapeutic drug is administered during the period of organogenesis, which occurs from the second to the eighth postconceptional week. Before organogenesis, in the preimplantation period, there seems to be an all-or-nothing effect.

Zemlickis and associates⁵⁷ performed a case-control study of 21 pregnant women treated with chemotherapy during a 30-year period at the Princess Margaret Hospital in Canada. Fetal anomalies were associated only with chemotherapy administered in the first trimester. They noted a statistically significant decrease in birth weight when adjusted for gestational age, as well as a decrease in gestational age at delivery. They also reported an increase in the stillbirth rate for all women who had had any form of cancer compared with the general population. The majority of these women had not received chemotherapy, and other factors related to their cancer history may have been responsible for the increased risk of stillbirth.

In utero exposure to chemotherapy poses some risk for the more mature fetus as well. There is an increased risk of growth restriction, preterm labor, and intrauterine fetal demise. Several studies have reported no increased risk of fetal anomalies, and no increase in psychological, neurologic, or immune dysfunction in these children.^58,59 An increased incidence of malignancy occurring in these children has not been observed. Unfortunately, the data are sparse and contain limited follow-up. Long-term abnormalities caused by in utero chemotherapy exposure may surface in the future.

When chemotherapy is indicated for breast cancer during pregnancy, a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide can be used as an alternative to the formerly commonly prescribed cyclophosphamide, methotrexate and 5-fluorouracil regimen. Anthracyclines appear relatively safe in pregnancy and, along with taxanes, may be better therapeutic options.^60,61

If possible, delivery should be timed to avoid complications to the mother and the fetus from the hematologic nadir or other complications of treatment. Neonatal pancytopenias have resulted from maternal chemotherapy. In addition, breastfeeding is not recommended during chemotherapy because the antineoplastic agents enter the breast milk and may have adverse neonatal effects.

There does not seem to be any contraindication to subsequent pregnancy in women treated for breast cancer.⁶² Some clinicians recommend that these women wait 2 years before attempting pregnancy. This would allow any early recurrences to be diagnosed and may discourage a woman from planning to increase the size of her family if her prognosis worsens. However, there are no data to indicate that conceptions less than 2 years after breast cancer therapy worsens her future prognosis. Pregnancy subsequent to mastectomy for cancer of the breast was previously discouraged. However, recent data have found no adverse effect on maternal survival. In fact, the preponderance of data suggest a survival benefit for women who conceive after a previous diagnosis of breast cancer.^63,64,65,66

As more women undergo breast-conserving therapy, the issue of posttherapy lactation will arise. Generally, the irradiated breast does not hypertrophy to the degree that the unirradiated breast does during pregnancy. Occasionally, women are able to successfully nurse from both breasts^67,68; however, the volume of milk is often diminished, and neonatal preference for the normal breast has been observed. Circumareolar incisions may also hamper lactation from the treated breast.⁶⁷

The peak incidence of Hodgkin disease is in patients in their 20s to 40s. It is estimated that Hodgkin disease affects 1 of every 5000 pregnant women.⁶⁹ Fortunately, the cure rate with modern therapy is higher than 75%,⁷⁰ and the prognosis is not altered by pregnancy.⁶⁹ The stage is determined based on the sites of involvement and whether the disease is present on both sides of the diaphragm or just one side (Table 3). Staging laparotomy is usually delayed until after delivery. Cesarean section can be considered as staging laparotomy can be performed at the same time. Most patients with Hodgkin disease diagnosed during pregnancy have localized supradiaphragmatic disease.⁷¹ Radiotherapy is the mainstay of treatment for localized disease.⁷²

Table 3. Staging Classification for Hodgkin Disease*

*Each stage is subdivded into “A” or “B” categories: A = asymptomatic; B = fever, sweats, weight loss >10% of body weight.
(Beahrs OH, Henson DE, Hutter RVP, Kennedy BJ: Handbood for Staging of Cancer, p 258. Philadelphia, JB Lippincott, 1993)

When Hodgkin disease is diagnosed during the first half of pregnancy, the patient is usually counseled to terminate the pregnancy to begin radiation therapy. If continuation of the pregnancy is elected, irradiation is best avoided during the period of organogenesis. Patients with diagnoses in the second trimester, who have elected to continue their pregnancy during radiation therapy, have delivered normal babies and have sustained long-term remission.^72,73,74 Generally in these cases, the radiation was directed to supradiaphragmatic sites, and the abdomen was shielded. Most of fetal radiation exposure results from internal scatter radiation and leakage from the radiotherapy unit.⁷⁵ Internal scatter radiation cannot be reduced by shielding. The dose of internal scatter received by the fetus depends on the distance of the fetus from the center of the irradiation field, the size of the field, and the energy of the radiation. Fetal dose increases as the distance to the field decreases and as the field size increases. Higher energy radiation provides less internal scatter directed at the fetus. Leakage from the radiotherapy unit should not exceed .1% of the direct beam exposure rate. Fetal exposure can be lessened by using external shielding and by increasing the distance of the fetus from the field center. Direct radiation to the fetus during the first trimester offers little risk as long as the total dose is less than 10 cGy.⁷⁶

Nisce and colleagues⁷⁴ recommended induced abortion only in the presence of one of the following: (1) infradiaphragmatic disease necessitating pelvic irradiation; (2) systemic symptoms and/or visceral disease best managed with multiagent chemotherapy; (3) disease diagnosed very early in gestation, wherein treatment delay would be unacceptable; (4) pelvic irradiation greater than 10 cGy in the first 8 weeks; or (5) bulky mediastinal disease requiring a combination of radiation and multiple chemotherapeutic agents. A questionnaire-based study of 152 patients with advanced Hodgkin disease did not show a clear excess of adverse pregnancy outcome. Specifically, there were no significant excesses of perinatal deaths, birth defects, or cancers in the offspring.⁷⁷ However, 83% of the pregnancies occurred before the diagnosis of Hodgkin disease was made. Metastatic involvement of the placenta by Hodgkin disease has been reported, but transplacental transmission to the fetus is extremely rare.⁷⁸

Approximately 25,700 new cases of nonHodgkin lymphoma will have been diagnosed in 2002, with 45% of these patients dying of their disease.⁵ NonHodgkin lymphoma of the intermediate and high-grade forms require intensive combination chemotherapeutic regimens, and salvage options are very limited. The delay from the first trimester to the second trimester may diminish the potential for cure. For low-grade nonHodgkin lymphomas, treatment delay until the postpartum period may be reasonable.⁵⁵

The incidence of acute leukemia during pregnancy is estimated at 1 in 100,000 pregnancies.⁷⁹ Acute leukemia is more common during pregnancy compared with chronic leukemia. Acute lymphocytic leukemia is usually a disease of children. Acute nonlymphocytic leukemia is more likely to complicate pregnancy. Symptoms of acute leukemia are the result of marrow dysfunction. They include fatigue, pallor, anemia, susceptibility to infection, bleeding diathesis, fever, and bone pain. The diagnosis is confirmed after examination of the peripheral blood smear and the bone marrow biopsy. Combination chemotherapy and better supportive care have improved the otherwise dismal prognosis for these patients.

Acute leukemia requires immediate, intensive, and prolonged chemotherapy that may be teratogenic when administered in the first trimester. Delay of therapy in this setting, however, may interfere with cure. Termination of early gestations would eliminate the increased risk of fetal anomalies and is generally recommended. During the second and third trimesters, intensive chemotherapy is not considered teratogenic.^79,80,81,82 Without treatment, these women and their fetuses do uniformly poorly. At delivery, women with active acute leukemia are prone to severe hemorrhagic and infectious complications. Delivery is accomplished as soon as a high probability of both fetal and maternal survival can be assured, preferably when the mother is in complete remission and fetal lung maturity is documented. The fetal status should be monitored and obstetric intervention pursued if the fetus demonstrates severe growth retardation or other signs of fetal demise, particularly if the woman is in remission. This subject is discussed in detail in an excellent review by Catanzarite and Ferguson.⁸³

Chronic lymphocytic leukemia is rarely seen in pregnant women, because it tends to be a disease of older patients. Chronic myelogenous leukemia constitutes 90% of the chronic leukemias diagnosed in pregnancy.⁷⁹ Chronic myelogenous leukemia is characterized by a proliferation of myelocytic or granulocytic cells. As long as either splenomegaly or leukocytosis is not symptomatic, expectant management during pregnancy is reasonable. When the disease enters the blast phase, however, these patients should be treated as aggressively as patients with acute leukemia. The long-term prognosis is poor; most patients eventually die of the disease. The average survival overall is 42 months. Survival after development of the accelerated phase is less than 1 year, and after blastic transformation, it is less than a few months. Pregnancy itself does not appear to affect the disease process. Survivors of childhood acute lymphoblastic leukemia do not appear to have adverse pregnancy outcomes.⁸⁴

The incidence of melanoma is estimated to be between .14 and 2.8 in 1000 deliveries.⁸⁵ Early reports suggested that women in whom melanoma developed during pregnancy had a worse prognosis; however, more recent reports controlling for known prognostic factors, such as lesion thickness and anatomic location, have shown equivalent survival between pregnant and nonpregnant patients.^85,86,87 One recent study of 100 pregnant women with melanoma demonstrated a significantly shorter period of disease-free survival in women with melanoma diagnosed during pregnancy as compared with matched controls,⁸⁸ but no difference in overall survival. Another study of 45 women with pregnancy-associated melanoma found these women to have thicker melanomas than their nonpregnant counterparts. Multivariate analysis, however, did not demonstrate a detrimental impact on survival in these women.⁸⁹ Treatment strategy is based on the depth of invasion. Surgical resection is the mainstay of therapy, as it would be in the nonpregnant patient.

Melanoma is the most common malignancy to metastasize to the placenta.^90,91,92 Very rarely, fetal metastasis is seen. Careful pathologic examination of the placenta and thorough physical examination of the neonate are warranted when maternal melanoma exists. At least three cases of primary melanoma of the fetus have been described, uniformly resulting in poor neonatal outcome.⁹¹

Manifestations of melanoma include variegation of color, irregular borders or elevations, and a change in a preexisting pigmented lesion. Suspicious skin lesions should undergo biopsy immediately, regardless of the pregnancy status. Referral to a surgical oncologist should follow a diagnosis of melanoma. Generally, lesions less than .76 mm can be treated with local resection only, because lymph node spread is extremely rare. Lymph node dissection for more deeply invasive lesions is generally recommended, although some controversy exists.

Chemotherapy for malignant melanoma has limited success. Dacarbazine is one of the more active agents. The probability of a complete response, however, is low. In one case report, dacarbazine administered in the third trimester resulted in a profound temporary improvement of maternal performance status, improving quality of life without untoward fetal effects.⁹³ The overall limited benefit of chemotherapy for melanoma must be weighed against the potential adverse effects to the fetus. Immunotherapy has become more popular for melanoma, yet experience with this type of treatment during pregnancy is limited. Radiation therapy is usually reserved for palliating pain caused by metastasis. During pregnancy, this goal may be better served by narcotic analgesics.

Pregnancy after treatment for melanoma does not appear to worsen the prognosis. Women with thick lesions may be best advised to delay childbearing for a few years, until they are beyond the period of time in which the highest risk of recurrence exists. The most important factor in survival remains early diagnosis. Pregnant women should have the same indications for biopsy as nonpregnant patients.

Gastrointestinal cancer rarely complicates pregnancy. The incidence is estimated at 1 in 13,000 pregnancies, with most being rectal cancers.⁹⁴ Delay in diagnosis of a colorectal carcinoma during pregnancy occurs because some symptoms may be mistakenly attributed to pregnancy. Symptoms include abdominal pain, nausea, vomiting, constipation, abdominal distension, and anemia. Conditions such as familial polyposis, ulcerative colitis, a history of villous adenoma, and Gardner syndrome increase the risk for colorectal cancer. Fecal occult blood testing and sigmoidoscopy or colonoscopy are the main diagnostic tools to evaluate symptomatic pregnant patients for colorectal cancer.

Early diagnosis followed by prompt surgical excision is the treatment of choice for curable patients. In the third trimester, cesarean delivery may be combined with wide excision of the tumor. Vaginal delivery is contraindicated in the presence of an anterior rectal wall carcinoma that is obstructive.⁹⁵ Survival after the diagnosis and treatment of rectal carcinoma is related to the stage and grade of the tumor. Pregnancy itself does not appear to affect prognosis.

Colon cancer located above the peritoneal reflection coincident with pregnancy is exceedingly rare. As of 2003, approximately 40 to 45 cases have been reported.^{96,97,98,99,100,101,102} There are reports of ultrasonography or magnetic resonance imaging aiding in the diagnosis of advanced colon cancer during pregnancy, but this finding is uncommon.^97,103 Also, in rare cases, a markedly elevated alpha-fetoprotein level may suggest liver involvement from colon cancer.¹⁰³

Management of colorectal cancer is determined by fetal gestational age as well as the presumed stage of the cancer. Early in pregnancy, the usual surgical bowel resection should be undertaken. The pregnancy can be left undisturbed. After 26 weeks, the pregnancy is usually allowed to progress until fetal lung maturity is demonstrated. A cesarean delivery can then be combined with the appropriate bowel resection and staging procedure. Alternatively vaginal delivery may be followed by laparotomy, if labor will not impinge on the tumor or be obstructed by it. Certainly, if bowel perforation or impending obstruction is an issue, prompt surgical intervention is necessary, regardless of the gestational age of the fetus. Perioperative magnesium sulfate tocolysis can be considered if risk of preterm delivery is high.

Postoperative adjuvant chemotherapy may be prescribed for high-risk lesions.⁹⁸ With the trend toward women delaying childbearing, colon cancer may be diagnosed more frequently in pregnant women in the future. The prognosis of women with colon cancer diagnosed during pregnancy is poor. Delayed diagnosis is once again thought to contribute to poor prognosis. Extensive metastases are often present. Poor outcome is related to advanced stage.¹⁰⁴

Carcinoma of the stomach associated with pregnancy is very uncommon outside of Asia. Since 1916, however, 104 cases have been reported in the Japanese literature, and the incidence appears to be increasing.¹⁰⁵ Again, as seen with colon cancer, the symptoms of gastric carcinoma may be mistakenly attributed to pregnancy. Common symptoms include nausea, vomiting, epigastric pain, anorexia, abdominal distension, and fullness of the stomach. In the Japanese series, almost all of the cases were advanced, and the incidence of hospital death was 58.9%.¹⁰⁵ Resectable cases also had a very poor prognosis. These authors recommended early referral for gastroendoscopy when gastric symptoms persist in pregnancy. Treatment is tailored to gestational age of the fetus and presumed stage of the carcinoma, similar to the approach for colon cancer. If cesarean delivery is performed, the ovaries can be inspected for evidence of Krukenberg tumors.

Thyroid carcinoma, although relatively uncommon, affects females three-times as often as males, with half of these cases occurring in women of reproductive age. Therefore, thyroid carcinoma may complicate pregnancy, but the prognosis is usually favorable. Data gleaned from the New Mexico Tumor Registry found that there was no statistically significant difference in observed survival rates between 22 pregnant women and 464 nonpregnant women of comparable ages with thyroid cancer.¹⁰⁶ Survival was in excess of 98% in pregnant and nonpregnant patients.

Treatment consists of surgery any time after the first trimester. Radioiodine scans and treatment should be delayed until after delivery because the fetal thyroid is capable of concentrating iodine after 10 weeks of gestation. A study examining the outcome of women with a history of well-differentiated thyroid carcinoma and radioactive iodine exposure who subsequently became pregnant did not report any adverse effects from the cancer or its treatment.¹⁰⁷ This confirmed earlier reports;^108,109 however, it is generally recommended that women avoid pregnancy until 12 months after iodine (I) 131 therapy. Thyroid hormone replacement is easily tolerated by the fetus during pregnancy.

Ovarian neoplasms complicate pregnancy in approximately 1 in 1000 to 1300 deliveries.^110,111 The incidence of benign incidental ovarian cysts detected with modern ultrasound equipment during pregnancy may be higher.¹¹² Fortunately, only 2% to 5% of these cysts are malignant.^113,114 The most common ovarian masses consist of corpus luteum cysts, benign cystic teratomas, serous cystadenomas, and mucinous cystadenomas.¹¹⁵ Patients with ovarian neoplasms may present with an acute abdomen resulting from torsion, rupture, or hemorrhage. Occasionally vaginal delivery is obstructed by a large neoplasm. Other neoplasms are found incidentally at the first prenatal visit, during an antenatal ultrasound, or at term during a cesarean delivery. Surgical exploration for asymptomatic ovarian masses should be delayed until the second trimester, but performed before 24 weeks' gestation or fetal viability, if possible. Beyond the first trimester, most corpus luteum cysts will have regressed and the incidence of spontaneous abortion will have decreased. Signs and symptoms of an acute abdomen require prompt surgical exploration, regardless of the gestational age. Hess and coworkers¹¹¹ found an improved pregnancy outcome in patients undergoing laparotomy for an adnexal mass compared with those who had emergency surgery. Persistent cysts that are greater than 6 cm should be explored to rule out malignancy, and to prevent rupture, torsion, or dystocia during vaginal delivery. Perioperative magnesium sulfate tocolysis can be considered if the fetus is approaching a gestational age for viability.

If malignancy is suspected, laparotomy should include at least salpingo-oophorectomy, partial omentectomy, and staging biopsies. More advanced lesions usually require total abdominal hysterectomy and bilateral salpingo-oophorectomy. With current improvements in neonatal survival at earlier gestations, fetal salvage is frequent when surgery is undertaken in the third trimester. A hysterectomy may be avoided and the pregnancy may be allowed to continue until term without further treatment if the tumor is: (1) of low malignant potential (borderline); (2) a stage IA, grade 1 epithelial carcinoma; or (3) stage I, grade 1 immature teratoma, stage IA dysgerminoma or granulosa cell tumor. Staging of epithelial ovarian carcinomas are presented in Table 4. Advanced ovarian cancers are rare in pregnant patients, and treatment must be individualized; however, the pregnancy is usually terminated early, either by hysterectomy or by cesarean section. Consultation with a gynecologic oncologist before intervention is preferable when an ovarian malignancy is suspected during pregnancy.

Table 4. Staging for Primary Carcinoma of the Ovary (FIGO 1974)

*Ascites is peritoneal effusion that in the opinion of the surgeon is pathologic and/or clearly exceeds normal amounts.
Based on findings at clinical examination and surgical exploration.
The final histology (and cytology when required) after surgery is to be considered in the staging.

In pregnant patients, ovarian carcinomas are often of early stage and favorable histologies.¹¹⁴ There appears to be a higher frequency of germ cell tumors and granulosa cell tumors. The maternal prognosis is related to the stage and histology of the lesion. The prognosis for these women appears to be no different than that for nonpregnant patients.

The standard treatment for endometrial cancer includes total abdominal hysterectomy and bilateral salpingo-oophorectomy. This therapy obviously precludes subsequent pregnancy. There are, however, a few reports of patients with endometrial cancer treated only with a dilatation and curettage and progestins who later conceived and sustained a normal pregnancy.¹¹⁶ As of 1996, 16 cases of pregnancy occurring in the presence of endometrial cancer have been reported.^1,117 In half of these cases, the pregnancy and cancer were both diagnosed at the time of dilatation and curettage for spontaneous abortion.

Invasive vulvar cancer is rare, constituting only 4% of gynecologic malignancies. It is predominantly a disease of older women; however, a small percentage of cases develop in women younger than 40. There are less than 20 reported cases of invasive squamous carcinoma of the vulva coincident with pregnancy. Prompt biopsy to establish the diagnosis, followed by radical vulvar resection and inguinal-femoral node dissection, is the mainstay of treatment.¹¹⁸ One patient with a grossly positive inguinal node who underwent radical vulvectomy and bilateral inguinal-femoral node dissection at 35 weeks followed by groin and pelvic irradiation at 6 weeks postpartum was without evidence of recurrent cancer after 28 months of follow-up.¹¹⁹ The mode of delivery may be influenced by the healing status of the vulva. Cesarean delivery, however, is not mandatory.

It is estimated that in the United States, approximately 90 women per year will have a brain tumor coincident with pregnancy.¹²⁰ The most common symptomatic intracranial lesions are gliomas, meningiomas, and acoustic neuromas.¹²¹ Headache is noted in 50% of patients, and nausea and vomiting in 25%. Lateralizing signs or seizures not associated with other eclamptic signs should be evaluated with magnetic resonance imaging of the brain.

Low-grade gliomas are slow-growing tumors, and treatment may be safely delayed until after pregnancy.¹²¹ High-grade gliomas, however, require prompt diagnosis and treatment. Unless delivery is anticipated shortly, craniotomy should not be delayed. Chemotherapy and radiotherapy usually follow surgery. Early in pregnancy, patients may choose to terminate the pregnancy as opposed to undergoing full brain irradiation with abdominal–pelvic shielding. Later in pregnancy, short delays may be tolerated when lesions are asymptomatic, but symptomatic lesions are best treated with radiation therapy in conjunction with abdominal–pelvic shielding. Chemotherapy has a less important role and can be delayed until after pregnancy.¹²¹

Meningiomas are benign, slow-growing tumors that cause problems because of a mass effect. Occasionally, meningiomas are observed to grow more rapidly during pregnancy attributed to pregnancy hormonal influence. If necessary, surgical excision is safe to perform during pregnancy. Definitive treatment often can be delayed to the postpartum period. Acoustic neuromas and pituitary adenomas are generally benign neoplasms that can also be problematic as a result of mass effect. The former is managed surgically, and the latter by either bromocriptine administration or surgery. Pregnant patients with an intracranial mass may require a cesarean delivery to avoid a substantial increase in intracranial pressure associated with pushing.¹²¹ Bromocriptine can be used safely in symptomatic women with pituitary adenomas during pregnancy. Women with pituitary adenomas can be followed with visual field examinations and MRI every trimester.

The treatment of pregnant cancer patients is often a multidisciplinary endeavor that includes the obstetrician; the medical, surgical, or gynecologic oncologist; the radiation oncologist; the neonatologists; specialized nurses; and, if available, cancer rehabilitation and supportive services. Pregnancy is not known to increase the risk of any cancer. However, pregnancy may unfortunately contribute to a delay in diagnosis. The obstetrician should investigate symptoms that are unusual in quality or duration for a pregnant patient. Most importantly, the obstetrician should advocate for the pregnant woman's right to full and prompt diagnostic testing. Treatment decisions will need to incorporate fetal effects, maternal attitudes toward abortion, and risks to the mother of delaying therapy. The literature contains useful information for the practitioner faced with the uncommon situation of cancer as a complication of pregnancy. It is the responsibility of today's physicians to continue to report the treatment effects of pregnant women with cancer as chemotherapy and radiation therapy practices change and develop over time. In utero exposure to chemotherapy and radiation therapy can be reported to the Pregnancy and Cancer Registry initiative at the National Cancer Institute and currently located in the Department of Human Genetics at the University of Pittsburgh.