CHAPTER 63: Neoplastic Disorders

Any neoplasm can complicate pregnancy, and as written by Williams, physical examination often suggests the diagnosis. Current imaging also allows a greater number of these to be identified antepartum. Most encountered neoplasms are benign, and uterine leiomyomas and ovarian cysts are the most frequent.

Cancer has an incidence approximating 1 per 1000 pregnancies (Parazzini, 2017; Salani, 2014). One third are diagnosed prenatally, and the others within 12 months of delivery. Some of the more frequent ones are shown in Figure 63-1. Breast cancer is found in 1 in 5000 pregnancies, thyroid—1 in 7000, and cervical—1 in 8500 (Smith, 2003). These, along with lymphoma and melanoma, account for 65 percent of malignancy cases in pregnancy (Eibye, 2013). For some cancers—ovary, endometrium, and breast—evidence suggests that high parity is protective (Högnäs, 2014).

During pregnancy, cancer management poses unique problems related to fetal concerns, and treatment must be individualized. Considerations include the type and stage of malignancy, the desire for pregnancy continuation, and inherent risks associated with modifying or delaying cancer treatment.

Surgery

Operative procedures indicated for cancer include those for diagnosis, staging, or therapy. Fortunately, most procedures that do not interfere with the reproductive tract are well tolerated by both mother and fetus (Chap. 46, Medications and Surgeries). Although many operations have classically been deferred until after 12 to 14 weeks’ gestation to minimize miscarriage risks, this probably is not necessary. We are of the opinion that surgery should be performed regardless of gestational age if maternal well-being is imperiled.

Both pregnancy and malignancy are risk factors for venous thromboembolism (VTE). In one study, Bleau and coworkers (2016) reported a higher risk of VTE in gravidas with myeloid leukemia, Hodgkin disease, cervical cancer, and ovarian cancer compared with that in pregnant women without a malignancy. The risk was not increased in those with brain or thyroid cancer, melanoma, or lymphoid leukemia. That said, current guidelines lack specific recommendations for pregnant women undergoing surgeries for cancer. Thus, depending on the complexity of the planned procedure, it seems reasonable to use prophylactic low-molecular-weight heparin combined with elastic stockings and/or intermittent pneumatic compression as described in Chapter 52 (Thromboprophylaxis).

Diagnostic Imaging

Sonography is a preferred imaging tool during pregnancy. Even so, according to the American College of Obstetricians and Gynecologists (2017a), most diagnostic radiographic procedures deliver very low x-ray doses and should not be delayed if they would directly affect therapy (Chap. 46, X-Ray Dosimetry). Magnetic resonance (MR) imaging can safely be performed in any trimester, but delay until after the first trimester may lower potential risks. Gadolinium should not be used in the first trimester and should be used later in pregnancy only when the benefits overwhelmingly outweigh the risks (American College of Radiology, 2016; Kanal, 2013). Computed tomography (CT) is less often selected due to ionizing radiation, and procedure-related doses are listed in Chapter 46 (Computed Tomography). Accordingly, CT is used in pregnancy most often to evaluate acute concerns that include pulmonary embolism, bowel or renal obstruction, and acute neurological events. To enhance CT, oral and intravenous contrasts may be added. These lack known fetal harm, and postpartum breastfeeding need not be interrupted. Last, some radioisotopes are relatively safe in pregnancy and are listed in Table 46-8.

Radiation Therapy

Therapeutic radiation often results in significant fetal exposure depending on the dose, tumor location, field size, and gestational age. Potential adverse effects include fetal malformation, intellectual disability, growth restriction, sterility, and carcinogenesis (Brent, 1999; Stovall, 1995). In the 2 weeks following fertilization, exposure typically leads to chromosomal damage and embryonic death. The next most susceptible period is during organogenesis in weeks 2 through 8, and exposure can cause malformation. These might develop above a threshold dose of 0.1 to 0.2 Gy. During weeks 8 through 25, the fetal central nervous system is especially vulnerable. The threshold dose for intellectual disability at 8 to 15 weeks’ gestation approximates 0.06 Gy, and at 16 to 25 weeks it is about 0.25 Gy (Kal, 2005; Otake, 1996). After 25 weeks’ gestation, susceptibility is less, although no gestational age is considered safe for therapeutic radiation exposure. Thus, radiotherapy to the maternal abdomen is contraindicated. With some head and neck cancers, however, radiotherapy to supradiaphragmatic areas can be used relatively safely with abdominal shielding of the fetus (Amant, 2015a).

Chemotherapy

Various antineoplastic drugs may be given for primary treatment or for adjunctive therapy. Although chemotherapy often improves long-term maternal outcomes, many are reluctant to employ it during pregnancy. Concerns for the fetus include malformations, growth restriction, intellectual disability, and the risk of future childhood malignancies. Risks are dependent primarily on fetal age at exposure, and most agents are potentially detrimental in the first trimester during organogenesis. Indeed, in one review, 14 percent of major malformations were attributable to first-trimester exposure to cytotoxic drugs (National Toxicology Program, 2013).

After the first trimester, most antineoplastic drugs are without immediate obvious adverse fetal sequelae (Abdel-Hady, 2012; Vercruysse, 2016). Similarly, late mutagenic effects appear limited (Amant, 2015b; Cardonick, 2015). Although not always practicable, some recommend that chemotherapy be withheld in the 3 weeks before expected delivery because neutropenia or pancytopenia might cause undue risk for maternal infection or hemorrhage. Another concern is that neonatal hepatic and renal clearance of chemotherapy metabolites is limited (Ko, 2011). For these reasons, most cytotoxic chemotherapy agents are contraindicated with breastfeeding (Pistilli, 2013).

Molecular Therapy

Drugs designed to stimulate hemopoiesis are commonly used with cancer treatments. Some of these include the granulocyte colony-stimulating factors filgrastim (Neupogen) and pegfilgrastim (Neulasta). If required in pregnancy, limited data support the safety of these agents (Boxer, 2015). Red blood cells can be stimulated by erythropoietin alfa (Procrit), which from case reports also appears safe in pregnancy (Sienas, 2013). However, maternal hypertension is a known potential risk.

Targeted Therapy

The two main types of targeted therapy are monoclonal antibodies and small molecule inhibitors. Both block the actions of specific enzymes, proteins, or other molecules involved in cancer cell growth. These drugs are designed to treat an ever-expanding list of cancers, and some are described in later discussions of specific tumors. Most of these compounds are labeled by the Food and Drug Administration (FDA) as class D, and data are limited regarding their pregnancy or breastfeeding effects.

Many of these drugs target tyrosine kinase, an important enzyme that regulates signaling pathways involved with cell division, differentiation, and apoptosis. With first-trimester use, embryo toxicity or teratogenicity has been attributed to these. Thus, this specific group of targeted agents is considered for use in pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus (Lodish, 2013).

Of other agents, the monoclonal antibody trastuzumab (Herceptin) inhibits the human epidermal growth factor receptor type 2 (HER2), which some breast cancers express. Although not teratogenic, its use in the second and third trimesters is associated with oligohydramnios, which appears to be reversible upon stopping the drug (Sarno, 2013; Zagouri, 2013b). Because of sparse available data, other HER2 inhibitors are best avoided in pregnancy (Lambertini, 2015).

Fertility and Pregnancy after Cancer Therapy

Fertility may be diminished after chemotherapy or radiotherapy. Counseling ideally takes place before cancer treatment, and guidelines for this have been developed (American Society for Reproductive Medicine, 2013a; Lambertini, 2016; Loren, 2013; Peccatori, 2013). Prior to therapy, cryopreservation of embryos or of oocytes is a recognized fertility-preserving option (American Society for Reproductive Medicine, 2013b,c). Surgical transposition of the ovaries can be considered if pelvic radiation is planned. For this, ovaries and their intact primary blood supply are carried out of the pelvis and fixed to the lateral abdominal wall at a site 3 to 4 cm above the level of the umbilicus. In one review, functional preservation was reported in 65 to 94 percent, depending on radiotherapy type (Gubbala, 2014). Also, such transposition requires transabdominal egg retrieval if later in vitro fertilization is planned (American Society for Reproductive Medicine, 2013a).

Ovarian suppression with gonadotropin-releasing hormone agonists is not beneficial, according to a recent review (Elgindy, 2015). At this time, cryopreservation of ovarian tissue is considered investigational. These methods currently are limited to referral centers.

In counseling cancer survivors, evidence suggests that exposure to most radiotherapy or chemotherapy agents in childhood or adulthood does not significantly increase the risk of congenital anomalies or genetic disease in their offspring (Haggar, 2014; Signorello, 2012; Stensheim, 2013; Winther, 2012). In those treated as children with chemotherapy, studies also do not show a consistent link to adverse obstetrical outcomes (Melin, 2015; Reulen, 2009). Data are limited regarding those with cancer treated as an adult, and some studies have shown slightly higher rates of preterm birth and cesarean delivery (Haggar, 2014; Stensheim, 2013).

Notably, prior abdominopelvic radiation more convincingly affects neonatal outcomes. Adverse effects include elevated rates of abortion, low birthweight, stillbirth, and preterm birth (Signorello, 2006, 2010; Winther, 2008). Radiation may lower reproductive potential by creating reduced uterine volume, a thinned endometrium, and impaired uterine blood flow (Critchley, 1992; Larsen, 2004). Greater effects are seen with direct uterine radiation and with radiotherapy at younger ages (Teh, 2014).

Importantly, many cancer survivors conceive by assisted reproductive technology, which by itself has associated obstetrical risks. This is discussed in Chapter 8 (Reproductive History).

Placental Metastases

Tumors infrequently metastasize to the placenta. As described in Chapter 6 (Amniochorion), the most common types are malignant melanomas, leukemias, lymphomas, and breast cancer (Al-Adnani, 2007). Placentas from pregnancies in these and all other women with a malignancy should be sent for histological evaluation. Because tumor cells are usually confined within the intervillous spaces, fetal metastases are infrequent.

Benign neoplasms are common and include leiomyomas, ovarian neoplasms, and endocervical polyps. Cancer in these organs may also complicate pregnancy, and of these, cervical neoplasia makes up the majority (Fig. 63-2).

Cervix

Endocervical Polyp

These are overgrowths of endocervical stroma covered by epithelium. They typically appear as single, red, elongated fleshy masses of variable size that extend outward from the endocervical canal. Usually benign, they can bleed and can be a source of Pap test results describing atypical glandular cells of undetermined significance—AGUS. With removal and histological evaluation of these polyps, dysplasia is diagnosed in up to 0.5 percent, and there is malignant transformation in up to 0.1 percent (Esim Buyukbayrak, 2011; Long, 2013).

Few formal data guide management in pregnancy. Small asymptomatic lesions may be left alone to slough during delivery or puerperal remodeling. Removal and histological evaluation is reasonable if malignancy is suspected or if bleeding is troublesome. For those with a slender stalk, the polyp is grasped with ring forceps and twisted repeatedly about its base to strangulate feeding vessels. With repeated twisting, the base narrows and avulses. Monsel paste, which is ferric subsulfate, can be applied with pressure to the stalk stub for hemostasis. A thick-pedicle polyp may sometimes warrant surgical ligation and excision.

Epithelial Neoplasia

Pregnancy provides an opportune time to screen for cervical intraepithelial neoplasia (CIN), especially in women without regular access to health care. With Pap test screening, pregnancy status is noted on the requisition form because interpretation may be hindered by pregnancy-associated physiological changes. Some of these changes include presence of decidual cells and less often, Arias-Stella reaction. The latter gives an appearance of endocervical gland hyperplasia, which can make differentiating this from truly atypical glandular cells difficult.

Screening guidelines also applicable in pregnant women were updated in 2012 by the American Society for Colposcopy and Cervical Pathology (ASCCP). These include: (1) no screening until age 21, (2) cytology alone every 3 years in those aged 21 to 29 years, and (3) in those older than 30, human papillomavirus (HPV) and cytology co-testing every 5 years, or cytology alone every 3 years (Massad, 2013). High-risk conditions for cervical neoplasia include human immunodeficiency virus (HIV) infection, other immunocompromised states, and in utero diethylstilbestrol (DES) exposure. For women with HIV infection, initiation of cervical cancer screening with cytology alone begins within the first year after HIV diagnosis (American College of Obstetricians and Gynecologists, 2016b).

Human Papillomavirus

This virus infects cervical epithelia. In most instances, the infection clears, but in a smaller number, the virus may promote benign, premalignant, or cancerous neoplastic growth. The prevalence of HPV infection in pregnant women approximates 15 percent (Hong, 2013; Liu, 2014). There are more than 100 serotypes, and several are associated with high-grade intraepithelial lesions and invasive cancer. The most prominent of these are serotypes 16 and 18. Cervical cancer screening that combines both cytology and testing for high-risk HPV serotypes is termed co-testing and is suitable for women 30 years and older. Notably, as a new paradigm for screening, primary HPV testing alone can be considered an appropriate sole method for women older than 25 years (Huh, 2015). With this, identification of serotypes 16 or 18 prompts colposcopic evaluation.

Serotypes HPV 6 and 11 are linked with benign maternal genital warts. Congenital HPV infection from vertical transmission—mother to fetus or newborn—beyond transient skin colonization is rare. Still, conjunctival, laryngeal, vulvar, or perianal warts present at birth in the neonate or that develop within 1 to 3 years of birth are most likely due to perinatal exposure to these maternal HPV serotypes. This is described further in Chapter 65 (Vaginitis). Importantly, cesarean delivery does not lower the risk of neonatal laryngeal papillomatosis.

The clear link between HPV infection and cervical neoplasia has prompted development of three approved vaccines. These are not administered during pregnancy, are compatible with breastfeeding, and are discussed in Chapter 65 (Vaginitis).

Abnormal Cytology and Histology

The incidence of abnormal cervical cytology during pregnancy is at least as high as that reported for nonpregnant women. Abnormal cytological findings and their suggested management according to consensus guidelines are summarized in Table 63-1. Many of these cytological abnormalities should prompt colposcopy, and the main goal during pregnancy is exclusion of invasive cancer. Accordingly, lesions suspicious for high-grade disease or cancer should undergo biopsy. Unsatisfactory colposcopic evaluation is less common during pregnancy because the transformation zone is better exposed due to cervical eversion. With insufficient visualization of the zone, colposcopy is repeated in 6 to 8 weeks. During this time, the squamocolumnar junction usually will further evert to permit satisfactory examination.

Women with histologically confirmed CIN during pregnancy may be allowed to deliver vaginally, with further evaluation planned after delivery. For those with CIN 1, the recommended management is reevaluation postpartum. For those with CIN 2 or 3 in which invasive disease has been excluded, deferring reevaluation until at least 6 weeks postpartum is acceptable. Alternatively, repeat colposcopic and cytological evaluations are performed at intervals no more frequent than 12 weeks. Repeat biopsy is recommended only if appearance of the lesion worsens or if cytology suggests invasive cancer (Massad, 2013).

Regression of a CIN lesion is common during pregnancy or postpartum. In a study of 1079 pregnant women with cervical dysplasia in which biopsy correlated with colposcopic findings, 61 percent of lesions reverted to normal postpartum (Fader, 2010). In another study, Yost and colleagues (1999) reported postpartum lesion regression in 70 percent of women with CIN 2 or 3. And, although 7 percent of women had CIN 2 lesions that progressed to CIN 3, no lesion progressed to invasive carcinoma. In another study of 77 women with carcinoma in situ (CIS) diagnosed during pregnancy, a third had postpartum regression of their lesion, two thirds had persistent CIS, and only two women had microinvasive cancer on cone biopsy after delivery (Ackermann, 2006).

Adenocarcinoma in situ (AIS) is managed similarly to CIN 3 (Dunton, 2008). Thus, unless invasive cancer is identified, treatment of AIS is not recommended until 6 weeks postpartum.

Cervical Conization

If invasive epithelial lesions are suspected, conization is indicated and may be done with loop electrosurgical excisional procedure (LEEP) or by cold-knife conization. However, the epithelium and underlying stroma within the endocervical canal cannot be extensively excised without the risk of membrane rupture. Logically, residual disease is common. Of 376 cone biopsies during pregnancy, Hacker and associates (1982) found residual neoplasia in 43 percent of subsequent specimens. In addition, nearly 10 percent of 180 pregnant women required transfusion after conization (Averette, 1970). Thus, if possible, conization is avoided in pregnancy because of its higher risks for abortion, membrane rupture, hemorrhage, and preterm delivery.

Women with CIN treated before pregnancy may also encounter pregnancy complications. First, cicatricial cervical stenosis is uncommon but may follow conization, LEEP, or laser surgery. Cervical stenosis almost always yields during labor. A so-called conglutinated cervix may undergo almost complete intrapartum effacement without dilation, and the presenting part is separated from the vagina by only a thin layer of cervical tissue. Spontaneous dilation usually promptly follows firm pressure with a fingertip, although instrumented dilation or cruciate incisions may be required.

Second, preconceptional cold-knife conization is associated with cervical insufficiency and preterm birth. That said, the relationship between preterm birth and LEEP continues to be debated (Castanon, 2012; Conner, 2014; Stout, 2015; Werner, 2010). The size of tissue excised seems to be directly related to adverse outcomes (Weinmann, 2017).

Invasive Cervical Cancer

The incidence of invasive cervical carcinoma has dramatically declined in the United States as a result of PAP testing (American College of Obstetricians and Gynecologists, 2016b). This cancer is found in approximately 1 in 8500 pregnancies (Bigelow, 2017; Pettersson, 2010). The diagnosis is confirmed with biopsies taken during colposcopy, with conization, or from a grossly abnormal lesion. Of the histological types, squamous cell carcinomas account for 75 percent of all cervical cancers, whereas adenocarcinomas compose the remainder. Cancers may appear as exophytic or endophytic growth; as a polypoid mass, papillary tissue, or barrel-shaped cervix; or as focal ulceration or necrosis. A watery, purulent, foul, or bloody discharge may also be present. Biopsy with Tischler forceps is warranted for suspicious lesions. Abnormal tumor vessels may cause heavier than expected biopsy-site bleeding, which is usually controlled by Monsel paste and pressure.

Cervical cancer is staged clinically, and 70 to 75 percent of cases that are diagnosed in pregnancy are stage I (Bigelow, 2017; Morice, 2012). Physiological pregnancy changes may impede accurate staging, and the extent of cancer is more likely to be underestimated in pregnant women. Specifically, induration of the broad ligament base, which characterizes tumor spread beyond the cervix, may be less prominent due to cervical, paracervical, and parametrial pregnancy-induced softening. Staging in pregnancy typically incorporates findings from pelvic examination and from renal sonography, chest radiography, cystoscopy, proctoscopy, and perhaps cone biopsy. Although MR imaging is not formally considered for clinical staging, it can be used without gadolinium contrast to ascertain involvement of the urinary tract and lymph nodes (Fig. 63-3).

Management and Prognosis

Cervical cancer treatment in pregnant women is individualized, and factors include the clinical stage, fetal age, and individual desire to continue pregnancy. Stage IA1 is termed microinvasive disease and describes lesions with deepest invasion ≤3 mm and widest lateral extension ≤7 mm (FIGO Committee on Gynecologic Oncology, 2009). If diagnosed by cone biopsy, then treatment follows guidelines similar to those for intraepithelial disease. In general, continuation of pregnancy and vaginal delivery are considered safe, and definitive therapy is reserved until 6 weeks postpartum.

In contrast, invasive cancer demands relatively prompt therapy. During the first half of pregnancy, immediate treatment is advised by most, but this depends on the decision whether to continue pregnancy. During the latter half of pregnancy, most agree that pregnancy can safely be continued until fetal lung maturity is attained (Greer, 1989). In two studies with a total of 40 women past 20 weeks’ gestation with either stage I or stage IIA carcinoma, delayed treatment was considered reasonable in women without bulky lesions (Takushi, 2002; van Vliet, 1998). Another option is to complete staging using laparoscopic lymphadenectomy and to delay treatment if metastases are excluded (Alouini, 2008; Favero, 2010). In a metaanalysis, neoadjuvant chemotherapy, that is, prior to surgery, with platinum derivatives was found to be promising for treatment in pregnancy (Zagouri, 2013a).

Although surgical therapy and radiation are equally effective, radical hysterectomy plus pelvic lymphadenectomy is the preferred treatment for invasive cervical cancer in most young women with stage I and early stage IIA lesions. Disadvantageously, radiotherapy for cervical cancer destroys ovarian and possibly sexual function, and frequently causes intestinal and urinary tract injury. In 49 women with pregnancy-associated stage IB cancer, a 30-percent severe complication rate accompanied radiotherapy compared with that of only 7 percent with radical surgery (Nisker, 1983). With surgery before 20 weeks’ gestation, radical hysterectomy is usually performed with the fetus in situ. In later pregnancy, however, hysterotomy is often performed first.

Although less commonly selected during pregnancy, other procedures have been investigated for early-stage cervical cancers. Ungár and colleagues (2006) performed abdominal radical trachelectomy before 20 weeks’ gestation for stage IB1 cancer in five pregnant women. Yahata and associates (2008) treated four women at 16 to 23 weeks for stage IA1 adenocarcinoma with laser conization, and all delivered at term. Van Calsteren and coworkers (2008) reported similar success.

For more advanced-stage cancer, radiotherapy is given. External beam radiation in early in pregnancy typically leads to spontaneous abortion. If miscarriage does not ensue, curettage is performed. During the second trimester, spontaneous abortion may not promptly occur and may necessitate hysterotomy in up to a fourth of cases. This is selected because labor induction or dilation and evacuation may pose serious hemorrhage risks.

Pregnancy does not have a negative effect on the prognosis of cervical cancer, and survival outcomes are similar for pregnant and nonpregnant women (Amant, 2014; Mogos, 2013). In a case-control study of 44 women with pregnancy-associated cervical cancer, the overall 5-year survival rate approximated 80 percent in both pregnant women and nonpregnant controls (van der Vange, 1995).

Delivery

Any adverse prognostic effects that vaginal delivery through a cancerous cervix might have are unknown. For this reason, the mode of delivery is controversial, especially for small, early-stage lesions. In some cases of bulky or friable tumors, significant hemorrhage from the cancer may complicate vaginal delivery. Also, recurrences have been reported in the episiotomy scar, which result from tumor cells apparently “seeding” the episiotomy (Goldman, 2003). Thus, most favor cesarean delivery.

Pregnancy after Radical Trachelectomy

There is growing experience with pregnancy in women who have undergone fertility-sparing radical trachelectomy for stage IB1 and IB2 cervical cancer before conception. During the typically vaginal procedure, the cervix is amputated at the level of the internal os, and a permanent-suture cerclage is placed around the isthmus for support in future pregnancies. The uterine isthmus is then reconstructed to the vagina. Because of the permanent cerclage, a classical cesarean incision is required for delivery.

Shepherd and colleagues (2006) presented outcomes for 123 such women cared for at their institution. Of 63 women who attempted pregnancy, 19 had 28 live births. All underwent classical cesarean delivery, and one fourth delivered before 32 weeks. Similar findings were reported by Kim (2012) and Park (2014) and their coworkers.

Uterus

Leiomyomas

Also known as myomas and somewhat erroneously called fibroids, uterine leiomyomas are common benign smooth-muscle tumors. Their incidence during pregnancy approximates 2 percent, and the cited range depends on the frequency of routine sonography and population characteristics (Qidwai, 2006; Stout, 2010). In one study of 4271 women, the first-trimester leiomyoma prevalence was highest in black women—18 percent—and lowest in whites—8 percent (Laughlin, 2009).

Leiomyomas vary in location and may develop as submucous, subserosal, or intramural growths. Less often, these develop in the cervix or broad ligament. Some become parasitic and their blood supply is derived from adjacent structures such as the highly vascularized omentum. In one rare manifestation–leiomyomatosis peritonealis disseminata–numerous, small, benign subperitoneal smooth-muscle tumors appear similar to carcinomatosis. The tumors are likely caused by estrogen stimulation of multicentric subcoelomic mesenchymal cells to become smooth-muscle cells (Bulun, 2015). These growths often regress after pregnancy.

The stimulatory effects of pregnancy progesterone on myoma growth are unpredictable and can be impressive. These tumors respond differently in individual women and may grow, regress, or remain unchanged in size during pregnancy (Laughlin, 2009; Neiger, 2006).

Especially during pregnancy, myomas can be confused with other adnexal masses, and sonographic imaging is indispensable (Fig. 63-4). In women in whom sonographic findings are unclear, MR imaging performed after the first trimester may be necessary. Once diagnosed, leiomyomas do not require surveillance with serial sonography unless associated complications are anticipated.

Symptoms

Most leiomyomas are asymptomatic, but acute or chronic pain or pressure may develop. Large myomas more often require admission for pain (Doğan, 2016). For chronic pain secondary to large tumor size, nonnarcotic analgesic drugs usually suffice. More acutely, some myomas can outgrow their blood supply and hemorrhagic infarction follows, which is termed red or carneous degeneration. Clinically, there is acute focal abdominal pain and tenderness, and sometimes a low-grade fever and leukocytosis. As such, tumor degeneration may be difficult to differentiate from appendicitis, placental abruption, ureteral stone, or pyelonephritis. Sonographic imaging can be helpful, but close observation is requisite because an infarcted myoma is essentially a diagnosis of exclusion. In some women, preterm labor is stimulated by associated inflammation.

Treatment of a degenerated myoma is analgesic medications, and symptoms usually abate within a few days. In severe cases, close observation may be needed to exclude a septic cause. Although surgery is rarely necessary during pregnancy, myomectomy in highly selected cases has resulted in good outcomes. Of 23 reported cases, women were 14 to 20 weeks’ gestation, and in almost half, surgery was performed because of pain (Celik, 2002; De Carolis, 2001). In some, an intramural leiomyoma was in contact with the implantation site. Except for one loss immediately following surgery at 19 weeks, most underwent cesarean delivery later, at term.

Occasionally, a pedunculated subserosal myoma will undergo torsion with subsequent painful necrosis. Laparoscopy or laparotomy can be used to ligate the stalk and resect the necrotic tumor. That said, we believe that surgery should be limited to tumors with a discrete pedicle that can be easily clamped and ligated.

Pregnancy Complications

Myomas are associated with several complications that include preterm labor, placental abruption, fetal malpresentation, obstructed labor, cesarean delivery, and postpartum hemorrhage. In a review of pregnancy outcomes in 2065 women with leiomyomas, Coronado and colleagues (2000) reported that placental abruption and breech presentation were each increased fourfold; first-trimester bleeding and dysfunctional labor, twofold; and cesarean delivery, sixfold. Salvador and associates (2002) reported an eightfold higher second-trimester abortion risk in these women.

Factors most important in determining morbidity in pregnancy are leiomyoma number, size, and location (Ciavattini, 2015; Jenabi, 2018; Lam, 2014). If the placenta is adjacent to or implanted over a leiomyoma, rates of abortion, preterm labor, placental abruption, and postpartum hemorrhage are all increased. Retroplacental myomas are also associated with fetal-growth restriction (Knight, 2016). Tumors in the cervix or lower uterine segment may obstruct labor, as did the one shown in Figure 63-5. Despite these complications, Qidwai and associates (2006) reported a 70-percent vaginal delivery rate in women in whom myomas measured ≥10 cm. These data argue against empirical cesarean delivery for leiomyomas, and we allow a trial of labor unless myomas clearly obstruct the birth canal. If cesarean delivery is indicated, uterine malrotation should be excluded prior to hysterotomy. Myomas are generally left alone unless they cause recalcitrant bleeding. An important caveat is that cesarean hysterectomy may be technically difficult because of lateral ureteral displacement by the masses.

Bleeding due to myomas may develop during pregnancy from any of several factors. Especially common is bleeding with miscarriage, preterm labor, placenta previa, and placental abruption. Much less often, bleeding may result from a submucous myoma that has prolapsed from the uterus and into the cervix or vagina. In this unusual circumstance, although heavy or persistent bleeding may require earlier intervention, the stalk, if accessible, can be ligated vaginally near term to avoid tumor avulsion during delivery.

Fortunately, myomas rarely become infected (Genta, 2001). When infection develops, it usually is postpartum, especially if the tumor is located immediately adjacent to the implantation site (Lin, 2002). They also may become infected with an associated septic abortion and myoma perforation by a sound, dilator, or curette.

Fertility Considerations

Despite the relatively high prevalence of myomas in young women, it is not clear whether they diminish fertility, other than by possibly causing miscarriage. In a review of 11 studies, Pritts (2001) concluded that submucous myomas did significantly affect fertility. He also found that hysteroscopic myomectomy improved infertility and early miscarriage rates in these women. If truly implicated in infertility, myomas in other locations may require laparoscopy or laparotomy for excision.

Some of these methods of treatment for infertility may affect subsequent pregnancies. For example, after myomectomy, the gravid uterus can rupture either before or during labor (American College of Obstetricians and Gynecologists, 2016a). Management is individualized, and review of the prior operative report is prudent. If resection resulted in a defect into or immediately adjacent to the endometrial cavity, then cesarean delivery is usually done before labor begins.

Although less effective than surgery, uterine artery embolization of myomas has also been used to treat infertility or symptoms (Mara, 2008). Women so treated have higher rates of miscarriage, cesarean delivery, and postpartum hemorrhage (Homer, 2010). The Society of Interventional Radiology considers myoma embolization relatively contraindicated in women who plan future pregnancies (Stokes, 2010).

Finally, outside the United States, ulipristal—a selective progesterone-receptor modulator—can be used for myoma regression. Successful subsequent pregnancies without tumor regrowth have been reported (Luyckx, 2014).

Endometrial Lesions

Occasionally, endometriosis can develop after delivery from endometrial tissue implanted within cesarean delivery or episiotomy scars (Bumpers, 2002). Here, they form a palpable mass and can cause cyclic localized pain. Endometriomas within an ovary are discussed in the next section.

Adenomyosis is traditionally found in late reproductive life and beyond. Its acquisition may be at least partially related to disruption of the endometrial-myometrial border during sharp curettage for abortion (Curtis, 2002). In a case-control study, Hashimoto and colleagues (2017) reported significantly higher associated rates of second-trimester abortion, preeclampsia, fetal malposition, and preterm delivery.

Endometrial carcinoma is an estrogen-dependent neoplasia also usually found in women older than 40 years. Thus, it is seen only rarely with pregnancy. Of 27 cases that were identified during pregnancy or within the first 4 months postpartum, most were found in first-trimester curettage specimens (Hannuna, 2009). These are usually early-stage, well-differentiated adenocarcinomas for which treatment consists primarily of total abdominal hysterectomy and bilateral salpingo-oophorectomy. Much less commonly, to preserve future fertility, curettage with or without postprocedural progestational therapy has been used for the rare patient with cancer identified in a miscarriage curettage specimen (Schammel, 1998).

Many more studies describe a conservative approach for well-selected nonpregnant women diagnosed with endometrial cancer who wish to preserve fertility. One study followed 13 women treated with progestins for early-stage, well-differentiated adenocarcinoma who then later conceived after apparent remission (Gotlieb, 2003). Nine had liveborn neonates, and four of six women with a recurrence responded to another course of therapy. Similar outcomes were described in 12 women by Niwa (2005) and in 21 women by Signorelli (2009), each with their coworkers. Despite these acceptable pregnancy rates, recurrences and death have been reported, and conservative management is not considered standard (Erkanli, 2010).

Ovary

Ovarian masses found during pregnancy are relatively common. Among studies, incidences vary depending on the frequency of prenatal sonography, the ovarian size threshold used to define a clinically significant “mass,” and whether the study site is tertiary or primary care. Thus, the incidence of ovarian masses not surprisingly ranges from 1 in 100 to 2000 pregnancies (Whitecar, 1999; Zanetta, 2003). Of ovarian malignancies, the absolute incidence in the California Cancer Registry was 1 in 19,000 pregnancies (Smith, 2003).

The most frequent types of ovarian masses are corpus luteum cysts, endometriomas, benign cystadenomas, and mature cystic teratomas. Because pregnant women are usually young, malignant tumors and those of low malignant potential are proportionately uncommon. Our experiences from Parkland Hospital are similar to those of Leiserowitz and associates (2006), who found that 1 percent of 9375 ovarian masses were frankly malignant and that another 1 percent were of low malignant potential. In surgically excised masses, rates of malignancy are higher, vary from 4 to 13 percent, and probably reflect a greater preoperative concern for cancer (Hoffman, 2007; Sherard, 2003).

Most ovarian masses are asymptomatic in pregnant women. Some cause pressure or chronic pain, and acute abdominal pain may be due to torsion, rupture, or hemorrhage. Seldom is blood loss significant enough to cause hypovolemia.

Diagnosis

Many ovarian masses are detected during routine prenatal sonography or during imaging done for other indications, including evaluation of symptoms. The typical sonographic appearance of these masses is shown in Figure 63-6. In some instances, MR imaging can be used to evaluate complicated anatomy.

Cancer antigen 125 (CA125) serves as a tumor marker, and levels are frequently elevated with ovarian malignancy. Importantly, concentrations of CA125 in early pregnancy and early puerperium are normally elevated, possibly from the decidua (Aslam, 2000; Spitzer, 1998). As shown in the Appendix (Serum and Blood Constituents), from the second trimester until term, levels are not normally higher than those in the nonpregnant woman (Szecsi, 2014). With severe preeclampsia, however, levels are abnormally elevated (Karaman, 2014). Other tumor markers that are not useful for diagnosis or posttreatment surveillance in pregnancy include human chorionic gonadotropin (hCG), alpha-fetoprotein, inhibins A and B, and the multimarker OVA1 test (Liu, 2011).

Complications

The two most common are torsion and hemorrhage. Torsion usually causes acute constant or episodic lower abdominal pain that frequently is accompanied by nausea and vomiting. Sonography often aids the diagnosis. With color Doppler, presence of an ovarian mass with absent flow strongly correlates with torsion. However, minimal or early twisting may compromise only venous flow, thus leaving the arterial supply intact. If torsion is suspected, laparoscopy or laparotomy is warranted. Contrary to prior teaching, adnexectomy is generally unnecessary to avoid clot release, thus, most recommend attempts at untwisting (McGovern, 1999; Zweizig, 1993). With a salvageable ovary, within minutes, congestion is relieved, and ovarian volume and cyanosis diminish. If cyanosis persists, however, then removal of the infarcted adnexum is typically indicated.

If the adnexum is healthy, there are options. First, neoplasms are resected. However, ovarian cystectomy in an ischemic, edematous ovary may be technically difficult, and adnexectomy may be necessary. Second, unilateral or bilateral oophoropexy has been described to minimize the risk of repeated torsion (Djavadian, 2004; Germain, 1996). Techniques described include shortening of the uteroovarian ligament or fixing the uteroovarian ligament to the posterior uterus, the lateral pelvic wall, or the round ligament (Fuchs, 2010; Weitzman, 2008).

The most common cause of ovarian hemorrhage follows rupture of a corpus luteum cyst. If the diagnosis is certain and symptoms abate, then observation and surveillance is usually sufficient. Concern for ongoing bleeding will typically prompt surgical evaluation. If the corpus luteum is removed before 10 weeks’ gestation, progestational support is recommended to maintain the pregnancy. Suitable regimens include: (1) micronized progesterone (Prometrium) 200 or 300 mg orally once daily; (2) 8-percent progesterone vaginal gel (Crinone), one premeasured applicator vaginally daily plus micronized progesterone 100 or 200 mg orally once daily; or (3) intramuscular 17-hydroxyprogesterone caproate, 150 mg. The first two regimens are given until 10 completed weeks. For the last, if given between 8 and 10 weeks’ gestation, only one injection is required immediately after surgery. If the corpus luteum is excised between 6 and 8 weeks’ gestation, then two additional doses should be given 1 and 2 weeks after the first.

Asymptomatic Adnexal Mass During Pregnancy

Because most of these are incidental findings, management considerations include whether resection is necessary and its timing. A cystic benign-appearing mass that is <5 cm often requires no additional antepartum surveillance. Early in pregnancy, this is likely a corpus luteum cyst, which typically resolves by the early second trimester. For cysts ≥10 cm, because of the substantial risk of malignancy, torsion, or labor obstruction, surgical removal is reasonable. Tumors between 5 and 10 cm should be carefully evaluated by sonography along with color Doppler and possibly MR imaging. If they have a simple cystic appearance, these cysts can be managed expectantly with sonographic surveillance (Schmeler, 2005; Zanetta, 2003). Resection is done if cysts grow, begin to display malignant qualities, or become symptomatic. Those with classic findings of endometrioma or mature cystic teratoma may be resected postpartum or during cesarean for obstetrical indications.

On the other hand, if sonographic characteristics suggest cancer—thick septa, nodules, papillary excrescences, or solid components—immediate resection is indicated (Caspi, 2000). In one review of 563 masses, approximately half were simple, and the other half complex (Webb, 2015). Among simple masses, 1 percent were malignant, and of complex masses, 9 percent were cancerous.

Approximately 1 in 1000 pregnant women undergoes surgical exploration for an adnexal mass (Boulay, 1998). In general, we plan resection at 14 to 20 weeks’ gestation because most masses that will regress will have done so by this time. As outlined in Chapter 46 (Medications and Surgeries), laparoscopic removal is ideal (Naqvi, 2015; Sisodia, 2015). Importantly, in any instance in which cancer is strongly suspected, the American College of Obstetricians and Gynecologists (2017b) recommends consultation with a gynecologic oncologist.

Pregnancy-Related Ovarian Tumors

Pregnancy Luteoma

One group of ovarian masses results directly from the stimulating effects of various pregnancy hormones on ovarian stroma. These include pregnancy luteoma, hyperreactio luteinalis, and ovarian hyperstimulation syndrome.

Of these, pregnancy luteoma is a rare, benign ovarian neoplasm that arises from luteinized stromal cells and classically causes elevated testosterone levels (Hakim, 2016; Irving, 2011). Up to 25 percent of affected women will be virilized, and of these affected women, nearly half of their female fetuses will have some degree of virilization. However, most mothers and their fetuses are unaffected because the placenta rapidly converts testosterone to estrogen (Kaňová, 2011).

In typical cases, an adnexal mass along with maternal virilization will prompt sonography and measurement of testosterone and CA125 levels. Luteomas range in size from microscopic to >20 cm. They appear as solid tumors, may be multiple or bilateral, and may be complex because of internal hemorrhage (Choi, 2000). Concerns for malignancy may be further investigated with MR imaging (Kao, 2005; Tannus, 2009).

Total testosterone levels are increased, but notably, levels in normal pregnancy can be substantially elevated (Appendix, Serum and Blood Constituents). Differential diagnoses include granulosa cell tumors, thecomas, Sertoli-Leydig cell tumors, Leydig cell tumors, stromal hyperthecosis, and hyperreactio luteinalis.

Generally, luteomas do not require surgical intervention unless there is torsion, rupture, or hemorrhage (Masarie, 2010). These tumors spontaneously regress during the first few months postpartum, and androgen levels drop precipitously during the first 2 weeks following delivery (Wang, 2005). Lactation may be delayed a week or so by hyperandrogenemia (Dahl, 2008). Recurrence in subsequent pregnancies is rare.

Hyperreactio Luteinalis

In this condition, one or both ovaries develop multiple, large theca-lutein cysts, typically after the first trimester. Cysts are caused by luteinization of the follicular theca interna layer, and most are in response to stimulation by exceptionally high hCG levels (Russell, 2009). For this reason, they are more common with gestational trophoblastic disease, twins, fetal hydrops, and other conditions with increased placental mass. Maternal virilization may develop, but fetal virilization has not been reported (Kaňová, 2011; Malinowski, 2015).

As reported by Baxi and coworkers (2014), these ovarian tumors appear sonographically to have a “spoke wheel” pattern (Fig. 20-3). If the diagnosis is confident, and unless complicated by torsion or hemorrhage, surgical intervention is not required. These masses resolve after delivery. Few data allow prediction of risk in a subsequent pregnancy, but in one case report, a woman had hyperreactio with three pregnancies (Bishop, 2016).

Ovarian Hyperstimulation Syndrome

This is typified by multiple ovarian follicular cysts accompanied by increased capillary permeability. It most often is a complication of ovulation-induction therapy for infertility, although it rarely may develop in an otherwise normal pregnancy. It has also been reported with a partial molar pregnancy (Suzuki, 2014). Its etiopathogenesis is thought to involve hCG stimulation of vascular endothelial growth factor (VEGF) expression in granulosa-lutein cells (Soares, 2008). This causes greater vascular permeability that can lead to ascites, pleural or pericardial effusion, hypovolemia with acute kidney injury, and hypercoagulability. Serious complications are renal dysfunction, adult respiratory distress syndrome, ovarian rupture with hemorrhage, and VTE. Unlike hyperreactio lutealis, virilization is absent (Suzuki, 2004).

Detailed guidelines for management are outlined by the American Society for Reproductive Medicine (2016). Treatment is primarily supportive with attention to maintaining vascular volume and thromboprophylaxis. In severe cases, paracentesis can be helpful.

Ovarian Cancer

Malignancies of the ovary are the leading cause of death from genital-tract cancers in all women (American Cancer Society, 2017). Still, it is uncommon in young women, and the incidence of ovarian malignancy ranges from 1 in 20,000 to 1 in 50,000 births (Eibye, 2013; Palmer, 2009). Fortunately, 75 percent of these found in pregnancy are early-stage cancers that carry a 5-year survival rate between 70 and 90 percent (Brewer, 2011). The types of malignancy are also markedly different in pregnant women compared with those in older women. In gravidas, these are, in decreasing order of frequency, germ cell and sex cord-stromal tumors, low-malignant-potential tumors, and epithelial tumors (Morice, 2012).

Pregnancy apparently does not alter the prognosis of most ovarian malignancies. Management is similar to that for nonpregnant women, with the usual proviso that it may be modified depending on gestational age. Thus, if frozen section histopathological analysis verifies malignancy, surgical staging is done with careful inspection of all accessible peritoneal and visceral surfaces (Giuntoli, 2006). Peritoneal washings are taken for cytology, biopsies are obtained from the diaphragmatic surface and peritoneum, omentectomy is completed, and pelvic and infrarenal paraaortic lymph nodes are sampled, if accessible.

If there is advanced disease, bilateral adnexectomy and omentectomy will decrease most tumor burden. In early pregnancy, hysterectomy and aggressive surgical debulking procedures may be elected. In other cases, minimal debulking as described in the previous paragraph is done and the operation terminated. In some cases of aggressive or large-volume disease, chemotherapy can be given during pregnancy while awaiting pulmonary maturation. Monitoring maternal CA125 serum levels during chemotherapy is not accurate in pregnancy (Aslam, 2000; Morice, 2012).

Adnexal Cysts

Paratubal and paroovarian cysts are either distended remnants of the paramesonephric ducts or are mesothelial inclusion cysts. Although most measure ≤3 cm, they occasionally attain worrisome dimensions. Their reported incidence is influenced by size, but one autopsy series in nonpregnant women cited this to be 5 percent (Dorum, 2005). The most common paramesonephric cyst is the hydatid of Morgagni, which is pedunculated and typically dangles from one of the fimbria. These cysts infrequently cause complications and are most often identified at the time of cesarean delivery or puerperal sterilization. In these instances, they can simply be excised or drained by creating a large window in the cyst wall. Neoplastic paraovarian cysts are rare, sonographically and histologically resemble tumors of ovarian origin, and rarely are of borderline potential or frankly malignant (Korbin, 1998).

Vulva and Vagina

Preinvasive disease in young women—vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN)— are seen more often than invasive disease and are commonly associated with HPV infection. As with cervical neoplasia, these premalignant conditions are treated after delivery.

Cancer of the vulva or vagina is generally a malignancy of older women, and thus, these are rarely associated with pregnancy. Even so, any suspicious lesions should be biopsied. Treatment is individualized according to the clinical stage and depth of invasion. In a review of 23 cases, investigators concluded that radical surgery for stage I disease was feasible during pregnancy—including in the last trimester (Heller, 2000).

We and others question the necessity of resection in late pregnancy because definitive therapy can often be delayed due to these cancers’ typically slow progression (Anderson, 2001). It appears that vaginal delivery is not contraindicated if vulvar and inguinal incisions are well healed. Vulvar sarcoma, vulvar melanoma, and vaginal malignancies are rare in pregnancy and are the subjects of case reports (Alexander, 2004; Kuller, 1990; Matsuo, 2009).

Breast cancer rates rise most acutely between ages 40 and 80 years. However, because of its overall high frequency, breast cancer is relatively common even in younger women and is the most frequent cancer found in gravidas. From the Nationwide Inpatient Sample of 11.8 million births, the incidence approximated 1 in 15,000 (Maor, 2017). And, as more women choose to delay childbearing, the frequency of associated breast cancer is certain to grow. Postponed childbearing was considered partially responsible for the increase in pregnancy-associated breast cancer in Sweden and Denmark (Andersson, 2015; Eibye, 2013).

Some studies suggest that women with a family history of breast cancer—especially those with BRCA1 and BRCA2 breast cancer gene mutations—are more likely to develop breast malignancy during pregnancy (Wohlfahrt, 2002). However, it may be that it is parity that modifies this risk. Namely, parous women older than 40 years with these mutations have a significantly lower cancer risk than nulliparas with these mutated genes (Andrieu, 2006; Antoniou, 2006). Women with BRCA1 and BRCA2 gene mutations who undergo induced abortion or those who breastfeed do not have an increased breast cancer risk (Friedman, 2006). Moreover, Jernström and associates (2004) found that breastfeeding conveyed a protective effect against this cancer in those with BRCA1 gene mutation, but not in those with BRCA2 mutations. Of other congenital factors, it is controversial whether DES exposure raises breast cancer risks (Hoover, 2011; Titus-Ernstoff, 2006).

Diagnosis

More than 90 percent of gravidas with breast cancer have a palpable mass, and greater than 80 percent of cases are self-reported (Brewer, 2011). In pregnancy, clinical assessment, diagnostic procedures, and treatment of women with breast tumors are often slightly delayed (Berry, 1999). This can be partially attributed to pregnancy-induced breast tissue that obscures masses.

The evaluation of pregnant women with a breast mass does not differ from that for nonpregnant women (Loibl, 2015). Thus, any suspicious breast mass should be pursued to diagnosis. Pragmatically, a palpable discrete mass can be biopsied or excised. If imaging is desirable to distinguish between a solid mass and a cystic lesion, sonography has high sensitivity and specificity (Navrozoglou, 2008). Mammography is appropriate if indicated, and the fetal radiation risk is negligible—0.04 mGy—with appropriate shielding (Krishna, 2013). But, because breast tissue is denser in pregnancy, mammography has a false-negative rate of 35 to 40 percent (Woo, 2003). If the decision to biopsy is uncertain, then MR imaging may be used. With such techniques, masses can usually be described as either solid or cystic.

Cystic breast lesions are simple, complicated, or complex (Berg, 2003). Simple cysts do not require special management or monitoring, but they may be aspirated if symptomatic. Complicated cysts show internal echoes during sonography, and they sometimes are indistinguishable from solid masses. These are typically aspirated, and if the sonographic abnormality does not resolve completely, a core-needle biopsy is usually performed. Complex cysts have septa or intracystic masses seen sonographically. Because some breast cancer may form complex cysts, excision is usually recommended.

For solid breast masses, evaluation is with the triple test, that is, clinical examination, imaging, and core needle biopsy. If all three suggest a benign lesion or if all three suggest a breast cancer, the test is said to be concordant. A concordant benign triple test is ≥99-percent accurate, and breast lumps in this category can be followed by clinical examination alone. Fortunately, most masses in pregnancy have these three reassuring features. In contrast, if any of the three assessments suggests malignancy, the mass should be excised.

Management

Once breast cancer is diagnosed, a limited search of the most common metastatic sites is completed. For most women, this includes a chest radiograph, liver sonography, and skeletal MR imaging (Becker, 2016; Krishna, 2013).

Treatment of breast cancer is multidisciplinary and includes an obstetrician, breast surgeon, and medical oncologist. Initially, desires for pregnancy continuation are addressed, and data indicate that pregnancy interruption does not influence the course or prognosis of breast cancer (Cardonick, 2010). With pregnancy continuation, treatment in general mirrors that for nonpregnant women. Important caveats are that chemotherapy and surgery are postponed to the second trimester, and adjuvant radiotherapy is withheld until after delivery (Brewer, 2011).

Surgical treatment may be definitive. In the absence of metastatic disease, either a wide excision or a modified or total mastectomy—each with axillary node staging—can be performed (Rosenkranz, 2006). Staging by sentinel lymph node biopsy and lymphoscintigraphy with technetium-99m is safe. Breast reconstruction, if desired, is typically delayed until after delivery (Viswanathan, 2011). That said, Caragacianu and coworkers (2016) described good results in 10 pregnant women who underwent immediate reconstruction after mastectomy.

Chemotherapy is usually given with both positive- and negative-node breast cancers. In premenopausal women, survival rates with this approach are improved, even if lymph nodes are cancer free. For node-positive disease, multiagent chemotherapy is begun if delivery is not anticipated within several weeks. Cyclophosphamide, doxorubicin, and cisplatin are currently used (Euhus, 2016). If an anthracycline-based agent such as doxorubicin is used, pretherapy maternal echocardiography is performed because of associated cardiotoxicity (Brewer, 2011). Good maternal and perinatal results have been reported (Berry, 1999; Hahn, 2006).

Immunotherapy for breast cancers is now commonplace. Trastuzumab (Herceptin) is a monoclonal antibody to the HER2/neu receptor, which is found in approximately a third of invasive breast cancers (Hudis, 2007). The drug is not recommended in pregnancy. This is because HER2/neu is strongly expressed in fetal renal epithelium, and trastuzumab has been linked with miscarriage, fetal renal failure and related oligohydramnios, and preterm birth (Amant, 2010; Azim, 2010).

The effects of pregnancy on the course of breast cancer and its prognosis are complex. Breast cancer is more aggressive in younger women, but whether it is more aggressive during pregnancy in these same women is debatable (Azim, 2014). Clinically, most studies indicate little difference in overall survival rates with pregnancy-associated breast cancer compared with similarly aged and staged nonpregnant women (Beadle, 2009). Other reports note worse overall survival rates with pregnancy-associated breast cancer (Rodriguez, 2008). These investigators do conclude, however, that later disease stages are more prevalent in pregnant women.

Indeed, breast cancer is usually found at a more advanced stage in pregnant women, and thus overall prognosis is diminished (Andersson, 2015). The aggregate of studies published after 1990 indicate that up to 60 percent of pregnant women have concomitant axillary node involvement at diagnosis. And although, stage for stage, the 5-year survival rate is comparable in pregnant and nonpregnant women, the more advanced stages that are typical of pregnant women worsen their prognosis (Kuo, 2017; Zemlickis, 1992).

Pregnancy Following Breast Cancer

After breast cancer treatment, chemotherapy will render some women infertile, and options for childbearing are limited (Kim, 2011). For those who become pregnant, long-term maternal survival rates are not adversely affected (Averette, 1999; Velentgas, 1999). One metaanalysis of 10 studies found that for women with early breast cancer, pregnancy that occurs 10 months after diagnosis may, in fact, confer a survival benefit (Valachis, 2010). Data do not indicate that breastfeeding adversely alters the course.

In women successfully treated for breast cancer, recurrence is a concern. Because recurrences are more common soon after treatment, it seems reasonable to delay conception for 2 to 3 years. Hormonal contraceptive methods are contraindicated, and a copper-containing intrauterine device is an excellent long-acting reversible method for many. That said, women who conceive do not appear to have diminished survival rates (Ives, 2006). Notably, women treated with tamoxifen are at risk for several months after its discontinuation to have a newborn with congenital anomalies. This drug has an extremely long half-life, and thus delaying conception is recommended for at least 2 months after tamoxifen completion (Braems, 2011).

Palpable thyroid nodules are detected in 4 to 7 percent of the population, and approximately 10 percent are malignant (Burman, 2015). Clinical nodules are typically evaluated with sonography and measurement of serum thyroid-stimulating hormone (TSH) and free thyroxine levels. Fine-needle aspiration is indicated for a suspicious nodule (Alexander, 2017; Gharib, 2016).

With a diagnosis of thyroid malignancy, pregnancy termination is not necessary. Primary therapy is thyroidectomy performed ideally during the second trimester. Postoperatively, replacement thyroxine is given. Most thyroid cancers are well differentiated and follow an indolent course. Thus, delayed surgical treatment does not usually alter outcome (Yazbeck, 2012; Yu, 2016).

In some types of thyroid cancer, radioiodine is used for primary or postoperative treatment. This is contraindicated in both pregnancy and lactation for several reasons. First, transplacental ¹³¹I is avidly trapped by the fetal thyroid gland to cause hypothyroidism. Second, during lactation, the breast also concentrates a substantial amount of iodide. This may pose neonatal risk due to radioiodine-contaminated milk ingestion and maternal risk from significant breast irradiation. To limit maternal exposure, a delay of 3 months between lactation and thyroid ablation will more reliably ensure complete breast involution (Sisson, 2011). In women with thyroid cancer who ultimately receive ¹³¹I doses, pregnancy should be avoided for 6 months to 1 year. This time ensures thyroid function stability and permits confirmation of cancer remission (Abalovich, 2007).

Hodgkin Disease

This lymphoma is probably B-cell derived and is cytologically distinguished from other lymphomas by Reed–Sternberg cells. Of cancers in pregnancy, lymphomas are common, and gestational rates are rising because of delayed childbearing (Horowitz, 2016). In pregnant women, Hodgkin lymphomas are more frequent than non–Hodgkin lymphomas. In one population-based review of 7.9 million births from the Nationwide Inpatient Sample, El-Messidi and colleagues (2015) reported its incidence to be 1 in 12,400.

In more than 70 percent of Hodgkin disease cases, lymph nodes painlessly enlarge at sites above the diaphragm, that is, in the axillary, cervical, or submandibular chains. Approximately one third of patients have symptoms such as fever, night sweats, malaise, weight loss, and pruritus. Diagnosis is by histological examination of involved nodes (Longo, 2015).

The Ann Arbor staging system, shown in Table 63-2, is applied to Hodgkin and other lymphomas. For staging, pregnancy limits the use of some radiographic studies, but at minimum, chest radiography, abdominal imaging with sonography or MR imaging, and bone marrow biopsy are completed (Williams, 2001). MR imaging is excellent for evaluating thoracic and abdominal paraaortic lymph nodes (Brenner, 2012). Staging laparotomy is seldom done today (Longo, 2015).

The current trend for nonpregnant individuals is to administer chemotherapy for all stages of Hodgkin disease. In pregnancy, for early-stage disease in the first trimester, options include observation until after 12 weeks’ gestation, single-agent vinblastine until the second trimester, pregnancy termination followed by multiagent chemotherapy, or radiotherapy alone for isolated neck or axillary sites (El-Hemaidi, 2012; Eyre, 2015).

For advanced-stage disease, chemotherapy is recommended regardless of gestational age. Before 20 weeks, therapeutic abortion is a consideration, but if termination is unacceptable, then treatment with vinblastine followed by multiagent therapy in the second trimester can be used (Eyre, 2015). For most advanced-stage disease after the first trimester, cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine are given, and radiotherapy can be added postpartum (Cohen, 2011). In general, postponement of therapy until fetal maturity is achieved seems justifiable only when the diagnosis is made late in pregnancy.

Women with Hodgkin lymphoma have a higher incidence of VTE (El-Messidi, 2015; Horowitz, 2016). Also, in our experiences, pregnant women with Hodgkin disease—even after they are “cured”—are inordinately susceptible to infection and sepsis. Active antineoplastic therapy only increases this vulnerability.

The overall prognosis with Hodgkin lymphoma is good, and survival rates exceed 70 percent. Pregnancy does not adversely affect the cancer course or pregnancy outcomes in women with this lymphoma. Specifically, neither chemotherapy after the first trimester nor mediastinal and neck irradiation has adverse fetal effects (Brenner, 2012; El-Messidi, 2015; Pinnix, 2016). For women with disease in remission, pregnancy does not stimulate a relapse (Weibull, 2016).

Non-Hodgkin Lymphomas

Although usually B-cell tumors, non-Hodgkin lymphomas can also be T-cell or natural-killer-cell neoplasms. Their biology, classification, and treatment are complex (Longo, 2015; O’Gara, 2009). They are associated with viral infections, and indeed, their incidence has risen sharply at least partly because 5 to 10 percent of HIV-infected persons develop lymphoma. Other associated viruses include Epstein-Barr virus, hepatitis C virus, and human herpes virus 8. Some of these lymphomas are aggressive, and survival rates vary with the type of cell line involved (Longo, 2015).

Non-Hodgkin lymphomas are infrequent during pregnancy (Brenner, 2012; Pinnix, 2016). They are also staged according to the Ann Arbor system. If diagnosed in the first trimester, pregnancy termination followed by multiagent chemotherapy is recommended for all but indolent or very early disease. These less aggressive forms may either be observed or be temporized with focal supradiaphragmatic radiotherapy and then full treatment in the second trimester. If one of these lymphomas is diagnosed after the first trimester, chemotherapy and immunotherapy with rituximab are given (Cohen, 2011; Rizack, 2009). In one follow-up of 55 individuals at 6 to 29 years after exposure to chemotherapy in utero during maternal lymphoma treatment, no congenital, neurological, or psychological abnormalities were noted (Avilés, 2001).

Burkitt lymphoma is an aggressive B-cell tumor associated with Epstein-Barr virus infection. Prognosis is poor, and treatment is given with multiagent chemotherapy. In a review of 19 women whose pregnancies were complicated by this lymphoma, 17 died within a year of diagnosis (Barnes, 1998).

Leukemias

In general, these malignancies arise either from lymphoid tissues—lymphoblastic or lymphocytic leukemias, or from bone marrow—myeloid leukemias. They can be acute or chronic. Although adult leukemias are more prevalent after age 40, they still are among the most common malignancies of young women (see Fig. 63-1). Leukemia was diagnosed in 1 in 40,000 pregnancies reported to the California Cancer Registry (Smith, 2003). In a review of 72 pregnancies complicated by leukemia from 1975 until 1988, 44 had acute myelogenous leukemia; 20 had acute lymphocytic leukemia; and eight had one of the chronic leukemias (Caligiuri, 1989).

Acute leukemias almost always cause marked peripheral blood count abnormalities, and often the white blood cell count is elevated with readily recognizable circulating blast cells. The diagnosis is made from bone marrow biopsy.

With current multiagent chemotherapy, remission during pregnancy is common, compared with an almost 100-percent mortality rate before 1970. Pregnancy termination does not further improve the prognosis, however, abortion is a consideration in early pregnancy to avoid potential chemotherapy teratogenesis. One example of the latter is treatment of acute promyelocytic leukemia with all-trans-retinoic acid, also known as tretinoin (Carradice, 2002; Sanz, 2015). This potent teratogen causes retinoic acid syndrome (Chap. 12, Retinoids). In another example, acute myeloid leukemia is treated with tyrosine kinase inhibitors, another teratogen group (Palani, 2015). In other cases, pregnancy termination before viability may simplify management of an acutely ill woman.

Other than these caveats, treatment of gravidas with leukemia is similar to that for nonpregnant women. Acute myeloid leukemia is treated without delay (Ali, 2015). After induction chemotherapy, postremission maintenance therapy is mandatory to prevent a relapse, which is then usually treated with stem-cell transplantation. If allogeneic stem-cell transplantation is indicated, early delivery is considered. With some chronic leukemias, it may be possible to delay therapy until after delivery (Fey, 2008). As with lymphoma, infection and hemorrhage are significant complications that should be anticipated in women with active disease.

Most descriptions of leukemia treatment in pregnancy are single cases or small series (Routledge, 2016; Sanz, 2015). In an earlier review of 58 cases, 75 percent were diagnosed after the first trimester (Reynoso, 1987). Half were acute myelogenous leukemia, which had a remission rate of 75 percent with chemotherapy. Only 40 percent of these pregnancies resulted in liveborn neonates (Caligiuri, 1989).

These most frequently originate from a preexisting skin nevus and its pigment-producing melanocytes. Melanomas should be suspected in pigmented lesions that show changes in contour, surface elevation, discoloration, bleeding, or ulceration, which should prompt biopsy (Richtig, 2017). They are most common in light-skinned whites and develop relatively frequently in women of childbearing age.

In some population studies, melanoma is the most frequent malignancy complicating pregnancy (Andersson, 2015; Bannister-Tyrrell, 2015). Still, the reported incidence ranges widely from 0.03 to 2.8 per 1000 live births (Eibye, 2013; Smith, 2003). One explanation is that many are treated as outpatients and thus are not entered into tumor registries. As noted earlier (Reproductive Tract Neoplasms), malignant melanoma is one of the tumors that is known to metastasize to the placenta and fetus. Placental evaluation for metastases should be performed after delivery.

Staging is clinical. Stage I is a melanoma with no palpable lymph nodes; in stage II, lymph nodes are palpable; and in stage III, there are distant metastases. For patients with stage I, tumor thickness is the single most important predictor of survival. The Clark classification includes five levels of involvement by depth into the epidermis, dermis, and subcutaneous fat. The Breslow scale measures tumor thickness and size, in addition to depth of invasion.

Primary surgical treatment for melanoma is determined by the stage and includes wide local resection, sometimes with extensive regional lymph node dissection. Schwartz and associates (2003) recommend sentinel lymph node mapping and biopsy using ^99mTc-sulfur colloid, which has a calculated fetal dose of 0.014 mSv or 0.014 mGy. Routine regional node dissection reportedly improves survival rates in nonpregnant patients with microscopic metastases (Cascinelli, 1998). For pregnant patients, an algorithm has been proposed that begins with resection of the primary tumor under local anesthesia but postpones sentinel lymph node biopsy until after delivery (Broer, 2012). Although prophylactic chemotherapy or immunotherapy is usually avoided during pregnancy, it may be given if indicated by tumor stage and maternal prognosis. In most cases of distant metastatic melanoma, treatment is at best palliative. Currently, the role of estrogen receptor-β in melanoma progression is under investigation, and it may be a target for future therapeutic intervention (de Giorgi, 2011).

Stage-for-stage, survival is equivalent between pregnant and nonpregnant women (Driscoll, 2016; Johansson, 2014). In one study, half of pregnant women had stage III or IV lesions (de Haan, 2017). Therapeutic abortion does not improve maternal survival rates. Clinical stage is the strongest determinant of survival, and women with deep cutaneous invasion or regional node involvement have the worst prognosis. Approximately 60 percent of recurrences will manifest within 2 years, and 90 percent by 5 years. Thus, most recommend that pregnancy be avoided for 3 to 5 years after surgical resection. Interim contraception can include combination oral contraceptives, as they do not appear to have adverse cancer effects (Gandini, 2011). Related, subsequent pregnancies in women with localized melanoma do not lower cancer survival rates (Driscoll, 2009).

Carcinomas of the colon and rectum are the third most frequent in women of all age groups in the United States (American Cancer Society, 2016). Their incidence in pregnancy is rising because of delayed childbearing (Rogers, 2016). Even so, colorectal tumors are uncommon before age 40. Smith and colleagues (2003) reported an approximate incidence of 1 per 150,000 deliveries in the California Cancer Registry. The incidence approximated 1 per 35,000 births in a Danish Registry (Eibye, 2013). Most—80 percent—of colorectal carcinomas in pregnant women arise from the rectum. In one review, only 41 cases in pregnancy were colon cancers above the peritoneal reflection (Chan, 1999).

The most frequent symptoms of colorectal cancer are abdominal pain, distention, nausea, constipation, and rectal bleeding. If symptoms of colon disease persist, digital rectal examination, stool tests for occult blood, and flexible sigmoidoscopy or colonoscopy are done. Some malignancies of the gastrointestinal tract are discovered because of metastases to the ovary. Kruckenberg tumors are tumor-laden ovaries from another primary, often gastrointestinal, and have a bleak prognosis (Glišić, 2006; Kodama, 2016).

Treatment of colon cancer in pregnant women mirrors the same general guidelines as for nonpregnant women. Without evidence of metastatic disease, surgical resection is preferred, but most gravidas have advanced lesions (Al-Ibrahim, 2014). During the first half of pregnancy, hysterectomy is not necessary to perform colon or rectal resection, and thus, therapeutic abortion is not mandated. During later pregnancy, therapy may be delayed until fetal maturation, however, bowel hemorrhage, obstruction, or perforation may force surgical intervention (Minter, 2005).

Gastric cancer is rarely associated with pregnancy, and most reported cases are from Japan. Hirabayashi and coworkers (1987) reviewed outcomes in 60 pregnant women during a 70-year period from 1916 to 1985. Delayed diagnosis during pregnancy is common, and the prognosis is consistently poor (Lee, 2009). Esophageal cancer has similar symptoms, but it is rare (Sahin, 2015). It is axiomatic that persistent unexplained upper gastrointestinal symptoms should be evaluated by endoscopy.

Various other neoplasms have been reported in pregnancy and are usually the subject of case reports. Examples include carcinoid tumors, which are usually of gastrointestinal origin (Durkin, 1983). Both pancreatic and hepatocellular cancer are rare during pregnancy (Kakoza, 2009; Marinoni, 2006; Papoutsis, 2012; Perera, 2011). Another report described a massive intrahepatic cholangiocarcinoma masquerading as HELLP syndrome (Bladerston, 1998). Except for thyroid cancer, malignant tumors of the head and neck are rare (Cheng, 2015). Lung cancer is also uncommon (Boussios, 2013). Central nervous system neoplasms had a reported frequency of 1 in 10,000 to 28,000 births (Eibye, 2013; Smith, 2003). Bladder and urachal duct carcinoma are rarely coincident with pregnancy (McNally, 2013; Yeaton-Massey, 2013). Last, bone tumors have been described (Kathiresan, 2011).