Cervical cancer is the most common malignancy diagnosed in pregnancy. This may be related to the fact that it is the one type of cancer for which screening is routinely performed on the first prenatal visit. The incidence of cervical cancer is 0.45–1 per 1000 livebirths in the United States, with carcinoma in situ occurring in 1 in 750 pregnancies [1]. In the United States from 2001 to 2005 the median age of diagnosis for cervical cancer was 48 years of age. Approximately 0.1% were diagnosed under age 20, 15.2% between 20 and 34, 25.9% between 35 and 44, 23.4% between 45 and 54, 15.5% between 55 and 64, 10.4% between 65 and 74, 6.8% between 75 and 84, and 2.5% at 85 years and above [2].

Screening and preinvasive cervical disease

Cervical dysplasia and cancer are strongly associated with infection from the human papilloma virus (HPV). HPV is the most commonly diagnosed sexually transmitted disease in the United States. It is a double-stranded DNA virus that causes condyloma acuminata (low-risk types) and cancer of the vagina, vulva, and anus as well as cervical dysplasia and cancer (oncogenic types). Oncogenic HPV types 16 and 18 account for nearly 70% of invasive cervical cancers in the US and are more frequently isolated in cervical cancer tissue than either intermediate (31,33,35,39,45,51,52,58) or low-risk types (6,11,42,43,44), with type 16 accounting for approximately 50% of cases [3]. However, not all infections with HPV types 16 or 18 progress to cervical cancer. In general, HPV infections in pregnancy that cause cervical dysplasia do not seem to be more aggressive despite the presumed immunosuppressed state [4–6]. However, the low-risk HPV types that account for the condylomatous changes can rapidly proliferate in pregnancy, presumably due to hormonal influences.

Screening in pregnancy is recommended at the first prenatal visit and again at 6 weeks post partum. Most experts advocate using liquid-based cytology because of a lower false-negative rate; this technique also allows for reflex HPV typing if an abnormality is found. During pregnancy Pap smears should be interpreted and evaluated as in the nonpregnant state following the 2006 Bethesda guidelines [7]. For the diagnosis of atypical squamous cells of unknown significance (ASCUS), it is appropriate to request HPV reflex testing and refer the patient for colposcopy only if the lesion is positive for a high- or intermediate-risk HPV type. If dysplasia is diagnosed, reflex HPV typing should be performed, but colposcopy is indicated regardless of the HPV type.

Colposcopy should be performed by an experienced practitioner who is familiar with the cervical changes associated with pregnancy, including the proliferation of the glandular epithelium. Endocervical curettage (ECC) is contraindicated during pregnancy. All squamous intraepithelial lesions, including both low and high grades (LSIL and HSIL, respectively) and any patient with HIV and an ASCUS Pap should undergo colposcopy [7]. Due to the increased risk of bleeding, biopsies should only be performed if an area is suspicious for invasive disease. Cervical conization should be performed only if invasive disease cannot be ruled out by biopsy and should be done by an expert with complete understanding of the potential impact to the pregnancy. Most of the time, conservative management is all that is required, with follow-up throughout gestation if needed, because cervical dysplasia rarely progresses to invasive cancer during the relatively short period of gestation [6]. The timing of the repeat Pap or colposcopy evaluation depends on the initial diagnosis and the point in gestation [6]. It is customary to repeat the Pap and colposcopy every 8–12 weeks [1], particularly for high-grade lesions in women at high risk for developing cervical cancer. In women at low risk for invasive cervical cancer, such as pregnant adolescent and young women, it is reasonable to defer colposcopy until after birth [7]. Postpartum colposcopy should be performed at 6 weeks for all cases of dysplasia followed during pregnancy. Regression of high- and low-grade lesions is not uncommon after delivery. Low-grade lesions are more likely to regress, just as in the nonpregnant state, and rates of regression for LSIL are reported to be 36–70% [8–10]. High-grade lesions and carcinoma in situ regress at rates of 48–70%, with the overall progression of premalignant lesions to cancer reported as being only 0.4% [6,10,11].

Treatment of cervical cancer

Treatment of cervical cancer during pregnancy is complicated by the need to preserve fertility and the ongoing pregnancy, and therapeutic options will be partly determined by the gestational age at presentation. As reviewed above, cervical conization should be reserved for definitive diagnosis of invasive malignant disease. The pregnant cervix is significantly more vascular than in the nonpregnant state. Therefore, if conization is required, caution must be exercised because of the increased risk of hemorrhage. If invasive disease is suspected early in gestation, between 16 and 20 weeks, a cone biopsy should be performed, and consideration should be given to the placement of a cerclage to maintain cervical competence [6]. At later gestational ages, a cone biopsy can also be performed when invasive cancer is suspected; however, it should not be performed within 4 weeks of anticipated delivery. This is due to the fact that cervical healing may not be complete by the time of labor, and the risk of hemorrhage could be significantly increased [6]. Instead of a complete cone biopsy, some providers perform a “wedge biopsy” or “coin-shaped resection” which may provide enough information without causing excessive bleeding or other deleterious effects on the pregnancy. Complications of cone biopsies of the cervix during pregnancy include preterm premature rupture membranes (PPROM) and preterm labor. A retrospective study showed a 1.9- and 2.7-fold increase in PPROM with loop electrocautery excision procedures (LEEP) or laser conization, respectively [12]. However, no difference was noted in preterm delivery rates, and the increased risk of PPROM was proportional to the amount of tissue that was removed [12]. Other data have supported an increased risk of preterm delivery with cone ablations of 10 mm depth or greater [13].

The management of pregnant patients diagnosed with invasive disease depends upon the stage, the gestational age, and whether the pregnancy is highly desired. Cervical cancer staging is described in Box 22.1. Each case should be individualized, and a multidisciplinary approach including input from obstetricians, gynecologists, oncologists, and neonatologists is required. For cancers diagnosed in the third trimester, there is substantial evidence that early-stage cancers are unlikely to spread significantly during pregnancy, and delay of definitive treatment until after pregnancy does not adversely affect outcome. For more advanced cases, it is often acceptable to delay therapy but to deliver early so that definitive treatment can be undertaken. However, the work-up of more advanced-stage cancers may require special imaging and are more difficult to manage with an ongoing pregnancy to consider. Fortunately, many pregnant women diagnosed with cervical cancer have early-stage cancer (IA1, IA2 microinvasive) or stages IB1 and IB2 (visible lesion confined to the cervix). If the stage has been diagnosed as very early microinvasive without lymphovascular invasion, a vaginal delivery is acceptable with therapeutic conization in the postpartum period. If the stage is IA1 (+lymphovascular invasion), IA2, IB1 or IB2, a cesarean radical hysterectomy should be considered with appropriate adjuvant therapy individualized to the patient following delivery. Vaginal delivery is contraindicated with any visible invasive cervical lesions (IB) [14–17].

In the first and second trimesters, the diagnosis of cervical cancer is more challenging. Accurate dating is important and may dictate the management. Prior to 20 weeks, management will first depend upon how strongly the patient wishes to maintain this pregnancy. If the pregnancy is not highly desired, then termination followed by the appropriate surgery may be offered. As viability approaches, particularly between 22 and 24 weeks of gestation, termination may be more difficult to accomplish depending on state and ethical concerns. Regardless of gestational age, if the pregnancy is desired, treatment for early-stage disease can generally be delayed to allow for fetal lung maturity. Advanced-stage cancers diagnosed early in the pregnancy are more difficult to manage, especially for desired pregnancies. For advanced disease, it is not as clear what risks may be incurred by waiting for definitive therapy. However, evidence suggests no difference in prognosis with delay in many cases [18]. For cases involving advanced cervical cancers diagnosed early in pregnancy, extensive counseling as to management options is warranted and documentation of informed consent is required.

Breast cancer is considered to be associated with pregnancy if the diagnosis is made during a pregnancy or within 1 year of delivery [19]. Approximately one in 3000–10,000 women will be diagnosed with a malignant breast tumor that is associated with a pregnancy [20–23]. For premenopausal women, it is striking that one in three to four breast cancers is associated with pregnancy according to the precise definition [24,25]. In addition, given the potentially prolonged occult growth period of breast tumors, it is likely that many more cancers are present during and influenced by a preceding pregnancy, perhaps years before the diagnosis is actually made.

The breast undergoes remarkable epithelial cell hypertrophy during pregnancy. Breast hypertrophy is related to hormonal changes during pregnancy with a rise in estradiol, estrone, estriol, progesterone, cortisol, insulin, and prolactin. The normal physiologic breast changes of pregnancy may mask a developing malignant mass and result in a significant delay in diagnosis [26] and this may partially explain why pregnancy is a risk factor for more advanced presentation of breast cancer.

Largent et al. described a study of 254 women diagnosed with invasive breast cancer under the age of 35 [27]. Compared with nulliparous women, those with three or more births were more likely to be diagnosed with a nonlocalized tumor, a poor prognostic finding. In addition, they found that women with two or more full-term pregnancies were more likely to die from their disease compared to women with one or no term pregnancy. These data appear to indicate that among younger women, tumors associated with pregnancy are more aggressive and more difficult to treat. A delay in diagnosis also contributes to the poor prognosis.

For women who carry either BRCA1 or BRCA2 mutations, the lifetime risk for breast cancer approaches 80%. Recent reports have addressed the effect of pregnancy on lifetime risk for breast cancer in this population. Interestingly, the effect of parity appears to be different depending upon whether the patient carries a mutation in BRCA1 or BRCA2, with BRCA1 carriers enjoying a modest protective effect from pregnancy, while BRCA2 carriers appear to have an increased risk due to pregnancy [28].

Screening, diagnosis, and staging of breast cancer in pregnancy

The diagnosis of breast cancer can be challenging during pregnancy. Mammography, the most important diagnostic test used in the work-up of a breast mass, is less reliable due to the density of the pregnant breast. In pregnancy, mammography is acceptable from the standpoint of radiation exposure to the fetus; however, the test is likely to be nondiagnostic due to the density of the pregnant breast and cannot be relied upon to rule out malignancy. In a small study of eight pregnant women with breast cancer who underwent mammograms, six of the eight studies were negative [29]. Ultrasonography can be used to distinguish fluid-filled cysts from solid masses. If cystic, aspiration of the fluid should be carried out, and the fluid should be sent for cytologic evaluation if it is bloody. Fine needle aspiration of a solid mass is less accurate in pregnancy due to the normal hyperplastic epithelial changes and must be interpreted by an experienced pathologist. Not infrequently, fine needle aspirations of breast masses during pregnancy are nondiagnostic and may be falsely labeled as malignant [30].

In general, if a solid mass is found, surgical excision is the standard practice and can usually be carried out under local anesthesia (although general anesthesia is certainly not contraindicated in pregnancy) [31]. Excisional biopsies may be complicated by infection, hematomas, and milk fistulas. Therefore, prophylactic antibiotics should be given, and patients should consider ceasing lactation if the biopsy is performed in the postpartum period. Byrd and colleagues reported that of 134 biopsies performed during pregnancy or lactation, 29 proved to be cancer [32].

Once the diagnosis of malignancy is established, the patient should be staged. Breast cancer staging is based upon the criteria in Boxes 22.2 and 22.3. Magnetic resonance imaging (MRI) and computed tomography (CT) scans are not contraindicated in pregnancy and should be performed if indicated.

For clinical stage I and II disease, bone scans are not indicated unless the patient has symptoms or serum chemistries suggestive of bone involvement; however, for clinical stage III disease, a modified bone scan using maternal hydration, as reported by Baker, will reduce the fetal radiation exposure to a very acceptable 76 millirems (mrem) resulting from the isotope 99mTc [33]. Unless the patient has central nervous system symptoms, a brain scan is rarely performed.

Treatment of breast cancer in pregnancy

The usual recommendation is to treat pregnant patients with breast cancer surgically with a modified radical mastectomy. An acceptable alternative for many nonpregnant patients is a lumpectomy followed by radiation. Most clinicians believe that this alternative is contraindicated during pregnancy because the dose of radiation exceeds recommended limits for the fetus. However, at least one review refutes this assertion; hence this is controversial [34]. For surgery, general anesthesia is indicated. Antacids should be given to raise the gastric pH. This is required because of the increased risk of aspiration with pregnancy. Prolonged preoxygenation prior to endotracheal intubation should be undertaken, and intraoperative fetal monitoring should be considered during the procedure so that anesthesia can be adjusted to avoid fetal hypoxia. The patient should also undergo fetal and uterine monitoring in the early postoperative period to identify a nonreassuring fetal heart rate pattern and/or preterm labor. Postoperative tocolysis should be instituted if necessary.

For stage II or greater disease, chemotherapy is the standard of care. Regardless of stage or node status, for tumors with high-risk factors, including lack of hormone receptors and high cellular ploidy, adjuvant and/or neo-adjuvant chemotherapy has been reported to improve clinical outcome and should not be withheld during pregnancy. Chemotherapy with a combination of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) versus cyclophosphamide alone is commonly employed. However, other regimens, including those with paclitaxel, have been reported [35–37]. Most clinicians avoid the folate inhibitor methotrexate during pregnancy because of the high malformation rate of 17–25% associated with this agent [38]. The most common anomaly associated with methotrexate is microcephaly, which is more common with exposure early in pregnancy.

Malignant melanoma originates from melanocytes, which are cells of neural crest origin that produce the pigment melanin [39,40]. Incidence rates for malignant melanoma have increased in the United States and other countries in recent decades and are highest among fair-skinned populations. Exposure to solar ultraviolet radiation is considered to be the primary risk factor for the disease; however, hormonal effects are also postulated to play a role [41].

Effect of pregnancy on melanoma

Malignant melanoma is one of the most common tumors reported in pregnancy [42,43]. Although the real incidence of malignant melanoma during pregnancy is unknown, it is estimated that melanoma accounts for about 8% of all malignant tumors diagnosed during gestation [43–45]. Smith & Randall published an incidence of 2.8 per 1000 deliveries in a report from 1969 [46]. Other studies have reported an incidence of 2.8–5 per 100,000 pregnancies [47]. Additionally, Lens et al. estimated that melanoma during pregnancy accounted for 967 cases per 100,000 women diagnosed with melanoma during reproductive years [48].

A number of case reports indicate that melanoma is more aggressive during pregnancy [49–53]; melanoma rates are higher in general in young women compared to men during the reproductive years [49] and pregnancy results in cutaneous hyperpigmentation (also seen with the use of exogenous hormones), suggesting that hormonal factors play a role in melanocyte proliferation [54]. In addition, preclinical models of melanoma strongly suggest that pregnancy has an effect on melanoma cell proliferation and angiogenesis, possibly in response to placental growth factors [55]. However, most epidemiologic studies have shown no association between prior pregnancy and an increased risk of developing melanoma, so the link between hormones and melanoma remains controversial.

Stage and prognosis of malignant melanoma in pregnancy

The maternal outcome depends upon well-established prognostic factors for melanoma. Melanoma staging is based upon the criteria in Box 22.4. The prognosis of melanoma is strongly associated with Breslow thickness, which is measured as the depth of the lesion from the granular cell layer of the epidermis to the deepest identifiable tumor cells. The location of the lesion is also associated with prognosis. Those that occur on the head, neck, and trunk are associated with lower survival [56].

Interestingly, melanoma is the most common tumor type that metastasizes to the placenta and/or the fetus. More than 28 cases of metastatic melanoma to the fetal compartment have been reported [57, 58]. It is important to notify the pathologist of the need to do a complete evaluation of the placenta after birth for any patient delivered with melanoma to rule out occult metastasis. In the setting of frank fetal metastasis, the outcome can be fatal for the neonate.

Treatment of melanoma during pregnancy

Most studies have indicated no overall difference in survival between pregnant and nonpregnant women with melanoma. When detected at an early stage, melanoma is highly curable with surgery alone. However, patients with lymph node involvement or thicker primary tumors with ulceration – stages IIB/IIC/III – require adjuvant therapy after surgery. Unfortunately cytotoxic chemotherapy has limited benefit; however, immunotherapy with adjuvant interferon-alpha-2b significantly reduces recurrences and results in a survival benefit for some patients [59–62]. Interferon therapy is considered to be generally contraindicated during pregnancy but because of its importance in the treatment of melanoma, it is important to understand the basis for the advice not to use it. Some studies do indicate an increased risk for early fetal loss and later growth restriction [63]; other investigators report no difference in pregnancy outcome in women treated with interferon during pregnancy [64–67]. Therefore, given the activity of this agent against melanoma and the need to optimize treatment during pregnancy on behalf of the mother, it is wise to consider using interferon if the need is encountered during the second and early third trimesters of pregnancy. Delaying adjuvant interferon treatment until after pregnancy is appropriate for pregnancies in the late third trimester on a case-by-case basis.