Cancer and Other Neoplasms in Pregnancy
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In the United States, benign gynecologic masses, known as myomas, account for more than 1 million hospital admissions per year.1
Benign masses may occur in pregnancy, and their management is complicated by the possible risk to the fetus. Knowledge of the natural history of these masses during pregnancy is essential to their proper management. Cancer during pregnancy is unusual. As a result of physiologic changes that normally occur in pregnancy, cancer during pregnancy may be more advanced because the diagnosis is not recognized as early as it might otherwise have been. However, stage-for-stage, cancer during pregnancy is no more virulent than cancer occurring in the nonpregnant state. The routine interruption of pregnancy to influence cancer progression has not been established.
Benign Masses in Pregnancy
Epidemiology and Etiology
Myomas are very common in the general population, especially in nonwhite women.1
They are a frequent cause of infertility and are less prevalent among pregnant women than among the same age group of nonpregnant women. Myomas which cause hospitalization are mostly seen in women aged 40 to 45 years. Complications occur in about 10% of pregnancies with uterine myomas.2,3,4,5,6,7,8
Several hormone receptors become amplified in myomas, the most notable of which are estrogen receptors.6
Estrogen is thought to stimulate the growth of uterine myomas, but the precise mechanism is not well understood. Traditionally, it was believed that uterine myomas grow during pregnancy due to elevated levels of estrogen produced, but this has been challenged by several prospective studies.7,8,9
Myomas can cause pain through degenerative changes or by direct compression of adjacent organs. Nongrowing myomas can cause symptoms during pregnancy as a result of the enlarging uterus which displaces them out of the pelvis. Symptoms may develop as asymptomatic myomas compress abdominal organs.
Uterine myomas can undergo central necrosis and degeneration, causing localized pain at the site. Degenerating myomas can provide a culture medium for pathogenic organisms with occasional leukocytosis and superimposed infection. Myomas are thought to increase the frequency of preterm labor and premature rupture of membranes. They have been implicated in first-trimester spontaneous abortions,10,11
and large cervical and lower uterine segment myomas can cause obstructed labor and infertility.9,12
Placental abruption, postpartum hemorrhage, and retained placenta are thought to be complications of uterine myomas during pregnancy. However, several studies failed to show statistically different rates of these complications compared with the general population.9,12
One study showed that women with leiomyomata are at increased risk of second-trimester spontaneous abortion.13
Management of Myomas in Pregnancy
Preconception myomectomy may be considered based on the patient’s age, reproductive history, size and location of the myomas, and symptoms. However, there is no good evidence that myomectomy will improve fertility or fecundity rates.5
Most of the symptoms can be managed medically in pregnant women. Surgical management is usually avoided during pregnancy. There are very few studies and no randomized trials available on the safety of myomectomy in pregnancy.14,15,16
Myomectomy during pregnancy is best avoided in all but the most extreme circumstances, such as torsion of a pedunculated myoma or when a malignancy is suspected. The 2013 Committee Opinion by the American College of Obstetricians and Gynecologists recommends that women with previous myomectomy which caused significant compromise of the uterine integrity undergo cesarean delivery rather than a trial of labor and vaginal delivery due to small but catastrophic risk of uterine rupture.17
Adnexal Masses in Pregnancy
Benign adnexal tumors are sometimes associated with normal pregnancies, but adnexal masses can be malignant (discussed later). The most common benign pelvic masses in pregnancy are persistent corpus luteum cysts, benign cystic teratomas, paratubal cysts, cystadenomas, and pedunculated myomas. Although the majority of benign pelvic neoplasms discovered during pregnancy are present before the beginning of the pregnancy, the hormonal changes of pregnancy, particularly the production of human chorionic gonadotropin (hCG), are associated with luteomas, theca lutein cysts, hyperreactio luteinalis, and large solitary luteinized follicular cyst of pregnancy.
Clinical features suspicious for malignancy, particularly ovarian cancer, include the presence of a fixed mass, lymphadenopathy, ascites, and constitutional symptoms such as pain, abdominal distention, dyspareunia, frequency, or constipation.20,21
Sonographic features of adnexal masses suspicious for malignancy include size greater than 6 cm, thick septations, papillary projections, complex echogenicity, and the presence of ascites.22,23
The negative predictive value of sonography as a method of excluding malignancy appears to improve in pregnancy.24
Magnetic resonance imaging (MRI) has been used to distinguish benign from malignant ovarian masses in pregnancy. This modality may prove particularly useful in the evaluation of adenopathy and tumor invasion. To date, there is little evidence to link exposure to diagnostic MRI with adverse fetal effects.25,26
Corpus Luteum Cysts
The corpus luteum is the most common hormone-producing functional unit of pregnancy. These unilateral, sonolucent structures contiguous with the ovary arise when granulosa-lutein cells in the postovulatory ovarian follicle are stimulated by the production of placental chorionic gonadotropin and, subsequently, produce progesterone. The corpus luteum maintains progesterone production until approximately 9 weeks’ gestation, when placental progesterone production is sufficient to maintain the pregnancy and the placenta becomes the primary site of progesterone production from week 12 onward. Corpus luteum cysts can complicate pregnancy if they undergo torsion or spontaneous rupture.
Luteomas of pregnancy are solid tumors that are characterized by hypertrophy of ovarian stroma. This hypertrophy may be secondary to stimulation by hCG. They are frequently bilateral and multinodular. Elevated levels of testosterone accompany luteomas in at least 25% of cases, although other hormones may be responsible for maternal virilization.27,28,29
When maternal virilization is present, female fetuses are at risk of virilization. The female fetus is usually not at significant risk of labioscrotal fusion because placental aromatization of maternal androgens is not usually overwhelmed by androgen production until fusion is complete.30,31
There does not appear to be any association between luteomas and multifetal gestation or gestational trophoblastic disease.
Hyperreactio luteinalis is a benign, nonneoplastic enlargement of theca lutein cysts, most likely due to stimulation by hCG.34
Hyperreactio luteinalis is strongly associated with conditions that produce abnormally elevated hCG, such as multifetal gestation, gestational trophoblastic disease, and ovarian hyperstimulation syndrome.35
Hyperreactio luteinalis is usually bilateral and multicystic with stromal edema. Ovarian enlargement can be massive. Although maternal androgen excess is occasionally present, virilization of female fetuses rarely occurs.36,37
Life-threatening ascites, electrolyte abnormalities, thromboembolism, intravascular depletion, hemoconcentration, renal failure, and pleural effusion with respiratory difficulties may be present when hyperreactio luteinalis complicates ovarian hyperstimulation syndrome or gestational trophoblastic disease.
Cancers in Pregnancy
Data reflecting the incidence of cancers during pregnancy are scant because of a lack of information accrued by population-based tumor registries. Estimates of cancer during pregnancy vary considerably (Table 42.1
). The most common neoplasms in pregnancy include melanoma, breast cancer, cervical cancer, lymphomas, and leukemias.39,40
Between 1994 and 2008, Lee et al50
examined the incidence and outcomes of pregnancy-associated cancer in Australia. The authors found an overall crude incidence of 137.3 per 100,000 pregnancies. A total of 1767 women had 1785 cancer-affected pregnancies and 1798 new cancer diagnoses, including 499 during pregnancy and 1299 during the postpartum period. From 1994 to 2007, the crude incidence rate of pregnancy-associated cancer increased from 112.3 to 191.5 per 100,000 pregnancies (P
< .001). During this period, maternal age also increased; the percentage of women aged 35 years and over increased from 13.2% to 23.6% (with women aged 40 years and over increasing from 1.9% to 4.0%). Cancer diagnosis was more common than expected in women aged 15 to 44 years (observed-to-expected ratio 1.49; 95% confidence interval [CI] 1.42-1.56). In order of decreasing frequency, the most common cancers found were melanoma, breast cancer, thyroid cancer, lymphohematopoietic cancer, and cervical cancer. Women with cancer diagnosed during pregnancy had high rates of labor induction (28.5%), caesarean delivery (40.0%), and planned preterm birth (19.7%).
Table 42.1 Estimates of Cancers Occurring in Pregnancy
Smith and Randal38
Carcinoma in situ
Sokol and Lessmann39
Sokol and Lessmann39
Benedet et al40
Wallack et al41
Nugent and O’Connell42
Nugent and O’Connell42
Ribeiro and Palmer43
Less than 1/75,000
Applewhite et al,44
Riva et al45
Morgan et al46; Stewart and Monto47
Fisher et al48; Clark et al49
Serum tumor markers are an essential tool for diagnosing and monitoring patients with cancer, but use of these markers should be done with caution during pregnancy. Levels of tumor markers, such as members of the cancer antigen (CA) family, may be affected by the pregnancy and may vary due to gestational age and pregnancy-related conditions. For example, variations by trimester have been noted for CA 15-3, with a sharp increase in the third trimester. Additionally, CA 15-3 concentration is higher among women with gestational diabetes, intrahepatic cholestasis of pregnancy, or heart disease than among those without any risk factors.51
Alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (β-hCG) levels rise significantly during pregnancy and cannot be used as tumor markers.
Management of Cancer in Pregnancy
Termination of a pregnancy affected by maternal neoplasia is rarely indicated. Although a fear expressed by pregnant patients is that the cancer might spread to the placenta and fetus, information collected during the past 2 decades suggests that transplacental metastasis is extremely unusual, and metastases to the fetus are rare. The most common malignancy to be associated with fetal and placenta metastases is malignant melanoma. However, the reported number of cases in the literature of such an event is fewer than 30.52
Occasionally, iatrogenic preterm birth should be considered as an alternative management strategy in treating pregnant patients with cancer. This strategy requires that sophisticated newborn special care units be available for maintaining premature infants. Antenatal corticosteroid therapy has been shown to decrease complications related to organ immaturity such as respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. Fetal interventions to promote maturation are most effective if delivery occurs from 2 to 7 days after the initiation of therapy. Tests of fetal lung maturity, such as the lecithin/sphingomyelin (L/S) ratio, could be considered in determining the timing of delivery.53
The cervix remains the most common site for precancerous and cancerous changes in pregnancy (see Table 42.1
). The current International Federation of Gynecology and Obstetrics (FIGO) staging
system for cervical cancer is seen in Table 42.3
. Invasive cervical cancer is on the decline in the United States. Effective Pap smear screening techniques in combination with colposcopy for directed biopsies have allowed physicians to recognize the presence of malignancy early and to treat patients with simple office procedures. Although the decline in invasive cancer is evident in the United States, an increase in cervical intraepithelial neoplasia (CIN) has occurred as a result of widescale cytologic screening.88,89
Epidemiologic studies suggest that women who develop CIN and invasive cancer in pregnancy tend to be married at an earlier age, have an earlier age of diagnosis of CIN and invasive
cancer, and have a higher parity than a control population.90,91,92
The most common histologic types of cancer occurring in the cervix are squamous cell. Four case reports of a small cell neuroendocrine carcinoma arising in the uterine cervix in pregnancy have also been reported.93,94
Table 42.3 International Federation of Gynecology and Obstetrics (FIGO) Staging of Cancer of the Cervix Uteri (2018)
The carcinoma is strictly confined to the cervix uteri (extension to the corpus should be disregarded)
IA: Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion <5 mma
IB: Invasive carcinoma with measured deepest invasion ≥5 mm (greater than stage IA), lesion limited to the cervix uteri
IB1: Invasive carcinoma ≥5 mm depth of stromal invasion and <2 cm in greatest dimension
IB2: Invasive carcinoma ≥2 cm and <4 cm in greatest dimension
IB3: Invasive carcinoma ≥4 cm in greatest dimension
The carcinoma invades beyond the uterus but has not extended onto the lower third of the vagina or to the pelvic wallb
The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph
IIIA: Carcinoma involves the lower third of the vagina, with no extension to the pelvic wall
IIIB: Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause)
IIIC: Involvement of pelvic and/or para-aortic lymph nodes, irrespective of tumor size and extent (with r and p notations)c
The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV
a Imaging and pathology can be used, when available, to supplement clinical findings with respect to tumor size and extent, in all stages.
b The involvement of vascular/lymphatic spaces does not change the staging. The lateral extent of the lesion is no longer considered.
c Adding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to stage IIIC. For example, if imaging indicates pelvic lymph node metastasis, the stage allocation would be stage IIIC1r, and if confirmed by pathological findings, it would be Stage IIIc1p. The type of imaging modality or pathology technique used should always be documented. When in doubt, the lower staging should be assigned.
Reprinted from Bhatla N, Berek JS, Cuello Fredes M, et al. Revised FIGO staging for carcinoma of the cervix uteri. Int J Gynaecol Obstet. 2019;145(1):129-135. doi:10.1002/ijgo.12749. Epub 2019 Jan 17. Erratum in: Int J Gynaecol Obstet. 2019;147(2):279-280.
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