Carcinoma of the Breast in Pregnancy and Lactation

Epidemiology

Breast cancer, along with carcinoma of the cervix and melanoma, is one of the most common malignancies to complicate pregnancy. The incidence of PABC ranges from 17.5 to 39.9 per 100,000 births. The rate of PABC diagnosed during pregnancy is lower than that of PABC diagnosed within 1 year postpartum (2.4–7.2 compared with 10.6–19.6 per 100,000 births, respectively). Among women diagnosed with breast cancer under the age of 45 years, 3% to 7% are associated with pregnancy or the lactation period. This proportion increases to approximately 20% of breast cancers diagnosed in women between the ages of 25 and 29 years.

Multiple studies have noted a rise in the incidence of cancer diagnosed during pregnancy over time. This rise is attributed to an increase in women delaying childbearing to later reproductive years, improvements in imaging detection, and close patient-physician interaction while a woman is pregnant. It is important to note that the true incidence of PABC is difficult to estimate, as population-based cancer registries do not include pregnancy information, the window of inclusion postpartum is variable, and calculations may differ between studies depending on inclusion or exclusion of elective or spontaneous abortions.

Pathologic Findings

As with nonpregnant women, the majority of PABCs are invasive ductal carcinomas, accounting for greater than 78% of cases. Invasive lobular carcinoma is the second most common histologic type. All subtypes are represented but are rare. PABC tumors are frequently of high nuclear grade and exhibit lymphovascular invasion. These more aggressive pathologic features correlate with the tumor’s underlying propensity for advanced disease presentation. Clinically, women with PABC are more likely to present with larger primary tumors and a higher burden of axillary nodal disease.

Similar to younger women with breast cancer who are not pregnant, women with PABC tend to have tumors that are estrogen receptor– and progesterone receptor–negative. A national case-control retrospective study from Japan demonstrated a higher rate of estrogen receptor–negative tumors in PABC, at 56%, compared with 43% in non-PABC women. A more recent population-based cohort, case-control study from Sweden also reported a higher proportion of estrogen receptor–negative tumors in women diagnosed with breast cancer during pregnancy and up to 6 months postdelivery compared with nulliparous women. A systematic review of 14 matched case-control studies by Marikakis and colleagues confirmed that women with PABC lack estrogen and progesterone receptor expression at a higher frequency than non-PABC women. Bae and colleagues examined 83,792 women with breast cancer between the ages of 20 and 49 years, of whom 83,381 were non-PABC and 411 were PABC patients, and found that triple-negative tumors were the most common subtype in PABC women (40% in PABC vs. 16% in non-PABC women); luminal A was the most common subtype in non-PABC women (21% in PABC vs. 51% in non-PABC women).

Fewer studies have examined human epidermal growth factor receptor-2 (HER2) positivity in women with PABC, particularly compared with age-matched controls. Two retrospective studies assessed rates of HER2 positivity in PABC and non-PABC women. The cumulative rate of HER2-positive tumors in PABC was 32% compared with 18% in nonpregnant patients. Johansson and colleagues also reported higher rates of HER2-positive tumors in women diagnosed with PABC compared with nulliparous women with breast cancer in a case-controlled, population-based cohort. Despite the increasing amount of literature on PABC, studies evaluating inflammatory breast cancer during pregnancy are scant. In an older study by Bonnier and colleagues, women with PABC compared with non-PABC age-matched controls had a higher proportion of inflammatory breast cancer.

A full family history is an important part of assessment for these patients. Given the aforementioned tendency toward estrogen receptor– and progesterone receptor–negative disease in a young age group, genetic counseling should certainly be offered to patients with PABC. The probability of detecting a germline mutation in a young patient with a triple-negative breast cancer is approximately 20%.

Presentation, Diagnostic Evaluation, and Staging During Pregnancy

The average woman diagnosed with PABC is between 32 and 38 years of age. In a contemporary cohort of PABC women age- and stage-matched to non-PABC controls, women with PABC were more likely to be of non-Caucasian race. Additionally, they were more likely to have their first full-term pregnancy after the age of 35 years.

Most often, women present with a palpable breast mass, most of which are detected on self-examination. During pregnancy, the breasts undergo physiologic hypertrophy and proliferative changes in response to high levels of estrogen and progesterone that stimulate and prepare the breast for lactation. These changes make physical examination of the breasts gradually more difficult as the pregnancy progresses due to increases in both breast mass and density. These changes continue into the postpartum period in women who are breastfeeding.

The index of suspicion for cancer must be high for women who present with a breast mass during the gestational or lactational period. Any abnormality encountered should be promptly evaluated, particularly when symptoms occur during the first trimester when the breasts have undergone the least change. The majority of these breast lumps will prove benign. The differential diagnoses of a breast mass more commonly seen in a pregnant woman include benign entities such as fibroadenoma, lactating adenoma, galactocele, cystic disease, lobular hyperplasia, breast abscess, lipoma, and fibrocystic disease. The combination of masked symptoms due to breast engorgement paired with the low index of suspicion among providers and patients can lead to a delay in diagnosis and presentation of late-stage disease.

A multi-institutional study of 192 patients in Japan found that the average time from symptom development to diagnosis was just over 6 months—1 month longer than in a series of age-matched controls. In keeping with other reports, patients with PABC presented with a more advanced T classification, N classification, and stage group compared with young nonpregnant women with breast cancers, which was attributed to diagnosis delay. Contemporary reports continue to point to delays in presentation and diagnosis as common occurrences in PABC.

Imaging Studies During Pregnancy

Young women typically do not undergo routine mammographic breast cancer screening, but it can be performed in pregnant women at high risk with lead shielding. The increased parenchymal density of the breast that accompanies the pregnant and lactating state period reduces the sensitivity of mammography. Usually, discovery of PABC is by presentation of a persistent palpable mass. The index of suspicion for cancer must be high for women who present with a breast mass during the gestational or lactational period, and imaging evaluation should not be delayed.

A postpartum woman should undergo breast imaging in a similar way to that of a nonpregnant/nonlactating woman. On the contrary, advanced breast imaging should be limited in a pregnant woman due to concerns of exposing the fetus to ionizing radiation. Prenatal radiation is teratogenic and may induce malformations, growth or mental retardation, future lifetime malignancies, or death. The effect of radiation, though, appears to be dose dependent and more caustic to earlier weeks of pregnancy (organogenesis). Studies evaluating diagnostic means to safely evaluate a childbearing woman for breast cancer while maintaining minimal risk to the fetus pose ethical and clinical challenges.

Breast ultrasound is the first-line focused imaging test in the workup of pregnant and lactating women, as it carries the highest sensitivity for diagnosis of PABC and allows for prompt biopsy of any suspicious lesion identified. If ultrasound is inconclusive, mammography or digital breast tomosynthesis can also be safely performed during pregnancy. No teratogenic effects have been seen when radiation doses are <50 mGy and a four-view mammogram is <0.03 mGy. Mammography may be useful in determining the extent of disease, including multifocality and multicentricity, and should be considered in any patient with a highly suspicious mass seen on ultrasound or when a diagnosis of PABC has been made. Lactating patients should be encouraged to nurse or express immediately before mammography to decrease parenchymal density related to retained milk products.

Although magnetic resonance imaging (MRI) has been used in the obstetric patient both for fetal imaging and for evaluation of maternal conditions such as appendicitis, its reported use for breast evaluation in pregnancy is limited. Breast MRI requires contrast-enhanced imaging with gadolinium. Gadolinium contrast agents cross the placenta; therefore its use is avoided during pregnancy due to the potentially long half-life in the fetus, its association with teratogenicity in animal studies, and the paucity of data on its safety in pregnancy. Its use may be considered in women who are postpartum, even if lactating, at the time of diagnosis, if it is felt that additional information beyond that provided by mammography and ultrasound is required. The American College of Radiology guidelines do not require that patients discontinue breastfeeding. Images obtained on MRI may be difficult to interpret during the pregnant or lactating state. Despite the increased parenchymal enhancement of the hypervascular lactating breast, MRI facilitates the diagnosis of carcinomas and satellite lesions through subtracted imaging technique. Myers and colleagues evaluated the impact of preoperative breast MRI among 53 women with PABC and concluded that MRI in PABC is important, as it changed surgical management in 15 women (28%), with 4 (8%) requiring a larger lumpectomy, 7 (13%) necessitating a mastectomy, 2 (4%) discovering contralateral disease, and 2 (4%) revealing metastasis.

Once the diagnosis of breast cancer has been made, many routine systemic staging studies use ionizing radiation, which complicates accurate and timely staging of distant disease in pregnant women. As noted earlier, PABC tends to present at a later stage, but the indication for systemic staging should follow National Comprehensive Cancer Network (NCCN) guidelines as for nonpregnant patients. Patients with clinical stage III (cT3N1 or any ≥N2) or stage IV disease or symptoms suggestive of distant metastases should undergo a systemic evaluation. The risks and benefits of obtaining these imaging examinations during pregnancy need to be carefully evaluated. A contemporary cohort study of women with PABC found a high proportion (31%) of women were upstaged when comprehensive radiologic imaging was delayed postdelivery.

Chest x-rays are considered safe during pregnancy because the dose with abdominal lead shielding is relatively low. Chest or abdominal computed tomography (CT) scans are generally avoided due to the large cumulative radiation dose, particularly when imaging anatomy that is closest to the uterus and results in higher radiation exposure. Although less sensitive than MRI or CT, liver ultrasound is a safe alternative to assess metastases in the pregnant patient. If brain metastases are suspected, noncontrast MRI may be performed, without significant risk to the fetus. Bone remains the most common site of breast cancer metastases. Alkaline phosphatase levels increase during normal pregnancy and cannot be used as an indicator of bone metastases. Bone scintigraphy has been reported as safe during pregnancy and is associated with a less than 5 mGy dose of radiation exposure to the fetus. Modifications of the technique, including adequate maternal hydration, which result in lower fetal radiation exposure, have been described. The use of positron emission tomography (PET) in pregnancy is very limited. Fetal radiation exposure from PET/CT includes the sum of direct radiation exposure from CT, maternal tissue irradiation, and placental uptake of radionucleotide. A fetal radiation dose from ¹⁸ F fluorodeoxyglucose ( ¹⁸ F-FDG) PET/CT is estimated at approximately 10 to 50 mGy, and is generally delayed until after delivery. Recent studies suggest that fetal dose exposure and risk from ¹⁸ F-FDG PET-only administration is low during pregnancy and is not an absolute contraindication. In a small case series of five pregnant patients with a biopsy-proven malignancy who underwent ¹⁸ F-FDG PET at different trimesters of pregnancy, all patients delivered healthy infants, with no visible abnormalities at term. Additional research assessing the safety of PET in pregnant women is warranted.

Breast Biopsy During Pregnancy

Any breast mass during pregnancy that is suspicious on either clinical or ultrasound evaluation requires biopsy, and the pathologist interpreting the tissue should be aware of the patient’s pregnancy.

Core biopsy is the most accurate means of establishing a diagnosis. These biopsies can be performed under local anesthesia with subcutaneous lidocaine, which has no known harmful fetal effects. Although less preferred than core biopsy, fine-needle aspiration can be used for the diagnostic evaluation of a breast mass in pregnancy. Reports have highlighted difficulties of interpreting the cytologic findings from fine-needle aspiration due to the proliferative changes in the breast tissue. Due to the increased cellularity and frequent mitosis that can be seen during pregnancy, it is important to have tissue examined by an experienced cytopathologist who is familiar with the cytologic appearances of physiologic changes of breast tissue in pregnancy in order to minimize the number of false-positive diagnoses.

The formation of a milk fistula after core needle biopsy has been reported, but the literature contains only sporadic case reports, and it appears that the overall rate of milk fistula formation is low. A systematic review found a total of 27 cases of milk fistula in nursing mothers among 17 studies, most of which occurred secondary to an iatrogenic procedure or after spontaneous drainage of a breast abscess. Sixteen women ceased lactation, while 11 women continued to breastfeed. Conservative management, including local wound care, antibiotics for evidence of infection, and application of pressure to the fistula opening while breastfeeding, were frequently used. Milk suppression with a dopamine agonist or fistulectomy were used less often. The risk is higher with an open surgical biopsy and for more centrally placed lesions.

Cessation of breastfeeding before the biopsy has been proposed as a means to reduce the risk of milk fistula formation, but the advantages of nursing are greater when considering the rare event of a milk fistula formation. Various techniques are recommended to minimize the risk of milk fistula formation, including emptying the breast prior to sampling procedures, using a higher gauge needle, performing the biopsy under image guidance, and prescribing prophylactic antibiotics.

Treatment

Postpartum women should be treated with standards similar to those for non-PABC women. Treatment of breast cancer in women diagnosed during the gestational period should be modified to achieve healthy fetal outcomes while providing management care that is as close as possible to that for non-PABC women ( Table 69.1 ).