Uncommon presentations of cancer affecting the breast and recurrent breast cancer

This chapter discusses uncommon diseases of the breast, including (i) pregnancy-associated breast cancer (PABC); (ii) male breast cancer (MBC); (iii) Paget’s disease of the breast; and (iv) other breast malignancies, including melanoma, lymphoma, angiosarcoma and metastases, as well as management of local recurrence (LR).

Uncommon presentations of cancer affecting the breast

Pregnancy-associated breast cancer

PABC includes breast cancer diagnosed during pregnancy, up to 1 year after delivery or during lactation. Although PABC is rare, it is the most common malignancy in pregnant women. PABC constitutes 0.2–3.8% of all breast cancers, occurring at a rate of 1 out of every 1000 to 10,000 pregnancies. The incidence of PABC has increased in recent years as more women delay childbearing. Because PABC is rare, detailed evaluations of risk factors for PABC development are lacking.

Pathology

Histologically, PABC and non-PABC are similar. Compared with non-PABC, PABC tends to be oestrogen receptor (ER) and progesterone receptor (PR) negative; data on the expression of human epidermal growth factor receptor 2 (HER2) are conflicting. PABC tumours are frequently high grade, have lymphovascular invasion, are larger in size and have a greater incidence of nodal involvement than non-PABC.

Clinical presentation

Compared with non-pregnant women, pregnant women with breast cancer tend to be diagnosed at later stages, the majority presenting with palpable masses. Gravid breasts undergo significant ductal and lobular proliferation and engorgement, and increase markedly in density and nodularity, making clinical breast exam difficult and potentially contributing to a delay in diagnosis. Moreover, the differential diagnosis of a breast mass in pregnant women is broad, including lactating adenoma, fibroadenoma, cystic disease, lobular hyperplasia, galactocele, abscess, lipoma, hamartoma, and PABC; approximately 80% of breast biopsies in pregnant women are benign.

Diagnosis

Dominant breast masses in pregnant or lactating women should be investigated with imaging and biopsy.

Ultrasound should be the initial imaging modality for the evaluation of a palpable breast mass in pregnancy, and has a high sensitivity and specificity in PABC. It is not teratogenic, and distinguishes and characterises solid and cystic lesions. Mammography can be performed safely with the use of abdominal shielding, with low risk to the fetus. Bilateral mammography should be performed in all women with a breast cancer diagnosis. Breast imaging with contrast-enhanced magnetic resonance imaging (MRI) is not recommended, as gadolinium is known to cross the placenta and to affect fetuses adversely in animals.

As in non-PABC, core-needle biopsy is the preferred method of diagnosis and offers specific advantages over fine-needle aspiration (FNA) in the work-up of a breast mass. Because the gravid breast is proliferative, FNA and cytological evaluation may result in false-positive diagnoses of atypia or carcinoma. Benign lesions, such as cysts and, particularly, fibroadenomas, can increase in size during pregnancy. A definitive benign core-needle biopsy diagnosis may obviate the need for excision. While core-needle biopsy can very rarely cause milk fistula in a lactating woman, the benefit of a definitive pathological diagnosis far outweighs the potential risk.

Metastatic work-up for PABC may be affected by the pregnancy, but is guided by clinical stage and symptoms. Chest radiography with abdominal shielding is safe. Liver ultrasound and MRI are preferred modalities to investigate for metastatic disease. Bone scans using lower doses of radioisotope have been performed in pregnant women, but are generally only recommended if there are uncertain MRI findings. ^, The role of positron emission tomography (PET) in pregnant patients has not been well studied, and its use is not recommended during pregnancy.

Ultrasound, bilateral mammography, and core-needle biopsy should be used as part of the work-up of PABC.

Treatment

Local therapy

In general, treatment should not be delayed by pregnancy unless there is a planned delivery within the next 2–4 weeks, and should be guided by a multidisciplinary team consisting of a surgical oncologist, a medical oncologist, and an obstetrician with expertise in dealing with women with PABC. Breast surgery is generally safe in all trimesters of pregnancy. A report of 2565 patients demonstrated no differences in congenital abnormalities between pregnant women who did and did not undergo surgery. Surgery during pregnancy was, however, associated with an increased rate of spontaneous abortion, which was highest in the first trimester; thus, the patient and surgeon may choose to defer surgery until after the 12th week of pregnancy.

The surgical team must be aware of the physiological changes of pregnancy, including increased plasma volume, increased cardiac output, decreased systemic vascular resistance, hypercoagulable state, dilutional anaemia with associated decreased oxygen-carrying capacity, and delayed gastric emptying. Additionally, a pillow should be placed on the right side of the patient to keep the gravid uterus from pressing upon the inferior vena cava. Starting at 24–26 weeks of gestation, the fetus should be monitored intraoperatively and postoperatively.

Surgery should be tailored according to the clinical stage of the PABC and the gestational age of the fetus. Mastectomy can be performed during any trimester, although breast reconstruction should ideally be performed postpartum due to concerns of increased operative time and asymmetry. Breast-conserving therapy (BCT) is generally not recommended in the first trimester because of a need to delay radiotherapy until after delivery, which may increase the risk of LR. However, for the patient who receives adjuvant chemotherapy, this delay is not typically longer than that of the non-pregnant patient, where radiation is delayed until after completion of chemotherapy, and this may be over 6 months after surgery. BCT is feasible in the second and third trimesters.

Axillary staging

The American Society of Clinical Oncology Clinical Practice Guidelines recommend use of sentinel lymph node biopsy (SLNB) in early-stage PABC. Lymphazurin (Isosulfan Blue), patent blue V, and methylene blue have not been studied in pregnant women, and their safety has not been established. Mapping with technetium-99 involves low doses of radiation (<1 μGy/MBq) absorbed by the fetus. Studies have reported SLNB success rates of 99% using radioisotope alone, with minimal fetal radiation exposure and no adverse fetal outcomes. ^, Consideration should be given to injecting technetium-99 the day of surgery to minimise exposure.

For PABC, BCT including radiation is contraindicated in the first trimester in the absence of plans for adjuvant chemotherapy, and SLNB with radioactive tracer should be offered in clinically node-negative women with PABC. ^, ^,

Systemic therapy

In general, chemotherapy is contraindicated during the first trimester because of an increased risk of fetal abortion and malformation. In a large series of 413 patients with PABC, 197 (48%) women received chemotherapy during pregnancy, with an anthracycline (90%), cyclophosphamide, methotrexate and fluorouracil (8%), and/or a taxane (7%). Compared with women who did not receive chemotherapy, there was no difference in premature delivery risk. Adverse events for infants, including congenital malformations and newborn complications, were more common in those who were exposed to chemotherapy in utero compared with those who did not have chemotherapy (15% vs 4%, P < 0.001), and birthweight was also lower in the chemotherapy group ( P = 0.018). However, there were no differences between groups in outcomes at birth and 4 weeks after delivery as measured by Apgar score, height, hematologic parameters, or length of hospital stay. A prospective cohort study of 57 women who received 5-fluorouracil, doxorubicin, and cyclophosphamide during the second and third trimesters found no congenital malformations, no short- or long-term complications, and ‘normal development’ in the vast majority of children who were age 2 months to 13 years at the time of the study.

During pregnancy, methotrexate should be avoided due to the risk of associated abnormalities. However, anthracyclines, cyclophosphamide, and taxanes can be given safely in the second and third trimesters without an increase in fetal malformation rates above background rates of approximately 3–6%. Trastuzumab is not recommended in pregnancy, as its administration is associated with oligohydramnios and/or anhydramnios in 60% of cases. About a quarter of patients treated with trastuzumab in the second and third trimester had children with respiratory distress after birth. Endocrine therapy is also not recommended during pregnancy, as tamoxifen has been shown to increase the risk of fetal abnormalities to 13%. ^,

In general, for women with PABC with positive lymph nodes, chemotherapy is ideally administered after the first trimester. For patients diagnosed early in the first trimester, this may be impossible. For women with PABC, negative lymph nodes, and low-risk cancers (where the survival benefit of chemotherapy is ≤ 5%), treatment during pregnancy is usually avoided. For women with PABC who have negative lymph nodes and high-risk cancers, treatment decisions must be made on an individual basis. Chemotherapy should be stopped 3 weeks prior to delivery to avoid myelosuppression and septic complications in mothers and their offspring.

Chemotherapy should be avoided in the first trimester, and trastuzumab and endocrine therapy should be delayed until the postpartum period. ^,

Termination of pregnancy and future pregnancy

Historically, the prognosis of PABC was considered to be so dismal that therapeutic abortion was advocated for all women. However, compared with women who terminated their pregnancies, women who continued their pregnancies did not have poorer overall survival (OS) or disease-free survival (DFS). ^, There are currently no formal recommendations for therapeutic abortions in patients with PABC. However, therapeutic abortion can simplify treatment in patients with locally advanced and inflammatory breast cancers.

Women should be counselled that chemotherapy may adversely affect future fertility. Although fertility may be hindered by patient age and chemotherapy, retrospective studies have demonstrated that pregnancy after diagnosis and treatment of breast cancer is safe. A population-based study conducted by the Danish Breast Cancer Group found no difference in survival among patients with PABC ( n = 371) who became pregnant after treatment and those who did not ( n = 9865). Despite the fact that the rate of relapse is fairly constant for the first 10 years after treatment, some experts advocate waiting 2–5 years for future pregnancies, contending that this affords a period of observation during which early and life-threatening recurrences occur—up to 2 years for high-risk cancers and up to 5 years for low-risk cancers. However, a population-based report showed that for women with localised disease and good prognosis, conception 6 months after completion of treatment was unlikely to reduce survival.

Prognosis

Because of the anatomical and physiological changes of the gravid and lactating breast, PABC tends to be diagnosed at a more advanced stage. In one study, only 36% were diagnosed prior to delivery, 58% had tumours > 2 cm in size at diagnosis, and 30% had N2 or N3 disease compared to 14% of matched controls. A review from the Swedish Cancer Registry comparing PABC ( n = 317) with non-PABC ( n = 2965) demonstrated more advanced stage at diagnosis in the PABC group but no difference in mortality on adjusted analysis. Several other retrospective cohort studies have demonstrated no difference in survival in patients with PABC. In the series by Loibl et al., factors associated with decreased DFS and OS in PABC were T4 (DFS hazard ratio 5.66, OS hazard ratio 4.44, P < 0.001) and node-positive disease (DFS hazard ratio 2.75, OS hazard ratio 6.57, P < 0.001), the same factors known to predict for poorer outcomes in non-PABC.

Male breast cancer

In Western countries, MBC accounts for <1% of all cancers in men. Like female breast cancer (FBC), incidence rates are higher in North America and Europe and lower in Asia. A high incidence also exists in some African countries, including 5% in Uganda and 15% in Zambia, which may be linked to increased oestrogen levels as result of liver damage from infectious diseases.

Pathology

Almost all histological types of breast cancer found in women have been described in men. Ninety per cent of MBCs are invasive; of these, 90% are no special type—formerly known as ductal—2% are papillary, and 1% are lobular. ^, The scarcity of lobular carcinoma probably reflects the paucity of terminal duct lobular units in male breasts. Paget’s disease of the breast and inflammatory breast cancer occur with equal incidence in men and women. Less common subtypes, i.e., medullary, mucinous, squamous and tubular, have been reported in men, but at lower frequencies than in women. Ten per cent of MBCs are non-invasive; the majority of these are ductal carcinoma in situ (DCIS). Lobular carcinoma in situ is rare.

When matched for age, stage, and grade, men with breast cancer have a higher rate of ER positivity than women with breast cancer. In 5494 cases of MBC and 838,805 cases of FBC reviewed over 30 years in the Surveillance, Epidemiology, and End Results (SEER) database, breast cancers were ER+ in 92% of men and 78% of women. Data from the International Male Breast Cancer Program of 1483 patients with MBC reported PR positivity of 82% and androgen receptor (AR) positivity of 97%.

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