Malignant Tumors of the Breast
Reshma Jagsi, Tari A. King, Constance Lehman, Monica Morrow, Jay R.
Harris, and Harold J. Burstein
INCIDENCE AND ETIOLOGY
• Breast cancer is a major public health problem for women throughout the world.
• In the United States, breastcancer remains the most frequent cancer in women and the second most
frequent cause of cancer death.
• In 2017, itwas estimated there were 255,180 new cases of breast cancer, with 41,070 deaths.
• Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer
death among females, accounting for 25%of cancer cases and 15% of the cancer deaths.
• The adoption of screening mammography and the use of adjuvant therapy have contributed
approximately equally tothis improvement.
Risk Factors for Breast Cancer
• Multiple factors are associated with an increased risk of developing breast cancer, but the majority
of these factors convey a small to moderate increase in risk for any individual woman.
• The importance of age as a breast cancer risk factor is sometimes overlooked.
• In 2017, it was estimated that 11,160 invasive breast cancers and 990 breast cancer deaths occurred
in U.S. women younger than age 40 years compared with 241,550 cancers and 39,620 deaths in
women aged 40 years and older.6
Familial Factors
• A family history of breast cancer has long been recognized as a risk factor for the disease, but only
5% to 10% of women who develop breast cancer have a true hereditary predisposition.
• Women with a family history may overestimate their risk of developing breast cancer or harboring
a predisposing genetic mutation.
• Inherited Predisposition to Breast Cancer
• Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with a significant
increase in the risk of breast and ovarian carcinoma and account for 5% to 10% of all breast cancers.
• These mutations are inherited in an autosomal dominant fashion with varying degrees of penetrance.
Familial Factors
• Other cancers associated with BRCA1 or BRCA2 mutations include male breast cancer, fallopian
tube cancer,pancreatic cancer, and prostate cancer.
• BRCA2 may also have an elevated risk of melanoma and gastric cancer.
• Women with BRCA1 mutations have a higher incidence of triple-negative/basal-like breast cancers
(see later in this chapter), with tumors more likely to be grade 3 and less likely to express estrogen
receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)
markers than sporadic cancers.
Hormonal Factors
• The development of breast cancer in many women appears to be related to female reproductive
hormones,particularly endogenous estrogens.
• Early age at menarche, nulliparity or late age at first full-term pregnancy, and late age at
menopause increase the risk of developing breast cancer.
• In postmenopausal women, obesity and postmenopausal hormone replacement therapy (HRT), both
of which are positively correlated with plasma estrogen levels and plasma estradiol levels, are
associated with increased breast cancer risk.
• The use of combined estrogen and progestin HRT also increases breast cancer risk.
• Initiative study, use of combined estrogen and progestin HRT was associated with a hazard ratio
(HR) of 1.24 (P< .001) for breast cancer development as compared to placebo.
Dietary and Lifestyle Factors
• Observational studies suggested that high-fat diets were associated with higher rates of breast cancer
than low-fatdiets.
• Breast cancer risk increases linearly with the amount of alcohol consumed.
• Decreased intake of nutrients such as vitamin C, folate and β-carotene may enhance the risk related to
alcohol consumption.
• Obesity is associated with both an increased risk of breast cancer development in postmenopausal
women and increased breast cancer mortality.
• Women with a body mass index of ≥31.1 have a 2.5-fold greater risk of developing breast cancer than
those with a body mass index of ≤22.6. Weight and weight gain appear to play an important but complex
role in breast cancer risk.
Benign Breast Disease
• Benign breast lesions are classified as proliferative or nonproliferative.
• Nonproliferative disease is not associated with an increased risk of breast cancer.
• Proliferative disease without atypia results in a small increase in risk (RR,1.5 to 2.0), whereas
proliferative disease with atypical hyperplasia is associated with a greater risk (RR, 4.0 to 5.0)
of breast cancer.
• Proliferative breast disease appears to be more common in women with a family history
of breast cancer than in controls, supporting its significance as a risk factor; however, the
majority of breast biopsies done for clinical indications demonstrate nonproliferative
disease.
Benign Breast Disease
• Lobular carcinoma in situ (LCIS) is a benign breast lesion that confers an elevated risk of
subsequent cancer (RR, 8 to 10).
• This risk was historically thought to be conferred equally to both breasts; yet, contemporary series
demonstrate that approximately two-third of subsequent malignancies occur in the breast ipsilateral
to the LCIS diagnosis.
Breast Density
• Mammographic breast density has emerged as an important predictor of breast cancer risk and
makes screening detection of cancer more difficult.
• Women with>75% breast density have a 4.7-fold increase in the odds of breast cancer development
compared with those with >10% breast density.
Environmental Factors
• Exposure to ionizing radiation increases breast cancer risk, and the increase is particularly marked
for exposure at a young age.
• A markedly increased risk of breast cancer development has been reported in women who received
mantle irradiation for the treatment of Hodgkin lymphoma before age 15 years, and risk of a
second, contralateral cancer in such patients approximates the level of risk seen in BRCA mutation
carriers.
MANAGEMENT OF THE HIGH-RISK PATIENT
• Women who carry mutations in either BRCA1 or BRCA2, who have mutations in other high-
penetrance genes such as PALB2 or CHEK2, or who have a family history consistent with
genetically transmitted breast cancer, as well as those who have received mantle irradiation,
usually for treatment of lymphoma, and those with LCIS or atypical hyperplasia, are generally
classified as high risk.
• Management strategies available for high-risk women include intensive surveillance,
chemoprevention, and prophylactic surgery.
• Surveillance, consisting of monthly breast self-examination, annual screening mammography, and
clinical breast examinations once or twice yearly.
• The utility of screening mammography is reduced in women at high risk for cancer due to higher
rates of interval cancer diagnoses in high-risk women.
• Screening with magnetic resonance imaging (MRI) of women at increased risk has demonstrated a
reduction in node-positive disease at time of diagnosis.
• For women at very high risk of breast cancer development, due to genetic factors, a history of prior
thoracic irradiation, or a lifetime risk of 20% or greater based on risk calculations including family
history, screening with MRI is recommended.
• For women with “average” risk, less than a <15% lifetime risk of breast cancer development, the
American Cancer Society (ACS) recommended against the use of MRI screening.
• For women with intermediate risk, such as women with prior history of breast cancer or for those
with high-risk lesions (such as LCIS or atypical hyperplasia), ACS considered the evidence
insufficient to recommend for or against MRI screening.
• The American Society of Clinical Oncology (ASCO) guideline on pharmacologic agents for breast
cancer risk reduction recommends discussion of tamoxifen for breast cancer risk reduction with
premenopausal women aged 35 years and older at increased risk for breast cancer development and
discussion of tamoxifen, raloxifene and exemestane with high-risk postmenopausal women.
• Histories of deep vein thrombosis, stroke, pulmonary
• embolism, or transient ischemic attacks are considered contraindications to the use of tamoxifen or
raloxifene.
• Prophylactic surgery, in the form of bilateral mastectomy or bilateral salpingo-oophorectomy, is
another option for breast cancer risk reduction and is generally considered only for those with the
highest level of risk.
• Prophylactic bilateral salpingo-oophorectomy is an alternative risk-reduction strategy in women at
risk due to BRCA mutations, which has the added benefit of reducing the risk of ovarian
carcinoma.
ANATOMY AND PATHOLOGY
Anatomy of the Breast
• The adult female breast lies between the second and sixth ribs and between the sternal edge and the
midaxillary line.
• The breast is composed of skin, subcutaneous tissue, and breast tissue, with the breast tissue including
both epithelial and stromal elements.
• Each breast consists of 15 to 20 lobes of glandular tissue supported by fibrous connective tissue.
• The space between lobes is filled with adipose tissue, and differences in the amount of adipose tissue are
responsible for variations in breast size.
• The blood supply of the breast is derived from the internal mammary and lateral thoracic arteries.
• The breast lymphatic drainage occurs through a superficial and deep lymphatic plexus and >95% of the
lymphatic drainage of the breast is through the axillary lymph nodes, with the remainder via the internal
mammary nodes.
Lobular Carcinoma In Situ
• LCIS was a precursor lesion of invasive cancer, and based on this, treatment with mastectomy was
recommended.
• More recently, the term atypical lobular hyperplasia (ALH) has been introduced to describe
morphologically similar, but less welldeveloped, lesions.
• Some centers use the term lobular neoplasia (LN) to cover both ALH and LCIS.
• Morphologically, LN is defined as “a proliferation of generally small and often loosely cohesive cells
originating in the terminal duct-lobular unit, with or without pagetoid involvement of terminal ducts.
• LCIS was most frequently diagnosed in women aged 40 to 50 years, a decade earlier than ductal carcinoma
in situ (DCIS), but recent literature indicates that the incidence in postmenopausal women is increasing.
• The prevalence of LN in otherwise benign breast biopsies has been reported to range from 0.5% and
4.3%.56 LCIS is both multifocal and bilateral in a large percentage of cases.
• Prophylactic mastectomy reduces breast cancer risk among high-risk women by approximately
90%.
• Chemoprevention with antiestrogens in patients with LCIS has been evaluated as part of the
NSABP P1 and Study of Tamoxifen and Raloxifene (STAR) trials and the Mammary Prevention.
• In the past, the finding of LN on a core needle biopsy prompted recommendation for surgical
biopsy to rule out coexisting DCIS or invasive cancer.
Ductal Carcinoma In Situ
• DCIS is defined as the proliferation of malignant-appearing mammary ductal epithelial cells without
evidence of invasion beyond the basement membrane.
• Before the widespread use of screening mammography, <5% of mammary cancers were DCIS.
• At present, 15% to 30% of the tumors detected in mammography screening programs are DCIS, and the
greatest increase in the incidence of DCIS has been seen in women aged 49 to 69 years.
• DCIS can present as a palpable or nonpalpable mass, Paget disease of the nipple, an incidental finding at
biopsy, or, most commonly, as mammographically detected calcifications.
• A central problem in the management of DCIS is the lack of understanding of its natural history and the
inability to determine which DCIS will progress to invasive carcinoma during a woman’s lifetime.
Pathology of Invasive Breast Cancer
• The most widely used classification is that of the WHO (fourth edition) based on the growth pattern and
cytologic features of the invasive tumor cells.
• Although the classification system recognizes invasive “ductal” and “lobular” carcinomas.
• Most invasive breast cancers arise in the terminal duct lobular unit, regardless of histologic type.
• The most common histologic type of breast cancer is invasive (infiltrating) ductal carcinoma, composing
70% to 80% of cases.
• The diagnosis of invasive ductal carcinoma is a diagnosis by exclusion (i.e., this tumor type is defined as
a type of cancer not classified into any of the other special categories of invasive mammary carcinoma,
such as invasive lobular, tubular, mucinous, medullary, and other special types).
• In practice, the terms invasive ductal carcinoma, infiltrating ductal carcinoma, and infiltrating or
invasive carcinoma of no special type are used interchangeably.
• Special types of cancers compose approximately 20% to 30% of invasive breast cancers.
• Example, classic tubular carcinoma or classic mucinous carcinoma if <1 cm in size, have a
very low incidence of axillary nodal metastases that may impact management decisions.
• Special types have classic histologic features (e.g., the lymphoplasmacytic infiltrate that
characterizes medullary carcinomas or the single-file appearance of lobular carcinomas).
• Over 90% of a tumor should demonstrate the defining histologic characteristics of a special type of
cancer to be designated as that histologic type.
• In histologic grading, breast carcinomas are categorized based on the evaluation of (1) tubule
formation, (2) nuclear pleomorphism, and (3) mitotic activity.
• Tubule formation (>75%, 10% to 75%, and <10%), nuclear pleomorphism (small and uniform,
moderate variation in size and shape, and marked nuclear pleomorphism), and mitotic activity (per
field area) are each scored on a scale of 1 to 3.
• The sum of the scores for these three parameters is the overall histologic grade.
• Tumors with a sum of the scores of 3 to 5 are designated grade 1 (well differentiated)
• Sums of 6 and 7 are designated grade 2 (moderately differentiated)
• Sums of 8 and 9 are designated grade 3 (poorly differentiated).
• Histologic grading, particularly the distinction between grades 1 and 3, has prognostic significance
as discussed in the section
• “Prognostic and Predictive Factors in Breast Cancer.”
Prognostic and Predictive Factors in Breast Cancer
• Prognosis and treatment of breast cancer are governed by the stage at diagnosis, which largely
reflects the anatomic extent of disease, and by the underlying biologic subset of the tumor.
• Important clinical subtypes of breast cancer are defined by the expression, or lack of expression, of
key biomarkers including ER, PR, and HER2, which correlate with a variety of pathologic
variables such as grade, and genomic features of breast cancer.
• The AJCC staging system is based on established clinical, pathologic, and now biologic prognostic
factors.
• Stage—particularly the extent of axillary lymph node involvement by breast cancer—remains a
significant prognostic factor for subsequent metastatic disease and survival. Tumor size and
histologic grading also have established prognostic significance.
• Tumor size is typically given as the microscopic size of the invasive cancer.
• Histologic grade is best determined by an established methodology, such as the Nottingham
combined histologic grading system described earlier.
• Patient age has been another prognostic factor.
• Approximately 20% of patients with breast cancer have HER2/neu gene amplification, which is
highly correlated with glycoprotein overexpression.
• HER2 amplification or overexpression has been associated with higher tumor grade, lower
expression or lack of hormone receptors, higher levels of tumor proliferation, heavier nodal tumor
burden, and poorer prognosis.
• Tumor involvement of lymphovascular spaces is associated with a greater likelihood of lymph node
metastases and is an independent adverse prognostic factor in node-negative patients. Rigid
pathologic criteria are required for this factor to be reliable.
Proliferation Markers
• Markers of proliferation, such as S-phase fraction, the percentage of cells labeling with thymidine
or bromodeoxyuridine or cellular expression of Ki-67 or MIB-1 (which measure the percentage of
cells in the G1 phase of the cell cycle), and mitotic index, are powerful prognostic factors in early-
stage breast cancer.
• However, interobserver variability and lack of uniform thresholds for clinical prognosis preclude
reliance on these measures as sole determinants for treatment decisions.
Molecular and Genomic Factors
• Breast cancer is a heterogeneous disease, and it has long been appreciated that tumors with
different biologic features have different clinical outcomes and responses to therapy.
• At present, prognosis and treatment selection in breast cancer are based on characterization of
tumor growth factor receptor status—ER, PR, and HER2.
• These markers can be used to define four functional groups of tumors: hormone receptor–positive,
HER2-negative tumors; hormone receptor–negative, HER2-negative tumors (“triple-negative”
tumors); and HER2-overexpressing tumors with or without hormone receptor expression.
DIAGNOSIS AND BIOPSY
• The presence or absence of carcinoma can only be reliably determined by tissue biopsy.
• An abnormal mammography, ultrasound (US), or MRI does not reliably indicate the presence of
cancer, and in the presence of an abnormal physical exam finding, normal imaging does not
reliably exclude carcinoma.
• FNA is easily performed but requires a trained cytopathologist for accurate specimen interpretation
and, when targeting primary breast lesions, does not reliably distinguish invasive cancer from
DCIS.
• The use of core biopsy for the diagnosis of mammographic abnormalities is cost-effective and
increases the likelihood that the patient will be able to undergo a single surgical procedure for
definitive cancer treatment.
• Excisional biopsy as a diagnostic technique should be reserved for patients with imaging
abnormalities that cannot be targeted for core biopsy.
STAGING
• As with all tumor types, the purpose of breast cancer staging is to convey a consistent method for
understanding the extent and, hence, risk of cancer and guiding therapeutic decisions.
• The widely used AJCC system is both a clinical and pathologic staging system and is based on the
TNM system in which “T” refers to tumor, “N” to nodes, and “M” to metastasis.
• For breast cancer, T refers to the extent of tumor within the breast proper, N to the extent of
regional lymph nodes in the axilla and supraclavicular and internal mammary chains, and M refers
to metastatic disease outside of the breast and regional lymph nodes, including bone, liver, lung,
brain, and distant lymph node basins.
Management by Stage: Ductal Carcinoma in Situ
• Treatment of the Breast
• DCIS has been treated with local therapy similar to that used for invasive
breast cancer, including excision, often with a recommendation for
adjuvant RT or mastectomy.
• Ultimately, the appropriate management option depends on the extent of
the DCIS lesion, the risk of LR with each form of treatment, and the
patient’s attitude toward the risks and benefits of a particular therapy.
• Total or simple mastectomy is curative in approximately 98% of patients
regardless of age, DCIS presentation, size, or grade.
• The primary medical indication for mastectomy in DCIS is a lesion too large
to be excised to negative margins with a cosmetically acceptable outcome.
• The Radiation Therapy Oncology Group (RTOG) 9804 study sought to
determine RT benefit after lumpectomy for patients with low-risk
DCIS.
• The 2017 NCCN guidelines endorse lumpectomy and whole-breast RT
as a category 1 recommendation, whereas lumpectomy without RT is
included as a category 2B recommendation.
Treatment of the Axilla
• In situ carcinoma by definition does not metastasize, so theoretically, axillary staging should be
unnecessary for DCIS.
• Studies of axillary lymph node dissection (ALND) in DCIS have demonstrated axillary nodal
metastases in only 1% to 2% of patients, presumably due to unrecognized microinvasion.
• Data from the NSABP B-17 and B-24 studies confirm that the risk of isolated axillary recurrence
with no axillary surgery is <0.1%, regardless of whether RT and tamoxifen are administered.
• The diagnosis of DCIS in a palpable breast mass and pathologic interpretation of a core biopsy
specimen as suspicious, but not diagnostic, of microinvasion are circumstances in which invasive
cancer is more frequently found when the lesion is completely examined, and sentinel node biopsy
should be considered.
