Malignant Disease of the Breast: The Role of Breast Imaging in Identification and Treatment

Rennette Timbrell RT(T), MRad (South Africa)

 ^*Supervisor–Radiation Therapy, Radiation Oncology Department, University of Colorado Hospital Denver, Aurora, Colorado.
 Address correspondence to: Rennette Timbrell, RT(T), MRad (South Africa), Supervisor–Radiation Therapy, Radiation Oncology Department, PO Box 6510, MS-F-706, University of Colorado Hospital Denver, Aurora, CO 80045. E-mail: Rennette.Timbrell@uch.edu.

Disclosure: Ms Timbrell reports having no significant financial or advisory relationships with corporate organizations related to this activity.

ABSTRACT

According to the National Cancer Institute estimates, each year approximately 192 000 women are diagnosed with breast cancer. Overall, breast cancer is second only to lung cancer as a cause of death in women in the United States, and among those aged 40 to 59 years, breast cancer is the most common cause of death. Tumors are the most important lesions of the breast, and there is often confusion clinically between benign and malignant tumors arising in the breast. Fibrocystic changes are the most dominant breast condition with cancer. Imaging studies are used to establish any abnormality in the breast, with mammography as the mainstay of screening for breast cancer. Other imaging techniques, including ultrasonography, computerized tomography, magnetic resonance imaging, and nuclear medicine procedures, have become an important aid in the identification of abnormalities in the breast tissues. This article will examine the anatomy of the breast, provide a detailed account of malignant pathology arising in the breast tissues, and discuss the role of imaging in detecting these abnormalities. A review of the treatment modalities for breast cancer also will be outlined.

Introduction
he National Cancer Institute (NCI) estimates that each year approximately 192 000 women are diagnosed with breast cancer.¹ Overall, breast cancer is second only to lung cancer as a cause of death in women in the United States and among those ages 40 to 59 years, breast cancer is the most common cause of death. Breast cancer also occurs in the male population. The NCI estimates that each year approximately 2000 men may develop breast cancer in the United States.¹ Male breast cancer is rare in contrast to female breast cancer² and for the purpose of this article, emphasis will be on the female breast.

Mortality rates from breast cancer have been declining since the mid 1970s, especially for women younger than 50 years. This decrease is believed to be the result of earlier detection through improved and more sensitive screening procedures, increased awareness of breast cancer, and improved treatment,³ including the development of image-guided radiation therapy and neoadjuvant chemotherapy. In the last few decades, there has been much progress in all imaging modalities used for identifying abnormalities of the breast, diagnosis, staging, treatment, and follow-up. In the past, breast lumps were most often discovered during self examination or during a routine clinical examination by a physician. Currently, mammography has become the gold standard screening method for identifying abnormalities. However, mammography is not without imperfection, and other modalities have gained ground as an adjuvant to mammography breast screening. Ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine all have a potential role in the identification, diagnosis, treatment and/or follow-up of breast cancer.

Cancer of the breast is a diverse group of epithelial neoplasms, which may arise in the ductal or the lobular epithelium of the breast. They are further classified into noninfiltrating and infiltrating carcinomas, with invasive ductal and invasive lobular tumors being the most common tumors. This article will examine the anatomy of the breast, provide a detailed account of malignant pathology arising in the breast tissues, and discuss the role of imaging in detecting these abnormalities. A review of the treatment modalities for breast cancer also will be outlined.

Anatomy of the Breast
In males and the females, the breasts are situated on the right and left anterior thorax. The base of the breast extends from the second to the sixth ribs and from the lateral aspect of the sternum to almost the mid-axillary line laterally. In the male and the pre-pubertal female the breast is a rudimentary organ.⁴ In the adult female, the breast is round and soft and consists mainly of glandular and fatty tissue. The undersurface of the breast lies over the pectoris major muscle and is anchored to the pectoralis major fascia by suspensory ligaments called Cooper's ligaments, which were first described by Dr Astley Cooper in 1840. The ligaments run throughout the breast parenchyma, providing support while allowing natural motion of the breast. The breast tissue projects obliquely into the axilla as the axillary tail of Spence. The nipple, which is surrounded by pigmented skin called the areola,⁴ forms the apex of the breast.

The breast comprises skin, subcutaneous, and breast tissue. Internally, breast tissue consists of parenchymal and stromal tissue. The parenchymal or glandular tissue is divided into 15 to 20 lobes of glandular tissue that converge at the nipple in a radial arrangement.⁵ Each lobe comprises clusters of alveoli (milk secreting cells) with draining ductules that unite to form a lactiferous duct which in turn pass toward the nipple. Deep to the nipple the lactiferous ducts dilate to form a lactiferous sinus, which opens on to the nipple. The stromal tissue of the breast consists of a framework of fatty connective tissue separating the lobes of the parenchyma (Figure 1).⁶

Blood Supply
The principal blood supply to the breasts is by the internal mammary and lateral thoracic arteries and branches of the internal thoracic, anterior intercostal, and lateral thoracic arteries, with venous drainage by veins of the same names.⁴

Lymph Drainage
Lymph, defined as a "usually clear coagulable fluid that passes from intercellular spaces of body tissue into the lymphatic vessels,"⁷ drains from the breast to a subcutaneous subareolar plexus and submammary plexus, from which it drains laterally to pectoral nodes in the axilla, superiorly to the infraclavicular and lower deep cervical nodes, and inferiorly via the subcutaneous plexus to the abdominal wall and the diaphragmatic nodes. Medially the lymph drains to the parasternal nodes and across the midline to communicate with the plexuses of the contralateral breast (Figure 2).^4,8

The complex network of the lymphatic drainage system of the breast plays an important role in the spread of breast cancer, and the axillary lymph nodes are studied as the major route of regional spread in primary breast cancer.⁵

Malignant Pathology of the Breast
Cancer of the breast is a diverse group of epithelial neoplasms, which may arise in the ductal or the lobular epithelium of the breast. The neoplasia are further classified into noninfiltrating (noninvasive) and infiltrating (invasive) carcinomas. Invasive ductal and invasive lobular are the most common tumors.

Epidemiology
In the United States, the chance of developing invasive breast cancer at some point in a woman's life is a little less than 1 in 8 (12%)³ while the lifetime probability of developing breast cancer is 1 in 6 overall.⁹ The last 3 decades have seen fluctuation in the incidence of breast cancer, starting with an increase in the early 1980s that peaked in 1998, and followed by a decrease of 3.7% per year from 2001 to 2004.¹⁰ This increase incidence was attributed to additional use of screening mammography, as well as an increased use of estrogen in hormone replacement therapy (HRT). In the late 1990s and early 2000s, there was a decline in incidence, particularly among women aged 50 to 69 years with estrogen-receptor-positive tumors, which has been attributed to decreased use of HRT.¹¹ Mortality rates for breast cancer have declined since the mid 1970s, also attributable to the increased use of screening mammography and adjuvant chemotherapy.⁹

Many risk factors have been associated with breast cancer, including:

• Age and gender: This is the strongest risk factor with incidence higher in women up to the age of 45 to 50 years.
• Race and ethnicity: Breast cancer in the United States is common in women of every major ethnic group. The role of ethnicity becomes apparent in black women who have a higher rate of mortality than white women, which is due in part to black women presenting with disease at a more advanced stage at time of diagnosis.
• Benign breast disease: Multiple non-proliferative lesions may have a modest influence on the risk of developing breast cancer.
• Personal history of breast cancer: A personal history of invasive or in situ breast cancer increases the risk of developing an invasive cancer in the contralateral breast. The risk for contralateral in situ lesions is a 5% chance in 10 years and for invasive cancer, the risk of contralateral breast cancer is 0.5% to 1%.
• Lifestyle and dietary factors: Breast cancer is more prevalent in women of a higher socioeconomic status. This is thought to be reflective of reproductive patterns with respect to parity, age at first birth, age at menarche, and utilization of screening mammography. Dietary factors, such as alcohol intake, fat intake, antioxidants, calcium, and vitamin B intake, have been cited as influencing the risk of developing breast cancer. Alcohol intake is the dietary factor with the strongest evidence of an association with breast cancer.⁴
• Reproductive and hormonal factors: Reproductive factors influence the risk of developing breast cancer. Early age of menarche and menopause is associated with a higher risk of breast cancer. The younger the woman is at the time of her first pregnancy, the lower the risk of breast cancer developing. In addition, breast feeding has been shown to have a protective effect on the development of breast cancer. Studies with obese and nonobese postmenopausal women have indicated that there is a link between breast cancer risk and serum estrogen levels. Obese postmenopausal women have higher estrogen levels than nonobese postmenopausal women and have a higher risk of developing breast cancer.
• Family history and genetic factors: Family history of breast cancer is a very important risk factor for breast cancer. In a large study using pooled analysis, the risk for a woman whose relative was diagnosed with breast cancer before the age of 30 was increased 2.9 fold; for a relative diagnosed after the age of 60, the risk increased 1.5 fold.⁴
• Exposure to ionizing radiation: Exposure of the chest to ionizing radiation at a young age (eg, treatment for Hodgkin's lymphoma, survivors of atomic bomb or nuclear plant accidents) is associated with an increased risk of breast cancer. The risk of developing breast cancer after low-dose exposures, such as radiological tests, is controversial.
• Environment factors: Many substances have been linked to increasing the risk of developing breast cancer including polychlorinated biphenyls and pesticides such as dichlorodiphenyltrichloroethane. However, most large studies have failed to find an association. Other factors, such as breast implants, deodorants, and hair dyes, have not been associated with increased risk in most studies.⁴

Carcinoma of the Breast
Breast tumors may be benign or malignant. The most common benign tumor is the fibroadenoma, which appears clinically as a solitary, discrete movable mass. Increased estrogen activity (puberty, menstrual cycle, and pregnancy) is thought to play a role in the development of tumors.⁹ The upper outer quadrant of the breast is the most common site of occurrence for tumors of the breast (50%), with the central portion of the breast next (20%), followed by the lower outer and upper and lower inner quadrants (10% each). The majority of malignant tumors (95%) arise in the glandular epithelial tissue lining the lactiferous ducts and the ductules and are classified as adenocarcinomas.¹² These are divided into 2 major groups:

• In situ carcinoma, also referred to as noninvasive intraductal carcinoma or ductus carcinoma in situ (DCIS): The tumor cells remain confined to the ducts or lobules with no evidence of microscopic invasion into the surrounding stroma.¹³
• Invasive carcinoma, also referred to as infiltrating carcinoma, where there is evidence of tumor cell invasion of the breast stroma which has the potential to metastasize to the lymphatic system and/or distant sites, such as the brain, bone, and liver.

In situ carcinomas make up between 5% to 8% of breast cancers and are either ductal or lobular. The difference is based primarily on the growth pattern and cytologic features.

In Situ Carcinomas
Ductal carcinoma in situ
Ductal carcinoma in situ refers to a heterogeneous histologic group of lesions that differ in clinical presentation, histology, and biologic potential.¹³ Several classification systems have been proposed for these tumors but all are based on the nuclear grade (high, intermediate, or low) and the presence or absence of necrosis:

• Comedocarcinoma presents as a palpable mass or as ropey cords within the breast.¹² The primary cytologic feature is prominent necrosis in the involved cell spaces, which may be detected by mammography as linear, branching calcification.¹³
• Intraductal papillary carcinoma shows intraluminal projections of tumor cells constituting true papillations.

The most common presentation for DCIS is an abnormal mammogram with clustered microcalcifications (Figure 3).^13,14 Involvement of the axillary lymph nodes is rare. The widespread use of screening mammograms has led to a significant increase in the detection of DCIS.

The major issue in the management of DCIS is the risk of progression to invasive carcinoma,¹⁵ and a frequent pathological finding is that of small foci of invasive carcinoma or microinvasion. According to the 2002 edition of the American Joint Committee on Cancer, microinvasion is defined as "the extension of cancer cells beyond the basement membrane into the adjacent tissues with no focus more than 1 mm in greatest dimension."¹⁵ The major significance of the presence of microinvasive carcinoma is predicting the behavior of the tumor.

Lobular carcinoma in situ
Lobular carcinoma in situ (LCIS) arises from the terminal ductules of the lobule. It is not palpable and is defined only by histology. LCIS occurs more often in women aged 40 to 50 years and is always an incidental finding in breast tissue removed for another reason such as an area of fibroadenoma.¹³ The significance of LCIS is the possibility of its transition to infiltrating carcinoma.¹² Once LCIS is diagnosed, subsequent invasive cancer can occur in either breast presenting as either ductal or lobular carcinoma. Infiltrating lobular carcinomas are more frequent in patients with LCIS than in the general population, thus LCIS has been considered as a risk factor for invasive carcinoma. Presently, the management of patients diagnosed with LCIS may be careful follow-up only¹³ or radiation therapy.

Invasive Carcinomas
The invasive breast cancers consist of several histologic subtypes, the most common of which are presented in Table 1.¹⁶ These cancers are a heterogeneous group of tumors that differ in their clinical presentation, radiographic characteristics, pathologic features, and biological potential.¹⁵ Infiltrating ductal carcinoma occurs most frequently, accounting for between 70% to 80% of invasive lesions. From 1987 to 1999, the incidence rate of invasive lobular cancer increased by 65%, and studies have suggested that these tumors are more likely to be hormone-receptor positive, indicating that postmenopausal use of progestin and estrogen is more strongly related to lobular carcinoma risk than to ductal carcinoma risk.¹⁷ Most invasive cancers have an element of in situ carcinoma, the extent of which may vary considerably.¹⁵

Invasive (infiltrating) ductal carcinoma
Invasive ductal carcinoma (IDC), which account for largest group of invasive carcinomas (70%–80%), is also termed "infiltrating carcinoma of no special type" or "infiltrating carcinoma not otherwise specified." IDC usually presents as a palpable mass or a radiographic abnormality on mammography. They are histologically diverse and have been further classified according to histology and nuclear grading as follows¹⁶:

• Well-differentiated (grade 1): Well-differentiated cells infiltrate the stroma and nuclei are relatively uniform.
• Moderately differentiated (grade 2): Moderately differentiated cells infiltrate as solid nests with some glandular differentiation and nuclei are pleomorphic.
• Poorly differentiated (grade 3): Poorly differentiated cells composed of solid nests of neoplastic cells with no evidence of gland formation. There is marked nuclear atypia.

The heterogeneity of these tumors allows for the presence of DCIS and LCIS component and may be described as mixed.¹⁵ IDC is associated with poor prognosis; however, prognosis also may be influenced by other factors, such as the age of the patient, estrogen receptor (ER) and progestogen receptor (PR)status, nodal status, tumor size, position, and pathological type.

Infiltrating lobular carcinoma
These tumors account for 8% to 10% of invasive cancers of the breast. Invasive lobular carcinoma is sometimes similar to IDC in its clinical presentation (ie, a palpable mass and mammographic abnormality). On physical examination these tumors also may present as a subtle mass without definable margins, with either no abnormality or poorly defined abnormality on mammography.¹⁵ As a group these tumors show distinctive cytologic features and patterns of tumor cell infiltration of the stroma.¹⁵ They are characterized by small neoplastic cells that invade the breast tissue in a single-file pattern, often growing in a target-like fashion around the normal breast ducts.¹⁶ It is common for LCIS elements to be present with invasive lobular carcinoma and in some cases, DCIS may be evident.

There are some interesting features that characterize invasive lobular carcinoma:

• On imaging, there is a high frequency of tumor multicentricity in the ipsilateral breast and an increased occurrence of lesions arising bilaterally.
• Classic invasive lobular tumors are usually ER positive and are more common in older women. This feature has been strongly associated with the use of HRT, with an approximate 3-fold increased risk associated with longer duration of HRT.¹⁸
• The pattern of metastatic spread differs from IDC. Lobular invasive carcinomas commonly metastasize to unusual sites, such as the peritoneum, meninges, and gastrointestinal tract.¹⁶

Ductal/lobular invasive carcinoma
A small percentage (between 2%–4%) of invasive breast carcinomas exhibit features of both ductal and lobular invasive carcinoma, making it difficult to categorize them definitively. This type of lesion may be categorized as "mixed."¹⁵ These tumors are heterogeneous in nature and data on the clinical features and outcomes are very difficult to interpret.¹⁵

Tubular carcinoma
Tubular carcinoma of the breast is characterized by the formation of elongated tubules infiltrating the breast stroma. The incidence of tubular cancer is low, accounting for between 10% to 20% of invasive cancers,¹⁶ and they are often diagnosed in tissues specimens obtained for reasons not related to diagnosis of cancer. Tubular carcinoma often does not metastasize and has a favorable prognosis.

Mucinous (colloid) carcinoma
Mucinous carcinoma makes up less than 5% of the invasive carcinomas. Microscopically, they are characterized by nests of tumor cells dispersed in pools of extracellular mucus. This type of carcinoma has a favorable prognosis, which is similar to tubular carcinoma.

Medullary carcinoma
Medullary carcinoma accounts for less that 1% to 5% incidence of invasive cancers¹⁵ and has uncertain prognostic implications. Medullary carcinoma appears as a well circumscribed palpable mass usually in the upper outer quadrant of the breast. The cells are poorly differentiated.¹⁶

Other Histologic and Clinical Types of Breast Cancer
Inflammatory breast cancer
Inflammatory breast cancer (IBC) is a distinct type of cancer, rapid in onset, which progresses with an aggressive nature. It is rare, accounting for 1% to 5% of breast cancers.¹⁶ In general, the patient presents with a painful, enlarged breast.¹⁹ The skin over the breast is usually reddened and thickened with dimpling of the skin that is similar to the skin of an orange and referred to as "peau d'orange." There is usually lymph node involvement at the time of diagnosis. IBC requires aggressive multimodal treatment, including chemotherapy, radiation therapy, and surgery. The long-term prognosis is relatively poor¹⁹ with a 5-year survival rate of 50%.¹⁶

Paget's disease of the breast
Paget's disease of the breast was first described in 1874 by Sir James Paget. It is a rare disorder of the nipple and areola, clinically defined as a persistent scaling, eczematous, or ulcerated lesion containing breast cancer cells.²⁰ Paget's disease makes up approximately 1% of all breast cancers, and the lesion is almost always associated with underlying in situ or invasive breast cancer.¹⁶ It occurs more often in younger women.

Other rare breast cancers
There are several other rare breast cancers. Micropapillary carcinoma is a particularly aggressive form of cancer that has early spread to the lymph nodes. Metaplastic carcinoma is a well circumscribed tumor consisting of various pathologic components. Finally, adenoid cystic carcinoma is a rare tumor associated with a favorable prognosis. This tumor is almost identical to a cystic tumor originating in the salivary glands.

Staging of Breast Cancer
Staging refers to the grouping of patients according to the extent of their disease.¹⁵ The staging of breast cancer is complex and has constantly been modified. There have been many attempts to devise a simple system; however, the internationally recognized system to determine the extent of breast cancer is the tumor node metastasis (TNM) staging system. This system provides a detailed description of the stage of disease referring to tumor size (T); the presence, site, and size of lymph node involvement (N); and the presence of distant metastases (M). Further modifications have been made to the system, taking into account pathologic grade and the endocrine receptor status of disease. A second system, known as stage grouping, is often used, where the size, node, and metastases are grouped into Stage I, II, III, and IV and then further classified into Stage IA, IB, IIA, IIB, and so forth. The stage grouping is used to assist in simplification of the detailed TNM system of staging. The TNM system is recognized as the official staging system for breast cancers. A detailed description of the staging of breast cancers is beyond the scope of this article.

Imaging Tools for Diagnosis of Breast Cancer
Since the 1970s the most common imaging tool for diagnosis of breast cancer has been film-screen mammography. Mammography has taken the place of clinical and self examination only as a method for detecting possible breast malignancies, for which it is primarily used. It is also used for diagnosis of suspected breast cancer, however, for a variety of reasons, the use of other imaging tools for breast cancer diagnosis has increased. These imaging modalities include ultrasonography, CT, MRI, and positron emission tomography (PET), among others. However, mammography remains the gold standard and first-line radiologic test for screening and diagnosis of breast cancers. The technology for mammography has advanced significantly over the years and digital mammography, where digital sensors replace the X-ray film, is known to increase the accuracy of diagnosis.

Mammography
By the mid 1980s in the United States, mammography was widely available and it has proven to be a cost effective procedure. Mammography is performed for 2 reasons: to screen for breast cancer and to diagnose breast cancer. Screening mammography is performed in women with no symptoms or complaints. The purpose is early detection of possible malignancy to decrease morbidity and mortality, although not necessarily to ensure a cure. The use of mammography for breast cancer screening is widely accepted but not without limitations. There is a 20% to 30% false-negative rate and tumors without associated calcifications and subtle masses are often difficult to diagnose with mammography.²¹ There are also several negative effects to be considered when using screening mammography, including patient anxiety about the mammogram and findings of any biopsy and then unnecessary biopsy of possibly benign lesions. The benefit of screening mammography to detect clinically occult cancer has been studied worldwide. Clinical trials conducted in Europe and North America showed a reduction in mortality rates in screened women¹⁵ and led to the international acceptance of incorporating screening mammography into preventive healthcare for women starting at 40 years of age and making it routine for women aged 50 to 70 years.¹⁰

Diagnostic mammography is performed in men and women who present with breast cancer symptoms, such as a lump detected at clinical or self examination, or in testing for those women who have suspicious findings at screening mammography. Diagnostic mammography for detecting breast cancer continues to be the initial test.

However, there are downfalls to using mammography, the biggest being decreased sensitivity in women with dense breasts²² and the fact that approximately 10% of cancers are mammographically occult even after they are palpable.^21,23 To improve clarity and visualization and to aid immobilization, as well as to reduce the dose of radiation, the breast is compressed for the imaging procedure. Approximately 50% of women experience moderate or greater discomfort with compression.²²

Standard film-screen mammography is the most common and cost-effective method for imaging breast tissue. Digital mammography, which is a recent advancement in mammography technology, has significantly improved the sensitivity and clarity of the images. Digital mammography uses computers and specially designed image (digital) detectors to convert the X-ray images into digital images to produce an image on high-resolution monitors.²⁴ Notable advantages to film-screen mammography:

• It has a higher contrast resolution, which is especially important when viewing dense breast tissue.²⁴
• It allows for electronic transmission and storage of images, which requires less space than is needed with film-screen mammography.
• The images can be manipulated to enhance visualization, which is especially useful for viewing subtle structures and calcifications.^21,25
• The wait time for film development is significantly decreased for patients with elimination of film artifacts.
• Digital mammography uses a lower dose of radiation.

However, there are also disadvantages to digital mammography. The major disadvantage of digital mammography is the cost, which is approximately 1 to 4 times that of film-screen systems.²¹ It is also not readily available at all imaging centers. There have been many studies comparing film-screen mammography with digital mammography. Most studies have found little difference in cancer detection rates¹⁴ and similar overall accuracy in diagnosis for both modalities. Digital mammography, when available, may offer a small screening advantage in women younger than 50 years.¹⁴ Despite the challenges posed by the cost, it is expected that in the future, digital mammography will be used with increasing frequency.

Ultrasonography
Ultrasonography has been used as a tool to supplement the diagnosis of breast cancer since the early 1950s. At that time, the technology was limited and ultrasonography was not used routinely as a tool for diagnosis of breast cancer. It was not until the mid 1980s, with the development of prone and supine automated breast scanners,¹⁵ that ultrasonography was used in conjunction with mammography to aide in the diagnosis of breast cancer. Although breast sonography is well established as a valuable imaging technique,²¹ ultrasonography of the breast is not established as routine for screening mammography procedures due its limited ability to depict microcalcifications (an indication of possible malignancy) and to differentiate between benign and malignant masses. The primary role of breast ultrasonography is as a diagnostic follow up to an abnormal screening mammogram.¹⁴ The American College of Radiology Practice Guideline for the Performance of Breast Ultrasound Examination listed the current indications for performing ultrasonography and is presented in Table 2.

Ultrasonography is the imaging technique of choice to evaluate palpable masses in women younger than 30 years and in lactating and pregnant women.^14,15,21 It is also used for image-guided biopsy, offering patient comfort, real-time continuous observation of needle passage, and speed.¹⁵ The main advantages of ultrasonography are that it does not involve the use of ionizing radiation, it is relatively cost effective, and it is easily accessible.

Magnetic Resonance Imaging
Over the past 2 decades, MRI has become a useful imaging procedure for the detection, diagnosis, and staging of breast cancer. To date, the role of MRI as a routine procedure in screening for breast cancer has not been established. The technology for breast MRI has improved significantly, allowing for increased sensitivity in detecting breast cancer. However, MRI has limited specificity with an overlap in the appearance of benign and malignant lesions.^15,21 Studies have shown nearly 100% sensitivity in detecting invasive breast carcinomas, although most show poor specificity²⁵ with some studies indicating a specificity as low as 37%.²¹

Breast MRI is performed with the patient in the prone position,²⁶ which minimizes the effects of respiratory motion and provides in improved image quality. Intravenous contrast agent is used with most patients and is considered essential in identifying breast cancers and distinguishing malignant (enhancing) from benign (nonenhancing) tumors.²⁵ Most reports indicate a dose of 0.1 mol gadolinium per kilogram of weight.²¹ Biopsy of the lesion is required to differentiate enhancing malignant breast cancers from nonenhancing benign lesions. Dedicated MRI-guided biopsy equipment is available that allows access to the medial side of the breast and minimizes the need to move the patient from the MRI suite to the biopsy suite. MRI-guided percutaneous biopsy is more expensive than those performed under ultrasound or stereotactic guidance and is usually reserved for those lesions detected under MRI.

The indications for MRI of the breast are still evolving and are not yet well established.^15,21,25 MRI is recommended by the American Cancer Society in women at high risk based on family history associated mainly with a genetic mutations BRCA1 and BRCA, which are associated with 5% to 6% incidence of breast cancer.⁴

The most common indication for MRI is as an adjunct to mammography and ultrasonography in the detection and diagnosis of breast cancer or for indeterminate findings on a mammogram,²⁵ and it is highly sensitive for the detection of both invasive carcinoma and DCIS.²⁶ MRI also may be performed in the planning of treatment for a patient as preoperative procedure to show the extent of disease in invasive lobular cancers and tumors with an extensive intraductal component. Multifocal and multicentric tumors are better imaged by MRI than by conventional methods.²⁵ MRI can have a huge impact on the surgical approach²⁵ to the treatment of breast carcinoma. It also may be used to detect occult disease in the contralateral breast for patients recently diagnosed with breast carcinoma. In a study conducted at Memorial Sloan-Kettering Cancer Center in 2003, MRI was found to detect cancer in the contralateral breast in 5% of women with known breast cancer.²⁵

Magnetic resonance imaging is contraindicated for patients who are not able to lie prone, for patients with claustrophobia, and for those with pacemakers. Major challenges include the high cost of MRI and the increased time to perform procedures.

Nuclear Breast Imaging
In contrast to anatomic imaging, nuclear breast imaging involves the use of radiopharmaceuticals to view changes in functional physiology where changes in cell metabolism due to malignant lesions can be imaged. It is a biological assay carried out without the need for an invasive procedure.²³ The most widely used agents are ¹⁸F-fluorodeoxyglucose (FDG) and ⁹⁹Tc-sestamibi, both administered intravenously.

The most common nuclear medicine procedure is PET. Whole body PET scanning is an expensive procedure. The need for a dedicated system to image the breast has resulted in the development of small, compact, dedicated PET scanners that may be incorporated into a breast imaging program. Positron emission mammography (PEM) allows improved spatial resolution and geometric sensitivity for the detection of emitted radiation and reduces photon attenuation.²⁵ The images for PEM are the same as for conventional mammography using gentle compression. PEM is not widely available and the disadvantage is that any spread of malignancy to distant sites is not seen. The use of PEM in the management of diagnosed breast cancer is based on the increased sensitivity of PEM in diagnosing breast cancers.

Positron Emission Tomography/Positron Emission Mammography
Breast cancer tumors have a higher metabolism than the surrounding normal tissue. PET and PEM offer the advantage of detecting metabolic changes before changes manifest anatomically²³ and of providing both metabolic and anatomic detail.²¹ FDG is used most commonly with breast cancer cells, which take up the glucose avidly because of their high metabolic rate.²³ The most common dose is 10 mCi (370 MBq) administered intravenously.

Increased sensitivity to detecting a malignant lesion, a major advantage of both PET and PEM, is not degraded by breast density, which as discussed earlier, is a major problem when using mammography. MRI and PET have the added advantage of whole-body staging, in which possible distant metastases to the brain, liver, lung, and bones can be detected. Some studies have indicated that with PEM lesions as small as 1.5 mm can be detected, smaller than lesions detected by PET, which is sensitive to lesions 1cm or larger.

Positron emission tomography is used for treatment monitoring and as an adjunct to conventional imaging.²¹ PEM is recommended for local staging of a new breast cancer, restaging, and monitoring patients on neoadjuvant chemotherapy.²³

Breast-Specific Gamma Imaging
In the 1990s, ⁹⁹Tc-sestamibi was used for cardiac perfusion and found to be taken up by breast tissue. Breast scintimammography was done at this time but was not reliable for lesions smaller than 1 cm due to the distance of the gamma camera detector from the patient. As with PET and PEM, a smaller gamma camera was developed and placed closer to the patient to improve the sensitivity. This imaging procedure is referred to as breast-specific gamma imaging (BSGI), sometimes known as molecular breast imaging.²³ BSGI uses intravenous ⁹⁹Tc-sestamibi with an uptake time for optimum imaging after injection of 10 minutes. Images are taken in a manner similar to that of conventional mammography, with the breast gently compressed.

The sensitivity of BSGI has been studied using both a single-head and double-head camera, The sensitivity of the dual-headed machine in detecting tumors smaller than 5 mm was significantly higher (at 69%) than that of the single-head device (29%).²³

Breast-specific gamma imaging may be used as an adjunct to diagnose breast cancer for staging and monitoring treatment, but has not yet been used in screening for breast cancer.

Computed Tomography
In the mid 1970s, with the implementation of CT as a diagnostic imaging tool, the use of CT mammography (CT/M) for breast imaging was studied. The results showed that despite the high sensitivity of CT imaging, the low specificity due to low special resolution, high cost, and high radiation dose compared to mammography were not acceptable and CT/M was dismissed from the market.²¹ However, in the last 10 to 12 years, with the advancements in technology, CT was again tested as a modality for breast imaging. Whole-body conventional and dedicated breast CT scanners have been developed and cone-beam technology has been shown to benefit image quality.²² Many studies have compared breast CT to mammography, MRI, and ultrasonography, and there is evidence to suggest that dedicated breast CTs are producing promising results.^22,27 Overall, CT is equal to mammography for visualization of breast lesions but mammography outperformed CT for visualization of microcalcifications.²⁷

One notable advantage of breast CT, which is also applicable to MRI mammography, is patient comfort. The patient lies prone with the breast pendant through a table aperture²⁷ and no compression is applied to the breast.

The role of CT in breast imaging is still in the developmental stage and remains in the research and experimental stage. The major role of CT in breast imaging is that of conventional CT in detection of metastases for staging of breast cancer, especially in those women diagnosed with stage III breast cancer.²⁸ Many women treated with breast conserving surgery (BCT; lumpectomy) undergo CT as part of the planning for radiation therapy treatment where CT simulation is utilized.¹⁵ These images are used to define the radiation treatment fields and determine the dosimetry for the treatment plan.

Overview of Breast Cancer Treatment
Breast cancer treatment is complex and dependent on many factors relative to each patient. Over the years, the mainstays of treatment have been surgery, radiation therapy, hormone therapy, and chemotherapy. Any of these options may form part of a treatment plan for patients diagnosed with breast cancer. The choice of treatment is dependent on the stage of disease. Staging includes establishing the diagnosis, the size of the tumor, whether the draining axillary lymph nodes are involved, whether the tumor expresses hormone receptors and/or the protein human epidermal growth factor receptor 2 (HER2), and the patients age and hormonal status.²⁹ Each of these factors will play a role in the final decision for treatment of breast cancer.

Surgery is required for all patients with invasive breast cancer. Surgical excision may be BCT, such as lumpectomy, in which only the tumor and a small amount of normal tissue is removed, or total mastectomy usually followed by radiation therapy and chemotherapy. Most women with stage I and II breast cancer are candidates for BCT.¹⁵ The major risk with BCT is locoregional recurrence of the tumor and for these patients, either part of the breast or the entire breast is irradiated. The aim of the radiation therapy is to minimize this risk of local recurrence and whole breast irradiation significantly reduces the risk of local recurrence in the preserved breast.¹⁵

The status of lymph nodes is required to rule out or establish that the cancer has spread and is an important prognostic factor. The status of the lymph nodes also will play a role in the selection of radiation and adjuvant systemic therapy (chemotherapy, hormone therapy, and trastuzumab, which is used for HER2-positive patients [see below]).²⁹ The primary route of lymph node spread is to the axillary nodes and for this reason, axillary lymph node dissection or sentinel lymph node biopsy is done at the time of surgery or may be deferred to a later date.²⁹

Breast cancer cell growth is stimulated by the presence of estrogen and progesterone. The growth is dependent on the presence or absence of estrogen and progesterone receptors (ER-positive or ER-negative; PR-positive or PR-negative) in the cells. Hormone receptor assays are an important component of the workup procedure. Patients with hormone receptor-positive tumors benefit from the addition of endocrine treatment, such as tamoxifen (anti-estrogen), or ovarian ablation in pre- and perimenopausal women or anastrozole or letrozole (aromatase inhibitors) in postmenopausal women.²⁹ There is evidence that there is a decline in mortality rate for women with ER-positive and PR-positive tumors.⁴

The oncogene HER2 and its protein products is a tumor marker that is used to select the treatment for breast cancer³⁰ and all primary tumors should be assayed for HER2 overexpression. Eighteen percent to twenty percent of women with an overexpression of HER2 will benefit from treatment with trastuzumab, a humanized anti-HER2 monoclonal antibody that targets HER2.²⁹ It appears that women whose tumors overexpress HER2 derive greater benefit from anthracycline-based chemotherapy than from the alkylating agent-based chemotherapy. Thus, HER2 overexpression will assist in the choice of adjuvant chemotherapy that best benefits the patient. Most of the available evidence supports the view that HER2 overexpression is associated with poor prognosis.³⁰

Adjuvant chemotherapy benefits both pre- and postmenopausal women, although the absolute benefit is greater in younger women as compared to older women.²⁹ The chemotherapy is administered as a multi-drug regimen (eg, cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]). As discussed earlier, the choice of drugs for each patient may be influenced by the overexpression of HER2.

Radiation therapy is used to minimize recurrent disease after surgery and chemotherapy, either as partial breast irradiation to the tumor bed only after BCT or to the whole breast and if necessary, the axillary lymph nodes. Radiation is delivered by external beam or brachytherapy, where the source of radiation is placed at the site of disease to ensure maximum dose to the tumor while sparing the normal tissue. For patients with metastatic spread to the liver, lung, brain, and bone, radiation therapy is of benefit as palliative treatment.

Conclusions
Research into various aspects of breast cancer is ongoing and receives a lot of attention from the general population, the media, and the medical community. Over the past 40 to 50 years there has been significant progress in the screening, diagnosis, and treatment of breast cancers. Screening for breast cancer is routine for women older than 50 years and there are efforts to develop screening strategies stratified according to the risk level for individual women, especially those considered to be at high risk.⁴ The gold standard for breast screening is mammography, either film-screen or digital mammography. The drive to convert conventional medical recording systems to electronic digital systems has influenced many centers to change to digital mammography despite the increased cost. Other imaging modalities for screening such as MRI, PET, and ultrasonography have been studied, but have not had the success expected.³¹

The improvement in technology of imaging modalities for patients with detected abnormalities and suspected malignant tumors has had a great impact on diagnosis, staging, and treatment of breast cancer. The increased sensitivity and specificity of imaging has contributed significantly to the improvement in the selection of treatment for patients with breast cancer. In addition, identifying genetic risk factors, the role of hormone receptors, and tumor markers such as HER2, has significantly influenced the selection of imaging and treatment for patients. With these advances, treatment options for early and late-stage breast cancer continue to evolve.

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