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Breast Pathology and Radiologic–Pathologic Correlation
Knowledge of breast anatomy and pathology is critical for accurate image interpretation. Understanding the spectrum of benign and malignant pathologies allows radiologists to confidently identify abnormal findings, give a reasonable differential diagnosis, and assign an accurate probability of malignancy with appropriate management recommendations.
Careful radiologic–pathologic correlation is a critical component of image-guided breast biopsy. American College of Radiology (ACR) practice parameters for stereotactic, ultrasound-guided, and magnetic resonance imaging (MRI)-guided biopsies highlight the importance of determining concordance after receiving pathology results. Appropriate determination of radiologic–pathologic concordance and subsequent management hinges on radiologists’ understanding of breast pathologies. If pathology results are felt to be discordant, repeat or excisional biopsy should be performed to prevent potential delays in cancer diagnosis. Further, although some pathologies may not be malignant, they may require further clinical management or surgical referral. This chapter provides a basic understanding of breast pathology and radiologic–pathologic correlation for radiologists.
Overview of Normal Breast Anatomy
Anatomy
The anatomic borders of the breast are defined as the sternum (medial), mid-axillary line (lateral), second rib (superior), sixth to seventh rib (inferior), superficial fascia (anterior), and deep/pectoral fascia (posterior). The majority of the breast lies anterior to the pectoralis muscle; a portion lies anterior to the serratus anterior muscle. Because the upper outer quadrant of the breast has an extension into the axilla, known as the tail of Spence, this quadrant contains more breast tissue than other quadrants.
The breast is composed of skin, subcutaneous fat, fascia, parenchymal tissue, and the nipple-areolar complex ( Fig. 9.1 ). The fascia envelops the breast parenchyma anteriorly and posteriorly. The parenchymal tissue is where breast pathologies arise, and consists of glandular tissue, stromal elements, fat, and suspensory (Cooper) ligaments, which travel through the breast parenchyma and insert in the dermis.
There is a branching system of ducts throughout the glandular tissue, which take milk from the acini where it is produced all the way to the nipple, where it is excreted during breast feeding. There are seven to nine lactiferous ducts, each of which open into an orifice in the nipple. Each lactiferous duct is connected to 15 to 20 lobes, each of which has several lobules. Within the lobules, terminal ducts are surrounded by acini; this forms the functional unit of the breast, known as the terminal ductal lobular unit (TDLU). The TDLU is generally 1 to 4 mm in diameter. The number of acini in each TDLU varies from about 11 in nulliparous women to about 80 acini during pregnancy and breast feeding. The ducts are lined by epithelium, which has an inner secretory epithelial cell layer and an outer myoepithelial cell layer. There is a continuous basement membrane along the course of the ductal epithelium. Stromal elements surround the glandular tissue and may be either interlobular or extralobular in location.
The areola consists of sebaceous, sweat, and accessory glands, which form Montgomery tubercles. Smooth muscle fibers are also present, which are responsible for nipple erection.
The arterial supply to the breast comes from the axillary artery branches (30%, mostly upper outer quadrant), internal mammary artery (60%, mostly medial and central breast), and lateral branches of the intercostal arteries. The venous drainage parallels the arterial supply and is also through axillary, internal mammary, and intercostal veins. The innervation of the breast is through the lateral cutaneous branches of the third through sixth intercostal nerves.
Lymphatic drainage of the breast parenchyma occurs through deep lymphatic vessels, which travel along the lactiferous ducts, mostly to ipsilateral axillary nodes (these are discussed in Chapter 17 ). Some deep lymphatic vessels in the medial breast also drain to internal mammary nodes. There is a superficial lymphatic plexus that drains the skin and nipple-areolar complex; this is known as Sappey plexus.
Breast Embryology and Development
Breast development in utero follows a predictable pattern that begins early in fetal development and results in differentiation of lobules, acini, lactiferous/mammary ducts, nipple-areolar complex, and Montgomery glands by birth. The ectodermal primitive milk streak develops between the axillae and groin during the fifth to sixth week of fetal development. Although most of the milk streak subsequently regresses, the thoracic portion does not. During the 12th week of fetal development, mesodermal ingrowth forms a breast bud, with formation of 16 to 24 secondary buds during the 12th week of fetal development. Differentiation then continues until birth. Under the influence of circulating maternal hormones, babies may have a breast bud under the nipple at birth, which can be asymmetric.
During early puberty, breast development occurs in response to hormonal changes; this stage of puberty is known as thelarche. Estrogen drives ductal development and progesterone leads to lobular development and epithelial differentiation. Alveolar buds form from the terminal ductules in the breast, forming type 1 breast lobules. There is also an increase in periductal connective tissue.
Menstrual Cycle and Menopause
Hormonal changes throughout the menstrual cycle are also reflected in the breast tissue. During the luteal phase (day 15–28), there are increased progesterone levels, leading to dilation of the mammary ducts and differentiation of the epithelial cells into secretory cells. There is also increased blood flow to the breasts prior to the onset of menses, which can contribute to cyclical breast pain.
During menopause, the ductal, glandular, and stromal elements of the breast undergo involution and atresia and are gradually replaced with adipose tissue. Type 1 lobules again predominate in the breast.
Radiologic–Pathologic Correlation and Recommendations
The imaging appearance of masses and calcifications reflects their underlying pathophysiology. Analysis of the margins of a mass gives information about the biological nature of the mass. Infiltrative lesions, such as most cancers, have no sharp interface between normal and abnormal tissue. This infiltrative appearance is associated with margin descriptors such as spiculated, indistinct, and angular. Infiltrative lesions and cancers may also be associated with surrounding desmoplastic response, leading to the imaging finding of architectural distortion. Benign masses, on the other hand, typically have “pushing borders” that are circumscribed, as there is no infiltration of benign tumor cells into adjacent tissue. Benign masses also commonly demonstrate parallel orientation, respecting the anatomic planes of the breast.
Similarly, analysis of the morphology and distribution of calcifications can guide the radiologist to the appropriate diagnosis and recommendation. Calcifications are often “casts” that form within an anatomic or pathologic space (e.g., within the lumen of a duct). Irregular calcifications are often associated with necrosis. Smooth calcifications are typically associated with a benign underlying process.
Radiologic–pathologic correlation is a critical component of breast biopsy procedures. The accuracy of core needle biopsy has been well established, with low false-negative rates ranging from 0.45% to 4.4%. Factors affecting the sensitivity of core needle biopsy include the type of biopsy device and gauge of biopsy needle ( Box 9.1 ). Lower upgrade rates were reported for vacuum-assisted 9- to 11-gauge biopsy devices, compared with 14- to 18-gauge spring-loaded devices. Among pathologists, histologic analysis is also subjective for many lesions, with particular overlap in the appearance of high-risk and malignant lesions; this may also contribute to variable upgrade rates.
Box 9.1
Factors Affecting Sensitivity of Core Needle Biopsy and Likelihood of Upgrade on Excision
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Type of biopsy device (spring-loaded versus vacuum-assisted)
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Needle gauge
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Number of cores
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Extent of lesion sampled
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Specimen processing
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Histopathologic analysis
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Radiologic–pathologic correlation
Given that many percutaneous biopsies are performed with imaging guidance, determination of concordance and subsequent management of benign, high-risk, and malignant pathology results are often the radiologist’s responsibility. Concordant biopsies are those in which the pathology result adequately accounts for the imaging finding. Concordant biopsies may be concordant and benign (e.g., oval circumscribed mass with pathology showing fibroadenoma) or concordant and malignant (e.g., irregular spiculated mass with pathology showing invasive ductal carcinoma). Determination of concordance depends on careful assessment of the imaging features of the biopsied finding. In general, lower-suspicion findings (Breast Imaging Reporting and Data System [BI-RADS] 4 A and 4B) are likely to be considered concordant if a benign biopsy result is obtained. Cases in which the biopsy result shows only benign breast tissue without other pathologic process should be reviewed carefully; in some circumstances, this result may be deemed concordant (mammographic asymmetry, non-mass enhancement on MRI, possible hamartoma on ultrasound), and follow-up imaging should be performed.
The radiologist also takes into consideration the adequacy of lesion sampling, including number of samples taken, presence of targeted lesion on specimen radiograph if performed, postbiopsy appearance of lesion, and location of biopsy clip on postprocedure mammogram. Because the adequacy of sampling is best assessed by the physician performing the biopsy, ACR practice parameters for image-guided biopsies recommend that the physician performing the biopsy should be responsible for assessing concordance. Patients who have benign, concordant findings but are symptomatic may also be referred to a breast surgeon for clinical management.
Discordant biopsies are those in which the pathology result does not adequately explain the imaging findings. In general, a benign core needle biopsy result should be considered discordant if the prebiopsy level of suspicion was high and the abnormality was given a BI-RADS 5 assessment. Discordant pathology results should either be rebiopsied using imaging guidance or be referred for excisional biopsy. A malignancy rate of 24% has been reported in a combined series of both stereotactic and ultrasound-guided discordant core needle biopsies. A close working relationship among the radiologist, pathologist, and surgeon is important when there are questions about the concordance of imaging findings with the pathologic result. Surgical consultation should be recommended for patients who have discordant, high-risk, or malignant findings.
Appearance and Management of Benign Lesions
Many benign and concordant pathologies do not require clinical management unless symptomatic. Often these patients may return for annual screening mammography or short-interval follow-up imaging. However, some pathologies do require clinical management or excision. The radiologist performing the biopsy must understand clinical management in order to ensure appropriate referral and care for the patient. The following is a description of benign pathologies that may be encountered in clinical breast imaging practice, with associated recommendations. Benign pathologies presenting most commonly as masses are described first ( Boxes 9.2 and 9.3 ), followed by benign pathologies more often presenting as calcifications ( Box 9.4 ).
Box 9.4
Benign Concordant Calcifications Requiring No Additional Clinical Management
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Fibrocystic changes
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Apocrine metaplasia
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Fat necrosis
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Usual ductal hyperplasia
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Sclerosing adenosis
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Columnar cell change
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Columnar cell hyperplasia
Benign Breast Masses Generally Not Requiring Additional Management
Many benign pathologies do not require surgical consultation or clinical management when concordant (see Box 9.2 ).
Box 9.2
Benign Concordant Masses Requiring No Additional Clinical Management (Unless Symptomatic or Enlarging)
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Fibroadenoma
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Lipoma
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Hamartoma
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Pseudoangiomatous stromal hyperplasia (PASH)
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Intramammary lymph node
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Fat necrosis
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Fibrocystic change/cyst
Fibroadenoma
Fibroadenomas are common benign masses that arise from proliferation of both the epithelial and stromal elements of the TDLU. This proliferation results in a confluence of lobules known as fibroadenomatoid nodules, which together form a fibroadenoma.
Fibroadenomas are the most common mass found in adolescents and younger women (10–30 years) and usually present as a palpable, slow-growing, painless mass ( Fig. 9.2 ). They may also be incidentally found on screening mammography or ultrasound. They may be of any size; fibroadenomas over 5 cm in size are called giant fibroadenomas. Juvenile fibroadenomas are seen in patients younger than 20 years and typically grow rapidly. Fibroadenomas involute after menopause and may calcify, resulting in classic popcorn calcifications visible on mammography.
The typical imaging appearance of fibroadenoma is an oval mass with circumscribed margins, usually hypoechoic with parallel orientation on ultrasound. Fibroadenomas with these features may be assessed as probably benign (BI-RADS 3) and be followed with serial imaging to establish 2- or 3-year stability. If not all these imaging features are seen, biopsy should be recommended. If the mass has a growth rate of 20% or more over 6 months, biopsy should also be recommended to exclude phyllodes tumor. Histologic appearance of fibroadenomas is that of compressed glands within collagenous stroma.
No treatment is needed for fibroadenomas unless they are symptomatic or enlarging. However, excision should be recommended when pathology is indeterminate; if phyllodes tumor cannot be excluded on the basis of the limited core biopsy sample, the lesion may be called a “fibroepithelial lesion.” Fibroadenomas do not confer significantly increased risk of breast cancer.
Lipoma
Lipomas are benign masses composed of bland adipose tissue. They may occur in any part of the body. Patients usually present with a soft, painless, mobile mass. Mammography shows a fat-containing circumscribed mass, correlating with a hyperechoic, circumscribed mass on ultrasound. Lesions with classic imaging features of lipoma can be assessed as benign (BI-RADS 2) and do not require biopsy. If biopsied, pathology shows an encapsulated mass with smooth borders, composed entirely of bland adipocytes. No treatment is needed unless the lipoma is bothersome to the patient, more commonly seen with larger masses. There is no association with breast cancer.
Hamartoma
Hamartomas are benign masses containing a combination of normal glandular, adipose, and stromal elements in a disorganized structure. They are also called fibroadenolipomas. Patients typically present with a palpable, soft, mobile mass; hamartomas may also be found incidentally on imaging. Mammographic appearance of hamartoma is that of a partially fat-containing, circumscribed mass. They have been described as a “breast in a breast” appearance. Hamartomas with classic imaging features do not require biopsy.
Gross pathologic analysis of hamartomas demonstrates a smoothly marginated mass that contains glandular, adipose, and stromal elements within a pseudocapsule ( Fig. 9.3 ). A diagnosis of hamartoma may not be able to be established from a core needle biopsy sample, as the appearance of the tissue within the hamartoma is so similar to normal breast tissue. Close correlation with the typical imaging appearance is needed in these cases. No management of hamartomas is required unless the patient is symptomatic. Hamartomas are not associated with increased risk of breast cancer.
Pseudoangiomatous Stromal Hyperplasia
Pseudoangiomatous stromal hyperplasia (PASH) is a benign proliferation of myofibroblasts that can mimic a vascular lesion on pathologic analysis, hence the term “pseudoangiomatous.” PASH may present as a mammographic developing asymmetry or a mass and is generally not associated with calcifications. PASH is thought to be hormonally driven and is more common in premenopausal women and postmenopausal women on hormone replacement therapy. Because of the indeterminate appearance of PASH, biopsy is required for diagnosis.
On pathologic analysis, a dense collagenous stroma is seen with myofibroblastic proliferation ( Fig. 9.4 ). Because the myofibroblasts can mimic the endothelial cells of blood vessels, the main differential diagnosis for PASH is angiosarcoma. If definitive diagnosis of PASH cannot be established from core biopsy, excision should be recommended. PASH does not otherwise require surgical consultation unless the lesion continues to grow.
Intramammary Lymph Node
Lymph nodes are secondary lymphoid organs; they are responsible for lymph filtration and are sites of proliferation of B and T cells in response to foreign antigens. Lymph nodes are commonly seen in the axilla but may also be seen within the breast; these are known as intramammary lymph nodes. Intramammary lymph nodes are usually found in the upper outer quadrant, may be seen in other parts of the breast, and may present as a palpable finding. Lymph nodes that demonstrate a classically benign appearance as an oval, circumscribed mass with fatty notch on mammography and echogenic hilum on ultrasound do not require biopsy. If classic findings are not seen, however, biopsy should be considered.
Pathologic analysis of lymph nodes demonstrates an encapsulated mass with cortical (outer) and medullary (inner) components. The cortex consists of B-cell containing lymphoid follicles and the medulla consists of lymphoid tissue aggregates and lymphatic channels. Blood vessels enter and exit the lymph node through the hilum.
No management of benign intramammary lymph nodes is required. However, intramammary lymph nodes may be involved with the same pathologic processes as other lymph nodes (e.g., lymphoma, metastatic disease, benign systemic disease).
Fat Necrosis
Fat necrosis is a benign process in which an area of fat in the breast saponifies, or breaks down. This is commonly the result of blunt trauma or surgery; eliciting this history can be helpful in establishing the diagnosis. It is often an incidental finding on mammography. However, patients may also present with a palpable mass. The appearance of fat necrosis evolves over time. In the acute setting, a focal asymmetry may be seen mammographically, corresponding to an area of increased echogenicity with cystic spaces on ultrasound. Over time, an oil cyst may form, seen as a round, fat-density mass with circumscribed margins. The wall of the oil cyst typically develops rim calcifications over time. When classically benign findings of fat necrosis are seen, no further management is needed. However, given the variable imaging appearance, biopsy is sometimes required to confirm the diagnosis.
The pathologic appearance of fat necrosis also depends on the temporal course. Areas of hemorrhage may be seen the early phase. Over time, anucleated adipocytes, lipid-laden histiocytes, and multinucleated giant cells are seen. Fibrosis is typically seen later and may persist for years. No management is required for benign and concordant pathology of fat necrosis.
Fibrocystic Change
Fibrocystic change is a general term that refers to a spectrum of both nonproliferative and proliferative changes, often seen in conjunction with one another. Pathologies included under the nonproliferative category are cysts, apocrine metaplasia, and fibrosis. Patients with fibrocystic change may present with breast pain or palpable mass. Fibrocystic change may also present as calcifications, sometimes requiring stereotactic biopsy if not classically benign in appearance ( Fig. 9.5 ).
Cysts are fluid-filled masses that are caused by fluid accumulation within terminal ducts. Cysts may be single or multiple and often fluctuate in size over time. Cysts are round or oval masses with circumscribed margins; simple cysts are anechoic on ultrasound. Definitively benign cysts do not require management unless symptomatic, in which case therapeutic cyst aspiration can be offered. If biopsied, a thin cyst wall lined by epithelial cells with adjacent fibrosis is often seen.
Apocrine metaplasia is often seen in the epithelial cells lining the cyst wall. Apocrine metaplasia refers to the transformation of normal breast epithelial cells to cells resembling apocrine sweat glands. This is a common, benign process and is not associated with increased risk of breast cancer.
Microscopic cysts may present as milk of calcium calcifications. Calcifications form within the cyst secretions and often layer on a lateral view mammogram. These calcifications are sometime composed of calcium oxalate crystals, which require polarized microscopy to visualize.
Nonproliferative fibrocystic changes are not associated with increased risk of breast cancer and do not require further management if concordant with imaging.
Benign Masses that May Warrant Surgical Consultation
There are some benign breast masses for which surgical consultation should be considered, either for clinical management or excision (see Box 9.3 ).
Box 9.3
Benign Concordant Masses Usually Warranting Surgical Consultation (for Excision or Clinical Management)
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Phyllodes tumor
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Granular cell tumor
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Desmoid tumor
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Granulomatous mastitis
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