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Diseases of the Breast
Pathology of Invasive Breast Cancer
Stuart J. Schnitt and Anthony J. Guidi

S. J. Schnitt: Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Surgical Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
A. J. Guidi: Department of Pathology, North Shore Medical Center, Salem, Massachusetts

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Introduction
Invasive (Infiltrating) Ductal Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Invasive (Infiltrating) Lobular Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Invasive Carcinomas with Ductal and Lobular Features
Tubular Carcinoma
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Mucinous Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Medullary Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Invasive Cribriform Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Invasive Papillary Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Invasive Micropapillary Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Metaplastic Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Invasive Carcinoma with Neuroendocrine Differentiation
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Adenoid Cystic Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Invasive Apocrine Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Secretory Carcinoma
 
Clinical Presentation
 
Gross Pathology
 
Histopathology
 
Clinical Course and Prognosis
Miscellaneous Rare Invasive Breast Cancers
 
Invasive Carcinoma with Osteoclastlike Giant Cells
 
Invasive Carcinoma with Choriocarcinomatous Features
 
Lipid-Rich Carcinoma
 
Glycogen-Rich Carcinoma
 
Mucinous Cystadenocarcinoma
 
Extramammary Malignancies Metastatic to the Breast
Pathologic Features of Breast Cancer in Patients with Brca1 and Brca2 Mutations
Pathologic Factors Useful in Assessing Prognosis
 
Tumor Size
 
Histologic Type
 
Histologic Grade
 
Lymphatic Vessel Invasion
 
Other Factors
 
Combination of Prognostic Factors
Specimen Processing
 
Core-Needle Biopsy
 
Incisional Biopsy
 
Excisional Biopsy (Lumpectomy, Partial Mastectomy) Performed for a Palpable Mass
 
Needle-Localization Breast Biopsy for Nonpalpable Lesions
 
Reexcision Specimens
 
Mastectomy Specimens
 
Axillary Lymph Nodes
Contents of the Final Surgical Pathology Report
Chapter References

INTRODUCTION
Invasive breast cancers constitute a heterogeneous group of lesions that differ with regard to their clinical presentation, radiographic characteristics, pathologic features, and biological potential. Despite these differences, however, these tumors have in common infiltration of neoplastic cells into the breast stroma and at least the potential for invasion of surrounding structures and distant metastasis. The most widely used classification of invasive breast cancers, and the one used in this chapter (with minor modifications), is that of the World Health Organization.1 This classification scheme is based on the growth pattern and cytologic features of the invasive tumor cells and does not imply histogenesis or site of origin within the mammary duct system. For example, although the classification system recognizes invasive carcinomas designated ductal and lobular, this categorization is not meant to indicate that the former originates in extralobular ducts and the latter in lobules. In fact, subgross whole-organ sectioning has demonstrated that most invasive breast cancers arise in the terminal duct lobular unit, regardless of histologic type.2
The most common histologic type of invasive breast cancer by far is invasive (infiltrating) ductal carcinoma.3,4,5 and 6 In fact, the diagnosis of invasive ductal carcinoma is a diagnosis by default, because this tumor type is defined as a type of cancer “not classified into any of the other categories of invasive mammary carcinoma.”1 To further emphasize this point, and to distinguish these tumors from invasive breast cancers with specific or special histologic features (e.g., invasive lobular, tubular, mucinous, medullary, and other rare types), some authorities prefer the term infiltrating ductal carcinoma, not otherwise specified (NOS)3 or infiltrating carcinoma of no special type (NST).5 In this chapter, the terms invasive ductal carcinoma, infiltrating ductal carcinoma, and infiltrating or invasive carcinoma of no special type are used interchangeably.
The distribution of histologic types of invasive breast cancer has varied among published series (Table 30-1). These differences may be related to a number of factors, including the nature of the patient population and variability in the definitions for the different histologic types. In general, special-type cancers comprise 20% to 30% of invasive carcinomas, and at least 90% of a tumor should demonstrate the defining histologic characteristics of a special-type cancer for the tumor to be designated as that histologic type.5,6

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TABLE 1. Histologic Types of Invasive Breast Cancer in Four Large Series before the Widespread Use of Mammographic Screening

The widespread use of screening mammography has had a dramatic impact on the nature of invasive breast cancers encountered in clinical practice.7 The value of mammography in detecting more cases of ductal carcinoma in situ (DCIS), smaller invasive breast cancers, and fewer cancers with axillary lymph node involvement is well recognized. Mammography, however, has also resulted in a change in the distribution of the histologic features of the invasive breast cancers detected. In particular, special-type cancers (especially tubular carcinomas)8,9,10,11 and 12 and cancers of lower histologic grade13,14 and 15 have been more frequently observed in mammographically screened populations than in patients who present with a palpable mass, particularly in the prevalent round of screening.16,17
Most invasive breast cancers have an associated component of in situ carcinoma, although the extent of the in situ component varies considerably.18 The prevailing view has long been that the invasive carcinomas derive from the in situ component. This view is based not only on the frequent coexistence of the two lesions, but also on the histologic similarities between the invasive and in situ components within the same lesion. For example, a number of studies have clearly documented that low-grade invasive cancers are most often associated with low-grade DCIS, and high-grade invasive cancers with high-grade in situ lesions.19,20 and 21 In addition, studies evaluating profiles of biological markers and genetic abnormalities have shown that coexisting invasive and in situ carcinomas often share the same immunophenotype and genetic alterations.22,23 and 24
The routine pathologic examination of invasive breast cancers has now extended beyond simply determining and reporting the histologic type of the tumor. Although histologic typing provides important prognostic information in and of itself,25 other morphologic features that are evaluable on routine histologic sections are also of prognostic value. In this chapter, the various histologic types of invasive breast cancer are discussed, as are pathologic features important in the assessment of prognosis (prognostic factors) and, possibly, response to therapy (predictive factors).
INVASIVE (INFILTRATING) DUCTAL CARCINOMA
As noted, invasive ductal carcinomas represent the single largest group of invasive breast cancers. Although these tumors are most commonly encountered in pure form, a substantial minority exhibit admixed foci of other histologic types. In one series examining 1,000 invasive breast cancers, such combinations of invasive ductal carcinoma and other types were seen in 28% of cases.3 The classification of tumors composed primarily of invasive ductal carcinoma with a minor component consisting of one or more other histologic types is problematic. Some authorities categorize such lesions as invasive ductal carcinomas (or invasive carcinomas of no special type) and simply note the presence of the other types,5 whereas others classify them as “mixed.”6
Clinical Presentation
Invasive ductal carcinomas most often present as a palpable mass or mammographic abnormality. No specific clinical or mammographic characteristics distinguish invasive ductal carcinomas from other histologic types of invasive cancer. Rarely, patients with these lesions present with Paget's disease of the nipple.
Gross Pathology
The classic macroscopic appearance of invasive ductal carcinoma is that of a scirrhous carcinoma, characterized by a firm, sometimes rock-hard mass that has a grey-white, gritty surface on cut section (Fig. 30-1). This consistency and appearance are due to the desmoplastic tumor stroma and not to the neoplastic cells themselves. Some invasive ductal carcinomas are composed primarily of tumor cells with little desmoplastic stromal reaction, and such lesions are tan and soft on gross examination. Although most invasive ductal cancers have a stellate or spiculated contour with irregular peripheral margins, some lesions have rounded, pushing margins, and still others are grossly well circumscribed.

FIG. 1. Cut surface of an excision specimen containing an invasive ductal carcinoma. The tumor appears as an irregular area of whitish tissue.

Histopathology
The microscopic appearance of invasive ductal carcinomas is highly heterogeneous with regard to growth pattern, cytologic features, mitotic activity, stromal desmoplasia, extent of the associated DCIS component, and contour. Variability in histologic features may even be seen within a single case. The tumor cells may be arranged as glandular structures; as nests, cords, or trabeculae of various sizes; or as solid sheets. Foci of necrosis are evident in some cases and may be extensive. Cytologically, the tumor cells range from those showing little deviation from normal breast epithelial cells to those exhibiting marked cellular pleomorphism and nuclear atypia. Mitotic activity can range from imperceptible to marked. Stromal desmoplasia is inapparent to minimal in some cases. At the other end of the spectrum, some tumors show such prominent stromal desmoplasia that the tumor cells constitute only a minor component of the lesion. Similarly, some invasive ductal carcinomas have no identifiable component of DCIS, whereas in others, the in situ carcinoma is the predominant component of the tumor. Finally, the microscopic margins of these cancers may be infiltrating, pushing, circumscribed, or mixed.
Recognizing that invasive ductal carcinomas are a histologically diverse group of lesions, many investigators have attempted to stratify them based on certain microscopic features. The most common method for subclassifying invasive ductal carcinomas is grading, which may be based solely on nuclear features (nuclear grading) or on a combination of architectural and nuclear characteristics (histologic grading). In nuclear grading, the appearance of the tumor cell nuclei is compared with those of normal breast epithelial cells. The nuclear grading system most commonly used is that of Black et al.26,27 In this system, nuclei are classified as well differentiated, intermediately differentiated, and poorly differentiated. That the numeric designations used for these three grades are the opposite of those used for histologic grading (i.e., well-differentiated nuclei are considered grade 3 and poorly differentiated nuclei are considered grade 1) is unfortunate. In current practice, however, histologic grading is the method of grading most often used. In histologic grading, breast carcinomas are categorized based on the evaluation of three features: tubule formation, nuclear pleomorphism, and mitotic activity. The histologic grading system currently in most widespread use is that described in detail by Elston and Ellis.28 This system is a modification of the grading system proposed by Bloom and Richardson in 1957, but provides strictly defined criteria that are lacking in the original description. Tubule formation, nuclear pleomorphism, and mitotic activity are each scored on a scale of 1 to 3. The sum of the scores for these three parameters provides the overall histologic grade; thus, tumors for which the sum of the scores is 3 to 5 are designated grade 1 (well differentiated), those with summed scores of 6 and 7 are designated grade 2 (moderately differentiated), and those with summed scores of 8 and 9 are designated grade 3 (poorly differentiated) (Fig. 30-2; Table 30-2). The prognostic significance of histologic grading is discussed in the section Pathologic Factors Useful in Assessing Prognosis).

FIG. 2. Invasive ductal carcinoma. A: Histologic grade 1. B: Histologic grade 2.C: Histologic grade 3.

TABLE 2. Histologic Grading System for Invasive Breast Cancers (Elston and Ellis Modification of Bloom and Richardson Grading System)

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