Staging of Breast Cancer

Jay R. Harris

Staging refers to the grouping of patients according to the extent of their disease. Staging is useful in (a) estimating prognosis for an individual patient, (b) comparing the results of different treatment programs, and (c) it may help in selecting treatment for an individual patient. Staging can be based on either clinical or pathologic findings. The staging of cancer is determined by the American Joint Committee on Cancer (AJCC). The AJCC comprises six founding organizations, four sponsoring organizations, and seven liaison organizations. Membership is reserved for those organizations whose missions or goals are consistent with, or complementary to, those of the AJCC. The founding organizations include the American Cancer Society, the American College of Surgeons, the American Society of Clinical Oncology, Centers for Disease Control and Prevention, National Cancer Institute, and the College of American Pathologists.

The AJCC staging system provides a strategy for grouping patients with respect to prognosis. The AJCC system uses the TNM classification where T describes the size of the primary and whether it has invaded nearby tissue, N describes the nearby (regional) that are involved, and M describes distant metastases. However, TNM staging, while still important, has been superseded by rapidly evolving molecular characterizations of breast cancers, which more precisely define subgroups with different outcomes, both in terms of prognosis and response to specific treatments. Therapeutic decisions are now formulated in part according to staging categories, but primarily according to tumor size and grade, lymph node status, estrogen-receptor and progesterone-receptor levels in the tumor tissue, human epidermal growth factor receptor 2 (HER2/neu) status, menopausal status, and the general health of the patient. Since the last edition, the development and use of multi-gene diagnostic tests, such as Oncotype Dx® and MammaPrint®, have increased substantially and it is anticipated that there will be further developments along these lines.

Staging is still important to determine whether the patient is operable. Generally, any patient with Stage 3B (or 4) is not considered operable. Such patients are treated with initial systemic therapy, discussed in the chapter on locally-advanced and inflammatory breast cancer (Chapters 58 and 59).

The 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. The current version is the Seventh Edition of the system and is provided later in this chapter (1).

Pathologic staging can be performed in patients treated with initial definitive surgery or in patients treated with initial (pre-operative or neoadjuvant) systemic therapy followed by definitive surgery. The AJCC system details rules for classification, definition of the anatomy, and stage groups. It represents a significant change from the Sixth Edition, published in 2003. A summary of the changes is given below.

SUMMARY OF CHANGES

Tumor (T)

Identified specific imaging modalities that can be used to estimate clinical tumor size, including mammography, ultrasound, and magnetic resonance imaging (MRI).
Made specific recommendations that (i) the microscopic measurement is the most accurate and preferred method
to determine pT with a small invasive cancer that can be entirely submitted in one paraffin block, and (ii) the gross measurement is the most accurate and preferred method to determine pT with larger invasive cancers that must be submitted in multiple paraffin blocks.
Made the specific recommendation to use the clinical measurement thought to be most accurate to determine the clinical T of breast cancers treated with neoadjuvant therapy. Pathologic (posttreatment) size should be estimated based on the best combination of gross and microscopic histological findings.
Made the specific recommendation to estimate the size of invasive cancers that are unapparent to any clinical modalities or gross pathologic examination by carefully measuring and recording the relative positions of tissue samples submitted for microscopic evaluation and determining which contain tumor.
Acknowledged “ductal intraepithelial neoplasia” (DIN) as uncommon, and still not widely accepted, terminology encompassing both DCIS and ADH, and clarification that only cases referred to as DIN containing DCIS (±ADH) are classified as Tis (DCIS).
Acknowledged “lobular intraepithelial neoplasia” (LIN) as uncommon, and still not widely accepted, terminology encompassing both LCIS and ALH, and clarification that only cases referred to as LIN containing LCIS (±ALH) are classified as Tis (LCIS).
Clarified that only Paget’s disease NOT associated with an underlying noninvasive (that is, DCIS and/or LCIS) or invasive breast cancer should be classified as Tis (Paget’s) and that Paget’s disease associated with an underlying cancer be classified according to the underlying cancer (Tis, T1, and so on).
Made the recommendation to estimate the size of noninvasive carcinomas (DCIS and LCIS), even though it does not currently change their T classification, because noninvasive cancer size may influence therapeutic decisions, acknowledging that providing a precise size for LCIS may be difficult.
Acknowledged that the prognosis of microinvasive carcinoma is generally thought to be quite favorable, although the clinical impact of multifocal microinvasive disease is not well understood at this time.
Acknowledged that it is not necessary for tumors to be in separate quadrants to be classified as multiple, simultaneous, ipsilateral carcinomas, providing that they can be unambiguously demonstrated to be macroscopically distinct and measurable using available clinical and pathologic techniques.
Maintained that the term “inflammatory carcinoma” be restricted to cases with typical skin changes involving a third or more of the skin of the breast. While the histologic presence of invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a diagnosis of inflammatory breast cancer.
Recommend that all invasive cancer should be graded using the Nottingham combined histologic grade (Elston-Ellis modification of Scarff-Bloom-Richardson grading system).

Nodes (N)

Classification of isolated tumor cell clusters and single cells is more stringent. Small clusters of cells not greater than 0.2 mm, or nonconfluent or nearly confluent clusters of cells not exceeding 200 cells in a single histologic lymph node cross section are classified as isolated tumor cells.
Use of the (sn) modifier for sentinel node has been clarified and restricted. When six or more sentinel nodes are identified on gross examination of pathology specimens the (sn) modifier should be omitted.
Stage I breast tumors have been subdivided into Stage IA and Stage IB; Stage IB includes small tumors (T1) with exclusively micrometastases in lymph nodes (N1mi).

Metastases (M)

Created new M0(i+) category, defined by presence of either disseminated tumor cells detectable in bone marrow or circulating tumor cells or found incidentally in other tissues (such as ovaries removed prophylactically) if not exceeding 0.2 mm. However, this category does not change the stage grouping. Assuming that they do not have clinically and/or radiographically detectable metastases, patients with M0(i+) are staged according to T and N.

Postneoadjuvant Therapy (yc or ypTNM)

In the setting of patients who received neoadjuvant therapy, pretreatment clinical T (cT) should be based on clinical or imaging findings.
Postneoadjuvant therapy T should be based on clinical or imaging (ycT) or pathologic findings (ypT).
A subscript will be added to the clinical N for both node negative and node positive patients to indicate whether the N was derived from clinical examination, fine-needle aspiration, core needle biopsy, or sentinel lymph node biopsy.
The posttreatment ypT will be defined as the largest contiguous focus of invasive cancer as defined histopathologically with a subscript to indicate the presence of multiple tumor foci. Note: Definition of posttreatment ypT remains controversial and an area in transition.
Posttreatment nodal metastases no greater than 0.2 mm are classified as ypN0(i+) in patients who have not received neoadjuvant systemic therapy. However, patients with this finding are not considered to have achieved a pathologic complete response (pCR).
A description of the degree of response to neoadjuvant therapy (complete, partial, no response) will be collected by the registrar with the posttreatment ypTNM. The registrars are requested to describe how they defined response (by physical examination, imaging techniques [mammogram, ultrasound, magnetic resonance imaging (MRI)] or pathologically).
Patients will be considered to have M1 (and therefore Stage IV) breast cancer if they have had clinically or radiographically detectable metastases, with or without biopsy, prior to neoadjuvant systemic therapy, regardless of their status after neoadjuvant systemic therapy. (Tables 32-1, 32-2, 32-3, 32-3, 32-4 and 32-5)

INTRODUCTION TO THE STAGING SYSTEM

This staging system for carcinoma of the breast applies to infiltrating (including microinvasive) and in situ carcinomas. Microscopic confirmation of the diagnosis is mandatory, and the histologic type and grade of carcinoma should be recorded.

Anatomy

Primary Site

The mammary gland, situated on the anterior chest wall, is composed of glandular tissue with a dense fibrous stroma. The glandular tissue consists of lobules that group together into 15 to 25 lobes arranged approximately in a spokelike
pattern. Multiple major and minor ducts connect the milksecreting lobular units to the nipple. Small milk ducts course throughout the breast, converging into larger collecting ducts that open into the lactiferous sinus at the base of the nipple. Most cancers form initially in the terminal duct lobular units of the breast. Glandular tissue is more abundant in the upper, outer portion of the breast; as a result, half of all breast cancers occur in this area.

TABLE 32-1 Primary Tumor (T)^a

TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
Tis (DCIS)	DCIS
Tis (LCIS)	LCIS
Tis (Paget)	Paget’s disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget’s disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget’s disease should still be noted.
T1	Tumor ≤20 mm in greatest dimension
T1mi	Tumor ≤1 mm in greatest dimension
T1a	Tumor >1 mm but ≤5 mm in greatest dimension
T1b	Tumor >5 mm but ≤10 mm in greatest dimension
T1c	Tumor >10 mm but ≤20 mm in greatest dimension
T2	Tumor >20 mm but ≤50 mm in greatest dimension
T3	Tumor >50 mm in greatest dimension
T4	Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)^b
T4a	Extension to the chest wall, not including only pectoralis muscle adherence/invasion
T4b	Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d’orange) of the skin, which do not meet the criteria for inflammatory carcinoma
T4c	Both T4a and T4b
T4d	Inflammatory carcinoma
DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ. ^aThe T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript “c” or “p” modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size. ^bInvasion of the dermis alone does not qualify as T4.

Chest Wall

The chest wall includes ribs, intercostal muscles, and serratus anterior muscle, but not the pectoral muscles.

Regional Lymph Nodes

The breast lymphatics drain by way of three major routes: axillary, transpectoral, and internal mammary. Intramammary lymph nodes are coded as axillary lymph nodes for staging purposes. Supraclavicular nodes (SCLNs) are classified as regional lymph nodes for staging purposes. Metastasis to any other lymph node, including cervical or contralateral internal mammary lymph nodes, is classified as distant (M1).

The regional lymph nodes are as follows:

Axillary (ipsilateral): interpectoral (Rotter’s) nodes and lymph nodes along the axillary vein and its tributaries that may be (but are not required to be) divided into the following levels:
- Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor muscle.
- Level II (mid-axilla): lymph nodes between the medial and lateral borders of the pectoralis minor muscle and the interpectoral (Rotter’s) lymph nodes.
- Level III (apical axilla): lymph nodes medial to the medial margin of the pectoralis minor muscle, including those designated as apical.
Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia.
Supraclavicular: lymph nodes in the supraclavicular fossa, a triangle defined by the omohyoid muscle and tendon (lateral and superior border), the internal jugular vein (medial border), and the clavicle and subclavian vein (lower border). Adjacent lymph nodes outside of this triangle are considered to be lower cervical nodes (M1) (1).

Metastatic Sites

Tumor cells may be disseminated by either the lymphatic or the blood vascular system. The four major sites of involvement are bone, lung, brain, and liver, but tumor cells are also capable of metastasizing to many other sites.

Rules for Classification

Clinical Staging

Clinical staging includes physical examination, with careful inspection and palpation of the skin, mammary gland, and lymph nodes (axillary, supraclavicular, and cervical), imaging, and pathologic examination of the breast or other

tissues as appropriate to establish the diagnosis of breast carcinoma. The extent of tissue examined pathologically for clinical staging is not so great as that required for pathologic staging (see next section, Pathologic Staging). Imaging findings are considered elements of staging if they are collected within 4 months of diagnosis in the absence of disease progression or through completion of surgery(ies), whichever is longer. Such imaging findings would include the size of the primary tumor and of chest wall invasion, and the presence or absence of regional or distant metastasis. Imaging findings and surgical findings obtained after a patient has been treated with neoadjuvant chemotherapy, hormonal therapy, immunotherapy, or radiation therapy are not considered elements of initial staging.

TABLE 32-2 Regional Lymph Nodes (N)

	Clinical
NX	Regional lymph nodes cannot be assessed (e.g., previously removed)
N0	No regional lymph node metastases
N1	Metastases to movable ipsilateral level I, II axillary lymph node(s)
N2	Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted
	OR
	Metastases in clinically detected^a ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases
N2a	Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures
N2b	Metastases only in clinically detected^a ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases
N3	Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement
	OR
	Metastases in clinically detected^a ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases
	OR
	Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
N3a	Metastases in ipsilateral infraclavicular lymph node(s)
N3b	Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
N3c	Metastases in ipsilateral supraclavicular lymph node(s)
^aClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination. Confirmation of clinically detected metastatic disease by fine-needle aspiration without excision biopsy is designated with an (f) suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine-needle aspiration, core biopsy, or sentinel lymph node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment.