Manual for Staging of Cancer; Fifth Edition; Edited by Irvin D. Fleming, M.D., Jay S. Cooper, M.D., Donald Earl Henson, M.D., Robert V.P. Hutter, M.D., B.J. Kennedy, M.D., Gerald Murphy, M.D., D.S.c., Brian O'Sullivan, M.B., F.R.C.P.C., F.R.C.P.I., Leslie H. Sobin, M.D., John W. Yarbro, M.D., Ph.D.; Copyright 1997, the American Joint Committee on Cancer. Published by Lippincott-Raven Publishers. Chapter 25, pp. 171 - 180.

The following TNM definitions and stage groupings for carcinoma of the breast are the same for the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC)/TNM projects. 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 within a dense fibroareolar stroma. The glandular tissue consists of approximately 20 lobes, each of which terminates in a separate excretory duct in the nipple.

Regional Lymph Nodes. The breast lymphatics drain by way of three major routes: axillary, transpectoral, and internal mammary. Intramammary lymph nodes are considered with, and coded as, axillary lymph nodes for staging purposes. Metastasis to any other lymph node is considered distant (M1), including supraclavicular, cervical, or contralateral internal mammary. (Please refer to diagram.) The regional lymph nodes are:

1. Axillary (ipsilateral): interpectoral (Rotter's) nodes and lymph nodes along the axillary vein and its tributaries which may be (but are not required to be) divided into the following levels:

   (i) Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor muscle.

(ii) Level II (mid-axilla): lymph nodes between the medial and lateral borders of the pectoralis minor muscle and the interpectoral (Rotter's) lymph nodes.

(iii) Level III (apical axilla): lymph nodes medial to the medial margin of the pectoralis minor muscle including those designated as subclavicular, infraclavicular, or apical.

Note: Intramammary lymph nodes are coded as axillary lymph nodes.

2. Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia.

Metastatic Sites. All distant visceral sites are potential sites of metastasis. The four major sites of involvement are bone, lung, brain, and liver, but this widely metastasizing disease has been found in 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 to establish the diagnosis of breast carcinoma. The extent of tissue examined pathologically for clinical staging is less than that required for pathologic staging (see Pathologic Staging). Appropriate operative findings are elements of clinical staging, including the size of the primary tumor and chest wall invasion, and the presence or absence of regional or distant metastasis.

Pathologic Staging. Pathologic staging includes all data used for clinical staging, surgical exploration and resection as well as pathologic examination of the primary carcinoma, including not less than excision of the primary carcinoma with no macroscopic tumor in any margin of resection by pathologic examination. A case can be classified pT for pathologic stage grouping if there is only microscopic, but not macroscopic, involvement at the margin. If there is tumor in the margin of resection by macroscopic examination, it is coded TX because the extent of the primary tumor cannot be assessed. If there is no clinical evidence of axillary metastasis, resection of at least the low axillary lymph nodes (Level I), that is, those lymph nodes located lateral to the lateral border of the pectoralis minor muscle should be performed for pathologic (pN) classification. Such a resection will ordinarily include 6 or more lymph nodes. Metastatic nodules in the fat adjacent to the mammary carcinoma within the breast, without evidence of residual lymph node tissue, are classified as regional lymph node metastases (N). Pathologic stage grouping includes any of the following combinations: pT pN pM, or pT pN cM, or cT cN pM.

TNM CLASSIFICATION

Primary Tumor

1. Use the largest primary carcinoma to classify T.

2. Enter into the record that this is a case of multiple simultaneous ipsilateral primary carcinomas. Such cases should be analyzed separately.

DEFINITION OF TNM

Note: Paget's disease associated with a tumor is classified according to the size of the tumor.

STAGE GROUPING

*Note: T1 includes T1mic

**Note: The prognosis of patients with N1a is similar to that of patients with pN0.

HISTOPATHOLOGIC TYPE

Carcinoma, NOS (not otherwise specified)
Ductal
     Intraductal (in situ)
     Invasive with predominant intraductal component
     Invasive, NOS (not otherwise specified)
     Comedo
     Inflammatory
     Medullary with lymphocytic infiltrate
     Mucinous (colloid)
     Papillary
     Scirrhous
     Tubular
     Other
Lobular
     In situ
     Invasive with predominant in situ component
     Invasive
Nipple
     Paget's disease, NOS (not otherwise specified)
     Paget's disease with intraductal carcinoma
     Paget's disease with invasive ductal carcinoma
Other
     Undifferentiated carcinoma

HISTOPATHOLOGIC GRADE (G)

PROGNOSTIC FACTORS

FIG. 25-1. Observed (A) and relative (B) survival rates for 50,383 patients with breast carcinoma classified by the current AJCC staging classification. Data taken from the National Cancer Data Base (Commission on Cancer of the American College of Surgeons and the American Cancer Society) for the year 1989. Stage 0 includes 5,686 patients; Stage I, 21,604; Stage IIA, 10,412; Stage IIB, 5,673; Stage IIIA, 1,864; Stage IIIB, 2,035; Stage IV, 3,109.

Table 25-1 itemizes the traditional prognostic parameters for human breast carcinoma. This cancer, like other mammalian neoplasms, results from a series of genetic alterations ("hits") induced by environment stimuli, genetic predisposition, or by concurrent activity of both events.

Table 25-1. Traditional Prognostic Parameters for Human Mammary Carcinoma ER = estrogen receptor; PR = progesterone receptor; EIC = extensive intraductal component (associated with invasive carcinoma). (From Bland KI, Konstadoulakis MM, Vezeridis MP, Wanebo HJ: Oncogene protein coexpression: value of Ha-ras, c-myc, c-fos, and p53 as prognostic discriminants for breast carcinoma. Ann Surg 1995;221:706-720)

Multiple serum biochemical markers have been included as potential prognostic indicators and have been reviewed by Stenman and Heikkinen and by Werner et al. These serum proteins include the breast mucin markers CA15-3, CA549, CAM26, CAM29, the adenocarcinoma marker carcinoembryonic antigen (CEA), cancer-associated serum antigen (CASA), mammary serum antigen (MSA), the reaction products hydroxyproline, ferritin and isoferritin (p43), tumor-associated trypsin inhibitor (TATI), the proliferation marker tissue polypeptide antigen (TPA), C-reactive protein (CRP), orosomucoid, and erythrocyte sedimentation rate (ESR) (Burke et al., 1995). The majority of these serum proteins represent a non-specific host response to tissue damage initiated by the neoplasm. Although approved for application in clinical practice, the predominant utilization of these markers has been in investigatory studies. The indiscriminate use of these tumor-derived proteins is ill-advised, as the available research suggests that the majority of these markers lack adequate sensitivity and specificity for prediction of outcome. However, identification of elevation specific to the cancerous growth is of value when sequential testing is utilized for the purposes of quantification of tumor burden, monitoring of disease, and determination of therapeutic outcome (Burke et al.).

Table 25-2. Anatomic and Cellular Prognostic Factors + Well supported; 0 equivocal support. a Factor VIII-related antigen and CD31 are vascular detection techniques for quantifying tumor angiogenesis. Basic fibroblast growth factor is an angiogenic peptide and can be measured in the urine [40]. The degree of correlation between vascular antigens and angiogenic peptide in tumor angiogenesis is not known. b (From Burke HB, Hutter RVP, Henson DE. Breast carcinoma. In: Prognostic Factors in Cancer, Hermanek P, Gospodarowicz MK, Henson DE, Hutter RVP, Sobin LH (editors). Union Internationale Contre le Cancer. New York: Springer-Verlag, 1995:165-176.)

Table 25-2 identifies anatomic and cellular prognostic factors that have been identified and that support their application in the search for new prognostic factors. Additionally, the identification of genetic mutations and gene deletions/substitutions are an integral part of active research models that are being clinically applied internationally. Integration of oncogene protein discriminants into prognostic models that have previously shown value to predict out come include Ha-ras, c-myc, c-fos, c-erbB-2 (HER-2/neu), NME-1, and int-2. Moreover, mutation of the tumor suppressor gene TP53 (p53) on chromosome 17p has been extensively studied and represents a common genetic mutation for multiple human neoplasms, including breast carcinogenesis. In 1993, the AJCC adopted criteria for definition of a prognostic factor that include:

     I. Statistically significant, i.e., its prognostic value only rarely occurs by chance;
     II. Independent, i.e., retains its prognostic value when combined with other factors; and
     III. Clinically relevant, i.e., has a major impact on prognostic accuracy.

Subsequent to this adoption of definition, the College of American Pathologists (CAP) convened a multidisciplinary conference in 1994 and placed further emphasis on the sensitivity of these prognostic factors and their subsets to predict outcome when judged as relevant prognostic factors by managing physicians. Group I includes prognostic variables well-supported biologically and clinically in the scientific literature. Such examples include TNM variables, histologic type, grade (histologic/nuclear), and steroid receptor activity (estrogen, progesterone). Group II was divided into two subsets of prognostic factors extensively studied both clinically and biologically. Group IIA utilized factors commonly applied in clinical trials, e.g., proliferative markers such as percent S-phase fraction and Ki-67 (M1B1), and mitotic index (thymidine-labeling indices). When expanded to the biological subset, Group IIB includes prognostic factors for which biologic and clinically correlative studies had been completed; however, this subset had few outcome studies (e.g., c-erbB-2 (HER-2/neu), p53, angiogenesis and vascular invasion [lymphatic/venous]). Finally, Group III represents factors that are clinically relevant and, therefore, have major implications for accuracy relative to prognosis. Group III includes some of the anatomic and cellular prognostic factors and the molecular-genetic prognostic factors that do not conform to Group I and II. With the enlarging literature relative to molecular and genetic translational research, it is highly probable that these factors will give increasing application to build prognostic models that are highly accurate for evaluation of tumor phenotype and accurately predict disease-free and overall survival outcomes when integrated with anatomic and cellular prognostic factors (Bland et al.).

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