2003年AJCC乳腺癌的新分期

Revis ion of the American Joint Committee on Cancer Staging System for Breast Cancer By S. Eva Singletary, Craig Allred, Pandora Ashley, Lawrence W. Bassett, Donald Berry, Kirby I. Bland, Patrick I. Borgen, Gary Clark, Stephen B. Edge, Daniel F. Hayes, Lorie L. Hughes, Robert V.P. Hutter, Monica Morrow, David L. Page, Abram Recht, Richard L. Theriault, Ann Thor, Donald L. Weaver, H. Samuel Wieand, and Frederick L. Greene Purpose: To revise the American Joint Committee on Cancer staging system for breast carcinoma. Materials and Methods: A Breast Task Force submit- ted recommended changes and additions to the exist- ing staging system that were (1) evidence-based and/or consistent with widespread clinical consensus about appropriate diagnostic and treatment standards and (2) useful for the uniform accrual of outcome infor- mation in national databases. Results: Major changes included the following: size- based discrimination between micrometastases and isolated tumor cells; identifiers to indicate usage of innovative technical approaches; classification of lymph node status by number of involved axillary lymph nodes; and new classifications for metastasis to the infraclavicular, internal mammary, and supraclavicular lymph nodes. Conclusion: This revised staging system will be officially adopted for use in tumor registries in Janu- ary 2003. J Clin Oncol 20:3628-3636. © 2002 by American Society of Clinical Oncology. TWO YEARS AGO, A Breast Task Force was consti-tuted to serve in an advisory role to the American Joint Committee on Cancer (AJCC) for the revision of the breast cancer chapter in the sixth edition of the Cancer Staging Manual. This task force comprised internationally recognized experts in the field of breast cancer management and was charged with recommending changes to the breast cancer staging system that reflected published clinical data and current treatment standards. The changes recommended by the Breast Task Force were submitted to the AJCC in the fall of 2001 and in the formulation of the final draft of the chapter. The need for substantive changes in the staging system for breast cancer stemmed from continuing developments in the field of breast cancer diagnosis and management. First, with the now widespread use of screening mammography, most breast tumors are first detected when they are very small. Even among these small tumors, however, there is a remarkable heterogeneity of outcomes. While some can be successfully treated with surgery alone, others are inher- ently more malignant and, if identified, would justify aggressive treatment. To assist in this differentiation, addi- tional descriptors, including histologic observations or mea- surement of serum or tumor markers, were suggested to complement the anatomic factors (tumor size, presence of nodal metastasis, presence of distant metastasis) represented in the tumor-node-metastasis (TNM) staging system. Much discussion has centered around whether such factors can predict outcome independently of TNM, and whether they can be reliably measured. Second, sentinel lymph node dissection has become a treatment standard in the management of early-stage breast cancer, fueling an increased use of immunochemical and molecular techniques for the detection of metastatic tumor deposits. Minute lesions that would have been undetect- able 10 years ago are now being considered in clinical treatment decisions, even though data to support such decisions remain scanty. A standard diagnostic approach and nomenclature system is needed to accrue the data that will be necessary to critically analyze the usefulness of these new approaches. Third, widespread clinical experience, supported by ma- turing clinical data, has called into question decisions made in the past about the clinical importance of metastases to level III axillary lymph nodes (infraclavicular) and to nodal From the University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine, Houston, and Scott and White Memorial Hospital, Temple, TX; University of California Los Angeles–Jonsson Comprehensive Cancer Center, Los Angeles, CA; University of Ala- bama at Birmingham, Birmingham, AL; Memorial Sloan-Kettering Cancer Center, New York, and Roswell Park Cancer Institute, Buffalo, NY; University of Michigan, Ann Arbor, MI; WellStar Kennestone Hospital, Atlanta, GA; International Union Against Cancer represen- tative, Livingston, NJ; Northwestern University, Chicago, IL; Vander- bilt University Medical Center, Nashville, TN; Beth Israel Deaconess Medical Center, Boston, MA; University of Oklahoma Health Science Center, Oklahoma City, OK; University of Vermont, Burlington, VT; National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; and Carolinas Medical Center, Charlotte NC. Submitted February 7, 2002; accepted May 22, 2002. This article was published ahead of print at www.jco.org. Address reprint requests to S. Eva Singletary, MD, Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 444, Houston, TX 77030-4095; email: esinglet@mdanderson.org. © 2002 by American Society of Clinical Oncology. 0732-183X/02/2017-3628/$20.00 3628 Journal of Clinical Oncology, Vol 20, No 17 (September 1), 2002: pp 3628-3636 DOI: 10.1200/JCO.2002.02.026 Copyright © 2002 by the American Society of Clinical Oncology. All rights reserved. Downloaded from www.jco.org on July 26, 2005 . For personal use only. No other uses without permission. basins outside of the axilla (eg, supraclavicular, internal mammary [IM]). Many of these issues were initially addressed during an AJCC consensus conference on cancer prognostic factors held in January 1998.1 The working group at that confer- ence believed that there were insufficient data to allow the incorporation of serum markers or tumor markers into the TNM system, a conclusion that was later supported in a consensus statement from the College of American Pathol- ogists.2 The AJCC working group suggested numerous changes for the TNM system, all of which were considered in depth by the Breast Task Force before final recommen- dations were made. The Breast Task Force used the following guidelines in deciding which changes and additions should be made to the TNM staging system for breast cancer. (1) The revisions should be evidence-based, stemming from published clini- cal outcome data. (2) The revisions should reflect a wide- spread clinical consensus about appropriate diagnostic and treatment standards. (3) The revisions should result in a nomenclature and coding system that support the uniform accrual of outcome information in national databanks. THE REVISED TNM STAGING SYSTEM FOR BREAST CANCER The revised TNM staging system for breast cancer, as approved by the AJCC, is shown in Table 1. The final stage groupings are shown in Table 2. The principle changes in this system, as compared with those presented in the fifth edition of the AJCC Cancer Staging Manual,3 are summa- rized in Table 3. These changes are of two types. Some reflect the growing use of molecular and immunohistochem- ical (IHC) technology since the publication of the fifth edition. Most changes proposed in this category define a nomenclature and coding system that will standardize the collection of important data that may affect treatment in the future. Other changes are amendments of prior staging criteria. These amendments were made in cases where clinical evidence or widespread clinical consensus no longer supported a previous criterion. These changes will signifi- cantly alter treatment recommendations for certain classes of patients. The new staging system will be officially adopted for use in tumor registries in January 2003. RATIONALE FOR CHANGES AND ADDITIONS Micrometastases and Isolated Tumor Cells The increasing use of IHC and molecular biologic tech- niques has enabled pathologists to detect microscopic le- sions down to the level of isolated tumor cells. Our knowledge of the clinical importance of these minute lesions remains sketchy, at best, with many unresolved questions. What is the lower size limit that distinguishes micrometastases from isolated tumor cells? Do isolated tumor cells have clinical significance? If a minute lesion is detected only by IHC staining and cannot be verified by standard hematoxylin and eosin (H&E) staining, should it be considered for staging? Given that reverse transcriptase polymerase chain reaction (RT-PCR) is theoretically capable of identifying a single malignant cell, is this of any importance in arriving at diagnostic and treatment decisions? In the fifth edition of the AJCC Cancer Staging Manual,3 micrometastases were defined as metastatic lesions no larger than 2.0 mm in greatest dimension. Such lesions were recognized as clinically relevant and classified as pN1 in the absence of larger nodal metastases. Is there a lower size limit, below which these lesions are no longer clinically relevant? Unfortunately, there are not yet sufficient data to answer this question. This is due in part to the lack of an adequate system to track these data and in part to the tendency of physicians to treat patients with any IHC- identified nodal lesions as node-positive, regardless of the size of the metastatic lesion. A definitive answer to this question will require the collection of a large body of outcome data in which the distinction between micrometas- tases and isolated tumor cells has been made according to uniform quantitative criteria. Thus, the sixth edition of the AJCC Cancer Staging Manual3a has assigned a lower size limit for micrometastases, which are now defined as meta- static lesions that are larger than 0.2 mm in diameter and no larger than 2.0 mm in diameter. These lesions may have histologic evidence of malignant activity, such as prolifer- ation or stromal reaction, but this is not an absolute requirement. Isolated tumor cells (single cells or cell depos- its) will now be defined as tumor cell deposits no larger than 0.2 mm in diameter that may or may not (but usually do not) show histologic evidence of malignant activity. Pending further information, isolated tumor cells will be classified as node-negative, because it is believed that the unknown benefits of providing treatment for these small lesions would not outweigh the morbidity caused by the treatment itself. What if lesions are detected only by IHC staining techniques? H&E staining viewed with conventional light microscopy is the gold standard for the detection of meta- static lesions in the axillary lymph nodes, and it offers more definitive histologic evidence of malignancy than is usually available from IHC preparations. However, IHC staining techniques have been able to detect micrometastases in 12% to 29% of patients who were judged to be node-negative by H&E staining,4-9 and some studies have shown decreased disease-free survival in patients in whom micrometastases were detected by IHC techniques.6,8,9 The recommended 3629REVISION OF AJCC BREAST CANCER STAGING SYSTEM Copyright © 2002 by the American Society of Clinical Oncology. All rights reserved. Downloaded from www.jco.org on July 26, 2005 . For personal use only. No other uses without permission. Table 1. TNM Staging System for Breast Cancer Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ Tis (DCIS) Ductal carcinoma in situ Tis (LCIS) Lobular carcinoma in situ Tis (Paget) Paget’s disease of the nipple with no tumor Note: Paget’s disease associated with a tumor is classified according to the size of the tumor. T1 Tumor � 2 cm in greatest dimension T1mic Microinvasion � 0.1 cm in greatest dimension T1a Tumor � 0.1 cm but not � 0.5 cm in greatest dimension T1b Tumor � 0.5 cm but not � 1 cm in greatest dimension T1c Tumor � 1 cm but not � 2 cm in greatest dimension T2 Tumor � 2 cm but not � 5 cm in greatest dimension T3 Tumor � 5 cm in greatest dimension T4 Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below T4a Extension to chest wall, not including pectoralis muscle T4b Edema (including peau d’orange) or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast T4c Both T4a and T4b T4d Inflammatory carcinoma Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed (eg, previously removed) N0 No regional lymph node metastasis N1 Metastasis in movable ipsilateral axillary lymph node(s) N2 Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent* ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis N2a Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures N2b Metastasis only in clinically apparent* ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis N3 Metastasis in ipsilateral infraclavicular lymph node(s), or in clinically apparent* ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement N3a Metastasis in ipsilateral infraclavicular lymph node(s) and axillary lymph node(s) N3b Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) N3c Metastasis in ipsilateral supraclavicular lymph node(s) Regional lymph nodes (pN)† pNX Regional lymph nodes cannot be assessed (eg, previously removed or not removed for pathologic study) pN0 No regional lymph node metastasis histologically, no additional examination for isolated tumor cells‡ pN0(i�) No regional lymph node metastasis histologically, negative IHC pN0(i�) No regional lymph node metastasis histologically, positive IHC, no IHC cluster � 0.2 mm pN0(mol�) No regional lymph node metastasis histologically, negative molecular findings (RT-PCR) pN0(mol�) No regional lymph node metastasis histologically, positive molecular findings (RT-PCR) pN1mi Micrometastasis (� 0.2 mm, none � 2.0 mm) pN1 Metastasis in one to three axillary lymph nodes and/or in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent§ pN1a Metastasis in one to three axillary lymph nodes pN1b Metastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent§ pN1c Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent§,� pN2 Metastasis in four to nine axillary lymph nodes, or in clinically apparent* internal mammary lymph nodes in the absence of axillary lymph node metastasis pN2a Metastasis in four to nine axillary lymph nodes (at least one tumor deposit � 2.0 mm) pN2b Metastasis in clinically apparent* internal mammary lymph nodes in the absence of axillary lymph node metastasis 3630 SINGLETARY ET AL Copyright © 2002 by the American Society of Clinical Oncology. All rights reserved. Downloaded from www.jco.org on July 26, 2005 . For personal use only. No other uses without permission. practice has been to verify the metastatic potential of lesions identified by IHC using follow-up H&E staining, and this is still the preferred approach because of the more detailed cytologic information that can be gained. However, this practice is being abandoned in many clinical venues, re- flecting the growing consensus among pathologists that it does not matter how you look for nodal metastases but Table 2. TNM Stage Grouping for Breast Cancer Stage Grouping 0 Tis N0 M0 I T1* N0 M0 IIA T0 N1 M0 T1* N1 M0 T2 N0 M0 IIB T2 N1 M0 T3 N0 M0 IIIA T0 N2 M0 T1* N2 M0 T2 N2 M0 T3 N1 M0 T3 N2 M0 IIIB T4 N0 M0 T4 N1 M0 T4 N2 M0 IIIC Any T N3 M0 IV Any T Any N M1 NOTE. Adapted with permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, www.springer-ny.com. *T1 includes T1mic. Table 3. Summary of Major Changes in the AJCC Cancer Staging Manual, Sixth Edition 1. Micrometastases are distinguished from isolated tumor cells on the basis of size. They are also more likely to show histologic evidence of malignant activity, but this is not an absolute requirement. 2. Identifiers have been added to indicate the use of sentinel lymph node dissection and immunohistochemical or molecular techniques. 3. Major classifications of lymph node status are designated according to the number of involved axillary lymph nodes as determined by routine hematoxylin and eosin staining (preferred method) or by immunohistochemical staining. 4. The classification of metastasis to the infraclavicular lymph nodes has been added as N3. 5. Metastasis to the internal mammary nodes, based on the method of detection and the presence or absence of axillary nodal involvement, has been reclassified. Microscopic involvement of the internal mammary nodes detected by sentinel lymph node dissection but not by imaging studies (excluding lymphscintigraphy) or clinical examination is classified as N1. Macroscopic involvement of the internal mammary nodes as detected by imaging studies (excluding lymphscintigraphy) or by clinical examination is classified as N2 if it occurs in the absence of metastases to the axillary lymph nodes or as N3 if it occurs in the presence of metastases to the axillary lymph nodes. 6. Metastasis to the supraclavicular lymph nodes has been reclassified as N3 rather than M1. Table 1. (Cont’d) pN3 Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparent* ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes pN3a Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit � 2.0 mm), or metastasis to the infraclavicular lymph nodes pN3b Metastasis in clinically apparent* ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent§ pN3c Metastasis in ipsilateral supraclavicular lymph nodes Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis NOTE. Adapted with permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, www.springer-ny.com. Abbreviations: IHC, immunohistochemistry; RT-PCR, reverse transcriptase polymerase chain reaction. *“Clinically apparent” is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination. †Classification is based on axillary lymph node dissection with or without sentinel lymph node dissection. Classification based solely on sentinel lymph node dissection without subsequent axillary lymph node dissection is designated (sn) for “sentinel node” (eg, pN0(i�)(sn)). ‡Isolated tumor cells are defined as single tumor cells or small cell clusters not greater than 0.2 mm, usually detected only by immunohistochemical or molecular methods but which may be verified on hematoxylin and eosin stains. Isolated tumor cells do not usually show evidence of metastatic activity (eg, proliferation or stromal reaction). §“Not clinically apparent