The TNM staging system and breast cancer.
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Breast Neoplasms↗
Biomedical subjects
Donald L Weaver
Publications and source records attributed to Donald L Weaver.
Sentinel lymph nodes and breast carcinoma: which micrometastases are clinically significant?
Sentinel lymph node biopsy is changing surgical management of breast cancer and pathologic evaluation of lymph nodes. Although it has long been known that lymph nodes contain occult metastases, pathologists have not generally pursued their identification. Compared with level I-II axillary dissection, the reduced number of sentinel lymph nodes has made additional evaluation more attractive; however, the consequences of increased detection of micrometastases has not been fully explored or appreciated. National data suggest that the composition of traditional TNM stage groupings is changing, with a recent increase in node-positive, stage II breast cancer, most likely the result of increased pathologic scrutiny. Clinical management of this new group of stage II patients is complicated by the lack of a historic prognostic comparison group because many of these patients would have been classified as stage I, node-negative in the past. Early outcome data in sentinel lymph node biopsy suggest no adverse outcome for patients with metastases no larger than 2.0 mm, a finding aligned with the current definition of micrometastasis. When sentinel lymph nodes are sliced at 2.0-mm intervals and totally embedded, the probability of identifying all metastases >2.0 mm is high. Using reasonable sampling strategies, minute metastases have a nearly equal chance of being missed or detected. New staging guidelines have established a lower limit for micrometastases and defined metastases no larger than 0.2 mm as isolated tumor cells or tumor cell clusters; nodes with isolated tumor cells will be classified as node negative (pN0) for stage grouping. Rigorous strategies designed to reliably detect single cells or small cell clusters in sentinel nodes remain time-intensive and cost prohibitive.
Breast Neoplasms↗
Comparison of pathologist-detected and automated computer-assisted image analysis detected sentinel lymph node micrometastases in breast cancer.
Sentinel lymph node biopsy has stimulated interest in identification of micrometastatic disease in lymph nodes, but identifying small clusters of tumor cells or single tumor cells in lymph nodes can be tedious and inaccurate. The optimal method of detecting micrometastases in sentinel nodes has not been established. Detection is dependent on node sectioning strategy and the ability to locate and confirm tumor cells on histologic sections. Immunohistochemical techniques have greatly enhanced detection in histologic sections; however, comparison of detection methodology has not been undertaken. Automated computer-assisted detection of candidate tumor cells may have the potential to significantly assist the pathologist. This study compares computer-assisted micrometastasis detection with routine detection by a pathologist. Cytokeratin-stained sentinel lymph node sections from 100 patients at the University of Vermont were evaluated by automated computer-assisted cell detection. Based on original routine light microscopy screening, 20 cases that were positive and 80 cases that were negative for micrometastases were selected. One-level (43 cases) or two-level (54 cases) cytokeratin-stained sections were examined per lymph node block. All 100 patients had previously been classified as node negative by using routine hematoxylin and eosin stained sections. Technical staining problems precluded computer-assisted cell detection scanning in three cases. Computer-assisted cell detection detected 19 of 20 (95.0%; 95% confidence interval, 75-100%) cases positive by routine light microscopy. Micrometastases missed by computer-assisted cell detection were caused by cells outside the instrument's scanning region. Computer-assisted cell detection detected additional micrometastases, undetected by light microscopy, in 8 of 77 (10.4%; 95% confidence interval, 5-20%) cases. The computer-assisted cell detection-positive, light microscopy-missed detection rate was similar for cases with one (3 of 30; 10.0%) or two (5 of 47; 10.6%) cytokeratin sections. Metastases detected by routine light microscopy tended to be larger (0.01-0.50 mm) than did metastases detected only by computer-assisted cell detection (0.01-0.03 mm). In a selected series of patients, automated computer-assisted cell detection identified more micrometastases than were identified by routine light microscopy screening of cytokeratin-stained sections. Computer-assisted detection of events that are limited in number or size may be more reliable than detection by a pathologist using routine light microscopy. Factors such as human fatigue, incomplete section screening, and variable staining contribute to missing metastases by routine light microscopy screening. Metastases identified exclusively by computer-assisted cell detection tend to be extremely small, and the clinical significance of their identification is currently unknown.
Breast Neoplasms↗
Detection of ductal carcinoma in situ in women undergoing screening mammography.
BACKGROUND: With the large number of women having mammography-an estimated 28.4 million U.S. women aged 40 years and older in 1998-the percentage of cancers detected as ductal carcinoma in situ (DCIS), which has an uncertain prognosis, has increased. We pooled data from seven regional mammography registries to determine the percentage of mammographically detected cancers that are DCIS and the rate of DCIS per 1000 mammograms. METHODS: We analyzed data on 653 833 mammograms from 540 738 women between 40 and 84 years of age who underwent screening mammography at facilities participating in the National Cancer Institute's Breast Cancer Surveillance Consortium (BCSC) throughout 1996 and 1997. Mammography results were linked to population-based cancer and pathology registries. We calculated the percentage of screen-detected breast cancers that were DCIS, the rate of screen-detected DCIS per 1000 mammograms by age and by previous mammography status, and the sensitivity of screening mammography. Statistical tests were two-sided. RESULTS: A total of 3266 cases of breast cancer were identified, 591 DCIS and 2675 invasive breast cancer. The percentage of screen-detected breast cancers that were DCIS decreased with age (from 28.2% [95% confidence interval (CI) = 23.9% to 32.5%] for women aged 40-49 years to 16.0% [95% CI = 13.3% to 18.7%] for women aged 70-84 years). However, the rate of screen-detected DCIS cases per 1000 mammograms increased with age (from 0.56 [95% CI = 0.41 to 0.70] for women aged 40-49 years to 1.07 [95% CI = 0.87 to 1.27] for women aged 70-84 years). Sensitivity of screening mammography in all age groups combined was higher for detecting DCIS (86.0% [95% CI = 83.2% to 88.8%]) than it was for detecting invasive breast cancer (75.1% [95% CI = 73.5% to 76.8%]). CONCLUSIONS: Overall, approximately 1 in every 1300 screening mammography examinations leads to a diagnosis of DCIS. Given uncertainty about the natural history of DCIS, the clinical significance of screen-detected DCIS needs further investigation.
Adult↗
Revision of the American Joint Committee on Cancer staging system for breast cancer.
PURPOSE: To revise the American Joint Committee on Cancer staging system for breast carcinoma. MATERIALS AND METHODS: A Breast Task Force submitted recommended changes and additions to the existing 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 information 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 January 2003.
Breast Neoplasms↗
Phage-displayed random peptide libraries in mice: toxicity after serial panning.
PURPOSE: In vivo screening of phage-displayed random peptide libraries (RPLs) has been used to identify peptide ligands to targets found on endothelial cells of blood vessels supplying specific tissues such as brain, kidney, and tumor tissue. Peptides that bind specifically to blood vessels supplying tumor tissue have been conjugated to cytotoxic agents and used to successfully eradicate tumors in a mouse model. With the ultimate goal of developing similar methods for treating human cancer, we describe an in vivo RPL screening process that, unlike previous in vivo experiments, does not harm the animal being screened. METHODS: RPLs were administered to FVB, BalbC, and tumor-bearing MRL/MpJ-fas(LPR) mice in a variety of dosing formats. Tumor nodules were excised 10 min following infusion and phage were amplified from the specimens. Phage were reinjected into the same animal within 48 h. This process was repeated twice for a total of three in vivo screens of mouse tumor tissue within the same animal. Mice were observed for systemic side effects, histopathologic damage, and presence of phage in organs. Peptide sequences were determined from several third-pan phage clones. RESULTS: Overall there was minimal toxicity from administration of single or repeat doses of RPLs. Amino acid consensus sequences were identified and some of the sequences were similar to those of peptide ligands that bind matrix metalloproteinases. CONCLUSIONS: Serial administration of an RPL is well tolerated and serial panning in individual mice leading to consensus sequence motifs is possible. Based on these preclinical data the Food and Drug Administration has approved the implementation of human clinical trials with this technique.
Amino Acid Sequence↗
Performance of diagnostic mammography for women with signs or symptoms of breast cancer.
BACKGROUND: The performance of diagnostic mammography for women with signs or symptoms of breast cancer has not been well studied. We evaluated whether age, breast density, self-reported breast lump, and previous mammography influence the performance of diagnostic mammography. METHODS: From January 1996 through March 1998, prospective diagnostic mammography data from women aged 25-89 years with no previous breast cancer were linked to cancer outcomes data in six mammography registries participating in the Breast Cancer Surveillance Consortium. We used the final mammographic assessment at the end of the imaging work-up to determine abnormal mammographic examination rate, positive predictive value (PPV), sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve. We used age, breast density, prior mammogram, and self-reported breast lump jointly as predictors of performance. All statistical tests were two-sided. RESULTS: Of 41 427 diagnostic mammograms, 6279 (15.2%) were judged abnormal. The overall PPV was 21.8%, sensitivity was 85.8%, and specificity was 87.7%. Multivariate analysis showed that sensitivity and specificity generally declined as breast density increased (P =.007 and P<.001, respectively), that previous mammography decreased sensitivity (odds ratio [OR] = 0.52, 95% confidence interval [CI] = 0.36 to 0.74; P<.001) but increased specificity (OR = 1.43, 95% CI = 1.31 to 1.57; P<.001), and that a self-reported breast lump increased sensitivity (OR = 1.64, 95% CI = 1.13 to 2.38; P =.013) but decreased specificity (OR = 0.54, 95% CI = 0.49 to 0.59; P<.001). ROC analysis showed that higher breast density and previous mammography were negatively related to accuracy (P<.001 for both). CONCLUSIONS: Diagnostic mammography in women with signs or symptoms of breast cancer shows higher sensitivity and lower specificity than screening mammography does. Higher breast density and previous mammographic examination appear to impair performance.
Adult↗
Increased mammography use and its impact on earlier breast cancer detection in Vermont, 1975-1999.
BACKGROUND: A trend toward earlier breast carcinoma detection in the United States has been attributed to screening mammography, although direct evidence linking this trend to the increased use of mammography in a general population is lacking. This study examined the effects of mammography on tumor size and axillary lymph node metastasis in Vermont over 25 years. METHODS: Pathology and mammography data from 3499 Vermont women who were diagnosed with invasive breast carcinoma during 1975-1984, 1989-1990, and 1995-1999 were compared. Logistic regression analysis was used to estimate the effects of age, mammography use, and period on the odds of a tumor < or = 2 cm and the odds of negative lymph nodes. RESULTS: The proportion of breast tumors that were detected by screening mammography increased from 2% during 1974-1984 to 36% during 1995-1999 (P < 0.001), and these tumors were more likely to measure < or = 2 cm than tumors that were detected by other methods. Among women age > 50 years, the odds ratio (OR) was 4.5, with a 95% confidence interval (95% CI) of 3.5-6.4. The effect was smaller in younger women (OR, 1.8; 95% CI, 1.1-3.0). Mammographic detection increased the odds of negative lymph nodes by a similar amount in both age groups, although women age > 50 years were more likely to have negative lymph nodes than younger women (OR, 1.3; 95% CI, 1.1-1.6). Tumor size and lymph node metastasis also were related to the number of mammograms and to the mammographic interval. CONCLUSIONS: Most of the trend toward earlier detection in Vermont was due to mammography. Mammography had a lesser effect on tumor size among younger women, which may be related to less frequent screening, although its effect on lymph node metastasis was not age dependent. Women age < 50 years were more likely to have positive lymph nodes, independent of the method of detection or the frequency of mammography.
Age Factors↗
Pathological and molecular assessment of sentinel lymph nodes in solid tumors.
Sentinel nodes (SNs) are the first set of nodes to receive drainage and cancer cells from a primary tumor. While there may be a single SN, frequently there are one to three or more SNs. The development of sentinel node surgery over the last decade has led to dramatic changes in the surgical approach to regional nodes draining solid tumors. The surgeon can now identify, to a level of accuracy previously impossible, the regional nodes most likely to be involved with cancer in any individual patient. This new capability comes at a cost; the principles guiding the extent of nodal surgery must be completely re-examined. The extent of surgical resection required to achieve each of the goals of regional node surgery-(1) establishing prognosis, (2) obtaining regional control, and (3) improving overall survival-may no longer be simply the default "regional node resection" and may vary depending on the clinical goals. Inseparable from this new surgical technology is the methodology employed for pathologic evaluation of SNs. It is critical that pathologists and clinicians conduct definitive clinical research directed toward defining the role and impact that SN surgery has on each of these surgical goals.
Breast Neoplasms↗
Assessing the significance of occult micrometastases in axillary lymph nodes from breast cancer patients.
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Axilla↗