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ORIGINAL ARTICLES |
From the Departments of Surgery (KJVZ, DMEM, JLBB, SKB, JVF, PIB, HSC), Pathology (LKT), and Urology, Epidemiology and Biostatistics (MWK), Memorial Sloan-Kettering Cancer Center, New York, New York.
Correspondence: Address correspondence and reprint requests to: Kimberly J. Van Zee, MS, MD, FACS, 1275 York Ave., MRI-1026, New York, NY 10021; Fax: 212-794–5812; E-mail: vanzeek{at}mskcc.org
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Pathological features of the primary tumor and SLN metastases of 702 patients who underwent complete ALND were assessed with multivariable logistic regression to predict the presence of additional disease in the non-SLNs of these patients. A nomogram was created using pathological size, tumor type and nuclear grade, lymphovascular invasion, multifocality, and estrogen-receptor status of the primary tumor; method of detection of SLN metastases; number of positive SLNs; and number of negative SLNs. The model was subsequently applied prospectively to 373 patients.
Results: The nomogram for the retrospective population was accurate and discriminating, with an area under the receiver operating characteristic (ROC) curve of 0.76. When applied to the prospective group, the model accurately predicted likelihood of non-SLN disease (ROC, 0.77).
Conclusions: We have developed a user-friendly nomogram that uses information commonly available to the surgeon to easily and accurately calculate the likelihood of having additional, non-SLN metastases for an individual patient.
Key Words: Axillary metastases • Breast cancer • Nomogram • Prediction • Sentinel node
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Proponents of performance of completion ALND after a positive SLN biopsy argue that further axillary clearance is critical to management. The total number of involved nodes is important prognostic information, as an increasing number of positive nodes portends worse survival.11–13 This is reflected in the new American Joint Committee on Cancer (AJCC) sixth edition staging system, wherein the number of positive nodes defines N1, N2, and N3 disease and ultimately the stage to which the patient is assigned.14 In addition, proponents of the performance of complete ALND after positive SLN biopsy argue that the additional information can benefit patients by guiding decisions about adjuvant chemotherapy. For the approximately one-half of patients in whom there is residual nodal disease, it is also argued that complete ALND can influence survival via local-regional control of the axilla,15–17 thereby eliminating a potential site of recurrent disease and, ultimately, a source for distant disease. A meta-analysis of randomized trials revealed a 5.4% survival benefit associated with ALND for clinically node-negative patients.18
Opponents of complete ALND performed after positive SLN biopsy argue that the therapeutic benefit of complete ALND is minimal.19 Furthermore, approximately 50% of patients with positive SLNs are found to have no other nodal metastases.1–6,20–24 Therefore, many patients are undergoing unnecessary ALND, with no additional therapeutic benefit or further staging information provided. It is also argued that because patients with SLN metastases will generally receive systemic therapy, regardless of the presence of any additional nodal metastases, any residual disease does not influence choice of therapy and may itself be eradicated by the systemic therapy. In addition, radiation therapy after breast-conserving surgery may contribute to control of any additional nodal disease. It is this debate that physicians and their patients are faced with in the office setting when a positive SLN is discovered on final pathology.
Several groups have identified histopathological variables of the primary tumor and its metastasis that can influence risk of additional disease in the non-SLNs9,10,21–29 (Table 1). Size of the primary tumor and size of the SLN metastasis are the two variables most commonly analyzed. Previous investigation at our institution found that size of the primary tumor and of the SLN metastasis are significantly predictive of likelihood of additional, non-SLN metastases.26 Most other studies that examined at least one of these two variables showed a statistically significant correlation with risk of additional, non-SLN disease,9,10,21–25,27–29 yet most have not been able to identify a subset that has no risk of additional disease in the non-SLNs.10,22–24,27,28,30 Those studies that have identified favorable subsets with an apparently negligible risk of additional nodal disease have all involved very small subsets (i.e., 5–24 patients).9,21,26,30–32
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show reported incidences by primary tumor size, presence of lymphovascular invasion (LVI) in the primary tumor size of SLN metastasis, and presence of immunohistochemically (IHC-) detected SLN metastases. This variation in reported incidences may be attributable to relatively small sample sizes or the result of differences among the study populations in terms of other variables influencing risk. Second, it is difficult to apply risk estimates to several patient characteristics simultaneously because of the generally univariate method of reporting in the literature.
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The goal of our study was to develop a tool that would allow greater individualization of a patient’s risk estimate by simultaneously taking into account several pertinent characteristics specific to the patient. With a more precise and individualized estimate, both physician and patient would be better able to weigh the pros and cons of further axillary dissection.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our technique for SLN biopsy includes the use of both blue dye and radioisotope, as previously outlined in earlier studies at our institution.33
SLN Histopathological Evaluation
Whenever possible, the SLN was bisected and sectioned at 2–3-mm intervals. The nodal tissue was quick-frozen in liquid nitrogen, and a single 5-µm-thick section stained with hematoxylin and eosin (H&E) was examined intraoperatively (frozen-section analysis). If the section was positive, a complete ALND was done immediately. After the frozen-section analysis, the remaining frozen tissue was fixed in formalin and embedded in paraffin. Another 5-µm-thick H&E-stained section was evaluated as a frozen-section control (routine histopathology). If this section showed evidence of metastatic disease, no further pathological workup of the SLN was performed. If the routine H&E section remained negative, enhanced pathological analysis was performed in the following fashion: two pairs of H&E- and cytokeratin IHC–stained sections with a distance of 50 µm between the pairs were prepared from the paraffin block. At one level, the cytokeratin antibody CAM 5.2 (Becton Dickinson Immunocytometry Systems, San Jose, CA) was used, whereas the cytokeratin cocktail AE1:AE3 (Ventana Medical Systems, Tucson, AZ) was applied for the other level. Patients with SLN metastases not detected by frozen-section analysis generally underwent completion ALND at a later date. For all additional nodes identified by completion ALND, routine H&E analysis was done on a single section of each node.
Data Analysis
Clinical data collected for each case from the database included age; pathological size of the invasive carcinoma, defined in centimeters; tumor type (ductal or lobular carcinoma); nuclear grade (I: slight or no variation in size and shape of nucleus; II: moderate variation in size and shape; III: marked variation in size and shape); presence of lymphovascular invasion (presence of one or more tumor cells in a lymphatic or vascular structure); multifocality of primary tumor (foci of carcinoma separate from primary tumor); estrogen-receptor (ER) status (negative, <10% of cells staining positive); method of detection of SLN metastases (frozen-section analysis [frozen], routine histopathology [routine], H&E stains of serial sections [serial HE], IHC); number of positive SLNs; and number of negative SLNs. Because lobular carcinomas generally are not assigned a nuclear grade, the tumor type and nuclear grade were combined into the following four categories: ductal carcinoma, nuclear grade I; ductal carcinoma, nuclear grade II; ductal carcinoma, nuclear grade III; and lobular carcinoma. To allow use of our model by groups that do not routinely perform frozen-section analysis, a second model was developed with only three levels for the method of detection variable: routine histopathology (routine), serial sectioning (serial HE), and immunohistochemistry (IHC). In this model, a node in which metastatic disease was detected by either frozen-section analysis or routine histopathology was categorized as routine. Data on additional variables such as progesterone-receptor status, histologic grade, and AJCC T stage were also collected; however, because these variables are highly correlated with ER status, nuclear grade, and pathological size, respectively, they were not considered to be of substantial benefit to the model. HER-2/neu amplification data were also collected but were not included because they were incomplete and variable, owing to evolving methods of assessment during the years of the study.
A nomogram was developed based on the patients in the retrospective group and then was validated with the patients in the prospective group. In the retrospective population (n = 702), multivariable logistic regression was used to analyze the association of each variable with the likelihood of non-SLN metastases, and a nomogram was created with all variables. This model was used in the prospective group (n = 373) to predict each individual patient’s probability of having positive non-SLNs. The discrimination of the model was measured by using the area under the receiver operating characteristic (ROC) curve. The calibration of the model was assessed graphically. Women were grouped into deciles based on their nomogram predictions. For each decile, the mean nomogram-predicted probability was compared with the proportion of women who actually had positive non-SLNs (actual probability). All analyses were performed with S-Plus Software Version 2000 Professional Edition with the Design Library (Mathsoft, Data Analysis Products Division, Seattle, WA).34
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Age was not included in the final nomograms because its effect was too small to be seen on the nomograms.
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The assigned points for all eight variables are summed, and the total is found in row 10 (TOTAL POINTS). Once the total is located in row 10 (TOTAL POINTS), a vertical line is made between it and the corresponding value in the final row, row 11 (Predicted Probability of +non-SLN). The version of the nomogram in Figure 1 is for use when information on frozen-section analysis is available; that in Figure 3 is for those cases where frozen-section information is not available.
In addition to the graphic nomograms, to facilitate ease of use in the clinical setting, we have made a personal digital assistant (PDA)-compatible application for use with hand-held Palm-type devices (Palm, Milpitas, CA). We will make these applications available at our Web site, www.mskcc.org/nomograms.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our nomograms utilize readily available clinical information and allow quick calculation. This approach may allow identification of extremely low-risk individuals for whom the risks associated with completion ALND are judged to outweigh the benefits. Conversely, our nomogram may allow identification of women at sufficient risk of additional nodal disease that they and their surgeon elect to proceed with completion ALND even though clinical "guesstimates" would suggest that they are at low risk.
The nomograms provide risk estimates that will have to be judged on an individual basis. A woman with a 1.8-cm, ER-positive, high-nuclear-grade ductal carcinoma with no LVI who has a single IHC-positive SLN might be considered to be at low risk. Our nomogram suggests that she has a 12% risk of having non-SLN metastases. Should she undergo completion ALND? Given this scenario, some will judge that a 12% risk of additional, non-SLN metastases justifies further ALND; others will not. The nomogram itself makes no actual treatment recommendations.
There are several limitations to our model. The nodes retrieved at completion ALND were examined by routine pathological analysis only. Other investigators25,35 have shown that if non-SLNs are examined with serial sectioning and IHC, a higher proportion of patients with additional, non-SLN disease at completion ALND are identified. Evaluation by enhanced pathological analysis would clearly alter our model.
Furthermore, the clinical relevance of resecting additional nodal disease (even that detected by routine analysis) remains unknown. Although some argue that surgical removal of subclinical nodal disease is associated with a small but nonzero survival benefit, others argue that current adjuvant systemic therapy and radiation therapy would likely treat the majority of patients adequately. This study does not address this issue but provides accurate and individualized estimates of the likelihood of finding additional disease at completion ALND. The American College of Surgeons Oncology Group Protocol Z0011 (ACOSOG Z0011), currently under way and randomizing women with a positive SLN to undergo ALND or no ALND, is designed to address this question directly.
In addition, the prognostic significance of micrometastatic nodal disease is a subject of debate. In his 1997 review of the published literature, Dowlatshahi36 concluded that all but one of the large (N 
147) and long-term (6-year) studies demonstrated a statistically significant decrement in survival associated with micrometastatic disease. At MSKCC, Tan et al.37 recently re-examined all axillary nodes from 373 patients treated in the 1970s who were deemed to be node-negative by routine histopathological analysis. Nodes were examined by serial sectioning and IHC, and the presence of any detectable micrometastatic disease was associated with worse disease-free and overall survival.
Another limitation of our data is the absence of size determination for the nodal metastases. The AJCC Cancer Staging Manual, 6th edition, now includes size of metastasis as an important determination of stage (and, therefore, of prognosis). However, we have had difficulty assigning a size to many cases because of the difference in pattern of distribution of malignant cells within the node. For example, some nodes may have scattered single cells or multiple small clusters of cells. How should these be measured? Ideally, an accurate estimate of volume could be assigned to each SLN metastasis. However, this is extremely time-consuming and somewhat impractical.
Nevertheless, it is clear that IHC is more sensitive than H&E in detecting micrometastases, that routine H&E analysis is more sensitive than frozen-section analysis, and that there is a correlation between method of detection and volume of disease. Others10,24 have demonstrated quantitatively that method of detection is correlated with measured size of the SLN metastasis. Therefore, in order to have a consistent, practical, and reproducible methodology of estimation, the method of detection of the nodal metastasis was used. This provides a general estimate of the amount of nodal disease and allows categorizing into four distinct groups.
Another potential weakness in our data is that some of our patients, especially those with a perceived low risk of additional, non-SLN metastases, did not undergo a completion ALND and therefore were not included in our model. However, as demonstrated in the histograms (Figs. 2 and 4
), the patients in the prospective population are distributed quite evenly across the range of predicted risk. Furthermore, as demonstrated on the calibration curves, the models do predict well in the prospective population, even for those in the lowest decile of predicted risk.
Some might express surprise at the effect of ER status in the nomogram. Intuitively, one might expect ER positivity to be associated with lower risk of additional, non-SLN metastases. In our model, the effect of ER status is of only borderline statistical significance (P = .08), but it was included to improve the overall predictive ability of the model. Furthermore, although the finding is counterintuitive, others have reported similar findings. Nationwide data from the American College of Surgeons38 also indicated that cases negative for ER had a lower risk of lymph node metastases, after adjustment for all other factors.
Last, our models are imperfect. For the first model, the area under the ROC curve was 0.77 for the prospective population. This means that if we randomly select two women, of whom one has at least one positive non-SLN and the other has negative non-SLNs, there is a 77% chance that the nomogram will predict a higher probability for the positive woman. This is a scale that ranges from 0.5, which would be achieved by tossing a coin, to 1.0, which would require perfect ability to tell the positive woman from the negative one.
Nevertheless, these models represent a significant improvement over estimates based on one or two variables in smaller populations. We have used our large, prospective database to develop the models and have proven their validity by testing them prospectively on a subsequent population. The calibration errors of our models are small (see Figs. 2 and 4), generally <10% across the spectrum of predictors. Other investigators have shown that removing statistically insignificant predictors actually worsens the predictive ability of the model.39 Here, we have incorporated all statistically significant variables, as well as other clinically available and relevant variables, to provide improved prediction capability. Nomograms provide improved predictive ability in comparison with the crude counting of risk factors, and in addition, nomograms usually outperform clinical judgment, according to numerous studies conducted in other areas of medicine.40
With the important clinical question of whether to perform a completion ALND in a patient with a positive SLN biopsy arising more and more frequently, our nomograms provide an easy-to-use tool with which to simultaneously incorporate several important variables into the estimate of risk of additional, non-SLN metastases. Further validation and follow-up studies such as ACOSOG Z0011 will ultimately provide additional guidance to the clinician and patient. These nomograms provide a risk estimate that can help in weighing the pros and cons of completion ALND for an individual patient with SLN metastases.
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ACKNOWLEDGMENTS |
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The authors acknowledge Drs. Mary Gemignani, Alexandra Heerdt, Leslie Montgomery, Jeanne Petrek, Elisa Port, Virgilio Sacchini, and Lisa Sclafani for contributing patients to the sentinel node database and acknowledge Alexandra MacDonald for her expert editorial assistance.
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FOOTNOTES |
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Dr. Bevilacqua is currently affiliated with Hospital Sírio Libanes, Instituto Brasileiro de Controle do Câncer, and Disciplina de Cirurgia Geral, Departamento de Cirurgia, Faculdade de Medicina da Univerdidade de Sao Paulo. São Paulo, Brazil; Dr. Boolbol is currently affiliated with Beth Israel Medical Center, New York, New York.
An accurate and easy-to-use nomogram was developed to predict the likelihood of non-sentinel node metastases in breast cancer patients with sentinel node metastases. The model was created with use of 702 cases and then prospectively validated in 373 cases.
Received for publication March 6, 2003. Accepted for publication August 19, 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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