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Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7497-7502 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.1147 Multifocal and Multicentric Breast Cancer: Does Each Focus Matter?From the New South Wales Breast Cancer Institute, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia Address reprint requests to: A/Professor John Boyages, New South Wales Breast Cancer Institute, Westmead Hospital, Westmead, Sydney, NSW 2145, Australia; e-mail: johnb{at}bci.org.au
PURPOSE: The identification of multiple tumors in the breast is associated with increased nodal involvement when compared with similar staged unifocal disease. This study compares two methods of tumor size assessment to predict tumor behavior in the relationship between size and axillary node involvement for patients with multifocal and multicentric breast cancer. METHODS: The histologic reports of every patient with multifocal breast cancer treated in New South Wales between April 1995 and September 1995 were examined. Tumors were assessed using two size estimates: (1) largest tumor focus diameter and (2) the aggregate diameters of all tumor foci. The dimensions were compared with unifocal tumors and against node positivity. RESULTS: Ninety-four (11.1%) of 848 women had multifocal breast cancer and of these 49 women (52.1%) had axillary node involvement compared with 37.5% with unifocal breast cancer (P =.007). The use of aggregate dimension reclassified significant numbers of multifocal tumors at a more advanced stage. Use of this method to stage cancers, rather than the largest tumor size, removed the excess node positivity when compared with unifocal, stage-matched breast carcinomas. CONCLUSION: The tendency of breast tumors to metastasize is a reflection of the total tumor load. Failure to measure the additional tumor burden provided by multiple small foci may understage a woman's disease. This may deny patients the opportunity of adjuvant therapies if the contribution of the smaller foci to the incidence of node positivity and survival is ignored.
Tumor size is an important predictor of axillary lymph node metastases with size demonstrating a direct correlation with the probability of node involvement.1-4 For unifocal disease, tumor staging is dependent on the maximum dimension of the tumor and is used as an approximation of tumor volume. Multifocality or multicentricity in breast cancer may be defined as the presence of two or more tumor foci within a single quadrant of the breast or within different quadrants of the same breast, respectively.5-7 Detailed serial-sectioning of mastectomy specimens identifies additional separate tumor deposits in approximately 30% of women with breast cancer.6,8 This is associated with adverse patient outcome, a propensity for axillary nodal involvement when compared with unifocal tumors,4 and a possible increased risk of local recurrence following breast conserving surgery.9 Whether multifocality confers any significant effect on overall survival when controlling for known prognostic factors remains controversial.10,11 Most authors use The American Joint Committee on Cancer (AJCC) and the International Union Against Cancer recommendations to assess multifocal tumors.12 This uses the diameter of the largest tumor focus and lymph node status to stage the disease. This assumes that the prognosis is dependent solely on the largest (and possibly more aggressive) foci and extent of axillary lymph node involvement. This is the convention used for studies of screen detected breast cancer and it takes no account of the total tumor load. The probability of node involvement increases with tumors of more advanced stage when classified by the AJCC criteria,1,4 but some authors have demonstrated that aggregate tumor size13 or estimates of tumor volume14 may be a more accurate predictor of tumor behavior in the presence of more than one focus. The aims of this study were to assess whether, in multifocal and multicentric disease, the largest foci dimension or the aggregate tumor size is a more accurate predictor of node status and, by inference, tumor behavior in the relationship between tumor size and axillary node involvement.
Patient Selection This retrospective study examined the original histologic reports of 865 consecutive patients with breast cancer treated in New South Wales between April 1, 1995, and September 30, 1995. A total of 154 surgeons performed the operations and 58 different pathology practices examined the breast specimens. Only patients who had treatment to their breast and axillary clearance surgery were included. Patients with known metastatic or locally advanced breast tumors and patients who had preoperative neoadjuvant chemotherapy were also excluded, along with patients with in situ tumors alone, leaving 848 cases for analysis and of these, 404 women (47.6%) were treated with breast conserving surgery.
Data Collection
Data Analysis
Histologic analysis of 848 women in New South Wales with invasive breast cancer treated with primary surgery and axillary dissection identified 94 women (11.1%) with multifocal breast tumors. Of these, 68 women (72.3%) had two tumor foci, 20 women (21.3%) had three foci and six women (6.4%) had four or more foci. A comparison of the demographic and clinicopathologic characteristics between the unifocal and multifocal groups is given in Table 1. The frequency of multifocal tumors was similar in younger (< 50 years) and older (  50 years) women but the mean age of patients with multifocal tumors was slightly younger than women with unifocal tumors (54.8 v 58.1; P = .02).
There was no difference in the mean diameter or size distribution of the largest focus between the unifocal and multifocal groups (20.3 mm v 21.1 mm, respectively; Table 2). The use of aggregate dimension to assess a tumor will increase the tumor size and reclassify significant numbers of multifocal tumors at a more advanced stage (Table 2).
Using the AJCC criteria,12 we identified 38 patients who were node-negative with multifocal tumors  20 mm and only two patients with T3 tumors (> 50 mm). Use of aggregate size would reclassify 16 out of 38 patients (42.1%) as having larger tumors (> 20 mm) and identify a total of eight patients with an aggregate size more than 50 mm.
Patients with multifocal tumors had an axillary positivity rate of 52.1% compared with 37.5% for patients with unifocal tumors (
When the aggregate dimensions of the tumor foci are used rather than the largest tumor size, the excess node positivity for multifocal tumors is less evident. By univariate analysis, identical rates of node positivity were observed between unifocal tumors and aggregate-size-matched, multifocal tumors. Using univariate analysis, age, histologic grade, multifocality, and tumor size were significant predictors of nodal positivity (Table 4). Multivariate analysis demonstrated that tumor grade, multifocality, and increasing tumor diameter remained significant independent predictors of nodal positivity (Table 5). However, when the aggregate size of all tumor foci is used to classify size, multifocality is no longer an independent risk factor of node positivity (Table 5, column 9).
The identification of multifocal or multicentric tumors is not uncommon. In agreement with many studies,15-17 we have demonstrated that approximately 10% of women in New South Wales have multifocal tumors. This is lower than other quoted rates,6,8 possibly as this cohort of women with primary breast carcinoma included the 404 women (47.6%) treated with breast-conserving surgery. Therefore, the whole breast could not be subjected to full serial–sectioning to identify additional tumor deposits. Women with multiple tumor foci display a significantly higher incidence of node positivity than unifocal tumors. This propensity is not likely to be as a result of histologic factors as there was no significant difference in distribution of grade and sub-type between the tumor groups (Table 1). The dimension of every tumor focus was recorded for each patient. The frequency distribution of the size of the largest focus was identical to unifocal tumors, and therefore, the stage, using the AJCC criteria,12 at presentation of the multifocal and unifocal tumor groups were identical. If the distribution of the tumor stage, subtype, and grade size was identical between the tumor groups, the increased incidence in node positivity may be explained by the additional tumor foci in the multifocal group. The dimensions and contribution of these foci would not normally be recognized for staging purposes. Although there is only a statistically significant difference observed in node positivity in multifocal tumors of 21 mm to 30 mm (measured using dominant focus size; Table 3) with larger numbers in each sub-group the observed differences may reach significance. However, by using the sum of the dimensions of every tumor focus to provide an aggregate size of the multifocal tumor, a more accurate estimate of the tumor load may be calculated. This aggregate dimension takes account of all measured foci and, when used, predicted nodal positivity at a rate that is identical with a size-matched group of unifocal tumors (Table 3). Indeed, by using this classification of tumor size, multifocality is no longer an independent risk factor of nodal metastases (Table 5). Use of aggregate size to classify tumor size upstaged an additional six women with T3 tumors and identified another 16 node-negative women with tumors more than 20 mm. The women may not have met criteria for adjuvant systemic therapies if their tumors were staged according to the AJCC criteria, but use of aggregate tumor size would increase the tumor stage in these 22 women (23.4%).
A recent study14 suggests that use of aggregate tumor foci volume may be a more accurate predictor of metastatic potential in multifocal breast cancer than aggregate size. However, use of this technique requires the magnitude of each tumor focus to be measured, in each of the three dimensions (d1, d2, and d3) and is given by the formula 1/6 With widespread use of mammographic screening and increased accuracy of diagnostic imaging, the identification of multiple, small tumor foci is increasing. Although the identification of multiple breast tumors by preoperative magnetic resonance imaging is associated with increased local recurrence,18 its use in the preoperative setting is not widespread. Whether this identifies patients at risk of poor long-term survival is unknown. The dilemma for clinicians is that by using the dominant focus size, there is an increased probability of nodal positivity and perhaps, poorer prognosis, compared with unifocal tumors of that size. Using the cumulative size of the foci within multifocal tumors demonstrates identical nodal positivity as size matched unifocal tumors. Using the dominant focus to assess multifocal tumors will under-stage the breast cancer (Table 2). The dimension and stage of the breast carcinoma may influence decisions regarding the use of adjuvant therapies. The tumor size and stage will be reduced by a failure to measure and adjust for the additional tumor burden provided by multiple small tumor foci. This may deny patients the opportunity of adjuvant chemotherapy or radiotherapy if the contribution of the smaller foci to tumor load and incidence of nodal positivity is ignored. We conclude that the tendency of breast tumors to metastases is a reflection on the total tumor load rather than the dimension of the largest focus. The impact of these data on patient outcome, particularly breast cancer mortality, is the subject of further study. However, as node status (and perhaps prognosis) is more accurately predicted by aggregate tumor size, the use of the current AJCC guidelines to stage multifocal breast tumors5 may require further evaluation. In agreement with other authors,6 we propose that an alternative staging scheme is used, measuring the aggregate dimensions of all tumor foci. This would allow clinicians to compare axillary staging and outcomes of treatment with similar sized unifocal breast carcinomas.
The authors indicated no potential conflicts of interest.
The NSW Breast Cancer Institute receives funding from the NSW Health Department. We are grateful to Greg Heard, PhD, for his advice and detailed editorial assistance in the preparation of this manuscript.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, P = .009). Multifocality appears to be a significant independent predictor of node positivity if the tumor size is classified by AJCC guidelines, according to the largest focus diameter (
· d1 · d2 · d3. However, use of this simple calculation is valid only for regular objects. This often will not reflect the true shape and nature if applied to breast tumor foci. Accurate estimates of tumor volume were not possible in our study as most reports recorded only the maximal diameter of each tumor focus. Although the maximum length and breadth (in two dimensions) may be measured from a microscope slide, estimates of the third dimension, depth, is often not recorded. Traditionally, staging has required only the maximum diameter of the largest focus.
