Multifocal Breast Cancer: Sum of the Parts Equals the Whole
Abstract & Commentary
Synopsis: Multifocal/multicentric breast cancer may be associated with a worse outcome than similarly staged unifocal cancers. This may be due to current staging rules that determine the T stage based on the size of the largest nodule only. This study presents data that the biology of these tumors is more closely related to the sum of the diameters of each nodule.
Source: Andea AA, et al. Cancer. 2002;94:1383-1390.
According to the current staging system, the t stage in multifocal/multicentric breast cancer is determined by using the size of the largest individual mass. Andea and colleagues hypothesized that the prognosis and behavior of a multifocal/multicentric breast cancer would be best determined by estimating the total tumor volume rather than using the largest lesion only. Therefore, Andea et al retrospectively identified 101 patients with multifocal/multicentric invasive breast cancer. Those with diffuse microinvasion or those in which the nodules could not be measured were excluded. Their study is entitled "Pathologic Analysis of Tumor Size and Lymph Node Status in Multifocal/Multicentric Breast Carcinoma."
Tumor "size" is conventionally estimated by the largest diameter of a mass even though tumor burden is more likely related to volume or surface area. In the study by Andea et al, the "size" of the tumor was recorded using either the standard procedure (diameter of the largest tumor nodule only) or the alternative approach (sum of the diameters of all tumor nodules present). For comparison, control cases of unifocal breast cancer were also retrospectively identified from their records.
Most of the multifocal/multicentric cancers had just 2 nodules (76%) with the remainder having 3 or 4 nodules. In cases where such information was available, 62% had tumor nodules located in the same quadrant whereas in the other 38% the nodules were in different quadrants. The histologic subtype of separate tumor nodules was different in 16% of cases. The grade of separate tumor nodules was dissimilar in 5% of cases.
The most important observation was the relationship between the risk of lymph node metastasis and "tumor size" in multifocal/multicentric breast cancer. Using standard staging rules, multifocal/multicentric carcinomas falling within the T1/T2 subgroups had a much higher risk of positive nodes compared with T1/T2 unifocal carcinomas. However, if the T stage of the multifocal/multicentric cases was calculated based on the combined diameters rather than the largest diameter alone, the incidence of positive nodes was comparable to unifocal carcinomas of similar total size. For example, unifocal T1 tumors had positive nodes in 35% of cases. Similarly, multifocal/multicentric tumors whose combined measurements were also classified as T1 had positive nodes in 33% of cases. However, multifocal/multicentric tumors classified as T1 using the standard staging classification had involved nodes in 60% of cases (P = 0.002). A multivariate analysis suggested that multifocality itself was not an independent risk factor after controlling for total tumor volume.
Comment by Kenneth W. Kotz, MD
In the fifth edition of the AJCC Cancer Staging Handbook, "multiple simultaneous ipsilateral primary carcinomas" are assigned the T stage based on the "largest primary carcinoma," and one should "enter into the record that this is a case of multiple simultaneous ipsilateral primary carcinoma" and "such cases should be analyzed separately."1 The sixth edition is scheduled for publication by Springer-Verlag with an expected release date in May 2002.2 The finding of separate invasive nodules in one breast has several potential explanations including: 1) intramammary metastases; 2) 2 or more independent tumors; or 3) multiple areas of invasion arising from extensive ductal carcinoma in situ. A distinction between these entities has sometimes been implied by the terms multifocal and multicentric. For some authors, multifocal and multicentric are used to differentiate intramammary metastases from synchronous primaries, respectively.3,4 For others, multifocal refers to tumors localized to 1 quadrant whereas multicentric means nodules in different quadrants.4,5 And for many, the terms are used interchangeably.3 The origin of multifocal/multicentric breast cancer has been studied using morphologic, immunohistochemical, and molecular techniques. These studies have generally shown that most multifocal/multicentric breast cancers are in fact due to intramammary metastases rather than separate primaries.3-5 In the study by Andea et al, cases with more than 1 histology or involving more than 1 quadrant were included but not analyzed separately.
In general, treatment of multifocal/multicentric tumors parallels that of unifocal tumors. There has been concern regarding the accuracy of sentinel lymph node mapping in multifocal/multicentric tumors.6 However, a study of 19 such patients whose sentinel node biopsies were followed by a complete axillary node dissection found complete concordance in all patients.7 Many studies (referenced by Andea et al4), but not all,5 have reported an adverse outcome in multifocal/multicentric tumors as staged by current rules. The data by Andea et al suggest that this is related to "understaging." Although limited by a retrospective design, they have found that the metastatic potential of multifocal/multicentric breast cancer is more closely related to the aggregate diameters rather than using the diameter of the largest nodule only. Even without clinical outcome data, this information might be useful in estimating systemic risk and designing adjuvant therapy.
Dr. Kotz of Hanover Medical Specialists, Wilmington, NC.
References
1. American Joint Committee on Cancer. Breast AJCC Cancer Staging Manual. 5th ed. Lippincott-Raven; 1997:127-133.
2. www.cancerstaging.org/initiatives.html
3. Dawson P. Cancer Control. 1996;3:258-266. http://www.moffitt.usf.edu/pubs/ccj/v3n3/dept6.html
4. Andea A, et al. Cancer. 2002;94:1383-1390.
5. Middleton L, et al. Cancer. 2002;94:1910-1916.
6. Cody H. Oncology. 1999;1:25-34. http://www.cancernetwork.com/journals/oncology/o9901a.htm
7. Schrenk P, et al. Lancet. 2001;357:122.
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