Multicentric and multifocal versus unifocal breast cancer: is the tumor-node-metastasis classification justified?

Abstract

For classification of breast cancer (BC), tumor-node-metastasis (TNM) staging has been considered state of the art for more than 50 years. The T category is well defined, and in multicentric and multifocal tumors, tumor size is assessed by the largest tumor focus. The aim of this study was to compare multicentric/multifocal tumor spread in breast cancer with unifocal disease and to evaluate the diagnostic relevance of multifocality. A retrospective analysis was performed on survival related events in a series of 5,691 breast cancer patients between 1963 and 2007. By matched-pair analysis, patients were entered into two comparable groups of 288 patients after categorizing them as having multifocal/multicentric or unifocal breast cancers. Matching criteria were tumor size, grading, and hormone receptor status, which were equally distributed between both groups (P = 1.000 each). Disease free survival and the occurrence of relapse or of metastatic disease were evaluated. Cox's regression analysis was used for multivariate analysis. In the unifocal group, the mean breast cancer-specific survival time was 221.6 months as opposed to 203.3 months in the multicentric/multifocal group (P < 0.001, log-rank test). The occurrence of local relapse and distant metastasis was significantly increased in the multifocal group in comparison to the unifocal equivalent group (P < 0.001 and P < 0.003, respectively). Cox regression analysis for multivariate analyses demonstrated focality and centricity to be highly significant predictors for reduced overall survival (P = 0.016), local relapse (P = 0.001) and distant metastasis (P = 0.038). Tumor size, histopathological grading, hormone receptor status, and staging of lymph nodes are well-established prognostic parameters. Additionally, the number of foci should be considered as an independent prognostic parameter, which is currently not reflected in the TNM classification. We conclude that multicentric/multifocal BC is an independent BC risk factor and should be included in the risk assessment by re-evaluating the current TNM classification of the UICC.

Systematic review of the impact of breast‐conserving surgery on cancer outcomes of multiple ipsilateral breast cancers

“…reported a significant association between MIBC and relapse‐free survival in a study of 1862 MIBC compared with 7073 unifocal cancers ( P = 0·007); however, this finding related to clinical non‐adherence to German guidelines. Weissenbacher and colleagues19 confirmed a significant association between MIBC and overall breast cancer recurrence ( P = 0·001) in matched‐pair multivariable analyses of MIBC compared with unifocal cancers (288 in each group). These conflicting reports support a future review of current TNM staging for MIBC.…”

“…Generally, evaluation of the largest cancer using standard immunohistochemical (IHC) biomarkers (oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki‐67) is performed3 9, 15. However in future, the potential to use extended IHC biomarkers and whole‐genome sequencing may increase the recognition of intertumoral heterogeneity14 16, 17, 18, with prognostic implications19, 20, 21, 22.…”

“…Standard imaging of MIBC may include digital mammography, ultrasound examination and MRI, with biopsy confirmation of any additional suspected cancers on MRI to minimize their misdiagnosis, which occurs in 30 per cent of ‘lesions’24 25. Studies6 10, 11 19, 20, 21 23, 26 are conflicting on the prognostic implications of MIBC, with suggestions of increased axillary lymph node involvement latterly using sentinel lymph node biopsy (SLNB), and with worse overall outcomes than those for unifocal cancers19 22, 23. Increased rates of locoregional recurrence (LRR)5 and breast cancer events22 23, 27 28 secondary to BCS for MIBC have been reported, but vary widely across studies.…”

Review on Practical Approach in Multiple Breast Carcinomas: Does Each Focus Matter?

“…Also, in multivariable analyses, multifocality was associated with significantly worse overall survival (61). However, studies regarding the prognostic significance of multiple foci in breast carcinomas are contradictory and the differences in data could be caused by many factors, such as: case inclusion criteria, variations in the definitions used, different statistical analysis methods and different interpretations (4,11,13,20,22,26,27,(62)(63)(64)(65)(66)(67)(68). (Table 3) We aimed to analyze survival in multiple breast carcinomas compared with unifocal ones, in order to assess the impact of multi-focality on prognosis.…”

“…Survival indicators Worse prognosis Egan,1982 (20) Mortality ↑ Dabakuyo,2008 (63) Mortality ↑ 5 and 10-year survival ↓ Yerushalmi,2009 (4) Survival rate slightly ↓ Boyages,2010 (62) Mortality rate ↑ 5 and 10-year survival ↓ Weissenbacher,2010 (68) Mean survival ↑ ↑ Local recurrence rate ↑ Rate of distant metastases Tot, 2011 (67) ↑ Risk of death due to breast carcinoma Ustaalioglu, 2012 (24) ↓Disease free survival Pekar, 2013 (53) ↓ Breast Cancer Specific Survival No influence on prognosis (no statistically significant differences between compared groups) Vlastos, 2000 (11) Breast Cancer Specific Survival at 10 years Disease-Free Survival Middleton, 2002 (22) Disease-Free Survival at 5 and 10 years Oh, 2006 (65) Overall Survival at 5 years Litton, 2007 (64) Overall Survival, Relapse-Free Survival Joergensen, 2008 (13) Overall Survival Cabioglu, 2009 (27) Disease-Free Survival at 5 years Rezo, 2011 (26) Overall Survival, Progression Free Survival Lynch, 2012 (66) Relapse-Free Survival, Breast Cancer Specific Survival -worse prognosis at 5 years (only in UVA, not in MVA -other factors are associated with ↓ survival rates)…”