breast cancer is the leading cause of cancer and is the fourth - ranked cause of cancer death . in taiwan in 2010 , more than 7500 breast cancers were diagnosed , causing 1600 deaths . the health promotion administration , ministry of health and welfare ( taiwan ) , provides biennial breast cancer mammogram screening for women aged 4569 years and to women older than 40 with high risk . axillary lymph node metastasis ( alnm ) is the most important prognostic factor in patients with invasive breast cancer [ 26 ] . metastases to more than 6 nodes demonstrated the risk of distant metastasis . in recent years , the concept of sentinel lymph node sampling has greatly change surgical procedure in breast cancer . with the advance of sentinel lymph node sampling , it has rapidly replaced standard axillary lymph node dissection in patients who are clinically axillary node metastasis negative . pre - operative assessment of axillary condition has become an essential issue in surgical planning . the aim of this study was to identify tumor characteristics associated with axillary lymph node metastasis . we studied consecutive patients with invasive breast cancer who underwent surgical breast and axillary procedures in our hospital and determined the predictive factor of axillary nodal disease by structure equation model ( sem ) . we hope to improve cancer counseling and provide optimal surgical planning in high - risk patients pre - operatively . we conducted a review analysis of retrospective databases of patients diagnosed with invasive breast cancer at changhua christian hospital between january 2004 and january 2010 . this study was approved by the institutional review board and the ethics committee of the changhua christian hospital . the inclusion criteria were : ( 1 ) female breast cancers diagnosed and treated at our hospital , and ( 2 ) patients with complete medical information . patients were excluded from this study if they had ductal carcinoma in situ or if they were treated with neoadjuvant therapy , had bilateral breast cancers , or if clinical data were not complete . all patients underwent breast - conserving surgery with axillary lymph node dissection , sentinel lymph node sampling , or modified radical mastectomy . the clinical characteristics included age at diagnosis , tumor size , lymph node metastasis , histology grade , hormonal receptor ( estrogen receptor and progesterone receptor ) status , human epidermal growth factor receptor 2 ( her2 ) status , and the presence of lymphovascular invasion ( lvi ) . the quality of the cancer registry database was reviewed and approved by a committee of radiologists , oncologists , pathologists , and surgeons , as well as an epidemiologist with special expertise in breast cancer . the hormonal receptor status was tested based on standard immunostaining . for determination of her2 expression , immunohistochemical no or weak incomplete membrane staining ( 0 to 1 + ) was considered to be a negative result ; 2 + staining with complete membrane was considered as equivocal over - expression ; and 3 + staining was considered over - expression . patients with equivocal her2 over - expression were further assessed by fluorescence in situ hybridization method . data analysis was conducted with spss ( statistical package for social science ) 16.0 version . all p values were two - tailed . a p value less than 0.05 was considered as statistically significant . model fitting : chi - squared values were significant ( p<0.05 ) and the fit indices had value more than 0.9 , which indicated good model fit . we conducted a review analysis of retrospective databases of patients diagnosed with invasive breast cancer at changhua christian hospital between january 2004 and january 2010 . this study was approved by the institutional review board and the ethics committee of the changhua christian hospital . the inclusion criteria were : ( 1 ) female breast cancers diagnosed and treated at our hospital , and ( 2 ) patients with complete medical information . patients were excluded from this study if they had ductal carcinoma in situ or if they were treated with neoadjuvant therapy , had bilateral breast cancers , or if clinical data were not complete . all patients underwent breast - conserving surgery with axillary lymph node dissection , sentinel lymph node sampling , or modified radical mastectomy . the clinical characteristics included age at diagnosis , tumor size , lymph node metastasis , histology grade , hormonal receptor ( estrogen receptor and progesterone receptor ) status , human epidermal growth factor receptor 2 ( her2 ) status , and the presence of lymphovascular invasion ( lvi ) . the quality of the cancer registry database was reviewed and approved by a committee of radiologists , oncologists , pathologists , and surgeons , as well as an epidemiologist with special expertise in breast cancer . the hormonal receptor status was tested based on standard immunostaining . for determination of her2 expression , immunohistochemical no or weak incomplete membrane staining ( 0 to 1 + ) was considered to be a negative result ; 2 + staining with complete membrane was considered as equivocal over - expression ; and 3 + staining was considered over - expression . patients with equivocal her2 over - expression were further assessed by fluorescence in situ hybridization method . data analysis was conducted with spss ( statistical package for social science ) 16.0 version . all p values were two - tailed . a p value less than 0.05 was considered as statistically significant . model fitting : chi - squared values were significant ( p<0.05 ) and the fit indices had value more than 0.9 , which indicated good model fit . there were 1325 female patients include in this analysis , with an average age of 51.3 years old ( sd=11.2 ) . clinical features and tumor characteristics among women with breast cancer were analyzed according to the axillary lymph node status . there was no significant difference between 2 groups with regard to age or estrogen receptor . the distributions of tumor size , histology grade , progesterone receptor , and her2 within the 2 groups were significantly different . univariate cox regression analysis of factors associated with axillary lymph node metastases was performed ( table 2 ) . five variables were found to be significant in the univariate analysis . they included tumor size , progesterone receptor , her2 status , lvi , and histology grade . tumor size was highly associated with axillary nodal involvement and increasing size with an increasing risk of alnm ( odds ratio = 1.56 , 95% confidence interval : 1.423 to 1.708 , p<0.0001 ) . a poor histology grade ( odds ratio = 1.69 , p=0.0008 ) and presence of lvi ( odds ratio = 9.282 , p<0.0001 ) progesterone receptor positivity ( p=0.0032 ) and her2 over - expression ( p=0.002 ) were significantly associated with positive axillary status . a multivariate logistic regression model was applied and results are presented in table 2 . in this model , the data showed that tumor size , lvi , and histology grade were associated with statistically significant differences in axillary nodal metastases ( p<0.05 ) . the clinical and pathology factors , as well as tumor size , progesterone receptor , her2 , lvi , and histology grade , were highly correlated with alnm . to determine the causal relationship among those factors we used sem to test the proposed model because it showed the correlation among all the variables , as well as showing the direction of the path among all the variables . within the model , all variables , including clinical factors and pathological factors , were calculated in the model , including her2 , progesterone receptor , histology grade , tumor size , and lvi . the optimal pathway among the 4 factors in the final model was that her2 status might have influenced alnm through histology grade ( =0.18 ) , and then tumor size ( =0.16 ) . tumor size was highly relevant to lvi and influenced alnm through lvi ( =0.26 ) . the strongest predictor of alnm in the final model was lvi ( =0.46 ) , followed by histology grade , tumor size , and her2 status . lvi was the highest risk factor for alnm ( odds ratio = 9.282 ; 95% confidence interval : 7.21811.936 ) . complete axillary lymph node dissection is the criterion standard for assessment of metastases . with advancements in surgical technique , sentinel lymph node ( sln ) biopsy has become popular in clinical axillary node negative patients . sln biopsy reduces the morbidity and complications of axillary lymphatic drainage and major vessel and nerve injury . an increase in breast cancer incidence was noted in taiwan ; fortunately , these tumors were being found at a smaller size than before and usually with less invasive axillary involvement ; therefore , patients with small tumors might be benefit from sln biopsy . assessment of axillary status has become a key step in cancer counseling and pre - operative planning . clinical features and pathologic characteristics are important information in the pre - operative treatment of breast cancer . barth et al . found lvi , tumor size , and histology grade can be used to estimate the risk of alnm . among these characteristics , lvi is the strongest predictor of alnm [ 1523 ] . the odds ratio ( lvi presence vs. negative ) is high in extensive axillary nodal involvement . lvi also increases the incidence of isolated tumor cells in sln . in our study , lvi was the strongest predictor of alnm ( odds ratio = 8.2 ) , which is concordant with the other published series referenced above . patients with lvi are not good candidates for sln biopsy and should be treated more aggressively . our study demonstrates tumor size is the significant independent predictive factor in univariant and multivariant analysis . patients with tumor size more than 40 mm are 3 times more likely to have axillary nodal involvement ( table 1 ) . in agreement with previous publications , breast cancer with smaller tumors ( < 20 mm in our study ) might benefit from sentinel lymph node biopsy . in patients with moderate - sized tumors ( 2040 mm ) , the risk of alnm is relatively high and should be evaluated based on tumor characteristics and other examination tools because of the probability of need for a secondary axillary operation . in patients with large tumor size ( > 40 mm ) , complete axillary lymph node dissection is a preferred surgical procedure , based on the high probability of alnm . her2 is associated with higher aggressiveness in invasive breast cancer , and is accepted as an important prognostic factor in breast cancer patients . however , the association between her2 and alnm is not clearly identified . in our research , her2 is a significant predictor in univariant analysis ( odds ratio = 1.53 ) . we constructed an optimal predictive model to differentiate the clinical pathway of alnm and tumor characteristics . in the structure equation model ( also called the causal model ) , pathway analysis is a statistical method for representing causal relationships among the variables in the model . figure 1b shows the final model in this study . in this model , lvi , tumor size , and histology grade are important predictors of alnm , which is compatible with findings reported in previous publications [ 1528 ] . presence of an her2-positive tumor was identified as a predictor in the base of the model . her2 status might influence alnm through histology grade ( =0.18 ) , and then tumor size ( =0.16 ) . tumor size was highly relevant to lymphovascular invasion and influenced alnm through lvi ( =0.26 ) . to apply this model in clinical practice , we suggest that lvi , tumor size , histology grade , and her2 status are important predictors in assessment of axillary nodal status . if a patient is at high risk of alnm in pre - operative cancer counseling , other advanced examinations ( e.g. , breast mr ) and the possible need for a second axillary operation should be considered pre - operatively . recent data from the american college of surgeons oncology group ( acosog ) z0011 trial suggest that alnd may be omitted in selected patients with less than 2 positive slns . in this study , patient characteristics , including tumor size , er , pr status , lvi , histology grade , tumor type , and lymph nodes metastases , were similar between the 2 groups . alnd may no longer be required in patients with the following characteristics : tumors smaller than 5 cm ; fewer than 2 positive slns ; without extracapsular extension ; good patient acceptance ; completion of whole breast radiation ; and completion of adjuvant therapy , including hormonal , cytotoxic , or both . in this study , as in the acosog study , tumor size was related with lvi , and lvi is the strongest predictor of alnm . however , the aim of this study is different to that of the acosog study . if a patient fulfills the acosog study criteria , but with a larger tumor ( t2 ) and lvi , according to our results the risk of alnm is relatively higher this study might suggest another option in surgical procedures ( alnd or slnd ) and post - operative treatment ( e.g. , chemotherapy and hormonal therapy ) . the strongest predictor of alnm was lvi , followed by histology grade , tumor size , and her2 status . this model might help physicians to assess axillary nodal condition and determine appropriate surgical procedures .
backgroundtumor characteristics was sought to be related to axillary lymph node metastasis ( alnm ) , the paramount prognostic factor in patients with invasive breast cancer . 
 this study was aimed to identify the alnm - associated tumor characteristics and to determine the predictive clinical pathway.material/methodsdata from 1325 patients diagnosed with invasive breast cancer between january 2004 and january 2010 were retrospectively reviewed . the structure equation model ( sem ) 
 was used to build the predictive clinical pathway.resultsamong the factors found in the final model , the status of human epidermal growth factor receptor 2 is the primary influence on alnm through histology grade ( =0.18 ) , followed by tumor size ( =0.16 ) . 
 tumor size was highly relevant to lymphovascular invasion ( lvi ) and influenced alnm through lvi ( =0.26 ) , the strongest predictor of alnm in the final model ( =0.46 ) and the highest risk of alnm ( odds ratio=9.282 ; 95% confidence interval : 7.21811.936).conclusionsthe structure equation model presented the relation of these important predictors , and might help physicians to assess axillary nodal condition and appropriate surgical procedures .