Status of axillary lymph node is one of the most important and reliable prognostic indicators and is an essential factor to detect staging and treatment of cancer breast cancer [1].
Prediction of axillary nodal status before surgery is important for many reasons. It can prepare patients psychologically for ANLD if required in addition to it can assist with contingency planning for patients who desire immediate breast reconstruction. Accurate prediction of axillary lymph node status can avoid ANLD and its associated complications [7, 8].
The lymphatic drainage system of the breast is a rich plexus of vessels in the dermis and subareolar region suggesting that tumors located closer to the dermis and subareolar region are at high risk of lymphatic dissemination with high incidence of axillary nodal metastasis. The superficial lymphatic drainage described by Sappey, was located 3 mm depth from the skin [4, 9].
There are many clinical, histopathological, and molecular features have been related to the likelihood of axillary nodal metastases in patients with cancer breast [10-14]. Several nomograms have been initiated for the prediction of axillary lymph node metastasis, such as those developed at Memorial Sloan Kettering Cancer Center (MSKCC) and MD Anderson Cancer Center. These nomograms have specified several predictors of axillary nodal deposits such as: size of the tumor, age of the patient, anatomical location, lymphovascular invasion(LVI), histological type of the tumor, tumor grading , hormonal status of the tumor (ER and PR), in addition to focality and centricity of the tumor. These developed nomograms did not involve breast cancer distance from the skin and nipple –areola complex in their validation [5, 6, 15].
In our study, 50 patients of early breast cancer (T1, T2) were involved in which they underwent breast conserving surgery. (46 patients) or modified radical mastectomy (4 patients), and for all the distance between the tumor and the skin was measured by US and then by the pathologist . 33 patients (66%) were node negative and 17 patient (34%) were node positive. N1 patients were 8 (16%) and n2 patients were 9 patients (18%). ANLD was done for all patients and the mean number of excised lymph nodes was 21.78. This compares well with the previous studies like, Cunningham et al., study that includes 209 patients. Of these, 61 (29%) had axillary nodal metastasis, and 148 (71%) had no known metastases and the study of Ansari et al. in which data were collected on 233 early breast cancer patients, of which 177 (76%) were node negative and 56 (24%) were node positive [4, 5].
The mean age of the patients in our study was 51.87±6.48 for node negative patients, 46.78± 4.73 for n1 patient group, and 52.67±8.57 for n2 patient group. Eom et al., reported that the mean age for node negative patients is 51.07 group, and for node positive patients is 48.69 while Ansari et al., reported that the mean age of all patients was 66.2 years while the mean age for node negative and positive patients was 66.9 and 63.9, respectively [16, 5]. In our study there was no statistically significant difference between the age of the patient and the incidence of axillary nodal metastasis (p value = 0.165). Cunningham et al., reported similar result and declared there was no statistical significant variation between the age of the patient and the incidence of axillary lymph node metastasis, (p value = 0.399) [4].
In our study there was no significant statistical variation between the location of the tumor and incidence of axillary lymph node deposits, (p value =0.185). This compares well with the study of Cunningham et al., that revealed there was no significant statistical variation between the tumor location and incidence of axillary nodal metastasis, (p value =0.138) [4]. However some studies like Ansari et al., showed that there was a significant statistical variation between the tumor location and incidence of axillary lymph node metastasis, (p value =0.001).This may be explained by sample size difference [5].
In our study there was no statistically significant variation between size of the tumor and the incidence of axillary nodal metastasis, (p value = 0.758). Mean tumour size in our study was 2.65cm. Eom et al., reported that the mean tumor size for node negative and positive patients was 1.92 and 2.76 cm, respectively and this matching with our result that there was no statistically significant relation between the tumor size (T) and incidence of axillary lymph node metastasis, (p value =0.709) [16]. Other studies reported different data like Ansari et al., in which the mean tumor size for all patients was 1.34cm and it was 1.24cm and 1.68 for node negative and positive patients, respectively and showed significant statistical difference between the size of tumor and incidence of axillary nodal metastasis. Patients T1c and T2 stages were 7.7 and 8.6 times more likely to have positive nodes, respectively than patients with T1a and T1b stages, (p value =0.001)[5]. Cunningham et al., reported that tumors in the node positive patients tended to be larger (P value = 0.002) [4].
In our study no significant statistical difference was observed for ER, PR, or HER2 status and axillary LN positivity, (p value =0.267, 0.124, 0.542) respectively. This similar to the study reported by Eom et al., IN which there is no significant variations were observed for ER, PR, or HER2 statuses between patients with positive and negative axillary LN (p value =0.478, 0.534 , 0.422) respectively [16]. Ansari et al. showed also that there were no significant variation noted for ER, PR, or HER2 statuses between patients with positive and negative axillary nodes, (p values =1.0, 0.14 , 1.0) respectively [5].
In this study, it was found that there is a statistically significant correlation between the incidence of axillary LN metastasis and the breast cancer distance from the skin as measured by US, (p value ˂ 0.001),and the most accurate cut off level, was at 2.6 cm from the skin that achieved 100% sensitivity and 72.7% specificity. Also, it was noted that there was a statistically significant correlation between the incidence of axillary LN metastasis and breast cancer distance from the skin as measured by the pathological assessment, (p value ˂ 0.001),and the most accurate cut off level, was at 2.56cm from the skin that achieved 100% sensitivity and 78.6% specificity. It was obvious in our study that no patient with cancer deep to 2.6 cm from the skin had any positive axillary LNs. This means that 2.6 cm is the most likely cut off distance at which positive axillary LNs is to be predicted. Eom et al., reported that patients with cancer breast closer to the skin are more likely to develop positive axillary LNs than those with tumor far from the skin, (P value= 0.047) [16]. This also compared well with Ansari et al., who reported that closer proximity of the cancer to the skin was associated with positive axillary LNs and each 1 mm decrease in the cancer distance from the skin was associated with a 15% increased likelihood of lymph node metastasis [5]. Ansari et al., studied also the relationship between the size of the largest metastatic axillary LN and the breast cancer distance from the skin and reported that there was no statistically significant association between the size of the largest LN metastasis and distance from the skin, (p value= 0.72) and also there was no significant statistical correlation between the number of positive axillary LNs and the distance of the tumor from the skin, (P value =0.29) [5].
Our study revealed that there was a statistically significant relation between the cancer proximity from the skin as detected by U/S and progression of axillary LN metastasis from N1 to N2 stage, (p value ˂ 0.014) and the most accurate cut off distance of the tumor from the skin at which progression of from N1 to N2 stage was most likely to occur was at 2.25 cm that achieved 100% sensitivity and 60% Specificity. Regarding pathological measurements we also found that there was a significant statistical correlation between the cancer distance from the skin as measured by pathology, and axillary LN metastasis progression from N1 to N2 stage, (p value ˂ 0.001) and the most accurate cut off distance was between 2.04 cm that achieved 83.3% sensitivity and 100% specificity, and 2.17cm that achieved 86.3 % sensitivity and 66.7% specificity.
We also compared radiological measurement (U/S) with the pathological measurements of the breast cancer distance from the skin in order to clarify the accuracy of U/S in detecting this distance. We found that the mean distance between the breast cancer and the skin that was measured by U/S was 2.575cm, while the mean distance that was measured by pathology was 2.65cm. The mean difference between both measurements was only 0.075 mm. There was no significant statistical variation between the 2 methods of measurement, (p value = 0.647). The overall accuracy of the US in this test was 88.6%. This means that U/S is considered to be a reliable investigating method detection of the distance between the breast cancer and the surface of the skin.
There is some limitations of this study that have to be addressed including technical factors that could have affected the distance from the skin i.e the scan technique and ability of the ultrasonography physician to obtain the proper image through the image plane that most accurately evaluate proximity of the tumor to the skin surface which may result in induced ultrasound measurement error. Some tumors had poorly defined edges, and others had hyperechoic halos surrounding the tumor, ultrasound characteristics that make accurate measurements are more difficult to obtain.
The size of breast was not involved in this study, and the relation between tumor size and breast size may influence proximity to the skin, especially in smaller breasts and it is well known that distance from the skin is shorter in smaller breasts than in larger breasts; therefore, effect of breast size on nodal metastases cannot be excluded. Sample size of the patients was small which was also a limiting factor, so further prospective studies with larger patient numbers and a standardized US protocol would be required.
Ultimately, in the future, we may be looking to detect which patients are able to avoid any axillary surgery including sentinel lymph node biopsy (SLNB).