The development of molecular biology of the breast cancer allowed the management to be personalized according to the molecular subtype. So identification of the breast cancer subtypes by ultrasonographic features could be of pivotal interest to the radiologist as it has a direct effect on the decision of the clinicians. As the axillary lymph node metastasis remains the most important prognostic factor in breast cancer and it has a considerable impact on the outcome of the patient and on the course of the disease, detection of the relationship of nodal metastasis to the molecular subtypes of the breast cancer is of great value [12].
Our data demonstrated that the main predictive SS of the LA subtype are spiculated or angular margin, post-acoustic shadowing, echogenic halo, absence of nodal metastasis, and unifocal mass. Similar data were described by Zhang et al. [13]. Two other studies done by Kim et al. and Ko et al. [14, 15] proved that echogenic halo and post-acoustic shadowing are more commonly seen in ER-positive/PR-negative/HER2-negative breast cancers that represent the LA subtype in our study. Similar to our results, Wiechmann et al. [16] reported that the LA subtype is less likely to be associated with multicentric or multifocal breast cancer and nodal metastasis than HER2 and LB subtypes, so when a breast mass encounters these sonographic features, the radiologist would be reminded that it has a minor chance to be LA subtype.
Jiang et al. [17] demonstrated that the absence of echogenic halo was a characteristic sign of the LB subtype using 2D ultrasound, and Yang et al. [18] reported that the absence of retraction phenomena and presence of calcification are predictive factor of LB subtype using 3D ultrasound; both results are inconsistent with our results that found the predictive SS of the LB subtype are the presence of nodal metastasis (OR = 9.54) and irregular tumor shape (OR = 3.65). Such discrepancy may be due to difference in the sample size of LB subtype between their study and ours. Similar to our results, Goldhirsch et al. [19] demonstrated that patients with LB subtype are more likely to associate with nodal metastasis.
As noted in our study that LA subtype followed by LB subtype shows the highest rate of low grade tumors (69% and 20%, respectively) and sonographically tend to have angular or spiculated margin, echogenic halo, and posterior shadowing. This was also described by Irshad et al. [20]. The mechanism of their formation could be attributed to the great desmoplastic reaction which strongly related to the low grade tumor [21]. As the absence of nodal metastasis is the strongest independent predictor of LA subtype (OR = 5.4) Thus, LN status could help to differentiate between these two subtypes that share certain SS as described, so its absence predicts with confidence the LA subtype, while its presence excludes LA subtype and increases the possibility of LB subtype.
In a study done by Seo et al. [22] found that the TN subtype is more likely than the other subtypes to have microlobulated margins, regular shape, and posterior acoustic enhancement and is less likely to have echogenic halo, spiculated margin, and calcifications. Similarly, in our study, the predictive SS of the TN subtype are the circumscribed or lobulated margin, oval or round shape, posterior enhancement or no posterior change, abrupt interface of the tumor boundary, and parallel orientation. Also, the absence of nodal metastases is a predictive SS of TN subtype that agrees with the study done by Yang et al. [23] who reported that the basal subtype (ER- and PR- and HER-2-) which represent the TN subtype in our study is less likely to show nodal involvement than the other subtypes.
The predictive SS of the HER2 subtype in our study are posterior acoustic enhancement or no posterior change, nodal metastases, calcification, unifocal mass, and abrupt interface of the mass boundary. Similar to our results, calcifications and post-acoustic enhancement were shown to be characteristics of the HER2 subtype by Yang et al. [23]. The HER2 subtype was also found to have more calcifications (80%) than the TN subtype (28%) and luminal (A or B) subtypes (41%) by mammography in the study done by Ko et al. [15]; this might be explained by the probability that HER2 breast cancers are more often accompanied by ductal carcinoma in situ. In agreement with our result, Yang et al. [23] observed higher frequency of nodal metastases in the HER2 followed by LB subtype (mostly HER2 positive) than in TN and LA subtype. Wiechmann et al. [16] found a higher frequency of multicentric or multifocal disease in HER2 subtype than other subtypes. On the contrary, our results showed that unifocal mass is one of the predictors SS of HER2 subtype. This could be explained by the big difference between the number of the patients of HER2 subtype in both studies (n = 16 in our study and n = 368 in Wiechman’s study).
This study demonstrated that most of the high grades were TN subtype followed by HER2 subtype (44% and 36%, respectively) and sonographically tend to have circumscribed or lobulated margin, posterior enhancement or no posterior change, and abrupt interface of the tumor boundary. This was also described by Kim et al. [24]. The mechanism of their formation attributed to the high mitotic rates and increased cellularity with less stromal and desmoplastic reaction.
Among the previous, predictive SS of HER2 subtype nodal metastasis are the strongest independent predictor of HER2 subtype (OR = 4.17). As TN and HER2 subtypes share certain SS, thus presence of nodal metastasis strongly predicts the HER2 subtype, and its absence excludes HER2 and predicts with great confidence the TN subtype.
There are some limitations of this study; small sample size in LB subtype may have limited the statistical significance of the data obtained. Using a combination of imaging modalities, including mammography, Doppler, and ultrasonographic elastography, may improve the diagnostic accuracy. There is no correlation between the presence of ductal carcinoma in situ and the molecular subtypes.