Immunohistochemical subtypes of the breast cancer in the ultrasound and clinical aspect – literature review

In imaging studies (US and MMG), this subtype often mimics benign lesions (no acoustic shadow effect behind the lesion and sparse vascularisation). In studies on US imaging features of TNBC subtypes, a characteristic pattern of features has been described. Yang et al. analysed 66 cases of TNBC and showed that microlobular margins occured significantly more often in ER+ and HER2+ subtypes⁽¹³⁾. This characterisation of the margins, according to the authors of the study, helps to avoid false negative cases. Another feature that characterised this subtype of BC was the enhancement effect behind the lesion, indicating a high cellularity of the lesions and high degree of histological malignancy. This was confirmed in another study, where the authors analysed 50 TNBC tumours, confirming the presence of microlobular margins and enhancement behind the lesion, and additionally noted their low echogenicity and lack of spicules⁽¹⁴⁾. The authors compared the deformability in SE of TNBC in relation to the other group of non-TNBC, and found no significant differences between the groups based on the 5-grade Tsukuba scale.

On the other hand, Li et al., analysing the material of 543 breast cancers (104 TNBC vs. 439 non-TNBC), showed that, statistically speaking, TNBC with higher histological malignancy (G3-grade 3) often present with benign lesions features. Therefore, they may be disqualified from biopsy, especially in young patients⁽¹⁵⁾. Authors of this study demonstrated the presence of the following features in TNBC: regular shape (OR = 1.8), no spiculated/angular margins (OR = 2.09), acoustic enhancement behind the lesion (2.49), and lack of calcifications (OR = 1.95), which are usually associated with benign lesions. Similarly, in a study published by Dogan et al. calcifications in TNBC were present in only 4.5% of cases⁽¹⁶⁾, whereas well-demarcated margins were identified in 32% of lesions. On the other hand, Ko et al. demonstrated the latter feature in 57% of the TNBC cases studied⁽¹⁷⁾. In such cases, SE seems to be a helpful tool in breast ultrasound diagnostics. Yeo et al. compared fibroadenomas (FA) with TNBC by ultrasound, including only lesions less than 2 cm in length⁽¹⁸⁾. SE proved to be the technique most accurately differentiating these two subtypes with the value of the area under the ROC curve (AUC = 0.869) compared to B-mode (AUC = 0.65) and CD (AUC = 0.576). The authors emphasised that with SE and CD, only two small (6 mm, 8 mm) TNBC cases were evaluated as false negative cases. In contrast, TNBC compared to other forms of BC, are characterised by similarly decreased deformability in the tumour as well as in the surrounding tissue. An example of a deformable TNBC with discrete non-circumscribed margins is shown in Fig. 1.

Fig. 1

Zhang L et al., in a study of 1000 BC, described this subtype (n = 125) using two independent patterns on US. One of them was characterised by an oval shape, lobular margins, and a lack of visible vessels. This pattern may mimic lesions that are classified as most likely benign BIRADS 3, and appear as fibroadenoma. In the second model, they were characterised by irregular shape, lobular margins, and lack of calcifications and vessels⁽¹⁹⁾. The presence of irregular shape allows this subgroup to be classified as BIRADS 4, and they will therefore undergo biopsy.

Overexpression of HER2 occurs in 15–25% of invasive BC and is associated with a poor prognosis. On the other hand, HER2+ cancers are characterised by a favourable response to targeted therapies⁽²⁰⁾. HER2 overexpression is associated with increased cell proliferation, cell survival, mobility and invasiveness, and neoangiogenesis due to increased production of vascular endothelial growth factor⁽²¹⁾. For this reason, HER2+ carcinomas have a different clinical course and show different features on imaging studies. Molecularly targeted therapy in combination with chemotherapy in patients with HER2 overexpression/ amplification in tumours greater than 1 cm reduces the risk of recurrence and mortality by approximately half, compared to chemotherapy alone, and translates into a 9% gain in 10-year OS^{(22, 23, 24)}.

In view of cardiotoxicity, anti-HER2 treatment is not used in combination with anthracyclines. In patients receiving sequential treatment, it begins with chemotherapy according to the AC (Adriamycin, Cyclophosphamide) regimen – 4 courses, then continues with trastuzumab with taxanes⁽²⁾. In special cases of low risk early BC with tumours <1 cm, encouraging results were obtained when taxanes were used with trastuzumab alone⁽²⁵⁾. In cases of preoperative treatment, in patients with poor prognostic factors, dual anti-HER2 blockade in combination with chemotherapy results in a higher percentage of pCR than that obtained by chemotherapy with trastuzumab only. The NeoSphere study demonstrated the superiority of the pertuzumab-trastuzumab combination with docetaxel compared to other anti-HER2 combinations with docetaxel. However, the study did not show any effect on disease-free survival (DFS)⁽²⁶⁾. Based on the pooled analysis (CTNeoBC), it seems that the achievement of pCR after preoperative treatment translates into a better prognosis for these patients, but the analysis covered the full spectrum of different types of BC⁽²⁷⁾.

A recently reported pooled analysis confirmed the association of pCR with long-term treatment outcomes, although traditional factors of poor prognosis are still relevant even after pCR has been obtained. Hence treatment with adjuvant anti-HER2 with trastuzumab⁽²⁸⁾ should be continued.

If pCR is not achieved after preoperative treatment, the use of trastuzumab emtansine (T-DM1) in adjuvant treatment reduces the relative risk of recurrence or death by half. However, this therapeutic option is not yet reimbursed in Poland⁽²⁹⁾.

Luminal breast cancer is an ER-positive type of tumour that accounts for almost 70% of all BC cases in Western populations⁽³⁶⁾. Luminal A tumours are characterised by high expression of the ER and PR (PR- greater than or equal to 20%), lack of HER2 overexpression or amplification, and Ki-67 proliferation index less than 20%. In this subtype, ER transcription factors activate genes whose expression is characteristic of the luminal epithelium that lines the mammary ducts⁽³⁷⁾. Additionally, these tumours show low expression of genes related to cell proliferation. Clinically, these cancers are mostly low grade, slow growing, and associated with the best prognosis. They are less sensitive to chemotherapy, and patients benefit more from primary hormone therapy. In general, hormone therapies are used as complementary treatments. In some cases, postmenopausal patients may receive NAC for 4–8 months prior to surgery or until a maximum response is achieved, and continued postoperatively. Aromatase inhibitors are more effective than tamoxifen in reducing tumour size and enabling breast-conserving surgery^{(38, 39, 40)}. A good response to preoperative hormone therapy, as expressed by a decrease in Ki67 or the preoperative prognostic index (PEPI), may, in combination with other clinical factors, guide the selection of patients with a favourable prognosis, not requiring adjuvant chemotherapy^{(41, 42, 43)}.

In contrast to the A subtype, the prognosis in cases of luminal B tumours is worse, and these tumours have a higher malignancy grade. They are characterised by the expression of ER, low level (<20%) or no expression of PR, the presence or absence of HER2 overexpression, and a higher fraction of Ki67 (>20%). Additionally, they have a high expression of genes related to proliferation, and lower expression of genes and proteins typical of luminal epithelium, such as PR and FOXA (but not of ER, which serves to distinguish luminal from non-luminal cancer types)^(44,45). Indications for chemotherapy should include both the risk of recurrence and patient preferences. It could be considered in the absence of response to hormonotherapy and in selected cases of luminal B BC, especially with a high proliferation index, as well as in patients with additional risk factors. In luminal B cancers overexpressing HER2, the principles for the treatment of HER2+ BC are applied, and after surgery, treatment with trastuzumab and hormonotherapy is continued⁽²⁾.

On imaging examinations, luminal A subtype show some features, the knowledge of which can improve the diagnostic process. On MMG, luminal A and B cancers are far more likely to present as spiculated lesions in comparison with other subtypes⁽⁴⁶⁾. Publications describing this subtype in US studies⁽¹⁹⁾ showed that luminal A cancers statistically more frequently show echogenic halo and acoustic shadow or no effect behind the lesion. An example of this type is presented in Fig. 3.

Fig. 3

Histologically, the echogenic halo corresponds to tumour cells infiltrating adipose tissue and interlacing connective tissue fibres. According to the literature, echogenic halomay correspond to very fine, densely packed spicules that are too small to be visualised accurately. A thick, fuzzy, hyperechoic halo may also be a manifestation of peritumoral oedema resulting from inflammation or lymphatic outflow obstruction; in such cases the halo is visible superficially between the tumour and the skin, following the physiological direction of lymph drainage⁽⁴⁷⁾.

Tumours showing acoustic shadow are characterised by increased desmoplasia. This is because the slow growth of the tumour allows the surrounding stroma to induce the mobilisation of fibroblasts and inflammatory cells, and the proliferation of vascular structures, which leads to fibrosis⁽¹⁴⁾. The acoustic shadow effect results from the reflection of the ultrasound beam or its attenuation by the neoplasm containing a significant connective/fibrous component⁽⁴⁷⁾. The shadow may not be visible behind the entire lesion but only part of it. In a 2019 paper by Liu H. et al.⁽⁴⁸⁾, it was shown that luminal A cancers are less likely to contain calcifications, rarely show blood flow, and display an intermediate wave propagation velocity value (SWV mean = 5.13 m/s) in dynamic SE, compared to other subtypes.

Luminal B subtype of BC on ultrasound is characterised by increased vascularity and lack of halo⁽¹⁹⁾. An example of this type is presented in Fig. 4. The lack of halo suggests a higher incidence of recurrence and a high histological grade⁽³²⁾. Subtypes with the presence of HER2 overexpression are also characterised by increased neovasularisation.

Fig. 4