MBC is rarely seen in clinical practice, representing about 4% of all diagnosed invasive breast cancer, prevails mainly in postmenopausal women and usually affects older patients compared to other invasive breast cancer types [8] and is extremely rarely diagnosed in younger women under 35 years of age (1%) [4]. The mean age at diagnosis was 66 years compared to 60 years for NST patients. Considering MBC subtypes, PMBC affected younger women than MMBC (64.1 versus 69.7 years, respectively). Molecularly, MBC belongs most frequently to the luminal A subtype of breast cancer, which is characterized by the expression of genes typical for glandular cells that form the inner layer of normal ducts and lobules of the breast (inner luminal cells). Luminal A cancers show a strong expression of estrogen receptor (ER) genes and genes associated with the regulation of its function (LIV-1, HNF3A, XBP1, GATA3).
Compared to NST cancer, MBC presented with a higher T stage and hence by larger tumor size (2.19 cm vs 1.92 cm, respectively) which was also reported by Park et al. (2010) [9]. Nevertheless mucinous breast cancers are usually associated with smaller tumor size [2, 10, 11]. Although in our study MBC was presented with a larger tumor size than NST at the time of primary diagnosis, tumor size (T) appears not to be a significant independent factor associated with the severity of the disease because the mucin component comprises the majority of the tumor mass [12]. It stays in concordance with the American Joint Committee on Cancer (AJCC) staging system in which tumor size is not a meaningful factor in MBC [13]. It is presumed that in some cases a large amount of mucin is answerable for hiding the disease until an extensive size is reached [14]. Some studies report tumor size as a prognostic factor, a less valuable one than nodal involvement [2, 4, 15].
In the present study MBC patients presented a higher hormonal receptors expression (ER, PR) and also HER2 gene overexpression, which is untypical, but probably depends on a non-representative group of only four HER2-positive MBC cases reported. Previous studies also investigated that MBC was more often associated with steroid hormone receptors (ER, PR) expression, which is followed by the present results, in which the positive rates for ER and PR were 70.8% and 62.5% in MBC and 63.7% and 59.3% in NST, respectively [16, 17]. The contemporary guidelines do not recommend chemotherapy or anti-HER2 therapy for hormone receptor-positive MBC, regardless of its HER2 status. In the study by Gwark et al. (2019) 11.8% of all 471 cases of PMBC were HER2-positive. Group of hormone-positive, lymph node-negative and HER2-positive cases with tumor size exceeding 3 cm presented worse disease-free survival (DFS) rates, thus authors suggested a potential role of trastuzumab usage in this particular subgroup [15].
Considering MBC subtypes, PMBC shows a higher T stage, and slightly lower N stage and tumor grade (G1-G3) when compared to MMBC. PMBC seems also to express steroid hormones receptors (ER, PR) more often than MMBC, which is reversed in the case of HER2 expression. The results concerning nodal involvement stays in concordance with data provided by other studies, in which MMBC presented a greater capacity to metastasize [14, 18]. On the other hand, in the study by Marrazzo et al. (2020) it was MMBC, that demonstrated a greater mass and higher T stage. What is worth mentioning, the obtained results were not statistically significant [14]. As far as hormonal status is concerned, the expression is suspected to be similar in both studied cases [18], nonetheless, some studies suggest a higher incidence of luminal-A type among PMBC and higher incidence of luminal-B type among MMBC [14].
Diagnostic procedures pose some difficulties as MBC might resemble a benign lesion. The differential diagnosis could be challenging, because MBC typically presents as a round -shaped, well-circumscribed lesion, with misleading homogeneous isoechoic and normal posterior acoustic appearance at ultrasound examination [19]. At radiological diagnostics, MBC often shows non-mass mammographic findings, and even calcifications or focal asymmetries may be missed. PMBC demonstrate less suspicious imaging features than cases of MMBC and could be mistaken for non-malignant breast lesions [20].
Typically MBC is a slow-growing tumor and shows infrequently regional lymph node involvement, nonetheless a metastatic disease worsens the survival rates and is regarded as the most significant prognostic factor [18]. Regional lymph node involvement and lymphovascular invasion were observed in the present study in the vast minority of MBC cases (12.5%), compared to NST (40.2%) (p = 0.007) which is comparable with other authors reporting the mean lymph node metastatic disease in 15% of MBCs [21]. It is also important to distinguish MMBC from PMBC in terms of nodal involvement frequency (22.2% in MMBC versus 13.3% in PMBC), which was also observed in the previous studies, e.g. study by Marrazzo et al. (2020) which reported nodal involvement in 31.58% of MMBC and in 11.11% PMBC patients respectively [14]. Differentiation of PMBC from MMBC is also important since pure type has a better prognosis [22].
It is also significant to search for additional microscopic features, such as micropapillary patterns, related to significantly worse overall prognosis [23]. A lobular component present in the tumor structure is usually associated with microscopic features of cell polarization loss, decreased cell to cell adhesion and lack of neuroendocrine differentiation. Calcifications seen in conjunction with MBC often correspond to the invasive ductal component, and whenever visible, should prompt to search for this component. Also, neuroendocrine differentiation, defined by cytoplasmic argyrophilia and/or immunoreactivity to markers such as chromogranin, synaptophysin and neuronal-specific enolase, might be present within the tumor. Previous studies reported that the presence of neuroendocrine differentiation is associated with unfovorable 5-year and 10-year survival rates, overal survival and desease-free survival therefore neuroendocrine differentiantion is a poor prognostic indicator for mucnous breast cancer patients [24].
Bearing in mind the mucinous biology of this type of breast cancer, it is worth mentioning that overexpression of mucin 1 (MUC1) – a glycoprotein involved in the metastasis in various malignancies, was proved to worsen the prognosis of patients with breast cancer, including mucinous ones [25]. The possible mechanism might be correlated with the elevation of programmed death-ligand 1 (PD-L1) transcription by MUC1, and consequently, contributing to the immune escape of the aggressive forms of tumors [26]. The majority of PMBC overexpress the secreted mucin, mucin 2 (MUC2) [27]. Moreover, these cases are more resistant to chemotherapy that might be linked to the MUC2 overexpression [28]. Astashchanka et al. (2019) demonstrated that MUC2 plays an essential role in mediating the processes of apoptosis, proliferation, and metastasizing in breast cancer cells [28].
MBC has a specific molecular identity different from NST [29]. Moreover, a lower genetic instability is a characteristic MBC feature, compared to NST and lobular breast cancers as well [30]. It was reported, that almost all MBCs have a normal diploid stem line, unlike NST and lobular cancers. It has been proved, that aneuploidy correlates with higher tumor grade (G) and stage (TNM) [31].
MBC prognosis is more favorable compared to NST cancers. PMBC patients showed better overall survival (OS) and DFS rates than those for NST patients, but not significantly different from MMBC. MBC patients had a 5-year DFS rate of 91.6% (versus 70.2% of NST) and a 5-year OS of 95.8% (versus 75.3% of NST), that is similar to findings reported by Bea et al. (2011) [32] and Cao et al. (2012) [10]. Some studies have reported that MMBC and NST patients are characterized by a significantly poorer prognosis than those with PMBC [4, 33].
Limitations of this study encompass a limited number of patients that might affect the achieved results. It brings us to another drawback that is the fact of a single-center study. The juxtaposition of results obtained in the different clinical centers would present a broader view of the discussed subject. Nonetheless, we strongly believe that outcomes acquired in our center are a meaningful puzzle piece in the knowledge concerning MBC.