The ultrastructure tumor cells features in the breast cancer secondary edematous form
Authors: Lukashova O.P. , Bilyy О.М. , Pakhomov V.S. , Shutov S.V. , Teslenko І.М. 
Published: October 2024

Background. Secondary edematous form of breast cancer (SEF BC) is a rather rare type of cancer that occurs in no more than 2–6% of cases of BC, but causes 7–10% of deaths from BC. Characteristic for SЕF BC is the simultaneous course of oncological and inflammatory processes. At the same time, the inflammatory nature of SEF is determined not so much by classical inflammation as by lymphovascular embolism, which occurs due to the property of tumor stem cells to form aggregates. There is still no complete understanding of the mechanisms of pathogenesis and progression of SEF BC, which is necessary for the development of specific means of therapy for this aggressive form of cancer. Further study of the morphological, immune, molecular and genetic aspects of SЕF BC will allow solving this problem.
Purpose – study of the tumor cells (TC) structural and functional features in groups of patients with different molecular subtypes of breast cancer secondary-edematous form.
Materials and methods. In 40 patients with secondary edematous breast cancer, the receptor status of tumors and the index of proliferative activity of Ki-67 were determined immunohistochemically. Patients were divided into 6 groups: 1 – triple-negative cancer, «3-neg»; 2 – expression of only the human epidermal growth factor receptor, «HER-2»; 3 – positive reaction to estrogen receptors «RE»; 4 – co-expression of receptors to both female hormones «RЕ+RР»; 5 – co-expression of receptors for estrogen and epidermal growth factor, «RЕ+HER-2»; 6 – positive reaction to all studied receptors, «RЕ+RР+HER-2». We determined the ratio of receptor groups in the total pool of tumors and calculated the average data of proliferative activity according to the Ki-67 index in each group. Using standard methods of electron microscopy, the ultrastructure of tumor cells was studied and the frequency of tumors with different electron microscopic features in each receptor subtype was calculated. The results of the study were compared with previously obtained data for the usual ВС without signs of inflammation and edema (control series, 75 patients). Results were processed using descriptive statistics and non-parametric tests using the Biostat PC software package and nonparametric criterion of the most plausible assessment of reliability for small selections.
Results. The conducted study showed that carcinomas with the absence of hormone receptors predominate in patients with SЕF BC (groups: «3-neg» and «HER-2»). In total this account for 40% of all cases studied which is reliably higher in comparison with 18.7% аn ordinary BC. When studying the proliferative activity of tumors of patients with SEF, it was established that in tumors with «3-neg» and hormone-receptor status («RE» and «RE+RP»), the Ki-67 level does not statistically differ from the indicators of the control series, while in the group with HER-2-positive tumors, it drops significantly compared to the corresponding control (37.1 vs. 71.7%). A similar effect is observed in co-expression of HER-2 with hormone receptors when combining the «RE+HER-2» and «RE+RP +HER-2» groups (21.4 vs. 35.5%). Ultrastructural studies have shown that for the majority of non-luminal tumors of both forms of ВС («3-neg» and «HER-2») the main type of ТC is large poorly differentiated (PD) cells and only a small proportion is made up of cells with structural and functional features characteristic of ТC with luminal status that reflects the phenomena of intratumoral heterogeneity. Since, according to the literature, 3-negative and HER-2-positive cancer cells have a high level of expression of stem cell markers, it can be assumed that the large TCs are the carriers of such markers. However, at the morphological level, large stem cells in the usual ВС form cannot be distinguished from those present in SEF and capable of aggregation. Іn the «3-neg» group of SЕF ВС tumors, the frequency of large cells remains unchanged, while with HER-2, this indicator noticeably, although unreliably, decreases. However, when compared with the 3-neg subtype, this drop is significant (42.9 vs. 88.9%). Tumors of hormone receptor subtypes consist mainly from small TCs, united in ductal structures with a small admixture of large PD cells. In case of SEF BC with this receptor subtype, the frequency of tumors with large cells significantly increases from 17.9 in controls to 41.2%. It should be noted that a significant increase in this indicator is also observed in the entire tumor population, which, obviously, can be the reason for the development of embolism processes. Thus, the presence of tumor emboli was detected in individual capillary vessels of SЕF BC. In SЕF electron microscopic examination also showed a significant increase in the frequency of tumors whose TCs contain phagosomes, both in the entire tumor population and for tumors with luminal status, which may be associated with inflammation in the surrounding environment. In addition, the highest level of this indicator in the group with HER-2 receptor status, both in the usual form of BC and in the secondary-edematous form, in comparison with tumors of other receptor subtypes, draws attention.
Conclusions. It was confirmed that the same receptor subtypes are observed in both forms of BC in which the heterogeneity of the cell population is noted, as well as the predominance of the frequency of non-luminal subtypes in inflammatory BC in contrast to its conventional form. It has been established that the most characteristic feature of SEF BC, in contrast to non-edematous BC, is a significant increase in the frequency of large TCs with signs of stem cells both in tumors positive for hormone receptors and in the entire tumor population, which can be the reason for the aggregation of TCs and the development of edema processes. Tumor emboli are detected in the capillary vessels of SEF BC. It is possible that the targeted therapy of stem cells will be suitable for the treatment of this form of BC. Unusual properties of tumors with HER-2 expression in the conditions of SEF BC were also revealed, such as a significant decrease in proliferative activity and a drop in the frequency of tumors with large TCs, which may be a consequence of the action of natural inhibitors of this receptor during inflammatory processes and requires additional research.