Abstract
Purpose
Invasive micropapillary carcinoma (IMPC) of the breast is known for its high metastatic potential, but the definition of pure and mixed IMPC remains unclear.
This retrospective cohort study aims to investigate the prognostic significance of the micropapillary component ratio and the expression of critical molecules of epithelial–mesenchymal transition (EMT), including E-cadherin (E-cad), N-cadherin (N-cad), CD44s, and β-catenin (β-cat), in distinguishing between pure and mixed IMPCs.
Methods
We analyzed 100 cases of locally advanced IMPC between 2000 and 2018 and excluded patients who received neoadjuvant chemotherapy. Pure IMPC was defined as having a micropapillary component of over 90%. A comprehensive recording of prognostic parameters was conducted. The IMPC areas were analyzed using the immunohistochemical (IHC) staining method on the microarray set for pure and mixed IMPC patients. Pearson's chi-square, Fisher’s exact tests, Kaplan–Meier analysis, and Cox proportional hazards analysis were employed.
Results
The comparative survival analysis of the entire group, based on overall survival (OS) and disease-free survival (DFS), revealed no significant difference between the pure and mixed groups (P = 0.480, HR = 1.474 [0.502–4.325] and P = 0.390, HR = 1.587 [0.550–4.640], respectively). However, in the pure IMPC group, certain factors were found to be associated with a higher risk of short survival. These factors included skin involvement (P = 0.050), pT3&4 category (P = 0.006), a ratio of intraductal component (> 5%) (P = 0.032), and high-level expression of N-cad (P = 0.020). Notably, none of the risk factors identified for short OS in pure IMPC cases were observed as significant risks in mixed cases and vice versa. Furthermore, N-cad was identified as a poor prognostic marker for OS in pure IMPCs (P = 0.002).
Conclusion
The selection of a 90% ratio for classifying pure IMPCs revealed significant differences in certain molecular and prognostic parameters between pure and mixed groups. Notably, the involvement of N-cadherin in the epithelial–mesenchymal transition (EMT) process provided crucial insights for predicting OS and DFS while also distinguishing between the two groups. These findings strongly support the notion that the pure IMPC subgroup represents a distinct entity characterized by unique molecular characteristics and behavioral patterns.
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Introduction
According to global cancer statistics from 2020, breast cancer is the most commonly diagnosed cancer and the fifth leading cause of cancer-related deaths worldwide [1]. The rate of metastasis in breast carcinomas is higher in comparison to other cancer types, except for Malignant Melanoma [2]. Invasive micropapillary carcinoma (IMPC) of the breast is a distinct form of breast cancer characterized by tumor cells arranged in morula-like clusters or pseudopapillary structures without a fibrovascular core. These structures are found within empty stromal spaces [3,4,5]. The IMPC was first described in 1980 and later included in the WHO classification as IMPC, naming it for the breast by Siriaunkgul and Tavassoli in 1993 [5, 6].
It is widely acknowledged in the literature that IMPC has a high metastasis rate [6,7,8,3, 5, 3, 16]. This distinctive staining pattern is recognized as evidence of “reverse polarity.” IMPC can generally be categorized as either pure or mixed based on the proportion of the micropapillary component. However, despite varying reports in the literature regarding the prognosis differences between IMPC and IBC-NST [5,6,7, 3, 11, 12]. However, it has also been argued that the extent of the micropapillary component does not significantly affect prognosis, as any proportion of IMPC still exhibits a higher incidence of LVI and LNM [8, 10, 14, 19].
Furthermore, recent studies have suggested that the prognosis of IMPC may not be worse than that of invasive breast carcinoma of no special type (IBC NST), despite its clinically unfavorable characteristics [5, 17, 18]. A study considering a rate above 90% has reported a shorter DFS for pure IMPC than for the mixed group [18].
The issue of defining breast cancer subtypes has been effectively addressed in the 5th WHO classification. In this classification, mixed IBC-NST is described when the special type carcinoma component is present at a rate of 10–90%. However, the classification does not consider cases where the specific types account for less than 10%. Pure breast carcinoma, on the other hand, is diagnosed when the predominant component constitutes more than 90% [3, 4].
In our study, we propose the classification of cases based on the concept that pure IMPC can be considered as a distinct entity. Following the guideline the World Health Organization set fifth in 2019, we categorized our cases using a > 90% IMPC component threshold. The criterion of > 90% ratio for pure IMPC has been mentioned in a few studies, such as the ones conducted by Zekioğlu et al. and Küpik et al. [11, 18], where it was defined as the presence of a complete micropapillary component. However, the existing literature has not clearly established this ratio definition.
The incidence rate of IMPC cases within our cohort group was found to be 4.68%. This rate aligns with the range of 2% to 8% reported in previous literature, as documented [8, 11, 17, 35]. Furthermore, studies examining mixed invasive breast cancers containing IMPC components have reported the presence of micropapillary growth patterns in focal areas, with rates ranging from 3 to 8.4% [7, 8, 10, 14, 17]. Upon considering cases that were classified as pure IMPC in our work, we observed a prevalence rate of 0.6%, which is lower than the reported pure rates in the literature. It has been reported that if the IMPC component ratio exceeds 75%, the prevalence of IMPC among all cases of IBC-NST decreases to a range of 0.7% to 2%. [4, 5, 8, 11, 14, 17, 35].
Given the uncertainty surrounding the literature findings on the rate of micropapillary components and prognostic parameters, it is imperative to classify our discoveries and engage in a comprehensive discussion based on the existing body of literature.
Lymph node involvement, distant metastasis, OS, and DFS
In the comparative survival analysis conducted on the entire group, no significant difference was observed between the pure and mixed groups (Fig. 3a, b; Table 2). When comparing our findings, it would be useful to remember that it is necessary to keep in mind the differences in the ratio of micropapillary components in different studies. Our findings concerning OS and DFS align with the studies conducted by Ide et al. and Kaya et al. [10, 19]
In our cohort group, we observed an LVI rate of 57.3% and a rate of 77.2% for LNM when considering all cases of IMPC. These findings align with the rates reported in the literature, which range from 78.7 to 94.7% for LVI and 72.3 to 79.6% for LN metastasis [14, 19].
Specifically, when we analyzed pure cases of IMPC, the LVI rate was 62.7%, while it was 52.0% for mixed cases. These rates are consistent with previous studies that compared IMPC with IBC-NST [6, 7, 10, 11, 14, 15, 19]. Furthermore, when we compared our results with studies focusing on IDC cases, we found that the LVI rates in IMPC were higher [6, 7]. Importantly, we did not observe a significant difference in LVI rates between pure and mixed IMPC groups (Table 1) [14, 19].
In our group of locally advanced IMPC cases, an examination of those with more than four positive lymph nodes (LNM > 4) revealed a significant 3.9-fold increase in mortality rate (< 0.001). Additionally, cases with lymph node size exceeding 17 mm showed a 2.7-fold increase in mortality rate (P = 0.025). However, when considering these parameters, no significant effect on survival was observed in the pure IMPC group (P = 0.079, 0.582, respectively). These findings are consistent with the results reported by Lewis et al. [3, 5, 12, 13]. However, despite the increased N-cad expression and higher metastatic potential observed in pure IMPC, the expected life expectancy is not shorter compared to mixed IMPC.
In the survival analyses of E-cad, β-cat, and CD44 markers, as well as in both pure and mixed patient groups, no significant effect on survival was observed (Table 3). Furthermore, in comparative analyses, no significant differences were found in the expression levels of these biomarkers between the two groups (Table 1). These findings suggest that the lack of change in E-cad expression in tightly attached groups may be expected, indicating that IMPC cancer cells maintained their epithelial properties. Notably, the increase in N-cad expression observed in the Pure IMPC group aligns with previous findings in basal-like or high-grade breast cancers [22, 27].
The obtained results provide potential evidence indicating that the molecular mechanisms involved in the process of EMT may exhibit distinct arrangements in pure IMPC compared to mixed IMPC. No other studies conducted in a similar manner have been found in the existing literature. Nevertheless, these findings exhibit similarities to previous studies exploring EMT-related molecules and genetic biomarkers [16].
Despite numerous studies in the literature investigating prognostic differences between pure&mixed and aggressive clinical features of IMPC [10, 12,13,14, 18, 19], it remains unclear whether the presence of IMPC leads to reduced OS compared to IBC-NST [6, 7, 9, 11, 15, 17]. Recent evidence suggests a diminishing gap in prognosis between IMPC and IBC-NST, with reports indicating no differences in cell polarity and adhesion-related gene expressions [37].
To summarize the findings, skin involvement, low intraductal component, high pathological stage, and increased N-cad expression in the pure IMPC group were found to have a more detrimental impact on survival rates compared to the mixed group in survival analyses. Due to a low mortality rate in the pure group, no conclusive results could be obtained regarding the presence of pericapsular invasion, distant recurrence, and high clinical stage. Interestingly, the pure group showed no significant association with LVI, tumor size, number of involved lymph nodes, metastatic lymph node size, or HER2 positivity, which affected survival in the mixed group. Despite these differences, no distinct prognostic disparities were observed between the two groups.
The number of cases in our study is limited due to the accepted ratio for pure IMPC. In line with our study objectives, our findings support the notion that pure IMPC can be considered a distinct entity, characterized by molecular level differences and a tendency for more aggressive clinical behavior compared to the mixed group. Although we did not observe any differences between the two groups in terms of OS and DFS, this does not invalidate the hypothesis that these groups possess distinct characteristics.
It is important to emphasize that this study defines pure IMPC as 90% or more in composition, and these findings are noteworthy given the limited data available in the literature on this subject. The detection of increased N-cad expression in the locally advanced IMPC group, aiding in the differentiation between pure and mixed IMPC, lends support to the involvement of EMT mechanisms in the pure IMPC group. These findings will serve as a foundation for further studies.
We firmly believe that our study will significantly contribute to the existing literature by discussing the proportion of micropapillary components in pure and mixed IMPC cases, a rare subtype of breast carcinoma with high metastatic potential. Moreover, our research displayed these two groups’ molecular differences regarding some EMT mechanisms. Our study is qualified to lead the studies to be planned in extensive series.
Data availability
Inquiries about data availability should be directed to the corresponding author.
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Open access funding provided by the Scientific and Technological Research Council of Türkiye (TÜBİTAK). The participants provided the funding source for this study.
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The entire process performed in this study was conducted in accordance with the Declaration of Helsinki on the medical protocols, following the 1964 Helsinki Declaration and its subsequent amendments. The study was approved by The National Research Ethical Review Board (Reference Number: 2022/64, Date: April 6th, 2022). Each author participated in the research and contributed to the preparation of the article.
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Oz, O., Irmak Yuzuguldu, R., Yazici, A. et al. The differences between pure and mixed invasive micropapillary breast cancer: the epithelial–mesenchymal transition molecules and prognosis. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07384-w
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DOI: https://doi.org/10.1007/s10549-024-07384-w