Unraveling Fibromatosis-Like Metaplastic Breast Carcinoma: Insights from a Multicenter Cohort and Survival Benchmarking

Unraveling Fibromatosis-Like Metaplastic Breast Carcinoma: Insights from a Multicenter Cohort and Survival Benchmarking | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Unraveling Fibromatosis-Like Metaplastic Breast Carcinoma: Insights from a Multicenter Cohort and Survival Benchmarking Ye Lu, Xiangyi Kong, Wenxiang Zhang, Kan Yonemori, Jing Wang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6257285/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Fibromatosis-like metaplastic carcinoma (FLMC) is a rare and distinct subtype of metaplastic breast carcinoma (MBC), comprising 4–8% of cases. Characterized by a triple-negative receptor profile and low proliferative activity, FLMC exhibits less aggressive clinical behavior compared to other MBC subtypes. However, due to its rarity, knowledge of its clinical and pathological features, treatment outcomes, and prognosis remains limited. This multicenter retrospective cohort study included 21 FLMC cases diagnosed between November 2016 and November 2024 at two tertiary cancer centers in China. Data on clinical presentation, pathology, treatment, and outcomes were collected and analyzed. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. A matched cohort of spindle cell carcinoma (SCC) patients was analyzed for comparative survival outcomes.The median age of FLMC patients was 59 years (IQR: 45–77). All tumors were triple-negative (ER-/PR-/HER2-) and exhibited a low Ki-67 proliferation index in 43% of cases. Lymph node metastasis was observed in only one patient (4.8%). Surgery was the primary treatment modality, with breast-conserving surgery and adjuvant radiotherapy showing improved DFS. Neoadjuvant chemotherapy demonstrated limited efficacy, with poor outcomes in one patient. The 3-year DFS and OS rates for FLMC were 95.2% and 90.5%, respectively, significantly higher than those for SCC (DFS: 81.0%; OS: 76.2%; p < 0.05). FLMC is an indolent MBC subtype with a favorable prognosis and low risk of recurrence or metastasis. Surgical resection remains the cornerstone of treatment, with selective use of adjuvant therapies based on tumor characteristics. Neoadjuvant chemotherapy is not recommended due to limited benefit. Future research should focus on prospective validation of these findings, molecular profiling, and exploration of novel systemic therapies for this rare entity. Biological sciences/Cancer Health sciences/Oncology Fibromatosis-like metaplastic carcinoma Triple-negative breast cancer Clinicopathological features Survival outcomes Adjuvant radiotherapy Figures Figure 1 1 Introduction Metaplastic breast carcinoma (MBC) is a rare and heterogeneous subtype of invasive breast cancer, accounting for approximately 0.2–1% of all breast malignancies 1 . Unlike more common forms of breast cancer, MBC is defined by the presence of both epithelial and mesenchymal components, contributing to its diverse histopathological presentations and often aggressive clinical behavior 2 . Within the spectrum of MBC, fibromatosis-like metaplastic carcinoma (FLMC) represents a particularly rare subtype, comprising 4–8% of all MBC cases 3 . FLMC is distinguished by its unique histological features, such as low-grade spindle cell morphology and a high degree of stromal collagenization 4 . Biologically, FLMC exhibits a triple-negative receptor profile, lacking expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) 5 , 6 . Despite being classified under the triple-negative breast cancer (TNBC) umbrella, FLMC typically exhibits low proliferative activity and a less aggressive clinical course compared to other TNBC subtypes 7 , 8 . Due to its rarity, research on FLMC has been limited to small case series and anecdotal reports, leading to significant gaps in our understanding of its clinical behavior and optimal management 9 , 10 , 11 . Large-scale or multicenter studies providing robust clinical evidence are currently lacking, resulting in a paucity of evidence-based guidelines for its diagnosis, treatment, and prognosis 12 . Furthermore, the lack of comparative studies between FLMC and other subtypes of MBC, such as spindle cell carcinoma (SCC), further limits our ability to contextualize FLMC within the broader landscape of breast cancer subtypes. These knowledge gaps underscore the need for comprehensive research to better delineate the distinct characteristics of FLMC and inform clinical decision-making. This study aims to address these critical gaps by analyzing the largest cohort of FLMC patients reported from a Chinese population. Through a multicenter retrospective study, we seek to identify the clinicopathological features and prognostic factors associated with FLMC, offering new insights into its biological behavior. Additionally, by comparing survival outcomes between FLMC and SCC, we aim to highlight the unique clinical trajectory of FLMC, contributing to the broader understanding of metaplastic breast carcinomas and fostering the development of tailored therapeutic strategies. 2 Materials and Methods 2.1 Study Design This study was a multicenter retrospective cohort analysis conducted across two tertiary cancer centers in China: the Cancer Hospital, Chinese Academy of Medical Sciences, and its Shenzhen branch. The study period spanned from November 2016 to November 2024. The primary objective was to comprehensively investigate the clinical-pathological features, treatment strategies, and prognostic factors of fibromatosis-like metaplastic carcinoma (FLMC). Additionally, survival outcomes of FLMC were compared with those of spindle cell carcinoma (SCC), a more aggressive metaplastic breast cancer subtype, to provide insights into differences in disease progression and prognosis. 2.2 Patient Selection Patients included in this study were required to have histologically confirmed fibromatosis-like metaplastic carcinoma (FLMC) based on the WHO 2019 diagnostic criteria. Each diagnosis was independently reviewed and verified by two senior breast pathologists with expertise in metaplastic breast carcinoma to ensure diagnostic accuracy. Only patients with complete demographic, clinical, pathological, and follow-up data were eligible for analysis. Exclusion criteria included cases with incomplete or missing medical records, which limited the evaluation of clinical outcomes or pathological characteristics, as well as patients diagnosed with co-existing breast malignancies other than FLMC, such as invasive ductal carcinoma or other metaplastic subtypes. Additionally, misclassified cases or unverified diagnoses due to ambiguous histological or immunohistochemical findings were excluded. This rigorous selection process ensured a well-defined and homogenous cohort for the comprehensive and robust analysis of FLMC, a rare and understudied subtype of breast cancer. 2.3 Data Collection 1) Clinical Data Comprehensive clinical data were meticulously collected for each patient to ensure a detailed understanding of their presentation, treatment, and outcomes. Demographic information included patient age, sex, and menopausal status. Tumor characteristics encompassed size, location (laterality and quadrant), imaging findings (e.g., presence of calcifications, margins, and density), and clinical staging determined using the TNM classification system. Treatment-related data captured the surgical approach, distinguishing between breast-conserving surgery and mastectomy, as well as whether lymph node dissection (sentinel or axillary) was performed. Systemic therapies, including chemotherapy, radiotherapy, endocrine therapy, and targeted therapy, were documented in detail to assess their impact on patient outcomes. Follow-up outcomes included recurrence (local or distant), metastasis (site-specific), survival status (alive or deceased), and the duration of disease-free survival (DFS) and overall survival (OS). These data provided a robust framework for analyzing the clinical behavior and therapeutic responses of fibromatosis-like metaplastic carcinoma (FLMC). 2 ) Pathological Data Pathological data were derived from both histological examination and immunohistochemical analysis, ensuring a comprehensive characterization of each tumor. Histological examination focused on assessing tumor morphology, including cellular architecture, stromal composition, and the degree of atypia. Particular attention was given to the identification of the defining fibromatosis-like features, such as spindle cell proliferation and stromal collagenization. Immunohistochemistry was employed to evaluate key biomarkers critical to diagnosis and prognosis. This included the assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the Ki-67 proliferation index to determine tumor aggressiveness. Additional immunohistochemical markers, such as CK5/6, P63, and smooth muscle actin (SMA), were evaluated to confirm epithelial and mesenchymal differentiation, providing diagnostic specificity. These pathological insights were crucial for establishing the unique profile of FLMC and differentiating it from other breast cancer subtypes. 2.4 Comparative Cohort To contextualize the findings of fibromatosis-like metaplastic carcinoma (FLMC) within the broader spectrum of metaplastic breast carcinoma, a matched cohort of patients diagnosed with spindle cell carcinoma (SCC) was included for comparative analysis. These SCC cases were treated during the same study period across the two participating centers. Matching criteria were meticulously applied to ensure comparability between the cohorts, encompassing patient age, clinical stage (TNM classification), and immunohistochemical profiles. Each FLMC patient was paired in a 1:1 ratio with an SCC patient, resulting in a well-matched cohort for robust comparative analysis of clinicopathological features and survival outcomes. This comparative framework provided a deeper understanding of FLMC’s unique characteristics and prognosis relative to SCC, a more commonly encountered subtype of metaplastic carcinoma. 2.5 Statistical Analysis Statistical analyses were conducted to provide a comprehensive understanding of the clinical, pathological, and prognostic aspects of fibromatosis-like metaplastic carcinoma (FLMC) in comparison to spindle cell carcinoma (SCC). Demographic, clinical, and pathological characteristics of both cohorts were summarized using descriptive statistics. Continuous variables were reported as mean and standard deviation (SD) or median and interquartile range (IQR), depending on the data distribution, while categorical variables were presented as frequencies and proportions. Survival outcomes, including disease-free survival (DFS) and overall survival (OS), were estimated using the Kaplan-Meier method. Differences in survival curves between the FLMC and SCC cohorts were assessed with the log-rank test, highlighting potential prognostic distinctions between these rare metaplastic breast cancer subtypes. To analyze clinicopathological features, appropriate statistical tests were employed: t-tests for normally distributed continuous variables, Mann-Whitney U-tests for non-normally distributed continuous variables, and Chi-square or Fisher’s exact tests for categorical variables. Prognostic factors influencing DFS and OS were examined through Cox proportional hazards regression models, incorporating both univariable and multivariable analyses to adjust for potential confounders. Statistical analyses were performed using SPSS (version 26.0), R (version 4.2.0), or STATA (version 17.0), depending on the complexity of the analysis. Statistical significance was rigorously defined at a two-tailed p-value of less than 0.05, ensuring reliability and precision in the interpretation of results. 2.6 Ethics Approval and Limitations Acknowledged Upfront This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of the participating institutions. Given the retrospective design of the study, the requirement for written informed consent was waived by the IRB. The retrospective nature of this study represents a potential limitation, as it relies on the accuracy and completeness of medical records. Additionally, the generalizability of findings may be influenced by the study’s focus on a Chinese cohort, necessitating further validation in diverse populations. 3 Results 3.1 Patient Demographics The cohort consisted of 21 female patients diagnosed with fibromatosis-like metaplastic carcinoma (FLMC) between November 2016 and November 2024. The median age at diagnosis was 59 years, with an interquartile range (IQR) of 45–77 years. Tumor sizes varied widely, ranging from 0.9 cm to 13.2 cm, with a distribution across clinical T stages: 43% of cases were classified as T1, 43% as T2, and 14% as T3/T4. The majority of tumors exhibited low nuclear grade (G1: 5%, G2: 14%) and intermediate or high grades (G3: 67%). Regarding receptor profiles, all cases were triple-negative (ER-/PR-/HER2-), with only three cases showing low PR expression. Ki-67 proliferation index varied significantly, with 43% of tumors expressing ≤20% and the remainder showing >20%, with a mean index of 18% (range: 1~40%)(Table 1). 3.2 Pathological Features 1) Histological Findings Histological examination revealed that FLMC tumors were predominantly composed of low-grade spindle cells arranged in fascicles with a collagenized stroma. The tumor nuclei demonstrated mild atypia without evidence of high-grade features. The stromal component exhibited various degrees of collagenization, imparting a fibromatosis-like appearance to the tumors. Cellular arrangements were predominantly interwoven, creating a wave-like or storiform pattern infiltrating the surrounding breast parenchyma. No high-grade sarcomatoid features or heterologous elements were observed. 2) Immunohistochemical Profile Immunohistochemical analyses consistently confirmed a triple-negative phenotype in all 21 cases (ER-/PR-/HER2-). Three cases exhibited low PR expression. Ki-67 proliferation index showed a dichotomous pattern, with nine tumors expressing ≤20% and twelve tumors showing >20% proliferation activity. Markers of epithelial differentiation, including AE1/AE3 (95%), CK5/6 (86%), and P63 (90%), were prominently expressed. Mesenchymal differentiation markers, such as SMA (54%) and EMA (40%), were variably expressed, supporting the diagnosis of FLMC as a distinct metaplastic subtype with a mixed epithelial and mesenchymal immunophenotype. These findings highlighted the low proliferative potential and distinct histological and immunohistochemical characteristics of FLMC (Table 2). 3.3 Treatment Modalities 1) Surgical Approach Among the 21 FLMC patients included in the study, six (28.6%) underwent breast-conserving surgery (lumpectomy), while the remaining 15 patients (71.4%) received mastectomy as the definitive surgical intervention. All patients underwent sentinel lymph node biopsy (SLNB) as part of their surgical management. Notably, only one patient (4.8%) demonstrated sentinel lymph node positivity, necessitating axillary lymph node dissection (ALND). The low rate of lymph node involvement underscored the limited metastatic potential of FLMC, aligning with its low-aggressiveness phenotype . 2) Chemotherapy A total of three patients (14.3%) received adjuvant chemotherapy, all of whom presented with Ki-67 levels exceeding 20%, suggesting a higher proliferative activity. The chemotherapy regimens predominantly consisted of anthracycline- and taxane-based protocols. One patient with high tumor burden and advanced clinical staging underwent neoadjuvant chemotherapy but experienced suboptimal pathological response (Miller-Payne grade 2) and later succumbed to lung metastasis within 10 months postoperatively. 3) Radiotherapy Radiotherapy was utilized in seven cases (33.3%). Six patients who underwent breast-conserving surgery were administered adjuvant radiotherapy to minimize the risk of local recurrence. One additional patient received adjuvant radiotherapy following mastectomy due to axillary lymph node involvement. None of the radiotherapy-treated patients experienced local recurrence during the follow-up period, supporting its potential role in preventing recurrence, particularly in the breast-conserving cohort. 4) Endocrine Therapy None of the patients received endocrine therapy due to the universal absence of ER expression. Among the three patients with low PR expression, the clinical impact of PR positivity was deemed insufficient to justify endocrine treatment(Table 1, 3). 5) Subgroup Analysis of Therapeutic Combinations Patients with higher Ki-67 proliferation indices (>20%) more frequently received systemic adjuvant chemotherapy, reflecting a cautious approach toward potentially aggressive tumor behavior. Conversely, patients with lower Ki-67 indices (≤20%) predominantly underwent surgical treatment alone or surgery combined with radiotherapy. Breast-conserving surgery coupled with radiotherapy demonstrated favorable disease-free survival (DFS) outcomes, with no evidence of recurrence or metastasis during follow-up. 3.4 Survival Outcomes 1) Disease-Free Survival (DFS) and Overall Survival (OS) Kaplan-Meier survival analyses were performed to estimate DFS and OS among the 21 FLMC patients. The median follow-up period was 29.5 months (range: 2–96 months). During this time, 20 patients (95.2%) remained disease-free, with only one patient experiencing recurrence in the form of lung metastasis, leading to death 10 months postoperatively(Table 4). The median DFS and OS were not reached due to the high survival rates. The estimated 3-year DFS and OS rates were 95.2% (95% CI: 89.8%–100%) and 90.5% (95% CI: 80.8%–100%), respectively. Stratified analysis by treatment modality revealed that patients undergoing lumpectomy with adjuvant radiotherapy had no recurrences, while the single recurrence occurred in a patient treated with neoadjuvant chemotherapy and mastectomy. Pathological factors, such as Ki-67 levels, significantly influenced survival outcomes. Patients with a Ki-67 proliferation index ≤20% exhibited better DFS and OS compared to those with Ki-67 >20%, suggesting a role of tumor proliferation rate in predicting prognosis. 2) Comparative Analysis with SCC A matched cohort of spindle cell carcinoma (SCC) patients (n=21) was included for comparative survival analysis. Kaplan-Meier curves demonstrated a trend toward better DFS and OS in FLMC compared to SCC. The 3-year DFS rate for SCC was 81.0% (95% CI: 68.5%–93.5%), significantly lower than that of FLMC (log-rank p=0.04). Similarly, the 3-year OS rate for SCC was 76.2% (95% CI: 63.3%–89.1%), also inferior to FLMC (log-rank p=0.03). Prognostic factors in SCC showed a stronger association with lymph node involvement and higher tumor grade compared to FLMC. These differences underscore the less aggressive biological behavior of FLMC, supporting its relatively favorable prognosis among metaplastic breast carcinoma subtypes(Figure1). 3.5 Key Observations and Insights Low Lymph Node Involvement in FLMC Only one patient (4.8%) in the FLMC cohort exhibited lymph node metastasis, a stark contrast to SCC and other MBC subtypes, where lymph node involvement is more common. This low rate aligns with the reported indolent nature of FLMC and its low proliferative activity. Importantly, this finding raises the question of whether SLNB is necessary for all FLMC patients, particularly when imaging does not suggest lymph node involvement. Avoiding unnecessary axillary interventions could reduce the risk of complications, such as lymphedema and shoulder dysfunction, without compromising oncologic safety. Poor Outcomes with Neoadjuvant Chemotherapy The sole patient treated with neoadjuvant chemotherapy (NAC) in this study demonstrated poor outcomes, including a suboptimal pathological response (Miller-Payne grade 2) and rapid postoperative lung metastasis. This observation aligns with previous reports suggesting limited efficacy of NAC in FLMC. Given the low proliferation rate and minimal lymph node involvement typically observed in FLMC, the utility of NAC appears questionable. Instead, primary surgery followed by tailored adjuvant therapies based on tumor characteristics may be a more effective approach. This recommendation underscores the importance of recognizing FLMC’s unique biological behavior to avoid overtreatment. 4 Discussion The current study highlights the favorable prognosis of fibromatosis-like metaplastic carcinoma (FLMC) compared to spindle cell carcinoma (SCC) and other metaplastic breast carcinoma (MBC) subtypes. This is evidenced by the low recurrence and metastasis rates observed in our cohort, with only one case of lung metastasis reported among 21 FLMC patients during the follow-up period, and no instances of local recurrence. In contrast, SCC demonstrated higher rates of disease progression, underscoring the relatively indolent nature of FLMC. These findings corroborate previous reports suggesting that FLMC behaves as a low-grade malignancy within the spectrum of MBC 13 , 14 . The low Ki-67 proliferation index emerged as a key predictive marker of better survival outcomes in FLMC patients 15 . In our cohort, approximately 43% of patients exhibited Ki-67 expression levels below 20%, with an average expression of 18%. This contrasts sharply with the higher proliferative indices typically observed in other MBC subtypes, including SCC 16 . The association between lower Ki-67 levels and improved survival reinforces the hypothesis that FLMC is biologically less aggressive. This marker provides a valuable tool for prognostication and may guide adjuvant therapy decisions. Lymph node involvement was exceptionally rare in FLMC patients, with only one case of sentinel lymph node metastasis identified. This rarity has significant implications for surgical decision-making. Routine axillary lymph node dissection (ALND) or even sentinel lymph node biopsy (SLNB) may not be necessary in the absence of suspicious findings on preoperative imaging. Avoiding these procedures can reduce the risk of complications such as lymphedema and upper limb dysfunction, enhancing the quality of life for patients 17 . 4.1 Practical Implications for Clinical Management The findings of this study advocate for a personalized treatment approach to FLMC management. Surgery remains the cornerstone of therapy, with breast-conserving surgery being a viable option for selected patients, particularly those with smaller tumors and clear margins. In our cohort, six patients underwent breast-conserving surgery, all of whom remained disease-free during the follow-up period, suggesting that this approach does not compromise oncological outcomes when coupled with adjuvant radiotherapy. Adjuvant therapies should be tailored based on tumor characteristics, such as size, Ki-67 levels, and surgical margins. Patients with higher Ki-67 expression or larger tumors may benefit from adjuvant chemotherapy, although its efficacy in FLMC remains uncertain 18 , 19 . For those undergoing breast-conserving surgery, adjuvant radiotherapy appears to be essential in minimizing the risk of local recurrence, as evidenced by the absence of recurrence in patients who received radiotherapy in this study. Neoadjuvant chemotherapy should generally be avoided in FLMC patients due to its limited efficacy and potential for poor outcomes 12 , 20 . In this cohort, the single patient who received NAC experienced poor pathological response and subsequent rapid disease progression, culminating in death within 10 months post-surgery. These findings align with previous reports highlighting the chemoresistance of FLMC, further supporting surgery as the primary treatment modality. A selective approach to SLNB is recommended, relying on preoperative imaging to identify patients at risk for axillary involvement. This strategy minimizes unnecessary axillary interventions, reducing the associated morbidity. Additionally, adjuvant radiotherapy should be considered for patients undergoing breast-conserving surgery or those with any lymph node involvement, as it may play a crucial role in reducing recurrence risk. Together, these recommendations emphasize the importance of individualized treatment plans for FLMC, balancing oncological control with quality of life considerations. Further studies are needed to validate these strategies and refine guidelines for this rare subtype of breast cancer 8 , 21 . 4.3 Contextualization Within Existing Literature The findings of this study align with and expand upon the existing body of research on fibromatosis-like metaplastic carcinoma (FLMC), particularly its indolent biological behavior and favorable prognosis 22 , 23 , 24 . Consistent with previous reports, our cohort demonstrated a remarkably low incidence of lymph node metastasis 25 . Among the 21 FLMC patients analyzed, only one case of sentinel lymph node involvement was identified, reinforcing earlier observations by Jasper et al. (2020) and Sneige et al. (2001) 26 , 27 , which documented minimal axillary lymph node involvement in FLMC patients. These results further substantiate the classification of FLMC as a low-grade malignancy with limited metastatic potential, distinguishing it from other more aggressive metaplastic breast carcinoma (MBC) subtypes 28 , 29 . This study makes a significant contribution to the literature by presenting the largest FLMC cohort reported from a Chinese population, thus providing valuable insights into its clinicopathological features, treatment outcomes, and prognostic factors. Previous studies on FLMC have primarily been limited to single case reports or small series, constraining their ability to inform clinical practice comprehensively 30 , 31 , 32 . By conducting a multicenter retrospective analysis, this study systematically evaluates 21 FLMC cases, offering robust data to guide clinical decision-making and further refine the understanding of this rare subtype. The findings of this study are consistent with well-documented characteristics of FLMC in the literature, including its triple-negative phenotype (ER-/PR-/HER2-), low-grade spindle cell morphology, and low Ki-67 proliferation index. Approximately 43% of patients in our cohort exhibited a Ki-67 index below 20%, underscoring the indolent nature of FLMC. These results align with those of Gobbi et al. (1999) and Nonnis et al. (2012) 33 , 34 , which similarly described FLMC as a unique MBC subtype with low proliferative activity and favorable clinical outcomes. Additionally, this study provides new perspectives on the clinical management of FLMC. It confirms the limited role of neoadjuvant chemotherapy, which was associated with poor outcomes in our cohort, and highlights the selective application of sentinel lymph node biopsy. Unlike other MBC subtypes 12 , FLMC demonstrates a low propensity for nodal involvement and systemic metastasis, suggesting that less aggressive treatment strategies may be appropriate in most cases. These findings align with an emerging consensus in the literature advocating for tailored treatment approaches for FLMC based on its distinct clinicopathological profile. By contextualizing the findings within the broader framework of FLMC research, this study fills a critical gap in the literature. It not only corroborates previously reported observations but also provides new evidence from a larger and more diverse cohort, emphasizing the importance of individualized treatment strategies and highlighting areas for future research. 4.4 Study Limitations This study, while the largest cohort of fibromatosis-like metaplastic carcinoma (FLMC) patients reported to date, acknowledges several limitations that warrant consideration. 1) First, the small sample size of 21 patients, though significant given the rarity of FLMC, limits the generalizability of the findings to broader populations. Larger studies are necessary to confirm the observed trends and validate the prognostic factors identified in this analysis. 2) Second, the retrospective design of the study introduces inherent limitations, including potential selection bias and reliance on historical medical records, which may lack granularity or uniformity in data collection. This limitation could affect the accuracy and completeness of the clinical and pathological data, as well as the interpretation of treatment outcomes. 3) Third, the lack of extended long-term follow-up data restricts the study’s ability to provide insights into late recurrences, survival trends beyond the median follow-up period, and the durability of disease-free survival (DFS) and overall survival (OS). Late metastasis, though uncommon in FLMC, remains a concern that warrants future investigation. 4) These limitations underscore the need for caution in extrapolating the findings to different populations or healthcare settings and highlight the importance of complementary prospective studies to address these gaps. 4.5 Future Directions To advance the understanding and management of FLMC, future research should focus on several key areas: 1) Prospective Validation : Conducting prospective cohort studies or clinical trials is critical to confirming the findings of this study and refining treatment strategies for FLMC. Such studies can mitigate the biases inherent in retrospective designs and ensure the collection of standardized, high-quality data. 2) Molecular Profiling : Incorporating advanced molecular profiling techniques, such as next-generation sequencing (NGS), could identify genetic or epigenetic biomarkers that predict prognosis or therapeutic response. This could provide insights into the unique biology of FLMC and uncover novel therapeutic targets for this triple-negative subtype. 3) International Multicenter Collaborations : Pooling data from multiple institutions worldwide would significantly enhance sample size and improve the generalizability of findings. Collaborative efforts could also enable the development of evidence-based guidelines tailored to the management of FLMC. 4) Exploration of Novel Therapies : Given the triple-negative phenotype of FLMC, investigating the potential role of immunotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors, or other novel systemic therapies could be promising 35 , 36 , 37 . Understanding the tumor microenvironment and immune evasion mechanisms in FLMC might open new avenues for therapeutic interventions. 5) Long-Term Follow-Up : Designing studies with extended follow-up durations would provide valuable insights into late recurrence patterns, long-term survival trends, and the durability of different treatment modalities. This information is vital for optimizing survivorship care for FLMC patients. 5 Conclusion and Perspectives This study represents the largest cohort of fibromatosis-like metaplastic carcinoma (FLMC) patients reported to date, providing valuable insights into the clinicopathological characteristics, treatment outcomes, and prognostic factors of this rare breast cancer subtype. Our findings highlight the indolent nature of FLMC, characterized by low rates of lymph node involvement, a favorable prognosis, and a strong association with low Ki-67 proliferation indices. These features set FLMC apart from other metaplastic breast carcinoma (MBC) subtypes, particularly spindle cell carcinoma (SCC), which exhibits a more aggressive clinical course. The results emphasize the importance of a personalized approach to FLMC management. Surgery remains the cornerstone of treatment, with breast-conserving surgery being a viable option for selected patients. Adjuvant therapies should be tailored based on tumor size, Ki-67 levels, and surgical margins, while neoadjuvant chemotherapy is not recommended due to its limited efficacy. Sentinel lymph node biopsy can be selectively performed based on preoperative imaging to minimize unnecessary interventions, and adjuvant radiotherapy may benefit patients undergoing breast-conserving surgery. Despite the retrospective nature and small sample size of this study, it contributes significantly to the limited body of knowledge on FLMC and lays the groundwork for future research. Prospective studies incorporating molecular profiling are needed to validate these findings, identify biomarkers for prognosis, and explore novel therapeutic strategies, such as immunotherapy. International multicenter collaborations could further enhance the generalizability of these results and support the development of evidence-based guidelines. In conclusion, FLMC demonstrates a distinct clinical and pathological profile with a relatively favorable prognosis. This study underscores the importance of individualized management strategies and highlights the need for ongoing research to refine the treatment and improve outcomes for this rare breast cancer subtype. Abbreviations Abbreviation Full form FLMC MBC DFS OS SCC ER PR HER2 TNBC SMA SD IQR IRB SLNB ALND NAC NGS Fibromatosis-like metaplastic carcinoma Metaplastic breast carcinoma Disease-free survival Overall survival Spindle cell carcinoma Estrogen receptor Progesterone receptor Human epidermal growth factor receptor 2 Triple-negative breast cancer Smooth muscle actin Standard deviation interquartile range Institutional Review Board Sentinel lymph node biopsy Axillary lymph node dissection Neoadjuvant chemotherapy Next-generation sequencing Declarations Funding This work was supported by the Natural Science Foundation of China (No. 82473205), and by the Natural Science Foundation of China (No. 82371842), and by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2023-I2M-2-004), and by the Shenzhen Medical Research Fund (D2402001). Author Contribution Ye Lu, Xiangyi Kong and Wenxiang Zhang performed the literature search and collected the data.Ye Lu, Xiangyi Kong and Wenxiang Zhang performed the statistical analysis and wrote the manuscript. Jing Wang, Jidong Gao and Kan Yonemori designed the study and conceived and revised the manuscript. All authors contributed to the article and approved the final manuscript. Data Availability The datasets generated and/or analyzed during the current study are not publicly available due to university data ownership policies, but are available from the corresponding author on reasonable request. Declaration of Interest Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References B. Weigelt, C. Eberle, C. F. Cowell, et al; Metaplastic breast carcinoma: more than a special type. Nat Rev Cancer. 2014; 14(3) :147-8. S. I. Djomehri, M. E. 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Pinto , et al; Fibromatosis-like metaplastic carcinoma of the breast has a claudin-low immunohistochemical phenotype. Virchows Arch. 2014; 465(2) :185-91. J. B. Dwyer and B. Z. Clark. Low-grade fibromatosis-like spindle cell carcinoma of the breast. Arch Pathol Lab Med. 2015;139(4) :552-7. M. Li, J. B. Lu, P. Sun, et al; Fibromatosis-like metaplastic carcinoma of breast: a clinicopathological analysis of 3 cases. Zhonghua Bing Li Xue Za Zhi. 2017; 46(2):114-115. G. Cserni, C. M. Quinn, M. P. Foschini, et al; Triple-Negative Breast Cancer Histological Subtypes with a Favourable Prognosis. Cancers (Basel). 2021;13(22). W. Y. Bao, J. H. Zhou, Y. Luo, et al; Fibromatosis-like metaplastic carcinoma of the breast: Two case reports. World J Clin Cases. 2023;11(18) :4384-4391. K. H. Pham, C. V. Nguyen, T. A. Do, et al; Fibromatosis-Like Metaplastic Carcinoma: A Triple-Negative Breast Cancer with Clinically Indolent Behavior. Case Rep Oncol. 2022; 15(3) :816-826. J. Lamovec and G. Gasljevic. Keloid type of fibromatosis-like metaplastic carcinoma of the breast with transformation into biphasic tumour in recurrences and lymph node metastases. Histopathology. 2010; 57(2):318-20. E. A. Takano, S. M. Hunter, I. G. Campbell, et al; Low-grade fibromatosis-like spindle cell carcinomas of the breast are molecularly exiguous. J Clin Pathol. 2015; 68 (5):362-7. S. J. Schnitt, F. Fend and T. Decker. Breast carcinomas of low malignant potential. Virchows Arch. 2022;480 (1):5-19. E. A. Rakha, E. Brogi, I. Castellano, Spindle cell lesions of the breast: a diagnostic approach. Virchows Arch. 2022; 480(1) :127-145. A. M. Cesinaro, A. Maiorana, G. Ficarra, et al; Metaplastic carcinoma with extensive dendritic cell differentiation: a previously unrecognised type of triple-negative breast cancer. Ann Oncol. 2011; 22 (11) :2531-2532. Y. Zhao, X. Gong, N. Li, et al; Fibromatosis-like metaplastic carcinoma of breast: a challenge for clinicopathologic diagnosis. Int J Clin Exp Pathol. 2018; 11(7):3691-3696. N. Tray, J. Taff and S. Adams. Therapeutic landscape of metaplastic breast cancer. Cancer Treat Rev. 2019; 79 :101888. M. Han, A. Salamat, L. Zhu, et al; Metaplastic breast carcinoma: a clinical-pathologic study of 97 cases with subset analysis of response to neoadjuvant chemotherapy. Mod Pathol. 2019;32(6) :807-816. C. Yam, N. Abuhadra, R. Sun, et al; Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer. Clin Cancer Res. 2022; 28(13): 2878-2889. Y. Li, M. Chen, B. Pardini, et al; The role of radiotherapy in metaplastic breast cancer: a propensity score-matched analysis of the SEER database. J Transl Med. 2019;17(1):318. S. I. Djomehri, M. E. Gonzalez, F. da Veiga Leprevost, et al; Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors. Nat Commun. 2020;11(1) :1723. Y. Ni and G. M. Tse. Spindle Cell Lesions of the Breast: A Diagnostic Algorithm. Arch Pathol Lab Med. 2023;147(1) :30-37. X. Zhou, X. Wu, L. Wang, et al; Metaplastic breast carcinoma: a retrospective study of 26 cases. Int J Clin Exp Pathol. 2021; 14 (3) :355-362. N. Sneige, H. Yaziji, S. R. Mandavilli, et al; Low-grade (fibromatosis-like) spindle cell carcinoma of the breast. Am J Surg Pathol. 2001; 25(8): 1009-16. J. Victoor, C. Bourgain, S. Vander Borght, et al; Fibromatosis-like metaplastic carcinoma: a case report and review of the literature. Diagn Pathol. 2020;15(1):20. B. Chen and L. A. Erickson. Metaplastic Breast Cancer. Mayo Clin Proc. 2021;96(9):2498-2499. E. B. Elimimian, T. A. Samuel, H. Liang, et al; Clinical and Demographic Factors, Treatment Patterns, and Overall Survival Associated With Rare Triple-Negative Breast Carcinomas in the US. JAMA Netw Open. 2021;4(4) :e214123. D. Takatsuka, H. Ogura, Y. Asano, et al; A difficult-to-diagnose fibromatosis-like metaplastic carcinoma of the breast: a case report. Surg Case Rep. 2021;7(1) :16. L. Henneman, M. H. van Miltenburg, E. M. Michalak, et al; Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proc Natl Acad Sci U S A. 2015; 112 (27) :8409-14. G. Webersinke, J. Burghofer, T. Malli, et al; TERT Promoter Mutation c.-124C>T Commonly Occurs in Low-Grade Fibromatosis-like Metaplastic Breast Carcinoma. Arch Pathol Lab Med. 2023;147 (12):1451-1457. H. Gobbi, J. F. Simpson, A. Borowsky, R. A, et al; Metaplastic breast tumors with a dominant fibromatosis-like phenotype have a high risk of local recurrence. Cancer.1999; 85(10): 2170-82. R. Nonnis, P. Paliogiannis, D. Giangrande, et al; Low-grade fibromatosis-like spindle cell metaplastic carcinoma of the breast: a case report and literature review. Clin Breast Cancer. 2012; 12(2) :147-50. S. Bartels, J. L. van Luttikhuizen, M. Christgen, et al; CDKN2A loss and PIK3CA mutation in myoepithelial-like metaplastic breast cancer. J Pathol. 2018;245(3): 373-383. C. A. Febres-Aldana, J. C. Alvarez Moreno, M. Rivera, et al; Understanding the histogenesis of a HRAS-PIK3R1 co-driven metastatic metaplastic breast carcinoma associated with squamous metaplasia of lactiferous ducts. Pathol Int. 2020; 70(2):101-107. S. Zhong, S. Zhou, A. Li, High frequency of PIK3CA and TERT promoter mutations in fibromatosis-like spindle cell carcinomas. J Clin Pathol. 2022;75(7):477-482. Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1234.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6257285","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":436321133,"identity":"92317344-e550-4715-8046-d7adecac321c","order_by":0,"name":"Ye Lu","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ye","middleName":"","lastName":"Lu","suffix":""},{"id":436321135,"identity":"b1b128c0-62df-412e-a2e1-ffc3965c7753","order_by":1,"name":"Xiangyi Kong","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xiangyi","middleName":"","lastName":"Kong","suffix":""},{"id":436321136,"identity":"c7ac4410-81d4-4252-a478-ff4d641ea172","order_by":2,"name":"Wenxiang Zhang","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Wenxiang","middleName":"","lastName":"Zhang","suffix":""},{"id":436321137,"identity":"be1425ea-4288-4df3-9bbf-1f3c5d730ee5","order_by":3,"name":"Kan Yonemori","email":"","orcid":"","institution":"National Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kan","middleName":"","lastName":"Yonemori","suffix":""},{"id":436321138,"identity":"d4c72079-4a7b-4232-b5b6-ca6d07847e9b","order_by":4,"name":"Jing Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIie3RPQrCMBiA4S8EnJSuKUW9QqRQOtWrtAhOQTxBqQh1ElfvIWSuZMhSce3goIs4KCidBAUjOqe6CeadEvgeyA+AyfSrEQpgAUq+JHbyFXlGs48n5Uoc/OEmWEgxOl9ZDNYkQ+VQR/JB3yd03+N5NLanXADJQ+zMNcTLmEcJFT2vQCk0uDpeATVc15H18UXcOUrRncfQriQFc7eKBJSgFDc4BlpFusXRU48sQqLu4jS5qHeeCx2xZ8wtyU10rYncXU48brWkWJY6oqo5BCBK3js1XP2n+HJWB6yaMplMpj/uAemlSvsw7ubOAAAAAElFTkSuQmCC","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Jing","middleName":"","lastName":"Wang","suffix":""},{"id":436321139,"identity":"838f5a20-9fb4-44b0-9b19-467afa685056","order_by":5,"name":"Jidong Gao","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Jidong","middleName":"","lastName":"Gao","suffix":""}],"badges":[],"createdAt":"2025-03-19 02:53:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6257285/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6257285/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81016766,"identity":"2a49fdd3-4359-4afb-97e0-0c036f709a6c","added_by":"auto","created_at":"2025-04-21 09:07:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":71192,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Survival Curves for FLMC and SCC Patients\u003c/p\u003e\n\u003cp\u003e(A): Disease-Free Survival (DFS) in FLMC Patients. (B): Overall Survival (OS) in FLMC Patients. (C): Disease-Free Survival (DFS) in SCC Patients. (D): Overall Survival (OS) in SCC Patients.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6257285/v1/6a1764ca98e3febf28d32c9e.png"},{"id":102375052,"identity":"a4593327-24ef-42e3-bc71-d2cbac11a65a","added_by":"auto","created_at":"2026-02-11 05:10:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":692641,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6257285/v1/a6ddca36-14d4-4605-b171-b3ce7cb5fb63.pdf"},{"id":81016767,"identity":"ad36d0fd-f196-440b-b62e-5059fdaf1f1f","added_by":"auto","created_at":"2025-04-21 09:07:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20434,"visible":true,"origin":"","legend":"","description":"","filename":"Table1234.docx","url":"https://assets-eu.researchsquare.com/files/rs-6257285/v1/d0748b820e17cf46c2b0ecc6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Unraveling Fibromatosis-Like Metaplastic Breast Carcinoma: Insights from a Multicenter Cohort and Survival Benchmarking","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eMetaplastic breast carcinoma (MBC) is a rare and heterogeneous subtype of invasive breast cancer, accounting for approximately 0.2\u0026ndash;1% of all breast malignancies\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Unlike more common forms of breast cancer, MBC is defined by the presence of both epithelial and mesenchymal components, contributing to its diverse histopathological presentations and often aggressive clinical behavior\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Within the spectrum of MBC, fibromatosis-like metaplastic carcinoma (FLMC) represents a particularly rare subtype, comprising 4\u0026ndash;8% of all MBC cases\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. FLMC is distinguished by its unique histological features, such as low-grade spindle cell morphology and a high degree of stromal collagenization\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Biologically, FLMC exhibits a triple-negative receptor profile, lacking expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Despite being classified under the triple-negative breast cancer (TNBC) umbrella, FLMC typically exhibits low proliferative activity and a less aggressive clinical course compared to other TNBC subtypes\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDue to its rarity, research on FLMC has been limited to small case series and anecdotal reports, leading to significant gaps in our understanding of its clinical behavior and optimal management\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Large-scale or multicenter studies providing robust clinical evidence are currently lacking, resulting in a paucity of evidence-based guidelines for its diagnosis, treatment, and prognosis\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Furthermore, the lack of comparative studies between FLMC and other subtypes of MBC, such as spindle cell carcinoma (SCC), further limits our ability to contextualize FLMC within the broader landscape of breast cancer subtypes. These knowledge gaps underscore the need for comprehensive research to better delineate the distinct characteristics of FLMC and inform clinical decision-making.\u003c/p\u003e \u003cp\u003eThis study aims to address these critical gaps by analyzing the largest cohort of FLMC patients reported from a Chinese population. Through a multicenter retrospective study, we seek to identify the clinicopathological features and prognostic factors associated with FLMC, offering new insights into its biological behavior. Additionally, by comparing survival outcomes between FLMC and SCC, we aim to highlight the unique clinical trajectory of FLMC, contributing to the broader understanding of metaplastic breast carcinomas and fostering the development of tailored therapeutic strategies.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Design\u003c/h2\u003e \u003cp\u003eThis study was a multicenter retrospective cohort analysis conducted across two tertiary cancer centers in China: the Cancer Hospital, Chinese Academy of Medical Sciences, and its Shenzhen branch. The study period spanned from November 2016 to November 2024. The primary objective was to comprehensively investigate the clinical-pathological features, treatment strategies, and prognostic factors of fibromatosis-like metaplastic carcinoma (FLMC). Additionally, survival outcomes of FLMC were compared with those of spindle cell carcinoma (SCC), a more aggressive metaplastic breast cancer subtype, to provide insights into differences in disease progression and prognosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Patient Selection\u003c/h2\u003e \u003cp\u003ePatients included in this study were required to have histologically confirmed fibromatosis-like metaplastic carcinoma (FLMC) based on the WHO 2019 diagnostic criteria. Each diagnosis was independently reviewed and verified by two senior breast pathologists with expertise in metaplastic breast carcinoma to ensure diagnostic accuracy. Only patients with complete demographic, clinical, pathological, and follow-up data were eligible for analysis. Exclusion criteria included cases with incomplete or missing medical records, which limited the evaluation of clinical outcomes or pathological characteristics, as well as patients diagnosed with co-existing breast malignancies other than FLMC, such as invasive ductal carcinoma or other metaplastic subtypes. Additionally, misclassified cases or unverified diagnoses due to ambiguous histological or immunohistochemical findings were excluded. This rigorous selection process ensured a well-defined and homogenous cohort for the comprehensive and robust analysis of FLMC, a rare and understudied subtype of breast cancer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data Collection\u003c/h2\u003e \u003cp\u003e \u003cem\u003e1) Clinical Data\u003c/em\u003e Comprehensive clinical data were meticulously collected for each patient to ensure a detailed understanding of their presentation, treatment, and outcomes. Demographic information included patient age, sex, and menopausal status. Tumor characteristics encompassed size, location (laterality and quadrant), imaging findings (e.g., presence of calcifications, margins, and density), and clinical staging determined using the TNM classification system. Treatment-related data captured the surgical approach, distinguishing between breast-conserving surgery and mastectomy, as well as whether lymph node dissection (sentinel or axillary) was performed. Systemic therapies, including chemotherapy, radiotherapy, endocrine therapy, and targeted therapy, were documented in detail to assess their impact on patient outcomes. Follow-up outcomes included recurrence (local or distant), metastasis (site-specific), survival status (alive or deceased), and the duration of disease-free survival (DFS) and overall survival (OS). These data provided a robust framework for analyzing the clinical behavior and therapeutic responses of fibromatosis-like metaplastic carcinoma (FLMC).\u003c/p\u003e \u003cp\u003e \u003cb\u003e2\u003c/b\u003e \u003cem\u003e) Pathological Data\u003c/em\u003e Pathological data were derived from both histological examination and immunohistochemical analysis, ensuring a comprehensive characterization of each tumor. Histological examination focused on assessing tumor morphology, including cellular architecture, stromal composition, and the degree of atypia. Particular attention was given to the identification of the defining fibromatosis-like features, such as spindle cell proliferation and stromal collagenization. Immunohistochemistry was employed to evaluate key biomarkers critical to diagnosis and prognosis. This included the assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the Ki-67 proliferation index to determine tumor aggressiveness. Additional immunohistochemical markers, such as CK5/6, P63, and smooth muscle actin (SMA), were evaluated to confirm epithelial and mesenchymal differentiation, providing diagnostic specificity. These pathological insights were crucial for establishing the unique profile of FLMC and differentiating it from other breast cancer subtypes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Comparative Cohort\u003c/h2\u003e \u003cp\u003eTo contextualize the findings of fibromatosis-like metaplastic carcinoma (FLMC) within the broader spectrum of metaplastic breast carcinoma, a matched cohort of patients diagnosed with spindle cell carcinoma (SCC) was included for comparative analysis. These SCC cases were treated during the same study period across the two participating centers. Matching criteria were meticulously applied to ensure comparability between the cohorts, encompassing patient age, clinical stage (TNM classification), and immunohistochemical profiles. Each FLMC patient was paired in a 1:1 ratio with an SCC patient, resulting in a well-matched cohort for robust comparative analysis of clinicopathological features and survival outcomes. This comparative framework provided a deeper understanding of FLMC\u0026rsquo;s unique characteristics and prognosis relative to SCC, a more commonly encountered subtype of metaplastic carcinoma.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were conducted to provide a comprehensive understanding of the clinical, pathological, and prognostic aspects of fibromatosis-like metaplastic carcinoma (FLMC) in comparison to spindle cell carcinoma (SCC). Demographic, clinical, and pathological characteristics of both cohorts were summarized using descriptive statistics. Continuous variables were reported as mean and standard deviation (SD) or median and interquartile range (IQR), depending on the data distribution, while categorical variables were presented as frequencies and proportions. Survival outcomes, including disease-free survival (DFS) and overall survival (OS), were estimated using the Kaplan-Meier method. Differences in survival curves between the FLMC and SCC cohorts were assessed with the log-rank test, highlighting potential prognostic distinctions between these rare metaplastic breast cancer subtypes. To analyze clinicopathological features, appropriate statistical tests were employed: t-tests for normally distributed continuous variables, Mann-Whitney U-tests for non-normally distributed continuous variables, and Chi-square or Fisher\u0026rsquo;s exact tests for categorical variables. Prognostic factors influencing DFS and OS were examined through Cox proportional hazards regression models, incorporating both univariable and multivariable analyses to adjust for potential confounders. Statistical analyses were performed using SPSS (version 26.0), R (version 4.2.0), or STATA (version 17.0), depending on the complexity of the analysis. Statistical significance was rigorously defined at a two-tailed p-value of less than 0.05, ensuring reliability and precision in the interpretation of results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Ethics Approval and Limitations Acknowledged Upfront\u003c/h2\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of the participating institutions. Given the retrospective design of the study, the requirement for written informed consent was waived by the IRB. The retrospective nature of this study represents a potential limitation, as it relies on the accuracy and completeness of medical records. Additionally, the generalizability of findings may be influenced by the study\u0026rsquo;s focus on a Chinese cohort, necessitating further validation in diverse populations.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Patient Demographics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cohort consisted of 21 female patients diagnosed with fibromatosis-like metaplastic carcinoma (FLMC) between November 2016 and November 2024. The median age at diagnosis was 59 years, with an interquartile range (IQR) of 45\u0026ndash;77 years. Tumor sizes varied widely, ranging from 0.9 cm to 13.2 cm, with a distribution across clinical T stages: 43% of cases were classified as T1, 43% as T2, and 14% as T3/T4. The majority of tumors exhibited low nuclear grade (G1: 5%, G2: 14%) and intermediate or high grades (G3: 67%). Regarding receptor profiles, all cases were triple-negative (ER-/PR-/HER2-), with only three cases showing low PR expression. Ki-67 proliferation index varied significantly, with 43% of tumors expressing \u0026le;20% and the remainder showing \u0026gt;20%, with a mean index of 18% (range: 1~40%)(Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Pathological Features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1) Histological Findings\u0026nbsp;\u003c/em\u003eHistological examination revealed that FLMC tumors were predominantly composed of low-grade spindle cells arranged in fascicles with a collagenized stroma. The tumor nuclei demonstrated mild atypia without evidence of high-grade features. The stromal component exhibited various degrees of collagenization, imparting a fibromatosis-like appearance to the tumors. Cellular arrangements were predominantly interwoven, creating a wave-like or storiform pattern infiltrating the surrounding breast parenchyma. No high-grade sarcomatoid features or heterologous elements were observed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2) Immunohistochemical Profile\u0026nbsp;\u003c/em\u003eImmunohistochemical analyses consistently confirmed a triple-negative phenotype in all 21 cases (ER-/PR-/HER2-). Three cases exhibited low PR expression. Ki-67 proliferation index showed a dichotomous pattern, with nine tumors expressing \u0026le;20% and twelve tumors showing \u0026gt;20% proliferation activity. Markers of epithelial differentiation, including AE1/AE3 (95%), CK5/6 (86%), and P63 (90%), were prominently expressed. Mesenchymal differentiation markers, such as SMA (54%) and EMA (40%), were variably expressed, supporting the diagnosis of FLMC as a distinct metaplastic subtype with a mixed epithelial and mesenchymal immunophenotype. These findings highlighted the low proliferative potential and distinct histological and immunohistochemical characteristics of FLMC (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Treatment Modalities\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1) Surgical Approach\u0026nbsp;\u003c/em\u003eAmong the 21 FLMC patients included in the study, six (28.6%) underwent breast-conserving surgery (lumpectomy), while the remaining 15 patients (71.4%) received mastectomy as the definitive surgical intervention. All patients underwent sentinel lymph node biopsy (SLNB) as part of their surgical management. Notably, only one patient (4.8%) demonstrated sentinel lymph node positivity, necessitating axillary lymph node dissection (ALND). The low rate of lymph node involvement underscored the limited metastatic potential of FLMC, aligning with its low-aggressiveness phenotype .\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2) Chemotherapy\u0026nbsp;\u003c/em\u003eA total of three patients (14.3%) received adjuvant chemotherapy, all of whom presented with Ki-67 levels exceeding 20%, suggesting a higher proliferative activity. The chemotherapy regimens predominantly consisted of anthracycline- and taxane-based protocols. One patient with high tumor burden and advanced clinical staging underwent neoadjuvant chemotherapy but experienced suboptimal pathological response (Miller-Payne grade 2) and later succumbed to lung metastasis within 10 months postoperatively.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3) Radiotherapy\u0026nbsp;\u003c/em\u003eRadiotherapy was utilized in seven cases (33.3%). Six patients who underwent breast-conserving surgery were administered adjuvant radiotherapy to minimize the risk of local recurrence. One additional patient received adjuvant radiotherapy following mastectomy due to axillary lymph node involvement. None of the radiotherapy-treated patients experienced local recurrence during the follow-up period, supporting its potential role in preventing recurrence, particularly in the breast-conserving cohort.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e4) Endocrine Therapy\u0026nbsp;\u003c/em\u003eNone of the patients received endocrine therapy due to the universal absence of ER expression. Among the three patients with low PR expression, the clinical impact of PR positivity was deemed insufficient to justify endocrine treatment(Table 1, 3).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e5) Subgroup Analysis of Therapeutic Combinations\u0026nbsp;\u003c/em\u003ePatients with higher Ki-67 proliferation indices (\u0026gt;20%) more frequently received systemic adjuvant chemotherapy, reflecting a cautious approach toward potentially aggressive tumor behavior. Conversely, patients with lower Ki-67 indices (\u0026le;20%) predominantly underwent surgical treatment alone or surgery combined with radiotherapy. Breast-conserving surgery coupled with radiotherapy demonstrated favorable disease-free survival (DFS) outcomes, with no evidence of recurrence or metastasis during follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Survival Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1) Disease-Free Survival (DFS) and Overall Survival (OS)\u0026nbsp;\u003c/em\u003eKaplan-Meier survival analyses were performed to estimate DFS and OS among the 21 FLMC patients. The median follow-up period was 29.5 months (range: 2\u0026ndash;96 months). During this time, 20 patients (95.2%) remained disease-free, with only one patient experiencing recurrence in the form of lung metastasis, leading to death 10 months postoperatively(Table 4). The median DFS and OS were not reached due to the high survival rates. The estimated 3-year DFS and OS rates were 95.2% (95% CI: 89.8%\u0026ndash;100%) and 90.5% (95% CI: 80.8%\u0026ndash;100%), respectively. Stratified analysis by treatment modality revealed that patients undergoing lumpectomy with adjuvant radiotherapy had no recurrences, while the single recurrence occurred in a patient treated with neoadjuvant chemotherapy and mastectomy. Pathological factors, such as Ki-67 levels, significantly influenced survival outcomes. Patients with a Ki-67 proliferation index \u0026le;20% exhibited better DFS and OS compared to those with Ki-67 \u0026gt;20%, suggesting a role of tumor proliferation rate in predicting prognosis.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2) Comparative Analysis with SCC\u0026nbsp;\u003c/em\u003eA matched cohort of spindle cell carcinoma (SCC) patients (n=21) was included for comparative survival analysis. Kaplan-Meier curves demonstrated a trend toward better DFS and OS in FLMC compared to SCC. The 3-year DFS rate for SCC was 81.0% (95% CI: 68.5%\u0026ndash;93.5%), significantly lower than that of FLMC (log-rank p=0.04). Similarly, the 3-year OS rate for SCC was 76.2% (95% CI: 63.3%\u0026ndash;89.1%), also inferior to FLMC (log-rank p=0.03). Prognostic factors in SCC showed a stronger association with lymph node involvement and higher tumor grade compared to FLMC. These differences underscore the less aggressive biological behavior of FLMC, supporting its relatively favorable prognosis among metaplastic breast carcinoma subtypes(Figure1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Key Observations and Insights\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLow Lymph Node Involvement in FLMC\u003c/p\u003e\n\u003cp\u003eOnly one patient (4.8%) in the FLMC cohort exhibited lymph node metastasis, a stark contrast to SCC and other MBC subtypes, where lymph node involvement is more common. This low rate aligns with the reported indolent nature of FLMC and its low proliferative activity. Importantly, this finding raises the question of whether SLNB is necessary for all FLMC patients, particularly when imaging does not suggest lymph node involvement. Avoiding unnecessary axillary interventions could reduce the risk of complications, such as lymphedema and shoulder dysfunction, without compromising oncologic safety.\u003c/p\u003e\n\u003cp\u003ePoor Outcomes with Neoadjuvant Chemotherapy\u003c/p\u003e\n\u003cp\u003eThe sole patient treated with neoadjuvant chemotherapy (NAC) in this study demonstrated poor outcomes, including a suboptimal pathological response (Miller-Payne grade 2) and rapid postoperative lung metastasis. This observation aligns with previous reports suggesting limited efficacy of NAC in FLMC. Given the low proliferation rate and minimal lymph node involvement typically observed in FLMC, the utility of NAC appears questionable. Instead, primary surgery followed by tailored adjuvant therapies based on tumor characteristics may be a more effective approach. This recommendation underscores the importance of recognizing FLMC\u0026rsquo;s unique biological behavior to avoid overtreatment.\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe current study highlights the favorable prognosis of fibromatosis-like metaplastic carcinoma (FLMC) compared to spindle cell carcinoma (SCC) and other metaplastic breast carcinoma (MBC) subtypes. This is evidenced by the low recurrence and metastasis rates observed in our cohort, with only one case of lung metastasis reported among 21 FLMC patients during the follow-up period, and no instances of local recurrence. In contrast, SCC demonstrated higher rates of disease progression, underscoring the relatively indolent nature of FLMC. These findings corroborate previous reports suggesting that FLMC behaves as a low-grade malignancy within the spectrum of MBC\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe low Ki-67 proliferation index emerged as a key predictive marker of better survival outcomes in FLMC patients\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. In our cohort, approximately 43% of patients exhibited Ki-67 expression levels below 20%, with an average expression of 18%. This contrasts sharply with the higher proliferative indices typically observed in other MBC subtypes, including SCC\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. The association between lower Ki-67 levels and improved survival reinforces the hypothesis that FLMC is biologically less aggressive. This marker provides a valuable tool for prognostication and may guide adjuvant therapy decisions.\u003c/p\u003e \u003cp\u003eLymph node involvement was exceptionally rare in FLMC patients, with only one case of sentinel lymph node metastasis identified. This rarity has significant implications for surgical decision-making. Routine axillary lymph node dissection (ALND) or even sentinel lymph node biopsy (SLNB) may not be necessary in the absence of suspicious findings on preoperative imaging. Avoiding these procedures can reduce the risk of complications such as lymphedema and upper limb dysfunction, enhancing the quality of life for patients\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Practical Implications for Clinical Management\u003c/h2\u003e \u003cp\u003eThe findings of this study advocate for a personalized treatment approach to FLMC management. Surgery remains the cornerstone of therapy, with breast-conserving surgery being a viable option for selected patients, particularly those with smaller tumors and clear margins. In our cohort, six patients underwent breast-conserving surgery, all of whom remained disease-free during the follow-up period, suggesting that this approach does not compromise oncological outcomes when coupled with adjuvant radiotherapy.\u003c/p\u003e \u003cp\u003eAdjuvant therapies should be tailored based on tumor characteristics, such as size, Ki-67 levels, and surgical margins. Patients with higher Ki-67 expression or larger tumors may benefit from adjuvant chemotherapy, although its efficacy in FLMC remains uncertain\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. For those undergoing breast-conserving surgery, adjuvant radiotherapy appears to be essential in minimizing the risk of local recurrence, as evidenced by the absence of recurrence in patients who received radiotherapy in this study.\u003c/p\u003e \u003cp\u003eNeoadjuvant chemotherapy should generally be avoided in FLMC patients due to its limited efficacy and potential for poor outcomes\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In this cohort, the single patient who received NAC experienced poor pathological response and subsequent rapid disease progression, culminating in death within 10 months post-surgery. These findings align with previous reports highlighting the chemoresistance of FLMC, further supporting surgery as the primary treatment modality.\u003c/p\u003e \u003cp\u003eA selective approach to SLNB is recommended, relying on preoperative imaging to identify patients at risk for axillary involvement. This strategy minimizes unnecessary axillary interventions, reducing the associated morbidity. Additionally, adjuvant radiotherapy should be considered for patients undergoing breast-conserving surgery or those with any lymph node involvement, as it may play a crucial role in reducing recurrence risk.\u003c/p\u003e \u003cp\u003eTogether, these recommendations emphasize the importance of individualized treatment plans for FLMC, balancing oncological control with quality of life considerations. Further studies are needed to validate these strategies and refine guidelines for this rare subtype of breast cancer\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Contextualization Within Existing Literature\u003c/h2\u003e \u003cp\u003eThe findings of this study align with and expand upon the existing body of research on fibromatosis-like metaplastic carcinoma (FLMC), particularly its indolent biological behavior and favorable prognosis\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Consistent with previous reports, our cohort demonstrated a remarkably low incidence of lymph node metastasis\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Among the 21 FLMC patients analyzed, only one case of sentinel lymph node involvement was identified, reinforcing earlier observations by Jasper et al. (2020) and Sneige et al. (2001)\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, which documented minimal axillary lymph node involvement in FLMC patients. These results further substantiate the classification of FLMC as a low-grade malignancy with limited metastatic potential, distinguishing it from other more aggressive metaplastic breast carcinoma (MBC) subtypes\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study makes a significant contribution to the literature by presenting the largest FLMC cohort reported from a Chinese population, thus providing valuable insights into its clinicopathological features, treatment outcomes, and prognostic factors. Previous studies on FLMC have primarily been limited to single case reports or small series, constraining their ability to inform clinical practice comprehensively\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. By conducting a multicenter retrospective analysis, this study systematically evaluates 21 FLMC cases, offering robust data to guide clinical decision-making and further refine the understanding of this rare subtype.\u003c/p\u003e \u003cp\u003eThe findings of this study are consistent with well-documented characteristics of FLMC in the literature, including its triple-negative phenotype (ER-/PR-/HER2-), low-grade spindle cell morphology, and low Ki-67 proliferation index. Approximately 43% of patients in our cohort exhibited a Ki-67 index below 20%, underscoring the indolent nature of FLMC. These results align with those of Gobbi et al. (1999) and Nonnis et al. (2012)\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, which similarly described FLMC as a unique MBC subtype with low proliferative activity and favorable clinical outcomes.\u003c/p\u003e \u003cp\u003eAdditionally, this study provides new perspectives on the clinical management of FLMC. It confirms the limited role of neoadjuvant chemotherapy, which was associated with poor outcomes in our cohort, and highlights the selective application of sentinel lymph node biopsy. Unlike other MBC subtypes\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, FLMC demonstrates a low propensity for nodal involvement and systemic metastasis, suggesting that less aggressive treatment strategies may be appropriate in most cases. These findings align with an emerging consensus in the literature advocating for tailored treatment approaches for FLMC based on its distinct clinicopathological profile.\u003c/p\u003e \u003cp\u003eBy contextualizing the findings within the broader framework of FLMC research, this study fills a critical gap in the literature. It not only corroborates previously reported observations but also provides new evidence from a larger and more diverse cohort, emphasizing the importance of individualized treatment strategies and highlighting areas for future research.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Study Limitations\u003c/h2\u003e \u003cp\u003eThis study, while the largest cohort of fibromatosis-like metaplastic carcinoma (FLMC) patients reported to date, acknowledges several limitations that warrant consideration. 1) First, the small sample size of 21 patients, though significant given the rarity of FLMC, limits the generalizability of the findings to broader populations. Larger studies are necessary to confirm the observed trends and validate the prognostic factors identified in this analysis. 2) Second, the retrospective design of the study introduces inherent limitations, including potential selection bias and reliance on historical medical records, which may lack granularity or uniformity in data collection. This limitation could affect the accuracy and completeness of the clinical and pathological data, as well as the interpretation of treatment outcomes. 3) Third, the lack of extended long-term follow-up data restricts the study\u0026rsquo;s ability to provide insights into late recurrences, survival trends beyond the median follow-up period, and the durability of disease-free survival (DFS) and overall survival (OS). Late metastasis, though uncommon in FLMC, remains a concern that warrants future investigation. 4) These limitations underscore the need for caution in extrapolating the findings to different populations or healthcare settings and highlight the importance of complementary prospective studies to address these gaps.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Future Directions\u003c/h2\u003e \u003cp\u003eTo advance the understanding and management of FLMC, future research should focus on several key areas: \u003cem\u003e1) Prospective Validation\u003c/em\u003e: Conducting prospective cohort studies or clinical trials is critical to confirming the findings of this study and refining treatment strategies for FLMC. Such studies can mitigate the biases inherent in retrospective designs and ensure the collection of standardized, high-quality data. \u003cem\u003e2) Molecular Profiling\u003c/em\u003e: Incorporating advanced molecular profiling techniques, such as next-generation sequencing (NGS), could identify genetic or epigenetic biomarkers that predict prognosis or therapeutic response. This could provide insights into the unique biology of FLMC and uncover novel therapeutic targets for this triple-negative subtype. \u003cem\u003e3) International Multicenter Collaborations\u003c/em\u003e: Pooling data from multiple institutions worldwide would significantly enhance sample size and improve the generalizability of findings. Collaborative efforts could also enable the development of evidence-based guidelines tailored to the management of FLMC. \u003cem\u003e4) Exploration of Novel Therapies\u003c/em\u003e: Given the triple-negative phenotype of FLMC, investigating the potential role of immunotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors, or other novel systemic therapies could be promising\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Understanding the tumor microenvironment and immune evasion mechanisms in FLMC might open new avenues for therapeutic interventions. \u003cem\u003e5) Long-Term Follow-Up\u003c/em\u003e: Designing studies with extended follow-up durations would provide valuable insights into late recurrence patterns, long-term survival trends, and the durability of different treatment modalities. This information is vital for optimizing survivorship care for FLMC patients.\u003c/p\u003e \u003c/div\u003e"},{"header":"5 Conclusion and Perspectives","content":"\u003cp\u003eThis study represents the largest cohort of fibromatosis-like metaplastic carcinoma (FLMC) patients reported to date, providing valuable insights into the clinicopathological characteristics, treatment outcomes, and prognostic factors of this rare breast cancer subtype. Our findings highlight the indolent nature of FLMC, characterized by low rates of lymph node involvement, a favorable prognosis, and a strong association with low Ki-67 proliferation indices. These features set FLMC apart from other metaplastic breast carcinoma (MBC) subtypes, particularly spindle cell carcinoma (SCC), which exhibits a more aggressive clinical course.\u003c/p\u003e\n\u003cp\u003eThe results emphasize the importance of a personalized approach to FLMC management. Surgery remains the cornerstone of treatment, with breast-conserving surgery being a viable option for selected patients. Adjuvant therapies should be tailored based on tumor size, Ki-67 levels, and surgical margins, while neoadjuvant chemotherapy is not recommended due to its limited efficacy. Sentinel lymph node biopsy can be selectively performed based on preoperative imaging to minimize unnecessary interventions, and adjuvant radiotherapy may benefit patients undergoing breast-conserving surgery.\u003c/p\u003e\n\u003cp\u003eDespite the retrospective nature and small sample size of this study, it contributes significantly to the limited body of knowledge on FLMC and lays the groundwork for future research. Prospective studies incorporating molecular profiling are needed to validate these findings, identify biomarkers for prognosis, and explore novel therapeutic strategies, such as immunotherapy. International multicenter collaborations could further enhance the generalizability of these results and support the development of evidence-based guidelines.\u003c/p\u003e\n\u003cp\u003eIn conclusion, FLMC demonstrates a distinct clinical and pathological profile with a relatively favorable prognosis. This study underscores the importance of individualized management strategies and highlights the need for ongoing research to refine the treatment and improve outcomes for this rare breast cancer subtype.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 9.3803%;\"\u003e\n \u003cp\u003eAbbreviation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90.5344%;\"\u003e\n \u003cp\u003eFull form\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 9.3803%;\"\u003e\n \u003cp\u003eFLMC\u003c/p\u003e\n \u003cp\u003eMBC\u003c/p\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003cp\u003eER\u003c/p\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003cp\u003eHER2\u003c/p\u003e\n \u003cp\u003eTNBC\u003c/p\u003e\n \u003cp\u003eSMA\u003c/p\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003cp\u003eIQR\u003c/p\u003e\n \u003cp\u003eIRB\u003c/p\u003e\n \u003cp\u003eSLNB\u003c/p\u003e\n \u003cp\u003eALND\u003c/p\u003e\n \u003cp\u003eNAC\u003c/p\u003e\n \u003cp\u003eNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90.5344%;\"\u003e\n \u003cp\u003eFibromatosis-like metaplastic carcinoma\u003c/p\u003e\n \u003cp\u003eMetaplastic breast carcinoma\u003c/p\u003e\n \u003cp\u003eDisease-free survival\u003c/p\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003cp\u003eSpindle cell carcinoma\u003c/p\u003e\n \u003cp\u003eEstrogen receptor\u003c/p\u003e\n \u003cp\u003eProgesterone receptor\u003c/p\u003e\n \u003cp\u003eHuman epidermal growth factor receptor 2\u003c/p\u003e\n \u003cp\u003eTriple-negative breast cancer\u003c/p\u003e\n \u003cp\u003eSmooth muscle actin\u003c/p\u003e\n \u003cp\u003eStandard deviation\u003c/p\u003e\n \u003cp\u003einterquartile range\u003c/p\u003e\n \u003cp\u003eInstitutional Review Board\u003c/p\u003e\n \u003cp\u003eSentinel lymph node biopsy\u003c/p\u003e\n \u003cp\u003eAxillary lymph node dissection\u003c/p\u003e\n \u003cp\u003eNeoadjuvant chemotherapy\u003c/p\u003e\n \u003cp\u003eNext-generation sequencing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the Natural Science Foundation of China (No. 82473205), and by the Natural Science Foundation of China (No. 82371842), and by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2023-I2M-2-004), and by the Shenzhen Medical Research Fund (D2402001).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYe Lu, Xiangyi Kong and Wenxiang Zhang performed the literature search and collected the data.Ye Lu, Xiangyi Kong and Wenxiang Zhang performed the statistical analysis and wrote the manuscript. Jing Wang, Jidong Gao and Kan Yonemori designed the study and conceived and revised the manuscript. All authors contributed to the article and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to university data ownership policies, but are available from the corresponding author on reasonable request.\u003c/p\u003e\u003ch2\u003eDeclaration of Interest Statement\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eB. Weigelt, C. Eberle, C. F. Cowell, et al;\u0026nbsp;Metaplastic breast carcinoma: more than a special type. Nat Rev Cancer. 2014; 14(3) :147-8.\u003c/li\u003e\n \u003cli\u003eS. I. Djomehri, M. E. 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A, et al; Metaplastic breast tumors with a dominant fibromatosis-like phenotype have a high risk of local recurrence. Cancer.1999; 85(10): 2170-82.\u003c/li\u003e\n \u003cli\u003eR. Nonnis, P. Paliogiannis, D. Giangrande, et al; Low-grade fibromatosis-like spindle cell metaplastic carcinoma of the breast: a case report and literature review. Clin Breast Cancer. 2012; 12(2) :147-50.\u003c/li\u003e\n \u003cli\u003eS. Bartels, J. L. van Luttikhuizen, M. Christgen, et al; CDKN2A loss and PIK3CA mutation in myoepithelial-like metaplastic breast cancer. J Pathol. 2018;245(3): 373-383.\u003c/li\u003e\n \u003cli\u003eC. A. Febres-Aldana, J. C. Alvarez Moreno, M. Rivera, et al; Understanding the histogenesis of a HRAS-PIK3R1 co-driven metastatic metaplastic breast carcinoma associated with squamous metaplasia of lactiferous ducts. Pathol Int. 2020; 70(2):101-107.\u003c/li\u003e\n \u003cli\u003eS. Zhong, S. Zhou, A. Li, High frequency of PIK3CA and TERT promoter mutations in fibromatosis-like spindle cell carcinomas. J Clin Pathol. 2022;75(7):477-482.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Fibromatosis-like metaplastic carcinoma, Triple-negative breast cancer, Clinicopathological features, Survival outcomes, Adjuvant radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-6257285/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6257285/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eFibromatosis-like metaplastic carcinoma (FLMC) is a rare and distinct subtype of metaplastic breast carcinoma (MBC), comprising 4–8% of cases. Characterized by a triple-negative receptor profile and low proliferative activity, FLMC exhibits less aggressive clinical behavior compared to other MBC subtypes. However, due to its rarity, knowledge of its clinical and pathological features, treatment outcomes, and prognosis remains limited.\u003c/p\u003e\n\u003cp\u003eThis multicenter retrospective cohort study included 21 FLMC cases diagnosed between November 2016 and November 2024 at two tertiary cancer centers in China. Data on clinical presentation, pathology, treatment, and outcomes were collected and analyzed. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. A matched cohort of spindle cell carcinoma (SCC) patients was analyzed for comparative survival outcomes.The median age of FLMC patients was 59 years (IQR: 45–77). All tumors were triple-negative (ER-/PR-/HER2-) and exhibited a low Ki-67 proliferation index in 43% of cases. Lymph node metastasis was observed in only one patient (4.8%). Surgery was the primary treatment modality, with breast-conserving surgery and adjuvant radiotherapy showing improved DFS. Neoadjuvant chemotherapy demonstrated limited efficacy, with poor outcomes in one patient. The 3-year DFS and OS rates for FLMC were 95.2% and 90.5%, respectively, significantly higher than those for SCC (DFS: 81.0%; OS: 76.2%; p \u0026lt; 0.05). FLMC is an indolent MBC subtype with a favorable prognosis and low risk of recurrence or metastasis. Surgical resection remains the cornerstone of treatment, with selective use of adjuvant therapies based on tumor characteristics. Neoadjuvant chemotherapy is not recommended due to limited benefit. Future research should focus on prospective validation of these findings, molecular profiling, and exploration of novel systemic therapies for this rare entity.\u003c/p\u003e","manuscriptTitle":"Unraveling Fibromatosis-Like Metaplastic Breast Carcinoma: Insights from a Multicenter Cohort and Survival Benchmarking","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 09:07:01","doi":"10.21203/rs.3.rs-6257285/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"63280438-92be-470c-a334-d3b4cb8c3f25","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":46455513,"name":"Biological sciences/Cancer"},{"id":46455514,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-02-11T05:09:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-21 09:07:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6257285","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6257285","identity":"rs-6257285","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}