Genomic alterations and evolution of cell clusters in metastatic invasive micropapillary carcinoma of the breast

Invasive micropapillary carcinoma (IMPC) has very high rates of lymphovascular invasion and lymph node metastasis and has been reported in several organs. However, the genomic mechanisms underlying its metastasis are unclear. Here, we perform whole-genome sequencing of tumor cell clusters from primary IMPC and paired axillary lymph node metastases. Cell clusters in multiple lymph node foci arise from a single subclone of the primary tumor. We find evidence that the monoclonal metastatic ancestor in primary IMPC shares high frequency copy-number loss of PRDM16 and IGSF9 and the copy number gain of ALDH2. Immunohistochemistry analysis further shows that low expression of IGSF9 and PRDM16 and high expression of ALDH2 are associated with lymph node metastasis and poor survival of patients with IMPC. We expect these genomic and evolutionary profiles to contribute to the accurate diagnosis of IMPC.

Nomogram for Predicting Overall Survival in Patients With Invasive Micropapillary Carcinoma After Breast-Conserving Surgery: A Population‐Based Analysis

Background: Due to the rarity of invasive micropapillary carcinoma (IMPC) of the breast, no randomized trial has investigated the prediction of overall survival (OS) for patients with IMPC after breast-conserving surgery (BCS). This study aimed to construct a nomogram for predicting OS in IMPC patients after BCS. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, 481 eligible cases diagnosed with IMPC were collected. OS in IMPC patients after BCS were assessed through multivariable Cox analyses, Harrell’s concordance indexes (C-indexes), receiver operating characteristics (ROCs) curves, calibration curves, decision curve analyses (DCA), and survival analyses. Results: 336 patients were randomly assigned into training cohort and 145 cases in validation cohort. The multivariate Cox regression analyses revealed that age at diagnosis, American Joint Committee on Cancer (AJCC) stage, marital status, hormone receptor status and chemotherapy were significant prognostic factors for OS in conservatively operated IMPC patients. The nomogram had a good prediction performance with the C-indices 0.771 (95%CI, 0.712-0.830) and 0.715 (95%CI, 0.603-0.827) in training and validation cohorts, respectively, and good consistency between the predicted and observed probability, with calibration curves plotted and the slope was close to 1. Based on calculation of the model, participants in low-risk group had a better OS in comparison with those in high-risk group (P < 0.001). Conclusions: A nomogram was developed to predict individualized risk of OS for IMPC patients after BCS. By risk stratification, this model is expected to guide treatment decision making in improving long-term follow-up strategies for IMPC patients.

Spatial transcriptomics reveals gene expression characteristics in invasive micropapillary carcinoma of the breast

Invasive micropapillary carcinoma (IMPC) is a special histological subtype of breast cancer, featured with extremely high rates of lymphovascular invasion and lymph node metastasis. Based on a previous series of studies, our team proposed the hypothesis of “clustered metastasis of IMPC tumor cells”. However, the transcriptomics characteristics underlying its metastasis are unknown, especially in spatial transcriptomics (ST). In this paper, we perform ST sequencing on four freshly frozen IMPC samples. We draw the transcriptomic maps of IMPC for the first time and reveal its extensive heterogeneity, associated with metabolic reprogramming. We also find that IMPC subpopulations with abnormal metabolism are arranged in different spatial areas, and higher levels of lipid metabolism are observed in all IMPC hierarchical clusters. Moreover, we find that the stromal regions show varieties of gene expression programs, and this difference depends on their distance from IMPC regions. Furthermore, a total of seven IMPC hierarchical clusters of four samples share a common higher expression level of the SREBF1 gene. Immunohistochemistry results further show that high SREBF1 protein expression is associated with lymph node metastasis and poor survival in IMPC patients. Together, these findings provide a valuable resource for exploring the inter- and intra-tumoral heterogeneity of IMPC and identify a new marker, SREBF1, which may facilitate accurate diagnosis and treatment of this disease.

Papillary lesions of the breast

Papillary lesions of the breast represent a heterogeneous group of lesions including benign papillomas, papillomas with focal epithelial atypia, fully fledged ductal carcinoma in situ (DCIS) or lobular neoplasia, papillary DCIS, encapsulated papillary carcinomas without or with invasion, solid papillary carcinomas, and invasive papillary carcinomas. A micropapillary pattern characterized by lack of fibrous stalks within the papillae is observed in micropapillary DCIS and invasive micropapillary carcinoma. In addition, a variety of other rare breast lesions reveals a papillary architecture such as tall cell carcinoma with reversed polarity (TCCRP) and mucinous cystadenocarcinoma, adenomyoepithelioma, and secretory carcinoma. In addition, benign lesions such as usual ductal hyperplasia, apocrine metaplasia, gynecomastia, and juvenile papillomatosis may show a papillary or micropapillary architecture. Fragments of a benign papilloma in a breast biopsy are considered a lesion of uncertain malignant potential (B3 in the European classification) and excision is mostly recommended. Although the knowledge about molecular pathology of papillary breast lesions has increased, there is not sufficient evidence for diagnostically useful molecular features, yet. The aim of this review is to provide an update on papillary and micropapillary lesions with emphasis on problematic areas for daily diagnostic work including biopsies.

Survival Outcomes After Breast-Conserving Therapy Compared With Mastectomy for Patients With Early-Stage Invasive Micropapillary Carcinoma of the Breast: A SEER Population-Based Study

BackgroundInvasive micropapillary breast carcinoma (IMPC) is a relatively rare pathological type of invasive breast cancer. Little is currently known on the efficacy and safety of breast-conserving treatment (BCT, lumpectomy plus postsurgical radiation) compared with mastectomy in women diagnosed with early-stage IMPC. Accordingly, we sought to investigate the long-term prognostic differences between BCT and mastectomy in patients with T1-3N0-3M0 invasive micropapillary breast carcinoma using data from the Surveillance, Epidemiology, and End Results (SEER) database.Materials and MethodsWe retrospectively analyzed 1,203 female patients diagnosed with early-stage IMPC between 2004 and 2015 from the SEER database. The impact of different surgical approaches on patient prognosis was assessed by the Kaplan-Meier method and Cox proportional risk models.ResultsA total of 609 and 594 patients underwent mastectomy and BCT, respectively. Compared with patients who underwent a mastectomy, patients in the BCT group were older and had lower tumor diameters, lower rates of lymph nodes metastasis, and higher rates of ER receptor positivity and PR receptor positivity (p &lt; 0.05). Kaplan-Meier plots showed that the overall survival (OS) and breast cancer-specific survival (BCSS) were higher in the BCT group than in the mastectomy group. In subgroup analysis, patients with T2 stage in the BCT group had better OS than the mastectomy group. Multivariate analysis showed no statistical difference in OS and BCSS for patients in the mastectomy group compared with the BCT group (hazard ratio (HR) = 0.727; 95% confidence interval (95% CI) 0.369–1.432, p = 0.357; HR = 0.762; 95% CI 0.302–1.923, p = 0.565; respectively). During the multivariate analysis and stratifying for the T stage, a better OS was found for patients with T2 stage in the BCT group than the mastectomy group (HR = 0.333, 95% CI: 0.149–0.741, p = 0.007). There was no significant difference in OS for patients with T1 and T3 stages between the BCT and mastectomy groups (p &gt; 0.05).ConclusionIn women with early-stage IMPC, BCT was at least equivalent to mastectomy in terms of survival outcomes. When both procedures are feasible, BCT should be recommended as the standard surgical treatment, especially for patients with T2 disease.

A Prognostic Nomogram based on Risk Assessment for Invasive Micropapillary Carcinoma of the Breast after Surgery

Background: Invasive micropapillary carcinoma (IMPC) is one of the rare subtypes of breast cancer. This study aimed to explore a novel predictive nomogram model for IMPC prognosis.Methods: A total of 1855 IMPC patients diagnosed after surgery between 2004 and 2014 were identified from the Surveillance, Epidemiology and End Results (SEER) database to build and validate nomograms. All the patients included were divided into a training group (n=1300) and a validation group (n=555). A nomogram was created based on univariate and multivariate Cox proportional hazards regression analysis. In addition, receiver operating characteristic (ROC) curves were used to demonstrate the accuracy of the prognostic model. Decision curve analysis (DCA) was performed to evaluate the safety of the model in the range of clinical applications, while calibration curves were used to validate the prediction consistency.Results: Cox regression analysis indicated that age ≥62 at diagnosis, negative ER status, and tumor stage were considered adverse independent factors for overall survival (OS), while patients who were married, white or of other races, received chemotherapy or radiotherapy, had a better postoperative prognosis. The nomogram accurately predicted OS with high internal and external validation consistency index (C index) (0.756 and 0.742, respectively). The areas under the ROC curve (AUCs) of the training group were 0.787, 0.774 and 0.764 for 3 years, 5 years and 10 years, respectively, while those of the validation group were 0.756, 0.766 and 0.762, respectively. The results of both DCA and calibration curves demonstrated the good performance of the model.Conclusion: A novel nomogram for IMPC of the breast patients after surgery was developed to estimate 3- and 5-OS based on independent risk factors. This model has good accuracy and consistency in predicting prognosis and has clinical application value.

Cell polarity and cell adhesion associated gene expression differences between invasive micropapillary and no special type breast carcinomas and their prognostic significance

Invasive micropapillary carcinoma of the breast (IMPC) has been in the focus of several studies given its specific histology and clinicopathological course. We analysed mRNA expression profiles and the prognostic value of 43 genes involved in cell polarity, cell-adhesion and epithelial–mesenchymal transition (EMT) in IMPC tumors and compared them to invasive breast carcinomas of no special type (IBC-NST). IMPCs (36 cases), IBC-NSTs (36 cases) and mixed IMPC-IBC NSTs (8 cases) were investigated. mRNA expression level of selected genes were analysed using the NanoString nCounter Analysis System. Distant metastases free survival (DMFS) intervals were determined. Statistical analysis was performed using Statistica 13.5 software. Twelve genes showed significantly different expression in the IMPC group. There was no difference in DMFS according to histological type (IBC-NST vs. IMPC). High CLDN3, PALS1 and low PAR6 expression levels in the entire cohort were associated with shorter DMFS, and PALS1 was proven to be grade independent prognostic factor. Positive lymph node status was associated with higher levels of AKT1 expression. Differences in gene expression in IMPC versus IBC-NST may contribute to the unique histological appearance of IMPCs. No marked differences were observed in DMFS of the two groups. Altered gene expression in the mTOR signaling pathway in both tumor subtypes highlights the potential benefit from AKT/mTOR inhibitors in IMPCs similarly to IBC-NSTs.

Invasive Micropapillary Carcinoma of Mixed Breast Cancer Metastasizing Faster Into Thyroid: A Rare Case Report

Background: The incidence of metastatic breast cancer tumors in the thyroid gland is very rare, however, invasive micropapillary carcinoma of breast metastasizes to thyroid gland is rarer. As far as we know, there has never been reported that both invasive ductal carcinoma– no special type (IDC-NST) and invasive micropapillary carcinoma (IMPC) exist in breast whereas only the latter metastasizes into the thyroid gland.Case presentation: we report a case of a 59-year-old Chinese woman first diagnosed as IDC-NST of breast with involvement of axillary lymph node, grade 2 in 2015. However, five years later, blood tests revealed increased tumor markers. Multiple solid nodules were found in both side of thyroid gland by imaging. Total thyroidectomy and bilateral cervical lymph nodes dissection were presentation: the findings showed both IDC-NST and IMPC in lymph nodes but only the later in thyroid gland. Immunohistochemically, these tumor cells were positive for ER, PR, GATA3 and Mammaglobin, but negative for TG and TTF-1. Ultimately, the patient was diagnosed as mixed breast cancer with metastatic IMPC in thyroid and radiation therapy was still continued.Conclusion: Apart from the possibility of metastatic no special type of breast cancer to thyroid tumor, IMPC of breast metastasis must be taken into consideration, especially when the patient has a history of breast cancer and thyroid nodes. Accurate diagnose of metastatic breast carcinoma is vital for precise treatment and can improve the prognosis for patients.