O39: THE HISTOPATHOLOGICAL AND MOLECULAR FEATURES OF BREAST CARCINOMA WITH HIGH-GRADE TUMOUR BUDDING

Abstract Background Tumour budding (TB) is an adverse histological feature in many cancers. It is thought to represent epithelial-to-mesenchymal transition, a key step in the metastatic process. The role of TB in breast carcinoma (BC) remains unclear. Aim To investigate the relationship between TB and other histological and molecular features of BC. Method A systematic search was performed to identify studies that compared features of BC based on the presence or absence of high-grade TB. Dichotomous variables were pooled as odds ratios (OR) using the Cochran–Mantel–Haenszel method. Quality assessment of the included studies was performed using the Newcastle-Ottawa scale (NOS). Result Seven studies with a total of 1040 patients (high grade TB n=519, 49.9%; low grade TB n=521, 50.1%) were included. A moderate- to high-risk of bias was noted. The median NOS was 7 (range 6-8). High-grade TB was significantly associated with lymph node involvement (OR 2.28, 95% c.i. 1.74 to 2.98, P<0.001) and lymphovascular invasion (OR 3.08, 95% c.i. 2.13 to 4.47, P<0.001). Regarding molecular subtypes, there was an increased likelihood of high-grade TB in oestrogen- (OR 1.66, 95% c.i. 1.21 to 2.29, P=0.002) and progesterone-receptor positive (OR 1.68, 95% c.i. 1.10 to 2.59, P=0.02) tumours. In contrast triple negative breast cancer had a reduced incidence of high-grade TB (OR 0.46, 95% c.i. 0.30 to 0.72, P=0.0006). Conclusion High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC. Take-home message High-grade TB is enriched in hormone-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic processes of luminal BC.

Download Full-text

AB031. The histopathological and molecular features of breast carcinoma with high-grade tumour budding

Mesentery and Peritoneum ◽

10.21037/map.2020.ab031 ◽

2020 ◽

Vol 4 ◽

pp. AB031-AB031

Author(s):

Angus James Lloyd ◽

Eanna Ryan ◽

Michael Boland ◽

Sami Medani Abd Elwahab ◽

Carmel Malone ◽

...

Keyword(s):

Breast Carcinoma ◽

High Grade ◽

Molecular Features ◽

Grade Tumour ◽

Tumour Budding

Download Full-text

Distinct epithelial-to-mesenchymal transitions induced by PIK3CAH1047R and PIK3CB

Journal of Cell Science ◽

10.1242/jcs.248294 ◽

2021 ◽

Vol 134 (4) ◽

pp. jcs248294

Author(s):

Ersa Gjelaj ◽

Paul A. Hamel

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Low Frequency ◽

Akt Pathway ◽

Low Grade ◽

High Grade ◽

Wild Type ◽

Mesenchymal Transition ◽

Epithelial Sheets ◽

Phosphoinositide 3 Kinase ◽

E Cadherin

ABSTRACTThe most common PIK3CA mutation, producing the H1047R mutant of p110α, arises in myriad malignancies and is typically observed in low-grade breast tumours. In contrast, amplification is observed for wild-type PIK3CB, encoding p110β, and occurs at low frequency but in aggressive, high-grade metastatic tumours. We hypothesized that mutant p110αH1047R and wild-type p110β give rise to distinct transformed phenotypes. We show that p110αH1047R and wild-type p110β, but not wild-type p110α, transform MCF-10A cells and constitutively stimulate phosphoinositide 3-kinase (PI3K)-AKT pathway signalling. However, their resultant morphological transformed phenotypes are distinct. p110αH1047R induced an epithelial-to-mesenchymal transition (EMT) commensurate with SNAIL (also known as SNAI1) induction and loss of E-cadherin. Upon p110β expression, however, E-cadherin expression was maintained despite cells readily delaminating from epithelial sheets. Distinct from the prominent filopodia in p110αH1047R-expressing cells, p110β induced formation of lamellipodia, and these cells migrated with significantly greater velocity and decreased directionality. p110β-induced phenotypic alterations were accompanied by hyperactivation of RAC1; the dependency of transformation of p110β-binding to Rac1 revealed using a Rac1-binding mutant of p110β. Thus, PIK3CB amplification induces a transformed phenotype that is dependent upon a p110β-Rac1 signalling loop and is distinct from the transformed phenotype induced by p110αH1047R.

Download Full-text

Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽

10.3390/cancers13051090 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1090

Author(s):

Hassan Sadozai ◽

Animesh Acharjee ◽

Thomas Gruber ◽

Beat Gloor ◽

Eva Karamitopoulou

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Disease Progression ◽

Immune Escape ◽

Epithelial Mesenchymal Transition ◽

Tumor Budding ◽

Ductal Adenocarcinoma ◽

Low Grade ◽

High Grade ◽

Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

Download Full-text

PATH-41. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG WITH FGFR3-TACC3 FUSION MIMICKING HIGH-GRADE GLIOMA: CASE REPORT AND SERIES OF HIGH-GRADE CORRELATES

Neuro-Oncology ◽

10.1093/neuonc/noab196.493 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi124-vi124

Author(s):

Danielle Golub ◽

Peter C Pan ◽

Benjamin Liechty ◽

Cheyanne Slocum ◽

Tejus Bale ◽

...

Keyword(s):

Progression Free Survival ◽

High Grade Glioma ◽

Proliferation Index ◽

Molecular Profile ◽

Low Grade ◽

High Grade ◽

Molecular Features ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

Abstract BACKGROUND Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently-described entity that can occasionally histologically and molecularly mimic high-grade glioma. The histologic and molecular features that predict aggressive behavior in FGFR3-TACC3 altered tumors are unclear. CASES We present a rare case of an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of high-grade glioma and analyze common molecular features between this case and a series of high-grade gliomas. After total resection, pathology of the case patient revealed predominantly low-grade cytomorphology, abundant microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34 immunoreactive and harbored both an FGFR3-TACC3 fusion and a TERT promoter mutation. Based on the overall histologic and molecular profile, a diagnosis of PLNTY was favored. The patient was thereafter observed without adjuvant therapy with no evidence of progression at 15-month follow-up. In contrast, a series of eight adult patients with glioblastomas harboring FGFR3-TACC3 fusions and correspondingly aggressive clinical courses are also presented. Common molecular findings included IDH-wildtype status, absence of 1p19q codeletion, and CDKN2A loss. TERT promoter mutations and lack of MGMT promoter methylation were also frequently observed. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. CONCLUSIONS PLNTY is a rare low-grade entity that can display characteristics of high-grade glioma, particularly in adults. The potential for a unique entity mimicking PLNTY which may act as a precursor lesion for a more malignant phenotype should be considered in cases with FGFR3-TACC3 fusions and other high-grade features.

Download Full-text

Exosome-Derived LINC00960 and LINC02470 Promote the Epithelial-Mesenchymal Transition and Aggressiveness of Bladder Cancer Cells

Cells ◽

10.3390/cells9061419 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1419

Author(s):

Cheng-Shuo Huang ◽

Jar-Yi Ho ◽

Jung-Hwa Chiang ◽

Cheng-Ping Yu ◽

Dah-Shyong Yu

Keyword(s):

Bladder Cancer ◽

Notch Signaling ◽

Cancer Cells ◽

Signaling Pathways ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Low Grade ◽

High Grade ◽

Mesenchymal Transition ◽

Bladder Cancer Cells

Exosomes are essential for several tumor progression-related processes, including the epithelial–mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) comprise a major group of exosomal components and regulate the neoplastic development of several cancer types; however, the progressive role of exosomal lncRNAs in bladder cancer have rarely been addressed. In this study, we identified two potential aggressiveness-promoting exosomal lncRNAs, LINC00960 and LINC02470. Exosomes derived from high-grade bladder cancer cells enhanced the viability, migration, invasion and clonogenicity of recipient low-grade bladder cancer cells and activated major EMT-upstream signaling pathways, including β-catenin signaling, Notch signaling, and Smad2/3 signaling pathways. Nevertheless, LINC00960 and LINC02470 were expressed at significantly higher levels in T24 and J82 cells and their secreted exosomes than in TSGH-8301 cells. Moreover, exosomes derived from LINC00960 knockdown or LINC02470 knockdown T24 cells significantly attenuated the ability of exosomes to promote cell aggressiveness and activate EMT-related signaling pathways in recipient TSGH-8301 cells. Our findings indicate that exosome-derived LINC00960 and LINC02470 from high-grade bladder cancer cells promote the malignant behaviors of recipient low-grade bladder cancer cells and induce EMT by upregulating β-catenin signaling, Notch signaling, and Smad2/3 signaling. Both lncRNAs may serve as potential liquid biomarkers for the prognostic surveillance of bladder cancer progression.

Download Full-text

Down-regulation of leucine zipper putative tumor suppressor 1 is associated with poor prognosis, increased cell motility and invasion, and epithelial-to-mesenchymal transition characteristics in human breast carcinoma

Human Pathology ◽

10.1016/j.humpath.2010.12.007 ◽

2011 ◽

Vol 42 (10) ◽

pp. 1410-1419 ◽

Cited By ~ 13

Author(s):

Xin-Xin Wang ◽

Zhengmao Zhu ◽

Dan Su ◽

Ting Lei ◽

Xiao Wu ◽

...

Keyword(s):

Breast Carcinoma ◽

Tumor Suppressor ◽

Cell Motility ◽

Poor Prognosis ◽

Leucine Zipper ◽

Epithelial To Mesenchymal Transition ◽

Human Breast ◽

Down Regulation ◽

Mesenchymal Transition ◽

Putative Tumor Suppressor

Download Full-text

Clinicopathologic characteristics of pure papillary breast carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e12521 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e12521-e12521

Author(s):

Fatma P. Turkoz ◽

Mustafa Solak ◽

Özge Keskin ◽

Zafer Arik ◽

Cagatay Arslan ◽

...

Keyword(s):

Breast Carcinoma ◽

Ductal Carcinoma ◽

Menopausal Status ◽

Survival Rates ◽

Disease Free Survival ◽

Lymph Node Involvement ◽

Low Grade ◽

Breast Cancer Patients ◽

Clinicopathologic Characteristics ◽

Node Involvement

e12521 Background: Pure papillary breast carcinoma (PPBC) is a very rare entity which usually occurs in older women with a favorable prognosis. The aim of this cohort study was to evaluate the demographic, clinicopathologic characteristics and survival rates of PPBC compared to invasive ductal carcinoma (IDC). Methods: A total of 2451 invasive breast cancer patients from a single center were analyzed retrospectively. Of these, 24 patients were PPBC (1%) and 1785 (73%) patients were pure IDC. Results: PPBC were significantly different from IDC with respect to the age at diagnosis, menopausal status, tumor size, grade and lymph node involvement (p<0.05) (Table 1). The median follow-up period was 26,5 months (4-400 months). Only one patient with PPBC had lung and bone metastasis, others were alive with no evidence of disease. PPBC was associated with a better 5-year overall survival (100 vs. 84%) and disease-free survival (75 vs. 54%) compared to IDC. Conclusions: Compared to IDC, PPBC is a small, low-grade tumor and less likely to involve the lymph nodes. Cases are usually older, postmenopausal women and have a better prognosis. [Table: see text]

Download Full-text

Prognostic Role of High-Grade Tumor Budding in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis with a Focus on Epithelial to Mesenchymal Transition

Cancers ◽

10.3390/cancers11010113 ◽

2019 ◽

Vol 11 (1) ◽

pp. 113 ◽

Cited By ~ 11

Author(s):

Rita Lawlor ◽

Nicola Veronese ◽

Alessia Nottegar ◽

Giuseppe Malleo ◽

Lee Smith ◽

...

Keyword(s):

Systematic Review ◽

Pancreatic Ductal Adenocarcinoma ◽

Epithelial To Mesenchymal Transition ◽

Meta Analysis ◽

Tumor Budding ◽

Ductal Adenocarcinoma ◽

High Grade ◽

Prognostic Role ◽

Mesenchymal Transition

This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13–1.88, p = 0.004; HR, 2.65; 95% CI, 1.79–3.91; p < 0.0001) and of recurrence (RR, 1.61; 95% CI, 1.05–2.47, p = 0.03) for PDAC patients with high-grade TB. Moreover, we found that EMT is a central process in determining the presence of TB in PDAC. Thanks to this meta-analysis, we demonstrate the potential clinical significance of high-grade TB for prognostic stratification of PDAC. TB also shows a clear association with the process of EMT. Based on the results of the present study, TB should be conveyed in pathology reports and taken into account by future oncologic staging systems.

Download Full-text