Tumor Budding: Prognostic Value in Muscle-invasive Bladder Cancer

Soriano, L. Lorenzo; Jurado, G. Ordaz; Moreno, J.L. Pontones; Castillo, Sara; Giron, Soraya Hernandez; Moreno, I. Pascual; Soler, David Ramos

doi:10.1016/j.urology.2019.04.006

Cited by 19 publications

(14 citation statements)

References 23 publications

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“…The phenomenon “tumor budding” is regarded as a specific “signal” indicating the onset of cancer invasion and metastasis. The presence of tumor buds in the invasive front was found to be associated with increased metastasis and poor prognosis in various cancers [28,29,30,31,32,33,34].…”

Section: Introductionmentioning

confidence: 99%

Markers of Cancer Cell Invasion: Are They Good Enough?

Gerashchenko

Novikov

Krakhmal

et al. 2019

JCM

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Invasion, or directed migration of tumor cells into adjacent tissues, is one of the hallmarks of cancer and the first step towards metastasis. Penetrating to adjacent tissues, tumor cells form the so-called invasive front/edge. The cellular plasticity afforded by different kinds of phenotypic transitions (epithelial–mesenchymal, collective–amoeboid, mesenchymal–amoeboid, and vice versa) significantly contributes to the diversity of cancer cell invasion patterns and mechanisms. Nevertheless, despite the advances in the understanding of invasion, it is problematic to identify tumor cells with the motile phenotype in cancer tissue specimens due to the absence of reliable and acceptable molecular markers. In this review, we summarize the current information about molecules such as extracellular matrix components, factors of epithelial–mesenchymal transition, proteases, cell adhesion, and actin cytoskeleton proteins involved in cell migration and invasion that could be used as invasive markers and discuss their advantages and limitations. Based on the reviewed data, we conclude that future studies focused on the identification of specific invasive markers should use new models one of which may be the intratumor morphological heterogeneity in breast cancer reflecting different patterns of cancer cell invasion.

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Section: Introductionmentioning

confidence: 99%

Markers of Cancer Cell Invasion: Are They Good Enough?

Gerashchenko

Novikov

Krakhmal

et al. 2019

JCM

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“…Tumor budding assessment with median bud count in 5 HPFs using pancytokeratin staining was easy and reproducible according to two independent reviewers. AE1/AE3 has been used to determine tumor budding in MIBC 9 , squamous cell carcinoma of the lung 14 and colorectal carcinoma 20 . Horcic et al and Karamitopoulou et al showed that performing pancytokeratin staining with AE1/AE3 in colorectal carcinoma and calculating tumor budding in HPFs was accurate and reproducible with high interobserver agreement 20 , 21 .…”

Section: Discussionmentioning

confidence: 99%

“…Another way to identify infiltrative and aggressive tumors could be by examining tumor budding. Tumor budding is defined as a single cell or a cluster of up to 5 cells at the tumor invasion front 9 . Tumor budding has been shown to be associated with adverse tumor features and worse survival in breast cancer 10 – 13 , squamous cell carcinoma of the lung 14 and colorectal cancer 15 , 16 .…”

Section: Introductionmentioning

confidence: 99%

“…In colorectal carcinoma, tumor budding has been widely investigated and shown to be prognostic in a prospective trial 16 and its incorporation into current guidelines has been proposed 17 . In MIBC, tumor budding is associated with worse cancer-specific survival (CSS) 9 , while it seems to be associated with worse progression-free survival (PFS) in T1 NMIBC 18 .…”

Section: Introductionmentioning

confidence: 99%

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Tumor budding correlates with tumor invasiveness and predicts worse survival in pT1 non-muscle-invasive bladder cancer

Eckstein

Kimmel

Bruendl

et al. 2021

Sci Rep

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Tumor budding is defined as a single cell or a cluster of up to 5 tumor cells at the invasion front. Due to the difficulty of identifying patients at high risk for pT1 non-muscle-invasive bladder cancer (NMIBC) and the difficulties in T1 substaging, tumor budding was evaluated as a potential alternative and prognostic parameter in these patients. Tumor budding as well as growth pattern, invasion pattern and lamina propria infiltration were retrospectively evaluated in transurethral resection of the bladder (TURB) specimens from 92 patients with stage pT1 NMIBC. The presence of tumor budding correlated with multifocal tumors (p = 0.003), discontinuous invasion pattern (p = 0.039), discohesive growth pattern (p < 0.001) and extensive lamina propria invasion (p < 0.001). In Kaplan–Meier analysis, tumor budding was associated with significantly worse RFS (p = 0.005), PFS (p = 0.017) and CSS (p = 0.002). In patients who received BCG instillation therapy (n = 65), the absence of tumor budding was associated with improved RFS (p = 0.012), PFS (p = 0.011) and CSS (p = 0.022), with none of the patients suffering from progression or dying from the disease. Tumor budding is associated with a more aggressive and invasive stage of pT1 NMIBC and a worse outcome. This easy-to-assess parameter could help stratify patients into BCG therapy or early cystectomy treatment groups.

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“…High‐grade TB has been established as a poor prognostic indicator that may be helpful for patient stratification [1,2]. TB has also been recognized as prognostic factor in other types of cancer, including gastric adenocarcinoma [3–7], esophageal squamous cell carcinoma [8–10], pancreatic adenocarcinoma [11–13], ampullary adenocarcinoma [14], head and neck squamous cell carcinoma [15–19], breast cancer [20], and bladder cancer [21]. In addition, TB has been reported to be a useful prognostic factor for cholangiocarcinoma [22–24].…”

Section: Introductionmentioning

confidence: 99%

Three‐dimensional analysis of extrahepatic cholangiocarcinoma and tumor budding

Yoshizawa

Hong

Jung

et al. 2020

The Journal of Pathology

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Advances in tissue clearing and microscopy make it possible to study human diseases in three dimensions (3D). Highgrade tumor budding is known to be associated with poor prognosis in various cancers; however, little is known about the 3D architecture of tumor budding. Using tissue clearing, we analyzed the 3D structure of tumor budding and Ecadherin expression in 31 extrahepatic cholangiocarcinomas. A total of 31 thick slabs (up to 5 mm) were harvested from surgically resected tumor tissue, including 27 hilar and 4 distal cholangiocarcinomas. Twenty-eight cases were adenocarcinoma, and three were undifferentiated carcinoma. After clearing, the tissues were immunolabeled with antibodies to cytokeratin 19 and to E-cadherin, and then visualized using light-sheet and confocal laser scanning microscopy. Tumor budding was evaluated in hematoxylin and eosin-stained sections (2D) using standard pathological criteria. Of the 31 cancers, 13 showed low-grade tumor budding and 18 showed high-grade tumor budding. First, 3D analysis revealed that the neoplastic cells in tumor buds of adenocarcinoma were typically not individual islands of cells, but rather tips of attenuated protrusions connected to the main tumor. Second, adenocarcinomas with low-grade tumor budding were composed predominantly of tubules that only focally form cords at the periphery. By contrast, adenocarcinomas with high-grade tumor budding predominantly formed cords in both centers and peripheries of the tumors. Third, adenocarcinoma with low-grade tumor budding was characterized by a few short protrusions with few branches, whereas adenocarcinoma with high-grade tumor budding was characterized by longer protrusions with more branching. Finally, immunolabeling of E-cadherin was stronger in the center of the adenocarcinoma but decreased at the tips of protrusions. E-cadherin loss was more extensive in the protrusions of high-grade tumor budding than in the protrusions of low-grade tumor budding. Our findings suggest that tumor buds as seen in 2D are, in fact, cross-sections of attenuated but contiguous protrusions extending from the main tumor.

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Tumor Budding: Prognostic Value in Muscle-invasive Bladder Cancer

Cited by 19 publications

References 23 publications

Markers of Cancer Cell Invasion: Are They Good Enough?

Markers of Cancer Cell Invasion: Are They Good Enough?

Tumor budding correlates with tumor invasiveness and predicts worse survival in pT1 non-muscle-invasive bladder cancer

Three‐dimensional analysis of extrahepatic cholangiocarcinoma and tumor budding

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