Meta-analysis of Histopathological Features of Primary Colorectal Cancers that Predict Lymph Node Metastases

Glasgow, Sean C.; Bleier, Joshua I. S.; Burgart, Lawrence J.; Finne, Charles O.; Lowry, Ann C.

doi:10.1007/s11605-012-1827-4

Cited by 89 publications

(70 citation statements)

References 79 publications

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“…3,4 Tumor budding at the invasive tumor margin is an established negative prognostic factor in resected colorectal cancer. [5][6][7][8][9][10][11][12] Widespread use of tumor budding as a prognostic factor has been impeded by a lack of standardized histopathological criteria, highlighted recently by Mitrovic et al 13 who state that 'although performing a tumor bud count is easy in theory, deciding what is or is not a bud can prove surprisingly difficult in practice'. Recent studies have addressed the role of tumor budding in resected colorectal specimens.…”

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confidence: 99%

Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy

et al. 2014

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Tumor budding is an increasingly important prognostic feature for pathologists to recognize. The aim of this study was to correlate intra-tumoral budding in pre-treatment rectal cancer biopsies with pathological response to neoadjuvant chemoradiotherapy and with long-term outcome. Data from a prospectively maintained database were acquired from patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy. Pre-treatment rectal biopsies were retrospectively reviewed for evidence of intra-tumoral budding. Multivariate logistic regression was used to identify factors contributing to cancer-specific death, expressed as hazard ratios with 95% confidence intervals. Of the 185 patients with locally advanced rectal cancer, 89 patients met the eligibility criteria, of whom 18 (20%) exhibited budding in a pre-treatment tumor biopsy. Intra-tumoral budding predicted a poor pathological response to neoadjuvant chemoradiotherapy (higher ypT stage, P ¼ 0.032; lymph node involvement, P ¼ 0.018; lymphovascular invasion, P ¼ 0.004; and residual poorly differentiated tumors, P ¼ 0.005). No patient with intra-tumoral budding exhibited a tumor regression grade 1 or complete pathological response, providing a 100% specificity and positive predictive value for non-response to neoadjuvant chemoradiotherapy. Intra-tumoral budding was associated with a lower disease-free 5-year survival rate (33 vs 78%, Po0.001), cancer-specific 5-year survival rate (61 vs 87%, P ¼ 0.021) and predicted cancer-specific death (hazard ratio 3.51, 95% confidence interval 1.03-11.93, P ¼ 0.040). Intratumoral budding at diagnosis of rectal cancer identifies those who will poorly respond to neoadjuvant chemoradiotherapy and those with a poor prognosis.

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Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy

et al. 2014

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“…A wealth of original studies, systematic and meta-analysis reviews have been published on the subject of lymphatic vessel invasion (LVI) [5-7], lymphatic vessel density (LVD) [8-10] and tumour budding (TB) [11-15] in CRC prognosis [16,17]. A number of these have concentrated on early stage disease and the ability to utilise histopathological features to predict lymph node metastasis or to stratify patients at high risk of disease recurrence and poor outcome [6,9,16,18-22].…”

Section: Introductionmentioning

confidence: 99%

Quantification of tumour budding, lymphatic vessel density and invasion through image analysis in colorectal cancer

Caie

Turnbull

Farrington

et al. 2014

Journal of Translational Medicine

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BackgroundTumour budding (TB), lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) have shown promise as prognostic factors in colorectal cancer (CRC) but reproducibility using conventional histopathology is challenging. We demonstrate image analysis methodology to quantify the histopathological features which could permit standardisation across institutes and aid risk stratification of Dukes B patients.MethodsMultiplexed immunofluorescence of pan-cytokeratin, D2-40 and DAPI identified epithelium, lymphatic vessels and all nuclei respectively in tissue sections from 50 patients diagnosed with Dukes A (n = 13), Dukes B (n = 29) and Dukes C (n = 8) CRC. An image analysis algorithm was developed and performed, on digitised images of the CRC tissue sections, to quantify TB, LVD, and LVI at the invasive front.ResultsTB (HR =5.7; 95% CI, 2.38-13.8), LVD (HR =5.1; 95% CI, 2.04-12.99) and LVI (HR =9.9; 95% CI, 3.57-27.98) were successfully quantified through image analysis and all were shown to be significantly associated with poor survival, in univariate analyses. LVI (HR =6.08; 95% CI, 1.17-31.41) is an independent prognostic factor within the study and was correlated to both TB (Pearson r =0.71, p <0.0003) and LVD (Pearson r =0.69, p <0.0003).ConclusionWe demonstrate methodology through image analysis which can standardise the quantification of TB, LVD and LVI from a single tissue section while decreasing observer variability. We suggest this technology is capable of stratifying a high risk Dukes B CRC subpopulation and we show the three histopathological features to be of prognostic significance.

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“…Of these, tumor budding at the invasive front has been recognized as a strong predictor of lymph node involvement, distant metastasis, local recurrence, and poor disease-free survival 60-63. However, a recent meta-analysis of 76 selected articles from 602 citations concluded that: (1) “no single histopathological feature of colorectal cancer reliably predicted lymph node metastases, and (2) several risk factors that correlate highly with nodal disease are not routine components of standard pathology reports” 64. More importantly, tumor budding at the invasive front is primarily, if not solely, seen at the invasive stage of disease, which is often beyond the point where surgery alone is curative.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, detection of tumor budding at the invasive front is unlikely to have significant value for early detection and intervention of CRC metastasis. Similarly, no other immunohistochemical feature can reliably predict the invasive or metastatic potential of a given CRC or identify the specific individuals with pending or at increased risk for metastatic CRC 64.…”

Section: Introductionmentioning

confidence: 99%

Cell Budding from Normal Appearing Epithelia: A Predictor of Colorectal Cancer Metastasis?

Jiang¹,

Mason²,

Jewett³

et al. 2013

Int. J. Biol. Sci.

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Background: Colorectal carcinogenesis is believed to be a multi-stage process that originates with a localized adenoma, which linearly progresses to an intra-mucosal carcinoma, to an invasive lesion, and finally to metastatic cancer. This progression model is supported by tissue culture and animal model studies, but it is difficult to reconcile with several well-established observations, principally among these are that up to 25% of early stage (Stage I/II), node-negative colorectal cancer (CRC) develop distant metastasis, and that circulating CRC cells are undetectable in peripheral blood samples of up to 50% of patients with confirmed metastasis, but more than 30% of patients with no detectable metastasis exhibit such cells. The mechanism responsible for this diverse behavior is unknown, and there are no effective means to identify patients with pending, or who are at high risk for, developing metastatic CRC.Novel findings: Our previous studies of human breast and prostate cancer have shown that cancer invasion arises from the convergence of a tissue injury, the innate immune response to that injury, and the presence of tumor stem cells within tumor capsules at the site of the injury. Focal degeneration of a capsule due to age or disease attracts lymphocyte infiltration that degrades the degenerating capsules resulting in the formation of a focal disruption in the capsule, which selectively favors proliferating or “budding” of the underlying tumor stem cells. Our recent studies suggest that lymphocyte infiltration also triggers metastasis by disrupting the intercellular junctions and surface adhesion molecules within the proliferating cell buds causing their dissociation. Then, lymphocytes and tumor cells are conjoined through membrane fusion to form tumor-lymphocyte chimeras (TLCs) that allows the tumor stem cell to avail itself of the lymphocyte's natural ability to migrate and breach cell barriers in order to intravasate and to travel to distant organs. Our most recent studies of human CRC have detected nearly identical focal capsule disruptions, lymphocyte infiltration, budding cells, and the formation of TLCs. Our studies have further shown that age- and type-matched node-positive and -negative CRC have a significantly different morphological and immunohistochemical profile and that the majority of lymphatic ducts with disseminated cells are located within the mucosa adjacent to morphologically normal appearing epithelial structures that express a stem cell-related marker.New hypothesis: Based on these findings and the growth patterns of budding cells revealed by double immunohistochemistry, we further hypothesize that metastatic spread is an early event of carcinogenesis and that budding cells overlying focal capsule disruptions represent invasion- and metastasis-initiating cells that follow one of four pathways to progress: (1) to undergo extensive in situ proliferation leading to the formation of tumor nests that subsequently invade the submucosa, (2) to migrate with associated lymphocytes functioning a...

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Meta-analysis of Histopathological Features of Primary Colorectal Cancers that Predict Lymph Node Metastases

Cited by 89 publications

References 79 publications

Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy

Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy

Quantification of tumour budding, lymphatic vessel density and invasion through image analysis in colorectal cancer

Cell Budding from Normal Appearing Epithelia: A Predictor of Colorectal Cancer Metastasis?

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