Prognostic Implication of Poorly Differentiated Clusters, Tumor Budding, and Tumor Regression in Resected Rectal Cancer Status Post Neoadjuvant Therapy

Abstract Background Budding is a complementary prognostic factor for colorectal cancer. In this study, we aimed to clarify the role of tumor budding in rectal cancer patients after preoperative chemoradiotherapy. Methods A total of 124 patients with rectal cancer treated with neoadjuvant chemoradiotherapy and consecutive surgery were included. Surgical specimens were evaluated for budding and routine clinicopathological features. Budding was evaluated on hematoxylin and eosin (H&E)-stained slides and by cytokeratin immunohistochemical (IHC) staining. Results A budding rate of 36.9% (n = 38) by H&E and 55.6% (n = 55) by IHC was observed. Budding was significantly associated with a high ypT and ypN status, poor differentiation, and low degrees of tumor regression. Moreover, budding was strongly predictive of a worse patient outcome, as measured by tumor recurrence or death. In multivariate analyses, budding remained the only significant parameter for overall survival and was even superior to the ypT and ypN status (budding in H&E: hazard ratio (HR) 2.72, 95% confidence interval (95% CI) 1.15–6.44, p = 0.023; budding in IHC: HR 5.19, 95% CI 1.62–16.61, p = 0.006). Conclusion Budding is a strong prognostic predictor of survival in rectal cancer patients after neoadjuvant therapy. A standardized evaluation of tumor budding after neoadjuvant therapy may thus aid in risk stratification and guide the clinical management of patients with rectal cancer. Immunostaining can help to enhance the diagnostic accuracy and prognostic significance.

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Rectal cancer – current treatment strategy and the tumor regression grade evaluation after neoadjuvant therapy in patients who underwent surgery at the I. Department of Surgery, General University Hospital in Prague between 2012 and 2016

10.33699/pis.2021.100.2.74-82 ◽

2021 ◽

Vol 100 (2) ◽

Keyword(s):

Rectal Cancer ◽

Neoadjuvant Therapy ◽

Tumor Regression ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Current Treatment ◽

University Hospital ◽

Tumor Regression Grade ◽

Oncological Treatment ◽

Regression Grade

Introduction: The article contains a summary of the issues of staging and therapy with an emphasis on the neoadjuvant treatment and associated tumor regression grade with the analysis of our own group of patients. Methods: Retrospective analysis of patients with rectal cancer who underwent a surgery at the 1st Department of Surgery – Thoratic, Abdominal and Injury Surgery; First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic, focusing on those who underwent neoadjuvant chemoradiotherapy and their pathologists evaluated tumor regression grade after the resection. Results: The group consists of 161 patients operated on between 2012 and 2016. 47 patients underwent neoadjuvant oncological treatment with further evaluation of the tumor regression grade by a pathologist, a scoring system according to Ryan was used. A complete pathological response was elicited in 10.4% of patients, no response in 35.4% of patients, and partial tumor regression in 54.2%. Conclusion: Although there is a difference in our results compared to foreign publications, the proportion of patients remains comparable. Studies evaluating the advantages versus disadvantages of neoadjuvant therapy will certainly follow, and the question of the suitability of surgical treatment as the only curative solution is partially raised.

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Comment on Jun, S.Y.; et al. “Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma” Cancers 2020, 12, 2199

Cancers ◽

10.3390/cancers12102982 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2982 ◽

Cited By ~ 1

Author(s):

Paolo Giuffrida ◽

Giovanni Arpa ◽

Alessandro Vanoli ◽

Antonio Di Sabatino

Keyword(s):

Tumor Budding ◽

Poorly Differentiated Clusters ◽

Poorly Differentiated ◽

Small Intestinal ◽

Small Intestinal Adenocarcinoma

We read with interest the paper by Jun S [...]

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The prognostic value of tumor budding in patients who had surgery for rectal cancer with and without neoadjuvant therapy

Techniques in Coloproctology ◽

10.1007/s10151-019-01959-2 ◽

2019 ◽

Vol 23 (4) ◽

pp. 333-342 ◽

Cited By ~ 3

Author(s):

A. H. Şirin ◽

S. Sökmen ◽

S. M. Ünlü ◽

H. Ellidokuz ◽

S. Sarioğlu

Keyword(s):

Rectal Cancer ◽

Neoadjuvant Therapy ◽

Prognostic Value ◽

Tumor Budding

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New tumor regression grade for rectal cancer after neoadjuvant therapy and radical surgery

Oncotarget ◽

10.18632/oncotarget.6008 ◽

2015 ◽

Vol 6 (39) ◽

pp. 42222-42231 ◽

Cited By ~ 3

Author(s):

Jun Li ◽

Hao Liu ◽

Junjie Hu ◽

Sai Liu ◽

Jie Yin ◽

...

Keyword(s):

Rectal Cancer ◽

Neoadjuvant Therapy ◽

Radical Surgery ◽

Tumor Regression ◽

Tumor Regression Grade ◽

Regression Grade

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Reply to Comment on “Jun, S.Y.; et al. Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma” Cancers 2020, 12, 2199

Cancers ◽

10.3390/cancers12102987 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2987

Author(s):

Sun-Young Jun ◽

Seung-Mo Hong

Keyword(s):

Tumor Budding ◽

Poorly Differentiated Clusters ◽

Poorly Differentiated ◽

Small Intestinal ◽

Small Intestinal Adenocarcinoma

We thank Giuffrida et al [...]

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Density and distribution of lymphocytes in pretherapeutic rectal cancer and response to neoadjuvant therapy

Gastroenterology Report ◽

10.1093/gastro/goaa016 ◽

2020 ◽

Author(s):

Sicong Lai ◽

Xiaoying Lou ◽

Xinjuan Fan ◽

Weipeng Sun ◽

Yanhong Deng ◽

...

Keyword(s):

Rectal Cancer ◽

Neoadjuvant Therapy ◽

Tumor Regression ◽

Tumor Infiltrating Lymphocytes ◽

Sensitivity Analyses ◽

Tumor Regression Grade ◽

Cancer Tissue ◽

Infiltrating Lymphocytes ◽

Regression Grade

Abstract Background Lymphocytic density in rectal cancer has been reported to be associated with therapeutic response, but the role of the lymphocytic distribution pattern remains to be determined. This study aimed to evaluate the association between the distribution and density of lymphocytes in rectal-cancer tissue with tumor response to neoadjuvant therapy. Methods We retrospectively analysed 134 patients with rectal cancer receiving neoadjuvant therapy within a prospectively maintained cohort. Pretherapeutic biopsy samples were stained with immunohistochemistry (CD4 and CD8). Densities of intratumoral periglandular lymphocytes (IPLs) and tumor-infiltrating lymphocytes (TILs) were assessed separately. Logistic-regression analysis was used to assess associations of lymphocyte densities with tumor regression grade (TRG), controlling for clinicopathological, molecular, and regimen features. Results Compared with cases in the lowest quartile of CD8+ TILs, those in the highest quartile were significantly associated with better TRG (multivariate odds ratio, 0.23; 95% confidence interval, 0.07 to 0.76; P < 0.001). In contrast, CD8+ IPLs, CD4+ IPLs, and CD4+ TILs were not significantly associated with TRG (P = 0.033, 0.156, and 0.170, respectively). Sensitivity analyses detected no interaction between CD8+ TILs and regimen of neoadjuvant radiation (Pinteraction = 0.831) or chemotherapy (Pinteraction = 0.879) on TRG. Conclusions Our data suggest that CD8+ TILs, but not IPLs, are independently associated with response to neoadjuvant therapy, regardless of the regimen of radiation or chemotherapy.

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

Modern Pathology ◽

10.1038/modpathol.2013.124 ◽

2013 ◽

Vol 27 (1) ◽

pp. 156-162 ◽

Cited By ~ 64

Author(s):

Ailín C Rogers ◽

David Gibbons ◽

Ann M Hanly ◽

John MP Hyland ◽

P Ronan O'Connell ◽

...

Keyword(s):

Rectal Cancer ◽

Neoadjuvant Therapy ◽

Prognostic Significance ◽

Tumor Budding

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Survival landscape of different tumor regression grades and pathologic complete response in rectal cancer after neoadjuvant therapy based on reconstructed individual patient data

BMC Cancer ◽

10.1186/s12885-021-08922-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jia-yi Li ◽

Xuan-zhang Huang ◽

Peng Gao ◽

Yong-xi Song ◽

Xiao-wan Chen ◽

...

Keyword(s):

Rectal Cancer ◽

Neoadjuvant Therapy ◽

Individual Patient Data ◽

Tumor Regression ◽

Pathologic Complete Response ◽

Disease Free Survival ◽

Direct Calculation ◽

Complete Response ◽

Patient Data ◽

Term Survival

Abstract Background Neoadjuvant therapy can lead to different tumor regression grades (TRG) in rectal cancer after neoadjuvant therapy. The purposes of this study are to investigate the relationships among TRG, pathologic complete response (pCR) and long-term survival, on the basis of reconstructed individual patient data (IPD). Methods The PubMed, Embase, Ovid and Cochrane CENTRAL databases were searched. The primary endpoint was to evaluate the survival landscape of different TRGs after neoadjuvant therapy and the secondary endpoint was to evaluate the associations between pCR and survival. IPD were reconstructed with Kaplan–Meier curves. Results The 10-year overall survival (OS) and 5-year disease-free survival (DFS) were clearly higher in the pCR group than in the non-pCR (npCR) group (80.5% vs. 48.3, 90.1% vs. 69.8%). Furthermore, the OS and DFS increased with improvement in tumor regression after neoadjuvant therapy. According to the IPD, the pCR group had longer OS (HR = 0.240, 95% CI = 0.177–0.325, p < 0.001) and DFS (HR = 0.274, 95% CI = 0.205–0.367, p < 0.001) than the npCR group. Better tumor regression was associated with better survival outcomes (p < 0.005). Direct calculation of published HR values yielded similar results. Conclusions Our results indicate a positive relationship between better tumor regressions and improved survival benefits among the npCR group and patients with rectal cancer achieving pCR had much longer OS and DFS than patients achieving npCR, presenting a survival landscape of different TRGs and pCR in rectal cancer after neoadjuvant therapy.

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Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma

Cancers ◽

10.3390/cancers12082199 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2199 ◽

Cited By ~ 2

Author(s):

Sun-Young Jun ◽

Joon-Yong Chung ◽

Nara Yoon ◽

Eun Sun Jung ◽

Young-Ha Oh ◽

...

Keyword(s):

Tumor Cells ◽

Single Cells ◽

Prognostic Indicator ◽

Tumor Budding ◽

High Grade ◽

Stage Grouping ◽

Lower Stage ◽

Poorly Differentiated Clusters ◽

Poorly Differentiated ◽

Small Intestinal

The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters ≤4 tumor cells) and PDC (clusters ≥5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (≤4), grade-2 (5–9), or grade-3 (≥10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months; p = 0.007) in the lower stage (stages I–II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages.

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