Research ArticleClinical Studies
Open Access

Tumor Budding as a Predictive Marker of Relapse and Survival in Patients With Stage II Colon Cancer

KAZUYUKI SAITO, TAKASHI OKUYAMA, SHUNYA MIYAZAKI, HARUKA OI, TAKASHI MITSUI, TAKUJI NORO, EMIKO TAKESHITA, YUKO ONO, TAIZEN URAHASHI, HIDEHIRO TAJIMA and HIDEYUKI YOSHITOMI
In Vivo July 2022, 36 (4) 1820-1828; DOI: https://doi.org/10.21873/invivo.12898

Abstract

Background/Aim: Tumor budding (TB) has recently been recognized worldwide as a prognostic predictor in several solid cancers. The objective of this study was to explore the relationship between TB and clinicopathological characteristics, postoperative relapse, and survival in patients with stage II colon cancer. Patients and Methods: A total of 213 patients with stage II colon cancer were retrospectively enrolled at Saitama Medical Center, Dokkyo Medical University from 2010 to 2016. TB was evaluated in hotspot areas on hematoxylin and eosin-stained slides at the invasive front of the tumor to define a low-grade group (BD1) and a high-grade group (BD2 or BD3). Results: High-grade TB was found in 38.3% of cases, and was associated with pT4, presence of lymphovascular invasion, and tumor relapse (p=0.02, p=0.03, p=0.002, respectively). Patients with highgrade TB showed worse relapse-free survival (RFS) and overall survival (OS) rates than patients with low-grade TB (5-year RFS: High 75.6% vs. Low 92.1%, p=0.001; 5-year OS: High 93.7% vs. Low 93.7%, p=0.001). On multivariate analysis for predictors of RFS and OS, high-grade TB was significant for both RFS and OS (RFS, p=0.003; OS, p=0.005). Patients with high-grade TB experienced lung and liver relapses significantly more frequently than patients with low-grade TB (p=0.03 each). Among patients who received adjuvant chemotherapy (AC), no patients showed lung or liver relapse even in the presence of high-grade TB. Conclusion: TB may offer a useful predictor of relapse in patients with stage II colon cancer after surgery, and AC should be considered for patients with high-grade TB.

Curative surgical resection is the fundamental treatment for patients with stage I and II colon cancer, whereas surgical resection and adjuvant chemotherapy (AC) using the combination of fluoropyrimidine and oxaliplatin is the standard treatment for patients with stage III colon cancer. Three landmark trials have shown that AC for patients with curatively resected stage III colon cancer reduced deaths by about 15% (1-3). However, the adaption of AC to patients with stage II colon cancer has been debated (4-6). The QUASAR trial showed only a small (3%) benefit to overall survival (OS) from AC with fluorouracil and folinic acid (7). Other large meta-analyses and randomized trials have shown survival rates in high-risk patients with stage II colon cancer comparable to those of patients with metastatic disease (8-10).

Current international guidelines have identified T4 lesions, lymphovascular or perineural invasions, poorly differentiated histology, examination of less than 12 lymph nodes, elevated levels of carcinoembryonic antigen (CEA), bowel perforation, and obstruction as poor prognostic factors for patients with stage II colon cancer (11, 12). Although sufficient supporting evidence is still lacking, these guidelines presently recommend AC for high-risk patients with stage II colon cancer.

Tumor budding (TB) is presently recognized as a morphological and adverse prognostic factor in many solid cancers, particularly colorectal cancer (CRC) (13). TB is generally defined as a single cancer cell or clusters of up to four cancer cells at the invasive front of the tumor, and standardized scoring systems for TB in CRC have been assessed at the International Tumor Budding Consensus Conference (ITBCC) (14). Regardless of clinical scenarios, the ITBCC scoring system has shown the potential to influence patients with pT1 (stage I) and stage II CRC.

The ITBCC scoring system addresses the lack of standardized and methodological assessments for TB but requires further refinement for the precise selection of high-risk patients. The present study aimed to evaluate the relationships between TB and clinicopathological findings, patterns of postoperative relapse, and survival in patients with stage II colon cancer, and whether TB is useful for deciding the adoption of AC to patients with stage II colon cancer.

Patients and Methods

Patients. This retrospective cohort study was conducted at Saitama Medical Center, Dokkyo Medical University using records from 2010 to 2016 regarding patients with stage II colon cancer who underwent curative resection. The study included 213 consecutive patients (112 men, 101 women) who had undergone surgery either alone or with fluorouracil-based AC. The primary and secondary end points of the present study were to explore the relationships between TB and RFS and OS.

Exclusion criteria were as follows: patients with all rectal cancers including rectosigmoid cancer; patients with hereditary CRC syndromes, inflammatory bowel disease, or familial adenomatous polyposis; patients who had received neoadjuvant chemotherapy; patients who had received non-curative surgery; patients with suspected stage IV disease; patients with an insufficient observation period (less than 6 months); patients who had died within 90 days; patients with other advanced malignant diseases; and patients with poorly differentiated adenocarcinoma or signet-ring cell carcinoma. Patients with poorly differentiated or signet ring cell carcinoma were excluded from the study, and those with mucinous carcinoma were included based on our previous study (15).

Tumor location was divided into right-side colon (including cecum, ascending colon, or transverse colon) and left-side colon (including descending colon or sigmoid colon). Tumor stage was diagnosed according to the TNM classification, and this study included patients with T3N0, T4aN0, and T4bN0. Lymph node dissection was considered adequate if at least 12 lymph nodes were investigated, in compliance with the recommendation by the American Joint Committee on Cancer (16). The application of AC after surgery was performed according to the ESMO guideline for patients with high-risk stage II colon cancer, physical state and patient preference, after obtaining sufficient informed consent (11). Regarding AC, oral (UFT/LV: uracil-tegafur/leucovorin or capecitabine) or intravenous [FOLFOX: oxaliplatin with folinic acid and 5-fluorouracil (5-FU) or XELOX: capecitabine plus oxaliplatin] treatments were administrated for 6 months.

This study was reviewed and approved by the Saitama Medical Center, Dokkyo Medical University (approval no. 2081).

Assessment of TB. TB was defined as a single cancer cell or a cell cluster consisting of ≤4 cancer cells at the invasive front of the primary tumor, as scored by two observers (K.S. and Y.O.). The process of counting TBs was performed in 10 high-power fields at medium power (10× objective) along the invasive front of the primary tumor using hematoxylin and eosin (HE)-stained sections. Among those “hotspots”, the number of TBs was counted under a 20× objective lens for the hotspot showing the most frequent TBs (hotspot method). These processes were evaluated for TB according to ITBCC criteria (14). The grade of TB was classified as low-grade (BD1, 0-4 TBs) or high-grade (BD2, 5-9 TBs or BD3, ≥10 TBs) (Figure 1). Inter-observer reliability as assessed using K-statistics was 0.68.

Figure 1.
Figure 1.

Hematoxylin and eosin-stained images for tumor budding (TB) in colon cancer. Tumor budding is evaluated at the hotspot at the invasive front of the tumor. A) Low-grade TB (BD1; 0 TBs per hotspot, magnification 200×); B) High-grade TB (BD3, 19 TBs per hotspot, magnification 200×).

Postoperative surveillances. Postoperative surveillance was based on the Japanese guideline for CRC (17). Physical examinations and determination of serum concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were conducted every 3 months for 3 years, then every 6 months for 2 years. Computed tomography of the chest, abdomen, and pelvis was performed every 6 months for 5 years. Colonoscopy was performed within 1 year after surgery, if no abnormality was detected, the subsequent colonoscopy was performed within 3 years. If tumor relapse was suspected, abdominal ultrasound, magnetic resonance imaging, and positron imaging tomography-computed tomography were immediately conducted for confirmation.

Statistical analysis. Continuous variables are shown as median and interquartile range (IQR) and were analyzed using the Mann-Whitney U-test. Categorical variables are presented as number and percentage and were analyzed using the chi-squared test or Fisher’s exact test. Relapse-free survival (RFS) rate was calculated from the date of operation to the date of relapse diagnosis, whereas OS rate was calculated from the date of operation to the date of death by any cause or last follow-up. RFS and OS rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Values of p<0.05 were considered statistically significant, and all analyses were performed using SPSS statistical software (version 27; IBM Japan, Tokyo, Japan).

Results

Demographics. Median tumor diameter was 47.0 cm (IQR=35-60 cm). Median RFS and OS were 62 months (IQR=42-81 months) and 66 months (IQR=47-84 months), respectively. Thirty-four patients underwent surgery with 5-FU-based AC. As the AC, UFT/LV, capecitabine, FOLFOX, and XELOX therapies were provided to 13, 7, 6, and 1 patient, respectively. High-grade TB was found in 38.3% of patients. Among patients who experienced relapse (27/213, 12.7%), 15 patients showed lung or liver relapse, with hematogenous metastasis suspected as the main route. Twenty-three patients (23/213, 14.1%) died of any causes within the observation period, of which 13 patients (56.5%, 13/23) died of causes other than colon cancer. The baseline characteristics are shown in Table I.

View this table:
Table I.

Baseline clinicopathological characteristics.

Relationship between TB and clinicopathological findings. Lymphatic and venous invasion and tumor relapse were significantly more frequent in patients with high-grade TB than in those with low-grade TB (p=0.025, p=0.044 and p=0.001, respectively). A marginal relationship between high-grade TB and pT4 was found (p=0.07). Relationships between TB and the investigated clinicopathological findings are presented in Table II.

View this table:
Table II.

The relationship between tumor budding and clinicopathological characteristics.

Influence of TB grade on RFS and OS rates. Five-year RFS and OS rates were 86.7% and 90.3% for the entire cohort. Patients with high-grade TB showed significantly lower 5 year RFS and OS rates than patients with low-grade TB (RFS: 75.2% vs. 93.7%, p<0.001; OS: 81.3% vs. 94.8%, p=0.001, respectively). Figure 2 shows the Kaplan-Meier survival curves for RFS and OS according to TB grade.

Figure 2.
Figure 2.

Relapse-free (A) and overall survival (B) curves in patients with low- and high-grade TB.

Uni- and multi-variate analyses of risk factors correlated with RFS and OS. Uni- and multivariate analyses for risk factors correlated with RFS and OS were performed using Cox proportional hazard modeling (Table III). Both pT category and TB were significant risk factors for postoperative relapse in univariate analysis (p=0.043 and p=0.001, respectively). In multivariate analysis, TB was an independent risk factor for postoperative relapse [hazard ratio (HR)=4.01, 95% confidence interval (CI)=1.744-9.201; p=0.001]. Regarding OS, univariate analysis identified TB as a significant risk factor, and preoperative serum CA19-9 level and pT category were marginally associated with OS (p=0.002, p=0.06 and p=0.06, respectively). In the multivariate analysis including these factors, TB remained a significant risk factor for OS (HR=4.02, 95%CI=1.643-9.841; p=0.002).

View this table:
Table III.

Uni- and multi-variate analyses of risk factors correlated with RFS and OS.

Influence of TB grade and AC on relapse site. The relationship between TB grade and site of first relapse is summarized in Table IV. Lung and liver relapses were significantly more frequent among patients with high-grade TB than among patients with low-grade TB (p=0.03 each). None of the 27 patients who received AC developed lung or liver relapses, even in the presence of high-grade TB (Table V).

View this table:
Table IV.

Comparison between the TB grade and first relapse site.

View this table:
Table V.

Comparison between the TB grade and relapse sites in patients who received postoperative adjuvant chemotherapy (n=27).

Discussion

The present findings suggest TB as a useful predictive marker for postoperative tumor relapse and survival in patients with stage II colon cancer who undergo curative surgery. In this study, patients with high-grade TB experienced tumor relapse more frequently than patients with low-grade TB. Patients with high-grade TB had significantly worse RFS and OS rates than patients with low-grade TB. In addition, TB was an independent risk factor for low RFS and OS rates in multivariate analyses. Lung or liver relapses were more frequently seen in patients with high-grade TB than in those with low-grade TB. Interestingly, no patients who received AC developed lung or liver relapses, even among patients with high-grade TB. Such results suggest that TB may represent an important pathological feature for selecting high-risk patients after surgery for stage II colon cancer.

Morodomi et al. first proposed the concept of TB for tumor cells detaching from the primary tumor along the invasive edge more than 30 years ago (18). TB is still recognized as a prognostic biomarker in CRC, despite many advances in surgical treatment and molecular biology. The usefulness of TB as a histological marker has been confirmed in a number of solid cancers, including esophageal, pancreatic, breast, nasopharyngeal, lung, gastric, and endometrioid cancers (19-24). Collective evidence supports the usefulness of TB as a histological feature relevant to prognosis in patients with CRC. The ITBCC grading recommendation published in 2017 provided the standard method for TB assessment in CRC (14).

The present study assessed TB using HE-stained slides in accordance with the ITBCC recommendation (14). Assessment using immunohistochemistry (IHC) has been reported to be as superior as that using HE staining, in terms of interobserver agreement and reproducibility (25-27). However, the ITBCC recommends evaluating TB using HE staining because of the possibility of miscounting stained apoptotic bodies and cellular debris, and the costeffectiveness and amount of data available from HE staining (14). In the terms of interobserver agreement, the present study showed a ĸ value of 0.68, representing adequate reliability. Interestingly, several meta-analyses have found no significant difference in prognostic power between HE staining and IHC (28, 29).

In the current study, lung and liver relapses were significantly more frequent among patients with high-grade TB than among patients with low-grade TB. The SACURA trial showed a significant correction between three-tier TB grade and organ of first relapse including the lung, liver, lymph nodes, and peritoneum (30). The difference in results between this study and the SACURA trial may be attributable to the sample size or differences in study populations. Further studies using molecular techniques may be required to clarify the relationship between TB and site of relapse in CRC patients. Interestingly, no patients in this study who received AC showed lung or liver relapses even if high-grade TB was present. The administration of AC to stage II colon cancer patients with high-grade TB may reduce postoperative relapse among high-risk patients.

A clinical advantage of TB is that TB in an intensitydependent prognostic factor (31). The number of TBs affects the risk of lymph node and distant metastases. The ITBCC has recommended the three-tier system and described only BD-3 as associated with an increased risk of relapse in patients with stage II CRC (14). The present study showed no difference in the relapse rate between patients with BD-2 and BD-3 (BD2 grade: 21% vs. BD-3 grade: 27%). This discrepancy might be due to the different patient characteristics or populations between the present study and those examined by the ITBCC. The ITBCC has indicated that the difference between 9 TBs (BD-2) and 10 TBs (BD-3) may be questionable in terms of differences in biological attitude of the primary cancer (14, 32). Further studies are necessary to clarify the utility of the grading system.

The molecular attributes of cancer cells influence the morphologic appearance on pathologic slides. Several studies have suggested that TB may represent the morphological feature of epithelial-mesenchymal transition (EMT) (33). EMT is commonly known as cellular plasticity in epithelial cells and represents the process of difference in wound healing and stem cell behaviors, contributing pathologically to fibrosis and cancer progression (34). EMT is known to allow migration of cancer cells through complex molecular mechanisms regulated by several genes. Molecular features such as loss of E-cadherin expression, β-catenin translocation, and acquisition of vimentin expression have been correlated with TB by several researchers (35, 36).

EMT-cancer cells need anoikis resistance to survive in the environment after detachment from the primary tumor. Neurotropic tyrosine receptor kinase B has been reported as a potent anoikis suppressor and is significantly overexpressed in TBs compared to the primary tumor (37). Although these findings suggest an association between TB and EMT, other studies have failed to verify the expression of EMT-related genes in TB (38). A better understanding of the molecular and pathogenetic mechanisms involved in TB and its interactions with the cellular microenvironment might provide key insights into the mechanisms governing cancer metastasis.

The present study suffered several limitations that deserve consideration when interpreting the results. This study had a retrospective design, analyzed only a small sample size, and encountered difficultly exploring the exact influence of TB and AC. Another limitation was that some biomarkers that could affect prognosis in patients with stage II colon cancer, including microsatellite instability, mismatch repair, and perineural invasion were not examined in the present study, which would have contributed some bias to the results.

Conclusion

The present study showed that 2-tier TB classification offers a predictive pathological marker of tumor relapse and survival in patients with stage II colon cancer. Although further large studies are warranted, tumors with ≥5 TBs at the invasive front may show high risk of relapse and poor prognosis compared with those with <5 TBs. Evaluation of TBs may be useful for identifying patients suitable for neoadjuvant therapy.

Footnotes

  • Authors’ Contributions

    KS, TO and MO designed the study. KS, TO, SM, HO, ET, HY and MO reviewed the clinical records. KS and YO reviewed the pathological records. All Authors participated in the study design, data interpretation, and critical discussion. KS, TO, and MO wrote the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare regarding this study.

  • Received March 5, 2022.
  • Revision received April 16, 2022.
  • Accepted April 18, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Kuebler JP,
    2. Wieand HS,
    3. O’Connell MJ,
    4. Smith RE,
    5. Colangelo LH,
    6. Yothers G,
    7. Petrelli NJ,
    8. Findlay MP,
    9. Seay TE,
    10. Atkins JN,
    11. Zapas JL,
    12. Goodwin JW,
    13. Fehrenbacher L,
    14. Ramanathan RK,
    15. Conley BA,
    16. Flynn PJ,
    17. Soori G,
    18. Colman LK,
    19. Levine EA,
    20. Lanier KS and
    21. Wolmark N
    : Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 25(16): 2198-2204, 2007. PMID: 17470851. DOI: 10.1200/JCO.2006.08.2974
    OpenUrlAbstract/FREE Full Text
    1. André T,
    2. Boni C,
    3. Navarro M,
    4. Tabernero J,
    5. Hickish T,
    6. Topham C,
    7. Bonetti A,
    8. Clingan P,
    9. Bridgewater J,
    10. Rivera F and
    11. de Gramont A
    : Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27(19): 3109-3116, 2009. PMID: 19451431. DOI: 10.1200/JCO.2008.20.6771
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Haller DG,
    2. Tabernero J,
    3. Maroun J,
    4. de Braud F,
    5. Price T,
    6. Van Cutsem E,
    7. Hill M,
    8. Gilberg F,
    9. Rittweger K and
    10. Schmoll HJ
    : Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 29(11): 1465-1471, 2011. PMID: 21383294. DOI: 10.1200/JCO.2010.33.6297
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Shi Q,
    2. Andre T,
    3. Grothey A,
    4. Yothers G,
    5. Hamilton SR,
    6. Bot BM,
    7. Haller DG,
    8. Van Cutsem E,
    9. Twelves C,
    10. Benedetti JK,
    11. O’Connell MJ and
    12. Sargent DJ
    : Comparison of outcomes after fluorouracilbased adjuvant therapy for stages II and III colon cancer between 1978 to 1995 and 1996 to 2007: evidence of stage migration from the ACCENT database. J Clin Oncol 31(29): 3656-3663, 2013. PMID: 23980089. DOI: 10.1200/JCO.2013.49.4344
    OpenUrlAbstract/FREE Full Text
    1. O’Connor ES,
    2. Greenblatt DY,
    3. LoConte NK,
    4. Gangnon RE,
    5. Liou JI,
    6. Heise CP and
    7. Smith MA
    : Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. J Clin Oncol 29(25): 3381-3388, 2011. PMID: 21788561. DOI: 10.1200/JCO.2010.34.3426
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Casadaban L,
    2. Rauscher G,
    3. Aklilu M,
    4. Villenes D,
    5. Freels S and
    6. Maker AV
    : Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer. Cancer 122(21): 3277-3287, 2016. PMID: 27417445. DOI: 10.1002/cncr.30181
    OpenUrlCrossRefPubMed
  7. ↵
    1. Quasar Collaborative Group,
    2. Gray R,
    3. Barnwell J,
    4. McConkey C,
    5. Hills RK,
    6. Williams NS and
    7. Kerr DJ
    : Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370(9604): 2020-2029, 2007. PMID: 18083404. DOI: 10.1016/S0140-6736(07)61866-2
    OpenUrlCrossRefPubMed
  8. ↵
    1. Benson AB 3rd.,
    2. Schrag D,
    3. Somerfield MR,
    4. Cohen AM,
    5. Figueredo AT,
    6. Flynn PJ,
    7. Krzyzanowska MK,
    8. Maroun J,
    9. McAllister P,
    10. Van Cutsem E,
    11. Brouwers M,
    12. Charette M and
    13. Haller DG
    : American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22(16): 3408-3419, 2004. PMID: 15199089. DOI: 10.1200/JCO.2004.05.063
    OpenUrlAbstract/FREE Full Text
    1. Hoshino N,
    2. Hasegawa S,
    3. Hida K,
    4. Kawada K,
    5. Ganeko R,
    6. Sugihara K and
    7. Sakai Y
    : Nomogram for predicting recurrence in stage II colorectal cancer. Acta Oncol 55(12): 1414-1417, 2016. PMID: 27581839. DOI: 10.1080/0284186X.2016.1223881
    OpenUrlCrossRefPubMed
  10. ↵
    1. Simillis C,
    2. Singh HKSI,
    3. Afxentiou T,
    4. Mills S,
    5. Warren OJ,
    6. Smith JJ,
    7. Riddle P,
    8. Adamina M,
    9. Cunningham D and
    10. Tekkis PP
    : Postoperative chemotherapy improves survival in patients with resected high-risk Stage II colorectal cancer: results of a systematic review and meta-analysis. Colorectal Dis 22(10): 1231-1244, 2020. PMID: 31999888. DOI: 10.1111/codi.14994
    OpenUrlCrossRefPubMed
  11. ↵
    1. Argilés G,
    2. Tabernero J,
    3. Labianca R,
    4. Hochhauser D,
    5. Salazar R,
    6. Iveson T,
    7. Laurent-Puig P,
    8. Quirke P,
    9. Yoshino T,
    10. Taieb J,
    11. Martinelli E,
    12. Arnold D and ESMO Guidelines Committee
    : Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 31(10): 1291-1305, 2020. PMID: 32702383. DOI: 10.1016/j.annonc.2020.06.022
    OpenUrlCrossRefPubMed
  12. ↵
    1. Benson AB,
    2. Venook AP,
    3. Al-Hawary MM,
    4. Arain MA,
    5. Chen YJ,
    6. Ciombor KK,
    7. Cohen S,
    8. Cooper HS,
    9. Deming D,
    10. Farkas L,
    11. Garrido-Laguna I,
    12. Grem JL,
    13. Gunn A,
    14. Hecht JR,
    15. Hoffe S,
    16. Hubbard J,
    17. Hunt S,
    18. Johung KL,
    19. Kirilcuk N,
    20. Krishnamurthi S,
    21. Messersmith WA,
    22. Meyerhardt J,
    23. Miller ED,
    24. Mulcahy MF,
    25. Nurkin S,
    26. Overman MJ,
    27. Parikh A,
    28. Patel H,
    29. Pedersen K,
    30. Saltz L,
    31. Schneider C,
    32. Shibata D,
    33. Skibber JM,
    34. Sofocleous CT,
    35. Stoffel EM,
    36. Stotsky-Himelfarb E,
    37. Willett CG,
    38. Gregory KM and
    39. Gurski LA
    : Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 19(3): 329-359, 2021. PMID: 33724754. DOI: 10.6004/jnccn.2021.0012
    OpenUrlCrossRefPubMed
  13. ↵
    1. Lugli A,
    2. Zlobec I,
    3. Berger MD,
    4. Kirsch R and
    5. Nagtegaal ID
    : Tumour budding in solid cancers. Nat Rev Clin Oncol 18(2): 101-115, 2021. PMID: 32901132. DOI: 10.1038/s41571-020-0422-y
    OpenUrlCrossRefPubMed
  14. ↵
    1. Lugli A,
    2. Kirsch R,
    3. Ajioka Y,
    4. Bosman F,
    5. Cathomas G,
    6. Dawson H,
    7. El Zimaity H,
    8. Fléjou JF,
    9. Hansen TP,
    10. Hartmann A,
    11. Kakar S,
    12. Langner C,
    13. Nagtegaal I,
    14. Puppa G,
    15. Riddell R,
    16. Ristimäki A,
    17. Sheahan K,
    18. Smyrk T,
    19. Sugihara K,
    20. Terris B,
    21. Ueno H,
    22. Vieth M,
    23. Zlobec I and
    24. Quirke P
    : Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol 30(9): 1299-1311, 2017. PMID: 28548122. DOI: 10.1038/modpathol.2017.46
    OpenUrlCrossRefPubMed
  15. ↵
    1. Okuyama T,
    2. Oya M and
    3. Yamaguchi M
    : Budding (sprouting) as a useful prognostic marker in colorectal mucinous carcinoma. Jpn J Clin Oncol 32(10): 412-416, 2002. PMID: 12451038. DOI: 10.1093/jjco/hyf089
    OpenUrlCrossRefPubMed
  16. ↵
    1. Brierley JD,
    2. Gospodarowics MK and
    3. Whitekind C
    (eds.): American Joint Committee on Cancer (AJCC) Cancer Staging Manual. 8th ed. New York, Springer, 2017.
  17. ↵
    1. Watanabe T,
    2. Muro K,
    3. Ajioka Y,
    4. Hashiguchi Y,
    5. Ito Y,
    6. Saito Y,
    7. Hamaguchi T,
    8. Ishida H,
    9. Ishiguro M,
    10. Ishihara S,
    11. Kanemitsu Y,
    12. Kawano H,
    13. Kinugasa Y,
    14. Kokudo N,
    15. Murofushi K,
    16. Nakajima T,
    17. Oka S,
    18. Sakai Y,
    19. Tsuji A,
    20. Uehara K,
    21. Ueno H,
    22. Yamazaki K,
    23. Yoshida M,
    24. Yoshino T,
    25. Boku N,
    26. Fujimori T,
    27. Itabashi M,
    28. Koinuma N,
    29. Morita T,
    30. Nishimura G,
    31. Sakata Y,
    32. Shimada Y,
    33. Takahashi K,
    34. Tanaka S,
    35. Tsuruta O,
    36. Yamaguchi T,
    37. Yamaguchi N,
    38. Tanaka T,
    39. Kotake K,
    40. Sugihara K and Japanese Society for Cancer of the Colon and Rectum
    : Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. Int J Clin Oncol 23(1): 1-34, 2018. PMID: 28349281. DOI: 10.1007/s10147-017-1101-6
    OpenUrlCrossRefPubMed
  18. ↵
    1. Morodomi T,
    2. Isomoto H,
    3. Shirouzu K,
    4. Kakegawa K,
    5. Irie K and
    6. Morimatsu M
    : An index for estimating the probability of lymph node metastasis in rectal cancers. Lymph node metastasis and the histopathology of actively invasive regions of cancer. Cancer 63(3): 539-543, 1989. PMID: 2912530. DOI: 10.1002/1097-0142(19890201)63:3<539::aid-cncr2820630323>3.0.co;2-s
    OpenUrlCrossRefPubMed
  19. ↵
    1. Roh MS,
    2. Lee JI and
    3. Choi PJ
    : Tumor budding as a useful prognostic marker in esophageal squamous cell carcinoma. Dis Esophagus 17(4): 333-337, 2004. PMID: 15569373. DOI: 10.1111/j.1442-2050.2004.00436.x
    OpenUrlCrossRefPubMed
    1. Karamitopoulou E,
    2. Zlobec I,
    3. Born D,
    4. Kondi-Pafiti A,
    5. Lykoudis P,
    6. Mellou A,
    7. Gennatas K,
    8. Gloor B and
    9. Lugli A
    : Tumour budding is a strong and independent prognostic factor in pancreatic cancer. Eur J Cancer 49(5): 1032-1039, 2013. PMID: 23177090. DOI: 10.1016/j.ejca.2012.10.022
    OpenUrlCrossRefPubMed
    1. Liang F,
    2. Cao W,
    3. Wang Y,
    4. Li L,
    5. Zhang G and
    6. Wang Z
    : The prognostic value of tumor budding in invasive breast cancer. Pathol Res Pract 209(5): 269-275, 2013. PMID: 23561623. DOI: 10.1016/j.prp.2013.01.009
    OpenUrlCrossRefPubMed
    1. Luo WR,
    2. Gao F,
    3. Li SY and
    4. Yao KT
    : Tumour budding and the expression of cancer stem cell marker aldehyde dehydrogenase 1 in nasopharyngeal carcinoma. Histopathology 61(6): 1072-1081, 2012. PMID: 23020521. DOI: 10.1111/j.1365-2559.2012.04350.x
    OpenUrlCrossRefPubMed
    1. Kadota K,
    2. Yeh YC,
    3. Villena-Vargas J,
    4. Cherkassky L,
    5. Drill EN,
    6. Sima CS,
    7. Jones DR,
    8. Travis WD and
    9. Adusumilli PS
    : Tumor budding correlates with the protumor immune microenvironment and is an independent prognostic factor for recurrence of stage I lung adenocarcinoma. Chest 148(3): 711-721, 2015. PMID: 25836013. DOI: 10.1378/chest.14-3005
    OpenUrlCrossRefPubMed
  24. ↵
    1. Koyuncuoglu M,
    2. Okyay E,
    3. Saatli B,
    4. Olgan S,
    5. Akin M and
    6. Saygili U
    : Tumor budding and E-Cadherin expression in endometrial carcinoma: are they prognostic factors in endometrial cancer? Gynecol Oncol 125(1): 208-213, 2012. PMID: 22198340. DOI: 10.1016/j.ygyno.2011.12.433
    OpenUrlCrossRefPubMed
  25. ↵
    1. Koelzer VH,
    2. Zlobec I,
    3. Berger MD,
    4. Cathomas G,
    5. Dawson H,
    6. Dirschmid K,
    7. Hädrich M,
    8. Inderbitzin D,
    9. Offner F,
    10. Puppa G,
    11. Seelentag W,
    12. Schnüriger B,
    13. Tornillo L and
    14. Lugli A
    : Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study. Virchows Arch 466(5): 485-493, 2015. PMID: 25701480. DOI: 10.1007/s00428-015-1740-9
    OpenUrlCrossRefPubMed
    1. Koelzer VH,
    2. Zlobec I and
    3. Lugli A
    : Tumor budding in colorectal cancer—ready for diagnostic practice? Hum Pathol 47(1): 4-19, 2016. PMID: 26476568. DOI: 10.1016/j.humpath.2015.08.007
    OpenUrlCrossRefPubMed
  27. ↵
    1. De Smedt L,
    2. Palmans S and
    3. Sagaert X
    : Tumour budding in colorectal cancer: what do we know and what can we do? Virchows Arch 468(4): 397-408, 2016. PMID: 26613731. DOI: 10.1007/s00428-015-1886-5
    OpenUrlCrossRefPubMed
  28. ↵
    1. Mitrovic B,
    2. Schaeffer DF,
    3. Riddell RH and
    4. Kirsch R
    : Tumor budding in colorectal carcinoma: time to take notice. Mod Pathol 25(10): 1315-1325, 2012. PMID: 22790014. DOI: 10.1038/modpathol.2012.94
    OpenUrlCrossRefPubMed
  29. ↵
    1. Rogers AC,
    2. Winter DC,
    3. Heeney A,
    4. Gibbons D,
    5. Lugli A,
    6. Puppa G and
    7. Sheahan K
    : Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer. Br J Cancer 115(7): 831-840, 2016. PMID: 27599041. DOI: 10.1038/bjc.2016.274
    OpenUrlCrossRefPubMed
  30. ↵
    1. Ueno H,
    2. Ishiguro M,
    3. Nakatani E,
    4. Ishikawa T,
    5. Uetake H,
    6. Matsuda C,
    7. Nakamoto Y,
    8. Kotake M,
    9. Kurachi K,
    10. Egawa T,
    11. Yasumasa K,
    12. Murata K,
    13. Ikawa O,
    14. Shinji S,
    15. Murotani K,
    16. Matsui S,
    17. Teramukai S,
    18. Tomita N,
    19. Sugihara K and SACURA Study Group
    : Prospective multicenter study on the prognostic and predictive impact of tumor budding in stage II colon cancer: results from the SACURA trial. J Clin Oncol 37(22): 1886-1894, 2019. PMID: 31180819. DOI: 10.1200/JCO.18.02059
    OpenUrlCrossRefPubMed
  31. ↵
    1. Naito A,
    2. Iwamoto K,
    3. Ohtsuka M,
    4. Imasato M,
    5. Nakahara Y,
    6. Mikamori M,
    7. Furukawa K,
    8. Moon J,
    9. Asaoka T,
    10. Kishi K and
    11. Akamatsu H
    : Risk factors for lymph node metastasis in pathological T1b colorectal cancer. In Vivo 35(2): 987-991, 2021. PMID: 33622893. DOI: 10.21873/invivo.12341
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Karlberg M,
    2. Stenstedt K,
    3. Hallström M,
    4. Ragnhammar P,
    5. Lenander C and
    6. Edler D
    : Tumor budding versus mismatch repair status in colorectal cancer - an exploratory analysis. Anticancer Res 38(8): 4713-4721, 2018. PMID: 30061240. DOI: 10.21873/anticanres.12778
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Maffeis V,
    2. Nicolè L and
    3. Cappellesso R
    : RAS, cellular plasticity, and tumor budding in colorectal cancer. Front Oncol 9: 1255, 2019. PMID: 31803624. DOI: 10.3389/fonc.2019.01255
    OpenUrlCrossRefPubMed
  34. ↵
    1. Lamouille S,
    2. Xu J and
    3. Derynck R
    : Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15(3): 178-196, 2014. PMID: 24556840. DOI: 10.1038/nrm3758
    OpenUrlCrossRefPubMed
  35. ↵
    1. Zlobec I and
    2. Lugli A
    : Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget. Oncotarget 1(7): 651-661, 2010. PMID: 21317460. DOI: 10.18632/oncotarget.199
    OpenUrlCrossRefPubMed
  36. ↵
    1. Grigore AD,
    2. Jolly MK,
    3. Jia D,
    4. Farach-Carson MC and
    5. Levine H
    : Tumor budding: The name is EMT. Partial EMT. J Clin Med 5(5): 51, 2016. PMID: 27136592. DOI: 10.3390/jcm5050051
    OpenUrlCrossRefPubMed
  37. ↵
    1. Dawson H,
    2. Grundmann S,
    3. Koelzer VH,
    4. Galván JA,
    5. Kirsch R,
    6. Karamitopoulou E,
    7. Lugli A,
    8. Inderbitzin D and
    9. Zlobec I
    : Tyrosine kinase receptor B (TrkB) expression in colorectal cancers highlights anoikis resistance as a survival mechanism of tumour budding cells. Histopathology 66(5): 715-725, 2015. PMID: 25382057. DOI: 10.1111/his.12603
    OpenUrlCrossRefPubMed
  38. ↵
    1. Yamada N,
    2. Sugai T,
    3. Eizuka M,
    4. Tsuchida K,
    5. Sugimoto R,
    6. Mue Y,
    7. Suzuki M,
    8. Osakabe M,
    9. Uesugi N,
    10. Ishida K,
    11. Otsuka K and
    12. Matsumoto T
    : Tumor budding at the invasive front of colorectal cancer may not be associated with the epithelial-mesenchymal transition. Hum Pathol 60: 151-159, 2017. PMID: 27836787. DOI: 10.1016/j.humpath.2016.10.007
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Tumor Budding as a Predictive Marker of Relapse and Survival in Patients With Stage II Colon Cancer
KAZUYUKI SAITO, TAKASHI OKUYAMA, SHUNYA MIYAZAKI, HARUKA OI, TAKASHI MITSUI, TAKUJI NORO, EMIKO TAKESHITA, YUKO ONO, TAIZEN URAHASHI, HIDEHIRO TAJIMA, HIDEYUKI YOSHITOMI
In Vivo Jul 2022, 36 (4) 1820-1828; DOI: 10.21873/invivo.12898
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo

Jump to section

Keywords