Interobserver variability in the H&E-based assessment of tumor budding in pT3/4 colon cancer: does it affect the prognostic relevance?
- 35 Downloads
Tumor budding is a mostly accepted adverse prognostic factor in colorectal carcinoma. It is on the cusp of a widespread use after agreement was reached recently on uniform assessment criteria. We investigated whether the interobserver variability has a direct influence on the prognostic relevance in pT3/4 colon cancer in the background of different levels of experience of the investigators. In total, six investigators with different levels of experience evaluated tumor budding on H&E slides in 244 cases with primary diagnosed (2002–2011) colon carcinoma (pT3/4, N+/−, M0). High-grade tumor budding/budding grade 3 (defined as majority assessment among the investigators) was significantly associated with an adverse outcome (overall survival p = 0.03, cancer-specific survival p = 0.08) and the occurrence of distant metastasis (p = 0.009). However, a detailed analysis of the rating results of the individual investigators revealed that only ratings of one investigator (advanced resident) were associated with an adverse outcome (p = 0.01 cancer-specific survival, overall survival p = 0.09, distant metastasis p = 0.002). The results of another investigator (consultant) were significantly associated with distant metastasis (p = 0.007). The kappa values among the investigators have a range between 0.077 and 0.357 (median 0.166). Total agreement of all investigators existed in 109 cases (44.7%). Our results demonstrate that the evaluation of tumor budding on H&E slides in pT3/4 colon cancer goes along with a considerable interobserver variability among investigators of different levels of experience. Furthermore, our results reveal that these findings directly influence the prognostic value.
KeywordsColon cancer Tumor budding Interobserver variability Prognostic factor Histology
Compliance with ethical standards
The Institutional Review Board of the Hospital Augsburg reviewed and approved the study protocol.
Conflict of interest
All authors declare that they have no conflict of interest.
- 4.Shinto E, Jass JR, Tsuda H, Sato T, Ueno H, Hase K, Mochizuki H, Matsubara O (2006) Differential prognostic significance of morphologic invasive markers in colorectal cancer: tumor budding and cytoplasmic podia. Dis Colon Rectum 49:1422–1430. https://doi.org/10.1007/s10350-006-0595-1 CrossRefPubMedGoogle Scholar
- 5.Koelzer VH, Assarzadegan N, Dawson H, Mitrovic B, Grin A, Messenger DE, Kirsch R, Riddell RH, Lugli A, Zlobec I (2017) Cytokeratin-based assessment of tumour budding in colorectal cancer: analysis in stage II patients and prospective diagnostic experience. J Pathol Clin Res 3:171–178. https://doi.org/10.1002/cjp2.73 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Dawson H, Assarzadegan N, Riddell R, Kirsch R, Blank A, Zlobec I, Lugli A (2017) Tumor budding is a strong predictor of disease-free survival in stage II colorectal cancer: validation study based on the International Tumor Budding Consensus Conference (ITBCC) recommendations. J Clin Oncol 35:594–594. https://doi.org/10.1200/JCO.2017.35.4_suppl.594 CrossRefGoogle Scholar
- 10.Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, el Zimaity H, Fléjou JF, Hansen TP, Hartmann A, Kakar S, Langner C, Nagtegaal I, Puppa G, Riddell R, Ristimäki A, Sheahan K, Smyrk T, Sugihara K, Terris B, Ueno H, Vieth M, Zlobec I, Quirke P (2017) Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol Off J U S Can Acad Pathol Inc 30:1299–1311. https://doi.org/10.1038/modpathol.2017.46 Google Scholar
- 11.Kai K, Aishima S, Aoki S, Takase Y, Uchihashi K, Masuda M, Nishijima-Matsunobu A, Yamamoto M, Ide K, Nakayama A, Yamasaki M, Toda S (2016) Cytokeratin immunohistochemistry improves interobserver variability between unskilled pathologists in the evaluation of tumor budding in T1 colorectal cancer. Pathol Int 66:75–82. https://doi.org/10.1111/pin.12374 CrossRefPubMedGoogle Scholar
- 12.Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang LM, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley SA, Herlin P, Lauwers GY, Risio M (2012) Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy. Histopathology 61:562–575. https://doi.org/10.1111/j.1365-2559.2012.04270.x CrossRefPubMedGoogle Scholar
- 17.Suzuki A, Togashi K, Nokubi M, Koinuma K, Miyakura Y, Horie H, Lefor AT, Yasuda Y (2009) Evaluation of venous invasion by Elastica van Gieson stain and tumor budding predicts local and distant metastases in patients with T1 stage colorectal cancer. Am J Surg Pathol 33:1601–1607. https://doi.org/10.1097/PAS.0b013e3181ae29d6 CrossRefPubMedGoogle Scholar
- 23.Okuyama T, Nakamura T, Yamaguchi M (2003) Budding is useful to select high-risk patients in stage II well-differentiated or moderately differentiated colon adenocarcinoma. Dis Colon Rectum 46:1400–1406. https://doi.org/10.1097/01.DCR.0000084413.78455.89 CrossRefPubMedGoogle Scholar
- 27.Cappellesso R, Luchini C, Veronese N, Lo Mele M, Rosa-Rizzotto E, Guido E, de Lazzari F, Pilati P, Farinati F, Realdon S, Solmi M, Fassan M, Rugge M (2017) Tumor budding as a risk factor for nodal metastasis in pT1 colorectal cancers: a meta-analysis. Hum Pathol 65:62–70. https://doi.org/10.1016/j.humpath.2017.04.013 CrossRefPubMedGoogle Scholar
- 28.Graham RP, Vierkant RA, Tillmans LS, Wang AH, Laird PW, Weisenberger DJ, Lynch CF, French AJ, Slager SL, Raissian Y, Garcia JJ, Kerr SE, Lee HE, Thibodeau SN, Cerhan JR, Limburg PJ, Smyrk TC (2015) Tumor budding in colorectal carcinoma: confirmation of prognostic significance and histologic cutoff in a population-based cohort. Am J Surg Pathol 39:1340–1346. https://doi.org/10.1097/PAS.0000000000000504 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Koelzer VH, Zlobec I, Berger MD, Cathomas G, Dawson H, Dirschmid K, Hädrich M, Inderbitzin D, Offner F, Puppa G, Seelentag W, Schnüriger B, Tornillo L, Lugli A (2015) Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study. Virchows Arch Int J Pathol 466:485–493. https://doi.org/10.1007/s00428-015-1740-9 CrossRefGoogle Scholar