Tumor budding is an independent prognostic marker in early stage oral squamous cell carcinoma: With special reference to the mode of invasion and worst pattern of invasion

PLoS One. 2018 Apr 19;13(4):e0195451. doi: 10.1371/journal.pone.0195451. eCollection 2018.

Abstract

Pathologically proven regional lymph node metastasis affects the prognosis in early stage oral cancer. Therefore we investigated invasive tumor patterns predicting nodal involvement and survival in patients with clinically node-negative T1 and T2 oral squamous cell carcinoma (cT1,2N0M0 OSCC). Ninety-one cases of cT1,2N0M0 OSCC treated with transoral resection of the primary tumor were assessed based on 3 types of invasive tumor patterns on histopathologic and pancytokeratin-stained immunohistological sections: the mode of invasion, worst pattern of invasion (WPOI), and tumor budding. The correlations among invasive tumor patterns, regional metastasis, and disease-free survival were analyzed. Of the 91 cases, 22 (24%) had pathologically proven regional metastasis. The mode of invasion (p<0.01) and tumor budding (p<0.01) were associated with regional metastasis as well as lymphovascular invasion (p = 0.04) in univariate analysis. In logistic regression analysis, however, tumor budding was the only independent predictor of regional metastasis (hazard ratio (HR) = 3.05, 95% confidence interval (CI) = 0.29-5.30, p<0.01). All three invasive patterns, the mode of invasion, WPOI, and tumor budding, were found to be significant predictors of 5-year disease-free survival (p<0.01, p = 0.03, and p<0.01, respectively) as well as lymphovascular invasion (p = 0.02) and perineural invasion (p = 0.02). A final model for Cox multivariate analysis identified the prognostic advantage of the intensity of tumor budding (HR = 2.19, 95% CI = 1.51-3.18, p<0.01) compared with the mode of invasion and WPOI in disease-free survival. Our results indicate that the intensity of tumor budding may be a novel diagnostic biomarker, as well as a therapeutic tool, for regional metastasis in patients with cT1,2N0M0 OSCC. If the pancytokeratin-based immunohistochemical features of more than five buds, and a grade 4C or 4D mode of invasion are identified, careful wait-and-see follow-up in a short period with the use of imaging modalities is desirable. If there are more than ten buds, a grade 4D mode of invasion, or WPOI-5 in the same section, wide resection of the primary tumor with elective neck dissection should be recommended.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Squamous Cell / diagnosis*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / physiopathology
  • Carcinoma, Squamous Cell / surgery
  • Follow-Up Studies
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Logistic Models
  • Middle Aged
  • Mouth Neoplasms / diagnosis*
  • Mouth Neoplasms / pathology
  • Mouth Neoplasms / physiopathology
  • Mouth Neoplasms / surgery
  • Multivariate Analysis
  • Neoplasm Grading
  • Neoplasm Invasiveness / diagnosis*
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / physiopathology
  • Neoplasm Metastasis / diagnosis
  • Neoplasm Metastasis / pathology
  • Neoplasm Metastasis / physiopathology
  • Prognosis
  • Proportional Hazards Models
  • Retrospective Studies

Associated data

  • figshare/5986810
  • figshare/5986819
  • figshare/5986822
  • figshare/5986831
  • figshare/5986852
  • figshare/5986861
  • figshare/5986864

Grants and funding

Financial support for this study was provided by JSPS KAKENHI (grant numbers 16K15872 and 16K11729). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.