Molecular staging of surgical margins in oral squamous cell carcinoma using promoter methylation of p16(INK4A), cytoglobin, E-cadherin, and TMEFF2

Ann Surg Oncol. 2013 Aug;20(8):2796-802. doi: 10.1245/s10434-012-2713-8. Epub 2012 Oct 31.


Background: Local recurrence in oral squamous cell carcinoma (OSCC) despite clear surgical margins may indicate the presence of residual, sub-microscopic disease. Molecular assessment of surgical margins may provide a greater prognostic sensitivity compared to histopathology. We aimed to determine whether promoter methylation in deep and mucosal resection margins can predict recurrence in OSCC.

Methods: Forty-eight consecutive OSCC cases were recruited and a 5 mm(3) tumor sample plus 5 deep and 5 mucosal margin samples were snap frozen. Clinical, pathological, adjuvant therapy, and outcome data were recorded. Tumors were informative if >5 % promoter methylation was found for ≥1 of 4 genes using qMSP. Margins were declared molecularly positive if >1 % promoter methylation was found in any margin.

Results: Thirty (63 %) of 48 cases were methylation informative. Mucosal margin samples were largely positive for methylation (26 of 30, 87 %), indicating the presence of field cancerization. Methylation at ≥1 gene promoters in ≥1 deep margin correlated with the presence of close/involved mucosal margins (P = 0.027) and increased pT status (P = 0.027) but not the status of deep margins, recurrence, or survival.

Conclusions: The current gene panel did not add prognostic information to histopathological reporting of resection margins. Future efforts should concentrate on improving gene selection, informativity, and assay performance in the patient group with intermediate indications for adjuvant therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cadherins / genetics
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / surgery
  • Cytoglobin
  • DNA Methylation*
  • Female
  • Genes, p16
  • Globins / genetics
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Mouth Neoplasms / genetics*
  • Mouth Neoplasms / pathology
  • Mouth Neoplasms / surgery
  • Neoplasm Proteins / genetics
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm, Residual
  • Promoter Regions, Genetic*


  • CYGB protein, human
  • Cadherins
  • Cytoglobin
  • Membrane Proteins
  • Neoplasm Proteins
  • TMEFF2 protein, human
  • Globins