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David Goldenberg, MD; Susan Harden, MD; Brett G. Masayesva, MD; Patrick Ha, MD; Nicole Benoit, BSc; William H. Westra, MD; Wayne M. Koch, MD; David Sidransky, MD; Joseph A. Califano, MD

Arch Otolaryngol Head Neck Surg. 2004;130:39-44.

Background  Tumor-specific molecular alterations in surgical margins have been shown to predict risk of local recurrence. However, assays used for these analyses are time-consuming and therefore cannot be used in the intraoperative setting.

Objective  To detect and quantify tumor-specific methylated promoter sequences in surgical margins in a time frame suitable for intraoperative use.

Design  A novel quantitative methylation-specific polymerase chain reaction (QMSP) protocol.

Methods  A total of 13 patients with head and neck squamous cell carcinoma (HNSCC) were initially characterized for molecular alterations in their tumor at the time of biopsy. Six primary tumors were found to harbor promoter hypermethylation for p16 and O⁶–methylguanine-DNA-methyltransferase (MGMT) genes. Rapid QMSP was then used to identify promoter hypermethylation of these genes in the surgical margins. Results were compared with standard intraoperative histologic frozen section analysis and with conventional QMSP.

Results  Using our rapid QMSP assay, we found that 3 patients had methylation-positive margins. Tumor margins from 2 patients were methylated for p16 alone, and margins from 1 patient were methylated for p16 and MGMT simultaneously. Molecular margin analysis was completed in less than 5 hours, a time frame appropriate for selected major HNSCC resections that require combined primary tumor resection, cervical lymphadenectomy, and complex reconstruction. This technique was comparable in sensitivity to conventional QMSP.

Conclusion  Rapid molecular margin analysis using QMSP is feasible and may be performed intraoperatively in selected patients with HNSCC that requires extensive resection.

From the Departments of Otolaryngology–Head and Neck Surgery (Drs Goldenberg, Harden, Masayesva, Ha, Koch, Sidransky, and Califano and Ms Benoit) and Pathology(Dr Westra), The Johns Hopkins University School of Medicine, Baltimore, Md. The authors have no relevant financial interest in this article.

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