Use of Lugol’s Iodine Stain May Reduce the Need for Repeat Resection of Oral and Oropharyngeal Cancers

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By identifying residual dysplasia in the tumor bed, Lugol’s iodine staining may improve pathologic outcomes with resection of oral and oropharyngeal cancers, according to interim findings of a UK randomized controlled trial reported at the 9th International Conference on Head and Neck Cancer.1 Compared with patients operated on with the gold standard procedure, patients in whom Lugol’s iodine was used were less than half as likely to need to undergo further resection and to have dysplasia at the surgical margins, the results indicated.

To put it bluntly, leaving behind cancer cells is a bad plan. But we know that leaving behind precancerous tissue is a bad plan also. So the question is where to start and where to stop with the resection.
— James A. McCaul, PhD, FRCSOMFS, FRCS

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On the basis of these positive findings, “We think this will be a game changer,” first author James A. McCaul, PhD, FRCSOMFS, FRCS, a consultant maxillofacial/head and neck surgeon at the Royal Marsden Hospital London and Northwick Park Hospital London, commented in an interview.

Five-year survival is being assessed to determine whether the observed improvement in pathologic outcomes translates to a better clinical outcome, he added. However, that analysis may be complicated by differential treatment of standard-arm patients found to have residual dysplasia.

Study Rationale

Stage at presentation is the major determinant of survival in patients with oral and oropharyngeal cancers, Dr. McCaul commented, giving some background. “But the thing you and I can really control is how much tissue we remove while trying to preserve function.”

“To put it bluntly, leaving behind cancer cells is a bad plan. But we know that leaving behind precancerous tissue is a bad plan also,” he elaborated. “So the question is where to start and where to stop with the resection.”

The trial investigators enrolled patients undergoing resection for oral or oropharyngeal squamous cell carcinoma. Enrollment was expanded beyond that initially planned to capture a large sample of patients with small tumors. “We felt, and Cancer Research UK agreed, this would be more effective and significant for small T1s and T2s,” Dr. McCaul explained. As a result, 301 of the 419 patients enrolled had tumors of those stages.

Study Details

The patients were randomized evenly to undergo visualization with Lugol’s iodine vital staining or the gold standard procedure of resection with a 1-cm clinical margin.

Use of the staining technique dates back to the 1920s, when it was realized it could be applied to exploit differences in the metabolism of healthy and precancerous cells, Dr. McCaul noted. Specifically, Lugol’s iodine interacts with glycogen in healthy mucosal cells to generate a brown stain. But dysplastic cells have aberrant metabolism that depletes them of glycogen, and they therefore remain pale yellow.

Local pathologists blinded to the patient’s treatment group assessed margin status, and the findings were re-reported after central review.

The results showed that 89% of patients found the Lugol’s iodine staining to be acceptable, Dr. McCaul reported. About 10% of patients in each group had a serious adverse event. The leading event in both groups was inpatient hospitalization or prolongation of the existing hospitalization.

Role of Staining in Excision

Overall, 61.3% of surgeons thought Lugol’s iodine staining assisted with the excision. Additionally, 69.1% reported they were able to visualize pale tissue at the resection margin, and within this subset, 96.9% reported that it was possible to resect that tissue. “We haven’t broken down the data yet to determine in which cases it was helpful,” Dr. McCaul commented.

Novel Approach to Improving Resection of Oral Cancers

  • In a randomized trial of 419 patients undergoing resection for oral and oropharyngeal cancers, use of Lugol’s iodine reduced the need for further resection and the presence of any-grade dysplasia at margins vs the gold standard procedure.
  • A total of 61% of surgeons thought the use of Lugol’s iodine assisted with the excision.

On average, surgeons removed about 25 mL of tumor in the Lugol’s iodine group and 23 mL in the standard-procedure group—a nonsignificant difference. These findings indicate that use of the stain did not lead to excess tissue removal.

Patients in the Lugol’s iodine group were less likely to have to undergo further resection after initial surgery (3.6% vs 10.8%, P < .006. Moreover, among the majority whose pathology was centrally reviewed, patient’s in the Lugol’s iodine group were less likely to have any grade of dysplasia found at margins (5.4% vs 11.7%, P = .003).

Quality-of-life data were collected in the trial and will be reported at a later date, according to Dr. McCaul. ■

Disclosure: Dr. McCaul reported no potential conflicts of interest.


1. McCaul JA, Gouldesbrough D, Robinson M, et al: Lugol’s iodine in head and neck cancer surgery: A multicentre prospective randomized controlled trial. 2016 International Conference of Head and Neck Cancer. Abstract S370. Presented July 19, 2016.