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News in BriefDNA ploidy changes the way we understand the behavior of oral epithelial dysplasiaOral squamous cell carcinoma (SCC) is one of the most aggressive and common malignant neoplasms of the oral cavity. Tens of thousands of manuscripts have been written on oral SCC covering its clinical presentation, behavior, treatment and prognosis. While many of these manuscripts have been dedicated to exploring markers to predict progression and prognosis, and while most of these studies represent good research with sound science, they represent little clinical application. In the last four years, however, a group of clinicians and researchers from the University of Oslo, Norway have successfully demonstrated that chromosomal changes defined by aneuploidy is a reliable marker in determining oral epithelial progression to squamous cell carcinoma. They addressed the question of oral epithelial transformation to SCC at different levels, including the progression of all three grades of oral epithelial dysplasia to SCC. They also looked at benign epithelial hyperplasia and its progression to SCC. They studied surgical margins of the treated oral leukoplakias and related it to recurrence and subsequent transformation to SCC. One of their studies evaluated 150 patients with oral epithelial dysplasia: 105 patients were diploid, 20 were tetraploid and 25 were aneuploid. The ploidy of the dysplastic lesions did not correlate to the histologic grading. For more details, see table 1. A total of 36 patients progressed to SCC. Of those 3 (3%) were diploid, 12 (60%) were tetraploid, and 21 (84%) were aneulpoid. The mean time of progression to SCC in the aneuploid lesions was 35 months compared to 49 months for the tetraploid group. Another study by the same group looked at benign epithelial hyperplasia (no evidence of dysplasia) in 45 patients and its transformation to SCC. Five of the 45 patients developed SCC, four of which had lesions with aneuploid DNA; one was diploid. There was also a fifth benign hyperplasia with aneuploid DNA that did not develop SCC after a 120-month follow-up. In a third study of the 150 cases of epithelial dysplasia lesions, researches tested for surgical margins of the treated lesions and correlated it to recurrence and progression to SCC. Of the 150, 113 had clean margins and 37 had positive margins (epithelial dysplasia was present at the surgical margin of the removed specimen). Squamous cell carcinoma developed in 32% of patients with negative margins and 30% with positive margins, clearly demonstrating that the surgical margin status has no bearing on subsequent cancer formation. As far terminal cases of SCC, 21 out of the 27 patients with aneuploid DNA died of the disease, while only four of the patients with the tetraploid DNA, and none of those with diploid DNA, died. These studies stand against most of our knowledge of oral epithelial dysplasia regarding behavior and progression to SCC. It is obvious that our set of criteria is not supported by the molecular tests and somehow needs to change. We teach dentists and dental specialists that oral epithelial dysplasia has reliable histological grades: mild, moderate and severe. We also teach that 20-30% of these lesions would progress to SCC and that progression to SCC is more likely to occur in the higher histological grade (moderate and severe). We teach that high-risk locations, including and especially ventro-lateral tongue and floor of mouth, are more important in terms of behavior being more aggressive. We also teach that positive surgical margins on moderate and higher epithelial dysplasias require further treatment to prevent recurrence. The Norway studies show that one thing is important: not the location, not the age, not the gender, but the DNA integrity. How important are the ploidy studies?These are very important studies that force us to consider changing the way we practice pathology and dentistry. The question is how soon can we put this knowledge to use and how available are these tests? In my opinion, unless a larger prospective study is performed in support of the retrospective study, it would be hard to justify a major change in the way we diagnose and treat epithelial dysplasia given the fact (as of today) that the technique is time-consuming, unique to a few laboratories in the world, and expensive. The technique would be an effective diagnostic tool for oral epithelial lesions from high-risk individuals (older men with history of heavy alcohol and tobacco use). However, it would be difficult to standardize a test for all oral epithelial lesions from the general population. It would be just as hard to apply this test to the general population as a screening tool. Moreover there still remains the question of what to do with the data. What if we identify the DNA aneuploidy in a patient that histologically has benign epithelial hypereplasia and benign hyperkeratosis? Does that translates into preventive treatment to change the patient’s course of disease? What, additionally, is an appropriate treatment? Based on Sudbo et al surgery did not seem to be an effective method. As important as these studies are, we still need to do more studies in order to establish reliable criteria to begin answering these types of questions and to establish effective treatment criteria for those that show aneuploidy. Referrences
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