DNA Content as a Prognostic Marker in Patients with Oral Leukoplakia
Jon Sudbo, M.D., D.D.S., Wanja Kildal, M.Sc., Bjorn Risberg, M.D., Ph.D., Hanna S. Koppang, D.D.S., Ph.D., Havard E. Danielsen, Ph.D., and Albrecht Reith, M.D., Ph.D.
Background Oral leukoplakia may develop into squamous-cell carcinoma,which has a poor prognosis. Risk factors for oral carcinomahave been identified, but there are no reliable predictors ofthe outcome in individual patients with oral leukoplakia.
Methods We identified 150 patients with oral leukoplakia thatwas classified as epithelial dysplasia and measured the nuclearDNA content (ploidy) of the lesions to determine whether DNAploidy could be used to predict the clinical outcome. Biopsyspecimens obtained at annual follow-up visits were graded histologicallyand classified with respect to DNA content in a blinded fashion.Disease-free survival was assessed in relation to DNA ploidyand the histologic grade. The mean duration of follow-up was103 months (range, 4 to 165).
Results Among 150 patients with verified epithelial dysplasia,a carcinoma developed in 36 (24 percent). Of the 150 patients,105 (70 percent) had diploid (normal) lesions, 20 (13 percent)had tetraploid (intermediate) lesions, and 25 (17 percent) hadaneuploid (abnormal) lesions at the time of the initial diagnosis.A carcinoma developed in 3 of the 105 patients with diploidlesions (3 percent), as compared with 21 of the 25 patientswith aneuploid lesions (84 percent), yielding a negative predictivevalue of 97 percent with respect to the diploid lesions anda positive predictive value of 84 percent with respect to theaneuploid lesions. Carcinoma developed in 12 of 20 patientswith tetraploid lesions (60 percent). The mean time from theinitial assessment of the DNA content to the development ofa carcinoma was 35 months (range, 4 to 57) in the group withaneuploid lesions and 49 months (range, 8 to 78) in the groupwith tetraploid lesions (P=0.02). The cumulative disease-freesurvival rate was 97 percent among the group with diploid lesions,40 percent among the group with tetraploid lesions, and 16 percentamong the group with aneuploid lesions (P<0.001).
Conclusions The DNA content in cells of oral leukoplakia canbe used to predict the risk of oral carcinoma.
Source Information
From the Divisions of Digital Pathology (J.S., W.K., H.E.D., A.R.) and Cytology (B.R.), Department of Pathology, Norwegian Radium Hospital and the University of Oslo; and the Department of Pathology and Forensic Odontology, Institute of Clinical Dentistry, University of Oslo (H.S.K.) all in Oslo, Norway.
Address reprint requests to Dr. Sudbø at the Division of Digital Pathology, Department of Pathology, Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway, at jon.sudbo{at}rh.uio.no.
Kulkarni, A. A., Loddo, M., Leo, E., Rashid, M., Eward, K. L., Fanshawe, T. R., Butcher, J., Frost, A., Ledermann, J. A., Williams, G. H., Stoeber, K.
(2007). DNA Replication Licensing Factors and Aurora Kinases are Linked to Aneuploidy and Clinical Outcome in Epithelial Ovarian Carcinoma. Clin. Cancer Res.
13: 6153-6161
[Abstract][Full Text]
Curfman, G. D., Morrissey, S., Drazen, J. M.
(2006). Retraction: Sudbo J et al. DNA Content as a Prognostic Marker in Patients with Oral Leukoplakia. N Engl J Med 2001;344:1270-8 and Sudbo J et al. The Influence of Resection and Aneuploidy on Mortality in Oral Leukoplakia. N Engl J Med 2004;350:1405-13. NEJM
355: 1927-1927
[Full Text]
Perez-Ordonez, B, Beauchemin, M, Jordan, R C K
(2006). Molecular biology of squamous cell carcinoma of the head and neck.. J. Clin. Pathol.
59: 445-453
[Abstract][Full Text]
Suzuki, R., Kohno, H., Suzui, M., Yoshimi, N., Tsuda, H., Wakabayashi, K., Tanaka, T.
(2006). An animal model for the rapid induction of tongue neoplasms in human c-Ha-ras proto-oncogene transgenic rats by 4-nitroquinoline 1-oxide: its potential use for preclinical chemoprevention studies. Carcinogenesis
27: 619-630
[Abstract][Full Text]
Curfman, G. D., Morrissey, S., Drazen, J. M.
(2006). Expression of Concern: Sudbo J et al. DNA Content as a Prognostic Marker in Patients with Oral Leukoplakia. N Engl J Med 2001;344:1270-8 and Sudbo J et al. The Influence of Resection and Aneuploidy on Mortality in Oral Leukoplakia. N Engl J Med 2004;350:1405-13. NEJM
354: 638-638
[Full Text]
Mitiae, T., McKay, J. S.
(2005). Immunohistochemical Analysis of Acetylation, Proliferation, Mitosis, and Apoptosis in Tumor Xenografts Following Administration of a Histone Deacetylase Inhibitor--A Pilot Study. Toxicol Pathol
33: 792-799
[Abstract][Full Text]
Ewart-Toland, A., Dai, Q., Gao, Y.-T., Nagase, H., Dunlop, M. G., Farrington, S. M., Barnetson, R. A., Anton-Culver, H., Peel, D., Ziogas, A., Lin, D., Miao, X., Sun, T., Ostrander, E. A., Stanford, J. L., Langlois, M., Chan, J. M., Yuan, J., Harris, C. C., Bowman, E. D., Clayman, G. L., Lippman, S. M., Lee, J. J., Zheng, W., Balmain, A.
(2005). Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis
26: 1368-1373
[Abstract][Full Text]
Braakhuis, B. J.M., Brakenhoff, R. H., Leemans, C. R.
(2005). Second Field Tumors: A New Opportunity for Cancer Prevention?. The Oncologist
10: 493-500
[Abstract][Full Text]
Heselmeyer-Haddad, K., Sommerfeld, K., White, N. M., Chaudhri, N., Morrison, L. E., Palanisamy, N., Wang, Z. Y., Auer, G., Steinberg, W., Ried, T.
(2005). Genomic Amplification of the Human Telomerase Gene (TERC) in Pap Smears Predicts the Development of Cervical Cancer. Am. J. Pathol.
166: 1229-1238
[Abstract][Full Text]
Sudbo, J., Samuelsson, R., Risberg, B., Heistein, S., Nyhus, C., Samuelsson, M., Puntervold, R., Sigstad, E., Davidson, B., Reith, A., Berner, A.
(2005). Risk Markers of Oral Cancer in Clinically Normal Mucosa As an Aid in Smoking Cessation Counseling. JCO
23: 1927-1933
[Abstract][Full Text]
Dannenberg, A. J., Lippman, S. M., Mann, J. R., Subbaramaiah, K., DuBois, R. N.
(2005). Cyclooxygenase-2 and Epidermal Growth Factor Receptor: Pharmacologic Targets for Chemoprevention. JCO
23: 254-266
[Abstract][Full Text]
Lippman, S. M., Sudbo, J., Hong, W. K.
(2005). Oral Cancer Prevention and the Evolution of Molecular-Targeted Drug Development. JCO
23: 346-356
[Abstract][Full Text]
Li, Y., St. John, M. A. R., Zhou, X., Kim, Y., Sinha, U., Jordan, R. C. K., Eisele, D., Abemayor, E., Elashoff, D., Park, N.-H., Wong, D. T.
(2004). Salivary Transcriptome Diagnostics for Oral Cancer Detection. Clin. Cancer Res.
10: 8442-8450
[Abstract][Full Text]
Sudbo, J.
(2004). Novel Management of Oral Cancer: A Paradigm of Predictive Oncology. Clin Med Res
2: 233-242
[Abstract][Full Text]
Schneider, B. L., Kulesz-Martin, M.
(2004). Destructive cycles: the role of genomic instability and adaptation in carcinogenesis. Carcinogenesis
25: 2033-2044
[Abstract][Full Text]
Jordan, R. C. K., Macabeo-Ong, M., Shiboski, C. H., Dekker, N., Ginzinger, D. G., Wong, D. T. W., Schmidt, B. L.
(2004). Overexpression of Matrix Metalloproteinase-1 and -9 mRNA Is Associated with Progression of Oral Dysplasia to Cancer. Clin. Cancer Res.
10: 6460-6465
[Abstract][Full Text]
Damm, D. D., Sollecito, T. P., Alawi, F., Sudbo, J., Reith, A., Lippman, S. M.
(2004). Dysplastic Leukoplakia. NEJM
350: 2718-2719
[Full Text]
Tabor, M. P., Brakenhoff, R. H., Ruijter-Schippers, H. J., Kummer, J. A., Leemans, C. R., Braakhuis, B. J. M.
(2004). Genetically Altered Fields as Origin of Locally Recurrent Head and Neck Cancer: A Retrospective Study. Clin. Cancer Res.
10: 3607-3613
[Abstract][Full Text]
Rhee, J. C., Khuri, F. R., Shin, D. M.
(2004). Advances in Chemoprevention of Head and Neck Cancer. The Oncologist
9: 302-311
[Abstract][Full Text]
Sudbo, J., Lippman, S. M., Lee, J. J., Mao, L., Kildal, W., Sudbo, A., Sagen, S., Bryne, M., El-Naggar, A., Risberg, B., Evensen, J. F., Reith, A.
(2004). The Influence of Resection and Aneuploidy on Mortality in Oral Leukoplakia. NEJM
350: 1405-1413
[Abstract][Full Text]
Boyle, J. O.
(2004). Cyclooxygenase Inhibition as a Target for Prevention of Tobacco-Related Cancers. Clin. Cancer Res.
10: 1557-1558
[Full Text]
Goodin, S., Shiff, S. J.
(2004). NSAIDs for the Chemoprevention of Oral Cancer: Promise or Pessimism?: Commentary re J. L. Mulshine et al., Randomized, Double-Blind, Placebo-Controlled, Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal Leukoplakia. Clin. Cancer Res., 10: 1565-1573, 2004.. Clin. Cancer Res.
10: 1561-1564
[Full Text]
McWilliams, A., Mayo, J., MacDonald, S., leRiche, J. C., Palcic, B., Szabo, E., Lam, S.
(2003). Lung Cancer Screening: A Different Paradigm. Am. J. Respir. Crit. Care Med.
168: 1167-1173
[Abstract][Full Text]
Sabichi, A. L., Demierre, M.-F., Hawk, E. T., Lerman, C. E., Lippman, S. M.
(2003). Frontiers in Cancer Prevention Research. Cancer Res.
63: 5649-5655
[Full Text]
Armstrong, W. B., Taylor, T. H., Meyskens, F. L. Jr.
(2003). Point: Surrogate End Point Biomarkers Are Likely To Be Limited in Their Usefulness in the Development of Cancer Chemoprevention Agents against Sporadic Cancers. Cancer Epidemiol. Biomarkers Prev.
12: 589-592
[Full Text]
Kelloff, G. J., O'Shaughnessy, J. A., Gordon, G. B., Hawk, E. T., Sigman, C. C.
(2003). Counterpoint: Because Some Surrogate End Point Biomarkers Measure the Neoplastic Process They Will Have High Utility in the Development of Cancer Chemopreventive Agents against Sporadic Cancers. Cancer Epidemiol. Biomarkers Prev.
12: 593-596
[Full Text]
Hasina, R., Hulett, K., Bicciato, S., Di Bello, C., Petruzzelli, G. J., Lingen, M. W.
(2003). Plasminogen Activator Inhibitor-2: A Molecular Biomarker for Head and Neck Cancer Progression. Cancer Res.
63: 555-559
[Abstract][Full Text]
Papadimitrakopoulou, V. A., Liu, D. D., Mao, L., Shin, D. M., El-Naggar, A., Ibarguen, H., Lee, J. J., Hong, W. K., Hittelman, W. N.
(2002). Biologic Correlates of a Biochemoprevention Trial in Advanced Upper Aerodigestive Tract Premalignant Lesions. Cancer Epidemiol. Biomarkers Prev.
11: 1605-1610
[Abstract][Full Text]
Mattsson, U., Jontell, M., Holmstrup, P.
(2002). ORAL LICHEN PLANUS AND MALIGNANT TRANSFORMATION: IS A RECALL OF PATIENTS JUSTIFIED?. Crit. Rev. Oral Biol. Med.
13: 390-396
[Abstract][Full Text]
Neville, B. W., Day, T. A.
(2002). Oral Cancer and Precancerous Lesions. CA Cancer J Clin
52: 195-215
[Abstract][Full Text]
Sudbo, J., Kildal, W., Johannessen, A. C., Koppang, H. S., Sudbo, A., Danielsen, H. E., Risberg, B., Reith, A.
(2002). Gross Genomic Aberrations in Precancers: Clinical Implications of a Long-Term Follow-Up Study in Oral Erythroplakias. JCO
20: 456-462
[Abstract][Full Text]
Forastiere, A., Koch, W., Trotti, A., Sidransky, D.
(2001). Head and Neck Cancer. NEJM
345: 1890-1900
[Full Text]
Barrera, J. E., Varella-Garcia, M.
(2001). Chromosomal Aneuploidy as a Predictor for Poor Outcome in Patients With Head and Neck Cancer. Arch Otolaryngol Head Neck Surg
127: 1519-1520
[Full Text]
HOROWITZ, A. M., ALFANO, M. C.
(2001). Performing a death-defying act. Journal of the American Dental Association
132: 5S-6S
[Full Text]
SCIUBBA, J. J.
(2001). Oral cancer and its detection: History-taking and the diagnostic phase of management. Journal of the American Dental Association
132: 12S-18S
[Abstract][Full Text]
Lippman, S. M., Hong, W. K.
(2001). Molecular Markers of the Risk of Oral Cancer. NEJM
344: 1323-1326
[Full Text]