Dysplastic Leukoplakia
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The article by Sudb? and colleagues (April 1 issue)1 advances the understanding of dysplastic oral leukoplakia, but the suggestion that surgical removal is ineffective in preventing oral carcinoma is highly debatable. There is agreement that advanced dysplasia appears to be incurable in many patients, and recurrences are common. Although the adjacent epithelium appears to be normal on clinical and microscopical examination, it most likely is altered genetically and destined to become dysplastic within a few cell generations. The study cohort was evaluated every six months, and many lesions were followed without biopsy if the clinical presentation did not change. Of the 26 aneuploid leukoplakias that evolved into carcinoma, 20 were clinical stage III or worse. Since it would be most unusual for clinically normal epithelium to evolve to cancer of stage III or higher during a six-month period, many of these carcinomas most likely arose in patients whose leukoplakias were treated by "watchful waiting." Until new effective treatments and preventive therapies are developed, these data strongly support early and repeated surgical removal of dysplastic oral leukoplakia and show the terrible toll that results from watchful waiting.
Douglas D. Damm, D.D.S.
University of Kentucky College of Dentistry
Lexington, KY 40536-0297
References
Sudb? J, Lippman SM, Lee JJ, et al. The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med 2004;350:1405-1413.
To the Editor: The conclusion that "aneuploid leukoplakia is tantamount to carcinoma" is potentially an understatement. The data presented by Sudb? et al. showed that, over a similar follow-up period, a subgroup of the diploid and tetraploid dysplastic lesions also progressed to carcinoma. Therefore, for this subgroup, the argument can be made that the lesions were also tantamount to carcinoma. Despite the results of this study, it remains impossible to predict which dysplastic lesions will eventually progress to carcinoma. Thus, it must be stressed that in all patients with biopsy-proven dysplastic oral leukoplakia (and erythroplakia), regardless of ploidy status, any residual lesion should be excised. These patients should then be followed over the long term, educated about the benefits of self-examination, and encouraged to stop smoking and to reduce or eliminate alcohol intake. The data suggest that aneuploid dysplastic leukoplakias may progress more rapidly to carcinoma than diploid and tetraploid lesions. However, the follow-up period of this study may not be sufficient to assess accurately the true frequency of malignant transformation for all dysplastic oral leukoplakias.
Thomas P. Sollecito, D.M.D.
Faizan Alawi, D.D.S.
University of Pennsylvania School of Dental Medicine
Philadelphia, PA 19104
tps@pobox.upenn.edu
The authors reply: Our data do not support the statement by Drs. Sollecito and Alawi that diploid and tetraploid dysplastic oral leukoplakia are tantamount to carcinoma. The long mean follow-up time of 80 months indicates that the low rate of cancer in patients with diploid lesions was not severely underestimated. In an extended follow-up with more patients, we found that complete resection of diploid leukoplakia reduced the already relatively low rate of cancer (unpublished data). With respect to patients with tetraploid dysplastic leukoplakia, cancers developed in 11 of 15 patients with a complete resection (negative margins; i.e., no dysplasia) and 5 of 5 with an incomplete resection (data not reported in our article). These data support resection of diploid dysplastic lesions and suggest a possible benefit of resection for tetraploid lesions.
On the other hand, the patients with aneuploid lesions had a 96 percent rate of oral cancer (26 of the 27 patients received the diagnosis) with a 70 percent rate within three years, an 81 percent rate of subsequent cancer (22 of 27), a 74 percent rate of death from cancer (21 of 27), and virtually no help from complete resection — all hallmarks of biologically aggressive cancer. Although not 100 percent accurate, ploidy analysis is an effective clinical tool for differentiating highest-risk (aneuploid) from relatively low-risk (diploid) oral leukoplakia. Unlike the findings with aneuploidy, the substantial risk conferred by tetraploidy has not yet been confirmed in other series.1
Traditional risk markers for oral leukoplakia, such as the type and grade of dysplasia, have a limited prognostic value,2,3 and ploidy assessment is now standard practice in Norway. Lesions with advanced genetic alterations, such as those marked by aneuploidy or extensive loss of heterozygosity, can migrate laterally beyond the resection margin,4 possibly explaining why complete resection of aneuploid leukoplakia does not prevent cancer. Regarding Dr. Damm's comment on watchful waiting and carcinomas in patients with aneuploid leukoplakia, several stage III (including T1 or T2) carcinomas (as shown in Table 2 of our article) developed in normal-appearing mucosa where lesions had been completely resected or had never existed. Therefore, we join Dr. Damm in calling for new preventive therapies for aneuploid dysplastic oral leukoplakia, a call that echoes the conclusion of our article. Complete resection of aneuploid lesions confirmed by molecular, rather than histologic, criteria also should be explored.5
Jon Sudb?, M.D., D.D.S., Ph.D.
Albrecht Reith, M.D., Ph.D.
Norwegian Radium Hospital
0310 Oslo, Norway
jon.sudbo@rh.uio.no
Scott M. Lippman, M.D.
University of Texas M.D. Anderson Cancer Center
Houston, TX 77030
References
Sudb? J, Lippman SM, Lee JJ, et al. The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med 2004;350:1405-1413.
Karabulut A, Reibel J, Therkildsen MH, Praetorius F, Nielsen HW, Dabelsteen E. Observer variability in the histologic assessment of oral premalignant lesions. J Oral Pathol Med 1995;24:198-200.
Sudb? J, Kildal W, Risberg B, Koppang HS, Danielsen HE, Reith A. DNA content as a prognostic marker in patients with oral leukoplakia. N Engl J Med 2001;344:1270-1278.
Lippman SM, Hong WK. Molecular markers of the risk of oral cancer. N Engl J Med 2001;344:1323-1326.
Brennan JA, Mao L, Hruban RH, et al. Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med 1995;332:429-435.
Douglas D. Damm, D.D.S.
University of Kentucky College of Dentistry
Lexington, KY 40536-0297
References
Sudb? J, Lippman SM, Lee JJ, et al. The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med 2004;350:1405-1413.
To the Editor: The conclusion that "aneuploid leukoplakia is tantamount to carcinoma" is potentially an understatement. The data presented by Sudb? et al. showed that, over a similar follow-up period, a subgroup of the diploid and tetraploid dysplastic lesions also progressed to carcinoma. Therefore, for this subgroup, the argument can be made that the lesions were also tantamount to carcinoma. Despite the results of this study, it remains impossible to predict which dysplastic lesions will eventually progress to carcinoma. Thus, it must be stressed that in all patients with biopsy-proven dysplastic oral leukoplakia (and erythroplakia), regardless of ploidy status, any residual lesion should be excised. These patients should then be followed over the long term, educated about the benefits of self-examination, and encouraged to stop smoking and to reduce or eliminate alcohol intake. The data suggest that aneuploid dysplastic leukoplakias may progress more rapidly to carcinoma than diploid and tetraploid lesions. However, the follow-up period of this study may not be sufficient to assess accurately the true frequency of malignant transformation for all dysplastic oral leukoplakias.
Thomas P. Sollecito, D.M.D.
Faizan Alawi, D.D.S.
University of Pennsylvania School of Dental Medicine
Philadelphia, PA 19104
tps@pobox.upenn.edu
The authors reply: Our data do not support the statement by Drs. Sollecito and Alawi that diploid and tetraploid dysplastic oral leukoplakia are tantamount to carcinoma. The long mean follow-up time of 80 months indicates that the low rate of cancer in patients with diploid lesions was not severely underestimated. In an extended follow-up with more patients, we found that complete resection of diploid leukoplakia reduced the already relatively low rate of cancer (unpublished data). With respect to patients with tetraploid dysplastic leukoplakia, cancers developed in 11 of 15 patients with a complete resection (negative margins; i.e., no dysplasia) and 5 of 5 with an incomplete resection (data not reported in our article). These data support resection of diploid dysplastic lesions and suggest a possible benefit of resection for tetraploid lesions.
On the other hand, the patients with aneuploid lesions had a 96 percent rate of oral cancer (26 of the 27 patients received the diagnosis) with a 70 percent rate within three years, an 81 percent rate of subsequent cancer (22 of 27), a 74 percent rate of death from cancer (21 of 27), and virtually no help from complete resection — all hallmarks of biologically aggressive cancer. Although not 100 percent accurate, ploidy analysis is an effective clinical tool for differentiating highest-risk (aneuploid) from relatively low-risk (diploid) oral leukoplakia. Unlike the findings with aneuploidy, the substantial risk conferred by tetraploidy has not yet been confirmed in other series.1
Traditional risk markers for oral leukoplakia, such as the type and grade of dysplasia, have a limited prognostic value,2,3 and ploidy assessment is now standard practice in Norway. Lesions with advanced genetic alterations, such as those marked by aneuploidy or extensive loss of heterozygosity, can migrate laterally beyond the resection margin,4 possibly explaining why complete resection of aneuploid leukoplakia does not prevent cancer. Regarding Dr. Damm's comment on watchful waiting and carcinomas in patients with aneuploid leukoplakia, several stage III (including T1 or T2) carcinomas (as shown in Table 2 of our article) developed in normal-appearing mucosa where lesions had been completely resected or had never existed. Therefore, we join Dr. Damm in calling for new preventive therapies for aneuploid dysplastic oral leukoplakia, a call that echoes the conclusion of our article. Complete resection of aneuploid lesions confirmed by molecular, rather than histologic, criteria also should be explored.5
Jon Sudb?, M.D., D.D.S., Ph.D.
Albrecht Reith, M.D., Ph.D.
Norwegian Radium Hospital
0310 Oslo, Norway
jon.sudbo@rh.uio.no
Scott M. Lippman, M.D.
University of Texas M.D. Anderson Cancer Center
Houston, TX 77030
References
Sudb? J, Lippman SM, Lee JJ, et al. The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med 2004;350:1405-1413.
Karabulut A, Reibel J, Therkildsen MH, Praetorius F, Nielsen HW, Dabelsteen E. Observer variability in the histologic assessment of oral premalignant lesions. J Oral Pathol Med 1995;24:198-200.
Sudb? J, Kildal W, Risberg B, Koppang HS, Danielsen HE, Reith A. DNA content as a prognostic marker in patients with oral leukoplakia. N Engl J Med 2001;344:1270-1278.
Lippman SM, Hong WK. Molecular markers of the risk of oral cancer. N Engl J Med 2001;344:1323-1326.
Brennan JA, Mao L, Hruban RH, et al. Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med 1995;332:429-435.