Malignant Transformation in Precancers of the Head & Neck
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Cancer development in major follow-up studies of oral leukoplakia.

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Precancers in Oral Cancer Patients

One would expect that at least some of the oral precancerous lesions would remain intact until the time of formal diagnosis of an associated cancer. Their frequency, then, among the group of oral cancer patients is expected to be much higher. A variety of studies have shown that, in fact, leukoplakia is found adjacent to or near a very large proportion of oral cancers, in some studies as much as 100% of them. The only population-based investigation has determined that the figure is more like 30% among a group of patients which represent all oral cancer patients in an entire population.

Mashberg et al have made a special effort to identify erythroplakic lesions adjacent to or near early oral cancers. According to their thorough review of 220 cancer patients, almost ____% have adjacent erythroplakia. When health care professionals have a high suspicion of oral white and red lesions, as many as 15% of all diagnosed oral cancers will be the preinvasive, carcinoma in situ type.

Progression to Malignancy

The precancerous nature of leukoplakia was initially suspected because a large number were found in close proximity to mucosal carcinomas, especially in arsenic-treated syphilis patients. Later investigation found dysplastic and/or microinvasive epithelium in 17-25% of leukoplakia biopsy samples. But true premalignancy was not proven until large numbers of leukoplakias were followed for long periods of time. For half a century now rates of malignant transformation have been available from numerous follow-up studies.

The concept of oral precancer now clearly assumes that only some of the premalignant lesions will actually transform (transform? degenerate?) into invasive carcinoma. A number of investigations, most reported during the 1960s and 1970s, have followed patients with clinically diagnosed leukoplakias. The ten largest of these studies are listed in Table 2, representing more than 3,300 individuals followed for up to 41 years each through periodic examinations or medical/dental records. Altogether this research represents a remarkable 30,616 person-years (sum of observations times for each individual followed) of total observation time, or to put it another way, 30,616 person-years at risk.

Progression to malignancy occurred in 4-20% of followed patients, some of whom had their lesions removed during the follow-up period. Taken as a whole, the 270 oral cancers developing in the patient cohorts represents an annualized transformation rate of just under 1% each year, that is, the risk of malignancy is one in a hundred during the course of a year. This is considerably higher that the 0.01% anticipated for a Western population.⁹⁹ At such a high annual transformation rate one would expect that should a person only live long enough a leukoplakic lesion would be guaranteed to become malignant.

While this may be the case, the data are skewed toward the early post-diagnosis experience because several of the investigations followed lesions for less than five years, and because even in the longest follow-up studies, the proportion of cases able to be evaluated diminishes with each passing year. Of the 248 patients, for example, followed by Pindborg et al,⁹⁹ fewer than 104 were followed for more than five years and only four were followed for the full ten year period. Likewise, of the 257 patients followed by Silverman et al, only 118 were followed beyond five years and fewer than 70 were followed more than ten years.

Fortunately, a few of the follow-up investigations have provided enough appropriate data to shed light on the question of when are the most likely times to anticipate malignant transformation. Figure 4 illustrates the cumulative risk of transformation of the four studies with appropriate data and compares them with the cumulative risk of oral cancer development in the general U.S. population, which is relatively representative of European oral cancer incidence rates also. For the most part, the risk of cancer in leukoplakia is greatest during the first two years of its existence, but it definitely does continue throughout the life of the lesion. When one considered that a quarter to a third of oral leukoplakias disappear within several years, it seems logical to presume that the leukoplakias with the longest duration are those with the highest risk of cancer progression.

Case-control studies have strongly implicated smoked tobacco and, to a lesser extent, alcohol abuse in the etiology of oral cancer, but such studies have not further correlated white mucosal plaques with malignant transformation. It is not known, then, whether oral cancers in the smokers identified in epidemiologic studies arise from leukoplakias or from clinically normal mucosa. Various investigations have, however, found leukoplakia adjacent to a third (range: 10-100%) of oral squamous cell carcinomas.

Numerous follow-up studies have established malignant transformation rates for leukoplakia, ranging from 4-20% (excluding clinical subtypes), with an average of 4% overall (Table 2). These figures are somewhat deceptive because follow-up studies exclude those cases with invasive disease at the time of initial diagnosis. The few investigations which have examined the latter feature have found that 7% (range: 0.1%-40%) of oral leukoplakias will have at least one focus of squamous carcinoma in the initial biopsy.

There are so few investigations of the biological behavior of oral leukoplakia, and the lesion itself is so common, that it seems worthwhile to briefly review each in turn. Sturgis and Lund reported the first follow-up study of the disease in a Western population in 1934, after discovering that a remarkable 12% of 143 leukoplakic lesions became malignant during an average follow-up period of five years.

Twenty nine years later Pindborg et al pointed out the microscopic features of cellular atypia which pointed toward increased risk of malignant transformation. He enhanced this data for a 1968 report of 214 patients followed for one to nine years (average: 3.7 years), finding that 4% went on to malignancy. His was the first report documenting all biological behaviors, including diminution of the lesions. He found, in fact, that 20% of oral leukoplakias disappear without surgical removal and another 18% decrease in size without therapy. Forty-five percent, however, increase in size and 3.3% eventually became malignant, usually within the first year, but also up to five years after diagnosis. Of the 21 cases completely excised at the time of biopsy, only two recurred, three and five years postoperatively.

Kramer also emphasized the various histopathologic features of prognostic significance, going so far as to attempt a detailed computer analysis which, unfortunately, is little used today. In 1970 he also gave, more significantly, a year-by-year listing of the biological behavior of leukoplakias with and without epithelial dysplasia.

Roed-Peterson of Copenhagen reported in 1971 on the follow-up of 331 patients with 422 oral leukoplakias. With an average observation time of 4.3 years, he found that nine carcinomas (3%) developed within leukoplakic lesions. Quite significantly, he also found that three cancers (1%) developed at oral sites other than those involved with leukoplakia. He reported, for the first time, a gender difference: 6% of the leukoplakias in females developed malignancy, while only 2% of the males did so. He also was the first the report that a leukoplakic lesion in a nonsmoker was much more dangerous than one in a smoker: 11% compared to only 2%, respectively. He mentioned that those leukoplakias interspersed with red lesions, i.e. erythroleukoplakias, were seven times more likely to become malignant than were those which were purely white lesions (9.1% vs. 1.3%). He was the first to point out that larger leukoplakias are at higher risk than smaller ones, with almost all cancer developing within lesions larger than 5.5 cm.  And finally, he pointed out the fact that leukoplakias of certain oral sites are more serious than those in other oral sites: 44% of his lesions which developed malignancy were located on the lateral border of the tongue, even though less than 2% of all leukoplakias were found at that site.

The typical cancer arising from a leukoplakic lesion is diagnosed two to four years after the leukoplakia is diagnosed, but transformation may occur within months or occur after decades.  Predicting the risk of malignant transformation of any particular precancer of the head and neck region is a formidable task.  The tremendous number of potential influencing factors and cofactors, along with great differences in study design and disease definitions, has led to considerable confusion on this subject.  Nevertheless, it is important to at least make the effort to establish or estimate relative risk, and to this end the following table provides a "best guess" relative risk for the various types of oral precancers.

Table 1: Estimated relative risk of developing oral cancer from various oral precancers.

Reference: Modified from: Bouquot JE. The pathology and progression of oral premalignancy. Proceedings, Epithelial Dysplasia Symposium, 5^th International Congress on Oral Cancer, Royal College of Physicians, London, United Kingdom; September, 1997.

  # reverse smoking: smoking with the lit end of the cigarette in one's mouth

Tables for Specific Precancers

Click on underlined table number to see data for specific lesions.

Table 2: Malignant transformation rates (%) of the largest leukoplakia follow-up studies from Europe and the United States, ranked by sample size (modified from Bouquot JE, Whitaker SB. Quint Internat 1994; 25:133-140).

         * includes 13 cases from the pharynx.
       ** weighed for different sample sizes; many studies include a disproportional sampling of high risk lesions;
            the overall malignant transformation rate is usually considered to be 4-6% when all lesions are assessed.

Table 3: Malignant transformation rates (%) for oral CIS and/or severe epithelial dysplasia, listed by year of publication. Lesions appeared clinically as red, white or combined red and white macules, i.e. not all were pure erythroplakias. Cancers not arising from the site of the precancer are excluded.

Table 4: Malignant transformation rates (5) for follow-up studies of laryngeal keratosis (leukoplakia), listed by year of publication.

         * includes only cancers developing in the anatomic area of the previously recorded dysplastic lesions
           n/a = data not available

References, by Date of Publication

Note: Click on underlined author(s)'s name to see abstract, summary or full paper 

Maerker R, Burkhardt A. Klinik oraler Leukoplakien und Prakanzerosen. Retrospektive Studie an 200 Patienten. Dtsch Z Mund Kiefer GesichtsChir 1978; 2:206_211.

Baric JM, Alman JE, et al. Influence of cigarette, pipe, and cigar smoking, removable partial dentures, and age on oral leukoplakia. Oral Surg Oral Med Oral Pathol 1982; 54:424-429.

Roed-Petersen B. Effect on oral leukoplakia of reducing or ceasing tobacco smoking. Acta Dermato-Venereol 1982; 62:164-167.

Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. Oral Surg Oral Med Oral Pathol 1985; 60:285_298.

Murti PR, Bhonsle RB, Pindborg JJ, et al. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community Dent Oral Epidemiol 1985; 13:340-341.

Bouquot JE, Gnepp D. Epidemiology of carcinoma in situ of the upper aerodigestive tract. Cancer 1988; 61: 1685-1690.

Bouquot JE, Kurland LT, Weiland LH. Carcinoma in situ of the upper aerodigestive tract: incidence, time trends and follow-up in Rochester, Minnesota, 1935-1984. Cancer 1988; 61:1691-1698.

Bouquot JE, Weiland LH, Kurland LT. Leukoplakia and carcinoma in situ synchronously associated with invasive oral/pharyngeal carcinoma in Rochester, Minnesota, 1935-1984. Oral Surg Oral Med Oral Pathol 1988; 65:199-207.

Bouquot JE, Gnepp DR. Laryngeal precancer--a review of the literature, commentary and comparison with oral leukoplakia. Head Neck 1991; 13: 488-497.

Lumerman H, Freedman P, Kerpel S. Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg Oral Med Oral Pathol 1995; 79:321-329.

Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 82:396-401.

Silverman S Jr, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 84:154-157.