Oral Precancer -- An Historical Review
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Drawing of "leukoplakia" of the tongue in syphilis patient, from the 1877 paper by Schwimmer.

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19th Century

From the beginning of the nineteenth century cancer began to be characterized as a disease with an "independent existence," a concept which was considerably different from all earlier theories.¹ Clinicians seemed to understand also that cancer was a systemic problem as opposed to benign neoplasms which remained localized. And while the pathophysiology of metastasis escaped them, they intuitively believed that primary malignancies somehow "induced" the nodes along adjacent lymphatics to undergo a "sympathetic tumefaction."  Fortunately, there was also a clear understanding that not all destructive ulcerations were cancers.  Cancrum oris, tuberculosis, osteomyelitis, and other similar diseases were well known and easily differentiated from malignancy, even though their exact etiologies and pathophysiologies were poorly understood.^2-4

Even in dental journals from the mid-19th century it is clear that health professionals of the time knew that cancers from different organs and tissues of origin were different one from another.⁵  Cartier,⁵ moreover, made the remarkable suggestion that the clinician always obtain a "microscopic analysis" of neoplasms and listed the lips, tongue and salivary glands as the third, fifth and sixteenth most commonly affected cancer sites, respectively, with uterine and breast cancer as the most common of all.

With the improved distinction between benign and malignant tumors, some questioned whether or not all benign tumors remained benign.  As early as 1806, for example, a few medical investigators where of the opinion that there was "an alteration in the structure of a part...preceding that more obvious change which is called cancer."¹  However, the first specific suggestion of an association between a benign oral mucosal lesion and the subsequent development of oral malignancy was not reported until the mid-nineteenth century. Sir James Paget⁶ of London wondered in 1851 about the cancer-producing potential of pipe smoker's palate or "leukokeratosis," and in 1870 he clearly implied that oral "ichthyosis" (white keratotic plaque) was a significant precursor to lingual carcinoma. The latter association was independently advanced in 1877 by Schwimmer⁷ of Budapest, who is usually credited with coining the term "leukoplakia" for white tongue changes seen prior to lingual cancer development in tertiary syphilis. Numerous papers, especially in the German-language literature, fleshed out the relationship between leukoplakia, tertiary syphilis and lingual carcinoma throughout the latter part of the nineteenth century.^8-20  The dental literature, interestingly enough, did not contain a single reference to white mucosal changes until toward the end of the 19th century.²¹

20th Century

By the time of the classic review by Goodale²² in 1900, leukoplakia was well established as a precursor to lingual cancer, always based on its close physical association with that cancer and on the fact that it is often seen in the area before the occurrence of the cancer.²³  Unfortunately, even well respected and knowledgeable authorities seemed to have a very poor understanding of the clinical presentations of the premalignancy, as illustrated by the fact that Bloodgood²⁴ in 1915 used a drawing of an obvious papilloma to represent leukoplakia (Figure 1).

At one time the term leukoplakia was used for all white keratotic lesions of the mouth and the lesion has had more than 75 names applied to it. It is a term that was also used, until recently, for similar lesions of the larynx, vagina, uterine cervix, and bladder. Today it is defined as a chronic white mucosal macule which cannot be scraped off, cannot be given another specific diagnostic name, and does not typically disappear with removal of known etiologic factors, excepting tobacco.^21,26,27

A red alteration of the vocal cords adjacent to a carcinoma, reported in 1853, may have been the first example of an erythematous plaque associated with malignancy of the head and neck region,¹⁰ but Queyrat¹¹ of Lebanon is usually credited with the first description and use of the term "erythroplasia." In 1911 he used the term to describe a red macule of the glans penis in a syphilitic patient, but two French dermatologists, Fournier and Darier,⁹⁹ had already described a red "benign epithelioma" of the penis in 1893. Bowen⁹⁹ appears to be the first to apply the word "precancerous" to these erythematous skin changes. In 1924 Darier¹² first applied the term "erythroplasia of Queyrat" to a lesion of the oral mucosa, and by 1931 Nuguer99 was discussing oral examples of de maladie de Bowen.

Today a variety of oral precancers are rather successfully evaluated and managed as a routine facet of oral health care, despite residual or ongoing controversies of some significance. Ironically, one of the major advances in this field has been the simple recognition that a premalignancy is not guaranteed to eventually transform into cancer. Most, in fact, do so in only a small proportion of cases and a premalignant (precancerous) lesion is now defined as an identifiable, benign tissue or cellular alteration associated with a greater than normal risk of malignant transformation or "degeneration." Much of contemporary oral oncology research is focused on the identification of clinical, histopathologic and molecular biological parameters of oral precancers and early cancers which might aid in the recognition of those lesions with the highest risk of transformation.. Because of the potentially fatal consequences of mistakes relating to premalignant lesions, this work is extremely important, but the state of the art at present leaves much to be desired.

References

1. Baillie, Simms, Willan, et al. Queries and responses from The Medical Committee of the Society for Investigating the Nature and Cure of Cancer. Edinburgh Med Surg J 1806; 2:382-389.

2. Bond TE Jr. A practical treatise on dental medicine. Philadelphia: Lindsay & Blakiston, 1848.

3. Middlethwait. Cancrum oris. Am J Dent Sc 1848; 9:135.

4. Tomes J. A course of lectures on dental physiology and surgery (lectures I-XV). Am J Dent Sc 1846-1848; 7:1-68, 121-134; 8:33-54, 120-147,313-350.

5. Cartier AL. On pseudoplasmata. Am J Dent Science 1858; 8 (new series):297-324.

6. Quoted in Paget J. Cancer following ichthyosis of the tongue. Tans Clin Soc Lond 3:88, 1870.

7. Schwimmer E. Die idiopathischen Schleimhautplauques der Mundhohle (Leukoplakia buccalis). Arch Dermat Syph 9:611-570, 1877.

8. Krueg. Leukoplakia linguae bei einem Geisteskranken. Winer mediz Wochenschrift 1878; 44(N): 1164.

9. Joseph G. Beitrag zur Therapie der Leukoplakia. Deutsche medizinishe Wochenschrift 1885; 43:738-739.

10. Garretson J. Ueber Leukoplakia buccalis. Interal Dent J 1889.

11. Rothmann M. Ueber Leukoplakia lingualis et buccalis in inhrem Zusanmenhange mit Karzinom. Dissertation. Berlin; University of Berlin, 1889.

12. Wallenberg P. Zur Aetiologie der Leukoplakie. Dissertation. Berlin; University of Berlin, 1890:1-31.

13. Meiners J. Aetiologie des Karizinoma linguae mit besonderer Berucksichtigung der Psoriasis linguae. Dissertation, Würzburg: University of Würzburg, 1891:1-39.

14. Erb. Bemerkungen uber die Plaquesnaben (Epitheltrübungen, Leukoplakie) der Mundhöhle und ihre Ursachen. Munchener medizinische Wochenschrift 1892; 42:739.

15. Miller. Ein Beitrag zur Aetiologie der Leukoplakia oris. D. M fur Z. 1892; 12(H):515.

16. Le Dentu. Ueber Leukoplasie und Epitheliom. Deutch Medizinal-Zeitung 1894; 95(N):1075.

17. Lieven WA. Bemerkungen zur Diagnose und Therapie der Leukoplakie. Weiner medizinische Wochenschrift 1897; 24(H):663.

18. Kirchner G. Leukoplakia oris. Deut zahnartz 1898-99; 17:179-182.

19. Lissauer W. Ueber das Verhaltnis von Leukoplakia oris und Psoriasis vulgaris. Die Medicin Woche (?) 1899; 31(N):____.

20. Ritter P. Beitrag zur Diagnose und Therapie syphilitischer Affecktioner der Mundhöhle und der Keiferknochen. Wiener Zahnarzttiche Monatsschrift 1899; 9(H):427.

21. Bouquot JE, Whitaker SB. Oral leukoplakia--rationale for diagnosis and prognosis of its clinical subtypes or "phases." Quint Internat 1994; 25:133-140.

22. Goodale, 1900. Leukoplakia review.

 23. Prinz H. Leukoplakia oris -- a clinical study. Dent Cosmos 70:663-672, 1928.

24. Bloodgood JC. What every dentist should know about surgical lesions of, and in the region of, the upper and lower jaw; with especial reference to the early recognition of the precancerous lesions. J Natl Dent Assoc (later the J Amer Dent Assoc) 1915; 2:3-19.

25. Bouquot JE. Reviewing oral leukoplakia-clinical concepts for the 1990s. J Amer Dent Assoc 122:80-82, 1991.

26. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. Philadelphia, W. B. Saunders; 1995.

References in Chronologic Order

Baillie, Simms, Willan, et al. Queries and responses from The Medical Committee of the Society for Investigating the Nature and Cure of Cancer. Edinburgh Med Surg J 1806; 2:382-389.

Bond TE Jr. A practical treatise on dental medicine. Philadelphia: Lindsay & Blakiston, 1848.

Middlethwait. Cancrum oris. Am J Dent Sc 1848; 9:135.

Tomes J. A course of lectures on dental physiology and surgery (lectures I-XV). Am J Dent Sc 1846-1848; 7:1-68, 121-134; 8:33-54, 120-147,313-350.

Cartier AL. On pseudoplasmata. Am J Dent Science 1858; 8 (new series):297-324.

Quoted in Paget J. Cancer following ichthyosis of the tongue. Tans Clin Soc Lond 1870; 3:88.

Schwimmer E. Die idiopathischen Schleimhautplauques der Mundhohle (Leukoplakia buccalis). Arch Dermat Syph 1877; 9:611-570.

Krueg. Leukoplakia linguae bei einem Geisteskranken. Winer mediz Wochenschrift 1878; 44(N): 1164.

Joseph G. Beitrag zur Therapie der Leukoplakia. Deutsche medizinishe Wochenschrift 1885; 43:738-739.

Garretson J. Ueber Leukoplakia buccalis. Internat Dent J 1889.

Rothmann M. Ueber Leukoplakia lingualis et buccalis in inhrem Zusanmenhange mit Karzinom. Dissertation. Berlin; University of Berlin, 1889.

Wallenberg P. Zur Aetiologie der Leukoplakie. Dissertation. Berlin; University of Berlin, 1890:1-31.

Meiners J. Aetiologie des Karizinoma linguae mit besonderer Berucksichtigung der Psoriasis linguae. Dissertation, Würzburg: University of Würzburg, 1891:1-39.

Erb. Bemerkungen uber die Plaquesnaben (Epitheltrübungen, Leukoplakie) der Mundhöhle und ihre Ursachen. Munchener medizinische Wochenschrift 1892; 42:739.

Miller. Ein Beitrag zur Aetiologie der Leukoplakia oris. D. M fur Z. 1892; 12(H):515.

Le Dentu. Ueber Leukoplasie und Epitheliom. Deutch Medizinal-Zeitung 1894; 95(N):1075.

Lieven WA. Bemerkungen zur Diagnose und Therapie der Leukoplakie. Weiner medizinische Wochenschrift 1897; 24(H):663.

18. Kirchner G. Leukoplakia oris. Deut zahnartz 1898-99; 17:179-182.

19. Lissauer W. Ueber das Verhaltnis von Leukoplakia oris und Psoriasis vulgaris. Die Medicin Woche (?) 1899; 31(N):____.

20. Ritter P. Beitrag zur Diagnose und Therapie syphilitischer Affecktioner der Mundhöhle und der Keiferknochen. Wiener Zahnarzttiche Monatsschrift 1899; 9(H):427.

Goodale, 1900. Leukoplakia review.

Prinz H. Leukoplakia oris -- a clinical study. Dent Cosmos 1928; 70:663-672.

Bloodgood JC. What every dentist should know about surgical lesions of, and in the region of, the upper and lower jaw; with especial reference to the early recognition of the precancerous lesions. J Natl Dent Assoc 1915; 2:3-19.

King H, Hamilton CM. Leukoplakia buccalis -- a study of 80 cases. South Med J 1931; 24:380-391.

Sturgis SH, Lund CC. Leukoplakia buccalis and keratosis labialis. N Eng J Med 1934; 210:996-1006.

Hobaek A. Leukoplakia oris. Acta Odont Scand 1946; 7:61-91.

Leonardelli GB, Talamazzi F. Leucoplasie del caro orale e precancerosi. Nota I. Arch Ital Otol 1950; 61:107-114.

Slaughter DP, Southwick H, Smejkol W. "Field cancerization" in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 1953; 6:963-968.

Shafer WG, Waldron CA. A clinical and histopathologic study of oral leukoplakia. Surg Gynec Obstet 1961; 112:411-____.

Pindborg JJ, Renstrup G, Poulsen HE, Silverman S Jr. Studies in oral leukoplakias. V. Clinical and histological signs of malignancy. Acta Odont Scand 1963; 21:407-414.

Einhorn J, Wersall J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer 1967; 20:2189-2193.

Spiessl B, Metz H-J. Differentialdiagnose und Behandlung der Leukoplakien. Dtsch Zahn- Mund- Kieferheilk 1967; 48:11.

Pindborg JJ, Jolst O, Renstrup G, Roed-Petersen B. Studies in oral leukoplakia. J Amer Dent Assoc 1968; 76:767-771.

Silverman S, Rozen R. Observations on the clinical characteristics and natural history of oral leukoplakia. J Am Dent Assoc 1968; 76:722-777.

Kramer IRH, Lucas RB, El-Labban N, et al. A computer-aided study on the tissue changes in oral keratoses and lichen planus, and an analysis of case groupings by subjective and objective criteria. Br J Cancer 1970; 29:408-426.

Mehta FS, Pindborg JJ, Hamner JE. Oral cancer and precancerous conditions in India. Copenhagen: Munksgaard, 1971.

Roed-Petersen B. Cancer development in oral leukoplakia: follow-up of 331 patients. J Dent Res 1971; 50:711.

Roed-Petersen B, Banoczy J, Pindborg JJ. Smoking habits and histological characteristics of oral leukoplakias in Denmark and Hungary. Br J Cancer 1973; 28:575-579.

Shafer WG, Waldron CA. Erythroplakia of the oral cavity. Cancer 1975; 36:1021-1024.

Waldron CA, Shafer WG. Leukoplakia revisited: a clinicopathologic study of 3256 oral leukoplakias. Cancer 1975; 36:1386-1392.

Axéll T. A prevalence study of oral mucosal lesions in an adult Swedish population. Odont Revy 1976; 27 (suppl 26):1-103.

Axéll T. The relation of the clinical picture to the histopathology of snuff dipper's lesions in a Swedish population. J Oral Pathol 1976; 5:229-236.

Banoczy J, Csiba A. Occurrence of epithelial dysplasia in oral leukoplakia. Oral Surg Oral Pathol Oral Med 1976; 42:766-744.

Banoczy, J. Follow-up studies in oral leukoplakia. J Maxillofac Surg 1977; 45:69- 75, .

Burkhardt A, Seifert G. Morphologischen Klassifikation der oralen Leukoplakien. Dtsch Med Wochenschr 1977; 102:223-229.

Maerker R, Burkhardt A. Klinik oraler Leukoplakien und Prakanzerosen. Retrospektive Studie an 200 Patienten. Dtsch Z Mund Kiefer GesichtsChir 1978; 2:206-211.

WHO Collaborating Centre for Oral Precancerous Lesions. Definitions of leukoplakia and related lesions: an aid to studies on oral precancers. Oral Surg Oral Med Oral Pathol 1978; 46:518-539.

Wilsch von L, Hornstein OP, Brunjing H, et al. Oral Leukoplakien. II. Ergebnisse einer 1 jarhrigen poliklinischen Pilotstudie. Dtsch Zahnarztl Z 1978; 33:132-142.

Mackenzie IC, Dabelsteen E, Squier CA (editors). Oral premalignancy. Iowa City: University of Iowa Press, 1980.

Pindborg JJ. Oral cancer and precancer. Bristol: John Wright and Sons, Ltd, 1980.

Eversole LR, Shopper TP. Oral leukoplakia: prevalence of dysplastic and carcinomatous change in verruciform and planar patterns. Calif Dent Assoc J 1981; 45-51.

Banoczy J. Oral leukoplakia. The Hague: Martinus Nijhoff Publishers, 1982.

Fishman SL, Ulmansky M, Sela J, Bab I, Gazit D. Correlative clinico-pathological evaluation of oral premalignancy. J Oral Pathol 1982; 11:283-289.

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

Rodriquez-Perez J, Banoczy J. Oral leukoplakia. A histopathological study. Acta Morphologica Acad Sci Hung 1982: 30:289-298.

Banoczy J. Clinical and histopathological aspects of premalignant lesions. In: van der Waal I, Snow GB (eds). Oral oncology. Boston: Martinus Nijhoff Publ, 1984:3-32.

Silverman S, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 1984; 53:563-568.

Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. Oral Surg Oral Med Oral Pathol 1985; 60:285-298.

Pindborg JJ. Oral precancer. In: Barnes L (ed). Surgical pathology of the head and neck. New York: Marcel Dekker, 1985: 279-301.

Silverman S Jr. (ed). Oral cancer, ed 2. New York: American Cancer Society, 1985:13-26.

Bouquot JE. Common oral lesions found during a mass screening examination. J Am Dent Assoc 1986; 112:50-57.

Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus and other oral keratoses in 23,616 white Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol 1986; 61:373-381.

Chiesa F, Sala L, Costa L, et al. Excision of oral leukoplakias by CO2 laser on an out-patient basis: a useful procedure for prevention and early detection of oral carcinoma. Tumori 1986; 72:307-312.

Axéll T. Occurrence of leukoplakia and some other oral white lesions among 20333 adult Swedish people. Community Dent Oral Epidemiol 1987; 15:46-51.

Bouquot JE. Epidemiology. In: Gnepp DG.: Pathology of the head and neck. New York: Churchill Livingstone, 1987, pp 263-314.

Crissman JD, et al. Preinvasive lesions of the upper aerodigestive tract: histologic definitions and clinical implications (a symposium). Pathol Annual 1987; 22:311-352.

Schell H, Schonberger A. Zur Lokalisationshaufigkeit von benignen und prakanzerosen Leukoplakien und von Karzinomen in der Mundhohle. Z Hautkr 1987; 62:798-804.

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 J, Weiland L, Ballard D, Kurland L. Leukoplakia of the mouth and pharynx in Rochester, MN, 1935-1984; incidence, clinical features and follow-up of 463 patients from a relatively unbiased patient pool. J Oral Pathol 1988; 17:436.

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.

Greenspan JS, Greenspan D. Oral hairy leukoplakia: diagnosis and management. Oral Surg 1989; 67:396-403.

Hojslet PE, Moesgaard Nielsen V, Palvio D. Premalignant lesions of the larynx. Acta Otolaryngol (Stockh) 1989; 107:150-155.

Mashberg A, Samit AM. Early detection, diagnosis, and management of oral and oropharyngeal cancer. CA 1989; 39:67-88.

Regezi JA, Sciubba JJ. Oral pathology; clinical-pathologic correlations. Philadelphia: W.B. Saunders, 1989, pp. 92-93.

Rossie KM, Guggenheimer J. Thermally induced 'nicotine' stomatitis: a case report. Oral Surg Oral Med Oral Pathol 1990; 70:597-599.

Bouquot JE, Glover ED, Schroeder KL. Leukoplakia and smokeless tobacco keratosis are two separate precancers. In: Varma, A.D. (ed). Oral oncology. Dehli: MacMillan India, Ltd, 1991, pp. 67-69 (vol 2).

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

Bouquot JE, Kurland LT, Weiland LH. Laryngeal keratosis and carcinoma in the Rochester, MN, population, 1935-1984. Cancer Detect Prevent 1991; 15:83-91.

Bouquot JE. Reviewing oral leukoplakia-clinical concepts for the 1990s. J Amer Dent Assoc 1991; 122:80-82.

Daftary DK, Murti PR, Bhonsle RB, et al. Oral precancerous lesions and conditions of tropical interest. In: Prabhu SR, Wilson DF, Daftary DK, Johnson NW (eds). Oral diseases in the tropics. Oxford: Oxford University Press, 1993:402-424.

Stotts RC, Schroeder KL, Burns DM. Smokeless tobacco or health, an international perspective. Bethesda, Maryland: National Institutes of Health, 1993. NIH Publication No. 93-3461.

Axell T, Pindborg JJ, Smith CJ, et al. Oral white lesions with special reference to precancers and tobacco-related lesions: conclusions of an international symposium held in Uppsala, Sweden, May 18-21, 1994. J Oral Pathol Med 1996; 25:49-54.

Bouquot JE, Whitaker SB. Oral leukoplakia--rationale for diagnosis and prognosis of its clinical subtypes or "phases." Quint Internat 1994; 25:133-140.

Bouquot JE. Leukoplakia and erythroplakia: a review and update. Pract Perio Aesth Dent 1994; 6:1-10.

Bouquot JE, Ephros H. Erythroplakia -- the dangerous red mucosa. Prac Perio Aesth Dent 1995; 7:59-68.

Neville B, Damm D, Allen C, Bouquot J. Oral and maxillofacial pathology. Philadelphia: W. B. Saunders, 1995: 280-292.

Click on photo to enlarge
	Figure 1: Bloodgood's mistaken diagnosis.  1915 drawing of obvious papilloma used as an illustration of leukoplakia of the tongue. [return to text]