Journal of Surgcal Oncology 721-26 (1975)
Squamous Cell Carcinoma of the Oral Cavity - Chronic Oral Ulcerative Disease as a Possible Etiologic Factor .......................................................................................... .......................................................................................... ROBERT P. FARACI, M.D., LIONEL SCHOUB, M A , M.D., and EDWARD A. GRAYKOWSKI, M,D., D.D.S. This report documents the association of carcinoma of the oral cavity with chronic oral ulcerative disease in two patients. This association has not previously been documen€scl in the surgical literature. Both patients in this report had chronic oral ulcerative disease preceding their cancers; however, the common etiologic factors for oral cancer were not detected in either case. Oral lichen planus and pemphigus vulgaris should be considered as potentially premallgnanf legions and should be treated accordingly.
.......................................................................................... .......................................................................................... Cancer of the oral cavity comprises 3% of all cancers in males and 2% of cancers in females. In 1973 in the United States, there were an estimated 7,500 deaths due to cancer of the buccal cavity and oropharynx, and approximately 15,000 new cases were diagnosed (Silverberg and Holleb, 1972). Etiologic factors in oral cancer have been discussed by many authors, and the importance of chronic local irritation has been emphasized. Cigarettes, alcohol, and snuff, as well as other agents, have been implicated as potential carcinogens. The possible role of chronic bullous lesions of the oral cavity in the development of oral cancer has received little attention, although it has been suggested that lichen planus can lead to the development of oral cancer. An example of this occurred in a 79-year-old female (NIH #03.64.76-4) who was first seen at the National Institutes of Health in December 1959 because of a 25-year history of intermittent oral pain and tenderness associated with the formation of whitish plaques which would break down and ulcerate. The patient gave a remote history of sporadic smoking; however, she had completely stopped smoking prior to her 1959 hospital admission. There was no history of tobacco chewing or snuff dipping, and the patient did not use mouthwashes or condiments with aromatic oils. Surgery Branch, National Cancer Institute, and the Laboratory of Oral Medicine, National InstitutF for Dental Research (Dr. Graykowski), National Institutes of Health, Bethesda, Maryland 20014. 21
OAlan R. Liss, Inc., 150 Fifth Avenue, New York, N.Y. 10011
22
Faraci, Schour, and Graykowski
Examination revealed white hyperkeratotic lesions involving the floor of the mouth and the lingual frenulum and extending to the ventral surface of the tongue and the buccal mucosa. There was a 1 cm ulcerated area at the left lower gingival mucosa, extending from the floor of the mouth to the gingiva adjacent to the left lower first bicuspid. On Dec. 23, 19.59, biopsy of these areas showed lichen planus (Fig. l), and the patient was treated symptomatically. The lichen planus persisted for the next 14 years, most notably in the left lateral tongue and gingiva. In March 1973, following a full mouth extraction, the patient complained of poor healing of the left mandibular alveolar ridge. Examination in April 1973 showed a 5 X 8.5 cm ulcerated mass at the left anterior alveolar mucus-membrane junction where lichen planus had been present for many years. A biopsy of this lesion showed well differentiated squamous carcinoma (Fig. 2). She then received 7,200 rads t o the mandible over a sevenweek period, and four months following treatment she remains free of tumor. A second patient (NIH #09-50-70-1) was seen at the National Cancer Institute in November 1972 because of diffuse carcinoma of the tongue. This 62-year-old white female’s problems began in 1967 with oral mucosal blisters. These progressed, necessitating examination at the dermatology clinic of a university hospital in September 1968, at which time a clinical diagnosis of pemphigus vulgaris was made. Because of persistent oral bullous lesions, she was hospitalized in January 1969. At that time there was no history of cigarette smoking, alcohol intake, or ingestion of irritating substances. Physical examination revealed vessicobullous lesions with associated erosions involving the entire buccal mucosa and gingiva, as well as the dorsum and undersurface of the tongue. Biopsy of the lower lip revealed a subacute inflammatory reaction; Tzanck’s smears (oral mucosal
Fig. 1. (Case 1) Biopsy obtained December 1959 shows lesion of floor of mouth and gingiva, interpreted as lichen planus. Note the hyperkeratosis, absence of epithelial cell atypia, degeneration of the basal-cell layer of the epithelium, and band-like subepithelial chronic inflammatory cell infiltrate. (Hematoxylin and eosin, 1 6 0 X )
23
Oral Cancer and Chronic Ulcerative Disease
cytology) were negative on three different occasions. Bacterial and fungal cultures were negative, as were PPD, coccidioidin, and histoplasmin skin tests. Prednisone treatment resulted in improvement, and by the time of discharge the oral lesions had regressed significantly. The clinical diagnosis remained pemphigus. Over the next three years, the oral lesions persisted, and in May 1972 she developed new lesions involving the tongue, right lateral hard palate, and right tonsil. Biopsies of all these areas revealed squamous cell carcinoma, and the patient was treated with 6,000 rads from a cobalt source. A brief period of remission was followed by biopsy-proven recurrence of multicentric invasive carcinoma of the tongue. She was referred to the Surgery Branch of the National Cancer Institute in November 1972 for further therapy. The patient subsequently underwent total glossectomy with bilateral suprahyoid neck dissections; the surgical specimen showed diffuse infiltration of tongue musculature by tumor (Fig. 3). Three months following surgery, recurrent squamous cell carcinoma developed in the right lateral pharynx. This was treated with cryosurgery but recurred two months later in the soft palate and right neck. Additional cryosurgical treatment of the right soft palate was again followed by recurrence. She then received bleomycin chemotherapy but died with massive local recurrence in the oropharynx.
Fig. 2. (Case 1) Biopsy obtained April 1973 shows invasive squamous cell carcinoma of the mandibular alveolar gingiva - the same area where biopsy of lichen planus (Fig. 1) was obtained. (Hematoxylin and eosin, 3 5 0 X )
24
Faraci, Schour, and Graykowski
DISCUSSION Chronic local irritation is of paramount importance in the development of oral cancer and is often associated with exposure to substances such as alcohol and tobacco. Wynder (1971) reported that the incidence of squamous cell carcinoma of the oral cavity in persons smoking over 35 cigarettes daily was almost four times that occurring in nonsmokers. Persons drinking over 180 cc of whiskey per day were found to have 16 times the incidence of oral cancer found in nondrinkers. Dipping of snuff and chewing of betel have also been associated with the development of oral cancer. Rosenfeld and Callaway (1963) noted in a study in Nashville, Tennessee, that 98%of women with squamous cell carcinoma of the gingival-buccal area were habitual snuff dippers. In India, where 47% of all malignant neoplasms have been reported to develop in the intraoral and pharyngeal region (Paymaster, 1957), betel chewing is practically ubiquitous. Sirsat and Doctor (1967) noted a high incidence of premalignant changes in the oral cavity of betel chewers. Finally, as evidence that almost any chronically irritating substance can be associated with oral cancer, Li, Miller, and Levene (1972) reported an 81-year-old woman with squamous cell carcinoma of the buccal mucosa developing in an area in the mouth where cotton had been placed daily for 30 years in order to improve the appearance of sunken cheeks. Some conditions characterized by abnormality of the epithelial lining of the oral cavity, such as leukoplakia (Sugar and Banoczy, 1969) have received considerable attention as predisposing factors in the development of cancer of the oral cavity. However, the role of other conditions, such as pemphigus and lichen planus, has not been extensively discussed. Although Lever (1965) describes pemphigus vulgaris as involving the oral mucosa in virtually all cases, with 50% of the patients presenting with oral lesions as their initial complaint, autopsy studies of patients dying from this disease showed no oral cancers.
Fig. 3. (Case 2) Invasive squamous squamous cell carcinoma of the tongue. Segments of a few skeletal muscle fibers are visible in the lower right-hand corner. (Hematoxylin and eosin, 5 6 X )
25
Oral Cancer and Chronic Ulcerative Disease
The role of lichen planus in the development of oral malignancy is difficult to define. Shklar (1968) found no evidence of malignancy in a review of 50 cases of oral lichen planus. However, Warin (1960), in a review of the literature, found cancer developing in 15 patients with oral lichen planus (Marshall, 195 1; Miller, 1947; Barker, 1947), and he reported four additional cases. Labayle et al., (1967) has described two further patients with lichen planus in whom carcinoma of the oral cavity developed. The exact etiology of the cancer in these patients is uncertain due to the fact that the majority had histories of smoking, alcoholism, or chronic irritation of the oral cavity - factors which in themselves are associated with the development of oral cancer. Questioning the two patients reported regarding exposure to the common etiologic agents of oral cancer was unrewarding. One had never smoked cigarettes, and the other had completely discontinued intermittent smoking 14 years prior to the development of oral cancer. Neither patient ingested alcohol or snuff, and application of caustic agents to the oral mucosa had not been carried out. This absence of known etiologic agents for oral cancer suggests that chronic irritation associated with long-standing epithelial disorders led t o the oral cancers which developed in these patients. The differential diagnosis of bullous lesions limited to the oral cavity may be difficult, as in the second case studied. Although the bullous nature of the oral lesions, their generalized distribution within the oral cavity, and the response to steroids suggested a diagnosis of pemphigus to the attending dermatologist, the clinical findings were also consistent with bullous lichen planus. The finding that both the lesions and the cancer were multicentric in origin supports the hypothesis that the diffuse epithelial abnormalities were responsible for development of her cancer. The first patient had microscopic evidence of oral lichen planus for many years prior to the development of squamous cancer in the same area. Oral cancer may become a more prominent feature of pemphigus. The previous high mortality of pemphigus vulgaris has decreased drastically with steroid treatment. Since these patients are now living longer, the lengthened life-span may permit the development of oral cancer in more of them. All patients with chronic disorders of the oral epithelium should be followed carefully and treated intensively in an attempt to secure complete healing of the oral lesions. Any abnormal areas which persist should be promptly biopsied. Even if only atypical or benign changes are found upon the initial histologic examination, biopsy should be repeated if clinical abnormalities persist, in an attempt to detect any transition to a malignant process.
REFERENCES Barker, L. P. (1947). (Discussion by J. L. Miller), Arch. Derm. Syphl. 55:154. Labayle, J., Legent, F., and Bismuth, R. (1967). Lichen planus buccalis. Ann. Otolaryngol. (Paris) 84: 346-349. Lever, W. F. (1965). “Pemphigus and pemphigoid.” Springfield, Ill: Charles C. Thomas pp. 15-39, 148-153. Li, F. P., Miller, R. W., and Levene, M. B. (1972). Cotton as a cause of cancer. Lancet 1:1014-1015. Marshall, H. (1951). Buccal lichen planus and carcinoma. S. Afr. Med. J. 25:561-563. Miller, J. L. (1947). Lichen planus. Arch. Derm Syphl. 55:153-154. Paymaster, J. C. (1957). The problem of oral, oropharyngeal, and hypopharyngeal carcinoma in Inida. Brit. J. Surg. 44:467-471.
26
Faraci, Schour, and Graykowski
Rosenfeld, L., and Callaway, J. (1963). Snuff dipper’s cancer. Amer. J. Surg. 106:840-844. Shklar, G. (1968). Erosive and bullous oral lesions of lichen planus. Arch. Derm. 97:411-416. Silverberg, E., and Holleb, A. (1972). Cancer statistics. Ca-a Cancer Journal for Clinicians 22:2-20. Sirsat, M. V., and Doctor, V. M. (1967). A histopathologic study on the effect of tobacco chewing o n the buccal mucosa in Indians and its relationship to cancer. Brit. J. Surg. 21 :277-284. Sugar, L., and Banoczy, J. (1969). Followup studies in oral leukoplakia. Bull. WHO 41:289-293. Warin, R. P. (1960). Epithelioma following lichen planus of the mouth. Brit. J. Derm. 72:288-298. Wynder, E. L. (1971). Etiological aspects of squamous cancers of the head and neck. JAMA 2 15 :45 2 -454.
Squamous Cell Carcinoma of the Oral Cavity - Chronic Oral Ulcerative Disease as a Possible Etiologic Factor .......................................................................................... .......................................................................................... ROBERT P. FARACI, M.D., LIONEL SCHOUB, M A , M.D., and EDWARD A. GRAYKOWSKI, M,D., D.D.S. This report documents the association of carcinoma of the oral cavity with chronic oral ulcerative disease in two patients. This association has not previously been documen€scl in the surgical literature. Both patients in this report had chronic oral ulcerative disease preceding their cancers; however, the common etiologic factors for oral cancer were not detected in either case. Oral lichen planus and pemphigus vulgaris should be considered as potentially premallgnanf legions and should be treated accordingly.
.......................................................................................... .......................................................................................... Cancer of the oral cavity comprises 3% of all cancers in males and 2% of cancers in females. In 1973 in the United States, there were an estimated 7,500 deaths due to cancer of the buccal cavity and oropharynx, and approximately 15,000 new cases were diagnosed (Silverberg and Holleb, 1972). Etiologic factors in oral cancer have been discussed by many authors, and the importance of chronic local irritation has been emphasized. Cigarettes, alcohol, and snuff, as well as other agents, have been implicated as potential carcinogens. The possible role of chronic bullous lesions of the oral cavity in the development of oral cancer has received little attention, although it has been suggested that lichen planus can lead to the development of oral cancer. An example of this occurred in a 79-year-old female (NIH #03.64.76-4) who was first seen at the National Institutes of Health in December 1959 because of a 25-year history of intermittent oral pain and tenderness associated with the formation of whitish plaques which would break down and ulcerate. The patient gave a remote history of sporadic smoking; however, she had completely stopped smoking prior to her 1959 hospital admission. There was no history of tobacco chewing or snuff dipping, and the patient did not use mouthwashes or condiments with aromatic oils. Surgery Branch, National Cancer Institute, and the Laboratory of Oral Medicine, National InstitutF for Dental Research (Dr. Graykowski), National Institutes of Health, Bethesda, Maryland 20014. 21
OAlan R. Liss, Inc., 150 Fifth Avenue, New York, N.Y. 10011
22
Faraci, Schour, and Graykowski
Examination revealed white hyperkeratotic lesions involving the floor of the mouth and the lingual frenulum and extending to the ventral surface of the tongue and the buccal mucosa. There was a 1 cm ulcerated area at the left lower gingival mucosa, extending from the floor of the mouth to the gingiva adjacent to the left lower first bicuspid. On Dec. 23, 19.59, biopsy of these areas showed lichen planus (Fig. l), and the patient was treated symptomatically. The lichen planus persisted for the next 14 years, most notably in the left lateral tongue and gingiva. In March 1973, following a full mouth extraction, the patient complained of poor healing of the left mandibular alveolar ridge. Examination in April 1973 showed a 5 X 8.5 cm ulcerated mass at the left anterior alveolar mucus-membrane junction where lichen planus had been present for many years. A biopsy of this lesion showed well differentiated squamous carcinoma (Fig. 2). She then received 7,200 rads t o the mandible over a sevenweek period, and four months following treatment she remains free of tumor. A second patient (NIH #09-50-70-1) was seen at the National Cancer Institute in November 1972 because of diffuse carcinoma of the tongue. This 62-year-old white female’s problems began in 1967 with oral mucosal blisters. These progressed, necessitating examination at the dermatology clinic of a university hospital in September 1968, at which time a clinical diagnosis of pemphigus vulgaris was made. Because of persistent oral bullous lesions, she was hospitalized in January 1969. At that time there was no history of cigarette smoking, alcohol intake, or ingestion of irritating substances. Physical examination revealed vessicobullous lesions with associated erosions involving the entire buccal mucosa and gingiva, as well as the dorsum and undersurface of the tongue. Biopsy of the lower lip revealed a subacute inflammatory reaction; Tzanck’s smears (oral mucosal
Fig. 1. (Case 1) Biopsy obtained December 1959 shows lesion of floor of mouth and gingiva, interpreted as lichen planus. Note the hyperkeratosis, absence of epithelial cell atypia, degeneration of the basal-cell layer of the epithelium, and band-like subepithelial chronic inflammatory cell infiltrate. (Hematoxylin and eosin, 1 6 0 X )
23
Oral Cancer and Chronic Ulcerative Disease
cytology) were negative on three different occasions. Bacterial and fungal cultures were negative, as were PPD, coccidioidin, and histoplasmin skin tests. Prednisone treatment resulted in improvement, and by the time of discharge the oral lesions had regressed significantly. The clinical diagnosis remained pemphigus. Over the next three years, the oral lesions persisted, and in May 1972 she developed new lesions involving the tongue, right lateral hard palate, and right tonsil. Biopsies of all these areas revealed squamous cell carcinoma, and the patient was treated with 6,000 rads from a cobalt source. A brief period of remission was followed by biopsy-proven recurrence of multicentric invasive carcinoma of the tongue. She was referred to the Surgery Branch of the National Cancer Institute in November 1972 for further therapy. The patient subsequently underwent total glossectomy with bilateral suprahyoid neck dissections; the surgical specimen showed diffuse infiltration of tongue musculature by tumor (Fig. 3). Three months following surgery, recurrent squamous cell carcinoma developed in the right lateral pharynx. This was treated with cryosurgery but recurred two months later in the soft palate and right neck. Additional cryosurgical treatment of the right soft palate was again followed by recurrence. She then received bleomycin chemotherapy but died with massive local recurrence in the oropharynx.
Fig. 2. (Case 1) Biopsy obtained April 1973 shows invasive squamous cell carcinoma of the mandibular alveolar gingiva - the same area where biopsy of lichen planus (Fig. 1) was obtained. (Hematoxylin and eosin, 3 5 0 X )
24
Faraci, Schour, and Graykowski
DISCUSSION Chronic local irritation is of paramount importance in the development of oral cancer and is often associated with exposure to substances such as alcohol and tobacco. Wynder (1971) reported that the incidence of squamous cell carcinoma of the oral cavity in persons smoking over 35 cigarettes daily was almost four times that occurring in nonsmokers. Persons drinking over 180 cc of whiskey per day were found to have 16 times the incidence of oral cancer found in nondrinkers. Dipping of snuff and chewing of betel have also been associated with the development of oral cancer. Rosenfeld and Callaway (1963) noted in a study in Nashville, Tennessee, that 98%of women with squamous cell carcinoma of the gingival-buccal area were habitual snuff dippers. In India, where 47% of all malignant neoplasms have been reported to develop in the intraoral and pharyngeal region (Paymaster, 1957), betel chewing is practically ubiquitous. Sirsat and Doctor (1967) noted a high incidence of premalignant changes in the oral cavity of betel chewers. Finally, as evidence that almost any chronically irritating substance can be associated with oral cancer, Li, Miller, and Levene (1972) reported an 81-year-old woman with squamous cell carcinoma of the buccal mucosa developing in an area in the mouth where cotton had been placed daily for 30 years in order to improve the appearance of sunken cheeks. Some conditions characterized by abnormality of the epithelial lining of the oral cavity, such as leukoplakia (Sugar and Banoczy, 1969) have received considerable attention as predisposing factors in the development of cancer of the oral cavity. However, the role of other conditions, such as pemphigus and lichen planus, has not been extensively discussed. Although Lever (1965) describes pemphigus vulgaris as involving the oral mucosa in virtually all cases, with 50% of the patients presenting with oral lesions as their initial complaint, autopsy studies of patients dying from this disease showed no oral cancers.
Fig. 3. (Case 2) Invasive squamous squamous cell carcinoma of the tongue. Segments of a few skeletal muscle fibers are visible in the lower right-hand corner. (Hematoxylin and eosin, 5 6 X )
25
Oral Cancer and Chronic Ulcerative Disease
The role of lichen planus in the development of oral malignancy is difficult to define. Shklar (1968) found no evidence of malignancy in a review of 50 cases of oral lichen planus. However, Warin (1960), in a review of the literature, found cancer developing in 15 patients with oral lichen planus (Marshall, 195 1; Miller, 1947; Barker, 1947), and he reported four additional cases. Labayle et al., (1967) has described two further patients with lichen planus in whom carcinoma of the oral cavity developed. The exact etiology of the cancer in these patients is uncertain due to the fact that the majority had histories of smoking, alcoholism, or chronic irritation of the oral cavity - factors which in themselves are associated with the development of oral cancer. Questioning the two patients reported regarding exposure to the common etiologic agents of oral cancer was unrewarding. One had never smoked cigarettes, and the other had completely discontinued intermittent smoking 14 years prior to the development of oral cancer. Neither patient ingested alcohol or snuff, and application of caustic agents to the oral mucosa had not been carried out. This absence of known etiologic agents for oral cancer suggests that chronic irritation associated with long-standing epithelial disorders led t o the oral cancers which developed in these patients. The differential diagnosis of bullous lesions limited to the oral cavity may be difficult, as in the second case studied. Although the bullous nature of the oral lesions, their generalized distribution within the oral cavity, and the response to steroids suggested a diagnosis of pemphigus to the attending dermatologist, the clinical findings were also consistent with bullous lichen planus. The finding that both the lesions and the cancer were multicentric in origin supports the hypothesis that the diffuse epithelial abnormalities were responsible for development of her cancer. The first patient had microscopic evidence of oral lichen planus for many years prior to the development of squamous cancer in the same area. Oral cancer may become a more prominent feature of pemphigus. The previous high mortality of pemphigus vulgaris has decreased drastically with steroid treatment. Since these patients are now living longer, the lengthened life-span may permit the development of oral cancer in more of them. All patients with chronic disorders of the oral epithelium should be followed carefully and treated intensively in an attempt to secure complete healing of the oral lesions. Any abnormal areas which persist should be promptly biopsied. Even if only atypical or benign changes are found upon the initial histologic examination, biopsy should be repeated if clinical abnormalities persist, in an attempt to detect any transition to a malignant process.
REFERENCES Barker, L. P. (1947). (Discussion by J. L. Miller), Arch. Derm. Syphl. 55:154. Labayle, J., Legent, F., and Bismuth, R. (1967). Lichen planus buccalis. Ann. Otolaryngol. (Paris) 84: 346-349. Lever, W. F. (1965). “Pemphigus and pemphigoid.” Springfield, Ill: Charles C. Thomas pp. 15-39, 148-153. Li, F. P., Miller, R. W., and Levene, M. B. (1972). Cotton as a cause of cancer. Lancet 1:1014-1015. Marshall, H. (1951). Buccal lichen planus and carcinoma. S. Afr. Med. J. 25:561-563. Miller, J. L. (1947). Lichen planus. Arch. Derm Syphl. 55:153-154. Paymaster, J. C. (1957). The problem of oral, oropharyngeal, and hypopharyngeal carcinoma in Inida. Brit. J. Surg. 44:467-471.
26
Faraci, Schour, and Graykowski
Rosenfeld, L., and Callaway, J. (1963). Snuff dipper’s cancer. Amer. J. Surg. 106:840-844. Shklar, G. (1968). Erosive and bullous oral lesions of lichen planus. Arch. Derm. 97:411-416. Silverberg, E., and Holleb, A. (1972). Cancer statistics. Ca-a Cancer Journal for Clinicians 22:2-20. Sirsat, M. V., and Doctor, V. M. (1967). A histopathologic study on the effect of tobacco chewing o n the buccal mucosa in Indians and its relationship to cancer. Brit. J. Surg. 21 :277-284. Sugar, L., and Banoczy, J. (1969). Followup studies in oral leukoplakia. Bull. WHO 41:289-293. Warin, R. P. (1960). Epithelioma following lichen planus of the mouth. Brit. J. Derm. 72:288-298. Wynder, E. L. (1971). Etiological aspects of squamous cancers of the head and neck. JAMA 2 15 :45 2 -454.
