J Oral Maxillofac 48:1044-1047,
Surg
1991
Association Between l$~elop Lower Lip Cancer and Tobacc GUNNAR BLOMQVIST, MD, pHe),* JAN-M. HIRSCH, DMD, PHD,jAND PER ALBERIUS, DMD, MD, PHD$ Tobacco use is considered to increase the risk of tumor induction. The purpose of this case-controlled investigation was to assess the association of tobacco habits and development of squamous cell carcinoma of the lower lip. Sixty-one patients treated for lower lip cancer, aged between 42 and 90 years, were studied. Age- and sex-matched healthy controls showed a similar exposure to tobacco in years and a comparable distribution of tobacco habits. Although the mean exposure factor (duration times exposure) was greater in the tumor group, no intimate correlation between lip cancer and tobacco was demonstrated. Wowever, an increased, although small, occurrence of herpes labialis lesions was found in cancer patients. The hypothesis is presented that smokers experiencing recurrent herpes simplex virus 1 (HSV-1) infections are more Biabie to tumor initiation, which issue will be subjected to a future study.
Squamous cell carcinoma of the lower lip occurs predominantly in males, and its incidence in Sweden is 4 in 100,000 inhabitants as compared with 1.8 in 100,000 in the United States.’ In Sweden, the tumor occurs most often in people aged more than 70 years and is generally located in the central third of the lip; its size seldom exceeds 2 cm.2 Consistently, this neoplasm is more common in rural areas and among outdoor workers than in urban areas and in those with indoor occupations.3” Histologically, these tumors usually are highly differentiated. The occurrence of lip cancer has been suggested to be associated with sun exposure and heavy alcohol intake,6-8 although the latter factor is disputed.4 The etiology of such cancer also is often associated with tobacco habits,’ and there appears to be general agreement that use of tobacco, both smoked and smokeless, markedly increases the risk of tu-
mor induction. Other exogenous factors, such as thermal, chemical, mechanical, and infectious agents, are considered cofactors in the pathogenesis. The purpose of the present investigation was ts elucidate the intluence of tobacco habits on the development of squamous cell carcinoma of the lower lip. Material and Methods
Sixty-one patients, 57 men and four women, were studied. All were treated at the Department of PIastic Surgery, Sahlgrenska hospital, Goteborg, for squamous cell carcinomas of the lower hp. They were operated on by a step technique for excision and immediate reconstruction, as suggested earlier,” which entails a 5-year survival rate exceeding 98%. A negative surgical margin was obtained in all patients. No local recurrences have come to our attention.
* Associate Professor, Department of Plastic Surgery, Sahlgrenska Hospital, University of Gijteborg, Sweden. t Associate Professor, Department of Oral Surgery, University of GBteborg, Sweden. t Associate Professor, Department of Plastic Surgery, University of Lund, Malmb, Sweden. Address correspondence and reprint requests to Dr Hirsch: Department of Oral Surgery, University of GBteborg, Box 33070, S-400 33 GBteborg, Sweden. 0 1991 American
Association
of Oral and Maxillofacial
Table 1. Number and Sex of Study Patients as Related to Age Group 1 2 3
Sur-
geons
Total
027%2391/91/4910-0003$3.00/0
1044
Age (yr)
n
M
F
42-70 71-80 81-90
15 28 18
14 27 16
1 1 2
61
BLOMQVIST,
1045
WBWZH, AND ALBERKJS
NO QF PATENTS
Goteborg and its surrounding areas). To avoid possible bias by excluding the small exposure to pipe and cigar smoking, a measure of total tobacco consumption was created. Total exposure to tobacco was calculated by means of an exposure factor (El?) obtained by the product sf the number of cigarettes (after conversion into the equivalent consumI9tion) and the number of years that the idual had been using tobacco. Fifty grams of was estimated to be equivalent to 20 cigarettes, 50 gm pipe tobacco equivalent to 40 cigarettes, and one cigar equivalent to three cigarettes. Assessment of nutritional status was not undertaken because retrospective dietary histoties usually do not detect differences between cases and controls. 11 Fifty-seven percent of cancer patients and 31% of controls had outdoor occnpations; the remaining patienats were involved mainly in indoor activities.
groups t
20
-- 2
3
i
10
0
AGE FIGURE I. age group.
Numbesand sex of patients as related to age and Resasits
Interviews were rcondncted with all patients before surgery, and their records were reviewed, The patients were requested to answer questionnaires on their previous and present tobacco habits, the occurrence of herpes labialis lesions (vesicular lesions at the mucocutaneous border of the lower lip, preceded by a pricking or burning sensation in the area and followed by rupture of the vesicles and formation of crusts) and on their occupation. The response rate was 100%. Nevertheless, some anamnestic details were incomplete in a few patients; most of this information was subsequently collected, but in four patients all information could not be obtained. The patients were divided into three age groups (Table 1, Fig 1). Mean age at the time of operation was 65 years. For each age class, age- and sexmatched controls were selected among non-tumorbearing patients not previously treated for malignant disease. No difference between the ratio of rural/urban population was found between the groups (all patients were referred from the city of Table 2,
Distrhtion
0%Tobacco Mabits Among Patients c
Age Group 1 2 3 Total
The prevalence of different tobacco habits is shown in Table 2. Cigarette smoking predominated in the control group. The remaining groups were roughly equal. The mean entire exposure to tobacco in years was similar between groups, altbough the exposure in the lip cancer group predominated over controls in the oldest age group (Table 3%).The calculated mean exposure factor to tobacco in the tumor group was 455, whereas that of controls was 40.5(Table 4). The individual variation was considerable. When this exposure was expressed in terms of e sure to cigarettes, the fignre of the cancer gro corresponded to a consumption equal to I5 cigarettes a day smoked during 30 years, ,whereas controls smoked 13 cigarettes during the same period. The heaviest smokers were in the control group. The variation between age groups was nonsignificant. The occurrence of herpes labialis lesions differed in two respects, The older lip cancer patients reported significantly more problems than controls; furthermore, the cancer group suffered frequent
tyr)
Ca
42-70 71-80* 81-90
5 10 5 20
T
S
CG
Ca
C
Ca
7 1.5 8
4 2
2 1 1
2
1
30
6
4
2
2
C
Nonsmokers
Ca
c
Ca
c
2
1 1
6 7 4
3 7 5
4 5 3
2 4 2
2
2
17
15
12
8
C
Ca
1
-
-
Mixed C
-
Abbreviations: C, cigarettes; T, pipe tobacco; S, snuff, CG, cigars; Ca, lip cancer; c, control. * Two patients in the lip cancer group were excluded owing to incomplete answers to questionnaires.
1046 Table 3.
EOWER&IPCANCERAND ‘FcmACBL10 Entire Tobacco Exposure (Years) Lip Cancer
Age Gl-0llp
1 2 3
n
Mean (SD)
REUlgC
”
Mean (SD)
Range
11 20* 15
31.4 (10.8) 32.2 (12.9) 46.8 (18.4)
9-45 10-51 5-67
13 24 16
34.2 (14.1) 34.7 (16.3) 37.6 (98.8)
20-5 I 2-60 1-66
46
36.7 (15.9)
53
35.5 (16.4)
(w-)
42-70 71-80 81-90
Total
Controls
Nonsmokers were excluded from analysis. Differences between variables and groups were not significant (nonparametric tests). * Gne patient record was incomplete (in addition to those two mentioned in Table 2).
outbreaks (2Uyear) significantly more often (Table 5). Thirty-nine percent of the tumor group reported cessation of smoking before surgery, whereas 60% of controls using tobacco had stopped such use before this study was undertaken (Table 6). Approximately 25% of the tumor patients continued smoking after the diagnosis was established and the operation performed. The mean latency period from start of tobacco use to diagnosis of lip cancer was 39.5 (SD, 14.1) years [group 1, 33.5 (SD, 7.0) years, n = 11; group 2, 34.8 (SD, 13.4) years, n = 23; group 3, 51.2 (SD, 12.5) years, n = 151. Discussion
From the present investigation, we deduced that exposure to tobacco in the total group treated for lower lip squamous cell carcinoma was more extensive than in controls. The two groups were age- and sex-matched; moreover, exposure to tobacco in years and distribution of tobacco habits did not differ between groups. Apparently, the groups are fully comparable with respect to important parameters. All patients with tumors were treated surgically for the same type of malignancy, ie, squamous cell carcinoma. Lip cancers are often included in studies of oral cancer, but only three extensive case-control studies of lip cancer provide information on the relationTable 4.
Exposure Factor as Related to Age and Groups Age
Group 1 2 3 Total
ship of lip cancer to tobacco smoking. Keller studied 314 cases in American maIe.r2 Two control. groups were identified by sampling, one consisting of patients with cancers of the oral cavity and pharynx, the other consisting of persons without oral and pharyngeal cancer. The author reported that smoking cigarettes and cigars was signifmantly associated with lip cancer, whereas pipe smoking appeared to be uncorrelated to this disease, but the data did not include information ‘regarding the amount smoked or the duration of smoking. Spitzer and colleagues studied 366 male Canadian patients with lip cancer. 4 Three control groups were used. Group 1 was composed of patients with oral cancer, group two was composed of patients with skin can cer of the head and neck, and group three was composed of randomly selected population controls. In contrast to the findings of Keller,‘z an increased risk of lip cancer among pipe smokers was reported. Moreover, the occupation of fisashing,was shown to be an additional independent contribution to the risk. Lindqvist studied 299 cases of lip cancer in Finland.’ Patients with squamous cell skin, cancer of the head and neck region served as controis. He concluded that a combination of tobacco use and outdoor work induces lip cancer, but that neither factor had a significantly independent effect. Most of his patients smoked cigarettes. @our study, we used healthy controls showing tobacco habits almost identical to those of the tumor group, although a discrepancy between the groups as to exposure to
Controls
Lip Cancer
(yr)
n
Mean(SD)
Range
42-70 71-80 81-90
11 19* 14t
524.3 (261.8) 371.2 (263.7) 515.1 (285.3)
200-920 45-890 10-950
44
455.3 (274.2)
Differences between variables and groups were not significant (nonparametric tests). * Two patient records were incomplete in addition to the two described in Table 2. 7 One patient record was incomplete.
”
Mean (SD)
Range
113 24 16
357.3 (205.0) 472.3 (600.6) 343.5 (268.8)
40-765 12-2,400 3-760
53
405.2 (440.3)
1049
BLGMCjVIST, HIRSCH, AND ALBERIUS
Table & Occurrence of Herpes Labialis Among the aroups Few
(One to Two per Year) Group 1
2 3
Frequent (More Than Three per Year)
Age (yr)
ChCeC
CO~WOlS
CFtllWI
COIltIOlS
42-70 71-80 81-90
4 8 9
4 7
5 7
1 1 1
Lip
hip
I
-
sunlight is suspected on the basis of occupational activities. Our findings do not specifically indicate an intimate correlation between lip cancer and tobacco. Ahhough the mean exposure factor (duration times tobacco consumption) was greater in the total tumor group, this did not apply to all age groups. None of the four women receiving tumor surgery were smokers. Considering the great variation aamtobacco exposure in terms of duration and total amount of tobacco consumed, and despite its importance to neoplasms of the upper respiratory and upper gastrointestinal tracts, other exogenous and endogenous factors probably are of greater and synergistic importance to development of squamous cell carcinoma of the lower lip. An extensive number of studies on the carcinogenicity of cigarette smoke condensate (CSC) on mouse skin have consistently demonstrated its induction potential of benign and malignant skin tumors. The carcinogenic effects appear to result from the interaction of various CSC constituents. CSC has been shown to possess both tumorinitiating and tumor-promoting constituents. l3 Exposure to other exogenous agents is considered a cofactor. One factor of particular interest is herpes simplex virus 1 (HSV-I). We registered an increased, although small, occurrence of herpes labiahs in cancer patients relative to controls. Although specific diagnosis was not possible in this study, critical evaluation of the descriptions of the sympTable . Cessation of Tobacco Use Among Groups arid Ranges of lime (Years) Without Tobacco Lip Cancer Group 1 2 3 Total
Controls
Age (yr)
” (%)
Range
n (%)
Range
42-70 71-80 51-90
2 (18) 12 (60) 4 (27)
9-14 l-33 OS-48
4 (31) 16 (67) 13 (81)
1-14 2-58 2.543
18 (39)
32 (60)
Percentage of individuals who have stopped using tobacco relative to the total population of individuals exposed to tobacco (Table 3) is shown in parentheses.
toms made by affected patients clearly suggested that they were due to HSV-1. HSV has tfhe potential to transform cells malignantly when the cytolytic action of the virus is inhibited. I4 Such an effect was previously demonstrated for tobacco extracts.” In ah, 60% to 70% of the adult population appear to have been exposed to H%V,‘6 and recurrent lesions are experienced by approximately 4Q%.‘7 Prequently, the site of such recurrences is the Bower lip. Accordingly, smokers experiencing recurrent HSV infections appear to have a risk for initiation and promotion of tumors. This hypothesis willi be examined further in a future study. Acknowledgment We thank Jdrgen Noren, DDS, PhD, for statistical advice.
References 1. Szpak CA, Stone MJ, Frenkel SK: Some observations concerning the demographic and geographic incidence of carcinoma of the lip and buccal cavity. Cancer 40:343, 1977 2. Blomgren I, Blomqvist G, Lauritzen C, et al: The step technique for the reconstruction of the lower lip after cancer resection. Stand J Plast Reconstr Surg 22:103, 1988 3. Ebenius B: Cancer of the lip. Acta Radio1 48: 1, 1943 (suppi) 4. Spitzer WG, Hill GB, Chambers LW, et al: The occupation offishing as a risk factor in cancer of the lip. N Engl J Med 293:419, 1975 5. Lindqvist C: Risk factors in lip cancer: A questionnaire survey. Am J Epidemiol 109:521, 1979 6. Baker SR: Risk factors in multiple carcinoma of the lip. Otolaryngol Head Neck Surg 88:248, 1980 7. Dardoni L, Gafa IL, Patemo R, et al: A case control study of lip cancer risk factors in Ragusa (Sicily). Int J Surg 34:335, 1984 8. Baker SW, Krause CJ: Carcinoma of the lip. Laryngoscope 90: 19, 1980 9. Hirsch JM: Snuff-induced lesions-A clinical and experimentti study. Thesis, University d GBteborg, Sweden, 1983 10. Johanspn B, Aspelund E, Breine U, et al: Surgical treatment of non-traumatic lower lip lesions with special reference to the step technique. A,foIlow-up on 149 patients. Stand J Plast Reconstr Surg 8232, 1974 11. Feldman JG, Hazan M: A case-control knvestigation of alcohol, tobacco, and diet in head and neck cancer. Prev Med 4:&t, 1975 12. Keller AZ: Cellular types, survival, race, nativity, occupations, habits and associated diseases in pathogenesis oflip cancers. Am 9 Epidemiol91:486, 1970 13. HARC: IARC monographs on the evahration of the carcinogenic risk of chemicals to humans. Tobacco Smoking 1985,,vol 38 14. Rapp F: Transformation by herpes simplex viruses, in Essex M, Todaro G, zur Hausen I-I (eds): Virnses in Naturally Occurring Cancers. New York, Cold Spring Harbor Laboratory, 1980, p 63 15. HBrsch: JM, Svennerholm B, Qahlne A: Inhibition of herpes simplex virus replication by tobacco extracts. Cancer Res 44:1991, 1984 16. Nahmias AJ, Roizman B: Infection with herpes simplex viruses, I and 2. N Engl .I Med 4:719, 11:781, 27:667, 1973 17. Ship II, ,Morris AW, Durocher RT, et al: Recurrent apthous ulcerations and recurrent herpes labialis in a professionaI schdol student population. I. Experience. Oral Surg 13:1191, 1960
Surg
1991
Association Between l$~elop Lower Lip Cancer and Tobacc GUNNAR BLOMQVIST, MD, pHe),* JAN-M. HIRSCH, DMD, PHD,jAND PER ALBERIUS, DMD, MD, PHD$ Tobacco use is considered to increase the risk of tumor induction. The purpose of this case-controlled investigation was to assess the association of tobacco habits and development of squamous cell carcinoma of the lower lip. Sixty-one patients treated for lower lip cancer, aged between 42 and 90 years, were studied. Age- and sex-matched healthy controls showed a similar exposure to tobacco in years and a comparable distribution of tobacco habits. Although the mean exposure factor (duration times exposure) was greater in the tumor group, no intimate correlation between lip cancer and tobacco was demonstrated. Wowever, an increased, although small, occurrence of herpes labialis lesions was found in cancer patients. The hypothesis is presented that smokers experiencing recurrent herpes simplex virus 1 (HSV-1) infections are more Biabie to tumor initiation, which issue will be subjected to a future study.
Squamous cell carcinoma of the lower lip occurs predominantly in males, and its incidence in Sweden is 4 in 100,000 inhabitants as compared with 1.8 in 100,000 in the United States.’ In Sweden, the tumor occurs most often in people aged more than 70 years and is generally located in the central third of the lip; its size seldom exceeds 2 cm.2 Consistently, this neoplasm is more common in rural areas and among outdoor workers than in urban areas and in those with indoor occupations.3” Histologically, these tumors usually are highly differentiated. The occurrence of lip cancer has been suggested to be associated with sun exposure and heavy alcohol intake,6-8 although the latter factor is disputed.4 The etiology of such cancer also is often associated with tobacco habits,’ and there appears to be general agreement that use of tobacco, both smoked and smokeless, markedly increases the risk of tu-
mor induction. Other exogenous factors, such as thermal, chemical, mechanical, and infectious agents, are considered cofactors in the pathogenesis. The purpose of the present investigation was ts elucidate the intluence of tobacco habits on the development of squamous cell carcinoma of the lower lip. Material and Methods
Sixty-one patients, 57 men and four women, were studied. All were treated at the Department of PIastic Surgery, Sahlgrenska hospital, Goteborg, for squamous cell carcinomas of the lower hp. They were operated on by a step technique for excision and immediate reconstruction, as suggested earlier,” which entails a 5-year survival rate exceeding 98%. A negative surgical margin was obtained in all patients. No local recurrences have come to our attention.
* Associate Professor, Department of Plastic Surgery, Sahlgrenska Hospital, University of Gijteborg, Sweden. t Associate Professor, Department of Oral Surgery, University of GBteborg, Sweden. t Associate Professor, Department of Plastic Surgery, University of Lund, Malmb, Sweden. Address correspondence and reprint requests to Dr Hirsch: Department of Oral Surgery, University of GBteborg, Box 33070, S-400 33 GBteborg, Sweden. 0 1991 American
Association
of Oral and Maxillofacial
Table 1. Number and Sex of Study Patients as Related to Age Group 1 2 3
Sur-
geons
Total
027%2391/91/4910-0003$3.00/0
1044
Age (yr)
n
M
F
42-70 71-80 81-90
15 28 18
14 27 16
1 1 2
61
BLOMQVIST,
1045
WBWZH, AND ALBERKJS
NO QF PATENTS
Goteborg and its surrounding areas). To avoid possible bias by excluding the small exposure to pipe and cigar smoking, a measure of total tobacco consumption was created. Total exposure to tobacco was calculated by means of an exposure factor (El?) obtained by the product sf the number of cigarettes (after conversion into the equivalent consumI9tion) and the number of years that the idual had been using tobacco. Fifty grams of was estimated to be equivalent to 20 cigarettes, 50 gm pipe tobacco equivalent to 40 cigarettes, and one cigar equivalent to three cigarettes. Assessment of nutritional status was not undertaken because retrospective dietary histoties usually do not detect differences between cases and controls. 11 Fifty-seven percent of cancer patients and 31% of controls had outdoor occnpations; the remaining patienats were involved mainly in indoor activities.
groups t
20
-- 2
3
i
10
0
AGE FIGURE I. age group.
Numbesand sex of patients as related to age and Resasits
Interviews were rcondncted with all patients before surgery, and their records were reviewed, The patients were requested to answer questionnaires on their previous and present tobacco habits, the occurrence of herpes labialis lesions (vesicular lesions at the mucocutaneous border of the lower lip, preceded by a pricking or burning sensation in the area and followed by rupture of the vesicles and formation of crusts) and on their occupation. The response rate was 100%. Nevertheless, some anamnestic details were incomplete in a few patients; most of this information was subsequently collected, but in four patients all information could not be obtained. The patients were divided into three age groups (Table 1, Fig 1). Mean age at the time of operation was 65 years. For each age class, age- and sexmatched controls were selected among non-tumorbearing patients not previously treated for malignant disease. No difference between the ratio of rural/urban population was found between the groups (all patients were referred from the city of Table 2,
Distrhtion
0%Tobacco Mabits Among Patients c
Age Group 1 2 3 Total
The prevalence of different tobacco habits is shown in Table 2. Cigarette smoking predominated in the control group. The remaining groups were roughly equal. The mean entire exposure to tobacco in years was similar between groups, altbough the exposure in the lip cancer group predominated over controls in the oldest age group (Table 3%).The calculated mean exposure factor to tobacco in the tumor group was 455, whereas that of controls was 40.5(Table 4). The individual variation was considerable. When this exposure was expressed in terms of e sure to cigarettes, the fignre of the cancer gro corresponded to a consumption equal to I5 cigarettes a day smoked during 30 years, ,whereas controls smoked 13 cigarettes during the same period. The heaviest smokers were in the control group. The variation between age groups was nonsignificant. The occurrence of herpes labialis lesions differed in two respects, The older lip cancer patients reported significantly more problems than controls; furthermore, the cancer group suffered frequent
tyr)
Ca
42-70 71-80* 81-90
5 10 5 20
T
S
CG
Ca
C
Ca
7 1.5 8
4 2
2 1 1
2
1
30
6
4
2
2
C
Nonsmokers
Ca
c
Ca
c
2
1 1
6 7 4
3 7 5
4 5 3
2 4 2
2
2
17
15
12
8
C
Ca
1
-
-
Mixed C
-
Abbreviations: C, cigarettes; T, pipe tobacco; S, snuff, CG, cigars; Ca, lip cancer; c, control. * Two patients in the lip cancer group were excluded owing to incomplete answers to questionnaires.
1046 Table 3.
EOWER&IPCANCERAND ‘FcmACBL10 Entire Tobacco Exposure (Years) Lip Cancer
Age Gl-0llp
1 2 3
n
Mean (SD)
REUlgC
”
Mean (SD)
Range
11 20* 15
31.4 (10.8) 32.2 (12.9) 46.8 (18.4)
9-45 10-51 5-67
13 24 16
34.2 (14.1) 34.7 (16.3) 37.6 (98.8)
20-5 I 2-60 1-66
46
36.7 (15.9)
53
35.5 (16.4)
(w-)
42-70 71-80 81-90
Total
Controls
Nonsmokers were excluded from analysis. Differences between variables and groups were not significant (nonparametric tests). * Gne patient record was incomplete (in addition to those two mentioned in Table 2).
outbreaks (2Uyear) significantly more often (Table 5). Thirty-nine percent of the tumor group reported cessation of smoking before surgery, whereas 60% of controls using tobacco had stopped such use before this study was undertaken (Table 6). Approximately 25% of the tumor patients continued smoking after the diagnosis was established and the operation performed. The mean latency period from start of tobacco use to diagnosis of lip cancer was 39.5 (SD, 14.1) years [group 1, 33.5 (SD, 7.0) years, n = 11; group 2, 34.8 (SD, 13.4) years, n = 23; group 3, 51.2 (SD, 12.5) years, n = 151. Discussion
From the present investigation, we deduced that exposure to tobacco in the total group treated for lower lip squamous cell carcinoma was more extensive than in controls. The two groups were age- and sex-matched; moreover, exposure to tobacco in years and distribution of tobacco habits did not differ between groups. Apparently, the groups are fully comparable with respect to important parameters. All patients with tumors were treated surgically for the same type of malignancy, ie, squamous cell carcinoma. Lip cancers are often included in studies of oral cancer, but only three extensive case-control studies of lip cancer provide information on the relationTable 4.
Exposure Factor as Related to Age and Groups Age
Group 1 2 3 Total
ship of lip cancer to tobacco smoking. Keller studied 314 cases in American maIe.r2 Two control. groups were identified by sampling, one consisting of patients with cancers of the oral cavity and pharynx, the other consisting of persons without oral and pharyngeal cancer. The author reported that smoking cigarettes and cigars was signifmantly associated with lip cancer, whereas pipe smoking appeared to be uncorrelated to this disease, but the data did not include information ‘regarding the amount smoked or the duration of smoking. Spitzer and colleagues studied 366 male Canadian patients with lip cancer. 4 Three control groups were used. Group 1 was composed of patients with oral cancer, group two was composed of patients with skin can cer of the head and neck, and group three was composed of randomly selected population controls. In contrast to the findings of Keller,‘z an increased risk of lip cancer among pipe smokers was reported. Moreover, the occupation of fisashing,was shown to be an additional independent contribution to the risk. Lindqvist studied 299 cases of lip cancer in Finland.’ Patients with squamous cell skin, cancer of the head and neck region served as controis. He concluded that a combination of tobacco use and outdoor work induces lip cancer, but that neither factor had a significantly independent effect. Most of his patients smoked cigarettes. @our study, we used healthy controls showing tobacco habits almost identical to those of the tumor group, although a discrepancy between the groups as to exposure to
Controls
Lip Cancer
(yr)
n
Mean(SD)
Range
42-70 71-80 81-90
11 19* 14t
524.3 (261.8) 371.2 (263.7) 515.1 (285.3)
200-920 45-890 10-950
44
455.3 (274.2)
Differences between variables and groups were not significant (nonparametric tests). * Two patient records were incomplete in addition to the two described in Table 2. 7 One patient record was incomplete.
”
Mean (SD)
Range
113 24 16
357.3 (205.0) 472.3 (600.6) 343.5 (268.8)
40-765 12-2,400 3-760
53
405.2 (440.3)
1049
BLGMCjVIST, HIRSCH, AND ALBERIUS
Table & Occurrence of Herpes Labialis Among the aroups Few
(One to Two per Year) Group 1
2 3
Frequent (More Than Three per Year)
Age (yr)
ChCeC
CO~WOlS
CFtllWI
COIltIOlS
42-70 71-80 81-90
4 8 9
4 7
5 7
1 1 1
Lip
hip
I
-
sunlight is suspected on the basis of occupational activities. Our findings do not specifically indicate an intimate correlation between lip cancer and tobacco. Ahhough the mean exposure factor (duration times tobacco consumption) was greater in the total tumor group, this did not apply to all age groups. None of the four women receiving tumor surgery were smokers. Considering the great variation aamtobacco exposure in terms of duration and total amount of tobacco consumed, and despite its importance to neoplasms of the upper respiratory and upper gastrointestinal tracts, other exogenous and endogenous factors probably are of greater and synergistic importance to development of squamous cell carcinoma of the lower lip. An extensive number of studies on the carcinogenicity of cigarette smoke condensate (CSC) on mouse skin have consistently demonstrated its induction potential of benign and malignant skin tumors. The carcinogenic effects appear to result from the interaction of various CSC constituents. CSC has been shown to possess both tumorinitiating and tumor-promoting constituents. l3 Exposure to other exogenous agents is considered a cofactor. One factor of particular interest is herpes simplex virus 1 (HSV-I). We registered an increased, although small, occurrence of herpes labiahs in cancer patients relative to controls. Although specific diagnosis was not possible in this study, critical evaluation of the descriptions of the sympTable . Cessation of Tobacco Use Among Groups arid Ranges of lime (Years) Without Tobacco Lip Cancer Group 1 2 3 Total
Controls
Age (yr)
” (%)
Range
n (%)
Range
42-70 71-80 51-90
2 (18) 12 (60) 4 (27)
9-14 l-33 OS-48
4 (31) 16 (67) 13 (81)
1-14 2-58 2.543
18 (39)
32 (60)
Percentage of individuals who have stopped using tobacco relative to the total population of individuals exposed to tobacco (Table 3) is shown in parentheses.
toms made by affected patients clearly suggested that they were due to HSV-1. HSV has tfhe potential to transform cells malignantly when the cytolytic action of the virus is inhibited. I4 Such an effect was previously demonstrated for tobacco extracts.” In ah, 60% to 70% of the adult population appear to have been exposed to H%V,‘6 and recurrent lesions are experienced by approximately 4Q%.‘7 Prequently, the site of such recurrences is the Bower lip. Accordingly, smokers experiencing recurrent HSV infections appear to have a risk for initiation and promotion of tumors. This hypothesis willi be examined further in a future study. Acknowledgment We thank Jdrgen Noren, DDS, PhD, for statistical advice.
References 1. Szpak CA, Stone MJ, Frenkel SK: Some observations concerning the demographic and geographic incidence of carcinoma of the lip and buccal cavity. Cancer 40:343, 1977 2. Blomgren I, Blomqvist G, Lauritzen C, et al: The step technique for the reconstruction of the lower lip after cancer resection. Stand J Plast Reconstr Surg 22:103, 1988 3. Ebenius B: Cancer of the lip. Acta Radio1 48: 1, 1943 (suppi) 4. Spitzer WG, Hill GB, Chambers LW, et al: The occupation offishing as a risk factor in cancer of the lip. N Engl J Med 293:419, 1975 5. Lindqvist C: Risk factors in lip cancer: A questionnaire survey. Am J Epidemiol 109:521, 1979 6. Baker SR: Risk factors in multiple carcinoma of the lip. Otolaryngol Head Neck Surg 88:248, 1980 7. Dardoni L, Gafa IL, Patemo R, et al: A case control study of lip cancer risk factors in Ragusa (Sicily). Int J Surg 34:335, 1984 8. Baker SW, Krause CJ: Carcinoma of the lip. Laryngoscope 90: 19, 1980 9. Hirsch JM: Snuff-induced lesions-A clinical and experimentti study. Thesis, University d GBteborg, Sweden, 1983 10. Johanspn B, Aspelund E, Breine U, et al: Surgical treatment of non-traumatic lower lip lesions with special reference to the step technique. A,foIlow-up on 149 patients. Stand J Plast Reconstr Surg 8232, 1974 11. Feldman JG, Hazan M: A case-control knvestigation of alcohol, tobacco, and diet in head and neck cancer. Prev Med 4:&t, 1975 12. Keller AZ: Cellular types, survival, race, nativity, occupations, habits and associated diseases in pathogenesis oflip cancers. Am 9 Epidemiol91:486, 1970 13. HARC: IARC monographs on the evahration of the carcinogenic risk of chemicals to humans. Tobacco Smoking 1985,,vol 38 14. Rapp F: Transformation by herpes simplex viruses, in Essex M, Todaro G, zur Hausen I-I (eds): Virnses in Naturally Occurring Cancers. New York, Cold Spring Harbor Laboratory, 1980, p 63 15. HBrsch: JM, Svennerholm B, Qahlne A: Inhibition of herpes simplex virus replication by tobacco extracts. Cancer Res 44:1991, 1984 16. Nahmias AJ, Roizman B: Infection with herpes simplex viruses, I and 2. N Engl .I Med 4:719, 11:781, 27:667, 1973 17. Ship II, ,Morris AW, Durocher RT, et al: Recurrent apthous ulcerations and recurrent herpes labialis in a professionaI schdol student population. I. Experience. Oral Surg 13:1191, 1960
