Epidemiological Comparisons

Risk Factors of Lip Cancer: A Critical Evaluation Based on Epidemiological Comparisons C. LINDQVIST, MD Abstract: A description is given of the occurrence of lip, skin, and intraoral cancers in Finland in the period 1953-1973 with the aim of testing certain etiologic hypotheses. In addition, data on lip cancer were correlated with those of some other types of cancer. Substantial differences with respect to various epidemiologic parameters were found between lip and skin cancers. However, there were similarities between lip cancer and cancers of the upper gastrointestinal canal and respiratory organs (especially lung cancer). Negative geographic correlation was found between the age-adjusted incidence rate of lip cancer and that of cancers of the colon and prostate. In addition, the correlation was highly negative for the median income per capita (p < 0.001). It was concluded that, in terms of cancer etiology, lip cancer is more closely related to cancer of the oral cavity than to that of the skin. Moreover, some specific socioeconomic factors associated with a low standard of living must be considered as noteworthy risk factors of lip cancer. (Am. J. Public Health 69:256-260, 1979.) Intr-oduction The risk factors of lip cancer have been reviewed by many authors.1-4 These factors include smoking (especially a pipe), actinic radiation, traumas, occupation of fishing, inflammatory processes, viral infections, and a number of endogenous factors. If smoking is a significant risk factor of lip cancer, then lip cancer should be etiologically related to oral cancer..5 On the other hand, an etiological similarity has been claimed to exist between lip cancer and cancer of the skin: actinic radiation has been suggested as a risk factor of both these cancer types.8'1 Recent results from the Third Naitonal Cancer Survey from the United States failed, however, to support the hypothesis of an association between actinic radiation and the risk of lip cancer. 12 In the study to be reported here, cancer of the lip was compared with cancers of the skin (face and neck), oral cavity, and some other sites with regard to various epidemiological parameters; these included trends over time, sex ratio, and geographic distribution of the risk in Finland. The object From the Finnish Cancer Registry, and the Department of Pathology, University of Helsinki. Address reprint requests to Dr. C. Lindqvist, Finnish Cancer Registry, Liisankatu 21 B, 00170 Helsinki 17, Finland. This paper, submitted to the Journal April 6, 1978, was revised and accepted for publication June 27, 1978. 256 of the study was to establish possible similarities and differences between these types of cancer in order to elucidate etiological factors. Material and Methods The series consisted of all cases of lip cancer (ICD 140, 7th revision), cancer of the skin of the head and neck (ICD 191, excluding basal cell carcinoma), and intraoral cancer excluding tongue (ICD 143-144) diagnosed in 1953-1973 and reported to the Finnish Cancer Registry (Table 1). The diagnosis of cancer was verified histologically in the vast majority of cases; precancerous lesions were excluded. All rates were adjusted for age to the "world standard population"13 by the direct method, and are given per 100,000 person years. The data on the incidence by province of other cancers were obtained from the Finnish Cancer Registry. The 1973 median income of the population living in different provinces was employed as a proxy to characterize socioeconomic status.'4 The Finnish Cancer Registry was established in 1952. It is population based and covers the entire country. All hospitals, pathological laboratories, and practitioners are requested to report to the Registry all cases of cancer that come to their attention. Since 1961, reporting has been com- AJPH March, 1979, Vol. 69, No. 3

RISK FACTORS OF LIP CANCER TABLE 1 Total Number of New Cases of Lip Cancer, Cancer of the Skin of the Head and Neck (Excluding Basal Cell Carcinomas), and lntraoral Cancer (Excluding Tongue) in Finland Diagnosed in 1953-1973 and the Percentage of Cases with Histological Confirmation of the Tumor Males Females Histological Histological No. of Confirmation No. of Confirmation Primary Site Cases (%) Cases (%) Lip 3169 95 303 92 Skin of the Head and Neck 1347 95 1377 94 lntraoral 369 93 316 97 pulsory. In addition, the Registry receives copies of all death certificates issued in the country which mention cancer. Various check-ups have indicated that the Registry files can be considered almost complete for cases of cancer diagnosed in Finland. 1 5 The population of Finland was 4.1 million in 1953 and increased to 4.7 million by 1973. In the analyses of the geographical distribution of the risks, the 12 administrative areas ("provinces") of Finland were used. Continuous immigration from rural areas to towns has taken place throughout the 20th century. An average of twofifths of the population lived in urban areas during the study period (about one-third in the early 1950s, one-half in the 1970s). Since a greater proportion of the population in southern Finland lives in urban areas, a weighted average of the urban and rural incidence rates was calculated for each province, the weights being urban:rural = 2:3. However, it has been shown previously'" that the geographical differences in the risk of lip cancer for both urban and rural populations separately are similar to those in the urban-rural-adjusted rates. The terms "urban" and "rural," as used here, are administrative in nature. However, a great majority of the "urban" population lived in areas with an urban character, while rural areas can in general be considered non-urban, i.e., mostly sparsely populated with occasional townships. The main occupations in Finland are agriculture and forestry (41 per cent in 1950, 36 per cent in 1960, and 20 per cent in 1970, respectively, of the economically active population), and industry (21 per cent in 1950, 22 per cent in 1960, and 26 per cent in 1970). 1 7 Results In 1953-1973, the mean annual number of new cases of lip cancer in Finland was 151 for males and 14 for females. In males, the annual number of cancers of the skin of face and neck (here referred to as skin cancer) and that of intraoral cancers was lower; the differences in the figures for females were smaller (Table 1). The age-adjusted incidence rate of lip cancer in males clearly exceeded that in females, while a much lower male-female ratio was found in the incidence rates of skin cancer and intraoral cancer (Table 2). Trends in the Incidence with Time The age-adjusted incidence of lip cancer in males was rather stable in the 1950s, and decreased in the 1960s (Figure 1). The incidence of skin cancer increased up to the beginning of the 1960s, after which a distinct decrease in the rate was observed. Due to the low incidence of intraoral cancer, the annual rate shows a wider variation, but there is also a slight decrease in the risk of this type of cancer in males (Figure 1). The age-adjusted incidence of lip cancer in females was low and the slightly decreasing trend curve similar to that of intraoral cancer (Figure 1). The trend with time in the incidence of skin cancer in females resembled that in males: an initial increase followed by a subsequent decrease. The male-female ratio of the incidence rates of lip, skin, and intraoral cancers remained relatively unchanged throughout this 20-year study period. Age-Incidence Curves The age-incidence curves for all three types of cancer revealed an increase in the risk with age in both males and 10- MALES 7 Li 7- - _ S k i~~~~~~kn 3-2 1 0.7\ - Oral 10] 5 * 2-0.51 0.5 1 - FEMALES 0.3' I I, I, 0.3'. 1953 1956 1959 1962 1965 1968 1971 1953 1956 1969 1962 1965 1968 1971-55 -58-61 -64-67 -70-73 -55-58 -61-64 -67-70 -73 FIGURE 1-Mean Annual Age-Adjusted Incidence Rates () of Cancers of the Lip and Skin of the Head and Neck, and Intraoral Cancer (Excluding Tongue) in Finland in 1953-1973, by Sex in Age Periods in 1953-1973, by Sex Skin Ora~~~~~~~l AJPH March, 1979, Vol. 69, No. 3 257

LINDOVIST TABLE 2-Mean Annual Age-adjusted Incidence Rates () of Lip, Skin, and Intraoral Cancer for Both Sexes in Finland, and the Male-Female and Urban-Rural Ratios of the Age-adjusted Incidence Rates, in 1961-1973 Urban Rural Total Urban/Rural Primary Site M F M:F M F M:F M F M:F M F Lip 4.6 0.4 13.3 7.7 0.5 15.6 6.4 0.4 14.9 0.6 0.7 Skin of the Head and Neck 4.4 2.9 1.5 3.9 2.3 1.7 4.1 2.6 1.6 1.1 1.3 lntraoral 1.0 0.6 1.5 0.7 0.4 2.0 0.8 0.5 1.7 1.3 1.8 females (Figure 2). On a semilogarithmic scale the age-specific curves for these cancers appeared almost as straight lines with different slopes (Figure 2). In males over age 50, the age-incidence curve was steepest for skin cancer and gentlest for lip cancer. The curves for skin and intraoral cancer had a parallel course in males and females, whereas the curves for lip cancer had different slopes in the two sexes. These observations are also reflected in the male-female ratio of the age-specific incidence rates: contrary to oral and skin cancers, the ratio for lip cancer showed a marked decrease towards the oldest age groups. Geographical Distribution The risk of contracting lip cancer was clearly higher in rural than urban areas (Table 2); this held for both sexes and for 11 out of 12 provinces. The opposite was true for skin and intraoral cancers where the risk in urban areas was higher in 10 and 9 provinces, respectively, in males and in 8 provinces in females. The urban-rural-adjusted incidence rates for each province showed that the incidence of lip cancer for both sexes was highest in the northern and eastern parts of the country and lowest in the south (Figure 3). For both sexes the incidence of skin cancer was low in the north and high in the center of the country (Figure 3). The incidence of intraoral cancer was high in the north and east in males, whereas the incidence in females did not show any consistent geographical pattern. The correlation coefficients between the age-adjusted incidence rates of lip cancer and those of a number of other cancers by province are given in Table 3. No consistent pattern could be established for different subsites of oral cancer. The correlation was negative for skin cancer and colon cancer (both sexes) and cancer of the prostate. All the coefficients were positive for cancer of the lung in both sexes, and for cancer of the larynx and stomach in males. The geographic correlation between the age-adjusted incidence rate of lip cancer in males and the median income was highly negative (r = -0.85, p < 0.001). On the other hand, the geographic correlation between the incidence of lip cancer in males by province and the proportion of those employed in agriculture18 from all rural males (range 24-56 per cent) was clearly positive (r = $0.86, p < 0.001). Discussion Difficulties arise in an international comparison of the data on the occurrence of lip, skin, and intraoral cancers. These difficulties are due to the variation in the methods of verification of the diagnosis, and to the difficulties in determining the borders between the skin, lip, and the oral mucosa. It can be concluded, however, that, according to the data available, substantial differences exist in the geographical distribution of these three types of cancer in the world.'16. 19, 2() A decreasing trend in the risk of lip and intraoral cancer reported in this study has been a common finding in other countries also. 13 19, 21, 22 The incidence of cancer of the skin of the head and neck did not follow any consistent trend in TABLE 3-Correlation Coefficients between the Age-adjusted Total, Urban, and Rural Incidence Rates of Lip Cancer in the 12 Provinces of Finland in 1961-70 and the Corresponding Incidence Rates for Cancers of the Tongue, Mouth, Skin of the Head and Neck, Larynx, Lung, Stomach, Colon, and Prostate, by Sex Tongue Mouth Skin Larynx Lung Stomach Colon Prostate (141) (141-144) (191,0-4) (161) (162) (151) (153) (177) Lip, Males Total -0.22 0.30-0.28 0.11 0.43 0.28-0.69x -0.69x Urban -0.11-0.35-0.30 0.42 0.60x 0.35-0.46-0.46 Rural 0.05 0.73xx -0.40 0.53 0.61x 0.31-0.28-0.62x Lip, Females Total 0.46-0.02-0.65x 0.31-0.04-0.45 Urban 0.68x -0.04-0.24 0.53-0.37-0.59 Rural 0.22-0.20-0.47 0.61x 0.33-0.52 x = p < 0.05, xx = p < 0.01 258 AJPH March, 1979, Vol. 69, No. 3

RISK FACTORS OF LIP CANCER 100 p 70 / 50 50, /_ / /g 30- / 20 / / / A. / I, 7~~~~~~~~~~~~~~~~~~~~~ 5 0- I, 71 - // 21 - /#/ / - 0.7 If Males Females _* 0_ O-O Lip 0.5 d-4 --0 Skin *_ *-4 o----'-ooral 0.3 l 50 60 70 80 Age (years) FIGURE 2-Mean Annual Age-Specific Incidence Rates () of Cancers of the Lip and Skin of the Head and Neck, and Intraoral Cancer (Excluding Tongue) in Finland in 1953-1973, by Sex in Age Groups Over 50 Finland, which is in accordance with the hypothesis that sunlight, being an unchanged risk factor, plays an important role in the etiology of this type of tumor. In general, the risk of contracting each of these three types of cancer increased considerably with age. The ageincidence pattern of lip cancer was closer to the pattern of oral cancer, however, than to that of skin cancer. In particular, the curves for lip and oral cancers in females were very similar. The distinct decrease with age in the male-female ratio of lip cancer incidences might suggest an occupationally-bound extra risk factor for working-age males. Solar radiation has been considered the major causative factor in the development of skin cancer and it has been demonstrated that squamous cell carcinomas are found on those areas of the head and neck which are exposed to maximum ultraviolet radiation.23 These findings are supported by unpublished data from the Finnish Cancer Registry which show that there is only slight geographic variations within the country in the incidence of skin cancer on locations other than the head and neck (ICD 191, 5-9). A negative geographic correlation has been found between the amount of total solar radiation energy and the risk of lip cancer in Finland.16 This finding, together with the differences in the geographic distribution of lip and skin cancers in Finland, makes it improbable that solar radiation is a major risk factor for lip cancer in this country. A similar general conclusion has also been reached in a recent report.12 Cancers of the lip and oral cavity belong to the few types of malignant neoplasms in which a decreasing trend in the risk with time has been observed in Finland; cancer of the esophagus and stomach are two further examples.24 In addition to the time trend, the risks of lip cancer and cancer of the stomach in Finland have other features in common as well: geographic distribution (in males), urban-rural difference, and the difference between Finland and the other Nordic countries.19' 24 However, the high male-female ratio found for the risk of lip cancer is not in accord with that of intraoral, esophageal, or gastric cancer. In fact, only lung and larynx cancers show a male-female incidence ratio higher than lip cancer in Finland. Another similarity is found in the incidence pattern between the Nordic countries, but again there are dissimilarities within Finland in the trend with time, urban-rural ratio, and age-specific incidences. The risk of cancers of the colon and prostate has been shown to be greater among persons with higher socioeconomic status.25' 26 Hence, the negative geographic correlation found between the incidence of lip cancer and that of cancers of the colon and prostate fits the hypothesis that low socioeconomic status is associated with higher risk of lip cancer.16' 27 This hypothesis is further supported by the highly negative geographic correlation between the incidence of lip cancer and the median income observed in this study Ṫaken together, the comparisons presented suggest that there are no epidemiological features in common between cancers of the lip and skin of the head and neck. However, there seem to be etiological relations between lip cancer and cancers of the upper gastrointestinal canal and those of the respiratory tract. The strong positive association between lip and lung cancers suggests that tobacco smoking is a major common risk factor. The importance of specific factors related to high standard of living (e.g., changes in diet, smoking habits, working conditions) that could account for the decrease in the risk of lip cancer, cannot be clarified by the data reported in this study, but is certainly worth further investigation. REFERENCES 1. Ebenius B: Cancer of the lip. Acta radiol. Suppl. 48, 1943. 2. Hamalainen MJ: Cancer of the lip. Ann Chir Gynaec Fenn 44:suppl. 6, 1955. 3. Anderson DL: Cause and prevention of lip cancer. J Canad Dent Ass 37:138-142, 1971. 4. Spitzer WO, Hill GB, Chambers LW, et al: The occupation of fishing as a risk factor in cancer of the lip. N Eng J Med 293:419-424, 1975. AJPH March, 1979, Vol. 69, No. 3 259

LINDQVIST cf up CI SKIN Cl' ORAL CAVITY > t.15 > 1.15 > 1.15 ED 0.85-1.15 J Q85-1.15 j 0.85-1.15 E <0.85 0.85 3.0 c0.85 Whole Whole Whole country country country 6.6 4.1 0.8 5 34O 4.6 0.7~~861. FIGURE 3-Weighted (2:3) Averages of the Mean Annual Urban and Rural Age-adjusted Incidence Rates () of Cancers of the Lip and Skin of the Head and Neck, and Intraoral Cancer (Excluding Tongue) in Males in Finland in 1961-1970, by Province. The Stratification Indicates Relative Rates (Whole Country = 1.00) 5. Wynder EL, Bross IJ, Feldman RM: A study of the etiological factors in cancer of the mouth. Cancer 10:1300-1323, 1957. 6. Trieger N, Shipp II, Taylor GM, Weisberger D: Cirrhosis and other predisposing factors in carcinoma of the tongue. Cancer 11:357-362, 1958. 7. Trieger N, Taylor GM, Weisberger D: The significance of liver dysfunction in mouth cancer. Surg Gynec Obstet 108:230-234, 1959. 8. MacLarei RGC: Review of the causes of cancer of the lip. In Proceedings of the Annual Clinical Conference of the Ontario Foundation of Carcinoma of the Lip. Ottawa, Ontario, 1962. 9. Nicolau SC and Balu:; L: Chronic actinic cheilitis and cancer of the lower lip. Br J Derm 76:278-289, 1964. 10. Stoddart TG: Conference of cancer of the lip (based on a series of 3166 cases). Canad Med Ass J 90:666-670, 1964. 11. Keller AZ: Cellular types, survival, race, nativity, occupation, habits and associated diseases in the pathogenesis of lip cancers. Am J Epidem 91:486-499, 1970. 12. Szpak CA, Stone MJ, Frenkel EP: Some observations concerning the demographic and geographic incidence of carcinoma of the lip and buccal cavity. Cancer 40:343-348, 1977. 13. Doll R, Muir C, Waterhouse J (ed.): Cancer Incidence in Five Continents. Vol. II. International Union Against Cancer. Berlin: Springer, 1970. 14. Central Statistical Office of Finland. Living conditions 1950-1975. Statistical information on the quality of life in Finland and factors influencing it. Helsinki, 1977. 15. Saxen E and Teppo L: Finnish Cancer Registry 1952-1977. Twenty-five years of a nationwide cancer registry. Helsinki: Finnish Cancer Registry, 1978. 16. Lindqvist C and Teppo L: Epidemiological evaluation of sunlight as a risk factor of lip zancer. Br J Cancer 37:983-989, 1978. 17. Central Statistical Office of Finland. Statistical year book of Finland 1975. Helsinki, 1976. 18. Central Statistical Office of Finland. Statistical year book of Finland 1973. Helsinki, 1974. 19. Waterhouse J, Muir C, Correa P, Powell J (ed.): Cancer Incidence in Five Continents. Vol. III. IARC Scientific Publications No. 15. Lyon: International Agency for Research on Cancer, 1976. 20. Segi M: World incidence and distribution of skin cancer. NatI Cancer Inst Monogr 10:245-255, 1963. 21. Doll R, Payne P, Waterhouse J (ed.): Cancer Incidence in Five Continents. A technical report. International Union Against Cancer. Berlin: Springer, 1966. 22. Pindborg JJ: Global aspects of oral cancer. Amer Inst Oral Biol Ann Meet 139-145, 1969. 23. Urbach F: Ultraviolet radiation and its relationships to skin cancer in man. In Advances in Biology of Skin. Vol. VII. Montagna W, Ed. Oxford: Pergamon Pr., 1966, p. 581. 24. Teppo L, Hakama M, Hakulinen T, et al: Cancer in Finland in 1953-1970: Incidence, Mortality, Prevalence. Acta Path Microbiol Scand Sect A, Suppl. 252, 1975. 25. Lynch HT, Guirgis H, Lynch J, et al: Cancer of the colon: socioeconomic variables in a community. Am J Epidem 102:119-127, 1975. 26. Blot WJ, Fraumeni JF Jr., Stone BJ, McKay FW: Geographic patterns of large bowel cancer in the United States. J NatI Cancer Inst 57:1225-1231, 1976. 27. Hoover R, Mason TJ, McKay FW, Fraumeni JF Jr.: Geographic patterns of cancer mortality in the United States. In Persons at high risk of cancer, an approach to cancer etiology and control. Fraumeni, JF, Jr., Ed. New York: Academic Press, 1975, pp 343-360. 260 AJPH March, 1979, Vol. 69, No. 3