- Email: [email protected]
Risk factors for adult soft tissue sarcoma in northern Italy
Annals of Oncology 3 (Suppl. 2): S85-S88, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Risk factors for adult soft tissue sarcoma in northern Italy S. Franceschi & D. Serraino Epidemiology Unit, Aviano Cancer Centre, Italy tors, tobacco smoking, consumption of alcoholic beverages, coffee and tea - seemed to affect STS risk. No risk elevation was found in subjects employed in agriculture (OR - for > 10 years employment = 0.8, 95% CI: 0.4-1.5), nor in those who reported exposure to pesticides or herbicides (OR = 0.4, 95% CI: 0.1-1.2). Workers who reported exposure to chemical agents or to benzene or other solvents for more than 10 years had, respectively, a 1.8-fold (95% CI: 0.7-4.4) and a 2.2-fold (95% CI: 0.9-5.5) higher risk of developing STS.
Introduction
years before interview, who had been admitted as in-patients or referred for follow-up to the out-patient clinics of the Aviano Cancer Center or to the general hospitals in the study area. The present analysis is based on 93 cases (53 men and 40 women), aged 16 to 79 years (median age: 52 years), interviewed before June 1991. According to the classification of Enzinger and Weiss [16|, the most frequent cell type was sarcoma of the fibrous tissue (43%), followed by myomatus sarcomas (17%), liposarcomas (13%) and various other cell types (27%). Kaposi's sarcoma linked to human immunodeficiency virus infection and visceral sarcomas were excluded.
Soft-tissue sarcomas (STS) are a group of rare malignancies, derived from mesenchymal tissues other than bones and cartilage, which account for less than 2% of the overall cancer mortality in western countries, in luding Italy [1-2]. Due to the rarity of STS and to the heterogeneous cell types, few epidemiologic studies have investigated the etiology of STS [3]. Most of the epidemiologic research has focused on occupational risks, namely occupation in agriculture and exposure to phenoxyherbicides and chlorinated phenols [5-7], but inconsistent results have been reported. A small fraction of STS seems to be attributable to genetic susceptibility [3, 8-10], heavy external ionizing radiation [3, 11, 12] and immunosuppression [13-15]. The role of other potential risk factors is not known, although some etiologic hypotheses have been made, in particular on the role of infectious agents [3]. In this paper, the results of a case-control study [4, 5] on the role of several occupational and non-occupational factors in the etiology of STS are reported.
Materials and methods Since June, 1985, we have been conducting a hospital-based casecontrol study on risk factors for STS in the Friuli-Venezia Giulia region, Northeast Italy. Cases The cases were histologically confirmed STS, diagnosed within two
Key words: case-control study, risk factors, soft-tissue sarcoma
Controls The control group consisted of 721 patients (371 men and 350 women), aged 17 to 79 years (median age: 54 years), admitted to the aforementioned hospitals for a wide spectrum of diseases. Specifically excluded from the comparison group were patients whose cause of hospital admission was of malignant disorders, conditions related to alcohol and tobacco consumption, as well as any disease which might have resulted in diet modification, e.g. disorders of respiratory and digestive tracts, cardiovascular diseases, diabetes, etc. Haematologic, allergic or autoimmune diseases were also excluded. Twenty-eight percent of the controls were admitted for traumatic conditions (mainly fractures and sprains), 32% for musculoskeletal diseases (mainly low-back pain and disk disorders), 17% for minor conditions requiring surgical operations and 23% for other illnesses such as disorders of ear, nose, throat, skin or teeth. Questionnaire The questionnaire included several socio-economic indicators like education, occupation, social class (based on the head of the household's occupation |17|, sibship size, birth order) and life style habits, such as smoking, frequency of consumption of alcoholic and methylxanthine-containing beverages and frequency of weekly consumption of selected food indicators. Information was obtained about acquired disorders potentially related to the immune system - chronic infectious diseases, auto-
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on June 19, 2015
Summary. The role of several potential risk factors in the etiology of soft-tissue sarcoma (STS) was examined in a hospital-based case-control study, conducted in the Friuli-Venezia Giulia region, northeast Italy, between 1985 and 1991. A total of 93 STS cases (53 males and 40 females, median age: 52 years) and of 721 controls (371 males and 350 females, median age: 54 years) were interviewed. Significant increased risks were associated with a history of herpes zoster infection (odds ratio (OR): 2.3, 95% confidence interval (CI): 1.1-4.9), chicken-pox (OR: 2.1, 95% CI: 1.2-4.1) and mumps (OR: 2.0, 95% CI: 1.1-3.8). None of the other medical conditions investigated - socio-economic and anthropometric indica-
86 immune diseases, allergic conditions, common childhood infections, immunization practices, tonsillectomy and radiation exposure for diagnostic and therapeutic purposes. Age at starting and stopping employment in 17 industries or occupations, the subject's role in the industry or occupation in terms of direct involvement in production aspects, and history of exposure to 15 occupational agents or groups of agents were also investigated. Data analysis
X ] for trend
Controls (n = 721) # (%)
19 (32) 40 (68)
233 (47) 263 (53)
2.11 (1.15-4.11)
16 (25) 49 (75)
211 (39) 327 (61)
1.98 (1.06-3.76)
11 (17) 54 (83)
121 (24) 384 (76)
84 (91) 8 (9)
644 (90) 73 (10)
0.79 (0.33-1.81)
82 (88) 11 (12)
680 (94) 40 (6)
2.26 (1.06-4.94)
72 (77) 21 (23)
565 (79) 153 (21)
91 (98) 2 (2)
697 (97) 23 (3)
69 (75) 23 (25)
565 (79) 151 (21)
1
Mumps 1
Cases (n = 93) # (%)
Controls (n-721) # (%)
MH-OR (95% CI)a
54 (58) 14(15) 25 (27)
425 (59) 143(20) 153(21)
1 0.73 (0.32-1.52) 1.30 (0.96-4.02) 1.04, p = 0.31
55 (59) 27 (29) 7(8)
446 (62) 211 (29) 34(5)
1 1.08 (0.64-1.84) 1.72 (0.65-4.46) 0.86, p = 0.35
4(4)
30(4)
19(20) 35 (38) 39 (42)
152(21) 240 (33) 327 (46)
1 1.14 (0.60-2.20) 0.79 (0.39-1.61) 0.27, p = 0.60
30 (33) 35 (38) 27 (29)
265 (37) 240 (33) 215 (30)
1 1.07 (0.60-1.95) 0.91 (0.49-1.68) 0.01, p = 0.99
No Yes
1
1.68 (0.82-3.58)
Chronic infectious diseases No Yes
1
Herpes-zoster No Yes
1
Allergic conditions No Yes
1
1.13 (0.65-1.97)
Past exposure to therapeutical radiations No Yes
1
0.73 (0.12-3.30)
Tonsillectomy No Yes
1
1.23 (0.70-2.16)
a
For some items, the sum does not add up to the total because of missing values. b Odds ratio (OR) and 95% confidence interval (CI), adjusted for age and sex according to the Mantel-Haenszel (MH) procedure.
eluding exposure to therapeutical radiations and tonsillectomy (Table 2). As concerns occupational risk factors, no significant association of STS risk with employment in agriculture (OR for >10 years = 0.8, 95% CI: 0.4-1.5), or exposure to herbicides and/or pesticides (OR = 0.4, 95% CI: 0.1-1.2) emerged (Table 3). Conversely, an approximately two-fold increase in STS risk was noted among subjects who reported more than 10-year exposure to chemical agents (other than pesticides or herbicides) (OR = 1.8, 95% CI: 0.7-4.4) or to benzene or other solvents (OR = 2.2, 95%: 0.9-5.5) (Table 3). Analysis according to strata of STS histologic subgroup did not suggest any discrepancy with the overall risk estimates (not shown). Discussion
* Odds ratio (OR) and 95% confidence interval (CI), adjusted for age and sex according to the Mantel-Haenszel (MH) procedure. b For some items, the sum does not add up to the total because of missing values.
The findings of the present study suggest that past viral infections may increase the risk of STS. Episodes of herpes-zoster infection were more common among STS cases than among controls, particularly in the three years preceding STS diagnosis. A similar relationship was reported in other studies on malignant lymphomas, with the greatest risk near the time of lymphoma diag-
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on June 19, 2015
Table I. Distribution of 93 cases of soft-tissue sarcomas and 721 controls, according to socio-economic and anthropometric indicators. Pordenone, Italy, 1985-1991.
24-26
MH-OR (95% CI)h
Cases (n = 93) # (%)
Measles
None of the socio-economic indicators investigated in the present study seemed to affect substantially the risk of STS, since cases and controls were similarly distributed as regards education, social class, sibship size and ponderal index (Table 1). Cases and controls also showed similar habits of tobacco use and alcohol consumption (not shown). Table 2 illustrates the distribution of STS cases and controls according to medical history. A similar proportion of cases and controls reported a history of chronic infectious diseases, while a positive association emerged for chicken-pox (OR= 2.1, 95% CI: 1.2-4.1) and mumps (OR = 2.0, 95% CI: 1.1-3.8) and a history of herpes zoster infection (OR = 2.3, 95% CI: 1.1-4.9). None of the other medical conditions investigated was associated with the probability of developing STS, in-
Other Sibship sizeb 1-2 3-4 »5 X f for trend Body massb index
No Yes No Yes
Results
X ] for trend Social class V - I V (lowest) III IT— 1 X ] for trend
Condition3
Chicken-pox
The effect of several potential risk factors on STS risk was estimated by means of odds ratios (ORs) adjusted for age and sex [18], and their 95% confidence intervals (CIs) [19].
Education (years) <5 6-8 >9
Table 2. Distribution of 93 cases of soft-tissue sarcoma and 721 controls, according to history of selected diseases and medical procedures. Pordenone, Italy, 1985-1991.
87 Table 3. Odds ratio of soft-tissue sarcoma for selected occupations and exposures.3 Pordenone, Italy 1985-91. Occupation or exposure
<10 years
>10 years
X? (trend)
0.4(0.1-1.7)
0.8(0.4-1.5)
0.79; p = 0.37
0.2 (0.0-1.5) 0.7 (0.1-3.3)
1.1 (0.4-2.7) 0.9 (0.3-2.4)
O.I l;p = 0.74 0.19;p = 0.66
1.4 (0.2-7.0) 1.1 (0.2-5.6) 1.8(0.6-5.0) 0.9 (0.3-2.9) 0.8 (0.3-2.3) 0.5 (0.1-2.2)
1.4 (0.6-3.0) 1.8(0.7-4.4) 0.9 (0.3-2.6) 0.9 (0.2-2.7) 0.9 (0.3-2.4) 2.2 (0.9-5.5)
0.96; p = 2.13; p = 0.13; p = 0.07; p = 0.09; p = 1.90; p =
0.7(0.2-2.5)
0.4(0.1-1.2)
3.14; p = 0.08
0.33 0.15 0.72 0.79 0.77 0.17
° Only occupations and exposures with at least 5 exposed cases. b Non-exposed subjects as reference category. c Adjusted for age in quinquennia and sex by the procedure of Mantel-Haenszel.
nosis [20, 21], indicating that first occurrence of herpes zoster infection may be favored by the early phases of STS, possibly on account of an early impairment of the immune system. Common childhood infections were more frequently reported by cases than controls, in particular a history of chicken-pox and mumps. Although none of such viruses have been directly linked with STS or with other malignancies, viruses have long been suspected to play some role in the origin of human sarcomas [22-25]. Attention has been recently focused on the association between cytomegalovirus and Kaposi's sarcoma, a type of STS which is overrepresented among the immunosuppressed patients [26]. The association between past infectious diseases and STS, if it exists, may have important implications for understanding STS etiology, and it should be further investigated in studies in which the medical histories can be confirmed through hospital records, and, possibly, by means of serologic markers. In agreement with other work showing no association between STS risk and exposure to radiations, neither diagnostic nor therapeutic exposure was associated with STS risk in the present study [27, 28]. Similarly, none of the socio-economic and anthropometric indicators was found to affect STS risk, nor were cigarette smoking, alcohol, coffee and tea consumption. These findings are consistent with a few previous investigations [27—29| which were also negative as concerns these factors, with the exception of a case-control study in which the risk of STS was directly associated with adult body weight [29]. As regards the association between occupation and STS risk, the results of the present study provide further evidence against the possibility that employment in agriculture and, in particular, exposure to pesticides or herbicides play an important role in the etiolo-
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on June 19, 2015
Agriculture Furniture/ upholstery Mechanics Livestock/meat processing Chemical agents Metal dust Dyes/paints Wood dust Benzene/solvents Herbicides/ pesticides
Odds ratio hc (95% CI) by duration of occupation or exposure
gy of STS. Although the study was based only on 93 cases of STS, and found no significant association, it was able to exclude, at the usual level of statistical significance, an increased STS risk from more than 10year exposure to herbicides or pesticides greater than 20%. This may, hence, be an useful contribution, particularly in consideration of the rarity of the disease and of the recent debate on the topic. The results of some epidemiologic studies seem to indicate that farmers have elevated risks for a few non-epithelial cancers, including STS [for a review, see 30 and 31]. However, the evidence remains inconclusive. A risk of 0.9 was found in a cohort of Swedish agricultural and forestry workers potentially exposed to phenoxy acid herbicides [32], and a case-control study conducted in New Zealand was also negative [33]. STS risks lower than unity were found among agricultural, gardeners and forestry workers in a study based on 15 cancer registries in England and Wales [34]. Conversely, in this study, workers who reported to have been exposed for more than 10 years to unspecified chemical agents or to benzene or other solvents had a nearly two-fold, albeit nonsignificant, increased risk of STS. Although benzene exposure was consistently associated with an elevated risk of acute leukemia [35], the few studies which have investigated the potential role of exposure to benzene on the risk of developing STS showed very modest, nonsignificant risk elevations [27, 36]. Weaknesses and strengths of hospital-based casecontrol studies have long been discussed [18]. The geographic area herein examined is not covered by a cancer registry, thus STS patients included in the study group may not be representative of all STS cases occurring in the population. The collaborating hospitals, however, included the majority of diagnostic and therapeutical facilities for STS available in the area and, therefore, most STS cases should have been referred there. Furthermore, a good comparability between cases and controls should have been achieved by interviewing controls coming from the same catchment area of STS cases and admitted to hospitals for a wide spectrum of acute conditions. A more important limitation of these data comes from the power of the study, which was low for many of the variables examined, thus hampering the interpretation of the findings. Most of all, as regards the purported role of past infectious diseases which emerges from the present study, the potential role of recall bias is of concern, particularly since only interview-data were available and no validation on past medical records or serology has been possible. The performance of the interviews in a hospital setting should have assured, however, a more complete ascertainment of medical history and a closer comparability between cancer cases and controls than those obtainable in a community setting [37]. In conclusion, also bearing in mind such limitations and the difficulties of studying epidemiologically the etiology of rare and heterogenous diseases like STS, the
88 present study investigated a few risk factors that were not previously considered. Some of the reported associations, like the increased risk related to history of past infectious diseases and exposure to chemical agents and benzene, may be useful in providing leads for further investigation. Acknowledgements The contribution of the Italian Association for Cancer Research, Milan, is gratefully acknowledged. We thank Mrs. Tiziana Angelin, Maria Grazia Valentini and Derna Gerdol for interviewing cases and controls, Mrs. Ilaria Calderan for editorial assistance.
1. Levi F, Maisonneuve P, Filiberti R, La Vecchia C, Boyle P. Cancer incidence and mortality in Europe. Soz Praeventivmed 1989;34(suppl.2). 2. La Vecchia C, Negri E, Decarli A, Fasoli M, and Cislaghi C. Cancer mortality in Italy: an overview of age-specific and agestandardized trends from 1955 to 1984. Tumori 1990; 76: 8 7 166. 3. Tucker MA, Fraumeni JF. Soft-tissue. In Schottenfeld D, Fraumeni JF Jr (eds): Cancer epidemiology and prevention. WB Saunders Company: Philadelphia, PA 1982; 827-36. 4. Serraino D, Franceschi S, Talamini R, Frustaci S, La Vecchia C. Non-occupational risk factors for adult soft-tissue sarcoma in Northern Italy. Cancer Causes and Control 1991; 2:157-64. 5. Serraino D, Franceschi S, La Vecchia C, Carbone A. Occupation and soft-tissue sarcoma in Northern Italy. Cancer Causes and Control, in press. 6. Vineis P, Terracini B, Ciccone G et al. Phenoxy herbicides and soft-tissue sarcomas in female rice weeders. A population based case-referent study. Scand J Work Environ Health 1987; 13:9-17. 7. Hoar SK, Blair A, Holmes F. Agriculture herbicide use and risk of lymphoma and soft-tissue sarcoma. JAMA 1986; 256: 1141-7. 8. Strong LC. Theories of pathogenesis: mutation and cancer. In Mulvihill JJ, Miller RW, Fraumeni JF Jr (eds): Genetics of human cancer. New York: Raven Press 1977; 401-15. 9. Baird PA, Worth AJ. Congenital generalized fibromatosis: an autosomal recessive condition? Clin Genet 1976; 9:488-94. 10. Li FP, Fraumeni JF. Rhabdomyosarcoma in children: epidemiologic study and identification of a family cancer syndrome. JNCI 1969; 43: 1365-73. 11. Kim JH, Chu FC, Woodward HO et al. Radiation induced softtissue and bone sarcoma. Radiol 1978; 129: 501 - 8 . 12. Czesin K, Wronkowski Z. Second malignancies of the irradiated area in patients treated for uterine cervix cancer. Gynecol Oncol 1978; 6: 309-15. 13. Hoover R, Fraumeni JF Jr. Risk of cancer in renal transplant recipients. Lancet 1973; ii: 55-7. 14. Kinlen LJ, Sheil AGR, Peto J et al. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. Br Med J 1979; 2: 1461-6. 15. Penn I. Cancers complicating organ transplantation. N Engl J Med 1990; 323: 1767-9. 16. Enzinger FM, Weiss SW. Soft-tissue tumors. St. Louis, CV Mosby 1983. 17. Office of population census and surveys. Classification of occupation 1980. HMSO 1980.
Correspondence to: Dr. S. Franceschi Div. Epidemiology Centro di Riferimento Oncologico V. Pedemontana Occ. 33081 Aviano, Italy
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on June 19, 2015
References
18. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. JNCI 1959; 22: 719-48. 19. Cornfield J. A statistical problem arising from retrospective studies. In Neyman J (ed): Proceeding of the third Berkeley Symposium, IV, Berkeley: University of California Press 1956. 20. Cartwright RA, McKinney PA, O'Brien C et al. Non-Hodgkin's lymphoma: case-control epidemiological study in Yorkshire. Leukema Res 1988; 12: 81-8. 21. Franceschi S, Serraino D, Bidoli E et al. The epidemiology of non-Hodgkin's lymphoma in the north-east of Italy: a hospitalbased case-control study. Leukemia Res 1989; 13:465—72. 22. Rous P. A sarcoma of the fowl transmisible by an agent separable from the tumor cells. J Exp Med 1911; 13: 397-411. 23. Morton DL. Soft-tissue sarcomas. In Holland JF, Frei E (eds): Cancer medicine. Philadelphia: Lea and Febiger 1973; 1845-61. 24. Hirshaut Y, Pei DT, Marcove RC et al. Seroepidemiology of human sarcoma antigen (SI). N Engl J Med 1974; 291: 1103-7. 25. Karpas A, McGeoch V, Tuckerman F et al. Viral-coded information in human rhabdomyosarcoma cells. Lancet 1974; ii: 1330-1. 26. Giraldo G, Beth E, Huang ES. Kaposi's sarcoma and its relationship to cytomegalovirus (CMV): III. CMV DNA and CMV early antigens in Kaposi's sarcoma. Int J Cancer 1978; 26: 23-9. 27. Woods JS, Polissar L, Severson RK et al. Soft-tissue sarcoma and non-Hodgkin's lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington. JNCI 1987; 78: 899-910. 28. Kang H, Ezinger F, Breslin P et al. Soft-tissue sarcoma and military service in Vietnam: a case-control study. JNCI 1987; 79:693-9. 29. Zahm SH, Blair A, Holmes FF, Boysen CD, Robel RJ, Fraumeni JF Jr. A case-control study of soft-tissue sarcoma. Am J Epidemiol 1989; 130:665-74. 30. Blair A, Malker H, Cantor KP, Burmeister L, Wiklund K. Cancer among farmers. A review. Scand J Work Environ Health 1985; 11: 397-407. 31. Blair A, Zahm SH. Herbicides and cancer: a review and discussion of methodologic issues. In: Recent results in cancer research, 1990. Berlin-Heidelberg: Springer-Verlag 1990; 120: 132-45. 32. Wiklund K, Holm LE. Soft-tissue sarcoma risk in Swedish agricultural and forestry workers. J Natl Cancer Inst 1986; 76: 229-34. 33. Smith AH, Pearce NE, Fisher DO, Giles HJ, Teague CA, Howard JK. Soft-tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. J Natl Cancer Inst 1984; 73: 1111-7. 34. Balarajan R, Acheson ED. Soft-tissue sarcomas in agriculture and forestry workers. J Epidemiol Community Health 1984; 38:113-6. 35. McCraw DS, Joyner RE, Cole P. Excess leukemia in a refinery population. J Occup Med 1985; 27: 220-2. 36. Eriksson M, Hardell L, Adami HO. Exposure to dioxins as a risk factor for soft-tissue sarcoma: a population-based casecontrol study. J Natl Cancer Inst 1990; 82:486-90. 37. Kelly JP, Rosenberg L, Kaufman DW, Shapiro S. Reliability of personal interview data in a hospital-based case-control study. Am J Epidemiol 1990; 131: 79-90.
Original article Risk factors for adult soft tissue sarcoma in northern Italy S. Franceschi & D. Serraino Epidemiology Unit, Aviano Cancer Centre, Italy tors, tobacco smoking, consumption of alcoholic beverages, coffee and tea - seemed to affect STS risk. No risk elevation was found in subjects employed in agriculture (OR - for > 10 years employment = 0.8, 95% CI: 0.4-1.5), nor in those who reported exposure to pesticides or herbicides (OR = 0.4, 95% CI: 0.1-1.2). Workers who reported exposure to chemical agents or to benzene or other solvents for more than 10 years had, respectively, a 1.8-fold (95% CI: 0.7-4.4) and a 2.2-fold (95% CI: 0.9-5.5) higher risk of developing STS.
Introduction
years before interview, who had been admitted as in-patients or referred for follow-up to the out-patient clinics of the Aviano Cancer Center or to the general hospitals in the study area. The present analysis is based on 93 cases (53 men and 40 women), aged 16 to 79 years (median age: 52 years), interviewed before June 1991. According to the classification of Enzinger and Weiss [16|, the most frequent cell type was sarcoma of the fibrous tissue (43%), followed by myomatus sarcomas (17%), liposarcomas (13%) and various other cell types (27%). Kaposi's sarcoma linked to human immunodeficiency virus infection and visceral sarcomas were excluded.
Soft-tissue sarcomas (STS) are a group of rare malignancies, derived from mesenchymal tissues other than bones and cartilage, which account for less than 2% of the overall cancer mortality in western countries, in luding Italy [1-2]. Due to the rarity of STS and to the heterogeneous cell types, few epidemiologic studies have investigated the etiology of STS [3]. Most of the epidemiologic research has focused on occupational risks, namely occupation in agriculture and exposure to phenoxyherbicides and chlorinated phenols [5-7], but inconsistent results have been reported. A small fraction of STS seems to be attributable to genetic susceptibility [3, 8-10], heavy external ionizing radiation [3, 11, 12] and immunosuppression [13-15]. The role of other potential risk factors is not known, although some etiologic hypotheses have been made, in particular on the role of infectious agents [3]. In this paper, the results of a case-control study [4, 5] on the role of several occupational and non-occupational factors in the etiology of STS are reported.
Materials and methods Since June, 1985, we have been conducting a hospital-based casecontrol study on risk factors for STS in the Friuli-Venezia Giulia region, Northeast Italy. Cases The cases were histologically confirmed STS, diagnosed within two
Key words: case-control study, risk factors, soft-tissue sarcoma
Controls The control group consisted of 721 patients (371 men and 350 women), aged 17 to 79 years (median age: 54 years), admitted to the aforementioned hospitals for a wide spectrum of diseases. Specifically excluded from the comparison group were patients whose cause of hospital admission was of malignant disorders, conditions related to alcohol and tobacco consumption, as well as any disease which might have resulted in diet modification, e.g. disorders of respiratory and digestive tracts, cardiovascular diseases, diabetes, etc. Haematologic, allergic or autoimmune diseases were also excluded. Twenty-eight percent of the controls were admitted for traumatic conditions (mainly fractures and sprains), 32% for musculoskeletal diseases (mainly low-back pain and disk disorders), 17% for minor conditions requiring surgical operations and 23% for other illnesses such as disorders of ear, nose, throat, skin or teeth. Questionnaire The questionnaire included several socio-economic indicators like education, occupation, social class (based on the head of the household's occupation |17|, sibship size, birth order) and life style habits, such as smoking, frequency of consumption of alcoholic and methylxanthine-containing beverages and frequency of weekly consumption of selected food indicators. Information was obtained about acquired disorders potentially related to the immune system - chronic infectious diseases, auto-
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on June 19, 2015
Summary. The role of several potential risk factors in the etiology of soft-tissue sarcoma (STS) was examined in a hospital-based case-control study, conducted in the Friuli-Venezia Giulia region, northeast Italy, between 1985 and 1991. A total of 93 STS cases (53 males and 40 females, median age: 52 years) and of 721 controls (371 males and 350 females, median age: 54 years) were interviewed. Significant increased risks were associated with a history of herpes zoster infection (odds ratio (OR): 2.3, 95% confidence interval (CI): 1.1-4.9), chicken-pox (OR: 2.1, 95% CI: 1.2-4.1) and mumps (OR: 2.0, 95% CI: 1.1-3.8). None of the other medical conditions investigated - socio-economic and anthropometric indica-
86 immune diseases, allergic conditions, common childhood infections, immunization practices, tonsillectomy and radiation exposure for diagnostic and therapeutic purposes. Age at starting and stopping employment in 17 industries or occupations, the subject's role in the industry or occupation in terms of direct involvement in production aspects, and history of exposure to 15 occupational agents or groups of agents were also investigated. Data analysis
X ] for trend
Controls (n = 721) # (%)
19 (32) 40 (68)
233 (47) 263 (53)
2.11 (1.15-4.11)
16 (25) 49 (75)
211 (39) 327 (61)
1.98 (1.06-3.76)
11 (17) 54 (83)
121 (24) 384 (76)
84 (91) 8 (9)
644 (90) 73 (10)
0.79 (0.33-1.81)
82 (88) 11 (12)
680 (94) 40 (6)
2.26 (1.06-4.94)
72 (77) 21 (23)
565 (79) 153 (21)
91 (98) 2 (2)
697 (97) 23 (3)
69 (75) 23 (25)
565 (79) 151 (21)
1
Mumps 1
Cases (n = 93) # (%)
Controls (n-721) # (%)
MH-OR (95% CI)a
54 (58) 14(15) 25 (27)
425 (59) 143(20) 153(21)
1 0.73 (0.32-1.52) 1.30 (0.96-4.02) 1.04, p = 0.31
55 (59) 27 (29) 7(8)
446 (62) 211 (29) 34(5)
1 1.08 (0.64-1.84) 1.72 (0.65-4.46) 0.86, p = 0.35
4(4)
30(4)
19(20) 35 (38) 39 (42)
152(21) 240 (33) 327 (46)
1 1.14 (0.60-2.20) 0.79 (0.39-1.61) 0.27, p = 0.60
30 (33) 35 (38) 27 (29)
265 (37) 240 (33) 215 (30)
1 1.07 (0.60-1.95) 0.91 (0.49-1.68) 0.01, p = 0.99
No Yes
1
1.68 (0.82-3.58)
Chronic infectious diseases No Yes
1
Herpes-zoster No Yes
1
Allergic conditions No Yes
1
1.13 (0.65-1.97)
Past exposure to therapeutical radiations No Yes
1
0.73 (0.12-3.30)
Tonsillectomy No Yes
1
1.23 (0.70-2.16)
a
For some items, the sum does not add up to the total because of missing values. b Odds ratio (OR) and 95% confidence interval (CI), adjusted for age and sex according to the Mantel-Haenszel (MH) procedure.
eluding exposure to therapeutical radiations and tonsillectomy (Table 2). As concerns occupational risk factors, no significant association of STS risk with employment in agriculture (OR for >10 years = 0.8, 95% CI: 0.4-1.5), or exposure to herbicides and/or pesticides (OR = 0.4, 95% CI: 0.1-1.2) emerged (Table 3). Conversely, an approximately two-fold increase in STS risk was noted among subjects who reported more than 10-year exposure to chemical agents (other than pesticides or herbicides) (OR = 1.8, 95% CI: 0.7-4.4) or to benzene or other solvents (OR = 2.2, 95%: 0.9-5.5) (Table 3). Analysis according to strata of STS histologic subgroup did not suggest any discrepancy with the overall risk estimates (not shown). Discussion
* Odds ratio (OR) and 95% confidence interval (CI), adjusted for age and sex according to the Mantel-Haenszel (MH) procedure. b For some items, the sum does not add up to the total because of missing values.
The findings of the present study suggest that past viral infections may increase the risk of STS. Episodes of herpes-zoster infection were more common among STS cases than among controls, particularly in the three years preceding STS diagnosis. A similar relationship was reported in other studies on malignant lymphomas, with the greatest risk near the time of lymphoma diag-
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on June 19, 2015
Table I. Distribution of 93 cases of soft-tissue sarcomas and 721 controls, according to socio-economic and anthropometric indicators. Pordenone, Italy, 1985-1991.
24-26
MH-OR (95% CI)h
Cases (n = 93) # (%)
Measles
None of the socio-economic indicators investigated in the present study seemed to affect substantially the risk of STS, since cases and controls were similarly distributed as regards education, social class, sibship size and ponderal index (Table 1). Cases and controls also showed similar habits of tobacco use and alcohol consumption (not shown). Table 2 illustrates the distribution of STS cases and controls according to medical history. A similar proportion of cases and controls reported a history of chronic infectious diseases, while a positive association emerged for chicken-pox (OR= 2.1, 95% CI: 1.2-4.1) and mumps (OR = 2.0, 95% CI: 1.1-3.8) and a history of herpes zoster infection (OR = 2.3, 95% CI: 1.1-4.9). None of the other medical conditions investigated was associated with the probability of developing STS, in-
Other Sibship sizeb 1-2 3-4 »5 X f for trend Body massb index
No Yes No Yes
Results
X ] for trend Social class V - I V (lowest) III IT— 1 X ] for trend
Condition3
Chicken-pox
The effect of several potential risk factors on STS risk was estimated by means of odds ratios (ORs) adjusted for age and sex [18], and their 95% confidence intervals (CIs) [19].
Education (years) <5 6-8 >9
Table 2. Distribution of 93 cases of soft-tissue sarcoma and 721 controls, according to history of selected diseases and medical procedures. Pordenone, Italy, 1985-1991.
87 Table 3. Odds ratio of soft-tissue sarcoma for selected occupations and exposures.3 Pordenone, Italy 1985-91. Occupation or exposure
<10 years
>10 years
X? (trend)
0.4(0.1-1.7)
0.8(0.4-1.5)
0.79; p = 0.37
0.2 (0.0-1.5) 0.7 (0.1-3.3)
1.1 (0.4-2.7) 0.9 (0.3-2.4)
O.I l;p = 0.74 0.19;p = 0.66
1.4 (0.2-7.0) 1.1 (0.2-5.6) 1.8(0.6-5.0) 0.9 (0.3-2.9) 0.8 (0.3-2.3) 0.5 (0.1-2.2)
1.4 (0.6-3.0) 1.8(0.7-4.4) 0.9 (0.3-2.6) 0.9 (0.2-2.7) 0.9 (0.3-2.4) 2.2 (0.9-5.5)
0.96; p = 2.13; p = 0.13; p = 0.07; p = 0.09; p = 1.90; p =
0.7(0.2-2.5)
0.4(0.1-1.2)
3.14; p = 0.08
0.33 0.15 0.72 0.79 0.77 0.17
° Only occupations and exposures with at least 5 exposed cases. b Non-exposed subjects as reference category. c Adjusted for age in quinquennia and sex by the procedure of Mantel-Haenszel.
nosis [20, 21], indicating that first occurrence of herpes zoster infection may be favored by the early phases of STS, possibly on account of an early impairment of the immune system. Common childhood infections were more frequently reported by cases than controls, in particular a history of chicken-pox and mumps. Although none of such viruses have been directly linked with STS or with other malignancies, viruses have long been suspected to play some role in the origin of human sarcomas [22-25]. Attention has been recently focused on the association between cytomegalovirus and Kaposi's sarcoma, a type of STS which is overrepresented among the immunosuppressed patients [26]. The association between past infectious diseases and STS, if it exists, may have important implications for understanding STS etiology, and it should be further investigated in studies in which the medical histories can be confirmed through hospital records, and, possibly, by means of serologic markers. In agreement with other work showing no association between STS risk and exposure to radiations, neither diagnostic nor therapeutic exposure was associated with STS risk in the present study [27, 28]. Similarly, none of the socio-economic and anthropometric indicators was found to affect STS risk, nor were cigarette smoking, alcohol, coffee and tea consumption. These findings are consistent with a few previous investigations [27—29| which were also negative as concerns these factors, with the exception of a case-control study in which the risk of STS was directly associated with adult body weight [29]. As regards the association between occupation and STS risk, the results of the present study provide further evidence against the possibility that employment in agriculture and, in particular, exposure to pesticides or herbicides play an important role in the etiolo-
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on June 19, 2015
Agriculture Furniture/ upholstery Mechanics Livestock/meat processing Chemical agents Metal dust Dyes/paints Wood dust Benzene/solvents Herbicides/ pesticides
Odds ratio hc (95% CI) by duration of occupation or exposure
gy of STS. Although the study was based only on 93 cases of STS, and found no significant association, it was able to exclude, at the usual level of statistical significance, an increased STS risk from more than 10year exposure to herbicides or pesticides greater than 20%. This may, hence, be an useful contribution, particularly in consideration of the rarity of the disease and of the recent debate on the topic. The results of some epidemiologic studies seem to indicate that farmers have elevated risks for a few non-epithelial cancers, including STS [for a review, see 30 and 31]. However, the evidence remains inconclusive. A risk of 0.9 was found in a cohort of Swedish agricultural and forestry workers potentially exposed to phenoxy acid herbicides [32], and a case-control study conducted in New Zealand was also negative [33]. STS risks lower than unity were found among agricultural, gardeners and forestry workers in a study based on 15 cancer registries in England and Wales [34]. Conversely, in this study, workers who reported to have been exposed for more than 10 years to unspecified chemical agents or to benzene or other solvents had a nearly two-fold, albeit nonsignificant, increased risk of STS. Although benzene exposure was consistently associated with an elevated risk of acute leukemia [35], the few studies which have investigated the potential role of exposure to benzene on the risk of developing STS showed very modest, nonsignificant risk elevations [27, 36]. Weaknesses and strengths of hospital-based casecontrol studies have long been discussed [18]. The geographic area herein examined is not covered by a cancer registry, thus STS patients included in the study group may not be representative of all STS cases occurring in the population. The collaborating hospitals, however, included the majority of diagnostic and therapeutical facilities for STS available in the area and, therefore, most STS cases should have been referred there. Furthermore, a good comparability between cases and controls should have been achieved by interviewing controls coming from the same catchment area of STS cases and admitted to hospitals for a wide spectrum of acute conditions. A more important limitation of these data comes from the power of the study, which was low for many of the variables examined, thus hampering the interpretation of the findings. Most of all, as regards the purported role of past infectious diseases which emerges from the present study, the potential role of recall bias is of concern, particularly since only interview-data were available and no validation on past medical records or serology has been possible. The performance of the interviews in a hospital setting should have assured, however, a more complete ascertainment of medical history and a closer comparability between cancer cases and controls than those obtainable in a community setting [37]. In conclusion, also bearing in mind such limitations and the difficulties of studying epidemiologically the etiology of rare and heterogenous diseases like STS, the
88 present study investigated a few risk factors that were not previously considered. Some of the reported associations, like the increased risk related to history of past infectious diseases and exposure to chemical agents and benzene, may be useful in providing leads for further investigation. Acknowledgements The contribution of the Italian Association for Cancer Research, Milan, is gratefully acknowledged. We thank Mrs. Tiziana Angelin, Maria Grazia Valentini and Derna Gerdol for interviewing cases and controls, Mrs. Ilaria Calderan for editorial assistance.
1. Levi F, Maisonneuve P, Filiberti R, La Vecchia C, Boyle P. Cancer incidence and mortality in Europe. Soz Praeventivmed 1989;34(suppl.2). 2. La Vecchia C, Negri E, Decarli A, Fasoli M, and Cislaghi C. Cancer mortality in Italy: an overview of age-specific and agestandardized trends from 1955 to 1984. Tumori 1990; 76: 8 7 166. 3. Tucker MA, Fraumeni JF. Soft-tissue. In Schottenfeld D, Fraumeni JF Jr (eds): Cancer epidemiology and prevention. WB Saunders Company: Philadelphia, PA 1982; 827-36. 4. Serraino D, Franceschi S, Talamini R, Frustaci S, La Vecchia C. Non-occupational risk factors for adult soft-tissue sarcoma in Northern Italy. Cancer Causes and Control 1991; 2:157-64. 5. Serraino D, Franceschi S, La Vecchia C, Carbone A. Occupation and soft-tissue sarcoma in Northern Italy. Cancer Causes and Control, in press. 6. Vineis P, Terracini B, Ciccone G et al. Phenoxy herbicides and soft-tissue sarcomas in female rice weeders. A population based case-referent study. Scand J Work Environ Health 1987; 13:9-17. 7. Hoar SK, Blair A, Holmes F. Agriculture herbicide use and risk of lymphoma and soft-tissue sarcoma. JAMA 1986; 256: 1141-7. 8. Strong LC. Theories of pathogenesis: mutation and cancer. In Mulvihill JJ, Miller RW, Fraumeni JF Jr (eds): Genetics of human cancer. New York: Raven Press 1977; 401-15. 9. Baird PA, Worth AJ. Congenital generalized fibromatosis: an autosomal recessive condition? Clin Genet 1976; 9:488-94. 10. Li FP, Fraumeni JF. Rhabdomyosarcoma in children: epidemiologic study and identification of a family cancer syndrome. JNCI 1969; 43: 1365-73. 11. Kim JH, Chu FC, Woodward HO et al. Radiation induced softtissue and bone sarcoma. Radiol 1978; 129: 501 - 8 . 12. Czesin K, Wronkowski Z. Second malignancies of the irradiated area in patients treated for uterine cervix cancer. Gynecol Oncol 1978; 6: 309-15. 13. Hoover R, Fraumeni JF Jr. Risk of cancer in renal transplant recipients. Lancet 1973; ii: 55-7. 14. Kinlen LJ, Sheil AGR, Peto J et al. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. Br Med J 1979; 2: 1461-6. 15. Penn I. Cancers complicating organ transplantation. N Engl J Med 1990; 323: 1767-9. 16. Enzinger FM, Weiss SW. Soft-tissue tumors. St. Louis, CV Mosby 1983. 17. Office of population census and surveys. Classification of occupation 1980. HMSO 1980.
Correspondence to: Dr. S. Franceschi Div. Epidemiology Centro di Riferimento Oncologico V. Pedemontana Occ. 33081 Aviano, Italy
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on June 19, 2015
References
18. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. JNCI 1959; 22: 719-48. 19. Cornfield J. A statistical problem arising from retrospective studies. In Neyman J (ed): Proceeding of the third Berkeley Symposium, IV, Berkeley: University of California Press 1956. 20. Cartwright RA, McKinney PA, O'Brien C et al. Non-Hodgkin's lymphoma: case-control epidemiological study in Yorkshire. Leukema Res 1988; 12: 81-8. 21. Franceschi S, Serraino D, Bidoli E et al. The epidemiology of non-Hodgkin's lymphoma in the north-east of Italy: a hospitalbased case-control study. Leukemia Res 1989; 13:465—72. 22. Rous P. A sarcoma of the fowl transmisible by an agent separable from the tumor cells. J Exp Med 1911; 13: 397-411. 23. Morton DL. Soft-tissue sarcomas. In Holland JF, Frei E (eds): Cancer medicine. Philadelphia: Lea and Febiger 1973; 1845-61. 24. Hirshaut Y, Pei DT, Marcove RC et al. Seroepidemiology of human sarcoma antigen (SI). N Engl J Med 1974; 291: 1103-7. 25. Karpas A, McGeoch V, Tuckerman F et al. Viral-coded information in human rhabdomyosarcoma cells. Lancet 1974; ii: 1330-1. 26. Giraldo G, Beth E, Huang ES. Kaposi's sarcoma and its relationship to cytomegalovirus (CMV): III. CMV DNA and CMV early antigens in Kaposi's sarcoma. Int J Cancer 1978; 26: 23-9. 27. Woods JS, Polissar L, Severson RK et al. Soft-tissue sarcoma and non-Hodgkin's lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington. JNCI 1987; 78: 899-910. 28. Kang H, Ezinger F, Breslin P et al. Soft-tissue sarcoma and military service in Vietnam: a case-control study. JNCI 1987; 79:693-9. 29. Zahm SH, Blair A, Holmes FF, Boysen CD, Robel RJ, Fraumeni JF Jr. A case-control study of soft-tissue sarcoma. Am J Epidemiol 1989; 130:665-74. 30. Blair A, Malker H, Cantor KP, Burmeister L, Wiklund K. Cancer among farmers. A review. Scand J Work Environ Health 1985; 11: 397-407. 31. Blair A, Zahm SH. Herbicides and cancer: a review and discussion of methodologic issues. In: Recent results in cancer research, 1990. Berlin-Heidelberg: Springer-Verlag 1990; 120: 132-45. 32. Wiklund K, Holm LE. Soft-tissue sarcoma risk in Swedish agricultural and forestry workers. J Natl Cancer Inst 1986; 76: 229-34. 33. Smith AH, Pearce NE, Fisher DO, Giles HJ, Teague CA, Howard JK. Soft-tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. J Natl Cancer Inst 1984; 73: 1111-7. 34. Balarajan R, Acheson ED. Soft-tissue sarcomas in agriculture and forestry workers. J Epidemiol Community Health 1984; 38:113-6. 35. McCraw DS, Joyner RE, Cole P. Excess leukemia in a refinery population. J Occup Med 1985; 27: 220-2. 36. Eriksson M, Hardell L, Adami HO. Exposure to dioxins as a risk factor for soft-tissue sarcoma: a population-based casecontrol study. J Natl Cancer Inst 1990; 82:486-90. 37. Kelly JP, Rosenberg L, Kaufman DW, Shapiro S. Reliability of personal interview data in a hospital-based case-control study. Am J Epidemiol 1990; 131: 79-90.