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Artificial implants and soft tissue sarcomas
J ClinEpidemiol Vol. 08954356(94)0021 l-8
ARTIFICIAL
IMPLANTS
AND
48, No. 4, pp. 545-549. 1995 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0895-4356/95-$9.50 + 0.00
SOFT TISSUE
Copyright 6
SARCOMAS
ROBERT W. MORGAN’* and MARYELLEN ELCOCK’ ‘EnvironmentalHealth Strategies,Inc., One Lagoon Drive, Suite 120, Redwood City, CA 94065, and *Orange County Health Department, Epidemiology Unit, 1719 West 17th Street, Santa Ana, CA 92706, U.S.A.
carcinogenic potential of artificial implants has been of concern in recent years. Case reports and animal studies, dating back to the 195Os,have reported possible associations between artificial implants and soft tissue sarcomas,but epidemiologic data have been lacking. In a recent study of soft tissue sarcomas and military service, data on artificial implants were collected but not presented. This paper examines a possible association between artificial implants and soft tissue sarcomas. Abstract-The
Artificial implants
Soft tissue sarcomas
Epidemiology
the implant alone has been implicated as a critical carcinogenic factor [6]. The use of breast implants, while confined Case reports of possible implant-associated almost entirely to women, stimulates renewed cancers, as well as the increased longevity of interest in the issue of whether foreign bodies implanted materials, have promoted speculation (implants) increase the risk of cancer, especially the carcinogenic potential of concerning soft tissue sarcomas. Extensive use of implants, implants. A review of case reports associating such as prostheses, pins, and plates, began in foreign body materials (e.g., bullets, shrapnel the late 1950s. The surgical use of implants for pieces, dacron grafts, plates, screws and bone joint replacement and internal fixation devices implants) with sarcomas has suggested that for treatment of fractures is now common. there is a causal connection [7]; however, there Approximately 350,000 hip replacements are is a lack of any definitive, well-controlled performed annually worldwide [ 11.The carcinoepidemiologic studies on this topic. genic potential of these implants has been the Bone and soft tissue sarcomas (STS) in subject of some concern in recent years. humans are uncommon neoplasms. It is estiAn association between artificial implants mated that approx. 0.7% of all cancers in the and sarcomas in rats and mice was reported United States reported during 1992 will be bone in the 1950s by Oppenheimer [2]. In vitro or soft tissue sarcomas [8]. The study of STS is models have indicated bacterial and mammalian complicated by the site-oriented International mutagenesis in cell culture [3]. In rodent models, Classification of Disease classification for “concertain materials used in hip replacements nective tissue cancers” which excludes some have demonstrated potential carcinogenicity; mesenchymal tumors and does not distinguish e.g. chrome-cobalt Cl], methyl methacrylate [4], between different cell types. polyethylene [5], and nickel, chromium and There are a number of exogenous factors cobalt [3]. Alternatively, the physical form of which have been associated with sarcomas. These factors include: radiation, chemothera*All correspondenceshould be addressedto: Robert W. peutic and other chemical agents, including Morgan, MD, Environmental Health Strategies, Inc., One Lagoon Drive, Suite 120,Redwood City, CA 94065, vinyl chloride and arsenical compounds 191. U.S.A. Family clustering of childhood sarcomas INTRODUCTION
545
Robert W. Morgan and Maryellen
546
Elcock
Statistical analysis includes measurement of relative risk as approximated by the odds ratio (OR) and exact 95% confidence intervals (95% CI). In a case control study, where participants are selected on the basis of disease status, the OR is calculated as the ratio of the odds of exposure among casesto that among controls. An OR of one (unity) indicates no difference in exposure between cases and controls; in other words, an OR of unity or less indicates no increase in disease risk from the exposure (implant). The 95% CI represents the range within which the true magnitude of effect lies with 95% assurance. If the 95% CI includes one, the result is considered not statistically significant. To control for confounding variables, the Mantel-Haenszel method was used to estimate METHODS the OR and calculate the 95% CI. CalcuKang et al. [ 1l] studied STS cases,diagnosed lations were done using the Statistical Analysis between 1 January 1975 and 31 December 1980, System (SAS Version 6.03) and Epi Info which were selected from the Armed Forces (Version 5). Institute of Pathology (AFIP). A total of 217 cases and 599 matched controls were included RESULTS in the study. Cases were defined as men who were diagnosed with STS by the AFIP between The demographic characteristics of casesand 1 January 1975 and 31 December 1980, and controls have previously been published [l 11. who were born between 1940 and 1955. Con- Cases and controls are almost identical with trols for each case were selected from referring respect to marital status, race and level of pathologists or their pathology departments. education. Controls were matched on age but not on The results of the analysis are summarized race or vital status. Patients with diagnoses of in Table 1. There is no statistically significant STS, non-Hodgkin’s Lymphoma or Hodgkin’s relationship between All Implants and STS Disease were excluded from participation. [OR = 0.66 (95% CI: 0.32-l .25)]. Since no cases Telephone interviews were conducted for reported having artificial joints, no OR could be 217 of 279 cases(78%) and 599 of 808 controls calculated for this category. No statistically (74%). Individuals were asked if they had significant association was found between STS ever had: (1) a joint replacement; (2) a pin, and pins, plates, staples or screws [OR =0.75 plate, staple or screw implanted; (3) or any (95% CI: 0.34-1.53)] or for other metal other pieces of metal or plastic implanted. For or plastic implants [OR = 0.50 (95% CI: the present analysis, the data for these three 0.05-2.30)]. categories of artificial implants were analyzed When the analysis is controlled for variations separately and in combination as “All in respondent status (i.e. response by subject or Implants” to determine the overall STS risk next of kin), the OR decreasesfor all implant of implants. categories as shown in Table 1. suggests genetic predisposition to a variety of tumors [lo]. Therapeutic immunosuppression for renal transplantation and other conditions has also been associated with STS [lo]. Kang et al. conducted a case control study to examine the association between STS and military service in Vietnam as well as other risk factors [ll]. As a part of this study, data were collected on artificial implants, including joints, pins, screws, staples and plates. The authors reported finding no association between STS and artificial implants; however, no data were presented. This paper presents a detailed analysis of the artificial implant data, provided by Dr Kang, and any possible association with STS.
Table 1. Artificial
Cases All implants Artificial joints Implants (pin, plate, staple, screw) Other implants (metal, plastic)
13 0 11 2
*Odds ratio and exact 95% confidence interval. **Mantel-Haenszel weighted odds ratio.
joints or implants and soft tissue sarcoma
Controls 53 4 40 I1
Odds radio (95% a)*
Odds ratio controlled for respondent status (95% a)**
0.66 (0.32-1.25)
0.58 (0.27-1.18)
0.75 (0.34-1.53) 0.50 (0.05-2.30)
0.70 (0.32-1.54) 0.43 (0.06-2.37)
Artificial
Implants and Soft Tissue Sarcomas
Table 2. Odds ratios controlling
for years since implant for all implants
Cases No implants Implanted 1970-1980 Implanted prior to 1970
547
204 8 5
Controls+ 546 25 26
Odds ratio (95% CI) 1.00 0.86 (0.33-2.00) 0.51 (0.15-1.39)
*Missing date of implantation for two controls. Used 1980 to calculate years since implant. Includes implants which have been removed (6 cases and 24 controls).
The effect of duration of implant for All Implants was calculated using implant year and 1980 as date of STS onset since no actual onset dates were available. No significant association was found between duration of implant and development of STS for those with implants done prior to 1980 or for those implants done prior to 1970 (see Table 2). Among cases,46% (6/l 3) of All Implants are still in place and 51% (25/49) of All Implants are still in place among controls. The limits of detectable risk for this study with 80% power are 2.21 (or greater) and 0.23 (or less). Thus, although we cannot eliminate a relative risk as high as 2.2 1, the overall direction of the effect (if any) appears to be protective, with all odds ratios being less than one. DISCUSSION
Epidemiologic evidence concerning implants and STS is sparse. Brand studied 50 patients with chronic foreign body reactions to a variety of implant materials that had been in place up
to 25 years [12]. None of the patients showed evidence of pre-neoplastic cells similar to those found in mice. One epidemiologic study of 1358 subjects addressesthe issue of cancer at remote sites and artificial implants [ 131.An increase in lymphatic and hematopoietic tumors was reported following total hip replacement. The short latencies reported for these tumors suggest an effect which preceded the implant. Drug therapy, which could produce such an effect, was not controlled for in the analysis. The English language scientific literature, published since 1956, reports 22 casesof sarcomatous lesions at the site of artificial implants [14-341. Latencies associated with these case reports are summarized in Table 3. The mean latency for these casesis 10.9 yr. Considering the hundreds of thousands of implant procedures that were performed in the 196Os,one would expect to see a large increase in incidence of implant-associated cancer cases if human susceptibility were similar to that observed in rodents. The paucity of STS case
Table 3. Latency of sarcomatous lesions in the presence of implants based on case reports Reference 27 15 14 17 16 29 26 34 31 19 33 24 22 28 30 22 20 23 32 21 25 18
Investigator Ryu et al. (1988) Bago-Granell et al. (1984) Arden and Bywaters (1978) Delgado (1958) Castleman and McNeeley (1965) Swann (1984) Penman and Ring (1984) Weber (1986) Tayton (1989) Haag and Adler (1989) Ward el al. (I 990) Martin et al. (1987) Lamovec et al. (1988) Scully et al. (1991) Tait (1988) Lamovec et al. (1988) Himmer er a/. (1991) Lee et al. (1984) Troop et al. (1990) Hughes et al. (1987) McDougall (I 956) Dube and Fisher (1972)
Age 53 27 56 40 53 63 75 76 11 69 65 66 65 18 56 62 74 44 39 14 42 84
Type of implant
Latency
Histology
Hip prosthesis Hip prosthesis Hip prosthesis Tibia pin/screw Femur nail/pin Total hip Total hip Knee prosthesis Femur pin/screw Total hip Hip nail Total hip Total hip Femur staples Total hip Total hip Knee prosthesis Femur pin/screw Total hip Hip screw Humerous pin/screw Tibia pin/screw Mean latency
1.0 2.0 2.5 3.0 3.0 3.0 5.0 5.0 7.0 9.0 9.0 10.0 10.0 10.0 11.0 12.0 13.0 14.0 15.0 29.0 30.0 36.0 10.9
Undifferentiated sarcoma Malignant fibrous histiocytoma Fibrosarcoma Unclassified sarcoma Giant cell rich sarcoma Malignant fibrous histiocytoma Osteosarcoma Epitheliod sarcoma Ewing’s sarcoma Malignant fibrous histiocytoma Osteosarcoma Telangiectatic osteosarcoma Osteosarcoma Osteogenic sarcoma Malignant fibrous histiocytoma Synovial sarcoma Angiosarcoma Malignant fibrous histiocytoma Malignant fibrous histiocytoma Malignant fibrous histiocytoma Ewing’s sarcoma Hemangioendothelioma
Robert W. Morgan and Maryellen Elcock
548
reports and the slow increase in U.S. mortality rates since 1950 [35,36] further support our conclusion that the risk of implant-associated STS is low or non-existent. Our study confirms the impression of Brand [37] that implants do not constitute an important health hazard to the recipients. CONCLUSION
This study is the first attempt to examine epidemiologic evidence concerning a causal association between implants and STS. The results of the present analysis indicate no association between implants and later development of soft tissue sarcoma. Previous case reports probably represent coincidental occurrence of malignancy after implant. Acknowledgement-The authors are grateful to Dr Kang for providing the data for this analysis and to Dow Corning Corporation for providing the funding. REFERENCES
1. Swanson SAV, Freeman MAR, Heath JC. Laboratory tests on total joint replacement prostheses. J Bone Joint Surg 1973; 55-B(4): 759-773. 2. Oppenheimer BS, Oppenheimer ET, Danishefsky I, Stout AP, Eirich FR. Further studies of polymers as carcinogenic agents in animals. Cancer Res 1955; 15: 333-340. 3. Sunderman FW. Carcinogenic effects of metals. Proc Sot Exp Biol 1978; 37(l): 40-46. 4. Laskin DM, Robinson IB, Weinmann JP. Experimental production of sarcomas by methyl methacrylate implants. Proe Sot Exp Biol Med 1954; 87: 329-332. 5. Carter RL, Roe FJC. Induction of sarcomas in rats by solid and fragmented polyethylene: experimental observations and clinical implications. Br J Cancer 1969; 23(2): 401-407. 6. Oppenheimer BS, Oppenheimer ET, Danishefsky I, Stout AP. Carcinogenic effects of metals in rodents. Cancer Res 1956; 16: 439-441. 7. Jennings TA, Peterson L, Axiotis CA, Griedlaender GE. Cooke RA, Rosai J. Anaiosarcoma associated with foreign body material. A report of three cases. Cancer 1988; 62: 2436-2444. 8. Miller BA, Gloeckler-Ries LA, Hankey BF, Kosary CL, Edwards BK. Eds. Cancer Statistics Review: 1973-1989. National Cancer Institute. 1992:NIH Pub1 No. 92-2789. 9. McClay EF. Epidemiology of bone and soft tissue sarcomas. Semin Oncol 1989; 16-4: 264272. 10. Tucker MA, Fraumeni JF, Jr. Soft tissue. In: Schottenfeld D, Fraumeni JF, Jr. Eds. Cancer Euidemiology and Prevention. Philadelphia, PA: W. B. Saunders Comoanv: 1982: 827-836. 11. Kang H, Enziger ‘F, Breslin P, Feil M, Lee Y, Service M, Shepard B. Soft tissue sarcoma and military service in Vietnam: a casecontrol study. J Nat1 Cancer Inst 1987; 79(4): 693-699.
12. Brand KG. Solid state carcinogenesis. Banbury Report 25: Nongenotoxic Mechanisms in Carcinogenesis. Cold Spring Harbor Laboratory; 1987. 13. Gillespie WJ, Frampton CMA, Henderson RJ, Ryan M. The incidence of cancer following total
hip replacement. J Bone Joint Surg 1988; 70-B(4): 539-542.
14. Arden GP, Bywaters EGL. Tissue Reaction. In: Arden GP, Instil BM, Eds. Surgical Management of Juvenile Chronic Polyarthritis. London: Academic Press; 1978: 263-275. 15. Bago-Granell J, Aguirre-Canyadell M, Nardi J, Tallada N. Malignant fibrous histiocytoma of bone at the site of a total hip arthroplasty. J Bone Joint Surg 1984; 66-B(1): 38-40. 16. Castleman B, McNeely BU. Case records of the MassachusettsGeneral Hospital. Weekly clinicopathological exercises. Case 38-1965. N Engl J Med 1965; 273(9): 494-504. 17. Delgado ER. Sarcoma following a surgically treated fractured tibia. A case report. Clin Orthop 1958; 12: 315-318. 18. Dube VE, Fisher DE. Hemangioendothelioma of the leg following metallic fixation of the tibia. Cancer 1972; 30(5): 1260-1266. 19. Haag M, Adler CP. Malignant fibrous histiocytoma in association with hip replacement. J Bone Joint Surg 1989; 71-B(4): 701.
20. Himmer 0, Lootvoet L, Deprez P, Monfort L, Ghosez JP. Angiosarcoma following total knee prosthesis. Rev. Chirurgie Orthoped 1991; 77: 125-128: 21. Hughes AW, Sherlock DA. Hamblen DL. Reid R. Sarioma at the site of a single hip screw. A casereport. J Bone Joint Surg 1987; 69-B(3): 470-472. 22. Lamovec J. Zidar A, Cucek-Plenicar M. Synovial sarcoma associated with total hip replacement. A case report. J Bone Joint Surg 1988; 70-A: 1561-1567. 23. Lee YS, Pho RWH, Nather A. Malignant fibrous histiocytoma at site of metal implant. Cancer 1984;54: 2286-2289. 24. Martin A, Bauer TW, Manley MT, Marks KE. Osteosarcoma at the site of total hip replacement. A case report. J Bone Joint Surg 1988; 70-A: 1561-1567. 25. McDougall A. Malignant tumor at site of bone plating. J Bone Joint Surg 1956; 38-B(3): 709-713. 26. Penman HG, Ring PA. Osteosarcoma in association with total hip replacement. J Bone Joint Surg 1984; 66-B(5): 632-634. 27. Ryu RKN, Bovill EG, Jr, Skinner HB, Murray WR. Soft tissue sarcoma associated with aluminum oxide ceramic total hip arthroplasty. Clin Orthop 1987; 216: 207-212. 28. Scully RE, Mark EJ, McNeely WF, McNeely BU. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 4-1991. N Engl J Med 1991; 324(4): 251-259. 29. Swann M. Malignant soft-tissue tumor at the site of a total hip replacement. J Bone Joint Surg 1984;66-B(5): 629-631. 30. Tait NP, Hacking PM, Malcolm AJ. Case reports. Malignant fibrous histiocytoma occurring at the site of a previous total hip replacement. Br J Radio1 1988;61: 73-76. 31. Tavton KJJ. Ewina’s sarcoma at the site of a metal plate. Cancer 1980;45: 413-425. 32. Trooo JK. Mallorv TH. Fisher DA. Vaughn BK. Malignant fibrous- histiocytoma after total hip arthroplasty. A case report. Clin Orthop 1990; 253: 297-300. 33. Ward JJ, Thornbury DD, Lemons JE, Dunham WK. Metal induced sarcoma. A case reoort and literature review. Ciin Orthop 1990; 252: 299-306. 34. Weber PC. Eoithelioid sarcoma in association with total knee replacement. A case report. J Bone Joint Surg 1986; 68-B: 824-826.
35. Pickle LW, Mason TJ, Howard N, Hoover R, Fraumeni JF, Jr, Eds. Atlas of U.S. Cancer Mortality
Artificial
36.
Implants and Soft Tissue Sarcomas
Among Whites: 1950-1980. National Cancer Institute; 1987. NIH Publ. No. 87-2900. Pickle LW, Mason TJ, Howard N, Hoover R, Fraumeni JF, Jr, Eds. Atlas of U.S. Cancer Mortality
37.
549
Among Non-Whites: 1950-1980. National Cancer Institute: 1990: NIH Publ. No. 90-1582. Brand KG. Do implanted medical devices cause cancer? J Biomater Appl 1994; 8: 325-343.
ARTIFICIAL
IMPLANTS
AND
48, No. 4, pp. 545-549. 1995 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0895-4356/95-$9.50 + 0.00
SOFT TISSUE
Copyright 6
SARCOMAS
ROBERT W. MORGAN’* and MARYELLEN ELCOCK’ ‘EnvironmentalHealth Strategies,Inc., One Lagoon Drive, Suite 120, Redwood City, CA 94065, and *Orange County Health Department, Epidemiology Unit, 1719 West 17th Street, Santa Ana, CA 92706, U.S.A.
carcinogenic potential of artificial implants has been of concern in recent years. Case reports and animal studies, dating back to the 195Os,have reported possible associations between artificial implants and soft tissue sarcomas,but epidemiologic data have been lacking. In a recent study of soft tissue sarcomas and military service, data on artificial implants were collected but not presented. This paper examines a possible association between artificial implants and soft tissue sarcomas. Abstract-The
Artificial implants
Soft tissue sarcomas
Epidemiology
the implant alone has been implicated as a critical carcinogenic factor [6]. The use of breast implants, while confined Case reports of possible implant-associated almost entirely to women, stimulates renewed cancers, as well as the increased longevity of interest in the issue of whether foreign bodies implanted materials, have promoted speculation (implants) increase the risk of cancer, especially the carcinogenic potential of concerning soft tissue sarcomas. Extensive use of implants, implants. A review of case reports associating such as prostheses, pins, and plates, began in foreign body materials (e.g., bullets, shrapnel the late 1950s. The surgical use of implants for pieces, dacron grafts, plates, screws and bone joint replacement and internal fixation devices implants) with sarcomas has suggested that for treatment of fractures is now common. there is a causal connection [7]; however, there Approximately 350,000 hip replacements are is a lack of any definitive, well-controlled performed annually worldwide [ 11.The carcinoepidemiologic studies on this topic. genic potential of these implants has been the Bone and soft tissue sarcomas (STS) in subject of some concern in recent years. humans are uncommon neoplasms. It is estiAn association between artificial implants mated that approx. 0.7% of all cancers in the and sarcomas in rats and mice was reported United States reported during 1992 will be bone in the 1950s by Oppenheimer [2]. In vitro or soft tissue sarcomas [8]. The study of STS is models have indicated bacterial and mammalian complicated by the site-oriented International mutagenesis in cell culture [3]. In rodent models, Classification of Disease classification for “concertain materials used in hip replacements nective tissue cancers” which excludes some have demonstrated potential carcinogenicity; mesenchymal tumors and does not distinguish e.g. chrome-cobalt Cl], methyl methacrylate [4], between different cell types. polyethylene [5], and nickel, chromium and There are a number of exogenous factors cobalt [3]. Alternatively, the physical form of which have been associated with sarcomas. These factors include: radiation, chemothera*All correspondenceshould be addressedto: Robert W. peutic and other chemical agents, including Morgan, MD, Environmental Health Strategies, Inc., One Lagoon Drive, Suite 120,Redwood City, CA 94065, vinyl chloride and arsenical compounds 191. U.S.A. Family clustering of childhood sarcomas INTRODUCTION
545
Robert W. Morgan and Maryellen
546
Elcock
Statistical analysis includes measurement of relative risk as approximated by the odds ratio (OR) and exact 95% confidence intervals (95% CI). In a case control study, where participants are selected on the basis of disease status, the OR is calculated as the ratio of the odds of exposure among casesto that among controls. An OR of one (unity) indicates no difference in exposure between cases and controls; in other words, an OR of unity or less indicates no increase in disease risk from the exposure (implant). The 95% CI represents the range within which the true magnitude of effect lies with 95% assurance. If the 95% CI includes one, the result is considered not statistically significant. To control for confounding variables, the Mantel-Haenszel method was used to estimate METHODS the OR and calculate the 95% CI. CalcuKang et al. [ 1l] studied STS cases,diagnosed lations were done using the Statistical Analysis between 1 January 1975 and 31 December 1980, System (SAS Version 6.03) and Epi Info which were selected from the Armed Forces (Version 5). Institute of Pathology (AFIP). A total of 217 cases and 599 matched controls were included RESULTS in the study. Cases were defined as men who were diagnosed with STS by the AFIP between The demographic characteristics of casesand 1 January 1975 and 31 December 1980, and controls have previously been published [l 11. who were born between 1940 and 1955. Con- Cases and controls are almost identical with trols for each case were selected from referring respect to marital status, race and level of pathologists or their pathology departments. education. Controls were matched on age but not on The results of the analysis are summarized race or vital status. Patients with diagnoses of in Table 1. There is no statistically significant STS, non-Hodgkin’s Lymphoma or Hodgkin’s relationship between All Implants and STS Disease were excluded from participation. [OR = 0.66 (95% CI: 0.32-l .25)]. Since no cases Telephone interviews were conducted for reported having artificial joints, no OR could be 217 of 279 cases(78%) and 599 of 808 controls calculated for this category. No statistically (74%). Individuals were asked if they had significant association was found between STS ever had: (1) a joint replacement; (2) a pin, and pins, plates, staples or screws [OR =0.75 plate, staple or screw implanted; (3) or any (95% CI: 0.34-1.53)] or for other metal other pieces of metal or plastic implanted. For or plastic implants [OR = 0.50 (95% CI: the present analysis, the data for these three 0.05-2.30)]. categories of artificial implants were analyzed When the analysis is controlled for variations separately and in combination as “All in respondent status (i.e. response by subject or Implants” to determine the overall STS risk next of kin), the OR decreasesfor all implant of implants. categories as shown in Table 1. suggests genetic predisposition to a variety of tumors [lo]. Therapeutic immunosuppression for renal transplantation and other conditions has also been associated with STS [lo]. Kang et al. conducted a case control study to examine the association between STS and military service in Vietnam as well as other risk factors [ll]. As a part of this study, data were collected on artificial implants, including joints, pins, screws, staples and plates. The authors reported finding no association between STS and artificial implants; however, no data were presented. This paper presents a detailed analysis of the artificial implant data, provided by Dr Kang, and any possible association with STS.
Table 1. Artificial
Cases All implants Artificial joints Implants (pin, plate, staple, screw) Other implants (metal, plastic)
13 0 11 2
*Odds ratio and exact 95% confidence interval. **Mantel-Haenszel weighted odds ratio.
joints or implants and soft tissue sarcoma
Controls 53 4 40 I1
Odds radio (95% a)*
Odds ratio controlled for respondent status (95% a)**
0.66 (0.32-1.25)
0.58 (0.27-1.18)
0.75 (0.34-1.53) 0.50 (0.05-2.30)
0.70 (0.32-1.54) 0.43 (0.06-2.37)
Artificial
Implants and Soft Tissue Sarcomas
Table 2. Odds ratios controlling
for years since implant for all implants
Cases No implants Implanted 1970-1980 Implanted prior to 1970
547
204 8 5
Controls+ 546 25 26
Odds ratio (95% CI) 1.00 0.86 (0.33-2.00) 0.51 (0.15-1.39)
*Missing date of implantation for two controls. Used 1980 to calculate years since implant. Includes implants which have been removed (6 cases and 24 controls).
The effect of duration of implant for All Implants was calculated using implant year and 1980 as date of STS onset since no actual onset dates were available. No significant association was found between duration of implant and development of STS for those with implants done prior to 1980 or for those implants done prior to 1970 (see Table 2). Among cases,46% (6/l 3) of All Implants are still in place and 51% (25/49) of All Implants are still in place among controls. The limits of detectable risk for this study with 80% power are 2.21 (or greater) and 0.23 (or less). Thus, although we cannot eliminate a relative risk as high as 2.2 1, the overall direction of the effect (if any) appears to be protective, with all odds ratios being less than one. DISCUSSION
Epidemiologic evidence concerning implants and STS is sparse. Brand studied 50 patients with chronic foreign body reactions to a variety of implant materials that had been in place up
to 25 years [12]. None of the patients showed evidence of pre-neoplastic cells similar to those found in mice. One epidemiologic study of 1358 subjects addressesthe issue of cancer at remote sites and artificial implants [ 131.An increase in lymphatic and hematopoietic tumors was reported following total hip replacement. The short latencies reported for these tumors suggest an effect which preceded the implant. Drug therapy, which could produce such an effect, was not controlled for in the analysis. The English language scientific literature, published since 1956, reports 22 casesof sarcomatous lesions at the site of artificial implants [14-341. Latencies associated with these case reports are summarized in Table 3. The mean latency for these casesis 10.9 yr. Considering the hundreds of thousands of implant procedures that were performed in the 196Os,one would expect to see a large increase in incidence of implant-associated cancer cases if human susceptibility were similar to that observed in rodents. The paucity of STS case
Table 3. Latency of sarcomatous lesions in the presence of implants based on case reports Reference 27 15 14 17 16 29 26 34 31 19 33 24 22 28 30 22 20 23 32 21 25 18
Investigator Ryu et al. (1988) Bago-Granell et al. (1984) Arden and Bywaters (1978) Delgado (1958) Castleman and McNeeley (1965) Swann (1984) Penman and Ring (1984) Weber (1986) Tayton (1989) Haag and Adler (1989) Ward el al. (I 990) Martin et al. (1987) Lamovec et al. (1988) Scully et al. (1991) Tait (1988) Lamovec et al. (1988) Himmer er a/. (1991) Lee et al. (1984) Troop et al. (1990) Hughes et al. (1987) McDougall (I 956) Dube and Fisher (1972)
Age 53 27 56 40 53 63 75 76 11 69 65 66 65 18 56 62 74 44 39 14 42 84
Type of implant
Latency
Histology
Hip prosthesis Hip prosthesis Hip prosthesis Tibia pin/screw Femur nail/pin Total hip Total hip Knee prosthesis Femur pin/screw Total hip Hip nail Total hip Total hip Femur staples Total hip Total hip Knee prosthesis Femur pin/screw Total hip Hip screw Humerous pin/screw Tibia pin/screw Mean latency
1.0 2.0 2.5 3.0 3.0 3.0 5.0 5.0 7.0 9.0 9.0 10.0 10.0 10.0 11.0 12.0 13.0 14.0 15.0 29.0 30.0 36.0 10.9
Undifferentiated sarcoma Malignant fibrous histiocytoma Fibrosarcoma Unclassified sarcoma Giant cell rich sarcoma Malignant fibrous histiocytoma Osteosarcoma Epitheliod sarcoma Ewing’s sarcoma Malignant fibrous histiocytoma Osteosarcoma Telangiectatic osteosarcoma Osteosarcoma Osteogenic sarcoma Malignant fibrous histiocytoma Synovial sarcoma Angiosarcoma Malignant fibrous histiocytoma Malignant fibrous histiocytoma Malignant fibrous histiocytoma Ewing’s sarcoma Hemangioendothelioma
Robert W. Morgan and Maryellen Elcock
548
reports and the slow increase in U.S. mortality rates since 1950 [35,36] further support our conclusion that the risk of implant-associated STS is low or non-existent. Our study confirms the impression of Brand [37] that implants do not constitute an important health hazard to the recipients. CONCLUSION
This study is the first attempt to examine epidemiologic evidence concerning a causal association between implants and STS. The results of the present analysis indicate no association between implants and later development of soft tissue sarcoma. Previous case reports probably represent coincidental occurrence of malignancy after implant. Acknowledgement-The authors are grateful to Dr Kang for providing the data for this analysis and to Dow Corning Corporation for providing the funding. REFERENCES
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