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The Epidemiology of Sarcoma

The Epidemiology of Sarcoma Sarcomas account for over 20% of all pediatric solid malignant cancers and less than 1% of all adult solid malignant cancers. The vast majority of diagnosed sarcomas will be soft tissue sarcomas, while malignant bone tumors make up just over 10% of sarcomas. The risks for sarcoma are not well-understood. We evaluated the existing literature on the epidemiology and etiology of sarcoma. Risks for sarcoma development can be divided into environmental exposures, genetic susceptibility, and an interaction between the two. HIV-positive individuals are at an increased risk for Kaposi’s sarcoma, even though HHV8 is the causative virus. Radiation exposure from radiotherapy has been strongly associated with secondary sarcoma development in certain cancer patients. In fact, the risk of malignant bone tumors increases as the cumulative dose of radiation to the bone increases (p for trend <0.001). A recent meta-analysis reported that children with a history of hernias have a greater risk of developing Ewing’s sarcoma (adjusted OR 3.2, 95% CI 1.9, 5.7). Bone development during pubertal growth spurts has been associated with osteosarcoma development. Occupational factors such as job type, industry, and exposures to chemicals such as herbicides and chlorophenols have been suggested as risk factors for sarcomas. A case-control study found a significant increase in soft tissue sarcoma risk among gardeners (adjusted OR 4.1, 95% CI 1.00, 14.00), but not among those strictly involved in farming. A European-based study reported an increased risk in bone tumors among blacksmiths, toolmakers, or machine-tool operators (adjusted OR 2.14, 95% CI 1.08, 4.26). Maternal and paternal characteristics such as occupation, age, smoking status, and health conditions experienced during pregnancy also have been suggested as sarcoma risk factors and would be important to assess in future studies. The limited studies we identified demonstrate significant relationships with sarcoma risk, but many of these results now require further validation on larger populations. Furthermore, little is known about the biologic mechanisms behind each epidemiologic association assessed in the literature. Future molecular epidemiology studies may increase our understanding of the genetic versus environmental contributions to tumorigenesis in this often deadly cancer in children and adults. Introduction epidemiology and etiology of sarcomas to be feasible, Sarcomas, tumors of putative mesenchymal origin, ac- this review will take a broad perspective, noting differ- count for nearly 21% of all pediatric solid malignant can- ences primarily between the two most common and dis- cers and less than 1% of all adult solid malignant tinct sarcoma groupings, malignant bone tumors and cancers [1]. In addition, sarcomas represent multiple soft tissue sarcomas [2]. malignancies rather than a single cancer [2]. For ex- Soft tissue sarcomas often form in the body’s muscles, ample, more than 50 distinct histologic sarcoma sub- joints, fat, nerves, deep skin tissues, and blood vessels. As types exist. Furthermore, many of these subtypes can the name implies, malignant bone tumors such as osteo- occur at any age and are not restricted to a specific loca- sarcomas and Ewing’s sarcomas are found throughout tion of the body. The rarity of the disease combined with the bones of the body, but also can commonly be found the diverse number of subtypes can make sarcomas very in the cartilage [3]. In 2010, the National Center for difficult to study. In order for the evaluation of the Health Statistics (NCHS) projected that 10,520 and 2,650 Americans, including all ages, will have been diagnosed with soft tissue and malignant bone tumors, respectively * Correspondence: Joshua.Schiffman@hci.utah.edu [4]. Furthermore, it is also projected that 3,920 and 1,460 Division of Pediatric Hematology/Oncology, Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, Americans will die in 2010 from soft tissue and malig- USA nant bone tumors, respectively. Full list of author information is available at the end of the article © 2012 Burningham et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 2 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Sarcomas, although relatively rare, are quite deadly, es- Descriptive epidemiology pecially soft tissue sarcomas. The primary reason for this In SEER data (1973–2008), we observed that soft tis- is due to delayed diagnosis and advanced disease, or me- sue sarcomas currently occur much more frequently tastasis, at presentation [3]. Early stage sarcomas lack than malignant bone tumors [1]. In 2008, soft tissue distinct symptoms that would potentially allow for early sarcomas accounted for nearly 87% of all sarcomas diagnosis. In addition to being a deadly disease, sarco- diagnosed, while the remaining 13% of the diagnoses mas also occur more frequently in young adults and were malignant bone tumors [1]. Osteosarcomas and adolescents compared to other cancers. Thus, despite chondrosarcomas were the most commonly diagnosed lower incidence rates, the years of life lost can often be malignant bone tumors, accounting for over half of all substantial. These facts present adequate evidence that the malignant bone tumor diagnoses. According to strategies to prevent sarcoma occurrence would prove to SEER, “other specified soft tissue sarcomas” accounted be beneficial. However, little scientific knowledge and for roughly 51% of all sarcomas diagnosed in 2008, consensus pertaining to the cause of sarcomas exists. It and clearly lead soft tissue sarcoma occurrence. is evident that further epidemiological research is war- Fibrosarcomas and Kaposi sarcomas were the two dis- ranted in order to more clearly define environmental tinct and individual soft tissue subtypes identified, and risk factors. The purpose of this review is to perform a predominantly diagnosed in 2008, accounting for thorough evaluation of the existing literature on the epi- roughly 7% and 9% of all sarcoma diagnoses respect- demiology and etiology of sarcomas. Thus, conclusions ively (Figure 1) [1]. will be made on the risk factors that are established, Age is an important determinant of sarcoma occur- which will be of benefit on drawing conclusions on ap- rence. Based on current statistics provided by the propriate preventative guidelines. NCHS and SEER, from 2004–2008, the mean age at diagnosis for soft tissue sarcomas and malignant bone tumors was 58 and 40 years of age, respectively [4]. Methods From 2003–2007, the mean age at death for soft tissue In order to identify the potential environmental risk fac- sarcomas and malignant bone tumors was 65 and tors for sarcomas, we reviewed all published articles 58 years of age, respectively. For further details on the that pertained to the epidemiology of sarcomas. In distribution of ages at time of diagnosis and death, addition, background information on the descriptive please refer to Figures 2 and 3. Generally, an increase epidemiology and basic genetics of sarcomas was also in the rate of soft tissue sarcomas occurs in new born obtained. For the environmental risk factor assessment, babies and young children, until they reach the age of we performed a literature search using the PubMed 5 [1]. Young adults experience the lowest incidence of database. Search terms included key words and phrases, soft tissue sarcomas, but occurrence steadily increases such as “epidemiology,”“risk factors,” and “case–control.” until the age of 50. At ages greater 50 years and In addition, common sarcoma subtype names of both above, incidence of soft tissue sarcomas increases malignant bone tumors and soft tissue sarcomas were much more dramatically. Malignant bone tumors, gen- also used in combination with our search terms in order erally have a fairly stable rate of incidence across all to yield the most relevant articles. The PubMed “all ages. However, noticeable increase in rates often occur related articles” feature was also used in our search for in adolescents and young adults due to osteosarcoma published papers that were related to our topic of inter- and Ewing’s sarcoma. Moderate increases in bone est, which may have not been listed, based on our tumor incidence also tend to occur in people in their search terms. 70s and 80s (Figure 4) [1]. Due to the sparsity of literature on sarcomas, a strict inclusion criterion was not vigorously followed. However, Race & geography the selected papers used must have followed an epide- Ewing’s sarcoma is a relatively rare bone tumor with lim- miologic study design. Thus, case reports were excluded. ited epidemiologic data; however one of the few well- All published papers used in this review were also described risk factors for this specific type of cancer is required to have been published after 1980, in order to race. It is known that whites are predominantly affected minimize inaccurate diagnoses conflicts. A total of 29 by Ewing’s sarcomas, whereas incidence rates in Asian adult studies and 22 pediatric studies were gathered, and African populations are often considerably less [66]. reviewed, and included in the environmental risk review This difference in incidence by race, suggests a genetic (Tables 1 and 2). The majority of the conducted research component to Ewing’s sarcoma, which has led research- were case–control studies, but some cohort, ecologic, ers to believe that that these racial differences are bio- and case-series studies (>250 cases) were also found and logically true. Jawad et al. (2009), found a 9-fold included. significant difference in Ewing’s sarcoma rates between Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 3 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Table 1 Adult sarcoma study descriptions Location & time Author N Cases N Controls/Cohort Risk cactors examined Cohort Studies UK & Le vu et al. (1998), OS 32, STS 25 4,400, 4,400 Radiotherapy France 1942–1986 [5,6] Menu-Branthomme et al. (2004) Finland 1953–2000 [7] Virtanen et al. (2006) STS & MBT 147 295,712 Radiotherapy France 1954–1983 [8] Rubino et al. (2005) STS & MBT 14 6,597 Radiotherapy Japan 1958–2001 [9] Samartzis et al. (2011) MBT 19 120,321 Ionizing radiation- atomic bomb USA 1973–1995 [10] Hwang et al. (2003) STS 135 194,798 Radiotherapy Amsterdam 1984–1996 [11] Renwick et al. (1998) KS 99 3,443 HHV8 infection Nested Case–control Hawkins et al. (1996) MBT 59 220 Radiotherapy UK 1940–1983 [12] International-multiple Kogevinas et al. (1995) STS 11 55 Phenoxy herbicides, chlorophenols, locations ?-1991 [13] dioxins Case–control England & Balarajan et al. (1984) STS 1,961 1,961 Agriculture and forestry occupations Wales 1968–1976 [14] Sweden 1975–1982 [15] Wingren et al. (1990) STS 96 650 Job type, chemical agents, and other occupational factors Kansas, USA 1976–1982 [16,17] Hoar et al. (1986), STS 228, STS 133 1610, 948 Agricultural herbicide use, tobacco Zahm et al. (1989) use, medical history, occupation Umea, Sweden 1978–1983 [18] Hardell et al. (1988) STS 54 311 Phenoxyacetic acids, chlorophenols Uppsala, Sweden 1978–1986 [19] Eriksson et al. (1990) STS 237 237 Occupation, occupational exposures, dioxins Wisconsin, USA 1979–1989 [20] Moss et al. (1995) OS 167 989 Fluoridated drinking water Wisconsin, USA 1980–1997 [21] Guse et al. (2002) OS 319 3,198 Radium in drinking water Washington, USA 1981–1984 [22] Woods et al. (1987) STS 128 694 Phenoxy herbicides, chlorophenols, and other occupational exposures Victoria, Australia 1982–1988 [23] Smith et al. (1992) STS 30 60 Phenoxy herbicides and chlorophenols New York & Washington DC, Engels et al. (2003) KS 29 57 Immunologic and virologic factors USA 1982-? [24] Northern Italy 1983–1998 [25] Fioretti et al. (2000) STS 104 505 Menstrual and reproductive factors USA-multiple locations Hoppin et al. (1998), STS 295, 1908, 1908 Chlorophenols and other 1984–1988 [26,27] Hoppin et al. (1999) STS 200 & MBT 51 occupational exposures USA-multiple locations 1984-? [28] Moore et al. (1996) KS 21 42 Kaposi's sarcoma-associated herpesvirus infection Northeast Italy 1985–1991 [29–31] Franceschi et al. (1992), STS 93, STS 93, 721, 721, 610 Occupational factors, tobacco, Serraino et al. (1992), STS 88 alcohol, drugs, pesticides, and Serraino et al. (1991) history of infection Manua, Italy 1989–1998 [32] Comba et al. (2003) STS 37 171 Residence near industrial waste incinerators Uganda 1994–1998 [33] Ziegler et al. (2003) KS 117 1,282 HHV8 infection Europe-multiple locations Merletti et al. (2006) MBT 96 2,632 Job type and occupational exposures 1995–1997 [34] Sicily, Naples, and Rome Goedert et al. (2002) KS 141 192 Birth order, sexual history, medical 1998–2001 [35] history, and cigarette consumption Ecologic France 1980–1995 [36] Viel et al. (2000) STS 110 N/A Residence near industrial waste incinerators Case-series USA-multiple locations Cope et al. (2000) ES 306 N/A Hernias 1960–1992 [37] Bologna, Italy 1981–2001 [38] Longhi et al. (2005) OS 962 N/A Height, stature, and growth rate STS = Soft tissue sarcoma, MBT = Malignant bone tumor, KS = Kaposi's sarcoma, OS = Osteosarcoma, ES = Ewing's sarcoma, CS = Chondrosarcoma. Caucasians and African Americans, clearly portraying are often found to be higher among American popula- that Caucasians are at greater risk for this particular sar- tions, versus, people living in Asian countries [68]. coma [67]. Racial disparities exist among other sarcoma We further attempted to investigate these racial rela- subtypes as well. For example, rates of chondrosarcomas tionships by assessing sarcoma incidence across several Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 4 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Table 2 Pediatric sarcoma study descriptions Location & time Author N Cases N Controls/Cohort Risk factors examined Pooled USA, UK, Sweden, Spain, Mirabello et al. (2011) OS 1501 1,501,000^ Height at diagnosis, birth weight Italy, Germany 1945–2001 [39] Austrailia and California Valery et al. (2005) ES 138 574 Hernias 1978–1996 [40] USA-multiple locations Spector et al. (2009), MBT 573 & STS 1067, 57966, 57966, Birth weight, birth order, (CA, MN, NY, TX, WA) Von Behren et al. (2010), MBT 550 & STS 1054, 57966, 57966 parental age, gestational age, 1980–2004 [41–44] Ognjanovic et al. (2009), RS 583, MBT 511 & and other birth characateristics Johnson et al (2009) STS 1000 Meta-analysis USA & Canada Valery et al. (2005) ES 357 745 Hernias 1980–2002 [40] Cohort Connecticut, USA Tucker et al. (1987) MBT 64 9,170 Radiotherapy (treatment of 1936–1979 [45] primary childhood cancers) Case–control Ontario, Canada Finkelstein et al. (1996) MBT 238 432 Radium in drinking water 1964–1988 [46] North Carolina, United States Grufferman et al. (1982) RS 33 99 Parental smoking habits, maternal 1967–1976 [47] age, maternal antibiotic use, and vaccination history Northern England 1968–2000 [48] Pearce et al. (2007) MBT 245 & 29,520 Paternal occupational exposure to STS 320 electro-magnetic fields USA-multiple locations 1972-? [47] Winn et al. (1992) ES 208 395 Parental smoking habits, hernias, and parental occupational factors USA 1972–1997 [49] Grufferman et al. (1993) RS 322 322 Parental cocaine and marijuana use Los Angeles, USA 1972–1981 [50] Operskalski et al. (1987) OS 64 124 Birth length, gestational age and height at diagnosis New York State, USA Gelberg et al. (1997) OS 130 130 Birth weight, birth height, and 1978–1988 [51] pubertal growth factors United Kingdom 1980–1983 [52,53] Hartley et al. (1988), MBT 30 & STS 43, 146, 146 Birth weight, pregnancy conditions, Hartley et al. (1988) MBT 30 & STS 43 antibiotic use after birth Ontario, Canada 1980–1988 [54] Hum et al. (1998) MBT 152 713 Parental occupations USA & Canada 1983–1987 [55] Buckley et al. (1998) OS 152 & ES 153 305 Birth weight, birth height, and pubertal growth factors United Kingdom 1991–1996 [56] Smith et al. (2009) MBT & STS 251 6,337 Birth weight and gender Austrailia 1991–1996 [57,58] Valery et al. (2003), ES 106, ES 106 344, 344 Parental occupation, hernias, Valery et al. (2002) and pubertal growth factors USA-multIple locations Bassin et al. (2006) 139 280 Fluoride levels in drinking water 1992–1995 [59] Germany 1992–1997 [60,61] Schuz et al. (2007), MBT 97 & STS 137, 2057, 2588 Birth weight, family size, maternal age, Shuz et al. (1999) MBT 97 & STS 137 gestational age, paternal smoking, birth weight for gestational age, and other birth characateristics USA-multiple locations Troisi et al. (2006) OS 158 141 Birth weight, birth length, birth order, 1994–2000 [62] height and weight at diagnosis, and other pubertal growth factors Case-series USA-multiple Pendergrass et al. ES 291 N/A Adolescence stature: height locations 1972–1978 [63] (1984) and weight United Kingdom 1978–1997 [64] Cotterill et al. (2004) MBT 720 N/A Adolescent height, stature, and growth factors STS = Soft tissue sarcoma, MBT = Malignant bone tumor, KS = Kaposi's sarcoma, OS = Osteosarcoma, ES = Ewing's sarcoma, CS = Chondrosarcoma, RS = Rhabdomyosarcoma. ^2000 U.S. National Center for Health Statistics Simulated Controls. a b c Already referenced studies included in pooled/meta analyses: [41,62,64] [57] [54,65]. geographical regions. Cancer Incidence in Five Conti- incidence rates for both males and females did not ap- nents, Volume IX, published by the International Agency pear to drastically differ between Asian countries and for Research on Cancer (IARC), provides an in-depth the United States as some investigators have reported look at sarcoma incidence by continent, country, and [68]. Overall, it appears that sarcoma incidence rates are small region [69]. Age-Standardized osteosarcoma comparable throughout much of the world. However, Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 5 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 All Sarcomas Malignant bone tumors Soft tissue sarcomas Figure 1 Distribution of new sarcoma cases by histology (2008). there are some instances where notable differences exist. Osteosarcoma incidence rates of similar magnitude were Japanese males living in the state of California, have a not observed throughout Japan. However, a high inci- reported osteosarcoma incidence rate of 1.3 per 100,000 dence of 1.1 cases per 100,000 was reported among Japa- males [69]. This rate is relatively high in comparison to nese males living in Hawaii [69]. These findings may incidence rates observed through much of the world. suggest that Japanese migrants living in “westernized” Typically, osteosarcoma incidence rates range from 0.2- regions may be subject to increase osteosarcoma risk 0.6 per 100,000 males, depending on geographic region. due to environmental or lifestyle factors. A relatively Figure 2 Distribution of ages at diagnosis, 2004-2008. Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 6 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Figure 3 Distribution of ages at death, 2003-2007. high osteosarcoma incidence rate of 1.4 per 100,000 Genetics females was also reported in Sondrio, Italy. The Several different inherited genetic syndromes increase remaining geographic regions of Italy reported signifi- the risk for subsequent sarcoma development. Some of cantly lower osteosarcoma incidence rates among the most well-known syndromes are neurofibromatosis females, ranging from 0.1-0.4 per 100,000. These geo- (NF1), also known as von Recklinghausen’s disease, Li- graphical differences in sarcoma incidence clearly war- Fraumeni syndrome (LFS), and Retinoblastoma (Rb) [2]. rant the need for further investigation, which goes Individuals diagnosed with NF1 have a 10% cumulative beyond the scope of this review. These findings reflect lifetime risk of developing malignant peripheral nerve that both genetic and environmental factors likely con- sheath tumors (MPNST) [70]. NF1 results from an auto- tribute to the etiology of sarcomas. somal dominant process that leads to improper function The literature available on racial differences in regards of the NF1 gene, which is responsible for producing to soft tissue sarcomas appeared to be lacking and Neurofibromin. Neurofibromin ultimately functions as a required us to further analyze the SEER database for ra- tumor suppressor gene through guanosine triphospha- cial disparities. We generated soft tissue sarcoma inci- tase (GTPase) activity from the proto-oncogene, Ras. dence rates, which included years 1973–2008, and found Thus, loss of function of the NF1 gene, leads to that Blacks had the highest overall incidence rate of 5.1 increased Ras activity, promoting tumor development. per 100,000 (the opposite of Ewing’s sarcoma, a bone Li-Fraumeni syndrome (LFS) was one of the first can- tumor sarcoma) [1]. Whites’ had an incidence rate of 4.5 cer genetic syndromes discovered to have a strong asso- per 100,000, followed by American Indian/Asian Pacific ciation with sarcomas [25]. In fact, LFS was initially Islanders, with a rate of 2.8 per 100,000. This is evidence clinically defined as having “a proband who had a sar- to show that race also influences disease occurrence coma diagnosed before 45 years of age and a first-degree among those with soft tissue sarcomas. Further investi- relative who had any cancer under 45 years of age and a gation of the biologic and genetic differences in sarcoma first- or second-degree relative who had any cancer tumors by race is needed in order to gain greater under- under 45 years of age or a sarcoma at any age [47]." standing of the potential mechanisms responsible for Newer definitions for LFS are based on the “Chompret these mentioned racial differences. Criteria” which define the diagnosis as: “Proband with Figure 4 Incidence of malignant bone tumors vs. soft tissue sarcomas by age (2004-2008). Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 7 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 LFS tumor (eg., soft tissue sarcoma, osteosarcoma, brain syndrome of Diamond-Blackfan Anemia (RPS19, RPL5, tumor, premenopausal breast cancer, adrenocortical car- RPL11, RPL35A, RPS24, RPS17, RPS7, RPS10, and RPS26 cinoma, leukemia, lung brochoalveolar cancer) before mutations) which has been associated with rare cases of age 46 years AND at least one first- or second-degree re- osteosarcoma. lation with LFS tumor before age 56 years or with mul- Ewing’s Sarcoma, on the other hand, is currently not tiple tumors; OR proband with multiple tumors (except associated with any known gene mutations or hereditary breast), two of which belong to LFS tumor spectrum cancer syndromes [44]. Nevertheless, the associations and first of which occurred before age 46 years; OR pa- described below with race and familial hernia risk sug- tient with adrenocortical carcinoma or choroid plexus gests a yet undefined genetic association. A recent publi- tumor” [65]. The syndrome results from germline cation has reported that common variants near TARDBP (constitutional) mutations in the tumor suppressor and EGR2 are associated with susceptibility to Ewing’s gene, TP53 [52]. The TP53 tumor suppressor gene is sarcoma [61]. As research continues into the etiology of responsible for inhibiting cell growth and stimulating Ewing’s sarcoma, it can be expected that more genetic cell apoptosis, as well as DNA repair [2]. Thus, muta- risk factors will be identified. tions in TP53 can lead to the early development of sarcomas and other tumors through the acquisition of Etiologic studies genomic instability. In fact, children with the soft tis- Investigations of the potential risk factors for sarcoma sue sarcoma rhabdomyosarcoma presenting at less occurrence commonly share similar study characteris- than 3 years of age appear to have an increased likeli- tics. Even though many different sarcoma subtypes exist, hood of harboring TP53 germline mutations [39,56]. they are commonly grouped together and studied as a It is also important to note that roughly 30-60% of single outcome because of the rarity of sarcoma occur- non-LFS soft tissue sarcomas will have somatic muta- rence. However, studies will commonly separate adult tions of the TP53 gene [53]. and pediatric cases, due to the potential for differences Retinoblastoma (Rb), hereditary or non-hereditary, is a in their etiologic properties. Furthermore, case–control relatively rare tumor that develops in the retinal cell studies are the standard approach for assessing many of found in the eye. Hereditary Rb survivors have a greater the environmental risk factors largely due to the rarity of risk of developing secondary malignancies, in particular sarcomas. This study design, commonly used as the osteosarcoma [60]. It was recognized early on that radi- method for investigating rare outcomes, can discourage ation treatment further increased the risk for secondary investigators and reviewers from making strong conclu- malignancies among Rb survivors. When possible, radi- sions. Case–control studies are simply prone to more ation is now avoided in Rb treatment strategies. However, bias than prospective studies and this has been evident patients with hereditary Rb are still at increased risk for while reviewing the literature. The majority of sarcoma- other tumors even without radiation exposure (including related case–control studies are relatively small and bone and soft tissue sarcomas, brain tumors, nasal cavity cover a wide-range of exposures and carcinogenic fac- cancer, melanoma, lung, gastrointestinal, and bladder tors. The following report contains a comprehensive re- cancer) and this risk increases as Rb patients continue to view of the major environmental risk factors that have age [41,50]. Rb develops by means of germline mutations been investigated. that lead to inactivation of an allele in the tumor sup- pressor gene, RB1. It has been estimated that Rb survi- vors have a 500-fold increase incidence of osteosarcomas as compared to the general population [42]. Female Hormones and Reproductive Factors (Adult Osteosarcomas, in particular, seem to be associated Sarcomas) with hereditary cancer syndromes [43]. Other familial Very few studies have assessed the potential role of fe- predisposition syndromes associated with osteosarcoma male hormones on sarcoma development. One case– risk include the very rare, autosomal recessive DNA heli- control study in Northern Italy investigated the potential case syndromes including: Rothmund Thomson II (REQ4 association across a wide array of female hormone mutations), RAPADILINO Syndrome (RA: RAdial apla- related factors [37]. There were 104 soft tissue sarcoma sia or hypoplasia, PA: PAtellae aplasia or hypoplasia and cases and 505 controls available for analysis, but no sig- cleft or high arched PAlate, DI: DIarrhea and DIslocated nificant associations were reported based on menstrual joints, LI: LIttle size and LImb malformations, NO: long, cycle patterns, age at menopause, parity, and number of slender NOse and NOrmal intelligence, REQ4 muta- abortions. The only suggestive association was for tions), Werner (WRN mutations), and Bloom Syndrome women who had become pregnant with their first child (BLM mutations). In addition, inherited defects in ribo- at later ages (>29 years of age) (adjusted OR = 3.16, 95% somal proteins lead to the autosomomal dominant CI 0.96, 10.44). Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 8 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Prenatal characteristics (Pediatric sarcomas) 1.79) [38]. The biological mechanisms that define the re- Three studies assessed the relationship between specific lationship between birth weight and childhood sarcomas prenatal characteristics and sarcoma occurrence [40,51,57]. are not clear [64]. Birth weight has also been assessed to Winn et al. (1992) reported in a case–control study of be possibly associated with the risk of soft tissue sarco- 208 cases and 395 sibling/regional controls, that women mas and other non-osteosarcoma bone tumors. How- who gave birth to children that later developed Ewing’s ever, no major statistically significant results were sarcoma were more likely to have used medications for observed among these studies [55,62–64]. nausea and vomiting during their pregnancy (adjusted Gestational age has also been investigated as a poten- OR = 2.6, 95% CI 1.2, 5.9) [40]. However, this result was tial factor that may be associated with an increased risk only found to be significant where siblings acted as study of pediatric sarcomas. A case–control study made up of controls. Such an association was not seen where re- 64 cases and 124 controls reported that osteosarcoma gional controls were used. Thus, this result could reflect risk increased among those born a week early (OR = 2.8, selective recall bias by the parent for the case child. 95% CI 1.1-6.8) [24]. A published reported based on a Grufferman et al. (1982) conducted a case–control study large pooled analysis of 573 malignant bone cases and in North Carolina, comprised of 33 cases and 99 con- 57,966 controls, also found an increased risk of Ewing’s trols, and reported that mothers who had used antibiotics sarcoma among those cases that had a recorded gesta- during or closely preceding pregnancy (adjusted RR =2.7, tional age of 32–36 weeks, versus those classified as 95% CI 1.1, 6.4), or had experienced an overdue or being born after 36 weeks of gestation (adjusted assisted delivery (adjusted RR = 2.6, 95% CI 1.1, 7.1) were OR =1.68, 95% CI 1.03-2.76) [63]. This pooled analysis at increased risk of giving birth to a child that would later linked birth and cancer registry data across five U.S. develop the soft tissue sarcoma known as rhabdomyosar- states, which allowed for the large sample size. Further- coma [57]. Interestingly enough, a study based in the more, a recent case–control study in Germany with 97 United Kingdom, comprised of 73 cases (43 soft tissue/ malignant bone cases and 137 soft tissue sarcoma cases 30 malignant bone) and 146 controls reportedly found found no significant increase in sarcoma risk among that soft tissue sarcoma occurrence in children has also those classified as small-for-gestational age, nor those been associated with antibiotic use in children closely classified as being large-for-gestational age [55]. after birth (adjusted RR = 6.81, 95% CI 1.13, 71.18) [51]. Birth order and maternal age have also been investi- This study also examined the pregnancy condition gated as risk factors for sarcoma. The previously men- known as toxemia and found that it increased the risk of tioned multi-U.S. pooled analysis with 57,966 controls, soft tissue sarcomas (adjusted RR = 2.71, 95% CI 1.05, included 583 rhabdomyosarcoma cases. A decreased risk 7.06). However, it is important to note that criteria for in rhabdomyosarcoma was reported, among third born the toxemia case mothers was based on recorded preg- children, where the firstborn child was classified as the nancy symptoms such as hypertension, edema, and albu- comparison group (adjusted OR = 0.70, 95% CI 0.54, minuria, rather than an actual record of having been 0.91) [28,71]. The same pooled analysis reported that the diagnosed with toxemia. risk of rhabdomyosarcoma increases among cases with mothers advancing in age (per 1-year increase, adjusted Birth characteristics (Pediatric sarcomas) OR =1.03, 95% CI 1.01, 1.04) (per 5-year increase, Many studies have assessed the potential relationship be- adjusted OR = 1.19, 95% CI 1.05, 1.34) [11,28]. Another tween pediatric cancer risk and many different birth fac- study including 137 soft tissue sarcoma cases and 2,588 tors. A recent study including 251 pediatric sarcoma controls reported an actual decrease in risk among cases cases and 6,337 controls investigated birth weight as a with older mothers (>35 years) (OR = 0.4, 95% CI 0.1, risk factor for pediatric sarcomas but no significant asso- 1.0) [33]. In addition, a significant increase in risk was observed for cases who had young mothers. (<20 years) ciation was observed [64]. The previously mentioned case–control study in the United Kingdom with 73 cases (OR = 2.2, 95% CI 1.0, 4.7). All soft tissue sarcomas were and 146 controls reported some evidence suggesting that also grouped together in this analysis which ultimately may not share common etiologic properties, thus leading a potential relationship might exist between Ewing’s sar- coma and birth weight [51]. They reported that Ewing’s to invalid conclusions. Studies have also observed in- sarcoma cases had a median weight of 3,015 g compared creasing linear trends of sarcoma risk, based on incre- mental increases in paternal age [11,28]. to the controls which had a median weight of 3,400 g (p = 0.02). A pooled analysis included 434 osteosarcoma Inguinal and umbilical hernias are a commonly studied cases and 1,000 controls studies, reported a significant birth anomaly that has been found to be associated with Ewing’s sarcoma [14,15,29,40]. The previously men- association between osteosarcoma risk and high birth weight (> = 4,046 g), compared to an average birth tioned case–control study conducted by Winn et al. weight (2,665-4,045 g) (adjusted OR = 1.35, 95% CI 1.01, (1992) reported that umbilical and inguinal hernias, Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 9 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 occurring early in life, are diagnosed six times more fre- factors in early adolescence with the risk of Ewing’s sar- quently in Ewing’s sarcoma cases than controls [40]. A coma. However, neither height nor weight was found to recent meta-analysis of 357 cases and 745 controls, be associated with Ewing’s sarcoma [23,34]. No studies which included the study by Winn et al. (1992) [40] and were found in our search that assessed the relationship two additional case–control studies, also reported that between growth and development in early adolescence children with a history of hernias have a greater risk of and soft tissue sarcomas. developing Ewing’s sarcoma (adjusted OR 3.2, 95% CI 1.9, 5.7) [15]. Cope et al. (2000) reported in a case-series Infection (Adult sarcomas) study of 324 cases, a significantly higher relative risk of It has long been known that people living with AIDS are inguinal hernias among Ewing’s sarcoma cases compared at very high risk for developing a soft tissue sarcoma to population estimates (females, RR = 13.3, 95% CI 3.6, known as Kaposi’s sarcoma. In fact, people with AIDS 34.1) (males, RR = 6.67, 95% CI 2.67, 13.7) [15]. Authors’ have a 100,000 fold greater risk of developing Kaposi’s hypothesized that these findings suggest a disruption in sarcoma [19]. However, AIDS does not cause Kaposi’s normal embryological development, which perhaps may sarcoma nor is it required to be HIV-positive in order to relate to an in utero exposure or indicate an underlying develop Kaposi’s sarcoma [13]. In recent years, studies genetic disorder. have attempted to narrow the causal pathway for Kaposi sarcoma, which has successfully led researchers to the Growth and development in early adolescence (Pediatric identification of the virus primarily responsible for sarcomas) Kaposi’s sarcoma [13,26,27,54]. Evidence has shown that Several studies have concluded that having a tall stature the human herpes virus 8 (HHV8), a sexually transmit- or experiencing an earlier pubertal growth spurt may be ted virus, is strongly associated with an increased risk of important factors in the etiology of osteosarcomas Kaposi’s sarcoma in both HIV-positive and HIV-negative [16,22,30,34,38]. Out of the six papers reviewed, three individuals. HHV8 is the greatest predictor of Kaposi’s were case–control studies [22,24,30], two were case- sarcoma development, thus leading researchers to be- series studies [16,34], and one study conducted a pooled lieve that HHV8 plays a central role in the causal path- analysis [38]. Only one paper did not report an associ- way for developing Kaposi’s sarcoma. ation between osteosarcoma and increased growth in The potential association of sarcoma development and early adolescence [24]. This paper was based on a previ- infections other than HHV8 appears to have been rarely ously mentioned case–control study that had assessed studied. However, one study with 93 cases and 721 con- gestational age and osteosarcoma risk. This case–control trols examined the potential risk of other viral infections study compared to the other reviewed studies was rela- on soft tissue sarcoma development [58]. They reported a tively small, with only with 64 cases and 124 controls. greater risk of soft tissue sarcomas among those indivi- Both case-series studies had over 700 cases and the duals who had a history of herpes zoster infection case–control studies had at least double the number of (adjusted OR = 2.3, 95% CI 1.1, 4.9), chicken pox (adjusted osteosarcoma cases to analyze. Thus, the small sample OR = 2.1, 95% CI 1.2, 4.1), and mumps (adjusted OR = 2.0, size may be one reason why the results were not similar 95% CI 1.1, 3.8). Caution must be taken in drawing to the other studies. Individuals with osteosarcoma, are strong conclusions from a single paper and a topic that commonly found to be taller than the general population appears to have been rarely studied. Nevertheless, the near the time of diagnosis [16,30,34,38]. It can be con- association between viruses and sarcoma warrants further cluded that rapid bone development during the pubertal consideration. time window may lead to an increased risk of osteosar- coma [38]. Further investigation is needed in order to Job type, industry, and occupational exposures (Adult understand the physiologic mechanisms that are respon- sarcomas) sible for this relationship. Buckley et al. 1998 found that Occupational factors such as job type and industry have the timing of pubertal development may also be an im- been among the most frequently studied risk factors in portant factor in osteosarcoma risk, especially among sarcoma research. Balarajan et al. (1984) reported that females [18]. Female cases with osteosarcoma tended to farmers, farm managers, and market gardeners have a experience breast development (11.4 vs. 11.8 years, significant increase in risk for developing soft tissue sar- P = 0.03) and menarche (12.1 vs. 12.5 years. P = 0.002) at comas. (adjusted OR 1.7, 95% CI 1.00, 2.88) [48]. How- significantly earlier times in their adolescent lives, com- ever, other studies did not find a significant increased pared to controls. Two studies also reported that females risk among those employed in all agriculture-based posi- are generally diagnosed with osteosarcomas at younger tions [8,45]. For example, one study of 96 cases and 650 ages than males [16,34]. Many of these studies also controls found a significant increase in soft tissue sar- examined the relationship of growth and development coma risk among gardeners (adjusted OR 4.1, 95% CI Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 10 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 1.00, 14.00), but not among those strictly involved in 1.68, 4.61), seamen (SIR 1.92, 95% CI 1.05, 3.22), and farming [8]. Other occupations such as railroad and con- drivers (SIR 1.45, 95% CI 1.09-1.88). Further investiga- struction work were also suggestive of an increase in risk tion will be needed in order to determine if these par- of soft tissue sarcomas, but these relationships have not ticular occupations are associated with ionizing radiation been shown to be statistically significant. The varying and other physical elements that have been shown to in- results among studies could potentially be due to the dif- crease the risk of malignant bone tumors. Elevated soft ferences in epidemiologic methodology. For example, tissue sarcoma SIRs were seen in men, classified as the results Balarajan et al. (1984) reported were based building caretakers (SIR 1.30, 95% CI 1.08, 1.56) and primarily on registry data, relying upon occupational military personnel (SIR 1.27, 95% CI 1.01, 1.59). There coding in order to study these relationships, while the were no reported statistical significant SIRs for women. other two studies, which did not find similar significant Besides job type and industry, several studies have associations, relied upon questionnaires and other simi- assessed the actual exposure to specific chemicals and pes- lar tools for obtaining occupational information. ticides at the occupation by administering detailed ques- The association between malignant bone tumors and tionnaires or through personal interviews. Six case–control occupation has not been studied as often as soft tissue studies assessed the relationship between herbicide and sarcomas. One European based-study, consisting of 96 chlorophenol exposure with soft tissue sarcoma risk, but cases and 2,632 controls, reported an increased risk in did not find significant relationships [6,7,9,10,45]. On the bone tumors (includes osteosarcomas and chondrosar- other hand, two case–control studies conducted in Sweden comas) among those who worked as blacksmiths, tool- and in the U.S., and one international nested case–control makers, or machine-tool operators (adjusted OR 2.14, study, found a strong relationship between these chemical 95% CI 1.08, 4.26) [12]. This study also found that indi- exposures and soft tissue sarcoma [20,46,59]. We believe viduals involved in bricklaying (adjusted OR 2.93, 95% these conflicting findings aredue to themethodological CI 1.55, 5.53) and carpentry, (adjusted OR 4.25, 95% CI limitations such as low statistical power, small sample sizes, 1.71, 10.50) were found to be at increased risk for bone proxy interviews, and the potential for multiple comparison tumor development. In addition, this study also reported issues because of the many occupational categories ana- that cases involved in the manufacturing of wood, cork lyzed. Hoppin et al. (1998) conducted the U.S. based case– products, and straw were found to have a significantly control study, which included 295 sarcoma cases and 1,908 increased risk of malignant bone tumor development controls that overcame many of these mentioned weak- (adjusted OR 3.58, 95% CI 1.70, 7.56). Individuals classi- nesses [46]. They reported a statistically significant relation- fied as manufacturers of machine and equipment, were ship between soft tissue sarcoma risk and ever having high- also found to be at greater risk for bone tumors intensity chlorophenol exposure (adjusted OR = 1.79, 95% (adjusted OR 2.02, 95% CI 1.00, 4.08). Interestingly, the CI 1.10, 2.88). In fact, among highly exposed subjects, risk study participants classified as being in the industry of increased as the duration of the chlorphenol exposure agriculture, growing of crops, and other related fields, increased (p for trend <0.001). Furthermore, complete oc- which might be frequent users of herbicides and pesti- cupational histories, spanning multiple years, were obtained cides, were not found to be related to bone tumor from the actual study participants rather than their proxies, development [12]. which improved the studies ability to successfully analyze The Nordic Occupational Cancer (NOCCA) project duration-response relationships with greater accuracy. In has collected roughly 45 years of cancer incidence data addition, Hoppin et al. (1999) also reported that exposure by occupational category for Denmark, Finland, Iceland, to cutting oils increased the risk of soft tissue sarcomas, but Norway, and Sweden [5]. Standardized incidence ratios not bone tumors. (adjusted OR 1.65, 95% CI 1.04, 2.61) (SIR) were utilized in describing the relationship be- [21]. Malignant bone tumors and occupational exposures tween cancer incidence and occupation. An SIR is used to determine whether the number of observed cases of have not been studied as heavily as the soft tissue sarco- cancer is higher or lower than expected, given the age mas, although among the limited papers published, no significant relationships were identified [12,21]. Other distribution and population under study. This NOCCA reported a statistically significant elevated SIR of malig- occupational exposures such as solvents, wood dust, as- nant bone tumors among men classified as “other health bestos, DDT, and benzene have also been studied, but none were found to be significantly associated with sar- workers.” (SIR 2.25, 95% CI 1.29, 3.66). This may suggest that health-related occupations such as radiologists and coma risk [21,45,59]. health technologists may be at increased risk for bone tumor development due to radiation exposure. Statisti- Parental occupation (Pediatric sarcomas) cally significant elevated SIRs were also reported among Only a few studies have examined the potential risks of men classified as military workers (SIR 2.88, 95% CI parental occupation on the development of cancer in the Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 11 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 offspring. A study in Ontario, Canada, of 152 cases and the increase in the number of secondary sarcoma can- 713 controls, reported that the risk of Ewing’s sarcoma cers diagnosed among individuals that have been treated was significantly elevated among children whose fathers by radiotherapy. Several studies have examined this pat- worked in the social sciences (adjusted OR = 6.2, 95% CI tern and relationship between primary cancers and sec- 1.6, 24.5) [32]. In addition, the same study reported a ondary development of sarcomas and have found greater risk of Ewing’s sarcoma in mothers who were ionizing radiation exposure from radiotherapy to be the teachers (adjusted OR = 3.1, 95% CI 1.1, 8.7). Investiga- key influential factor [31,35,49,72–75]. Virtanen et al. tors found it difficult to hypothesize the possible (2006) reported that radiotherapy appears to be asso- mechanisms behind these relationships, because these ciated with an increased risk of developing sarcomas, particular occupational settings do not appear to expose especially among younger patients under the age of 55 the parents to hazardous substances. According to (SIR =4.2, 95% CI 2.9, 5.8) [75]. Furthermore, Hawkins authors, it may be possible that these findings are being et al. (1996) reported that the risk of malignant bone influenced by socioeconomic status. However, this study tumors also increased as the cumulative dose of radi- was not able to adjust on this potential confounding fac- ation to the bone increased (p for trend <0.001) [49]. Le tor because data was not available on parental education Vu et al. (1998) implemented a case–control study and income. Three other case–control studies also have within a childhood cancer cohort of 4,400 3-year survi- reported that a potential relationship exists between vors of a first solid cancer and also found that the risk of farming and the development of Ewing’s sarcoma in off- a secondary bone tumor (osteosarcoma) to be a linear spring [32,36,40]. The case–control study in Australia of function of the local dose of radiation received [72]. 106 cases and 344 controls reported that fathers who Studies on other potential sources of low dose ionizing worked on a farm at conception or time of pregnancy radiation and sarcoma risk are relatively infrequent. had offspring with a 3.5 fold greater risk of developing However, one recently published study that followed Ewing’s sarcoma, which was statistically significant [36]. atomic bomb survivors from 1958 to 2001 reported that This conclusion was only drawn based on offspring that lower doses of ionizing radiation increased the occur- were diagnosed before the age of 20. These conclusions rence of bone sarcoma diagnoses (RR = 7.5 per Gy, 95% support the general consensus that many of the pesti- CI 1.34, 23.14) [76]. However, this conclusion was based cides and chemicals used in farming are carcinogens and only on the development of 19 cases during the cohort lead to sarcoma development. study period. The previously mentioned case–control study in On- tario, Canada also investigated the osteosarcoma bone Drinking water (Adult & pediatric sarcomas) tumor risk in offspring with fathers who were farmers, Fluoride exposure in drinking water has been studied as mothers involved in managerial and administrative a potential risk factor in the development of osteosar- work, and mothers involved in product fabricating, as- comas. Fluoride is known to act as a mitogen, increasing sembling, and manufacturing, but did not report any the proliferation of osteoblasts and the uptake of fluor- associations [32]. A very large case–control study in ide in the bone during periods of growth [77]. This leads Northern England of 565 sarcoma cases and 29,520 to the plausible theory that fluoridated water exposure controls, reported that parental occupations that to individuals during times of growth could be asso- involved exposure to electromagnetic fields and non- ciated with osteosarcomas. The topic has not been ex- ionizing radiation were associated with increased risk in tensively studied and conflicting results exist. Moss et al. chondrosarcomas, a malignant bone tumor subtype (1995) reported no significant association in a study of (adjusted OR = 8.7, 95% CI 1.55, 49.4) [17]. This par- 167 cases and 989 controls [78]. Bassin et al. (2006) ticular bone tumor subtype is relatively rare and has reported from a study of 139 cases and 280 controls that not been extensively studied. Caution must be taken in a greater risk of osteosarcoma occurrence was seen only drawing conclusions based on this single study, until in males [77]. Bassin et al. (2006) limited their analysis similar results are replicated elsewhere. In addition, the to include only those cases under 20 years of age, while potential mechanism(s) responsible for such an associ- Moss et al. (1995) included cases of all ages, which likely ation is unclear, but researchers believe low doses of explains the conflicting results. non-ionizing radiation may result in pre-conceptional Radium at relatively high doses is known to cause malig- carcinogenic effects. nant bone tumors, but risk assessment of radium at lower doses, appears also to be conflicting and infrequently stud- Radiation (Adult & pediatric sarcomas) ied [79]. An ecologic study conducted in Wisconsin, High doses of radiation are known to strongly increase which classified radium exposure in drinking water by the risk of both soft tissue sarcomas and malignant bone average levels observed in each zip code, found no associ- tumors [31]. This association is primarily reflected by ation between osteosarcoma risk and corresponding zip Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 12 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 codes that reportedly had higher radium concentrations in prevalence of male smokers enrolled as controls was the water compared to other surrounding areas [80]. A higher than expected for the study area (86%). population-based case–control study, which included 238 We also retrieved a few studies on the potential risks cases and 438 controls, also explored the relationship be- that parental smoking and recreational drug use might tween radium in drinking water and bone tumor risk. confer on sarcoma development in children. One study They reported a moderate increased risk of osteosarcomas found that the risk of Ewing’s sarcoma rose with the in individuals that had higher radium levels in their water number of cigarettes the mother smoked during preg- at birth place. (adjusted OR = 1.77, 95% CI 1.03, 3.00) [79]. nancy [40]. However, this association was only seen when siblings were used as controls, rather than regional Other environmental risk (Adult sarcomas) controls, which as previously mentioned, could reflect Industrial waste incinerators are known to release high selective recall bias by the parent for the case child. An emissions of dioxins. Dioxins have been classified as car- additional paper, which assessed both maternal and pa- cinogens, but little is known about the potential risks ternal smoking habits did not find any significant asso- lower doses of dioxin exposure may have on a popula- ciated risks [33]. One particular case–control study, of tion [81]. Two studies examined the relationship be- 322 cases and 322 controls, found that parents’ use of tween low dose dioxin exposure from incinerators and marijuana and cocaine during the year prior to their soft tissue sarcoma risk. Comba et al. (2003) reported an child’s birth may increase the risk of developing rhabdo- elevated risk of soft tissue sarcomas for those whose myosarcoma by 2 to 5 fold [86]. Similar to the other residence was within 2 km of the incinerator (OR 31.4, findings described thus far, further studies must be 95% CI 5.6, 176.1) [81]. However, caution must be taken implemented to draw a consensus on such results. with the interpretation of this result since it was based on only 5 exposed cases. Viel et. al (2003) reported the identification of a significant cluster of soft tissue sar- Discussion coma cases, that were closest in proximity to the incin- The studies included in this review have analyzed various erator out of all the geographic regions included in the potential risk factors for sarcoma development (Table 3). analysis [82]. This conclusion was based on spatial scan The majority of the assessed exposures lacked enough statistic techniques, which successfully identified an ex- evidence needed to draw strong conclusions, because cess of 14 observed cases that lived near the incinerator these exposures have not been adequately studied. More plant. frequently studied exposures, which were found to be significantly associated with sarcoma occurrence in the Tobacco, alcohol, and drug use (Adult & pediatric majority of circumstances, suffered from the occasional sarcomas) inconsistent result. In these circumstances, we could A few studies assessed the risks tobacco, alcohol, and conclude that suggestive evidence of an association other drugs may have on the development of sarcomas. existed. If an exposure had been studied extensively and Acase–control study in Kansas, based on 228 cases and the results from these studies were overwhelmingly con- 1,610 controls, found a greater risk of soft tissue sarco- sistent then we classified these exposures as being mas among those that chewed tobacco (adjusted OR = strongly associated with sarcomas. HIV-positive indivi- 1.8, 95% CI 1.1, 2.9) [83]. However, an additional study duals are clearly at an increased risk for Kaposi’s sar- of 93 cases and 721 controls, which also examined the coma, even though it has been recently discovered that relationship between soft tissue sarcomas and tobacco HHV8 is the particular virus known to be central in the and alcohol, did not find a significant association be- causal pathway. Furthermore, radiation exposure by tween these factors [84]. In addition, a case–control means of radiotherapy has been shown to be strongly study consisting of 141 cases and 192 controls, found associated with secondary sarcoma development. This that Kaposi’s sarcoma risk decreased among those that evidence has been replicated several times in several dif- smoked cigarettes [85]. In fact, a dose–response relation- ferent studies as previously discussed and has been ship was observed, where as the consumption of cigar- demonstrated to be quite consistent [31,35,49,72–75]. ettes smoked per day increased, the risk of developing The risk of radiation exposure and sarcoma also explains Kaposi’s sarcoma continually decreased (p for trend the increase in risk for secondary cancers among those <0.001). Further study result replication would be who had been diagnosed with childhood cancer. Such needed in drawing strong conclusions on this potential evidence suggests precaution must be taken with radiation inverse relationship. However, the investigators did men- exposure during cancer treatment and effective early can- tion that this identified relationship could have been cer surveillance strategies must be implemented for early influenced through participation bias. An unbiased con- detection of radiation-induced secondary malignancies. trol sample was pursued, but it was reported that the Other effective treatment options must continually be Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 13 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Table 3 Summary of findings Strong evidence Cancer Suggestive evidence Cancer No evidence of Cancer Too little evidence to Cancer of association of association association draw conclusions HIV/HHV8 Infections KS Hernias (P) ES Menstrual and STS Birth weight (P) [41,50,60] STS, MBT (A)[14,15,29,30,33,34] [38,53,62,64] reproductive factors (A) [56] Radiotherapy STS, Adolescence growth OS DDT, asbestos, wood STS, Birth order (P) [37,57]RS (secondary sarcomas) MBT & pubertal factors (P) dust (A) [18,45,58] MBT (AP)[6,7,9,20,21,32,46,59] [24,28,50,55,63,71] Occupation: job STS, Flouride in drinking OS Maternal age (P) STS, RS type/industry MBT water (AP) [17,36] [37,40,51,57] (A) [16,19,23] Herbicides & STS Pregnancy medications STS, ES, RS chlorophenols (P) [39,53,60] (A) [8,48,58] Place of residence, STS Pregnancy conditions STS industrial emissions (P) [39,53,60] (A) [49,72] History of infection: chicken STS pox & mumps (A) [34] Parental occupation (P) MBT [5,10,12,53] Radium in drinking OS water (AP) [31,35] Ionizing radiation -low dose MBT (A) [32] Tobacco, alcohol, & drug use STS, RS, (AP) [51,53,73–76] KS, ES STS = Soft tissue sarcoma, MBT = Malignant bone tumor, KS = Kaposi's sarcoma, OS = Osteosarcoma, ES = Ewing's sarcoma, CS = Chondrosarcoma, RS = Rhabdomyosarcoma. (A) = Adult sarcomas, (P) = Pediatric sarcomas, (AP) = Adult & Pediatric sarcomas. investigated to further reduce the risk of sarcomas as sec- relatively weak to base the foundation of this conclusion ondary tumors. on only an ecologic study with 110 cases and a case–con- Occupational factors such as job type, industry, and trol study of 37 cases. Maternal and paternal characteris- exposures to chemicals such as herbicides and chloro- tics such as occupation, age, smoking status, and health phenols have all been found to be suggestive risks for conditions experienced during pregnancy are other factors sarcomas. However, no clear consensus exists about the that would also be important for future research to assess. accuracy of these risk factors for sarcoma development, The very limited findings available on these risk factors because a good number of completed studies have appear to show significant relationships with sarcoma risk, yielded inconsistent results. Improved study designs with but these results now require further validation on larger increases in sample size would more clearly define the populations. Again, it is difficult to draw any conclusions evidence of these associations. Furthermore, bone devel- based on minimally studied and very few replicated sig- opment during pubertal growth spurts and history of nificant findings. hernias have also all been found to be associated with The available literature and research on sarcoma risk sarcoma development. In fact, the majority of studies has shown that these rare diseases are difficult to have consistently found statistically significant associa- study. The challenge of studying a rare outcome is tions to exist. These two factors will likely soon become that it often requires the assessment of rare exposures. accepted as strongly associated risk factors for sarcoma Implementing studies with these characteristics often development once a few additional studies are able to results in the creation of null or conflicting results. replicate current findings. For example, the relationship between occupational Ultimately, drawing strong conclusions can be difficult factors and the risk of sarcoma development appears to make because many of results from these studies to be one of the more common and frequently studied have not been adequately replicated. For example, only topics [5–10,12,20,21,32,36,45,46,48,59]. However, even two studies were retrieved that assessed the potential im- with the plethora of papers published on this particular pact dioxin releasing-industrial incinerators may have on subject matter, clear conclusions can be difficult to draw. soft tissue sarcoma development [81,82]. However, it is Many of the occupational exposure studies lacked the Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 14 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 statistical power and adequate sample sizes needed in References 1. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer. order to create strong conclusions, thus again, we only cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs Research Data, can conclude that the identified associations are suggest- Nov 2010 Sub (1973–2008) <Katrina/Rita Population Adjustment> − Linked ive. Furthermore, many of these studies were required to To County Attributes - Total U.S., 1969–2009 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, group sarcoma subtypes together in order to gain enough released April 2011, based on the November 2010 submission. statistical power to fully implement their study, which 2. 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The authors declare that they have no competing interests. 13. Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D: The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated Authors’ contributions herpesvirus): distribution of infection in KS risk groups and evidence for ZB conducted the systematic review and drafted the manuscript. MH sexual transmission. Nat Med 1996, 2(8):918–924. participated in the systematic review and contributed to drafting of the 14. Valery PC, McWhirter W, Sleigh A, Williams G, Bain C: A national manuscript. LS & JS conceived the study and participated in the systematic case–control study of Ewing's sarcoma family of tumours in Australia. review and contributed to the drafting of the manuscript. All authors read Int J Cancer 2003, 105(6):825–830. and approved the final manuscript. 15. Valery PC, Holly EA, Sleigh AC, Williams G, Kreiger N, Bain C: Hernias and Ewing's sarcoma family of tumours: a pooled analysis and meta-analysis. Lancet Oncol 2005, 6(7):485–490. Acknowledgements 16. Longhi A, Pasini A, Cicognani A, Baronio F, Pellacani A, Baldini N, Bacci G: J.D.S. acknowledges the generous support of the Damon Runyon Cancer Height as a risk factor for osteosarcoma. J Pediatr Hematol Oncol 2005, Research Foundation (Clinical Investigator Award) and Alex's Lemonade 27(6):314–318. Stand Foundation (Epidemiology Award). He also acknowledges the 17. Pearce MS, Hammal DM, Dorak MT, McNally RJ, Parker L: Paternal Sarcoma Services at Huntsman Cancer Institute & Primary Children's Medical occupational exposure to electro-magnetic fields as a risk factor for Center, University of Utah. cancer in children and young adults: a case–control study from the North of England. Pediatr Blood Cancer 2007, Author details 49(3):280–286. Department of Family And Preventive Medicine, University of Utah, 2000 18. Buckley JD, Pendergrass TW, Buckley CM, Pritchard DJ, Nesbit ME, Circle of Hope, HCI-4245, Salt Lake City, UT 84112, USA. 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Viel JF, Arveux P, Baverel J, Cahn JY: Soft-tissue sarcoma and • Convenient online submission non-Hodgkin's lymphoma clusters around a municipal solid waste • Thorough peer review incinerator with high dioxin emission levels. Am J Epidemiol 2000, 152(1):13–19. • No space constraints or color figure charges 83. Zahm SH, Blair A, Holmes FF, Boysen CD, Robel RJ, Fraumeni JF Jr: • Immediate publication on acceptance A case–control study of soft-tissue sarcoma. Am J Epidemiol 1989, 130(4):665–674. • Inclusion in PubMed, CAS, Scopus and Google Scholar 84. Serraino D, Franceschi S, Talamini R, Frustaci S, La Vecchia C: • Research which is freely available for redistribution Non-occupational risk factors for adult soft-tissue sarcoma in northern Italy. Cancer Causes Control 1991, 2(3):157–164. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

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Copyright © 2012 by Burningham et al.; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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Abstract

Sarcomas account for over 20% of all pediatric solid malignant cancers and less than 1% of all adult solid malignant cancers. The vast majority of diagnosed sarcomas will be soft tissue sarcomas, while malignant bone tumors make up just over 10% of sarcomas. The risks for sarcoma are not well-understood. We evaluated the existing literature on the epidemiology and etiology of sarcoma. Risks for sarcoma development can be divided into environmental exposures, genetic susceptibility, and an interaction between the two. HIV-positive individuals are at an increased risk for Kaposi’s sarcoma, even though HHV8 is the causative virus. Radiation exposure from radiotherapy has been strongly associated with secondary sarcoma development in certain cancer patients. In fact, the risk of malignant bone tumors increases as the cumulative dose of radiation to the bone increases (p for trend <0.001). A recent meta-analysis reported that children with a history of hernias have a greater risk of developing Ewing’s sarcoma (adjusted OR 3.2, 95% CI 1.9, 5.7). Bone development during pubertal growth spurts has been associated with osteosarcoma development. Occupational factors such as job type, industry, and exposures to chemicals such as herbicides and chlorophenols have been suggested as risk factors for sarcomas. A case-control study found a significant increase in soft tissue sarcoma risk among gardeners (adjusted OR 4.1, 95% CI 1.00, 14.00), but not among those strictly involved in farming. A European-based study reported an increased risk in bone tumors among blacksmiths, toolmakers, or machine-tool operators (adjusted OR 2.14, 95% CI 1.08, 4.26). Maternal and paternal characteristics such as occupation, age, smoking status, and health conditions experienced during pregnancy also have been suggested as sarcoma risk factors and would be important to assess in future studies. The limited studies we identified demonstrate significant relationships with sarcoma risk, but many of these results now require further validation on larger populations. Furthermore, little is known about the biologic mechanisms behind each epidemiologic association assessed in the literature. Future molecular epidemiology studies may increase our understanding of the genetic versus environmental contributions to tumorigenesis in this often deadly cancer in children and adults. Introduction epidemiology and etiology of sarcomas to be feasible, Sarcomas, tumors of putative mesenchymal origin, ac- this review will take a broad perspective, noting differ- count for nearly 21% of all pediatric solid malignant can- ences primarily between the two most common and dis- cers and less than 1% of all adult solid malignant tinct sarcoma groupings, malignant bone tumors and cancers [1]. In addition, sarcomas represent multiple soft tissue sarcomas [2]. malignancies rather than a single cancer [2]. For ex- Soft tissue sarcomas often form in the body’s muscles, ample, more than 50 distinct histologic sarcoma sub- joints, fat, nerves, deep skin tissues, and blood vessels. As types exist. Furthermore, many of these subtypes can the name implies, malignant bone tumors such as osteo- occur at any age and are not restricted to a specific loca- sarcomas and Ewing’s sarcomas are found throughout tion of the body. The rarity of the disease combined with the bones of the body, but also can commonly be found the diverse number of subtypes can make sarcomas very in the cartilage [3]. In 2010, the National Center for difficult to study. In order for the evaluation of the Health Statistics (NCHS) projected that 10,520 and 2,650 Americans, including all ages, will have been diagnosed with soft tissue and malignant bone tumors, respectively * Correspondence: Joshua.Schiffman@hci.utah.edu [4]. Furthermore, it is also projected that 3,920 and 1,460 Division of Pediatric Hematology/Oncology, Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, Americans will die in 2010 from soft tissue and malig- USA nant bone tumors, respectively. Full list of author information is available at the end of the article © 2012 Burningham et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 2 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Sarcomas, although relatively rare, are quite deadly, es- Descriptive epidemiology pecially soft tissue sarcomas. The primary reason for this In SEER data (1973–2008), we observed that soft tis- is due to delayed diagnosis and advanced disease, or me- sue sarcomas currently occur much more frequently tastasis, at presentation [3]. Early stage sarcomas lack than malignant bone tumors [1]. In 2008, soft tissue distinct symptoms that would potentially allow for early sarcomas accounted for nearly 87% of all sarcomas diagnosis. In addition to being a deadly disease, sarco- diagnosed, while the remaining 13% of the diagnoses mas also occur more frequently in young adults and were malignant bone tumors [1]. Osteosarcomas and adolescents compared to other cancers. Thus, despite chondrosarcomas were the most commonly diagnosed lower incidence rates, the years of life lost can often be malignant bone tumors, accounting for over half of all substantial. These facts present adequate evidence that the malignant bone tumor diagnoses. According to strategies to prevent sarcoma occurrence would prove to SEER, “other specified soft tissue sarcomas” accounted be beneficial. However, little scientific knowledge and for roughly 51% of all sarcomas diagnosed in 2008, consensus pertaining to the cause of sarcomas exists. It and clearly lead soft tissue sarcoma occurrence. is evident that further epidemiological research is war- Fibrosarcomas and Kaposi sarcomas were the two dis- ranted in order to more clearly define environmental tinct and individual soft tissue subtypes identified, and risk factors. The purpose of this review is to perform a predominantly diagnosed in 2008, accounting for thorough evaluation of the existing literature on the epi- roughly 7% and 9% of all sarcoma diagnoses respect- demiology and etiology of sarcomas. Thus, conclusions ively (Figure 1) [1]. will be made on the risk factors that are established, Age is an important determinant of sarcoma occur- which will be of benefit on drawing conclusions on ap- rence. Based on current statistics provided by the propriate preventative guidelines. NCHS and SEER, from 2004–2008, the mean age at diagnosis for soft tissue sarcomas and malignant bone tumors was 58 and 40 years of age, respectively [4]. Methods From 2003–2007, the mean age at death for soft tissue In order to identify the potential environmental risk fac- sarcomas and malignant bone tumors was 65 and tors for sarcomas, we reviewed all published articles 58 years of age, respectively. For further details on the that pertained to the epidemiology of sarcomas. In distribution of ages at time of diagnosis and death, addition, background information on the descriptive please refer to Figures 2 and 3. Generally, an increase epidemiology and basic genetics of sarcomas was also in the rate of soft tissue sarcomas occurs in new born obtained. For the environmental risk factor assessment, babies and young children, until they reach the age of we performed a literature search using the PubMed 5 [1]. Young adults experience the lowest incidence of database. Search terms included key words and phrases, soft tissue sarcomas, but occurrence steadily increases such as “epidemiology,”“risk factors,” and “case–control.” until the age of 50. At ages greater 50 years and In addition, common sarcoma subtype names of both above, incidence of soft tissue sarcomas increases malignant bone tumors and soft tissue sarcomas were much more dramatically. Malignant bone tumors, gen- also used in combination with our search terms in order erally have a fairly stable rate of incidence across all to yield the most relevant articles. The PubMed “all ages. However, noticeable increase in rates often occur related articles” feature was also used in our search for in adolescents and young adults due to osteosarcoma published papers that were related to our topic of inter- and Ewing’s sarcoma. Moderate increases in bone est, which may have not been listed, based on our tumor incidence also tend to occur in people in their search terms. 70s and 80s (Figure 4) [1]. Due to the sparsity of literature on sarcomas, a strict inclusion criterion was not vigorously followed. However, Race & geography the selected papers used must have followed an epide- Ewing’s sarcoma is a relatively rare bone tumor with lim- miologic study design. Thus, case reports were excluded. ited epidemiologic data; however one of the few well- All published papers used in this review were also described risk factors for this specific type of cancer is required to have been published after 1980, in order to race. It is known that whites are predominantly affected minimize inaccurate diagnoses conflicts. A total of 29 by Ewing’s sarcomas, whereas incidence rates in Asian adult studies and 22 pediatric studies were gathered, and African populations are often considerably less [66]. reviewed, and included in the environmental risk review This difference in incidence by race, suggests a genetic (Tables 1 and 2). The majority of the conducted research component to Ewing’s sarcoma, which has led research- were case–control studies, but some cohort, ecologic, ers to believe that that these racial differences are bio- and case-series studies (>250 cases) were also found and logically true. Jawad et al. (2009), found a 9-fold included. significant difference in Ewing’s sarcoma rates between Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 3 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Table 1 Adult sarcoma study descriptions Location & time Author N Cases N Controls/Cohort Risk cactors examined Cohort Studies UK & Le vu et al. (1998), OS 32, STS 25 4,400, 4,400 Radiotherapy France 1942–1986 [5,6] Menu-Branthomme et al. (2004) Finland 1953–2000 [7] Virtanen et al. (2006) STS & MBT 147 295,712 Radiotherapy France 1954–1983 [8] Rubino et al. (2005) STS & MBT 14 6,597 Radiotherapy Japan 1958–2001 [9] Samartzis et al. (2011) MBT 19 120,321 Ionizing radiation- atomic bomb USA 1973–1995 [10] Hwang et al. (2003) STS 135 194,798 Radiotherapy Amsterdam 1984–1996 [11] Renwick et al. (1998) KS 99 3,443 HHV8 infection Nested Case–control Hawkins et al. (1996) MBT 59 220 Radiotherapy UK 1940–1983 [12] International-multiple Kogevinas et al. (1995) STS 11 55 Phenoxy herbicides, chlorophenols, locations ?-1991 [13] dioxins Case–control England & Balarajan et al. (1984) STS 1,961 1,961 Agriculture and forestry occupations Wales 1968–1976 [14] Sweden 1975–1982 [15] Wingren et al. (1990) STS 96 650 Job type, chemical agents, and other occupational factors Kansas, USA 1976–1982 [16,17] Hoar et al. (1986), STS 228, STS 133 1610, 948 Agricultural herbicide use, tobacco Zahm et al. (1989) use, medical history, occupation Umea, Sweden 1978–1983 [18] Hardell et al. (1988) STS 54 311 Phenoxyacetic acids, chlorophenols Uppsala, Sweden 1978–1986 [19] Eriksson et al. (1990) STS 237 237 Occupation, occupational exposures, dioxins Wisconsin, USA 1979–1989 [20] Moss et al. (1995) OS 167 989 Fluoridated drinking water Wisconsin, USA 1980–1997 [21] Guse et al. (2002) OS 319 3,198 Radium in drinking water Washington, USA 1981–1984 [22] Woods et al. (1987) STS 128 694 Phenoxy herbicides, chlorophenols, and other occupational exposures Victoria, Australia 1982–1988 [23] Smith et al. (1992) STS 30 60 Phenoxy herbicides and chlorophenols New York & Washington DC, Engels et al. (2003) KS 29 57 Immunologic and virologic factors USA 1982-? [24] Northern Italy 1983–1998 [25] Fioretti et al. (2000) STS 104 505 Menstrual and reproductive factors USA-multiple locations Hoppin et al. (1998), STS 295, 1908, 1908 Chlorophenols and other 1984–1988 [26,27] Hoppin et al. (1999) STS 200 & MBT 51 occupational exposures USA-multiple locations 1984-? [28] Moore et al. (1996) KS 21 42 Kaposi's sarcoma-associated herpesvirus infection Northeast Italy 1985–1991 [29–31] Franceschi et al. (1992), STS 93, STS 93, 721, 721, 610 Occupational factors, tobacco, Serraino et al. (1992), STS 88 alcohol, drugs, pesticides, and Serraino et al. (1991) history of infection Manua, Italy 1989–1998 [32] Comba et al. (2003) STS 37 171 Residence near industrial waste incinerators Uganda 1994–1998 [33] Ziegler et al. (2003) KS 117 1,282 HHV8 infection Europe-multiple locations Merletti et al. (2006) MBT 96 2,632 Job type and occupational exposures 1995–1997 [34] Sicily, Naples, and Rome Goedert et al. (2002) KS 141 192 Birth order, sexual history, medical 1998–2001 [35] history, and cigarette consumption Ecologic France 1980–1995 [36] Viel et al. (2000) STS 110 N/A Residence near industrial waste incinerators Case-series USA-multiple locations Cope et al. (2000) ES 306 N/A Hernias 1960–1992 [37] Bologna, Italy 1981–2001 [38] Longhi et al. (2005) OS 962 N/A Height, stature, and growth rate STS = Soft tissue sarcoma, MBT = Malignant bone tumor, KS = Kaposi's sarcoma, OS = Osteosarcoma, ES = Ewing's sarcoma, CS = Chondrosarcoma. Caucasians and African Americans, clearly portraying are often found to be higher among American popula- that Caucasians are at greater risk for this particular sar- tions, versus, people living in Asian countries [68]. coma [67]. Racial disparities exist among other sarcoma We further attempted to investigate these racial rela- subtypes as well. For example, rates of chondrosarcomas tionships by assessing sarcoma incidence across several Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 4 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Table 2 Pediatric sarcoma study descriptions Location & time Author N Cases N Controls/Cohort Risk factors examined Pooled USA, UK, Sweden, Spain, Mirabello et al. (2011) OS 1501 1,501,000^ Height at diagnosis, birth weight Italy, Germany 1945–2001 [39] Austrailia and California Valery et al. (2005) ES 138 574 Hernias 1978–1996 [40] USA-multiple locations Spector et al. (2009), MBT 573 & STS 1067, 57966, 57966, Birth weight, birth order, (CA, MN, NY, TX, WA) Von Behren et al. (2010), MBT 550 & STS 1054, 57966, 57966 parental age, gestational age, 1980–2004 [41–44] Ognjanovic et al. (2009), RS 583, MBT 511 & and other birth characateristics Johnson et al (2009) STS 1000 Meta-analysis USA & Canada Valery et al. (2005) ES 357 745 Hernias 1980–2002 [40] Cohort Connecticut, USA Tucker et al. (1987) MBT 64 9,170 Radiotherapy (treatment of 1936–1979 [45] primary childhood cancers) Case–control Ontario, Canada Finkelstein et al. (1996) MBT 238 432 Radium in drinking water 1964–1988 [46] North Carolina, United States Grufferman et al. (1982) RS 33 99 Parental smoking habits, maternal 1967–1976 [47] age, maternal antibiotic use, and vaccination history Northern England 1968–2000 [48] Pearce et al. (2007) MBT 245 & 29,520 Paternal occupational exposure to STS 320 electro-magnetic fields USA-multiple locations 1972-? [47] Winn et al. (1992) ES 208 395 Parental smoking habits, hernias, and parental occupational factors USA 1972–1997 [49] Grufferman et al. (1993) RS 322 322 Parental cocaine and marijuana use Los Angeles, USA 1972–1981 [50] Operskalski et al. (1987) OS 64 124 Birth length, gestational age and height at diagnosis New York State, USA Gelberg et al. (1997) OS 130 130 Birth weight, birth height, and 1978–1988 [51] pubertal growth factors United Kingdom 1980–1983 [52,53] Hartley et al. (1988), MBT 30 & STS 43, 146, 146 Birth weight, pregnancy conditions, Hartley et al. (1988) MBT 30 & STS 43 antibiotic use after birth Ontario, Canada 1980–1988 [54] Hum et al. (1998) MBT 152 713 Parental occupations USA & Canada 1983–1987 [55] Buckley et al. (1998) OS 152 & ES 153 305 Birth weight, birth height, and pubertal growth factors United Kingdom 1991–1996 [56] Smith et al. (2009) MBT & STS 251 6,337 Birth weight and gender Austrailia 1991–1996 [57,58] Valery et al. (2003), ES 106, ES 106 344, 344 Parental occupation, hernias, Valery et al. (2002) and pubertal growth factors USA-multIple locations Bassin et al. (2006) 139 280 Fluoride levels in drinking water 1992–1995 [59] Germany 1992–1997 [60,61] Schuz et al. (2007), MBT 97 & STS 137, 2057, 2588 Birth weight, family size, maternal age, Shuz et al. (1999) MBT 97 & STS 137 gestational age, paternal smoking, birth weight for gestational age, and other birth characateristics USA-multiple locations Troisi et al. (2006) OS 158 141 Birth weight, birth length, birth order, 1994–2000 [62] height and weight at diagnosis, and other pubertal growth factors Case-series USA-multiple Pendergrass et al. ES 291 N/A Adolescence stature: height locations 1972–1978 [63] (1984) and weight United Kingdom 1978–1997 [64] Cotterill et al. (2004) MBT 720 N/A Adolescent height, stature, and growth factors STS = Soft tissue sarcoma, MBT = Malignant bone tumor, KS = Kaposi's sarcoma, OS = Osteosarcoma, ES = Ewing's sarcoma, CS = Chondrosarcoma, RS = Rhabdomyosarcoma. ^2000 U.S. National Center for Health Statistics Simulated Controls. a b c Already referenced studies included in pooled/meta analyses: [41,62,64] [57] [54,65]. geographical regions. Cancer Incidence in Five Conti- incidence rates for both males and females did not ap- nents, Volume IX, published by the International Agency pear to drastically differ between Asian countries and for Research on Cancer (IARC), provides an in-depth the United States as some investigators have reported look at sarcoma incidence by continent, country, and [68]. Overall, it appears that sarcoma incidence rates are small region [69]. Age-Standardized osteosarcoma comparable throughout much of the world. However, Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 5 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 All Sarcomas Malignant bone tumors Soft tissue sarcomas Figure 1 Distribution of new sarcoma cases by histology (2008). there are some instances where notable differences exist. Osteosarcoma incidence rates of similar magnitude were Japanese males living in the state of California, have a not observed throughout Japan. However, a high inci- reported osteosarcoma incidence rate of 1.3 per 100,000 dence of 1.1 cases per 100,000 was reported among Japa- males [69]. This rate is relatively high in comparison to nese males living in Hawaii [69]. These findings may incidence rates observed through much of the world. suggest that Japanese migrants living in “westernized” Typically, osteosarcoma incidence rates range from 0.2- regions may be subject to increase osteosarcoma risk 0.6 per 100,000 males, depending on geographic region. due to environmental or lifestyle factors. A relatively Figure 2 Distribution of ages at diagnosis, 2004-2008. Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 6 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Figure 3 Distribution of ages at death, 2003-2007. high osteosarcoma incidence rate of 1.4 per 100,000 Genetics females was also reported in Sondrio, Italy. The Several different inherited genetic syndromes increase remaining geographic regions of Italy reported signifi- the risk for subsequent sarcoma development. Some of cantly lower osteosarcoma incidence rates among the most well-known syndromes are neurofibromatosis females, ranging from 0.1-0.4 per 100,000. These geo- (NF1), also known as von Recklinghausen’s disease, Li- graphical differences in sarcoma incidence clearly war- Fraumeni syndrome (LFS), and Retinoblastoma (Rb) [2]. rant the need for further investigation, which goes Individuals diagnosed with NF1 have a 10% cumulative beyond the scope of this review. These findings reflect lifetime risk of developing malignant peripheral nerve that both genetic and environmental factors likely con- sheath tumors (MPNST) [70]. NF1 results from an auto- tribute to the etiology of sarcomas. somal dominant process that leads to improper function The literature available on racial differences in regards of the NF1 gene, which is responsible for producing to soft tissue sarcomas appeared to be lacking and Neurofibromin. Neurofibromin ultimately functions as a required us to further analyze the SEER database for ra- tumor suppressor gene through guanosine triphospha- cial disparities. We generated soft tissue sarcoma inci- tase (GTPase) activity from the proto-oncogene, Ras. dence rates, which included years 1973–2008, and found Thus, loss of function of the NF1 gene, leads to that Blacks had the highest overall incidence rate of 5.1 increased Ras activity, promoting tumor development. per 100,000 (the opposite of Ewing’s sarcoma, a bone Li-Fraumeni syndrome (LFS) was one of the first can- tumor sarcoma) [1]. Whites’ had an incidence rate of 4.5 cer genetic syndromes discovered to have a strong asso- per 100,000, followed by American Indian/Asian Pacific ciation with sarcomas [25]. In fact, LFS was initially Islanders, with a rate of 2.8 per 100,000. This is evidence clinically defined as having “a proband who had a sar- to show that race also influences disease occurrence coma diagnosed before 45 years of age and a first-degree among those with soft tissue sarcomas. Further investi- relative who had any cancer under 45 years of age and a gation of the biologic and genetic differences in sarcoma first- or second-degree relative who had any cancer tumors by race is needed in order to gain greater under- under 45 years of age or a sarcoma at any age [47]." standing of the potential mechanisms responsible for Newer definitions for LFS are based on the “Chompret these mentioned racial differences. Criteria” which define the diagnosis as: “Proband with Figure 4 Incidence of malignant bone tumors vs. soft tissue sarcomas by age (2004-2008). Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 7 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 LFS tumor (eg., soft tissue sarcoma, osteosarcoma, brain syndrome of Diamond-Blackfan Anemia (RPS19, RPL5, tumor, premenopausal breast cancer, adrenocortical car- RPL11, RPL35A, RPS24, RPS17, RPS7, RPS10, and RPS26 cinoma, leukemia, lung brochoalveolar cancer) before mutations) which has been associated with rare cases of age 46 years AND at least one first- or second-degree re- osteosarcoma. lation with LFS tumor before age 56 years or with mul- Ewing’s Sarcoma, on the other hand, is currently not tiple tumors; OR proband with multiple tumors (except associated with any known gene mutations or hereditary breast), two of which belong to LFS tumor spectrum cancer syndromes [44]. Nevertheless, the associations and first of which occurred before age 46 years; OR pa- described below with race and familial hernia risk sug- tient with adrenocortical carcinoma or choroid plexus gests a yet undefined genetic association. A recent publi- tumor” [65]. The syndrome results from germline cation has reported that common variants near TARDBP (constitutional) mutations in the tumor suppressor and EGR2 are associated with susceptibility to Ewing’s gene, TP53 [52]. The TP53 tumor suppressor gene is sarcoma [61]. As research continues into the etiology of responsible for inhibiting cell growth and stimulating Ewing’s sarcoma, it can be expected that more genetic cell apoptosis, as well as DNA repair [2]. Thus, muta- risk factors will be identified. tions in TP53 can lead to the early development of sarcomas and other tumors through the acquisition of Etiologic studies genomic instability. In fact, children with the soft tis- Investigations of the potential risk factors for sarcoma sue sarcoma rhabdomyosarcoma presenting at less occurrence commonly share similar study characteris- than 3 years of age appear to have an increased likeli- tics. Even though many different sarcoma subtypes exist, hood of harboring TP53 germline mutations [39,56]. they are commonly grouped together and studied as a It is also important to note that roughly 30-60% of single outcome because of the rarity of sarcoma occur- non-LFS soft tissue sarcomas will have somatic muta- rence. However, studies will commonly separate adult tions of the TP53 gene [53]. and pediatric cases, due to the potential for differences Retinoblastoma (Rb), hereditary or non-hereditary, is a in their etiologic properties. Furthermore, case–control relatively rare tumor that develops in the retinal cell studies are the standard approach for assessing many of found in the eye. Hereditary Rb survivors have a greater the environmental risk factors largely due to the rarity of risk of developing secondary malignancies, in particular sarcomas. This study design, commonly used as the osteosarcoma [60]. It was recognized early on that radi- method for investigating rare outcomes, can discourage ation treatment further increased the risk for secondary investigators and reviewers from making strong conclu- malignancies among Rb survivors. When possible, radi- sions. Case–control studies are simply prone to more ation is now avoided in Rb treatment strategies. However, bias than prospective studies and this has been evident patients with hereditary Rb are still at increased risk for while reviewing the literature. The majority of sarcoma- other tumors even without radiation exposure (including related case–control studies are relatively small and bone and soft tissue sarcomas, brain tumors, nasal cavity cover a wide-range of exposures and carcinogenic fac- cancer, melanoma, lung, gastrointestinal, and bladder tors. The following report contains a comprehensive re- cancer) and this risk increases as Rb patients continue to view of the major environmental risk factors that have age [41,50]. Rb develops by means of germline mutations been investigated. that lead to inactivation of an allele in the tumor sup- pressor gene, RB1. It has been estimated that Rb survi- vors have a 500-fold increase incidence of osteosarcomas as compared to the general population [42]. Female Hormones and Reproductive Factors (Adult Osteosarcomas, in particular, seem to be associated Sarcomas) with hereditary cancer syndromes [43]. Other familial Very few studies have assessed the potential role of fe- predisposition syndromes associated with osteosarcoma male hormones on sarcoma development. One case– risk include the very rare, autosomal recessive DNA heli- control study in Northern Italy investigated the potential case syndromes including: Rothmund Thomson II (REQ4 association across a wide array of female hormone mutations), RAPADILINO Syndrome (RA: RAdial apla- related factors [37]. There were 104 soft tissue sarcoma sia or hypoplasia, PA: PAtellae aplasia or hypoplasia and cases and 505 controls available for analysis, but no sig- cleft or high arched PAlate, DI: DIarrhea and DIslocated nificant associations were reported based on menstrual joints, LI: LIttle size and LImb malformations, NO: long, cycle patterns, age at menopause, parity, and number of slender NOse and NOrmal intelligence, REQ4 muta- abortions. The only suggestive association was for tions), Werner (WRN mutations), and Bloom Syndrome women who had become pregnant with their first child (BLM mutations). In addition, inherited defects in ribo- at later ages (>29 years of age) (adjusted OR = 3.16, 95% somal proteins lead to the autosomomal dominant CI 0.96, 10.44). Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 8 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Prenatal characteristics (Pediatric sarcomas) 1.79) [38]. The biological mechanisms that define the re- Three studies assessed the relationship between specific lationship between birth weight and childhood sarcomas prenatal characteristics and sarcoma occurrence [40,51,57]. are not clear [64]. Birth weight has also been assessed to Winn et al. (1992) reported in a case–control study of be possibly associated with the risk of soft tissue sarco- 208 cases and 395 sibling/regional controls, that women mas and other non-osteosarcoma bone tumors. How- who gave birth to children that later developed Ewing’s ever, no major statistically significant results were sarcoma were more likely to have used medications for observed among these studies [55,62–64]. nausea and vomiting during their pregnancy (adjusted Gestational age has also been investigated as a poten- OR = 2.6, 95% CI 1.2, 5.9) [40]. However, this result was tial factor that may be associated with an increased risk only found to be significant where siblings acted as study of pediatric sarcomas. A case–control study made up of controls. Such an association was not seen where re- 64 cases and 124 controls reported that osteosarcoma gional controls were used. Thus, this result could reflect risk increased among those born a week early (OR = 2.8, selective recall bias by the parent for the case child. 95% CI 1.1-6.8) [24]. A published reported based on a Grufferman et al. (1982) conducted a case–control study large pooled analysis of 573 malignant bone cases and in North Carolina, comprised of 33 cases and 99 con- 57,966 controls, also found an increased risk of Ewing’s trols, and reported that mothers who had used antibiotics sarcoma among those cases that had a recorded gesta- during or closely preceding pregnancy (adjusted RR =2.7, tional age of 32–36 weeks, versus those classified as 95% CI 1.1, 6.4), or had experienced an overdue or being born after 36 weeks of gestation (adjusted assisted delivery (adjusted RR = 2.6, 95% CI 1.1, 7.1) were OR =1.68, 95% CI 1.03-2.76) [63]. This pooled analysis at increased risk of giving birth to a child that would later linked birth and cancer registry data across five U.S. develop the soft tissue sarcoma known as rhabdomyosar- states, which allowed for the large sample size. Further- coma [57]. Interestingly enough, a study based in the more, a recent case–control study in Germany with 97 United Kingdom, comprised of 73 cases (43 soft tissue/ malignant bone cases and 137 soft tissue sarcoma cases 30 malignant bone) and 146 controls reportedly found found no significant increase in sarcoma risk among that soft tissue sarcoma occurrence in children has also those classified as small-for-gestational age, nor those been associated with antibiotic use in children closely classified as being large-for-gestational age [55]. after birth (adjusted RR = 6.81, 95% CI 1.13, 71.18) [51]. Birth order and maternal age have also been investi- This study also examined the pregnancy condition gated as risk factors for sarcoma. The previously men- known as toxemia and found that it increased the risk of tioned multi-U.S. pooled analysis with 57,966 controls, soft tissue sarcomas (adjusted RR = 2.71, 95% CI 1.05, included 583 rhabdomyosarcoma cases. A decreased risk 7.06). However, it is important to note that criteria for in rhabdomyosarcoma was reported, among third born the toxemia case mothers was based on recorded preg- children, where the firstborn child was classified as the nancy symptoms such as hypertension, edema, and albu- comparison group (adjusted OR = 0.70, 95% CI 0.54, minuria, rather than an actual record of having been 0.91) [28,71]. The same pooled analysis reported that the diagnosed with toxemia. risk of rhabdomyosarcoma increases among cases with mothers advancing in age (per 1-year increase, adjusted Birth characteristics (Pediatric sarcomas) OR =1.03, 95% CI 1.01, 1.04) (per 5-year increase, Many studies have assessed the potential relationship be- adjusted OR = 1.19, 95% CI 1.05, 1.34) [11,28]. Another tween pediatric cancer risk and many different birth fac- study including 137 soft tissue sarcoma cases and 2,588 tors. A recent study including 251 pediatric sarcoma controls reported an actual decrease in risk among cases cases and 6,337 controls investigated birth weight as a with older mothers (>35 years) (OR = 0.4, 95% CI 0.1, risk factor for pediatric sarcomas but no significant asso- 1.0) [33]. In addition, a significant increase in risk was observed for cases who had young mothers. (<20 years) ciation was observed [64]. The previously mentioned case–control study in the United Kingdom with 73 cases (OR = 2.2, 95% CI 1.0, 4.7). All soft tissue sarcomas were and 146 controls reported some evidence suggesting that also grouped together in this analysis which ultimately may not share common etiologic properties, thus leading a potential relationship might exist between Ewing’s sar- coma and birth weight [51]. They reported that Ewing’s to invalid conclusions. Studies have also observed in- sarcoma cases had a median weight of 3,015 g compared creasing linear trends of sarcoma risk, based on incre- mental increases in paternal age [11,28]. to the controls which had a median weight of 3,400 g (p = 0.02). A pooled analysis included 434 osteosarcoma Inguinal and umbilical hernias are a commonly studied cases and 1,000 controls studies, reported a significant birth anomaly that has been found to be associated with Ewing’s sarcoma [14,15,29,40]. The previously men- association between osteosarcoma risk and high birth weight (> = 4,046 g), compared to an average birth tioned case–control study conducted by Winn et al. weight (2,665-4,045 g) (adjusted OR = 1.35, 95% CI 1.01, (1992) reported that umbilical and inguinal hernias, Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 9 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 occurring early in life, are diagnosed six times more fre- factors in early adolescence with the risk of Ewing’s sar- quently in Ewing’s sarcoma cases than controls [40]. A coma. However, neither height nor weight was found to recent meta-analysis of 357 cases and 745 controls, be associated with Ewing’s sarcoma [23,34]. No studies which included the study by Winn et al. (1992) [40] and were found in our search that assessed the relationship two additional case–control studies, also reported that between growth and development in early adolescence children with a history of hernias have a greater risk of and soft tissue sarcomas. developing Ewing’s sarcoma (adjusted OR 3.2, 95% CI 1.9, 5.7) [15]. Cope et al. (2000) reported in a case-series Infection (Adult sarcomas) study of 324 cases, a significantly higher relative risk of It has long been known that people living with AIDS are inguinal hernias among Ewing’s sarcoma cases compared at very high risk for developing a soft tissue sarcoma to population estimates (females, RR = 13.3, 95% CI 3.6, known as Kaposi’s sarcoma. In fact, people with AIDS 34.1) (males, RR = 6.67, 95% CI 2.67, 13.7) [15]. Authors’ have a 100,000 fold greater risk of developing Kaposi’s hypothesized that these findings suggest a disruption in sarcoma [19]. However, AIDS does not cause Kaposi’s normal embryological development, which perhaps may sarcoma nor is it required to be HIV-positive in order to relate to an in utero exposure or indicate an underlying develop Kaposi’s sarcoma [13]. In recent years, studies genetic disorder. have attempted to narrow the causal pathway for Kaposi sarcoma, which has successfully led researchers to the Growth and development in early adolescence (Pediatric identification of the virus primarily responsible for sarcomas) Kaposi’s sarcoma [13,26,27,54]. Evidence has shown that Several studies have concluded that having a tall stature the human herpes virus 8 (HHV8), a sexually transmit- or experiencing an earlier pubertal growth spurt may be ted virus, is strongly associated with an increased risk of important factors in the etiology of osteosarcomas Kaposi’s sarcoma in both HIV-positive and HIV-negative [16,22,30,34,38]. Out of the six papers reviewed, three individuals. HHV8 is the greatest predictor of Kaposi’s were case–control studies [22,24,30], two were case- sarcoma development, thus leading researchers to be- series studies [16,34], and one study conducted a pooled lieve that HHV8 plays a central role in the causal path- analysis [38]. Only one paper did not report an associ- way for developing Kaposi’s sarcoma. ation between osteosarcoma and increased growth in The potential association of sarcoma development and early adolescence [24]. This paper was based on a previ- infections other than HHV8 appears to have been rarely ously mentioned case–control study that had assessed studied. However, one study with 93 cases and 721 con- gestational age and osteosarcoma risk. This case–control trols examined the potential risk of other viral infections study compared to the other reviewed studies was rela- on soft tissue sarcoma development [58]. They reported a tively small, with only with 64 cases and 124 controls. greater risk of soft tissue sarcomas among those indivi- Both case-series studies had over 700 cases and the duals who had a history of herpes zoster infection case–control studies had at least double the number of (adjusted OR = 2.3, 95% CI 1.1, 4.9), chicken pox (adjusted osteosarcoma cases to analyze. Thus, the small sample OR = 2.1, 95% CI 1.2, 4.1), and mumps (adjusted OR = 2.0, size may be one reason why the results were not similar 95% CI 1.1, 3.8). Caution must be taken in drawing to the other studies. Individuals with osteosarcoma, are strong conclusions from a single paper and a topic that commonly found to be taller than the general population appears to have been rarely studied. Nevertheless, the near the time of diagnosis [16,30,34,38]. It can be con- association between viruses and sarcoma warrants further cluded that rapid bone development during the pubertal consideration. time window may lead to an increased risk of osteosar- coma [38]. Further investigation is needed in order to Job type, industry, and occupational exposures (Adult understand the physiologic mechanisms that are respon- sarcomas) sible for this relationship. Buckley et al. 1998 found that Occupational factors such as job type and industry have the timing of pubertal development may also be an im- been among the most frequently studied risk factors in portant factor in osteosarcoma risk, especially among sarcoma research. Balarajan et al. (1984) reported that females [18]. Female cases with osteosarcoma tended to farmers, farm managers, and market gardeners have a experience breast development (11.4 vs. 11.8 years, significant increase in risk for developing soft tissue sar- P = 0.03) and menarche (12.1 vs. 12.5 years. P = 0.002) at comas. (adjusted OR 1.7, 95% CI 1.00, 2.88) [48]. How- significantly earlier times in their adolescent lives, com- ever, other studies did not find a significant increased pared to controls. Two studies also reported that females risk among those employed in all agriculture-based posi- are generally diagnosed with osteosarcomas at younger tions [8,45]. For example, one study of 96 cases and 650 ages than males [16,34]. Many of these studies also controls found a significant increase in soft tissue sar- examined the relationship of growth and development coma risk among gardeners (adjusted OR 4.1, 95% CI Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 10 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 1.00, 14.00), but not among those strictly involved in 1.68, 4.61), seamen (SIR 1.92, 95% CI 1.05, 3.22), and farming [8]. Other occupations such as railroad and con- drivers (SIR 1.45, 95% CI 1.09-1.88). Further investiga- struction work were also suggestive of an increase in risk tion will be needed in order to determine if these par- of soft tissue sarcomas, but these relationships have not ticular occupations are associated with ionizing radiation been shown to be statistically significant. The varying and other physical elements that have been shown to in- results among studies could potentially be due to the dif- crease the risk of malignant bone tumors. Elevated soft ferences in epidemiologic methodology. For example, tissue sarcoma SIRs were seen in men, classified as the results Balarajan et al. (1984) reported were based building caretakers (SIR 1.30, 95% CI 1.08, 1.56) and primarily on registry data, relying upon occupational military personnel (SIR 1.27, 95% CI 1.01, 1.59). There coding in order to study these relationships, while the were no reported statistical significant SIRs for women. other two studies, which did not find similar significant Besides job type and industry, several studies have associations, relied upon questionnaires and other simi- assessed the actual exposure to specific chemicals and pes- lar tools for obtaining occupational information. ticides at the occupation by administering detailed ques- The association between malignant bone tumors and tionnaires or through personal interviews. Six case–control occupation has not been studied as often as soft tissue studies assessed the relationship between herbicide and sarcomas. One European based-study, consisting of 96 chlorophenol exposure with soft tissue sarcoma risk, but cases and 2,632 controls, reported an increased risk in did not find significant relationships [6,7,9,10,45]. On the bone tumors (includes osteosarcomas and chondrosar- other hand, two case–control studies conducted in Sweden comas) among those who worked as blacksmiths, tool- and in the U.S., and one international nested case–control makers, or machine-tool operators (adjusted OR 2.14, study, found a strong relationship between these chemical 95% CI 1.08, 4.26) [12]. This study also found that indi- exposures and soft tissue sarcoma [20,46,59]. We believe viduals involved in bricklaying (adjusted OR 2.93, 95% these conflicting findings aredue to themethodological CI 1.55, 5.53) and carpentry, (adjusted OR 4.25, 95% CI limitations such as low statistical power, small sample sizes, 1.71, 10.50) were found to be at increased risk for bone proxy interviews, and the potential for multiple comparison tumor development. In addition, this study also reported issues because of the many occupational categories ana- that cases involved in the manufacturing of wood, cork lyzed. Hoppin et al. (1998) conducted the U.S. based case– products, and straw were found to have a significantly control study, which included 295 sarcoma cases and 1,908 increased risk of malignant bone tumor development controls that overcame many of these mentioned weak- (adjusted OR 3.58, 95% CI 1.70, 7.56). Individuals classi- nesses [46]. They reported a statistically significant relation- fied as manufacturers of machine and equipment, were ship between soft tissue sarcoma risk and ever having high- also found to be at greater risk for bone tumors intensity chlorophenol exposure (adjusted OR = 1.79, 95% (adjusted OR 2.02, 95% CI 1.00, 4.08). Interestingly, the CI 1.10, 2.88). In fact, among highly exposed subjects, risk study participants classified as being in the industry of increased as the duration of the chlorphenol exposure agriculture, growing of crops, and other related fields, increased (p for trend <0.001). Furthermore, complete oc- which might be frequent users of herbicides and pesti- cupational histories, spanning multiple years, were obtained cides, were not found to be related to bone tumor from the actual study participants rather than their proxies, development [12]. which improved the studies ability to successfully analyze The Nordic Occupational Cancer (NOCCA) project duration-response relationships with greater accuracy. In has collected roughly 45 years of cancer incidence data addition, Hoppin et al. (1999) also reported that exposure by occupational category for Denmark, Finland, Iceland, to cutting oils increased the risk of soft tissue sarcomas, but Norway, and Sweden [5]. Standardized incidence ratios not bone tumors. (adjusted OR 1.65, 95% CI 1.04, 2.61) (SIR) were utilized in describing the relationship be- [21]. Malignant bone tumors and occupational exposures tween cancer incidence and occupation. An SIR is used to determine whether the number of observed cases of have not been studied as heavily as the soft tissue sarco- cancer is higher or lower than expected, given the age mas, although among the limited papers published, no significant relationships were identified [12,21]. Other distribution and population under study. This NOCCA reported a statistically significant elevated SIR of malig- occupational exposures such as solvents, wood dust, as- nant bone tumors among men classified as “other health bestos, DDT, and benzene have also been studied, but none were found to be significantly associated with sar- workers.” (SIR 2.25, 95% CI 1.29, 3.66). This may suggest that health-related occupations such as radiologists and coma risk [21,45,59]. health technologists may be at increased risk for bone tumor development due to radiation exposure. Statisti- Parental occupation (Pediatric sarcomas) cally significant elevated SIRs were also reported among Only a few studies have examined the potential risks of men classified as military workers (SIR 2.88, 95% CI parental occupation on the development of cancer in the Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 11 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 offspring. A study in Ontario, Canada, of 152 cases and the increase in the number of secondary sarcoma can- 713 controls, reported that the risk of Ewing’s sarcoma cers diagnosed among individuals that have been treated was significantly elevated among children whose fathers by radiotherapy. Several studies have examined this pat- worked in the social sciences (adjusted OR = 6.2, 95% CI tern and relationship between primary cancers and sec- 1.6, 24.5) [32]. In addition, the same study reported a ondary development of sarcomas and have found greater risk of Ewing’s sarcoma in mothers who were ionizing radiation exposure from radiotherapy to be the teachers (adjusted OR = 3.1, 95% CI 1.1, 8.7). Investiga- key influential factor [31,35,49,72–75]. Virtanen et al. tors found it difficult to hypothesize the possible (2006) reported that radiotherapy appears to be asso- mechanisms behind these relationships, because these ciated with an increased risk of developing sarcomas, particular occupational settings do not appear to expose especially among younger patients under the age of 55 the parents to hazardous substances. According to (SIR =4.2, 95% CI 2.9, 5.8) [75]. Furthermore, Hawkins authors, it may be possible that these findings are being et al. (1996) reported that the risk of malignant bone influenced by socioeconomic status. However, this study tumors also increased as the cumulative dose of radi- was not able to adjust on this potential confounding fac- ation to the bone increased (p for trend <0.001) [49]. Le tor because data was not available on parental education Vu et al. (1998) implemented a case–control study and income. Three other case–control studies also have within a childhood cancer cohort of 4,400 3-year survi- reported that a potential relationship exists between vors of a first solid cancer and also found that the risk of farming and the development of Ewing’s sarcoma in off- a secondary bone tumor (osteosarcoma) to be a linear spring [32,36,40]. The case–control study in Australia of function of the local dose of radiation received [72]. 106 cases and 344 controls reported that fathers who Studies on other potential sources of low dose ionizing worked on a farm at conception or time of pregnancy radiation and sarcoma risk are relatively infrequent. had offspring with a 3.5 fold greater risk of developing However, one recently published study that followed Ewing’s sarcoma, which was statistically significant [36]. atomic bomb survivors from 1958 to 2001 reported that This conclusion was only drawn based on offspring that lower doses of ionizing radiation increased the occur- were diagnosed before the age of 20. These conclusions rence of bone sarcoma diagnoses (RR = 7.5 per Gy, 95% support the general consensus that many of the pesti- CI 1.34, 23.14) [76]. However, this conclusion was based cides and chemicals used in farming are carcinogens and only on the development of 19 cases during the cohort lead to sarcoma development. study period. The previously mentioned case–control study in On- tario, Canada also investigated the osteosarcoma bone Drinking water (Adult & pediatric sarcomas) tumor risk in offspring with fathers who were farmers, Fluoride exposure in drinking water has been studied as mothers involved in managerial and administrative a potential risk factor in the development of osteosar- work, and mothers involved in product fabricating, as- comas. Fluoride is known to act as a mitogen, increasing sembling, and manufacturing, but did not report any the proliferation of osteoblasts and the uptake of fluor- associations [32]. A very large case–control study in ide in the bone during periods of growth [77]. This leads Northern England of 565 sarcoma cases and 29,520 to the plausible theory that fluoridated water exposure controls, reported that parental occupations that to individuals during times of growth could be asso- involved exposure to electromagnetic fields and non- ciated with osteosarcomas. The topic has not been ex- ionizing radiation were associated with increased risk in tensively studied and conflicting results exist. Moss et al. chondrosarcomas, a malignant bone tumor subtype (1995) reported no significant association in a study of (adjusted OR = 8.7, 95% CI 1.55, 49.4) [17]. This par- 167 cases and 989 controls [78]. Bassin et al. (2006) ticular bone tumor subtype is relatively rare and has reported from a study of 139 cases and 280 controls that not been extensively studied. Caution must be taken in a greater risk of osteosarcoma occurrence was seen only drawing conclusions based on this single study, until in males [77]. Bassin et al. (2006) limited their analysis similar results are replicated elsewhere. In addition, the to include only those cases under 20 years of age, while potential mechanism(s) responsible for such an associ- Moss et al. (1995) included cases of all ages, which likely ation is unclear, but researchers believe low doses of explains the conflicting results. non-ionizing radiation may result in pre-conceptional Radium at relatively high doses is known to cause malig- carcinogenic effects. nant bone tumors, but risk assessment of radium at lower doses, appears also to be conflicting and infrequently stud- Radiation (Adult & pediatric sarcomas) ied [79]. An ecologic study conducted in Wisconsin, High doses of radiation are known to strongly increase which classified radium exposure in drinking water by the risk of both soft tissue sarcomas and malignant bone average levels observed in each zip code, found no associ- tumors [31]. This association is primarily reflected by ation between osteosarcoma risk and corresponding zip Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 12 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 codes that reportedly had higher radium concentrations in prevalence of male smokers enrolled as controls was the water compared to other surrounding areas [80]. A higher than expected for the study area (86%). population-based case–control study, which included 238 We also retrieved a few studies on the potential risks cases and 438 controls, also explored the relationship be- that parental smoking and recreational drug use might tween radium in drinking water and bone tumor risk. confer on sarcoma development in children. One study They reported a moderate increased risk of osteosarcomas found that the risk of Ewing’s sarcoma rose with the in individuals that had higher radium levels in their water number of cigarettes the mother smoked during preg- at birth place. (adjusted OR = 1.77, 95% CI 1.03, 3.00) [79]. nancy [40]. However, this association was only seen when siblings were used as controls, rather than regional Other environmental risk (Adult sarcomas) controls, which as previously mentioned, could reflect Industrial waste incinerators are known to release high selective recall bias by the parent for the case child. An emissions of dioxins. Dioxins have been classified as car- additional paper, which assessed both maternal and pa- cinogens, but little is known about the potential risks ternal smoking habits did not find any significant asso- lower doses of dioxin exposure may have on a popula- ciated risks [33]. One particular case–control study, of tion [81]. Two studies examined the relationship be- 322 cases and 322 controls, found that parents’ use of tween low dose dioxin exposure from incinerators and marijuana and cocaine during the year prior to their soft tissue sarcoma risk. Comba et al. (2003) reported an child’s birth may increase the risk of developing rhabdo- elevated risk of soft tissue sarcomas for those whose myosarcoma by 2 to 5 fold [86]. Similar to the other residence was within 2 km of the incinerator (OR 31.4, findings described thus far, further studies must be 95% CI 5.6, 176.1) [81]. However, caution must be taken implemented to draw a consensus on such results. with the interpretation of this result since it was based on only 5 exposed cases. Viel et. al (2003) reported the identification of a significant cluster of soft tissue sar- Discussion coma cases, that were closest in proximity to the incin- The studies included in this review have analyzed various erator out of all the geographic regions included in the potential risk factors for sarcoma development (Table 3). analysis [82]. This conclusion was based on spatial scan The majority of the assessed exposures lacked enough statistic techniques, which successfully identified an ex- evidence needed to draw strong conclusions, because cess of 14 observed cases that lived near the incinerator these exposures have not been adequately studied. More plant. frequently studied exposures, which were found to be significantly associated with sarcoma occurrence in the Tobacco, alcohol, and drug use (Adult & pediatric majority of circumstances, suffered from the occasional sarcomas) inconsistent result. In these circumstances, we could A few studies assessed the risks tobacco, alcohol, and conclude that suggestive evidence of an association other drugs may have on the development of sarcomas. existed. If an exposure had been studied extensively and Acase–control study in Kansas, based on 228 cases and the results from these studies were overwhelmingly con- 1,610 controls, found a greater risk of soft tissue sarco- sistent then we classified these exposures as being mas among those that chewed tobacco (adjusted OR = strongly associated with sarcomas. HIV-positive indivi- 1.8, 95% CI 1.1, 2.9) [83]. However, an additional study duals are clearly at an increased risk for Kaposi’s sar- of 93 cases and 721 controls, which also examined the coma, even though it has been recently discovered that relationship between soft tissue sarcomas and tobacco HHV8 is the particular virus known to be central in the and alcohol, did not find a significant association be- causal pathway. Furthermore, radiation exposure by tween these factors [84]. In addition, a case–control means of radiotherapy has been shown to be strongly study consisting of 141 cases and 192 controls, found associated with secondary sarcoma development. This that Kaposi’s sarcoma risk decreased among those that evidence has been replicated several times in several dif- smoked cigarettes [85]. In fact, a dose–response relation- ferent studies as previously discussed and has been ship was observed, where as the consumption of cigar- demonstrated to be quite consistent [31,35,49,72–75]. ettes smoked per day increased, the risk of developing The risk of radiation exposure and sarcoma also explains Kaposi’s sarcoma continually decreased (p for trend the increase in risk for secondary cancers among those <0.001). Further study result replication would be who had been diagnosed with childhood cancer. Such needed in drawing strong conclusions on this potential evidence suggests precaution must be taken with radiation inverse relationship. However, the investigators did men- exposure during cancer treatment and effective early can- tion that this identified relationship could have been cer surveillance strategies must be implemented for early influenced through participation bias. An unbiased con- detection of radiation-induced secondary malignancies. trol sample was pursued, but it was reported that the Other effective treatment options must continually be Burningham et al. Clinical Sarcoma Research 2012, 2:14 Page 13 of 16 http://www.clinicalsarcomaresearch.com/content/2/1/14 Table 3 Summary of findings Strong evidence Cancer Suggestive evidence Cancer No evidence of Cancer Too little evidence to Cancer of association of association association draw conclusions HIV/HHV8 Infections KS Hernias (P) ES Menstrual and STS Birth weight (P) [41,50,60] STS, MBT (A)[14,15,29,30,33,34] [38,53,62,64] reproductive factors (A) [56] Radiotherapy STS, Adolescence growth OS DDT, asbestos, wood STS, Birth order (P) [37,57]RS (secondary sarcomas) MBT & pubertal factors (P) dust (A) [18,45,58] MBT (AP)[6,7,9,20,21,32,46,59] [24,28,50,55,63,71] Occupation: job STS, Flouride in drinking OS Maternal age (P) STS, RS type/industry MBT water (AP) [17,36] [37,40,51,57] (A) [16,19,23] Herbicides & STS Pregnancy medications STS, ES, RS chlorophenols (P) [39,53,60] (A) [8,48,58] Place of residence, STS Pregnancy conditions STS industrial emissions (P) [39,53,60] (A) [49,72] History of infection: chicken STS pox & mumps (A) [34] Parental occupation (P) MBT [5,10,12,53] Radium in drinking OS water (AP) [31,35] Ionizing radiation -low dose MBT (A) [32] Tobacco, alcohol, & drug use STS, RS, (AP) [51,53,73–76] KS, ES STS = Soft tissue sarcoma, MBT = Malignant bone tumor, KS = Kaposi's sarcoma, OS = Osteosarcoma, ES = Ewing's sarcoma, CS = Chondrosarcoma, RS = Rhabdomyosarcoma. (A) = Adult sarcomas, (P) = Pediatric sarcomas, (AP) = Adult & Pediatric sarcomas. investigated to further reduce the risk of sarcomas as sec- relatively weak to base the foundation of this conclusion ondary tumors. on only an ecologic study with 110 cases and a case–con- Occupational factors such as job type, industry, and trol study of 37 cases. Maternal and paternal characteris- exposures to chemicals such as herbicides and chloro- tics such as occupation, age, smoking status, and health phenols have all been found to be suggestive risks for conditions experienced during pregnancy are other factors sarcomas. However, no clear consensus exists about the that would also be important for future research to assess. accuracy of these risk factors for sarcoma development, The very limited findings available on these risk factors because a good number of completed studies have appear to show significant relationships with sarcoma risk, yielded inconsistent results. Improved study designs with but these results now require further validation on larger increases in sample size would more clearly define the populations. Again, it is difficult to draw any conclusions evidence of these associations. Furthermore, bone devel- based on minimally studied and very few replicated sig- opment during pubertal growth spurts and history of nificant findings. hernias have also all been found to be associated with The available literature and research on sarcoma risk sarcoma development. In fact, the majority of studies has shown that these rare diseases are difficult to have consistently found statistically significant associa- study. The challenge of studying a rare outcome is tions to exist. These two factors will likely soon become that it often requires the assessment of rare exposures. accepted as strongly associated risk factors for sarcoma Implementing studies with these characteristics often development once a few additional studies are able to results in the creation of null or conflicting results. replicate current findings. For example, the relationship between occupational Ultimately, drawing strong conclusions can be difficult factors and the risk of sarcoma development appears to make because many of results from these studies to be one of the more common and frequently studied have not been adequately replicated. For example, only topics [5–10,12,20,21,32,36,45,46,48,59]. However, even two studies were retrieved that assessed the potential im- with the plethora of papers published on this particular pact dioxin releasing-industrial incinerators may have on subject matter, clear conclusions can be difficult to draw. soft tissue sarcoma development [81,82]. 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