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Cancer Epidemiology and Prevention$

David Schottenfeld and Joseph F. Fraumeni

Print publication date: 2006

Print ISBN-13: 9780195149616

Published to Oxford Scholarship Online: September 2009

DOI: 10.1093/acprof:oso/9780195149616.001.0001

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Bone Cancer

Bone Cancer

Chapter:
(p.946) 48 Bone Cancer
Source:
Cancer Epidemiology and Prevention
Author(s):

ROBERT W. MILLER

JOHN D. BOICE

ROCHELLE E. CURTIS

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780195149616.003.0048

Abstract and Keywords

Cancers arising from bone or cartilage account for about 0.5% of all malignant neoplasms in humans. This chapter reviews the epidemiology of bone cancer. Topics covered include demographic patterns, environmental factors, genetic susceptibility, and prevention.

Keywords:   bones, cancer risk, cancer epidemiology, cancer prevention, cartilage

Cancers that arise from bone or cartilage account for about 0.5% of all malignant neoplasms in humans. Great progress has been made recently in understanding the genesis of these cancers, beginning with clues from clinical observations and epidemiology.

DEMOGRAPHY

Descriptive studies in the past have been handicapped because all cell types were combined under “Bone Cancer” in the International Classification of Diseases (ICD). When classified by cell type one can see that they differ epidemiologically, which reflects differences in etiology and pathogenesis. The three main types are osteosarcoma, which arises most often from the growing ends of long bones; chondrosarcoma, which develops in cartilage; and Ewing sarcoma, most commonly in the axial skeleton.

Histologic diagnoses are required, as from population-based cancer registries. of particular value in this regard are data from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (Percy et al., 1995), which has covered about 10% of the US population since 1973. Ninety-seven percent of bone cancers were histologically confirmed. The locations of SEER registries used here are shown in the footnote to Table 48–1.

There were 3634 primary bone cancers among whites and 356 among blacks registered in the SEER Program from 1980 through 2000. Among whites, osteosarcoma was reported in 32%, chondrosarcoma in 30%, and Ewing sarcoma in 16%. Age-adjusted rates by histologic type are presented in Figure 48–1.

Osteosarcoma has a bimodal age-distribution with peaks in adolescence and late in life (Fig. 48–2). Study by single year of age revealed that the rate for males exceeded that for females at 13 years of age as it rose to a peak at 15–19 years (Miller, 1981). In 1958 Price first noted the apparent relationship between bone cancer and the adolescent growth spurt. The peak late in life especially for males (Fig. 48–2) is attributed to Paget disease. There is no peak among Japanese, who rarely develop this disease (Ishikawa et al., 1996).

It has also long been known that giant breeds of dogs have much higher relative risks of osteosarcoma than do small dogs (Priester and Mantel, 1971). The relative risks of bone cancer in St. Bernards and Great Danes were 8.8 and 5.7, respectively, compared with 0.2 for toy poodles and 0.6 for mixed breeds (Priester and McKay, 1980). Osteosarcomas account for 80% of canine bone cancers.

Chondrosarcoma is rare in childhood and rises with advancing age for unknown reasons. Studies of substantial case series have been made of clinical course and treatment (e.g., Bjornsson et al., 1998), but not for associated disease (past history, physical examination, or subsequent disease).

The age distribution of Ewing sarcoma resembles that of osteosarcoma early in life, but it rarely develops over 35 years of age (Fig. 48–2). In 1986 Dehner proposed that it be designated a primitive neuroectodermal tumor of bone (PNET). It is derived from the neural crest, and identified by a distinctive chromosomal translocation and immunohistochemical staining (Dagher et al., 2001; Ginsberg et al., 2002). The translocation is in somatic cells, not the germ line, and is therefore not transmitted from parent to child. Ewing sarcoma now refers to the much more common undifferentiated form of the neoplasm, and PNET refers to the differentiated form. The SEER registries have only nine cases since the term was introduced in 1990, through 2000.

In a case-control study of 208 cases of Ewing sarcoma no clues to etiology were found (Winn et al., 1992). The study included data on demography, maternal reproduction, child health, parental occupation, and family history.

Chordoma, thought to arise from vestigeal notochord, was the diagnosis for 400 cases registered by SEER, 1973–1995 (McMaster et al., 2001). The rates rose steadily to a peak at 70–79 years of age. The anatomic distribution was about equal for the cranium, spine, and sacrum. The median age for cranial occurrence, however, was 49 years as contrasted with 69 years for sacral chordomas. Table 48–1 shows three chordomas in blacks, when about 13 were expected if the ratio of blacks to whites is the same as it is for osteosarcoma. Among blacks there is also a rarity of giant cell and vascular tumors (Table 48–1).

Fibrosarcoma and malignant fibrous histiocytomas are rare malignant bone tumors arising from the fibrous elements of the medullary cavity of bones. In the SEER program 188 were listed, 1980–2000 (Table 48–1). The numbers are changing as new entities are being defined through molecular biology (Sandberg and Bridge, 2003).

There is a male predominance of each major form of bone cancer among whites and blacks (Fig. 48–1). The two races have similar incidence rates for childhood osteosarcoma, but blacks have almost no cases of Ewing sarcoma, either in the United States (Fig. 48–1) or Africa (Parkin et al., 1999). Rates of Ewing sarcoma are also low among Asians, but less so than in blacks (Table 48–2). These racial differences indicate that gene mutation for osteosarcoma occurs in both races, but in Ewing sarcoma mutation is rare in blacks and Asians. SEER data show that chondrosarcoma is substantially less common in blacks than in whites (Fig. 48–1). So too is fibrosarcoma of bone.

Mortality rates, 1969–2000, for all forms of bone cancer combined reached a plateau in 1985 (Fig. 48–3). Five-year relative survival rates for each of the three main types of bone cancer were substantially better for females than males, 1985–2000, as shown in Fig. 4A and 4B. The survival rates for childhood osteosarcoma, Ewing sarcoma, and chondrosarcoma in seven European countries, sexes combined, had averages of 70%, 59%, and 63% in 1985–1989, compared with 60%, 56%, and 59% in 1978–1989 (Stiller et al., 2001). Neither the United States (all ages) nor Europe (children) has shown much improvement in survival over the past 15 years.

ENVIRONMENTAL FACTERS

Ionizing Radiation

The main environmental exposures that induce osteosarcomas are ionizing radiation (Table 48–3) and/or certain types of chemotherapy. High-dose exposures to radionuclides occurred in radium dial painters (US), patients treated with intravenous 224-radium for bone tuberculosis or ankylosing spondylitis (Germany), others given intravenous Thorotrast for arteriography (various countries), and occupational and environmental exposure to plutonium in and around a nuclear weapons factory near Siberia. Table 48–3 shows the numbers of people exposed, how many are known to have developed bone sarcomas, the (p.947)

Table 48–1. Number of Patients with Primary Bone Cancer Among Whites and Blacks According to Histologic Type, 9 SEER Cancer Registries, 1980–2000*

All Races

Whites

Blacks

Histology

Frequency

%

Frequency

%

Frequency

%

Bones and joints, malignant

4304

100.0

3634

100.0

356

100.0

Fibrosarcoma (8810–8814, 8830–8831)

188

4.4

164

4.5

17

4.8

Fibrous histiocytoma, malignant (8830–8831)

136

3.2

123

3.4

9

2.5

Other (8810–8814)

52

1.2

41

1.1

8

2.3

Osteosarcoma (9180–9200)

1492

34.7

1163

32.0

187

52.5

Osteosarcoma, NOS (9180)

1117

26.0

865

23.8

144

40.5

Chondroblastic osteosarcoma (9181)

139

3.2

110

3.0

18

5.1

Fibroblastic osteosarcoma (9182)

76

1.8

60

1.7

9

2.5

Telangiectatic osteosarcoma (9183)

34

0.8

26

0.7

3

0.8

Osteosarcoma in Paget disease of bone (9184)

35

0.8

33

0.9

1

0.3

Juxtacortical osteosarcoma (9190)

83

1.9

62

1.7

11

3.1

Other osteosarcoma (9185, 9200)

8

0.2

7

0.2

1

0.3

Chondrosarcoma (9229–9240)

1215

28.2

1082

29.8

70

19.7

Ewing sarcoma (9260, 9364)

627

14.6

580

16.0

8

2.3

Giant cell sarcoma (9250)

63

1.5

42

1.2

11

3.1

Adamantinoma of long bones (9261)

22

0.5

14

0.4

5

1.4

Hemangiosarcoma and malignant hemangio endothelioma (9120–9133)

55

1.3

47

1.3

6

1.7

Chordoma (9370)

241

5.6

218

6.0

3

0.8

Sarcoma, NOS (8800–8803)

116

2.7

95

2.6

11

3.1

Unspecified (8000–8004)

116

2.7

96

2.6

15

4.2

All other types

169

3.9

133

3.7

23

6.5

(*) Data from 9 SEER registries, including the states of Connecticut, Hawaii, Iowa, New Mexico, Utah and the metropolitan areas of Detroit, Atlanta, Seattle, and San Francisco–Oakland. Histologic categories based on Dorfman and Czerniak, 1995.

() In addition to 3634 whites and 356 blacks, total includes 277 bone cancers for other races and 37 for unknown race.

                      Bone Cancer

Figure 48–1. Age-adjusted incidence rates for bone cancer by sex, race (whites, blacks), and histologic type (12 SEER areas, 1992–2000). Rates are per 100,000 and age-adjusted to the 2000 US standard population by 5-year age groups. Age-adjusted incidence rates not shown in graph: Hispanic females: osteosarcoma, 0.31; chondrosarcoma, 0.19; Ewing sarcoma, 0.069. Hispanic males: osteosarcoma, 0.31; chondrosarcoma, 0.22; Ewing sarcoma, 0.085. Hispanic is not mutually exclusive from whites, blacks, Asian/Pacific Islanders. Incidence rates for Hispanics exclude registries from Detroit, Hawaii, and Alaska native registry. Age-adjusted incidence rates for Asian/Pacific Islanders are available for osteosarcoma: females, 0.28; and males, 0.34.

                      Bone Cancer

Figure 48–2. Age- and sex-specific incidence rates for three major types of bone cancer (9 SEER areas, 1980–2000, all races combined).

(p.948)

Table 48–2. We do not have permission to reproduce this table electronically

average bone dose, and relative risk. Note that radiotherapy for cancer has induced osteosarcoma, but A-bomb exposure in Japan and occupational exposures in other countries have not. Ewing sarcoma is not induced by ionizing radiation.

226,228-Radium

In about 1913 radium was first painted on dials of watches and clocks in the United States to make them luminous. The history, as described by Fry (1998), revealed that the industry hired 4318 women, 1915–1979. 226-Radium and later 228-Radium (mesothorium) were

                      Bone Cancer

Figure 48–3. Age-adjusted mortality rates for bone cancer for white males and females, 1969–2000. Points represent 4-year calendar-year groupings. Rates are per 100,000 and age adjusted to the 2000 US standard population by 5-year age groups. Break in graph indicates change in mortality coding in 1980 with the introduction of ICD-9, which reclassified bone cancers not specified as primary to metastatic.

used to enhance the glow. The women used their lips to make the brushes come to a point. The daily intake before 1925 was estimated to be 3–43μg. Dr. T. Blum, a dentist in Orange, NJ, is credited with calling attention to a dial painter with osteomyelitis of the jaw in 1923. Two years later, Martland, the chief medical examiner for Essex County, NJ, wrote the first of a series of reports on the autopsies of dial painters who died of illnesses related to their work. The first two cases of osteosarcoma were found in 1924 and 1928 (Martland et al., 1925; Fry, 1998). Then, in 1938 the first malignancy of the epithelial lining of paranasal or mastoid sinuses was reported. Centers for the study of radium-induced tumors were established by the Atomic Energy Commission at the New Jersey Department of Health, MIT and the Argonne National Laboratory. Among 2403 persons who had a measured exposure occupationally or therapeutically, 60 developed osteosarcomas and 32 developed carcinoma of paranasal or mastoid sinuses (Rowland, 1995; Carnes et al., 1997; Stebbings, 2001).

Radium decays by emitting high-LET alpha particles, and the resulting bone dose can be very high. Among 759 women whose bone doses have been determined (1700 cGy average), an S-shaped dose-effect curve was found. A linear relationship could be rejected. The downturn at very high doses may be due to cell killing or an otherwise inability of cells to divide. Interestingly, no osteosarcomas occurred below a dose of about 1000 cGy (Priest, 2001). It has been suggested that a practical threshold could exist for cancer induced by radium isotopes (NAS, 1972), which is consistent with recent evaluations of the US radium dial study (Rowland, 1995). A threshold would explain why only 1 osteosarcoma was reported among 1203 radium

                      Bone Cancer

Figure 48–4. Relative survival rates (%) for males (a) and females (b) with bone cancer, by histologic type (all races, 9 SEER areas, 1985–1999, follow-up for vital status to 2000).

(p.949)

Table 48–3. Epidemiologic Studies of Radiation-Induced Bone Cancer

Study

Type of Exposure

Number Exposed

Duration of

Follow-up (years)

Person-Years

at Risk

Average Bone

Dose (cGy)

Relative Risk

(O/E)

ADULT–EXTERNAL RADIATION

1. Cervical cancer

(Boice et al., 1985a, 1988)

External radiotherapy

Brachytherapy

82,616

1–35

547,222

2,200

11/5.7

2. Cervical cancer

(Kleinerman et al., 1995)

External radiotherapy

Brachytherapy

49,828

1–30+

532,740

2,200

17/5.7

3. Bone marrow transplanta

(Curtis et al., 1997)

External radiotherapy

∼10,200

0–10+

∼33,000

∼1,000

5/0.4

4. Hodgkin’s diseasea (Dores et al., 2002)

External radiotherapy

13,793

1–25+

115,794

∼3,500

23/0.5

5. Ankylosing spondylitis

(Weiss et al., 1994)

External radiotherapy

14,556

5–25+

355,350

454–1,856

9/2.7

6. Benign gynecological disease

(Inskip et al., 1990)

Brachytherapy

(intrauterine 226Radium)

4,153

1–60

109,911

∼150

0/2.7

7. Metropathia hemorrhagica (Darby et al., 1994)

External radiotherapy

2,067

1–30+

∼58,000

∼310

0/0.9

8. Atomic bomb survivors (Thompson et al., 1994; UNSCEAR, 2000)

Gamma rays, neutrons

79,972

13–42

1,950,567

∼23

16/12.1

9. Radiation workers—3 countries (Cardis et al., 1995)

Gamma rays

95,673

1–30+

2,124,526

4

11/11i

10. Radiological technologists—US (Doody et al., 1998)

X-rays, gamma rays

143,429

2–40+

2,839,466

NA

4/10.3

CHILDHOOD/FETAL—EXTERNAL RADIATION

11. Childhood cancer—LESGb,c

(Tucker et al., 1984)

External radiotherapy

9,170

2–29

50,609

0–7,000

48/0.36

12. Childhood cancer—UKb,c

(Hawkins et al., 1996)

External radiotherapy

13,175

3–35+

∼141,000

∼1,000

54/1.3

13. Childhood cancer—CCSSb,c

(Neglia et al., 2001)

External radiotherapy

13,581

5–25

140,792

NA

28/1.5

14. Childhood cancer—France, UKb (Le Vu et al., 1998)

External radiotherapy

4,257

3–48

63,900

0–7,000

32/0.32

15. Retinoblastoma—NYb

(Abramson et al., 1984)

External radiotherapy Radium plaque

688b

1–32

∼5,000

3,000–15,000

45/small

16. Retinoblastoma—UKb

(Hawkins et al., 1996; Draper et al., 1986)

External radiotherapy

Radium plaque

504b

3–35+

∼9,000

∼2,000

24/0.13

17. Retinoblastoma—NY, MAb,d

(Wong et al., 1997)

External radiotherapy

Radium plaque

961b

1–50

∼30,000

3,280

65/0.15

18. Childhood cancer—LESG

(Tucker et al., 1987)

External radiotherapy

84% of 64 cases

73% of 209 controls

NA

NA

2,690

2.7

19. Hemangioma—Stockholm

(Fürst et al., 1988)

226Radium applicator

Orthovoltage X-ray

15,336

1–62

323,895

∼1–4,000

3/2.7

20. Hemangioma—Göteborg

(Lindberg et al., 1995)

226Radium applicator

11,807

1–59

370,517

∼1–4,000

2/2.8

21. Oxford survey

(Bithell and Stewart, 1975)

Prenatal X-ray

10.7% of 244 cases

9% of 244 controls

NA

NA

<10

1.11

RADIONUCLIDES—INTERNAL RADIATION

22. Radium-dial painterse

(Rowland et al., 1978; Polednak et al., 1978)

226Radium, 228Radium

757

1–56

33,597

1,700

38/0.4

23. Bone disease—Germanyf

(Spiess et al., 1989; Nekolla et al., 2000)

224Radium

899

1–43

21,600+

∼3,600f

56/<1

24. Ankylosing spondylitis—Germanyf

(Wick and Gössner, 1989; Wick et al., 1999)

224Radium

1,577

1–38

∼32,800

500f

4/1.3

25. Thorotrast patients—Portugalg (dos Santos Silva et al., 2003)

232Thorium (translocating

224Ra, 228Th, 228Ra)

1,096

1–50+

16,717

26.3mlg

5/0.7

26. Thorotrast patients—Germanyg (van Kaick et al., 1989; 1999)

As above

2,326

1–45

>20,000

26.3mlg

4/1.2

27. Thorotrast patients—Denmarkg (Faber, 1979; Andersson et al., 1995)

As above

999

1–50+

19,365

∼20mlg

0/0.2

28. Thorotrast patients—Swedeng,h

(Nyberg et al., 2002)

As above

432

10–40+

7,284

16.1mlg

2/1.2

29. Mayak workers—Plutonium

(Koshirnakova et al., 2000)

239Plutonium,External gamma

11,000

1–40+

427,500

4–14,400

24/13.3

30. UK plutonium workers

(Omar et al., 1999)

239Plutonium,External gamma

5,203

1–45

134,817

∼3j

0/1.1

31. Uranium workers (CRS, 2001)j

238U, 235U

120,000

1–50

NA

NA

30/32.3

(a) Includes children.

(b) Includes genetic retinoblastoma; these children are genetically predisposed to develop osteosarcoma.

(c) Radiotherapy status not reported.

(d) 643 non-hereditary retinoblastoma cases were similarly followed and the O/E/ was 0/0.11.

(e) Only data for women with known doses are presented. Overall 61 bone sarcomas have occurred in 1,474 women employed prior to 1930.

(f) Bone surface dose. Skeletal dose is factor of 9 lower (Nekolla et al., 2000).

(g) Amount of Thorotrast administered.

(h) Includes soft tissue sarcoma.

(i) Negative dose response.

(j) A radiation weighting factor of 20 was used (∼630 mSv was average equivalent dose).

NA = Not applicable or not available.

() = Estimated or approximate.

(p.950) luminizers studied in the United Kingdom who ingested much lower amounts of 226,228-Ra than US dial painters did (Baverstock and Papworth, 1989).

224-Radium

Peteosthor, a colloidal drug containing 224-Ra, platinum, and eosin dye was used in Germany after World War II to treat bone tuberculosis and ankylosing spondylitis (Spiess, 2002). The short half-life (3.8 days) indicates that radiation dose to bone would have been received over a period of about 1 month as opposed to over a lifetime for 226-Ra. Among 899 patients injected with 224-Ra, 56 (6%) developed bone cancer, particularly osteosarcoma of the fibroblastic or fibrohistiocytic type (Gossner, 1999), with latent periods from 4 to 22 years (Spiess et al., 1989). The average dose to bone surface was approximately 3600 cGy. Subsequent follow-up revealed 56 malignant bone tumors as compared with 1 case expected (Nekolla et al., 2000). The pattern of incidence over time for 224-Ra–induced bone sarcomas was generally similar to that observed for leukemia in A-bomb survivors, spondylitis patients given radiotherapy, and cervical cancer patients treated with radiation. Excess bone sarcomas appeared within 5 years after injection, peaked between 6 to 8 years, and decreased to normal levels after about 33 years. This wave of induced cancers is contrary to observations on other forms of solid cancer, which have a sustained rise. The lowest skeletal dose was 90 cGy; however, the dose to bone surface, where most of the energy was deposited, was approximately 800 cGy (Nekolla et al., 2000). Four bone cancers compared to 1.3 expected were found in a series of 1577 patients treated with lower doses of 224-Ra (Wick and Gossman, 1989; Wick et al., 1999). Dose calculations and pathology have been recently re-evaluated (Leenhouts and Brugmans, 2000); excesses of fibrosarcoma of bone were observed in patients who received high doses of 226/228-Ra, 224-Ra, or external radiotherapy (Gossner, 1999).

The difference in carcinogenic effectiveness, as well as in latency period and shape of the dose-effect curve, appears to be related to the different radium isotopes involved. The isotope 226-Ra has a long half-life (1600 years) and deposits its energy throughout the entire bone, whereas 224-Ra deposits its energy almost entirely on the bone surfaces. The long latent periods observed are probably related to continuous irradiation of bone by 226-Ra.

Plutonium

In 1948 the Soviet Union established the Mayak Production Association to make plutonium nuclear weapons. The Mayak facility is located in the Southern Urals on the Techa River. From 1949–1956 about 3 million curies of liquid waste were discharged by the factory into the river (Dicus, 1997; Anspaugh et al., 2002). The primary exposure to the population living downstream was to external gamma rays from short-lived fusion products and to internal beta particles from ingested 90-strontium (Kellerer, 2002). Between 1950–1989, 12 deaths from bone malignancies were observed in a cohort of 26,485 residents in the Techa River region (Kossenko et al., 1997). Risk estimates are difficult at the moment because of incomplete information on vital status and uncertainties in the dose estimates (UNSCEAR, 2000).

Other contamination occurred. In 1957 chemicals exploded in a high-level storage tank, and about 20 million curies of radioactivity were thrown from the tank, and 2 million curies were carried downwind. About 270,000 people were exposed to the fallout. In 1967 the last major accident occurred when a reservoir used to store waste evaporated after a dry hot summer, and windstorms carried radioactive dust (600,000 curies) over 2700 square kilometers. These and other misadventures could have brought the total to billion curies (Dicus, 1997).

The radiation level of the discharge at the Mayak facility in 1951 was 180 rem per hour (5.4 rem per hour downstream). Over time about 21,500 workers were exposed to radiation (highest dose, greater than 10 Gy, mean dose 0.8 Gy) (Shilnikova et al., 2003). Nearly 11,000 workers were exposed to 239-plutonium with bone doses ranging from 0.04 to 14.4 Gy (Koshurnikova et al., 2000). The half-life of 239-plutonium is 24,000 years.

Plutonium concentrates in liver, lungs, and bone where its alpha particles bombard tissue, and at sufficiently high doses, can raise cancer rates in these organs. In a study of 11,000 workers who began working at Mayak in 1948–1958 (exposed to external radiation and particles internally), 16 osteosarcomas and 8 chondrosarcomas occurred. Only one osteosarcoma developed in a worker hired after 1958 (Koshurnikova et al., 2000). Also there were nine soft tissue sarcomas adjacent to bone. Most of these cancers occurred at least 20 years after the date of first hire. Statistical analyses showed an RR of 7.9 for the four cases with body-burdens of 7.4 kBq or greater, and 4.1 for the seven other workers who were exposed but not monitored (Koshurnikova et al., 2000). In addition, some of these workers had external doses greater than 1 Gy. In these analyses, the data on 16 osteosarcomas and 3 chondrosarcomas were combined with 8 soft tissue sarcomas. The plutonium exposures received by the Mayak workers were enormous and much larger than experienced anywhere else in the world (IARC, 2001). Other studies of workers exposed to substantially lower plutonium doses have found no excess bone cancers (Omar et al., 1999; IARC, 2001; Voltz et al., 1997).

Thorotrast

Another disaster began in 1932 when Thorotrast was introduced in radiology as a contrast medium for arteriography. It was given by intravenous injection and had essentially no acute side effects. The radioactive particles were, however, permanently retained in reticuloendothelial cells, particularly in the liver and spleen. Thorotrast is a colloidal suspension of millimicron-size thorium oxide particles. Thousands of patients have been followed up for cause of death. The main sites of cancer were the liver and bile ducts, lung, and other organs where the concentration of Thorotrast was high or prolonged (e.g., the brain and urinary bladder). Bone cancer in Thorotrast recipients was found in five Portuguese (dos Santos Silva et al., 2003), four Germans (van Kaick et al., 1999), two Japanese (Mori et al., 1999), and two Swedes (Nyberg et al., 2002), but no Danes (Andersson et al., 1995). The cell types, given only for the Japanese, were osteosarcoma and hemangiosarcoma.

By 1979, seven case reports of osteosarcoma had also been published on patients after Thorotrast (Harrist et al., 1979). One was a 24-year-old male who had been injected with the contrast medium at 2 years of age. At autopsy his vertebrae showed dense sclerosis of the innermost bone (exposed at 2 years of age), surrounded by normal bone laid down in the 22 years since then (Fig. 48–5A). Autoradiography of a lymph node was teeming with alpha radiation tracks (Fig. 5B) (Miller, 1985). Sindelar et al. (1978), who first reported this case, did not publish the Figure. Thorium has a half-life of 14 billion years. In its natural state, thorium is excreted rather rapidly from the body, but the colloid Thorotrast remained essentially for life. Estimated dose to the skeleton from 25 ml of Thorotrast is about 4 Gy (Kathren and Hill, 1992).

Radiotherapy

Although primary cancers of bone have been associated with external high-dose radiation, used especially in the therapy of various cancers, the fraction of bone cancers that result from this exposure appears to be small (i.e., less than 0.05%–0.02% of patients treated) (Boice et al., 1985a, 1985b; Robinson et al., 1988). Between 1935 and 1982 in Connecticut, 30 bone cancers developed vs. 17 expected in 253,536 patients treated for cancer (30.8% of whom received radiotherapy) (Boice et al., 1985b). Among 379,941 cancer patients in Denmark treated between 1946 and 1980, 43 bone cancers occurred vs. 23 expected. Among 82,616 patients with cervical cancer treated with high-dose pelvic radiation, only 11 bone cancers were reported vs. 5.7 expected (Boice et al., 1985a); the dose to exposed bone was estimated to be 2200cGy (rad) on average (Boice et al., 1988). In each of these three studies, 0.01% of the patients given radiotherapy developed bone sarcoma—about twice the expected frequency. Excess bone cancers have also been reported following radiotherapy for breast cancer (Doherty et al., 1986), Hodgkin disease (Woodard et al., 1988; Dores et al., 2002), cervical cancer (Kleinerman et al., 1995), and childhood cancer (Hawkins et al., 1996; Neglia et al., 2001).

(p.951)

                      Bone Cancer

Figure 48–5. Thorotrast effects, 24-year-old male. (A) Transverse section of a vertebral body showing sclerosis of the innermost portion due to a-irradiation since 2 years of age. Normal bone was laid down in the subsequent 22 years. (B) Lymph node, autoradiograph, showing short linear alpha radiation tracks.

Children with certain cancers, however, seem to be particularly susceptible to radiogenic bone cancer. High risks have been reported following treatment, primarily with radiation, for retinoblastoma (12 vs. 0.01 expected), Wilms tumor (6 vs. 0.05), Hodgkin disease (5 vs. 0.05), neuroblastoma (4 vs. 0.03), and Ewing sarcoma (7 vs. 0.01) (Tucker et al., 1984). A radiation dose response from the Late Effects Study Group was based on 64 secondary osteosarcomas from 9120 two-year childhood cancer survivors as compared with 209 matched controls (Tucker et al., 1987). A recent study was made of 32 secondary osteosarcomas among 4400 three-year survivors of childhood cancer in France and Britain, compared with 160 matched controls for dose-response analyses (Le Vu et al., 1998). In comparison with general population rates, the observed vs. expected numbers of primary tumors were excessive after soft tissue sarcomas (11 vs. 0.04), Ewing sarcoma (8 vs. 0.01), and bilateral retinoblastoma (5 vs. 0.00). Only Ewing sarcoma and bilateral retinoblastoma were excessive in both studies, seemingly due to an interaction of environment and host susceptibility.

Several other large series of patients treated for heritable retinoblastoma reveal very large increases in osteosarcoma (Abramson et al., 1984; Draper et al., 1986; Hawkins et al., 1996; Wong et al., 1997). Dose-response data rarely find increases below 5–9 Gy for heritable retinoblastoma treatments (Tucker et al., 1987; Wong et al., 1997).

Perhaps the greatest risk of radiogenic cancer is in marrow transplant patients after the administration of immunosuppressive drugs and high exposure to total-body irradiation. The cancers include osteosarcoma reported in eight children after allogeneic marrow transplantation, four of them studied by Bielack et al. (2003). All four had received chemotherapy with alkylators, and three had total-body irradiation. The cancers were diagnosed 32–80 months after transplantation.

In a study of nearly 20,000 patients who received bone marrow transplantation in the United States, 1964–1992, one (included in the previously mentioned case series) had osteosarcoma, and three (not mentioned there) developed chondrosarcomas (Curtis et al., 1997). This finding led us to look for chondrosarcomas in other series of radiogenic cancers. We found that Gossner (1999) had made a comprehensive review that provided new information on chondrosarcomas and fibrosarcomas in various groups who were heavily exposed to ionizing radiation. Table 48–4 shows the relative frequencies of osteosarcomas, chondrosarcomas, and fibrosarcomas after various types of radiation exposure. Osteosarcomas after heavy radiation exposures (p.952)

Table 48–4. Bone Cancer Cell Types: Numbers and Percentages by Sources of Radiation Exposure (Three Cell Types Add to 100%)

Osteosarcoma

Chondrosarcoma

Fibrosarcoma

Source

Number

%

Number

%

Number

%

References

224-Radium

22

53

6

14

14

33

Gossner

226/228-Radium

32

70

0

0

14

30

Gossner

Plutonium

16

80

3

15

1

5

Koshurnikova

Marrow implant

8

73

3

27

0

0

Bielack/Curtis

External irradiation

155

63

9

4

82

33

Gossner

General pop, white

1163

48

1082

45

164

7

Table 48–1

were more common than they are in the general population (53–80% vs. 48%). Chondrosarcoma has not been reported in radium-dial painters. It was far less common among the other irradiated groups than in the general population (4–27% vs. 45%).

Fibrosarcoma of bone was not described as an entity until 1972 and the first radiogenic case was recognized in 1977 (reviewed by Gossner, 1999). Most radiation-induced bone tumors were studied before that date, but reclassification of the pathology has been made in recent years based on stored specimens (Gossner, 1999). In the SEER Program the frequency of fibrosarcoma in the general US white population was only 7% compared with 30–33% among those exposed to 224-Ra, 226/228-Ra, or external radiation (Table 48–4). Soft tissue sarcomas are frequently induced by radiotherapy, especially in children with heritable retinoblastoma, so it is not surprising that fibrosarcoma is induced, because this soft tissue is widely distributed in bone. It is noteworthy that hereditary retinoblastoma has a shorter latent period than usual for radiotherapy-induced osteosarcoma and soft tissue sarcomas of the face (Chauveinc et al., 2001).

Radiation-induced bone cancer appears, it seems, only at very high doses (IARC, 2000; UNSCEAR, 2000), and is rarely reported at doses under 5 Gy. Patients treated for benign conditions with low-dose radiotherapy have not shown increased bone cancers (Inskip et al., 1990; Darby et al., 1994; Fürst et al., 1988; Lindberg et al., 1995), nor have studies of prenatal X-ray (Bithell and Stewart, 1975) or occupational exposures (Cardis et al., 1995; Darby et al., 1998; Council of the Royal Society, 2001).

Chemicals

Treatment of childhood cancer with alkylating agents has been linked to a 4.7-fold risk of bone cancer, with risk increasing as cumulative drug exposures rose (Tucker et al., 1987; Kingston et al., 1987; Newton et al., 1991; Hawkins et al., 1996; Le Vu et al., 1998; Neglia et al., 2001). Half of the 64 children who developed bone cancer as a second malignancy received chemotherapeutic agents, most commonly cyclophosphamide, triethylene-melamine, and chlorambucil. Radiotherapy and hereditary retinoblastoma were ruled out as potential confounders. There is no clear evidence that systemic exposure to other chemical agents are related to bone cancers. Concerns about the role of fluoridated drinking water and osteosarcoma based on animal studies were dispelled by epidemiological studies (Hoover et al., 1991).

Viruses

Osteosarcomas and cancers of connective tissue have been induced by certain viruses in experimental animals since Rous’s work in 1912. There is no epidemiological evidence of horizontal transmission (clustering) of bone tumors. The British have made a tremendous effort to no avail to find statistical support for such transmission of solid childhood tumors other than lymphoma (e.g., McNally et al., 2003; Parslow et al., 2002; Gilman and Knox, 1995). Silcocks and Murrells (1987) focused on osteosarcoma and found no geographic clustering. Occasionally clusters of bone cancer have been reported, but virtually all forms of neoplasia, no matter how rare, may cluster geographically by chance, given that in the United States alone, for example, there are 29,000 towns (Neutra et al., 1990) and various other ways to group people, as in neighborhoods, schools, churches, clubs, and date of birth. As noted below, an adenovirus has been suggested in the formation of the EWS/FLI1 translocation found in Ewing sarcoma.

Implants and Other Foreign Bodies

Occasional case reports have led to the suspicion that implants (metal, ceramic, polymer) can cause bone or soft tissue sarcomas. The International Agency for Research on Cancer (IARC, 1999) has issued an exhaustive review of the literature (from humans, domestic animals, experimental animals, and laboratory tests for carcinogenicity) and concluded that the evidence for inducing cancer fell into IARC category 2B, which is borderline at best regarding exposures to polymeric implants prepared as thin smooth films, metallic implants prepared as thin smooth films, implanted foreign bodies of metallic cobalt, metallic nickel, and an alloy powder containing 66%–67% nickel, 13%–16% chromium and 7% iron. In IARC category 3, not classifiable as to their carcinogenicity to humans, are organic polymeric materials as a group, orthopedic implants of complex composition, implanted foreign bodies of metallic chromium or titanium and of cobalt-based, chromium-based, and titanium-based alloys, stainless steel and depleted uranium, and dental materials.

A number of large-scale epidemiologic studies of cancer risk among patients with implants have been conducted since the publication of the 1999 IARC monograph. These studies provide further evidence of the lack of association between bone cancer and metallic implants in humans (Olsen et al., 1999; Signorello et al., 2001; Fryzek et al., 2002).

Millions of people throughout the world have received implants, and by 1999, when the IARC report was published, a total of 35 cases had been reported of malignant neoplasms arising from the bone or the soft tissue in the region of an implant. Prior to the IARC study there had been 10 reports of non-metallic foreign bodies followed by various bone tumors. At the site of osseous metallic foreign bodies (mainly bullets and shrapnel fragments), there were 23 sarcomas and 23 carcinomas. No conclusions can be drawn from these case reports. The same is true of osteosarcomas reported at the sites of previous fractures. An excess of osteosarcomas at the ankle in Werner premature aging syndrome, however, may be due to the trauma of walking, at a site predisposed by the severe connective tissue disorder in the syndrome (see below) (Ishikawa et al., 2000).

GENETIC SUSCEPTIBILITY

Osteosarcoma after Retinoblastoma

In 1970 an excess of osteosarcoma after retinoblastoma was first reported (Jensen and Miller, 1971). In 1986 the gene for retinoblastoma (OMIM 180200) was isolated (Friend et al., 1986), and it was thought that mutation of the RB1 gene was involved in the genesis of both cancers. Most of the osteosarcomas have been in the field of radiotherapy, but 29% occur near the knee, well outside the field of radiation (Wong et al., 1997). Radiogenic osteosarcomas were reported to develop only when external beam radiation was given before 12 months of age (Abramson and Frank, 1998).

(p.953) Study of childhood osteosarcomas showed that 13 of 47 tumors had point mutations and 5 of 37 had gross rearrangements of TP53 (Miller et al., 1996). RB1 was either rearranged or deleted in 7 of 37 osteosarcomas, five of which also had TP53 mutations. Osteosarcomas in dogs have similar histology to those in humans, but study of the tumor in 21 dogs revealed normal RB1 in all. Thirty-eight percent had TP53 mutations (Mendoza et al., 1998; Loukopoulos et al., 2003). It should be noted that dogs do not develop retinoblastoma (Priester and McKay, 1980).

RB1 was the first recognized tumor suppressor gene, and led the way to understanding a class of genes that are involved in the origins of a wide variety of common cancers (Knudson, 2000, 2002). Patients with this neoplasm have a germline mutation in about 40% of cases and a somatic cell mutation in the rest. RB1 plays a role in the development of other cancers, including the breast, lung, soft tissue, and genitourinary tract (Eng et al., 1993). In addition, various cancers occur excessively in patients with hereditary retinoblastoma. Follow-up study of retinoblastoma patients revealed that the cumulative incidence of a second cancer at age 50 was 51% when retinoblastoma was hereditary, and 5% when it was non-hereditary (Wong et al., 1997). A substantial number were in the radiation field, indicating a gene–environment interaction.

Li-Fraumeni Syndrome, TP53

A spectacular example of familial aggregation of cancer is found in Li-Fraumeni syndrome (OMIM 191170) (Li and Fraumeni, 1969; Friend et al., 1986; Li et al., 1988). In the syndrome, a variety of cancers occur in excess singly or in combination in children or young adults, notably osteosarcoma, soft tissue sarcoma, breast carcinoma, brain cancer, adrenocortical carcinoma, and leukemia. Study of patients with multiple primary cancers in Li-Fraumeni syndrome has shown that 8 of 27 new cancers occurred in the radiation field for treatment of a previous cancer (Hisada et al., 1998)—again, a possible gene–environment interaction.

Molecular studies showed germline mutation of the tumor-suppressor gene, TP53, located at chromosome 17p13 (Malkin et al., 1990). There are now nearly 250 independent germline TP53 mutations in Li-Fraumeni syndrome described in over 100 publications according to Varley (2003), whose report is in a supplement of Human Mutation devoted to TP53. Varley described the spectrum of mutations, the methods for their detection, and the associated tumors.

The mutated gene can be sought to diagnose the syndrome if the aggregation of cancer is limited by small family size, or if an individual develops multiple primary cancers of types found in LiFraumeni syndrome.

The TP53 gene, like the RB1 gene, regulates normal growth of specific organs; when the tumor-suppressor function is inactivated, as by chromosomal deletion or degradation, growth becomes abnormal and cancerous. This class of genes, first recognized in rare cancers of childhood, now has counterparts in adult cancers that are far more common, and may lead to new strategies for cancer prevention, early detection, and treatment.

DNA Helicase Mutations

Three DNA helicase mutations unwind duplex DNA, which results in three separate syndromes that increase genomic instability and thus predispose to cancer and premature aging. These mutations occur in what is now known as the RecQ family of helicases (Nakayama, 2002). In an overview, Furuichi (2001) described the expression of the genes in the tissues, highly correlated with the phenotypes, and tissue-specific genomic instability, as, for example, in the pancreas (diabetes mellitus), ovary, and testis (hypogonadism) in Werner syndrome. A comparison of the molecular and clinical findings in the three syndromes has been published (Lindor et al., 2000).

Werner Syndrome (OMIM 27770)

Osteosarcoma is one of six neoplasms that occur excessively in Werner syndrome (Goto et al., 1996; Goto and Miller, 2001). The other cancers are soft tissue sarcomas, acral lentiginous melanomas, myeloid disorders, thyroid carcinoma, and benign meningiomas. Due to genotype differences, non-Japanese have shown no excess of melanoma or thyroid cancer (Goto et al., 1996). In Japanese, the ratio of carcinomas to sarcomas was 1:1 instead of the usual 10: 1 (Miller and Myers, 1981). The syndrome, an autosomal recessive trait, is characterized by premature aging, graying of the hair, diabetes mellitus, atrophy of the skin, connective tissue disorders, arteriosclerosis, unusual cancers, and death on average at 46 years. The syndrome is far more common in Japan than elsewhere because of the mutant gene in cousin marriages. The osteosarcomas are atypical in that they cluster at the ankle at 35–57 years of age (Ishikawa et al., 2000). In this age range, patients with the syndrome have poor circulation and severe wasting of the soft tissue of the lower legs that concentrates weight bearing at the ankle. The acral lentiginous melanomas have the same distribution on the feet as were reported in a series of Caucasian patients with no underlying disease. The authors noted that the distribution matched that of weight-bearing sites (Feibleman et al., 1980).

In Werner syndrome a DNA helicase gene mutation has been found at chromosome 8p12-11.2. Through the use of a monoclonal antibody directed against the DNA helicase gene-product a molecular defect could be found without the need for more complex mutational analysis (Furuichi, 2001; Shimizu et al., 2002). Moser et al. (1999) have reviewed the possible mechanistic links between loss of WRN protein function and the pathogenesis of clinical and cellular abnormalities.

Roth mund-Thomson Syndrome (OMIM 268400)

This syndrome, an autosomal recessive trait, is also attributed to a DNA helicase mutation (RecQL4) (Kitao et al., 1999). The disease is characterized by a sun-sensitive rash usually at 3–6 months of age, short stature, poikiloderma (marbled dermal atrophy) among other skin disorders, and 75% had skeletal dysplasias on X-ray examination. In a series of 41 cases, 13 (32%) developed osteosarcoma at 3–41 years (median 11.6 years). Twenty-two patients were still under age 15 years so more osteosarcomas can occur among the 41 in this series (Wang et al., 2001). None had soft tissue sarcomas, in contrast to Werner syndrome.

Osteosarcoma was associated with a distinctive pattern of mutations in the RecQL4 gene (Wang et al., 2003). In a series of 11 cases, all had at least 1 of 19 truncating mutations. Ten patients with the syndrome who did not have truncating mutation did not have osteosarcoma. Thus, molecular diagnosis may identify children with the syndrome who are at high risk of osteosarcoma.

At chromosome 8q24.3 a gene was found that belonged in the RecQ family of helicases, but its effect on health was not known (Kitao et al., 1999). Because Rothmund-Thomson syndrome, first described in 1868, had features of premature aging, Werner in 1904 had to differentiate it from the premature aging syndrome he was describing (Martin, 2001). The overlap in clinical findings led to the testing of two Mayo Clinic patients (brothers) with Rothmund-Thomson syndrome and osteosarcoma (Lindor et al., 1996, 2000; Kitao et al., 1999). The brothers had the newly discovered mutated gene. The syndrome has since been shown to have substantial genetic heterogeneity (Wang et al., 2003). Certain genotypes have been linked by these authors to high risk of osteosarcoma, thus providing the physician with the opportunity for early detection and treatment. RecQ5 is another member of the helicase family found along with RecQL4, now known as the RTS gene, but it has not yet been linked to any disease.

RTS is an excellent tool for diagnosing Rothmund-Thomson syndrome and studying its molecular basis. The diagnosis can be made by an immunoblot technique. Further details about the clinical and laboratory features and pathophysiology are well described by Kitao et al. (2003).

Bloom Syndrome (OMIM 210900)

Bloom syndrome, due to a third helicase mutation, located on chromosome 15q26. 1, is characterized by dwarfism, a sun-sensitive rash, immunodeficiency, male infertility, and an excess of cancers—mainly (p.954) acute leukemia and non-Hodgkin lymphoma in childhood, and carcinomas in adulthood. Males are sterile. The gene is expressed in the testes but not in the ovaries (Furuichi, 2001). In the first 100 cancers in the Bloom Syndrome Registry, there were only two patients with osteosarcomas and none with soft tissue sarcomas (German, 1997), markedly different from the syndromes of Werner and RothmundThomson.

Osteosarcoma in Other Syndromes

Case reports also describe osteosarcoma and fibrosarcoma with polyostotic fibrous dysplasia (Yabut et al., 1988), and osteogenesis imperfecta (Lasson et al., 1978). Osteosarcoma has also been described with Hutchinson-Gilford progeria (King et al., 1978) and with incompletely defined syndromes involving growth disturbances (Parry et al., 1978).

Cancers of various types have been observed on the walls of bone cysts, and have arisen from benign giant cell tumors, osteomas, osteoblastomas, bone infarcts, fibrous dysplasia, and chronic osteomyelitic sinuses (Unni and Dahlin, 1979). Long before these observations were made, Johnson (1953) suggested that bone disorders with prolonged periods of excessive cell activity are prone to neoplastic change.

Genetics of Ewing Sarcoma

Ewing sarcoma (OMIM 133450) rarely occurs in siblings (Joyce et al., 1984; Zamora et al., 1986). As noted previously, it is rare in blacks and Asians, suggesting a genetic influence. Ewing sarcoma occurs excessively only after retinoblastoma, substantially outnumbered by osteosarcoma in this regard. A case series, assembled through a search of PubMed, revealed 10 cases of Ewing tumor following retinoblastoma, when only one or two cases were expected based on the percentage distribution of Ewing sarcoma among cancers in the general population (Cope et al., 2001).

A somatic cell mutation, t (11,22), found in almost all cases, forms an EWS-FLI1 fusion product, in which the Ewing sarcoma gene, EWS, on chromosome 22 is a powerful transcriptional activator; FLI1 (friend leukemia insertion [OMIM 193067]) on chromosome 11, is a gene in the ets family. These translocations are limited to somatic cells.

Sanchez-Prieto et al. (1999) noted the close resemblance between Ewing sarcoma cells and tumor cells expressing the adenovirus E1A gene. They postulated that this gene induces the translocation and the oncogenic fusion protein. They tested the hypothesis and demonstrated the fusion product after E1A expression. An accompanying commentary (Kirn and Hermiston, 1999) hailed the finding for its novelty in suggesting a link between a virus and this human cancer. They said it may open a new area for study of carcinogenesis, which if it transpires, may provide a basis for developing antiviral vaccines. After failures by two other investigators to confirm the finding, the original authors stated that they found E1A sequences in all three Ewing tumor lines they had studied and in 14 of 32 Ewing tumors from patients (deAlava et al., 2000).

Genetics of Chordoma

Chordoma (OMIM 215400), when familial, is transmitted as an autosomal dominant trait. A genome-wide linkage study of 11 members of a family with chordoma plus five affected members of two unrelated families mapped the gene locus to chromosome 7q33 (Kelley et al., 2001). Another study of 16 chordomas, using genetic hybridization and cytogenetics, suggested that an oncogene at 7q36 might be involved (Scheil et al., 2001).

Genetics of Chondrosarcoma

Although chondrosarcoma is the second most common bone cancer, it has not yielded much information about its genetic origins. It is not familial. It is less common in blacks than whites, and it does occur in syndromes due to malignant degeneration of benign cartilaginous tumors. Multiple exostoses (diaphyseal aclasia) are osteochondromas on the surfaces of growing bone. This dominantly inherited condition may produce severe deformities, and transformation to chondrosarcoma has been reported in 5%–11% of patients. However, no malignant change was seen in in the follow-up of 43 patients, 20 of whom had a family history of the disorder (Pierz et al., 2002). Chondrosarcoma also occurs excessively with enchondromatosis (Ollier syndrome) or with the combination of enchondromatosis and skin hemangiomas (Maffucci syndrome), but neither syndrome is inherited in a simple Mendelian fashion (Schwartz et al., 1987).

Cytogenetic studies have to date shown that chondrosarcomas, except when they are extraskeletal, are not associated with specific translocations (Avery, 2002). See also Avery and Bridge (2003) for an extensive review of the literature and their own work on cartilaginous tumors.

Paget Disease

Paget disease (osteitis deformans) (OMIM 167250) predisposes mainly to osteosarcoma, but also to fibrosarcoma, chondrosarcoma, and giant cell tumor (Haibach et al., 1985). Localized bone destruction occurs for an unknown reason, and it makes the bone susceptible to the effects of stress. Repair occurs almost simultaneously with resorption, and the bone enlarges (Fallon and Schwamm, 1989). The skull is commonly involved, and one sign of the disease is the need for a larger hat size than before. of 101 osteosarcomas in a series of patients older than 60 years of age, 55% were associated with Paget disease (Huvos, 1986).

In the United Kingdom, a survey was made of abdominal radiographs of patients 55+ years old, 1970–1977 (Cooper et al., 1999). About 1000 radiographs were examined from each of 31 towns for evidence of Paget disease. Each film showed both femoral heads and all the lumbar vertebrae. There was a steep increase in frequency with advancing age, from 2% in men at 50–59 years to 20% in those at 85+ years. The rates in women at these ages rose from 1% to about 7%.

The prevalence in British towns ranged from 2.7% to 5.6%, except for the highest rates, 6.3% to 8.3%, in a cluster around Lancashire (Barker et al., 1980). A repeat survey of 10 towns, 1993–1995, indicated that the prevalence had diminished in the population from 5% to 2%, and the Lancashire cluster was less prominent (Cooper et al., 1999).

Through the use of a large record-linkage resource (the General Practice Research Database) in England and Wales, 2465 patients with a diagnosis of Paget disease of bone were ascertained, 1988–1999 (van Staa et al., 2002). The incidence of clinically diagnosed Paget disease declined from 1.1 to 0.7 per 100,000 person-years. A decrease was also noted in the Mayo Clinic’s population-based study of residents in Olmstead County MN (Tiegs et al., 2000), and in a Spanish hospital-based study (Morales-Piga et al., 2002), where, as in the British experience, the disease appeared to be less severe. This decline and within-country variations in rates indicate an environmental influence, as do variations from country to country. Among British migrants to Australia, the rates were midway between those in Britain and native-born Australians (Gardner et al., 1978).

In a case-control study, a history of Paget disease in parents or siblings was given by 12.3% of 788 cases compared with 2.1% of 387 spouse controls (Siris et al., 1991). Among relatives of cases, the cumulative risk was highest when the case was diagnosed under 55 years of age and had bone deformity, an indication of severity of the disease. Familial Paget disease is consistent with autosomal dominant transmission (McKusick, 1994). A recent genome-wide search for the gene involved 319 individuals in 62 kindreds predominantly of British descent (Hocking et al., 2001). Several susceptibility loci were identified, the strongest of which is on chromosome 5q35.

Multiple Neoplasms

Osteosarcoma and retinoblastoma tend to aggregate individually among close relatives. Such observations, including those in Li-Fraumeni (p.955) syndrome, have prompted the generalization that cancers occurring excessively as double primaries may also aggregate excessively in families (Hansen and Cavenee, 1987). These clinical observations provide clues for laboratory scientists in their search for genes of diverse cancers that are familial or occur as multiple primaries.

PREVENTION

High exposure to alpha-emitting radionuclides is not a problem at present, nor is unrestrained use of radioisotopes after the 1950s (Advisory Committee on Human Radiation Experiments, 1995). Radiotherapy is supposed to be used only when the benefits outweigh the risk of carcinogenesis.

The possibility that a vaccine may be developed against Ewing sarcoma has been raised by the recent report that a specific adenovirus may induce the translocation and oncogenic fusion protein characteristic of this neoplasm. Wang et al. (2003) have reported that osteosarcoma in Rothmund-Thomson syndrome may be anticipated by testing for a particular genotype. Early detection and treatment of osteosarcoma are facilitated by medical surveillance of individuals with predisposing genetic disorders.

Paget disease, which predisposes to osteosarcoma in the elderly, has been decreasing in frequency especially in Great Britain. The British have first-class record systems for following these trends, a great advantage in seeking the explanation, which when found, may lead to improved prevention and earlier detection.

FUTURE DIRECTIONS

Progress in bone cancer etiology in the past 5 years has been immense. It comes from subtyping by pathology, linkage of subtypes to genetic syndromes (clinical and molecular epidemiologic studies), and radiation accidents (fallout from Chernobyl and the contamination of air, water and soil with plutonium at the Mayak Complex in Chelyabinsk). Most of these developments could not have been foreseen. What lies in the near future now?

Demography

Data should be evaluated by subtype insofar as possible. Mortality and survival rates have been unchanged since the 1980s. Therapy may improve based on advances in molecular genetics and immunology.

Genetics

As described previously, there are many genotypes in RothmundThomson syndrome, only one of which has been linked to osteosarcoma in the syndrome. The presence of this genotype, detected by laboratory study, makes possible early detection and treatment. This observation illustrates an approach to identifying those at highest risk of this and other cancers.

In the past 5 years DNA helicase gene mutations have been found in two conditions with an excess of osteosarcoma, Werner syndrome and Rothmund-Thomson syndrome, and one in which there is no such excess, Bloom syndrome. There is a fourth helicase gene mutation to which no disease has yet been linked, RecQL-5. It may be a syndrome in which premature aging is a feature (as it was in linking RTS to RecQ4 [Kitao et al., 1999]). Mulvihill-Smith syndrome is a possibility (Mulvihill and Smith, 1975), but no specimens for study have been available.

Bone cancers have also been central in the new understanding of two other major findings in cancer genetics. Clinical and epidemiological findings concerning retinoblastoma (and osteosarcoma) provided data that led Knudson to develop the concept of tumor suppressor genes. The Li-Fraumeni syndrome of multiple familial cancers including osteosarcoma implicated TP53 in their genesis. The individual genes, TP53 and RB1, play major roles in protecting the genome from damage that can lead to cancer and aging. Molecular epidemiology of osteosarcoma will continue to be a fertile field for new laboratory and clinical developments.

Environmental Exposures

Longer-term study of accidental exposures in the manufacture of alpha-particle emitters in the Russian Federation should add to information already published. Apart from radiation, the changing rates of Paget disease, with its elevated risk of osteosarcoma, may be tracked to an environmental cause.

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