Paget's osteosarcoma and post-radiation osteosarcoma: secondary osteosarcoma at Middlemore Hospital, New Zealand

Pathology (October 2008) 40(6), pp. 604–610

ANATOMICAL PATHOLOGY

Paget’s osteosarcoma and post-radiation osteosarcoma: secondary osteosarcoma at Middlemore Hospital, New Zealand MICHAEL S. DRAY*{{

AND

MARY V. MILLER*{

*Department of Anatomical Pathology, Laboratory Services, and {New Zealand Bone and Soft Tissue Tumour Registry, Middlemore Hospital, Auckland; {Department of Molecular Medicine and Pathology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Summary Aims: To review the clinical and histological features of our cases of Paget’s osteosarcoma and post-radiation osteosarcoma. Methods: A search through the files of the New Zealand Bone and Soft Tissue Tumour Registry was performed, patients were identified and the relevant details were collated. Results: Thirty-one cases of Paget’s osteosarcoma and eight cases of post-radiation osteosarcoma were identified. Patients with Paget’s osteosarcoma were aged between 48 and 67 years, predominantly female, and axial and appendicular skeleton were equally affected. The outcome was known in 29 cases, with a median survival of 7.25 months and 5 year overall survival of 10%. Patients with post-radiation osteosarcoma were aged between 17 and 68 years, equally male or female, and axial and appendicular skeleton were equally affected. Index lesions included benign or malignant osseous and non-osseous conditions. The average age at diagnosis of the index lesion was 30.1 years and the average latent period was 13.5 years. The outcome was known in all eight cases, with a median survival of 33 months and 5 year overall survival of 38%. Conclusions: Paget’s osteosarcoma and post-radiation osteosarcoma are examples of secondary osteosarcoma. The former affects elderly patients, and has a poor prognosis and response to treatment. The later affects a wide age group, and has a prognosis and response to treatment comparable with primary osteosarcoma. Key words: Secondary osteosarcoma, Paget’s osteosarcoma, post-radiation osteosarcoma. Received 26 August, revised 25 October, accepted 29 October 2007

INTRODUCTION Most tumours of bone, including malignant bone tumours, are primary tumours and arise in apparently normal bone. However, a small subset of tumours arises secondary to a pre-existing lesion (Table 1). Rare cases of osteosarcoma arise secondary to giant cell tumour of bone,1 osteoblastoma2 and fibrous dysplasia.3 The two most well documented causes of secondary osteosarcoma are Paget’s disease of bone and therapeutic radiotherapy.4–11

This paper describes our experience over a 50 year period with osteosarcomas secondary to these conditions and follows on from an earlier report from our institution.12

MATERIAL AND METHODS The New Zealand Bone and Soft Tissue Tumour Registry is located at Middlemore Hospital, Auckland, New Zealand. The paper records from 1950 onwards and the computerised files from 1993 to 2005 were searched for cases of osteosarcoma. A total of 261 cases were registered. From these cases, 31 patients with Paget’s osteosarcoma and eight patients with postradiation osteosarcoma were identified. For both groups of patients the gender, age at diagnosis, site, histological grade, clinical stage, treatment and outcome were recorded. Further details such as the age at diagnosis and nature of the index lesion, dose of radiotherapy received, and latent period until diagnosis of osteosarcoma were recorded for the post-radiation group. Note was also taken of the occurrence of other malignant sarcomas. The glass slides and tissue blocks were retrieved from storage and where required new H&E stained slides were prepared. The slides were all reviewed to confirm the original diagnosis of osteosarcoma. The presence of osteoid production within a malignant spindle cell tumour was considered diagnostic of osteosarcoma. Statistical calculation of survival data was performed using Life Tables analysis in SPSS 15.0 for Windows (SPSS, USA).

RESULTS Paget’s osteosarcoma (Table 2) Thirty-five cases of sarcoma with Paget’s disease of bone were identified, 31 of which were osteosarcomas, representing 11.9% of all our cases of osteosarcoma; these formed the basis of this study. The remaining four cases, comprising three cases of chondrosarcoma and a case of fibrosarcoma were excluded from further discussion. Female patients outnumbered males (17 versus 14). The age at diagnosis ranged between 48 and 87 years (median 72 years). Extensive polyostotic disease was identified by conventional radiography or bone scans in 22 patients and monostotic disease in a further two patients. The details were not available in the remaining seven patients. The bones affected were an equal mix of the appendicular and axial skeleton, with the femur most common, followed by the pelvis then the humerus. The histology was high grade in 30 cases, with two cases having a chondroblastic appearance. The single remaining patient (Case 19)

Print ISSN 0031-3025/Online ISSN 1465-3931 # 2008 Royal College of Pathologists of Australasia DOI: 10.1080/00313020802320663

PAGET’S OSTEOSARCOMA AND POST-RADIATION OSTEOSARCOMA

declined biopsy, but otherwise had diagnostic clinical and radiographic evidence of Paget’s osteosarcoma. Clinical staging as per Enneking et al.13 was performed retrospectively, taking into account the histological grade and the X-ray appearances of the lesion along with chest Xray findings (where available). Fifteen cases were staged as IIB, nine cases were staged as provisional IIB (recorded as IIBþ) but potentially stage III as the relevant chest X-rays were unavailable for review, and

TABLE 1

Precursor conditions of bone and associated malignant lesion

Precursor condition

Malignant lesion

Osteochondroma (single and multiple) Chondroma (single and multiple) Giant cell tumour of bone Paget’s disease of bone Radiotherapy Chronic osteomyelitis Fibrous dysplasia Osteoblastoma

Chondrosarcoma29 Chondrosarcoma30,31 Malignant GCT, osteosarcoma32,33 Paget’s osteo/sarcoma21 Post-radiation osteo/sarcoma10 Squamous cell carcinoma34 Osteosarcoma, fibrosarcoma3 Osteosarcoma2

GCT, giant cell tumour of bone.

TABLE 2

605

seven cases were stage IIIB. The various treatment regimes were dependant upon the era of presentation. Two patients were diagnosed only at post-mortem examination. Nineteen patients elected to have no treatment, or at most an initial biopsy. One patient had insertion of intramedullary rod to stabilise a pathological fracture of the femur, a second had limb salvage surgery for stabilisation of a post-biopsy pathological fracture, and a third had a femoral resection. The remaining seven patients had radical surgery comprising above knee amputations (n ¼ 4), above elbow amputation (n ¼ 1), forequarter amputation (n ¼ 1) and hindquarter amputation (n ¼ 1). Macroscopic details of tumour size and margin status were available in five patients, with all the margins clear, and tumour size ranged from 65 to 100 mm. Three patients had radiotherapy, and one had chemotherapy. Follow-up was available on 29 of the 31 patients. Twenty-seven patients were deceased, surviving a median 7.25 months (range 0–279 months). The two remaining patients have survived 117 and 243 months, respectively. The overall 5 year survival rate was 10%, whilst the stage related 5 year survival was 13% for the stage IIB group, 14% for the stage IIBþ group, and 0% for the stage IIIB group (Table 3).

Demographic, pathological, clinical staging and outcome data of Paget’s osteosarcoma

Case

Year

Age

Sex

Site

Poly/Mono

1 2

1960 1965

66 73

F M

Femur (prox) Femur (NOS)

Poly Poly

3 4 5 6 7 8

1965 1968 1968 1968 1970 1973

60 67 72 82 65 67

M M F F F M

Scapula Vertebra Skull Humerus (dist) Femur (prox) Femur (dist)

? Poly Poly Poly Poly ?

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

1974 1975 1981 1981 1984 1985 1986 1986 1987 1991 1993 1994 1994 1995 1995 1995 1995 1996 1997 1997 1999

48 71 72 84 79 63 52 86 66 73 87 80 67 86 68 82 77 71 76 73 78

F F F F M F M F M M F F F F M F F M M M M

Pelvis Tibia (dist) Pelvis Femur (dist) Vertebra Femur (prox) Ulna Sacrum Femur (prox) Femur (dist) Pelvis Pelvis Pelvis Skull Pelvis Pelvis Femur (NOS) Femur (dist) Pelvis Humerus (prox) Humerus (prox)

? Mono Poly ? Mono Poly Poly Poly Poly Poly Poly Poly Poly Poly Poly ? Poly Poly ? Poly Poly

30 31

2002 2004

83 66

F M

Femur (dist) Sacrum

? Poly

Maximum tumour size and margin

Stage* IIBþ IIBþ

100 mm, clear

No details 120 mm, clear No details

90 mm, clear

65 mm, clear

No details

90 mm, clear

IIB IIBþ IIIB IIB IIBþ IIBþ IIBþ IIBþ IIB IIB IIB IIBþ IIB IIB IIIB IIB IIB IIBþ IIIB IIB IIIB IIIB IIB IIB IIIB IIIB IIB IIB IIB

Survival (months)

Treatment

Outcome

Biopsy Biopsy and radRx FQA and radRx Biopsy PM Biopsy Resection AKA and radRx HQA AKA Biopsy Intramed rod Biopsy Biopsy AEA Biopsy Biopsy AKA Declined Biopsy Biopsy PM Biopsy Biopsy Biopsy AKA Biopsy Biopsy Limb salvage and chemRx Biopsy Biopsy

Deceased ?

3

Deceased Deceased Deceased Deceased Deceased Deceased

27 3 0 7 9 279

? Deceased Deceased Deceased Deceased Deceased Alive Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Alive Deceased Deceased Deceased

13 15 6 1 2 243 7 2 10 9 1 1 0 2 2 1 117 13 1 9

Deceased Deceased

8 15

*Stage as per Enneking et al.:13 IIB, histological high-grade tumour with extra-osseous (extra-compartmental) component; IIBþ, histological high-grade tumour with extra-osseous (extra-compartmental) component but with no chest X-ray available precluding assessment for pulmonary metastases; IIIB, skip lesions and or metastatic disease with extra-osseous (extra-compartmental) component. ?, unknown; AEA, above elbow amputation; AKA, above knee amputation; chemRx, chemotherapy; dist, distal; F, female; FQA, forequarter amputation; HQA, hindquarter amputation; intramed, intramedullary; M, male; Mono, monostotic; NOS, not otherwise specified; PM, post-mortem; Poly, polyostotic; prox, proximal; radRx, radiotherapy.

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Post-radiation osteosarcoma (Table 4) Fifteen post-radiation sarcomas were identified, eight of which were osteosarcomas, representing 3.1% of all our cases of osteosarcoma; these formed the basis of this study. The remaining seven, comprising two cases with features typical of a giant cell tumour of bone in the index lesions and high grade osteosarcoma in the subsequent tumour, but with short latent periods of only 23 and 31 months, four cases of sarcoma, not otherwise specified (NOS), and a single case of fibrosarcoma, were excluded from further discussion. There was no gender bias with an equal number of male and female patients (4 versus 4). The age at diagnosis of osteosarcoma ranged between 17 and 68 years (median 34 years). The bones affected were an equal mix of appendicular and axial skeleton, with tibia and scapula being the most common. The histology was high grade in all cases, with two cases having a fibroblastic appearance. Clinical staging as per Enneking et al.13 was performed retrospectively, taking into account the histological grade and the X-ray appearances of the lesion, along with chest X-ray findings

(where available). Seven cases were staged as IIB, and the remaining single case was unable to be staged due to lack of records. The index lesions included both benign and malignant osseous lesions [Ewing’s sarcoma (n ¼ 2), osteosarcoma (n ¼ 1) and giant cell tumour of bone (n ¼ 1)], and non-osseous lesions [lymphoma (n ¼ 2), breast carcinoma (n ¼ 1) and rhabdomyosarcoma (n ¼ 1)]. The age of the patient at the time of the index lesion and radiotherapy ranged between 1 and 60 years (average 30.1 years). The dose of radiotherapy was not documented in the registry case details. The latent period until diagnosis of osteosarcoma was on average 13.5 years (range 7.8–23.6 years). Two patients had a biopsy only, one patient had localised resection of the maxilla, one had a limb salvage procedure, and four had radical surgery with a hip disarticulation (n ¼ 1), forequarter amputation (n ¼ 1) and above knee amputations (n ¼ 2). Six patients received palliative or adjuvant chemotherapy. Follow up was available for all eight patients. Six are deceased, surviving a median 33 months (range 4–66 months). The two remaining patients have survived 77 and 318 months, respectively. The overall 5 year survival rate was 38% (Table 3).

TABLE 3 Survival data* for Paget’s osteosarcoma and post-radiation osteosarcoma

DISCUSSION

Stage{

5 year survival %

Standard error

Median survival time (months)

13 14 0 10

9 13 0 6

9.25 3.75 2.17 7.25

38

17

Paget’s osteosarcoma IIB IIBþ IIIB Overall Post-radiation osteosarcoma Overall

Paget’s osteosarcoma arises in the context of Paget’s disease of bone, a disease of disordered bone metabolism that is a common condition in the elderly with an estimated, although declining, prevalence of 2.5% of British males,14 4% of Australians15 and 4.4% of European New Zealanders.16,17 The incidence of malignancy on a background of Paget’s disease of bone is variably estimated as 0.3% in England and Wales,18 0.95% in USA,7 rising to 10% in the context of polyostotic Paget’s disease.19 Osteosarcoma is the most common form of sarcomatous change, with fibrosarcoma and sarcoma, NOS, being recognised in lesser numbers.4,7,20 Our current series noted three cases of chondrosarcoma as well as a single case of fibrosarcoma. The proportion of registry cases of osteosarcoma secondary to Paget’s disease of bone was 11.9% in our series. This is much higher than reported by other groups; Dahlin and Coventry21 described a proportion of 3.3% (20 cases of

33.0

*Statistical calculation of survival data was performed using Life Tables analysis in SPSS 15.0 for Windows. {Stage as per Enneking et al.:13 IIB, histological high-grade tumour with extra-osseous (extra-compartmental) component; IIBþ, histological highgrade tumour with extra-osseous (extra-compartmental) component but with no chest X-ray available precluding assessment for pulmonary metastases; IIIB, skip lesions and or metastatic disease with extra-osseous (extra-compartmental) component.

TABLE 4

Demographic, pathological, clinical staging and outcome data of post-radiation osteosarcoma Age at index

Latency (years)

Age at OS (years)

Stage*

57 20 1 42

8.1 18.7 18.3 12.2

65 38 19 54

NR IIB IIB IIB

9

8.3

17

IIB

Femur (dist)

13

11.2

24

IIB

Breast carcinoma

Scapula

39

23.6

62

IIB

Lymphoma

Pelvis

60

7.8

68

IIB

Year

Index lesion

Site

1 2 3 4

1966 1974 1991 1993

GCT of bone OS RMS Lymphoma

Tibia (prox) Tibia (prox) Scapula Maxilla

5

2000

Ewing’s sarcoma

Humerus (prox)

6

2002

Ewing’s sarcoma

7

2003

8

2004

Treatment

Outcome

Survival (months)

AKA AKA FQA, chemRx Resection, chemRx Limb salvage, chemRx Hip dis-art, chemRx Bx, palliative chemRx Bx, chemRx

Deceased Alive Deceased Deceased

33 318 66 19

Alive

77

Deceased

13

Deceased

9

Deceased

4

*Stage as per Enneking et al.:13 IIB, histological high-grade tumour with extra-osseous (extra-compartmental) component. AKA, above knee amputation; Bx, biopsy; chemRx, chemotherapy; dis-art, disarticulation; FQA, forequarter amputation; GCT, giant cell tumour; NR, no records; OS, osteosarcoma; prox, proximal; RMS, rhabdomyosarcoma.

PAGET’S OSTEOSARCOMA AND POST-RADIATION OSTEOSARCOMA

600), Unni and Dahlin4 3% (30 cases of 962), and Huvos et al.22 5.5% (65 cases of 1177). The possible reason for our high incidence may relate to a higher incidence in New Zealand of Paget’s disease of bone16,17 as a consequence of our predominant British ethnicity. It may also be argued that as we see a large proportion of the bone tumours arising in our community, the higher proportion may be an accurate reflection of the true incidence of Paget’s osteosarcoma. Paget’s osteosarcoma typically occurs in elderly male patients with a mean age between 64 and 75 years (range 31–86 years) and gender ratio 2:1.4,6,7,20–21 The demographics of our patient population are also elderly, median age 72 years (range 48–87 years), but with a female bias (17 versus 14). The clinical presentation is often one of unrelenting pain, tender swelling and/or a pathological fracture. These symptoms in some cases are downplayed, being interpreted as an exacerbation of the underlying Paget’s disease of bone. This may account for the number of patients presenting with high stage (IIIB) disease, and with two also being diagnosed at post-mortem examination. Radiological imaging (Fig. 1) typically shows a lytic destructive lesion of the bony cortex and features of Paget’s disease of bone in non-symptomatic bones, demonstrating polyostotic disease. In some situations there may be a sclerotic pattern, mixed lytic and sclerotic pattern, or a permeative pattern. Often a soft tissue mass is seen. Paget’s osteosarcoma has a different skeletal distribution to that of primary osteosarcoma and can arise in any bone affected by Paget’s disease of bone. The most common sites

607

are the femur, pelvis, humerus and skull, with the spine described as the least common.7 Our series included a similar range of sites, and included the spine in two cases. The majority of our cases of sarcoma arose in the context of polyostotic Paget’s disease. Biochemical measurement of total alkaline phosphatase (an iso-enzyme of which is a marker of bone metabolic activity and by default Paget’s disease of bone) does not predict Paget’s osteosarcoma.5 The histological features of Paget’s osteosarcoma are indistinguishable from any other high grade osteosarcoma (Fig. 2). The additional features of Paget’s disease of bone are also seen, allowing a histological distinction to be made. The treatment of Paget’s osteosarcoma is primarily surgery. Limb salvage procedures may be undertaken, often for relief of symptoms, but can be made more difficult by the presence of underlying abnormal Pagetic bone. The presence of co-morbidities in the elderly limits the use of chemotherapy. The impact of medical management of Paget’s disease of bone with calcitonin or biphosphonates on the incidence of osteosarcoma is so far unknown. The overall survival of patients with Paget’s osteosarcoma is poor, and our patients fared equally with an overall 5 year survival of 10%. It does not appear to have changed with the introduction of more modern management.6 The 5 year survival rates of various groups reported from 1979 to 2005, range from 4.6% to 14%4–7,22 (Table 5). Interestingly, there are often two or three patients in each report who are long term survivors. The reasons for poor outcome are uncertain and may relate to the late presentation of

FIG. 1 Paget’s osteosarcoma, Patient 29. (A) Plain X-ray shows an extensive lytic destructive bone lesion involving the proximal head of the humerus on a background of architectural bone abnormality that consists of cortical thickening and prominent bone trabeculae. Within the thickened cortices of the shaft there are foci of permeative bone destruction. (B) Coronal T2 weighted MRI confirms a large intraosseous mixed intermediate and high signal intensity mass with multiple areas of focal cortical bone destruction and adjacent soft tissue reaction and mass. (C) Gross specimen shows similar features.

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TABLE 6 Reported index lesions associated with documented postradiation osteosarcoma9–11

FIG. 2 Paget’s osteosarcoma, Patient 29. High grade features and osteoid (H&E, 6100; inset, 6400).

TABLE 5 Reported overall survival of Paget’s osteosarcoma and postradiation osteosarcoma Report Paget’s osteosarcoma Unni and Dahlin, 19794 Wick et al., 19817 Huvos et al., 198322 Healy and Buss, 19915 Mankin and Hornicek, 20056 Our data, 2007 Post-radiation osteosarcoma Weatherby et al., 19819 Huvos et al., 198523 Healy and Buss, 19915 Koshy et al., 200528 Shaheen et al., 20068 Our data, 2007

Malignant

Benign

Osseous lesions (possible abnormal bone)

Osteosarcoma Ewing’s sarcoma

Non-osseous lesions (normal bone)

Carcinoma (uterus, cervix, breast and prostate) Lymphoma Rhabdomyosarcoma Malignant fibrous histiocytoma Brain tumours (NOS) Retinoblastoma Melanoma

Bone cyst (NOS) Osteochondroma Osteomyelitis (tuberculosis and bacterial) Giant cell tumour of bone Fibrous dysplasia Aneurysmal bone cyst Osteoblastoma/ osteoid osteoma Acne Haemangioma Congenital naevus Keloid scar Uterine leiomyoma Paraganglioma

NOS, not otherwise specified.

Survival data

(3/30) 10% 5 year survival 7.9% 5 year survival (3/65) 4.6% 5 year survival 510% 5 year survival 1942–1967 (2/13) 15% 1976–2001 (3/22) 14% 10% overall 5 year survival 30% 5 year survival (appendicular and craniofacial tumours) 0% 5 year survival (axial tumours) 17% 5 year survival 20% 5 year survival (approximate) 68% overall 5 year survival 69% 5 year survival for localised disease 38% overall 5 year survival (standard error 17%)

tumour with high stage disease, the presence of comorbidities in an elderly population, and possible inherent properties of Paget’s osteosarcoma such as increased vascularity.6 It will be interesting to note whether the number of cases will alter in light of the falling incidence of Paget’s disease of bone and the aging population. Post-radiation osteosarcoma is a recognised complication of therapeutic radiation.10,11 Preconditions for the diagnosis of post-radiation osteosarcoma include a history of the affected bone being in the field of radiation, a latent period between the radiation exposure and subsequent malignancy, and histological verification of a sarcoma.10 The index lesions are benign or malignant osseous or non-osseous lesions (Table 6). The index lesions in our cases were predominantly malignant. This reflects the benefits of treatment outweighing the risk of post-radiation sarcoma.5,8,9,23 Sarcoma is more likely to occur in patients treated for a prior malignancy.24 The dose of therapeutic radiation administered (orthovoltage) ranges from 8 Gy to 115 Gy, and a minimum dose is not established.5,8,25,26

The minimum latent period between irradiation and the development of sarcoma is considered to be 3–5 years,4,5,8,27 the duration of which is associated with neither the dose of radiation received nor the nature of the index lesion.5 The latent period may extend up to 55 years with an overall average of 8 to 16 years4,5,8,9 which includes the average latent period in our study of 13.5 years. The wide range of age groups (infants to elderly) and skeletal sites (axial and appendicular) affected by postradiation osteosarcoma reflects the variety of index lesions and the variable latent period. Our cases conform with a wide age range (17–68 years) reflecting the age of irradiation of the index lesion (1–60 years) and the variable latent period (7.8–23.6 years) (Table 4). Radiological imaging typically shows a sclerotic pattern with admixed lytic areas (Fig. 3). The periosteal reaction is minor compared with that often seen in primary osteosarcoma. Differentiating between areas of osteonecrosis, radiation osteitis and osteosarcoma can be troublesome and may require the use of multiple imaging modalities.5 Realistically, the radiological differential diagnoses of any lytic or sclerosing bony lesion with an associated soft tissue mass arising in an area exposed to radiation should include the possibility of post-radiation osteosarcoma. The histological features are those of a high grade osteosarcoma (Fig. 4). Early reports suggested a predilection for a chondroblastic appearance,10 whilst later papers report a fibroblastic appearance,5 similar to our experience. The outcome of post-radiation osteosarcoma has traditionally been poor with 5 year survival in the order of 20%,5,9,23 but recent papers describe a markedly improved survival with Koshy et al.28 describing up to 68% overall 5 year survival for patients receiving modern surgery and chemotherapy. Our overall 5 year survival of 38% (standard error 17%) is comparable, recognising an albeit small sample size. In summary, Paget’s osteosarcoma is a secondary osteosarcoma that affects perhaps 1% of patients with

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609

FIG. 3 Post-radiation osteosarcoma, Patient 5. (A) Initial plain X-ray at age 9 years shows a skeletally immature proximal humerus with a poorly defined lesion with a wide zone of transition, a partly sclerotic and partly lytic destructive bone lesion in the proximal diaphysis. There are areas of permeative cortical and medullary bone destruction and a markedly aggressive periosteal reaction including ‘sun burst’ features and periosteal elevation in classical ‘onion skin’ appearance. Radiographic features are typical of Ewing’s sarcoma. (B) Plain X-ray at age 17 years shows extensive and ill defined partly sclerotic and partly lytic areas. In the lytic portion there are areas of endosteal scalloping. There is minimal periosteal reaction. These appearances are not consistent with postradiation changes. (C) Coronal T2 weighted MRI shows a complex heterogeneous signal intensity intraosseous mass in the radiotherapy field with extension of tumour from the humeral head into the glenohumeral joint with an associated joint effusion. (D) Gross specimen shows similar features.

Post-radiation osteosarcoma is a rarer type of secondary osteosarcoma that can arise in patients of any age and in any bone after treatment of benign or malignant osseous or non-osseous index lesions in which the bone is included in the radiation field. The latent period is variable, being generally greater than 3–5 years and may be much longer. The radiation dose is variable, ranging from 8 Gy to 115 Gy. Treatment is similar to that for primary osteosarcoma and, whilst traditionally regarded as poor, outcomes have now improved. ACKNOWLEDGEMENTS The authors wish to acknowledge and thank Ms Aileen Isaac, Dr J. Gary French and Dr Clinton Pinto for their assistance in the preparation of this manuscript.

FIG. 4 Post-radiation osteosarcoma, Patient 5. High grade features and osteoid (H&E, 6 100; inset, 6 400).

Address for correspondence: Dr M. S. Dray, Department of Anatomical Pathology, Laboratory Services, Middlemore Hospital, Private Bag, Otahuhu, Auckland, New Zealand. E-mail: [email protected]

References Paget’s disease of bone and tends to arise in those with polyostotic disease. The incidence of Paget’s disease of bone, though falling, implies a significant number of cases of osteosarcoma. It affects predominantly the elderly, with both axial and appendicular skeleton involved in approximately equal proportions, and continues to have a poor prognosis that has changed little over the previous century.

1. Hashimoto K, Hatori M, Hosaka M, et al. Osteosarcoma arising from giant cell tumor of bone ten years after primary surgery: a case report and review of the literature. Tohoku J Exp Med 2006; 208: 157–62. 2. Seki T, Fukuda H, Ishii Y, et al. Malignant transformation of benign osteoblastoma. A case report. J Bone Joint Surg Am 1975; 57: 424–6. 3. Hoshi M, Matsumoto S, Manabe J, et al. Malignant change secondary to fibrous dysplasia. Int J Clin Oncol 2006; 11: 229–35. 4. Unni KK, Dahlin DC. Premalignant tumors and conditions of bone. Am J Surg Pathol 1979; 3: 47–60. 5. Healey JH, Buss D. Radiation and pagetic osteogenic sarcomas. Clin Orthop 1991; 270: 128–34.

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