Purpose: The aim of the study was to document the trends in survival from childhood osteosarcoma in Scotland using clinical data held in the Scottish Bone Tumor Registry from 1933 onwards.

Methods and Results: From 217 osteosarcoma patients identified in Scotland aged 18 and under with case notes in the BTR, 184 with non-metastatic appendicular disease were included in the analysis. Kaplan Meier curves were constructed and log rank statistics calculated for univariate analysis. Multivariate analysis was performed using the Cox regression proportional hazards model.

Epidemiological figures reflect those of other studies. The male: female ratio was 1.4: 1, most common age at diagnosis was 16 – 18 and the most common site of tumor was the distal femur, 71% of tumors occurred at the knee. 5 year and median survival were 30% and 26 months for the entire period. 5 year survival was found to have improved from 21% between 1933–1959 to 62% in 1990 – 1999. On univariate analysis the most significant factor influencing outcome was use of chemotherapy in treatment (p< 0.00005). On multivariate analysis, date of diagnosis had most influence on the hazard ratio, the greatest difference being found between diagnoses pre and post – 1980. Site of tumor was also found to be a significant factor (p=0.044). The survival from Osteosarcoma in Scotland in recent years was found to be no worse than the rest of the UK as had previously been suggested.

Conclusion: Survival from childhood osteosarcoma in Scotland has improved significantly from the 1930s to the present day. This is largely due to the introduction of effective chemotherapy protocols into the treatment regimen. These improvements reflect those seen in other countries over the same period.

Introduction: Swellings of the medial end of the clavicle in children and adolescents are common. The vast majority represent either osteomyelitis, or a benign conditions such as eosinophilic granuloma. Their radiographic and early clinical appearance, however, are difficult often to discriminate from Ewing’s sarcoma. Unrewarding biopsies are often performed.

Aims: To identify incidences of malignant neoplasm at the medial end of clavicle in patients aged 18 and under from the Scottish Bone Tumour Registry (SBTR), and by questionnaire from European tumour databases.

Methods: The SBTR was searched for childhood malignant neoplasms as above. Questionnaires were sent to 171 European regional and national tumour databases. Information requested included details of patients with malignant neoplasms as above, longevity of database operation and population served. An estimate of European child population rates was made based on a conservative (North Italian) calculation of children aged under 18 representing 14.4% of the population (comparison our region 21.9%). Confidence intervals were calculated using Wilson method.

Results: The SBTR identified 7 children with neoplasms of the clavicle out of a total register of 4009 cases. Only 1 was malignant and this at the lateral end.

Responses were gained from 56 European databases. National databases were less able to identify this detailed anatomical site than regional ones. 30 databases from 12 countries responded with complete data representing 1.619 billion total population person-years. Four malignant tumours at the medial end of clavicle were identified from a total of 233.2 million children-years at risk.

Discussion: By extrapolation, in our region (population 779,000) a malignant childhood medial clavicle tumours is estimated to occur once every 342 years (95%CI 91 years – ∞). It is recommended that biopsy of such childhood swellings should be restricted to patients who present with features atypical of infection or benign lesions.

Introduction: The aims of the study were to analyse the presenting features of chondroasarcoma for prognostic significance, to observe the effects of grade and surgical management on local recurrence, metastasis and survival: and to assess the significance of delays to consultation and treatment.

Methods: From Scottish Bone Tumour Registry Records, 24 proximal humeral chondrosarcomas were treated between 1937 and 2002 in several hospitals in Scotland. Clinical records were available for all patients. Only 4 patients were eventually lost to follow-up. Age at presentation ranged for 16 to 79 (median 56) and male to female ration was 2:1. Patients were followed up for a range of 5 months to 24 years (median 6.5 years). Tumour histology was systematically reviewed: 5 (22%) were grade 1, 12 (52%) were grade 2, and 6 (26%) were grade 3. Dedifferentiated tumours were considered as grade 3.

Results: Pain was almost invariable (23/24), but its severity increased with grade. In the absence of pathological fracture (fracture in 4 Patients), swelling was significantly associated with increasing grade (X2+8.56, p+0.0139), as was symptom progression (X2=7.52, p=0.0232). Delay in diagnosis was calculated separately as ‘patient delay’ (range 0–69 months) and ‘doctor delay’ (range 0–132 months). No improvement in diagnostic delay was noted in this time period (1937–2002)

All cases were biopsied. 37% of these were excisional biopsies, 29% were incisional biopsies and 17% were needle biopsies. 21 patients (88%) received definitive surgery. Of these 5 had forequarter amputations (24%), 11 cases were excised marginally (52%), and 5 cases curetted (24%). Surgical choice was highly dependent on grade (X2=4.9256, p=0.005). In all cases the intent was curative.

2 patients had metastasis disease at diagnosis, and 5 developed metastases after definitive surgery. 4 patients had local recurrence (all had undergone wide local excision). All patients with grade 1 tumours remained disease free. Cumulative survival at 5 years was 57% and at 10 years 42%. Patient age did not affect survival. 5 year survival in grade 1, 2 and 3 tumours was 100%, 83% and 20% respectively. 4 of 5 patients undergoing amputation developed metastases and survival was significantly worse in the amputation group. Local recurrence in the wide local excision group did not diminish prospects for survival.

Discussion: Swelling predicts aggressive disease; as found in studies in childhood sarcomas. Progressive symptoms and serve pain are additional features indicative of high histological grade. In contract to improvements noted in several other studies, patient delay is highly variable and has not been demonstrably reduced over time.

Curettage was chosen for most grade 1 and some grade 2 tumours. Although maintenance of function is far better, our study provides no evidence that curettage results in increased local recurrence rates. Indeed, local recurrence in the wide local excision group did not depress survival figures. Because of early death in the amputation group, we would recommend avoidance of amputation in favour of wide local excision in almost all cases if possible. Age alone should not be a factor in determining surgical treatment.

Malignant peripheral nerve sheath tumours (MPNSTs) constitute 10% of soft tissue sarcomas. A significant proportion arise in neurofibromatosis type 1 (NF1). Several publications have compared MPNST survival in sporadic and NF1 patients, without consensus on whether NF1 is an independent factor for poor prognosis.

Clinical and histological data from 135 proven MPNSTs were analysed from 2 national centres for soft tissue tumour surgery diagnosed from 1979 to 2000. 129 patients had follow-up data from 6 months to 21 years. 35 were from patients with NF1. Local treatment involved surgery in surgery in 95%, radiotherapy in 44% and chemotherapy in 21%.

NF1 patients were younger than those with sporadic tumours (median age 26 years vs 53 years, p< 0. 001). Overall MPNST survival was almost identical to that in soft tissue sarcomas as a whole, but was worse in NF1 than in sporadic tumours (33% vs 72% at 30 months [p< 0. 01], 17% vs 39% at 60 months, 6% vs 21% at 120 months). A trend towards shorter time to local recurrence was seen in NF1, but not time to metastasis. Superficial tumours gave improved prognosis. Tumour volume over 100ml was associated with worse survival (46% vs 91% at 30 months, p< 0. 02), as was histological grade (80% high grade vs 25% low grade at 60 months, p< 0. 01). In terms of location, a non-significant over-representation of NF1 MPNSTs in the sciatic and brachial plexii was identified.

NF1 and sporadic MPNSTs exhibited no difference in depth or tumour volume profile, although NF1 tended towards higher grade. Analysis of survival in only high grade tumours, however, still resulted in a significant survival disadvantage in NF1 (33% vs 70% at 30 months, p< 0. 01). Removal of brachial and sciatic plexus tumours from analysis did not affect survivorship profiles in NF1 and sporadic MPNSTs.

Grade, volume and tumour depth correlate with survival; only 7 of 45 patients with deep high grade tumours over 100ml volume were observed to survive beyond 2 years. MPNST survival is worse in NF1 than sporadic tumours. Grade, depth, site and volume differences could not explain this disadvantage.

To determine whether the spectrum of genetic mutation in Hereditary Multiple Exostoses supports a neoplastic aetiology for this condition.

Historically, experts have been cautious in attributing neoplastic qualities to the osteochondroma. Solomon states ‘[osteochondromas] are not neoplastic in the ordinary sense of the word’; Morton that it ‘is not a tumour but a growth-aberration; Peterson that the ‘osteochondroma is not a true neoplasm’; and Schmale that ‘exostoses are the result of dysplasia of the lateral apect of the growth-plate’. There are, however, several features of osteochondroma behaviour common to other neoplasms which suggest a neoplastic aetiology:

the existence of an autosomal dominant inherited multiple form, in which lesions are histologically identical to the solitary form.

Recent genetic data has supported a fresh look at the neoplastic nature of osteochondromas. EXT1 and EXT2 genes are responsible for Hereditary Multiple Exostoses (HME). EXT1 codes for a protein which alters the synthesis and display of cell-surface heparan sulphate glycosaminoglycans; molecules which affect cellular growth, differentiation, motility and adhesion. Loss-of-function of such a gene may initiate a neoplastic pathogenesis in osteochondromas.

From 1996–1999, 51 families with HME were screened for EXT mutation, with mutations identified in 41 families. EXT mutation was assessed by means of fluorescent single-strand conformational polymorphism (f-SSCP) screening, followed by sequencing analysis.

Results : All missense mutations had previously been reported in the literature. In contrast, only 9 of 34 loss-of function mutations (frame-shift, splice-site and nonsense) had previously been reported.

All frame-shift, splice-site and nonsense mutations are loss-of-function. Missense mutations may result in partial or complete dysfunction if a crucial folding or binding site is involved. Since no missense mutations were new, this suggested their mutation sites are important, and may effectively result in loss-of-function. These data strongly support a tumour suppressor gene function for EXT genes, and a neoplastic pathogenesis for HME.