Shoulder exostoses in hereditary multiple exostoses: probability of surgery and malignant change

Shoulder exostoses in hereditary multiple exostoses: probability of surgery and malignant change

J Shoulder Elbow Surg (2011) 20, 290-294 www.elsevier.com/locate/ymse Shoulder exostoses in hereditary multiple exostoses: probability of surgery an...

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J Shoulder Elbow Surg (2011) 20, 290-294

www.elsevier.com/locate/ymse

Shoulder exostoses in hereditary multiple exostoses: probability of surgery and malignant change Nicholas David Clement, MRCSEd*, Che E. Ng, MBBS, Daniel E. Porter, FRCSEd (Tr & Orth) Department of Orthopaedics and Trauma, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom Hypothesis: Patients with hereditary multiple exostoses (HME) in association with palpable shoulder exostoses are more severely affected by their disease. Materials and methods: From a prospective database of 78 families with HME identified, 172 patients were identified. Demographic details, deformity, functional scores, standing height, number of exostoses, site, exostosin genotype (EXT1 and EXT2), surgical excision, and malignant change were recorded. Nonparametric tests were used to compare patients with and without shoulder exostoses (clavicle, scapula, and humerus). Results: There were 5361 palpable exostoses, of which 14% were of the shoulder and were present in 145 patients (84.3%). There was a younger mean age (26.8 vs 37.9 years) and a male predominance in those individuals with shoulder exostoses (P ¼ .0005). Patients with shoulder exostoses had significantly worse disease (P < .05). EXT1 mutations were more commonly observed in those with shoulder exostoses (odds ratio [OR], 20.6; 95% confidence interval [CI], 11.2-28.5; P ¼ .001). The likelihood of surgical excision was greater in those with shoulder exostoses (OR, 2.8) and highest for scapular exostoses (OR, 3.7). Risk factors for surgical excision of shoulder exostoses were younger age (P ¼ .03) and male gender (P < .008). Seven chondrosarcomas occurred, 2 scapular and a proximal humeral. The probability of malignant change of was highest for palpable scapular exostoses relative to any other anatomic site (OR, 12.3; P ¼ .05). Conclusion: Shoulder exostoses have a male predominance, and patients are more likely to have an EXT1 mutation. The presence of shoulder exostoses could serve as a tool to identify those individuals at high probability of malignant change. Discussion: The existence of shoulder exostoses identifies those individuals with a high probability of having an EXT1 genotype (OR 20.6, 94.4% sensitivity, 84.8% positive predictive value), which is associated with sarcomatous change. Level of evidence: Level III, Restrospective Case Control, Treatment Study. Ó 2011 Journal of Shoulder and Elbow Surgery Board of Trustees. Keywords: Hereditary multiple exostoses; shoulder; sarcoma; function; EXT

*Reprint requests: N.D. Clement, MRCSEd, Speciality Trainee Registrar, Department of Orthopaedics and Trauma, Royal Infirmary of Edinburgh, Little France, EH16 4SA, United Kingdom. E-mail address: [email protected] (N.D. Clement).

Hereditary multiple exostoses (HME) is one of the most common inherited musculoskeletal conditions, with an incidence of 1 in 50,000, and has an autosomal-dominant trait.9 The osteochondromas are distributed throughout the

1058-2746/$ - see front matter Ó 2011 Journal of Shoulder and Elbow Surgery Board of Trustees. doi:10.1016/j.jse.2010.07.020

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Materials and methods Ethical approval was obtained from the Central Oxford Research Ethics Committee (COREC code: 93.257) for the DNA sample collection and genetic analysis.

Patients

Figure 1

Exostoses of the proximal humerus.

skeleton, most commonly at the metaphysis of long bones. Invariably, the proximal humerus is affected radiographically10 and accounts for 7% of all palpable exostoses.8 Disease severity is known to be related to genotype, with those patients with mutations of the gene expressing exostosin-1 (EXT1) being affected more severely than those with EXT2 mutations.8 The risk of sarcomatous change is also greater in patients with EXT1 mutations.3 Despite the common occurrence of exostoses around the shoulder in HME (Fig. 1), no published study to date has described the epidemiology of shoulder exostoses or the associated disease severity, nor have the risk factors for surgical excision been identified. We hypothesized that patients with shoulder exostoses have more severe disease. If this were the case, these patients would be more likely to have EXT1 mutation, which is associated with an increased risk of sarcomatous change of the exostoses.3,6,12,14 Hence, palpable exostoses of the shoulder could be used as a marker for inclusion within a screening program. The purpose of the present study was to describe the epidemiology, disease severity, and surgical probability of excision and malignant change of shoulder exostoses in patients with HME. We used an existing prospectively complied database of patients with HME8 and compared those with and without shoulder exostoses.

The database was prospectively compiled between 1996 and 2000 and comprised 172 patients (90 females, 82 males; age range, 2 years to 76 years) from 78 families with HME. Those researchers collecting genotype data were blind to the outcome of phenotype data, and vice versa. The patients were identified and referred by orthopedic surgeons, geneticists, and by self-presentation. All patients were informed of the study and agreed to take part. Patients with an isolated exostosis were excluded. A single examiner collected all of the clinical data, including clinical history, demographic details, and family pedigree. The severity of the disease was graded according to deformity and functional scores (Table I).8 Standing height was measured and recorded in centiles, matched for age and sex.7 The site and number of exostoses was recorded. The number and site of surgical excisions and malignant change was also recorded. All surgery was performed for symptomatic exostoses or, more rarely, as an excisional biopsy. The genotype data were compiled as previously described by Porter et al.8 Genomic DNA was obtained from blood or buccal swabs. EXT1 and EXT2 exons were amplified by polymerase chain reaction from the DNA. The analysis was performed by confirmative sensitive gel electrophoresis and fluorescent singlestrand conformational polymorphism analysis, but most of the study was done using denaturing high-performance liquid chromatography.

Statistical analysis The 172 patients were divided into those with and without proximal humerus, clavicle, and scapular exostoses and further stratified into those individuals who did or did not undergo surgical excision. Statistical analysis of all data was undertaken using nonparametric tests, including the Fisher exact test, MannWhitney U test, and Kendall’s test of rank correlation.

Results The number of palpable exostoses in the 172 patients varied according to anatomic site, which is illustrated in Fig. 2. The absolute number of palpable exostoses per individual ranged from 0 to 172. No correlation with age and number of exostoses was observed (rank coefficient ¼ 0.027, P ¼ .296). There were 5361 palpable exostoses, of which there were 374 proximal humeral (7.0%), 212 clavicular (4.0%), and 171 (3.2%) scapular exostoses. Genotyping showed 29 individuals had no identifiable mutation, 71 individuals had an EXT1 mutation, and 72 had an EXT2 mutation. No significant gender difference was observed between EXT1 and EXT2 mutations.

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Table I Severity scoring criteria for deformity and functional scores in hereditary multiple exostoses disease) Criterion

Severity

Score

Ulnar length proportional to height (%)

>14

0

Forearm deformity

Knee deformity, deg

Functional Forearm range of rotation, deg

Elbow range of flexion, deg

Knee range of flexion, deg

13-13.9 12-12.9 <12 None Ulnar negative variance, no bowing Forearm bowing Radial head dislocation None Genu vaga 5-10 Genu vaga 11-15 Genu vaga >15

1 2 3 0 1 2 3 0 1 2 3

>180

0

160-179 140-159 <140 >140

1 2 3 0

130-139 120-129 <120 >130

1 2 3 0

120-129 110-119 <110

1 2 3

)Range

0-36 per side (bilateral assessment) with a minimum score of 0, maximum score of 72. A higher score signifies a more severe disease.

Shoulder exostoses were palpable in 145 of the 172 individuals. The mean age was 26.8 years for those individuals with shoulder exostoses and 37.9 years for those without (P ¼ .005); however, there was no association with age and number of exostoses (rank correlation coefficient ¼ 0.03, P ¼ .5; Fig. 3). There was a male predominance in those with shoulder exostoses (1:1.3 ratio); in contrast, there was a female predominance (1:1.1 ratio) in those individuals without (n ¼ 27). Those individuals with shoulder exostoses had significantly worse disease than those without, according to several severity parameters (Fig. 4). A significant difference was demonstrated for all severity parameters (Fig. 4; P < .05). In those for whom a mutation was identified, EXT1 and EXT2 mutations were observed in 67 (83.7%) and 13 (16.3%) of individuals with shoulder exostoses and in 4 (20.0%) and 16 (80.0%) of those individuals without shoulder exostoses, respectively. This difference in prevalence of EXT1 and EXT2 mutations according to the presence or absence of shoulder exostoses was significant (odds

Clavicle 3.7% Scapula 3.4% Proximal humerus 6.9% Ribs 4.2% Distal humerus 0.4%

Proximal femur 0 2%

Spine 0.1%

Proximal radius 1.0% Proximal ulna 0.2%

Pelvis 2.1%

Distal radius 9.7% Distal ulna 5.5%

Hand 17.3%

Distal femur 10.9% Proximal tibia 8.4% Proximal fibula 6.2%

Distal tibia 8.3% Distal fibula 6.9%

Foot 4.6%

Figure 2 Anatomic distribution of the 5361 exostoses (%) in this study.

ratio [OR], 20.6; 95% confidence interval [CI], 11.2-28.5, P ¼ .001). The presence of shoulder exostoses is 94.4% sensitive and 55.2% specific of an individual with an EXT1 mutation, with a positive predictive value of 84.8% and negative predictive value of 80.0%. The 172 individuals, with 5361 exostoses, underwent 278 operations; of which, 83 operations were performed in 49 individuals for shoulder exostoses, with excision of 44 proximal humeral, 12 clavicular, and 27 scapular exostoses. There was a significantly increased likelihood of surgical excision of shoulder exostoses relative to all other exostoses (OR, 2.8; 95% CI, 1.4-3.2; P ¼ .002). This increased likelihood varied according to anatomic site around the shoulder: proximal humeral (OR, 2.7; P ¼ .02), clavicular (OR, 1.2; P ¼ .04), and scapular (OR, 3.7; P ¼ .007). Risk factors for surgical excision of shoulder exostoses were younger age (28.5 years vs 33.1 years, P ¼ .03) and male sex (OR, 1.6; P ¼ .008). No correlation was observed between number of shoulder exostoses and surgery. There was no significant difference in the severity of disease parameters between those who underwent surgery and those who did not for all individuals with shoulder exostoses. Seven chondrosarcomas occurred within the study cohort, comprising 2 scapular and 2 spinal chondrosarcomas, and a single pelvic, rib, and proximal humeral chondrosarcoma. There was an increased probability of

Probability of surgery, malignant change

293

25

Exostose

20 15 10 5 0 0

10

20

30

40

50

60

70

80

Age

Figure 3 Number of palpable exostoses in the shoulder according to the age of the individual. Shoulder Exos tos es

60

No Shoulder Exos tos es

50

50

40.7

40 30

22

14.8 16.5

20

19.6

21.1

7.7

10

15.9

17.6 4.4

8.2

1.3 0.8 ro ce ed ur es

xo st os es

Su rg ic a lp

To ta lS co re

Nu m be ro fE

io na lS co re

Sc or e

Fu nc t

ity

en t il De fo rm

gh tC He i

He i

gh t(

dm

e

)

0

Figure 4 Disease severity according to the presence or absence of shoulder exostoses is presented as the mean score for each parameter. The difference between the 2 groups for all disease severity parameters was significant (P < .05).

malignant change for palpable scapular exostoses relative to all other exostoses (OR, 12.3; P ¼ .05). An EXT1 mutation was identified in 6 of the 7 individuals, but no mutation was identified in the other, which was affecting the pelvis.

Discussion We have shown that shoulder exostoses account for 14% of all palpable exostoses in individuals with HME and predominately occur in young men. Individuals with shoulder exostoses are affected more severely than those without. This finding is affirmed with an increased prevalence of EXT1 mutations in those with shoulder exostoses, which is associated with more severe disease.8 There is an increased probability of surgical excision of shoulder exostoses relative to all other exostoses, which is even greater for scapular exostoses (OR, 3.7). Risk factors for surgical excision of shoulder exostoses are younger age and male sex. From our cohort, scapular exostoses are at an increased probability of malignant change compared with other anatomic sites. The reported sex distribution of HME differs in the literature, ranging from an equal11 distribution to a 1:1.5 ratio in favor of males.9 In contrast, our cohort consisted mainly of females(1:1.1), but this ratio was reversed for the group that had shoulder exostoses (1:1.3), being

predominantly male. There is a tendency towards more severe disease in males.9,11 This trend is consistent with our shoulder exostoses group, who were more severely affected by their disease. The younger age of the shoulder exostoses group and associated increased probability of excision may be due to the change in both surgical practice and a greater importance of cosmetic appearance to the patient. Schmale et al9 reported that 50% of individuals with HME had palpable exostoses of the proximal humerus; however, we report a greater number with 73% (126 of 172) of our patients having exostoses of the proximal humerus. Our figure is supported by x-ray imaging studies that have reported a prevalence of 85% to 98% for exostoses of the proximal humerus, with approximately 20% of exostoses being impalpable.10,11 The need for surgical excision is poorly reported. Two of the largest case series report that between 74% and 100% of individuals with HME will undergo operative excision of their exostoses, and each will have approximately 3 procedures.9,10 We have demonstrated a similar rate, with 95 of 172 patients (55.2%) undergoing a surgical procedure, with average of 1.6 surgical excisions per patient. Relative to all other exostoses, we have demonstrated an increased likelihood of surgical excision with shoulder exostoses (OR, 2.8), and this increased further with scapular exostoses (OR, 3.7). An explanation for this may be the subcutaneous nature of the scapula and potential interference of the scapulothoracic rhythm. Disruption of shoulder function may inhibit sporting activities, and this may explain why we have identified male sex and younger age as risk factors for excision of shoulder exostoses. The lifetime risk of sarcoma in HME is thought to be approximately 2% to 4%.6,12-14 The commonest sites of malignant change are the ilium (39.9%), scapula (10.9%), and pubic rami (10.9%).1 The scapula, clavicle, and proximal humerus account for 17.4% (8 of 46) of secondary chondrosarcomas in patients with HME.1 The scapula accounted for 2 of the 7 chondrosarcomas within our cohort, and there was an increased probability of malignant change of scapular exostoses compared with all other exostoses (OR, 12.3). The reason for this increased probability is not clear, but may relate to the anatomic shape of the scapula and the unique epiphyseal features compared with long bones. The increased risk due to the flat shape is supported by the high incidence of secondary iliac chondrosarcomas in HME, which has a similar embryologic origin and anatomic form. The scapula has 7 ossification centers and has an unusually long, thin epiphysis at its medial border,2 where the reported incidence of scapular exostoses is greatest.11 This suggests that the epiphyseal anatomy is related to the occurrence of the exostoses and may relate to the likelihood of malignant change. Some have suggested that individuals with HME should enter a screening program in an effort to identify malignant change early.8 The annual risk of sarcomatous change is hypothesized to be 0.1% per annum between the ages of

294 30 and 50 years, which are the highest-risk decades. This figure may be double in those individuals with EXT1 mutations, being associated with chondrosarcoma.8 This annual incidence is comparable to the occurrence of breast cancer, for which there is currently a screening program in the United Kingdom.5 The radiologic survey might be restricted to the axial skeleton, where 80%1 of chondrosarcomas occur, and in which only 13.5% of palpable exostoses occur.8 Traditional plain radiographs deliver a significant radiation dose, which would be multiplied over 2 or 3 decades. The use of magnetic resonance imaging (MRI) has been proposed as a potential screening tool.8 This would be costly and time consuming, and there are currently no data published regarding the efficacy of an MRI screening program. A tool or algorithm to target those individuals with HME to be at the highest risk of sarcomatous change would allow resources to be concentrated. No association to date has been demonstrated with family history, sex, age, or disease severity and malignant change. The presence of shoulder exostoses could be used as a potential targeting tool for screening individuals with HME. The existence of shoulder exostoses identifies those individuals with a high probability to have an EXT1 genotype (OR, 20.6; 94.4% sensitivity, 84.8% positive predictive value). Although most of the reported sarcomas in HME occur in patients with the EXT1 genotype, 2 cases have been reported in patients with an EXT2 mutation.4,8 This would decrease the screening population by 15.7% if only those with shoulder exostoses where included. Continued annual clinical assessment of these patients could still occur in conjunction with radiographic assessment. Further studies regarding the efficacy and a cost-benefit analysis of such a screening program would need to be performed to confirm an overall benefit.

Conclusion Shoulder exostoses are common in individuals with HME and are associated with more severe disease than in those without. There is an increased probability of surgical excision of shoulder exostoses that is even greater for the scapula. The presence of shoulder exostoses could be used as a tool to better define those individuals at high chance of malignant change who should undergo serial radiographic surveillance.

N.D. Clement et al.

Disclaimer No outside funding or grants were received to assist with this study. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

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