- Email: [email protected]
Osteomyelitis with proliferative periostitis: an unusual case
Osteomyelitis with proliferative periostitis: an unusual case Antonio C. K. Tong, BDS, PhD, FRACDS(OMS),a Irene O. L. Ng, MD, PhD, FRCPath,b and K. M. Au Yeung, MBBS, FRCR, FRANZCR,c Hong Kong THE GOVERNMENT OF THE HKSAR, THE UNIVERSITY OF HONG KONG, AND CANOSSA HOSPITAL
Chronic osteomyelitis with subperiosteal new bone formation results from periosteal reaction to chronic inflammatory/infectious stimulation. In the maxillofacial region, it has traditionally been termed Garrè’s osteomyelitis with proliferative periostitis and more recently periostitis ossificans. The term Garrè’s osteomyelitis has been regarded as a misnomer by many authors in the recent literature. The term chronic osteomyelitis with proliferative periostitis, although cumbersome, is considered to be the most accurate description of the pathology. It usually affects the mandible of young patients secondary to dental infection. Management involves removal of the source of infection and antibiotic treatment. We present an unusual case of chronic osteomyelitis with proliferative periostitis affecting the mandible of a 12-year-old patient. The source of infection was related to the developing lower left third molar, which had apparently no communication with the oral cavity. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102:e14-e19)
Bone formation as a result of periosteal reaction occurs secondary to a number of bony pathoses. These include osteomyelitis, trauma, and neoplastic diseases. Chronic osteomyelitis with associated periosteal new bone formation has been described under different clinical terms including Garrè’s osteomyelitis, proliferative periostitis, and periostitis ossificans. Since the publication of C. Garrè1 on the pattern of acute osteomyelitis, his name had been associated with a form of inflammatory periosteal new bone formation with an onionskin pattern of cortical bone duplication. The term “Garrè’s osteomyelitis” is generally taken to be synonymous with chronic osteomyelitis with proliferative periostitis. However, Neville et al.2 point out that Garrè did not have any specimens for histopatholgic studies and Roentgen did not discover x-rays until 2 years after Garrè’s publication. They therefore suggested that the term “Garrè’s osteomyelitis” is not a proper designation for such pathology. In the orthopedic literature, periostitis ossificans of the tibia is a well-known pathology. The first cases of proliferative periostitis affecting the jawbone were described by Berger3 and Pell.4 This condition usually involves the anterior aspect of the tibia and the lateral
surface of the body of the mandible. It commonly occurs in young patients with a mean age of 13 years. Sporadic cases had been reported in patients in their twenties and in infants around 2 years old. This is related to periosteal osteoblastic activity. Formation of subperiosteal bone represents a periosteal reaction to inflammation. The histopathology of osteomyelitis with proliferative periostitis is actually distinct. The affected periosteum forms several layers of vital bone parallel to each other and to the surface of the affected bone. An intact cortex is present below the new bone formation. The most common provoking factors are dental caries with associated periapical inflammation, periodontal infections, fractures, and nonodontogenic infections. Most cases arise in the molar premolar area. Radiographic examination showed bony laminations parallel to each other and to the cortical surface of the involved bone. Appropriate radiographic angulation may bring out the radiolucent zone of soft tissue between the original bony cortex and the newly formed reactive bone. Lesions that must be considered in the differential diagnosis of proliferative periostitis are Ewing’s sarcoma, fibrous dysplasia, osteogenic sarcoma, infantile cortical hyperostosis, callus, exostosis, calcifying hematoma, and osteotomas.5
a
Senior Dental Officer, Department of Health, The Government of the HKSAR, Hong Kong. b Professor, Department of Pathology, The University of Hong Kong, Hong Kong. c Specialist Radiologist, Canossa Hospital, Hong Kong. Received for publication Jan 10, 2006; returned for revision Mar 2, 2006; accepted for publication Mar 29, 2006. 1079-2104/$ - see front matter © 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2006.03.025
e14
CASE REPORT A 12-year-old male patient presented with a progressive left facial swelling of 6-week duration. There was no related history of trauma or dental treatment involving the region. Clinical examination showed a firm 2 ⫻ 3-cm swelling involving the left masseteric region with severe trismus. Intraoral examination showed no overt pathology. No carious lesions or periodontal patholo-
OOOOE Volume 102, Number 5
Tong et al e15
Fig. 1. Superiosteal new bone formation in the left angular region of the mandible lateral to the tooth germ of the unerupted lower left third molar.
gies were found on dental and periodontal examinations. There was an associated left submandibular lymphadenopathy. There was no associated sensory dysfunction of the inferior alveolar nerve or other abnormal neurologic signs. Plain radiographic findings showed an unerupted lower left wisdom tooth with incomplete root formation and a periapical radiolucent area. An area of possible cortical bone formation was present lateral to the left angle region of the mandible on the postero-anterior radiograph (Fig. 1). This was more clearly seen on computed tomography (CT) (Fig. 2). Inflammatory response of the associated muscles and soft tissue were seen on magnetic resonance (MR) imaging (Fig. 3). Based on the clinical-radiographic features of deposition of extracortical new bone outside the existing intact bony cortex, and the presence of an unerupted wisdom tooth with a periapical radiolucency, a provisional diagnosis of chronic osteomyelitis with proliferative periostitis was considered to be most likely. As an obvious dental or periodontal source of infection was not apparent, it was considered necessary to perform a bone biopsy to rule out lesions showing similar radiographic features. These include Ewing’s sarcoma, endosteal, parosteal osteosarcomas, osteosarcomas, and chrondrosarcomas. An exploration of the left mandibular third molar and angle region via an intraoral approach was made under general anesthesia. An incision was made along the external oblique ridge lateral to the left mandible mo-
Fig. 2. Coronal CT showing new bone formation over the lateral cortical surface of the mandible extending from the third molar region to the posterior border of the ramus. The associated masseteric muscle was enlarged.
lars. The mucoperiosteal soft tissue lateral to the left mandibular angle region was reflected to reach the angle region of the ramus. Multiple fragments of spongy bone were found lateral to the cortical surface of the mandible in the region of the lower left third molar extending to the angle region. Multiple foci of
e16
Tong et al
OOOOE November 2006
Fig. 3. Postcontrast axial T1-weighted (fat-suppressed) images depict the abnormal contrast-enhancement of the masseter muscle, marrow of the mandible extending to the medial pterygoid muscle. Periosteal thickening is also demonstrated lateral to the angle of mandible. No gross bony destruction is seen at the mandible.
pus collection were found in association with the spongy bone islands. The third molar was removed surgically. Pus and hard and soft tissue samples including the subperiosteal bony tissue were taken for microbiology and histopathology. The surgical site was irrigated with high doses of antibiotics (ampicillin, salbactum, and metronidazole). Microbiologic examination of hard and soft tissue was performed. Staining for aerobic, anaerobic, and acid-fast bacillus yielded only commensal organisms. Histological study of the bony tissue lateral to the unerupted tooth showed reactive woven bone formation with osteoblastic rimming of the woven bony trabeculae (Figs. 4 and 5). The fibrous stroma in-between the bony trabeculae was vascular and contained a mild lymphoplasmacytic inflammatory infiltrate. Scattered osteoclasts were present. The subperiosteal “new” bone also showed reactive woven bone formation with the bony trabeculae arranged in parallel to one another. Osteoblastic rimming of the woven bony trabeculae was prominent. Inflammatory cells were scant. The soft tissue adjacent to the unerupted tooth consisted of inflamed granulation tissue. The histopathologic features were consistent with a diagnosis of chronic osteomyelitis with proliferative periostitis. Antibiotic treatment with ampicillin and salbactum
was continued for 4 weeks after the surgical exploration. Resolution of inflammation and trismus was achieved 3 to 4 weeks after the surgical exploration. Radiographic examination 2 years after the surgical intervention showed restoration of normal bony contour in the left angular region of the mandible (Fig. 6). DISCUSSION Proliferative periostitis is a distinctive type of chronic osteomyelitis. It has commonly been regarded as synonymous with Garrè’s osteomyelitis. In a literature review, Wood et al.6 found that Garré did not describe this type of osteomyelitis at all and his name had been consistently misspelled in the literature. Therefore the term Garrè’s osteomyelitis may not be appropriate for describing this condition and is actually considered a misnomer by most authors in the recent literature. The term “periostitis ossificans” is also not ideal as the periosteum does not become ossified. It merely deposits new bone as the inflammatory process lifts it off the cortex. Chronic osteomyelitis with proliferative periostitis, although cumbersome, is a more accurate description of the pathology. Poliferative periostitis is characterized by new bone formation over the surface of the involved bone. This is a response of the periosteal tissue to persistent low-grade infection.
OOOOE Volume 102, Number 5
Tong et al e17
Fig. 4. The subperiosteal “new” bone showing reactive woven bone formation with the bony trabeculae arranged in parallel to one another. The arrowed area represents the granulation tissue.
Fig. 5. Higher magnification shows osteoblasts rimming the bony trabeculae. Note the scant inflammatory infiltrate in the fibrovascular stroma.
Wood and Goaz5 proposed that for such lesions to develop, an active periosteum (as in young patients), a source of chronic infection, and a fine balance between
host resistance and microbial virulence must be present so as to allow a continued low-grade infection to persist. The most common cause of proliferative periostitis
e18
OOOOE November 2006
Tong et al
Fig. 6. PA mandibular view taken 2 years after decortication showing restoration of normal bony contour at the left mandibular angular region.
is odontogenic infection. The most common site of involvement is the inferior border of the mandible in the first molar region. The characteristic radiographic appearance is a convex radiopaque shadow with a smooth contour. A laminated appearance with radiolucent zones may be seen. The adjacent jawbone usually appears normal. In a literature review, Eversole et al.7 outlined the following criteria for the differentiation of proliferative periostitis from other periostoses. These include (1) facial asymmetry resulting from localized osseous enlargement, (2) histologic findings of a benign periosteal fibroosseous lesion, (3) complete or partial remodeling of excess bone after elimination of the cause. The usual cause of proliferative periostitis involving the jawbone is odontogenic infection, usually secondary to dental caries. It is generally accepted that removal of the cause results in resolution of the infection and remodeling of the excessive bone. If the bony proliferation is extensive, surgical remodeling may be indicated. This has the additional advantage of providing tissue for histologic confirmation of the diagnosis and exclusion of more sinister pathologies.8 The present case is unusual in that a definitive source of infection could not be identified. One can only speculate that it was likely to be related to the tooth
germ of the unerupted lower left wisdom tooth because of the presence of a periapical radiolucent area. However, no overt communication of the tooth germ with the oral cavity could be found on clinical examination. It was therefore appropriate to consider surgical exploration for biopsy in this case to rule out other pathologies. A search of the literature did not show any previously reported case of chronic osteomyelitis with proliferative periostitis in association with an erupted tooth. The possible occurrence of periosteal hyperplasia in patients without any detectable cause except for the close proximity of an unerupted tooth surrounded by its dental follicle was mentioned by Neville et al.2 However, they did not present an actual case. In these instances, hematogeneous spread of infection is a possibility but the exact cause of the infection and periosteal infection is unclear. REFERENCES 1. Garrè C. Uber besondere Formen und Folgeszustande der akuten infektiosen osteomyelitis. Beitr Z Klin Chir 1893;10:241-98. 2. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral & maxillofacial pathology. 2nd ed. Philadelphia: WB Saunders; 2002. p. 131-2. 3. Berger A. Perimandibular ossification of possible traumatic origin: report of a case. J Oral Surg 1948;6:353-6. 4. Pell GJ. Garrè’s osteomyelitis of the mandible: a report of a case. J Oral Surg 1955;13:248-52. 5. Wood NK, Goaz PW. Differential diagnosis of oral & maxillofacial lesions. 5th ed. St Louis: Mosby; 1997. p. 488-92.
OOOOE Volume 102, Number 5 6. Wood RE, Nortjé CJ, Grotepass F, Schmidt S, Harris AM. Periostitis ossificans versus Garré’s osteomyelitis. I. What did Garré really say? Oral Surg 1988;65:773-7. 7. Eversole LR, Leider AS, Corwin JO, Karian BK. Proliferative periostitis of Garré’s: its differentiation from other neoperiostoses. J Oral Surg 1979;37:725-31. 8. Belli E, Metteini C, Andreano T. Sclerosing osteomyelitis of Garrè periostitis ossificans. J Craniofac Surg 2002;13:765-8.
Tong et al e19 Reprint requests: Antonio C. K. Tong, BDS, PhD, FRACDS(OMS) Oral Maxillofacial Surgery and Dental Unit A1, Queen Mary Hospital 102, Pokfulam Road Hong Kong [email protected]
Chronic osteomyelitis with subperiosteal new bone formation results from periosteal reaction to chronic inflammatory/infectious stimulation. In the maxillofacial region, it has traditionally been termed Garrè’s osteomyelitis with proliferative periostitis and more recently periostitis ossificans. The term Garrè’s osteomyelitis has been regarded as a misnomer by many authors in the recent literature. The term chronic osteomyelitis with proliferative periostitis, although cumbersome, is considered to be the most accurate description of the pathology. It usually affects the mandible of young patients secondary to dental infection. Management involves removal of the source of infection and antibiotic treatment. We present an unusual case of chronic osteomyelitis with proliferative periostitis affecting the mandible of a 12-year-old patient. The source of infection was related to the developing lower left third molar, which had apparently no communication with the oral cavity. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102:e14-e19)
Bone formation as a result of periosteal reaction occurs secondary to a number of bony pathoses. These include osteomyelitis, trauma, and neoplastic diseases. Chronic osteomyelitis with associated periosteal new bone formation has been described under different clinical terms including Garrè’s osteomyelitis, proliferative periostitis, and periostitis ossificans. Since the publication of C. Garrè1 on the pattern of acute osteomyelitis, his name had been associated with a form of inflammatory periosteal new bone formation with an onionskin pattern of cortical bone duplication. The term “Garrè’s osteomyelitis” is generally taken to be synonymous with chronic osteomyelitis with proliferative periostitis. However, Neville et al.2 point out that Garrè did not have any specimens for histopatholgic studies and Roentgen did not discover x-rays until 2 years after Garrè’s publication. They therefore suggested that the term “Garrè’s osteomyelitis” is not a proper designation for such pathology. In the orthopedic literature, periostitis ossificans of the tibia is a well-known pathology. The first cases of proliferative periostitis affecting the jawbone were described by Berger3 and Pell.4 This condition usually involves the anterior aspect of the tibia and the lateral
surface of the body of the mandible. It commonly occurs in young patients with a mean age of 13 years. Sporadic cases had been reported in patients in their twenties and in infants around 2 years old. This is related to periosteal osteoblastic activity. Formation of subperiosteal bone represents a periosteal reaction to inflammation. The histopathology of osteomyelitis with proliferative periostitis is actually distinct. The affected periosteum forms several layers of vital bone parallel to each other and to the surface of the affected bone. An intact cortex is present below the new bone formation. The most common provoking factors are dental caries with associated periapical inflammation, periodontal infections, fractures, and nonodontogenic infections. Most cases arise in the molar premolar area. Radiographic examination showed bony laminations parallel to each other and to the cortical surface of the involved bone. Appropriate radiographic angulation may bring out the radiolucent zone of soft tissue between the original bony cortex and the newly formed reactive bone. Lesions that must be considered in the differential diagnosis of proliferative periostitis are Ewing’s sarcoma, fibrous dysplasia, osteogenic sarcoma, infantile cortical hyperostosis, callus, exostosis, calcifying hematoma, and osteotomas.5
a
Senior Dental Officer, Department of Health, The Government of the HKSAR, Hong Kong. b Professor, Department of Pathology, The University of Hong Kong, Hong Kong. c Specialist Radiologist, Canossa Hospital, Hong Kong. Received for publication Jan 10, 2006; returned for revision Mar 2, 2006; accepted for publication Mar 29, 2006. 1079-2104/$ - see front matter © 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2006.03.025
e14
CASE REPORT A 12-year-old male patient presented with a progressive left facial swelling of 6-week duration. There was no related history of trauma or dental treatment involving the region. Clinical examination showed a firm 2 ⫻ 3-cm swelling involving the left masseteric region with severe trismus. Intraoral examination showed no overt pathology. No carious lesions or periodontal patholo-
OOOOE Volume 102, Number 5
Tong et al e15
Fig. 1. Superiosteal new bone formation in the left angular region of the mandible lateral to the tooth germ of the unerupted lower left third molar.
gies were found on dental and periodontal examinations. There was an associated left submandibular lymphadenopathy. There was no associated sensory dysfunction of the inferior alveolar nerve or other abnormal neurologic signs. Plain radiographic findings showed an unerupted lower left wisdom tooth with incomplete root formation and a periapical radiolucent area. An area of possible cortical bone formation was present lateral to the left angle region of the mandible on the postero-anterior radiograph (Fig. 1). This was more clearly seen on computed tomography (CT) (Fig. 2). Inflammatory response of the associated muscles and soft tissue were seen on magnetic resonance (MR) imaging (Fig. 3). Based on the clinical-radiographic features of deposition of extracortical new bone outside the existing intact bony cortex, and the presence of an unerupted wisdom tooth with a periapical radiolucency, a provisional diagnosis of chronic osteomyelitis with proliferative periostitis was considered to be most likely. As an obvious dental or periodontal source of infection was not apparent, it was considered necessary to perform a bone biopsy to rule out lesions showing similar radiographic features. These include Ewing’s sarcoma, endosteal, parosteal osteosarcomas, osteosarcomas, and chrondrosarcomas. An exploration of the left mandibular third molar and angle region via an intraoral approach was made under general anesthesia. An incision was made along the external oblique ridge lateral to the left mandible mo-
Fig. 2. Coronal CT showing new bone formation over the lateral cortical surface of the mandible extending from the third molar region to the posterior border of the ramus. The associated masseteric muscle was enlarged.
lars. The mucoperiosteal soft tissue lateral to the left mandibular angle region was reflected to reach the angle region of the ramus. Multiple fragments of spongy bone were found lateral to the cortical surface of the mandible in the region of the lower left third molar extending to the angle region. Multiple foci of
e16
Tong et al
OOOOE November 2006
Fig. 3. Postcontrast axial T1-weighted (fat-suppressed) images depict the abnormal contrast-enhancement of the masseter muscle, marrow of the mandible extending to the medial pterygoid muscle. Periosteal thickening is also demonstrated lateral to the angle of mandible. No gross bony destruction is seen at the mandible.
pus collection were found in association with the spongy bone islands. The third molar was removed surgically. Pus and hard and soft tissue samples including the subperiosteal bony tissue were taken for microbiology and histopathology. The surgical site was irrigated with high doses of antibiotics (ampicillin, salbactum, and metronidazole). Microbiologic examination of hard and soft tissue was performed. Staining for aerobic, anaerobic, and acid-fast bacillus yielded only commensal organisms. Histological study of the bony tissue lateral to the unerupted tooth showed reactive woven bone formation with osteoblastic rimming of the woven bony trabeculae (Figs. 4 and 5). The fibrous stroma in-between the bony trabeculae was vascular and contained a mild lymphoplasmacytic inflammatory infiltrate. Scattered osteoclasts were present. The subperiosteal “new” bone also showed reactive woven bone formation with the bony trabeculae arranged in parallel to one another. Osteoblastic rimming of the woven bony trabeculae was prominent. Inflammatory cells were scant. The soft tissue adjacent to the unerupted tooth consisted of inflamed granulation tissue. The histopathologic features were consistent with a diagnosis of chronic osteomyelitis with proliferative periostitis. Antibiotic treatment with ampicillin and salbactum
was continued for 4 weeks after the surgical exploration. Resolution of inflammation and trismus was achieved 3 to 4 weeks after the surgical exploration. Radiographic examination 2 years after the surgical intervention showed restoration of normal bony contour in the left angular region of the mandible (Fig. 6). DISCUSSION Proliferative periostitis is a distinctive type of chronic osteomyelitis. It has commonly been regarded as synonymous with Garrè’s osteomyelitis. In a literature review, Wood et al.6 found that Garré did not describe this type of osteomyelitis at all and his name had been consistently misspelled in the literature. Therefore the term Garrè’s osteomyelitis may not be appropriate for describing this condition and is actually considered a misnomer by most authors in the recent literature. The term “periostitis ossificans” is also not ideal as the periosteum does not become ossified. It merely deposits new bone as the inflammatory process lifts it off the cortex. Chronic osteomyelitis with proliferative periostitis, although cumbersome, is a more accurate description of the pathology. Poliferative periostitis is characterized by new bone formation over the surface of the involved bone. This is a response of the periosteal tissue to persistent low-grade infection.
OOOOE Volume 102, Number 5
Tong et al e17
Fig. 4. The subperiosteal “new” bone showing reactive woven bone formation with the bony trabeculae arranged in parallel to one another. The arrowed area represents the granulation tissue.
Fig. 5. Higher magnification shows osteoblasts rimming the bony trabeculae. Note the scant inflammatory infiltrate in the fibrovascular stroma.
Wood and Goaz5 proposed that for such lesions to develop, an active periosteum (as in young patients), a source of chronic infection, and a fine balance between
host resistance and microbial virulence must be present so as to allow a continued low-grade infection to persist. The most common cause of proliferative periostitis
e18
OOOOE November 2006
Tong et al
Fig. 6. PA mandibular view taken 2 years after decortication showing restoration of normal bony contour at the left mandibular angular region.
is odontogenic infection. The most common site of involvement is the inferior border of the mandible in the first molar region. The characteristic radiographic appearance is a convex radiopaque shadow with a smooth contour. A laminated appearance with radiolucent zones may be seen. The adjacent jawbone usually appears normal. In a literature review, Eversole et al.7 outlined the following criteria for the differentiation of proliferative periostitis from other periostoses. These include (1) facial asymmetry resulting from localized osseous enlargement, (2) histologic findings of a benign periosteal fibroosseous lesion, (3) complete or partial remodeling of excess bone after elimination of the cause. The usual cause of proliferative periostitis involving the jawbone is odontogenic infection, usually secondary to dental caries. It is generally accepted that removal of the cause results in resolution of the infection and remodeling of the excessive bone. If the bony proliferation is extensive, surgical remodeling may be indicated. This has the additional advantage of providing tissue for histologic confirmation of the diagnosis and exclusion of more sinister pathologies.8 The present case is unusual in that a definitive source of infection could not be identified. One can only speculate that it was likely to be related to the tooth
germ of the unerupted lower left wisdom tooth because of the presence of a periapical radiolucent area. However, no overt communication of the tooth germ with the oral cavity could be found on clinical examination. It was therefore appropriate to consider surgical exploration for biopsy in this case to rule out other pathologies. A search of the literature did not show any previously reported case of chronic osteomyelitis with proliferative periostitis in association with an erupted tooth. The possible occurrence of periosteal hyperplasia in patients without any detectable cause except for the close proximity of an unerupted tooth surrounded by its dental follicle was mentioned by Neville et al.2 However, they did not present an actual case. In these instances, hematogeneous spread of infection is a possibility but the exact cause of the infection and periosteal infection is unclear. REFERENCES 1. Garrè C. Uber besondere Formen und Folgeszustande der akuten infektiosen osteomyelitis. Beitr Z Klin Chir 1893;10:241-98. 2. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral & maxillofacial pathology. 2nd ed. Philadelphia: WB Saunders; 2002. p. 131-2. 3. Berger A. Perimandibular ossification of possible traumatic origin: report of a case. J Oral Surg 1948;6:353-6. 4. Pell GJ. Garrè’s osteomyelitis of the mandible: a report of a case. J Oral Surg 1955;13:248-52. 5. Wood NK, Goaz PW. Differential diagnosis of oral & maxillofacial lesions. 5th ed. St Louis: Mosby; 1997. p. 488-92.
OOOOE Volume 102, Number 5 6. Wood RE, Nortjé CJ, Grotepass F, Schmidt S, Harris AM. Periostitis ossificans versus Garré’s osteomyelitis. I. What did Garré really say? Oral Surg 1988;65:773-7. 7. Eversole LR, Leider AS, Corwin JO, Karian BK. Proliferative periostitis of Garré’s: its differentiation from other neoperiostoses. J Oral Surg 1979;37:725-31. 8. Belli E, Metteini C, Andreano T. Sclerosing osteomyelitis of Garrè periostitis ossificans. J Craniofac Surg 2002;13:765-8.
Tong et al e19 Reprint requests: Antonio C. K. Tong, BDS, PhD, FRACDS(OMS) Oral Maxillofacial Surgery and Dental Unit A1, Queen Mary Hospital 102, Pokfulam Road Hong Kong [email protected]