ORIGINAL ARTICLE A retrospective clinicopathological study of 59 osteogenic sarcoma of jaw bone archived in a stomatology unit

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1 Malaysian J Pathol 2010; 32(1) : ORIGINAL ARTICLE A retrospective clinicopathological study of 59 osteogenic sarcoma of jaw bone archived in a stomatology unit AJURA AJ MClinDent (Mal) and LAU SH FDSRCS (Eng) Stomatology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur Abstract Objectives: To determine the clinicopathological features of osteogenic sarcomas of the mandible and maxilla. Materials and methods: A retrospective study was carried out on all osteosarcoma from the jaw diagnosed in the Stomatology Unit, Institute for Medical Research, Kuala Lumpur from 1967 to All data regarding the age at presentation, gender, race, clinical presentation, radiographical findings and diagnoses were retrieved from computerized records. Results: There were 59 cases (36 males and 23 females) with ages ranging from 7 to 68 years. The patients comprised 28 Malays, 16 Chinese, 2 Indians and 13 of other ethnicity. Forty cases involved the mandible and 19 the maxilla. The main complaint was painless or painful bony swelling. Nine cases presented with numbness of the associated region. Four patients had history of prior radiotherapy. The radiographic findings which varied from radiolucent to radiopaque lesions were mentioned in only 26 cases. Histologically, the majority (30) were osteoblastic, 19 chondroblastic, 6 fibroblastic and 4 telangiectatic in type. No small cell type osteosarcoma was identified. Conclusion: Osteogenic sarcoma of the jaws is a rare malignant bone tumour. Over 40 years, there were only 59 cases diagnosed by our institution and to date this is the first report of jaw osteosarcoma in Malaysia. Keywords: osteosarcoma, mandible, maxilla INTRODUCTION Osteosarcoma or osteogenic sarcoma is defined as a primary intramedullary high grade malignant tumour in which the neoplastic cells produce osteoid. 1 It is a malignant bone tumour that commonly occurs in the long bones of the lower extremity followed by long bones of the upper extremity and pelvic bones. 2 Approximately 5% of all osteosarcomas are reported occur in the maxillofacial region. 2-4 Osteosarcoma of the jaw commonly occurs in the third and fourth decade of life. 4 There is scarce published information on osteogenic sarcoma of the jaw bones in Malaysia. This study records the clinicopathological features of jaw osteosarcomas diagnosed histologically in the Malaysian Ministry of Health s main oral histopathology laboratory over a 40-year-period ( ). MATERIALS AND METHODS A retrospective study was carried out on all osteogenic sarcoma (osteosarcoma) cases diagnosed in the Stomatology Unit, Institute for Medical Research, Kuala Lumpur from 1967 to All data regarding the age at presentation, gender, race, clinical features, radiographical findings and diagnoses were retrieved from computerized records. The histological sections of the tumours were reviewed and classified according to the histological subtype (osteoblastic, chondroblastic, fibroblastic and others) based on the World Health Organization Classification of Tumours. 1 If archival slides were of insufficient quality, the original blocks were retrieved and new sections prepared. Immunostaining was carried out using a panel of antibodies commonly used in our laboratory 5 in a few cases to further rule out other differential diagnoses. RESULTS Initially we identified 61 cases of osteosarcomas, however 2 cases were excluded after reviewing the restained slides because the histological features were not classifiable. There were 59 cases (36 males and 23 females) with ages ranging from 7 to 68 years. The patients comprised 28 Address for correspondence and reprint requests: Dr. Ajura bt. Abdul Jalil, Stomatology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, Kuala Lumpur, Malaysia. 27

2 Malaysian J Pathol June 2010 Malays, 16 Chinese, 2 Indians and 13 of other ethnicity. Forty cases involved the mandible and 19 the maxilla. For the mandible, there were more male patients compared to females with a ratio of 2.3:1. As for the maxilla, there were marginally more male patients (n=10) than females (n=9). The clinicopathological features are summarized in Table 1. The main clinical presentation was either painless or painful bony swelling of the jaws. The duration of the swelling ranged from 3 weeks to 2 years. Other symptoms included numbness of the associated region in nine cases, limited mouth opening (1 case) and suppuration with maggot infestation (1 case). Four patients had history of prior radiotherapy for nasopharyngeal carcinoma (n=2), tumour of the nose (n=1) and aneurysmal bone cyst of the jaw (n=1). In only 26 cases were the radiographical findings recorded. These were described as either radiolucent or radiopaque lesions or a mixture of both. In all the cases, microscopical examination showed presence of malignant osteoid although the matrix formation varied from osteoblastic to fibroblastic. The majority of the cases were osteoblastic in type (n=30), followed by chondroblastic (n=19), fibroblastic (n=6) and telangiectatic (n=4) (Figure 1). We did not identify any small cell type osteosarcoma in this study. DISCUSSION Fifty-nine osteosarcomas of the jaws were reported in our laboratory over 40 years. In comparison, 25 cases of jaw osteosarcomas were histologically diagnosed in a 30-year review 6 while Mardinger et al 4 reported 14 cases within a decade. Forty-eight patients with jaw osteosarcomas were reported by a Dutch group over a period of 29 years 7. Fourteen cases were seen over 6.5 years by a Kenyan team 8 and 8 cases within a 7 year period by a group from India 3. Nineteen cases with a histopathological diagnosis of jaw osteosarcomas were seen during a period of 10 years in a Sri Lankan study. 9 A large study by Ogunlewe et al reported 17 out of 59 primary malignant bone tumours of the jaws as osteosarcoma over a period of 21 years % of osteosarcomas of the bones of skull and face as well as 4.1% osteosarcomas occurring in the mandible were registered in the National TABLE 1. Clinicopathological features of 59 cases of jaw osteosarcoma Case Age Gender Race Site Clinical presentation Radiographic features Duration of Histological (yrs) symptoms type 1 43 M O Left mandible Painless swelling Radiopacity mixed with 2 years fibroblastic radioluceny 2 64 M M Left mandible Painless swelling Periapical radiolucency 1 month osteoblastic 3 27 M M Right mandible Painless swelling, NA 3 week chondroblastic parasthesia 4 16 M M Symphysis Swelling NA 1 month telangiectatic 5 28 M O maxilla Swelling NA 3 month chondroblastic 6 6 F M Right mandible Painful swelling, Bony destruction right 1 month fibroblastic limited mouth opening angle mandible 7 23 M M Right maxilla Swelling NA NA osteoblastic 8 16 M O Right maxilla Fast growing growth NA NA fibroblastic 9 27 F O Right mandible Swelling 1 year chondroblasti M C Right mandible Swelling, numbness Cotton-wool radiopacity 3 month osteoblastic M C Anterior Swelling NA 1 month osteoblastic mandible M C Right mandible Painless swelling NA 3 month chondroblastic M M Left mandible Swelling NA NA chondroblastic F M Right maxilla Swelling NA 4 month osteoblastic M O Left mandible Swelling Radiopacity NA osteoblastic M I Right mandible Swelling, radiotherapy Sunray appearance 4 month osteoblastic for aneurysmal bone cyst radiopacity F C Right maxilla Painless swelling, NA NA osteoblastic radiation for nose cancer 20 years ago M M Right mandible Swelling Radiolucency 2 years osteoblastic M: Malay, C: Chinese, I: Indian, O: Others NA: Not available 28

3 OSTEOGENIC SARCOMA OF JAW Case Age Gender Race Site Clinical presentation Radiographic features Duration of Histological (yrs) symptoms type M M Left mandible Painful swelling Sunray appearance 6 month chondroblastic radiopacity M M Left mandible Painless swelling NA 5 month telangiectatic F M Right mandible Swelling, numbness Orange-peel appearance NA osteoblastic M O Right maxilla Swelling Radiopacity NA chondroblastic F M Right maxilla Swelling NA 2 month osteoblastic F O Right mandible Swelling NA 4 month chondroblastic F M Right mandible Swelling, numbness Moth-eaten appearance, 3 month osteoblastic periodontal space widening M C Anterior maxilla Swelling Calcified spots 2 years chondroblastic M C Right mandible NA NA NA osteoblastic F O Left maxilla Swelling NA 1 month telangiectatic F M Right maxilla Swelling Bony destruction 2 week osteoblastic F M Right mandible Swelling, lower lip Cotton-wool radiopacity 2 month chondroblastic parasthesia M M Left mandible Swelling Radiolucency NA chondroblastic M M Right maxilla Swelling, radiotherapy NA 4 month osteoblastic for NPC 15 years ago 33 7 M M Left mandible Swelling, removal NA NA osteoblastic retinoblastoma of left eye 2 years ago M M Right mandible Swelling, lower lip Radiolucency 2 month osteoblastic & chin parasthesia 35 7 M M Left mandible Painless swelling No obvious bone pathology 1 month osteoblastic M M Left mandible Painless swelling, NA 2 month telangiectatic parasthesia M O Right mandible Swelling, pus discharge Multiple foci calcification NA chondroblastic with maggots infestation F C Left mandible Swelling, parasthesia Scattered radiolucency 1 month osteoblastic F C Left mandible Swelling Calcification NA osteoblastic F M Right mandible Swelling No obvious bony pathology 3 month chondroblastic 41 7 F M Anterior Painless swelling radiolucency NA fibroblastic mandible M C Mandible Swelling NA NA osteoblastic M I Premaxilla Swelling NA 5 month osteoblastic F M Right maxilla Swelling NA 9 month chondroblasti M M Left mandible Swelling NA NA chondroblasti M C Right mandible Painless swelling Radiopacity and 2 month chondroblasti radiolucency F C Right mandible Swelling NA NA osteoblastic F O Right maxilla Swelling NA NA fibroblastic F C Right maxilla Painless swelling Sunray appearance NA osteoblastic F M Right maxilla Swelling, numbness Unhealing socket 6 month osteoblastic M C Left maxilla Swelling Radiopacity 1 year fibroblastic M C Right maxilla NA NA NA chondroblasti F C Right maxilla Swelling, radiotherapy NA NA osteoblastic M C Right mandible Swelling NA 1 month chondroblasti M M Right mandible NA NA NA chondroblasti M O Left maxilla Painless swelling NA 6 month osteoblastic F O Left maxilla Painless swelling NA 6 month osteoblastic F M Right maxilla Painful swelling NA 2 years osteoblastic M O Right maxilla Painful swelling, h/o NA NA osteoblastic NPC M: Malay, C: Chinese, I: Indian, O: Others NA: Not available 29

4 Malaysian J Pathol June 2010 Histology subtype of jaw osteosarcomas osteoblastic chondroblastic fi broblastic telangiectactic Histology subtype FIG. 1: Prevalence of jaw osteosarcoma according to histology subtype. Cancer Data Base of the American College of Surgeons. 2 In comparison with these studies, our laboratory is receiving one to two cases of osteosarcoma of the jaws in a year. Most of our cases were in the third and fourth decade (n=16, n=11 respectively) at presentation, with a mean age of 34 years. This finding concurs with other studies. 4,10 On the other hand, Bennet et al 6 reported a peak incidence in the fourth decade. As to the gender distribution, our data revealed 36 males and 23 females with a ratio of 1.60:1. Male predominance has also been reported by others 4,7,10 while Bennet et al 6 reported otherwise. In one literature review of jaw osteosarcomas which comprised of 774 cases, the male to female ratio was 1.20:1. 4 As for the site, the mandible was found to be more frequently affected compared to the maxilla and similar findings had been reported. 6,9 However, others 4,7,10 had reported more maxillary osteosarcomas. In a review by Mardinger et al 4, they demonstrated that out of 720 cases reported, 380 were in the mandible and 340 in the maxilla. Our figures also showed more male patients with mandibular osteosarcomas compared to females. In contrast, Ogunlewe et al 10 reported more mandibular tumours in female patients. From our records, nearly all of the cases presented as either painless or painful bony swelling. This was also consistent with previous reports. 3,4,10 Nine of our patients complained of numbness of associated region. Symptoms of parasthesia was also reported by Mardinger et al 4 and Bennet et al. 6 The development of osteosarcoma due to previous irradiation is known. The risk of developing osteosarcoma in irradiated bone is approximately %. 1 Four of our cases had previous radiotherapy which may have induced the neoplastic process and growth. Two of our cases had irradiation for nasopharygeal carcinoma with latent period of 15 and 13 years before the presentation of the osteosarcomas. One patient (case no.17) had irradiation for nose cancer which was probably a nasopharyngeal carcinoma. She had a latent period of twenty years. A recent case report described a patient who was treated for nasopharyngeal carcinoma with radiotherapy who subsequently developed maxillary osteosarcoma 14 years thereafter. 11 van Es et al 7 reported previous radiotherapy in one patient for tuberculosis 35 years before diagnosis of osteosarcoma and in another patient, radiotherapy was carried out for fibrosarcoma of the cheek 7 years prior to the development of the osteosarcoma. They also reported two cases with previous chemotherapy; one for multiple myeloma and another one for abdominal Burkitt s lymphoma. 7 In one of our cases (case no.33), a 7-year old boy had removal of a retinoblastoma from his left eye when he was aged three years. However there was no mention as to whether any irradiation had been given to the patient. Metastatic osteosarcoma involving the jaw is known to occur, although it is rare. 12 Distant metastasis was found in 10 out of 48 patients in 30

5 OSTEOGENIC SARCOMA OF JAW whom the sites involved were the lungs, skeleton, liver and neck nodes. 7 From the clinical information provided, only 26 of our cases mentioned the radiographical findings. Earlier cases in this study which were without the radiographical descriptions may probably be attributed to the lack of radiology equipment in the clinics then. Some of the radiographical findings in our series were described as sunray, orange peel, or cotton-wool appearances; widening of the periodontal space and calcified spots. Widening of the mental foramen was reported to be the only radiological finding in a case reported by Doval et al 3. Since the features are variable, it is not advisable to make a definite diagnosis of jaw osteosarcoma solely by radiograph investigations. Osteosarcoma is a malignant mesenchymal sarcoma characterized by direct formation of bone or osteoid by neoplastic cells. 1 There are three major subtypes of osteosarcoma depending on the predominant cell type: osteoblastic, chondroblastic and fibroblastic. Other rare subtypes of osteosarcoma include telangiectatic and small-cell osteosarcoma. Osteoblastic osteosarcoma is composed of bone and/or osteoid as the predominant matrix. Its morphology ranges from thin, arborising osteoid (filigree) (Figure 2) to dense compact osteoid and bone (sclerotic) (Figure 3). As for the chondroblastic osteosarcoma, the predominant feature is the chondroid matrix (Figure 4). Fibroblastic osteosarcoma is characterized histologically by fibroblastic proliferation (Figure 5) with only minimal amounts of osseous matrix present with or without cartilage. The telangiectatic subtype contains blood-filled or empty spaces separated by thin septae. The septae are cellular and contain malignant atypical mononuclear tumour cells which are hyperchromatic, pleomorphic with high mitotic activity (Figure 6). Microscopically, the small-cell osteosarcoma is composed of small cells associated with osteoid production. Many of the cases diagnosed by our Unit are of the osteoblastic type (n=30). Doval et al 3 and Nissanka et al 9 both reported mainly the osteoblastic type whereas other authors 4,10 reported chondroblastic type to be the most predominant variant. There is still no definite correlation between the histology of the tumour and its prognosis. In a large study done by Hauben et al 13 involving 570 FIG. 2: Sheets of malignant pleomorphic cells with extensive malignant osteoid (arrow) formation (osteoblastic type) (H&E x100) 31

6 Malaysian J Pathol June 2010 FIG. 3: Formation of malignant compact osteoid (arrow) (osteoblastic type) (H&E x40) FIG. 4: Sheets of malignant chondroid formation laid down by pleomorphic tumour cells. Areas of malignant osteoid (arrow-head) are also seen. (Chondroblastic type) (H&E x40) 32

7 OSTEOGENIC SARCOMA OF JAW FIG. 5: Fascicles of malignant spindle cells (on the left hand side) with formation of malignant osteoid (arrowhead) (fibroblastic type) (H&E x40) FIG. 6. Malignant osteoid (arrow-head) formation and some large angiomatous spaces (telangiectatic type) (H&E x40) 33

8 Malaysian J Pathol June 2010 patients with high-grade central osteosarcoma undergoing chemotherapy, it was concluded that chondroblastic subtype of osteosarcomas responds poorly to chemotherapy and this subtype could be a prognostic factor for survival. On the other hand, Doval et al 3 reported three patients with chondroblastic osteosarcoma with good prognosis. In another study, three distant metastases and five deaths were recorded; and all were of osteoblastic type 9. Currently, there is still no definite immunostaining for the diagnosis of osteosarcoma. A review of the literature 14 concluded that monoclonal antibodies against osteocalcin which is an intra-osseous protein associated with osteoblasts have a 70% sensitivity and nearly 100% specificity for osteoblastic differentiation. On the other hand, osteonectin which is produced by bone cells lacks specificity for bone tumours due to its wide expression. The main reason for carrying out immunohistochemistry staining is to exclude other differential diagnoses, such as metastatic sarcomatoid carcinoma, synovial sarcoma, Ewing s sarcoma/primitive neuroectodermal tumour and especially in cases in which the production of osteoid matrix by the tumour cells is not evident. 14 Diagnosis is generally achieved by microscopical examination using routine haematoxylin and eosin staining. Since our unit is the main oral histopathology laboratory in Malaysia, the specimens are received from various government dental clinics and private dental practitioners. As such, only limited information such as clinical presentation and the radiographical findings were available from the histopathology request forms. Data on further management and follow-up of the patients were also not accessible to us. Usually, osteosarcomas of the jaw are treated by surgery, chemotherapy or a combination of the both. Adequate chemotherapy with radical surgery plays an important part in locoregional control and survival of patients with jaw osteosarcomas. 3 CONCLUSION Osteogenic sarcoma of the jaws is a rare malignant bone tumour. Our records show 59 cases of jaw osteosarcomas diagnosed in our laboratory over a 40-year period. Up to now this is the first clinicopathological study of osteosarcomas of the jaws in Malaysia. ACKNOWLEDGEMENT The authors thank the Director-General of Health Malaysia and also to Director of Institute for Medical Research, Kuala Lumpur for their kind permission to publish this paper. REFERENCES 1. Fletcher CDM, Unni KK, Mertens F (Eds). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. IARC Press: Lyon p Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma and Ewing s sarcoma National cancer data base report. Clin Orthop Relat Res 2007; 459: Doval DC, Kumar RV, Kannan V, Sabitha KS, Misra S, Vijay Kumar M et al. Osteosarcoma of the jaw bones. Br J Oral Maxillofac Surg 1997; 35: Mardinger O, Givol N, Talmi YO, Taicher S, Saba K, Hashomer T. Osteosarcoma of the jaw. The Chaim Sheba Medical Center experience. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 91: Ajura AJ, Sumairi I, Lau SH. The use of immunohistochemistry in an oral pathology laboratory. Malays J Pathol 2007; 29(2): Bennet JH, Thomas G, Evans AW, Speight PM. Ostesarcoma of the jaws: A 30-year retrospective review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 90: van Es RJJ, Keus RB, van der Waal I, Koole R, Vermey A. Osteosarcoma of the jaw bones. Longterm follow up of 48 cases. Int J Oral Maxillofac Surg 1997; 26: Chindia ML, Guthua SW, Awange DO, Wakoli KA. Osteosarcoma of the maxillofacial bones on Kenyans. J Cranio-Maxillofac Surg 1998; 26: Nissanka EH, Amaratunge EAPD, Tilakaratne WM. Clinicopathological analysis of osteosarcoma of jaw bones. Oral Diseases 2007; 13: Ogunlewe MO, Ajayi OF, Adeyemo WL, Ladeinde AL, James O. Osteogenic sarcoma of the jaw bones: A single institution experience over a 21-year period. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 101: Chabchoub I, Gharbi O, Remadi S, Limem S, Trabelsi A, Hochlef M et al. Postirradiation osteosarcoma of the maxilla: A case report and current review of literature. J Oncol 2009; doi: /2009/ Nakamura T, Ishimaru JI, Mizui T, Kobayashi A, Toida M, Makita H et al. Osteosarcoma metastatic to the mandible: A case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 91: Hauben EI, Weeden S, Pringle J, Marck EA, Hodenddorn PCW. Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup. European J Can 2002: 38: Gao Z, Kahn LB. The application of immunohistochemistry in the diagnosis of bone tumors and tumor-like lesions. Skeletal Radiol 2005; 34: