Osteogenic Sarcoma of the Jaw: A 10-Year Experience

BASIC AND PATIENT-ORIENTED RESEARCH J Oral Maxillofac Surg 65:1286-1291, 2007

Osteogenic Sarcoma of the Jaw: A 10-Year Experience Rui Fernandes, DMD, MD,* Nikolaos G. Nikitakis, DDS, PhD,† Alexander Pazoki, DDS, MD,‡ and Robert A. Ord, DDS, MD§ Background: Osteosarcomas (OS) of all sites account for approximately 40% to 60% of primary malignant bone tumors. About 10% of OS occur in the head and neck; most are located in the mandible or maxilla. Jaw lesions are diagnosed on average 2 decades later than their long bone counterparts, which have a peak incidence between the ages of 10 and 14 years. Head and neck OS are associated with a lower metastatic rate than long bone OS, and they have a better 5-year survival rate, ranging between 27% and 84%. Patients and Methods: We present our experience at the Department of Oral and Maxillofacial Surgery, University of Maryland, Baltimore, MD, with 16 patients with OS of the jaw during a period from 1993 to 2003. Results: In a retrospective chart review, 16 cases of OS of the jaw were identified. Patients ranged in age from 14 to 51 years (mean age, 41 years). The gender distribution consisted of 10 females and 6 males, at a ratio of 1.6:1. Evaluation of site distribution revealed a more frequent occurrence in the mandible than in the maxilla (9 and 7 cases, respectively). The main histologic subtype was chondroblastic (8 cases), followed by osteoblastic (4 cases). According to histologic grading, 8 tumors were high grade, 1 intermediate, 5 low grade, and 2 unknown. Overall, the primary treatment modality consisted of surgery in all 14 patients treated at the University of Maryland; 2 patients opted for treatment at other institutions. Chemotherapy, consisting primarily of cisplatin and Adriamycin (doxorubicin hydrochloride; Pharmacia, Kalamazoo, MI), was used as adjuvant treatment in 4 cases of high-grade OS. Follow-up ranges from 14 months to 108 months (mean, 46 months). To date, of the 14 patients treated at our institution, 12 (86%) had no evidence of disease at last appointment, and 2 patients died of the disease. Conclusion: In light of the rarity of this disease, this series represents a large single-center experience with OS of the jaw. Our data show an older patient population, different gender distribution, and higher survival rate compared with overall published reports. © 2007 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 65:1286-1291, 2007

Osteosarcomas (OS) of all sites account for approximately 40% to 60% of primary malignant bone tumors.1 About 10% of osteosarcomas occur in the head and neck; most are located in the mandible or maxilla.2 Jaw lesions are diagnosed on average 2 decades *Assistant Professor and Program Director, Division of Maxillofacial Surgery, Department of Surgery, University of Florida College of Medicine, Jacksonville, FL. †Assistant Professor and Program Director, Department of Diagnostic Sciences and Pathology, Dental School, Greenebaum Cancer Center, University of Maryland, Baltimore, MD. ‡Formerly, Assistant Professor of Oral and Maxillofacial Surgery, Department of Oral and Maxillofacial Surgery, Dental School, University of Maryland, Baltimore, MD; and Currently, Private Practice, Baltimore, MD.

later than their long bone counterparts, which have a peak incidence between the ages of 10 and 14 years. Head and neck OS are associated with a lower metastatic rate than are long bone OS, and they have a better 5-year survival rate, ranging between 27% and §Professor and Chair, Department of Oral and Maxillofacial Surgery, Dental School, Greenebaum Cancer Center, University of Maryland, Baltimore, MD. Address correspondence and reprint requests to Dr Fernandes: Department of Surgery, Division of Maxillofacial Surgery, University of Florida College of Medicine, 653-1 West Eighth Street, Jacksonville, FL 32209; e-mail: [email protected] © 2007 American Association of Oral and Maxillofacial Surgeons

0278-2391/07/6507-0004$32.00/0 doi:10.1016/j.joms.2006.10.030

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Table 1. PATIENT DEMOGRAPHICS FOR 16 STUDY PATIENTS WITH OSTEOSARCOMA

Age, yr Gender, n Male Female Ratio (M:F) Site, n Mandible Maxilla Histologic grade, n Low Intermediate High Unknown

14 to 51 (mean, 41) 6 10 1:1.6 9 7 5 1 8 2

Fernandes et al. Osteogenic Sarcoma of the Jaw. J Oral Maxillofac Surg 2007.

84%.3-5 Because of the rarity of jaw OS and the paucity of previously published series, we present our experience with a cohort of patients managed primarily by a single surgeon (R.A.O.).

Patients and Methods We carried out a retrospective chart review of all patients seen in the Department of Oral and Maxillofacial Surgery at the University of Maryland, Baltimore, from July 1993 to June 2003. Inclusion criteria for the present study included a histologic diagnosis of OS confirmed by the oral pathologist, no history of previous therapy, and availability of complete medical records. Exclusion criteria consisted of lack of initial treatment in our department and incomplete medical records. A total of 16 patients met the inclusion criteria. Clinical records of all eligible patients were reviewed for demographics, risk factors, presenting symptoms, radiographic data, treatment history, follow-up, and survival data. Treatment and follow-up information was not available for 2 patients who elected to receive therapy at another institution. Histologic slides were reviewed by the oral pathologist (N.G.N.) for histologic subtyping (into osteoblastic, chondroblastic, and fibroblastic OS) and histologic grading (into low-, intermediate-, and high-grade tumors). Patients with presurgical panoramic radiographs were assessed for the presence of a widened periodontal ligament, so-called Garrington’s sign,5 and sunburst appearance. Both findings have been associated with a diagnosis of OS.6 The follow-up period was calculated in months, from the date of first treatment to the date of last follow-up or death. Individual survival was defined as the interval between initial diagnosis of jaw OS and death (with or without disease) or last recorded clin-

FIGURE 1. Intraoral view of right mandibular osteosarcoma. Fernandes et al. Osteogenic Sarcoma of the Jaw. J Oral Maxillofac Surg 2007.

ical visit. Survival curves were estimated by the method of Kaplan and Meier.7 Data then were compared with published reports.

Results In the retrospective chart review, 16 cases of OS of the jaw were identified. Patients ranged in age from 14 to 51 years (mean age, 41 years) (Table 1). The gender distribution consisted of 10 females and 6 males, corresponding to a ratio of 1.6:1. Overall evaluation of site distribution revealed a greater occurrence in the mandible than in the maxilla (9 to 7 cases, respectively). Evaluation of site distribution between maxilla and mandible as related to gender revealed no statistical difference. Male patients had a nearly equal distribution between the maxilla (4 cases) and the mandible (3 cases); female patients had more frequent occurrence in the mandible than in the maxilla (6 vs 3 cases). Evaluation of risk factors indicated that 3 of the 16 patients had risks factors for OS. Specifically, 1 patient had been given a diagnosis of Li-Fraumani syndrome, 1 had received a diagnosis of polyostotic fibrous dysplasia, and the last patient had a history of radiation

Table 2. PRESENTING SIGNS AND SYMPTOMS FOR 14 PATIENTS WITH JAW OSTEOSARCOMA

Swelling Loosening of teeth Pain Hypoesthesia Garrington’s sign Sunray appearance

14/14 3/14 2/14 1/14 5/11* 6/11*

*These variables were evaluated for all patients on the basis of complete radiographic imaging, including panoramic radiographs and computed tomography scans. Fernandes et al. Osteogenic Sarcoma of the Jaw. J Oral Maxillofac Surg 2007.

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FIGURE 2. Computed tomography scan of a mandibular osteosarcoma with sunray appearance. Fernandes et al. Osteogenic Sarcoma of the Jaw. J Oral Maxillofac Surg 2007.

therapy to the head and neck for a thyroid malignancy. Among 14 patients for whom information was available, the most common presenting symptom was swelling at the site of disease (14 of 14; 100%) (Fig 1). This was followed by loosening of the teeth (3 of 14), pain (2 of 14), and hypoesthesia (1 of 14) (Table 2). The main histologic subtype was chondroblastic (8 cases) followed by osteoblastic (4 cases). Distribution of cases according to histologic grade was as follows: 8 high grade, 1 intermediate grade, 5 low grade, and 2 unknown. Panoramic radiographs, which were available for review in 11 cases, were evaluated for the presence of a widened periodontal ligament and/or a sunburst pattern associated with the tumor. A positive widened periodontal ligament space (PDL) was identified on 5 of 11 panoramic radiographs (45%). Sunray appearance was noted in 6 cases, accounting for an overall incidence of 55%. The latter feature also was apparent on available computed tomography (CT) scans of corresponding cases (Fig 2). Two patients opted for treatment at other institutions. Surgery was the primary treatment modality used in all 14 cases for which treatment was provided at our institution. A chemotherapy regimen that consisted primarily of cisplatin and Adriamycin (Pharmacia, Kalamazoo, MI) was used as adjuvant treatment in

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4 patients, all of whom had high-grade OS. Of 8 patients with high-grade OS, 4 received adjuvant chemotherapy. These 4 patients were alive at last followup. Of 4 patients with high-grade disease who were not given chemotherapy, 2 were alive at last follow-up and 2 had died of the disease (1 of these patients had presented with distant metastasis but developed renal failure related to diabetes and was not medically fit for chemotherapy). Outcomes revealed a trend toward improved survival with chemotherapy, but the trend was not statistically significant (P ⬍ .2). The 2 patients just described provided the only examples of recurrence noted in this study. One patient experienced local recurrence (at the skull base), and the other presented with distant metastasis (lungs). Both patients died of their disease. Duration of follow-up of the 14 patients treated at our institution ranged from 14 to 108 months (mean, 46 months). To date, 12 of 14 (86%) patients continue to have no evidence of disease at last appointment, and 2 patients are dead as a result of the disease. The Kaplan-Meier estimate of cumulative overall 5-year survival for study patients was 86% (Fig 3). To evaluate the possibility that patient age has a bearing on prognosis, patients were stratified into 2 groups: patients 40 years and younger and those older than 40 years at the time of diagnosis. Statistical analysis was conducted to evaluate survival differences between the 2 groups. Although a trend toward increased survival was evident among patients younger than 40, this trend was not statistically significant (P ⬍ .2). The prognostic significance of tumor location also was assessed. The site of occurrence, however, did not translate into a statistically significant survival difference (P ⬍ 1.0).

FIGURE 3. Kaplan-Meier estimate of cumulative 5 year survival for all patients: ⬃86%. Fernandes et al. Osteogenic Sarcoma of the Jaw. J Oral Maxillofac Surg 2007.

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Discussion Osteosarcoma is a malignancy of mesenchymal cells that have the ability to produce osteoid or immature bone. The origin of these tumors is largely unknown. Head and neck OS are rare tumors that are reported to represent only 10% of all OS. Jaw OS are even rarer, accounting for 4% of all documented cases.3 In the jaws, the biologic behavior of OS differs from that of tumors involving other skeletal bones. The average age at onset of OS of the jaw is 10 to 20 years later than that reported for skeletal lesions, and survival rates are higher.8-10 The average age in our series was 41 years. Although this represents the higher end of the reported range for OS of the jaw, it is still in keeping with data presented in the literature.3,4 In a retrospective review, August and colleagues3 evaluated 30 cases of OS of the jaw found in the tumor registry of Boston area hospitals. They noted that patient age may influence prognosis—average age for survivors was 27 years, and for nonsurvivors, 40 years. Using a similar approach, we stratified our patients into 2 groups: those younger than 40 years old and those older than 40 years of age. Statistical analysis was conducted to evaluate survival differences between the 2 groups. Although a trend toward increased survival was evident among patients younger than 40 years, this trend was not statistically significant. Whereas OS of the long bones show a slight male preponderance, head and neck OS typically have an equal gender predilection.4,11,12 In the present study, a female predilection accounted for a 1.6:1 ratio of females over males. The reason for this difference in gender distribution between our patient population and those reported in the literature is unknown, but the small numbers used in this series are probably a factor. The mandible was involved more often than the maxilla (9 to 7). The difference in survival between patients with tumors in the mandible versus those with tumor in the maxilla was not statistically significant. Similarly, Kassir et al14 found no statistical difference in survival between maxillary and mandibular OS. The most common signs and symptoms associated with OS of the jaw as reported in the literature consist of persistent pain, swelling, and paresthesia/anesthesia.13,14 In the series reported here, the most common presenting symptom was swelling, which was reported in 100% of patients. The second most common sign or symptom at presentation was loose teeth, which were noted in 21% of patients. Only a small percentage of patients (14%) reported that they experienced pain. Imaging studies in patients with OS of the jaw should include panoramic radiographs and CT scans

1289 of the head and neck, which are used to evaluate cortical bone involvement and possible lymphadenopathy. In addition, whenever possible, magnetic resonance imaging is useful for assessing the extent of marrow spread. This modality is now used routinely in our center but was not used consistently during the time of this retrospective study. Chest and abdominal CT, as well as isotope bone scan to rule out metastasis to other bones, are required for staging. Investigators in the present study evaluated the incidence of widened periodontal ligament for its association with OS of the jaw, as reported by Garrington et al.6 Of 11 patients with complete radiologic records, 5 presented with a widened periodontal ligament in the area of the tumor (45%). This early radiographic change, which results in symmetric widening of the PDL around a tooth or several teeth, is the result of tumor infiltration along the PDL. Although this finding is not specific to OS and may be noted with other malignancies and non-neoplastic conditions, it may be of great importance in the early diagnosis of OS when accompanied by pain or discomfort and other minimal radiographic changes. A widened PDL is visualized best on periapical radiographs, and structural changes in the inferior alveolar canal are seen most clearly on Panorex films.15 Similarly, we looked for the presence of the “classic” sunburst or sunray appearance caused by osteophytic bone production on the surface of the lesion. We identified 6 patients with sunray appearance on their radiographs, accounting for 55% of the patient population. A recent article reports a significant association between survival outcome and the pattern of osteogenesis seen on CT. The CT appearance of jaw osteosarcoma was thought to be a prognostic factor.16 Although these findings are not pathognomonic for OS, we believe that when taken together with other clinical data, they help in the diagnosis of OS, especially with early-stage tumors. OS of the jaw should be treated always with radical surgery as the primary modality. The single most important factor in curative therapy for OS of the jaw is its amenability to radical resection with clear margins.3,17-21 Clear margins may be technically difficult to achieve, particularly in the maxilla and skull base, where positive margin rates of 31% to 52.4% have been reported.17,19,20 In this series, whenever possible, a 3-cm margin was taken when tumors in the mandible were resected. In the maxilla, this could not be achieved always. A single close or positive margin occurred in a maxillary tumor; this then led to 1 case of local recurrence. Multimodality treatment of patients with OS has been established well for OS in long bones. The incorporation of multiagent chemotherapy for OS has played a pivotal role in the increased survival ob-

1290 served in the treatment of patients with OS of the extremities. In long bone OS, chemotherapy is given as induction (neoadjuvant). After resection is performed, the specimen is examined, and histologic response determines whether the same chemotherapy regimen is used adjuvantly or whether the regimen is changed.22 The benefits of chemotherapy in long bones have been defined clearly, leading to a dramatic change in disease-related survival rates, from 20% in the 1960s to 60% to 70% in the 1980s.23-25 Neoadjuvant chemotherapy, although often applied in head and neck OS, has not been established conclusively as superior to prompt postoperative chemotherapy. Nonetheless, it does permit the potential advantages of early eradication of micrometastatic disease, delivery of chemotherapy to an intact blood supply, and assessment of the effectiveness of the preoperative chemotherapy regimen used.4 Two published meta-analyses evaluated neoadjuvant chemotherapy for OS of the jaw on the basis of multiinstitutional, retrospective data. One study found a significant survival benefit,26 and the other found no benefit.14 Even in the article that described a significant benefit for chemotherapy alone (18 of 201 patients received neoadjuvant chemotherapy) after adjustments were made for surgical status, no significant difference was seen between adjuvant and neoadjuvant chemotherapy.26 Chemotherapy has not proved as effective in jaw OS for several reasons. First, the distant metastatic rate of 18% for the jaw contrasts with the rate of 80% for microscopic subclinical metastatic disease in long bone OS.27 Second, high-grade long bone OS is reported in 85% of cases, but in the jaw, only 56% to 79% of cases are high grade.27,28 Third, histologic response to neoadjuvant chemotherapy was less than 25% for jaw OS17 compared with 41% for long bone OS.29 In addition, most OS of the jaw are of the chondroblastic type (41% of 316 in 1 series,27 and 72% of 25 in another30) as opposed to long bone OS, in which the osteoblastic type predominates. The osteoblastic type has a worse prognosis,30 but all of these factors may play a role. Because we have regarded resectability as the most crucial factor in cure, all patients treated at our institution received up-front surgery and would prefer to avoid delaying surgery in a growing tumor that may not respond to neoadjuvant chemotherapy. Of 8 patients with high-grade OS who would qualify for neoadjuvant chemotherapy today, 4 actually received adjuvant postoperative chemotherapy. One patient refused chemotherapy, and another was medically unfit for this treatment. However, when we looked at the difference in survival between patients who had received chemotherapy and those who had not been treated in this way, we could not determine a statistically significant survival difference between the 2

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groups. Although a clear trend toward improved survival was noted in the group treated with chemotherapy, the lack of statistical significance of this finding (P ⬍ .2) may be a result of the small number of patients studied. Other series have shown a trend that is not significant statistically toward better survival with chemotherapy18 or toward a favorable histologic response to neoadjuvant chemotherapy.17 We have used postoperative radiation therapy (RT) for patients with high-grade tumor or close margins. Although OS has been regarded as a radioresistant tumor, other series also have followed this protocol.17 However, Delgado et al31 reported no improvement in survival for patients with positive margins who were treated with RT. The Kaplan-Meier estimate of cumulative overall 5-year survival was 86% in the present study (Fig 3). Several factors may account for this high survival rate. First, mean duration of follow-up was 48 months (ie, less than the 5-year standard used for most malignancies). Second, the location of our tumors (more in the mandible) made them more amenable to complete resection with negative margins. Indeed, only 1 patient had a close margin after ablative surgery. However, other recent articles have shown improved outcomes with OS of the jaw (3-year overall survival, 81%), citing advances in diagnostic imaging, craniofacial resection, and microvascular reconstruction as possible factors.17 Certainly, treatment with less than radical resection (eg, the intralesional and marginal resections reported by Bertoni et al32) explains their 23% 5-year survival. Regarding follow-up, we have seen our patients at 2-month intervals post surgery. We obtained chest/ abdominal CT at 3-month intervals for 2 years because most distant metastases occur within 2 years. We also ordered isotope bone scans at 6-month intervals for 2 years. After 2 years, we rely on clinical examination and yearly chest x-rays. In light of the rarity of this disease, this series represents a large single-center experience with OS of the jaw. Our data show an older patient population, different gender distribution, and higher survival rate compared with overall published reports. Given the major limitations of this study (ie, small sample size and retrospective design), these findings should be correlated with those of other series.

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