Malignant nonodontogenic tumors of the jaws, both primary and metastatic, are rare in comparisons of soft tissue and mucosal malignancies. Despite their infrequent occurrence, diagnosis of a malignant jaw tumor has serious prognostic implications, often requiring oncologic surgery, radiation, and/or chemotherapy. Generally, these tumors cause signs and symptoms that often are highly suggestive of malignancy (Box 14-1). Tumors discussed in this chapter are those arising from the hard tissues (osteosarcoma and chondrosarcoma) and those nonosseous tumors that frequently involve the mandible and the maxilla (Ewing’s sarcoma, Burkitt’s lymphoma, plasma cell malignancies, and metastatic carcinoma).
Osteosarcomas account for approximately 20% of all sarcomas and, after plasma cell neoplasias, are the most common primary bone tumors. Approximately 5% of osteosarcomas occur in the jaws, with an incidence of less than 1 case in 1.5 million persons per year (Box 14-2). Osteosarcomas can arise de novo or in the setting of several preexisting bone abnormalities such as Paget’s disease, fibrous dysplasia, multiple osteochondromas, bone infarct, chronic osteomyelitis, and osteogenesis imperfecta. Osteosarcoma can also arise in two cancer susceptibility syndromes: hereditary retinoblastoma (RB) and Li-Fraumeni syndrome. Patients with RB inherit a mutation of the retinoblastoma gene on one chromosome and then develop a second mutation of the other retinoblastoma allele. Affected patients develop retinoblastoma of the eye and have an increased risk of sarcoma such as osteosarcoma later in life. Patients with Li-Fraumeni syndrome inherit germline mutations of the p53 gene and have an increased risk of developing a variety of tumors including osteosarcoma. Some osteosarcomas have been preceded by radiation therapy to the affected bone for unrelated or antecedent disease. A vast majority of osteosarcomas involve the long bones, especially in the knee. Osteosarcomas can also be classified by their site of origin as (1) the conventional type, arising within the medullary cavity; (2) juxtacortical tumors, arising from the periosteal surface; and (3) extraskeletal osteosarcomas, arising in soft tissue.
Osteosarcomas are characterized by complex chromosomal aberrations in both number and structure. Gains of 8q23 are present in up to 50% of tumors and correlate with poor prognosis. Increased copy number of the 8q24 region containing the MYC gene has been identified in up to 40% of tumors. Despite the complex karyotype, no specific chromosomal translocation has been identified in osteosarcoma. Alterations in several genes have been consistently identified in osteosarcoma and may contribute to development of the tumor. These include amplifications of MET, FOS, SAS, MDM2, CDK4, and PRIM1. Protein expression of defective/amplified genes results in loss of control of cell proliferation and differentiation (see the discussion on pathogenesis of squamous cell carcinoma in Chapter 2).
Similar to their counterpart in the long bones, conventional osteosarcomas involving the mandible and maxilla display a slight predilection for males (60%). Although the peak incidence of osteosarcoma of the skeleton occurs in the second decade, cases arising in the jaws generally present one to two decades later, with a mean age of 35 years (range, 8 to 85 years). About 10% of osteosarcomas of the jaws occur in persons older than 60 years of age; more than half of these individuals have some underlying bone condition such as Paget’s disease. The mandible is more commonly affected than the maxilla by a ratio of 1.7 to 1. A majority (60%) of mandibular osteosarcomas arise in the body of the mandible; other common sites include the symphysis, angle of the mandible, ascending ramus, and temporomandibular joint. A nearly equal incidence of tumors involving the alveolar ridge and maxillary antrum is found in the maxilla, with few cases affecting the palate.
The most common presentation of jaw osteosarcoma is localized pain and swelling. In some cases, loosening and displacement of teeth may occur, as well as paresthesia caused by involvement of the inferior alveolar nerve. Maxillary tumors display similar clinical symptoms but may also cause paresthesia of the infraorbital nerve, epistaxis, nasal obstruction, or eye problems such as proptosis and diplopia. Mucosal ulceration usually is not seen until late-stage disease. The average duration of symptoms before diagnosis is 3 to 4 months.
The radiographic appearance of conventional (intramedullary) osteosarcoma is variable, reflecting the degree of calcification of the tumor. There appears to be little relationship between the radiographic pattern and the histologic subtype of osteosarcoma. Early osteosarcomas that involve the alveolar process may be characterized by localized widening of the periodontal ligament space of one or two teeth (Figures 14-1 and 14-2). The widened space results from tumor invasion of the periodontal ligament and resorption of surrounding alveolar bone (Figure 14-3). Advanced tumors can be visualized as “moth-eaten” radiolucencies or as irregular, poorly marginated radiopacities. Most of these neoplasms have mixed radiographic features. A characteristic “sunray” or “sunburst” radiopaque appearance due to periosteal reaction may be seen in jaw lesions but is not diagnostic of osteosarcoma (Figures 14-4 and 14-5).
Microscopically, all osteosarcomas have in common a sarcomatous (malignant spindle cell) stroma that directly produces osteoid (Figures 14-6 and 14-7). Histologic subtypes are recognized and have been designated as chondroblastic when formed malignant cartilage predominates (most common) (Figure 14-8), osteoblastic when malignant bone and osteoid predominate, and fibroblastic when spindle cells predominate (Figure 14-9). An additional variant, designated as telangiectatic, contains multiple blood-filled aneurysmal spaces lined by malignant cells but rarely occurs in the head and neck region. Some osteosarcomas contain multinucleated giant cells so plentiful that this form may be mistaken for a central giant cell granuloma.
Central low-grade osteosarcoma is a rare variant that may involve the jaws. Microscopically, it resembles fibrous dysplasia because of the minimally atypical spindle cell proliferation with occasional mitotic figures and bone spicules. The microscopic diagnosis poses a challenge because of its deceptively bland features. Unlike fibrous dysplasia, the radiographic appearance is usually that of an invasive intramedullary growth with poor margination and cortical destruction. Also unlike fibrous dysplasia, the proliferation permeates bone marrow, may extend through the periosteum, and may invade soft tissues. Recurrent tumor or long-standing low-grade osteosarcoma may transform to conventional high-grade osteosarcoma (Figure 14-10).
All histologic variants of conventional osteosarcoma reflect the multipotentiality of neoplastic mesenchymal cells in producing osteoid, cartilage, and fibrous tissue (see earlier). Such histologic subclassification, however, bears no prognostic significance. Attempts to further grade conventional intramedullary osteosarcomas are often problematic because of the heterogeneity of tumor morphology and, with the exception of central low-grade osteosarcoma, have proved to have little prognostic value.
Uniform widening of the periodontal ligament space of involved teeth appears to be characteristic of early osteosarcoma that involves the alveolus. However, this focal radiographic defect may also be seen with other malignancies surrounding the teeth. Uniform widening of periodontal ligament spaces surrounding all teeth may be seen in scleroderma. Moth-eaten radiolucencies are common to other malignancies, chronic osteomyelitis, and several benign neoplasms. A sclerotic radiographic appearance of osteosarcoma may be seen in other entities such as metastatic carcinoma (particularly prostatic carcinoma) and in the calcifying epithelial odontogenic tumor, which is often associated with an impacted tooth.
The histologic diagnosis hinges on identification of the malignant spindle cells producing osteoid. Many jaw osteosarcomas are predominantly chondroblastic, however, and may be misdiagnosed as chondrosarcoma. Osteosarcoma with a predominant fibroblastic component may be misdiagnosed as fibrous dysplasia, fibrosarcoma, or another pleomorphic sarcoma of bone. It has been suggested that overexpression of MDM2 and CDK4 proteins may help differentiate low-grade osteosarcomas from benign bone conditions and tumors.
Management of sarcomas of the facial skeleton involves combinations of surgery, chemotherapy, and radiotherapy. Surgical management of osteosarcoma of the mandible, however, is the mainstay of therapy and possesses numerous characteristics similar to the management of carcinoma of the jaw, with some notable differences. These similarities include required attention to surrounding anatomic barriers with their appropriate sacrifice (Figure 14-11). Invasion of anatomic barriers surrounding any head and neck tumor may be assessed by physical examination and/or special imaging studies. When a small sarcoma originates within the medullary component of the mandible, cortical bone is the first anatomic barrier the tumor encounters that forestalls its growth. Once the cortical bone is violated, the less robust periosteum is subsequently encountered. With continued growth, muscle, mucosa, and skin ultimately become invaded by the malignancy. The general approach to malignant tumor surgery of the head and neck is that at least one uninvolved anatomic barrier margin should be included on the tumor specimen as part of the en bloc resection. This practice allows better analysis of tumor margins. The main difference between resection of carcinoma in bone and resection of sarcoma lies in the recommended linear bony margin. Whereas carcinomas may be resected with a 2 cm linear margin in bone, it generally is recommended that sarcoma resections should include a 3 cm margin. Attention to proper anatomic barrier sacrifice, as well as inclusion of the recommended linear bony margin, enhances the potential for long-term palliation or cure of patients with sarcoma of the jaw.
Although sarcomas most commonly are managed surgically, it is now recognized that chemotherapy plays an important role in some patients with these tumors. Chemotherapy may be administered preoperatively (neoadjuvant chemotherapy) or postoperatively (adjuvant chemotherapy). In fact, it has been a time-honored protocol to strongly consider the administration of neoadjuvant chemotherapy in most of these patients, and the administration of adjuvant chemotherapy in all of these patients. One study examined the effects of neoadjuvant chemotherapy on histology of the tumor following this therapy. Neoadjuvant chemotherapy was utilized in 30 of 44 patients with osteosarcoma of the head and neck. The histologic response to neoadjuvant chemotherapy was classified as unfavorable in 22 of 30 patients (73%). An unfavorable response was one in which little or no response to chemotherapy occurred, or in which tumors had areas of acellular tumor osteoid and necrotic and/or fibrotic material attributable to the effects of chemotherapy in the background of viable tumor. By contrast, a favorable response to neoadjuvant chemotherapy was one with predominant areas of acellular tumor osteoid, necrosis, and/or fibrotic material with only scattered foci of histologically viable tumor cells, or no areas of histologically viable tumor following chemotherapy. Neoadjuvant chemotherapy was not found to significantly improve local control, distant metastases, or recurrence-free survival. This notwithstanding, when a favorable response to neoadjuvant chemotherapy was observed histologically, improved local recurrence-free survival, distant recurrence-free survival, and overall recurrence-free survival were realized. Therefore administration of neoadjuvant chemotherapy may be recommended for patients with high-grade osteosarcoma of the head and neck, or for whom initial resection is likely to incur the risk of positive surgical margins or a poor functional result.
The administration of adjuvant chemotherapy is perhaps as controversial as the administration of neoadjuvant chemotherapy, and certainly is contested to a similar degree. Of particular note is the observation of the National Cancer Database that no difference in 5-year survival rates is seen between patients treated with surgery and adjuvant chemotherapy and those treated with just surgery for osteosarcoma of the head and neck. Nonetheless, it is common practice for patients to receive adjuvant chemotherapy following resection of most sarcomas of the head and neck. However, the most favorable prognostic index in this cohort of patients is the attainment of negative surgical margins.
Most studies indicate that intramedullary sarcomas of the jawbones show no response to radiation therapy. The principles of management of sarcoma of the jaw are consistent for all subtypes of sarcoma.
Moreover, management of all variants of osteosarcoma, including low-grade osteosarcoma, postradiation osteosarcoma, intramedullary osteosarcoma, and juxtacortical osteosarcoma, is identical. Studies demonstrate that conservative management of those sarcomas with an otherwise inherently better prognosis than the others will lead to local recurrence and will increase the tendency toward distant metastasis. These two scenarios are associated with greatly diminished survival rates, thereby justifying aggressive surgical management from the outset.
Overall, 5-year survival rates of 25% to 40% are reported for jaw osteosarcoma. Patients with mandibular tumors generally fare better than those with maxillary tumors. As with most malignant jaw tumors, initial radical surgery results in a superior survival rate of 80% as compared with a 25% survival rate with local or conservative surgery. Osteosarcoma of the jaw commonly recurs (40% to 70%), with a metastatic rate of 25% to 50%. Osteosarcomas are more likely to metastasize to lung and to brain than to regional lymph nodes. Once the disease has become metastatic, the mean survival time is 6 months. Nearly 80% of patients who die of the disease do so within the first 2 years. Local recurrences and isolated metastatic deposits are treated by surgical excision and chemotherapy.
In contrast to conventional (intramedullary) osteosarcomas, juxtacortical (parosteal and periosteal) osteosarcomas arise at the periphery of bone at the periosteal surface, with distinct clinical, histologic, and radiographic features, as well as different biological behaviors. Juxtacortical osteosarcomas are uncommon neoplasms that account for approximately 5% of all osteosarcomas of the skeleton; they are rarely seen in the jaw. Most juxtacortical osteosarcomas arising in the jaw are of the biologically low-grade parosteal subtype or, rarely, the periosteal subtype.
Parosteal osteosarcoma occurs over a wide age range, with a peak incidence at 39 years (Figures 14-12 and 14-13). More than 95% of cases affect the long bones, most commonly the distal femoral metaphysis, and at these sites there is a female predominance (3 to 2); when the jaws are affected, there is a male predominance. The tumor typically presents as a long-standing, slow-growing, swelling or palpable mass, often accompanied by a dull, aching sensation. Radiographically, the tumor often is radiodense (radiopaque) and is attached to the external surface of bone by a broad sessile base. It often is more radiodense at the base than at the periphery. The broad pedicle is not continuous radiographically with the underlying marrow cavity. A radiolucent clear space, corresponding to the periosteum, often can be identified between the tumor and the underlying cortex.
Histologically, parosteal osteosarcomas are well differentiated and are characterized by a spindle cell stroma with minimal atypia and rare mitotic figures separating irregular trabeculae of woven bone (Figure 14-14). The periphery is less ossified than the base; the lesion may have a lobulated cartilaginous cap, or it may be irregular because of linear extensions into soft tissue. Medullary involvement is unusual at initial presentation, but approximately 20% of tumors, especially recurrent ones, exhibit invasion of the underlying bone. This does not seem to affect the prognosis adversely. The bland histologic appearance of parosteal osteosarcoma raises the possibility of osteoma, osteochondroma, and exostosis.